Hiroaki Yasuzaki

Urinary Oxidative Stress Markers Closely Reflect the Efficacy of Candesartan Treatment for Diabetic Nephropathy

Backgrounds/Aims: It has been reported that urinary oxidative stress markers are higher in diabetic patients with proteinuria. We performed the present study to elucidate the relationship between urinary excretion of oxidative stress markers, albumin excretion, and histological changes, and to confirm the potential utility of oxidative stress markers for clinical treatment. Methods: Diabetic db/db mice or nondiabetic db/m mice were administered candesartan (10 mg/kg/day) or hydralazine (50 mg/kg/day) for 18 weeks. Results: Thirty-week-old male db/db mice treated with control vehicle revealed elevated urinary excretion and immunohistological levels of 8-hydroxydeoxyguanosine in glomeruli when compared to db/m mice. Treatment with candesartan, but not hydralazine, reduced these values to levels in db/m mice. Increased mesangial expansion, urinary excretion of albumin and 8-isoprostane, and glomerular immunohistological levels of nitrotyrosine in db/db mice were also decreased markedly by candesartan but not hydralazine. Interestingly, correlations between levels of albumin and oxidative stress markers in urine were very high, even when groups undergoing long-term (44 weeks) treatment were included (correlation coefficient 0.767 with respect to 8-hydroxydeoxyguanosine, 0.888 with respect to 8-isoprostane). Conclusion: It is anticipated that urinary concentrations of oxidative stress markers will be direct barometers of glomerulus-derived oxidative stress and glomerular injury in diabetic nephropathy.

Involvement of the apelin receptor APJ in Fas-induced liver injury.

Apelin‐APJ signalling is known to play important roles in heart physiology and pathology; however, its functions in liver physiology and pathology remain unclear. On the other hand, Fas is an important molecule in hepatitis and other liver disease that belongs to the death receptor family. The aim of this study was to assess the relationship between apelin‐APJ signaling and Fas‐mediated liver injury in mice.

Eosinophilic gastroenteritis cured with Helicobacter pylori eradication.

To the Editor: Eosinophilic gastroenteritis is a rare disease characterized by eosinophilic infiltration of the gastrointestinal mucosa and various gastrointestinal symptoms including nausea, vomiting, diarrhea, and abdominal pain. Although the cause of eosinophilic gastroenteritis is unknown, it most likely represents a heterogeneous group of disorders. We present a patient with eosinophilic gastroenteritis coexistent with Helicobacter pylori gastritis, who was cured with H. pylori eradication, and review the literature. A 26-year-old man, who was a Japanese professional football player, presented with a 2-week history of abdominal pain and diarrhea. He denied any fever, bloody stools, loss of appetite, weight loss, or joint pain. There was no exposure to raw food. He had no past medical history of note and was not taking any medication. No food allergy or intolerance was reported. He did not smoke or drink alcohol, and was very healthy. Physical examination revealed only mild epigastric tenderness. Laboratory evaluation revealed a white blood cell count of 23,200 cells/mm (normal 3300 to 9400) with an eosinophil count of 16,704 cells/mm (normal 0 to 564), protein of 5.4 g/ dL (normal 6.9 to 8.3), and albumin of 3.6 g/dL (normal 4.3 to 5.4). C reactive protein was 0.1mg/dL (normal 0.0 to 0.2) and erythrocyte sedimentation rate 0mm/1 h (normal 2 to 10). Serum IgE was normal. Stool studies for ova and parasites and stool cultures were negative. Radioallergosorbent (RAST) test was within normal limits. Abdominal ultrasound and computed tomography revealed mild thickening of the small intestinal wall and bowel fluid collection. No findings of abdominal malignancy or ascites were evident. Colonoscopy with terminal ileoscopy showed only small erosions. Colonic biopsies showed eosinophilic infiltration of the colonic mucosal layer. Gastroscopy showed edema and erosions of the mucosa. Gastric biopsies showed eosinophilic infiltration of the gastric mucosal layer. Rapid urease test was positive for H. pylori. He was diagnosed as having coexistence of H. pylori gastritis and eosinophilic gastroenteritis, and was treated with lansoprazole (60mg/d), amoxycillin (1500mg/d), and clarithromycin (800mg/d) for 7 days. No treatment was given for eosinophilia. After treatment, he became asymptomatic, and the white blood cell count and eosinophil count decreased rapidly and normalized. Three months after eradication therapy, repeat gastroscopy showed marked improvement. Gastric biopsies showed only trivial eosinophilic infiltration, and gastric biopsy, rapid urease test, and urea breath test showed no H. pylori infection. Though H. pylori IgG antibody was negative on admission, 3 months after eradication therapy the antibody had become positive. We think he had first become infected with H. pylori during this time interval. He remained asymptomatic, with a normal white blood count of 6000 cells/mm and normal eosinophil count of 276 cells/mm. Protein and albumin also normalized gradually. There has been no admission for recurrence. Eosinophilic gastroenteritis is a rare disease that was first described by Kaijser in 1937. Klein et al classified this disease into 3 types: mucosal, muscle layer, and subserosal disease. Abdominal pain, nausea, vomiting, weight loss, diarrhea, iron-deficiency anemia, and protein-losing enteropathy characterize the mucosal type. Our patient had mucosal disease, and presented with a 2-week history of abdominal pain and diarrhea. Although the etiology is unknown, associations with various conditions, including allergies, connective tissue diseases, paraneoplastic syndromes, and parasitic infection, have been proposed. Though 50% to 70% of reported cases have a history of allergy, our patient did not. Serum IgE level and RAST test were also normal. Though steroid therapy is often given, 50% of patients have recurrent symptoms. Our patient also showed no evidence of connective tissue disease, paraneoplastic syndrome, or parasitic infection. Our patient seemed to have coexisting mucosal type eosinophilic gastroenteritis and H. pylori gastritis. A literature search to determine whether these 2 diseases are related revealed only 4 cases. Ours is the fifth reported case of coexistence of H. pylori infection and eosinophilic gastroenteritis, and is the second case in which blood and tissue eosinophilia resolved completely after successful eradication of H. pylori infection, and the first case of H. pylori first infection. In 3 of the previous cases, H. pylori gastritis persisted despite eradication, but blood and tissue eosinophilia resolved; however, as the symptoms recurred, in 2 cases a steroid was used, and in 1 case acid suppression was used. Successful eradication prevented recurrence in 1 case and in ours. We cannot confirm an association between H. pylori gastritis and eosinophilic gastroenteritis in the literature, but our case shows that H. pylori may play a pathogenic role in the development of blood eosinophilia and eosinophilic gastroenteritis, and that its eradication may be of value in treating certain cases of this disease. In future cases of eosinophilic gastroenteritis, attention should be paid to the possibility of H. pylori infection.

Influence of pretreatment with H2 receptor antagonists on the cure rates of Helicobacter pylori eradication

Summary Background Pretreatment with a proton pump inhibitor (PPI) reportedly decreases the efficacy of Helicobacter pylori (H. pylori) eradication, however, the effect of pretreatment with an H2 receptor antagonist (H2RA) on H. pylori eradication has not yet been studied. We compared the efficacy of eradication regimen (lansoprazole/amoxicillin/clarithromycin) in patients with H. pylori infection with or without H2RA pretreatment. Material/Methods In this retrospective study conducted at three centers, 310 patients with H. pylori infection were treated. The diagnosis of H. pylori infection was made using the rapid urease test, bacterial cultures and histological examination of endoscopic biopsy specimens. The patients were assigned to receive an eradication regimen first or following pretreatment with H2RA. Eradication was assessed using the 13C-urea breath test more than 4 weeks after the completion of therapy. Results Overall, H. pylori was eradicated in 79.7% of the cases: the eradication rate was 81.6% in the pretreatment group, and 77.6% in the eradication first group (p=0.3799, chi-square test). No significant difference in the eradication rate was observed between the two groups. Conclusions Pretreatment with H2RA had no significant influence on the efficacy of H. pylori eradication therapy.

Efficacy of granulocytapheresis for the treatment of active ulcerative colitis and avoidance of systemic corticosteroid administration.

All the patients had active colitis at baseline. The median CAI (range) decreased from 8 (5–16) to 3 (0–5; p ! 0.001, Wilcoxon signed-rank test; fig. 1 ). All the patients completed the GCAP therapy Dear Sir, The infiltration of granulocytes into the colonic mucosa plays an important role in the pathogenesis of ulcerative colitis (UC), and the removal of granulocytes may be a logical therapeutic strategy. Granulocytapheresis (GCAP) is a new technique that removes a significant amount of circulating granulocytes, reducing their migration into the intestinal mucosa [1–3] . The aim of this study was to evaluate the efficacy of GCAP in outpatients with active UC prior to the administration of systemic corticosteroids, which is the standard treatment for moderate to severe UC but which sometimes causes serious adverse effects. We enrolled 16 consecutive outpatients (7 women and 9 men; age range 22–57 years) with UC who exhibited signs of acute disease but had not yet received systemic corticosteroid treatment. The disease activity was evaluated using the clinical activity index (CAI; Truelove-Witts criteria) [4] . All the patients received 5 or 10 GCAP treatments (1 treatment/week). We evaluated the patients’ statuses before and after completion of GCAP therapy. Published online: February 26, 2010

Arterial wall hypertrophy is ameliorated by α2-adrenergic receptor antagonist or aliskiren in kidneys of angiotensinogen-knockout mice

BackgroundArterial hypertrophy and interstitial fibrosis are important characteristics in kidneys of angiotensinogen-knockout (Atg−/−) mice. In these mice, which exhibit polyuria and hypotension, sympathetic nerve signaling is estimated to be compensatorily hyperactive. Furthermore, transforming growth factor (TGF)-β1 is overexpressed in mice kidneys. To determine whether sympathetic nerve signaling and TGF-β1 exacerbate arterial hypertrophy and interstitial fibrosis, intervention studies of such signaling are required.MethodsWe performed renal denervation and administered the α2-adrenergic receptor (AR) antagonist, atipamezole, to Atg−/− mice. A renin inhibitor, aliskiren, which was preliminarily confirmed to reduce TGF-β1 gene expression in kidneys of the mice, was additionally administered to assess the effect on the arterial hypertrophy and interstitial fibrosis.ResultsNorepinephrine content in kidneys of Atg−/− mice was three times higher than in kidneys of wild-type mice. Interventions by renal denervation and atipamezole resulted in amelioration of the histological findings. Overexpression of TGF-β1 gene in kidneys of Atg−/− mice was altered in a manner linked to the histological findings. Surprisingly, aliskiren reduced α2-AR gene expression, interstitial fibrosis, and arterial hypertrophy in kidneys of Atg−/− mice, which lack renin substrate.ConclusionsAlpha2-AR signaling is one of the causes of persistent renal arterial hypertrophy in Atg−/− mice. Aliskiren also angiotensinogen-independently reduces the extent of renal arterial hypertrophy, partly thorough downregulation of α2-ARs. Although renal arterial hypertrophy in Atg−/− mice appears to be of multifactorial origin, TGF-β1 may play a key role in the persistence of such hypertrophy.