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).

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).(AU)

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).

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.

Primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: changing patterns of vascular access, radial versus femoral artery.

OBJECTIVE: To examine the safety and efficacy of emergency transradial primary percutaneous coronary intervention for ST-elevation myocardial infarction. DESIGN: Single-centre observational study with prospective data collection. SETTING: A regional cardiac centre, United Kingdom. PATIENTS: 1051 consecutive patients admitted with ST-elevation myocardial infarction, without cardiogenic shock, between November 2004 and October 2008. INTERVENTIONS: Percutaneous coronary interventions by radial and femoral access MAIN OUTCOME MEASURES: The primary outcome measures were procedural success, major vascular complication and failed initial access strategy. Secondary outcomes were in-hospital mortality and major adverse cardiac and cerebrovascular events, needle-to-balloon times, contrast volume used, radiation dose absorbed and time to discharge. Multiple regression analysis was used to adjust for potential differences between the groups. RESULTS: 571 patients underwent radial access and 480 femoral. A variable preference for radial access was observed among the lead operators (between 21% and 90%). Procedural success was similar between the radial and femoral groups, but major vascular complications were more frequent at the site of femoral access (0% radial versus 1.9% femoral, p = 0.001). Failure of the initial access strategy was more frequent in the radial group (7.7% versus 0.6%, p<0.001). Adjustment for other procedural and clinical predictors did not alter these findings. Needle-to-balloon time, as a measure of procedural efficiency, was equal for radial and femoral groups. CONCLUSIONS: In the setting of acute ST-elevation myocardial infarction without cardiogenic shock, transradial primary angioplasty is safe, with comparable outcomes to a femoral approach and a lower risk of vascular complications.

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.

Delay to angiography and outcomes following presentation with high-risk, non-ST-elevation acute coronary syndromes: results from the Global Registry of Acute Coronary Events.

OBJECTIVE: To test if delay-to-angiography (>72 hours from admission) in patients presenting with high-risk non-ST-elevation acute coronary syndromes (NSTE-ACS) is associated with adverse outcomes. DESIGN: GRACE (Global Registry of Acute Coronary Events) is a multinational registry of patients admitted with NSTE-ACS. SETTING: 14 countries with varying healthcare systems. PATIENTS: 23 396 high-risk NSTE-ACS patients with complete initial data collection entered into GRACE between 1999 and 2006 were analysed. INTERVENTIONS: Data were analysed according to delay-to-angiography and subsequent in-hospital or post-discharge adverse outcomes. MAIN OUTCOME MEASURES: Outcomes recorded included death, myocardial infarction, recurrent ischaemia, stroke, new heart failure and composite major adverse cardiovascular event (MACE) comprising death, cerebrovascular accident and myocardial infarction. Revascularisation procedures were recorded. RESULTS: 10 089 (43.1%) had no in-hospital angiography. Median delay-to-angiography was 46 hours; 3680 (34%) patients waited >72 hours. 9.3% waited >7 days before angiography. Patients waiting longest were more often older, diabetic, women and had a history of heart failure, previous myocardial infarction or hypertension. Recurrent in-hospital ischaemia (33% vs 22%), reinfarction (8.4% vs 5.0%) and heart failure (14% vs 9.1%) were more common with delayed angiography. Delayed angiography was associated with better outcomes than no angiography (MACE 18.9% vs 22.2%, p = 0.015). MACE rates within six months of admission were higher with longer delay-to-angiography and highest of all with no angiography. CONCLUSIONS: High-risk NSTE-ACS is suboptimally managed with 43% not undergoing angiography. One-third of those undergoing angiography are delayed >72 hours. Longer delays were more likely with higher risk, sicker patients. These delays were associated with adverse outcomes at six months. Very long delay was associated with lower MACE, but not mortality, compared to conservative management.

Spontaneously immortalized mouse mesothelial cells display characteristics of malignant transformation.

OBJECTIVES: Mesotheliomas occur in occult serous cavities after chronic exposure of mesothelial cells to asbestos fibres. Molecular events that contribute to the development of this cancer are therefore not readily accessible for study. We have used in vitro culture systems to study and compare induced and spontaneous transformation events in primary mouse mesothelial cells. MATERIALS AND METHODS: Mouse mesothelial cells were cultivated until small populations of proliferating cells emerged from senescing cultures. Spontaneously transformed cultures of cells were characterized and compared to malignantly transformed cells. RESULTS: Human mesothelial cells had a finite lifespan of 10-15 population doublings when cultured in vitro; mouse mesothelial cells typically exhibit this same pattern. Here, we show that mouse mesothelial cells can be cultured for extended periods and that these cells can transform spontaneously. Lines of spontaneously transformed cells generated in this study are immortal and growth factor-independent. They display the salient characteristic features of transformation, including increased proliferation rate, lack of contact inhibition, aneuploidy and ability to grow in anchorage-independent conditions. A subset of these cell lines developed into tumours in syngeneic mice. Comparative gene expression analysis demonstrated that spontaneously transformed cell lines were more closely related to neoplastic cells than to primary cells. CONCLUSION: These findings have implications for interpretation of in vitro transformation studies, demonstrating broad similarity between spontaneous and induced genetic changes.

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.

Tattoo ink darkening of a yellow tattoo after Q-switched laser treatment.

The popularity of tattoos is burgeoning with 20-30 million tattooed individuals in the Western World. Requests for removal can be expected to rise concurrently with increased applications. Laser removal of tattoos is potentially a more cosmetically acceptable method of removing tattoos than surgical excision or dermabrasion. Nevertheless, complications and side-effects can result from laser treatment and include scarring, hypopigmentation, hyperpigmentation, partial removal, infection, bleeding and tattoo ink darkening. The latter has been reported for flesh-toned and red tattoos. Such a complication has never been reported for the laser treatment of a yellow tattoo in the dermatological literature. We describe a case of tattoo ink darkening of a yellow tattoo after treatment with the 532 nm quality-switched Neodymium : Ytrrium-Aluminium Garnet laser to highlight clinicopathological features. The mechanism by which some tattoos darken after laser treatment is not clearly understood. We review darkening of tattoos after laser treatment to raise awareness of this important complication. This paper will help to facilitate discussions with the patient and in obtaining informed consent prior to commencing treatment. Tattoo ink darkening of a yellow tattoo adds to the growing list of complications resulting from attempts at tattoo removal.

Mohs' micrographic surgery using frozen sections alone may be unsuitable for detecting single atypical melanocytes at the margins of melanoma in situ.

BACKGROUND: It remains questionable whether micrographic surgery with frozen sections is an appropriate technique for excision of melanoma in situ (MIS) of the lentigo maligna type. Advocates of the technique have interpreted MIS as being histologically defined by nests and contiguous atypical melanocytes on the basal layer. Others, however, have viewed the periphery of MIS as consisting of scattered single atypical melanocytes, a finding that may be difficult or impossible to establish on frozen sections. OBJECTIVES: To examine the reliability of micrographic surgery using frozen sections interpreted by an experienced Mohs' surgeon, in the excision of MIS. METHODS: From a total of 154 specimens, frozen sections from the 50 specimens with margins that were considered difficult to interpret were thawed, sent for routine processing and then examined 'blind' by a dermatopathologist. RESULTS: Using the dermatopathologist's report on paraffin-embedded sections as a reference point, the sensitivity and specificity of frozen sections were calculated to be 59% and 81%, respectively. CONCLUSIONS: Using these histological criteria, micrographic surgery with frozen sections alone is unreliable in the excision of MIS.

Current perspectives on British use of adjunctive therapies during coronary interventions.

BACKGROUND: Interventional techniques are commonly performed with adjunctive therapy including clopidogrel, ticlopidine, abciximab and heparin. We wished to assess the current British use of antiplatelet and anticoagulant agents as adjunctive therapies in interventional cardiology in the light of the available evidence base regarding their usage. METHODS: A simple structured questionnaire was sent between August and October 1999 to all interventional cardiology consultants working in the UK regarding their usage of abciximab (ReoPro), heparin, clopidogrel (Plavix) and ticlopidine (Ticlid) peri-procedurally. RESULTS: 68% of consultants responded over the next 4 months, with many replying jointly for a centre rather than individually. Average abciximab use was 8.3% of interventional cases. Eighty-two percent of clinicians used clopidogrel in stented patients. Exact dosages varied considerably. Fifty-three percent of clinicians gave 10000 IU or more of heparin routinely. CONCLUSIONS: These figures are not in line with the published evidence and British interventionists appear to have adopted various strategies to target the use of these agents. In particular, abciximab appears to be being administered reactively, as and when problems arise in the catheterisation lab.

Plasminogen activator and plasminogen activator inhibitor gene expression in human saphenous vein organ culture.

We describe the expression of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) in saphenous vein culture. Smooth muscle cells (SMC) are quiescent in fresh tissue, whereas these cells acquire a proliferating phenotype when venous segments are cultured in the presence of serum. t-PA and PAI-1 were localized immunohistochemically and quantified using biochemical techniques. t-PA and PAI-1 mRNA was quantified by reverse transcription polymerase chain reaction (RT--PCR) assay. Immunostaining showed an increase in the positivity of proliferating cell nuclear antigen (PCNA) from 10-day tissue culture. Tissue sections from fresh vein showed minimal t-PA and maximal PAI-1 immunostaining. In contrast, 10-day cultures showed an increase in t-PA and a decline in PAI-1 staining. Biochemical analysis revealed a 118% increase in t-PA and a 50% decrease in PAI-1 antigen levels from 10-day tissue cultures. RT--PCR demonstrated that the mRNA encoding t-PA increased, while PAI-1 decreased after 10 days of culture. In conclusion, venous culture showed an up-regulation of t-PA and a repression of PAI-1 gene expression during SMC proliferation in the vessel wall. The PAI-1 repression observed in venous culture is in contrast to the situation observed in human atheroma. A shift in the t-PA/PAI-1 balance may have a role in vascular remodeling.

Impact of added rest breaks on the productivity and well being of workers.

The impact of frequent short rest breaks on the productivity and well being of a group of 30 workers in a meat-processing plant was studied. Two rest break schedules were tested, both of which provided 36 min of extra break time over the regular break schedule (30-min lunch and two 15-min breaks). In the first experimental rest break schedule, workers were given 12 3-min breaks evenly distributed over the workday (3-min break for every 27 min of work). In the second schedule, workers were given four 9-min breaks evenly distributed over the workday (9-min break every 51 min of work). Outcome measures included production rate and discomfort and stress ratings. Results showed that neither of the two experimental rest break schedules had a negative effect on production, and the 9-min break schedule improved discomfort ratings for the lower extremities. The workers in the study mostly preferred the 9-min rest break schedule, indicating that workers in general might not as readily accept fragmentation of break time into short, frequent breaks.

Limits of the small-angle approximation to the radiative transport equation.

The small-angle approximation to the radiative transport equation is used extensively in imaging models in which the transport medium is optically thick. The small-angle approximation is generally considered valid when the particles are very large compared with the wavelength, when the refractive-index ratio of the particle to the medium is close to 1, and when the optical thickness is not too large. We report results showing the limits of the validity of the small-angle approximation as a function of particle size and concentration for a particle-to-medium fixed refractive-index ratio of 1.196. This refractive-index ratio is comparable with that of minerals or diatoms suspended in water.

Application of the small-angle approximation to ocean water types.

The small-angle approximation to the radiative transport equation is applied to particle suspensions that emulate ocean water. A particle size distribution is constructed from polystyrene and glass spheres with the best available data for particle size distributions in the ocean. A volume scattering function is calculated from the Mie theory for the particles in water and in oil. The refractive-index ratios of particles in water and particles in oil are 1.19 and 1.01, respectively. The ratio 1.19 is comparable to minerals and nonliving diatoms in ocean water, and the ratio 1.01 is comparable to the lower limit for microbes in water. The point-spread functions are measured as a function of optical thickness for both water and oil mixtures and compared with the point-spread functions generated from the small-angle approximation. Our results show that, under conditions that emulate ocean water, the small-angle approximation is valid only for small optical thicknesses. Specifically, the approximation is valid only for optical thicknesses less than 3.

Semiparametric ARX neural-network models with an application to forecasting inflation.

We examine semiparametric nonlinear autoregressive models with exogenous variables (NLARX) via three classes of artificial neural networks: the first one uses smooth sigmoid activation functions; the second one uses radial basis activation functions; and the third one uses ridgelet activation functions. We provide root mean squared error convergence rates for these ANN estimators of the conditional mean and median functions with stationary beta-mixing data. As an empirical application, we compare the forecasting performance of linear and semiparametric NLARX models of US inflation. We find that all of our semiparametric models outperform a benchmark linear model based on various forecast performance measures. In addition, a semiparametric ridgelet NLARX model which includes various lags of historical inflation and the GDP gap is best in terms of both forecast mean squared error and forecast mean absolute deviation error.

The history of dermatologic surgical reconstruction.

Over the last 40-50 years, reconstructive surgery in dermatology has undergone expansive growth and development. As dermatologists began to provide a greater array of surgical services during this period, it became apparent that new skills and techniques in the area of reconstruction would be required. Initially many of the procedures and concepts were adopted from other specialties, however, in the years since, significant contributions have been made by dermatologists which in turn have benefited other specialties as well. This review attempts to summarize some of the significant historical events and innovations that have established and supported dermatologic surgical reconstruction.

Melanocytes are not absent in lesional skin of long duration vitiligo.

This paper provides evidence that melanocytes are still present in the depigmented epidermis of patients with vitiligo even after stable disease of 25 years' duration. Melanocyte cultures were successfully established from depigmented epidermal suction blister tissue of all 12 randomly selected patients and these cells produced melanin. Even under in vitro conditions, vacuolation of melanocytes was demonstrated in five patients with active disease, which was reversible upon exogenous addition of bovine catalase to the culture medium. Full skin biopsies from 17 patients with vitiligo, obtained from depigmented and normally pigmented areas, confirmed the involvement of melanocytes, keratinocytes, and Langerhans cells in this disorder. In addition, the presence of clustered and single pre-melanosomes in basal and supra-basal keratinocytes of lesional and normal epidermis, as well as the retention of single melanocytes in lesional epidermis, was demonstrated by light and electron microscopy. Upon topical application of a narrow band UVB-activated pseudocatalase, vacuolation, granulation, and dilatation of the endoplasmic reticulum completely recovered, but the ectopic pre-melanosome shedding remained. Taken together, these observations indicate that melanocytes are never completely absent in the depigmented epidermis and that these melanocytes can recover their functionality in vivo and in vitro upon the removal of hydrogen peroxide. Furthermore, this study supports the concept that vitiligo involves the entire epidermal unit in both depigmented and 'normal' pigmented skin.