High-concentration topical capsaicin in the management of refractory neuropathic pain in patients with neurofibromatosis type 1: a case series.

AIM: The aim of this case series was to report the use of 8% topical capsaicin patch (marketed under the trade name Qutenza®) a in the management of refractory neuropathic pain (NP) in adult patients with type 1 neurofibromatosis (NF1). METHODS: Capsaicin has been suggested for NF1 patients suffering from refractory peripheral NP despite several years of analgesic treatments. The patch was applied for 60 minutes on the painful area, with tolerability control (blood pressure, intensity of pain and dermal reaction). The evaluation was done at the beginning of treatment and during the 2 months following the first treatment (phone calls at weeks 1, 2, 4 and 8). The primary efficacy criterion was the response rate: a patient was considered to be responding if he or she reported an average relief ≥30% at the time of the follow-up calls. The secondary criteria were: interference scores (QCD), Patient Global Impression of Change (PGIC) and overall treatment satisfaction, self-reported by the patient. RESULTS: Eight patients (5 females/3 males, 41.8 ± 8.2 years of age) received a first treatment with capsaicin. Patients had pre-existing pain for 6.6 years (±6.0) and were currently receiving an average of 6.1 (±3.9) different analgesics. The response rate was 37.5%. The three responders felt globally improved and satisfied, with the improvement in overall condition as interference scores decreased. Apart from the expected local reactions, the treatment was not accompanied by systemic side effects. CONCLUSIONS: As suggested in this case series, capsaicin provided pain relief in certain NF1 patients with resistant NP. The response rate is that expected in multi-line refractory NP. A significant benefit on the overall condition of some patients was observed. In addition, this topical treatment is administered every 3 months without systemic effects. This study is limited by the small number of patients, but was intended to describe a new and well tolerated alternative treatment.

Analgesic effects of navigated motor cortex rTMS in patients with chronic neuropathic pain.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) can relieve neuropathic pain when applied at high frequency (HF: 5-20 Hz) over the primary motor cortex (M1), contralateral to pain side. In most studies, rTMS is delivered over the hand motor hot spot (hMHS), whatever pain location. Navigation systems have been developed to guide rTMS targeting, but their value to improve rTMS efficacy remains to be demonstrated. OBJECTIVE: To compare the analgesic efficacy of HF-rTMS targeting the hMHS (non-navigated procedure) or the M1 representation of the pain region (navigated procedure). METHODS: The analgesic effect of a single session of 10 Hz-rTMS of M1 was assessed in 66 patients with neuropathic pain of various causes and locations, according to three conditions: sham or active non-navigated rTMS of the hMHS and active navigated rTMS of the pain region. RESULTS: Pain was relieved by both active rTMS conditions, and not by sham. Pain location influenced the results: upper or lower limb pain was significantly relieved, but not facial or hemibody pain. Pain relief lasted 1 week only after navigated rTMS, compared to sham. CONCLUSION: Navigation may improve HF-rTMS efficacy in patients with limb pain, whereas targeting remains to be optimized for more diffuse or facial pain. WHAT DOES THIS STUDY ADD?: To produce analgesic effects, HF-rTMS should be applied over the precentral cortex contralaterally to the painful side. Although the hMHS is the target normally chosen for stimulation, the optimal target has not been defined yet. Neuronavigational methods have been recently developed; they allow the integration of MRI data and are thought to improve rTMS efficacy.

Analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex in neuropathic pain: influence of theta burst stimulation priming.

BACKGROUND: 'Conventional' protocols of high-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to M1 can produce analgesia. Theta burst stimulation (TBS), a novel rTMS paradigm, is thought to produce greater changes in M1 excitability than 'conventional' protocols. After a preliminary experiment showing no analgesic effect of continuous or intermittent TBS trains (cTBS or iTBS) delivered to M1 as single procedures, we used TBS to prime a subsequent session of 'conventional' 10 Hz-rTMS. METHODS: In 14 patients with chronic refractory neuropathic pain, navigated rTMS was targeted over M1 hand region, contralateral to painful side. Analgesic effects were daily assessed on a visual analogue scale for the week after each 10 Hz-rTMS session, preceded or not by TBS priming. In an additional experiment, the effects on cortical excitability parameters provided by single- and paired-pulse TMS paradigms were studied. RESULTS: Pain level was reduced after any type of rTMS procedure compared to baseline, but iTBS priming produced greater analgesia than the other protocols. Regarding motor cortex excitability changes, the analgesic effects were associated with an increase in intracortical inhibition, whatever the type of stimulation, primed or non-primed. CONCLUSIONS: The present results show that the analgesic effects of 'conventional' 10 Hz-rTMS delivered to M1 can be enhanced by TBS priming, at least using iTBS. Interestingly, the application of cTBS and iTBS did not produce opposite modulations, unlike previously reported in other systems. It remains to be determined whether the interest of TBS priming is to generate a simple additive effect or a more specific process of cortical plasticity.

[Long term persistence of yellow fever neutralising antibodies in elderly persons]. / Persistance à long terme des anticorps neutralisants de la fièvre jaune chez les personnes âgées de 60 ans et plus.

The activity of the yellow fever virus is reemerging in areas without recent transmission history, such as northern Argentina and Paraguay, and persists in an epidemic mode in other countries in Africa and Latin America. Thus more and more travelers are at risk of being exposed to this disease. The population is becoming older, sometimes suffering from multiple pathologies. Moreover, the risk of serious adverse events associated with live-attenuated YF17D vaccine, such as multiple organ failure (YEL-AVD), reaches 1/50,000 vaccines in people over 65 versus 1/200,000 in the general population. We analyzed, in a retrospective study, the results of neutralizing antibody titers against yellow fever in people aged 60 and older, who had been previously vaccinated against yellow fever and had visited the International Vaccination Centre of the Institut Pasteur between January 2005 and February 2009. In this population of 84 persons (median age 69 years), the date of the last vaccination was always more than 10 years: it was precisely known in 68 subjects and alleged in 16 subjects. The median time since the previous vaccination was 14 years, with a maximum of 60 years. The indications of serology were: immunosuppressive therapy (19% of cases), cancer (32%), hemopathy (10.7%), HIV infection (3.6%), chronic hepatitis/chronic renal failure/dialysis (2.4%), autoimmune diseases (2.4%), and in 29.8% of cases, age alone was the indication of serology. The antibody titer was at a protective level in 95.2% of cases. The four individuals with negative serology had no formal documented proof of a previous vaccination against yellow fever. This serological study was able to show a persistent protective antibody titer, after a previous vaccination, even going back 60 years, allowing patients to travel in a yellow-fever endemic area despite a contraindication, and without requiring any vaccine booster.

[The relevance of diagnostic criteria for latent tuberculosis before initiation of TNF-alpha inhibitors in psoriasis patients]. / Pertinence des critères diagnostiques de tuberculose latente avant traitement du psoriasis par anti-TNF-alpha.

BACKGROUND: Initiation of anti-TNF-alpha therapy requires prior screening for and treatment of tuberculosis. Diagnosis of relating to tuberculosis is based primarily on measurement of the papule induced by intradermal reaction to tuberculin (IDR). In this article, we discuss the validity of this criterion and the potential consequences of its use in relation to 15 patients. PATIENTS AND METHODS: This was a retrospective case study of patients presenting psoriasis and eligible for antibiotic therapy in whom latent tuberculosis was diagnosed and who received combined prophylactic antitubercular treatment for three months. All patients underwent thorough questioning and clinical examination, chest x-ray and QuantiFERON (QTF) testing, and all except one were tested for IDR. RESULTS: Thirteen patients were considered carriers of latent tuberculosis based on IDR greater than 5 mm, and on positive QTF for two others, one of whom had a documented history of primary tubercular infection. Six of these 15 patients (40%) developed hepatic cytolysis ascribable to their antitubercular treatment. DISCUSSION: Analysis of the respective characteristics of the IDR and QTF tests showed that only five of the 15 patients in our study were in fact presenting authentic latent tuberculosis, thereby suggesting that the diagnostic criteria for latent tuberculosis recommended by the French Medicines Agency (AFSSAPS), which are based solely on the size of the papule arising from IDR, are unsuitable for patients with psoriasis pending anti-TNF therapy. In our view, screening for latent tuberculosis in this patient population should involve both IDR for its sensitivity and QTF for its specificity, thereby avoiding overdiagnosis of tuberculosis leading to pointless exposure of patients to the risk of hepatic toxicity associated with antitubercular medication. CONCLUSION: We strongly recommend a change in the recommendations for prevention of tuberculosis by antibiotic therapy in patients with psoriasis, and that the review panels should include at least one dermatologist.

[Long-term seroprotection against Japanese encephalitis using an inactivated vaccine (Jevax)]. / Séroprotection à long terme avec le vaccin inactivé contre l'encéphalite japonaise (Jevax).

Japanese encephalitis vaccine (Jevax) is an inactivated vaccine using the Nakayama viral strain. Until 2007, Jevax was the only Japanese encephalitis vaccine available in France but the duration of seroprotection after vaccination and exact timing of booster injections was unclear for travelers from non-endemic areas. The purpose of this report is to describe the results of a retrospective study in which neutralizing antibody levels were measured in 71 subjects previously vaccinated with Jevax. All subjects underwent testing at the Pasteur Institute Medical Center as part of preparation for humanitarian missions to endemic Japanese encephalitis areas in 2005-2006. A neutralizing antibody level greater than or equal to 20 was considered as protective. Findings showed that 49 of the 71 subjects (69%) still had protective antibody levels at a median of 4 years after the last Jevax immunization. In multivariate analysis, the only factor correlated with long-term seroprotection was the total number of vaccinations received. Based on these findings, it was concluded that long-term seroprotection after Jevax vaccination requires repeated booster injections even in subjects frequently exposed to the virus. No correlation was found between seroprotection and the interval between the booster injections.

Comparison of "standard" and "navigated" procedures of TMS coil positioning over motor, premotor and prefrontal targets in patients with chronic pain and depression.

Since about 15 years, transcranial magnetic stimulation (TMS) is used as a technique to investigate the function of specific cortical regions. Single pulse TMS studies have targeted the dorsolateral premotor cortex (dlPMC) to characterize premotor-motor interactions in movement disorders. Repetitive TMS (rTMS) trials have targeted the dorsolateral prefrontal cortex (dlPFC) to treat depression. In almost all previous studies, these targets have been defined according to a "standard" scalp distance to the site of stimulation evoking motor responses of maximal amplitude in the contralateral hand ("hand motor hotspot" corresponding to the primary motor cortex, M1). The "standard" procedure of coil positioning locates the dlPMC and dlPFC as 2-3 and 5cm, respectively, anterior to the "hand motor hotspot". The aim of our study was to compare the locations of M1, dlPMC and dlPFC targets provided by the "standard" procedure of coil positioning and those provided by using a neuronavigation system integrating individual brain magnetic resonance imaging (MRI). Twenty-two patients were enrolled, all being treated for depressive symptoms in the context of chronic pain syndrome. The centers of the dlPMC and dlPFC regions were accurately targeted by the "standard" procedure in 14 and eight patients (64 and 36% of the series), respectively. In the other patients, the "standard" procedure located the dlPMC target on the M1/dlPMC border and the dlPFC target on the dlPMC/dlPFC border. On average, the MRI-guided location of M1, dlPMC, and dlPFC was, respectively, 6.1mm posterior, 31.7mm anterior and 69.0mm anterior to the "hand motor hotspot". The "standard" procedure failed to accurately locate the dlPMC and dlPFC targets by about 1 and 2cm, respectively. A statistical analysis of the MRI coordinates (x, y, z) of the targets revealed that the M1 target was more posterior, the dlPMC target more superficial and the dlPFC target more anterior, lateral, and deeper, using neuronavigation compared to the "standard" procedure. This study confirms that the "standard" procedure of coil positioning is not accurate to target a desired cortical region. Target location can be improved by the use of a navigation system taking individual brain anatomy into account. The present results incline to be cautious on the pathophysiological interpretations of previous results reported in TMS studies based on "standard" targeting, e.g. regarding premotor-motor interactions. Similarly, the inaccuracy of the "standard" procedure of coil positioning could partly explain the between-study variability of the therapeutic effects produced by rTMS in patients with depression. Our results strongly support a more anterior and lateral placement of the TMS coil for dlPFC stimulation in the treatment of depression.

SIVMAC Vpx improves the transduction of dendritic cells with nonintegrative HIV-1-derived vectors.

Lentiviral vector (LV)-mediated gene therapy bears an intrinsic risk of insertional mutagenesis following integration into the host genome. Nonintegrative LVs may offer an alternative avenue at least in nondividing cells where episomal viral DNA persists stably. Owing to their central role in immune system functions, differentiated dendritic cells (DCs) offer an interesting cell target for these vectors. We have previously described that the transduction of DCs with wild-type HIV-1-derived vectors can be considerably improved by providing DCs with noninfectious virion-like particles (VLPs) carrying Vpx (Vpx-VLPs), a nonstructural protein coded by members of the SIV(SM)/HIV-2 lineage that removes a specific restriction to lentiviral infection in these cells. Here, we describe that the transduction efficiency of DCs with nonintegrative HIV-1 vectors can also be improved via Vpx-VLPs that promote the accumulation of complete and episomal viral DNA. In this setting, Vpx increases both the number of transduced cells and the levels of transgene expression. Thus, these results describe a simple procedure by which transduction of differentiated DCs can be achieved at low viral inputs with safer LVs to improve both the number of transduced cells and the levels of transgene expression.

Bidisperse granular avalanches on inclined planes: a rich variety of behaviors.

Experiments were performed to provide insight into the flow behavior and structure of bimodal mixtures of grains in gravity-driven, free-surface flows. Unsteady unconfined flows were produced by releasing instantaneously a dry granular mass, composed of two particle sizes, over a rough inclined plane. As a result of size segregation, the small particles are found at the bottom of the flow and final deposit, the large particles are found at the free surface, but also on the lateral borders and at the front of the flow. The lateral and vertical inhomogeneous repartitions of particles lead to two main effects that are completely absent in monodispersed flows. The outline effect results from the accumulation of large beads on the periphery of the flow depending on the value of the relative friction of each particle species on the plane. This effect in turn causes a narrowing of the flow and/or an increase of length of the final deposit. The interface effect results of the interaction between layers of different size particles and causes the modification of the thickness of the deposit. These effects occur simultaneously and their combination leads to a great variety of behaviors. In this investigation, evidence of the diversity of behaviors is presented as the size ratio, relative friction and concentration of each particle species are varied.

The skin allergenic properties of chemicals may depend on contaminants--evidence from studies on coumarin.

BACKGROUND/AIMS: Positive patch tests are considered representative of a contact allergy to the tested chemical. However, contaminants and derivatives rather than the suspected chemical itself could be responsible for the allergic skin reactions. Here, we tested the importance of contaminants in the sensitizing and allergenic properties of coumarin in mice and humans. Coumarin, an ingredient in cosmetics and fragrances, was chosen as the reference chemical since conflicting results have been obtained regarding its ability to induce contact allergy. In some chemical preparations, this could be explained by the presence of coumarin derivatives endowed with allergenic properties. METHODS: In mice, three different coumarin preparations were tested in the local lymph node assay. In humans, we assessed the irritant and allergenic properties of highly pure coumarin in nonallergic and fragrance-allergic patients. RESULTS: Pure coumarin did not exhibit irritant or sensitizing properties in the local lymph node assay. In contrast, two other commercially available coumarins and three contaminants that were detected in these coumarin preparations were identified as weak and moderate sensitizers, respectively. In humans, pure coumarin was extremely well tolerated since only 1 out of 512 patients exhibited a positive patch test to the chemical. CONCLUSIONS: These results indicate that coumarin cannot be considered as a common contact allergen and further emphasize that purity of chemicals is mandatory for the assessment of their allergenicity.

With a little help from a friend: increasing HIV transduction of monocyte-derived dendritic cells with virion-like particles of SIV(MAC).

Modification of dendritic cells (DCs) is a promising avenue for gene therapy purposes, given the versatility and the multiplicity of functions of these cells. In this study, we show that preincubation of monocyte-derived DCs with low amounts of non-infectious virion-like particles derived from the simian immunodeficiency virus (SIV(MAC) VLPs) increases up to 10-fold the efficiency of transduction by HIV-1 lentiviral vectors at low multiplicity of infections yielding up to 90% of transduced cells, in the absence of alterations of DCs behavior. This effect is restricted to DCs and specified by the viral accessory protein Vpx. Thus, preincubation with empty VLPs of SIV(MAC) can be used in transduction protocols to increase the efficacy of HIV-1-mediated modification of DCs.