Biomedical subjects
Publications and source records attributed to K Neuber.
Since birth, a 43 year-old man displayed a nevus sebaceus on the right temple. The histopathology revealed two distinct adnexal neoplasms associated with this lesion: a syringocystadenoma papilliferum and a trichoblastoma. We describe the combination of these entities in this report.
To study the effects of apneic pauses, sighs, and breathing patterns on functional residual capacity (FRC), we measured FRC repeatedly in 48 healthy preterm infants (weight at study 2,042 +/- 316 g [mean +/- SD], postconceptional age 36.6 +/- 2.0 wk), during unsedated sleep using a modified heliox/nitrogen washout technique. Breathing movements and pulse oximeter saturation (SpO2) were recorded throughout and recordings analyzed for the presence of regular and nonregular breathing pattern, apneic pauses, sighs, and desaturations (SpO2 < 90%) during the last 2 min prior to each FRC measurement. FRC was lower during nonregular than during regular breathing pattern (23.3 +/- 7.2 ml/kg versus 26.9 +/- 7.8 ml/kg, p < 0.02); however, this apparent effect of breathing pattern disappeared after controlling the data for apneic pauses. Apneic pauses resulted in a significant decrease in FRC: mean FRC was 20.0 +/- 6.8 ml/kg if measured within 2 min of an apneic pause, 26.0 +/- 6.9 ml/kg if measured after a sigh (p < 0.001), and 24.0 +/- 7.7 ml/kg if there had been neither a sigh nor an apneic pause (p < 0.05). The interval between the apneic pause and the FRC measurement had no effect on FRC. There was an inverse correlation between FRC and the speed with which SpO2 fell during desaturation (r = -O.5, p < 0.03). Apneic pauses resulted in a persistent reduction in FRC in these preterm infants. Sighs appeared to restore FRC. The significant relationship between FRC and the speed of desaturation found in this study underscores the importance of endogenous or exogenous strategies that help to increase FRC, such as sighs or the application of continuous positive airway pressure, for the stability of oxygenation in preterm infants who have difficulty maintaining their oxygenation.
BACKGROUND: Chronic lymphocytic leukemia of the B-cell type (B-CLL) associated with highly elevated serum IgE levels and skin involvement has rarely been observed. Furthermore, not much is known about therapeutic strategies in such diseases. OBJECTIVE: We describe a 56-year-old male patient with a 5-year history of chronic and relapsing pruritic skin lesions as well as recurrent Staphylococcus aureus infections of the skin. RESULTS: Histologically, a lymphocytic and eosinophilic skin infiltrate was seen. Laboratory analysis revealed lymphocytosis (46.5%), eosinophilia (11.9%) as well as markedly elevated serum IgE levels (140,000 IU/ml). Immunohistology showed dermal B cells with intracytoplasmic IgE. Bone marrow biopsy showed a diffuse infiltrate of small lymphoplasmacytic lymphocytes. Over 80% of blood and bone marrow lymphocytes were CD5 +, CD19 +, CD20 +, CD23 + and CD38 +. Based on these findings, the diagnosis of B-CLL was made. The strong pruritus was resistant to antihistamines and steroids. Therefore, a trial with interferon (IFN) gamma 50 micrograms s.c. daily was started in order to suppress elevated serum IgE but failed. After 1.5 million units s.c. of IFN-alpha 2b every second day for 2 weeks, pruritus and serum IgE levels diminished markedly (48,000 IU/ml). Skin lesions, pruritus as well as skin infection and serum IgE level improved under continuing IFN-alpha 2b therapy for 2 years. CONCLUSION: In cases with suspected hyper-IgE syndrome, hematological neoplasias have to be excluded. The results argue for a benefical effect of IFN-alpha 2b in suppressing IgE production and symptoms of pruritus in an early-stage B-CLL.
Chronic skin colonization with Staphylococcus aureus is a characteristic feature of atopic eczema, and about 60% of S. aureus strains isolated from the skin of patients with atopic eczema secrete enterotoxins. T-cell stimulation by staphylococcal enterotoxins is restricted to the V beta-chain of the T-cell receptor. Therefore, the expression of different V beta-chains (V beta 3, 5 a,b,c, 6, 8, 12) on peripheral blood T-cells (CD4+) from patients with atopic eczema was measured by flowcytometry before and after stimulation with staphylococcal enterotoxin B. Lymphocytes from healthy donors served as controls. Additionally, the expression of V beta-chains in normal skin and in lesional skin of patients with atopic eczema was determined by immunofluorescence histology. In atopic eczema, higher numbers of CD4+ T-cells expressed V beta 3, V beta 8 and V beta 12 compared to the control group. No correlation between S. aureus enterotoxin B-stimulated V beta-expression and HLA-haplotypes was found. In lesional skin of patients with atopic eczema most of the infiltrating T-cells were V beta 3+, whereas in normal skin only very few T-cell receptor-expressing cells were detected. To evaluate the significance of these T-cell clones for allergic inflammation, T-cells from patients with atopic eczema and normal donors were stimulated with monoclonal antibodies against V beta 3, 5(c) and 8. Afterwards, the proliferative response of lymphocytes as well as IL-5 and IFN gamma synthesis were measured. T-cells from patients with atopic eczema showed a significantly higher proliferation and IL-5 secretion than normal donors after stimulation with monoclonal antibodies against V beta 3 and V beta 8. In contrast, the monoclonal antibodies directed to V beta 5(c) induced a markedly elevated proliferation and IFN gamma production of normal lymphocytes compared to patients with atopic eczema. Our results suggest a preferential expression of certain V beta-subgroups during inflammation in atopic eczema; this may be explained by a selective stimulation of TH2-cells via S. aureus-derived enterotoxins.
Flow cytometric analysis of T-cell surface markers in peripheral blood has revealed abnormal patterns in patients with cutaneous T-cell lymphomas (CTCL). Here we investigated CD7, CD25, CD45RO and CD45RA expression on CD4+ T-lymphocytes in patients with CTCL stage I/II and III/IV and in patients with severe inflammatory skin diseases (ISD), as well as in healthy controls. Only late stage CTCL (III/IV) showed a lymphocytosis with a distinct surface marker pattern: CD3+, CD4+, CD8-, CD7-, CD45RO+, CD45RA-. Early stage CTCL (I/II) showed normal lymphocyte counts, a normal T-helper cell expression of CD7, CD45RO and CD45RA, and a slightly increased percentage of CD4+ CD25+ lymphocytes, which was also found in ISD. It is concluded that flow cytometric analysis of the above T-cell surface markers may be useful in the diagnosis of patients with late stage CTCL. However it does not allow us to distinguish patients with early stage CTCL from patients with ISD or controls.
The aetiology of seborrhoeic dermatitis (SD) is still unknown. An increased number of Pityrosposurm ovale in lesional skin of patients with SD has been suggested to play a crucial role in the pathogenesis of the disease since double-blind trials with antifungal drugs (e.g. ketoconazole) have shown that these agents result in a significantly reduced disease intensity. The frequent association of HIV infection and SD may be due to a suppressed cell-mediated immunity. In order to characterize the role of the humoral and cellular immune response in patients with SD the effects of a P. ovale extract on the proliferation of, and interleukin-2 (IL-2), IL-10 by an interferon-gamma (IFN gamma) production, and immunoglobulin (IgA, IgG, IgM) synthesis by peripheral blood mononuclear cells (PBMC) from patients with SD were studied in vitro. Healthy volunteers served as controls. PBMC from normal donors responded with a significantly increased proliferation to P. ovale antigen, whereas cells from patients with SD did not. Additionally, IL-2 and IFN gamma production by PBMC from patients with SD was markedly depressed compared with normal cells after stimulation with P. ovale. However, stimulation of PBMC from SD patients with P. ovale antigen induced significantly increased IL-10 synthesis. IgA, IgG and IgM synthesis was significantly increased in cultures of PBMC from patients with SD whether the cells were antigen-stimulated or not. Our results support the assumption that strong skin colonization with P. ovale in SD is due to an altered cellular immunity, which may be induced by increased IL-10 secretion.
Interactions between keratinocytes and mononuclear cells via cytokines and adhesion molecules are thought to play a crucial part in inflammatory skin diseases. The cytokine-mediated effects of peripheral blood mononuclear cells (PBMC) from patients with atopic eczema (AE) and healthy individuals on keratinocytes (HaCaT) were investigated in vitro. A new coculture model (Transwell system) which consists of a lower and an upper compartment, which are separated by a polycarbonate-treated membrane, was established. 3[H]thymidine incorporation of keratinocytes and lymphocytes, as well as IL-6, IL-8 and IFN-gamma synthesis, were measured. Keratinocyte proliferation was significantly enhanced in the presence of PBMC from patients with AE. In contrast, PBMC from normal donors did not enhance HaCaT cell proliferation when they were cocultured. Lymphocytes from patients with AE showed a significantly enhanced proliferation after coculture with keratinocytes. However, PBMC from normal donors did not proliferate in the presence of HaCaT cells. Keratinocyte supernatants incubated with PBMC from either atopic or normal volunteers induced a suppression of lymphocyte 3[H]thymidine incorporation. In supernatants from cocultures of PBMC from patients with AE and keratinocytes, significantly enhanced amounts of IL-6 and IL-8, compared with normal donor's lymphocytes and HaCaT cells, were measured. No differences in IFN gamma production were observed. When PBMC were cultured without HaCaT cells, supernatants contained equal levels of IL-6, IL-8 and IFN-gamma in normal donors and in patients with AE. Interestingly, HaCaT cells spontaneously secrete measurable amounts of IL-6, IL-8 and IFN-gamma. Blocking experiments with neutralizing antibodies against these interleukins showed a complete inhibition of keratinocyte proliferation when PBMC from normal donors were used whereas the proliferative potency of PBMC supernatants from patients with AE on keratinocytes remained. Our data indicate that (i) PBMC from patients with AE stimulate keratinocyte proliferation via soluble factor(s) that are different from IL-6, IL-8 and IFN-gamma; (ii) probably, HaCaT cells spontaneously produce lymphocyte/monocyte inhibitory soluble factors and IL-6, IL-8 as well as IFN-gamma; and (iii) secretion and/or activity of keratinocyte-derived inhibitory mediators is regulated via cytokines of PBMC infiltrating inflammatory skin.
It has been suggested that in atopic eczema (AE) a reduced lymphocyte response to T-cell mitogens in vitro is secondary to altered production of cytokines or inflammatory mediators. We investigated, in parallel, the mitogen-induced T-cell proliferation, monocyte interleukin-1 beta (IL-1 beta) production, and prostaglandin E2 (PGE2) production of monocytes and of peripheral blood mononuclear cells (PBMC) in AE patients and non-atopic controls. After stimulation with concanavalin A (Con A) PBMC of AE patients showed a significantly reduced proliferative response compared with the controls. The monocyte production of IL-1 beta after stimulation with lipopolysaccharide (LPS) was significantly decreased in AE. No differences between AE patients and controls were observed with regard to the PGE2 production of PBMC after stimulation with Con A or the monocyte release of PGE2 after LPS stimulation. Because IL-1 plays a central role in the activation of T-cell proliferation, the decreased monocyte IL-1 beta production may provide a plausible explanation for the reduced mitogen response of T cells in AE.
To study the possible influence of sleeping position on arterial oxygen saturation, measured by pulse oximetry (SpO2), 7-h overnight recordings of breathing movements and ECG were performed in 43 infants (median age 2.4 months, range 0.2-11 months) at increased risk of sudden infant death syndrome (SIDS). Infants were randomly allocated to start sleeping either in their usual sleeping position or in the opposite position. After 3.5 h, all infants were gently turned over. Thus, each infant served as their own control. Recordings were analysed for sleep time, baseline SpO2 (only during regular breathing), and the number and duration of desaturations (a decrease in SpO2 to < or = 80%). In the prone position, a significantly higher proportion of time was spent asleep (median 79% versus 70%; p < 0.05). Median baseline SpO2 was 98.8% (91.7-100%) in the prone and 99.0% (92.0-100%) in the supine position (ns). A total of 191 desaturations were found in 29 recordings; 96 in the prone and 95 in the supine position (ns). One infant subsequently died of SIDS while sleeping in the prone position. He had a relatively high number of desaturations (n = 12) which all occurred in the prone position. These results confirm earlier studies which could not find a significant influence of sleeping position on baseline oxygenation. The occurrence of desaturations in the prone position only in the infant who subsequently died requires further investigation.
Patients with atopic dermatitis (AD) are frequently colonized with Staphylococcus aureus strains secreting exotoxins such as the staphylococcal enterotoxin B (SEB) and A (SEA). Nonetheless the role of SEB and SEA in AD is yet unknown. We analyzed the responsiveness of peripheral blood mononuclear cells (PBMCs) and isolated T cells from donors with AD and from normal donors to SEB and SEA. PBMCs as well as T cells from normal donors showed a significantly enhanced proliferation after stimulation with enterotoxin B, whereas the 3H-thymidine uptake of the T lymphocytes from patients with AD was markedly suppressed. Furthermore, we show that IFN-gamma mRNA and protein and mRNA for both chains of IL-12 (p35 and p40) are produced in human PBMCs from normal donors upon stimulation with SEB and SEA. In contrast to normal donors T cells from donors with AD predominantly express mRNA for IL-4, IL-5, and only diminished levels for IFN-gamma and IL-12 upon stimulation with SEB and SEA. Furthermore, in contrast to normal donors, PBMCs from donors with AD spontaneously produce high levels of IgE and express increased levels of CD23, the low-affinity receptor for IgE. Nonetheless, the superantigens by themselves, from 0.1 fg up to 1 microgram/10(6) cells, induced neither IgE secretion nor CD23 expression on PBMCs. Moreover, the addition of superantigens to IL-4-treated PBMC cultures diminished or totally suppressed the IL-4-induced IgE synthesis and CD23 expression. No differences were observed between PBMCs from normal donors of donors with AD. Both PBMCs isolated from normal and atopic donors produced high levels of soluble IL-4-receptor (up to 210 +/- 90 pg/ml). Addition of soluble IL-4-receptor to PBMC cultures downregulated the IL-4-induced IgE synthesis and CD23 expression in unstimulated as well as in SEB-stimulated PBMCs from normal donors and donors with AD. Our results suggest that superantigen-producing staphylococcal strains on the skin of patients with AD may modulate and/or amplify allergic inflammation.
BACKGROUND: ICAM-1 is known to be strongly expressed on keratinocytes in lesional atopic eczema correlating with the degree of inflammation. ELAM-1 was found to be expressed on dermal vascular endothelium in lesional atopic eczematous skin. OBJECTIVE: The present study was performed to investigate whether elevated serum levels of soluble forms of these molecules are detectable in patients with severe atopic eczema and whether these parameters could be useful markers for disease activity. METHODS: Serum levels of soluble ICAM-1 (sICAM-1) and ELAM-1 (sELAM-1) were measured by ELISA in 18 patients with severe atopic eczema before and after UVA1 therapy. RESULTS: Before onset of treatment, serum sICAM-1 (565 +/- 99 ng/ml) and sELAM-1 (89.7 +/- 29.9 ng/ml) levels were significantly (p < 0.001) elevated compared to 22 healthy control persons (296 +/- 46 and 48.8 +/- 22.7 ng/ml). After achievement of significant clinical improvement after 3 weeks of UVA1 therapy, there was neither a decrease in serum sICAM-1 nor in sELAM-1 levels. The posttherapeutic serum sICAM-1 and sELAM-1 values remained elevated (p < 0.001) above the normal range. CONCLUSION: Based on these data we suggest that (1) serum sICAM-1 and sELAM-1 are elevated in patients with severe atopic eczema, (2) sICAM-1 does not decrease together with reduction of ICAM-1-positive keratinocytes in atopic eczema following clinical improvement and might therefore be mainly of a different origin, i.e. leukocytes/endothelial cells, and that (3) sICAM-1 and sELAM-1 seem not to be suitable markers of actual disease activity in severe atopic eczema.
Evidence for a possible role of the lipophilic yeast Pityrosporum ovale in the pathophysiology of atopic eczema has been found both in laboratory and therapeutical studies. Positive type I prick test reactions to P. ovale correlate with the intensity of eczematous skin lesions in the head and neck regions of patients with atopic eczema. Furthermore, antifungal treatment has been shown to be helpful in atopic eczema. In the present study the effect of P. ovale on IgE synthesis and cytokine production (IL-2, IFN gamma, IL-4, IL-10) was investigated in patients with atopic eczema, in vitro. Eight patients with atopic eczema were studied; of these, 5 patients had specific IgE antibodies against P. ovale, as determined by fluoroimmunoassay (RAST). The control group consisted of 5 healthy non-atopic, P. ovale IgE-antibody-negative volunteers. Freshly isolated peripheral blood mononuclear cells (PBMC) were incubated in the presence of different antigen concentrations (0.01, 0.1, 1.0, 10 micrograms/l x 10(6) cells) of P. ovale. IgE contents in the cell culture supematants were significantly elevated in RAST(+) patients with atopic eczema (p < 0.05), compared with RAST(-) atopic eczema patients and healthy volunteers. Coincubation of P. ovale-stimulated PBMC with IL-4 (50 U/l/ 1 x 10(6) cells) resulted in a significantly higher IgE synthesis only in the RAST(+) atopic eczema patients. Additionally, incubation of PBMC from RAST(+) patients with atopic eczema led to an elevated synthesis of the TH2 related cytokines IL-4 and IL-10. Within the atopic eczema group, two subgroups differed markedly in their response to P. ovale antigen stimulation with a good correlation to the presence of specific IgE in serum and in vitro IL-4 and IL-10 production. The data support the assumption that P. ovale antigens might play a role in skin inflammation in at least a subgroup of patients with atopic eczema characterized by the presence of specific IgE antibodies to P. ovale.
Twenty-two patients with severe atopic eczema were included in a therapy study with UV-A1 (wavelengths > 340 nm) treatment. The patients were divided into two dose groups, each consisting of 11 patients. One group received 10 J/cm2 and the other 50 J/cm2 five times a week for 3 consecutive weeks. No topical or systemical steroids or antihistamines were allowed. Using the SCORAD index as a measure of disease activity before onset of therapy and after 10 and 15 treatments, we observed a significant improvement in both dose groups after 15 treatments (10 J/cm2: p < 0.05, 50 J/cm2: p < 0.005). After 10 treatments only the improvement in the 50 J/cm2 group was significant (p < 0.005); the difference between the two dose groups was significant (p < 0.05). The clinical efficacy of treatment was reflected neither by a decrease of serum IgE nor by a decrease of elevated serum levels of soluble adhesion molecules sICAM-1 and sELAM-1 in the two dose groups. In contrast, a marked but not significant decrease of serum ECP could be observed in the 50 J/cm2 group only. We conclude from these and other published data that although 10 J/cm2 UV-A1 has a limited effect on patients with severe atopic eczema, higher doses are of higher efficiency in the treatment of this condition.
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The bacterial skin flora of patients with atopic eczema is different from that in healthy normal persons. In addition, such patients more often suffer from microbial infections. Differences in sebum and sweat secretion and increased bacterial adhesion to epithelial cells in atopic eczema may predispose to enhanced amounts of Staphylococcus aureus, for example, on the skin. Defective host-defence mechanisms with dysfunction of cellular and humoral immune reactions have been suggested. On the other hand, bacterial antigens may induce allergic reactions, e.g. increased IgE synthesis and enhanced expression of the low-affinity receptor for IgE (CD23, Fc epsilon RII), and the release of inflammatory mediators such as leukotrienes and histamine. The production of bacterial toxins might be important for the pathophysiology of atopic eczema. This paper summarizes the present data and tries to integrate them into a model for the induction of atopic eczema.
The pathophysiology of atopic eczema (AE) is still poorly understood. One possible concept favors IgE-mediated reactivity towards allergens that enter the skin from the outside or through the blood. Microorganisms of the cutaneous flora also might represent a stimulus for allergic skin reactions. Abnormal bacterial skin colonization is a characteristic feature of AE. Staphylococcus aureus (S. aureus) is the most common pathogen. Binding to host cells involves special receptors, such as fibronectin or laminin. Specific IgE antibodies to S. aureus can be detected in the blood. Whereas the clinical relevance of anti-staphylococcal antibodies is still controversial, specific IgE antibodies to Pityrosporum species as well as positive type I prick test reactions to these yeasts seem to correlate with the intensity of eczematous lesions in the head and neck regions of patients with AE. Both antimicrobial and antifungal treatment has been shown helpful in some cases of AE.