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Biomedical subjects

E Fuchs

Publications and source records attributed to E Fuchs.

At least 37 records · Page 2Linked to original sources
PubMed1992

[Infections with Borrelia burgdorferi in Würzburg blood donors: antibody prevalence, clinical aspects and pathogen detection in antibody positive donors].

The prevalence of antibodies against Borrelia burgdorferi, the etiologic agent of Lyme borreliosis, was determined in a group of blood donors from the Würzburg area (Southern Germany). 26 of 472 donors (5.5%) tested positive in a hemagglutination test. When performing immunoblots only 13 donors (2.7%) gave rise to B. burgdorferi-specific antibodies. 9 of them were examined in more detail by anamnesis, physical examination, determination of inflammation parameters of the blood and polymerase chain reaction (PCR) analysis of urine. All persons were asymptomatic for Lyme borreliosis. One of 4, who remembered a tick bite, actually had suffered from an erythema migrans 5 years ago. Another one had been affected by fever, headaches and pains in the limbs, arthralgia and motoric disorder in both hands 6 months before examination. Analysis of the blood did not provide any evidence of an acute infection. In the urine of 2 donors we detected B. burgdorferi-specific DNA by PCR. No seroconversion due to blood transfusion could be observed, when 9 recipients of blood products provided by the 13 seropositive donors were serologically reexamined. PCR analysis of urine samples of 5 recipients was also negative.

Antibodies, Bacterial↗
PubMed1992

Quantification and excretion profiles of pteridines in primate urine.

Biopterin, 6-hydroxymethyl-pterin, isoxanthopterin, neopterin and, pterin were quantified in stress-free collected spontaneous morning urine samples from Callithrix jacchus, Saguinus fuscicollis, Saguinus labiatus, Saimiri sciureus, Presbytis entellus, Cercopithecus albogularis, Cercocebus torquatus, Macaca fascicularis, Hylobates concolor, Pongo pygmaeus, and Gorilla gorilla. In most species, biopterin was the most frequent urinary pteridine followed by neopterin. Sex differences in biopterin and neopterin excretion were observed in Gorilla gorilla and Pongo pygmaeus. Pterin and isoxanthopterin were only present in minor concentrations. 6-hydroxymethyl-pterin was barely detectable and not present in the urine of Saguinus labiatus, Saimiri sciureus, and both male Gorilla gorilla and Pongo pygmaeus.

Animals↗
PubMed1992

Localization and characterization of IGF-I receptors in fetal and adult human kidneys.

Human insulin-like growth factor I (IGF-I) is a growth and differentiating factor produced by various adult and fetal tissues. In the kidney, it has been linked to the proliferative response of renal tubular and glomerular cells, following unilateral or partial nephrectomy, in acromegaly, in diabetes mellitus and in glomerulonephritis. To gain insight into the potential effects of IGF-I in human kidney, a quantitative analysis of IGF-I-binding sites was performed in fetal and adult tissue using 125I-IGF-I. The ligand consistently labelled renal cortex, medulla, and glomeruli while renal vessels were not uniformly marked. The highest affinity of binding sites was found in glomeruli (adult kidneys: Kd 24.7 +/- 5.1 pM; Bmax 5.2 +/- 0.5 fmol/mg tissue equivalent (TE); n = 4; fetal kidneys: Kd 17.0 +/- 2.5 pM; Bmax 4.5 +/- 0.7 fmol/mg TE; n = 4) and cortical tubules, while vessels and renal medulla (adult kidneys: kd 47 +/- 3.9 pM, Bmax 2.6 +/- 0.3 fmol/mg TE; n = 4; fetal kidneys: kd 41.6 +/- 9.2 pM, Bmax 3.5 +/- 0.4 fmol/mg TE; n = 3) had only about half the affinity of binding and a significantly reduced maximal capacity. The strong binding of 125I-IGF-I to glomeruli supports the view that IGF-I may be involved in modulating glomerular structure and function. Fetal renal growth may depend on the action of IGF-I on glomerular cells and tubular epithelia of the kidney.

Autoradiography↗
PubMed1991

Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses.

Previously we demonstrated that transgenic mice expressing mutant basal epidermal keratin genes exhibited a phenotype resembling a group of autosomal dominant human skin disorders known as epidermolysis bullosa simplex (EBS). EBS diseases affect approximately 1: 50,000 and are of unknown etiology, although all subtypes exhibit blistering arising from basal cell cytolysis. We now demonstrate that two patients with spontaneous cases of Dowling-Meara EBS have point mutations in a critical region in one (K14) of two basal keratin genes. To demonstrate function, we engineered one of these point mutations in a cloned human K14 cDNA, and showed that a K14 with an Arg-125----Cys mutation disrupted keratin network formation in transfected keratinocytes and perturbed filament assembly in vitro. Since we had previously shown that keratin network perturbation is an essential component of EBS diseases, these data suggest that the basis for the phenotype in this patient resides in this point mutation.

Amino Acid Sequence↗
PubMed1991

Transcription factor AP2 and its role in epidermal-specific gene expression.

The epidermis is a stratified squamous epithelium whose major differentiation-specific products are keratins. To elucidate factors controlling keratinocyte-specific gene expression, we previously identified proximal and distal regulatory elements that act synergistically to drive keratinocyte-specific expression of the gene encoding human epidermal keratin K14. Control by the proximal element is mediated by a transcription factor, KER1, which is more abundant in nuclear extracts of keratinocytes than in extracts of other cell types, including fibroblasts, lymphocytes, and simple epithelial cells. In this report, we identify this factor as transcription factor AP2, shown to be transcribed in cells of epidermal and neural crest lineages. Furthermore, we demonstrate functional AP2 binding sites upstream from three additional epidermal genes, suggesting that AP2 may be generally involved in epidermal gene regulation. Finally, although AP2 is necessary, it is not sufficient for epidermal gene expression: a distal element contributes to tissue-specific expression of the human keratin K14 gene as judged by its ability to enhance expression of a heterologous promoter in keratinocytes but not in hepatoma cells. These results imply that a combination of factors is likely to contribute to epidermal-specific expression of the human keratin K14 gene.

Base Sequence↗
PubMed1991

Retinoid-mediated transcriptional regulation of keratin genes in human epidermal and squamous cell carcinoma cells.

Vitamin A and other retinoids profoundly inhibit morphological and biochemical features of epidermal differentiation in vivo and in vitro. To elucidate the molecular mechanisms underlying the differential expression of epidermal keratins and their regulation by retinoids, we examined retinoid-mediated changes in total protein expression, protein synthesis, mRNA expression, and transcription in cultured human keratinocytes and in squamous cell carcinoma (SCC-13) cells of epidermal origin. Our studies revealed that the epidermal keratins, K5, K6, K14, and K16, their mRNAs, and their transcripts were diminished relative to actin as a consequence of retinoic acid (RA) treatment. The effects were most pronounced in SCC-13 and were detected as early as 6 hr post-RA treatment, with enhancement over an additional 24-48 hr. Repression was also observed when 5' upstream sequences of K14 or K5 genes were used to drive expression of a chloramphenicol acetyltransferase reporter gene in SCC-13 keratinocytes. Both cell types were found to express mRNAs for the RA receptors alpha and gamma, which may be involved in the RA-mediated transcriptional changes in these cells. The rapid transcriptional changes in epidermal keratin genes were in striking contrast to the previously reported slow transcriptional changes in simple epithelial keratin genes.

Carcinoma, Squamous Cell↗
PubMed1991

Mutant keratin expression in transgenic mice causes marked abnormalities resembling a human genetic skin disease.

To explore the relationship between keratin gene mutations and genetic disease, we made transgenic mice expressing a mutant keratin in the basal layer of their stratified squamous epithelia. These mice exhibited abnormalities in epidermal architecture and often died prematurely. Blistering occurred easily, and basal cell cytolysis was evidence at the light and electron microscopy levels. Keratin filament formation was markedly altered, with keratin aggregates in basal cells. In contrast, terminally differentiating cells made keratin filaments and formed a stratum corneum. Recovery of outer layer cells was attributed to down-regulation of mutant keratin expression and concomitant induction of differentiation-specific keratins as cells terminally differentiate, and the fact that these cells arose from basal cells developing at a time when keratin expression was relatively low. Collectively, the pathobiology and biochemistry of the transgenic mice and their cultured keratinocytes bore a resemblance to a group of genetic disorders known as epidermolysis bullosa simplex.

Animals↗
PubMed1991

[Malaria prophylaxis and self-care 1990--problems and current solutions].

For successful malaria prophylaxis, future travelers need to be informed about the risks of infection and about systematic measures to be taken against mosquito bites. For visits in areas of high transmission, continuous chemoprophylaxis is recommended, whereas in regions with low transmission a stand-by medication for self-therapy is sufficient. Each of these four measures has some problems which are discussed here in addition to the recently published recommendations by the Swiss Working Group for Medical Advice to Travelers.

Antimalarials↗
PubMed1991

Keratin genes, epidermal differentiation and animal models for the study of human skin diseases.

The examples shown here illustrate the power of gene targeting to the epidermis as a means of developing animal models for the study of human skin diseases. In this short review, I have focused on contributions which stem predominantly from my own laboratory [31, 32, 34, 37, 47]. However, other laboratories have also contributed heavily to the development of this technology [28-30, 35, 36]. The opportunities for these models are vast: there are a myriad of human skin diseases which have been characterized extensively at a biological level, but whose aetiology is presently unknown. A combined knowledge of (a) the biochemistry of epidermal differentiation; (b) epidermal-specific gene expression; and (c) transgenic mouse technology has provided the foundation for these and future studies in this area.

Animals↗
PubMed1991

Sorting out IF networks: consequences of domain swapping on IF recognition and assembly.

Vimentin and keratin are coexpressed in many cells, but they segregate into two distinct intermediate filament (IF) networks. To understand the molecular basis for the sorting out of these IF subunits, we genetically engineered cDNAs encoding hybrid IF proteins composed of part vimentin and part type I keratin. When these cDNAs were transiently expressed in cells containing vimentin, keratin, or both IFs, the hybrid IF proteins all recognized one or the other or both networks. The ability to distinguish networks was dependent upon which segments of IF proteins were present in each construct. Constructs containing sequences encoding either helix 1B or helix 2B seemed to be the most critical in conferring IF recognition. At least for type I keratins, recognition was exerted at the level of dimer formation with wild-type type II keratin, as demonstrated by anion exchange chromatography. Interestingly, despite the fact that swapping of helical domains was not as deleterious to IF structure/function as deletion of helical domains, keratin/vimentin hybrids still caused structural aberrations in one or more of the cytoplasmic IF network. Thus, sequence diversity among IF proteins seems to influence not only coiled-coil but also higher ordered associations leading to 10-nm filament formation and/or IF interactions with other cellular organelles/proteins.

Amino Acid Sequence↗
PubMed1991

A function for keratins and a common thread among different types of epidermolysis bullosa simplex diseases.

Previously we demonstrated that transgenic mice expressing a mutant keratin in the basal layer of their stratified squamous epithelia exhibited a phenotype bearing resemblance to a subclass (Dowling Meara) of a heterogeneous group of human skin disorders known as epidermolysis bullosa simplex (EBS) (Vassar, R., P. A. Coulombe, L. Degenstein, K. Albers, E. Fuchs. 1991. Cell. 64:365-380.). The extent to which subtypes of EBS diseases might be genetically related is unknown, although they all exhibit skin blistering as a consequence of basal cell cytolysis. We have now examined transgenic mice expressing a range of keratin mutants which perturb keratin filament assembly to varying degrees. We have generated phenotypes which include most subtypes of EBS, demonstrating for the first time that at least in mice, these diseases can be generated by different mutations within a single gene. A strong correlation existed between the severity of the disease and the extent to which the keratin filament network was disrupted, implicating perturbations in keratin networks as an essential component of these diseases. Some keratin mutants elicited subtle perturbations, with no signs of the tonofilament clumping typical of Dowling-Meara EBS and our previous transgenic mice. Importantly, basal cell cytolysis still occurred, thereby uncoupling cytolysis from the generation of large, insoluble cytoplasmic protein aggregates. Moreover, cell rupture occurred in a narrowly defined subnuclear zone, and seemed to involve three factors: (a) filament perturbation, (b) the columnar shape of the basal cell, and (c) physical trauma. This work provides the best evidence to date for a structural function of a cytoplasmic intermediate filament network, namely to impart mechanical integrity to the cell in the context of its tissue.

Animals↗
PubMed1991

Transforming growth factor alpha induces collagen degradation and cell migration in differentiating human epidermal raft cultures.

When cultured on plastic and treated with transforming growth factor alpha (TGF alpha), human keratinocytes exhibit an increase in proliferation at the colony periphery, apparently as a consequence of enhanced cell migration (Barrandon and Green, 1987). To investigate the effects of TGF alpha on a differentiating stratified squamous epithelium and to begin to examine the molecular basis mediating this influence, we cultured human epidermal cells on a gelled lattice of collagen and fibroblasts, floating on the air-liquid interface. Under these conditions, raft cultures differentiate and exhibit morphological and biochemical features of human skin in vivo (Asselineau et al., 1986; Kopan et al., 1987). When 3-wk-old raft cultures were treated with TGF alpha, basal cells showed a marked increase in cell proliferation. At elevated concentrations of TGF alpha, the organization of cells within the artificial tissue changed and islands of basal cells entered the collagen matrix. Biochemical analysis of the response revealed that type I collagenase and gelatinase were induced by keratinocytes within 12 h after TGF alpha treatment. In contrast, invasion of basal cells into the collagen matrix was not significant until 48-72 h post-treatment, suggesting that collagenase and gelatinase production may be a prerequisite to this phenomenon. These results have important implications for the possible role of TGF alpha in squamous cell carcinoma and tumor invasion.

Cell Differentiation↗
PubMed1991

Racial heterogeneity of HIV antigenemia in people with HIV infection.

We compared the prevalence of HIV p24 antigenemia in black and white US patients with HIV infection. The prevalence of HIV antigenemia increased with severity of HIV disease (P less than 0.001). In all clinical categories, whites were more likely to be HIV-antigenemic than blacks (overall prevalence 38 versus 18%; P less than 0.01). Anti-p24 antibodies were detected in a higher proportion of blacks (84%) than whites (65%; P = 0.02). Blacks had significantly higher total serum immunoglobulin levels than whites (median 3.8 versus 3.2 mg/dl; P less than 0.00001). Racial differences in HIV antigen expression may result from differences in humoral response to HIV infection. These differences should be considered when HIV antigen is used as a surrogate marker in clinical trials.

Adult↗
PubMed1991

Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation.

Transforming growth factor-alpha (TGF-alpha) is thought to be the major autocrine factor controlling growth in epidermal cells. To explore further the role of TGF-alpha in epidermal growth and differentiation, we used a human keratin K14 promoter to target expression of rat TGF-alpha cDNA to the stratified squamous epithelia of transgenic mice. Unexpectedly, the only regions of epidermis especially responsive to TGF-alpha overexpression were those that were normally thick and where hair follicle density was typically low. This included most, if not all, body skin from 2-day- to 2-week-old mice, and ear, footpad, tail, and scrotum skin in adult mice. In these regions, excess TGF-alpha resulted in thicker epidermis and more stunted hair growth. Epidermal thickening was attributed both to cell hypertrophy and to a proportional increase in the number of basal, spinous, granular, and stratum corneum cells. During both postnatal development and epidermal differentiation, responsiveness to elevated TGF-alpha seemed to correlate with existing epidermal growth factor (EGF) receptor levels, and we saw no evidence for TGF-alpha-mediated control of EGF receptor (EGFR) expression. In adults, no squamous cell carcinomas were detected, but benign papillomas were common, developing primarily in regions of mechanical irritation or wounding. In addition, adult transgenic skin that was still both sensitive to TGF-alpha and subject to mild irritation displayed localized regions of leukocytic infiltration and granular layer loss, characteristics frequently seen in psoriasis in humans. These unusual regional and developmental effects of TGF-alpha suggest a natural role for the growth factor in (1) controlling epidermal thickness during development and differentiation, (2) involvement in papilloma formation, presumably in conjunction with TGF-beta, and (3) involvement in psoriasis, in conjunction with some as yet unidentified secondary stimulus stemming from mild mechanical irritation/bacterial infection.

Animals↗
PubMed1991

Three epidermal and one simple epithelial type II keratin genes map to human chromosome 12.

We have localized the genes which encode the human type II epidermal keratins K5, K6a, and K6b and the simple epithelial keratin K7 (KRT5, KRT6A, KRT6B, and KRT7, respectively) to chromosome 12 using Southern blot analysis of somatic cell hybrids. In addition, we have sublocalized the genes for K6a and K7 to bands 12q12----q14 on the long arm of this chromosome by in situ hybridization of metaphase chromosomes.

Blotting, Southern↗