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  • 1
    ISSN: 1600-0536
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The accepted approach to the interpretation of local lymph node assay (LLNA) data requires comparison of responses in the test groups with background activity found in concurrent vehicle-treated controls. However, of established value in the interpretation of toxicity test data is the use of historical control values that provide one criterion against which to judge the integrity of individual experiments. Specifically, the availability of robust and relevant historical control data permits examination of whether, in any individual experiment, control values fall within the expected range. With the most commonly used vehicle employed in the LLNA, acetone/olive oil (4 : 1) (v/v), the mean values, standard deviations and normal ranges are increasingly well established for a given laboratory, although there is some variation between laboratories, particularly with regard to expected ranges. Against this background, it is possible to identify (and, if appropriate, eliminate) a concurrent vehicle-control value that falls well outside the expected range. To explore critically the potential merits of this approach, one specific example is examined in detail.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1600-0536
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The murine local lymph node assay (LLNA) assesses skin sensitization potential as a function of proliferative responses induced in lymph nodes draining the site of topical exposure to test chemical. It has been shown that interpolation of LLNA dose-response data to define the concentration of test chemical required to induce a 3-fold stimulation of proliferation (EC3) offers the prospect of a quantitative index of the relative potency of a contact allergen. Initial studies have demonstrated that there exists a strong (inverse) correlation between EC3 values and contact allergenic potency in humans. Thus, materials with a low EC3 value were more potent contact allergens in humans. However, it is necessary to examine a wide range of allergens to demonstrate that such correlations are generally true. Thus, in the present study, 10 aldehydes of varying degrees of allergenicity in man were evaluated in the LLNA and their EC3 values derived. Formaldehyde was regarded as the strongest allergen in man and also had the lowest EC3 value, 0.35% (equivalent to 0.93% formalin). In contrast, the extremely weak allergen vanillin and the non-sensitizer ethyl vanillin both had EC3 values of 〉50%. For the remaining 7 aldehydes, there was a close similarity between what is judged to be their rank order of allergenicity in humans and EC3 values derived from analysis of LLNA data. These results support further the utility of EC3 determinations in the LLNA as a measure of the relative potency of a contact allergen.
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  • 3
    ISSN: 1600-0536
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The effective toxicological evaluation of skin sensitization demands that potential contact allergens are identified and that the likely risks of sensitization among exposed populations assessed. By definition, chemicals which possess the toxicological property of skin sensitization potentially are capable of causing allergic contact dermatitis (ACD) in humans. However, this hazard is not an all-or-none phenomenon; clear dose-response relationships can be discerned and thresholds identified for both the induction of sensitization and the elicitation of contact dermatitis. Commonly, these parameters are grouped under the heading of potency, determination of which is vital for risk assessment. In the present investigation, the local lymph node assay (LLNA) has been employed to determine the relative potency of a range of 20 chemicals. The parameter used is the estimated concentration required to produce a 3-fold increase in draining lymph-node cell proliferative activity, the EC3 value. These measurements have been compared with an assessment of the human sensitizing potency of the 20 selected chemicals, each being assigned to 1 of 5 classes based on their human sensitizing potency. The EC3 value, derived from LLNA work carried out in acetone/olive oil vehicle, correlated well with the human classification, with the strongest sensitizers having low EC3 values (〈0.1%), weaker sensitizers having EC3 values generally in the 1–10% range, and non-sensitizing chemicals having EC3 values in excess of 100%. In conclusion, the derivation of the EC3 for a chemical provides an objective and quantitative estimate of potency that is of considerable utility for skin sensitization risk assessment.
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  • 4
    ISSN: 1600-0536
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The development of new ingredients and products for the consumer market requires a thorough assessment of their potential for skin sensitization and the possible clinical manifestation of allergic contact dermatitis. The process by which low molecular weight chemicals induce and elicit skin sensitization reactions is complex and dependent on many factors relevant to the ability of the chemical to penetrate the skin, react with protein, and trigger the cell-mediated immune response. These major factors include inherent potency, chemical dose, duration and frequency of exposure, vehicle or product matrix, and occlusion. The fact that a chemical is a contact allergen does not mean that it cannot be formulated into a consumer product at levels well tolerated by most individuals. Many common ingredients (e.g., fragrances, preservatives) are known skin allergens. However, all allergens show dose-response and threshold characteristics. Therefore, one should be able to incorporate these chemicals into products at levels that produce acceptably low incidences of skin sensitization under foreseeable conditions of exposure. The critical exposure determinant for evaluating skin sensitization risk is dose per unit area of skin exposed. Use of this parameter allows for comparative assessments from different types of skin sensitization tests (including cross-species comparisons), and, at least for known potent allergens, there is remarkable similarity in threshold dose/unit area determinations across species. The dose/unit area calculation enables a judgment of the sensitization risk for different product types. This is illustrated using the chemical preservative methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) as a case study.
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  • 5
    ISSN: 1600-0536
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The murine local lymph node assay (LLNA) for the prospective identification of contact allergens assesses skin sensitization potential as a function of proliferative activity induced in lymph nodes draining the site of topical exposure to test chemical. This method has been endorsed recently as a stand alone test for the identification of contact allergens. We have now examined the suitability of hexyl cinnamic aldehyde (HCA), a recommended positive control for skin sensitization testing, as a calibrant for comparing the consistency of LLNA responses with time, and between laboratories, and thus for the routine assessment of assay reliability. Standard LLNAs were performed with CBA strain mice in 3 independent laboratories over a period of 8 years. Dose-response curves were used to derive mathematically the EC3 value (the estimated concentration of chemical necessary to cause a stimulation index (SI) of 3 compared with proliferation induced by concurrent vehicle controls). In each laboratory, 6 separate experiments were conducted using a single concentration of HCA (25%). Very similar stimulation indices were achieved, with mean values of 9.0, 6.5 and 6.6 recorded. A total of 10 dose-response experiments were performed independently in the 3 laboratories and these revealed that there was very little inter-laboratory, or temporal, variation in EC3 values. These data confirm that HCA responses in the LLNA are very stable and demonstrate that HCA provides a suitable calibrant for determining assay sensitivity and performance.
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  • 6
    ISSN: 1600-0560
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background:  Pseudoepitheliomatous hyperplasia (PEH) is a reactive epithelial proliferation that occurs in response to underlying infectious, inflammatory, and neoplastic conditions. The histologic features of PEH may simulate squamous cell carcinoma and may obscure an underlying malignant process. The association of PEH with benign melanocytic nevi is well described in the literature. However, reports documenting the association of PEH with melanoma are rare.Methods:  We examined the demographic and histologic features in 13 cases of melanoma in association with PEH. In addition, we evaluated the possible pathogenic role of epidermal growth factor receptor (EGFR) using immunohistochemical methods.Results:  In each case, histologic examination revealed epidermal hyperplasia with irregular cords of well-differentiated epithelial cells extending into the dermis and infiltrating the melanoma. Although overlap existed, two patterns of epidermal hyperplasia were noted. The majority of cases (69%) exhibited acanthosis, hyperkeratosis, papillomatosis, and irregular infiltrating epithelial cords with squamous eddies. The remaining cases demonstrated basaloid acanthosis, laminated orthokeratosis, and horn cysts. EGFR immunohistochemical studies revealed strong staining within the basal layer of the epithelium, with no discernible difference between the hyperplastic epithelium overlying the melanoma cells and adjacent normal skin. Immunostaining among the melanoma cells was absent to weak in each of the cases. All cases exhibited intense EGFR immunoreactivity in macrophages underlying the epidermal lesions.Conclusions:  Melanoma is capable of presenting in a variety of histologic guises, including a pattern with PEH. The etiology of PEH, as rarely seen in conjunction with melanoma, unlikely involves EGFR and remains to be elucidated.
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  • 7
    Electronic Resource
    Electronic Resource
    Oxford, UK; Malden, USA : Munksgaard International Publishers
    Experimental dermatology 13 (2004), S. 0 
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract:  Both the production of the hair shaft in anagen and the initiation of a new hair cycle at telogen are the result of reciprocal interactions between the dermal papilla and the overlying epithelial cells. Secreted factors, such as those of the bone morphogenetic protein (BMP) family, play a crucial role in moderating these interactions. Analysis of hair follicles in different stages of the hair cycle showed that BMP signalling was only active during anagen and again during telogen. During catagen, no BMP signalling occurred in the dermal papilla. ID3, a gene expressed in the dermal papilla of both vibrissa and pelage follicles, is a BMP target, and as such, we found that ID3 was expressed from the earliest stages of morphogenesis. During the hair cycle, ID3 was only expressed in the dermal papilla at middle anagen and telogen. To test the significance of ID3 expression in the dermal papilla, we cultured dermal papilla cells and found that ID3 expression fell significantly after a single passage. ID3 expression was returned to in vivo levels in low- and high-passage cells by culturing to high confluence or by the addition of BMP4. These studies reinforce the requirement for active BMP signalling and cell–cell contacts in the dermal papilla during specific stages in the hair cycle.
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  • 8
    Electronic Resource
    Electronic Resource
    Copenhagen : Munksgaard International Publishers
    Periodontology 2000 24 (2000), S. 0 
    ISSN: 1600-0757
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract:  Aminolevulinic acid (ALA) is a charged, hydrophilic molecule that penetrates poorly through cellular structures. This property has been implicated in the poor clinical response of non-superficial basal cell carcinomas (BCCs) to photodynamic therapy (PDT). Release of ALA hydrochloride from a 20% w/w formulation was found to be incomplete and that approximately 36.8% of the total dose is released during the application period of 4 h. Using scintillation spectroscopy and a precise tissue sectioning protocol, it was demonstrated that depths of penetration of at least 2 mm from the lesion surface had been reached. Using cumulative stratal ALA concentrations, it was found that 10% of the total applied dose permeated into the lesion. In spite of this, comparisons drawn with photodynamic concentrations used in tissue culture work reported elsewhere revealed that estimations of the ALA concentration at 2 mm were sufficient to elicit a possible therapeutic response. Results from this work question the reasons given for poor outcomes of PDT in nodular BCC based solely on depth as a hindering factor.
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  • 10
    Electronic Resource
    Electronic Resource
    Copenhagen : Munksgaard International Publishers
    Immunological reviews 173 (2000), S. 0 
    ISSN: 1600-065X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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