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.     

Correlation between human immunodeficiency virus type 1 RNA levels in the female genital tract and immune activation associated with ulceration of the cervix

To address the hypothesis that local immune activation resulting from genital ulceration enhances human immunodeficiency virus type 1 (HIV-1) replication and shedding into the genital tract, paired plasma and cervicovaginal lavage (CVL) samples were obtained from 12 HIV-infected women before and after treatment of cervical intraepithelial lesions. Two weeks after treatment, inflammation and ulceration of the cervix were accompanied by major increases in mean concentrations of HIV-1 RNA (200-fold), tumor necrosis factor-alpha, interleukin 6, and soluble markers shed by activated lymphocytes and macrophages (sCD25 and sCD14, respectively) in CVL samples (P<.01 for each), but not plasma. Strong temporal and quantitative correlations were observed between concentrations of immunological markers and HIV-1 load in this compartment during a 10-week follow-up. Furthermore, in the presence of genital ulceration, HIV-1 in CVL samples was more readily captured by antibodies directed against virion-associated HLA-DR, a marker of host-cell activation, compared with virus in plasma. We suggest that local immune activation increases HIV-1 load in genital secretions, potentially increasing the risk of HIV-1 transmission.     

Cytogenetic and immunophenotypic analysis of cell lines established from patients with T cell leukemia/lymphoma

Cell lines were established from five patients with T cell malignancies. Two patients had T cell lymphoblastic lymphoma (T-LL), whereas three patients had T cell acute lymphoblastic leukemia (T-ALL). Both T-LL cell lines expressed cell surface antigens characteristic of midthymocytes (Leu 2, 3, 6+). One T-ALL cell line also expressed this immunophenotype, one expressed suppressor/cytotoxic antigens (Leu 2+; Leu 3, 6-), and one expressed antigens of a mature but uncommitted T cell (Leu 4+; Leu 2, 3, 6-). Cytogenetic analysis showed that each cell line had 46 chromosomes with pseudodiploidy. The three T-ALL cell lines had only a few chromosome changes; one cell line had one deletion, another had two deletions, and the third had a translocation and two deletions (including loss of part of 9p). In comparison, both T-LL cell lines had complex chromosome changes, including most notably a rearrangement of band 14q11.2. The immunophenotypes and chromosome breakpoints showed patterns of interlock between the T-LL and T-ALL cell lines because common abnormalities occurred at six distinct chromosome sites. Cell lines with limited and specific chromosomal abnormalities are important because they can provide the basic material for molecular genetic studies that could elucidate the genetic mechanisms involved in neoplasia.     

An increased HLA DR2 frequency is seen in aplastic anemia patients

The underlying etiology of aplastic anemia is unknown in the majority of patients, although medications, chemical exposure, or viral infections can be implicated in some. Genetic susceptibility to a variety of diseases has been shown and it has recently been suggested that aplastic anemia is more common in individuals who are HLA DR2+ than in the general population. To examine this question, we retrospectively analyzed the results of HLA-DR typing in 75 aplastic anemia patients who received antithymocyte globulin (ATG) therapy or an HLA-matched sibling bone marrow transplant at UCLA between 1978 and 1989. Thirty-one patients were DR2+, a 1.9-fold higher incidence than the expected number of 16.6 patients (P < .0005). Of the 37 patients who received ATG, 33 were evaluable for a response; 14 patients had either a complete (4 patients) or partial (10 patients) response, for an overall response rate of 42.4%. Of the 14 DR2+ patients who received ATG, 7 responded, for a 50% response rate, which is not significantly higher than the response rate for the DR2- patients (7 of 19 [36.8%]; P = .50). The median survival of patients who are DR2+ was slightly, but not significantly, longer than that of the DR2- patients in the ATG group (P = .19). Although the incidence of HLA DR2 was clearly increased in these patients with aplastic anemia, response rates to ATG were not significantly different in the DR2+ and DR2- patients.     

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。     

Homing receptors on human and rodent lymphocytes--evidence for a conserved carbohydrate-binding specificity

Lymphocyte recirculation begins with the attachment of circulating cells to the structurally distinctive postcapillary venules of lymphoid organs termed high-endothelial venules (HEVs). In both rodents and humans, the attachment of lymphocytes to the HEVs of peripheral lymph nodes (PNs) on the one hand and gut-associated lymphoid tissues (GALTs) on the other appears to involve discrete adhesive structures on the surfaces of the interacting cells. In rodents, we previously showed that a carbohydrate-binding receptor at the lymphocyte surface participates in the attachment to the HEV of peripheral nodes. The studies reported herein document the involvement of a similar receptor in the selective attachment of human peripheral blood lymphocytes to the HEVs of PNs. We argue that the close functional relationship between the human and rodent receptors indicates that this component of the adhesive interaction has been conserved through evolution.     

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.