Biomedical subjects
Publications and source records attributed to U R Hengge.
A 72-year-old patient with esophageal carcinoma developed a severe hand-foot syndrome during second-line therapy with the oral fluoropyrimidine capecitabine. We also summarize the current knowledge with regard to the hand-foot syndrome and distinguish it from palmoplantar erythrodysesthesia.
Significant progress has been made in corrective gene therapy of inherited skin diseases. This includes advances in vector technology, targeted gene expression, gene replacement, and the availability of appropriate animal models for a variety of candidate diseases. In addition, an increased understanding of the uptake and trafficking mechanisms inside keratinocytes has evolved. Topical application facilitates DNA vaccination through the skin, albeit clinical benefits have not yet materialized. However, the translation into clinical trials has only been partially mastered. The latter and the control of immune responses represent challenges for the research community.
We report on two female patients who presented with painful recurrent palpable purpura, ulcers and necroses on the extremities. The results of all examinations and laboratory tests considered together suggested a diagnosis of necrotizing leukocytoclastic vasculitis. Leukocytoclastic vasculitis is an inflammatory necrotizing condition of the superficial dermal vessels, presenting with variable clinical symptoms. In most cases it becomes manifest as palpable purpura, but hemorrhagic-necrotizing, bullous, nodular and urticarial presentations also occur. Common etiological factors include bacterial, viral or drug antigens, chronic infections (hepatitis B and C), non-Hodgkin lymphomas (monoclonal gammopathy, multiple myeloma), leukemia (hairy cell leukemia), and tumors (bronchial, breast, and gastric cancer) and also connective tissue disorders. In the course of the work-up, a plasmocytoma was discovered as the cause of the leukocytoclastic vasculitis, presenting in a similar way to livedo reticularis in one case and to pyoderma gangraenosum in the other.
HIV patients develop a variety of infectious and non-infectious diseases of the skin and mucous membranes. Some of these serve as indicator diseases for a weakening immune system. While none of the dermatological complications is pathognomonic, conditions such as oral hairy leukoplakia, herpes zoster, thrush, and eosinophilic folliculitis should make physicians consider the possibility of underlying HIV disease. Moreover, one has to consider HIV if these skin diseases take an atypical or severe course, or if they do not respond properly to appropriate medication. Frequent and rare dermatoses occurring in HIV infection are discussed.
BACKGROUND: Lichen sclerosus is a chronic inflammatory autoimmune disease causing significant sclerosis, atrophy and pruritus. Treatment remains unsatisfactory, with potent corticosteroids being the most effective therapy. OBJECTIVES: To conduct a multicentre, phase II trial to assess the safety and efficacy of tacrolimus ointment 0.1% for the treatment of lichen sclerosus with a follow-up period of 18 months at 10 university and teaching hospitals in Germany and Austria. METHODS: Eighty-four patients (49 women, 32 men and three girls) aged between 5 and 85 years with long-standing, active lichen sclerosus (79 with anogenital and five with extragenital localization) were treated with topical tacrolimus ointment 0.1% twice daily for 16 weeks. Computerized analysis of the lesional area was performed. The primary endpoint was clearance of active lichen sclerosus. Secondary endpoints were time to optimal response, reduction of sclerosis and duration of remission. RESULTS: The primary endpoint (clearance of active lichen sclerosus) was reached by 43% of patients at 24 weeks of treatment. Partial resolution was reached in 34% of patients. Maximal effects occurred between week 10 and 24 of therapy. Treatment led to a significant reduction of the total lesional area (P < 0.01) and to a significant decline in the total symptom score (P < 0.005). Symptoms (e.g. itching) and findings (erythema, erosions and induration) showed significant improvement. No serious adverse events were observed. There were three (9%) recurrences during the follow-up period. CONCLUSIONS: Topical tacrolimus ointment 0.1% was safe and effective for the treatment of long-standing active lichen sclerosus.
BACKGROUND: We describe a patient with an in situ carcinoma with the clinical presentation of an erythroplakia of the tongue in an area where DNA-aneuploidy was detected by means of exfoliative cytology (EC) and DNA-image-cytometry 32 months before. METHODS: Brush- and scalpel biopsies were obtained from a suspicious lesion of the right border of the tongue prior to scalpel biopsy. After Feulgen restaining of the specimens on glass slides, nuclear DNA-contents were measured using a TV image analysis system. RESULTS: A small reddish lesion of the tongue was diagnosed as malignant through EC and DNA-image-cytometry, whereas the synchronous histology from the same area showed only mild dysplasia. A subsequent scalpel biopsy 32 months after the first examination showed an in situ carcinoma. CONCLUSIONS: Non-invasive brush biopsies are of great importance for the very early identification of mucosal areas with a high risk for malignant transformation through cytological and DNA-cytometric examination.
We describe a general strategy for the identification of functional genes that, when downregulated, result in a selectable phenotype. This strategy is based on expression selection of cDNA fragments that counteract their cognate genes. A cDNA library containing random fragments expressed in human HepG2, A375 and CLS-354 cells was used to identify functional genes whose inhibition conferred resistance to Fas-induced apoptosis. Thirty-five clones were isolated, 28 of which were derived from unknown genes, that tagged 19 individual genes and 7 of which referred to known genes that tagged the apoptosis-related protein (APR)-1, -2 and indoleamine-pyrrole 2,3,-dioxygenase (IDO). The ability of APR-1-, -2- and IDO-derived antisense RNAs to induce resistance to Fas in HepG2, A375 and CLS-354 cells suggested that APR-1, -2 and IDO genes are involved in the machinery of Fas-mediated apoptosis. Our gene discovery strategy provides a generally applicable procedure to identify functional genes that interfere with apoptosis, and may therefore be clinically relevant for tumor therapy.
Lichen sclerosus et atrophicus is a chronic inflammatory disease that mainly affects women in the 5th decade. Although lichen sclerosus most often affects the anogenital region, it may occur in other cutaneous or mucosal sites. Increased fibroblast activity causes cutaneous sclerosis. Recent studies have identified lichen sclerosus as an autoantibody-mediated chronic inflammatory dermatosis. Autoantibodies against the extracellular matrix protein-1 are present in up to 80% of affected patients. In addition to the well-accepted therapy with potent corticosteroids, promising results have been obtained using calcineurin antagonists in the treatment of lichen sclerosus. Interdisciplinary management with regular monitoring can improve the clinical manifestations and quality of life.
Pigmented lesions of the genital mucosa are more frequent in women than in men. They represent a spectrum of different benign entities. A biopsy is always recommended when the diagnosis cannot be made with certainty on clinical examination and dermatoscopy. Differential diagnostic considerations include melanocytic nevi, blue nevi and syndromes featuring lentigines. Malignant melanomas of the penis and vulva are uncommon tumors which usually appear in elderly patients. They frequently present as painless palpable nodules at routine examination. The treatment consists of excision with histological control of the margins. An aggressive surgical approach has not been shown to prolong the poor 5-year survival. Cooperation with gynecologists and urologists is essential for the optimal management of such patients.
Vulvodynia (vulvar dysesthesia) refers to vulvar pain (burning, irritation and rawness) of the external female genitalia for more than 3 months without other dermatological or gynecological causes. The term primary vulvodynia should be reserved for vulvar vestibulitis and essential (dysesthetic) vulvodynia. Vulvar vestibulitis is characterized by dyspareunia, allodynia and vulvar erythema. Most patients are Caucasian, premenopausal and sexually active. The prevalence is estimated as high as 15%. Damage to the sympathetic nerves with an increased pain sensitivity is the likely explanation for the burning sensation. Psychological impairment, which is common in many patients, rather seems to be the consequence of the chronic disease than a primary condition. Essential vulvodynia is characterized by vulvar burning, which is characteristically not limited to the vestibulum. The patients are generally older and dyspareunia is less severe. The prevalence of essential vulvodynia is 1-3%. Various interdisciplinary approaches to these two rather frequent genital diseases are discussed.
A cross-sectional study was performed in 60 Cuban women of child-bearing age who were seropositive for human immunodeficiency virus (HIV) and 60 controls. Human papillomavirus (HPV) was identified most frequently, with oncogenic HPV serotypes 16, 33 and 58 detected in HIV-positive patients, and serotypes 11, 33 and 51 in the controls (relative risk 4.41; 95% CI 2.21-8.29). Syphilis and hepatitis B and C viruses were detected exclusively in HIV-seropositive women (p<0.05). Sexually transmitted diseases (STDs) appeared to pose a substantial health problem, especially for HIV-positive women. Clinics should consider screening and treatment for STDs as part of their HIV prevention programmes.
Significant progress has been made during the past decade in corrective gene therapy of the skin. This includes advances in vector technology, targeted gene expression, gene replacement, gene correction, and the availability of appropriate animal models for a variety of candidate diseases. While non-viral integration of large genes such as essential basement membrane proteins has been mastered, new challenges such as the control of immune responses lie ahead of the research community. Among the first skin diseases, patients with junctional epidermolysis bullosa (JEB) and xeroderma pigmentosum (XP) will enter clinical trials.
Papillomaviruses are prevalent throughout the world. They can cause warts or papillomas. Some papillomaviruses are also involved in the pathogenesis of malignant tumors. Cutaneous and anogenital warts are the most frequent viral disease of the skin. The incidence of verrucae vulgaris and condylomata is estimated to be 7-10% in the European population and 1% in the American population. HPV infections can be verified by clinical examination, cytology and histology, detection of antibodies, molecular techniques and directly via viral structures. Antibodies against HPV are considered markers for prolonged infection and cumulatively high expression of viral particles since they persist with low titers years after a lesion has resolved. Sensitivity only reaches 50-60% even in HPV DNA-positive patients. Serodiagnosis does not appear to be appropriate for routine practice. No virustatic treatment exists. Depending on wart-specific factors, compliance of the patient, and experience of the attending therapist, all ablative, chemodestructive or novel immuno modulatory procedures are comparable. However, there are enormous differences in price and effort required for treatment, which should be considered when choosing the method.
A 37-year-old patient presented with a generalized maculopapular rash, white oral plaques, and blurred vision of the left eye. Laboratory tests revealed the diagnosis of syphilis II and neurosyphilis in the context of HIV infection.
The skin is an interesting organ for human gene therapy due to accessibility, immunologic potential and synthesis capabilities. In this study, we attempted to visualize and measure the uptake of naked FITC-labeled plasmid by FACS analysis detecting up to 15% internalization in a dose- and time-dependent manner. Cycloheximide treatment inhibited the uptake by >90%, suggesting a protein-mediated uptake. The inhibition of different internalization pathways demonstrated that blocking macropinocytosis (by amiloride and N,N-dimethylamylorid) reduced DNA uptake by >85%, while the inhibition of clathrin-coated pits (by chlorpromazine) and caveolae (by nystatin/filipin III) did not limit the uptake. Colocalization studies using confocal laser microscopy revealed a time-dependent accumulation of plasmid DNA in endosomes and lysosomes. When a green fluorescent protein (GFP) expression vector was used, specific GFP-RNA became detectable by reverse transcriptase-PCR, whereas measurable amounts of protein could not be identified in FACS experiments. To detect the potential DNA receptors on the keratinocyte surface, membrane proteins were extracted and subjected to South-Western blotting using digoxigenin-labeled calf thymus and lambda-phage DNA. Two DNA-binding proteins, ezrin and moesin, known as plasma membrane-actin linkers, were identified by one- and two-dimensional-South-Western blots and matrix-assisted laser desorption and ionization-mass spectrometry. Ezrin and moesin are functionally associated with a number of transmembrane receptors such as the EGF, CD44 or ICAM-1 receptor. Taken together, naked plasmid DNA seems to enter human keratinocytes through different pathways, mainly by macropinocytosis. Two DNA-binding proteins were identified that seemed to be involved in binding/trafficking of internalized DNA.
BACKGROUND: Actinic keratoses (AKs) are premalignant lesions that can progress into squamous cell carcinoma. Imiquimod, which belongs to the new class of immune-response modifiers, was recently shown to be effective in the treatment of AKs. The underlying mechanisms are not fully understood. OBJECTIVES: To study the expression of individual genes in uninvolved skin and AKs before therapy and to elucidate the way in which the expression of these genes is influenced by imiquimod therapy. METHODS: We treated 13 patients with AK with imiquimod and compared gene expression before, during (five patients) and after (eight patients) therapy with that in uninvolved skin. We analysed genes coding for inflammatory cytokines or their receptors, adhesion molecules, anti-apoptotic proteins, p53 and toll-like receptors (TLRs) by reverse-transcriptase polymerase chain reaction. RESULTS: Comparing uninvolved skin and untreated AK, we found significant differences in the expression of interleukin (IL)-6, hurpin, TLR7 and TLR8. During imiquimod therapy, we detected a further upregulation of interferon-alpha, IL-6, IL-10 receptor 1 and TLR7. In contrast, two anti-apoptotic genes, hurpin and HAX-1, were downregulated. We did not detect significant differences in gene expression for p53, tumour necrosis factor-alpha and alpha- and beta-catenins. Clinically, the upregulated expression of the proinflammatory cytokines correlated with the local inflammation induced by imiquimod. CONCLUSIONS: Our results indicate that specific differences in gene expression are detectable between AK and uninvolved skin. Imiquimod influenced the expression of most genes analysed in this study. This work extends previous findings on the effects of imiquimod on gene regulation in AKs.
Immunomodulators include both immunostimulatory and immunosuppressive agents. Obligate contact sensitizers such as diphencyprone or dinitrochlorobenzene have been used against viral and autoimmune diseases. Newer agents such as the toll-like receptor agonists imiquimod and resiquimod have been clinically used to treat viral infections and skin cancers in immunocompetent and immunosuppressed patients. On the other hand, the topical immunosuppressive agents tacrolimus and pimecrolimus have been used with great success in the treatment of chronic inflammatory diseases in children and adults. The introduction of this new class of drugs (i.e. Calcineurin inhibitors) marked the beginning of the post-cortisone era in clinical dermatology. Toll-like receptor agonists and calcineurin antagonists will supplement corticosteroids to improve specific dermatological therapy. Topical immunotherapy with both immunostimulatory and immunosuppressive agents show potential for effective and patient-friendly treatment of inflammatory, infectious and neoplastic skin diseases. Long-term evaluation will define the tolerability and the safety profile.
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