Factors influencing prognosis for occupational hand eczema: new trends.

BACKGROUND: Variables traditionally reported to influence the prognosis of occupational hand eczema (OHE) are atopic dermatitis (AD) and contact sensitization. However, recent studies indicate that lifestyle factors may be of major importance. OBJECTIVES: To identify factors influencing the prognosis in a cohort of patients with recognized OHE. METHODS: In this register-based cohort study, individuals with hand eczema recognized as occupational disease in the period January 2010-December 2011 were identified using files from Labor Market Insurance Denmark and included in the study. At baseline, information on sex, age, occupation, wet work, AD and contact sensitization was collected. In 2015 participants received a questionnaire with questions about lifestyle factors, current occupation and healing of OHE. RESULTS: In total, 2703 patients received the questionnaire; 1491 responded to the question about healing of OHE and were included in the study. Altogether, 19·3% of patients reported complete healing at follow-up. Current tobacco smoking and a high level of stress were factors inversely associated with healing of hand eczema (P < 0·001 and P = 0·030, respectively), while a high level of exercise was significantly related to healing of eczema (P = 0·011). Change of profession was a favourable prognostic factor, while age, sex, AD, contact sensitization and education did not significantly influence prognosis. CONCLUSIONS: Traditionally important risk factors such as AD and contact sensitization had no marked influence on prognosis, while lifestyle factors were of major importance. Our findings indicate that risk factors may vary over time, allowing for new perspectives on prevention. What's already known about this topic? Occupational hand eczema has a relapsing course and a poor overall prognosis. Atopic dermatitis and contact sensitization have previously been reported as risk factors for a poor prognosis. What does this study add? The results indicate that lifestyle factors are of importance for the prognosis of occupational hand eczema. Traditionally reported risk factors such as atopic dermatitis and contact sensitization do not currently influence prognosis.

Treatment of atopic dermatitis with dupilumab: experience from a tertiary referral centre.

BACKGROUND: Management of moderate-to-severe atopic dermatitis (AD) frequently requires treatment with systemic therapies. Dupilumab is the first biological agent approved for treatment of moderate-to-severe AD. Although promising results have appeared in clinical trials, real-life data on efficacy and safety are lacking. OBJECTIVES: To assess effectiveness and safety of treatment with dupilumab in the real-life clinical setting at a Danish tertiary referral centre. METHODS: All patients with AD treated with dupilumab from October 2017 to October 2018 at Bispebjerg Hospital, Denmark, were included in the study. Patients were evaluated three times: at treatment initiation and at 1 and 3 months after first dupilumab injection. At each visit, disease activity was assessed by severity score (Eczema Area and Severity Index, EASI), patient-reported outcomes (Dermatology Life Quality Index, DLQI, pruritus and sleep score) and serological markers [immunoglobulin (Ig)E, eosinophil count and lactate dehydrogenase (LDH)]. RESULTS: A total of 43 patients were included in the study. The mean reduction in EASI score from baseline was 19.6 points (72.4%) at 1-month and 22.6 points (76.7%) at 3-month follow-up. EASI, DLQI, pruritus score, sleep score, IgE and LDH were all statistically significantly reduced between baseline and 1- and 3-month follow-up. Mean reductions in EASI score and LDH at 3-month follow-up were significantly correlated (P = 0.003). One patient (2.3%) discontinued treatment due to side-effects, and seven patients (18.4%) developed conjunctivitis during the study period. CONCLUSION: The effectiveness and safety of dupilumab treatment in a real-life clinical setting are comparable to that of phase 3 clinical trials. LDH is suggested as a potential serological marker predictive of treatment response.

Clinical segmentation in 22q11.2 deletion syndrome: Cognitive impairments and additional genetic load.

The 22q11.2 deletion syndrome (22q11.2DS) is associated with high psychiatric morbidity. However, large phenotypic heterogeneity hampers early detection of 22q11.2DS individuals at highest risk. Here, we investigated whether individuals with 22q11.2DS can be subdivided into clinically relevant subgroups based on their severity of cognitive impairments and whether such subgroups differ in polygenic risk. Using a cross-sectional design, we examined the number of lifetime psychiatric diagnoses and polygenic risk scores for schizophrenia in an unselected nationwide biobank cohort of individuals with 22q11.2DS (n = 183). Approximately 35% of this sample, aged 10-30 years, had a history with one or more psychiatric diagnosis. In a representative nested subgroup of 28 children and youth, we performed additional comprehensive cognitive evaluation and assessed psychiatric symptoms. Unsupervised hierarchical cluster analysis was performed to divide the subgroup of 22q11.2DS individuals, based on their performance on the cognitive testing battery. This produced two groups that did not differ in mean age or gender composition, but were characterized by low cognitive (LF) and high cognitive (HF) functional levels. The LF group, which had significantly lower global cognitive functioning scores, also displayed higher negative symptom scores; whereas, the HF group displayed lower rate of current psychiatric disorders than the LF group and the reminder of the biobank cohort. The polygenic risk score for schizophrenia was insignificantly lower for the low functioning group than for the high functioning group, after adjustment. Cognitive functioning may provide useful information on psychiatric risk.

Novel alkali earth borohydride Sr(BH4)2 and borohydride-chloride Sr(BH4)Cl.

Two novel alkali earth borohydrides, Sr(BH4)2 and Sr(BH4)Cl, have been synthesized and investigated by in-situ synchrotron radiation powder X-ray diffraction (SR-PXD) and Raman spectroscopy. Strontium borohydride, Sr(BH4)2, was synthesized via a metathesis reaction between LiBH4 and SrCl2 by two complementary methods, i.e., solvent-mediated and mechanochemical synthesis, while Sr(BH4)Cl was obtained from mechanochemical synthesis, i.e., ball milling. Sr(BH4)2 crystallizes in the orthorhombic crystal system, a = 6.97833(9) Å, b = 8.39651(11) Å, and c = 7.55931(10) Å (V = 442.927(10) Å(3)) at RT with space group symmetry Pbcn. The compound crystallizes in α-PbO2 structure type and is built from half-occupied brucite-like layers of slightly distorted [Sr(BH4)6] octahedra stacked in the a-axis direction. Strontium borohydride chloride, Sr(BH4)Cl, is a stoichiometric, ordered compound, which also crystallizes in the orthorhombic crystal system, a = 10.8873(8) Å, b = 4.6035(3) Å, and c = 7.4398(6) Å (V = 372.91(3) Å(3)) at RT, with space group symmetry Pnma and structure type Sr(OH)2. Sr(BH4)Cl dissociates into Sr(BH4)2 and SrCl2 at ~170 °C, while Sr(BH4)2 is found to decompose in multiple steps between 270 and 465 °C with formation of several decomposition products, e.g., SrB6. Furthermore, partly characterized new compounds are also reported here, e.g., a solvate of Sr(BH4)2 and two Li-Sr-BH4 compounds.

Absence of 'over-the-counter' medicinal products in on-line prescription records: a risk factor of overlooking interactions in the elderly.

PURPOSE: To assess possible origins of harmful interactions in elderly patients arising from the current absence of information on over-the-counter (OTC) medicines in the Danish 'on-line prescription record'. METHODS: Information on current use of prescription drugs and OTC medicinal products (non-prescription drugs, herbal medicine, dietary supplements, and others) was collected by home visit interviews. The latter OTC products were not listed in an on-line prescription record that covered the previous two years. Information on interactions between OTC medicines and between OTC products and prescription drugs was obtained from the Danish National Drug Interaction Database. RESULTS: Of the 309 patients recruited (median age 75 years, interquartile range (IQR) 70-81), 229 (74%) used 568 OTC medicines not listed in the Danish 'on-line prescription record', amongst which we identified 166 potential interactions - between OTC treatments or between OTC and prescription drugs. Fifty percent of patients taking OTC medicines were exposed to potential interactions, i.e. one to three instances per patient. Twenty-five percent of patients exposed to interactions experienced interaction listed as 'Can be used with certain precautions'. CONCLUSION: The absence of information on OTC products in an on-line prescription record entails a risk of overlooking interactions in elderly patients. Such products should be included in on-line medication records to prevent adverse effects from interactions. However, online medication records are not available in all countries and as inclusion of data on OTC drugs seem not to be feasible presently. Still, it is highly recommended that the patient's drug list is reviewed on a regular basis.

Prenatal and postnatal exposures to endocrine disrupting chemicals and timing of pubertal onset in girls and boys: a systematic review and meta-analysis.

BACKGROUND: Globally, the ages at pubertal onset for girls and boys have been decreasing during recent decades, partly attributed to excess body fat accumulation. However, a growing body of literature has recognized that endocrine disrupting chemicals (EDCs) may play an important role in this global trend, but the association has not yet been fully established. OBJECTIVE AND RATIONALE: EDCs can interfere with normal hormone function and metabolism and play a role in pubertal onset. We aimed to systematically identify and evaluate the current evidence on the timing of pubertal onset in girls and boys following prenatal or postnatal exposures to xenobiotic EDCs. SEARCH METHODS: Following PRISMA guidelines, we performed a systematic literature search of original peer-reviewed publications in the PubMed database through a block search approach using a combination of index MeSH and free text search terms. Publications were considered if they covered biomarkers of prenatal or postnatal exposures to xenobiotic EDCs (European Commission's list of category 1 EDCs) measured in maternal or child biospecimen and pubertal onset defined by the progression of the following milestones (and assessed in terms of the following measures): menarche (age), thelarche (Tanner staging) and pubarche (Tanner staging), in girls, and genital stage (Tanner staging), testicular volume (ml) and pubarche (Tanner staging), in boys. OUTCOMES: The literature search resulted in 703 references, of which we identified 52 publications fulfilling the eligibility criteria for the qualitative trend synthesis and 23 publications for the meta-analysis. The qualitative trend synthesis provided data on 103 combinations of associations between prenatal or postnatal exposure to EDC compounds groups and puberty outcomes and the meta-analysis enabled 18 summary risk estimates of meta-associations. WIDER IMPLICATIONS: Statistically significant associations in the qualitative trend synthesis suggested that postnatal exposure to phthalates may be associated with earlier thelarche and later pubarche. However, we did not find consistent evidence in the meta-analysis for associations between timing of pubertal onset in girls and boys and exposures to any of the studied xenobiotic EDCs. We were not able to identify specific pre- or postnatal windows of exposure as particularly critical and susceptible for effects of EDCs. Current evidence is subject to several methodological challenges and inconsistencies and evidence on specific exposure-outcome associations remains too scarce to firmly confirm EDC exposure as a risk factor for changes in age of pubertal onset in the general child population. To create a more uniform foundation for future comparison of evidence and to strengthen pooled studies, we recommend the use of more standardized approaches in the choice of statistical analyses, with exposure transformations, and in the definitions and assessments of puberty outcomes. The impact of mixtures of EDC exposures on the association also remains unestablished and would be valuable to elucidate for prenatal and postnatal windows of exposure. Future large, longitudinal epidemiological studies are needed to clarify the overall association.

Cytokine concentration across the stratum corneum in atopic dermatitis and healthy controls.

Tape stripping is a promising technique for assessment of epidermal biomarkers in inflammatory skin diseases. However, to facilitate its implementation in the clinical practice, a thorough validation regarding sampling strategy is needed. Knowledge of biomarkers variation in concentration across stratum corneum is scarce. Therefore, this study aimed to assess the variability of cytokines across stratum corneum using tape stripping technique by consecutive application of 21 adhesive tapes (D-squame) to lesional and non-lesional skin from 15 patients with atopic dermatitis (AD) and 16 healthy controls. Concentration of cytokines (IL-1α, IL-1b, IL-5, IL-18, IFN-γ, CCL17, CCL22, CCL27, CXCL8, CXCL10, TNF-α, TSLP, VEGFA) was determined in five different depths, using multiplex immunoassay. Comparing tape 4 with tape 21, no cytokine changed significantly in concentration in AD lesional skin. In AD non-lesional skin a small decrease was found for CCL17, CXCL8 and CXCL10. For healthy controls, a decrease was found for IL-1a, IL-1b, VEGFA and an increase for IL-18. Differences were found between AD skin and healthy control skin. Concentration of cytokines was stable across stratum corneum, indicating that sampling of only one tape from the stratum corneum is reliable in reflecting the overall cytokine milieu. Differences between AD and healthy skin confirm robustness of tape stripping for measuring cytokine levels.

Risk of incarceration in children with inguinal hernia: a systematic review.

BACKGROUND: Surgical repair is recommended for all children with inguinal hernia due to fear of incarceration. The aim of this study was to assess the risk of incarceration and strangulation of inguinal hernias in children treated with delayed surgery or no surgery. METHODS: Systematic searches were conducted in three databases. We included studies reporting on children with inguinal hernia, with the majority ≤ 10 years old. The interventions were non-acute inguinal hernia surgery or no surgery. The main outcomes were incarceration and strangulation. Secondary outcomes were postoperative complications. Randomized controlled trials, non-randomized controlled trials, and observational studies were included. RESULTS: We included 22 studies with 14,959 children. All studies reported on elective repairs. None of the studies specifically reported on watchful waiting. Of the studies reporting wait time as mean or median, the median wait time was 46 days (range 1-552). The crude incarceration rate across the included studies was 7% for all children and 11% for preterm children. The testicular atrophy rate was 1% and the recurrence rate was 1%. CONCLUSIONS: The risk of incarceration in children awaiting inguinal hernia surgery is substantial. In general, we cannot support delaying surgery unnecessarily. However, there may be benefits of delaying surgery in individual cases. In such cases, the surgeon should assess if the benefits may overrule the risk of incarceration.

Associations between social cognition, skills, and function and subclinical negative and positive symptoms in 22q11.2 deletion syndrome.

BACKGROUND: Identification of the early signs of schizophrenia would be a major achievement for the early intervention and prevention strategies in psychiatry. Social impairments are defining features of schizophrenia. Impairments of individual layers of social competencies are frequently described in individuals with 22q11.2 deletion syndrome (22q11.2DS), who have high risk of schizophrenia. It is unclear whether and to what extent social impairments associate with subclinical negative and positive symptoms in 22q11.2DS, and which layer of social impairments are more correlated with schizophrenia-related symptoms. The aims of this study were to conduct a comprehensive investigation of social impairments at three different levels (function, skill, and cognition) and their interrelationship and to determine to what degree the social impairments correlate to subclinical levels of negative and positive symptoms, respectively, in a young cohort of 22q11.2DS not diagnosed with schizophrenia. METHODS: The level of social impairment was addressed using questionnaires and objective measures of social functioning (The Adaptive Behavior Assessment System), skills (Social Responsiveness Scale), and cognition (The Awareness of Social Inference Test and CANTAB Emotional Recognition Task), and the presence of subclinical symptoms of schizophrenia were evaluated using the Structured Interview for Prodromal Syndromes in a cross-sectional case-control study of 29 cases and 29 controls, aged 12 to 25 years. Association between social impairment and negative and positive symptoms levels was examined in cases only. RESULTS: Subjects with 22q11.2DS were highly impaired in social function, social skills, and social cognition (p ≤ 6.2 × 10-9) relative to control peers and presented with more negative (p = 5.8 × 10-11) and positive (p = 7.5 × 10-4) symptoms. In particular, social functional and skill levels were highly associated with notably subclinical negative symptoms levels. CONCLUSIONS: This study shows strong correlations between levels of social impairments and subclinical negative and positive symptoms. However, longitudinal studies are required to show if social impairments represent early disease manifestations. If parental or self-reporting suggests severe social impairment, it should advocate for clinical awareness not only to social deficits per se but also of potential subclinical psychosis symptoms.

Development of a grinding-specific performance test set-up.

The aim of this study was to develop a performance test set-up for America's Cup grinders. The test set-up had to mimic the on-boat grinding activity and be capable of collecting data for analysis and evaluation of grinding performance. This study included a literature-based analysis of grinding demands and a test protocol developed to accommodate the necessary physiological loads. This study resulted in a test protocol consisting of 10 intervals of 20 revolutions each interspersed with active resting periods of 50 s. The 20 revolutions are a combination of both forward and backward grinding and an exponentially rising resistance. A custom-made grinding ergometer was developed with computer-controlled resistance and capable of collecting data during the test. The data collected can be used to find measures of grinding performance such as peak power, time to complete and the decline in repeated grinding performance.

The glyoxysomal 3-ketoacyl-CoA thiolase precursor from Brassica napus has enzymatic activity when synthesized in Escherichia coli.

Glyoxysomal 3-ketoacyl-CoA thiolase is the last enzyme in the beta-oxidation of fatty acids in plant glyoxysomes. A full-length cDNA of the glyoxysomal 3-ketoacyl-CoA thiolase from Brassica napus and a truncated version, lacking the N-terminal targeting signal were cloned in a T7 promoter-based vector. Both recombinant proteins were expressed in Escherichia coli and activity was measured. Full-length and truncated 3-ketoacyl-CoA thiolase have comparable activity in E. coli. Moreover, full-length 3-ketoacyl-CoA thiolase was purified from E. coli and N-terminal sequencing of the protein confirmed that the precursor form indeed is enzymatically active.

Immunoassay protocol for quantitation of protein kinase activities.

Quantitation of at least two orders of magnitude of kinase enzyme concentration is achieved with detection of less than 0.1 U/well of src kinase activity (Fig. 3). A comparison between a sequential protocol, in which biotinylated peptide substance is captured prior to incubation with the kinase enzyme, and a simultaneous protocol, in which peptide capture and the kinase reaction proceed concurrently, demonstrates that the simpler simultaneous protocol provides similar detection sensitivity. these have also been demonstrated with 0.1 microM peptide substrate in a protein kinase A assay.5 Quantitation of protein kinase activity with chemiluminescent detection has been demonstrated with several different protein kinases, including both tyrosine and serine/threonine kinases.5 An immunoassay format provides high sensitivity and can be performed under conditions that most closely mimic physiological substrate and ATP concentrations with chemiluminescent detection. This assay format is also automated easily for use in high-throughput screening.

Chemiluminescent immunodetection protocols with 1,2-dioxetane substrates. 4.

Chemiluminescent 1,2-dioxetane enzyme substrates provide a highly sensitive and versatile detection method for immunoblots and other membrane-based detections. 1,2-Dioxetane substrates, coupled with either alkaline phosphatase or beta-galactosidase enzyme labels, generate glow light emission kinetics, with a signal duration that is significantly longer than most enhanced luminol/horseradish peroxidase chemiluminescent detection systems. The long-lived, high-intensity light signal is ideal for imaging using a variety of formats, including X-ray film, photographic film, chemiluminescence phosphor imaging screens, and the rapidly expanding selection of camera imaging systems.

Chemiluminescent reporter gene assays with 1,2-dioxetane enzyme substrates.

1,2-Dioxetane chemiluminescent substrates provide highly sensitive, quantitative detection with simple, rapid assay formats for the detection of reporter enzymes that are widely used in gene expression studies. Chemiluminescent detection methodologies typically provide up to 100-1000x higher sensitivities than can be achieved with the corresponding fluorescent or colorimetric enzyme substrates. The varieties of 1,2-dioxetane substrates available provides assay versatility, allowing optimization of assay formats with the available instrumentation, and are ideal for use in gene expression assays performed in both biomedical and pharmaceutical research. These assays are amenable to automation with a broad range of instrumentation for high throughput compound screening.

Novel methods for chemiluminescent detection of reporter enzymes.

Chemiluminescent reporter gene assays provide highly sensitive, quantitative detection in simple, rapid assay formats for detection of reporter enzymes that are widely employed in gene expression studies. Chemiluminescent detection methodologies typically provide up to 100-1000x higher sensitivities than may be achieved with fluorescent or colorimetric enzyme substrates. The variety of chemiluminescent 1,2-dioxetane substrates available enable assay versatility, allowing optimization of assay formats with the available instrumentation, and are ideal for use in gene expression assays performed in both biomedical and pharmaceutical research. In addition, 1,2,-dioxetane chemistries can be multiplexed with luciferase detection reagents for dual detection of multiple enzymes in a single sample. These assays are amenable to automation with a broad range of instrumentation for high throughput compound screening.

Chemiluminescent DNA sequencing with multiplex labeling.

Chemiluminescent detection techniques provide a sensitive, nonradioactive method for DNA sequencing. Standard Sanger dideoxy DNA sequencing reactions are initiated with biotinylated primers, separated by gel electrophoresis, transferred to nylon membrane and detected utilizing chemiluminescent 1,2-dioxetane substrates for alkaline phosphatase. A multiplex-labeling method was developed to permit detection of several overlapping sets of DNA sequence information on a single membrane, thereby increasing the productivity of a single gel electrophoretic separation. Primers labeled with different haptens at the 5' end were used to perform separate sequencing reactions. These were mixed together prior to electrophoresis, and the individual sequencing products sequentially detected using hapten-specific reagents. We incorporated primers labeled with biotin, digoxigenin, 2,4-dinitrophenyl or fluorescein, each consecutively detected with a hapten-specific alkaline phosphatase conjugate and CSPD 1,2-dioxetane chemiluminescent substrate. To further increase the amount of DNA sequence data that can be obtained from a single membrane, a direct transfer electrophoresis apparatus was used for simultaneous separation of the DNA sequencing reactions and membrane transfer. The resulting increased separation of the high molecular weight fragments yields 350-450 bp of readable DNA sequence data from each template. Chemiluminescent detection of overlapping sets of DNA sequencing reactions utilizing multiplex labeling, combined with direct transfer electrophoresis, provides an efficient, nonradioactive method for DNA sequencing.

Chemiluminescent reporter gene assays: sensitive detection of the GUS and SEAP gene products.

Chemiluminescent assays are described for the secreted alkaline phosphatase (SEAP) and beta-glucuronidase (GUS) reporter gene products. These assays provide simple, sensitive, non-isotopic alternatives to existing detection methods and are performed in microplate or tube luminometers or in a scintillation counter. The SEAP reporter gene product is secreted from mammalian cells and is thus easily detected in a sample of culture medium. Sensitive detection of secreted placental alkaline phosphatase is performed with CSPD chemiluminescent alkaline phosphatase substrate, and approximately 3 fg of enzyme can be detected. GUS has become the major reporter gene used for the analysis of plant gene expression. Sensitive chemiluminescent detection of GUS activity can be performed with an assay system we have developed using Glucuron, a beta-glucuronidase substrate. This chemiluminescent assay detects 60 fg of GUS and is linear over six orders of magnitude of enzyme concentration. CSPD and Glucuron substrates have been incorporated into two new chemiluminescent reporter gene assay kits for SEAP and GUS.

Human FATE is a novel X-linked gene expressed in fetal and adult testis.

Previously, we identified a partial cDNA sequence of a novel human transcript, designated fetal and adult testis expressed transcript (FATE). FATE is testis-specific in fetal life and co-expressed with SRY in a 7 weeks old fetal testis, suggesting a function in early testicular differentiation. Herein, full-length cDNA clones of human and porcine FATE were isolated and the gene structure and promoter region of the human FATE gene was characterized. The human FATE gene, which maps to Xq28, consists of five exons spanning approximately 7 kb of genomic DNA. Examination of 1 kb of the FATE promoter region revealed the presence of a putative steroidogenic factor 1 (SF-1) binding site at position -79 to -71 upstream of the transcription start site. We propose that FATE might represent a novel target gene of SF-1 in human testicular differentiation and/or germ cell development.

The safety of proton pump inhibitors in pregnancy.

AIM: To assess the safety of proton pump inhibitors during pregnancy. METHODS: Fifty-one pregnant women exposed to proton pump inhibitors around the time of conception or during pregnancy were compared with 13 327 controls without exposure to any prescribed drug in a population-based study based on The Pharmaco-Epidemiological Prescription Database of North Jutland and the Danish Hospital Discharge Registry. RESULTS: Three babies with malformations were found among 38 women exposed to proton pump inhibitors from 30 days before conception to the end of the first trimester. No cases of stillbirth were recorded. Crude relative risks of malformation, low birth weight and preterm delivery were 1.6 (95% CI: 0.5-5.1), 1.8 (95% CI: 0.2-13.0) and 2.3 (95% CI: 0.9-6.0), respectively. CONCLUSIONS: In this population-based follow-up study, we found no substantially elevated risk in terms of malformations, low birth weight or number of preterm deliveries in pregnancies exposed to proton pump inhibitors. However, further monitoring is warranted in order to establish or rule out a potential association between the use of proton pump inhibitors and increased risk of either cardiac malformations or preterm birth.