Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two-staged, adaptive placebo-controlled trial (APRICOT).

BACKGROUND: Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease that affects the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1. OBJECTIVES: To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit in PPP. METHODS: This was a randomized (1 : 1), double-blind, two-staged, adaptive, UK multicentre, placebo-controlled trial [ISCRTN13127147 (registered 1 August 2016); EudraCT number: 2015-003600-23 (registered 1 April 2016)]. Participants had a diagnosis of PPP (> 6 months) requiring systemic therapy. Treatment was 8 weeks of anakinra or placebo via daily, self-administered subcutaneous injections. Primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. RESULTS: A total of 374 patients were screened; 64 were enrolled (31 in the anakinra arm and 33 in the placebo arm) with a mean (SD) baseline PPPASI of 17·8 (10·5) and a PPP investigator's global assessment of severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in the intention-to-treat analysis [-1·65, 95% confidence interval (CI) -4·77 to 1·47; P = 0·30]. Similarly, secondary objective measures, including fresh pustule count (2·94, 95% CI -26·44 to 32·33; favouring anakinra), total pustule count (-30·08, 95% CI -83·20 to 23·05; favouring placebo) and patient-reported outcomes, did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect for an individual who received ≥ 90% of the total treatment (48% in the anakinra group) was -3·80 (95% CI -10·76 to 3·16; P = 0·285). No serious adverse events occurred. CONCLUSIONS: No evidence for the superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.

Treatment of superficial vascular lesions with the KTP 532-nm laser: experience with 647 patients.

Superficial vascular lesions are a common dermatological diagnosis but are often difficult to treat. Numerous lasers (especially the dye laser) and intense pulsed light sources have been used, but there have been very few reports on the effectiveness of the potassium-titanyl phosphate (KTP) laser. We have extensive experience of this modality at our institution, and the purpose of this survey is to report on the safety and efficacy of the KTP laser. Using an in-house database, we retrospectively collected data from patients who had undergone treatment with the KTP laser for superficial vascular lesions. Patients of Fitzpatrick skin type I-IV were included. Exclusion criteria were Fitzpatrick skin type V, patients with obvious suntan and those on potentially phototoxic medications or minocycline therapy. Diagnoses included discrete or matted telangiectasia, strawberry naevus, spider angioma, rosaceal erythema, rosaceal telangiectasia, telangiectatic naevus, angioma, combined rosaceal erythema/telangiectasia, port-wine stain, venous lake haemangioma and hereditary haemorrhagic telangiectasia. Patients underwent an initial test treatment and further treatment at 6-week intervals as required. Clinical photographs were taken pre- and post-treatment, and outcome was graded by patient and physician. Adverse effects were recorded including scarring, hypo- or hyperpigmentation, marked swelling, blistering, scabbing and bruising. Six hundred forty-seven patients with 13 diagnoses on 9 different body sites were recorded. Four hundred eighty-six were female, and the median age was 39.5 years. Of the lesions treated, 33.7 % (n = 218) were discrete telangiectases and 31.8 % (n = 206) were spider angiomas. A 92.7 % of lesions were on the face. Four hundred thirteen (77.6 %) patients who had outcomes recorded at 6 weeks were graded as "clearance" or "marked improvement". Only 38 (5.8 %) patients experienced adverse effects, all of which were minor; the main adverse effect was swelling. Unlike the dye laser, there was only one case of bruising out of 647 patients. This is the largest survey of patients to have undergone KTP laser treatment reported in the literature. Our results show that the KTP laser is a safe and effective modality for the treatment of superficial vascular lesions.

Long-term effects of prenatal exposure to perfluoroalkyl substances on female reproduction.

STUDY QUESTION: Does prenatal exposure to perfluoroalkyl substances (PFASs) have long-term effects on female reproductive function?. SUMMARY ANSWER: Our results suggest an association between in utero exposure to perfluorooctanoic acid (PFOA) and delay in age of menarche. WHAT IS KNOWN ALREADY: Previous cross-sectional studies have reported possible effects of PFASs on female reproduction including reduced fecundity, delayed puberty and accelerated age at menopause. Only limited data exist from follow-up studies on long-term implications of prenatal exposure to PFASs. STUDY DESIGN, SIZE, DURATION: In this study we used data from a Danish population-based cohort established in 1988-1989. Of 1212 eligible pregnant women, 965 participated. Follow-up was initiated in 2008 on the female offspring at ∼20 years of age. Three hundred and sixty seven (84%) daughters answered a questionnaire and 267 (61%) daughters furthermore attended clinical examinations which were conducted in 2008-2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: The final study population consisted of 343 daughters of which 254 had attended the clinical examinations and 89 had answered the questionnaire only. Levels of PFASs in maternal serum from pregnancy week 30 were used as a measure of prenatal exposure and related to age of menarche, menstrual cycle length, levels of reproductive hormones and follicle number of the daughters. Data were divided into three groups according to tertiles of maternal concentrations of PFASs (low, medium, high). MAIN RESULTS AND THE ROLE OF CHANCE: In adjusted regression analyses, daughters exposed to higher levels of PFOA in utero had a 5.3 (95% confidence interval: 1.3; 9.3) months later age of menarche compared with the reference group of lower PFOA. Crude (P = 0.05) and adjusted (P = 0.01) trend tests also indicated a relationship between higher prenatal PFOA exposure and delay of menarche. LIMITATIONS, REASONS FOR CAUTION: We did not measure the exact amount of PFASs to which the daughters had been exposed prenatally. Instead we used PFAS concentrations in maternal serum as surrogates. However, PFASs are efficiently transferred to the fetus via placenta. Information on age of menarche was collected retrospectively but the time interval for recall in our study was relatively short (2-10 years). The remaining outcome measures depended on participation in clinical examination which reduced the number of observations leading to limited statistical power and risk of selection bias. WIDER IMPLICATIONS OF THE FINDINGS: Since PFASs can be detected in humans all over the world, effects of prenatal exposure on female reproductive function later in life may have wide health implications. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Danish Council for Independent Research (271-05-0296, 09-065631), the Danish Ministry of Interior and Health (0-302-02-18/5), the Danish Council for Strategic Research (09-067124 (Centre for Fetal Programming), 09-063072, 2101-06-0005), the Novo Nordisk Foundation, the Aarhus University Research Foundation, the Frimodt-Heineke Foundation, the Foundation of Maria Dorthea and Holger From, the Beckett-Foundation, the Research Grant of Organon and the Foundation of Lily Benthine Lund. There are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Differential ion mobility spectroscopy: non-invasive real-time diagnostics and therapy control in metabolic diseases.

BACKGROUND: Over the last few years, differential ion mobility spectroscopy (DMS) has become an important tool in medical research. There are attempts to find markers for specific diseases in exhaled air, using this technology as a non-invasive early diagnosis. OBJECTIVE: In the present research, exhaled air from 78 patients with known diagnosis and 39 control persons were tested with a DMS system from Sionex. RESULTS: Bronchial asthma showed a pattern of 6 characteristic points in a discriminant analysis. Patients with diagnosed hypertension showed a characteristic pattern with 4 points, hypothyroidism 2 points; increased LDL cholesterol 3 points, and type II diabetics treated with insulin 4 spots. No significant differences with respect to the control group were found in chronic obstructive pulmonary disease patients. The DMS pattern in the tested asthmatics showed a partial change depending on different medications used. CONCLUSION: Differential ion mobility spectroscopy offers promise as a helpful diagnostic tool.

Enantiomer-specific accumulation of hexabromocyclododecanes in eggs of predatory birds.

The diastereomeric composition of hexabromocyclododecane (HBCD) in eggs of peregrine falcon (Falco peregrinus), white-tailed sea eagle (Haliaeetus albicilla), guillemot (Uria aalge) and common tern (Sterna hirundo) as well as the guillemots' main prey, herring (Clupea harengus) was determined by reversed-phase chromatography with triple-stage quadrupole mass spectrometric detection (LC-MS-MS). alpha-HBCD was the predominant diastereomer in all bird species, while in herring, gamma-HBCD made a substantial contribution. Two, as yet unidentified diastereomers, were detected in common tern egg. The alpha-, beta- and gamma-HBCD (+) and (-) enantiomers were separated using a chiral stationary phase. The enantiomer fractions for alpha-HBCD differed substantially between different bird species as well as between guillemot and its prey, herring. Total HBCD levels determined by LC-MS-MS were comparable to those previously obtained by GC-MS.

[Measurements of L-lactate and H2O2 in exhaled breath condensate at rest and mild to moderate exercise in young and healthy subjects]. / L-Laktat und H2O2-Bestimmungen im Atemkondensat unter Ruhebedingungen sowie unter leichter bis mittelgradiger Belastung von jungen gesunden Probanden.

BACKGROUND: The recently developed microenzyme detectors make a non-invasive measurement of inflammatory markers and L-lactate in exhaled breath condensate (EBC) possible. In a group of young and healthy subjects, we examined whether L-lactate and H (2)O (2) can be detected in EBC. METHODS: During resting conditions as well as at 60 and 120 Watt external load on a cycle ergospirometer 100 l exhaled air were collected under stationary load conditions from 19 healthy subjects. Exhaled breath condensate (EBC) was obtained by cooling the expired air volume. The analysis was performed within 90 min using an ECo-Check amperometer (Viasys Health Care). The H (2)O (2) measurement was performed amperometrically by means of a biosensor after chemical reaction catalysed by peroxidase. Lactate measurements were performed using a bienzyme sensor after lactate oxidase-induced oxidation of L-lactate to pyruvate and H (2)O (2). The rates of release of L-lactate in nmol/min und H (2)O (2) in pmol/min were calculated from the concentrations of L-lactate and H (2)O (2) in the EBC and the time of collection. RESULTS: At rest 100 l exhaled air were collected in 10.6 +/- 5.1 min, and 0.99 +/- 0.3 ml EBC were obtained, at the 60 Watt step 1.23 +/- 0.47 ml EBC were collected in 6.7 +/- 1.8 min, and at 120 Watt 1.09 +/- 0.38 ml EBC in 4.8 +/- 0.8 min. At rest, there was a mean rate of L-lactate release of 3.3 +/- 3.1 nmol/min, which increased at the 60 Watt step to 8.4 +/- 5.1 nmol/min (p < 0.05), and at 120 Watt to 5.0 +/- 12.6 nmol/min (p < 0.02). The rate of L-lactate was proportional to the metabolic rate (r = 0.99). The rate of H (2)O (2) release at rest was 49.1 +/- 37.9 pmol/min, it increased at 60 Watt to 159 +/- 113 pmol/min (p < 0.05) and decreased at 120 Watt to 96.5 +/- 49.5 pmol/min (p < 0.05). CONCLUSIONS: Significant measurable concentrations of L-lactate and H (2)O (2) in the exhaled breath condensate were found already under resting conditions. During external load, an increase in the L-lactate concentration was found, correlating with the metabolic rate. H (2)O (2) is an inflammatory marker, its concentration in the EBC was markedly increased during the first step of applied external load, but less during the second. A probable correlation between L-lactate concentration in EBC and arterialized blood will be studied in future investigations.

Monitoring of omalizumab therapy in children and adolescents.

BACKGROUND: Omalizumab is a successfully implemented supplementary therapy for improving asthma control in children aged 6 years and older with severe persistent allergic asthma. The dosage of omalizumab depends on body weight and IgE level, yet no parameter has been established to guide dosage changes during therapy. Clinical studies in patients with allergic asthma or allergic rhinitis revealed a clinically relevant improvement by using omalizumab leading to concentrations of free serum IgE reported to be lower than 50 ng/ml. Therefore, only the question concerning the concentrations of free IgE used in a therapy with omalizumab is regarded of clinical importance, while total IgE (free and omalizumab-bound IgE) increases during treatment. PATIENTS AND METHODS: Ten patients, 8 to 17 years of age, received therapy with omalizumab due to severe allergic asthma. In addition, the patients had pronounced rhinoconjunctivitis, food allergy, insect sting allergy, and/or neurodermitis. The total IgE in the serum was measured in the patients 3 - 6 months before each omalizumab injection as a potential progress parameter (Sandwich-Immunoassay ADVIA Centaur). RESULTS: Six months after beginning of the therapy with omalizumab, a significant decrease of the total IgE concentration was found, in comparison to the baseline values (p < 0.003). In all patients the tolerability of omalizumab was very good: there was a reduction in the frequency of the asthma exacerbations and rescue medications. All patients reported a clearly improved quality of life. CONCLUSIONS: A general increase in IgE was not observed in any of the children we treated with omalizumab. Apart from the development of routine assays to determine free serum IgE levels, the significance of the total serum IgE as a suitable control of an omalizumab therapy should be further investigated in controlled studies with regard to sensitivity and specificity. In order to only administer the lowest necessary dose of omalizumab especially in children and adolescents, the establishment of laboratory parameters (free IgE and/or total IgE) to adequately monitor the therapy is urgently needed. Patients undergoing an omalizumab therapy require medical supervision at close intervals.

Pyrazolo[3,4-d]pyrimidine nucleic acids: adjustment of dA-dT to dG-dC base pair stability.

Oligonucleotides incorporating 8-aza-7-deazapurin-2,6-diamine (pyrazolo[3,4-d]pyrimidin-4,6-diamine) nucleoside 2a or its 7-bromo derivative 2b show enhanced duplex stability compared to those containing dA. While incorporation of 2a opposite dT increases the T(m) value only slightly, the 7-bromo compound 2b forms a very stable base pair which is as strong as the dG-dC pair. Compound 2b shows a similar base discrimination in duplex DNA as dA. The base-modified nucleosides 2a,b have a significantly more stable N-glycosylic bond than the rather labile purin-2,6-diamine 2'-deoxyribonucleoside 1. Base protection with acyl groups, with which we had difficulties in the case of purine nucleoside 1, was effective with pyrazolo[3,4-d]-pyrimidine nucleosides 2a,b. Oligonucleotides containing 2a,b were obtained by solid phase synthesis employing phosphoramidite chemistry. Compound 2b harmonizes the stability of DNA duplexes. Their stability is no longer dependent on the base pair composition while they still maintain their sequence specificity. Thus, they have the potential to reduce the number of mispairs when hybridized in solution or immobilized on arrays.

Determination of polycyclic aromatic hydrocarbons in the urine, benzo(a)pyrene diol epoxide-DNA adducts in lymphocyte DNA, and antibodies to the adducts in sera from coke oven workers exposed to measured amounts of polycyclic aromatic hydrocarbons in the work atmosphere.

Workers in coke oven plants have a higher incidence of lung cancer than the general population. They are exposed to a variety of chemicals, in particular the polycyclic aromatic hydrocarbons (PAH), including benzo(a)pyrene. To evaluate the genotoxic effects of PAH exposure, air samples and urine samples were analyzed for PAH by capillary gas chromatography and high-performance liquid chromatography, respectively. Since benzo(a)pyrene is activated to 7 beta,8 alpha-dihydroxy-(9 alpha,10 alpha)-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE) and binds to DNA, we have used ultrasensitive enzymatic radioimmunoassay and synchronous fluorescence spectrophotometry to measure BPDE-DNA adducts in lymphocyte DNA. The results show that workers were exposed to high concentrations of atmospheric PAH. However, the mean PAH exposure levels are reduced 60% when the workers wore masks during work. When compared to exposure levels, the urinary excretion of PAH was relatively low. Approximately one-third of the workers had detectable putative BPDE-DNA adducts in lymphocytes by ultrasensitive enzymatic radioimmunoassay, and 10% of the samples had emission peaks at 379 nm by synchronous fluorescence spectrophotometry. The four most positive samples were the same in both of the assays. Antibodies to an epitope(s) on BPDE-DNA were found in the sera of approximately one-third of the workers. Detection of DNA adducts and antibodies to these adducts are internal indicators of exposure to benzo(a)pyrene.

Brominated flame retardants - Exposure and risk assessment for the general population.

Brominated flame retardants (BFRs) are a large group of different substances used in numerous products to prevent fire hazards. Some of them are persistent in the environment, accumulate in the food chain and are of toxicological concern, while for others current data are limited. Meanwhile, BFRs have been found in many environmental media, foods, and biota including humans. This review presents recent findings obtained from monitoring data in environmental media relevant for human exposure, as well as dietary exposure. In this context, concentrations in indoor and ambient air and in house dust are outlined. Furthermore, we summarize human biomonitoring data on BFR levels in blood and breast milk. Current estimates of the overall exposure of the general population using different relevant subsets are also addressed. All of these data are discussed in relation to currently available toxicological reference values used for risk assessment purposes. Obviously, the exposure of the general population varies considerably in different parts of the world and even within countries. Polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD) show the highest intake during infancy. While the highest intake for BDE 47 for all groups was observed in the US, the total BDE 209 and HBCD intake was highest in the UK. For HBCD and all PBDEs except BDE 209, diet accounts for a large proportion of the total intake during infancy in all countries. With regard to toddlers and adults, the contribution of diet to total intake is high in Germany and the UK, while in the US, the high concentrations of PBDE in dust resulted in a notably smaller proportion of the intake being attributed to diet.