German evidence and consensus-based (S3) guideline: Vaccination recommendations for the prevention of HPV-associated lesions.

Anogenital and oropharyngeal infections with human papilloma viruses (HPV) are common. Clinically manifest disease may significantly impact quality of life; the treatment of HPV-associated lesions is associated with a high rate of recurrence and invasive neoplasms, such as cervical, anal, vulvar, penile, and oropharyngeal cancers, which are characterized by significant morbidity and mortality. Vaccination against HPV is an effective and safe measure for the primary prevention of HPV-associated lesions, but immunization rates are still low in Germany. The present publication is an abridged version of the German evidence and consensus-based guideline "Vaccination recommendations for the prevention of HPV-associated lesions", which is available on the website of the German Association of the Scientific Medical Societies (AWMF). On the basis of a systematic review with meta-analyses, a representative panel developed and agreed upon recommendations for the vaccination of different populations against HPV. In addition, consensus-based recommendations were developed for specific issues relevant to everyday practice. Based on current evidence and a representative expert consensus, these recommendations are intended to provide guidance in a field in which there is often uncertainty and in which both patients and health care providers are sometimes confronted with controversial and emotionally charged points of view.

[S2k guideline for the diagnosis and therapy of zoster and post-zoster neuralgia]. / S2k-Leitlinie zur Diagnostik und Therapie des Zoster und der Postzosterneuralgie.

This guideline is aimed at registrars and consultants in dermatology, ophthalmology, ENT, pediatrics, neurology, virology as well as infectiology, anaesthesia and generell medicine as well as policymakers and payers and purchasers of care. It was developed by dermatologists, virologists, ophthalmologists, ENT physicians, neurologists, pediatrician and anesthetists using a formal consensus process (S2k).The guideline provides an overview of clinical and molecular diagnostics as well as antigen detection, antibody culture and viral culture. Diagnostic special situations and complicated courses of the disease are also considered. The antiviral therapy of zoster and postzoster neuralgia is presented in general and for special situations. Detailed information on the treatment of pain is mentioned and presented in an overview. Likewise, the local therapeutic measures are discussed.

S2k guidelines for the diagnosis and treatment of herpes zoster and postherpetic neuralgia.

The present guidelines are aimed at residents and board-certified specialists in the fields of dermatology, ophthalmology, ENT, pediatrics, neurology, virology, infectious diseases, anesthesiology, general medicine and any other medical specialties involved in the management of patients with herpes zoster. They are also intended as a guide for policymakers and health insurance funds. The guidelines were developed by dermatologists, virologists, ophthalmologists, ENT physicians, neurologists, pediatricians and anesthesiologists/pain specialists using a formal consensus process (S2k). Readers are provided with an overview of the clinical and molecular diagnostic workup, including antigen detection, antibody tests and viral culture. Special diagnostic situations and complicated disease courses are discussed. The authors address general and special aspects of antiviral therapy for herpes zoster and postherpetic neuralgia. Furthermore, the guidelines provide detailed information on pain management including a schematic overview, and they conclude with a discussion of topical treatment options.

Frequency and profile of Parkinson's disease prodromi in patients with malignant melanoma.

OBJECTIVE: The results of register studies suggest an association between Parkinson's disease (PD) and melanoma. We studied the frequency and profile of early markers of PD in patients with malignant melanoma. METHODS: 100 participants were enrolled in a prospective observational study, of whom 65 had a history of high-risk cutaneous (n=53) or uveal (n=12) melanoma (31 women; age, 61.2±14.9 years) and another 35 served as control participants (19 women; 54.6±20.5 years). Participants underwent assessments of motor function (Unified PD Rating Scale; keyboard tapping test), olfactory function, colour vision, depressive symptoms, the Non-Motor Symptoms Questionnaire, and transcranial brain sonography. Raters were blinded to the diagnosis and clinical data of study participants. RESULTS: Patients with melanoma showed increased frequency of substantia nigra hyperechogenicity and prodromal motor and non-motor features of PD, especially asymmetric motor slowing and apathy. Hyposmia and colour vision disturbance were, however, infrequent. Larger echogenicity of substantia nigra correlated with lower serum iron in patients with melanoma, similar to previously reported findings in PD, and independently from the earlier findings, with lighter skin pigmentation. Substantia nigra hyperechogenicity, combined with motor asymmetry or hyposmia, was present at baseline in all participants with mild or definite parkinsonism diagnosed after 1 year. Parkinsonism was specifically related to melanoma location at the sun-exposed skin of the head or neck. CONCLUSIONS: History of melanoma was associated with increased prevalence of prodromal markers of PD. Their predictive value needs to be established in long-term investigations. The similarity of serum iron characteristics found in patients with melanoma and PD deserves further research.

Genitoanal human papillomavirus infection and associated neoplasias.

Human papillomavirus (HPV) infection is the most common sexually transmitted virus infection; about 40 out of 150 known HPV genotypes have been associated with genitoanal lesions in the female and male. They have been divided into low-risk (LR) and high-risk (HR) HPV types according to the association of each HPV genotype with genitoanal benign warts, genitoanal cancer and precursor lesions. For the most part, genitoanal HPV infection is equally common in men and in women. Genitoanal HPVs are predominantly transmitted by sexual intercourse. In a minor number of individuals where HR HPV infection has persisted, malignant squamous-cell tumors may develop. There are 15 mucosal oncogenic HPV types which are the etiological factor of cervical cancer and other genitoanal cancers. DNAs of HR HPV types are present in 100% of all cervical carcinomas and in 100% of the precursor lesions, the cervical intraepithelial neoplasias 2 and 3. HPV-16 and -18 alone account for 70% of the oncogenic mucosal HPV types identified. HR HPV types, mostly HPV-16 and -18, are the causes of vaginal and vulvar cancers in females, anal cancers in both genders and cancer of the penis in men. While anal cancers are linked to HR HPVs in more than 80% of cases, only 40% of vulvar cancers and 50% of penile cancers are HPV positive. Genitoanal cancers have a similar anatomy, histology and similar risk factors as well as natural histories. About 60% of vulvar and 50% of penile cancers are HPV negative, but associated with chronic inflammatory disorders, mainly lichen sclerosus. Clinical manifestations of LR HPVs in both sexes are genitoanal warts (condylomata acuminata), which are benign highly infectious tumors. The highest rate of warts is observed in females 16-24 years of age. In males the peak is at the age of 20-24 years. Diagnosis of genitoanal warts should exclude other sexually transmitted infections and diseases. A high number of genitoanal dermatoses, benign tumors, malignant squamous-cell neoplasias and cancer precursors may mimic condylomata acuminata. These malignant counterparts have to be ruled out by biopsy and a thorough histological workup. Therapy of manifest genitoanal HPV-associated lesions has profited from the development of local immunotherapy with imiquimod and local therapy with green tea derivatives (sinecatechin) 10% (Europe) and 15% (USA). Disease recurrence is a crucial problem with treatment, one that could potentially be reduced with the use of immunomodulating agents such as immuquimod and sinecatachins. Recently primary prevention of genitoanal clinical manifestations associated with HPV-6, -11, -16 and -18 including cancer precursors (intraepithelial neoplasias) has become true by the release of prophylactic quadrivalent (HPV-6, -11, -16, -18) and bivalent (HPV-16, -18) vaccines. These vaccines consist of HPV L1 virus-like particles which induce high anti-L1 serum-neutralizing antibody concentrations. Dermatologists and venereologists, general practitioners and pediatricians should cooperate with gynecologists to vaccinate young women and men in order to increase vaccination rates. In Australia and Scotland, an immense efficacy has been observed both regarding the prevention of benign genitoanal warts and cancer precursors caused by the vaccine HPV types. An absolute prerequisite of such a successful prevention against HPV-associated neoplasias is the administration of the vaccine before the first sexual contact.

DNp73 exerts function in metastasis initiation by disconnecting the inhibitory role of EPLIN on IGF1R-AKT/STAT3 signaling.

Dissemination of cancer cells from primary tumors is the key event in metastasis, but specific determinants are widely unknown. Here, we show that DNp73, an inhibitor of the p53 tumor suppressor family, drives migration and invasion of nonmetastatic melanoma cells. Knockdown of endogenous DNp73 reduces this behavior in highly metastatic cell lines. Tumor xenografts expressing DNp73 show a higher ability to invade and metastasize, while growth remains unaffected. DNp73 facilitates an EMT-like phenotype with loss of E-cadherin and Slug upregulation. We provide mechanistic insight toward regulation of LIMA1/EPLIN by p73/DNp73 and demonstrate a direct link between the DNp73-EPLIN axis and IGF1R-AKT/STAT3 activation. These findings establish initiation of the invasion-metastasis cascade via EPLIN-dependent IGF1R regulation as major activity of DNp73.

Time-dependent decrement of dermal gadolinium deposits and significant improvement of skin symptoms in a patient with nephrogenic systemic fibrosis after temporary renal failure.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) represents a rare fibrosing disorder occurring after administration of gadolinium-containing contrast agents during renal insufficiency. In order to prove the effect of gadolinium elimination on clinical signs, we identified and quantified gadolinium in skin biopsies of a 62-year-old patient with NSF with regard to improving skin lesions after recovery of renal function. METHODS: Gadolinium deposits were visualized and identified in NSF skin biopsies by light microscopy and transmission electron microscopy (EM) and by scanning EM. Inductively coupled plasma-mass spectrometry (ICPMS) was used for quantifying gadolinium concentration. RESULTS: Transmission EM studies revealed electron-dense material in connective matrix around blood vessels and inside lysosomes of histiocytes and fibroblasts. A remarkable reduction of gadolinium deposits was observed in transmission EM and scanning EM and confirmed by ICPMS in follow-up biopsies. After spontaneous recovery of renal function, his skin induration improved notably over the next 2 years. CONCLUSIONS: The reduction of clinical and histomorphological signs of NSF correlated with decreasing gadolinium concentration in skin biopsies within 3 years. Our study suggests a possible pathogenetic mechanism of NSF including a chance for recovery after elimination of gadolinium and reduced histamine liberation by mast cells.

Diagnostics of autoimmune bullous diseases in German dermatology departments.

BACKGROUND: No consistent data are available on the currently employed diagnostic tools for autoimmune bullous diseases in Germany. The aim of this survey was to describe currently performed diagnostic methods for bullous autoimmune diseases in German dermatology departments. METHODS: A standardized questionnaire evaluated the available diagnostic methods i. e. direct immunofluorescence microscopy (IFM), indirect IFM, commercial ELISA systems, and non-commercial serological tests as well as the number of samples per year in all 34 university and 39 non-university dermatology departments. RESULTS: The overall return rate was 89 %, 100 % and 79 % for the university and non-university departments, respectively. Direct IFM was the most frequently used method and was applied in 98 % of the responding departments. In 74 % of the responding departments, indirect IFM was used mainly on monkey esophagus and human salt-split skin. Commercial ELISA systems were employed in 58 % of the clinics; all of them used anti-desmoglein ELISA, while anti-BP180 and anti-BP230 ELISA were established in 49 % and 48 % of departments, respectively. Non-commercial analytic methods were only performed in 22 % of the departments. CONCLUSIONS: The high return rate of this survey allows a relatively precise description of the current diagnostic methods used in German dermatology departments. Standard diagnostic tests are available nationwide and in bullous pemphigoid and pemphigus, the antigen-specific detection of autoantibodies is routinely performed in half of the departments. Rare disorders may be diagnosed by cooperation with some specialized centers.

Rice-induced anaphylaxis: IgE-mediated allergy against a 56-kDa glycoprotein.

BACKGROUND: Although rice (Oryza sativa) is one of the most common cereals produced and consumed around the world, there have been only a few reports on immediate hypersensitivity reactions after ingestion of rice. Few clinical studies on rice allergy in Asia have been reported concerning rhinitis, asthma and atopic dermatitis. In this case study, we identify allergens presumably responsible for anaphylaxis after ingestion of rice in a German patient. METHODS: Prick-to-prick tests, determination of specific IgE and the basophil activation test (BAT) were performed to confirm IgE-mediated allergy. IgE reactivity was further analyzed by immunoblotting of protein extracts from cooked commercial rice products. Rice allergens were purified, subjected to N-terminal sequencing and characterized by IgE binding and IgE inhibition assays using additional sera from 8 subjects with sensitization to rice and/or a history of hypersensitivity symptoms after rice ingestion. RESULTS: Prick-to-prick tests were positive to raw and cooked rice (basmati rice and long-grain rice) and preparations of different rice extracts. Specific IgE against rice (f9) was 1.87 kU(A)/l. The BAT showed specific IgE-mediated activation of basophils after stimulation with rice extracts. Four IgE-reactive rice proteins with an apparent molecular weight of 49, 52, 56 and 98 kDa were identified. Interestingly, only binding to the 56-kDa glycoprotein was at least partially independent from cross-reactive carbohydrate determinants (CCD), whereas IgE binding to the other rice proteins was completely inhibited by pre-incubation with the CCD MUXF derived from bromelain. CONCLUSIONS: Yet unidentified high-molecular-weight allergens from rice seeds, predominantly a 56-kDa glycoprotein, seem to be responsible for anaphylaxis after consumption of rice in a German patient.

Novel approach to differentiate subclades of varicella-zoster virus genotypes E1 and E2 in Germany.

Varicella-zoster virus (VZV) is the causative agent of chicken pox (varicella) in children and reactivation of VZV in elderly or immunocompromised persons can cause shingles (zoster). A subclade differentiation of the most prevalent VZV genotypes E1 and E2 in Germany was not possible with the current genotyping methods in use, but is highly important to understand the VZV molecular evolution in more detail and especially to follow up the routes of infection. Therefore the objective of this study was to develop a simple PCR-based method for differentiation of E1 and E2 subclades. Viral DNA was isolated from vesicle fluid samples of six selected German zoster patients and used to amplify nine complete open reading frames (ORFs) of the VZV genome by different PCR assays. Phylogenetic analysis was performed by a Bayesian approach. Based on the analysis of a total of nine ORFs, a 7482 bp stretch consisting of ORFs 5, 37 and 62 contained informative sites for identification of novel subclades E1a, E2a and E2b for VZV genotypes E1 and E2. Specific single nucleotide polymorphisms (SNPs) were demonstrated for subclades E2a and E2b within the ORFs 5, 37 and 62, whereas a subclade E1a-specific SNP was found in ORF 56. The classification of E1 and E2 subclades may facilitate a more exact and in-depth monitoring of the molecular evolution of VZV in Germany in the future.

The functional -443T/C osteopontin promoter polymorphism influences osteopontin gene expression in melanoma cells via binding of c-Myb transcription factor.

In the present report, the possible role of a recently described functional polymorphism of the osteopontin (OPN) promoter at position -443 (-443T/C) for OPN expression in melanoma cells was addressed. As shown by real-time PCR analysis, melanoma metastases that were homozygous for the -443C allele expressed significantly higher levels of OPN mRNA compared with those that were either heterozygous (-443T/C) or homozygous for the -443T allele. In line with this, immunoblotting showed significantly enhanced baseline and bFGF-induced OPN protein expression in melanoma cell lines which were homozygous for the -443C allele, compared with cell lines with other allelic variants. Similar results were obtained in in vitro luciferase assays. Chromatin immunoprecipitation (ChIP) demonstrated binding of c-Myb to the -443 OPN promoter region, and binding could significantly be enhanced after bFGF stimulation. Moreover, as shown by electrophoretic mobility shift assays (EMSA), recombinant DNA-binding domain of c-Myb bound in a sequence-specific manner to this region. Finally, the role of c-Myb for OPN gene regulation via binding to the -443 promoter region could be further substantiated by ectopic overexpression of c-Myb in melanoma cells, using different reporter gene constructs. Taken together, it is demonstrated that the -443 promoter region exerts influence on OPN gene expression in melanoma cells, and differential binding of c-Myb transcription factor appears to play a major role in this process. These findings might be a feasible explanation for different OPN expression levels in metastatic tumors and may also have prognostic and therapeutic relevance.

MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth.

A microRNA expression screen was performed analyzing 157 different microRNAs in laser-microdissected tissues from benign melanocytic nevi (n = 10) and primary malignant melanomas (n = 10), using quantitative real-time PCR. Differential expression was found for 72 microRNAs. Members of the let-7 family of microRNAs were significantly downregulated in primary melanomas as compared with benign nevi, suggestive for a possible role of these molecules as tumor suppressors in malignant melanoma. Interestingly, similar findings had been described for lung and colon cancer. Overexpression of let-7b in melanoma cells in vitro downregulated the expression of cyclins D1, D3, and A, and cyclin-dependent kinase (Cdk) 4, all of which had been described to play a role in melanoma development. The effect of let-7b on protein expression was due to targeting of 3'-untranslated regions (3'UTRs) of individual mRNAs, as exemplified by reporter gene analyses for cyclin D1. In line with its downmodulating effects on cell cycle regulators, let-7b inhibited cell cycle progression and anchorage-independent growth of melanoma cells. Taken together, these findings not only point to new regulatory mechanisms of early melanoma development, but also may open avenues for future targeted therapies of this tumor.

Anaphylaxis to iodinated contrast material: nonallergic hypersensitivity or IgE-mediated allergy?

OBJECTIVE: Contrast material is generally well tolerated although approximately 1% of patients who receive low-osmolar nonionic contrast material will develop anaphylaxis symptoms. Because most anaphylactic reactions are mild and nonallergic, clinically mimicking immunoglobulin E (IgE)-mediated allergy, diagnostic skin testing has been discussed controversially in the past and prophylactic pretreatment drug regimens are recommended instead. In the past 6 years, all patients with contrast material-induced anaphylaxis have been subjected to allergologic diagnostic procedures to clearly differentiate allergic and nonallergic anaphylaxis. Thus the purpose of our study was to identify and differentiate IgE-mediated allergy and nonallergic contrast material-induced hypersensitivity. Furthermore, the objective of our diagnostic procedures was not only to identify the culprit contrast material but also to find alternative contrast material for future radiologic interventions. SUBJECTS AND METHODS: We evaluated 96 patients with anaphylaxis symptoms after contrast material application using standardized intradermal skin testing. In patients with positive skin tests, the IgE-mediated allergy was further evaluated with in vitro and challenge tests. RESULTS: In four patients (suffering from anaphylaxis grades 2 and 3) out of the 96 (4.2%), skin tests and basophil activation tests strongly suggested IgE-mediated allergy to the contrast materials iopromide (two patients), iomeprol, and iopentol. In two patients with allergies to iopromide and iomeprol, alternative nonionic monomer contrast materials were tolerated, as identified in controlled challenge tests with iopamidol and iopromide, respectively. CONCLUSION: The evaluation of patients with contrast material-induced anaphylaxis (at least those with anaphylaxis > or = grade 2) should always include appropriate skin tests ensuring that patients with an IgE-mediated allergy are not missed. Moreover, allergologic testing may identify a contrast material of the group of nonionic monomers that will be tolerated in future radiologic interventions.