Involvement of nitric oxide in the pathogenesis of cyclophosphamide-induced hemorrhagic cystitis.

The involvement of nitric oxide (NO) and the potential modulation of NO synthase (NOS) activity by platelet-activating factor were investigated in a rat model of cyclophosphamide-induced hemorrhagic cystitis. Male Wistar rats received a single intraperitoneal injection of cyclophosphamide, and cystitis was evaluated 6, 12, 24, 48, and 72 hours later by determining the changes in bladder wet weight and plasma protein extravasation and the macro- and microscopic morphological alterations. In addition, NOS activity and NADPH-diaphorase histochemistry were studied in bladder tissues. Normal bladders showed extensive NADPH-diaphorase staining and a high level of constitutive NOS whereas the activity of inducible NOS was almost undetectable. Cyclophosphamide dose- and time-dependently increased the bladder wet weight and bladder plasma protein extravasation. These events were accompanied at a microscopic level by urothelial necrosis, sloughing, ulceration, hemorrhage, and leukocyte infiltration. Cyclophosphamide also increased the levels of inducible NOS but reduced those of constitutive NOS. The NOS inhibitors L-NG-nitroarginine methyl ester and L-NG-nitroarginine significantly reduced the cyclophosphamide-induced plasma protein extravasation and urothelial damage. This reduction was completely reversed by L-arginine but not by D-arginine. The administration of the platelet-activating factor antagonist BN 52021 decreased the cyclophosphamide-induced plasma protein extravasation as well as the rise in inducible NOS activity but had no effect on the fall in constitutive NOS activity. These results suggest that endogenous NO participates in the urothelial damage and in the inflammatory events leading to cyclophosphamide-induced hemorrhagic cystitis. Platelet-activating factor also seems to be involved in the pathogenesis of this condition, possibly by inducing NOS.     

Rhythmic profiles of the late phase of acute myocardial infarction as a function of age]

OBJECTIVES: To evaluate the incidence of ventricular arrhythmias in the late phase of acute myocardial infarction (AMI) and to compare it with the following clinical parameters: age, sex, AMI localization, ventricular function (Killip classes), maximal creatinokinase (CK max) and the presence of sinus tachycardia. DESIGN: Prospective study, during a period of 31 months, of a non-selected group of patients with AMI. SETTING: Coronary Care Unit (UTIC-Arsénio Cordiero). PATIENTS: Non-selected group of 153 patients with acute myocardial infarction who survived the second week of disease. MATERIAL AND METHODS: 24-hour Holter ECG performed between the 4th and the 25th day of AMI. The patients were divided into two groups according to the hourly frequency of premature ventricular beats (PVB): less than 3 per hour (PVB less than 3/h) and 3 or more per hour (PVB greater than or equal to 3/h). RESULTS: PVB greater than or equal to 3/h occurred in 36 patients (24%). There was no differences in the occurrence of ventricular arrhythmias between sex, AMI localization, AMI size evaluated by CK max, and the presence of sinus tachycardia. Patients in Killip class III had more ventricular arrhythmias (67%) than patients in Killip class I (23%) (p less than 0.005), in Killip class II (18%) (p = 0.007), and in Killip IV (0%) (p = 0.017). In patients with serious left ventricular failure (classes III + IV) the ventricular arrhythmias were not significantly higher (40%) than in patients without serious left ventricular failure (classes I + II) (22%) (chi 2 = 2.5; p less than 0.25 NS). Patients with less than 41 years old had less PVB greater than or equal to 3/h (4%) than patients between ages 41-69 (24%) (p less than 0.05), and than patients over 70 years old (47%) (p = 0.00075). CONCLUSIONS: The majority of patients (76%) showed a low risk rithmic profile (PVB less than 3/h) in the late phase of AMI. Among all parameters the age of the patients was the one best related to the occurrence of ventricular arrhythmias. Sex, AMI localization, AMI size, and the presence of sinus tachycardia were not related to the presence of PVB. A slight tendency was found in patients with heart failure to have more PVB. On the other hand the elder group carried a statistically significant risk factor for a higher occurrence of ventricular premature beats.     

Modulation of mRNAs P450 and hepatocarcinogenesis promotion

The adaptive response of the liver to phenobarbital is characterized by a strong cell hypertrophy and coordinate induction of specific P450 forms (IIB1, 2; IIC7, IIIA1). The pattern of active mRNA is significantly changed, demonstrating the establishment of PB phenotype. Employed as a promoting agent in experimental hepatocarcinogenesis, PB triggers a significantly different, uncoordinated response. Only P450 IIB1 is positively modulated while P450 IIC7 mRNA becomes repressed. Mechanisms underlying the differential P450 adaptative response to PB in the initiated versus non-initiated liver are discussed in the light of both the importance of epigenetic events and the possible role of P450 mono-oxygenases in hepatocarcinogenic promotion by PB.     

Slc11a1 (formerly NRAMP1) gene modulates both acute inflammatory reactions and pristane-induced arthritis in mice

Mice selected for the maximum acute inflammatory reaction (AIRmax) are highly susceptible to pristane-induced arthritis (PIA), whereas mice selected for the minimum response (AIRmin) are resistant. These lines show distinct patterns of leukocyte infiltration and R and S allele frequency disequilibrium of the solute carrier family 11a member 1 (Slc11a1) gene. In order to study the interactions of the Slc11a1 R and S alleles with the inflammation modulating Quantitative Trait Loci (QTL) during PIA development, homozygous AIRmax(RR), AIRmax(SS), AIRmin(RR) and AIRmin(SS) lines were produced by genotype-assisted breedings. These mice received two intraperitoneal injections of 0.5 ml pristane at 60-day intervals, and the subsequent development of arthritis was assessed for 210 days. Cytokine-secreting cell profiles were investigated using enzyme-linked immunospot. Arthritis incidence in AIRmax(RR) mice reached 29%, whereas PIA incidence in AIRmax(SS) mice was 70% by day 180. AIRmin(RR) mice were resistant, whereas 13.3% of AIRmin(SS) mice became arthritic. The presence of the defective S allele also increased arthritis severity, although acute inflammation was higher in mice bearing the R allele. A predominant Th0/Th2-type response in Slc11a1(SS) mice was observed. These results indicate that Slc11a1 is a strong candidate for the QTL modulating acute inflammation and for PIA.     

Association of adiposity, cardiorespiratory fitness and exercise practice with the prevalence of type 2 diabetes in Brazilian elderly women

BACKGROUND: Diabetes incidence in people with advanced age is increasing at an alarming rate, and for this reason the screening of high-risk individuals such as elderly women is critically important. OBJECTIVE: To analyze the association of adiposity, cardiorespiratory fitness and exercise practice with type 2 diabetes (T2D) in elderly Brazilian women. METHODS: Participated of this cross sectional study 1,059 elderly women (mean 69.5 yr; SD 6.1), who self-reported family history of cardiovascular disease, smoking status, hypertension, and T2D diagnosed previously by a physician. The following independent variables were assessed: exercise practice, body mass index, waist circumference, and cardiorespiratory fitness. Logistic regression analysis was used to investigate the association between each independent variable with T2D using adjusted-models. RESULTS: T2D prevalence was 16%. General and central adiposity were directly associated with T2D, whereas cardiorespiratory fitness was inversely related with T2D. The joint effect of exercise practice and central adiposity showed that inactive women had higher odds ratio for T2D when compared with active ones, within the same WC group. Inactive women with WC > or = 94.0 cm had an odds ratio of 5.8 (95%IC 1.3-25.3). CONCLUSIONS: A direct positive association was found between general and central adiposity, as well as an inverse relation between CRF and exercise practice with T2D. Elderly women who practice exercise regularly had lower odds for T2D. Health professionals should encourage individuals of all ages to engage on regular exercise practice, which could reduce body fatness and may be beneficial in reducing the prevalence of T2D in older ages.