Major histocompatibility complex diversity is positively associated with stream water temperatures in proximate populations of sockeye salmon.

Local adaptation to heterogeneous environments generates population diversity within species, significantly increasing ecosystem stability and flows of ecosystem services. However, few studies have isolated the specific mechanisms that create and maintain this diversity. Here, we examined the relationship between water temperature in streams used for spawning and genetic diversity at a gene involved in immune function [the major histocompatibility complex (MHC)] in 14 populations of sockeye salmon (Oncorhynchus nerka) sampled across the Wood River basin in south-western Alaska. The largest influence on MHC diversity was lake basin, but we also found a significant positive correlation between average water temperature and MHC diversity. This positive relationship between temperature and MHC diversity appears to have been produced by natural selection at very local scales rather than neutral processes, as no correlation was observed between temperature and genetic diversity at 90 neutral markers. Additionally, no significant relationship was observed between temperature variability and MHC diversity. Although lake basin was the largest driver of differences in MHC diversity, our results also demonstrate that fine-scale differences in water temperature may generate variable selection regimes in populations that spawn in habitats separated by as little as 1 km. Additionally, our results indicated that some populations may be reaching a maximum level of MHC diversity. We postulate that salmon from populations in warm streams may delay spawning until late summer to avoid thermal stress as well as the elevated levels of pathogen prevalence and virulence associated with warm temperatures earlier in the summer.

Histopathologic features of erythematous papulopustular eruption to epidermal growth factor receptor inhibitors in cancer patients.

BACKGROUND: Erythematous papulopustular eruption (EPPE) is the most frequent skin adverse event to epidermal growth factor receptor (EGFR) inhibitors but its histopathologic features have been poorly studied. As EPPE is a strong predictor of patient's treatment response, the EPPE histopathologic features and their correlations with skin eruption severity and involved drug were investigated. METHOD: An involved skin biopsy was carried out in 39 informed patients treated with EGFR inhibitors (mainly cetuximab and erlotinib). The cutaneous changes in hematoxylin-eosin stained sections were evaluated. RESULTS: The EPPE to EGFR inhibitors is histopathologically characterized by neutrophilic subcorneal or intraepidermal pustules and polymorphous infiltrate of the superficial dermis during the earliest phases and by lymphocytic perifolliculitis and/or suppurative folliculitis at a later phase. The widespread dermis inflammation was more frequent in severe EPPEs and in patients treated with cetuximab, while the hair follicle inflammation was observed only in mild/moderate EPPEs. CONCLUSION: Our study shows the histopathologic signs of EPPE and their correlation with clinical severity and the offending drug.

Clinical epidemiology of hand eczema in patients accessing dermatological reference centres: results from Italy.

BACKGROUND: Data on the epidemiological impact and clinical characteristics of chronic hand eczema in Southern Europe are lacking. OBJECTIVES: To estimate the prevalence of chronic hand eczema in its different stages of severity and refractoriness to standard therapy in patients accessing Italian dermatological reference centres, and to evaluate sociodemographic and clinical factors associated with each stage. METHODS: A cross-sectional multicentre study was conducted. Adult patients with hand eczema, consecutively accessing 14 centres over a 6-month period, were enrolled. Patients were classified according to disease duration, severity and response to standard therapy with potent topical corticosteroids. Logistical regression was performed to investigate the relationship between sociodemographic and clinical data with different stages of eczema. RESULTS: The total number of participants was 981. Hand eczema was chronic in 83·5% of patients; 21·3% had severe eczema, with 62·0% of these patients refractory to standard therapy. Food processing and related work, the health professions, craft and related trade works (building, plumbing, electrical), hairdressing/beauty and handicraft work were most frequently associated with chronic hand eczema. Severe chronic hand eczema was more likely to be seen in men, older patients and those with less education. Severe and refractory hand eczema was also more likely among the unemployed and patients with allergic rhinitis and/or atopic dermatitis. CONCLUSIONS: Chronic hand eczema is frequent among patients with hand eczema accessing dermatology centres. Many patients were severe and refractory to standard therapy. The appropriate identification of hand eczema is the first step in implementing effective and efficient treatments.

Differences in clinicopathological features and distribution of risk factors in Italian melanoma patients.

BACKGROUND: No studies are available in the literature on the distribution of different melanoma features and risk factors in the Italian geographical areas. OBJECTIVE: To identify the differences in clinical-pathological features of melanoma, the distribution of risk factors and sun exposure in various Italian macro-areas. METHODS: Multicentric-observational study involving 1,472 melanoma cases (713 north, 345 centre, 414 south) from 26 referral centres belonging to the Italian Multidisciplinary Group for Melanoma. RESULTS: Melanoma patients in northern regions are younger, with thinner melanoma, multiple primaries, lower-intermediate phototype and higher counts of naevi with respect to southern patients; detection of a primary was mostly connected with a physician examination, while relatives were more involved in the south. Northern patients reported a more frequent use of sunbeds and occurrence of sunburns before melanoma despite sunscreen use and a lower sun exposure during the central hours of the day. CONCLUSIONS: The understanding of differences in risk factors distribution could represent the basis for tailored prevention programmes.

Histopathological and immunohistochemical features of drug-induced exanthems.

Exanthematic eruptions, together with urticaria-angioedema syndrome and fixed drug eruption, are the most frequent cutaneous adverse drug reactions. Among the drug-induced exanthems (DIEs), erythematous maculopapular eruptions are the most common. Their management, especially when retrospective, is often not easy, and it is based on the use of clinical criteria, history, results of some laboratory tests, drug elimination test, skin tests, and oral challenge test. The superficial perivascular and spongiotic dermatitis, which is the prevalent histopathological features of DIEs, is not very useful in the differential diagnosis with virus- and bacteria-induced exanthems (VBIEs). On the contrary, some immune-histochemical findings (interleukin-5 overexpression, concomitant enhancement of perforin, interleukin-5, and granzyme B production, positivity for fatty acid synthase-ligand-L in amoxicillin-induced exanthems) seem to be more important. These data justifie the inclusion of DIEs in the subtypes IVb and IVc of delayed hypersensitivity reactions.

Investigation of new vehicles to patch test corticosteroids: our experience with ethoxydiglycol to detect contact allergy to hydrocortisone butyrate.

Topical corticosteroids (CS) are widely used in dermatology because of their anti-inflammatory, anti-proliferative and immuno-suppressive properties. On the other hand, the prolonged application of corticosteroids may induce adverse reactions such as allergic contact dermatitis (ACD). Patch testing CS often poses methodological issues correlated to their drug properties that may hide the manifestations of a positive reaction. Furthermore, the ideal concentration to patch test corticosteroid is still a matter of study and some vehicles have some well-known limitations. This article is divided into two parts: the first one investigated vehicles that may efficiently dissolve the corticosteroids, according to the polarity of the latter; the second part compared the results of the patch tests with hydrocortistone-17-butyrate using two different vehicles: ethanol, which is the standard one, and another vehicle selected as suitable from our CS solubility test.

Differential diagnosis of psoriasis.

The clinical diagnosis of psoriasis is relatively easy, especially when the lesions consist of erythematous, silvery white scaly, sharply demarcated, indurated plaques, distributed symmetrically on the extensor surfaces of limbs, the lower back and the scalp. These clinical features reflect the histopathological findings observed in active lesions, characterized by parakeratosis, acanthosis of the epidermal ridges, tortuous and dilated blood vessels, and perivascular leukocytic infiltrate; the Munro microabscess and the spongiform pustule of Kogoj are diagnostic. Diagnostic doubts, however, may arise in several clinical variants and atypical cases (guttate psoriasis, follicular or spinulosic psoriasis, erythrodermic psoriasis, pustular psoriasis) or when the psoriatic lesions are localized in particular sites (palms, soles, scalp, body folds, penis, nails). The value of erythemato-papulosquamous psoriasiform eruptions occurring during or after the administration of a diagnostic or therapeutic agent especially in psoriatic subjects is discussed.

Regulation by interferon gamma of function in the acute monocytic leukemia cell line, THP-1.

THP-1 is an acute monocytic leukemia cell line which acquires phenotypic and functional monocytoid-like features following incubation with mezerein. The current study concerned the modulation of these features by rIFN gamma. rIFN gamma induces the time-dependent enhancement of HLA-DR expression in the presence or absence of mezerein but has no effect on the expression of Leu-M1, Leu-M2, or Leu-M3 antigens. CSF-1 production following mezerein activation was reduced by incubation in the presence of 10(3) and 10(4) units/ml rIFN gamma. This was confirmed through both biological assays with mouse bone marrow cells and an indirect ELISA. In contrast, the concentration of growth inhibitory activity in conditioned medium was increased by rIFN gamma. A small but significant increase in IL-1 beta concentration in conditioned medium was detected using a sensitive double-antibody ELISA and a radioimmunoassay. The results infer that the functional characteristics of this leukemia cell line are modulated by rIFN gamma in a manner qualitatively similar to that reported for IFN gamma treated normal monocytes.

The incidence of antibody formation to OKT3 consequent to its use in organ transplantation.

Enzyme-linked immunosorbent assays were performed on 12,133 serum samples to determine the incidence of anti-OKT3 antibody formation among transplant recipients who had received OKT3 for rejection treatment or prophylaxis. High anti-OKT3 antibody titers (> or = 1:1000) were detected in 5.8% of samples drawn 2 to 8 weeks following initiation of OKT3 therapy. The frequency of high titers differed by organ (6.9%, 2.7%, and 5.3% for kidney, heart, and liver, respectively; P < 0.001) and by sampling times (P < 0.001). The highest frequency of positive titers was obtained in samples obtained between 2 and 4 weeks following the initiation of OKT3. For all transplant recipients and for kidney recipients alone, multivariate logistic regression showed that the risk of high anti-OKT3 titers varied significantly at 2 to 4 weeks and at 4 to 6 weeks (but not at 6 to 8 weeks) with age (the youngest patients had the highest incidence, with a steady decline after age 30; P < 0.05), course of therapy (lowest frequencies followed a first course of OKT3; P < 0.001), and transplant number (lowest frequencies followed a first transplant; P < 0.01). Analyses of a set of patients on whom immunosuppressive regimen information was available indicated that prophylactic or maintenance treatment with CsA was associated with a significantly lower frequency of high-titer anti-OKT3 antibodies than was therapy without CsA (P < 0.001). In conclusion, this series provides confirming evidence that high-titer anti-OKT3 antibodies, which are of concern whenever retreatment with OKT3 is contemplated, occur in a low percentage of patients and are associated with such factors as age, previous transplantation or courses of therapy with OKT3, and treatment with CsA.

The OKT3 Antibody Response Study: a multicentre study of human anti-mouse antibody (HAMA) production following OKT3 use in solid organ transplantation.

Human anti-murine antibody titres following patient exposure to the monoclonal antibody Orthoclone OKT3 (muromonab-CD3) are determined by laboratories using diverse analytical methods which are not standardized and whose concordance is not established. A multicentre study group therefore compared testing for IgG anti-OKT3 antibody among seven laboratories. A set of 270 sera was obtained from 30 heart, 30 kidney and 30 liver transplant recipients with no previous exposure to OKT3 who were receiving OKT3 for induction immunosuppression. Sera were collected from each patient prior to and at 24 +/- 2 days and 31 +/- 2 days following initial OKT3 exposure. Identical aliquots of all 270 sera were tested for IgG anti-OKT3 antibody by each laboratory. In addition, the limit of detection of each laboratory's method was estimated by titration of an affinity-purified IgG anti-OKT3 reference material of known concentration. Anti-OKT3 antibody formation differed greatly among the three organ groups. Cardiac patients demonstrated the least sensitization and almost exclusively lower titres, while kidney recipients had more frequent and higher titre antibody formation. Liver recipients yielded the highest sensitization rate and the most frequent high titre sera. Importantly, the seven laboratories differed widely in the number of pretreatment sera reported as positive (ranging from 0% to 41% among laboratories), the number of post-OKT3 sera reported as positive (17-63%), the number of post-OKT3 samples with titre > or = 1000 (2-31%), and the number of patients sensitized 19-69%). Concordance among laboratories was highly variable, with interlaboratory agreement ranging from 38% to 83% on the sample titres assigned to 180 post-OKT3 sera. Many of the discordant results were consistent with differences in the limit of detection of the analytical methods, which ranged from 0.19 microgram/ml to > or = 15 micrograms/ml, a nearly 100-fold difference among laboratories. This study demonstrated the presence of both good concordance and significant discordance among laboratories in determining human anti-mouse antibody titres, and demonstrated that common titre categories (100, 1000, 10,000) were not equivalent among laboratories. The level of concordance among methods should be considered when comparing anti-OKT3 antibody results from different centres and their correlation with clinical events. Universal comparative testing, patterned after proficiency testing programmes, is needed to assess differences among laboratories and to bring uniformity and a sound interpretative basis to this field of testing.

beta-N-acetyl-D-glucosaminidase isoenzymes by chromatofocusing from serum and skin in diabetes.

beta-N-Acetyl-D-glucosaminidase and its kinetic characteristics were determined in serum and skin from both diabetes mellitus and impaired glucose tolerance patients and controls. Mean total activity was reduced (p less than 0.05) in the skin of both patient groups. beta-N-Acetyl-D-glucosaminidase isoenzyme expression was investigated using chromatofocusing on PBE-94 coupled with automated enzyme assay. The isoenzyme profiles from serum showed two major forms (A and B) whose ratio varied from 2:1 in controls to 3:1 in diabetics. Moreover, diabetes mellitus and impaired glucose tolerance subjects displayed an intermediate (I) form. The A/B isoenzyme ratio was completely reversed in skin.

Improved radioimmunoassay technique for measuring serum thymopoietin.

An improved radioimmunoassay technique for measuring serum thymopoietin has been developed which obviates the spurious displacements previously obtained with serum samples, and increases sensitivity to 20 pg. Key improvements involved further purification of labeled thymopoietin, sequential incubations to enhance sensitivity and the use of charcoal-treated serum blanks to render controls and unknown samples comparable to the standard curve.

A fluorescence immunoassay for soluble antigens employing flow cytometric detection.

A "sandwich" fluorescence immunoassay is described which does not require the physical separation of bound from free label. Antibody coated microspheres, sample and fluorescent antibody are reacted together as in a conventional 'sandwich' immunoassay except that separation and washing steps are omitted. After the reaction is completed, the suspension is introduced directly into a flow cytometer equipped with a laser light source and both fluorescent and scattered light detection capabilities. By gating fluorescence light accumulation on scattered light pulses, particles associated fluorescence may be selectively measured. The system was evaluated in a model immunoassay for human immunoglobulin (hIgG), employing anti-hIgG coated microspheres (1--5 micrometer and 40--50 micrometer polyacrylamide beads and 30--40 micrometer dextran beads), fluorescein-labeled rabbit anti-hIgG and a Spectrum III flow cytometer. Sensitivities of 10 ng/ml and intra-assay precisions of 2--10% were achieved in a serum matrix. The approach potentially provides a general nonseparation immunoassay format for quantitatively measuring both small and large molecular weight soluble antigens, as well as cell surface antigens.

Cellular and humoral immunity in psoriatic patients.

The degree of cellular immunity was found to be reduced in about 23% of 56 psoriatics, especially so in those with flexural and arthropathic lesions. Humoral immunity was only slightly reduced. Lysozyme activity levels in serum were normal, while those of healthy skin were depressed in 6 patients.