Lumbar plexus block in children: a comparison of two procedures in 50 patients

Two techniques for blocking the lumbar plexus were prospectively evaluated in 50 children undergoing surgery in the hip region and randomly allocated to one of two equal groups. A variant of the "psoas compartment block" and the classic technique were used in groups 1 (n = 25) and 2 (n = 25), respectively. All procedures were carried out under light general anesthesia with the patients in the lateral position using insulated needles and electrical stimulation. Both procedures were effective, allowing completion of surgery without additional treatment in almost all patients. However, the distribution of analgesia differed: 23 (ipsilateral) lumbar and sacral plexus blocks and 2 (ipsilateral) lumbar blocks alone were produced in group 2, compared to 22 areas of anesthesia comparable to those that might be associated with a lumbar epidural block and two ipsilateral lumbar plexus blocks in group 1. The two techniques are not, therefore, mere variants of the same basic approach to the lumbar plexus. The procedure described by Winnie et al. (Anesthesiol Rev 1974;1:11-6) was more suitable for providing unilateral blockade than the "psoas compartment block."     

Matched adaptations of electrophysiological, physiological, and histological properties of skeletal muscles in response to chronic hypoxia

This study tried to differentiate the consequences of chronic hypoxia on the electrophysiological and physiological properties and the histological characteristics of slow and fast muscles in rats. Animals inhaled a 10% O₂ concentration for a 1-month period. Then, slow [soleus (SOL)] and fast [extensor digitorum longus (EDL)] muscles were analyzed in vitro by physiological and electrophysiological measurements and histological analyses. The results were compared to those obtained in corresponding muscles of an age-matched normoxic group. After exposure to hypoxia: (1) in SOL, there was a tendency to elevated F_max, a significant increase in twitch force and tetanic frequency and a shortening of M-wave duration, and a reduced percentage of type I fibres, whereas the proportion of type IIa fibres doubled; (2) in EDL, F_max and tetanic frequency were lowered, the muscle became less resistant to fatigue, and the proportion of type IId/x fibres was halved. Then, after 1 month of hypoxia, in the SOL muscle, both the contractile and histological properties resemble those of a fast muscle. By contrast, the EDL became slower, despite its histology was modestly affected. Reduced muscle use in hypoxia could explain the tendency for deteriorating adaptations in EDL, and the faster properties of SOL could result from hypoxia-induced inhibition of the growth-related fast-to-slow shift in muscle fibre types.     

Influence of epidural anesthesia on postoperative nitrogen sparing in major digestive surgery

In order to determine the role of epidural anaesthesia on protein sparing, eighteen patients undergoing major visceral surgery were randomly divided into three different groups according to the mode of anaesthesia used (general anaesthesia, epidural anaesthesia, continuous epidural anaesthesia for 24 h). These patients were intravenously fed for five days postoperatively; their nitrogen balance was studied. Compared with the "general anaesthesia" group, only the daily averages of nitrogen balance of the "continuous epidural" group were significantly better. IN order to correlate stress with nitrogen saving, the early evolution of several parameters (cortisol, glucose, prolactin) used as "stress markers" was studied : there was no evidence of any significant difference between the three groups.     

Maternally acquired genotoxic Escherichia coli alters offspring’s intestinal homeostasis

The neonatal gut is rapidly colonized by a newly dominant group of commensal Escherichia coli strains among which a large proportion produces a genotoxin called colibactin. In order to analyze the short- and long-term effects resulting from such evolution, we developed a rat model mimicking the natural transmission of E. coli from mothers to neonates. Genotoxic and non-genotoxic E. coli strains were equally transmitted to the offspring and stably colonized the gut across generations. DNA damage was only detected in neonates colonized with genotoxic E. coli strains. Signs of genotoxic stress such as anaphase bridges, higher occurrence of crypt fission and accelerated renewal of the mature epithelium were detected at adulthood. In addition, we observed alterations of secretory cell populations and gut epithelial barrier. Our findings illustrate how critical is the genotype of E. coli strains acquired at birth for gut homeostasis at adulthood.     

Integrins protect sensory neurons in models of paclitaxel-induced peripheral sensory neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect from cancer treatment with no known method for prevention or cure in clinics. CIPN often affects unmyelinated nociceptive sensory terminals. Despite the high prevalence, molecular and cellular mechanisms that lead to CIPN are still poorly understood. Here, we used a genetically tractable Drosophila model and primary sensory neurons isolated from adult mouse to examine the mechanisms underlying CIPN and identify protective pathways. We found that chronic treatment of Drosophila larvae with paclitaxel caused degeneration and altered the branching pattern of nociceptive neurons, and reduced thermal nociceptive responses. We further found that nociceptive neuron-specific overexpression of integrins, which are known to support neuronal maintenance in several systems, conferred protection from paclitaxel-induced cellular and behavioral phenotypes. Live imaging and superresolution approaches provide evidence that paclitaxel treatment causes cellular changes that are consistent with alterations in endosome-mediated trafficking of integrins. Paclitaxel-induced changes in recycling endosomes precede morphological degeneration of nociceptive neuron arbors, which could be prevented by integrin overexpression. We used primary dorsal root ganglia (DRG) neuron cultures to test conservation of integrin-mediated protection. We show that transduction of a human integrin β-subunit 1 also prevented degeneration following paclitaxel treatment. Furthermore, endogenous levels of surface integrins were decreased in paclitaxel-treated mouse DRG neurons, suggesting that paclitaxel disrupts recycling in vertebrate sensory neurons. Altogether, our study supports conserved mechanisms of paclitaxel-induced perturbation of integrin trafficking and a therapeutic potential of restoring neuronal interactions with the extracellular environment to antagonize paclitaxel-induced toxicity in sensory neurons.

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent adverse effect of treatment in cancer patients and survivors (1). CIPN significantly impacts quality of life as damage to sensory nerves may be permanent, and is often a dose-limiting factor during cancer treatment (2–4). Patients with CIPN report pain-related symptoms, including allodynia, hyper- or hypoalgesia, or pain that can be more severe than the pain associated with the original cancer (4). Despite increasing data on agents that protect sensory nerves, our limited understanding of the mechanisms of CIPN impedes effective treatment (5). Studies from model systems may be helpful in identifying molecules that protect sensory neuron morphology and function from the effects of chemotherapeutics.In the present study, we explored the mechanisms of CIPN induced by paclitaxel using two established models: Drosophila larval nociceptive neurons (6, 7) and primary dorsal root ganglia (DRG) neurons isolated from adult mouse (8). Similar to other peripheral neuropathies, CIPN models using paclitaxel, bortezomib, oxaliplatin, and vincristine report changes in unmyelinated intraepidermal nerve fibers (IENFs) that detect painful or noxious stimuli (9–14). These small fibers are embedded in the epidermis, and continuously turn over coincident with the turnover of skin (9, 15). Drosophila class IV nociceptive neurons are a favored model for genetic studies of nociceptive neuron development and signaling mechanisms (16). Prior studies showed that class IV neuron morphology is sensitive to paclitaxel and demonstrated morphological changes of nociceptive neurons at the onset and the end stage of paclitaxel-induced pathology (6, 7). Specifically, chronic treatment of high doses (30 μM) induce fragmentation and simplification of branching of sensory terminals (6). Additionally, acute treatments of moderate doses (10 to 20 μM) induced hyperbranching of sensory arbors without changing the branch patterns or degeneration (7). Nociceptive neurons in Drosophila larvae detect multiple qualities of noxious stimuli (17, 18), and project naked nerve terminals that are partially embedded in the epidermis (19, 20). Larvae have a stereotyped behavioral response toward noxious stimuli that can serve as a readout of nociceptive neuron function (17, 21). Nociceptive neurons in Drosophila larvae may therefore serve as a good in vivo model to study morphological and functional changes to sensory neurons induced by chemotherapeutics.Paclitaxel binds to tubulin and prevents microtubule disassembly. It is a commonly used chemotherapeutic drug for treatment of solid cancers, such as breast, ovarian, and lung cancers, by virtue of its ability to inhibit cell division. Paclitaxel causes chronic sensory neuropathy in patients and animal models (22–24). Several CIPN animal and in vitro models have also revealed acute effects of paclitaxel (7, 8, 24–26). While the mechanisms of acute and chronic neurodegeneration are likely to be distinct (27), how long-term treatment of paclitaxel can affect sensory neuron morphology and function, and how neuronal arbors can be protected against long-term toxicity is not understood.Several studies have shown that nociceptive sensory terminals share a close relationship with specific extracellular structures, most notably epidermal cells and the extracellular matrix (ECM). Thus, in addition to direct effects on neurons, paclitaxel could conceivably destabilize terminals by disrupting relationships with the extracellular environment. Indeed, a study in zebrafish indicates that epidermal cells are directly affected by paclitaxel and that epidermal changes precede neuronal degradation, indicating that degradation of neuronal substrates contributes to degeneration of adjacent arbors (25). For the most part, however, extracellular contributions to neuropathy induced by chemotherapeutics are still poorly characterized. It is therefore important to determine how sensory terminals are maintained in the context of a dynamic extracellular environment that itself may be sensitive to chemotherapeutics. Integrins are a key mediator of the interaction between cells and the ECM, and impact dendrite stabilization and maintenance in both vertebrate and invertebrate systems (20, 28, 29). Prior studies in other systems indicate that integrin levels at the surface are maintained by continuous recycling via tight regulation of the endosomal pathway rather than degradation and de novo synthesis (30). Decreased recycling or increased degradation could lead to depletion of the surface receptors (31, 32) responsible for arbor maintenance and, in turn, degeneration of nociceptive terminals. We therefore explored whether integrin–ECM interactions may impact sensory neuron maintenance upon paclitaxel-induced toxicity and how the endosomal–lysosomal pathway may be linked to the maintenance of sensory neurons.Here, we have used Drosophila and isolated mouse DRG neurons to investigate the pathological effect of paclitaxel in sensory neurons. Morphological changes in Drosophila neurons occurred at paclitaxel doses that also caused changes in thermal nociceptive behaviors. Cell-specific overexpression of integrins protected nociceptive neurons from morphological alterations and prevented the thermal nociceptive behavior deficits caused by paclitaxel in Drosophila. Transduction of integrins also protected adult mouse DRG sensory neurons from paclitaxel-induced toxicity in vitro, indicating that integrin-mediated protection is conserved in a vertebrate model of CIPN. We provide evidence that paclitaxel alters intracellular trafficking in both Drosophila and mouse models of CIPN. Furthermore, our biochemical analysis indicates a reduction of integrin surface availability, suggesting paclitaxel-induced recycling defects in mouse DRG neurons in vitro. Our study suggests that altered interactions between sensory neurons and their extracellular environment are an important contributor to paclitaxel-induced neuronal pathology, and that preventing these changes may offer a therapeutic approach.     

Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Société Française de Greffe de Moelle (SFGM)

To assess the place of allogeneic hematopoietic stem cell transplantation (HSCT) in the advanced stage of acute myeloid leukemia (AML), we retrospectively analyzed 379 consecutive patients who underwent allogeneic HSCT for advanced AML. The median follow-up of the entire cohort was 7.5 years. Sixty-nine patients (18%) were transplanted with primary resistant disease. Three hundred and ten (82%) were relapsed patients, 94 (30%) of whom were in untreated relapse, 67 (22%) in refractory relapse and 149 (48%) in 2nd or 3rd complete remission at time of transplantation. The 5-year probabilities of overall survival (OS), disease-free survival (DFS), and transplant-related mortality (TRM) were 22 +/- 4%, 20 +/- 4%, 45 +/- 6%, respectively. In multivariate analysis, we demonstrated the favorable impact on OS, DFS and TRM of two factors over which we have no control (age <15 years, complete remission achievement) and three factors over which we have some control (female donor, acute and chronic graft-versus-host disease). The results of this study suggest that the graft-versus-leukemia effect is important in advanced AML and that new HSCT modalities are needed for some patients with this indication.     

Targeting the histone demethylase LSD1 prevents cardiomyopathy in a mouse model of laminopathy

LMNA mutations in patients are responsible for a dilated cardiomyopathy. Molecular mechanisms underlying the origin and development of the pathology are unknown. Herein, using mouse pluripotent embryonic stem cells (ESCs) and a mouse model both harboring the p.H222P Lmna mutation, we found early defects in cardiac differentiation of mutated ESCs and dilatation of mutated embryonic hearts at E13.5, pointing to a developmental origin of the disease. Using mouse ESCs, we demonstrated that cardiac differentiation of Lmna^H222P/+ was impaired at the mesodermal stage. Expression of Mesp1, a mesodermal cardiogenic gene involved in epithelial-to-mesenchymal transition of epiblast cells, as well as Snai1 and Twist expression, was decreased in Lmna^H222P/+ cells compared with WT cells in the course of differentiation. In turn, cardiomyocyte differentiation was impaired. ChIP assay of H3K4me1 in differentiating cells revealed a specific decrease of this histone mark on regulatory regions of Mesp1 and Twist in Lmna^H222P/+ cells. Downregulation or inhibition of LSD1 that specifically demethylated H3K4me1 rescued the epigenetic landscape of mesodermal Lmna^H222P/+ cells and in turn contraction of cardiomyocytes. Inhibition of LSD1 in pregnant mice or neonatal mice prevented cardiomyopathy in E13.5 Lmna^H222P/H222P offspring and adults, respectively. Thus, LSD1 appeared to be a therapeutic target to prevent or cure dilated cardiomyopathy associated with a laminopathy.     

How cerebral cortex protects itself from interictal spikes: The alpha/beta inhibition mechanism

Interactions between interictal epileptiform discharges (IEDs) and distant cortical regions subserve potential effects on cognition of patients with focal epilepsy. We hypothesize that “healthy” brain areas at a distance from the epileptic focus may respond to the interference of IEDs by generating inhibitory alpha and beta oscillations. We predict that more prominent alpha‐beta oscillations can be found in patients with less impaired neurocognitive profile. We performed a source imaging magnetoencephalography study, including 41 focal epilepsy patients: 21 with frontal lobe epilepsy (FLE) and 20 with mesial temporal lobe epilepsy. We investigated the effect of anterior (i.e., frontal and temporal) IEDs on the oscillatory pattern over posterior head regions. We compared cortical oscillations (5–80 Hz) temporally linked to 3,749 IEDs (1,945 frontal and 1,803 temporal) versus an equal number of IED‐free segments. We correlated results from IED triggered oscillations to global neurocognitive performance. Only frontal IEDs triggered alpha‐beta oscillations over posterior head regions. IEDs with higher amplitude triggered alpha‐beta oscillations of higher magnitude. The intensity of posterior head region alpha‐beta oscillations significantly correlated with a better neuropsychological profile. Our study demonstrated that cerebral cortex protects itself from IEDs with generation of inhibitory alpha‐beta oscillations at distant cortical regions. The association of more prominent oscillations with a better cognitive status suggests that this mechanism might play a role in determining the cognitive resilience in patients with FLE.