Pharmacological and histopathological study of cyclophosphamide-induced hemorrhagic cystitis - comparison of the effects of dexamethasone and Mesna

Chemotherapy with oxazaphosphorines, such as cyclophosphamide (CYP), is often limited by unacceptable urotoxicity. Without uroprotection, hemorrhagic cystitis (HC) becomes dose-limiting. To compare the uroprotective efficacy of classical 2-mercaptoethanesulfonic acid (Mesna) treatment with dexamethasone in CYP-induced HC, male Wistar rats (150-200 g; N = 6 in each group) were treated with saline or Mesna (40 mg/kg, ip) immediately and 4 and 8 h after ip administration of CYP (200 mg/kg). One, 2 or 3 doses of Mesna were replaced with dexamethasone (1 mg/kg, ip). The animals were sacrificed 24 h later. Cystitis was evaluated by determining the changes in bladder wet weight (BWW) and by macroscopic and microscopic analysis. CYP treatment induced a marked increased in BWW (162%, P<0.05), which was significantly inhibited by treatment with 3 doses of Mesna (P<0.05; 80%). The replacement of 1 or 2 doses of Mesna with dexamethasone reduced the increase in BWW by 83.3 and 95%, respectively. Macroscopic analysis of the bladder of rats with CYP-induced HC showed severe edema and hemorrhage, confirmed by microscopic analysis, that also showed mucosal erosion, inflammatory cell infiltration and ulcerations. The replacement of 1 or 2 doses of Mesna with dexamethasone inhibited the CYP-induced increase in BWW and almost abolished the macroscopic and microscopic alterations, with no significant difference between the effects of Mesna and dexamethasone, indicating that both drugs were efficient in blocking HC. However, although the replacement of all Mesna doses with dexamethasone reduced the edema, it did not prevent HC, suggesting that Mesna is necessary for the initial uroprotection.

A model of hemorrhagic cystitis induced with acrolein in mice

Acrolein is a urinary metabolite of cyclophosphamide and ifosfamide, which has been reported to be the causative agent of hemorrhagic cystitis induced by these compounds. A direct cytotoxic effect of acrolein, however, has not yet been demonstrated. In the present study, the effects of intravesical injection of acrolein and mesna, the classical acrolein chemical inhibitor, were evaluated. Male Swiss mice weighing 25 to 35 g (N = 6 per group) received saline or acrolein (25, 75, 225 µg) intravesically 3, 6, 12, and 24 h before sacrifice for evaluation of bladder wet weight, macroscopic and histopathological changes by Gray's criteria, and 3 and 24 h for assessment of increase in vascular permeability. In other animals, mesna was administered intravesically (2 mg) or systemically (80 mg/kg) 1 h before acrolein. Intravesical administration of acrolein induced a dose- and time-dependent increase in vascular permeability and bladder wet weight (within 3 h: 2.2- and 21-fold increases in bladder wet weight and Evans blue dye exuded, respectively, at doses of 75 µg/bladder), as confirmed by Gray's criteria. Pretreatment with mesna (2-mercaptoethanesulfonic acid), which interacts with acrolein resulting in an inactive compound, inhibited all changes induced by acrolein. Our results are the first demonstration that intravesical administration of acrolein induces hemorrhagic cystitis. This model of acrolein-induced hemorrhagic cystitis in mice may be an important tool for the evaluation of the mechanism by which acrolein induces bladder lesion, as well as for investigation of new uroprotective drugs.

Hind limb ischemic preconditioning induces an anti-inflammatory response by remote organs in rats

Ischemic preconditioning (IPC), a strategy used to attenuate ischemia-reperfusion injury, consists of brief ischemic periods, each followed by reperfusion, prior to a sustained ischemic insult. The purpose of the present study was to evaluate the local and systemic anti-inflammatory effects of hind limb IPC in male Wistar rat (200-250 g) models of acute inflammation. IPC was induced with right hind limb ischemia for 10 min by placing an elastic rubber band tourniquet on the proximal part of the limb followed by 30 min of reperfusion. Groups (N = 6-8) were submitted to right or left paw edema (PE) with carrageenan (100 µg) or Dextran (200 µg), hemorrhagic cystitis with ifosfamide (200 mg/kg, ip) or gastric injury (GI) with indomethacin (20 mg/kg, vo). Controls received similar treatments, without IPC (Sham-IPC). PE is reported as variation of paw volume (mL), vesical edema (VE) as vesical wet weight (mg), vascular permeability (VP) with Evans blue extravasation (µg), GI with the gastric lesion index (GLI; total length of all erosions, mm), and neutrophil migration (NM) from myeloperoxidase activity. The statistical significance (P < 0.05) was determined by ANOVA, followed by the Tukey test. Carrageenan or Dextran-induced PE and VP in either paw were reduced by IPC (42-58.7%). IPC inhibited VE (38.8%) and VP (54%) in ifosfamide-induced hemorrhagic cystitis. GI and NM induced by indomethacin were inhibited by IPC (GLI: 90.3%; NM: 64%). This study shows for the first time that IPC produces local and systemic anti-inflammatory effects in models of acute inflammation other than ischemia-reperfusion injury.

BK polyomavirus in Kidney transplant recipients: screening, monitoring and clinical management

BK polyomavirus (BKPyV) is a causal agent of nephropathy, ureteral stenosis and hemorrhagic cystitis in kidney transplant recipients, and is considered an important emerging disease in transplantation. Regular screening for BKPyV reactivation mainly during the first 2 years posttransplant, with subsequent pre-emptive reduction of immunosuppression is considered the best option to avoid disease progression, since successful clearance or reduction of viremia is achieved in the vast majority of patients within 6 months. The use of drugs with antiviral properties for patients with persistent viremia has been attempted despite unclear benefits. Clinical manifestations of BKPyV nephropathy, current strategies for diagnosis and monitoring of BKPyV infection, management of immunosuppressive regimen after detection of BKPyV reactivation and the use of antiviral drugs are discussed in this review.

Hemorrhagic syndrome and Acute renal failure in a pregnant woman after contact with Lonomia caterpillars: a case report

A case of a 37-week pregnant woman who developed a hemorrhagic syndrome and acute renal failure after contact with Lonomia caterpillars is reported. The accident also initiated labour and the patient gave birth to an alive child. Some pathophysiological aspects of the genital bleeding and of the acute renal failure are discussed.

Genotypic characterization of virulence factors in Escherichia coli strains from patients with cystitis

Adhesins (P-fimbriae, S-fimbriae, type 1 fimbriae and afimbrial adhesin), toxins (α-hemolysin and cytotoxic necrotizing factor type 1), iron acquisition systems (aerobactin) and host defense avoidance mechanisms (capsule or lipopolysaccharide) have been shown to be prevalent in Escherichia coli strains associated with urinary tract infections. In this work, 162 Uropathogenic Escherichia coli (UPEC) strains from patients with cystitis were genotypically characterized by polymerase chain reaction (PCR) assay. We developed three multiplex PCR assays for virulence-related genes papC, papE/F, papG alleles, fimH, sfa/foc, afaE, hly, cnf-1, usp, cdtB, iucD, and kpsMTII, all of them previously identified in UPEC strains. The PCR assay results identified 158 fimH (97.5%), 86 kpsMTII (53.1%), 53 papC/papEF/papG (32.7%), 45 sfa (27.8%), 42 iucD (25.9%), 41 hly (25.3%), 36 usp (22.2%), 30 cnf-1(18.5%) and 10 afa (6.2%) strains. No strain was positive for cdtB. In this work, we also demonstrated that adhesins may be multiple within a single strain and that several virulence genes can occur combined in association.

DISTINCT CELLULAR MIGRATION INDUCED BY Leishmania infantum chagasi AND SALIVA FROM Lutzomyia longipalpis IN A HEMORRHAGIC POOL MODEL

Recruitment of a specific cell population after Leishmania infection can influence the outcome of the disease. Cellular migration in response to Leishmania or vector saliva has been reported in air pouch model, however, cellular migration induced by Leishmania associated with host's blood and vector saliva in this model has not been described. Herein we investigated cellular migration into air pouch of hamster after stimulation with combination of L. chagasi and host's blood and Lutzomyia longipalpis saliva. Migration induced by saliva was 3-fold more than those induced by L. chagasi alone. Additionally, L. chagasi associated with blood and saliva induced significantly even more leukocytes into air pouch than Leishmania alone. L. chagasi recruited a diverse cell population; however, most of these cells seem to have not migrated to the inflammatory exudate, remaining in the pouch lining tissue. These results indicate that L. chagasi can reduce leukocyte accumulation to the initial site of infection, and when associated with vector saliva in the presence of blood components, increase the influx of more neutrophils than macrophages, suggesting that the parasite has developed a strategy to minimize the initial inflammatory response, allowing an unlimited progression within the host. This work reinforces the importance of studies on the salivary components of sand fly vectors of leishmaniasis in the transmission process and the establishment of the infection.

The hemorrhagic syndrome of leptospirosis: an experimental study in guinea pigs

The hemorrhagic syndrome of leptospirosis was studied in guinea pigs. The study correlates hematological, histopathological and immunohistochemical alterations in sixty animals inoculated by the intraperitoneal route with lml of the culture of virulent strain of Leptospira interrogans serovar copenhageni. Leptospirae antigens were detected by immunoperoxidase, chiefly in liver, kidney and heart muscle capillaries. Possible pathogenic mechanisms responsible for hemorrhagic syndrome are discussed with emphasis on toxic and anoxic attacks causing damage to endothelia, platelet depletion and alterations to hemostasia rates: prothrombin time [FT], partial thromboplastin time [PIT] and fibrinogen concentrations. Tide clinical-laboratoiy picture is compatible with the histopathological observation of disseminated intravascular coagulation [D1C] in most of the guinea pigs from day 4 of infection.

Dengue and dengue hemorrhagic fever in the State of Pernambuco, 1995-2006

In Pernambuco, the first dengue cases occurred in 1987. After a seven-year interval without autochthonous cases, a new epidemic occurred in 1995. Important aspects of the dengue epidemics during the period 1995-2006 have been analyzed here, using epidemiological, clinical and laboratory data. A total of 378,374 cases were notified, with 612 confirmed cases of dengue hemorrhagic fever and 33 deaths. The mortality rate was 5.4%. The incidence rate increased from 134 to 1,438/100,000 inhabitants, corresponding to the epidemics due to serotypes 2 and 3, in 1995 and 2002, respectively. Dengue mainly affected adults (20-49 years); 40.7% were male and 59.3% were female. From 2003 onwards, the number of cases among individuals younger than 15 years old increased. Out of 225 dengue hemorrhagic fever cases, 42.7% primary and 57.3% secondary infections were identified (p = 0.0279). Neurological manifestations were also observed. From 2002 onwards, serotypes 1, 2 and 3 were circulating; serotype 3 was predominant.

Hemorrhagic pulmonary leptospirosis: three cases from the Yucatan peninsula, Mexico

Three leptospirosis cases with lung involvement are reported from the Yucatan Peninsula, Mexico. All three patients were admitted to the intensive care unit due to acute respiratory failure. Treatment with antibiotics resulted in favorable evolution despite the negative prognosis. Leptospirosis should be included in the differential diagnosis of patients with fever and lung involvement.

Clinical and epidemiological characterization of dengue hemorrhagic fever cases in northeastern, Brazil

INTRODUCTION: The dengue hemorrhagic dengue (DHF) remains an important public health problem in Brazil. The objective of this study was to analyze the epidemiological characteristics of DHF cases during the 2003 epidemic in Ceará. METHODS: Suspected DHF cases with onset of symptoms between January and December 2003 were investigated. RESULTS: 37,964 classic dengue cases and 291 DHF cases were reported. Among the cases discarded, 75.5% were serologically positive but did not meet the criteria recommended by the World Health Organization (WHO). The DHF patients' median age was 30 years (2 - 88). Among the hemorrhagic manifestations, petechiae were the most (32.6%) frequent. Cases of gastrointestinal bleeding, ascites, pericardial pleural effusion, hepatomegaly, hypotension and shock showed higher risk of progression to death (p <0.05). CONCLUSIONS: The introduction of a new serotype (DENV-3) in Ceará, which encountered a susceptible population and high vector density, may have been the primary agent responsible for the magnitude of the epidemic. Timely and appropriate medical care, along with an organized care structure are essential for reducing its lethality.

Conservative therapies for hemorrhagic radiation proctitis: a review

Chronic radiation proctitis represents a challenging condition seen with increased frequency due to the common use of radiation for treatment of pelvic cancer. Hemorrhagic radiation proctitis represents the most feared complication of chronic radiation proctitis. There is no consensus for the management of this condition despite the great number of clinical approaches and techniques that have been employed. Rectal resection represents an available option although associated with high morbidity and risk of permanent colostomy. The effectiveness of nonoperative approaches remains far from desirable, and hemorrhagic recurrence represents a major drawback that leads to a need for consecutive therapeutic sessions and combination of techniques. We conducted a critical review of published reports regarding conservative management of hemorrhagic chronic radiation proctitis. Although prospective randomized trials about hemorrhagic radiation proctitis are still lacking, there is enough evidence to conclude that topical formalin therapy and an endoscopic approach delivering an argon plasma coagulation represent available options associated with elevated effectiveness for interruption of rectal bleeding in patients with chronic radiation proctitis.

Detection of circulant tumor necrosis factor-alpha , soluble tumor necrosis factor p75 and interferon-gamma in Brazilian patients with dengue fever and dengue hemorrhagic fever

Pro-inflammatory cytokines are believed to play an important role in the pathogenesis of dengue infection. This study reports cytokine levels in a total of 54 patients examined in Recife, State of Pernambuco, Brazil. Five out of eight patients who had hemorrhagic manifestations presented tumor necrosis factor-alpha (TNF-alpha) levels in sera which were statistically higher than those recorded for controls. In contrast, only one out of 16 patients with mild manifestations had elevated TNF-alpha levels. The levels of interleukin-6 (IL), IL-1beta tested in 24 samples and IL-12 in 30 samples were not significantly increased. Interferon-g was present in 10 out of 30 patients with dengue. The data support the concept that the increased level of TNF-alpha is related to the severity of the disease. Soluble TNF receptor p75 was found in most patients but it is unlikely to be related to severity since it was found with an equivalent frequency and levels in 15 patients with dengue fever and another 15 with dengue hemorrhagic fever.