Improvement in Hidradenitis Suppurativa and quality of life in patients treated with adalimumab: Real-world results from the HARMONY Study.

BACKGROUND: Hidradenitis suppurativa (HS), a chronic, recurrent, debilitating skin disease, is characterized by painful, inflammatory, subcutaneous lesions of the axilla, inguinal and anogenital regions. Overall prevalence of HS is ˜1%, and the impact of disease on patient quality of life (QoL) and healthcare resource utilization (HRU) is high. OBJECTIVES: To estimate the real-world effectiveness of adalimumab (Humira®) treatment in patients with moderate-to-severe HS on disease severity, pain, QoL, work productivity and HRU. METHODS: HARMONY (Effectiveness of Adalimumab in Moderate to Severe HidrAdenitis SuppuRativa Patients - a Multi-cOuNtry studY in Real Life Setting) is a multicentre, postmarketing observational study in adult patients with moderate-to-severe HS. Disease severity and QoL parameters were evaluated using validated measures at 12-week intervals over 52 weeks of treatment. The primary endpoint was the proportion of patients achieving a Hidradenitis Suppurativa Clinical Response (HiSCR: ≥50% reduction in abscess and inflammatory nodule count, with no increase in abscess and draining fistula counts relative to baseline) at 12 weeks. Secondary endpoints were HiSCR at 24, 36 and 52 weeks and changes in QoL parameters and work productivity assessments. Analyses were conducted using as-observed data. RESULTS: The proportion of patients reaching the primary HiSCR endpoint was 70.2% (n = 132/188 enrolled) and remained ≥70% until study completion. There were statistically significant (P < 0.0001) reductions in worst and average skin pain. All of the QoL measures evaluated improved significantly (P < 0.0001) by 12 weeks of adalimumab treatment, as did work productivity assessments (P < 0.05), and there was a ˜50% decrease in HRU between baseline and week 52. Adalimumab was well tolerated. CONCLUSIONS: In this real-world setting, adalimumab treatment of moderate-to-severe HS resulted in decreased disease severity and improvements in QoL and productivity. Response to adalimumab was rapid (within 12 weeks) and sustained (52 weeks). No unexpected safety signals were reported.

European Position Paper on Rhinosinusitis and Nasal Polyps 2020.

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.

EPOS2020: development strategy and goals for the latest European Position Paper on Rhinosinusitis.

BACKGROUND: The European Position Papers on Rhinosinusitis from 2005, 2007 and 2012 have had a measurable impact on the way this common condition with high impact on quality of life is managed around the world. EPOS2020 will be the latest iteration of the guideline, addressing new stakeholders and target users, presenting a summary of the latest literature and evolving treatment modalities, and formulating clear recommendations based on all available evidence. METHODOLOGY: Based on the AGREE II framework, this article demonstrates how the EPOS2020 steering group will address six key areas to ensure consistency in quality and presentation of information in the latest rhinosinusitis clinical practice guideline: scope and purpose; stakeholder involvement; rigour of development; clarity of presentation; recommendations and applicability; editorial independence. RESULTS: By analysing the guidance from AGREE II, we formulated a detailed development strategy for EPOS2020. We identify new stakeholders and target users and ratify the importance of patient involvement in the latest EPOS guideline. New and expanded areas of research to be addressed are highlighted. We confirm our intention to use mixed methodologies, combining evidence-based medicine with real life studies; when no evidence can be found, use Delphi rounds to achieve clear, inclusive recommendations. We also introduce new concepts for dissemination of the guideline, using Internet and social media to improve accessibility. CONCLUSION: This article is an introduction to the EPOS2020 project, and presents the key goals, core stakeholders, planned methodology and dissemination strategies for the latest version of this influential guideline.

A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN.

BACKGROUND: Dowling-Degos disease (DDD), featuring reticulate pigmentation, and familial hidradenitis suppurativa (HS) share many clinical features including autosomal dominant inheritance, flexural location and follicular defects. The coexistence of the two disorders was recently found to result from mutations in PSENEN, encoding the γ-secretase subunit protein presenilin enhancer. OBJECTIVES: To investigate PSENEN mutations in a series of four unrelated patients who presented with combined DDD and HS. METHODS: Mutation and haplotype analysis of PSENEN by polymerase chain reaction, and cellular assays investigating the Notch signalling pathway. RESULTS: Here we report four families of Jewish Ashkenazi origin who presented with clinical features characteristic of both disorders. All patients were found to carry the same, heterozygous mutation in PSENEN (c.168T>G, p.Y56X). Haplotype analysis revealed that the mutation originated from a common ancestor. Genes associated with DDD, as well as HS, have been shown to encode important regulators of Notch signalling. Accordingly, using a reporter assay, we demonstrated decreased Notch activity in a patient's keratinocytes. CONCLUSIONS: The present data confirm the genetic basis of the combined DDD-HS phenotype and suggest that Notch signalling may play a central role in the pathogenesis of this rare condition.

Industrial applications of nanoparticles.

Research efforts in the past two decades have resulted in thousands of potential application areas for nanoparticles - which materials have become industrially relevant? Where are sustainable applications of nanoparticles replacing traditional processing and materials? This tutorial review starts with a brief analysis on what makes nanoparticles attractive to chemical product design. The article highlights established industrial applications of nanoparticles and then moves to rapidly emerging applications in the chemical industry and discusses future research directions. Contributions from large companies, academia and high-tech start-ups are used to elucidate where academic nanoparticle research has revolutionized industry practice. A nanomaterial-focused analysis discusses new trends, such as particles with an identity, and the influence of modern instrument advances in the development of novel industrial products.

A mutation in Tubb2b, a human polymicrogyria gene, leads to lethality and abnormal cortical development in the mouse.

Human cortical malformations, including lissencephaly, polymicrogyria and other diseases of neurodevelopment, have been associated with mutations in microtubule subunits and microtubule-associated proteins. Here we report our cloning of the brain dimple (brdp) mouse mutation, which we recovered from an ENU screen for recessive perinatal phenotypes affecting neurodevelopment. We identify the causal mutation in the tubulin, beta-2b (Tubb2b) gene as a missense mutation at a highly conserved residue (N247S). Brdp/brdp homozygous mutants have significant thinning of the cortical epithelium, which is markedly more severe in the caudo-lateral portion of the telencephalon, and do not survive past birth. The cortical defects are largely due to a major increase in apoptosis and we note abnormal proliferation of the basal progenitors. Adult brdp/+ mice are viable and fertile but exhibit behavioral phenotypes. This allele of Tubb2b represents the most severely affected mouse tubulin phenotype reported to date and this is the first report of a tubulin mutation affecting neuronal proliferation and survival.

Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule.

The plasticity of excitatory synapses is an essential brain process involved in cognitive functions, and dysfunctions of such adaptations have been linked to psychiatric disorders such as depression. Although the intracellular cascades that are altered in models of depression and stress-related disorders have been under considerable scrutiny, the molecular interplay between antidepressants and glutamatergic signaling remains elusive. Using a combination of electrophysiological and single nanoparticle tracking approaches, we here report that the cognitive enhancer and antidepressant tianeptine (S 1574, [3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt) favors synaptic plasticity in hippocampal neurons both under basal conditions and after acute stress. Strikingly, tianeptine rapidly reduces the surface diffusion of AMPA receptor (AMPAR) through a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent mechanism that enhances the binding of AMPAR auxiliary subunit stargazin with PSD-95. This prevents corticosterone-induced AMPAR surface dispersal and restores long-term potentiation of acutely stressed mice. Collectively, these data provide the first evidence that a therapeutically used drug targets the surface diffusion of AMPAR through a CaMKII-stargazin-PSD-95 pathway, to promote long-term synaptic plasticity.

The expanding spectrum of IgA pemphigus: a case report and review of the literature.

IgA pemphigus (IGAP) is a rare, distinct variant of pemphigus, currently classified, depending upon the histological features, immunofluorescence staining pattern and autoantibody profile, into two types: subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic IgA dermatosis. In a patient with a widespread blistering disease of the skin resembling SPD-type IGAP, we demonstrate the coexistence of IgA reactivity to both epidermal (desmocollins 2 and 3) and basement membrane-associated (BP180) proteins, suggesting the coexistence of atypical IGAP and linear IgA bullous dermatosis, respectively. This case, together with 20 previous reports of atypical IGAP, underscores the limitations of current classification schemes. Therefore, we suggest reclassifying these cases under the general term 'IGAP spectrum'.

Seasonal variation in food intake, physical activity, and body weight in a predominantly overweight population.

OBJECTIVE: To describe seasonal variation in food intake, physical activity, and body weight in a predominantly overweight population. DESIGN: A longitudinal observational study. SETTING: Most of the study participants were recruited from a health maintenance organization (HMO) in central Massachusetts, USA. Additional individuals of Hispanic descent were recruited from outside of the HMO population to increase the ethnic diversity of this sample. SUBJECTS: Data from 593 participants, aged 20-70, were used for this investigation. Each participant was followed quarterly (five sampling points: baseline and four consecutive quarters) for 1-year period. Body weight measurements and three 24-h dietary and physical activity recalls were obtained on randomly selected days (including 2 weekdays and 1 weekend day) per quarter. Sinusoidal regression models were used to estimate peak-to-trough amplitude and phase of the peaks. RESULTS: Daily caloric intake was higher by 86 kcal/day during the fall compared to the spring. Percentage of calories from carbohydrate, fat and saturated fat showed slight seasonal variation, with a peak in the spring for carbohydrate and in the fall for total fat and saturated fat intake. The lowest physical activity level was observed in the winter and the highest in the spring. Body weight varied by about 1/2 kg throughout the year, with a peak in the winter (P<0.001 winter versus summer). Greater seasonal variation was observed in subjects who were male, middle aged, nonwhite, and less educated. CONCLUSIONS: Although there is seasonal variation in diet, physical activity and body weight, the magnitude of the change is generally small in this population. SPONSORSHIP: US National Heart, Lung and Blood Institute.

PDA-assisted low glycemic index dietary intervention for type II diabetes: a pilot study.

BACKGROUND: Epidemiological and dietary intervention studies suggest that a low-glycemic index (GI) diet is beneficial for blood glucose control; however, long-term clinical utility of the low GI diet has not been fully investigated. OBJECTIVES: To evaluate the feasibility and efficacy of a nutritionist-delivered low-GI dietary intervention, with the support of a personal digital assistant (PDA), for adult patients with poorly controlled type II diabetes. METHOD: The low-GI intervention consisted of six counseling sessions and the use of a PDA-based food database with GI scores for 6 months. Study outcomes included feasibility measures, glycosylated hemoglobin levels (HbA1c), GI and glycemic load (GL) score of self-reported dietary intake, body weight, depression and quality of life (QOL). Measures were obtained at baseline, 3 and 6 months. RESULTS: Of 31 adult patients approached, 15 met study eligibility criteria and were enrolled in the study. Thirteen patients (87%) completed all study assessments. Findings included decreases in average HbA1c (-0.5% P = 0.02), body weight, hip circumference, blood pressure, dietary GI and daily caloric intake. Diabetes impact scores also decreased. All but one participant completed all components of the intervention. There were mixed reports regarding the usefulness of the PDAs; however, participants offered helpful suggestions for further development. CONCLUSIONS: Results of this pilot study support the feasibility of implementing a nutritionist-delivered, PDA-assisted low-GI dietary intervention for patients with poorly controlled type II diabetes. Encouraging initial efficacy data require further testing in the context of a randomized clinical trial.

The crisis facing printed medical literature. Acid paper.

Medicine strives to preserve the achievements of the past for the benefit of future clinicians and scientists. However, the paper on which medical journals are printed is steadily and irreversibly decaying. Since the late 1800s, most medical journals have been published on paper prepared with acids. In recent years, publishers, authors, and archivists have become aware of the destructive effects of acid decay on medical journals. Though the cause of deterioration is well understood, the choice of a remedy is still controversial. Remedies include acid-free paper, computerization, deacidification, and microfilm. These techniques are reviewed for their reliability, comprehensiveness, and cost-effectiveness. Microfilm is recommended above other techniques as the most immediately promising solution. The authors propose that publishers be required by law to submit archival quality microfilm as a condition for copyright protection.

Women, myocardial infarction, and dementia in the very old.

Dementia is a major public health problem among the very old. Available information on incidence and prevalence is sparse and variable; however, there appears to be a higher prevalence among very old women. We present data from a prospective study of initially nondemented community-residing elderly. There were 75 incident dementia cases (up to 7 years of follow-up) of which at least 47% were probable Alzheimer's disease. Based on a proportional hazards analysis, women were over 3 times more likely to develop dementia than men despite controlling for baseline demographic, psychosocial, and medical history variables. Poor word fluency and a high normal Blessed test score at baseline were also strong predictors of dementia. We did not find age, head trauma, thyroid disease, or family history of dementia to be risk factors. A new finding is that history of myocardial infarction (MI) is associated with dementia, such that women with a history of MI were 5 times more prone to dementia than those without a history. This observation was not true for men.

Chicken egg antibodies for immunohistochemical labeling of growth hormone and prolactin in bovine pituitary gland.

We describe the production of polyclonal chicken antibodies specific for bovine growth hormone (bGH) and prolactin (PRL). Antibodies were generated by immunization of laying hens with recombinant bGH (rbGH), pituitary derived bGH (pbGH), and ovine PRL (oPRL). After the lipoprotein fraction was removed by dextran sulfate precipitation the antibodies were isolated from the egg yolks by ammonium sulfate precipitation. Immunization with rbGH and oPRL generated large amounts of specific antibodies, as revealed by ELISA and Western blot analysis. Antibodies against pbGH showed pronounced crossreactions with oPRL. The antibodies against rbGH and oPRL were well suited for sensitive and specific labeling of the GH- and PRL-synthesizing cells in bovine pituitary glands by immunohistochemistry. In addition, a quick and sensitive procedure for demonstration of both bGH- and PRL-synthesizing cells in a single paraffin section by double immunohistochemistry is presented. The chicken anti-bGH antibodies showed excellent results in combination with rabbit anti-PRL antibodies. The main advantage of avian antibodies in double immunostaining methods is the lack of crossreactions between avian antibodies and mammalian immunoglobulins and receptors which bind to the crystalline fragment of mammalian immunoglobulins (Fc receptors).

Risk factors and outcome of human immunodeficiency virus-infected patients with sporadic multidrug-resistant tuberculosis in New York City.

SETTING: An 880 bed university teaching hospital in New York City. OBJECTIVE: To assess risk factors and outcome for sporadic cases of multidrug-resistant tuberculosis (MDR-TB) in persons with human immunodeficiency virus (HIV) infection. DESIGN: In a retrospective cohort analysis, 13 HIV-positive patients with MDR-TB (cases) diagnosed between January 1991 and December 1993 were compared to 31 HIV-infected patients with susceptible or single drug-resistant tuberculosis (controls) diagnosed during the same time period to assess for differences in risk factors and outcome. RESULTS: Risk factors for MDR-TB included homosexual contact as a risk for HIV transmission, prior antiretroviral therapy and Pneumocystis carinii prophylaxis. Fatality rates were 62% for MDR-TB patients and 26% for controls (P < 0.04). The median survival time was 5.8 months for cases and 9.8 months for controls. Risk factors associated with death included multidrug-resistance and CD4-lymphocyte counts below 200. CONCLUSION: Sporadic MDR-TB infection in HIV-infected patients is associated with increased morbidity and mortality compared to infection with susceptible or single-drug-resistant TB. The median survival for HIV-infected patients with MDR-TB in this study is, however, two to three times longer than previously reported in MDR-TB outbreaks.

Citation classics in clinical dermatologic journals. Citation analysis, biomedical journals, and landmark articles, 1945-1990.

BACKGROUND AND DESIGN: Analysis of the most frequently cited dermatology articles and the journals in which they appear identifies and emphasizes the impact of works of colleagues and predecessors, recognizes key advances in cutaneous medicine and surgery, and adds useful data about historical developments in dermatology. Use of citation analysis to examine the dermatologic literature reveals quantitative information about authors, articles, and journals helpful in identifying classic works and high-impact journals. We analyze the characteristics of all dermatology articles cited 100 or more times in one of the 10 most highly ranked clinical dermatology journals as indicated by the Institute of Scientific Information (Philadelphia, Pa) database from 1945 through 1990 and also discuss the standard and, as well, more recently described bibliometric indexes for dermatologic journals. RESULTS: Thirty-one institutions located in 11 different countries produced 129 landmark articles. Ninety-two percent of the citation classics originated in the United States, United Kingdom, Sweden, and Germany. There were 16 authors with three or more top-cited articles. Fifty-two percent of the articles were of the clinical type, 22% were clinical review articles, and 26% discussed basic science topics. The mean number of authors has increased gradually over the past 80 years. The average classic article was published in 1969, peaked in popularity 9 years later with 26 peer citations, and received only 11 citations in 1990. CONCLUSIONS: Citation frequency and citation analysis reveal useful and interesting information about scientific communication. The data on citation classics we describe can be interpreted in many ways, but certainly reflects the attention that articles have received over the past 48 years. The half-life of the average citation classic of about 10 years reflects the rapid pace of advances in the science and practice of dermatology over the past several decades. This information, along with current bibliometric indexes, may assist physicians in optimizing the time they spend reading the medical literature.

Spongiform central nervous system myelinopathy in African dwarf goats.

A novel spongiform myelinopathy of the central nervous system (CNS) of eleven African dwarf goats was examined by light and electron microscopy. Histological lesions consisted of extensive vacuolation predominantly of the white matter of the diencephalon, midbrain and cerebellar peduncles, as well as of spinal white matter. Ultrastructurally, vacuoles were shown to be intramyelinic, resulting from the splitting of the outer myelin lamellae at the intraperiod line. A few oligodendrocytes showed vacuolar degeneration of cell bodies and processes. Inflammatory reactions were absent. The observed lesions point to an unknown primary damage of oligodendroglia and central myelin. A hereditary background of the disorder is suspected as all investigated dwarf goats were half-brothers or -sisters and partly descended from the mating of adult females with their own sire.

In-situ hybridization for demonstration of equine herpesvirus type 1 DNA in paraffin wax-embedded tissues and its use in horses with disseminated necrotizing myeloencephalitis.

The detection of equine herpesvirus type 1 (EHV-1) in infected cell cultures, and in tissues taken at necropsy, by the in-situ hybridization technique is described. A 4.9 kb Bam HI fragment of EHV-1 vaccine strain RacH was used as a probe after labelling with [alpha-32P] thymidine 5'-triphosphate ([32P]TTP) or digoxigenin-deoxyuridine 5'-triphosphate (dUTP). Both probes specifically detected EHV-1 DNA in either cytospin or paraffin wax-embedded preparations of infected cells. The digoxigenin-labelled probe was further used to examine tissue sections of equine fetuses which had been aborted due to EHV-1 infection. In all cases positive hybridization signals were mainly associated with the nuclei. Positive results were confirmed by immunostaining of EHV-1 antigen in adjacent sections. However, both methods failed to detect EHV-1 in spinal cord sections of six horses suffering from disseminated necrotizing myeloencephalitis (DNM). These results support the hypothesis that DNM is not caused by a productive viral infection of parenchyma of the nervous system but is immunologically mediated.

Congenital myopathy in Braunvieh x Brown Swiss calves.

A hitherto unknown skeletal muscle disorder is described in six Braunvieh x Brown Swiss calves. The animals showed rapidly progressing muscular weakness and became recumbent within 2 weeks of birth. Histological examination of skeletal muscle revealed a marked variation in muscle fibre size, internally placed nuclei, segmental loss of cross-striation with disorganization of myofibrils, and accumulation of nemaline rods. The most distinctive histological finding was intracytoplasmic, homogeneous, mostly crescent-shaped areas at the periphery of numerous muscle fibres. Electron microscopically, accumulations of tightly packed, parallel filamentous structures, about 20 nm in diameter, were detected in these areas. Enzyme histochemistry showed that all muscle fibre types were affected. Vimentin and dystrophin immunohistochemistry revealed normal antigen distribution within connective tissue components and at the periphery of each muscle fibre, respectively. The lesions could be readily distinguished from other neurological and neuromuscular disorders previously described in Braunvieh x Brown Swiss or American Brown Swiss Cattle. The disease appears to be a novel congenital myopathy in this breed, and a hereditary aetiology is suspected.

[Phototherapeutic keratectomy (o-PTK) with 193 nm excimer laser for superficial corneal scars. Prospective long-term results of 31 consecutive operations]. / Phototherapeutische Keratektomie (o-PTK) mittels 193-nm-Excimerlaser bei oberflächlichen HornhautnarbenProspektive Langzeitergebnisse von 31 konsekutiven Eingriffen.

PURPOSE: To investigate the functional and morphological long-term outcome of phototherapeutic keratectomy (PTK) for superficial corneal scars of varying origin. PATIENTS AND METHODS: Between 1989 and 11/2002, 317 PTKs were performed in Erlangen, of which 31 consecutive procedures were assessed in this prospective study. The intended laser ablation depth after epithelial debridement and pannectomy varied from 12 to 150 microm. We used the slit-scanning-mode (Carl Zeiss Meditec AG) with a repetition rate of 20/s or 25/s, a pulse energy of 14.5 mJ (median) and a pulse rate of 2565+/-2036 (222-6962). In most cases a 6.0 mm metal mask was used to protect peripheral Bowman's layer. RESULTS: After a mean follow-up of 2.0+/-1.9 (maximum 6.9) years, best-corrected visual acuity increased from preoperatively 0.3+/-0.2 to 0.5+/-0.3 (increase 87%, no change 10%, decrease 3%). Corneal surface topography regularized significantly (p=0.02). The spherical equivalent increased only slightly from -0.4+/-2.5 D preoperatively to 0.2+/-2.9 D postoperatively. Likewise, mean keratometric central power did not change significantly. In 10 eyes the maximum postoperative haze was mild, in 4 eyes moderate, and there was only one recurrent scar after delayed epithelial healing following epidemic keratoconjunctivitis. CONCLUSIONS: In superficial corneal scars of varying origin an o-PTK using the 193 nm excimer laser can moderately increase visual acuity in most cases. Therefore, a lamellar or penetrating keratoplasty might be avoided.