Tight glycemic control in the ICU - is the earth flat?

Tight glycemic control in the ICU has been shown to reduce mortality in some but not all prospective randomized control trials. Confounding the interpretation of these studies are differences in how the control was achieved and underlying incidence of hypoglycemia, which can be expected to be affected by the introduction of continuous glucose monitoring (CGM). In this issue of Critical Care, a consensus panel provides a list of the research priorities they believe are needed for CGM to become routine practice in the ICU. We reflect on these recommendations and consider the implications for using CGM today.Continuous glucose control in the ICU: report of a 2013 Round Table meeting, published in this issue of Critical Care[1], summarizes the discussion and recommendations of a round table meeting on the management of blood glucose levels in the ICU. The self-selected panel of authors recommends eight areas where it believes research is needed, beginning with head-to-head comparisons of different continuous glucose monitoring (CGM) devices and ending with randomized controlled studies validating closed-loop insulin delivery.Appropriately, the recommendations focus on what is needed to advance CGM into the ICU and do not address whether tight glycemic control is beneficial or what the appropriate target range should be. Nonetheless, the answers to these questions will impact the importance of the recommendations. Of the prospective randomized controlled studies performed to date, many have failed to show a clinical benefit to tight glycemic control (TGC) - including our own study in children less than 3 years of age following cardiac surgery [2]. Our current study assessing the possible benefit of TGC in hyperglycemic critically ill children with cardiovascular and/or respiratory failure ({"type":"clinical-trial","attrs":{"text":"NCT01565941","term_id":"NCT01565941"}}NCT01565941) seeks to answer the question whether control in the target range 80 to 110 mg/dL results in better outcomes than control in the 150 to 180 mg/dL target range. Clearly, if the 80 to 110 mg/dL range proves beneficial, the need to introduce CGM into the ICU will be paramount as this target range is difficult to achieve without increasing the incidence of hypoglycemia. This may be less important if the 150 to 180 mg/dL range is shown to be equally effective. It is possible that TGC with CGM will reduce glucose variability irrespective of the target range, and the panel’s recommendations appropriately call for study of the effect of different treatment algorithms on this metric. However, it should be noted that the evidence the authors cite supporting the importance of glycemic variability [3] is based on retrospective analysis, which cannot be used to infer causality.Still, the question remains as to how best to manage glucose levels in critically ill patients today. Putting aside whether control in a low target range is better than in a higher range, or whether a reduction in glucose variability per se improves clinical outcomes, there are low and high glucose levels that would be treated today in virtually every ICU. Every effort needs to be made to avoid these ends of the spectrum. To this end, one might ask whether CGM devices should be used in the ICU now. One can correctly infer from the recommendations that there have been no head-to-head comparisons of different CGM devices, and that the trends reported have also not been validated. Likewise, investigators who have established insulin protocols at their institutions might ask whether the protocols need to be re-evaluated given the marked differences in insulin recommendations noted by Wilson and colleagues [4] in work highlighted by the consensus panel. Our own review of TGC protocols concurs with that of Wilson and colleagues [4] in that we also noted substantive differences among the existing protocols [5]; however, we concluded that virtually all the protocols could be expected to achieve and maintain their desired target glucose ranges and each could be reasonably expected to benefit from the use of CGM devices.     

世界胃肠病学组织(WGO-OMGE)临床指南——发展中国家幽门螺杆菌感染

我非常高兴向大家推荐这份发展中国家幽门螺杆菌（H．priori）临床指南。该指南的编译是由数位在该领域具有丰富临床经验的世界知名专家共同完成的。     

美国白人与中国人原发性结直肠癌病理特点对照

目的　比较研究美国白人与中国患者原发性结直肠癌 (CRC)的病理学特征。方法　回顾性分析 1990～ 2 0 0 0年美国克里夫兰佛罗里达临床中心结直肠外科 6 90例和中国第一军医大学南方医院普外科 870例连续完整的CRC患者资料。结果　美国白人与中国患者比较 :36 .3%比 2 6 .0 %的肿瘤位于近侧 (右侧 )结肠 (P <0 .0 0 1) ,6 3.7%比 74 .0 %位于远侧 (左侧 )结肠 (P <0 .0 0 1) ;中位年龄 72比5 4岁 (P <0 .0 0 1) ;腺癌 84 .3%比 85 .3% ,黏液腺癌 13.6 %比 11.4 % ,印戒细胞癌 1.5 %比 2 .7% ,腺鳞癌 0 .6 %比 0 .6 % (P >0 .0 5 ) ;高分化癌 16 .7%比 4 0 .2 % ,中分化 6 1.9%比 4 8.5 % ,低分化 2 1.4 %比11.3% (P <0 .0 0 1) ,近侧结肠癌中低分化比例在两种族患者中均较高 ;TNM分期 ,0期 5 .4 %比 1.3%(P <0 .0 0 1) ,Ⅰ期 34.8%比 18.9% (P <0 .0 0 1) ,Ⅱ期 2 9.9%比 33.2 % (P >0 .0 5 ) ,Ⅲ期 2 0 .3%比2 2 .8% (P >0 .0 5 ) ,Ⅳ期 9.6 %比 17.0 % (P <0 .0 0 1)。进展期癌更常见于近侧结肠和中国患者。结论　美国白人易患近侧结肠癌 ,中国患者远侧结直肠癌更常见 ,进展期比例高 ,年龄明显小。低分化和进展期癌更常见于近侧结肠。     

Molecular cloning, chromosomal location, and tissue-specific expression of the murine cathepsin G gene

We previously have characterized a cluster of genes encoding cathepsin G (CG) and two other CG-like hematopoietic serine proteases, CGL-1 and CGL-2, on human chromosome 14. In this report, we clone and characterize a novel, related murine hematopoietic serine protease gene using human CG (hCG) cDNA as the probe. This murine gene spans approximately 2.5 kb of genomic DNA, is organized into five exons and four introns, and bears a high degree of homology to hCG at both nucleic acid (73%) and deduced amino acid (66%) levels. The predicted cDNA contains an open reading frame of 783 nucleotides that encodes a nascent protein of 261 amino acids. Processing of a putative signal (pre) peptide of 18 residues and an activation (pro) dipeptide would generate a mature enzyme of approximately 27 Kd that has an estimated pI of 12.0. Conserved residues at His44, Asp88, and Ser181 form the characteristic catalytic triad of the serine protease superfamily. The gene is tightly linked to the CTLA-1 locus on murine chromosome 14, where the serine protease genes mCCP1-4 are clustered. Expression of this gene is detected only in the bone marrow and is restricted to a small population of early myeloid cells. These findings are consistent with the identification of the gene encoding murine CG.     

Characterization of CD33 as a new member of the sialoadhesin family of cellular interaction molecules

CD33 is a member of the Ig superfamily that is restricted to cells of the myelomonocytic lineage but whose functions and binding properties are unknown. It shares sequence similarity with sialoadhesin, CD22, and the myelin-associated glycoprotein, which constitute the Sialoadhesin family of sialic acid-dependent cell adhesion molecules. In the present study, we show that CD33 is a fourth member of this family. As a model for sialic acid-dependent binding, human erythrocytes were derivatized with N-acetylneuraminic acid (NeuAc) in different linkages. A recombinant soluble form of CD33, Fc-CD33, bound red blood cells with a specificity similar to that of sialoadhesin, preferring NeuAc alpha 2,3Gal in N- and O-glycans over NeuAc alpha 2,6Gal in N-glycans. Fc- CD33 also bound selectively to the myeloid cell lines HL-60 and U937. However, CD33 was unable to mediate cell binding after transient expression in COS cells, despite high levels of surface expression. Pretreatment of the CD33-transfected cells with sialidase rendered them capable of mediating sialic acid-dependent binding. These results show that CD33 can function as a sialic acid-dependent cell adhesion molecule and that binding can be modulated by endogenous sialoglycoconjugates when CD33 is expressed in a plasma membrane.     

Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

Therapies to prevent transmission of malaria parasites to the mosquito vector are a vital part of the global malaria elimination agenda. Primaquine is currently the only drug with such activity; however, its use is limited by side effects. The development of transmission-blocking strategies requires an understanding of sexual stage malaria parasite (gametocyte) biology and the identification of new drug leads. Lysine acetylation is an important posttranslational modification involved in regulating eukaryotic gene expression and other essential processes. Interfering with this process with histone deacetylase (HDAC) inhibitors is a validated strategy for cancer and other diseases, including asexual stage malaria parasites. Here we confirm the expression of at least one HDAC protein in Plasmodium falciparum gametocytes and show that histone and nonhistone protein acetylation occurs in this life cycle stage. The activity of the canonical HDAC inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; Vorinostat) and a panel of novel HDAC inhibitors on early/late-stage gametocytes and on gamete formation was examined. Several compounds displayed early/late-stage gametocytocidal activity, with TSA being the most potent (50% inhibitory concentration, 70 to 90 nM). In contrast, no inhibitory activity was observed in P. falciparum gametocyte exflagellation experiments. Gametocytocidal HDAC inhibitors caused hyperacetylation of gametocyte histones, consistent with a mode of action targeting HDAC activity. Our data identify HDAC inhibitors as being among a limited number of compounds that target both asexual and sexual stage malaria parasites, making them a potential new starting point for gametocytocidal drug leads and valuable tools for dissecting gametocyte biology.