Ranking of parameters of pain hypersensitivity according to their discriminative ability in chronic low back pain

Low back pain is associated with plasticity changes and central hypersensitivity in a subset of patients. We performed a case-control study to explore the discriminative ability of different quantitative sensory tests in distinguishing between 40 cases with chronic low back pain and 300 pain-free controls, and to rank these tests according to the extent of their association with chronic pain. Gender, age, height, weight, body mass index, and psychological measures were recorded as potential confounders. We used 26 quantitative sensory tests, including different modalities of pressure, heat, cold, and electrical stimulation. As measures of discrimination, we estimated receiver operating characteristics (ROC) and likelihood ratios. Six tests seemed useful (in order of their discriminative ability): (1) pressure pain detection threshold at the site of most severe pain (fitted area under the ROC, 0.87), (2) single electrical stimulation pain detection threshold (0.87), (3) single electrical stimulation reflex threshold (0.83), (4) pressure pain tolerance threshold at the site of most severe pain (0.81), (5) pressure pain detection threshold at suprascapular region (0.80), and (6) temporal summation pain threshold (0.80). Pressure and electrical pain modalities seemed most promising and may be used for diagnosis of pain hypersensitivity and potentially for identifying individuals at risk of developing chronic low back pain over time.

Desensitization of thermal hyperemia in the skin is reproducible

Local heating increases skin blood flow SkBF (thermal hyperemia). In a previous study, we reported that a first local thermal stimulus could attenuate the hyperemic response to a second one applied later on the same skin spot, a phenomenon that we termed desensitization. However, other studies found no evidence for desensitization in similar conditions. The aim of the present work was to test whether it was related to differences in instrumentation.

Characterization of canine dendritic cells in healthy, atopic, and non-allergic inflamed skin

Atopic dermatitis in humans and dogs is a chronic relapsing allergic skin disease. Dogs show a spontaneous disease similar to the human counterpart and represent a model to improve our understanding of the immunological mechanisms, the pathogenesis of the disease, and new therapy development. The aim of the study was to determine the frequency and phenotype of dendritic cells (DC) in the epidermis and dermis of healthy, canine atopic dermatitis lesional, and non-allergic inflammatory skin to further validate the model and to obtain insights into the contribution of DC to the pathogenesis of skin diseases in dogs. We first characterized canine skin DC using flow-cytometric analysis of isolated skin DC combined with an immunohistochemical approach. A major population of canine skin dendritic cells was identified as CD1c(+)CD11c(+)CD14(-)CD80(+)MHCII(+)MAC387(-) cells, with dermal DC but not Langerhans cells expressing CD11b. In the epidermis of lesional canine atopic dermatitis and non-allergic inflammatory skin, we found significantly more dendritic cells compared with nonlesional and control skin. Only in canine atopic dermatitis skin did we find a subset of dendritic cells positive for IgE, in the epidermis and the dermis. Under all inflammatory conditions, dermal dendritic cells expressed more CD14 and CD206. MAC387(+) putative macrophages were absent in healthy but present in inflamed skin, in particular during non-allergic diseases. This study permits a phenotypic identification and differentiation of canine skin dendritic cells and has identified markers and changes in dendritic cells and macrophage populations related to allergic and non-allergic inflammatory conditions. Our data suggest the participation of dendritic cells in the pathogenesis of canine atopic dermatitis similar to human atopic dermatitis and further validate the only non-murine spontaneous animal model for this disease.

Topical application of 17β-estradiol (E2) improves skin flap survival through activation of endothelial nitric oxide synthase in rats

This study investigates the influence of 17β-estradiol (E2) on nitric oxide (NO) production in endothelial cell cultures and the effect of topical E2 on the survival of skin flap transplants in a rat model. Human umbilical vein endothelial cells were treated with three different E2 concentrations and nitrite (NO2) concentrations, as well as endothelial nitric oxide synthase (eNOS) protein expressions were analyzed. In vivo, random-pattern skin flaps were raised in female Wistar rats 14 days following ovariectomy and treated with placebo ointment (group 1), E2 as gel (group 2), and E2 via plaster (group 3). Flap perfusion, survival, and NO2 levels were measured on postoperative day 7. In vitro, E2 treatment increased NO2 concentration in cell supernatant and eNOS expression in cell lysates (p < 0.05). In vivo, E2 treated (gel and plaster groups) demonstrated significantly increased skin flap survival compared to the placebo group (p < 0.05). E2 plaster-treated animals exhibited higher NO2 blood levels than placebo (p < 0.05) paralleling the in vitro observations. E2 increases NO production in endothelial cells via eNOS activation. Topical E2 application can significantly increase survival of ischemically challenged skin flaps in a rat model and may augment wound healing in other ischemic situations via activation of NO production.

The role of androgens on hypoxia-inducible factor (HIF)-1α-induced angiogenesis and on the survival of ischemically challenged skin flaps in a rat model

Effects of androgens on angiogenesis are controversial. Hypoxia-inducible factor (HIF)-1α promotes expression of vascular endothelial growth factor (VEGF) that stimulates angiogenesis.

She, With a Warm Palm, the Skin Over My Spine

She, with a Warm Palm, the Skin over My Spine is a collection of sixnonfiction essays and three vignettes divided into two parts. The first part tells the stories of my great-grandmother, my grandmother and my mother, and is entitled Home; the second part is entitled Away and consists of travel writing set in Thailand, Egypt and India.

Improvement of interferon-beta related skin reactions after diluent halving: first experience of five patients

The spectrum of side effects related to interferon beta-1b (INF-1b) treatment may compromise long-term adherence.

Nonlethal Screening of Bat-Wing Skin with the Use of Ultraviolet Fluorescence to Detect Lesions Indicative of White-Nose Syndrome

Definitive diagnosis of the bat disease white-nose syndrome (WNS) requires histologic analysis to identify the cutaneous erosions caused by the fungal pathogen Pseudogymnoascus [formerly Geomyces] destructans (Pd). Gross visual inspection does not distinguish bats with or without WNS, and no nonlethal, on-site, preliminary screening methods are available for WNS in bats. We demonstrate that long-wave ultraviolet (UV) light (wavelength 366-385 nm) elicits a distinct orange yellow fluorescence in bat-wing membranes (skin) that corresponds directly with the fungal cupping erosions in histologic sections of skin that are the current gold standard for diagnosis of WNS. Between March 2009 and April 2012, wing membranes from 168 North American bat carcasses submitted to the US Geological Survey National Wildlife Health Center were examined with the use of both UV light and histology. Comparison of these techniques showed that 98.8% of the bats with foci of orange yellow wing fluorescence (n=80) were WNS-positive based on histologic diagnosis; bat wings that did not fluoresce under UV light (n=88) were all histologically negative for WNS lesions. Punch biopsy samples as small as 3 mm taken from areas of wing with UV fluorescence were effective for identifying lesions diagnostic for WNS by histopathology. In a nonlethal biopsy-based study of 62 bats sampled (4-mm diameter) in hibernacula of the Czech Republic during 2012, 95.5% of fluorescent (n=22) and 100% of nonfluorescent (n=40) wing samples were confirmed by histopathology to be WNS positive and negative, respectively. This evidence supports use of long-wave UV light as a nonlethal and field-applicable method to screen bats for lesions indicative of WNS. Further, UV fluorescence can be used to guide targeted, nonlethal biopsy sampling for follow-up molecular testing, fungal culture analysis, and histologic confirmation of WNS.

Etiology and pathogenesis of adverse drug reactions

In clinical routine, adverse drug reactions (ADR) are common, and they should be included in the differential diagnosis in all patients undergoing drug treatment. Only part of those ADR are immune-mediated hypersensitivity reactions and thus true drug allergies. Far more common are non-immune-mediated ADR, e.g. due to the pharmacological properties of the drug or to the individual predisposition of the patient (enzymopathies, cytokine dysbalance, mast cell hyperreactivity). In true drug allergiesT cell- and immunoglobulin E (lgE)-mediated reactions dominate the clinical presentation. T cell-mediated ADR usually have a delayed appearance and include skin eruptions in most cases. Nevertheless, it should not be forgotten that they may involve systemic T cell activation and thus take a severe, sometimes lethal turn. Clinical danger signs are involvement of mucosal surfaces, blistering within the exanthematous skin areas and systemic symptoms, e.g. fever or malaise. Drug presentation via antigen-presenting cells to T cells can either involve the classical pathway of haptenization of endogenous proteins or be directly mediated via noncovalent binding to immune receptors (MHC molecules or T cell receptors), the so-called p-i concept. Flare-up reactions during the acute phase of T cell-mediated ADR should not be mistaken for true drug allergies, as they only occur in the setting of a highly activated T cell pool. IgE-mediated ADR are less frequent and involve mast cells and/or basophils as peripheral effector cells. Recent data suggest that certain patients with drug allergy have a preexistent sensitization although they have never been exposed to the culprit drug, probably due to cross-reactivity. Thus, allergic drug reactions on first encounter are possible. In general, the extent of cross-reactivity is higher in IgE-compared to T cell-mediated ADR. Based on a specific ethnic background and only for severe T cell-mediated ADR to certain drugs, a strong HLA association has been established recently.

Human leukocyte antigens (HLA) associated drug hypersensitivity: consequences of drug binding to HLA

Recent publications have shown that certain human leukocyte antigen (HLA) alleles are strongly associated with hypersensitivity to particular drugs. As HLA molecules are a critical element in T-cell stimulation, it is no surprise that particular HLA alleles have a direct functional role in the pathogenesis of drug hypersensitivity. In this context, a direct interaction of the relevant drug with HLA molecules as described by the p-i concept appears to be more relevant than presentation of hapten-modified peptides. In some HLA-associated drug hypersensitivity reactions, the presence of a risk allele is a necessary but incomplete factor for disease development. In carbamazepine and HLA-B*15:02, certain T-cell receptor (TCR) repertoires are required for immune activation. This additional requirement may be one of the 'missing links' in explaining why most individuals carrying this allele can tolerate the drug. In contrast, abacavir generates polyclonal T-cell response by interacting specifically with HLA-B*57:01 molecules. T cell stimulation may be due to presentation of abacavir or of altered peptides. While the presence of HLA-B*58:01 allele substantially increases the risk of allopurinol hypersensitivity, it is not an absolute requirement, suggesting that other factors also play an important role. In summary, drug hypersensitivity is the end result of a drug interaction with certain HLA molecules and TCRs, the sum of which determines whether the ensuing immune response is going to be harmful or not.

Avidity determines T-cell reactivity in abacavir hypersensitivity

The antiretroviral drug abacavir (abc) elicits severe drug hypersensitivity reactions in HLA-B*5701(+) individuals. To understand the abc-specific activation of CD8(+) T cells, we generated abc-specific T-cell clones (abc-TCCs). Abc reactivity could not be linked to the metabolism and/or processing of the drug, since abc metabolizing enzymes were not expressed in immune cells and inhibition of the proteasome in APCs did not affect TCC reactivity. Ca(2+) influx assays revealed different reactivity patterns of abc-TCCs. While all TCCs reacted to abc presented on HLA-B*5701 molecules, a minority also reacted immediately to abc in solution. Titration experiments showed that the ability to react immediately to abc correlated significantly with the TCR avidity of the T cells. Modifications of soluble abc concentrations revealed that the reactivity patterns of abc-TCCs were not fixed but dynamic. When TCCs with an intermediate TCR avidity were stimulated with increasing abc concentrations, they showed an accelerated activation kinetic. Thus, they reacted immediately to the drug, similar to the reaction of TCCs of high avidity. The observed immediate activation and the noninvolvement of the proteasome suggest that, in contrast to haptens, abc-specific T-cell stimulation does not require the formation of covalent bonds to produce a neo-antigenic determinant.