Pregnant Women Infected with Zika Virus Show Higher Viral Load and Immunoregulatory Cytokines Profile with CXCL10 Increase.

BACKGROUND: Zika virus (ZIKV) infection during pregnancy usually shows only mild symptoms and is frequently subclinical. However, it can be vertically transmitted to the fetus, causing microcephaly and other congenital defects. During pregnancy, the immune environment modifications can alter the response to viruses in general and ZIKV in particular. OBJECTIVE: To describe the role of pregnancy in the systemic pro- and anti-inflammatory response during symptomatic ZIKV infection. MATERIALS AND METHODS: A multiplex assay was used to measure 25 cytokines, chemokines, and receptors in 110 serum samples from pregnant and nonpregnant women with and without ZIKV infection with and without symptoms. Samples were collected through an epidemiological surveillance system. RESULTS: Samples from pregnant women with ZIKV infection showed a higher viral load but had similar profiles of inflammatory markers as compared with nonpregnant infected women, except for CXCL10 that was higher in infected pregnant women. Notably, the presence of ZIKV in pregnancy favored a regulatory profile by significantly increasing anti-inflammatory cytokines such as interleukin (IL)-10, receptors IL-1RA, and IL-2R, but only those pro-inflammatory cytokines such as IL-6, interferon (IFN)-α, IFN-γ and IL-17 that are essential for the antiviral response. Interestingly, there were no differences between symptomatic and weakly symptomatic ZIKV-infected groups. CONCLUSION: Our results revealed a systemic anti-inflammatory cytokine and chemokine profile that could participate in the control of the virus. The anti-inflammatory response in pregnant women infected with ZIKA was characterized by high CXCL10, a cytokine that has been correlated with congenital malformations.

Double hemispheric Microdialysis study in poor-grade SAH patients.

Delayed cerebral ischemia (DCI) is a dreadful complication present in 30% of subarachnoid hemorrhage (SAH) patients. DCI prediction and prevention are burdensome in poor grade SAH patients (WFNS 4-5). Therefore, defining an optimal neuromonitoring strategy might be cumbersome. Cerebral microdialysis (CMD) offers near-real-time regional metabolic data of the surrounding brain. However, unilateral neuromonitoring strategies obviate the diffuse repercussions of SAH. To assess the utility, indications and therapeutic implications of bilateral CMD in poor grade SAH patients. Poor grade SAH patients eligible for multimodal neuromonitoring were prospectively collected. Aneurysm location and blood volume were assessed on initial Angio-CT scans. CMD probes were bilaterally implanted and maintained, at least, for 48 hours (h). Ischemic events were defined as a Lactate/Pyruvate ratio >40 and Glucose concentration <0.7 mmol/L. 16 patients were monitored for 1725 h, observing ischemic events during 260 h (15.1%). Simultaneous bilateral ischemic events were rare (5 h, 1.9%). The established threshold of ≥7 ischemic events displayed a specificity and sensitivity for DCI of 96.2% and 83.3%, respectively. Bilateral CMD is a safe and useful strategy to evaluate areas at risk of suffering DCI in SAH patients. Metabolic crises occur bilaterally but rarely simultaneously. Hence, unilateral neuromonitoring strategies underestimate the risk of infarction and the possibility to offset its consequences.

A vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndrome.

BACKGROUND: The acute respiratory distress syndrome (ARDS) is one of the main causes of mortality in adults admitted to intensive care units. Previous studies have demonstrated the existence of genetic variants involved in the susceptibility and outcomes of this syndrome. We aimed to identify novel genes implicated in sepsis-induced ARDS susceptibility. METHODS: We first performed a prioritization of candidate genes by integrating our own genomic data from a transcriptomic study in an animal model of ARDS and from the only published genome-wide association study of ARDS study in humans. Then, we selected single nucleotide polymorphisms (SNPs) from prioritized genes to conduct a case-control discovery association study in patients with sepsis-induced ARDS (n = 225) and population-based controls (n = 899). Finally, we validated our findings in an independent sample of 661 sepsis-induced ARDS cases and 234 at-risk controls. RESULTS: Three candidate genes were prioritized: dynein cytoplasmic-2 heavy chain-1, fms-related tyrosine kinase 1 (FLT1), and integrin alpha-1. Of those, a SNP from FLT1 gene (rs9513106) was associated with ARDS in the discovery study, with an odds ratio (OR) for the C allele of 0.76, 95% confidence interval (CI) 0.58-0.98 (p = 0.037). This result was replicated in an independent study (OR = 0.78, 95% CI = 0.62-0.98, p = 0.039), showing consistent direction of effects in a meta-analysis (OR = 0.77, 95% CI = 0.65-0.92, p = 0.003). CONCLUSIONS: We identified FLT1 as a novel ARDS susceptibility gene and demonstrated that integration of genomic data can be a valid procedure to identify novel susceptibility genes. These results contribute to previous firm associations and functional evidences implicating FLT1 gene in other complex traits that are mechanistically linked, through the key role of endothelium, to the pathophysiology of ARDS.

Targeting skeletal muscle tissue oxygenation (StO2) in adults with severe sepsis and septic shock: a randomised controlled trial (OTO-StS Study).

OBJECTIVE: Evaluation of the ratio of oxyhaemoglobin to total haemoglobin in skeletal muscle (StO2) using near-infrared spectroscopy may aid in the monitoring of patients with sepsis. This study assessed the benefits and risks of targeting StO2 in adults with severe sepsis or septic shock. DESIGN: A European randomised controlled trial was performed on two parallel groups. SETTING: Five intensive care units (ICU) in France, Greece, Spain and Germany were used for the study. PARTICIPANTS: A total of 103 adults with severe sepsis or septic shock on ICU admission were randomised (54 subjects in the experimental arm and 49 subjects in the control arm). INTERVENTIONS: Haemodynamic management using an algorithm that was adapted from the 2004 Surviving Sepsis Campaign guidelines with (experimental arm) or without (control arm) targeting an StO2 value greater than 80% at a minimum of two different sites. OUTCOMES: The primary outcome was a composite: 7-day all-cause mortality or worsening of organ function, defined as a positive difference in Sepsis-related Organ Failure Assessment (SOFA) score between day 7 and randomisation (ie, delta SOFA >0). Secondary endpoints: 30-day mortality, duration of mechanical ventilation and vasopressor therapy up to 30 days from randomisation. RESULTS: The study ended prematurely due to lack of funding after enrolment of 103/190 patients. Eighteen patients (33.3%) in the experimental arm and 14 (28.6%, P=0.67) in the control arm died or exhibited delta SOFA >0 on day 7. The mean number of days on mechanical ventilation was 12.2±10.6 in the experimental group and 7.6±7.9 in the control group (P=0.03). Thirty-one (57%) patients in the experimental arm and 14 (29%) patients in the control arm received red cells by day 7 (P=0.01). CONCLUSION: Despite the limitation related to premature termination, this study provides no data to support the routine implementation of resuscitation protocols incorporating StO2 >80% at two or more muscle sites as a target. StO2-guided therapy may be associated with prolonged use of mechanical ventilation and an increased number of red blood cell transfusions. TRIAL REGISTRATION NUMBER: NCT00167596; Results.

Consensus statement from the 2014 International Microdialysis Forum.

Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.

Clinical evidence of the relationship between aspirin and breast cancer risk (review).

In the search for new therapeutic alternatives against cancer, either as a preventive treatment or for advanced stages, it is common to appeal to well-known drugs used for the treatment of other diseases that may interfere with the metabolic pathways involved in carcinogenesis. Non-steroidal anti-inflammatory drugs (NSAIDs) display anticancer activity through the inhibition of the COX-2 enzyme, triggering processes such as apoptosis, a reduction in proliferation and inhibition of carcinogenesis. Breast cancer is a neoplasm with the highest incidence and mortality rate among young women worldwide. Epidemiologic data have shown that drugs such as NSAIDs, particularly aspirin, reduce the relative risk of breast cancer. However, in the subgroup of responsive patients, dose, time and frequency of use have not yet been established. Here, we review the reports published during the last 10 years regarding the relationship between breast cancer and aspirin.

An assessment of thromboelastometry to monitor blood coagulation and guide transfusion support in liver transplantation.

BACKGROUND: Rotation thromboelastometry (TEM) has been proposed as a convenient alternative to standard coagulation tests in guiding the treatment of coagulopathy during orthotopic liver transplantation (OLT). This study was aimed at assessing the value of TEM in monitoring blood coagulation and guide transfusion support in OLT. STUDY DESIGN AND METHODS: Standard coagulation and TEM (EXTEM and FIBTEM) tests were performed at four preestablished intraoperative time points in 236 OLTs and prospectively recorded in a dedicated database together with the main operative and transfusion data. Transfusion thresholds were based on standard coagulation tests. Spearman's rank correlation (ρ), linear regression, and receiver operating characteristic curves were used when appropriate. RESULTS: EXTEM maximum clot firmness (MCF(EXTEM)) was the TEM variable that best correlated with the platelet (PLT) and fibrinogen levels (ρ = 0.62 and ρ = 0.69, respectively). MCF(FIBTEM) correlated with fibrinogen level (ρ = 0.70). EXTEM clot amplitude at 10 minutes (A10(EXTEM)) was a good linear predictor of MCF(EXTEM) (R(2) =0.93). The cutoff values that best predicted the transfusion threshold for PLTs and fibrinogen were A10(EXTEM) = 35 mm and A10(FIBTEM) = 8 mm. At these values, the negative and positive predictive accuracies of TEM to predict the transfusion thresholds were 95 and 27%, respectively. CONCLUSION: A10(EXTEM) is an adequate TEM variable to guide therapeutic decisions during OLT. Patients with A10(EXTEM) of greater than 35 mm are unlikely to bleed because of coagulation deficiencies, but using A10(EXTEM) of not more than 35 mm as the sole transfusion criterion can lead to unnecessary utilization of PLTs and fibrinogen-rich products.

A risk tertiles model for predicting mortality in patients with acute respiratory distress syndrome: age, plateau pressure, and P(aO(2))/F(IO(2)) at ARDS onset can predict mortality.

BACKGROUND: Predicting mortality has become a necessary step for selecting patients for clinical trials and defining outcomes. We examined whether stratification by tertiles of respiratory and ventilatory variables at the onset of acute respiratory distress syndrome (ARDS) identifies patients with different risks of death in the intensive care unit. METHODS: We performed a secondary analysis of data from 220 patients included in 2 multicenter prospective independent trials of ARDS patients mechanically ventilated with a lung-protective strategy. Using demographic, pulmonary, and ventilation data collected at ARDS onset, we derived and validated a simple prediction model based on a population-based stratification of variable values into low, middle, and high tertiles. The derivation cohort included 170 patients (all from one trial) and the validation cohort included 50 patients (all from a second trial). RESULTS: Tertile distribution for age, plateau airway pressure (P(plat)), and P(aO(2))/F(IO(2)) at ARDS onset identified subgroups with different mortalities, particularly for the highest-risk tertiles: age (> 62 years), P(plat) (> 29 cm H(2)O), and P(aO(2))/F(IO(2)) (< 112 mm Hg). Risk was defined by the number of coexisting high-risk tertiles: patients with no high-risk tertiles had a mortality of 12%, whereas patients with 3 high-risk tertiles had 90% mortality (P < .001). CONCLUSIONS: A prediction model based on tertiles of patient age, P(plat), and P(aO(2))/F(IO(2)) at the time the patient meets ARDS criteria identifies patients with the lowest and highest risk of intensive care unit death.

Common variants of TLR1 associate with organ dysfunction and sustained pro-inflammatory responses during sepsis.

BACKGROUND: Toll-like receptors (TLRs) are critical components for host pathogen recognition and variants in genes participating in this response influence susceptibility to infections. Recently, TLR1 gene polymorphisms have been found correlated with whole blood hyper-inflammatory responses to pathogen-associated molecules and associated with sepsis-associated multiorgan dysfunction and acute lung injury (ALI). We examined the association of common variants of TLR1 gene with sepsis-derived complications in an independent study and with serum levels for four inflammatory biomarkers among septic patients. METHODOLOGY/PRINCIPAL FINDINGS: Seven tagging single nucleotide polymorphisms of the TLR1 gene were genotyped in samples from a prospective multicenter case-only study of patients with severe sepsis admitted into a network of intensive care units followed for disease severity. Interleukin (IL)-1ß, IL-6, IL-10, and C-reactive protein (CRP) serum levels were measured at study entry, at 48 h and at 7(th) day. Alleles -7202G and 248Ser, and the 248Ser-602Ile haplotype were associated with circulatory dysfunction among severe septic patients (0.001 ≤ p ≤ 0.022), and with reduced IL-10 (0.012 ≤ p ≤ 0.047) and elevated CRP (0.011 ≤ p ≤ 0.036) serum levels during the first week of sepsis development. Additionally, the -7202GG genotype was found to be associated with hospital mortality (p = 0.017) and ALI (p = 0.050) in a combined analysis with European Americans, suggesting common risk effects among studies. CONCLUSIONS/SIGNIFICANCE: These results partially replicate and extend previous findings, supporting that variants of TLR1 gene are determinants of severe complications during sepsis.

The influence of the explant technique on the hemodynamic profile during sequential domino liver transplantation in familial amyloid polyneuropathy patients.

Familial amyloidotic polyneuropathy (FAP) patients present adrenergic cardiac input blockade secondary to amyloid deposits and sympathetic neuropathy. Consequently, their capacity to compensate for hemodynamic changes is limited. To avoid hemodynamic disturbances in sequential liver transplants, a standard procedure with venovenous bypass or inferior vena cava preservation is contemplated. The aim of this study was to evaluate the impact of both techniques on the hemodynamic management and outcome of patients affected by FAP and scheduled for a domino liver transplantation program. We evaluated 36 FAP patients. Venovenous bypass was performed for 20 patients (the venovenous bypass group), whereas the vena cava preservation technique was used for the remaining 16 patients (the cava preservation group). The time that elapsed from FAP diagnosis to liver transplantation was 3.2 +/- 2.7 years. Peripheral neuropathy was present in all patients, autonomic dysfunction was present in 71%, and cardiac involvement was present in 69%. Renal and gastrointestinal manifestations were reported in 19% and 53% of patients, respectively. The 1-, 3-, and 5-year survival rates were 97%, 93%, and 93%, respectively. Intraoperative hemodynamic and cardiac disorders, need for vasoactive drugs, blood loss, and transfusion requirements were recorded. Postoperative outcome and cardiac and renal complications were also recorded. No significant differences in disease severity or demographic characteristics were observed. Among all the variables studied, only the total ischemia time and time in surgery were significantly longer in the venovenous bypass group patients (P < or = 0.05). During the postoperative period, the incidence of minor cardiovascular events, incidence of acute renal dysfunction, and outcomes were similar in the 2 groups. In conclusion, either preservation of the vena cava or the standard technique with venovenous bypass can be safely used in FAP patients during liver transplantation. Liver Transpl 15:869-875, 2009. (c) 2009 AASLD.

Intravascular cooling for rapid induction of moderate hypothermia in severely head-injured patients: results of a multicenter study (IntraCool).

OBJECTIVES: To evaluate the feasibility, safety and effectiveness of a new method of intravascular temperature management for inducing moderate hypothermia (MHT). DESIGN AND SETTINGS: Prospective, international-multicenter clinical trial conducted in four university hospitals. PATIENTS: In a 2-year period 24 patients with severe head injury and refractory high ICP were treated with MHT (32.5 degrees C) by intravascular methods. RESULTS: Seventeen were males and seven females, with a median age of 25 years (range 15-60). The median Glasgow Coma Scale upon admission was 7 (range 3-13) and the median Injury Severity Score was 22 (range 13-43). A total of 75% of patients presented a diffuse lesion in the pre-enrollment computed tomography. Median time from injury until reaching refractory high ICP was 71.5 h after injury (minimum 14 h, maximum 251 h). Twelve patients (50%) reached this situation within the first 72 h after injury. MHT was attained in a median time of 3 h. Pre-enrollment median ICP was 23.8 mmHg and was reduced to 16.8 mmHg upon reaching target temperature. At 6 months after injury, nine patients had died (37.5%), six were severely disabled (25%), two moderately disabled (8.3%) and seven had a good recovery (29.2%). Of the nine patients who died, in four the cause was rebound ICP during rewarming, one death was attributed to accidental potassium overload, two to septic shock, one to cardiac arrest of unknown origin and the ninth to a pulmonary embolism. CONCLUSION: Intravascular methods to induce MHT combined with precooling with cold saline at 4 degrees C appear to be feasible and effective in reducing ICP in patients with high ICP refractory to first-line therapeutic measures.