Electrochemically promoted carbon-halide bond cleavage in 4-nitrobenzyl halides

This manuscript reports the study of the carbon-halide bond cleavage in 4-nitrobenzyl halides, taking special attention to the iodide and fluoride derivatives. The electrochemical reduction mechanism has been disclosed for both compounds by terms of cyclic voltammetry and controlled potential electrolysis. In the case of 4-nitrobenzyl iodide, a first one electron irreversible wave leads to the corresponding 4-nitrobenzyl radical and iodide. However, in the case of 4-nitrobenzyl fluoride, a first one-electron reversible wave appears at –1.02 vs. SCE followed by one electron irreversible wave. In this second electron transfer process, the cleavage of the C-F bond is taking place, so the bond cleavage reaction occurs at the dianion level. To disclose and understand the electrochemical reduction mechanisms that allows to obtain important thermodynamic and kinetic data that would help in the understanding of C-X bond cleavage. This type of bond dissociation reactions are involved in the metabolism pathways of the human body.

Hypertension portale et prise en charge de l'ascite [Management of ascites due to portal hypertension].

Portal hypertension is regularly encountered by the general practitioner. It is defined by an elevation of the porto-systemic pressure gradient, with complications such as ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, variceal bleeding, hypersplenism, hepatopulmonary syndrome or hepatic encephalopathy occuring when a significant elevation of this gradient is reached. Cirrhosis is the primary cause of portal hypertension in industrialized countries. Symptomatic portal hypertension carries a poor prognosis. Management should be initiated rapidly, including the identification and correction of any reversible underlying condition. Liver transplantation should be considered in advanced cases.

Modelling of non-linear viscoelastic tissues with bar elements

In this work we develop a viscoelastic bar element that can handle multiple rheo- logical laws with non-linear elastic and non-linear viscous material models. The bar element is built by joining in series an elastic and viscous bar, constraining the middle node position to the bar axis with a reduction method, and stati- cally condensing the internal degrees of freedom. We apply the methodology to the modelling of reversible softening with sti ness recovery both in 2D and 3D, a phenomenology also experimentally observed during stretching cycles on epithelial lung cell monolayers.

Funció gonadal en pacients obesos abans i després de cirurgia bariàtrica

Estudio observacional en 33 hombres obesos mórbidos sometidos a cirugía bariátrica con objetivo de analizar cambios del perfil gonadal tras pérdida de peso. La prevalencia de hipogonadismo basal (TT & 300 ng/dL y TL & 65 ng/dL) era 78,8% y 51,5%; y un año tras cirugía 6% y 15%. Al año de la cirugía se observó incremento de TT, TL, SHBG y FSH y disminución de estradiol y prolactina. La edad y PPP se asociaban significativa e independientemente al porcentaje de cambio de TT. El hipogonadismo asociado a hombres con obesidad mórbida es muy prevalente y reversible con pérdida ponderal.

The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the neuromodulation appropriateness consensus committee.

INTRODUCTION: The Neuromodulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society (INS) evaluated evidence regarding the safety and efficacy of neurostimulation to treat chronic pain, chronic critical limb ischemia, and refractory angina and recommended appropriate clinical applications. METHODS: The NACC used literature reviews, expert opinion, clinical experience, and individual research. Authors consulted the Practice Parameters for the Use of Spinal Cord Stimulation in the Treatment of Neuropathic Pain (2006), systematic reviews (1984 to 2013), and prospective and randomized controlled trials (2005 to 2013) identified through PubMed, EMBASE, and Google Scholar. RESULTS: Neurostimulation is relatively safe because of its minimally invasive and reversible characteristics. Comparison with medical management is difficult, as patients considered for neurostimulation have failed conservative management. Unlike alternative therapies, neurostimulation is not associated with medication-related side effects and has enduring effect. Device-related complications are not uncommon; however, the incidence is becoming less frequent as technology progresses and surgical skills improve. Randomized controlled studies support the efficacy of spinal cord stimulation in treating failed back surgery syndrome and complex regional pain syndrome. Similar studies of neurostimulation for peripheral neuropathic pain, postamputation pain, postherpetic neuralgia, and other causes of nerve injury are needed. International guidelines recommend spinal cord stimulation to treat refractory angina; other indications, such as congestive heart failure, are being investigated. CONCLUSIONS: Appropriate neurostimulation is safe and effective in some chronic pain conditions. Technological refinements and clinical evidence will continue to expand its use. The NACC seeks to facilitate the efficacy and safety of neurostimulation.

Analysis of significant factors influencing visual acuity in ocular syphilis.

BACKGROUND: The aim of this study is to determine whether statistical associations can be demonstrated in ocular syphilis between baseline clinical and laboratory parameters with visual acuity at presentation and with any change in visual acuity after treatment. METHODS: Charts of 26 patients (42 eyes) with ocular syphilis presenting to the Uveitis clinic of the Jules-Gonin Eye Hospital were reviewed. A baseline cross-sectional analysis was performed in order to identify any association between visual acuity at presentation and demographic, clinical or laboratory parameters. After treatment, any analogy between these parameters and a change in visual acuity was subsequently assessed in a series of univariate comparisons. RESULTS: The following factors were associated with worse initial visual acuity: severity of visual field impairment at presentation (p=0.012), macular oedema (p=0.004) and optic neuropathy (p=0.031). There was a borderline association with the presence of vasculitis on fluroangiography (p=0.072). Improvement in best corrected visual acuity after treatment was significantly associated with the presence of vasculitis on fluroangiography (p=0.005), neurosyphilis, according to lumbar puncture findings (p=0.037) and marginally with anterior uveitis (p=0.070). Inflammation relapse was associated with the coexistence of pain as presenting sign (p<0.001) and with a longer duration of symptoms prior to the initial visit (p=0.023). CONCLUSIONS: Severe ocular inflammation associated with vasculitis, vitritis or anterior uveitis in ocular syphilis would appear to be a reversible phenomenon that responds well to appropriate antibiotic treatment, resulting in improvement in visual acuity. Prompt treatment enables a good visual prognosis, while any delay in therapy increases the risk of subsequent relapse.

Inducible gene and shRNA expression in resident hematopoietic stem cells in vivo.

Hematopoietic stem cells (HSC) are probably the best understood somatic stem cells and often serve as a paradigm for other stem cells. Nevertheless, most current techniques to genetically manipulate them in vivo are either constitutive and/or induced in settings of hematopoietic stress such as after irradiation. Here, we present a conditional expression system that allows for externally controllable transgenesis and knockdown in resident HSCs, based on a lentiviral vector containing a tet-O sequence and a transgenic mouse line expressing a doxycyclin-regulated tTR-KRAB repressor protein. HSCs harvested from tTR-KRAB mice are transduced with the lentiviral vector containing a cDNA (i.e., Green Fluorescent Protein (GFP)) and/or shRNA (i.e., p53) of interest and then transplanted into lethally irradiated recipients. While the vector is effectively repressed by tTR-KRAB during homing and engraftment, robust GFP/shp53 expression is induced on doxycyclin treatment in HSCs and their progeny. Doxycylin-controllable transcription is maintained on serial transplantation, indicating that repopulating HSCs are stably modified by this approach. In summary, this easy to implement conditional system provides inducible and reversible overexpression or knock down of genes in resident HSCs in vivo using a drug devoid of toxic or activating effects.

Combined modality treatment with full-dose chemotherapy and concomitant boost radiotherapy for advanced head and neck carcinoma

Résumé Le but de cette étude est d'évaluer la faisabilité et l'efficacité d'un traitement des carcinomes pharyngo-laryngés avancés par combinaison de chimiothérapie intensive associé à une radiothérapie accélérée. Vingt-trois patients ont été inclus (age médian 54 ans, entre 35 et 70 ans). Les localisations tumorales étaient l'hypopharynx (n=7), base de langue (n=10), nasopharynx (n=2) ou l'oesophage proximal (n.1), ou sans porte d'entrée (n=3). Le traitement comprend trois cycles de chimiothérapie (cisplatin 100mg/m2 à J1 ; 5-FU 1000mg/m2 par jour pendant 5 jours en perfusion continue, précédé par de l'amifostine 910mg/m2 ; répété toutes les trois semaines). La radiothérapie concomitante, accélérée (dose totale de 70Gy en 6 semaines) a été débuté au premier jour du deuxième cycle de chimiothérapie. Vingt et un patients ont pu achever la radiothérapie. Dix-huit patients étaient en rémission complète à la fin du traitement. Avec un suivi médian de 45 mois, le taux de survie globale atteint 56% (95% Cl, 32-79%). Le contrôle loco-régional était de 71% (95% CI, 52-91%). La toxicité associée au traitement consistait en une insuffisance rénale réversible (≥grade II) chez 9 patients (43%) et une agranulocytose fébrile chez 9 patients (43%). Tous les patients ont présenté une mucite modérée à sévère (grade II/III) et 19 patients ont montré une toxicité cutanée de grade III. En conclusion, le traitement combiné de radiothérapie accélérée avec une chimiothérapie concomitante à base de Cisplatin/5-FU full-dose avec amifostine est faisable. La toxicité est importante mais reste maîtrisable dans le cadre d'un centre multidisciplinaire. Le taux de survie globale à 4 ans est prometteur, la recherche en vue de traitements moins toxiques doit se poursuivre. Abstract The purpose of this study was to evaluate the feasibility and efficacy of a treatment concept combining three cycles of full-dose chemotherapy (CT) with concomitant accelerated uninterrupted radiotherapy (RI). Twenty- three patients (median age: 54 years, range: 35-70) with locally advanced squamous cell carcinoma of the head and neck (SCCHN) were included. The primary tumor involved the hypopharynx (n=7), base of the tongue (n=10), nasopharynx (n=2) or upper esophagus (n=1) or its location was unknown (n=3). Treatment consisted of three cycles of chemotherapy (cisplatin 100 mg/m2 on day 1; 5-FU 1,000 mg/m2 per day for 5 days as a continuous infusion, preceded by amifostine 910 mg/m2). repeated every 3 weeks. Uninterrupted concomitant boost-accelerated RI (total dose of 70 Gy in 6 weeks) started together on day 1 of the second cycle. All but two patients received the full course of RT. Eighteen patients achieved complete remission (78%). At a median follow-up of 45 months the overall survival was 56% (95% c.i. 32-79%) and the loco-regional control 71% (95% c.i. 52-91%). Toxicity involved reversible renal insufficiency of grade II in 9 patients (39%) and neutropenic fever in 9 patients (39%). All patients suffered from moderate to severe mucositis (grade HMI), and 19 patients presented cutaneous toxicity grade III. Concomitant boost-accelerated RI combined with concurrent full-dose cisplatin/5-FU chemotherapy and amifostine is feasible with manageable, although substantial, toxicity. The overall survival of 4 years is promising. Newer regimens causing less acute mucosal and skin toxicity are needed.

Intrauterine devices and endometrial cancer risk : a pooled analysis of the Epidemiology of Endometrial Cancer Consortium

Intrauterine devices (IUDs), long-acting and reversible contraceptives, induce a number of immunological and biochemical changes in the uterine environment that could affect endometrial cancer (EC) risk. We addressed this relationship through a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We combined individual-level data from 4 cohort and 14 case-control studies, in total 8,801 EC cases and 15,357 controls. Using multivariable logistic regression, we estimated pooled odds ratios (pooled-ORs) and 95% confidence intervals (CIs) for EC risk associated with ever use, type of device, ages at first and last use, duration of use and time since last use, stratified by study and adjusted for confounders. Ever use of IUDs was inversely related to EC risk (pooled-OR = 0.81, 95% CI = 0.74-0.90). Compared with never use, reduced risk of EC was observed for inert IUDs (pooled-OR = 0.69, 95% CI = 0.58-0.82), older age at first use (≥35 years pooled-OR = 0.53, 95% CI = 0.43-0.67), older age at last use (≥45 years pooled-OR = 0.60, 95% CI = 0.50-0.72), longer duration of use (≥10 years pooled-OR = 0.61, 95% CI = 0.52-0.71) and recent use (within 1 year of study entry pooled-OR = 0.39, 95% CI = 0.30-0.49). Future studies are needed to assess the respective roles of detection biases and biologic effects related to foreign body responses in the endometrium, heavier bleeding (and increased clearance of carcinogenic cells) and localized hormonal changes.

Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin's lymphoma: results of a phase I study.

PURPOSE Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. This was a phase I study to determine the maximum-tolerated dose (MTD), safety, and preliminary efficacy of inotuzumab ozogamicin in an expanded MTD cohort of patients with relapsed or refractory CD22(+) B-cell non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS Inotuzumab ozogamicin was administered intravenously as a single agent once every 3 or 4 weeks at doses ranging from 0.4 to 2.4 mg/m(2). Outcomes included MTD, safety, pharmacokinetics, response, progression-free survival (PFS), and overall survival. Results Seventy-nine patients were enrolled. The MTD was determined to be 1.8 mg/m(2). Common adverse events at the MTD were thrombocytopenia (90%), asthenia (67%), and nausea and neutropenia (51% each). The objective response rate at the end of treatment was 39% for the 79 enrolled patients, 68% for all patients with follicular NHL treated at the MTD, and 15% for all patients with diffuse large B-cell lymphoma treated at the MTD. Median PFS was 317 days (approximately 10.4 months) and 49 days for patients with follicular NHL and diffuse large B-cell lymphoma, respectively. CONCLUSION Inotuzumab ozogamicin has demonstrated efficacy against CD22(+) B-cell NHL, with reversible thrombocytopenia as the main toxicity.

An exquisite cross-control mechanism among endothelial cell fate regulators directs the plasticity and heterogeneity of lymphatic endothelial cells.

Arteriovenous-lymphatic endothelial cell fates are specified by the master regulators, namely, Notch, COUP-TFII, and Prox1. Whereas Notch is expressed in the arteries and COUP-TFII in the veins, the lymphatics express all 3 cell fate regulators. Previous studies show that lymphatic endothelial cell (LEC) fate is highly plastic and reversible, raising a new concept that all 3 endothelial cell fates may co-reside in LECs and a subtle alteration can result in a reprogramming of LEC fate. We provide a molecular basis verifying this concept by identifying a cross-control mechanism among these cell fate regulators. We found that Notch signal down-regulates Prox1 and COUP-TFII through Hey1 and Hey2 and that activated Notch receptor suppresses the lymphatic phenotypes and induces the arterial cell fate. On the contrary, Prox1 and COUP-TFII attenuate vascular endothelial growth factor signaling, known to induce Notch, by repressing vascular endothelial growth factor receptor-2 and neuropilin-1. We show that previously reported podoplanin-based LEC heterogeneity is associated with differential expression of Notch1 in human cutaneous lymphatics. We propose that the expression of the 3 cell fate regulators is controlled by an exquisite feedback mechanism working in LECs and that LEC fate is a consequence of the Prox1-directed lymphatic equilibrium among the cell fate regulators.

Late removal of retrievable caval filters.

The advent of retrievable caval filters was a game changer in the sense, that the previously irreversible act of implanting a medical device into the main venous blood stream of the body requiring careful evaluation of the pros and cons prior to execution suddenly became a "reversible" procedure where potential hazards in the late future of the patient lost most of their weight at the time of decision making. This review was designed to assess the rate of success with late retrieval of so called retrievable caval filters in order to get some indication about reasonable implant duration with respect to relatively "easy" implant removal with conventional means, i.e., catheters, hooks and lassos. A PubMed search (www.pubmed.gov) was performed with the search term "cava filter retrieval after 30 days clinical", and 20 reports between 1994 and 2013 dealing with late retrieval of caval filters were identified, covering approximately 7,000 devices with 600 removed filters. The maximal duration of implant reported is 2,599 days and the maximal implant duration of removed filters is also 2,599 days. The maximal duration reported with standard retrieval techniques, i.e., catheter, hook and/or lasso, is 475 days, whereas for the retrievals after this period more sophisticated techniques including lasers, etc. were required. The maximal implant duration for series with 100% retrieval accounts for 84 days, which is equivalent to 12 weeks or almost 3 months. We conclude that retrievable caval filters often become permanent despite the initial decision of temporary use. However, such "forgotten" retrievable devices can still be removed with a great chance of success up to three months after implantation. Conventional percutaneous removal techniques may be sufficient up to sixteen months after implantation whereas more sophisticated catheter techniques have been shown to be successful up to 83 months or more than seven years of implant duration. Tilting, migrating, or misplaced devices should be removed early on, and replaced if indicated with a device which is both, efficient and retrievable.

High-dose intravenous immunoglobulin treatment and cerebral vasospasm : a possible mechanism of ischemic encephalopathy?

A 46-year-old woman with a severe polyradiculoneuropathy treated with high-dose intravenous immunoglobulin (IVIg) presented an encephalopathy with increased blood flow velocities of the middle cerebral arteries (MCAs) detected by transcranial Doppler (TCD) studies. The similitude between this observation and another case recently reported of a patient suffering from Guillain-Barré syndrome (GBS) and cerebral blood flow abnormalities after IVIg treatment prompted us to investigate the responsibility of the IVIg therapy in the genesis of these blood flow alterations. We studied therefore by TCD 10 consecutive patients who underwent this treatment for different reasons. In 1 case we observed an asymptomatic, spontaneously reversible increase in the blood flow velocities of the MCAs consistent with a vasospasm and occurring 3-10 days after completion of the therapy. Stroke and ischemic encephalopathy have been reported as possible complications of IVIg treatment. In the case under discussion, clinical events appeared shortly after the administration of the IVIg therapy and responded favorably to a treatment with nimodipine. Other etiopathogenic mechanisms, in particular a CNS vasculopathic process related to the GBS itself, have to be considered as well. Further studies, with a larger number of patients, are therefore needed to evaluate the underlying mechanisms of blood flow abnormalities occurring sometimes in GBS patients after IVIg treatment.

A TARBP2-dependent miRNA expression profile underlies cancer stem cell properties and provides candidate therapeutic reagents in Ewing sarcoma.

We have recently demonstrated that human pediatric mesenchymal stem cells can be reprogrammed toward a Ewing sarcoma family tumor (ESFT) cancer stem cell (CSC) phenotype by mechanisms that implicate microRNAs (miRNAs). Here, we show that the miRNA profile of ESFT CSCs is shared by embryonic stem cells and CSCs from divergent tumor types. We also provide evidence that the miRNA profile of ESFT CSCs is the result of reversible disruption of TARBP2-dependent miRNA maturation. Restoration of TARBP2 activity and systemic delivery of synthetic forms of either of two of its targets, miRNA-143 or miRNA-145, inhibited ESFT CSC clonogenicity and tumor growth in vivo. Our observations suggest that CSC self-renewal and tumor maintenance may depend on deregulation of TARBP2-dependent miRNA expression.

The Lausanne cohort Lc65+: a population-based prospective study of the manifestations, determinants and outcomes of frailty

BACKGROUND: Frailty is a relatively new geriatric concept referring to an increased vulnerability to stressors. Various definitions have been proposed, as well as a range of multidimensional instruments for its measurement. More recently, a frailty phenotype that predicts a range of adverse outcomes has been described. Understanding frailty is a particular challenge both from a clinical and a public health perspective because it may be a reversible precursor of functional dependence. The Lausanne cohort Lc65+ is a longitudinal study specifically designed to investigate the manifestations of frailty from its first signs in the youngest old, identify medical and psychosocial determinants, and describe its evolution and related outcomes. METHODS/DESIGN: The Lc65+ cohort was launched in 2004 with the random selection of 3054 eligible individuals aged 65 to 70 (birth year 1934-1938) in the non-institutionalized population of Lausanne (Switzerland). The baseline data collection was completed among 1422 participants in 2004-2005 through questionnaires, examination and performance tests. It comprised a wide range of medical and psychosocial dimensions, including a life course history of adverse events. Outcomes measures comprise subjective health, limitations in activities of daily living, mobility impairments, development of medical conditions or chronic health problems, falls, institutionalization, health services utilization, and death. Two additional random samples of 65-70 years old subjects will be surveyed in 2009 (birth year 1939-1943) and in 2014 (birth year 1944-1948). DISCUSSION: The Lc65+ study focuses on the sequence "Determinants --> Components --> Consequences" of frailty. It currently provides information on health in the youngest old and will allow comparisons to be made between the profiles of aging individuals born before, during and at the end of the Second World War.