Amelioration of lipopolysaccharides-induced impairment of fear memory acquisition by alpha-glycosyl isoquercitrin through suppression of neuroinflammation in rats.

This study investigated the role of neuroinflammation in a lipopolysaccharides (LPS)-induced cognitive dysfunction model in rats using an antioxidant, α-glycosyl isoquercitrin (AGIQ). Six-week-old rats were dietary treated with 0.5% (w/w) AGIQ for 38 days, and LPS at 1 mg/kg body weight was administered intraperitoneally once daily on Days 8 and 10. On Day 11, LPS alone increased or tended to increase interleukin-1ß and tumor necrosis factor-α in the hippocampus and cerebral cortex. Immunohistochemically, LPS alone increased the number of Iba1+ and CD68+ microglia, and GFAP+ astrocytes in the hilus of the hippocampal dentate gyrus (DG). AGIQ treatment decreased or tended to decrease brain proinflammatory cytokine levels and the number of CD68+ microglia in the DG hilus. In the contextual fear conditioning test during Day 34 and Day 38, LPS alone impaired fear memory acquisition, and AGIQ tended to recover this impairment. On Day 38, LPS alone decreased the number of DCX+ cells in the neurogenic niche, and AGIQ increased the numbers of PCNA+ cells in the subgranular zone and CALB2+ hilar interneurons. Additionally, LPS alone decreased or tended to decrease the number of synaptic plasticity-related FOS+ and COX2+ granule cells and AGIQ recovered them. The results suggest that LPS administration induced acute neuroinflammation and subsequent impairment of fear memory acquisition caused by suppressed synaptic plasticity of newborn granule cells following disruptive neurogenesis. In contrast, AGIQ exhibited anti-inflammatory effects and ameliorated LPS-induced adverse effects. These results suggest that neuroinflammation is a key factor in the development of LPS-induced impairment of fear memory acquisition.

Phenobarbital, a hepatic metabolic enzyme inducer, inhibits preneoplastic hepatic lesions with expression of selective autophagy receptor p62 and ER-phagy receptor FAM134B in high-fat diet-fed rats through the inhibition of ER stress.

We investigated the role of endoplasmic reticulum (ER)-phagy in NAFLD-related hepatocarcinogenesis in high-fat diet (HFD)-fed and/or phenobarbital (PB)-treated rats by clustering the expression levels of the selective autophagy receptor p62 and the ER-phagy-specific receptor FAM134B in preneoplastic hepatic lesions. We obtained four clusters with variable expression levels of p62 and FAM134B in preneoplastic lesions, and a variable population of clusters in each group. PB administration increased the clusters with high expression levels of p62 while HFD feeding increased the clusters with high expression levels of both p62 and FAM134B. The areas of preneoplastic lesions of these clusters were significantly increased than those of other clusters with low expression levels of p62 and FAM134B. The combination of HFD feeding with PB counteracted the effects of each other, and the cluster composition was similar to that in the control group. The results were associated with decreased gene expression of ER stress, inflammatory cytokine, autophagy, and increased expression of antioxidant enzyme. The present study demonstrated that clustering analysis is useful for understanding the role of autophagy in each preneoplastic lesion, and that HFD feeding increased preneoplastic lesions through the inhibition of ER-phagy, which was cancelled with PB administration through the induction of ER-phagy.

Oral exposure to aluminum chloride for 28 days suppresses neural stem cell proliferation and increases mature granule cells in adult hippocampal neurogenesis of young-adult rats.

Aluminum (Al), a common light metal, affects the developing nervous system. Developmental exposure to Al chloride (AlCl3 ) induces aberrant neurogenesis by targeting neural stem cells (NSCs) and/or neural progenitor cells (NPCs) in the dentate gyrus (DG) of rats and mice. To investigate whether hippocampal neurogenesis is similarly affected by AlCl3 exposure in a general toxicity study, AlCl3 was orally administered to 5-week-old Sprague Dawley rats at dosages of 0, 4000, or 8000 ppm in drinking water for 28 days. AlCl3 downregulated Sox2 transcript level in the DG at the highest dosage and produced a dose-dependent decrease of SOX2+ cells without altering numbers of GFAP+ or TBR2+ cells in the subgranular zone, suggesting that AlCl3 decreases Type 2a NPCs. High-dose exposure downregulated Pcna, upregulated Pvalb, and altered expression of genes suggestive of oxidative stress induction (upregulation of Nos2 and downregulation of antioxidant enzyme genes), indicating suppressed proliferation and differentiation of Type 1 NSCs. AlCl3 doses also increased mature granule cells in the DG. Upregulation of Reln may have contributed to an increase of granule cells to compensate for the decrease of Type 2a NPCs. Moreover, upregulation of Calb2, Gria2, Mapk3, and Tgfb3, as well as increased numbers of activated astrocytes in the DG hilus, may represent ameliorating responses against suppressed neurogenesis. These results suggest that 28-day exposure of young-adult rats to AlCl3 differentially targeted NPCs and mature granule cells in hippocampal neurogenesis, yielding a different pattern of disrupted neurogenesis from developmental exposure.

Leptospiral meningoencephalitis in a raccoon dog.

Neuroleptospirosis is a rare disease caused by pathogenic Leptospira interrogans in humans; however, it has not been fully studied in animals. A young wild raccoon dog was found convulsing in the recumbent position and died the next day. Histologic examination revealed nonsuppurative meningoencephalitis in the cerebrum, cerebellum, midbrain, and medulla oblongata. The lesions consisted of mixed infiltrates of Iba1-positive macrophages and CD3-positive T cells, with a small number of CD79α-positive B cells and myeloperoxidase-positive neutrophils. In the frontal cortex, perivascular cuffs and adjacent microglial nodules were distributed diffusely, especially in the molecular layer. Glial nodules were comprised of Iba1- and myeloperoxidase-positive activated microglia. Immunohistochemistry revealed leptospires in mononuclear cell perivascular cuffs, but not in glial nodules. Neuroleptospirosis was accompanied by Leptospira-related nonsuppurative interstitial nephritis, pulmonary edema and hemorrhage, and coronary periarteritis, as well as Toxocara tanuki in the small intestine and nonspecific foreign-body granulomas in the lungs and stomach.

Squamous cell carcinoma in a digit of the hind limb with systemic metastasis in a 17-year-old female koala.

We encountered a case of cutaneous squamous cell carcinoma (SCC) in a 17-year-old female koala at a zoo. A fragile, papillary, elevated mass was found on the third digit of the right hind limb. SCC was identified histopathologically: squamous cell-like polygonal tumor cells showed a nest-like growth pattern with epidermal down growth, central keratinization and necrotic foci, and invaded dermal connective tissues. Metastatic lesions were observed in various organs, including the lung and axillary lymph node: in the lung, multiple metastatic foci similar to the primary lesion, and in the axillary lymph node, individual polygonal tumor cells infiltrated the sinusoids. Immunohistochemistry revealed that the tumor cells were positive for proliferating cell nuclear antigen, which exhibited 32-33% of labeling indices in the tumor cells. To our knowledge, this is the first report of a case of SCC in a digit of a koala.

Resistance to Erythropoiesis-Stimulating Agents in Pre-Dialysis and Post-Dialysis Mortality in Japanese Incident Hemodialysis Patients.

BACKGROUND/AIMS: There is lack of definitive evidence about the association between erythropoiesis-stimulating agent (ESA) responsiveness in the pre-dialysis phase and mortality. Therefore, we conducted a hospital-based, retrospective, cohort study to assess the predictive value of ESA response for prognosis in incident hemodialysis patients. METHODS: A total of 108 patients without preexisting cardiovascular disease who had been started on maintenance hemodialysis were studied. ESA responsiveness just before starting dialysis was estimated using an erythropoietin resistance index (ERI). The endpoint was defined as all-cause death. RESULTS: During a mean follow-up period of 3.1 ± 1.6 years, 18 (17%) patients died. Overall, the multivariate Cox regression analysis revealed that the log-transformed ERI remained an independent predictor of all-cause death after adjustment using a propensity score (hazard ratio 2.25, 95% CI 1.25-4.06). CONCLUSIONS: Among incident hemodialysis patients, hyporesponsiveness to ESA may be associated with mortality.

Usefulness of multidisciplinary care to prevent worsening renal function in chronic kidney disease.

BACKGROUND: Comprehensive education about lifestyle, nutrition, medications and other types of treatment is important to prevent renal dysfunction in patients with chronic kidney disease (CKD). However, the effectiveness of multidisciplinary care on CKD progression has not been evaluated in detail. We aimed to determine whether multidisciplinary care at our hospital could help prevent worsening renal function associated with CKD. METHODS: A total of 150 pre-dialysis CKD outpatients accompanied (n = 68) or not (n = 82) with diabetes mellitus (DM) were enrolled into this study. We assessed annual decreases in estimated glomerular filtration rates (ΔeGFR), and measured systolic blood pressure (SBP), diastolic blood pressure (DBP), hemoglobin (Hb), uric acid (UA), low-density lipoprotein cholesterol (LDL), hemoglobin A1c (HbA1c) values and urinary protein to creatinine ratios (UPCR) 12 months before and after multidisciplinary care. In addition, changes in the number of medications and prescription ratio before and after multidisciplinary care were assessed in 90 patients with CKD who could confirm their prescribed medications. RESULTS: The ΔeGFR significantly improved between before and after multidisciplinary care from - 5.46 to - 0.56 mL/min/1.73 m2/year, respectively. The number of medications and prescription ratio showed no significant changes before and after multidisciplinary care. The ratios of improved ΔeGFR were found in 66.7% of all patients, comprising 63.1% of males and 76.9% of females, 64.8% without DM and 69.4% with DM. Values for UA, LDL, and HbA1c were significantly reduced among patients with improved ΔeGFR. CONCLUSION: Comprehensive multidisciplinary care of outpatients might help prevent worsening renal function among patients with CKD.

Chemical analysis and in vitro toxicological evaluation of aerosol from a novel tobacco vapor product: A comparison with cigarette smoke.

The recent rapid increase in the prevalence of emerging tobacco- and nicotine-containing products, such as e-cigarettes, is being driven in part by their reduced-risk potential compared to tobacco smoking. In this study, we examined emission levels for selected cigarette smoke constituents, so-called "Hoffmann analytes", and in vitro toxicity of aerosol from a novel tobacco vapor product (NTV). The NTV thermally vaporizes a nicotine-free carrier liquid to form an aerosol which then passes through tobacco, where it absorbs tobacco-derived flavors and nicotine. The NTV results were compared with those for 3R4F cigarette smoke. Chemical analysis of the NTV aerosol demonstrated that Hoffmann analyte levels were substantially lower than in 3R4F smoke and that the most were below quantifiable levels. Results from in vitro bacterial reverse mutation, micronucleus and neutral red uptake assays showed that, in contrast with 3R4F smoke, the NTV aerosol failed to demonstrate any measurable genotoxicity or cytotoxicity. The temperature of tobacco during NTV use was measured at approximately 30 °C, which may explain the lower Hoffmann analyte emission and in vitro toxicity levels. These results suggest that the aerosol from the NTV has a very different toxicological profile when compared with combustible cigarette smoke.

Optimum second screening point for detection of coronary artery disease in hemodialysis patients without advanced coronary artery disease.

BACKGROUND: Screening for coronary artery disease (CAD) at the initiation of dialysis is a K/DOQI recommendation. However, it remains unclear when screening for CAD should be repeated in patients without significant disease at the time of starting dialysis. The objectives of this study were to determine: (1) the survival of hemodialysis (HD) patients without CAD at the initiation of dialysis, (2) the major predictors of CAD events, and (3) the best time to repeat screening for CAD after the initiation of HD. METHODS: In order to assess the occurrence of de novo major adverse cardiac events (MACE) in HD patients without CAD, we prospectively followed patients who were normal according to screening tests for CAD performed at the initiation of HD. To detect CAD, 177 of 305 new HD patients underwent coronary angiography and/or pharmacologic stress thallium-201 single photon emission computed tomography within 1 month after starting HD. Among these 177 patients, 100 did not have significant CAD and they were followed for a median of 24 months. RESULTS: Five MACE occurred during follow-up, but no events were observed within 1 year after starting HD. All 5 events occurred during the second year of HD (two events occurred immediately after the end of the first year). An increased level of C-reactive protein (CRP) was the only independent predictor of MACE (hazard ratio: 1.39; 95% CI: 1.03-1.78, p = 0.008) according to Cox regression analysis. The optimum cut-off value of CRP for predicting MACE was 3.5 mg/l. The MACE-free rate at 2 years (99 vs. 79%, p = 0.0008) was significantly higher in patients with a CRP level (3.5 mg/l than in those with a level <3.5 mg/l). CONCLUSION: One year after the initiation of HD could be the optimum time to repeat screening for CAD in patients without disease at the initiation of HD. If the serum CRP level is less than 3.5 mg/l, postponing repeat screening for CAD could be considered.

Independent risk factors for progression of coronary atherosclerosis in hemodialysis patients.

Not uncommonly, hemodialysis patients with normal results in myocardial perfusion tests can still have a cardiac event within 2 years of evaluation. We examined possible risk factors for progression of coronary atherosclerosis in hemodialysis patients. We prospectively evaluated ability of myocardial perfusion imaging carried out under pharmacologic stress to predict 2-year outcomes in 77 hemodialysis patients, specifically thallium-201 single-photon emission computed tomography (SPECT) using high-dose adenosine triphosphate as the stressor. The primary end-point was a cardiac event (cardiac death, non-fatal acute coronary syndrome, or hospitalization for acute ischemic heart failure). Factors independently influencing duration until a cardiac event in hemodialysis patients were identified using stepwise multiple regression analysis. Myocardial perfusion defects were shown in 36 patients. Patients with a perfusion defect were more likely to have cardiac events than those with normal perfusion (78% vs. 15%, P < 0.001). Time until occurrence of a cardiac event in hemodialysis patients showed a significant, independent association with known coronary artery disease [regression coefficient (RC) = -3.391, P = 0.046], elevated C-reactive protein (RC = -5.813, P = 0.005), and a reversible myocardial perfusion defect (RC = -7.386, P < 0.001). An analysis based on the 'best cut-off' of CRP as identified on the basis of the ROC curve augmented the positive and negative predict value of CRP for the prediction of coronary events to 65 and 74%, respectively. Myocardial perfusion SPECT and measuring the plasma concentration of CRP might be useful for the prediction of hemodialysis patients with progression of coronary atherosclerosis.

Prognostic value of stress myocardial perfusion imaging using adenosine triphosphate at the beginning of haemodialysis treatment in patients with end-stage renal disease.

BACKGROUND: Non-invasive detection of coronary artery disease (CAD) remains difficult in patients with end-stage renal disease (ESRD). This study evaluated the ability of pharmacologic stress myocardial perfusion imaging to predict cardiac events in patients with ESRD. METHODS: A prospective study was carried out in 49 consecutive patients with ESRD. Thallium-201 single photon emission computed tomography (SPECT) using high-dose adenosine triphosphate (ATP) was performed within 1 month of the beginning of haemodialysis. The study end-point was a cardiac event or the 1-year anniversary of the SPECT study. RESULTS: Twenty-four patients (17 diabetics, 57% and seven non-diabetics, 37%) had myocardial perfusion defects. The remaining 25 patients had normal perfusion images. Fifteen patients had non-fatal cardiac events and two patients died of a cardiac cause. All patients who had non-fatal cardiac events underwent myocardial revascularization and survived until the end of follow-up. The 1-year cardiac event-free survival rate was 34% among patients with perfusion defects and 96% among patients without perfusion defects (P<0.001). The presence of a myocardial perfusion defect was the only independent predictor of 1-year cardiac events both in overall (HR, 49.91; 95% CI, 5.15-484.00; P<0.001) and in diabetic patients (HR, 33.72; 95% CI, 2.96-383.5; P = 0.005). Diabetes and an increased C-reactive protein were associated with the progression of CAD. CONCLUSIONS: Normal myocardial perfusion imaging by stress thallium-201 SPECT using high-dose ATP performed within 1 month after the beginning of haemodialysis treatment is a powerful predictor of cardiac event-free survival in patients with ESRD.

Favourable long-term outcome by repeated percutaneous coronary revascularization in diabetic haemodialysis patients.

BACKGROUND: Diabetic haemodialysis patients have a high prevalence of coronary events and very high mortality rates. Percutaneous coronary intervention has become a well-established and routine procedure for coronary revascularization. This study investigated the long-term outcome of multiple repeated interventions in diabetic haemodialysis patients with coronary artery disease. METHODS: A retrospective study compared 37 type II diabetic haemodialysis patients with coronary artery disease and 26 non-diabetic patients matched for age, angiographic morphology, and devices of percutaneous intervention. All patients had undergone successful percutaneous intervention prior to enrollment. Percutaneous interventions were repeated in the event of restenosis or the development of a de novo lesion. RESULTS: Diabetic and non-diabetic patients were similar in terms of the number of follow-up angiograms (2.3+/-1.6 vs 2.4+/-1.5/patient) and interventions (2.2+/-1.4 vs 2.2+/-1.5/patient), incidence of target lesion revascularization (85 vs 82%), and number of de novo lesions (15 vs 17%). The cumulative survival rates after the initial percutaneous intervention were similar in the groups (42% vs 31% at 80 months). Cardiac death occurred in 33% of diabetic patients and 42% of non-diabetic patients. Repeated intervention (regression coefficient=16.0, P<0.001) and a lower left ventricular ejection fraction (regression coefficient=-12.9, P=0.047) were determined for the important clinical factors associated with the survival duration after initial coronary intervention. CONCLUSIONS: Multiple repeated percutaneous interventions reduce the long-term mortality of diabetic and non-diabetic haemodialysis patients with coronary artery disease similarly. Multiple repeated percutaneous coronary interventions are a viable option for controlling myocardial ischaemia and improving the long-term outcome in high-risk diabetic haemodialysis patients.