Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version.

BACKGROUND: Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. OBJECTIVES: The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. METHODS: The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies. RESULTS: Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. CONCLUSIONS: International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).

Suberoylanilide hydroxamic acid: a potential epigenetic therapeutic agent for lung fibrosis?

Pulmonary fibrosis represents a fatal stage of interstitial lung diseases of known and idiopathic aetiology. No effective therapy is currently available. Based on an indication-discovery approach we present novel in vitro evidence that the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA), an FDA approved anti-cancer drug, has antifibrotic and anti-inflammatory potential. Human lung fibroblasts (fetal, adult and idiopathic adult pulmonary fibrosis) were treated with transforming growth factor (TGF)-beta 1 with or without SAHA. Collagen deposition, alpha-smooth muscle actin (alpha-SMA) expression, matrix metalloproteinase (MMP)1 activity, tissue inhibitor of MMP (TIMP)1 production, apoptosis and cell proliferation were assessed. Pro-inflammatory cytokines relevant to pulmonary fibrosis were assayed in SAHA-treated human peripheral blood mononuclear cells (PBMC) and its subpopulations. SAHA abrogated TGF-beta 1 effects on all the fibroblast lines by preventing their transdifferentiation into alpha-SMA positive myofibroblasts and increased collagen deposition without inducing apoptosis. However, MMP1 activity and TIMP1 production was modulated without a clear fibrolytic effect. SAHA also inhibited serum-induced proliferation of the fibroblast lines and caused hyperacetylation of alpha-tubulin and histone. Cytokine secretion was inhibited from PBMC and lymphocytes at nonapoptotic concentrations. Taken together, these data demonstrate combined antifibrotic and anti-inflammatory properties of SAHA, suggesting its therapeutic potential for pulmonary fibrosis.

Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin.

The participation of (6R) 5,6,7,8-tetrahydrobiopterin (6-BH4) in regulating the tyrosine supply for melanin biosynthesis was investigated by the examination of human keratinocytes, melanocytes, and epidermal suction blisters from normal human skin and from patients with the depigmentation disorder vitiligo. Cells, as well as total epidermis, contained high phenylalanine hydroxylase activities and also displayed the capacity to synthesize and recycle 6-BH4, the essential cofactor for this enzyme. In vitiligo, 4a-hydroxy-BH4 dehydratase activity was extremely low or absent, yielding an accumulation of the nonenzymatic by-product 7-tetrahydrobiopterin (7-BH4) at concentrations up to 8 x 10(-6) M in the epidermis. This by-product is a potent competitive inhibitor in the phenylalanine hydroxylase reaction with an inhibition constant of 10(-6) M. Thus, 6-BH4 seems to control melanin biosynthesis in the human epidermis, whereas 7-BH4 may initiate depigmentation in patients with vitiligo.

Active cigarette smoking, secondhand smoke exposure at work and home, and self-rated health.

OBJECTIVES: Although active smoking has been reported to be associated with poor self-rated health (SRH), its association with secondhand smoke (SHS) is not well understood. STUDY DESIGN: A cross-sectional study was conducted to examine the association of active smoking and SHS exposure with SRH. METHODS: A total of 2558 workers (1899 men and 689 women), aged 16-83 (mean 45) years, in 296 small and medium-sized enterprises were surveyed by means of a self-administered questionnaire. Smoking status and exposure levels to SHS (no, occasional or regular) among lifetime non-smokers were assessed separately at work and at home. SRH was assessed with the question: How would you describe your health during the past 1-year period (very poor, poor, good, very good)? SRH was dichotomized into suboptimal (poor, very poor) and optimal (good, very good). Odds ratios (ORs) with 95% confidence intervals (CIs) for reporting suboptimal vs optimal SRH according to smoking status and smoke exposure were calculated. RESULTS: Current heavy smokers (20+ cigarettes/day) had a significantly increased suboptimal SRH than lifetime non-smokers after adjusting for sociodemographic, lifestyle, physical and occupational factors (OR 1.34, 95% CI 1.06-1.69). Similarly, lifetime non-smokers occasionally exposed to SHS at work alone had worse SRH than their unexposed counterparts (OR 1.50, 95% CI 1.02-2.11). In contrast, lifetime non-smokers exposed at home alone had no significant increase in suboptimal SRH. CONCLUSIONS: The present study indicates an increase in suboptimal SRH among current heavy smokers, and suggests that SHS exposure at work is a possible risk factor for non-smokers. Whether or not the association is causal, control of smoking at work may protect workers from developing future health conditions.

The SSTARS (STeroids and Stents Against Re-Stenosis) Trial: Different stent alloys and the use of peri-procedural oral corticosteroids to prevent in-segment restenosis after percutaneous coronary intervention.

BACKGROUND: Stent design and technological modifications to allow for anti-proliferative drug elution influence restenosis rates following percutaneous coronary intervention (PCI). We aimed to investigate whether peri-procedural administration of corticosteroids or the use of thinner strut cobalt alloy stents would reduce rates of binary angiographic restenosis (BAR) after PCI. METHODS: This was a two centre, mixed single and double blinded, randomised controlled trial using a factorial design. We compared (a) the use of prednisolone to placebo, starting at least six hours pre-PCI and continued for 28days post-PCI, and (b) cobalt chromium (CoCr) to stainless steel (SS) alloy stents, in patients admitted for PCI. The primary end-point was BAR at six months. RESULTS: 315 patients (359 lesions) were randomly assigned to either placebo (n=145) or prednisolone (n=170) and SS (n=160) or CoCr (n=160). The majority (58%) presented with an ACS, 11% had diabetes and 287 (91%) completed angiographic follow up. BAR occurred in 26 cases in the placebo group (19.7%) versus 31 cases in the prednisolone group (20.0%) respectively, p=1.00. For the comparison between SS and CoCr stents, BAR occurred in 32 patients (21.6%) versus 25 patients (18.0%) respectively, p=0.46. CONCLUSION: Our study showed that treating patients with a moderately high dose of prednisolone for 28days following PCI with BMS did not reduce the incidence of BAR. In addition, we showed no significant reduction in 6month restenosis rates with stents composed of CoCr alloy compared to SS (http://www.isrctn.com/ISRCTN05886349).

Drug eluting stents in interventional cardiology -- current evidence and emerging uses.

Intervention in coronary artery disease is an area of cardiology where novel drugs, in the form of drug-eluting stents (DES), are being used increasingly commonly. DES are used across the whole range of coronary intervention, from stable angina patients with single or multivessel disease, acute coronary syndromes and acute myocardial infarction (i.e. primary angioplasty). Most recently, they are being tested in a particularly challenging subset of patients, those experiencing symptoms due to restenosis within a previously stented area of vessel (in-stent restenosis, ISR). This article summarises the rationale for the use of DES, across all these areas, focussing specifically on the emerging results of trials and registries examining the effectiveness of DES in acute myocardial infarction (AMI) and ISR. Drug-eluting stents represent a significant shift in the use of locally-delivered drugs in interventional cardiology. On the basis of encouraging trial data, including in the specific areas of in-stent restenosis and myocardial infarction, their use is becoming extremely widespread in place of bare-metal (drug-free) stents. This change is happening despite their high costs, relatively short follow-up data and concerns of possible unwanted effects, because of the weight of evidence that they are superior in preventing restenosis in many patient groups. This reduction is highly significant in angiographic terms and, to a lesser degree, in the prevention of clinically important restenosis requiring revascularisation, but not clearly in terms of overall mortality.

Sex, drugs and HIV counseling and testing: a prospective study of behavior-change among methadone-maintenance clients in New England.

OBJECTIVES: To determine whether changes in injecting drug use and sexual behavior over a 12-month follow-up are associated with HIV counseling and testing (C and T) of injecting drug users in methadone maintenance treatment programs (MMTP) in Massachusetts and Connecticut. METHODS: Clients were invited to participate in a longitudinal study involving five interviews. Data were also obtained by ethnographers and from clinical records. Behavioral outcomes of interest were number of drug injections, sharing of unclean 'works' (injecting equipment), number of unprotected sex partners, and number of unprotected sexual episodes. Data analyses included multiple regression, odds ratios, and quantitative analysis of text-based data. RESULTS: Subjects reported reductions in both injecting drug use and sexual behavior Primary associations with reduced injecting drug use were remaining in the MMTP and attending HIV-positive support groups. A reduction in high-risk sexual behavior was associated with an HIV-positive test result and duration of HIV counseling in the MMTP. Increase in drug injecting use was associated with an HIV-positive test result. Inconsistent condom use was associated with enrollment in the MMTP where condoms were available only upon request and abstinence and monogamy between uninfected partners were promoted. CONCLUSIONS: Injecting drug users who self-select to participate in MMTP and HIV C and T, two public health HIV-prevention interventions, reduce their HIV-risk behaviors. Clients should be encouraged to remain in MMTP and HIV-infected clients should attend support groups for HIV-positive persons. MMTP staff should promote a variety of safer sex behaviors and provide condoms without request.

Perturbed epidermal pterin metabolism in Hermansky-Pudlak syndrome.

In Hermansky-Pudlak Syndrome (HPS) a mutation in a 79.3 kDa transmembrane protein has been shown. The function of this protein has escaped definition so far. This study unveils a defective (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (6BH4) de novo synthesis/recycling for this cofactor in HPS, where activities of the key enzyme GTP-cyclohydrolase I are in the normal range, but total biopterin levels are significantly decreased in homozygotes (n = 5) compared with unaffected controls (n = 4) (p = 0.00001). Phenylalanine hydroxylase and 4a-hydroxy-6BH4-dehydratase activities are significantly lower. mRNA of all enzymes involved in 6BH4 biosynthesis/recycling and GTP-cyclohydrolase I feedback regulatory protein were expressed in keratinocytes from homozygotes, heterozygotes, and healthy controls. Thioredoxin/thioredoxin reductase can directly control the redox status of 6BH4. These activities are allosterically controlled by calcium. Therefore calcium would directly affect this redox status. In HPS these enzyme activities are low concomitant with a defective calcium uptake, suggesting an extracellular accumulation of this second messenger. In this context phenylalanine hydroxylase is subject to phosphorylation/activation by calcium/calmodulin activated kinases. Therefore it was anticipated that calcium could directly affect the cellular L-phenylalanine turnover to L-tyrosine. A significantly more rapid L-phenylalanine uptake and its turnover to L-tyrosine was identified in normal human melanocytes (n = 5) and keratinocytes (n = 2), and was more enhanced in melanocytes in the presence of 2 x 10(-3) M calcium. The turnover to L-tyrosine was significantly slower. Based on all evidence to date, we speculate that the mutated protein in HPS could be primarily involved in maintaining calcium homeostasis in this patient group.

Decreased urinary polyamines in patients with psoriasis treated with etretinate.

Oral administration of the aromatic retinoid etretinate is effective therapy for psoriasis and other epidermal hyperproliferative disorders. Since polyamine metabolism is known to be important in cell growth and differentiation, we measured urinary levels of the polyamines putrescine, spermidine, and spermine as a reflection of cutaneous polyamine metabolism in 19 psoriatic patients treated with etretinate for 16 weeks. Using thin-layer chromatography, polyamine determinations were performed on urine collected pretherapy, during therapy, and 8 weeks after therapy was concluded. Good to excellent clearing of psoriasis occurred in 18 of 19 patients. All urinary polyamines showed a downward trend in the first week of therapy, prior to significant clinical improvement. At week 16 of therapy, the greatest reduction in mean urinary polyamine content occurred. Mean putrescine levels decreased from pretherapy to week 16 by 27% (p less than 0.001), mean spermidine values fell by 34% (p less than 0.001), and mean spermine levels declined by 37% (p = 0.005). These data are consistent with the hypothesis that etretinate inhibits polyamine biosynthesis.

An enzyme-linked immunosorbent assay for antistriational antibodies associated with myasthenia gravis and thymoma: comparison with indirect immunofluorescence.

Autoantibodies to the striations of skeletal muscle (AStrA) detected by immunofluorescence are useful in the diagnosis of a thymoma associated with myasthenia gravis (MG). With the intention of developing a better method, an enzyme-linked immunosorbent assay (ELISA) has been evaluated in 147 MG patients and 200 healthy controls. An additional 107 patients with various autoimmune diseases and autoantibodies were also tested. With a crude actomyosin preparation, the ELISA gave similar results to immunofluorescence, viz. positives in 42% of MG patients, but in all with a histologically proven thymoma. Less than 1% of the healthy controls were positive but false positives were found in patients with liver disease and anti-smooth muscle antibodies. After treatment of rheumatoid arthritis with D-penicillamine the titre of AStrA may rise. The ELISA was shown to be sensitive and reproducible, but immunofluorescence is a more practical method of distinguishing between the different categories of anti-muscle antibodies. ELISA should prove particularly useful for quantitation and sequential monitoring.

An enzyme-linked immunosorbent assay for the detection of hepatocyte plasma membrane antibodies.

An enzyme-linked immunosorbent assay (ELISA) using plates coated with hepatocyte plasma membranes (HPM) was developed for the measurement of antibodies directed at hepatocyte surface antigens. Precoating ELISA plates with poly-L-lysine (PLL) provided firm attachment for the adsorption of HPM. The use of HPM, in preference to whole hepatocytes, excludes pathologically irrelevant cytoplasmic antigens. In addition, there is no necessity for glutaraldehyde fixation which is commonly used in cellular assays to maintain cellular integrity and which may result in loss or alteration in antigenic specificities. The assay was used to study loss of tolerance to mouse HPM in mice immunized with rat HPM. Three mouse strains were immunized, each strain developed antibodies to rat HPM and autoantibodies to mouse HPM with autoantibody levels reaching a peak 6-10 weeks after commencement of immunization. The correlation between ELISA and indirect immunofluorescence for the measurement of HPM autoantibodies was 0.79 (P less than 0.001) within the serum titration range of 1:25 to 1:200. Antibody to control kidney plasma membrane (KPM) was also measured by ELISA, after elimination of endogenous alkaline phosphatase activity using levamisole. Immunization with rat HPM elicited organ-non-specific autoantibodies to KPM, but these were at lower levels than autoantibodies to HPM.

Search for persistent infection with poliovirus or other enteroviruses in amyotrophic lateral sclerosis-motor neurone disease.

A longstanding hypothesis proposes that amyotrophic lateral sclerosis-motor neurone disease (ALS-MND) is a late consequence of subclinical poliovirus (PV) infection. In this study, RNA extracts of CNS tissue from 28 patients with ALS-MND and 7 controls were assayed by nested polymerase chain reaction (PCR) using primers to the 5'-untranslated region (UTR) of the enterovirus (EV) genome which is highly conserved between EVs including PV, echovirus and coxsackie viruses. The integrity of RNA extracted from either archival paraffin-embedded or frozen CNS tissue was assessed by detection of constitutive Ableson tyrosine kinase (ABL) mRNA by PCR. Of 63 tissue samples assayed, 81% (51/63) were ABL-positive corresponding to 78% (22/28) of the ALS-MND cases and all controls. None of the 27 ALS-MND cases (i.e. 21 ABL+ and 6 ABL-) in which paraffin-embedded tissue was used nor any of the age and sex matched controls were positive for specific PV/EV RNA. Moreover, CNS tissue from 14 different locations obtained from one patient < 2 hrs after death and immediately frozen, showed no evidence of PV/EV at any site by PCR. Disease duration, degree of tissue autolysis and duration of tissue storage were all excluded as factors which may predispose to negative results. The sensitivity of the PV PCR was determined to be 40-400 copies (12.5 - 125 ag) of synthetic EV RNA transcripts in 1 microgram of cellular RNA and the assay was shown to detect all types of PV and and other EVs tested. Thus it seems unlikely that a persistent PV or related EV infection is implicated in ALS-MND unless there has been alteration in the 5'-UTR of the virus genome.

Rapid and sensitive genotyping of hepatitis C virus by single-strand conformation polymorphism.

There is an increasing demand for genotyping hepatitis C virus (HCV) isolates due to the rapidly expanding list of distinct HCV genotypes and the mounting evidence of genotype-specific clinical consequences. We describe an SSCP-based assay for determining genotypes in HCV infections. HCV RNA extracted from serum was amplified by a sensitive nested-PCR assay producing a 287 bp fragment of the conserved 5' non-coding region (NCR) and analysed by non-denaturing polyacrylamide gel electrophoresis. Following empirical optimisation of the SSCP assay we identified distinct conformation polymorphisms (characteristic band patterns) corresponding to types 1a, 1b, 2a, 2b, 2c, 3 and 4 found in the Western Australian population. Seventy-three HCV RNA-positive samples were used to evaluate the SSCP genotyping assay for accuracy and efficiency by comparison with the previously established genotyping methods of manual direct sequencing and dideoxy fingerprinting. SSCP genotyping was in concord with control methods while performing more rapidly and at a fraction of the cost. Moreover, SSCP detected two co-infected samples that were not shown by the control methods. The PCR-SSCP assay provides an accurate and rapid method for genotyping of HCV RNA-positive samples at the 5' NCR by type-specific sequence polymorphisms which is applicable to large-scale screening.

Rapid genotyping of hepatitis C virus isolates by dideoxy fingerprinting.

A number of distinct hepatitis C virus (HCV) types and subtypes have been identified by DNA sequencing of multiple genome regions. It has been postulated that these might also reflect phenotypic differences in the nature of HCV infection. Recent evidence suggests a relationship between HCV genotype and alpha-interferon response in patients with chronic hepatitis C. A simplified method of genotyping in comparison to direct DNA sequencing was investigated with the intention of providing a rapid, less labour-intensive method for routine genotyping. HCV RNA was extracted from serum by a modified guanidinium/acid-phenol extraction and peripheral blood lymphocytes using RNAzol B (Cinna-Biotecx). The RNA was reverse transcribed and a 287 bp segment of the 5' non-coding region (5' NCR) amplified using a nested-PCR reaction. PCR products were purified using Qiaquick spin columns. Products were directly sequenced by cycle sequencing. Dideoxy termination analysis was carried out by cyclic extension of a 33P-labelled primer by Tth polymerase with termination by dideoxy thiamine (ddT) or cytosine (ddC). Reaction products were analysed by electrophoresis on denaturing 7 M urea/6% acrylamide gels followed by autoradiography. Computer aided sequence analysis indicated that conserved 5' NCR sequence variation alone was sufficient to identify HCV types 1a, 1b, 2a, 2b, 3 and 4. Dideoxy fingerprinting improved greatly the efficiency of genotyping with an approximate four-fold increase in throughput. In addition, the results were very easily analysed although it was essential to run appropriate controls for each genotype. Reactions incorporating ddT distinguished types 1, 2a, 2b, 3 (provisionally 1a & 1b); a ddC reaction confirmed 1a and 1b typing.(ABSTRACT TRUNCATED AT 250 WORDS)

Complete microscopic controlled surgery for head and neck cancer.

Mohs surgery, as it has evolved since its inception by Mohs, is a technique for removing certain cancers using careful, precise microscopic marginal control. The contemporary technique using fresh tissue has enabled the application of Mohs surgery to the treatment of malignancies of the upper aerodigestive tract. Mohs surgery, once limited to large recurrent basal cell carcinomas, has expanded to include several cutaneous and noncutaneous neoplasms. With better understanding of the Mohs technique, its indications, applications, and advantages, an interdisciplinary approach to manage certain head and neck neoplasms is proposed.

Mohs surgery: techniques, indications, and applications in head and neck surgery.

Mohs surgery, as it has evolved since its inception by Dr. Mohs, is a technique for removal of certain cancers using careful, precise microscopic marginal control. The contemporary technique using fresh tissue is detailed, illustrating advantages that include maximal conservation of normal surrounding tissue and structures, an extremely high cure rate, and a tumor-free defect which can be reconstructed immediately. The indications and applications for Mohs surgery, once limited to large recurrent basal cell carcinomas, have expanded to include several cutaneous and paracutaneous neoplasms. These, with an emphasis on certain basal cell carcinomas, are discussed in detail. With better understanding of the Mohs technique, its indications, applications, and advantages, an interdisciplinary approach to certain cutaneous and paracutaneous neoplasms is proposed.

Mohs surgery. Technique, indications, applications, and the future.

Each year, it is estimated, more than 500,000 new cases of nonmelanoma skin cancer develop. The majority of these cutaneous neoplasms are treated by various modalities that include excision, electrodesiccation and curettage, cryosurgery, and irradiation, with greater than 90% success. Certain of the remaining primary tumors, as well as recurrent carcinomas, present a demanding therapeutic challenge. For these lesions, Mohs surgery has evolved as the most reliable and cost-effective treatment modality, offering maximal preservation of normal tissue and therefore the lowest functional and cosmetic morbidity. In this review, the history and evolution of Mohs surgery and the technique itself will be briefly outlined. The indications for Mohs surgery, together with methods of handling the postoperative wound and future applications of the technique, will be discussed in detail.

Plantar verrucous carcinoma. Literature review and treatment by the Mohs' chemosurgery technique.

Verrucous carcinoma, a variant of squamous cell carcinoma, is recognized as a distinct clinicopathologic entity. It occurs principally in three anatomic sites: panoral, genitogluteal, and plantar. Two cases of plantar verrucous carcinoma treated by the Mohs' chemosurgery technique are reported, and the literature is reviewed. The clinical and pathologic appearance of these lesions make them recognizable in a patient with a persistent plantar lesion usually diagnosed as a wart but unresponsive to conventional therapy. The role of irradiation, a possible viral etiology of the tumor, and the necessity for a deep biopsy are discussed. Because these tumors are characterized by extensive local growth, Mohs' chemosurgery is proposed as the treatment of choice. In this way, total tumor ablation is obtained with maximum preservation of normal tissue structure and function.

Phenol alcohol technique for permanent matricectomy.

A simple technique for partial or complete destruction of the nail matrix with the use of phenol alcohol is outlined. A retrospective analysis of 30 random patients suggests that it has a low morbidity, is easy to perform, and has a high success rate. Therefore, it offers an excellent option to cold steel surgery, especially for the nonsurgically oriented dermatologist.