Tamoxifen and bone morphogenic protein-7 modulate fibrosis and inflammation in the peritoneal fibrosis model developed in uremic rats.

BACKGROUND: Peritoneal fibrosis (PF) represents a long-term complication of peritoneal dialysis (PD), affecting peritoneal membrane (PM) integrity and function. Understanding the mechanisms underlying PF development in an uremic environment aiming alternative therapeutic strategies for treating this process is of great interest. The aim of this study was to analyze the effects of tamoxifen (TAM) and recombinant BMP7 (rBMP7) in an experimental model of PF developed in uremic rats. METHODS: To mimic the clinical situation of patients on long-term PD, a combo model, characterized by the combination of PF and CKD with severe uremia, was developed in Wistar rats. PF was induced by intraperitoneal (IP) injections of chlorhexidine gluconate (CG), and CKD was induced by an adenine-rich diet. Uremia was confirmed by severe hypertension, increased blood urea nitrogen (BUN> 120 mg/dL) and serum creatinine levels (> 2 mg/dL). Uremic rats with PF were treated with TAM (10 mg/Kg by gavage) or BMP7 (30 µg/Kg, IP). Animals were followed up for 30 days. RESULTS: CG administration in uremic rats induced a striking increase in PM thickness, neoangiogenesis, demonstrated by increased capillary density, and failure of ultrafiltration capacity. These morphological and functional changes were blocked by TAM or rBMP7 treatment. In parallel, TAM and rBMP7 significantly ameliorated the PM fibrotic response by reducing α-SMA, extracellular matrix proteins and TGF-ß expression. TAM or rBMP7 administration significantly inhibited peritoneal Smad3 expression in uremic rats with PF, prevented Smad3 phosphorylation, and induced a remarkable up-regulation of Smad7, an intracellular inhibitor of TGFß/Smad signaling, contributing to a negative modulation of profibrotic genes. Both treatments were also effective in reducing local inflammation, possibly by upregulating IκB-α expression in the PM of uremic rats with PF. In vitro experiments using primary peritoneal fibroblasts activated by TGF-ß confirmed the capacity of TAM or rBMP7 in blocking inflammatory mediators, such as IL-1ß expression. CONCLUSIONS: In conclusion, these findings indicate important roles of TGF-ß/Smad signaling in PF aggravated by uremia, providing data regarding potential therapeutic approaches with TAM or rBMP7 to block this process.

Thalidomide suppresses inflammation in adenine-induced CKD with uraemia in mice.

BACKGROUND: Persistent systemic inflammation has been widely recognized in patients with chronic kidney disease (CKD), and is associated with increased risk of morbidity and mortality. Intervention therapies aiming for the blockade of inflammatory cytokines are considered attractive approaches for CKD patients with signs of chronic inflammation. In this context, thalidomide, due to its potent anti-inflammatory and immunomodulatory properties, may represent an alternative strategy of treatment. In the present study, we developed an experimental model of CKD with uraemia in mice, induced by a diet rich in adenine, which causes progressive renal dysfunction, resembling the human uraemic features. Inflammatory parameters were analysed in this model of CKD and the potential beneficial effects of thalidomide as an anti-inflammatory drug was also investigated. METHODS: C57/BL-6 mice were fed with an adenine-containing diet during a period of 6 weeks. Thirty mice were divided into three groups: Control group (animals receiving normal diet), ADE group (mice receiving adenine-containing diet) and ADE + TLD group (CKD mice receiving thalidomide, 30 mg/kg/day, by gavage). Besides biochemical and histopathological changes, local and systemic inflammatory parameters were also analysed, including expression of cytokines interleukin (IL)-1ß, tumour necrosis factor-α, IL-6, IL-4 and IL-10 in kidney samples by real-time RT-PCR and quantification of serum levels of cytokines. Finally, the electrophoretic mobility shift assay (EMSA) for NF-κB was also examined. RESULTS: Adenine-fed mice developed advanced CKD characterized by a marked increase in serum urea, creatinine, phosphorus and intact parathyroid hormone (iPTH) levels. In addition, histological changes of tubulointerstitial injury, characterized by deposition of crystals in the kidney, accompanied by tubular dilatation, degeneration of proximal tubular epithelium with loss of the brush border, inflammatory cellular infiltration, foreign-body granuloma formation and interstitial fibrosis were also evident. By immunohistochemistry, Mac-2- and α-SMA-positive cells were identified in the tubulointerstitial compartment. Treatment with thalidomide significantly reduced serum urea, creatinine, phosphorus and iPTH levels and protected against tubulointerstitial injury. Local and systemic inflammation in the mice model of adenine-induced CKD was confirmed by the findings of significantly high expression of cytokine mRNA levels and NF-κB activation in the kidney tissue as well as marked increased serum levels of inflammatory cytokines. Thalidomide treatment significantly reduced gene expression of these cytokines and the activation of the NF-κB in the renal tissue and the circulating levels of cytokines. CONCLUSIONS: Dietary adenine caused advanced CKD with uraemia in mice providing a useful experimental model to study molecular and morphological changes associated with this disease. The negative impact of inflammation in this CKD model was overcome by the marked anti-inflammatory effects of thalidomide, promoting renal protection.

Effects of the COVID-19 pandemic on delays in diagnosis-to-treatment initiation for breast cancer in Brazil: a nationwide study.

Background: Short period from diagnosis to breast cancer (BC) treatment initiation remains challenging for the public health system in Brazil, which may have been further affected by the coronavirus disease-2019 (COVID-19) pandemic. This study assessed BC diagnosis-to-treatment intervals (DTi) in Brazil and the possible effects of the COVID-19 outbreak on delays. Methods: The Painel de Monitoramento de Tratamento Oncológico database was queried to obtain the number of Brazilian patients with a BC confirmed diagnosis and initiating cancer treatment in the pre-COVID-19 (2013-2019) and during the COVID-19 (2020-2021) periods, adopting a 60-day limit as timely treatment. A p-value of <0.05 was considered significant. Results: A total of 315,951 cases were included (females: 99.3% and males: 0.7%), of which 251,667 and 64,284 records were computed before and during the COVID-19 years, respectively. Most patients failed to perform the first cancer treatment within 60 days (>60: 51.8%). We observed an upward trend in the number of BC treatments provided in the pre-COVID-19 years (r2 = 0.9575; p < 0.05), but the volume of treatments exhibited an average reduction of 24.6% yearly during the COVID-19 pandemic. The average DTi in days was 122.4, 122.5 and 122.3 in the total period studied, before and during the COVID-19 outbreak, respectively. The arrival of COVID-19 in Brazil increased the chances of treatment delay (OR = 1.043; p < 0.05) and inverted the proportion of early/advanced stages at BC diagnosis (55.8%/44.2%-48.4%/51.6%). Conclusion: COVID-19 has imposed changes in BC care in Brazil, reducing the number of treatments provided by the Brazilian public health system, increasing the chances of delayed treatment initiation despite no differences in DTi averages being identified, and raising the proportion of advanced-stage diagnoses.

Terlipressin combined with conservative fluid management attenuates hemorrhagic shock-induced acute kidney injury in rats.

Hemorrhagic shock (HS), a major cause of trauma-related mortality, is mainly treated by crystalloid fluid administration, typically with lactated Ringer's (LR). Despite beneficial hemodynamic effects, such as the restoration of mean arterial pressure (MAP), LR administration has major side effects, including organ damage due to edema. One strategy to avoid such effects is pre-hospitalization intravenous administration of the potent vasoconstrictor terlipressin, which can restore hemodynamic stability/homeostasis and has anti-inflammatory effects. Wistar rats were subjected to HS for 60 min, at a target MAP of 30-40 mmHg, thereafter being allocated to receive LR infusion at 3 times the volume of the blood withdrawn (liberal fluid management); at 2 times the volume (conservative fluid management), plus terlipressin (10 µg/100 g body weight); and at an equal volume (conservative fluid management), plus terlipressin (10 µg/100 g body weight). A control group comprised rats not subjected to HS and receiving no fluid resuscitation or treatment. At 15 min after fluid resuscitation/treatment, the blood previously withdrawn was reinfused. At 24 h after HS, MAP was higher among the terlipressin-treated animals. Terlipressin also improved post-HS survival and provided significant improvements in glomerular/tubular function (creatinine clearance), neutrophil gelatinase-associated lipocalin expression, fractional excretion of sodium, aquaporin 2 expression, tubular injury, macrophage infiltration, interleukin 6 levels, interleukin 18 levels, and nuclear factor kappa B expression. In terlipressin-treated animals, there was also significantly higher angiotensin II type 1 receptor expression and normalization of arginine vasopressin 1a receptor expression. Terlipressin associated with conservative fluid management could be a viable therapy for HS-induced acute kidney injury, likely attenuating such injury by modulating the inflammatory response via the arginine vasopressin 1a receptor.

Inhibition of hydrogen sulphide formation reduces cisplatin-induced renal damage.

BACKGROUND: Cisplatin (CP)-induced renal damage is associated with inflammation. Hydrogen sulphide (H2S) is involved in models of inflammation. This study evaluates the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H2S formation, on the renal damage induced by CP. METHODS: The rats were injected with CP (5 mg/kg, i.p.) or PAG (5 mg/kg twice a day, i.p.) for 4 days, starting 1 h before CP injection. Control rats were injected with 0.15 M NaCl or PAG only. Blood and urine samples were collected 5 days after saline or CP injections for renal function evaluation. The kidneys were removed for tumour necrosis factor (TNF)-α quantification, histological, immunohistochemical and Western blot analysis. The cystathionine γ-lyase (CSE) activity and expression were assessed. The direct toxicity of H(2)S in renal tubular cells was evaluated by the incubation of these cells with NaHS, a donor of H2S. RESULTS: CP-treated rats presented increases in plasma creatinine levels and in sodium and potassium fractional excretions associated with tubulointerstitial lesions in the outer medulla. Increased expression of TNF-α, macrophages, neutrophils and T lymphocytes, associated with increased H2S formation rate and CSE expression, were also observed in the outer medulla from CP-injected rats. All these alterations were reduced by treatment with PAG. A direct toxicity of NaHS for renal tubular epithelial cells was not observed. CONCLUSIONS: Treatment with PAG reduces the renal damage induced by CP. This effect seems to be related to the H2S formation and the restriction of the inflammation in the kidneys from PAG + CP-treated rats.

Postnatal renal abnormalities in rats exposed to losartan during lactation.

BACKGROUND/AIMS: Rats exposed to losartan during lactation exhibit progressive changes in renal function and structure. This study analyzed the early events in pups from dams that received losartan during lactation. METHODS: Male Wistar rats from dams that received 2% sucrose (control, n = 25) or losartan (100 mg/kg/day) diluted in 2% sucrose (n = 33) during lactation were anesthetized 21 days after birth. Blood and urine samples were collected to assess renal function, and kidneys were removed for histological, immunohistochemical, Western blot, lipid peroxidation and glutathione analyses. RESULTS: The group exposed to losartan exhibited increased albuminuria and fractional sodium and potassium excretion, decreased glomerular area and interstitial expansion. Immunohistochemical analyses demonstrated increased tubulointerstitial macrophage infiltration, apoptosis and increased vimentin and α-smooth-muscle-actin expression in animals exposed to losartan. In addition, the glomeruli of animals exposed to losartan exhibited increased peripheral desmin expression and reduced glomerular epithelial protein 1 and podocin expression compared to controls. Lastly, renal lipid peroxidation and glutathione levels were higher in the losartan-treated pups. CONCLUSION: Pups exposed to losartan during lactation exhibited adverse changes in renal function and structure, and tubulointerstitial inflammation at 21 days of age that were associated with apoptosis and oxidative stress.

Role of endogenous hydrogen sulfide on renal damage induced by adriamycin injection.

A single injection of adriamycin (ADR) induces marked and persistent proteinuria in rats that progress to glomerular and tubulointerstitial lesions. It has been shown that ADR-induced nephrotoxicity is mediated, at least in part, by oxidative stress that lead to inflammation. Endogenous hydrogen sulfide (H2S) is synthesized from L-cysteine and is an important signaling molecule in inflammation. This study evaluates the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H2S formation, on the evolution of renal damage induced by ADR. The rats were injected i.p. with 0.15 M NaCl or PAG (50 mg/kg) 2 h after ADR injection (3.5 mg/kg). Control rats were injected with 0.15 M NaCl or PAG only. Twenty hours urine samples were collected for albuminuria and creatinine measurements on days 1 and 14 after saline or ADR injections and on days 2 and 15 blood samples were collected to measure plasma creatinine, then the rats were killed. The kidneys were removed for H2S formation evaluation, renal lipid peroxidation and glutathione levels, and histological and immunohistochemical analysis. On day 2 after ADR injection the rats presented increase in oxidative stress associated with neutrophils and macrophages influx in renal tissue. On day 15 the rats also presented increased desmin expression at glomerular edge and vimentin in cortical tubulointerstitium, as well as albuminuria. All these alterations were reduced by PAG injection. The protective effect of PAG on ADR nephrotoxicity was associated to decreased H2S formation and to restriction of oxidative stress and inflammation in the renal cortex.

Effect of Calcitriol on the Renal Microvasculature Differentiation Disturbances Induced by AT1 Blockade During Nephrogenesis in Rats.

Alterations in the renal vasculature during fetal programming can cause disturbances in renal structure and function that persist into adulthood. Calcitriol can affect cellular differentiation and proliferation, and promote endothelial cell maintenance, each of which is a key event in nephrogenesis. Calcitriol is a negative endocrine regulator of the renin gene. Rats exposed to renin-angiotensin system (RAS) antagonists during lactation have been shown to develop renal disorders, which demonstrated that the RAS may play an important role in mammalian kidney development. We evaluated the effects of calcitriol administration on losartan [angiotensin II receptor antagonist (ANGII), AT1]-induced changes in renal differentiation in rats during lactation. Rats treated with losartan showed alterations in renal function and structure that persisted into adulthood. These disruptions included hydronephrosis, papillary atrophy, endothelial dysfunction, and aberrant endothelial structure. These changes were mitigated by treatment with calcitriol. The results of our study showed that animals exposed to AT1 blockade during lactation exhibited altered renal microvasculature differentiation in adulthood that was attenuated by treatment with calcitriol.

Imbalance of Pro- and Anti-Angiogenic Factors Due to Maternal Vitamin D Deficiency Causes Renal Microvasculature Alterations Affecting the Adult Kidney Function.

Vitamin D (Vit.D) is involved in cellular proliferation and differentiation and regulation of the renin gene, which are important aspects of nephrogenesis and quiescence of renal health in adulthood. This study evaluated the angiogenic mechanisms involved in long term renal disturbances induced by Vit.D deficiency persistent in adulthood in rats. First-generation male Hannover offspring from mothers fed either a control diet (control group, CG) or Vit.D-deficient diet (Vit.D- group) were evaluated. Systolic blood pressure (SBP) was measured monthly during the first 6 months after birth, and blood and urine samples were collected to evaluate renal function. Nitric oxide (NO), angiotensin II (ANGII), parathyroid hormone (PTH), calcium, and Vit.D were measured. The kidneys were then removed for morphometric, NO, immunohistochemical, and Western blot studies. We evaluated the expression of vascular growth factor (VEGF) and angiopoietins 1 and 2 and their receptors since this intrinsic renal axis is responsible for endothelial quiescence. Compared to CG, the Vit.D- group presented higher SBP, ANG II plasma levels, renin expression, and AT1 receptor expression levels. Capillary rarefaction was observed, as well as an imbalance between pro- and anti-angiogenic factors. Collectively, the present findings support the role of Vit.D for maintaining the integrity of renal microcirculation.

Protective effect of calcitriol on rhabdomyolysis-induced acute kidney injury in rats.

Glycerol injection in rats can lead to rhabdomyolysis, with the release of the intracellular muscle content to the extracellular compartment and acute kidney injury (AKI). Oxidative stress and the inflammatory processes contribute to the disturbances in renal function and structure observed in this model. This study evaluated the effect of calcitriol administration in AKI induced by rhabdomyolysis and its relationship with oxidative damage and inflammatory process. Male Wistar Hannover rats were treated with calcitriol (6 ng/day) or vehicle (0.9% NaCl) for 7 days and were injected with 50% glycerol or saline 3 days after the beginning of calcitriol or saline administration. Four days after glycerol or saline injection, urine, plasma and renal tissue samples were collected for renal function and structural analysis. The oxidative stress and the inflammatory processes were also evaluated. Glycerol-injected rats presented increased sodium fractional excretion and decreased glomerular filtration rates. These alterations were associated with tubular injury in the renal cortex. These animals also presented increased oxidative damage, apoptosis, inflammation, higher urinary excretion of vitamin D-binding protein and decreased cubilin expression in renal tissue. All these alterations were less intense in calcitriol-treated animals. This effect was associated with decreases in oxidative damage and inflammation.

Renal structure and function evaluation of rats from dams that received increased sodium intake during pregnancy and lactation submitted or not to 5/6 nephrectomy.

Adult rats submitted to perinatal salt overload presented renin-angiotensin system (RAS) functional disturbances. The RAS contributes to the renal development and renal damage in a 5/6 nephrectomy model. The aim of the present study was to analyze the renal structure and function of offspring from dams that received a high-salt intake during pregnancy and lactation. We also evaluated the influence of the prenatal high-salt intake on the evolution of 5/6 nephrectomy in adult rats. A total of 111 sixty-day-old rat pups from dams that received saline or water during pregnancy and lactation were submitted to 5/6 nephrectomy (nephrectomized) or to a sham operation (sham). The animals were killed 120 days after surgery, and the kidneys were removed for immunohistochemical and histological analysis. Systolic blood pressure (SBP), albuminuria, and glomerular filtration rate (GFR) were evaluated. Increased SBP, albuminuria, and decreased GFR were observed in the rats from dams submitted to high-sodium intake before surgery. However, there was no difference in these parameters between the groups after the 5/6 nephrectomy. The scores for tubulointerstitial lesions and glomerulosclerosis were higher in the rats from the sham saline group compared to the same age control rats, but there was no difference in the histological findings between the groups of nephrectomized rats. In conclusion, our data showed that the high-salt intake during pregnancy and lactation in rats leads to structural changes in the kidney of adult offspring. However, the progression of the renal lesions after 5/6 nephrectomy was similar in both groups.

Effects of resveratrol on glycerol-induced renal injury.

Glycerol-induced renal lesions can have many causes, including increased oxidative stress and inflammation. Resveratrol, a polyphenolic phytoalexin found in grapes and red wine, is an antioxidant agent with anti-inflammatory effects. In the present study, we investigated the possible protective effect of resveratrol on glycerol-induced nephrotoxicity. Male Wistar rats were injected intramuscularly with 8 ml/kg of either 50% glycerol (n=18), glycerol+resveratrol (n=22), 0.15 M saline (n=14), saline+carboxymethylcellulose (n=10) or saline+resveratrol (n=8). The rats were killed 3 days after the injections, at which time the kidneys were removed for histological and immunohistochemical studies and lipid peroxidation determination. Blood and urine samples were collected in order to quantify sodium and creatinine. The results of the histological and immunohistochemical studies were scored according to the extent of damage and immunostaining, respectively, in the cortical tubulointerstitium. Lipid peroxidation was estimated by measuring malondialdehyde in renal tissue samples collected from control rats and glycerol-injected rats. By postinjection day 3, glycerol-only treated rats presented increases in plasma creatinine levels, as well as in fractional excretion of sodium and potassium (P<0.001). These increases were less pronounced in glycerol+resveratrol-treated rats (P<0.05). Cortical expression of macrophages, lymphocytes, nuclear factor-kappa B, heme oxygenase-1 and nitrotyrosine was greater in glycerol-treated rats than in controls (P<0.001). In addition, the histological findings for glycerol-treated rats were characteristic of acute tubular necrosis. Resveratrol attenuated all of these alterations (P<0.001). We conclude that resveratrol ameliorates glycerol-induced renal injury by suppressing the inflammatory process and by inhibiting lipid peroxidation.

Calcitriol reduces kidney development disorders in rats provoked by losartan administration during lactation.

Calcitriol has important effects on cellular differentiation and proliferation, as well as on the regulation of the renin gene. Disturbances in renal development can be observed in rats exposed to angiotensin II (AngII) antagonists during lactation period. The lack of tubular differentiation in losartan-treated rats can affect calcitriol uptake. This study evaluated the effect of calcitriol administration in renal development disturbances in rats provoked by losartan (AngII type 1 receptor antagonist) administration during lactation. Animals exposed to losartan presented higher albuminuria, systolic blood pressure, increased sodium and potassium fractional excretion, and decreased glomerular filtration rate compared to controls. These animals also showed a decreased glomerular area and a higher interstitial relative area from the renal cortex, with increased expression of fibronectin, alpha-SM-actin, vimentin, and p-JNK; and an increased number of macrophages, p-p38, PCNA and decreased cubilin expression. Increased urinary excretion of MCP-1 and TGF-ß was also observed. All these alterations were less intense in the losartan + calcitriol group.The animals treated with calcitriol showed an improvement in cellular differentiation, and in renal function and structure. This effect was associated with reduction of cell proliferation and inflammation.

Effects of previous physical training on adriamycin nephropathy and its relationship with endothelial lesions and angiogenesis in the renal cortex.

AIMS: Adriamycin (ADR)-induced nephropathy is one of the most experimental models used in progressive kidney disease. A single dose of this drug induces a progressive and irreversible proteinuria that progresses to focal segmental glomerulosclerosis and tubulointerstitial lesions. Regular physical activity has been considered as a therapeutic intervention in several diseases. This study evaluated the influence of previous physical training in renal damage induced by ADR and the role of endothelial lesions and angiogenesis in this process. MAIN METHODS: Male Wistar rats were subjected or not to treadmill running for 4weeks and then injected with ADR (2.5mg/kg, i.v.) or saline. Twenty-four-hour urine samples were collected for albuminuria measurement, and blood samples were collected to measure plasma creatinine 60days after the injections. The kidneys were removed for histological, immunohistochemical, Western blot and ELISA studies. KEY FINDINGS: ADR-treated rats presented increases in plasma creatinine levels, albuminuria, podocyte damage, and enlargement of the tubular interstitial relative area, as well as higher macrophage numbers in the renal cortex, interleukin (IL)-1ß levels in renal tissue and urinary monocyte chemoattractant protein (MCP)-1, which were associated with reduction in vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS) expressions and peritubular capillary (PTC) density in renal cortex. These alterations were less intense in the animals subjected to previous exercise training. SIGNIFICANCE: Physical training prior to ADR injection reduced the renal damage induced by this drug. This effect was related to angiogenesis and reduction in the endothelial lesions and inflammatory process in the renal cortex of these animals.

Churg-Strauss syndrome: high resolution CT and pathologic findings.

OBJECTIVES: The purpose of this study was to evaluate high-resolution CT findings in 7 patients with Churg-Strauss syndrome and to compare the CT with the histopathologic findings. MATERIALS AND METHODS: High-resolution CT scans of 7 asthmatic patients (4 women, 3 men, age range, 34-62 years, mean 49 years) with Churg-Strauss syndrome were reviewed by 2 observers. Histologic specimens of lung obtained at surgical (n = 3) or transbronchial (n = 3) biopsy or autopsy (n = 1) were reviewed by an expert lung pathologist. The diagnosis of Churg-Strauss was based on clinical, laboratory, and histologic findings. RESULTS: Parenchymal and airway abnormalities included ground-glass opacities (n = 5), areas of air-space consolidation (n = 4), centrilobular nodules (n = 5), nodules 1-3 cm in diameter (n = 3), interlobular septal thickening (n = 4), bronchial wall thickening (n = 4), and areas of atelectasis (n = 1). Surgical biopsy (n = 3) and autopsy (n = 1) specimens demonstrated airspace disease in 3 patients, interlobular septal thickening in 3 patients, and airway abnormalities in 2 patients. Histologically, the airspace disease included eosinophilic pneumonia (n = 2) and small foci of organizing pneumonia (n = 1). The septal thickening was due to edema combined with numerous (n = 2) or few (n = 1) eosinophils. The airway abnormalities (n = 2) included muscle hypertrophy and large airway wall necrosis (n = 1) and eosinophilic infiltration of the airway walls (n = 1). Transbronchial biopsy (n = 3) demonstrated increased eosinophils. CONCLUSION: The main high-resolution CT findings of Churg-Strauss syndrome consist of airspace consolidation or ground-glass opacities, septal lines, and bronchial wall thickening. These reflect the presence of eosinophilic infiltration of the airspaces, interstitium, and airways, and interstitial edema.

Inhibition of nuclear factor-kappaB activation attenuates tubulointerstitial nephritis induced by gentamicin.

BACKGROUND: Animals treated with gentamicin can show residual areas of interstitial fibrosis in the renal cortex. This study investigated the expression of nuclear factor-kappaB (NF-kappaB), mitogen-activated protein (MAP) kinases and macrophages in the renal cortex and structural and functional renal changes of rats treated with gentamicin or gentamicin + pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor. METHODS: 38 female Wistar rats were injected with gentamicin, 40 mg/kg, twice a day for 9 days, 38 with gentamicin + PDTC, and 28 with 0.15 M NaCl solution. The animals were killed 5 and 30 days after these injections and the kidneys were removed for histological and immunohistochemical studies. The results of the immunohistochemical studies were scored according to the extent of staining. The fractional interstitial area was determined by morphometry. RESULTS: Gentamicin-treated rats presented a transitory increase in plasma creatinine levels. Increased ED-1, MAP kinases and NF-kappaB staining were also observed in the renal cortex from all gentamicin-treated rats compared to control (p < 0.05). The animals killed on day 30 also presented fibrosis in the renal cortex despite the recovery of renal function. Treatment with PDTC reduced the functional and structural changes induced by gentamicin. CONCLUSIONS: These data show that inhibition of NF-kappaB activation attenuates tubulointerstitial nephritis induced by gentamicin.

[Intramedullary cavernous angioma of the spinal cord: case report]. / Angioma cavernoso intramedular: relato de caso.

We report a case of intramedullary cavernous angioma in a 56 years old woman with history of back pain. MRI show discal protrusion and disclose an intramedullary lesion, with heterogeneous sinal. The MRI is more sensitive than CT and the most appropriate technique is the sequence eco-gradient. The diagnosis is relevant because there is a possibility of acute neurological deficit and it is frequently accompanied by cranial cavernous angiomas.

[Reversible posterior encephalopathy syndrome: case report]. / Sindrome de encefalopatia posterior reversível: relato de caso.

The posterior reversible leukoencephalopathy syndrome (PRES) is a recently proposed cliniconeuroradiologic entity. The most common causes of PRES are hypertensive encephalopathy, eclampsia, cyclosporin A neurotoxicity and the uremic encephalopathies. Most patients are markedly hypertensive at presentation, although some have only mildly elevated or even normal blood pressure. Symptoms may include headache, nausea, vomiting, altered mental status, seizures,stupor, and visual disturbances. On CT and MR studies, edema has been reported in a relatively symmetrical pattern, typically in the subcortical white matter and occasionally in the cortex of the occipital and parietal lobes. These often striking imaging findings usually are resolved on follow-up studies obtained after appropriate therapy. Diffusion-weighted images would not show hyperintense signal because of the presence of interstitial rather than cytotoxic edema. We report a case of PRES due to hypertensive encephalopathy studied by CT and MRI.

The role of oxidative stress in renal injury induced in rats by losartan exposure during lactation.

INTRODUCTION: Rats exposed to angiotensin II (AII) receptor antagonists during lactation present progressive disturbances in renal development that lead to progressive alterations in renal function and structure. This study evaluates the role of oxidative stress in the renal changes induced by exposure to losartan, a type 1 AII receptor antagonist, in rats during lactation. MATERIALS AND METHODS: Male Wistar pups were divided into: Control, pups of dams that received 2% sucrose solution; Control-tempol, pups of dams that received tempol (0.34 g/l), a superoxide dismutase mimetic compound; Losartan, pups of dams that received losartan (100 mg/kg/day), and Losartan-tempol, pups of dams that received losartan and tempol. Losartan and/or tempol were administered during lactation. Blood and urine samples were collected at 21 or 60 days, and the kidneys were removed. RESULTS: Losartan-treated pups exhibited disturbances in renal function and structure that persisted into adulthood. Tempol treatment reduced oxidative stress and attenuated the changes induced by losartan in the glomerular filtration rate, desmin expression at the glomerular edge, vimentin in tubular cells, as well as apoptosis and inflammatory infiltration in the renal cortex. CONCLUSION: Oxidative stress contributes at least in part to the renal injury observed in pups exposed to losartan during lactation.

Chronic pulmonary microaspiration: high-resolution computed tomographic findings in 13 patients.

PURPOSE: The aim of the study was to describe the high-resolution computed tomography (CT) manifestations of chronic pulmonary microaspiration, a condition characterized by recurrent subclinical aspiration of small droplets of gastric contents or foreign particles into the lungs. MATERIALS AND METHODS: We reviewed the CT findings in 13 consecutive patients with clinical (n=13) and histologic (n=1) diagnosis of chronic pulmonary microaspiration. Twelve patients presented with persistent cough, but none had a clinical history of acute aspiration. One patient was asymptomatic. All patients had volumetric CT of the chest reconstructed using thin sections (1 to 1.3 mm) at the time of diagnosis. The CT scans were interpreted by 3 chest radiologists who reached a final decision by consensus. RESULTS: All 13 patients had centrilobular nodules and ground-glass opacities that involved mainly the dependent lung regions in 11 patients and had a random distribution in 2. Other common findings included branching opacities (n=10), small foci of consolidation (n=7), septal lines (n=5), and bronchiectasis (n=7). The 13 patients had at least 1 risk factor for aspiration including gastroesophageal reflux (n=9), hiatus hernia (n=6), esophageal dysfunction (n=3), oropharyngeal dysphagia (n=1), esophageal carcinoma (n=1), and use of sedatives (n=2). CONCLUSIONS: The high-resolution CT manifestations of chronic pulmonary microaspiration consist mainly of centrilobular nodules and ground-glass opacities that tend to involve predominately the dependent regions. Branching opacities and small foci of consolidation are seen in the majority of cases.