High-dimensional immune cell profiling of cerebrospinal fluid from patients with metastatic breast cancer and leptomeningeal disease.

Leptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer (MBC). In this non-therapeutic study, we enrolled 12 patients with MBC and known or suspected LMD who were undergoing a lumbar puncture as part of clinical care and collected extra cerebrospinal fluid (CSF) and a paired blood sample from each patient at a single time point. Of the 12 patients, 7 patients are confirmed to have LMD based on positive cytology and/or convincing MRI imaging (LMDpos), and 5 patients are deemed not to have LMD based on similar criteria (LMDneg). Using high-dimensional, multiplexed flow cytometry, we profile and compare the CSF and peripheral blood mononuclear cell (PBMCs) immune populations between patients with LMD and those without. Patients with LMD observe a lower overall frequency of CD45+ cells (29.51% vs. 51.12%, p < 0.05), lower frequencies of CD8+ T cells (12.03% vs. 30.40%, p < 0.01), and higher frequency of Tregs than patients without LMD. Interestingly, the frequency of partially exhausted CD8+ T cells (CD38hiTIM3lo) is ~6.5-fold higher among patients with LMD vs. those without (2.99% vs. 0.44%, p < 0.05). Taken together, these data suggest that patients with LMD may have lower overall immune infiltrates than patients without LMD, suggesting a more permissive CSF immune microenvironment but a higher frequency of partially exhausted CD8+ T cells, which may offer an important therapeutic target.

[Refractory pulmonary edema under ECMO: Is there a place for Rashkind atrioseptotomy?] / Œdème aigu pulmonaire réfractaire sous ECMO : une place pour l'atrioseptotomie de Rashkind ?

Hydrostatic pulmonary edema is a well-known complication of veinoarterial extracorporeal membrane oxygenation (VA-ECMO) caused by increased left ventricle afterload due to reverse blood flow in the aorta. Several techniques are commonly used for left ventricle venting such as intra-aortic balloon pump, Impella® (Abiomed, Danvers, MA), central surgical cannulation or Rahskind atrial septostomy. We reported two cases of hydrostatic pulmonary edema in patients under VA-ECMO for whom it was decided to perform Rashkind technique. The first is a late anterior myocardial infarction complicated with cardiac arrest and cardiogenic shock. Refractory hypoxemia due to hydrostatic pulmonary edema conducted us to perform atrial septostomy. The second case is a refractory cardiogenic shock due to left main stent thrombosis myocardial infarction. Procedural transesophageal echocardiography revealed a large left atrial thrombus extended to pulmonary veins preventing the procedure. These two cases illustrate the importance and gravity of pulmonary edema induced by VA-ECMO. The first shows that this technique is feasible, allows great left ventricle unloading and improves hypoxemia. The second underlines the interest of performing transesophageal echocardiography to look for pulmonary veins thrombosis that can take part in the elevation of hydrostatic pressure and forbid Rashkind manoeuver.

A 2-year multicenter, observational, prospective, cohort study on extracorporeal CO2 removal in a large metropolis area.

BACKGROUND: Extracorporeal carbon dioxide removal (ECCO2R) is a promising technique for the management of acute respiratory failure, but with a limited level of evidence to support its use outside clinical trials and/or data collection initiatives. We report a collaborative initiative in a large metropolis. METHODS: To assess on a structural basis the rate of utilization as well as efficacy and safety parameters of 2 ECCO2R devices in 10 intensive care units (ICU) during a 2-year period. RESULTS: Seventy patients were recruited in 10 voluntary and specifically trained centers. The median utilization rate was 0.19 patient/month/center (min 0.04; max 1.20). ECCO2R was started under invasive mechanical ventilation (IMV) in 59 patients and non-invasive ventilation in 11 patients. The Hemolung Respiratory Assist System (Alung) was used in 53 patients and the iLA Activve iLA kit (Xenios Novalung) in 17 patients. Main indications were ultraprotective ventilation for ARDS patients (n = 24), shortening the duration of IMV in COPD patients (n = 21), preventing intubation in COPD patients (n = 9), and controlling hypercapnia and dynamic hyperinflation in mechanically ventilated patients with severe acute asthma (n = 6). A reduction in median V T was observed in ARDS patients from 5.9 to 4.1 ml/kg (p <0.001). A reduction in PaCO2 values was observed in AE-COPD patients from 67.5 to 51 mmHg (p< 0.001). Median duration of ECCO2R was 5 days (IQR 3-8). Reasons for ECCO2R discontinuation were improvement (n = 33), ECCO2R-related complications (n = 18), limitation of life-sustaining therapies or measures decision (n = 10), and death (n = 9). Main adverse events were hemolysis (n = 21), bleeding (n = 17), and lung membrane clotting (n = 11), with different profiles between the devices. Thirty-five deaths occurred during the ICU stay, 3 of which being ECCO2R-related. CONCLUSIONS: Based on a registry, we report a low rate of ECCO2R device utilization, mainly in severe COPD and ARDS patients. Physiological efficacy was confirmed in these two populations. We confirmed safety concerns such as hemolysis, bleeding, and thrombosis, with different profiles between the devices. Such results could help to design future studies aiming to enhance safety, to demonstrate a still-lacking strong clinical benefit of ECCO2R, and to guide the choice between different devices. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier: NCT02965079 retrospectively registered https://clinicaltrials.gov/ct2/show/NCT02965079.

[Mediastinitis following endobronchial ultrasound-guided transbronchial needle aspiration]. / Médiastinite au décours d'une échoendoscopie bronchique (EEB) avec cyto-aspiration ganglionnaire.

INTRODUCTION: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure designed to explore mediastinal lymphadenopathy. Its use and indications have increased recently and severe, though rare, complications have been reported. CASE REPORT: EBUS-TBNA was performed in a 64-year-old patient presenting with mediastinal lymphadenopathy, probably due to sarcoidosis, but without histological proof. Within hours of the aspiration of subcarinal lymph nodes (station 7), the patient developed fever and dry cough associated with progressive dysphagia and dysphonia that persisted for four weeks. Mediastinitis was diagnosed after a CT-scan revealed a collection in the subcarinal space previously tapped using CT guidance. Intravenous antibiotics were started and both symptoms and the mediastinal collection resolved without need of a surgical procedure. The patient recovered fully. CONCLUSION: EBUS-TBNA is associated with a risk of mediastinitis that may manifest as an isolated fever arising within hours of the procedure. The pathogens responsible are usually contaminants from the oropharynx such as Streptococcus sp, probably inoculated directly into the mediastinum during transbronchial needle aspiration. Rapid diagnosis and treatment are necessary in order to reduce morbidity and mortality associated with mediastinitis.

Molecularly imprinted polymers for the determination of organophosphorus pesticides in complex samples.

Organophosphorus compounds constitute an important class of pesticides whose the toxicity of which arises from the inhibition of the acetylcholinesterase enzyme. They exhibit a wide range of physico-chemical properties, thus rendering their determination in complex oil samples particularly difficult. To facilitate their analysis at the trace level in various samples (environmental waters, soils, vegetables…), molecularly imprinted polymers (MIPs) that are synthetic polymers possessing specific cavities designed for a target molecule have been prepared. Often called synthetic antibodies, MIPs can replace antibodies in different application fields. Indeed, as immunosorbents, MIPs can be used as selective sorbents for the solid phase extraction of target analytes from complex matrices or as recognition elements in sensors. Their synthesis, characterization and use as selective sorbent for the selective recognition of organophosphorus pesticides have been already largely described and are summarized in this review.

Indications for extracorporeal support: why do we need the results of the EOLIA trial?

Acute respiratory distress syndrome (ARDS) is a severe lung disease, with an associated mortality rate exceeding 60% for the most severe forms of the disease. In these situations, establishing an extracorporeal circuit, combining a centrifugal pump and a membrane oxygenator (extra-corporeal membrane oxygenation, ECMO), can ensure total pulmonary assistance and allow the lungs to rest under ultraprotective mechanical ventilation. Unfortunately, former trials of ECMO in ARDS were negative or highly criticized due to many technical and methodological shortcomings. Prior to the widespread use of venovenous ECMO for severe ARDS, new trials are needed to test the efficacy of early initiation of the technique with tight control of mechanical ventilation in the control group, initiation of ECMO prior to transportation to ECMO centers, and the use of ECMO in all patients randomly assigned to receive this treatment. Therefore, the international multicenter randomized EOLIA (ECMO to rescue Lung Injury in severe ARDS) trial was designed to test the benefit of systematic and early installation of the latest-generation ECMO circuits in patients with very severe ARDS. Patients randomized to the control group were managed with tight control of mechanical ventilation and recourse to paralyzing agents and prone positioning, while an ethical crossover option to ECMO was permitted only if refractory hypoxemia (SaO2 < 80%) lasted for > 6 h despite all possible conventional emergency interventions. The primary endpoint of the study was the 60-day mortality rate, with an expected 20% absolute mortality reduction with ECMO.

What are the risk factors for dislocation in primary total hip arthroplasty? A multicenter case-control study of 128 unstable and 438 stable hips.

INTRODUCTION: Dislocation after total hip arthroplasty (THA) is a leading reason for surgical revision. The risk factors for dislocation are controversial, particularly those related to the patient and to the surgical procedure itself. The differences in opinion on the impact of these factors stem from the fact they are often evaluated using retrospective studies or in limited patient populations. This led us to carry out a prospective case-control study on a large population to determine: 1) the risk factors for dislocation after THA, 2) the features of these dislocations, and 3) the contribution of patient-related factors and surgery-related factors. HYPOTHESIS: Risk factors for dislocation related to the patient and procedure can be identified using a large case-control study. PATIENTS AND METHODS: A multicenter, prospective case-control study was performed between January 1 and December 31, 2013. Four patients with stable THAs were matched to each patient with a dislocated THA. This led to 566 primary THA cases being included: 128 unstable, 438 stable. The primary matching factors were sex, age, initial diagnosis, surgical approach, implantation date and type of implants (bearing size, standard or dual-mobility cup). RESULTS: The patients with unstable THAs were 67±12 [37-73]years old on average; there were 61 women (48%) and 67 men (52%). Hip osteoarthritis (OA) was the main reason for the THA procedure in 71% (91/128) of the unstable group. The dislocation was posterior in 84 cases and anterior in 44 cases. The dislocation occurred within 3 months of the primary surgery in 48 cases (38%), 3 to 12 months after in 23 cases (18%), 1 to 5years after in 20 cases (16%), 5 to 10years after in 17 cases (13%) and more than 10years later in 20 cases. The dislocation recurred within 6 months of the initial dislocation in 23 of the 128 cases (18%). The risk factors for instability were a high ASA score with an odds ratio (OR) of 1.93 (95% CI: 1.4-2.6), neurological disability (cognitive, motor or psychiatric disorders) with an OR of 3.9 (95% CI: 2.15-7.1), history of spinal disease (lumbar stenosis, spinal fusion, discectomy, scoliosis and injury sequelae) with an OR of 1.89 (95% CI: 1.0-3.6), unrepaired joint capsule (all approaches) with an OR of 4.1 (95% CI: 2.3-7.37), unrepaired joint capsule (posterior approach) with an OR of 6.0 (95% CI: 2.2-15.9), and cup inclination outside Lewinnek's safe zone (30°-50°) with OR of 2.4 (95% CI: 1.4-4.0). DISCUSSION: This large comparative study isolated important patient-related factors for dislocation that surgeons must be aware of. We also found evidence that implanting the cup in 30° to 50° inclination has a major impact on preventing dislocation. LEVEL OF EVIDENCE: Level III; case-control study.

Congenital lobar emphysema in a kitten.

A five-month-old ragdoll cat presented with severe respiratory signs, unresponsive to medical therapy. Hyperinflation of the right middle lung lobe was diagnosed with radiography and computed tomography. Lung lobectomy following a median sternotomy led to full recovery. Histopathological analysis revealed lobar emphysema and, based on the animal's age, congenital lobar emphysema was considered the most likely diagnosis.

[Myocarditis]. / Myocardites.

Acute myocarditis must be considered in patients with recent onset of cardiac failure or arrhythmia. Fulminant myocarditis is a distinct entity characterized by sudden onset of severe congestive heart failure or cardiogenic shock, usually following a flu-like illness, parvovirus B19, human herpesvirus 6, coxsackie virus and adenovirus being the most frequently viruses responsible for the disease. In this setting, early recognition of patients rapidly progressing to refractory cardiac failure and their immediate transfer to a medical-surgical center experienced in mechanical circulatory support is warranted. Treatment of acute myocarditis relies on conventional heart failure therapy. Immunosuppression of autoreactive myocarditis or immuno-stimulants such as interferons for chronic viral myocarditis could be of interest but their potential therapeutic role requires further investigation.

A spatially-averaged mathematical model of kidney branching morphogenesis.

Kidney development is initiated by the outgrowth of an epithelial ureteric bud into a population of mesenchymal cells. Reciprocal morphogenetic responses between these two populations generate a highly branched epithelial ureteric tree with the mesenchyme differentiating into nephrons, the functional units of the kidney. While we understand some of the mechanisms involved, current knowledge fails to explain the variability of organ sizes and nephron endowment in mice and humans. Here we present a spatially-averaged mathematical model of kidney morphogenesis in which the growth of the two key populations is described by a system of time-dependant ordinary differential equations. We assume that branching is symmetric and is invoked when the number of epithelial cells per tip reaches a threshold value. This process continues until the number of mesenchymal cells falls below a critical value that triggers cessation of branching. The mathematical model and its predictions are validated against experimentally quantified C57Bl6 mouse embryonic kidneys. Numerical simulations are performed to determine how the final number of branches changes as key system parameters are varied (such as the growth rate of tip cells, mesenchyme cells, or component cell population exit rate). Our results predict that the developing kidney responds differently to loss of cap and tip cells. They also indicate that the final number of kidney branches is less sensitive to changes in the growth rate of the ureteric tip cells than to changes in the growth rate of the mesenchymal cells. By inference, increasing the growth rate of mesenchymal cells should maximise branch number. Our model also provides a framework for predicting the branching outcome when ureteric tip or mesenchyme cells change behaviour in response to different genetic or environmental developmental stresses.

Modelling cell turnover in a complex tissue during development.

The growth of organs results from proliferation within distinct cellular compartments. Organ development also involves transitions between cell types and variations in cell cycle duration as development progresses, and is regulated by a balance between entry into the compartment, proliferation of cells within the compartment, acquisition of quiescence and exit from that cell state via differentiation or death. While it is important to understand how environmental or genetic alterations can perturb such development, most approaches employed to date are descriptive rather than quantitative. This is because the identification and quantification of such parameters, while tractable in vitro, is challenging in the context of a complex tissue in vivo. Here we present a new framework for determining cell turnover in developing organs in vivo that combines cumulative cell-labelling and quantification of distinct cell-cycle phases without assuming homogeneity of behaviour within that compartment. A mathematical model is given that allows the calculation of cell cycle length in the context of a specific biological example and assesses the uncertainty of this calculation due to incomplete knowledge of cell cycle dynamics. This includes the development of a two population model to quantify possible heterogeneity of cell cycle length within a compartment and estimate the aggregate proliferation rate. These models are demonstrated on data collected from a progenitor cell compartment within the developing mouse kidney, the cap mesenchyme. This tissue was labelled by cumulative infusion, volumetrically quantified across time, and temporally analysed for the proportion of cells undergoing proliferation. By combining the cell cycle length predicted by the model with measurements of total cell population and mitotic rate, this approach facilitates the quantification of exit from this compartment without the need for a direct marker of that event. As a method specifically designed with assumptions appropriate to developing organs we believe this approach will be applicable to a range of developmental systems, facilitating estimations of cell cycle length and compartment behaviour that extend beyond simple comparisons of mitotic rates between normal and perturbed states.

Do bone loss and reconstruction procedures differ at revision of cemented unicompartmental knee prostheses according to the use of metal-back or all-polyethylene tibial component?

INTRODUCTION: Results of unicompartmental knee arthroplasty (UKA) revision are known but the severity of bone loss and the need for reconstruction are not detailed for different tibial implants. HYPOTHESIS: Metal-backing UKA revision exposes the patient to more severe tibial bone loss and requires more substantial reconstruction procedures than cemented polyethylene UKA revision. MATERIALS AND METHODS: This retrospective series of 23 revisions of UKA to total knee arthroplasty (TKA) compared 11 all-polyethylene UKAs with 12 metal-backing UKAs. Factors that contributed to failure were aseptic loosening (n=12) and osteoarthritis evolution (n=11). Both groups were similar regarding the demographic and clinical features. We reported bone loss and the reconstruction procedure to fill it according to the initially used tibial implant. The results were evaluated with the IKS score to a follow-up of 37 months (range, 24-67 months). RESULTS: There were more tibial segmental bone loss (10 versus 3) and more metal wedges (8/12 versus 2/11) in metal-backing UKA revision (P<0.05). Tibial stems were more often used in metal-backing UKA revision (12/12 versus 7/11) (P=0.04). The results of TKA at follow-up did not differ according to whether the revised tibial implant was all polyethylene (IKS=155 [range, 107-195]) or metal-back (IKS=155 [range, 127-172]). DISCUSSION: This study suggests that metal-backing UKA revision exposes the patient to more severe tibial bone loss requiring more substantial reconstruction. These results must be confirmed on a larger population, but surgeons should be alerted to this kind of revision surgery, which warrants having available a revision knee prothesis. LEVEL OF EVIDENCE: Level III, case-control study.

Ultrasonographic adrenal gland measurements in healthy Yorkshire Terriers and Labrador Retrievers.

An upper threshold of 7.4 mm for maximal adrenal gland diameter is commonly used to detect pituitary-dependent hyperadrenocorticism ultrasonographically in dogs. There is a substantial overlap between adrenal gland diameter of healthy dogs and of those with pituitary-dependent hyperadrenocorticism. The aim of this study is to determine the measurements of both adrenal glands, in particular, of the height at the caudal glandular pole in a longitudinal plane, in the Labrador retriever and Yorkshire terrier, two breeds widely represented in the population suspected of hyperadrenocorticism. Seventeen Labrador retrievers and 24 Yorkshire terriers considered healthy were included in the study. Adrenal gland measurements were taken on static images and comprised in measurements of the length in a longitudinal plane (L), of the height at the cranial (CrHLG) and caudal pole (CdHLG) in a longitudinal plane and in a transverse plane (CrHTR and CdHTR, respectively), and of the width at the cranial and caudal poles in a transverse plane (CrWTR and CdWTR, respectively). This study established new upper thresholds for the left and right height at the caudal pole measured in a longitudinal plane: 7.9 mm (left) and 9.5 mm (right) for the Labrador retrievers and 5.4 mm (left) and 6.7 mm (right) for the Yorkshire terriers. All the measurements were significantly different between the two breeds. There was a significant relationship between CdHTR and CdHLG, and the age of the dogs for both breeds.

Expression and functional analysis of Dkk1 during early gonadal development.

WNT signalling plays a central role in mammalian sex determination by promoting ovarian development and repressing aspects of testis development in the early gonad. Dickkopf homolog 1 (DKK1) is a WNT signalling antagonist that plays critical roles in multiple developmental systems by modulating WNT activity. Here, we examined the role of DKK1 in mouse sex determination and early gonadal development. Dkk1 mRNA was upregulated sex-specifically during testis differentiation, suggesting that DKK1 could repress WNT signalling in the developing testis. However, we observed overtly normal testis development in Dkk1-null XY gonads, and found no significant upregulation of Axin2 or Sp5 that would indicate increased canonical WNT signalling. Nor did we find significant differences in expression of key markers of testis and ovarian development. We propose that DKK1 may play a protective role that is not unmasked by loss-of-function in the absence of other stressors.

Knee arthodesis using a modular customized intramedullary nail.

INTRODUCTION: Arthrodesis of the knee, particularly in infectious situations, can be achieved using either an external fixator or an intramedullary device. The objective of this study is to report the clinical, functional, and radiographic outcomes of a continuous series of 19 cases of knee arthrodesis using a customized modular intramedullary nailing system. HYPOTHESIS: The modular intramedullary nail offers a satisfactory functional result while maintaining limb length, in spite of a nonunion risk, since acting like a true endoprosthesis. MATERIAL AND METHODS: In our retrospective series of 19 patients, the main source of patients were infected total knee replacements. The nail was customized from assembling a dual surface-sanded titanium component (femoral and tibial). The Lequesne Algofunctional score and the WOMAC score were recorded, as well as the length discrepancy between the lower extremities. Arthrodesis consolidation and the nail's fit in the shaft were verified on anterior-posterior (AP) and lateral radiographs. RESULTS: Five complications were observed: one anterior cortical break, one excessive tibial rotation, two cases of delayed union, and one nail revision due to residual nail instability. The postoperative Lequesne Algofunctional score was 13/24 and the WOMAC score 57/100. The nonunion rate was 32%. From a functional point of view, the patients who did not achieve complete union and those who did had similar scores. The subjective results were not as good in patients who did not achieve final consolidation. DISCUSSION: Modular intramedullary nailing simplifies the technique, shortens the procedure, and reduces the amount of blood loss at surgery. Our nonunion rate was high, although the functional result did not seem compromised by such nonunion. The risk of long-term implant failure was not studied and requires longer follow-up studies. LEVEL OF EVIDENCE: Level IV therapeutic study.