The association between the neutrophil-to-lymphocyte ratio and mortality in critical illness: an observational cohort study

IntroductionThe neutrophil-to-lymphocyte ratio (NLR) is a biological marker that has been shown to be associated with outcomes in patients with a number of different malignancies. The objective of this study was to assess the relationship between NLR and mortality in a population of adult critically ill patients.MethodsWe performed an observational cohort study of unselected intensive care unit (ICU) patients based on records in a large clinical database. We computed individual patient NLR and categorized patients by quartile of this ratio. The association of NLR quartiles and 28-day mortality was assessed using multivariable logistic regression. Secondary outcomes included mortality in the ICU, in-hospital mortality and 1-year mortality. An a priori subgroup analysis of patients with versus without sepsis was performed to assess any differences in the relationship between the NLR and outcomes in these cohorts.ResultsA total of 5,056 patients were included. Their 28-day mortality rate was 19%. The median age of the cohort was 65 years, and 47% were female. The median NLR for the entire cohort was 8.9 (interquartile range, 4.99 to 16.21). Following multivariable adjustments, there was a stepwise increase in mortality with increasing quartiles of NLR (first quartile: reference category; second quartile odds ratio (OR) = 1.32; 95% confidence interval (CI), 1.03 to 1.71; third quartile OR = 1.43; 95% CI, 1.12 to 1.83; 4th quartile OR = 1.71; 95% CI, 1.35 to 2.16). A similar stepwise relationship was identified in the subgroup of patients who presented without sepsis. The NLR was not associated with 28-day mortality in patients with sepsis. Increasing quartile of NLR was statistically significantly associated with secondary outcome.ConclusionThe NLR is associated with outcomes in unselected critically ill patients. In patients with sepsis, there was no statistically significant relationship between NLR and mortality. Further investigation is required to increase understanding of the pathophysiology of this relationship and to validate these findings with data collected prospectively.

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The online version of this article (doi:10.1186/s13054-014-0731-6) contains supplementary material, which is available to authorized users.     

Hysterosalpingo contrast sonography (HyCoSy) with SH U 454 (Echovist) for the assessment of tubal patency

A total of 88 Fallopian tubes from 44 patients was examined with hysterosalpingo contrast sonography (HyCoSy), hysterosalpingogram (HSG), and laparoscopic chromopertubation (LC) in order to assess their relative accuracy for measuring tubal patency. HyCoSy was done by transvaginal ultrasound and the contrast was SH U 454 (Echovist). The flow of multiple fractions of the contrast medium through each Fallopian tube was observed in real time in appropriate imaging planes by means of a transvaginal probe. Compared with laparoscopic results, we found a sensitivity of 85.2%, a specificity of 85.2%, a positive predictive value (PPV) of 71.9%, a negative predictive value (NPV) of 92.9% and concordance (HyCoSy/LC) of 85.2%, while the corresponding values for HSG were sensitivity = 85.2%, specificity = 83.6%, PPV = 69.7%, NPV = 92.7% and concordance (HSG/LC) of 84.1%. Compared with HSG results, HyCoSy obtained a co-positivity of 66.7%, a co-negativity of 81.8% and a concordance of 76.1%. In conclusion, HyCoSy with SH U 454 proved to be a reliable and safe modality for evaluating tubal patency; it is suitable as an outpatient diagnostic procedure to be used before more invasive procedures.      

Craniofacial and dental development in cardio‐facio‐cutaneous syndrome: the importance of Ras signaling homeostasis

Cardio‐facio‐cutaneous syndrome (CFC) is a RASopathy that is characterized by craniofacial, dermatologic, gastrointestinal, ocular, cardiac, and neurologic anomalies. CFC is caused by activating mutations in the Ras/mitogen‐activated protein kinase (MAPK) signaling pathway that is downstream of receptor tyrosine kinase (RTK) signaling. RTK signaling is known to play a central role in craniofacial and dental development, but to date, no studies have systematically examined individuals with CFC to define key craniofacial and dental features. To fill this critical gap in our knowledge, we evaluated the craniofacial and dental phenotype of a large cohort (n = 32) of CFC individuals who attended the 2009 and 2011 CFC International Family Conferences. We quantified common craniofacial features in CFC which include macrocephaly, bitemporal narrowing, convex facial profile, and hypoplastic supraorbital ridges. In addition, there is a characteristic dental phenotype in CFC syndrome that includes malocclusion with open bite, posterior crossbite, and a high‐arched palate. This thorough evaluation of the craniofacial and dental phenotype in CFC individuals provides a step forward in our understanding of the role of RTK/MAPK signaling in human craniofacial development and will aid clinicians who treat patients with CFC.     

Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial

Butyrate analogues have been shown to increase fetal hemoglobin (HbF) production in vitro and in vivo. Sodium phenylbutyrate (SPB), an oral agent used to treat individuals with urea-cycle disorders, has been shown to increase HbF in nonanemic individuals and in individuals with sickle cell disease. We have treated eleven patients with homozygous beta thalassemia (three transfusion dependent) and one sickle-beta- thalassemia patient with 20 g/d (forty 500-mg tablets) of SPB for 41 to 460 days. All patients showed an increase in the percent of F reticulocytes associated with treatment, but only four patients responded by increasing their Hb levels by greater than 1 g/dL (mean increase, 2.1 g/dL; range, 1.2 to 2.8 g/dL). None of the transfusion- dependent thalassemia subjects responded. Increase in Hb was associated with an increase in red blood cell number (mean increase, 0.62 x 10(12)/L), and mean corpuscular volume (mean increase, 6 fL). Changes in percent HbF, absolute HbF levels, or alpha- to non-alpha-globin ratios as measured by levels of mRNA and globin protein in peripheral blood did not correlate with response to treatment. Response to treatment was not associated with the type of beta-globin mutation, but baseline erythropoietin levels of greater than 120 mU/mL was seen in all responders and only two of eight nonresponders to SPB. Compliance with treatment was greater than 90% as measured by pill counts. Side effects of the drug included weight gain and/or edema caused by increase salt load in 2/12, transient epigastric discomfort in 7/12, and abnormal body odor in 3/12 subjects. Two splenectomized patients who were not on prophylactic antibiotics developed sepsis while on treatment. We conclude that SPB increases Hb in some patients with thalassemia, but the precise mechanism of action is unknown.     

Ultrastructural analysis of human natural killer cell activation

In this study we describe characteristic ultrastructural changes of CD3- large granular lymphocytes (LGL), ie, natural killer (NK) cells, following stimulation with recombinant (r) interleukin 2 (IL 2) or r- gamma interferon (r-gamma IFN) and after interaction with K562 target cells (TC) or Sepharose-bound anti-Fc gamma receptor (FcR) monoclonal antibody (MoAb). When compared to resting cells the cytolytic activity of r-IL 2- and r-gamma IFN-stimulated cells against K562 TC was enhanced. The r-IL 2-stimulated LGL were larger and consistently displayed the shape and cytoskeletal rearrangement characteristic of activated cells. The Golgi apparatus was expanded, and the number of electron-dense granules and vesicles was increased. The ultrastructural changes in r-gamma IFN-stimulated LGL were markedly different from those observed following r-IL 2 activation. Cells did not exhibit changes in size, shape, cytoskeletal organization, or in the structure of the Golgi apparatus. However, r-gamma IFN-stimulated cells exhibited distinctive changes in the structure and content of electron-dense granules with deaggregation of the matrix and parallel tubular arrays (PTAs). Within organelles apparently derived from the electron-dense granules, vesicular and tubular structures were noted that may be the morphological equivalent of cytotoxic factors produced by cytolytic effector cells. These ultrastructural observations indicate that r-IL 2 and r-gamma IFN enhance the lytic ability of NK cells by acting on distinct cell machineries. The cytolytic ability was decreased when LGL were pretreated with K562 TC or immobilized anti-FcR antibody. In both experimental conditions cells displayed ultrastructural features indicating activation as well as loss of cytoplasmic granules and other Golgi-derived organelles. Stimulation of r-gamma IFN- or r-IL 2- activated LGL with K562 TC or Sepharose-bound anti-FcR antibody decreased their cytolytic ability, with cells depleted of granules at the ultrastructural level. Intracytoplasmic fusion of granules and a massive release of the granule content were found in r-IL 2-stimulated cells, reminiscent of the mechanism of basophil degranulation. These observations suggest that multiple activation signals involving distinct surface membrane molecules induce release of cytolytic factors by both resting and activated NK cells.     

Inhibiting interleukin-1 and tumor necrosis factor-alpha does not reduce induction of plasminogen activator inhibitor type-1 by endotoxin in rats in vivo

In experimental animals and humans, intravenous (i.v.) injection of endotoxin induces large increases in circulating plasminogen activator inhibitor type-1 (PAI-1), a major inhibitor of blood fibrinolysis. A similar increase is seen after the injection of interleukin-1 (IL-1) or of tumor necrosis factor-alpha (TNF-alpha), suggesting that these cytokines mediate the induction, by endotoxin, of PAI-1. To test this hypothesis we pretreated rats, before i.v. endotoxin, with compounds that inhibit the formation of cytokines (pentoxifylline; dexamethasone), or with compounds that inhibit the action of these cytokines (anti-TNF antiserum for TNF-alpha; IL-1 receptor antagonist for IL-1). None of these pretreatments affected the induction of PAI-1 synthesis by endotoxin. However, pretreatment did reduce the endotoxin- induced increase in plasma tPA antigen concentration. Thus, the data suggest that, in rats in vivo, TNF-alpha and IL-1 are not significantly involved in the induction of PAI-1 by endotoxin.     

Worldwide clinical experience with a new dual-chamber implantable cardioverter defibrillator system

INTRODUCTION: Management of atrial tachyarrhythmias represents a significant challenge in patients with implantable cardioverter defibrillators (ICDs). Drug therapy of these arrhythmias is limited by moderate efficacy, ventricular proarrhythmia, and drug-device interactions. This study tested the safety and efficacy of a new dual-chamber ICD to detect and treat atrial as well as ventricular tachyarrhythmias. METHODS AND RESULTS: A dual-chamber ICD (Medtronic 7250 Jewel AF) was implanted in 293 of 303 patients at 49 centers in Europe, Canada, and North America. Specific data were collected at implant and during a mean follow-up period of 7.9+/-4.7 months. There were no clinically evident failures to detect and treat ventricular arrhythmias. In patients with at least one of the dual-chamber detection criteria activated, 1,056 of 1,192 episodes of ventricular tachycardia or fibrillation detected were judged to be appropriate (89% positive predictive accuracy). Therapy efficacy was 100% in the ventricular fibrillation zone and 98% in the ventricular tachycardia zone. Positive predictive accuracy for detection of atrial episodes was 95% (1,052/1,107). For episodes classified as atrial tachycardia by the device, the efficacy of atrial antitachycardia pacing and high-frequency (50-Hz) burst pacing was 55% and 17%, respectively. High-frequency burst pacing terminated 16.8% of episodes classified as atrial fibrillation, and atrial defibrillation had an estimated efficacy of 76%. The actuarial estimates of 6-month complication-free survival and total survival were 88% and 94%, respectively. CONCLUSION: This novel dual-chamber ICD is capable of safely and effectively discriminating atrial from ventricular tachyarrhythmias and of treating atrial tachyarrhythmias without compromising detection and treatment of ventricular tachyarrhythmias.