Rational treatment of chemotherapy-induced peripheral neuropathy with capsaicin 8% patch: from pain relief towards disease modification

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) with associated chronic pain is a common and disabling condition. Current treatments for neuropathic pain in CIPN are largely ineffective, with unfavorable side-effects. The capsaicin 8% patch (capsaicin 179 mg patch) is approved for the treatment of neuropathic pain: a single topical cutaneous application can produce effective pain relief for up to 12 weeks. We assessed the therapeutic potential of capsaicin 8% patch in patients with painful CIPN, and its mechanism of action. Patients and methods: 16 patients with chronic painful CIPN (mean duration 2.5 years), in remission for cancer and not receiving chemotherapy, were treated with 30 min application of capsaicin 8% patch to the feet. Symptoms were monitored using the 11-point numerical pain rating scale (NPRS), and questionnaires. Investigations were performed at baseline and three months after patch application, including skin biopsies with a range of markers, and quantitative sensory testing (QST). Results: Patients reported significant reduction in spontaneous pain (mean NPRS: −1.27; 95% CI 0.2409 to 2.301; p=0.02), touch-evoked pain (−1.823; p=0.03) and cold-evoked pain (−1.456; p=0.03). Short-Form McGill questionnaire showed a reduction in neuropathic (p=0.0007), continuous (p=0.01) and overall pain (p=0.004); Patient Global Impression of Change showed improvement (p=0.001). Baseline skin biopsies showed loss of intra-epidermal nerve fibers (IENF), and also of sub-epidermal nerve fibers quantified by image analysis. Post-patch application skin biopsies showed a significant increase towards normalization of intra-epidermal and sub-epidermal nerve fibers (for IENF: structural marker PGP9.5, p=0.009; heat receptor TRPV1, p=0.027; regenerating nerve marker GAP43, p=0.04). Epidermal levels of Nerve Growth Factor (NGF), Neurotrophin-3 (NT-3), and Langerhans cells were also normalized. QST remained unchanged and there were no systemic side-effects, as in previous studies. Conclusion: Capsaicin 8% patch provides significant pain relief in CIPN, and may lead to regeneration and restoration of sensory nerve fibers ie, disease modification

Etude observationnelle sur l’hémovigilance transfusionnelle à Kinshasa, République Démocratique du Congo: Haemovigilance in blood transfusion: an observational study from Kinshasa, the Democratic Republic of the Congo

Context and objective. Although most countries in sub-Saharan Africa have transfusion centers, haemovigilance data are paradoxically scarce. The objective of the present study was to identify the recipient adverse effect (RAT) of blood transfusion. Methods. We conducted a cross-sectional observational study in two blood transfusion centers in Kinshasa, between July and November 2015. The general principles of haemovigilance during the transfusion episode were observed to identify the EIR. On each blood product, bacteriological, immunological, serological and parasitic analyzes were systematically performed. Results. 346 subjects were enrolled (female, 53.2%).The overall frequency of RAT during transfusion was 2.9%. It was most commonly urticaria (5 cases), pruritus (4 cases), fever (3 cases) and vomiting (3 cases). Control tests on patients with RAT yielded the following results: 2 seropositive for Human Immunodeficiency Virus (HIV), 2 seropositive for Hepatitis C virus (HVC), and 1 seropositive for Rapid Plasma Reagent (RPR) test. Conclusion. RAT is relatively common in Kinshasa due partially to compatibility error. The observance of the protocols of haemovigilance system is not optimal in both hospitals studied. A large multicenter study should be performed to better identify the concerns and thus secure blood products. Contexte et objectif. Bien que la plupart de pays d’Afrique subsaharienne aient de centres transfusionnels, mais les données sur l’hémovigilance sont paradoxalement fragmentaires. L’objectif de la présente étude était d’identifier l’effet indésirable du receveur (EIR) transfusionnel. Méthodes. Nous avons réalisé une étude observationnelle transversale dans deux centres de transfusion sanguine à Kinshasa, entre juillet et novembre 2015.Les principes généraux de l’hémovigilance au cours de l’épisode transfusionnel ont été observés en vue d’identifier l’EIR. Pour tout cas d’EIR, le contrôle du groupe sanguin, des analyses bactériologique, immunologique (test de compatibilité), sérologique et parasitaire ont été systématiquement effectués dans la poche du produit sanguin labile (PSL) et du receveur. Résultats.346 sujets ont été enrôlés (sexe féminin, 53,2%).La fréquence globale d’EIR durant la transfusion a été de 2,9%.Il s’agissait de l’urticaire (5 cas), d’un prurit (4 cas), de la fièvre (3 cas) et de vomissements (3 cas). Alors qu’en milieu alcalin, tous les tests étaient compatibles, deux cas d’incompatibilités ont été observés à la fois en milieu albumineux et de Coombs. Après contrôle de qualité des cas ayant présenté l’EIR, 5 PSL de donneurs se sont révélés positifs (HIV, 2 cas ; HVC, 2 cas et rapid plasma reagen test, RPR, 1 cas). Conclusion. L’EIR est relativement fréquente à Kinshasa due en partie par une erreur de compatibilité. L’observance des protocoles du système de l’hémovigilance n’est pas optimale dans les deux formations étudiées. Une étude multicentrique à grande échelle est à envisager pour mieux identifier les écueils de l’hémovigilance et ainsi sécuriser les PSL

Reversing painful and non-painful diabetic neuropathy with the capsaicin 8% patch: Clinical evidence for pain relief and restoration of function via nerve fiber regeneration

Introduction: Current oral treatments for pain in diabetic peripheral neuropathy (DPN) do not affect the progression of DPN i.e. “disease modification”. We assessed whether Capsaicin 8% patch treatment can provide pain relief and also restore nerve density and function via nerve regeneration, in both painful (PDPN) and non-painful (NPDPN) diabetic peripheral neuropathy. Methods: 50 participants with PDPN were randomized to receive Capsaicin 8% patch Qutenza with Standard of Care (SOC) (PDPN Q+SOC group), or SOC alone (PDPN SOC group). Pain symptoms were assessed with a diary (Numerical Pain Rating Scale, NRPS) and questionnaires. Investigations included quantitative sensory testing (QST) and distal calf skin biopsies, at baseline and 3 months after baseline visit; subsequent options were 3-monthly visits over 1 year. 25 participants with NPDPN had tests at baseline, and 3 months after all received Capsaicin 8% patch treatment. Results: At 3 months after baseline, PDPN Q+SOC group had reduction in NPRS score (p=0.0001), but not PDPN SOC group. Short-Form McGill Pain Questionnaire (SF-MPQ) showed significant reductions in scores for overall and other pain descriptors only in the PDPN Q+SOC group. Warm perception thresholds were significantly improved only in the PDPN Q+SOC group (p=0.02), and correlated with reduction in SF-MPQ overall pain score (p=0.04). NPDPN Q+SOC group did not report pain during the entire study. Density of intra-epidermal nerve fibres (IENF) with PGP9.5 was increased at 3 months in PDPN Q+SOC (p=0.0002) and NPDPN Q+SOC (p=0.002) groups, but not in the PDPN SOC group. Increased sub-epidermal nerve fibres (SENF) were observed with GAP43 (marker of regenerating nerve fibres) only in PDPN Q+SOC (p=0.003) and NPDPN Q+SOC (p=0.0005) groups. Pain relief in the PDPN Q+SOC group was correlated with the increased PGP9.5 IENF (p=0.0008) and GAP43 (p=0.004), whereas those with lack of pain relief showed no such increase; in some subjects pain relief and increased nerve fibres persisted over months. PGP9.5 IENF increase correlated with axon-reflex vasodilatation in a NPDPN Q+SOC subset (p=0.006). Conclusions: Capsaicin 8% patch can provide pain relief via nerve regeneration and restoration of function in DPN (disease modification). It may thereby potentially prevent diabetic foot complications, including ulcers

Nerve and vascular biomarkers in skin biopsies differentiate painful from painless peripheral neuropathy in type 2 diabetes

Painful diabetic peripheral neuropathy can be intractable with a major impact, yet the underlying pain mechanisms remain uncertain. A range of neuronal and vascular biomarkers was investigated in painful diabetic peripheral neuropathy (painful-DPN) and painless-DPN and used to differentiate painful-DPN from painless-DPN. Skin biopsies were collected from 61 patients with type 2 diabetes (T2D), and 19 healthy volunteers (HV). All subjects underwent detailed clinical and neurophysiological assessments. Based on the neuropathy composite score of the lower limbs [NIS(LL)] plus seven tests, the T2D subjects were subsequently divided into three groups: painful-DPN (n = 23), painless-DPN (n = 19), and No-DPN (n = 19). All subjects underwent punch skin biopsy, and immunohistochemistry used to quantify total intraepidermal nerve fibers (IENF) with protein gene product 9.5 (PGP9.5), regenerating nerve fibers with growth-associated protein 43 (GAP43), peptidergic nerve fibers with calcitonin gene-related peptide (CGRP), and blood vessels with von Willebrand Factor (vWF). The results showed that IENF density was severely decreased (p < 0.001) in both DPN groups, with no differences for PGP9.5, GAP43, CGRP, or GAP43/PGP9.5 ratios. There was a significant increase in blood vessel (vWF) density in painless-DPN and No-DPN groups compared to the HV group, but this was markedly greater in the painful-DPN group, and significantly higher than in the painless-DPN group (p < 0.0001). The ratio of sub-epidermal nerve fiber (SENF) density of CGRP:vWF showed a significant decrease in painful-DPN vs. painless-DPN (p = 0.014). In patients with T2D with advanced DPN, increased dermal vasculature and its ratio to nociceptors may differentiate painful-DPN from painless-DPN. We hypothesized that hypoxia-induced increase of blood vessels, which secrete algogenic substances including nerve growth factor (NGF), may expose their associated nociceptor fibers to a relative excess of algogens, thus leading to painful-DPN

Direct microscopic examination of imprints in patients undergoing cardiac valve replacement

BACKGROUND: Bacteriological analysis of cardiac valves might be indicated in patients with suspected endocarditis. METHODS: We report here a prospective study on fifty-three consecutive patients whose native valves were sent to the bacteriological and pathological laboratories, to investigate the performance of direct microscopic examination of imprints and valve culture. RESULTS: On the basis of a histopathological gold standard to classify the inflammatory valve process, the sensitivity, the specificity, the positive and the negative predictive values of direct microscopic examination of imprints and valve culture were 21%, 100%, 100%, 60%, and 21%, 72%, 38%, 52% respectively. This weak threshold of the direct microscopic examination of imprints could be due to antimicrobial therapy prescribed before cardiac surgery and the fact that the patients came from a tertiary hospital receiving patients with a prolonged history of endocarditis. CONCLUSION: Clinical context and histopathology are indispensable when analyzing the imprints and valve culture

Targeting Antibody Responses to the Membrane Proximal External Region of the Envelope Glycoprotein of Human Immunodeficiency Virus

Although human immunodeficiency type 1 (HIV-1) infection induces strong antibody responses to the viral envelope glycoprotein (Env) only a few of these antibodies possess the capacity to neutralize a broad range of strains. The induction of such antibodies represents an important goal in the development of a preventive vaccine against the infection. Among the broadly neutralizing monoclonal antibodies discovered so far, three (2F5, Z13 and 4E10) target the short and hidden membrane proximal external region (MPER) of the gp41 transmembrane protein. Antibody responses to MPER are rarely observed in HIV-infected individuals or after immunization with Env immunogens. To initiate antibody responses to MPER in its membrane-embedded native conformation, we generated expression plasmids encoding the membrane-anchored ectodomain of gp41 with N-terminal deletions of various sizes. Following transfection of these plasmids, the MPER domains are displayed on the cell surface and incorporated into HIV virus like particles (VLP). Transfected cells displaying MPER mutants bound as efficiently to both 2F5 and 4E10 as cells transfected with a plasmid encoding full-length Env. Mice immunized with VLPs containing the MPER mutants produced MPER-specific antibodies, the levels of which could be increased by the trimerization of the displayed proteins as well as by a DNA prime-VLP boost immunization strategy. Although 2F5 competed for binding to MPER with antibodies in sera of some of the immunized mice, neutralizing activity could not be detected. Whether this is due to inefficient binding of the induced antibodies to MPER in the context of wild type Env or whether the overall MPER-specific antibody response induced by the MPER display mutants is too low to reveal neutralizing activity, remains to be determined

Anti-inflammatory and anti-invasive effects of α-melanocyte-stimulating hormone in human melanoma cells

Alpha-melanocyte stimulating hormone (alpha-MSH) is known to have pleiotrophic functions including pigmentary, anti-inflammatory, antipyretic and immunoregulatory roles in the mammalian body. It is also reported to influence melanoma invasion with levels of alpha-, beta- and gamma-MSH correlated clinically with malignant melanoma development, but other studies suggest alpha-MSH acts to retard invasion. In the present study, we investigated the action of alpha-MSH on three human melanoma cell lines (HBL, A375-SM and C8161) differing in metastatic potential. alpha-melanocyte-simulating hormone reduced invasion through fibronectin and also through a human reconstructed skin composite model for the HBL line, and inhibited proinflammatory cytokine-stimulated activation of the NF-kappaB transcription factor. However, A375-SM and C8161 cells did not respond to alpha-MSH. Immunofluorescent microscopy and Western blotting identified melanocortin-1 receptor (MC-1R) expression for all three lines and MC-2R on HBL and A375-SM lines. Receptor binding identified a similar affinity for alpha-MSH for all three lines with the highest number of binding sites on HBL cells. Only the HBL melanoma line demonstrated a detectable cyclic adenosine monophosphate (cAMP) response to alpha-MSH, although all three lines responded to acute alpha-MSH addition (+(-)-N(6)-(2-phenylisopropyl)-adenosine (PIA)) with an elevation in intracellular calcium. The nonresponsive lines displayed MC-1R polymorphisms (C8161, Arg (wt) 151/Cys 151; A375-SM, homozygous Cys 151), whereas the HBL line was wild type. Stable transfection of the C8161 line with wild-type MC-1R produced cells whose invasion was significantly inhibited by alpha-MSH. From this data, we conclude that alpha-MSH can reduce melanoma cell invasion and protect cells against proinflammatory cytokine attack in cells with the wild-type receptor (HBL).Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe