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Introduction: Seasonal epidemic influenza and SARS-CoV-2 are the most frequent viruses causing acute respiratory distress syndrome (ARDS). To what extent these two etiologies differ in ICU patients remains uncertain. We, therefore, aimed at comparing the severity and outcomes of influenza and SARS-CoV-2-induced ARDS in mechanically ventilated patients., Methods: This retrospective, analytic, single-center study was conducted in the medical ICU of Nancy University Hospital in France. Adult patients hospitalized with confirmed influenza (from 2009 to 2019) or SARS-CoV-2-induced ARDS (between March 2020 and May 2021) and those under mechanical ventilation were included. Each patient with influenza was matched with two patients with COVID-19, with the same severity of ARDS. The primary endpoint was death in ICU on day 28. The secondary endpoints were the duration of vasopressors, the use of renal replacement therapy, the duration of mechanical ventilation, and the ICU length of stay., Results: A total of 42 patients with influenza were matched with 84 patients with COVID-19. They had similar sex distribution, age, Charlson comorbidity index, and ARDS severity. On day 28, 11 (26.2%) patients in the influenza group and nine (10.7%) patients in the COVID-19 group had died ( p = 0.0084, HR = 3.31, CI 95% [1.36-8.06]). In the univariate Cox model, being infected with SARS-CoV-2, SOFA and SAPS II scores, initial arterial pH, PaCO2, PaO2/FiO2, serum lactate level, platelet count, and use of renal replacement therapy were significantly associated with mortality. In the multivariate Cox model, the SOFA score at admission ( p < 0.01, HR = 1.284, CI 95% [1.081; 1.525]) and the initial pH ( p < 0.01, HR = 0.618, CI 95% [0.461; 0.828]) were the only predictors of mortality. The type of virus had no influence on mortality, though patients with COVID-19 underwent longer mechanical ventilation and received more neuromuscular blockers and prone positioning., Conclusion: In mechanically ventilated patients with ARDS, 28-day mortality was higher among patients with influenza as compared to patients with COVID-19 because of a higher initial extra-pulmonary severity. However, the type of virus was not, by itself, correlated with mortality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Volkov, Delpuech, Conrad, Courte, Cravoisy, Nace, Baumann and Gibot.)

The neurons of the medial superior olive (MSO) of mammals extract azimuthal information from the delays between sounds reaching the two ears [interaural time differences (ITDs)]. Traditionally, all models of sound localization have assumed that MSO neurons represent a single population of cells with specialized and homogeneous intrinsic and synaptic properties that enable the detection of synaptic coincidence on a timescale of tens to hundreds of microseconds. Here, using patch-clamp recordings from large populations of anatomically labeled neurons in brainstem slices from male and female Mongolian gerbils ( Meriones unguiculatu s), we show that MSO neurons are far more physiologically diverse than previously appreciated, with properties that depend regionally on cell position along the topographic map of frequency. Despite exhibiting a similar morphology, neurons in the MSO exhibit subthreshold oscillations of differing magnitudes that drive action potentials at rates between 100 and 800 Hz. These oscillations are driven primarily by voltage-gated sodium channels and are distinct from resonant properties derived from other active membrane properties. We show that graded differences in these and other physiological properties across the MSO neuron population enable the MSO to duplex the encoding of ITD information in both fast, submillisecond time-varying signals as well as in slower envelopes. SIGNIFICANCE STATEMENT Neurons in the medial superior olive (MSO) encode sound localization cues by detecting microsecond differences in the arrival times of inputs from the left and right ears, and it has been assumed that this computation is made possible by highly stereotyped structural and physiological specializations. Here we report using a large (>400) sample size in which MSO neurons show a strikingly large continuum of functional properties despite exhibiting similar morphologies. We demonstrate that subthreshold oscillations mediated by voltage-gated Na + channels play a key role in conferring graded differences in firing properties. This functional diversity likely confers capabilities of processing both fast, submillisecond-scale synaptic activity (acoustic "fine structure"), and slow-rising envelope information that is found in amplitude-modulated sounds and speech patterns., (Copyright © 2021 the authors.)

Locomotion generates adventitious sounds which enable detection and localization of predators and prey. Such sounds contain brisk changes or transients in amplitude. We investigated the hypothesis that ill-understood temporal specializations in binaural circuits subserve lateralization of such sound transients, based on different time of arrival at the ears (interaural time differences, ITDs). We find that Lateral Superior Olive (LSO) neurons show exquisite ITD-sensitivity, reflecting extreme precision and reliability of excitatory and inhibitory postsynaptic potentials, in contrast to Medial Superior Olive neurons, traditionally viewed as the ultimate ITD-detectors. In vivo, inhibition blocks LSO excitation over an extremely short window, which, in vitro, required synaptically evoked inhibition. Light and electron microscopy revealed inhibitory synapses on the axon initial segment as the structural basis of this observation. These results reveal a neural vetoing mechanism with extreme temporal and spatial precision and establish the LSO as the primary nucleus for binaural processing of sound transients., Competing Interests: TF, BB, DH, JG, NG, PS, PJ No competing interests declared, (© 2021, Franken et al.)

Introduction: Mechanical thrombectomy (MT) increases functional independence in patients with acute ischaemic stroke with anterior circulation large vessel occlusion (LVO), and the probability to achieve functional independence decreases by 20% for each 1-hour delay to reperfusion. Therefore, we aim to investigate whether direct angiosuite transfer (DAT) is superior to standard imaging/emergency department-based management in achieving 90-day functional independence in patients presenting with an acute severe neurological deficit likely due to LVO and requiring emergent treatment with MT., Methods and Analysis: DIRECT ANGIO (Effect of DIRECT transfer to ANGIOsuite on functional outcome in patient with severe acute stroke treated with thrombectomy: the randomised DIRECT ANGIO Trial) trial is an investigator-initiated, multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) study. Eligibility requires a patient ≤75 years, pre-stroke modified Rankin Scale (mRS) 0-2, presenting an acute severe neurological deficit and admitted within 5 hours of symptoms onset in an endovascular-capable centre. A total of 208 patients are randomly allocated in a 1:1 ratio to DAT or standard management. The primary outcome is the rate of patients achieving a functional independence, assessed as mRS 0-2 at 90 days. Secondary endpoints include patients presenting confirmed LVO, patients eligible to intravenous thrombolysis alone, patients with intracerebral haemorrhage and stroke-mimics, intrahospital time metrics, early neurological improvement (reduction in National Institutes of Health Stroke Scale by ≥8 points or reaching 0-1 at 24 hours) and mRS overall distribution at 90 days and 12 months. Safety outcomes are death and intracerebral haemorrhage transformation. Medico-economics analyses include health-related quality of life and cost utility assessment., Ethics and Dissemination: The DIRECT ANGIO trial was approved by the ethics committee of Ile de France 1. Study began in April 2020. Results will be published in an international peer-reviewed medical journal., Trial Registration Number: NCT03969511., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The central nucleus of the inferior colliculus (ICC) integrates information about different features of sound and then distributes this information to thalamocortical circuits. However, the lack of clear definitions of circuit elements in the ICC has limited our understanding of the nature of these circuit transformations. Here, we combine virus-based genetic access with electrophysiological and optogenetic approaches to identify a large family of excitatory, cholecystokinin-expressing thalamic projection neurons in the ICC of the Mongolian gerbil. We show that these neurons form a distinct cell type, displaying uniform morphology and intrinsic firing features, and provide powerful, spatially restricted excitation exclusively to the ventral auditory thalamus. In vivo, these neurons consistently exhibit V-shaped receptive field properties but strikingly diverse temporal responses to sound. Our results indicate that temporal response diversity is maintained within this population of otherwise uniform cells in the ICC and then relayed to cortex through spatially restricted thalamic subdomains., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Background: Yellow fever vaccine exists for over 80 years and is considered to be relatively safe. However, in rare cases it can produce serious neurotropic and viscerotropic complications. We report a case of a patient who presented both viscerotropic and neurological manifestations after yellow fever vaccination., Case Presentation: We describe the case of a 37 years old man who developed after the yellow fever vaccination a yellow fever vaccine-associated viscerotropic disease followed by acute uveitis. Prolonged detection of yellow fever RNA in blood and urine was consistent with yellow fever vaccine-associated adverse event. The final outcome was good, although with persistent fatigue over a few months., Conclusions: Even if the yellow fever vaccine is relatively safe, physicians should be aware of its possible serious adverse effects.

Background: Early appropriate diagnosis of acute heart failure (AHF) is recommended by international guidelines. This study assessed the value of several lung ultrasound (LUS) strategies for identifying AHF in the ED., Methods: This prospective study, conducted in four EDs, included patients with diagnostic uncertainty based on initial clinical judgment. A clinical diagnosis score for AHF (Brest score) was quantified, followed by an extensive LUS examination performed according to the 4-point (BLUE protocol) and 6-, 8-, and 28-point methods. The primary outcome was AHF discharge diagnosis adjudicated by two senior physicians blinded to LUS measurements. The C-index was used to quantify discrimination., Results: Among the 117 included patients, AHF (n = 69) was identified in 27.4%, 56.2%, 54.8%, and 76.7% of patients with the 4-point (two bilateral positive points), 6-point, 8-point (≥ 1 bilateral positive point), and 28-point (B-line count ≥ 30) methods, respectively. The C-index (95% CI) of the Brest score was 72.8 (65.3-80.3), whereas the C-index of the 4-, 6-, 8-, and 28-point methods were 63.7 (58.5-68.8), 72.4 (65.0-79.8), 74.0 (67.1-80.9), and 72.4 (63.9-80.9). The highest increase in the C-index on top of the BREST score was observed with the 8-point method in the whole population (6.9; 95% CI, 1.6-12.2; P = .010) and in the population with an intermediate Brest score, followed by the 6-point method., Conclusions: In patients with diagnostic uncertainty, the 6-point/8-point LUS method (using the 1 bilateral positive point threshold) improves AHF diagnosis accuracy on top of the BREST score., Trial Registry: ClinicalTrials.gov; No.: NCT03194243; URL: www.clinicaltrials.gov., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Although early identification of sepsis improves outcome, prompt and correct diagnostic remains often challenging. The expression of the high affinity immunoglobulin-Fc fragment receptor I CD64 on neutrophils is upregulated during acute inflammation. We here aimed at determining the usefulness of its rapid measurement in diagnosing sepsis., Methods: Seventy-two consecutive patients were enrolled upon admission to Intensive Care Unit within a two-month period. Sequential determination of serum C-reactive protein (CRP) and procalcitonin (PCT) concentrations was obtained. The neutrophil CD64 index was measured using Accellix-CD64® device, an in vitro diagnosis system allowing for an automatic and standardized measure., Results: Serum concentrations of CRP and PCT as well as the neutrophil CD64 index were higher in septic patients compared to all others (P<0.05 for the three markers). Only CD64 index was an independent predictor of sepsis, though with modest sensitivity and specificity (78% and 70%, respectively). Repeat determination of CD64 index at day 2 correctly classified 85% of patients., Conclusions: This prospective study demonstrates the moderate performance of the neutrophil CD64 index, assessed through the Accellix-CD64® device, in diagnosing sepsis in the critically ill patient. However, repeat measurements improve its accuracy and may help to predict ICU-acquired infections.

Background: Systemic congestion, evaluated by estimated plasma volume status (ePVS), is associated with in-hospital mortality in acute heart failure (AHF). However, the diagnostic and prognostic value of ePVS in patients with acute dyspnea has been insufficiently studied., Objectives: To assess the association between the first ePVS calculated from blood samples on admission in the emergency department (ED) and discharge diagnosis of AHF and in-hospital mortality in patients admitted for acute dyspnea., Methods: The study included 1369 patients admitted for dyspnea in the ED in 2015. ePVS was calculated from hematocrit and hemoglobin values at admission. Comparisons of baseline characteristics according to ePVS tertiles were carried out and then associations between ePVS and the two outcomes "AHF diagnosis" and "intra-hospital mortality" were assessed using a logistic regression model., Results: 36.6% had a BNP > 400 pg/mL and median ePVS was 4.58 dL/g [3.96-5.55]. Overall in-hospital mortality was 11.1% (n = 149). In multivariable analysis, the third ePVS tertile (> 5.12 dL/g) had a significantly increased risk of having AHF (OR = 1.64 [1.16-2.33], p = 0.005). In-hospital mortality rose across ePVS tertiles (8.4-13.8% p < 0.01). ePVS greater than the first or second tertile threshold (respectively, 4.17 dL/g and 5.12 dL/g) were both significantly associated with a higher risk of in-hospital mortality (OR for 2nd/3rd tertile = 2.06 [1.25-3.38], p = 0.004 and OR for 3rd tertile = 1.54 [1.01-2.36], p = 0.04)., Conclusion: Higher ePVS values determined from first blood sample at admission are associated with a higher probability of AHF and in-hospital mortality in patients admitted in the ED for acute dyspnea.

The Mongolian gerbil (Meriones unguiculatus) is a member of the rodent family that displays several features not found in mice or rats, including sensory specializations and social patterns more similar to those in humans. These features have made gerbils a valuable animal for research studies of auditory and visual processing, brain development, learning and memory, and neurological disorders. Here, we report the whole gerbil annotated genome sequence, and identify important similarities and differences to the human and mouse genomes. We further analyze the chromosomal structure of eight genes with high relevance for controlling neural signaling and demonstrate a high degree of homology between these genes in mouse and gerbil. This homology increases the likelihood that individual genes can be rapidly identified in gerbil and used for genetic manipulations. The availability of the gerbil genome provides a foundation for advancing our knowledge towards understanding evolution, behavior and neural function in mammals. ACCESSION NUMBER: The Whole Genome Shotgun sequence data from this project has been deposited at DDBJ/ENA/GenBank under the accession NHTI00000000. The version described in this paper is version NHTI01000000. The fragment reads, and mate pair reads have been deposited in the Sequence Read Archive under BioSample accession SAMN06897401., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To assess the use of CT with unfolded cylindrical projection (UCP) for rib fracture detection and characterization., Methods: The images from 60 polytraumatized patients who underwent whole body CT were evaluated for the presence and characterization of rib fractures (displaced or not, single or multiple). Two readers independently evaluated conventional CT images and UCP images in two readout sessions at least one month apart. All readouts were timed. A gold standard was established by two radiologists with 12 and 22 years of clinical experience based on the combined analysis of conventional and UCP reformats., Results: Using UCP, the mean evaluation time was 27%-54% shorter (P = 0.01 and <0.0001) while maintaining a comparable diagnostic performance (sensitivity and specificity of 68.4-79.1% and 99.5-99.6% for conventional reformats and 70.6-91.0% and 96.8-97.7% for UCP) and a good reproducibility (Kappa of 0.71). The multiple fracture detection ratio of UCP was similar to that of conventional reformats (>80%). There were more false positives and false negatives using UCP and displaced fractures were harder to characterize., Conclusion: UCP yielded a diagnostic performance similar to that of conventional reformats for the detection of rib fractures with a good reproducibility and a noticeable reduction in evaluation time., (Copyright © 2018. Published by Elsevier B.V.)

Utilization of timing-based sound localization cues by neurons in the medial superior olive (MSO) depends critically on glycinergic inhibitory inputs. After hearing onset, the strength and subcellular location of these inhibitory inputs are dramatically altered, but the cellular processes underlying this experience-dependent refinement are unknown. Here we reveal a form of inhibitory long-term potentiation (iLTP) in MSO neurons that is dependent on spiking and synaptic activation but is not affected by their fine-scale relative timing at higher frequencies prevalent in auditory circuits. We find that iLTP reinforces inhibitory inputs coactive with binaural excitation in a cumulative manner, likely well suited for networks featuring persistent high-frequency activity. We also show that a steep drop in action potential size and backpropagation limits induction of iLTP to the first 2 weeks of hearing. These intrinsic changes would deprive more distal inhibitory synapses of reinforcement, conceivably establishing the mature, soma-biased pattern of inhibition., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To assess the prognostic value of hyponatraemia, hyperglycaemia and impaired estimated glomerular filtration rate (eGFR) in predicting in-hospital death in patients with acute heart failure (AHF) admitted for acute dyspnoea in the emergency department., Design: Retrospective observational study., Setting: Emergency Department of the University Hospital of Nancy. Data were collected from August 2013 to October 2015., Participants: The analysis included 405 patients with AHF admitted for acute dyspnoea in an emergency department., Results: The population was elderly (mean age 82 years), 20.1% had hyponatraemia, 45.1% had hyperglycaemia and 48.6% had eGFR <50 mL/min/1.73 m 2 . Sixty-one patients (15.1%) died in hospital, mostly due to cardiac aetiology (58.3%). In multivariable analysis adjusted for key potential confounders, adjusted hyponatraemia (OR=2.40, (1.16 to 4.98), p=0.02), hyperglycaemia (OR=2.00, 1.06 to 3.76, p=0.03) and eGFR <50 mL/min/1.73 m 2 (OR=1.97 (1.00 to 3.80), p=0.04*) were all identified as significant independent predictors of in-hospital death., Conclusions: Results of basic routine laboratory tests (hyponatraemia, hyperglycaemia and impaired eGFR) performed on admission in the emergency department are independently associated with in-hospital death. These inexpensive tests, performed as early as patient admission in the emergency department, could allow the early identification of patients admitted for AHF who are at high risk of in-hospital death., Trial Registration Number: NCT02800122., Competing Interests: Competing interests: TC and NG have received Board Membership Fees from Novartis. PR received fees from Relypsa. FZ has received fees for serving on the board of Boston Scientific; consulting fees from Novartis, Takeda, AstraZeneca, Boehringer Ingelheim, GE Healthcare, Relypsa, Servier, Boston Scientific, Bayer, Johnson and Johnson, and Resmed; and speakers’ fees from Pfizer and AstraZeneca. FZ and PR are co-founders of CardioRenal diagnostics., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Despite recent management improvement, including Extracorporeal Life Support (ECLS), refractory out of hospital cardiac arrest (ROHCA) survival remains dramatically low., Methods: We assessed an innovative strategy (Out of hoSpital Cardiac ARrest-ExtraCorporeal Life Support-"OSCAR-ECLS") to optimize access to ECLS of ROHCA patients and reduce the delay between recognition and ECLS implantation., Methods: This study, conducted in a tertiary teaching hospital, compared the survival and delay times of ROHCA patients treated by ECLS before and after OSCAR-ECLS implementation. This procedure included an early recognition of ROHCA 10 min after initiation of advanced cardiopulmonary resuscitation; the optimization of patient selection and reduction in time from collapse to ECLS initiation., Results: Fourteen patients before and 32 patients after OSCAR-ECLS implementation were identified between 2013 and 2016. Time to ECLS initiation was 99 (90-107) min before OSCAR-ECLS vs. 80 (65-94) min during the OSCAR-ECLS period (P = 0.0007), mostly due to a reduction in time spent on site: 48 (40.0-54.0) min vs. 24 (20.0-28.0) min (P = 0.0001). Survival at hospital discharge was 7% (1/14) before OSCAR-ECLS and 25% (8/32) during the OSCAR-ECLS period (P = 0.20). Only one patient survived with a Glasgow Pittsburgh Cerebral Performance Category (CPC) score = 1 before the OSCAR-ECLS procedure while during the OSCAR-ECLS procedure, eight patients (25%) survived, six with a CPC score = 1, one with a CPC score = 2, and one with a CPC score = 3., Conclusions: The use of a new paradigm of ROHCA dramatically shortened the time to ECLS initiation by reducing the time spent on site by more than 20 min. Survival improved from 7% to 25% after implementation of OSCAR-ECLS.

The principal neurons of the medial superior olive (MSO) encode cues for horizontal sound localization through comparisons of the relative timing of EPSPs. To understand how the timing and amplitude of EPSPs are maintained during propagation in the dendrites, we made dendritic and somatic whole-cell recordings from MSO principal neurons in brain slices from Mongolian gerbils. In somatic recordings, EPSP amplitudes were largely uniform following minimal stimulation of excitatory synapses at visualized locations along the dendrites. Similar results were obtained when excitatory synaptic transmission was eliminated in a low calcium solution and then restored at specific dendritic sites by pairing input stimulation and focal application of a higher calcium solution. We performed dual dendritic and somatic whole-cell recordings to measure spontaneous EPSPs using a dual-channel template-matching algorithm to separate out those events initiated at or distal to the dendritic recording location. Local dendritic spontaneous EPSP amplitudes increased sharply in the dendrite with distance from the soma (length constant, 53.6 μm), but their attenuation during propagation resulted in a uniform amplitude of ∼0.2 mV at the soma. The amplitude gradient of dendritic EPSPs was also apparent in responses to injections of identical simulated excitatory synaptic currents in the dendrites. Compartmental models support the view that these results extensively reflect the influence of dendritic cable properties. With relatively few excitatory axons innervating MSO neurons, the normalization of dendritic EPSPs at the soma would increase the importance of input timing versus location during the processing of interaural time difference cues in vivo SIGNIFICANCE STATEMENT The neurons of the medial superior olive analyze cues for sound localization by detecting the coincidence of binaural excitatory synaptic inputs distributed along the dendrites. Previous studies have shown that dendritic voltages undergo severe attenuation as they propagate to the soma, potentially reducing the influence of distal inputs. However, using dendritic and somatic patch recordings, we found that dendritic EPSP amplitude increased with distance from the soma, compensating for dendritic attenuation and normalizing EPSP amplitude at the soma. Much of this normalization reflected the influence of dendritic morphology. As different combinations of presynaptic axons may be active during consecutive cycles of sound stimuli, somatic EPSP normalization renders spike initiation more sensitive to synapse timing than dendritic location., (Copyright © 2017 the authors 0270-6474/17/373138-12$15.00/0.)

The axon initial segment (AIS) serves as the site of action potential initiation in most neurons, but difficulties in isolating the effects of voltage-gated ion channels in the AIS from those of the soma and dendrites have hampered understanding how AIS properties influence neural coding. Here we have combined confocal microscopy, patch-clamp recordings and light-sensitive channel blockers ('photoswitches') in binaural auditory gerbil neurons to show that hyperpolarization and cyclic-nucleotide-gated (HCN) channels are expressed in the AIS and decrease spike probability, in a manner distinct from that of HCN channels in the soma and dendrites. Furthermore, the control of spike threshold by HCN channels in the AIS can be altered through serotonergic modulation of 5-hydroxytryptamine 1A (5-HT1A) receptors, which hyperpolarizes the activation range of HCN channels. As release of serotonin signals changes in motivation and attention states, axonal HCN channels provide a mechanism to translate these signals into changes in the threshold for sensory stimuli.

Sound localization critically depends on detection of differences in arrival time of sounds at the two ears (acoustic delay). The fundamental mechanisms are debated, but all proposals include a process of coincidence detection and a separate source of internal delay that offsets the acoustic delay and determines neural tuning. We used in vivo patch-clamp recordings of binaural neurons in the Mongolian gerbil and pharmacological manipulations to directly compare neuronal input to output and to separate excitation from inhibition. Our results cannot be accounted for by existing models and reveal that coincidence detection is not an instantaneous process, but is instead shaped by the interaction of intrinsic conductances with preceding synaptic activity. This interaction generates an internal delay as an intrinsic part of the process of coincidence detection. The multiplication and time-shifting stages thought to extract synchronous activity in many brain areas can therefore be combined in a single operation.

The medial superior olive (MSO) senses microsecond differences in the coincidence of binaural signals, a critical cue for detecting sound location along the azimuth. An important component of this circuit is provided by inhibitory neurons of the medial and lateral nuclei of the trapezoid body (MNTB and LNTB, respectively). While MNTB neurons are fairly well described, little is known about the physiology of LNTB neurons. Using whole cell recordings from gerbil brainstem slices, we found that LNTB and MNTB neurons have similar membrane time constants and input resistances and fire brief action potentials, but only LNTB neurons fire repetitively in response to current steps. We observed that LNTB neurons receive graded excitatory and inhibitory synaptic inputs, with at least some of the latter arriving from other LNTB neurons. To address the relative timing of inhibition to the MSO from the LNTB versus the MNTB, we examined inhibitory responses to auditory nerve stimulation using a slice preparation that retains the circuitry from the auditory nerve to the MSO intact. Despite the longer physical path length of excitatory inputs driving contralateral inhibition, inhibition from both pathways arrived with similar latency and jitter. An analysis of paired whole cell recordings between MSO and MNTB neurons revealed a short and reliable delay between the action potential peak in MNTB neurons and the onset of the resulting IPSP (0.55 ± 0.01 ms, n = 4, mean ± SEM). Reconstructions of biocytin-labeled neurons showed that MNTB axons ranged from 580 to 858 μm in length (n = 4). We conclude that while both LNTB and MNTB neurons provide similarly timed inhibition to MSO neurons, the reliability of inhibition from the LNTB at higher frequencies is more constrained relative to that from the MNTB due to differences in intrinsic properties, the strength of excitatory inputs, and the presence of feedforward inhibition.

Introduction: A rational use of antibiotics is of paramount importance in order to prevent the emergence of multidrug resistant bacteria that can lead to therapeutic impasse, especially in intensive care units (ICUs). A de-escalation strategy is therefore naturally advocated as part of better antibiotics usage. However, the clinical impact of such a strategy has not been widely studied. We aimed to assess the feasibility and the clinical impact of a de-escalation strategy in a medical ICU and to identify factors associated when de-escalation was possible., Methods: We performed a retrospective study of patients hospitalized in a medical ICU over a period of six months. Independent factors associated with de-escalation and its clinical impact were assessed., Results: Two hundred and twenty-nine patients were included in the study. Antibiotics were de-escalated in 117 patients (51%). The appropriateness of initial antibiotic therapy was the only independent factor associated with the performance of de-escalation (OR = 2.9, 95% CI, 1.5-5.7; P = 0.002). By contrast, inadequacy of initial antibiotic therapy (OR = 0.1, 0.0 to 0.1, P <0.001) and the presence of multidrug resistant bacteria (OR = 0.2, 0.1 to 0.7, P = 0.006) prevented from de-escalation. There were no differences in terms of short (ICU) or long-term (at 1 year) mortality rates or any secondary criteria such as ICU length of stay, duration of antibiotic therapy, mechanical ventilation, incidence of ICU-acquired infection, or multi-drug resistant bacteria emergence., Conclusions: De-escalation appears feasible in most cases without any obvious negative clinical impact in a medical ICU.

Feedforward inhibition sharpens the precision of neurons throughout ascending auditory pathways, including the binaural neurons of the medial superior olive (MSO). However, the biophysical influence of inhibition is poorly understood, particularly at higher frequencies at which the relative phase of inhibition and excitation becomes ambiguous. Here, we show in gerbil MSO principal cells in vitro that feedforward inhibition precedes direct excitation, providing a concurrent hyperpolarization and conductance shunt during EPSP summation. We show with dual-patch recordings and dynamic clamp that both the linearity and temporal fidelity of synaptic integration is improved by reducing Kv1 potassium channel conductance during inhibition, which counters membrane shunting even at high frequencies at which IPSPs sum. The reduction of peak excitation by preceding inhibition lowers spike probability, narrowing but not shifting the window for detecting binaural coincidence. The interplay between inhibition and potassium conductances thus improves the consistency and resolution of ITD coding across different frequencies., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Neurons in the medial superior olive (MSO) enable sound localization by their remarkable sensitivity to submillisecond interaural time differences (ITDs). Each MSO neuron has its own "best ITD" to which it responds optimally. A difference in physical path length of the excitatory inputs from both ears cannot fully account for the ITD tuning of MSO neurons. As a result, it is still debated how these inputs interact and whether the segregation of inputs to opposite dendrites, well-timed synaptic inhibition, or asymmetries in synaptic potentials or cellular morphology further optimize coincidence detection or ITD tuning. Using in vivo whole-cell and juxtacellular recordings, we show here that ITD tuning of MSO neurons is determined by the timing of their excitatory inputs. The inputs from both ears sum linearly, whereas spike probability depends nonlinearly on the size of synaptic inputs. This simple coincidence detection scheme thus makes accurate sound localization possible., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The effect of family presence during cardiopulmonary resuscitation (CPR) on the family members themselves and the medical team remains controversial., Methods: We enrolled 570 relatives of patients who were in cardiac arrest and were given CPR by 15 prehospital emergency medical service units. The units were randomly assigned either to systematically offer the family member the opportunity to observe CPR (intervention group) or to follow standard practice regarding family presence (control group). The primary end point was the proportion of relatives with post-traumatic stress disorder (PTSD)-related symptoms on day 90. Secondary end points included the presence of anxiety and depression symptoms and the effect of family presence on medical efforts at resuscitation, the well-being of the health care team, and the occurrence of medicolegal claims., Results: In the intervention group, 211 of 266 relatives (79%) witnessed CPR, as compared with 131 of 304 relatives (43%) in the control group. In the intention-to-treat analysis, the frequency of PTSD-related symptoms was significantly higher in the control group than in the intervention group (adjusted odds ratio, 1.7; 95% confidence interval [CI], 1.2 to 2.5; P=0.004) and among family members who did not witness CPR than among those who did (adjusted odds ratio, 1.6; 95% CI, 1.1 to 2.5; P=0.02). Relatives who did not witness CPR had symptoms of anxiety and depression more frequently than those who did witness CPR. Family-witnessed CPR did not affect resuscitation characteristics, patient survival, or the level of emotional stress in the medical team and did not result in medicolegal claims., Conclusions: Family presence during CPR was associated with positive results on psychological variables and did not interfere with medical efforts, increase stress in the health care team, or result in medicolegal conflicts. (Funded by Programme Hospitalier de Recherche Clinique 2008 of the French Ministry of Health; ClinicalTrials.gov number, NCT01009606.).

Some neurons in the mammalian auditory system are able to detect and report the coincident firing of inputs with remarkable temporal precision. A strong, low-voltage-activated potassium conductance (g(KL)) at the cell body and dendrites gives these neurons sensitivity to the rate of depolarization by EPSPs, allowing neurons to assess the coincidence of the rising slopes of unitary EPSPs. Two groups of neurons in the brain stem, octopus cells in the posteroventral cochlear nucleus and principal cells of the medial superior olive (MSO), extract acoustic information by assessing coincident firing of their inputs over a submillisecond timescale and convey that information at rates of up to 1000 spikes s(-1). Octopus cells detect the coincident activation of groups of auditory nerve fibres by broadband transient sounds, compensating for the travelling wave delay by dendritic filtering, while MSO neurons detect coincident activation of similarly tuned neurons from each of the two ears through separate dendritic tufts. Each makes use of filtering that is introduced by the spatial distribution of inputs on dendrites.

In sensory circuits of the brain, developmental changes in the expression and modulation of voltage-gated ion channels are a common occurrence, but such changes are often difficult to assign to clear functional roles. We have explored this issue in the binaural neurons of the medial superior olive (MSO), whose temporal precision in detecting the coincidence of binaural inputs dictates the resolution of azimuthal sound localization. We show that in MSO principal neurons of gerbils during the first week of hearing, a hyperpolarization-activated current (I(h)) progressively undergoes a 13-fold increase in maximal conductance, a >10-fold acceleration of kinetics, and, most surprisingly, a 30 mV depolarizing shift in the voltage dependence of activation. This period is associated with an upregulation of the hyperpolarization-activated and cyclic nucleotide-gated (HCN) channel subunits HCN1, HCN2, and HCN4 in the MSO, but only HCN1 and HCN4 were expressed strongly in principal neurons. I(h) recorded in nucleated patches from electrophysiologically mature MSO neurons (>P18) exhibited kinetics and an activation range nearly identical to the I(h) found in whole-cell recordings before hearing onset. These results indicate that the developmental changes in I(h) in MSO neurons can be explained predominantly by modulation from diffusible intracellular factors, and not changes in channel subunit composition. The exceptionally large modulatory changes in I(h), together with refinements in synaptic properties transform the coding strategy from one of summation and integration to the submillisecond coincidence detection known to be required for transmission of sound localization cues.

In neurons of the medial superior olive (MSO), voltage-gated ion channels control the submillisecond time resolution of binaural coincidence detection, but little is known about their interplay during trains of synaptic activity that would be experienced during auditory stimuli. Here, using modeling and patch-clamp recordings from MSO principal neurons in gerbil brainstem slices, we examined interactions between two major currents controlling subthreshold synaptic integration: a low-voltage-activated potassium current (I(K-LVA)) and a hyperpolarization-activated cation current (I(h)). Both I(h) and I(K-LVA) contributed strongly to the resting membrane conductance and, during trains of simulated EPSPs, exhibited cumulative deactivation and inactivation, respectively. In current-clamp recordings, regular and irregular trains of simulated EPSCs increased input resistance up to 60%, effects that accumulated and decayed (after train) over hundreds of milliseconds. Surprisingly, the mean voltage and peaks of EPSPs increased by only a few millivolts during trains. Using a model of an MSO cell, we demonstrated that the nearly uniform response during modest depolarizing stimuli relied on changes in I(h) and I(K-LVA), such that their sum remained nearly constant over time. Experiments and modeling showed that, for simplified binaural stimuli (EPSC pairs in a noisy background), spike probability gradually increased in parallel with the increasing input resistance. Nevertheless, the interplay between I(h) and I(K-LVA) helps to maintain a nearly uniform shape of individual synaptic responses, and we show that the time resolution of synaptic coincidence detection can be maintained during trains if EPSC size gradually decreases (as in synaptic depression), counteracting slow increases in excitability.

Purpose: Probiotics have been shown to be able to restore a non-pathogenic digestive flora, to prevent digestive colonization by pathogenic bacteria, and to modulate immunity. The aim of this study was to assess the effects of prophylactic probiotic administration in patients ventilated for up to 2 days., Methods: This study was performed as a double-blind, concealed randomized, placebo-controlled trial in a French medical intensive care unit (ICU). Adult patients mechanically ventilated for a period of more than 48 h received enterally administered probiotics (Ergyphilus, 2 x 10(10) lactic acid bacteria, mostly Lactobacillus rhamnosus GG, once a day) or placebo until successful weaning., Results: A total of 167 patients were included. The two groups were comparable at baseline. The 28-day mortality rates were not different in the probiotic (25.3%) and placebo groups (23.7%). Mortality rates in ICU and at 90 days were also unaffected by the treatment. The incidence of ICU-acquired infections did not differ significantly except for that of catheter-related bloodstream infections that was lowered by probiotics. On a prespecified subgroup analysis, we found a reduction of the 28-day mortality among severe sepsis patients (total n = 101) treated with probiotics (n = 52) with an odds ratio (OR) for death at 0.38 (95% CI 0.16-0.93, p = 0.035). By contrast, probiotics were associated with a higher mortality rate in non-severe sepsis patients (OR 3.09, 95% CI 0.87-11.01, p = 0.08)., Conclusions: Although numerous uncertainties remain (type and the number of strains to use, delay and length of administration), and despite an acceptable safety profile, the daily prophylactic administration of probiotics cannot be encouraged in the critically ill patient.

To determine whether an epinephrine-induced early increase in arterial lactate concentration can prognosticate the outcome during shock state, we conducted a retrospective study in a 16-bed medical intensive care unit of a teaching hospital in France. One hundred consecutive patients admitted because of a shock state irrespective of etiology and treated with epinephrine were included. Patients were not enrolled if they received epinephrine administration before intensive care unit admission. Sequential arterial lactate measurements were performed at the time of epinephrine infusion (H0) and 4 h later (H4) in which Deltalactate was defined as (100 x [arterial lactate(H4)-arterial lactate(H0)]/arterial lactate(H0)) and expressed as a percentage. Etiology of shock was septic (82%), cardiogenic (10%), or hemorrhagic (8%). Twenty-eight-day mortality rate was 72%. At admission, arterial lactate concentration was elevated (4.96 +/- 3.8 mmol/L) and was further increased upon epinephrine administration, reaching a peak at H4 (8.22 +/- 3.66). When patients were stratified according to their outcome, nonsurvivors displayed the same pattern as survivors, although with a significant upward shift in values (ANOVA, P = 0.0003). The Sequential Organ Failure Assessment score and Deltalactate were the only variables associated with the 28-day risk of death, with an odds ratio of 1.32 (95% confidence interval [CI], 1.06-1.65; P = 0.01) and 0.99 (95% CI, 0.99-0.99; P = 0.03), respectively, in multivariate analysis. At a value of 100%, Deltalactate predicted death, with a 71% sensitivity (95% CI, 51%-87%) and a 67% specificity (95% CI, 43%-85%). Kaplan-Meier survival analysis confirmed this finding, with a 52.4% death rate among patients with Deltalactate greater than 100 comparatively to 84.7% when Deltalactate was less than 100 (log-rank test, P = 0.0002). An adapted response (lactate production) to a pharmacological trigger (epinephrine) is associated with better prognosis during shock of various etiologies.

Neurons in the medial superior olive process sound-localization cues via binaural coincidence detection, in which excitatory synaptic inputs from each ear are segregated onto different branches of a bipolar dendritic structure and summed at the soma and axon with submillisecond time resolution. Although synaptic timing and dynamics critically shape this computation, synaptic interactions with intrinsic ion channels have received less attention. Using paired somatic and dendritic patch-clamp recordings in gerbil brainstem slices together with compartmental modeling, we found that activation of K(v)1 channels by dendritic excitatory postsynaptic potentials (EPSPs) accelerated membrane repolarization in a voltage-dependent manner and actively improved the time resolution of synaptic integration. We found that a somatically biased gradient of K(v)1 channels underlies the degree of compensation for passive cable filtering during propagation of EPSPs in dendrites. Thus, both the spatial distribution and properties of K(v)1 channels are important for preserving binaural synaptic timing.

Principal neurons of the medial superior olive (MSO) compute azimuthal sound location by integrating phase-locked inputs from each ear. While previous experimental and modeling studies have proposed that voltage-gated sodium channels (VGSCs) play an important role in synaptic integration in the MSO, these studies appear at odds with the unusually weak active backpropagation of action potentials into the soma and dendrites. To understand the spatial localization and biophysical properties of VGSCs, we isolated sodium currents in MSO principal neurons in gerbil brainstem slices. Nucleated and cell-attached patches revealed that VGSC density at the soma is comparable to that of many other neuron types, but channel expression is largely absent from the dendrites. Further, while somatic VGSCs activated with conventional voltage dependence (V(1/2) = -30 mV), they exhibited an unusually negative range of steady-state inactivation (V(1/2) = -77 mV), leaving approximately 92% of VGSCs inactivated at the resting potential (approximately -58 mV). In current-clamp experiments, non-inactivated VGSCs were sufficient to amplify subthreshold EPSPs near action potential threshold, counterbalancing the suppression of EPSP peaks by low voltage-activated potassium channels. EPSP amplification was restricted to the perisomatic region of the neuron, and relatively insensitive to preceding inhibition. Finally, computational modeling showed that the exclusion of VGSCs from the dendrites equalizes somatic EPSP amplification across synaptic locations and lowered the threshold for bilateral versus unilateral excitatory synaptic inputs. Together, these findings suggest that the pattern of sodium channel expression in MSO neurons contributes to these neurons' selectivity for coincident binaural inputs.

Introduction: Metformin-associated lactic acidosis (MALA) is a classic side effect of metformin and is known to be a severe disease with a high mortality rate. The treatment of MALA with dialysis is controversial and is the subject of many case reports in the literature. We aimed to assess the prevalence of MALA in a 16-bed, university-affiliated, intensive care unit (ICU), and the effect of dialysis on patient outcome., Methods: Over a five-year period, we retrospectively identified all patients who were either admitted to the ICU with metformin as a usual medication, or who attempted suicide by metformin ingestion. Within this population, we selected patients presenting with lactic acidosis, thus defining MALA, and described their clinical and biological features., Results: MALA accounted for 0.84% of all admissions during the study period (30 MALA admissions over five years) and was associated with a 30% mortality rate. The only factors associated with a fatal outcome were the reason for admission in the ICU and the initial prothrombin time. Although patients who went on to haemodialysis had higher illness severity scores, as compared with those who were not dialysed, the mortality rates were similar between the two groups (31.3% versus 28.6%)., Conclusions: MALA can be encountered in the ICU several times a year and still remains a life-threatening condition. Treatment is restricted mostly to supportive measures, although haemodialysis may possess a protective effect.

Principal neurons of the medial superior olive (MSO) convey azimuthal sound localization cues through modulation of their rate of action potential firing. Previous intracellular studies in vitro have shown that action potentials appear highly attenuated at the soma of MSO neurons, potentially reflecting specialized action potential initiation and/or a physically distant site of generation. To examine this more directly, we made dual patch-clamp recordings from MSO principal neurons in gerbil brainstem slices. Using somatic and dendritic whole-cell recordings, we show that graded action potentials at the soma are highly sensitive to the rate of rise of excitation and undergo strong attenuation in their backpropagation into the dendrites (length constant, 76 microm), particularly during strong dendritic excitation. Using paired somatic whole-cell and axonal loose-patch recordings, we show that action potentials recorded in the axon at distances > 25 microm are all-or-none, and uniform in amplitude even when action potentials appear graded at the soma. This proximal zone corresponded to the start of myelination in the axon, as assessed with immunocytochemical staining for myelin basic protein in single-labelled neurons. Finally, the axon was capable of sustaining remarkably high firing rates, with perfect entrainment occurring at frequencies of up to 1 kHz. Together, our findings show that action potential signalling in MSO principal neurons is highly secure, but shows a restricted invasion of the somatodendritic compartment of the cell. This restriction may be important for minimizing distortions in synaptic integration during the high frequencies of synaptic input encountered in the MSO.

Objective: To investigate plasma high-mobility group box 1 protein (HMGB1) concentration and its relationship with organ dysfunction and outcome in septic shock patients., Design and Setting: Prospective, noninterventional study. Medical adult intensive care unit at a university hospital in France., Patients: 42 critically ill patients with septic shock., Methods: Arterial blood was drawn within 12 h of admission for the measurement of plasma HMGB1 concentration by ELISA. Repeated sampling was performed on days 3, 7, and 14., Results: Median HMGB1 concentration was 4.4 ng/ml (IQR 1.2-12.5) at admission, with no difference between survivors and nonsurvivors. A positive correlation was observed between HMGB1 and SOFA score and lactate, and procalcitonin concentrations. There was a progressive but statistically nonsignificant decline in HMGB1 concentration among the survivors, while nonsurvivors showed an increase in HMGB1 level between days 1 and 3. SOFA score and lactate and procalcitonin concentrations did not vary significantly between days 1 and 3. When measured on day 3, HMGB1 discriminated survivors from nonsurvivors with 66% sensitivity and 67% specificity, and concentration greater than 4 ng/ml was associated with an odds ratio of death of 5.5 (95% CI 1.3-23.6).

Care and therapy of patients experiencing an anaphylactic reaction should be known by the physicians working in the emergency medical unit or in pre-hospital care. The epidemiology of these reactions varies according to the countries. The main aetiologies are due to food, hymenoptera or drugs. The clinical scale proposed by Ring and Messmer aims to classify the reactions in 4 grades according to their severity and is useful to stratify therapy. According to the grade of the reaction, the drug of choice for the treatment of anaphylaxis is epinephrine associated to vascular expansion. Anaphylaxis during pregnancy is described. Patients who experienced an immediate hypersensitivity reaction should undergo an allergological investigation to prove the immune mechanism and to identify the culprit allergen. Reporting to the Drug Safety Monitoring Authorities when a drug is implicated should not be forgotten.

Objective: To analyze patients' assessment of quality of care in our intensive care unit., Method: We sent questionnaires to the homes of all patients admitted to intensive care from November 2002 through August 2003 who received mechanical ventilation for more than 24 hours., Results: In all, we received 70 analyzable questionnaires. Patients' average age was 56.3 years and the mean duration of stay 13.6 days. Pain was mentioned by 47% of patients and was associated, in decreasing order of frequency, with endotracheal suctioning, placement of a urinary catheter, venipuncture, movement into a different position by staff and arterial punctures. Pain intensity evaluated by an analogic visual scale classified these procedures in the following order: endotracheal suctioning, urinary catheterization, position changing by staff, arterial punctures, venipunctures. 54% of the patients remembered mechanical ventilation. Overall, 17% reported feeling fear often or continuously. Aspects of the ICU environment that bothered them were, in order of decreasing frequency, communication difficulties, thirst, lack of sleep, staff discussions at the patient's bedside, noise and light. Finally, 34% no longer remembered the reason for their stay in the ICU and 19% reported they would have liked to be allowed more frequent visits from their relatives., Conclusion: Nearly half of the respondents underwent painful procedures, primarily endotracheal suctioning. One third did not know why they had been in the ICU. To improve the quality of intensive care, it is essential to make the nursing and medical teams aware of these findings.

Purpose: Our purpose was to determine the incidence of infection after routine arthroscopic meniscectomy of the knee with and without preoperative prophylactic intravenous antibiotics., Methods: A retrospective review of 3,231 arthroscopic knee surgeries was performed at a physician-owned in-office ambulatory surgery center over a 3-year period, of which 2,780 were arthroscopic meniscectomies. The cases were evaluated with respect to the incidence of deep infection as evidenced by a positive joint aspirate. Approximately 30% of the patients had prophylactic intravenous antibiotics within 1 hour before the arthroscopic procedure., Results: The infection rate was 0.15% in those patients who received antibiotics and 0.16% in those who did not receive antibiotics (P = .59)., Conclusions: The results of this study confirm that there is no value in administering antibiotics before routine arthroscopic meniscectomy to prevent joint sepsis., Level of Evidence: Level III, retrospective comparative study.

Introduction: The product of growth arrest-specific gene 6 (Gas6) is a vitamin K dependent protein that is secreted by leucocytes and endothelial cells in response to injury and participates in cell survival, proliferation, migration and adhesion. Our purpose was to investigate plasma Gas6 concentration and its relation to organ dysfunction in patients with septic shock., Methods: Forty-five patients with septic shock admitted to a medical adult intensive care unit were enrolled. Plasma Gas6 concentration was determined using enzyme-linked immunosorbent assay at days 1, 3, 7 and 14., Results: The median (interquartile range) Gas6 concentration was 51 (5 to 95) pg/ml at admission. A positive correlation (Spearman rank-order coefficient [rs] = 0.37, P = 0.01) was found between Gas6 level and Sepsis-related Organ Failure Assessment score. Patients requiring renal support had higher Gas6 concentration that those without need for haemofiltration (76.5 [52 to 164] pg/ml versus 10.5 [1.5 to 80.5] pg/ml; P = 0.04). Moreover, there was a positive correlation between Gas6 and aspartate transaminase (rs = 0.42, P = 0.006) and between Gas6 and prothrombin time (rs = 0.45, P = 0.02). Although there was a progressive decline in Gas6 concentration in survivors (analysis of variance, P = 0.01), nonsurvivors exhibited persistently elevated Gas6. However, the two populations diverged only after day 7 (P = 0.04)., Conclusion: Plasma concentrations of Gas6 correlate with disease severity, especially with renal and hepatic dysfunction, in septic shock.

This prospective, non-interventional study was conducted in a medical adult intensive care unit to determine the usefulness of procalcitonin (PCT) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) determinations in the diagnosis of nosocomial sepsis. Serum PCT and bronchoalveolar lavage fluid sTREM-1 concentrations were measured in 50 critically ill patients suffering from nosocomial sepsis. Ventilator-associated pneumonia (VAP) was diagnosed in 31 patients and extrapulmonary sepsis in 19. Increase serum PCT concentration (>0.15 ng/ml) was found in 44 (88%) patients and was higher in those suffering from a non-pulmonary sepsis. The concomitant BAL sTREM-1 determination correctly classified pulmonary (VAP) versus non-pulmonary origin in 41 out of 44 cases (93%). Even when PCT concentration remained low, sTREM-1 assessment allowed for the detection of the sepsis (VAP) in 50% of cases. Both PCT and sTREM-1 concentrations were low in only 3 patients (6%) in whom sepsis could have been missed if only diagnosed by the measurement of these 2 biomarkers. We therefore concluded that the combined measurement of serum PCT and BAL sTREM-1 concentrations could be of interest in detecting the presence of a nosocomial sepsis and in discriminating VAP versus extrapulmonary infection.

We performed simultaneous patch-electrode recordings from the soma and apical dendrite of CA1 pyramidal neurons in hippocampal slices, in order to determine the degree of voltage attenuation along CA1 dendrites. Fifty per cent attenuation of steady-state somatic voltage changes occurred at a distance of 238 microm from the soma in control and 409 microm after blocking the hyperpolarization-activated (H) conductance. The morphology of three neurons was reconstructed and used to generate computer models, which were adjusted to fit the somatic and dendritic voltage responses. These models identify several factors contributing to the voltage attenuation along CA1 dendrites, including high axial cytoplasmic resistivity, low membrane resistivity, and large H conductance. In most cells the resting membrane conductances, including the H conductances, were larger in the dendrites than the soma. Simulations suggest that synaptic potentials attenuate enormously as they propagate from the dendrite to the soma, with greater than 100-fold attenuation for synapses on many small, distal dendrites. A prediction of this powerful EPSP attenuation is that distal synaptic inputs are likely only to be effective in the presence of conductance scaling, dendritic excitability, or both.

In mammals, principal neurons of the medial superior olive (MSO) exhibit biophysical specializations that enable them to detect sound localization cues with microsecond precision. In the present study, we used whole-cell patch recordings to examine the development of the intrinsic electrical properties of these neurons in brainstem slices from postnatal day 14 (P14) to P38 gerbils. In the week after hearing onset (P14-P21), we observed dramatic reductions in somatic EPSP duration, input resistance, and membrane time constant. Surprisingly, somatically recorded action potentials also dramatically declined in amplitude over a similar period (38 +/- 3 to 17 +/- 2 mV; tau = 5.2 d). Simultaneous somatic and dendritic patch recordings revealed that these action potentials were initiated in the axon, which primarily emerged from the soma. In older gerbils, the rapid speed of membrane voltage changes and the attenuation of action potential amplitudes were mediated extensively by low voltage-activated potassium channels containing the Kv1.1 subunit. In addition, whole-cell voltage-clamp recordings revealed that these potassium channels increase nearly fourfold from P14 to P23 and are thus a major component of developmental changes in excitability. Finally, the electrophysiological features of principal neurons of the medial nucleus of the trapezoid body did not change after P14, indicating that posthearing regulation of intrinsic membrane properties is not a general feature of all time-coding auditory neurons. We suggest that the striking electrical segregation of the axon from the soma and dendrites of MSO principal neurons minimizes spike-induced distortion of synaptic potentials and thus preserves the accuracy of binaural comparisons.

Objective: To study the factors associated with relative adrenocortical deficiency in mechanically ventilated, critically ill patients., Design and Setting: Prospective observational study in a multidisciplinary ICU of a university-affiliated teaching hospital., Patients: Sixty-two consecutive, acutely ill patients needing mechanical ventilation for more than 24 h., Measurements and Results: A high-dose short corticotropin test 24 h after endotracheal intubation. Relative adrenocortical deficiency ("nonresponder" group of patients) was defined by a rise in cortisol less than 90 microg/l after stimulation. Twenty-seven patients were classified as nonresponders and 35 as responders. On univariate analysis nonresponders were more often men, had lower mean arterial pressure, required vasoactive agents more often, had lower creatinine clearance, higher SAPS II, higher organ dysfunction scores, and received etomidate as a single bolus for endotracheal intubation more often than responders. On multivariate analysis, only etomidate administration was related to relative adrenocortical deficiency (OR 12.21; 95% CI 2.99-49.74) while female gender was protective (OR 0.13; 95% CI 0.03-0.57)., Conclusions: A single bolus infusion of etomidate could be a major risk factor for the development of relative adrenocortical deficiency in ICU patients for at least 24 h after administration. Female gender is an independent protective factor.

Context: Contrary to tonometer gastric intramucosal pH, there is currently no validated threshold prognostic value for Pco2 gap (tonometer gastric mucosal Pco2 minus arterial Pco2) in the critically ill patient., Objective: To demonstrate a relationship between Pco2 gap and mortality in mechanically ventilated patients., Design and Setting: Inception cohort study from a 9-month prospective survey of 95 consecutively ventilated critically ill patients in a teaching hospital., Patients: All the ventilated patients of the intensive care unit were included at their admission., Measurements and Main Results: Gastric Pco2 using regional capnometry with air-automated tonometry, arterial gas, lactate, and organ system failure score were measured at admission and after 6, 12, 24, 48, 72, 96, and 120 hrs. For the entire population, the 28-day mortality was 44%. In multivariate analysis, independent predictors of death were organ system failure score (odds ratio, 2.12; 95% confidence interval, 1.02-3.14), 24-hr Pco2 gap (odds ratio, 1.57; 95% confidence interval, 1.10-2.24), and 24-hr lactate (odds ratio, 1.48; 95% confidence interval, 1.06-2.05). We found a threshold value of 20 mm Hg for Pco2 gap and 2.5 mmol/L for lactate, which was associated with a sensitivity of 0.70 and 0.72, respectively, and a specificity of 0.72 and 0.73, respectively., Conclusion: The Pco2 gap is a marker of mortality in ventilated patients in the intensive care unit.

Strengthening of synaptic connections following coincident pre- and postsynaptic activity was proposed by Hebb as a cellular mechanism for learning. Contemporary models assume that multiple synapses must act cooperatively to induce the postsynaptic activity required for hebbian synaptic plasticity. One mechanism for the implementation of this cooperation is action potential firing, which begins in the axon, but which can influence synaptic potentiation following active backpropagation into dendrites. Backpropagation is limited, however, and action potentials often fail to invade the most distal dendrites. Here we show that long-term potentiation of synapses on the distal dendrites of hippocampal CA1 pyramidal neurons does require cooperative synaptic inputs, but does not require axonal action potential firing and backpropagation. Rather, locally generated and spatially restricted regenerative potentials (dendritic spikes) contribute to the postsynaptic depolarization and calcium entry necessary to trigger potentiation of distal synapses. We find that this mechanism can also function at proximal synapses, suggesting that dendritic spikes participate generally in a form of synaptic potentiation that does not require postsynaptic action potential firing in the axon.

Objective: To determine whether nutrient intake by early enteral nutrition with parenteral nutrition improves levels of retinol-binding protein and prealbumin (primary endpoint) and reduce morbidity and mortality (secondary endpoint) in ICU patients., Design: Prospective, double-blind, and randomized, placebo-controlled study., Setting: Two intensive care units in a tertiary institution., Patients and Participants: 120 patients in two groups of 60., Interventions: Patients received either enteral plus parenteral nutrition (treatment group) or enteral nutrition plus placebo (placebo group) for 4-7 days after initiation of nutritional support., Measurements and Results: Retinol-binding protein (P = 0.0496) and prealbumin (P = 0.0369) increased significantly in the treatment group from day 0 to day 7. There was no reduction in morbidity in ICU. There was no difference in OMEGA score (263 vs. 244) and length of stay in the ICU (16.9 vs. 17.3), but a reduction in length of stay at hospital (31.2+/-18.5 vs. 33.7+/-27.7, P = 0.0022). Mortality on day 90 (17 vs. 18) and after 2 years (24 vs. 24) was identical., Conclusions: Although it enhances nutrient intake and corrects nutritional parameters such as RBP and prealbumin more rapidly, within 1 week, supplemental parenteral nutrition has no clinically relevant effect on outcome in ICU patients at the early phase of nutritional support.

Objectives: To compare the effects of dobutamine and dopexamine on systemic hemodynamics, lactate metabolism, renal function and the intramucosal-arterial PCO(2) gap in norepinephrine-treated septic shock., Design: A prospective, interventional, randomized clinical trial., Setting: Adult medical/surgical intensive care unit in a university hospital., Patients: After volume resuscitation, 24 patients were treated with norepinephrine alone titrated to obtain a mean arterial pressure of 75 mmHg and a cardiac index greater than 3. 5 l/min(-1). m(-2)., Interventions: Patients were randomized to receive an infusion of dobutamine (n = 12) (5 microg/kg per min) or dopexamine (n = 12) (1 microg/kg per min)., Measurements and Main Results: Baseline measurements included: hemodynamic parameters, renal parameters (diuresis, creatinine clearance and urinary sodium excretion), gastric mucosal-arterial PCO(2) gap, arterial and mixed venous gases and arterial lactate and pyruvate levels. These measurements were repeated after 1 (H(1)), 4 (H(4)) and 24 (H(24)) h. No difference was found between dobutamine and dopexamine among H(0) and H(1), H(4) and H(24) values for hemodynamics. Dobutamine and dopexamine at low doses had no significant effect on mean arterial pressure, heart rate, cardiac index, oxygen delivery, oxygen consumption and pulmonary artery occlusion pressure. No patients developed arrhythmia or electrocardiographic signs of myocardial ischemia. After 4 and 24 h lactate concentration decreased in the dobutamine group from 2.4 +/- 1 mmol/l to 1.7 +/- 0. 7 mmol/l and 1.5 +/- 0.4 mmol/l, respectively, while it increased in the dopexamine group from 2.3 +/- 1 mmol/l to 2.7 +/- 1 mmol/l after 4 h and returned to baseline values after 24 h (2.2 +/- 0.6). After 24 h the lactate/pyruvate ratio decreased in the dobutamine group from 15 +/- 5 to 12 +/- 3 (p < 0.05) while it was unchanged in the dopexamine group (from 16 +/- 6 to 17 +/- 4). Arterial pH increased in the dobutamine group from 7.35 +/- 0.05 to 7.38 +/- 0.07 (p < 0. 05) while it was unchanged in the dopexamine group (from 7.34 +/- 0. 01 to 7.35 +/- 0.10). The PCO(2) gap decreased after 1 and 4 h in both the dobutamine and dopexamine groups (p < 0.05 with respect to baseline). When looking at individual responses, however, patients from both groups exhibited an increased gastric PCO(2) gap. No difference was found between dobutamine and dopexamine for renal parameters., Conclusions: In norepinephrine-treated septic shock, low doses of neither dobutamine nor dopexamine caused significant effects on systemic hemodynamics and renal function and both dobutamine and dopexamine inconsistently improved the PCO(2) gap. The present results support the need for individual measurement of the effects of catecholamine on the PCO(2) gap.

Objective: This retrospective evaluation aimed to assess the adequacy of prophylaxis against thromboembolism prescribed to surgical patients at the authors' institution, and to compare it with generally accepted published guidelines. Aspects considered were indications for prophylaxis, regimens used and monitoring., Methods: Eleven units (nine surgical and two surgical intensive care) took part in the survey on a voluntary basis. The clinical audit system used involved developing a set of criteria based on existing guidelines, comparing observed practice with those recommendations, analysing the factors underlying any deviation and developing corrective measures., Results: When the medical records of 117 patients hospitalized in October 1995 were examined, prophylaxis against deep vein thrombosis was documented in 86 (low molecular weight heparin in 85, dextran in one). No associated physical preventative measures were recorded. Indications and dosage were appropriately handled in 90.7% and 75.2% of patients, respectively. Ninety-five cases were outside the reference criteria: 74 for excluded surgical indications, 13 which involved laparoscopy, and eight in which spinal or epidural anaesthesia was administered. Platelet count was performed in 73.8% of cases before prophylactic treatment, and in 23.10% during its course. Anti-Xa activity was measured in 0.4% of cases. Analysis of causes showed that guidelines were not complied with either because of lack of organization, or because of disagreement with them., Discussion: In this study, indications for prophylaxis were well established and heparin dosages used were not fundamentally flawed. The weak point in practice was a failure to carry out platelet counts, particularly during the course of treatment. Appropriate corrective action consists of disseminating guidelines and relevant information, and using a preoperative checklist to assess thromboembolic risk., Conclusion: Physicians agree that opportunities to improve preventative practices exist, and that the quality improvement programme should be pursued.

Vascular surgery, which in certain life-threatening situations is the only possible therapeutic option, has progressed considerably since its beginning in the 1950s. Because of the constant progression of vascular diseases, this surgery will present, in the forthcoming years, a major public health problem. Because of advances in medico-surgical management, evermore elderly and frail patients can be treated. Perioperative mortality is constantly decreasing, but much progress remains to be accomplished to prevent, avoid or treat, postoperative complications. They are common and serious in these typical patients with cardiovascular diseases (men over 50 years of age, heavy smokers, atheromatous ...). The AA divide these complications into 3 main groups depending on the surgical procedure: abdominal aortic surgery, carotid surgery and arterial and venous surgery of the lower limbs. There is much data on abdominal aortic surgery because these long and complex procedures produce repercussions often involving many systems. The postoperative complications are treated according to the system they involve: cardiovascular, the most serious, respiratory, the commonest, alimentary, neurological, renal, others, as well as combined systems. The AA do not deal with the specific problems associated with cardiac and cardio-thoracic surgery. The AA discuss the different epidemiological findings of the large surgical series published in the 1970s and 1980s. The more recent literature analyses the relationship between preoperative risk factors (atheroma, COAD, hypertension ...), peroperative problems (surgical difficulties, emergencies, massive transfusions, others) and the corresponding postoperative morbidity. Thus a few general outlines of the physiopathology of these different complications emerge. In the light of these notions the few proposed methods will be evaluated in order to improve the preoperative condition of the vascular patient. The AA also review the relevance of the preoperative investigation in patients for vascular surgery. All these measures aim at reducing the incidence and severity of perioperative morbidity.

Objectives: In an effort to improve the prevention of venous thromboembolism, the Nancy University Hospitals conducted a survey of medical practice concerning indications for preventive therapy and surveillance of platelet counts and anti Xa activity., Methods: The survey involved 163 medical files. Questionnaires were filled out in 6 units (3 medical wards and 3 intensive care units)., Results: Indications for preventive therapy were found to be quite variable with the exception of very low risk of thromboembolism where the treat/do not treat ratio was 0.1/1, indicating a clear tendency for abstention. This ratio was 0.77/1 and 0.38/1 respectively for low and moderate risk and 2/1 for high risk. There was undoubtedly a ward effect. The attitudes in practice tended toward non-prevention in patients without limited mobility. For platelet counts, an initial count was performed in 95% of the cases and during treatment in 38% although the specific rates were not the same for different types of units. Anti-Xa activity, which according to prevention recommendations need not to be determined, was not monitored in 88% of the cases. In accordance with prevention recommendations, anti-Xa activity was not determined in 88% of the cases., Conclusion: Further progress is needed in the prevention of venous thromboembolism and should be based on wider use of existing methods.

The distribution of oxygen to many victims can be necessary all along the medical help chain: operations of extraction, stand up, recovery, transport, life supporting care, surviving and transportation in mobile processing formations installed to proximity of the site, evacuations by road or by fly. Moreover, hospital in situation of crisis has an increased oxygen consumption (especially for ventilators). An estimable need calculation, a census of stocking and distribution ways have to allow to adapt resources to needs. Proposed solutions are the strengthening of vehicles in oxygen tanks, utilization of liquid oxygen tanks in large mobile formations and particular procedures to supply hospital crisis situation.