Inhibition of proliferation and differentiation during early T cell development by anti-transferrin receptor antibody

Proliferating cells require iron and, therefore, express the transferrin receptor (CD71) that mediates cellular iron uptake. Cycling thymocytes, which have the CD4−8−3−, CD4−8+3−, or CD4+8+3− phenotypes, also express CD71. The importance of CD71-mediated iron uptake for proliferation and maturation of thymocytes was studied using fetal thymus organ cultures at day 14 of gestation and treating them for 7 days with a CD71 monoclonal antibody (mAb). The intracellular iron deficiency caused by this treatment, inhibits both proliferation and maturation of the thymocytes. Cell recovery was reduced by 60%, but cells still expanded tenfold during the culture. Remarkably, the final maturation of αβ T cells was completely blocked as no thymocytes with low or high CD3/αβTcR expression developed. Moreover, only few cells reached the CD4+8+3− stage of T cell development. CD4−8−3− thymocytes, however, as well as its CD44−25+ subset developed in normal numbers, suggesting that CD44−25+ CD4−8−3− cells, or their immediate progeny, were most vulnerable to CD71 mAb treatment. The development of γδ T cells, which also express CD71, was not affected in these cultures. This suggests that γδ T cells are either less iron-dependent or possess alternative iron-uptake mechanisms. Thus, our observation

Geriatric polytrauma patients should not be excluded from aggressive injury treatment based on age alone

Purpose: Age in severely injured patients has been increasing for decades. Older age is associated with increasing mortality. However, morbidity and mortality could possibly be reduced when accurate and aggressive treatment is provided. This study investigated age-related morbidity and mortality in polytrauma including age-related decisions in initial injury management and withdrawal of life-sustaining therapy (WLST). Methods: A 6.5-year prospective cohort study included consecutive severely injured trauma patients admitted to a Level-1 Trauma Center ICU. Demographics, data on physiology, resuscitation, MODS/ARDS, and infectious complications were prospectively collected. Patients were divided into age subgroups (< 25, 25–49, 50–69, and ≥ 70 years) to make clinically relevant comparisons. Results: 391 patients (70% males) were included with median ISS of 29 (22–36), 95% sustained blunt injuries. There was no difference in injury severity, resuscitation, urgent surgeries, nor in ventilator days, ICU-LOS, and H-LOS between age groups. Adjusted odds of MODS, ARDS and infectious complications were similar between age groups. 47% of patients ≥ 70 years died, compared to 10–16% in other age groups (P < 0.001). WLST increased with older age, contributing to more than half of deaths ≥ 70 years. TBI was the most common cause of death and decision for treatment withdrawal in all age groups. Conclusions: Patients ≥ 70 years had higher mortality risk even though injury severity and complication rates were similar to other age groups. WLST increased with age with the vast majority due to brain injury. More than half of patients ≥ 70 years survived suggesting geriatric polytrauma patients should not be excluded from aggressive injury treatment based on age alone

Physiology dictated treatment after severe trauma: timing is everything

INTRODUCTION: Damage control strategies in resuscitation and (fracture) surgery have become standard of care in the treatment of severely injured patients. It is suggested that damage control improves survival and decreases the incidence of organ failure. However, these strategies can possibly increase the risk of complications such as infections. Indication for damage control procedures is guided by physiological parameters, type of injury, and the surgeon's experience. We analyzed outcomes of severely injured patients who underwent emergency surgery. METHODS: Severely injured patients, admitted to a level-1 trauma center ICU from 2016 to 2020 who were in need of ventilator support and required immediate surgical intervention ( ≤24 h) were included. Demographics, treatment, and outcome parameters were analyzed. RESULTS: Hundred ninety-five patients were identified with a median ISS of 33 (IQR 25-38). Ninety-seven patients underwent immediate definitive surgery (ETC group), while 98 patients were first treated according to damage control principles with abbreviated surgery (DCS group). Although ISS was similar in both groups, DCS patients were younger, suffered from more severe truncal injuries, were more frequently in shock with more severe acidosis and coagulopathy, and received more blood products. ETC patients with traumatic brain injury needed more often a craniotomy. Seventy-four percent of DCS patients received definitive surgery in the second surgical procedure. There was no difference in mortality, nor any other outcome including organ failure and infections. CONCLUSIONS: When in severely injured patients treatment is dictated by physiology into either early definitive surgery or damage control with multiple shorter procedures stretched over several days combined with aggressive resuscitation with blood products, outcome is comparable in terms of complications

Clinical Outcome of Intra-Arterial Embolization for Treatment of Patients with Pelvic Trauma

Purpose. To analyse the technical success of pelvic embolization in our institution and to assess periprocedural hemodynamic status and morbidity/mortality of all pelvic trauma patients who underwent pelvic embolization. Methods. A retrospective analysis of patients with a pelvic fracture due to trauma who underwent arterial embolization was performed. Clinical data, pelvic radiographs, contrast-enhanced CT-scans, and angiographic findings were reviewed. Subsequently, the technical success and peri-procedural hemodynamic status were evaluated and described. Results. 19 trauma patients with fractures of the pelvis underwent arterial embolization. Initially, 10/19 patients (53%) were hemodynamically unstable prior to embolization. Technical success of embolization was 100%. 14/19 patients (74%) were stable after embolization, and treatment success was high as 74%. Conclusion. Angiography with subsequent embolization should be performed in patients with a pelvic fracture due to trauma and hemodynamic instability, after surgical intervention or with a persistent arterial blush indicative of an active bleeding on CT

Ionospheric quasi-static electric field anomalies during seismic activity in August–September 1981

The paper proposes new results, analyses and information for the plate tectonic situation in the processing of INTERCOSMOS-BULGARIA-1300 satellite data about anomalies of the quasi-static electric field in the upper ionosphere over activated earthquake source regions at different latitudes. The earthquake catalogue is made on the basis of information from the United State Geological Survey (USGS) website. The disturbances in ionospheric quasi-static electric fields are recorded by IESP-1 instrument aboard the INTERCOSMOS-BULGARIA-1300 satellite and they are compared with significant seismic events from the period 14 August–20 September 1981 in magnetically very quiet, quiet and medium quiet days. The main tectonic characteristics of the seismically activated territories are also taken in account. The main goal of the above research work is to enlarge the research of possible connections between anomalous vertical electric field penetrations into the ionosphere and the earthquake manifestations, also to propose tectonic arguments for the observed phenomena. The studies are represented in four main blocks: (i) previous studies of similar problems, (ii) selection of satellite, seismic and plate tectonic data, (iii) data processing with new specialized software and observations of the quasi-static electric field and (iiii) summary, comparison of new with previous results in our studies and conclusion. We establish the high informativity of the vertical component &lt;i&gt;Ez&lt;/i&gt; of the quasi-static electric field in the upper ionosphere according observations by INTERCOSMOS-BULGARIA-1300 that are placed above considerably activated earthquake sources. This component shows an increase of about 2–10 mV/m above sources, situated on mobile structures of the plates. The paper discusses the observed effects. It is represented also a statistical study of ionospheric effects 5–15 days before and 5–15 days after the earthquakes with magnitude M 4.8–7.9

Demographic patterns and outcomes of patients in level I trauma centers in three international trauma systems

Introduction: Trauma systems were developed to improve the care for the injured. The designation and elements comprising these systems vary across countries. In this study, we have compared the demographic patterns and patient outcomes of Level I trauma centers in three international trauma systems. Methods: International multicenter prospective trauma registry-based study, performed in the University Medical Center Utrecht (UMCU), Utrecht, the Netherlands, John Hunter Hospital (JHH), Newcastle, Australia, and Harborview Medical Center (HMC), Seattle, the United States. Inclusion: patients =18 years, admitted in 2012, registered in the institutional trauma registry. Results: In UMCU, JHH, and HMC, respectively, 955, 1146, and 4049 patients met the inclusion criteria of which 300, 412, and 1375 patients with Injury Severity Score (ISS) > 15. Mean ISS was higher in JHH (13.5; p < 0.001) and HMC (13.4; p < 0.001) compared to UMCU (11.7). Unadjusted mortality: UMCU = 6.5 %, JHH = 3.6 %, and HMC = 4.8 %. Adjusted odds of death: JHH = 0.498 [95 % confidence interval (CI) 0.303-0.818] and HMC = 0.473 (95 % CI 0.325-0.690) compared to UMCU. HMC compared to JHH was 1.002 (95 % CI 0.664-1.514). Odds of death patients ISS > 15: JHH = 0.507 (95 % CI 0.300-0.857) and HMC = 0.451 (95 % CI 0.297-0.683) compared to UMCU. HMC = 0.931 (95 % CI 0.608-1.425) compared to JHH. TRISS analysis: UMCU: Ws = 0.787, Z = 1.31, M = 0.87; JHH, Ws = 3.583, Z = 6.7, M = 0.89; HMC, Ws = 3.902, Z = 14.6, M = 0.84. Conclusion: This study demonstrated substantial differences across centers in patient characteristics and mortality, mainly of neurological cause. Future research must investigate whether the outcome differences remain with nonfatal and long-term outcomes. Furthermore, we must focus on the development of a more valid method to compare systems

Two distinct repressive mechanisms for histone 3 lysine 4 methylation through promoting 3'-end antisense transcription

International audienceHistone H3 di- and trimethylation on lysine 4 are major chromatin marks that correlate with active transcription. The influence of these modifications on transcription itself is, however, poorly understood. We have investigated the roles of H3K4 methylation in Saccharomyces cerevisiae by determining genome-wide expression-profiles of mutants in the Set1 complex, COMPASS, that lays down these marks. Loss of H3K4 trimethylation has virtually no effect on steady-state or dynamically-changing mRNA levels. Combined loss of H3K4 tri- and dimethylation results in steady-state mRNA upregulation and delays in the repression kinetics of specific groups of genes. COMPASS-repressed genes have distinct H3K4 methylation patterns, with enrichment of H3K4me3 at the 3'-end, indicating that repression is coupled to 3'-end antisense transcription. Further analyses reveal that repression is mediated by H3K4me3-dependent 3'-end antisense transcription in two ways. For a small group of genes including PHO84, repression is mediated by a previously reported trans-effect that requires the antisense transcript itself. For the majority of COMPASS-repressed genes, however, it is the process of 3'-end antisense transcription itself that is the important factor for repression. Strand-specific qPCR analyses of various mutants indicate that this more prevalent mechanism of COMPASS-mediated repression requires H3K4me3-dependent 3'-end antisense transcription to lay down H3K4me2, which seems to serve as the actual repressive mark. Removal of the 3'-end antisense promoter also results in derepression of sense transcription and renders sense transcription insensitive to the additional loss of SET1. The derepression observed in COMPASS mutants is mimicked by reduction of global histone H3 and H4 levels, suggesting that the H3K4me2 repressive effect is linked to establishment of a repressive chromatin structure. These results indicate that in S. cerevisiae, the non-redundant role of H3K4 methylation by Set1 is repression, achieved through promotion of 3'-end antisense transcription to achieve specific rather than global effects through two distinct mechanisms