Dynamin 1 depletion and memory deficits in rats treated with Aβ and cerebral ischemia

Alzheimer's disease (AD) is progressive dementia with senile plaques composed of β‐amyloid (Aβ). Recent studies suggest that synaptic dysfunction is one of the earliest events in the pathogenesis of AD. Here we provide the first experimental evidence that a change in the level of dynamin 1 induced by Aβ correlates with memory impairment in vivo. We treated rats with transient cerebral ischemia with oligomeric forms of Aβ (Aβ oligomers), including dimers, trimers, and tetramers, intracerebroventricularly. The combination of Aβ oligomers and cerebral ischemia, but not cerebral ischemia alone, significantly impaired memory and decreased the level of dynamin 1, which plays a critical role in synaptic vesicle recycling, but did not affect the levels of other synaptic proteins, such as synaptophysin and synaptobrevin, in the hippocampus. Furthermore, the N‐methyl‐D ‐aspartate (NMDA) receptor antagonist memantine prevented memory impairment and dynamin 1 degradation, suggesting that these changes might be mediated by NMDA receptors. These results suggest that Aβ oligomers induce memory impairment via dynamin 1 degradation, which may imply that dynamin 1 degradation is one of the causes of synaptic dysfunction in AD. © 2010 Wiley‐Liss, Inc.     

Measurement of health-related quality of life in patients with chronic kidney disease in Japan with EuroQol (EQ-5D)

Background  

Chronic kidney disease (CKD) is a health-related quality-of-life (HRQOL) deteriorating disease which is not only a public health but also a socioeconomic problem. Interest in developing cost-effective interventions to control CKD has increased. The aim of this study was to measure HRQOL in terms of quality-adjustment weights for cost-effectiveness analysis using EQ-5D in patients with CKD. The relationships between the measured HRQOL and clinical indices/complications were also analyzed.     

The Effect of CKD on Associations between Lifestyle Factors and All-cause,Cancer, and Cardiovascular Mortality: A Population-based Cohort Study

Objective Results from previous studies on the dose-dependent effect of adhering to multiple lifestyle factors on all-cause mortality in patients with chronic kidney disease (CKD) are inconsistent, despite the reported dose-dependent effect in the general population. This study aimed to examine whether CKD modifies the dose-dependent effect of adhering to multiple lifestyle factors on mortality. Methods This population-based prospective cohort study targeted 262,011 men and women aged 40-74 years at baseline. Of these, 18.5% had CKD, which was defined as GFR <60 mL/min/1.73 m², ≥1+ proteinuria on urinalysis, or both. The following lifestyle behaviors were considered healthy: no smoking, body mass index <25 kg/m², moderate or lower alcohol consumption, regular exercise, and healthy eating habits. Healthy lifestyle scores were calculated by adding the total number of lifestyle factors for which each participant was at low risk. Cox proportional hazards models were used to examine associations between healthy lifestyle scores and all-cause, cancer, and cardiovascular mortality, and whether CKD modified these associations. Results During a median follow-up of 4.7 years, 3,471 participants died. The risks of all-cause and cancer mortality decreased as the number of five healthy lifestyle factors that were adhered to increased, irrespective of the CKD status. The risk of cardiovascular mortality, however, was modified by CKD (interaction p=0.07), and an unhealthy lifestyle and CKD synergistically increased cardiovascular mortality. Conclusion A healthy lifestyle can reduce the risk of all-cause and cancer death in patients with or without CKD, while the prevention of CKD is essential for reducing the risk of cardiovascular death.     

IL‐2 is positively involved in the development of colitogenic CD4+ IL‐7Rαhigh memory T cells in chronic colitis

IL‐2 and IL‐7 share a common γ‐chain receptor and are critical for T‐cell homeostasis. We aimed to clarify the reciprocal roles of IL‐2 and IL‐7 in the development and persistence of chronic colitis. We performed a series of adoptive transfers of IL‐2^?/? CD4⁺CD45RB^high T cells into RAG‐2^?/? mice and assessed the role of IL‐2 in the induction of IL‐7Rα on colitogenic CD4⁺ T cells and the development of chronic colitis. RAG‐2^?/? mice transferred with WT but not with IL‐2^?/? CD4⁺CD45RB^high T cells developed Th1/Th17‐mediated colitis. Consistently, re‐expression of IL‐7Rα was severely impaired on IL‐2^?/? but not on WT CD4⁺ T cells from the transferred mice. To exclude a contribution of the preclinical autoimmunity of IL‐2^?/?mice, WT Ly5.1⁺ or IL‐2^?/? Ly5.2⁺ CD4⁺CD45RB^high T cells from GFP mice previously transplanted with the same number of WT and IL‐2^?/? BM cells were transferred into RAG‐2^?/? mice. RAG‐2^?/? mice transferred with IL‐2^?/?‐derived CD4⁺CD45RB^high T cells did not develop colitis, but their splenic CD4⁺ T cells changed from effector‐memory to central‐memory type. These results show that IL‐2 is critically involved in the establishment and maintenance of IL‐7‐dependent colitogenic memory CD4⁺IL‐7Rα^high T cells.     

Neuronal vulnerability of stroke-prone spontaneously hypertensive rats to ischemia and its prevention with antioxidants such as vitamin E

Stroke-prone spontaneously hypertensive rats (SHRSP/Izm) develop severe hypertension, and more than 95% of them die of cerebral stroke. Hypoxic stimulation followed by oxygen reperfusion induces neuronal damage in both normotensive Wistar Kyoto/Izm (WKY/Izm) and SHRSP/Izm rats, and the percentage of neurons that undergo apoptosis during hypoxia-reperfusion is markedly higher in SHRSP/Izm rats than in WKY/Izm rats. The biochemical characteristics of the SHRSP/Izm rats, unlike those of WKY/Izm rats, might act as a factor in the stroke proneness of SHRSP/Izm rats. In the hippocampus, the formation of hydroxyl radicals and the cerebral blood flow-independent formation of nitric oxide (NO) were strongly increased after reperfusion in SHRSP/Izm rats, and the neuronal expression of the thioredoxin and Bcl-2 genes was significantly decreased in the SHRSP/Izm rats compared with the WKY/Izm rats. On the other hand, the effects of antioxidants against neuronal death associated with cerebral ischemia-reperfusion were stronger in the SHRSP/Izm rats, in which the addition of vitamin E or ebselen almost completely inhibited neuronal death. Namely, the addition of 100 μg/ml of vitamin E under hypoxia/reoxygenation (H/R) conditions completely inhibited WKY and SHRSP/Izm neuronal death. Vitamin E exerts a marked inhibitory effect against neuronal damage via its incorporation into mitochondrial membranes, where it captures reactive oxygen and free radicals. The susceptibility of neurons to apoptosis in SHRSP/Izm rats is partly due to an insufficiency of mitochondrial redox regulation and apoptosis-inhibitory proteins. In this review, we describe the neuronal vulnerability of SHRSP/Izm rats induced by cerebral ischemia and the effects of antioxidants such as vitamin E.     

Evaluation of the appropriate root pressure for maintaining heartbeat during an aortic cross-clamp for primary repair of the aortic arch in premature infants with associated cardiac anomalies

We developed a new cardiopulmonary bypass (CPB) method to minimize myocardial damage during aortic arch reconstruction. In this method, coronary flow and heartbeat were stabilized by maintaining the aortic root pressure with an adjusted preload of the ventricle during aortic cross-clamping. This study was performed to determine the appropriate root pressure to maintain the heartbeat without causing deterioration of ventricular function. Study 1. Under partial CPB, the ascending aorta was cross-clamped in 6 pigs (group 1). Experimental data at various systolic aortic root pressures was analysed to determine the appropriate root pressure. Study 2. In group 2 (control, n＝6), the aorta was not clamped, while in group 3 (n＝6), the aorta was cross-clamped for 60 min and the systolic aortic root pressure was maintained at the pressure determined in study 1. Study 1. The diastolic coronary flow was stabilized at values comparable to that before initiation of CPB (6.6±1.4 ml/beat) when the systolic aortic root pressure was above 80 mmHg. Intracardiac pressure and the myocardial oxygen consumption (MvO2) seemed to be acceptable when the systolic aortic root pressure was below 100 mmHg. Therefore, 90 mmHg was selected for study 2. Study 2. Perioperative cardiac function did not differ between the groups. We concluded that 90 mmHg was the systolic aortic root pressure appropriate for this method.     

Thiol-oxidation reduces the release of amylase induced by β-adrenergic receptor activation in rat parotid acinar cells

In parotid acinar cells, the activation of β-adrenergic receptors induces the accumulation of intracellular cAMP, and consequently provokes the exocytotic release of amylase, a digestive enzyme. The cellular redox status plays a pivotal role in regulating various cellular functions. Cellular redox imbalance caused by the oxidation of cellular antioxidants, as a result of oxidative stress, induces significant biological damage. In this study, we examined the effects of diamide, a thiol-oxidizing reagent, on amylase release by rat parotid acinar cells. In cells treated with diamide, the formation of cAMP and the release of amylase induced by the β-agonist isoproterenol (IPR) were partially reduced. The inhibitory effect of diamide on the IPR-induced release of amylase could be abrogated by reduced glutathione or dithiothreitol. Diamide had no effect on the amylase release induced by forskolin, an adenylate cyclase activator, or by mastoparan, a heterotrimeric GTPbinding protein activator. In cells treated with diamide, the binding affinity for [(3)H]DHA, but not the number of binding sites, was reduced. These results suggest that β-adrenergic receptor function is reduced by thiol-oxidation, which inhibits amylase secretion by parotid acinar cells.     

Immunohistochemical analysis of pyloric gland adenomas using a series of Mucin 2, Mucin 5AC, Mucin 6, CD10, Ki67 and p53

A pyloric gland adenoma (PGA) of the stomach was first described in a book chapter in 1976 by Kurt Elster and has been rarely reported in the literature. We expanded the current immunohistochemical data of these adenomas in a detailed series to further analyse the immunhistochemical status of PGA. From 60 patients with PGA with and without adenocarcinomas of the gastrointestinal tract, an immunhistochemical panel of Mucin 2, Mucin 5AC, Mucin 6, CD10, Ki67 and p53 was used to define the expression of these markers. All PGA were positive for Mucin 6 (deep mucoid glands), which they express over the whole lesion up to the surface. Mucin 5AC expression varies from case to case. A transition from gastric to intestinal differentiation can be observed focally as depicted by Mucin 2 and CD10 in 65% of the cases. The gastric corpus mucosa of elderly patients with either Helicobacter pylori gastritis or autoimmune gastritis is highly affected. Almost 47% of all PGA already underwent malignant transformation into adenocarcinoma. Significant immunohistochemical differences could be detected between PGA with and without adenocarcinoma regarding ki67 and p53. The diagnosis of PGA can be confirmed immunohistochemically by staining against apomucin 6 and apomucin 5AC. Focal intestinal differentiation supports the hypothesis that gastric adenocarcinomas can initially develop from carcinomas of the gastric type and transform into intestinal type later on. The high frequency of malignant transformation of PGA underlines its high potential for invasive malignancy.     

The surface expression of HLA-F on decidual trophoblasts increases from mid to term gestation

HLA-F has recently only begun to be studied in earnest, and has been thought not to be expressed on the cell surface. However, in our previous report, we demonstrated surface expression of HLA-F on extravillous trophoblasts (EVTs) invading the decidua in term placental tissues. To better understand its function, we attempted to determine when surface expression of HLA-F begins during normal pregnancy, and whether there is a difference in expression between normal and preeclamptic placentas, by comparing the expression of HLA-G and -E by immunohistochemical staining with anti-HLA-E, -F and -G antibodies (3D12, 3D11 and 87G, respectively). In EVTs, HLA-F was expressed only in the cytoplasm weakly during the first trimester, after which expression increased and moved to the cell surface with the progression of pregnancy from the second trimester, which was confirmed by the results of double-labeled immunofluorescence staining with anti-HLA-F and anti-HLA-G antibodies, and by flow cytometry using trophoblasts isolated from the decidua. HLA-E showed similar expression as HLA-F, though it was expressed on the cell surface from the first trimester, while HLA-G was expressed strongly in the cytoplasm and on the cell surface during all stages of pregnancy. The expressions of HLA-E, -F and -G in preeclamptic placentas were not different from those in normal placentas, though there were a greater number of necrotic EVTs in preeclampsia. The increase in expression of HLA-E and HLA-F from the second trimester to full term was coincident with the timing of rapid growth of the fetus. Our results suggest that these may function together to prepare an environment that supports fetal growth.     

Analysis of national representative opinion surveys concerning gestational surrogacy in Japan

OBJECTIVE: Although gestational surrogacy offers several advantages, this procedure has given rise to some ethical and legal issues. We aimed to clarify the factors affecting the attitude of the Japanese toward gestational surrogacy. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Nationwide opinion surveys concerning assisted reproductive technologies (ART) were carried out in 1999 and 2003. Participants included 2568 and 3647 people from the general public surveyed in 1999 and 2003, respectively (1564 people received only the questionnaire, and 2083 people received a questionnaire and brochure about ART). MAIN OUTCOME MEASURE: Multivariate-adjusted odds ratio and 95% confidence interval from logistic regression models for factors affecting the attitude toward gestational surrogacy. RESULTS: In both surveys, approximately half of respondents approved of gestational surrogacy; 20-30% disapproved of the procedure. People with high socioeconomic status clearly expressed their opinion on this issue. A liberal attitude toward gender role promoted approval of gestational surrogacy; a liberal attitude toward family had the opposite effect. CONCLUSION: Our findings suggest that socioeconomic status affects people's expression of their opinion regarding this issue, while attitudes toward this procedure were influenced by individual belief. Considering socioeconomic status and diversity of individual belief is required for further discussion on this topic.