Biomedical subjects
E M Spiers
Publications and source records attributed to E M Spiers.
Partial restoration of hair growth in the DEBR model for Alopecia areata after in vivo depletion of CD4+ T cells.
Alopecia areata (AA) is widely believed to be an autoimmune disease. Hair loss is associated with a peri- and intrafollicular inflammatory infiltrate of anagen hair follicles primarily composed of CD4 + and CD8 + cells. A previous investigation involved in vivo depletion of CD8 + cells in the DEBR rat model to examine the cells' potential pathogenic activity in AA. The rat model is used here in a comparable study of CD4 + cell pathogenic activity. Eight AA affected DEBR rats were given intraperitoneal injections of a CD4 + cell depleting OX-35/OX-38 monoclonal antibody (MoAb) cocktail over a 15-day therapy course. A further eight AA-affected rats comprised a control group and were injected with equivalent volumes of an irrelevant MoAb, OX-21. Changes in both CD4 + and CD8 + peripheral blood cell populations were analysed by flow cytometry, and macrophotography was used to record any changes in hair growth. Of the eight CD4 + cell-depleted rats six responded with hair growth. The rats revealed significant hair growth within 23 days of treatment initiation. With rapid replacement of the CD4 + cell population the newly generated pelage hair was eventually lost. Two control rats also showed limited hair growth within the 112-day study period. In vivo depletion of CD4 + cells partially restores hair growth in AA affected rats. The response suggests that CD4 + cells may be actively involved in the pathogenesis of AA. Further research may elucidate whether CD4 + cells have a direct effect on hair follicles or exert their influence through their classic T helper cell supporting role for CD8 + cells.
Agminated xanthogranuloma: an unusual presentation of juvenile xanthogranuloma.
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Cutaneous necrosis associated with recombinant interferon injection. Report of three cases with interferon beta-1b and review of the literature.
Interferons are cytokines produced by cells in response to stimulation by certain antigens and infectious agents. In recent years, recombinant interferons have been developed, which have antiviral, antiproliferative, and immunomodulatory functions. Several cutaneous reactions have been reported, including cutaneous ulceration at injection sites. We now report three cases of cutaneous ulceration caused by interferon beta-1b injections. In addition, we review all of the previously reported cases of cutaneous ulceration caused by recombinant interferons and discuss the different mechanisms by which these substances may produce this effect.
Diving suit dermatitis: a manifestation of Pseudomonas folliculitis.
Pseudomonas aeruginosa causes a variety of cutaneous infections. Pseudomonas folliculitis has been associated with a number of activities, particularly bathing in contaminated water and the use of contaminated objects while bathing. We present two unique cases in which the subjects noted Pseudomonas folliculitis after recreational use of diving suits.
Expression of plasminogen activators in basal cell carcinoma.
The plasminogen activators, tissue type and urokinase type (tPA and uPA, respectively), have been identified in various malignancies and have been implicated in both local growth and metastatic spread. To characterize plasminogen activator expression more fully in human basal cell carcinoma, the localization of uPA and tPA mRNAs was evaluated by in situ hybridization. Nodular basal cell carcinomas demonstrated uPA expression in most cases, whereas the non-nodular subtypes were negative. Message for uPA was identified within tumour islands (11/12 cases), scattered fibroblast-like stromal cells (6/12 cases), and the basal layer of the overlying epidermis (10/12 cases). In addition, signal for uPA was elevated and pronounced in areas where the epidermis merged into invasive basal cell carcinoma in the superficial papillary dermis in some cases. Message for uPA was often associated with ulceration or erosion of the overlying epithelium. Expression of tPA was noted in the epidermis (3/12 cases) and in tumour cells (4/12 cases), but tended to be focal and sparse. These results suggest that complex interactions involving uPA expression occur between the tumour, the stroma, and the overlying epidermis. Both the stroma and the epidermis may contribute to local spread of the tumour through production of uPA and consequent plasmin-mediated activation of collagenases and metalloproteinases.
In vivo depletion of CD8+ T cells restores hair growth in the DEBR model for alopecia areata.
Alopecia areata (AA) is a putative autoimmune disease in which anagen hair follicles are the target of immune cell attack. While both CD4+ and CD8+ T lymphocytes are prominent in the infiltrate, their respective roles in the pathogenesis of AA remain unknown. Here we directly investigated the activity of CD8+ cells in the inhibition of hair growth using the Dundee experimental bald rat (DEBR) model for AA. Eight lesional DEBRs were fully depleted of their CD8+ cells by intraperitoneal injection of OX-8 monoclonal antibody (MoAb) specific for these cells over a 15-day therapy course. A control group of eight lesional rats was injected with the irrelevant MoAb OX-21. Sequential blood samples were analysed by flow cytometry to observe changes in the CD8+ cell population and macrophotography used to record changes in hair growth activity. All eight CD8+ depleted rats started to regrow hair within 29 days from the start of treatment, the final response ranging from sparse regrowth to a near normal coat. While two rats maintained their new pelage, the remainder lost hair as the CD8+ population in peripheral blood increased. Two of the control rats also showed hair regrowth over the experimental period of 156 days. These results suggest that CD8+ cells play an active part in the pathogenesis of AA. As hair production did not fully recover in all animals, immune mechanisms other than CD8+ cells may be involved in effecting hair loss. However, analysis of CD8+ cell levels in the skin of CD8+ depleted rats may help resolve their full importance in AA.
Endocytosis of fluorescent microspheres by human oesophageal epithelial cells: comparison between normal and inflamed tissue.
This paper examines the presence and characteristics of endocytosis by oesophageal epithelial cells. Biopsy specimens from normal and inflamed oesophagus were incubated in organ culture with fluorescent microspheres (0.1 and 0.01 microns diameter). These markers were taken into early endosomes and the lysosomes of both the smaller differentiating prickle cells and the larger mature squamous cells. Confocal and electron microscopy showed that markers passed to the early endosomes and the lysosomes by endocytosis. The process was energy dependent. Larger, 1 micron microspheres adhered to the epithelial cells but were not phagocytosed. Disaggregated cells were analysed by flow cytometry. Microspheres were endocytosed in proportion to the concentration in the culture medium in a dose dependent manner. Cells from inflamed oesophagus were significantly smaller (p = 0.013) and took up significantly more microspheres than cells from normal biopsy specimens (p = 0.015). In conclusion, endocytosis occurs in oesophageal epithelial cells and is increased in inflammation.
C-reactive protein. A clinical marker in community-acquired pneumonia.
STUDY OBJECTIVE: To assess the range of plasma C-reactive protein (CRP) in patients presenting with community-acquired pneumonia and to compare the serial changes of this acute-phase protein with clinical outcome. DESIGN: Prospective hospital-based study, including separate retrospective case series. PATIENTS: Twenty-eight consecutive patients (mean age, 60 years) admitted to our hospital with community-acquired pneumonia were studied. Serial daily plasma samples were taken and assayed for CRP, tumor necrosis factor-alpha (TNF-alpha), and interleukin 6 (IL-6). Clinical parameters, laboratory data, and response to treatment were recorded. Four other patients considered to be antibiotic failures (three empyemas, one death) were studied separately. RESULTS: Two patients died. Of those who survived, mean (+/- SD) CRP values for days 1,2,3,4, and 5 were as follows: 136 +/- 43, 96 +/- 44, 53 +/- 36, 54 +/- 43, and 44 +/- 31 mg/L. CRP levels on day 1 in patients who had received antibiotics prior to hospital admission were significantly lower than those who had not, 107 +/- 42 and 152 +/- 44 mg/L (p < 0.05). CRP levels did not correlate with other laboratory parameters or with recognized predictors of mortality. A CRP value that continued to rise despite antibiotic treatment was associated with infective complications or death. Only 52% of patients had detectable TNF-alpha and 24% detectable IL-6 at some point during their hospital stay. CONCLUSIONS: CRP is a sensitive marker of pneumonia. A persistently high or rising CRP level suggests antibiotic treatment failure or the development of an infective complication. These results suggest that CRP, rather than TNF-alpha or IL-6, may have a role as a clinical marker in pneumonia.
Livedo reticularis and inflammatory carcinoma of the breast.
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An epidermal proliferative reaction associated with a silicone gel breast implant.
A variety of local and systemic adverse reactions has been attributed to silicone prostheses used for augmentation or reconstructive mammoplasty. We present a patient who developed an unusual local cutaneous reaction to a silicone breast implant, which was characterized clinically by macular erythema and focal ulceration and histologically by a basaloid proliferative epidermal reaction. The epidermal changes seen histologically simulated those overlying dermatofibromas and were felt to be reactive secondary to silicone leakage and fibrosis. The process resolved postexplantation of the prosthesis.
Expression of plasminogen activator enzymes in psoriatic epidermis.
The plasminogen activators, tissue type and urokinase type (tPA and uPA, respectively) have been identified in human skin under normal conditions and in various inflammatory dermatoses, including psoriasis. By Northern blot analyses, mRNA for uPA, but not for tPA, has been previously identified in epidermal extracts from normal skin, whereas in psoriasis, mRNA for tPA is readily detected. To further characterize uPA and tPA expression in psoriasis, the localization of uPA and tPA mRNAs was evaluated by in situ hybridization. Studies were conducted using lesional and nonlesional skin of patients with psoriasis as well as normal skin. Additionally, in situ zymography using casein gel overlays was utilized to assess enzymatic activity. In psoriatic lesional skin, both uPA and tPA mRNAs were demonstrated by in situ hybridization. Message for tPA was observed throughout the epidermis with areas of accentuation in the superficial stratum spinosum. Message for uPA was more focal and was localized primarily in the basal layer. Zymography showed tPA activity was coordinately increased in psoriatic lesions. Uninvolved skin of psoriatic patients was similar to that of normal skin with respect to expression of plasminogen activators. In normal epidermis, neither tPA nor uPA mRNA could be detected by in situ hybridization. Activity for uPA, but not tPA, was observed by zymography. These studies suggest that alterations in plasminogen activators expression may contribute to the pathogenesis of psoriasis.
The effect of fenclofenac on the regeneration of lymphocytes in rats following total body irradiation.
The effect of fenclofenac on the regeneration of white blood cells in Sprague-Dawley rats following total body irradiation was investigated. The lowest dose of total body irradiation that would suppress the peripheral blood lymphocyte count by at least 50% was found to be 1.0 Gray in a preliminary experiment. Fenclofenac in a dose of 150 mg/kg/day retarded the regeneration of lymphocytes following total body irradiation of 1 Gray: this effect was also seen in the CD4, CD8 and B-lymphocyte subsets. This suppressive effect in vivo may be due to interference with replicative growth of white blood cells since previous in vitro experiments have shown suppression of lymphocyte growth at a stage later than activation in the cell cycle. The suppressive effects on leucocyte regeneration in vivo suggest that fenclofenac may have promise as an immunosuppressive drug with fewer serious side effects than the currently available immunosuppressive drugs.
Response of soluble IL-2 receptor levels to repeated cycles of IL-2 immunotherapy/chemotherapy.
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Noninflammatory bullae associated with epsilon-aminocaproic acid infusion.
Three patients who had cardiac surgery developed a transient, noninflammatory subepidermal bullous eruption on the legs after epsilon-aminocaproic acid infusion. Fibrin thrombi were demonstrated in papillary dermal vessels. The use of epsilon-aminocaproic acid as an antifibrinolytic agent may predispose patients to cutaneous vascular thromboses.
Inter- and intra-subject variation of the suppression of mitogen-induced proliferation of human lymphocytes by cyclosporin-A: reduction of response with delayed addition may be relevant to timing of therapy.
In vitro, CsA is capable of suppressing mitogen-stimulated growth of human peripheral blood lymphocytes. Dose--response studies on lymphocytes from normal volunteers have shown that the variation between subjects is greater than the variation between repeated studies on the same subject in the 72 h uptake of 3H-TdR. The tests are easy to perform and they could be used to help in deciding, prior to transplantation, the dose of CsA to be used and whether other immunosuppressive therapy is needed. Activation of lymphocyte proliferation in vivo is a continuous process and recruitment to growth in vitro takes place over 24 h after mitogen stimulation. CsA was most effective in suppressing the replicative growth of lymphocytes in vitro when added up to 4 h after the start of the culture, but it was much less effective when added at 8 h. The experiments suggest that 8 hourly administration of CsA will optimise suppression of activation of the lymphocytes in vivo. If the suppressive activity of the metabolite M17 and the individual variation in sensitivity of the patients' lymphocytes to CsA are also taken into account it may be possible to reduce the dose of CsA to achieve effective immunosuppression and thereby minimise toxicity.
Reactivation of rheumatoid arthritis during continuous infusion of interleukin 2: evidence of lymphocytic control of rheumatoid disease.
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Clinical and histologic features of primary oxalosis.
Primary oxalosis should be considered in patients with multisystem disease of the kidneys, heart, peripheral vasculature, and skin. Crystalline deposits can lead to nephrolithiasis with kidney failure, complete heart block, peripheral vasospasm, and livedo reticularis, as in our patient. Crystals were first observed in the myocardial biopsy specimen and then identified as calcium oxalate in skin from an area of livedo reticularis.