Acute norovirus-induced agranulocytosis in a pediatric kidney transplant recipient.

Norovirus (NoV) infection is usually limited to the gastrointestinal (GI) tract. However, in immunocompromised patients, this infection might lead to severe life-threatening complications. We herein describe a pediatric kidney transplant patient who presented with an acute NoV infection complicated by febrile agranulocytosis that resolved with improvement of her GI illness. This unusual presentation has not been described before, to our knowledge. The aim of this article is to highlight the sometimes dramatic clinical presentation of NoV infection in immunosuppressed patients, and the importance of including this infection in the differential diagnosis of neutropenia in that specific population.

Genetic potential for an acute inflammatory response in IgA glomerulonephritis in mice

Mice selected on the basis of an acute inflammatory response (AIR) can provide information about the immunopathological mechanisms of glomerulonephritis. We studied the differences between mice selected for a maximal AIR (AIRmax that attract more polymorphonuclear cells to the site of injury) or a minimal AIR (AIRmin that attract more mononuclear cells) in an experimental model of IgA nephropathy in order to investigate the effect of genetic background on glomerular disease progression and the participation of the monocyte chemoattractant protein-1 (MCP-1) chemokine. IgA nephropathy was induced by intraperitoneal ovalbumin injection and bile duct ligation in AIRmax and AIRmin mice. Histological changes, urinary protein/creatinine ratio, serum IgA levels, immunofluorescence for IgA, IgG and complement C3 fraction, immunohistochemistry for macrophages and MCP-1, and MCP-1 levels in macerated kidney were determined. Mesangial IgA deposition was seen only in AIRmin mice, which presented more renal lesions. Increased serum IgA levels (1.5 ± 0.4 vs 0.3 ± 0.1 mg/mL, P < 0.001), high glomerular MCP-1 expression and decreased monocyte/macrophage infiltration in the interstitial area (0.3 ± 0.3 vs 1.1 ± 0.9 macrophages/field, P < 0.05) were detected in AIRmin mice compared to AIRmax mice. No glomerular monocyte/macrophage infiltration was detected in either strain. In spite of the absence of IgA deposition, AIRmax mice presented discrete or absent mesangial proliferation. The study showed that there are differences between mice selected for AIRmax and AIRmin with respect to serum IgA levels, histological damage and MCP-1 chemokine production after ovalbumin injection in combination with bile duct ligation.

Collagen XVIII/endostatin expression in experimental endotoxemic acute renal failure

Acute renal failure (ARF) is a frequent complication of Gram-negative sepsis, with a high risk of mortality. Lipopolysaccharide (LPS)-induced ARF is associated with hemodynamic changes that are strongly influenced by the overproduction of nitric oxide (NO) through the cytokine-mediated up-regulation of inducible NO synthase. LPS-induced reductions in systemic vascular resistance paradoxically culminate in renal vasoconstriction. Collagen XVIII is an important component of the extracellular matrix expressed in basement membranes. Its degradation by matrix metalloproteases, cathepsins and elastases results in the formation of endostatin, claimed to have antiangiogenic activity and to be a prominent vasorelaxing agent. We evaluated the expression of endostatin/collagen XVIII in an endotoxemic ARF model. ARF was induced in C57BL/6 mice by intraperitoneal injection of LPS (10 mg/kg) followed by sacrifice 4 and 12 h later. Kidney tissue was the source of RNA and protein and the subject of histological analysis. As early as 4 h after LPS administration, blood urea, creatinine and NO levels were significantly increased compared to control. Endostatin/collagen XVIII mRNA levels were 0.71 times lower than sham-inoculated mice 4 h after LPS inoculation, returning to normal levels 12 h after LPS inoculation. Immunohistological examination revealed that acute injury caused by LPS leads to an increase of endostatin basement membrane staining in association with the decrease of CD31 endothelial basement membrane staining. These results indicate that in the early phase of endotoxemic ARF the endostatin levels were not regulated by gene expression, but by the metabolism of collagen XVIII.

Effects of sirolimus alone or in combination with cyclosporine A on renal ischemia/reperfusion injury

Calcineurin inhibitors exacerbate ischemic injury in transplanted kidneys, but it is not known if sirolimus protects or exacerbates the transplanted kidney from ischemic injury. We determined the effects of sirolimus alone or in combination with cyclosporin A (CsA) on oxygenated and hypoxic/reoxygenated rat proximal tubules in the following in vitro groups containing 6-9 rats per group: sirolimus (10, 50, 100, 250, 500, and 1000 ηg/mL); CsA (100 µg/mL); sirolimus (50 and 250 ηg/mL) + CsA (100 µg/mL); control; vehicle (20% ethanol). For in vivo studies, 3-week-old Wistar rats (150-250 g) were submitted to left nephrectomy and 30-min renal artery clamping. Renal function and histological evaluation were performed 24 h and 7 days after ischemia (I) in five groups: sham, I, I + SRL (3 mg·kg-1·day-1, po), I + CsA (3 mg·kg-1·day-1, sc), I + SRL + CsA. Sirolimus did not injure oxygenated or hypoxic/reoxygenated proximal tubules and did not potentiate the tubular toxic effects of CsA. Neither drug affected the glomerular filtration rate (GFR) at 24 h. GFR was reduced in CsA-treated rats on day 7 (0.5 ± 0.1 mL/min) but not in rats receiving sirolimus + CsA (0.8 ± 0.1 mL/min) despite the reduction in renal blood flow (3.9 ± 0.5 mL/min). Acute tubular necrosis regeneration was similar for all groups. Sirolimus alone was not toxic and did not enhance hypoxia/reoxygenation injury or CsA toxicity to proximal tubules. Despite its hemodynamic effects, sirolimus protected post-ischemic kidneys against CsA toxicity.

Acute inactivation of the contralesional hemisphere for longer durations improves recovery after cortical injury

Au cours des dernières années, des méthodes non-invasives de stimulations permettant de moduler l’excitabilité des neurones suivant des lésions du système nerveux central ont été développées. Ces méthodes sont maintenant couramment utilisées pour étudier l’effet de l’inhibition du cortex contralésionnel sur la récupération motrice à la suite d’un accident vasculocérébral (AVC). Bien que plusieurs de ces études rapportent des résultats prometteurs, les paramètres permettant une récupération optimale demeurent encore inconnus. Chez les patients victimes d'un AVC, il est difficile de débuter les traitements rapidement et d'initier l’inhibition dans les heures suivant la lésion. L'impact de ce délai est toujours inconnu. De plus, aucune étude n’a jusqu’à maintenant évalué l’effet de la durée de l’inhibition sur la récupération du membre parétique. Dans le laboratoire du Dr Numa Dancause, nous avons utilisé un modèle bien établi de lésion ischémique chez le rat pour explorer ces questions. Nos objectifs étaient d’évaluer 1) si une inactivation de l’hémisphère contralésionnel initiée dans les heures qui suivent la lésion peut favoriser la récupération et 2) l’effet de la durée de l’inactivation sur la récupération du membre parétique. Suite à une lésion dans le cortex moteur induite par injections d’un vasoconstricteur, nous avons inactivé l’hémisphère contralésionnel à l’aide d’une pompe osmotique assurant l’infusion continue d’un agoniste du GABA (Muscimol). Dans différents groupes expérimentaux, nous avons inactivé l’hémisphère contralésionnel pour une durée de 3, 7 et 14 jours suivant la lésion. Dans un autre groupe, le Muscimol a été infusé pour 14 jours mais à un débit moindre de façon à pouvoir étudier le lien entre la fonction du membre non-parétique et la récupération du membre parétique. Les données comportementales de ces groupes ont été comparées à celles d’animaux ayant récupéré de façon spontanée d'une lésion similaire. Nos résultats indiquent que l’augmentation de la durée de l’inactivation (de 3 à 14 jours) accélère la récupération du membre parétique. De plus, les deux groupes ayant reçu une inactivation d'une durée de 14 jours ont montré une plus grande récupération fonctionnelle que le groupe n’ayant pas reçu d’inactivation de l’hémisphère contralésionnel, le groupe contrôle. Nos résultats suggèrent donc que l’inactivation de l’hémisphère contralésionnel initiée dans les heures suivant la lésion favorise la récupération du membre parétique. La durée d’inhibition la plus efficace (14 jours) dans notre modèle animal est beaucoup plus longues que celles utilisées jusqu’à maintenant chez l’homme. Bien qu’il soit difficile d’extrapoler la durée idéale à utiliser chez les patients à partir de nos données, nos résultats suggèrent que des traitements de plus longue durée pourraient être bénéfiques. Finalement, un message clair ressort de nos études sur la récupération fonctionnelle après un AVC: dans le développement de traitements basés sur l’inhibition de l’hémisphère contralésionnel, la durée de l’inactivation est un facteur clef à considérer.

Rest-activity cycle disturbances in the acute phase of moderate to severe traumatic brain injury

Background. Sleep-wake disturbances are among the most persistent sequelae after traumatic brain injury (TBI) and probably arise during the hospital stay following TBI. These disturbances are characterized by difficulties sleeping at night and staying awake during the day. Objective. The aim of the present study was to document rest-activity cycle consolidation in acute moderate/severe TBI using actigraphy and to assess its association with injury severity and outcome. Methods. In all, 16 hospitalized patients (27.1 ± 11.3 years) with moderate/severe TBI wore actigraphs for 10 days, starting in the intensive care unit (ICU) when continuous sedation was discontinued and patients had reached medical stability. Activity counts were summed for daytime (7:00-21:59 hours) and nighttime periods (22:00-6:59 hours). The ratio of daytime period activity to total 24-hour activity was used to quantify rest-activity cycle consolidation. An analysis of variance was carried out to characterize the evolution of the daytime activity ratio over the recording period. Results. Rest-activity cycle was consolidated only 46.6% of all days; however, a significant linear trend of improvement was observed over time. Greater TBI severity and longer ICU and hospital lengths of stay were associated with poorer rest-activity cycle consolidation and evolution. Patients with more rapid return to consolidated rest-activity cycle were more likely to have cleared posttraumatic amnesia and have lower disability at hospital discharge. Conclusions. Patients with acute moderate/ severe TBI had an altered rest-activity cycle, probably reflecting severe fragmentation of sleep and wake episodes, which globally improved over time. A faster return to rest-activity cycle consolidation may predict enhanced brain recovery.

A Role for galectin-3 in renal tissue damage triggered by ischemia and reperfusion injury

Ischemic-reperfusion injury (IRI) triggers an inflammatory response involving neutrophils/macrophages, lymphocytes and endothelial cells. Galectin-3 is a multi-functional lectin with a broad range of action such as promotion of neutrophil adhesion, induction of oxidative stress, mastocyte migration and degranulation, and production of pro-inflammatory cytokines. The aim of this study was evaluate the role of galectin-3 in the inflammation triggered by IRI. Galectin-3 knockout (KO) and wild type (wt) mice were subjected to 45 min of renal pedicle occlusion. Blood and kidney samples were collected at 6, 24, 48 and 120 h. Blood urea was analyzed enzymatically, while MCP-1, IL-6 and IL-1 beta were studied by real-time PCR. Reactive oxygen species (ROS) was investigated by flow cytometry. Morphometric analyses were performed at 6, 24, 48 and 120 h after reperfusion. Urea peaked at 24 h, being significantly lower in knockout animals (wt = 264.4 +/- 85.21 mg/dl vs. gal-3 KO = 123.74 +/- 29.64 mg/dl, P = 0.001). Galectin-3 knockout animals presented less acute tubular necrosis and a more prominent tubular regeneration when compared with controls concurrently with lower expression of MCP-1, IL-6, IL-1 beta, less macrophage infiltration and lower ROS production at early time points. Galectin-3 seems to play a role in renal IRI involving the secretion of macrophage-related chemokine, pro-inflammatory cytokines and ROS production.

Acute toxicity of a single gavage dose of fumonisin B(1) in rabbits

The aim of this study was to determine the clinical, pathological and mycotoxicological effects of oral administration of fumonisin B, (FBI) in rabbits. Eighteen rabbits were randomly assigned to two experimental groups: control group, 0 mg FB(1): fumonisin group. 31.5 mg FB(1)/kg body weight, corresponding to about 630 mg FB(1)/kg diet. Fumonisin administered as a single oral dose to rabbits resulted in acute toxicity, significantly interfering with body and liver weight. Serum biochemical analysis revealed a significant increase of total protein, alkaline phosphatase (AP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), urea and creatinine in the group receiving FBI compared to control animals, a finding characterizing hepatic and renal injury in this group. Urinary protein concentrations were markedly elevated at 12,24,48 and 72 h after dosing, although visible pathological abnormalities were not observed, probably because of rapid repair of the damage. FBI was detected in feces, with a maximum concentration at 24h after administration, indicating that the enterohepatic circulation is important in rabbits. FBI concentrations found in urine were low, with peak elimination at 12 h after intoxication. The highest FBI concentrations were observed in feces compared to urine and liver, demonstrating that feces are the main routes of excretion. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Effect of sildenafil in renal ischemia/reperfusion injury in rats

To evaluate the effect of sildenafil, administered prior to renal ischemia/reperfusion (I/R), by scintigraphy and histopathological evaluation in rats. Methods: Twenty-four rats were divided randomly into two groups. They received 0.1 ml of 99mTechnetium-etilenodicisteine intravenous, and a baseline (initial) renal scintigraphy was performed. The rats underwent 60 minutes of ischemia by left renal artery clamping. The right kidney was not manipulated. The sildenafil group (n=12) received orally 1 mg/kg of sildenafil suspension 60 minutes before ischemia. Treatment with saline 0.9% in the control group (n=12). Half of the rats was assessed after 24 hours and half after seven days I/R, with new renal scintigraphy to study differential function. After euthanasia, kidneys were removed and subjected to histopathological examination. For statistical evaluation, Student t and Mann-Whitney tests were used. Results: In the control group rats, the left kidneys had significant functional deficit, seven days after I/R, whose scintigraphic pattern was consistent with acute tubular necrosis, compared with the initial scintigraphy (p<0.05). Sildenafil treatment resulted in better differential function of the left kidneys 24h after reperfusion, compared with controls. Histopathologically, the left kidney of control rats (24 hours after I/R) showed a higher degree of cellular necrosis when compared with the sildenafil treated rats (p<0.05). Conclusion: Sildenafil had a protective effect in rat kidneys subjected to normothermic I/R, demonstrated by scintigraphy and histomorphometry

Absence of DNA damage in multiple organs (blood, liver, kidney, thyroid gland and urinary bladder) after acute fluoride exposure in rats

Fluoride has been widely used in dentistry as a caries prophylactic agent. However, there has been some speculation that excess fluoride could cause an impact on genome integrity. In the current study, the potential DNA damage associated with exposure to fluoride was assessed in cells of blood, liver, kidney, thyroid gland and urinary bladder by the single cell gel (comet) assay. Male Wistar rats aging 75 days were distributed into seven groups: Groups 1 (control), 2, 3, 4, 5, 6 and 7 received 0 (deionized water), 10, 20, 40, 60, 80 and 100 mgF/Kg body weight from sodium fluoride (NaF), respectively, by gastrogavage. These groups were killed at 2 h after the administration of the fluoride doses. The level of DNA strand breaks did not increase in all organs evaluated and at all doses of NaF tested, as depicted by the mean tail moment. Taken together, our results suggest that oral exposure to NaF did not result in systemic genotoxic effect in multiple organs related to fluoride toxicity. Since DNA damage is an important step in events leading to carcinogenesis, this study represents a relevant contribution to the correct evaluation of the potential health risk associated with chemical exposure.

Mechanisms of the Gastric Antiulcerogenic Activity of Anacardium humile St. Hil on Ethanol-Induced Acute Gastric Mucosal Injury in Rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Dexmedetomidine and S(+)-ketamine in ischemia and reperfusion injury in the rat kidney

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Does propofol and isoflurane protect the kidney against ischemia/reperfusion injury during transient hyperglycemia?

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)