Effects of Transglutaminase 2 Inhibition on Ventilator-Induced Lung Injury

This study was performed to examine the role of transglutaminase 2 (TG2) in ventilator-induced lung injury (VILI). C57BL/6 mice were divided into six experimental groups: 1) control group; 2) lipopolysaccharide (LPS) group; 3) lung protective ventilation (LPV) group; 4) VILI group; 5) VILI with cystamine, a TG2 inhibitor, pretreatment (Cyst+VILI) group; and 6) LPV with cystamine pretreatment (Cyst+LPV) group. Acute lung injury (ALI) score, TG2 activity and gene expression, inflammatory cytokines, and nuclear factor-κB (NF-κB) activity were measured. TG2 activity and gene expression were significantly increased in the VILI group (P < 0.05). Cystamine pretreatment significantly decreased TG2 activity and gene expression in the Cyst+VILI group (P < 0.05). Inflammatory cytokines were higher in the VILI group than in the LPS and LPV groups (P < 0.05), and significantly lower in the Cyst+VILI group than the VILI group (P < 0.05). NF-κB activity was increased in the VILI group compared with the LPS and LPV groups (P < 0.05), and significantly decreased in the Cyst+VILI group compared to the VILI group (P = 0.029). The ALI score of the Cyst+VILI group was lower than the VILI group, but the difference was not statistically significant (P = 0.105). These results suggest potential roles of TG2 in the pathogenesis of VILI.

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Hemoglobin A1c values are affected by hemoglobin level and gender in non‐anemic Koreans

Aims/Introduction

To evaluate whether hemoglobin A1c (HbA1c) levels are affected by hemoglobin level and gender.

Materials and Methods

A cross‐sectional analysis was carried out in a sample of 87,284 non‐diabetic Koreans without anemia who participated in comprehensive health check‐ups between January and December 2009 at the Kangbuk Samsung Hospital Total Healthcare Center in Seoul, Korea. We categorized men and women separately according to fasting plasma glucose and hemoglobin level to carry out the analysis.

Results

HbA1c increased steadily with increasing fasting plasma glucose level. Both men and women with lower hemoglobin had significantly higher HbA1c at a given fasting glucose level, and this result was consistent across the fasting glucose quintiles within the non‐diabetic range. Women had a lower mean hemoglobin value compared with men, and women had higher HbA1c levels at a given fasting glucose level consistently across the fasting glucose deciles. There was also a gender‐specific association between age and HbA1c (P < 0.001 for interaction).

Conclusions

HbA1c values were affected by hemoglobin level and gender in non‐anemic Koreans. Thus, hemoglobin level and gender should be considered in the diagnosis of diabetes using HbA1c.     

Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice

Aims/hypothesis

The unfolded protein response (UPR) in endoplasmic reticulum (ER) and autophagy are known to be related. We investigated the role of autophagy in UPR of pancreatic beta cells and the susceptibility of autophagy-deficient beta cells to the ER stress that is implicated in the development of diabetes.

Methods

Rat insulin promoter (RIP)-Cre ⁺;autophagy-related 7 (Atg7)^F/W mice were bred with ob/w mice to derive RIP-Cre ⁺;Atg7 ^F/F-ob/ob mice and to induce ER stress in vivo. GFP-LC3 ⁺-ob/ob mice were generated to examine in vivo autophagic activity. Real-time RT-PCR was performed to study the expression of the genes of the UPR machinery. Proteolysis was assessed by determining release of incorporated radioactive leucine.

Results

Production of UPR machinery was reduced in autophagy-deficient beta cells, which was associated with diminished production of p85?? and p85?? regulatory subunits of phosphoinositide 3-kinase. Because of compromised UPR machinery, autophagy-deficient beta cells were susceptible to ER stressors in vitro. When mice with beta cell-specific autophagy deficiency, which have mild hyperglycaemia, were bred with ob/ob mice to induce ER stress in vivo, severe diabetes developed, which was accompanied by an increase in beta cell death and accumulation of reactive oxygen species. The increased demand for UPR present in obesity was unmet in autophagy-deficient beta cells. Autophagy level and autophagic activity were enhanced by lipid, while proteolysis was reduced.

Conclusions/interpretation

These results suggest that autophagy is important for intact UPR machinery and appropriate UPR in response to lipid injury that increases demand for UPR. Autophagy deficiency in pancreatic beta cells may contribute to the progression from obesity to diabetes.     

Certolizumab Pegol Compared to Natalizumab in Patients with Moderate to Severe Crohn’s Disease: Results of a Decision Analysis

Introduction  

A significant proportion of patients with Crohn’s disease (CD) lose response to antibodies directed against tumor necrosis factor α (TNF). Prior TNF-antagonist failure is associated with lower rates of response to subsequent TNF-antagonist therapy. In patients failing two anti-TNF agents, a choice exists between using a third-anti-TNF therapy or natalizumab (NAT), an α-4 integrin inhibitor. A cost-effectiveness analysis comparing these competing strategies has not been performed.     

The Efficacy and Perioperative Complications Associated with Lumbar Spinal Fusion Surgery,Focusing on Geriatric Patients in the Republic of Korea

Objective

The purpose of this study was to examine the efficacy and perioperative complications associated with lumbar spinal fusion surgery, focusing on geriatric patients in the Republic of Korea.

Methods

We retrospectively investigated 485 patients with degenerative spinal diseases who had lumbar spinal fusion surgeries between March 2006 and December 2010 at our institution. Age, sex, comorbidity, American Society of Anesthesiologists (ASA) class, fusion segments, perioperative complications, and outcomes were analyzed in this study. Risk factors for complications and their association with age were analyzed.

Results

In this study, 81 patients presented complications (16.7%). The rate of perioperative complications was significantly higher in patients 70 years or older than in other age groups (univariate analysis, p=0.015; multivariate analysis, p=0.024). The perioperative complications were not significantly associated with the other factors tested (sex, comorbidity, ASA class, and fusion segments). Post-operative outcomes of lumbar spinal fusion surgeries for the patients were determined on the basis of MacNab''s criteria (average follow up period : 19.7 months), and 412 patients (85.0%) were classified as having "excellent" or "good" results.

Conclusion

Increasing age was an important risk factor for perioperative complications in patients undergoing lumbar spinal fusion surgery, whereas other factors were not significant. However, patients'' satisfaction or return to daily activities when compared with younger patients did not show much difference. We recommend good clinical judgment as well as careful selection of geriatric patients for lumbar spinal fusion surgery.