Observational study of a series of basal cell carcinomas: Evaluation of location as a risk factor for recurrence.

Basal cell carcinoma (BCC) is locally aggressive and its prognosis depends on the risk of recurrence. The initial location of the tumor is a key criterion for calculating the risk of recurrence. The aim of this study was to evaluate the sites that appear to be most at risk of recurrence of BCC. All cases of BCC analyzed at the anatomopathology laboratory of the University Hospital of Montpellier for 1 year were retrospectively included. In case of recurrence on the same site, only carcinomas that had previously been completely removed were analyzed. Among 803 BCC, 37 (4.6%) were confirmed as recurrent, including 34 (92%) on the head. The locations statistically at higher risk of recurrence were the temporal and frontal/temporal areas (32.4%), the medial canthus and lower eyelid area (18.9%), the ala and tip of the nose (16.2%), and the ears (8.1%). The frontal/temporal regions appear to be an area of major interest in this series. A high risk of recurrence was confirmed in the periorificial locations for the ear, the nose, and periorbital area, but not for the perioral area. In addition, the entire nose did not appear to be at risk, only the tip and the ala.

Disorder-Promoted Splitting in Quasiparticle Interference at Nesting Vectors.

Inelastic interactions of quantum systems with the environment usually wash coherent effects out. In the case of Friedel oscillations, the presence of disorder leads to a fast decay of the oscillation amplitude. Here we show both experimentally and theoretically that in three-dimensional topological insulator Bi2Te3 there is a nesting-induced splitting of coherent scattering vectors which follows a peculiar evolution in energy. The effect becomes experimentally observable when the lifetime of quasiparticles shortens due to disorder. The amplitude of the splitting allows an evaluation of the lifetime of the electrons. A similar phenomenon should be observed in any system with a well-defined scattering vector regardless of its topological properties.

GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons.

Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow glutamatergic transmission mediated by metabotropic receptor mGlu1 in midbrain dopamine neurons, whose dysfunction is a hallmark of schizophrenia. We found that an mGlu1 agonist elicits a slow depolarizing current in HEK cells co-expressing mGlu1 and GluD1, but not in cells expressing mGlu1 or GluD1 alone. This current is abolished by additional co-expression of a dominant-negative GluD1 dead pore mutant. We then characterized mGlu1-dependent currents in dopamine neurons from midbrain slices. Both the agonist-evoked and the slow postsynaptic currents are abolished by expression of the dominant-negative GluD1 mutant, pointing to the involvement of native GluD1 channels in these currents. Likewise, both mGlu1-dependent currents are suppressed in GRID1 knockout mice, which reportedly display endophenotypes relevant for schizophrenia. It is known that mGlu1 activation triggers the transition from tonic to burst firing of dopamine neurons, which signals salient stimuli and encodes reward prediction. In vivo recordings of dopamine neurons showed that their spontaneous burst firing is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant in wild-type mice. Our results de-orphanize GluD1, unravel its key role in slow glutamatergic transmission and provide insights into how GRID1 gene alterations can lead to dopaminergic dysfunctions in schizophrenia.

RACK1 cooperates with NRASQ61K to promote melanoma in vivo.

Melanoma is the deadliest skin cancer. RACK1 (Receptor for activated protein kinase C) protein was proposed as a biological marker of melanoma in human and domestic animal species harboring spontaneous melanomas. As a scaffold protein, RACK1 is able to coordinate the interaction of key signaling molecules implicated in both physiological cellular functions and tumorigenesis. A role for RACK1 in rewiring ERK and JNK signaling pathways in melanoma cell lines had been proposed. Here, we used a genetic approach to test this hypothesis in vivo in the mouse. We show that Rack1 knock-down in the mouse melanoma cell line B16 reduces invasiveness and induces cell differentiation. We have developed the first mouse model for RACK1 gain of function, Tyr::Rack1-HA transgenic mice, targeting RACK1 to melanocytes in vivo. RACK1 overexpression was not sufficient to initiate melanomas despite activated ERK and AKT. However, in a context of melanoma predisposition, RACK1 overexpression reduced latency and increased incidence and metastatic rate. In primary melanoma cells from Tyr::Rack1-HA, Tyr::NRasQ61K mice, activated JNK (c-Jun N-terminal kinase) and activated STAT3 (signal transducer and activator of transcription 3) acted as RACK1 oncogenic partners in tumoral progression. A sequential and coordinated activation of ERK, JNK and STAT3 with RACK1 is shown to accelerate aggressive melanoma development in vivo.

The cardioprotectant 3',4'-dihydroxyflavonol inhibits opening of the mitochondrial permeability transition pore after myocardial ischemia and reperfusion in rats.

The study aimed to determine the effect of 3',4'-dihydroxyflavonol (DiOHF) on mitochondrial function, in particular opening of the mitochondrial permeability transition pore (mPTP), respiratory function and reactive oxygen species (ROS) production, in isolated cardiac mitochondria after coronary artery occlusion and reperfusion in vivo. Opening of the mPTP, oxygen consumption and ROS production (assessed by measurement of H2O2) was determined in mitochondria isolated from normal hearts or from the ischemic zone of rat hearts subjected to 30min coronary artery occlusion and 15min reperfusion. Treatment of sham rats with DiOHF (10mgkg(-1) iv) significantly increased the concentration of Ca(2+) required to stimulate mPTP opening. This was accompanied by increased state 3 oxygen consumption and decreased H2O2 release. Ischemia and reperfusion (IR) significantly decreased the concentration of Ca(2+) required to stimulate mPTP opening, decreased state 3 oxygen consumption and increased H2O2 release, when pyruvate plus malate was provided as a substrate. Treatment with DiOHF prevented IR-induced changes in mPTP opening, state 3 oxygen consumption and H2O2 release so that there was no difference compared to sham. In isolated cardiac mitochondria from normal rats DiOHF had no effect on mPTP opening or on state 3 respiration but caused a small increase in state 4 respiration and decreased the respiratory control ratio. DiOHF, administered during ischemia just before reperfusion, inhibits mPTP opening and preserves mitochondrial function through a mechanism likely to be independent of its antioxidant activity or any direct effect on the mPTP.

Nicotine consumption is regulated by a human polymorphism in dopamine neurons.

Smoking is the most important preventable cause of morbidity and mortality worldwide. Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer. Several polymorphisms in the CHRNA3-CHRNA5-CHRNB4 cluster coding for the nicotinic acetylcholine receptor (nAChR) α3, α5 and ß4 subunits were implicated. In mouse models, we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). We first investigated the reinforcing effects of nicotine in drug-naive α5(-/-) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation. We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA, in general, or in DA neurons exclusively. Our results establish a crucial role for α5*-nAChRs in DAergic neurons. These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement. Finally, we demonstrate that a single-nucleotide polymorphism, the non-synonymous α5 variant rs16969968, frequent in many human populations, exhibits a partial loss of function of the protein in vivo. This leads to increased nicotine consumption in the self-administration paradigm. We thus define a critical link between a human predisposition marker, its expression in DA neurons and nicotine intake.

[Guillain-Barré syndrome heralding acute query fever]. / Syndrome de Guillain-Barré révélant une fièvre Q aiguë.

INTRODUCTION: Q fever is a polymorphic disease, which can induce neurological disturbances. The central nervous system is mainly involved while peripheral neuropathies are rare with less than 15 cases reported in the literature. CASE-REPORT: We report here a case of acute polyradiculoneuritis associated with acute Q fever, with favorable outcome after antibiotic and intravenous immunoglobulin therapies. CONCLUSION: Serologic tests for Coxiella burnetii should be performed in case of unusual polyradiculoneuritis with fever, headache and neuro-ophthalmologic disorders, even when environmental exposure is lacking, because Q fever requires specific antibiotic treatment and serological follow-up.

Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement.

Smoking is the most important preventable cause of mortality and morbidity worldwide. This nicotine addiction is mediated through the nicotinic acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within the ventral tegmental area (VTA), the key brain area responsible for the reinforcing properties of all drugs of abuse, nicotine acts on several different cell types and afferents. Identifying the precise action of nicotine on this microcircuit, in vivo, is important to understand reinforcement, and finally to develop efficient smoking cessation treatments. We used a novel lentiviral system to re-express exclusively high-affinity nAChRs on either dopaminergic (DAergic) or γ-aminobutyric acid-releasing (GABAergic) neurons, or both, in the VTA. Using in vivo electrophysiology, we show that, contrary to widely accepted models, the activation of GABA neurons in the VTA plays a crucial role in the control of nicotine-elicited DAergic activity. Our results demonstrate that both positive and negative motivational values are transmitted through the dopamine (DA) neuron, but that the concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons. This work identifies the GABAergic interneuron as a potential target for smoking cessation drug development.

Mycophenolate as induction therapy in lupus nephritis with renal function impairment.

BACKGROUND: Mycophenolate (MF) is effective as induction therapy for lupus nephritis (LN) in patients with normal renal function; however, little is known about its role in patients with impaired renal failure. The purpose of this study was to evaluate the response to MF in LN and its association with baseline renal function. METHODS: Data were obtained for 90 patients from 12 Spanish renal units who were receiving MF as induction therapy for LN. Patients were classified into 2 groups: group 1 (estimated glomerular filtration rate [eGFR] ≥60 ml/min/1.73 m(2)) and group 2 (eGFR <60 ml/min/ 1.73 m(2)). The primary outcome measure was the percentage of patients who achieved any response and its relationship with initial eGFR. The secondary outcome measures were the percentage of patients who achieved a complete response (CR) or partial response (PR) and the appearance of relapses during treatment and side effects. RESULTS: At initiation of MF treatment, there were no differences in the main parameters between group 1 (n = 63; eGFR 87 ± 23 ml/min/ 1.73 m(2)) and group 2 (n = 27; eGFR 44 ± 12 ml/min/1.73 m(2)). Exposure to prednisone and MF was similar. The percentages of patients who achieved a response in groups 1 and 2 were, respectively, 69.2 and 43.8% at 6 months and 81.3 and 73.7% at 12 months. CR was more frequent in group 1, whereas PR was similar in both groups. Four patients relapsed and side effects were unremarkable. CONCLUSIONS: MF is effective and safe as induction therapy for LN, and response is even achieved in patients with baseline renal impairment.

Jagged2 controls the generation of motor neuron and oligodendrocyte progenitors in the ventral spinal cord.

In the developing spinal cord, motor neurons (MNs) and oligodendrocytes arise sequentially from a common pool of progenitors. However, the genetic network responsible for this neurogenesis to gliogenesis switch is largely unknown. A transcriptome analysis identified the Notch ligand Jagged2 (JAG2) as a Sonic hedgehog-regulated factor transiently expressed in MN progenitors (pMNs). In vivo loss- and gain-of-function experiments show that JAG2 schedules the differentiation of the pMN progenitors. At early developmental stages, Olig2 expressing pMN progenitors that enter the differentiation pathway exclusively generate MNs. At these times, the activation of the Notch pathway by JAG2 maintains selected pMN progenitors in an undifferentiated state by two mechanisms; first it inhibits MN generation by reducing Olig2 proteins levels, and second it directly inhibits the premature generation of oligodendrocyte progenitors (OLPs) by maintaining high levels of Hes5. Later, extinction of JAG2 from the pMN results in the loss of Hes5 expression, heralding the gliogenic phase of pMN progenitors. Strikingly, downregulation of JAG2 in pMN progenitors is sufficient to promote the precocious generation of OLPs. Together these data provide evidence that JAG2 is a key regulator of the timely and ordered generation of two of the defining cell types in the spinal cord, MNs and OLPs.

Ultrafast and whole-body cooling with total liquid ventilation induces favorable neurological and cardiac outcomes after cardiac arrest in rabbits.

BACKGROUND: In animal models of cardiac arrest, the benefit afforded by hypothermia is closely linked to the rapidity of the decrease in body temperature after resuscitation. Because total liquid ventilation (TLV) with temperature-controlled perfluorocarbons induces a very rapid and generalized cooling, we aimed to determine whether this could limit the post-cardiac arrest syndrome in a rabbit model. We especially focused on neurological, cardiac, pulmonary, liver and kidney dysfunctions. METHODS AND RESULTS: Anesthetized rabbits were submitted to either 5 or 10 minutes of untreated ventricular fibrillation. After cardiopulmonary resuscitation and resumption of a spontaneous circulation, the animals underwent either normothermic life support (control) or therapeutic hypothermia induced by TLV. The latter procedure decreased esophageal and tympanic temperatures to 32°C to 33°C within only 10 minutes. After rewarming, the animals submitted to TLV exhibited an attenuated neurological dysfunction and decreased mortality 7 days later compared with control. The neuroprotective effect of TLV was confirmed by a significant reduction in brain histological damages. We also observed limitation of myocardial necrosis, along with a decrease in troponin I release and a reduced myocardial caspase 3 activity, with TLV. The beneficial effects of TLV were directly related to the rapidity of hypothermia induction because neither conventional cooling (cold saline infusion plus external cooling) nor normothermic TLV elicited a similar protection. CONCLUSIONS: Ultrafast cooling instituted by TLV exerts potent neurological and cardiac protection in an experimental model of cardiac arrest in rabbits. This could be a relevant approach to provide a global and protective hypothermia against the post-cardiac arrest syndrome.

[Myelodysplastic syndrome with erythroblastopenia]. / Syndromes myélodysplasiques érythroblastopéniques.

Myelodysplastic syndrome with erythroid hypoplasia or erythroblastopenia has not yet been clearly defined, and in most patients it is mistaken for acquired pure red cell aplasia. Including one additional patient reported in this article, a literature review revealed only 50 cases over the last 20 years. These patients were predominantly elderly males, all required regular packed red cell transfusions, and they had a poor prognosis, mainly because of acute transformation. The mechanisms of erythroid aplasia remain unclear. However, recent data suggest the association of an intrinsic stem cell defect with immunological implication.

Effects of enoxaparin preparations on thrombin generation and their correlation with their anti-FXa activity.

OBJECTIVE: Anticoagulant effect of LMWHs is monitored by anti-factor Xa (anti-FXa) activity assay. Since this test has several limitations, the aim of this study was to explore the activity of two LMWHs by thrombin generation assay (TG, which presents an overall picture of hemostatic balance) and its correlation with their anti-FXa activity. METHODS: In an open-label, randomized cross-over study, 40 mg of two enoxaparins, the original branded formulation (R) and another one, also marketed in Argentina (T), were daily injected subcutaneously, for 7 days, to 20 healthy volunteers, with a 7-day washout interval. Blood samples were collected before treatment and 180 minutes after the injection on days 3 and 7. TG in platelet-poor plasma activated with tissue factor was assessed by lag time (LT), time to peak (TTP), peak (PTG), and endogenous thrombin potential (ETP). Anti-FXa and anti-FIIa activities, free tissue factor pathway inhibitor (free TFPI), tissue plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1), and euglobulin lysis time (ELT) were also assayed. RESULTS: The mean (SD) anti-FXa (UI/ml) for T and R increased on days 3 and 7. LT and TTP were significantly prolonged by both LMWHs, with no differences between them. The mean ETP (nmol/L) for T and R at 3 and 7 days after treatment were significantly reduced when compared with basal values (p = 0.001 for all). On day 3, a significant correlation was shown between the variables describing TG and anti-FXa for T and R, without differences between them, for LT (r: 0.516 and 0486), ETP (r: 0.532 and 0.574), PEAK (r: 0.482 and 0.501), and TTP (r: 0.577 and 0.503), respectively. This correlation was also significant on day 7. Anti-FIIa activity and free TFPI increased significantly at 3 and 7 days for both LMWHs, without differences between them. R and T decreased ELT and PAI-1, but had no effect on t-PA. There were no differences between both LMWHs in routine hemostatic tests. No adverse events were reported. CONCLUSIONS: Correlation between TG and anti-FXa activity was good. Both enoxaparins induced similar change of coagulation parameters, with a significant increase in fibrinolytic activity.

[Synchronous detection of T-cell clonality and FIP1L1-PDGFRA fusion gene in a hypereosinophilic syndrome]. / Détection simultanée d'une clonalité T et d'un transcrit FIP1L1-PDGFRA au cours d'un syndrome hyperéosinophilique.

We report a 49-year-old man suffering from chronic hypereosinophilia whose biological tests revealed a gene rearrangement between FIP1L1 and PDGFRA as well as a T-cell clonality. After 1 year of therapy with imatinib mesylate (100 mg daily), the patient was clinically asymptomatic, the fusion transcript was undetectable using RTQ-PCR and no lymphoproliferative disorders occurred. This unique combination raises the question of the physiopathology of such a grey zone hypereosinophilia and their management.

[Macrophage activation syndrome as the presenting feature of a Hodgkin's lymphoma in an elderly patient]. / Syndrome d'activation macrophagique révélant une maladie de Hodgkin chez un sujet âgé.

Macrophage activation syndrome (MAS) is a rare immunological disorder, rapidly life-threatening in the absence of specific treatment. Malignant lymphoma is common cause of MAS, but Hodgkin's lymphoma has been rarely associated with MAS. We report a 79-year-old man who presented a MAS as the presenting feature of Hodgkin's lymphoma, with a rapidly fatal outcome. We discuss the usefulness of sCD25 and interleukine 18 assays when diagnosis is difficult to obtain. We also review the literature data related to Hodgkin's lymphoma-associated MAS.

Características clínicas de dos poblaciones diagnosticadas de enfermedad pulmonar obstructiva crónica por criterios espirométricos GOLD o por el límite inferior de la normalidad / Clinical characteristics of two populations diagnosed of chronic obstructive pulmonary disease with GOLD spirometric criteria or by lower limit of normality

Objetivo: Evaluar la relevancia clínica de modificar el criterio diagnóstico de enfermedad pulmonar obstructiva crónica (EPOC) utilizando el límite inferior de la normalidad (LIN) en una cohorte de pacientes diagnosticados de EPOC. Material y métodos: La población de estudio se reclutó entre pacientes previamente diagnosticados de EPOC por criterio GOLD y con un seguimiento previo por el médico responsable superior a un año. Resultados: Cuando la EPOC se definió por criterio LIN se identificaron pacientes con mayor repercusión clínica y funcional que cuando se utilizó el criterio GOLD. Los pacientes con EPOC por criterio LIN presentaban valores significativamente más bajos de volumen espiratorio forzado en el primer segundo (FEV1) sobre la capacidad vital forzada (FVC) FEV1/FVC: 0,52 (0,9) frente a 0,67 (0,2), p = 0,000; de FEV1: 49,5% (16,5) frente a 62% (14,2), p = 0,0000; de FVC 69,4 (18,7) frente a 73,3, p = 0,04; mayor grado de disnea valorada mediante la escala del Medical Research Council (MRC) 2,98 (1,1) frente a 2,67 (1,12), p = 0,003; un mayor número de exacerbaciones anuales 2,32 (1,5) frente a 1,84 (0,9), p = 0,001; más visitas a Urgencias 2,17 (1,6) frente a 1,45 (0,74), p = 0,001; y más ingresos hospitalarios 1,75 (1,2) frente a 1,1 (80,4), p = 0,005. Sin embargo, los pacientes no incluidos como EPOC por el criterio LIN presentaron grados clínicamente relevantes de disnea y un elevado consumo de recursos sanitarios. Utilizando el criterio del LIN para establecer el diagnóstico, la EPOC no se asoció con un incremento del riesgo cardiovascular, cerebrovascular ni del riesgo de enfermedad vascular periférica. Conclusiones: El uso del LIN como criterio para establecer el diagnóstico de EPOC, frente al criterio GOLD, excluye un elevado número de pacientes con repercusión clínica y con un elevado consumo de recursos sanitarios. El uso de este criterio no proporciona información adicional a la hora de establecer una posible relación entre EPOC y enfermedad vascular (AU)

Purpose: The purpose of this study has been to evaluate the clinical importance of modifying the COPD diagnostic criterion using the lower limit of normality (LLN) in a cohort of COPD diagnosed patients. Material and methods: The study population was recruited among patients previously diagnosed COPD with the GOLD criterion who had a previous follow-up by their attending position greater than one year. Results: When the COPD was defined by a LLN criterion, patients were identified with greater clinical and functional repercussion then when the GOLD criterion was used. The patients with COPD by the LLN criterion had significantly lower values of FEV1/FVC: 0.52 (0.9) vs 0.67 (0.2), p = 0.000; of FEV1: 49.5% (16.5) vs 62% (14.2), p = 0.0000; of FVC 69.4 (18.7) vs 73.3, p = 0,04; greater grade of dyspnea evaluated with the Medical Research Council (MRC) scale 2.98 (1.1) vs 2.67 (1.12), p = 0.003; a higher number of yearly exacerbations 2.32 (1.5) vs 1.84 (0.9), p = 0.001; more visits to the emergency service 2.17 (1.6) vs 1.45 (0.74), p = 0.001; and more hospital admissions 1.75 (1.2) vs 1.1 (80.4), p = 0.005. However, patients not included as COPD by the LLN criterion had clinically relevant grades of dyspnea and elevated use of health care resources. Using the LLN criterion to establish the diagnoses, COPD was not associated with an increased cardiovascular, cerebrovascular risk or risk of peripheral vascular disease. Conclusions: The use of the LLN as a criterion to establish the diagnosis of COPD versus the GOLD criterion excludes an elevated number of patients with clinical repercussions and with elevated use of health care resources. The use of this criterion does not provide additional information when establishing a possible relationship between COPD and vascular disease (AU)