Microglia contributes to plaque growth by cell death due to uptake of amyloid β in the brain of Alzheimer's disease mouse model

Pathological hallmarks of Alzheimer's disease (AD) include extracellularly accumulated amyloid β (Aβ) plaques and intracellular neurofibrillary tangles in the brain. Activated microglia, brain‐resident macrophages, are also found surrounding Aβ plaques. The study of the brain of AD mouse models revealed that Aβ plaque formation is completed by the consolidation of newly generated plaque clusters in vicinity of existed plaques. However, the dynamics of Aβ plaque formation, growth and the mechanisms by which microglia contribute to Aβ plaque formation are unknown. In the present study, we confirmed how microglia are involved in Aβ plaque formation and their growth in the brain of 5XFAD mice, the Aβ‐overexpressing AD transgenic mouse model, and performed serial intravital two‐photon microscopy (TPM) imaging of the brains of 5XFAD mice crossed with macrophage/microglia‐specific GFP‐expressing CX3CR1^GFP/GFP mice. We found that activated microglia surrounding Aβ plaques take up Aβ, which are clusters developed inside activated microglia in vivo and this was followed by microglial cell death. These dying microglia release the accumulated Aβ into the extracellular space, which contributes to Aβ plaque growth. This process was confirmed by live TPM in vivo imaging and flow cytometry. These results suggest that activated microglia can contribute to formation and growth of Aβ plaques by causing microglial cell death in the brain. GLIA 2016;64:2274–2290     

Universal monoclonal antibody-based influenza hemagglutinin quantitative enzyme-linked immunosorbent assay

Seasonal and pandemic influenza infections remain a serious public health concern. Many health authorities recommend annual vaccination as the most effective way to control influenza infection. Accordingly, regulatory guidelines ask vaccine manufacturers to determine vaccine potency at the time of release and throughout shelf-life to ensure vaccine quality. The potency of inactivated influenza vaccine is related to the quantity of hemagglutinin (HA). Since 1970s, single radial immunodiffusion (SRID) assay has been standardly used for the quantitation of HA in influenza vaccine. However, SRID is labor-intensive, inaccurate, and requires standard reference reagents that should be updated annually. Therefore, there have been extensive efforts to develop alternative potency assays. In this study, we developed and tested a new HA quantitative enzyme-linked immunosorbent assay (ELISA) using a universal monoclonal antibody that can bind to HAs from various subtypes in group 1 influenza A virus (IAV). We analyzed the conserved stalk domain of HA via a library approach to design a consensus HA antigen for group 1 IAV. The antigens were expressed as a soluble form in E. coli and were purified by Ni-affinity chromatography. When tested with variety of HAs from IAVs or influenza B viruses (IBVs), the mAbs exhibited specific binding to group 1 HAs, with potential exception to H9 subtype. Among various conditions of pH, urea, and reducing agents, pretreatment of HA at low pH exposing the conserved stalk domain was crucially important for optimal ELISA performance. Calibration curves for various HAs were generated to determine accuracy, specificity, sensitivity, and linear dynamic range. The ELISA method shows high sensitivity and accuracy compared with the SRID assay. The HA group specific universal mAbs against the consensus stalk domain of HA are conducive to establishing an ELISA-based standard procedure for the quantitation of HA antigens for annual vaccination against influenza infection.     

Haemodynamic evaluation by Doppler ultrasonography in patients with portal hypertension: a review

Doppler ultrasonography (US) has an advantage of being non‐invasive; therefore, several attempts have been made to investigate the haemodynamic alterations in cirrhosis and the response to medical treatment of portal hypertension. Doppler indices, which have been commonly used for the evaluation of portal hypertension, include the measurement of portal and splenic venous blood velocity and flows, and the resistive and pulsatility index at hepatic, splenic, renal, superior mesenteric artery. Although many positive evidences have been suggested, its clinical usefulness in portal hypertension remains unsettled because of being plagued by lack of reproducibility and accuracy characterized by intra‐ and interobserver variation. However, recently, Doppler's usefulness in assessment of severity of portal hypertension in terms of reproducibility, technical ease and accuracy and response to drugs that reduce the portal pressure has been proposed. In addition, because most of the patients with cirrhosis and portal hypertension have intrahepatic shunts, they show a decrease in intrahepatic circulatory time (IHCT). Doppler US using microbubble contrast agents allows measurement of IHCT. Therefore, application of contrast‐enhanced Doppler US can be prospective for the assessment of the severity of portal hypertension. Several reports have demonstrated that colour Doppler endoscopic US enable haemodynamic study to assess the portal hypertension and has a role of guidance to measure the imaging‐based variceal pressure. We have reviewed briefly the clinical usefulness of Doppler US in assessing the severity of portal hypertension and its response to treatment.     

Portal Hypertensive Gastropathy: Correlation with Portal Hypertension and Prognosis in Cirrhosis

Background

Portal hypertensive gastropathy (PHG) is a common endoscopic finding in patients with cirrhosis. However, the relationship between PHG and portal hypertension is controversial. Furthermore, nothing is known regarding the correlation between PHG and prognosis in patients with cirrhosis.

Methods

The hepatic venous pressure gradient (HVPG), endoscopic PHG grade, Child–Pugh score, and model for end-stage liver disease (MELD) score were assessed at baseline and were followed prospectively in 331 cirrhotic patients (284 males, 85.8%; mean age, 52.16 ± 9.05 years) from January 2001 to April 2009. The relationship between PHG with HVPG and survival was investigated.

Results

The HVPG was significantly higher in patients with severe PHG than in those with mild or no PHG (absent, 4.9 ± 1.7 mmHg; mild, 10.7 ± 4.1 mmHg; severe, 15.6 ± 4.6 mmHg; P < 0.001). During follow-up, 28 patients (8.5%) died from liver-related disease. In the Cox regression analysis, severe PHG (none and mild vs. severe) (hazard ratio 1.153, 95% confidence interval: 1.048–1.269) showed a significantly high relative risk of mortality, and in the Kaplan–Meier analysis, severe PHG showed a significantly shorter expected survival time than none or mild PHG (median survival time, 77.6 ± 9.6 months in severe PHG; log-rank test, P = 0.030).

Conclusions

PHG was associated with portal hypertension severity and prognosis in patients with cirrhosis.     

Transarterial coil embolization of a carotid-cavernous fistula which occurred during stent angioplasty

Intracranial endovascular procedures are less invasive and relatively safe; however, these procedures do carry a risk of complications, such as thromboembolization, arterial injury, and vessel occlusion. We present a case of carotid-cavernous fistula development secondary to injury of the cavernous segment of the internal carotid artery (ICA) during stent angioplasty and its treatment by transarterial coil embolization. Probable causes of this complication and its treatment method are discussed. To the best of our knowledge, this is the first report of such a case.     

Robotic Versus Laparoscopic Low Anterior Resection of Rectal Cancer: Short-Term Outcome of a Prospective Comparative Study

Background

The aim of this study is to compare the short-term results between robotic-assisted low anterior resection (R-LAR), using the da Vinci^® Surgical System, and standard laparoscopic low anterior resection (L-LAR) in rectal cancer patients.

Methods

113 patients were assigned to receive either R-LAR (n = 56) or L-LAR (n = 57) between April 2006 and September 2007. Patient characteristics, perioperative clinical results, complications, and pathologic details were compared between the groups. Moreover, macroscopic grading of the specimen was evaluated.

Results

Patient characteristics were not significantly different between the groups. The mean operation time was 190.1 ± 45.0 min in the R-LAR group and 191.1 ± 65.3 min in the L-LAR group (P = 0.924). The conversion rate was 0.0% in the R-LAR groups and 10.5% in the L-LAR group (P = 0.013). The serious complication rate was 5.4% in the R-LAR group and 19.3% in the L-LAR group (P = 0.025). The specimen quality was acceptable in both groups. However, the mesorectal grade was complete (n = 52) and nearly complete (n = 4) in the R-LAR group and complete (n = 43), nearly complete (n = 12), and incomplete (n = 2) in the L-LAR group (P = 0.033).

Conclusion

R-LAR was performed safely and effectively, using the da Vinci^® Surgical System. The use of the system resulted in acceptable perioperative outcomes compared to L-LAR.