Anti-cyclic citrullinated peptide antibodies are associated with radiographic damage but not disease activity in early rheumatoid arthritis diagnosed in 2006-2011.

Objective: The discovery of anti-citrullinated protein antibodies (ACPAs) and the introduction of new therapeutic options have had profound impacts on early rheumatoid arthritis (RA) care. Since ACPA status, most widely assessed as reactivity to cyclic citrullinated peptides (CCPs), influences treatment decisions in early RA, we aimed to determine whether anti-CCP remains a predictor of disease activity and radiographic joint damage in more recent 'real-world' early RA. Method: Two observational early RA cohorts from Sweden enrolled patients in 1996-1999 (TIRA-1, n = 239) and 2006-2009 (TIRA-2, n = 444). Clinical and radiographic data and ongoing treatment were prospectively collected up to 3 years. Two other cohorts served as confirmation cohorts (TRAM-1, with enrolment 1996-2000, n = 249; and TRAM-2, 2006-2011, n = 528). Baseline anti-CCP status was related to disease activity, pharmacotherapy, and radiographic joint damage according to Larsen score. Results: In the TIRA-1 cohort, anti-CCP-positive patients had significantly higher 28-joint Disease Activity Score, swollen joint count, C-reactive protein level, and erythrocyte sedimentation rate during follow-up compared with anti-CCP-negative patients. In TIRA-2, no such differences were found, but baseline anti-CCP positivity was associated with higher 3 year Larsen score (5.4 vs 3.5, p = 0.039). In TRAM-2, anti-CCP also predicted radiographic damage (8.9 vs 6.7, p = 0.027), with no significant differences in disease activity. Conclusion: In the early RA cohorts recruiting patients in 2006-2011, baseline anti-CCP positivity was not associated with disease activity over time, but was associated with increased radiographic damage at follow-up. Hence, close radiographic monitoring is warranted in early anti-CCP-positive RA regardless of disease activity.

Three-dimensional imaging of active acid sulfate soil using a DUALEM-21S and EM inversion software.

One of the major environmental issues in Finland is the presence of large tracts of acid sulfate soil (ASS) landscapes along the coast. Accurately identifying the distribution of ASS sediments, and in particular soil pH, is essential for developing targeted management strategies. One approach is the use of digital soil mapping (DSM) with various ancillary information. Although electromagnetic (EM) induction data has shown potential in mapping ASS, few studies have been conducted to map the spatial distribution of pH at different depths. In this study, a DUALEM-21S was used to collect apparent soil electrical conductivity (ECa) data across a 23-ha field near Vaasa, which lies along the western coast of Finland. A quasi-3D inversion algorithm was used to calculate the estimated true electrical conductivity (σ - mS m-1). A calibration relationship was developed between σ and incubation-pH measured at various depths from topsoil (0-0.2 m), subsurface (0.2-0.4 m) and subsoil (e.g. 0.4-0.6 and 1.8-2 m) using an artificial neural network (ANN) model. The performance of the ANN model was good given the large R2 values for calibration (0.72) and validation (0.65). It was concluded that the combination of ECa data and quasi-3D inversion algorithm (in EM4Soil) was able to map the spatial distribution of incubation-pH associated within an ASS landscape. The approach has the potential to be applied across the coastal areas of Finland and elsewhere to map incubation-pH and identify active-ASS areas and thereby improve the management of these areas.

Pay for performance associated with increased volume of medication reviews but not with less inappropriate use of medications among the elderly - an observational study.

OBJECTIVE: A pay for performance programme was introduced in 2009 by a Swedish county with 1.6 million inhabitants. A process measure with payment linked to coding for medication reviews among the elderly was adopted. We assessed the association with inappropriate medication for five years after baseline. DESIGN AND SETTING: Observational study that compared medication for elderly patients enrolled at primary care units that coded for a high or low volume of medication reviews. PATIENTS: 144,222 individuals at 196 primary care centres, age 75 or older. MAIN OUTCOME MEASURES: Percentage of patients receiving inappropriate drugs or polypharmacy during five years at primary care units with various levels of reported medication reviews. RESULTS: The proportion of patients with a registered medication review had increased from 3.2% to 44.1% after five years. The high-coding units performed better for most indicators but had already done so at baseline. Primary care units with the lowest payment for coding for medication reviews improved just as well in terms of inappropriate drugs as units with the highest payment - from 13.0 to 8.5%, compared to 11.6 to 7.4% and from 13.6 to 7.2% vs 11.8 to 6.5% for polypharmacy. CONCLUSIONS: Payment linked to coding for medication reviews was associated with an increase in the percentage of patients for whom a medication review had been registered. However, the impact of payment on quality improvement is uncertain, given that units with the lowest payment for medication reviews improved equally well as units with the highest payment.

Minimum standards on prevention, diagnosis and treatment of occupational and work-related skin diseases in Europe - position paper of the COST Action StanDerm (TD 1206).

BACKGROUND: Skin diseases constitute up to 40% of all notified occupational diseases in most European countries, predominantly comprising contact dermatitis, contact urticaria, and skin cancer. While insufficient prevention of work-related skin diseases (WRSD) is a top-priority problem in Europe, common standards for prevention of these conditions are lacking. OBJECTIVE: To develop common European standards on prevention and management of WRSD and occupational skin diseases (OSD). METHOD: Consensus amongst experts within occupational dermatology was achieved with regard to the definition of minimum evidence-based standards on prevention and management of WRSD/OSD. RESULTS: By definition, WRSDs/OSDs are (partially or fully) caused by occupational exposure. The definition of OSD sensu stricto additionally includes diverging national legal requirements, with an impact on registration, prevention, management, and compensation. With the implementation of the classification of WRSD/OSD in the International Classification of Diseases (ICD) 11th Revision in future, a valid surveillance and comparability across countries will be possible. Currently, WRDS and OSD are still under-reported. Depending on legislation and regulations, huge differences exist in notification procedures in Europe, although notification is crucial to prevent chronic and relapsing disease. Facilities for early diagnosis, essential for individual patient management, should be based on existing guidelines and include a multidisciplinary approach. Patch testing is essential if contact dermatitis persists or relapses. Workplace exposure assessment of WRSD/OSD requires full labelling of product ingredients on material safety data sheets helping to identify allergens, irritants and skin carcinogens. Comparable standards in primary, secondary and tertiary prevention must be established in Europe to reduce the burden of WRSD/OSD in Europe. CONCLUSION: The adoption of common European standards on prevention of WRSD/OSD will contribute to reduce the incidence of OSD and their socio-economic burden.

Occupational skin diseases: actual state analysis of patient management pathways in 28 European countries.

BACKGROUND: Work-related skin diseases (WSD) are caused or worsened by a professional activity. Occupational skin diseases (OSD) need to fulfil additional legal criteria which differ from country to country. OSD range amongst the five most frequently notified occupational diseases (musculoskeletal diseases, neurologic diseases, lung diseases, diseases of the sensory organs, skin diseases) in Europe. OBJECTIVE: To retrieve information and compare the current state of national frameworks and pathways to manage patients with occupational skin disease with regard to prevention, diagnosis, treatment and rehabilitation in different European countries. METHODS: A questionnaire-based survey of the current situation regarding OSD patient management pathways was carried out with experts on occupational dermatology and/or occupational medicine from 28 European countries contributing to the European Cooperation in Science and Technology (COST) Action TD 1206 (StanDerm) (www.standerm.eu). RESULTS: Besides a national health service or a statutory health insurance, most European member states implemented a second insurance scheme specifically geared at occupational diseases [insurance against occupational risks (synonyms: insurance against work accidents and occupational injuries; statutory social accident insurance)]. Legal standards for the assessment of occupationally triggered diseases with a genetic background differ between different countries, however, in most European member states recognition as OSD is possible. In one-third of the countries UV light-induced tumours can be recognized as OSD under specific conditions. CONCLUSION: OSD definitions vary between European countries and are not directly comparable, which hampers comparisons between statistics collected in different countries. Awareness of this fact and further efforts for standardization are necessary.

Methylisothiazolinone in rinse-off products causes allergic contact dermatitis: a repeated open-application study.

BACKGROUND: In recent years, the prevalence of contact allergy to the preservative methylisothiazolinone (MI) has increased dramatically. Cosmetic products are one of the major sources of exposure. OBJECTIVES: To examine whether allowed concentrations of MI in cosmetic rinse-off products have the potential to cause allergic contact dermatitis. METHODS: Nineteen MI-allergic subjects and 19 controls without MI allergy applied two liquid hand soaps five times per day on areas of 5 × 10 cm(2) on the ventral side of their forearms. One soap contained 100 ppm MI, the maximum allowed concentration in cosmetics, and was used by 10 allergic subjects and all controls. Another liquid soap with 50 ppm MI was used by nine allergic subjects. As the negative control, all subjects used a similar soap that did not contain MI. The repeated open applications proceeded until a positive reaction occurred or up to 21 days. The study was conducted in a randomized and blinded fashion. RESULTS: Ten out of 10 MI-allergic subjects developed positive reactions to the soap with 100 ppm and seven out of nine reacted to the 50 ppm soap, while none of the 19 controls had a positive reaction during 21 days of application. No reactivity was seen to the soap without MI. The difference in reactivity to MI between MI-allergic subjects and controls was statistically significant (Fisher's exact test, P ˂ 0.0001). CONCLUSIONS: Rinse-off products preserved with 50 ppm MI or more are not safe for consumers. No safe level has yet been identified.

Study of innervation, sensory neuropeptides, and serotonin in murine contact allergic skin.

Density of nerve fibers, axonal growth, calcitonin gene-related peptide (CGRP), and substance P, and serotonin immunoreactivity as well as concentration were all determined in a murine model of contact allergy. Female Balb/c mice were sensitized on the back with oxazolone and 6 days later challenged with the same antigen on the dorsal surface of the ears, while control mice received the vehicle only. Then, 24 hr postchallenge, one ear was processed for immunohistochemical staining, while the other was frozen and processed for gas chromatography-mass spectrometry or radioimmunoassay (RIA). Protein gene product 9.5 (PGP 9.5) positive nerve fibers showed a tendency to increase in inflamed ears versus control ears in epidermis as well as the dermis. Growth-associated protein-43 (GAP-43) positive fibers in the epidermis were increased (p < .01) in inflamed ears, compared with control ears, as was the case for the dermal fibers, indicating increased axonal growth. Total (epidermis and dermis) numbers of CGRP and substance P positive nerve fibers tended to increase in the inflamed skin in contrast to control skin. In contrast, RIA demonstrated a lower (p < .05) concentration of CGRP in the inflamed ears compared with controls and a tendency for substance P to decrease in concentration in eczematous ears versus controls. There was no difference in serotonin concentration, or in the number of serotonin positive mast cells, between the inflamed and control skin, whereas semiquantification of serotonin positive platelets showed an increase in the inflamed (+/+) compared with control ears (+). Our results indicate that 24 hr after being challenged with the antigen, at the peak of murine skin inflammation, axonal growth, sensory neuropeptides, as well as serotonin may be involved.

Increased airway responsiveness of a common fragrance component, 3-carene, after skin sensitisation--a study in isolated guinea pig lungs.

Lungs from skin-sensitised and non-sensitised guinea pigs were exposed via the airways to 3-carene (1900 mg/m3) and perfused with buffer containing either autologous plasma or lymphocytes. The experiments were performed in order to investigate the importance of blood components for the increased lung responsiveness seen in skin-sensitised animals. A reduction in lung function was noted in all lungs during 3-carene exposure. There was no difference in the 3-carene response between lungs from skin-sensitised animals versus lungs from non-sensitised animals when the perfusion buffer contained lymphocytes. However, when plasma diluted with buffer was used as perfusion medium, there was a significant enhancement in the response in lungs from sensitised versus lungs from non-sensitised animals. This implies that skin sensitisation increases lung responses to inhaled 3-carene and those components in plasma, and not the lymphocyte fraction, contributes to the observed increased lung responsiveness.

Ascaris nematodes from pig and human make three antibacterial peptides: isolation of cecropin P1 and two ASABF peptides.

Organisms co-habiting with bacteria have developed efficient bactericidal agents to control their microbe-rich environment. The Ascaris nematode lives in its final development stages in the gut of its host and is believed to feed on bacteria. Ascaris suum survive in pig intestine while A. lumbricoides is the principal species in humans. Here we show that A. suum and A. lumbricoides both produce linear (cecropin P1) and cysteine-rich (ASABF) peptides with activity against either gram-negative or gram-positive bacteria, respectively. Thus nematodes rely in part on a peptide-based antibacterial system for digestion of bacteria, which may also confer protection against infection. Cecropin P1 was previously isolated from pig intestine but we can now conclude that was due to contaminating nematodes.

GGA proteins: new players in the sorting game.

The GGA proteins are a novel family of proteins that were discovered nearly simultaneously by several labs studying very different aspects of membrane trafficking. Since then, several studies have described the GGA proteins and their functions in yeast and mammalian cells. Four protein domains are present in all GGA proteins, as defined by sequence homology and function. These different domains interact directly with ARF proteins, cargo and clathrin. Alteration of the levels of GGA proteins by gene knockout or overexpression affects specific trafficking events between the trans-Golgi network and endosomes. These data suggest that GGAs function as ARF-dependent, monomeric clathrin adaptors to facilitate cargo sorting and vesicle formation at the trans-Golgi network.

ARF binds the C-terminal region of the Escherichia coli heat-labile toxin (LTA1) and competes for the binding of LTA2.

Cholera toxin (CT) and the heat-labile enterotoxin (LT) from Escherichia coli are highly related in terms of structure and biochemical activities and are the causative agents of cholera and traveler's diarrhea, respectively. The pathophysiological action of these toxins requires their activity as ADP-ribosyltransferases, transferring the ADP-ribose moiety from NAD onto the stimulatory, regulatory component of adenylyl cyclase, Gs. This reaction is highly dependent on the protein cofactor, termed ADP-ribosylation factor (ARF), that is itself a 20 kDa regulatory GTPase. In this study, we define sites of interaction between LTA and human ARF3. The residues identified as important to ARF binding include several of those previously shown to bind to the A2 subunit of the toxin and those important to the organization of two flexible loops, previously implicated as regulators of substrate entry. A model for how ARF acts to enhance the catalytic activity is proposed. A critical portion of the overlap between ARF and LTA(2) in binding LTA(1) includes a short region of sequence homology between LTA(2) and the switch II region of ARF. LTA(2) also interacted with ARF effectors in two-hybrid assays, and thus, we discuss the possibility that the LTA(2) subunit may function in cells as a partial ARF mimetic to compete for the binding of ARF to LTA(1) or regulate aspects of the toxin's transport from the cell surface to the ER.

[Task and task time should dictate the choice of gloves in health care services]. / Uppgiften och arbetets längd bör styra valet av handskar i vården.

Worldwide consumption of medical gloves increased during the 1980's due to the recognized risk of cross infections in medical and dental care. In Stockholm County Council around 1 million pairs of surgical gloves and 18 millions pairs of examination gloves are purchased per year. In the following paper different glove materials and types are presented and also regulations on use and purchase. The protective capacity of gloves and contact hypersensitivity reactions are also discussed and advice is provided on glove usage.

Yeast GGA proteins interact with GTP-bound Arf and facilitate transport through the Golgi.

ARF proteins regulate the formation of transport vesicles at many steps of the secretory and endocytic pathways. A recently identified family of ARF effectors, named GGAs, appears to regulate membrane traffic exiting the trans-Golgi network in mammalian cells (Boman et al., 2000). We have identified two GGA homologues in the yeast S. cerevisiae. These previously uncharacterized open reading frames, YDR358w and YHR108w, have been named GGA1 and GGA2, respectively. Using the two-hybrid assay and GST-affinity chromatography, we show that Gga1p and Gga2p interact with Arf1p and Arf2p in a GTP-dependent manner, suggesting that both are functional homologues of the human GGA proteins. The Arf-binding domain resides in the amino-terminal half of Gga1p (amino acids 170-330), and the carboxy-terminal 100 amino acids resemble the gamma-adaptin 'ear domain'. Gene deletion experiments indicate that GGA1 and GGA2 are not essential genes, as single and double knockouts are viable at both 30 degrees C and 37 degrees C. However, cells lacking GGA1 and GGA2 exhibit defects in invertase processing and CPY sorting, but not endocytosis. We conclude that yeast Gga proteins are effectors of Arf in yeast that facilitate traffic through the late Golgi.

Sensitizing potential of chlorothalonil in the guinea pig and the mouse.

The fungicide chlorothalonil is used extensively under several tradenames for the protection of various horticultural and fruit crops and bananas against fungal infections. It is also used as fungicide in wood preservation and as a preservative in paints. Clinical experience has shown chlorothalonil to be a contact allergen and several cases of allergic contact dermatitis attributed to chlorothalonil have been described. 2 previous guinea pig maximization test studies have shown the sensitizing potential of chlorothalonil to be high. The sensitizing property of chlorothalonil was studied by us with the predictive test methods the local lymph node assay and the cumulative contact enhancement test. In the local lymph node assay, chlorothalonil induced a dose-dependent increase in proliferation with a maximal stimulation index of 19.2 and 27.2. In the cumulative contact enhancement test, a statistically significant dose-dependent high sensitization rate was seen with a maximal sensitization rate of 100%. In conclusion, it is evident that chlorothalonil is an extremely potent contact allergen, inducing sensitization using only topical exposure on intact skin.

Germ-free and colonized mice generate the same products from enteric prodefensins.

The use of germ-free mice offers the possibility to study antibacterial components in a gut uncolonized by bacteria. We have developed a method to extract and high pressure liquid chromatography-fractionate the antibacterial factors present in the small intestine of a single mouse. By mass spectrometry and sequence analyses of fractions exhibiting antimicrobial activity, we identified and characterized the defensin region in germ-free mice as well as in colonized mice. Defensins made up around 15% of the total antibacterial activity both in germ-free and colonized mice. The intestine of germ-free mice exhibited the same set of mature enteric defensins (defensins 1, 2, 3, 4, and 6) as mice colonized by a normal microflora. Mature defensins are generated through processing of larger precursors by enzymatic removal of a signal peptide and a propiece. We found that all prodefensins were cleaved at a Ser/Ala-Leu bond, giving 34-residue propiece peptides and only trace amounts of the predicted 39-residue peptide. This first step must be followed by the removal of a residual peptide to render the mature defensins, indicating that the processing is more complex than previously anticipated. The same propieces were found in both germ-free and colonized mice, suggesting that the same processing operates independent of bacterial presence in the intestine.

Increased airway responsiveness after skin sensitisation to 3-carene, studied in isolated guinea pig lungs.

Inhalation of 3-carene has been shown to induce bronchoconstriction in concentrations not far from the threshold limit value. In this study, one group of guinea-pigs were sensitised by dermal exposure to 3-carene according to the modified Cumulative Contact Enhancement Test protocol and another group of animals was used as controls. Lungs from the skin-sensitised and control guinea-pigs were perfused with diluted autologous blood (13 ml blood/87 ml buffer) and exposed to 3-carene at an air concentration of 3000 mg/m(3). In both groups there was a reduction in compliance and conductance but this reduction was significantly (P<0.05) more pronounced (2.5-3 times) in lungs obtained from sensitised animals than from control animals. In a previous study with similar design, but with plain buffer instead of diluted autologous blood as perfusate, we found no statistically significant difference in lung bronchoconstriction. Thus, it is concluded that skin sensitisation can increase lung reactivity to 3-carene and that important mediators of this effect seem to be present in the blood.

Effectors increase the affinity of ADP-ribosylation factor for GTP to increase binding.

The stoichiometry of the binding of GTP to ADP-ribosylation factor (ARF) proteins, normally quite low at approximately 0.05 mol/mol protein, was found to increase to a maximum of 1 mol/mol in the presence of effectors. The mechanism of this action was found to result from the ability of these effectors to increase the affinity of ARF for activating guanine nucleotide triphosphates. The existence of a conformation of ARF with low affinity (>100 micrometer) for GTP is proposed. The actions of effectors to increase the equilibrium binding of GTP is interpreted as evidence that these same effectors interact with and modulate the affinity of the inactive ARF for GTP. A new model for these interactions among ARF, effectors, and GTP is proposed, and a preliminary test in cells is supportive of these observations with relevance to signaling in cells.

Percutaneous absorption of organic solvents.

Organic solvents pass the cutaneous barriers and may quickly be absorbed in substantial amounts, such that several solvents have "skin" denotations in lists of occupational exposure limit values. Solvents may be absorbed from liquids, upon direct skin contact, and in some cases also from contact with vapors. Environmental factors such as temperature, humidity, vehicle, and ventilation influence absorption. Absorption rates vary considerably; several amphiphilic solvents are absorbed at high rates. Since solvents are volatile, unoccluded repeated exposures result in less absorption than does continuous contact, and adequate ventilation may reduce absorption considerably. Risk assessments of skin absorption of organic solvents have benefited from calculation of quantitative structure-activity relationships based on log P(o/w), which enables skin absorption to be calculated with reasonable accuracy.

A family of ADP-ribosylation factor effectors that can alter membrane transport through the trans-Golgi.

A family of three structurally related proteins were cloned from human cDNA libraries by their ability to interact preferentially with the activated form of human ADP-ribosylation factor 3 (ARF3) in two-hybrid assays. The specific and GTP-dependent binding was later confirmed through direct protein binding of recombinant proteins. The three proteins share large ( approximately 300 residues) domains at their N termini that are 60-70% identical to each other and a shorter (73 residues) domain at their C termini with 70% homology to the C-terminal "ear" domain of gamma-adaptin. Although GGA1 is found predominantly as a soluble protein by cell fractionation, all three proteins were found to localize to the trans-Golgi network (TGN) by indirect immunofluorescence. The binding of GGAs to TGN was sensitive to brefeldin A, consistent with this being an ARF-dependent event. Thus, these proteins have been named Golgi-localizing, gamma-adaptin ear homology domain, ARF-binding proteins, or GGAs. The finding that overexpression of GGAs was sufficient to alter the distribution of markers of the TGN (TGN38 and mannose 6-phosphate receptors) led us to propose that GGAs are effectors for ARFs that function in the regulation of membrane traffic through the TGN.