Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration

There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I : C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3(-/-) mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I : C)-induced retinal degeneration. Moreover, after poly(I : C) injection, Rip3(-/-) mice displayed decreased levels of pro-inflammatory cytokines (such as TNF-α and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I : C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF-α and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF-α and IL-6 production after poly(I : C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD

Rebleeding rate after interventional therapy directed by capsule endoscopy in patients with obscure gastrointestinal bleeding

<p>Abstract</p> <p>Background</p> <p>The precise role of capsule endoscopy in the diagnostic algorithm of obscure gastrointestinal bleeding has yet to be determined. Despite the higher diagnostic yield of capsule endoscopy, the actual impact on clinical outcome remains poorly defined. The aim of this study was to evaluate the follow-up results of patients with obscure gastrointestinal bleeding to determine which management strategies after capsule endoscopy reduced rebleeding.</p> <p>Methods</p> <p>All patients in whom the cause of obscure gastrointestinal bleeding was investigated between May 2004 and March 2007 were studied retrospectively. We evaluated the clinical outcome of patients with obscure gastrointestinal bleeding after capsule endoscopy using the rebleeding rate as the primary outcome.</p> <p>Results</p> <p>Seventy-seven patients with obscure gastrointestinal bleeding underwent capsule endoscopy. Capsule endoscopy identified clinically significant findings that were thought to be the sources of obscure gastrointestinal bleeding in 58.4% of the patients. The overall rebleeding rate was 36.4%. The rebleeding rate was significantly higher among patients with insignificant findings than among those with significant findings (<it>p </it>= 0.036). Among the patients in whom capsule endoscopy produced significant findings, the rebleeding rate of the patients who underwent therapeutic interventions was significantly lower than that in those who did not undergo intervention (9.5% vs 40.0%, <it>p </it>= 0.046).</p> <p>Conclusion</p> <p>Follow-up and further aggressive interventions are necessary for patients with obscure gastrointestinal bleeding and significant capsule endoscopy findings to reduce the chance of rebleeding.</p

Association of Red Meat Intake with the Risk of Cardiovascular Mortality in General Japanese Stratified by Kidney Function: NIPPON DATA80.

The consumption of red meat has been recommended for individuals with reduced kidney function. However, red meat intake was recently suspected to increase cardiovascular disease (CVD) risk. We evaluated the association of red meat intake with CVD mortality risk in Japanese with/without reduced kidney function. Overall, 9112 participants of a Japanese national survey in 1980, aged ≥30 years, were followed for 29 years. Red meat intake was assessed using weighed dietary record. Cox proportional hazards models were used to estimate the hazard ratio (HR) of CVD mortality according to sex-specific tertiles of red meat intake. We also performed stratified analyses with/without reduced kidney function defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2. Red meat intake was not associated with CVD mortality risk in men and women. In stratified analyses, the HR of the highest compared with the lowest tertile of red meat intake was lower only in women with reduced kidney function (0.67, 95% confidence interval 0.46-0.98). In conclusion, there were no clear associations between red meat intake and CVD mortality risk in Japanese population; however, a higher intake of red meat was associated with lower risk of future CVD mortality in women with reduced kidney function

Changes in brain tissue and behavior patterns induced by single short-term fasting in mice.

In humans, emaciation from long-term dietary deficiencies, such as anorexia, reportedly increases physical activity and brain atrophy. However, the effects of single short-term fasting on brain tissue or behavioral activity patterns remain unclear. To clarify the impact of malnutrition on brain function, we conducted a single short-term fasting study as an anorexia model using male adult mice and determined if changes occurred in migratory behavior as an expression of brain function and in brain tissue structure. Sixteen-week-old C57BL/6J male mice were divided into either the fasted group or the control group. Experiments were conducted in a fixed indoor environment. We examined the effects of fasting on the number of nerve cells, structural changes in the myelin and axon density, and brain atrophy. For behavior observation, the amount of food and water consumed, ingestion time, and the pattern of movement were measured using a time-recording system. The fasted mice showed a significant increase in physical activity and their rhythm of movement was disturbed. Since the brain was in an abnormal state after fasting, mice that were normally active during the night became active regardless of day or night and performed strenuous exercise at a high frequency. The brain weight did not change by a fast, and brain atrophy was not observed. Although no textural change was apparent by fasting, the neuronal neogenesis in the subventricular zone and hippocampus was inhibited, causing disorder of the brain function. A clear association between the suppression of encephalic neuropoiesis and overactivity was not established. However, it is interesting that the results of this study suggest that single short-term fasting has an effect on encephalic neuropoiesis

Experimental design.

<p>The mice were given CE-2 (CLEA Rodent Diet CE-2 for breeding) standard pellet chow. Tap water was used for drinking and was given ad libitum. Before the start of the experiment, mice were fed powder chow during a week-long acclimatization period in order to measure the feed intake in normal mice. In the first period, we measured food and water intake, and intake time using K2CABIN (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080085#pone-0080085-g002" target="_blank">Figure 2</a>). In the second period, we measured the amount and rhythm of movement behavior using KUROBOX (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080085#pone-0080085-g002" target="_blank">Figure 2</a>). In the third period, mice were fasted for 3 days, only drinking water was given ad libitum.</p

Movement behavioral patterns and running distance of mice in the second period given ad libitum intake of food and water.

<p>(A) An example of the movement behavioral pattern of a mouse in the second period. (B) Running distance in a dark and light phase in the second period. Values are Mean ± S.D. (n = 10). P < 0.001, significantly different from the dark phase value.</p

K2CABIN system and KUROBOX system.

<p>(A) K2CABIN system used to measure eating patterns and KUROBOX system used to measure movement patterns of behavior. (B),(C) KUROBOX; This measures the movement of mice by infrared sensors. We calculated the distance travelled by the mouse, the speed and the movement angle over time.</p

Macroscopic images of brain tissue.

<p>Macroscopically, upon dissection, we could not see any atrophy upon fasting and there was no change in wet weight of the brain. However, the surface of brain tissue appeared less glossy and seemed to have lost precision.</p

Optical microscopy images of brain tissue.

<p>Kluver–Barrera stained images of Frontal cross section of the brain (A) and the hippocampal region (B). </p