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Biomedical subjects

P S Friedmann

Publications and source records attributed to P S Friedmann.

At least 19 recordsLinked to original sources
PubMed1992

Delayed type hypersensitivity is abnormal in patients with lichen planus.

Lichen planus is characterized by the histological features of a cell-mediated attack on the epidermis. To see whether there is any defect in cutaneous immunity in non-lesional skin, we measured the response to a contact sensitizer in 17 patients with lichen planus and 27 control subjects. Sensitization was induced with 30 micrograms dinitrochlorobenzene applied to the thigh. The subjects were challenged 4 weeks later with three doses of dinitrochlorobenzene (8.8, 12.5 and 17.7 micrograms), and responses were quantified with calipers as the change in skinfold thickness at 48 h. Patients with lichen planus were significantly less responsive with smaller reactions at all challenge doses. These abnormalities suggest that the skin is abnormal in areas unaffected by the rash, and raise the possibility that there may be a primary defect in the cutaneous immune system in lichen planus.

Female↗
PubMed1992

Quantifying anti-inflammatory agents' potency by measurement of response to dinitrochlorobenzene challenge.

Classical assays of topical corticosteroid potency based on the induction of vasoconstriction are unsatisfactory for a number of reasons. These include the doubtful relevance of vasoconstriction to immune inflammation, and more importantly, the inability to compare non-steroidal agents with corticosteroids. Here we describe a simple assay in which the inhibitory effect of agents upon delayed type hypersensitivity response to dinitrochlorobenzene can be quantified by measurements of reaction as skinfold thickness with Harpenden callipers. Using this system we have confirmed the greater potency of clobetasol propionate (Dermovate) compared with betamethasone valerate (Betnovate), but the evidence for an inhibitory effect of topical cyclosporin (10% cream) compared with base on this response is less convincing.

Administration, Topical↗
PubMed1992

The use of cimetidine to reduce dapsone-dependent methaemoglobinaemia in dermatitis herpetiformis patients.

1. We have attempted to reduce dapsone-dependent methaemoglobinaemia formation in six dermatitis herpetiformis patients stabilised on dapsone by the co-administration of cimetidine. 2. In comparison with control, i.e. dapsone alone, methaemoglobinaemia due to dapsone fell by 27.3 +/- 6.7% and 26.6 +/- 5.6% the first and second weeks after commencement of cimetidine administration. The normally cyanotic appearance of the patient on the highest dose of dapsone (350 mg day-1), underwent marked improvement. 3. There was a significant increase in the trough plasma concentration of dapsone (2.8 +/- 0.8 x 10(-5)% dose ml-1) at day 21 in the presence of cimetidine compared with control (day 7, 1.9 +/- 0.6 x 10(-5)% dose ml-1, P less than 0.01). During the period of the study, dapsone-mediated control of the dermatitis herpetiformis in all six patients was unchanged. 4. Trough plasma concentrations of monoacetyl dapsone were significantly increased (P less than 0.05) at day 21 (1.9 +/- 1.0 x 10(-5)% dose ml-1) compared with day 7 (1.6 +/- 0.9 x 10(-5)% dose ml-1:control). 5. Over a 12 h period, 20.6 +/- 8.9% (day 0) of a dose of dapsone was detectable in urine as dapsone hydroxylamine. Significantly less dapsone hydroxylamine was recovered from urine at day 14 (15.0 +/- 8.4) in the presence of cimetidine, compared with day 0 (control: P less than 0.05). 6. The co-administration of cimetidine may be of value in increasing patient tolerance to dapsone, a widely used, effective, but comparatively toxic drug.

Adult↗
PubMed1992

Abnormal immunoglobulin G subclass production in response to keyhole limpet haemocyanin in atopic patients.

A proportion of patients with atopic dermatitis have elevated serum levels of IgG4. In order to investigate further this abnormality of IgG subclass production, atopic patients were immunized with the protein antigen keyhole limpet haemocyanin (KLH), and IgG subclass responses following primary and secondary immunization were analysed. In the primary response, titres of IgG1, 2 and 3 antibodies were lower in the atopic patients than in the controls. In contrast, titres of IgG4 were much higher for the patient group. In both patients and controls, the kinetics of IgG4 antibody production following the initial immunization with KLH showed a slow rise reaching a peak at 30 weeks. This time course indicated that the high IgG4 response was unlikely to be due to previous exposure of the patients to a cross-reacting antigen. A higher proportion of IgG4 was also seen in the atopic patients following secondary immunization; indeed, IgG4 was the major subclass in the secondary response in the patient group. In the controls, but not in the patients, titres of IgG4 anti-KLH correlated with total serum levels of IgG4, and some of the highest IgG4 antibody responses were detected in atopic patients whose serum IgG4 concentration was in the normal range. The results suggest that raised serum levels of IgG4 in atopy may reflect abnormal isotype regulation in response to protein antigens.

Adult↗
PubMed1992

A comparison of the ultraviolet B-induced erythemal response of back and buttock skin.

Thirty-six subjects (dermatology patients and normal volunteers) were phototested on back and buttock skin to determine their erythemal response to a geometrically increasing series of doses of ultraviolet B (UVB) radiation. The minimal erythema doses (MED) were recorded at 24 h post-irradiation and dose-response curves were constructed. A significant difference in MED was found between the 2 sites, with a higher value for buttock skin (median 38 mJ/cm2) than for the back (median 25 mJ/cm2). The slopes of response for the 2 sites were, however, found to be comparable, and there was no correlation between the slope of dose response and sun-reactive skin type at either site. Buttock skin, representing the constitutional skin colour, may provide a useful site for phototesting, especially in otherwise tanned individuals, providing that full dose-response curves are analysed.

Adolescent↗
PubMed1991

Lipids, proteins and corneocyte adhesion.

Three factors were examined for their relative contribution to corneocyte cohesion in normal adult pig ear: (1) extracellular lipids derived from membrane-coating granules (MCG); (2) corneosomes (modified stratum corneum desmosomes); and (3) corneocyte covalently bound lipid envelopes. Cohesion strength of the outer stratum corneum was measured directly by cohesometry, then altered by removing MCG lipids with solvents of varying potency. Cohesion changes were related to degree of lipid removal and ultrastructural alterations. Trypsin was also used to see if proteolysis of corneosomes promoted squame shedding. Potent solvents increased cohesion in relation to the amount of MCG lipid extracted. Tighter cohesion was due to fusion of the outer leaflets from covalently bound lipid envelopes on adjacent corneocytes. However, lipid envelopes are unlikely to mediate normal stratum corneum cohesion since MCG lipids play a significant anti-cohesive role preventing their apposition. Mild solvents partially removed MCG lipids causing a slight decrease in cohesion compared with untreated samples. This suggests a minor cohesive role for MCG lipids, consistent with maintaining their barrier function. We believe that corneosomes are the major determinant of stratum corneum cohesiveness because, in untreated skin, both cohesion and the number of corneosomes increased from the surface towards the granular layer. Furthermore, corneosome digestion with trypsin induced superficial squame shedding.

Animals↗
PubMed1991

Oral cyclosporin inhibits the expression of contact hypersensitivity in man.

The expression of delayed contact hypersensitivity was studied in 6 patients with chronic contact dermatitis treated with cyclosporin A (CsA) 5 mg/Kg/day. Quantitative patch test challenge was used to establish individual dose-response curves and threshold concentration to certain allergens in the European Standard Battery. In all 6 patients, responses were reduced over the whole range of allergen concentrations, and in the 5 in whom the threshold for expression of contact hypersensitivity could be determined, the threshold was raised by CsA therapy. In addition, the clinical manifestations of allergic contact dermatitis underwent complete resolution within 2-3 weeks of CsA therapy. It was concluded that CsA inhibits expression of delayed contact hypersensitivity reactions in human skin.

Administration, Oral↗
PubMed1991

Cyclosporin A in atopic dermatitis: therapeutic response is dissociated from effects on allergic reactions.

Fourteen patients with severe chronic atopic dermatitis were treated with cyclosporin A (CyA, Sandimmun; 5 mg/kg/day) for 7-16 weeks. All showed a marked clinical improvement and half could omit topical corticosteroid treatment during therapy. Adverse effects were minor, but two patients relapsed despite continued treatment. In the others, the disease recurred soon after stopping CyA. Serum IgE levels and prick-test responses were unchanged by CyA. Immediate and late-phase cutaneous responses to intradermal house dust mite antigen (HDM) were significantly increased during treatment; but a delayed response, present at 24 and 48 h, was unaffected. Four of six patients challenged with HDM patch tests to tape-stripped skin during treatment showed eczematous reactions at 48 h. Thus, cyclosporin A has a powerful therapeutic effect in atopic dermatitis but does not reduce allergic responses to inhalant antigens.

Adolescent↗
PubMed1991

Induction of lesions of dermatitis herpetiformis by autologous serum.

In the present study various factors which contribute to the initiation of lesions in dermatitis herpetiformis (DH) were examined. Thirty-one patients with DH, seven with bullous pemphigoid, two with linear IgA disease and two healthy subjects were studied either before starting treatment or after stopping dapsone for up to 5 days. Intradermal inoculation of freshly prepared autologous serum was followed after 18-24 h by the formation of DH-like lesions in 24/31 DH patients. The lesions were erythematous papules, often with vesicles and microscopically showed papillary tip microabscesses. Serum-induced formation of lesions only occurred in patients with active DH with some spontaneous lesion formation: it did not occur in any of the non-DH controls. The formation of lesions was dose-related, declining proportionately with dilution of the serum down to 1/16. Plasma prepared by various methods of anticoagulation (heparin, citrate, EDTA) caused lesser reactions, while addition of heparin or epsilon-amino caproic acid (EACA), but not citrate, to serum substantially inhibited the formation of lesions. This suggested the responsible factor might be a protease. Other vasoactive agents including histamine (1-4 micrograms) and compound 48/80 (1-5 micrograms) caused normal immediate wealing. DH-like lesions occurred in only one of 13 subjects challenged with histamine and two of nine challenged with 48/80. In all these, autologous serum elicited large vesicular responses. There is a factor(s) in serum in DH which can initiate the formation of lesions. This factor appears to be activated by clotting and can be inhibited by heparin and EACA, suggesting it may be a protease.

Blood↗
PubMed1991

Clinical report and investigation of a patient with localized heat urticaria.

Localized heat urticaria is a rare disorder, in which the nature of the mediator is not fully established. We report the case of a 41-year-old woman with the condition, dependent upon mast cell integrity, in which histamine was demonstrated as the dominant, if not sole mediator. Non-sedative antihistamines conferred some therapeutic benefit, but subsequent sequential desensitization has enabled her to lead a full and active life again.

Adult↗
PubMed1991

[Cyclosporin A in atopic dermatitis: therapeutic effect and effect on allergic reactions are dissociated from each other].

Fourteen patients with severe chronic atopic dermatitis were treated with cyclosporin A (CyA, Sandimmun; 5 mg/kg/day) for 7-16 weeks. All showed a marked clinical improvement and half could omit topical corticosteroid treatment during therapy. Adverse effects were minor, but two patients relapsed despite continued treatment. In the others, the disease recurred soon after stopping CyA. Serum IgE levels and prick-test responses were unchanged by CyA. Immediate and late-phase cutaneous responses to intradermal house dust mite antigen (HDM) were significantly increased during treatment; but a delayed response, present at 24 and 48 h, was unaffected. Four of six patients challenged with HDM patch tests to tape-stripped skin during treatment showed eczematous reactions at 48 h. Thus, cyclosporin A has a powerful therapeutic effect in atopic dermatitis but does not reduce allergic responses to inhalant antigens.

Adolescent↗
PubMed1990

Ultraviolet stimulated melanogenesis by human melanocytes is augmented by di-acyl glycerol but not TPA.

Epidermal melanocytes (MC) synthesize melanin in response to ultraviolet radiation (UVR). The mechanisms mediating the UV-induced activation of melanogenesis are unknown but since UVR induces turnover of membrane phospholipids generating prostaglandins (PGs) and other products, it is possible that one of these might provide the activating signal. We have examined the effects of prostaglandins (PGs) E1, E2, D2, F2 alpha, and di-acyl glycerol upon the UV-induced responses of cultured human MC and the Cloudman S91 melanoma cell line. The PGs had little effect on unirradiated cells and did not alter the response to UVR in either human MC or S91 melanoma cells. However, a synthetic analogue of di-acyl glycerol, 1-oleyl 2-acetyl glycerol (OAG), caused a significant (P less than 0.0001), dose-related augmentation of melanin content both in human MC (seven-fold) and S91 cells (three-fold). UVR caused a significant augmentation of the OAG-induced melanogenesis of both human MC and S91 cells. Since OAG is known to activate protein kinase C, it was possible that the observed modulation of the UVR signal could be via that pathway. Di-octanoyl glycerol, another di-acyl glycerol, which activates kinase C, caused a small (70%) increase in melanogenesis in MC which was not altered by UVR. However, 12-0 tetradecanoyl phorbol 13-acetate (TPA), a potent activator of protein kinase C, had no significant effect on either basal or UV-induced melanin synthesis in either cell type. These data suggest that the UV-induced signal activating melanogenesis could be mediated by di-acyl glycerol. Furthermore, they imply that the signal is transduced via an alternative, pathway that might be independent of protein kinase C.

Alprostadil↗
PubMed1990

Alpha-MSH causes a small rise in cAMP but has no effect on basal or ultraviolet-stimulated melanogenesis in human melanocytes.

The effects of alpha-melanocyte stimulating hormone (alpha-MSH) were studied on levels of cyclic adenosine 3',5'-monophosphate (cAMP), melanin content and response to ultraviolet radiation (UVR) in cultured human melanocytes (HuMC). Foreskin HuMC were cultured in a hormone-supplemented system not dependent on the presence of phorbol esters. Following addition of alpha-MSH (10(-6) M) there was a rise in cAMP levels maximal between 5 and 15 min to 9.4 +/- 3.2 pM/10(5) cells, while control levels were 3.6 +/- 0.7 pM/10(5) cells. After 7 days' culture in the presence of alpha-MSH (10(-8) -10(-6) M) the melanin content increased by only 35%, whereas Forskolin (10(-5) M) induced a 9.5-fold rise in cAMP after 5 min and a 10.9-fold rise in melanin content after 7 days. When HuMC were irradiated daily for 6 days with UVR (Helarium fluorescent lamps emitting 20% UVB, 80% UVA) melanin content rose 2.7-fold (SE 0.3). This was unchanged or slightly reduced in the presence of alpha-MSH (10(-8)-10(-6) M). Parallel observations on Cloudman S91 melanoma cells showed that alpha-MSH caused only an 80% increase in melanin content after 4 days. The rise in melanin content induced by three daily UV-irradiations (2.4-fold, SE 0.5) was unchanged by alpha-MSH (10(-8)-10(-6) M). Although alpha-MSH induces a small rise in cAMP in HuMC this does not result in melanogenesis, and the response to UVR is not affected by alpha-MSH in either HuMC or S91 cells.

1-Methyl-3-isobutylxanthine↗
PubMed1990

The influence of area of application on sensitization by dinitrochlorobenzene.

We have investigated the effect on sensitization of altering the area of application of 2,4,dinitrochlorobenzene (DNCB) at a constant dose per unit area. We showed that, when an area of less than 1 cm2 is used, this area is critical in determining the degree of sensitization. This contrasts with previous work that showed, for larger areas, an alteration in the area of application had little effect on sensitization, whereas keeping the area constant and increasing the concentration of DNCB increased the degree of sensitization. We suggest that not only is the amount of antigen important in determining response, but also the distribution of the antigen as presented to the afferent limb of the immune system.

Dermatitis, Contact↗
PubMed1990

Low-dose exposure to antigen induces sub-clinical sensitization.

We examined the effects of a small initial sensitizing dose of antigen (dinitrochlorobenzene, DNCB) on the subsequent response to a second, defined sensitizing stimulus. The second stimulus was actually the regimen of four doses of DNCB (3.125, 6.25, 12.5, and 25 micrograms) normally used as the elicitation challenge. In two separate experiments 13 and 18 control subjects received an initial 'challenge' with the four doses to induce sensitivity, and 4 weeks later their responses were determined with a second, elicitation challenge. Two groups of 12 and 15 experimental subjects received an initial dose predicted to induce clinically detectable sensitivity in 50% or 25%, respectively. Four weeks later, their responsiveness was determined with quantitative challenge and the subjects who gave no response received a further challenge 4 weeks later. Their responses, compared with those from the control subjects, were augmented, indicating that sub-clinical priming of the immune system had indeed occurred.

Analysis of Variance↗