The benefits of tight glycemic control in critical illness: Sweeter than assumed?

Hyperglycemia has long been observed amongst critically ill patients and associated with increased mortality and morbidity. Tight glycemic control (TGC) is the clinical practice of controlling blood glucose (BG) down to the “normal” 4.4–6.1 mmol/L range of a healthy adult, aiming to avoid any potential deleterious effects of hyperglycemia. The ground-breaking Leuven trials reported a mortality benefit of approximately 10% when using this technique, which led many to endorse its benefits. In stark contrast, the multi-center normoglycemia in intensive care evaluation–survival using glucose algorithm regulation (NICE-SUGAR) trial, not only failed to replicate this outcome, but showed TGC appeared to be harmful. This review attempts to re-analyze the current literature and suggests that hope for a benefit from TGC should not be so hastily abandoned. Inconsistencies in study design make a like-for-like comparison of the Leuven and NICE-SUGAR trials challenging. Inadequate measures preventing hypoglycemic events are likely to have contributed to the increased mortality observed in the NICE-SUGAR treatment group. New technologies, including predictive models, are being developed to improve the safety of TGC, primarily by minimizing hypoglycemia. Intensive Care Units which are unequipped in trained staff and monitoring capacity would be unwise to attempt TGC, especially considering its yet undefined benefit and the deleterious nature of hypoglycemia. International recommendations now advise clinicians to ensure critically ill patients maintain a BG of <10 mmol/L. Despite encouraging evidence, currently we can only speculate and remain optimistic that the benefit of TGC in clinical practice is sweeter than assumed.     

The tight junction of pancreatic exocrine cells is a morphometrically dynamic structure altered by intraductal hypertension

The tight junction of pancreatic exocrine cells is thought to regulate paracellular permeability, and is a possible reflux route of pancreatic juice into the blood flow. Morphological changes in the tight junction of canine pancreatic acinar cells following intraductal hypertension and secretin stimulation were morphometrically analyzed to obtain evidence of the control of the paracellular reflux. Pancreatic tissues obtained from 25 dogs after intraductal hypertension, 3 dogs after secretin stimulation, and 5 control dogs were studied. Intraductal pressure was either 20 cmH2O, 30 cmH2O, or 40 cmH2O. Freeze fracture replicas of these pancreatic tissues were observed by electron microscopy. Tight junctions were classified into six morphometric types. Reticular type, parallel type, and mixed type comprised the common types predominantly found in all groups, and three special types were found, infrequently, only after intraductal hypertension. The percentages of the common types were significantly different between the groups. The areas of the tight junctions, and other morphometric parameters, were significantly less after 20 cmH2O intraductal hypertension and secretin stimulation than in the controls. However, these findings after 30 cmH2O or 40 cmH2O intraductal hypertension did not differ from those in the controls. The areas of the three special types of tight junctions were larger than those of the common types. These results suggest that the tight junction of pancreatic exocrine cells is a morphologically dynamic structure that is altered by the extent of intraductal hypertension, and support the hypothesis that paracellular permeability is the mechanism of the reflux of pancreatic juice. Received: November 10, 1999 / Accepted: April 28, 2000     

Acrylamide exposure impairs blood-cerebrospinal fluid barrier function

Previous studies show that chronic acrylamide exposure leads to central and peripheral neu- ropathy. However, the underlying mechanisms remained unclear. In this study, we examined the permeability of the blood-cerebrospinal fluid barrier, and its ability to secrete transthyretin and transport leptin of rats exposed to acrylamide for 7, 14, 21 or 28 days. Transthyretin levels in cerebrospinal fluid began to decline on day 7 after acrylamide exposure. The sodium fluorescein level in cerebrospinal fluid was increased on day 14 after exposure. Evans blue concentration in cerebrospinal fluid was increased and the cerebrospinal fluid/serum leptin ratio was decreased on days 21 and 28 after exposure. In comparison, the cerebrospinal fluid/serum albumin ratio was increased on day 28 after exposure. Our findings show that acrylamide exposure damages the blood-cerebrospinal fluid barrier and impairs secretory and transport functions. These changes may underlie acrylamide-induced neurotoxicity.     

温阳解毒化瘀颗粒对肠源性内毒素血症大鼠肠黏膜上皮紧密连接的影响

目的：研究温阳解毒化瘀颗粒对肠源性内毒素血症（ IETM ）模型大鼠结肠黏膜上皮紧密连接的影响,探索其抗肝衰竭的作用机制。方法：将大鼠随机分为正常组、模型组、温阳解毒化瘀颗粒（实验组）和对照组4组,采用D-半乳糖胺（D-gal）腹腔注射致肝衰竭ITEM大鼠模型。正常组在腹腔注射生理盐水24h后处死,模型组、实验组、对照组分别于造模后24h、48h、72h各取6只、7只、7只大鼠处死,检测各组肝功能、内毒素、结肠黏膜上皮咬合蛋白（occludin）及肌球蛋白轻链激酶（MLCK）。结果：模型组血清ALT/AST、内毒素、 MLCK表达水平均高于正常组, occludin表达低于模型组（ P＜0.01）;实验组血清ALT/AST、内毒素、 MLCK表达水平均低于模型组, occlu-din表达高于模型组（ P＜0.05）。结论：增强结肠粘膜上皮紧密连接功能,降低内毒素的吸收是温阳解毒化瘀颗粒抗肝衰竭的作用机制之一。     

In Vitro Analysis of Human Periodontal Microvascular Endothelial Cells

Background: Endothelial cells (ECs) participate in key aspects of vascular biology, such as maintenance of capillary permeability, initiation of coagulation, and regulation of inflammation. According to previous reports, ECs have revealed highly specific characteristics depending on the organs and tissues. However, some reports have described the characteristics of the capillaries formed by human periodontal ECs. Therefore, the aim of the present study is to examine the functional characteristics of the periodontal microvascular ECs in vitro. Methods: Human periodontal ligament‐endothelial cells (HPDL‐ECs) and human gingiva‐endothelial cells (HG‐ECs) were isolated by immunoprecipitation with magnetic beads conjugated to a monoclonal anti‐CD31 antibody. The isolated HPDL‐ECs and HG‐ECs were characterized to definitively demonstrate that these cell cultures represented pure ECs. Human umbilical‐vein ECs and human dermal microvascular ECs were used for comparison. These cells were compared according to the proliferation potential, the formation of capillary‐like tubes, the transendothelial electric resistance (TEER), and the expression of tight junction proteins. Results: HPDL‐ECs and HG‐ECs with characteristic cobblestone monolayer morphology were obtained, as determined by light microscopy at confluence. Furthermore, the HPDL‐ECs and HG‐ECs expressed the EC markers platelet endothelial cell adhesion molecule‐1 (also known as CD31), von Willebrand factor, and Ulex europaeus agglutinin 1, and the cells stained strongly positive for CD31 and CD309. In addition, the HPDL‐ECs and HG‐ECs were observed to form capillary‐like tubes, and they demonstrated uptake of acetylated low‐density lipoprotein. Functional analyses of the HPDL‐ECs and HG‐ECs showed that, compared to the control cells, tube formation persisted for only a brief period of time, and TEER was substantially reduced at confluence. Furthermore, the cells exhibited delocalization of zonula occludens‐1 and occludin at cell–cell contact sites. Conclusions: The present results provide new evidence that HPDL‐ECs and HG‐ECs have characteristics of fenestrated capillaries. Therefore, capillaries in human periodontal tissues have functional characteristics of fenestrated capillaries, which might be related to the onset and the progression of systemic diseases and inflammation.