Occupational exposure to polycyclic aromatic hydrocarbons and DNA damage by industry: a nationwide study in Germany

Exposure to polycyclic aromatic hydrocarbons (PAH) and DNA damage were analyzed in coke oven (n = 37), refractory (n = 96), graphite electrode (n = 26), and converter workers (n = 12), whereas construction workers (n = 48) served as referents. PAH exposure was assessed by personal air sampling during shift and biological monitoring in urine post shift (1-hydroxypyrene, 1-OHP and 1-, 2 + 9-, 3-, 4-hydroxyphenanthrenes, SigmaOHPHE). DNA damage was measured by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and DNA strand breaks in blood post shift. Median 1-OHP and SigmaOHPHE were highest in converter workers (13.5 and 37.2 microg/g crea). The industrial setting contributed to the metabolite concentrations rather than the air-borne concentration alone. Other routes of uptake, probably dermal, influenced associations between air-borne concentrations and levels of PAH metabolites in urine making biomonitoring results preferred parameters to assess exposure to PAH. DNA damage in terms of 8-oxo-dGuo and DNA strand breaks was higher in exposed workers compared to referents ranking highest for graphite-electrode production. The type of industry contributed to genotoxic DNA damage and DNA damage was not unequivocally associated to PAH on the individual level most likely due to potential contributions of co-exposures.

Cerebral extension of steroid-responsive meningitis arteritis in a boxer

A comatose 30-month-old, entire male boxer was presented because of an acute history of a cluster of three to four seizures. Neurological examination suggested a diffuse to multifocal intracranial lesion. Magnetic resonance tomography revealed symmetrical multifocal to diffuse changes of the cerebral grey matter and ependymal lining with sediment in the lateral ventricles. Haematological examination revealed leucocytosis with neutrophilia. Cerebrospinal fluid examination revealed high protein concentration and polymorphonuclear pleocytosis. Despite antiepileptic treatment, therapy against increased intracranial pressure and antibiosis, the dog's condition continued to deteriorate and he was euthanased. Pathological examination revealed fibrinosuppurative meningo-ependymitis and necrotising arteritis throughout the brain. In addition, chronic inflammation and arterial stenosis was found in the spinal meninges. No infectious agent was found. A diagnosis of steroid-responsive meningitis arteritis was made. The massive extension into the meninges and ventricular system of the forebrain has not been described previously in dogs with steroid-responsive meningitis arteritis and should be considered in the differential diagnosis when an intracranial suppurative infection is suspected.

Anti-eosinophil activity and clinical efficacy of the CRTH2 antagonist OC000459 in eosinophilic esophagitis

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic, Th2-type inflammatory disease. Chemoattractant receptor-homologous molecule on Th2 cells (CRTH2) is a prostaglandin D(2) (PGD(2)) receptor, expressed by Th2 cells and other inflammatory cells, including eosinophils and basophils, that mediates chemotaxis and activation. OC000459 is a selective CRTH2 antagonist and would be expected to suppress eosinophilic tissue inflammation. The purpose of this study was to evaluate the efficacy and safety of an OC000459 monotherapy in adult patients with active, corticosteroid-dependent or corticosteroid-refractory EoE. METHODS: In this randomized, double-blind, placebo-controlled trial, 26 adult patients (m/f = 22/4; mean age 41 years, range 22-69 years) with active EoE, dependent or resistant to corticosteroids, were treated either with 100 mg OC000459 (n = 14) or placebo (n = 12) twice daily. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, and via biomarkers. The primary end point was the reduction in esophageal eosinophil infiltration. RESULTS: After an 8-week OC000459 treatment, the esophageal eosinophil load decreased significantly, from 114.83 to 73.26 eosinophils per high-power field [(eos/hpf), P = 0.0256], whereas no reduction was observed with placebo (102.80-99.47 eos/hpf, P = 0.870). With OC000459, the physician's global assessment of disease activity improved from 7.13 to 5.18 (P = 0.035). OC000459 likewise reduced extracellular deposits of eosinophil peroxidase and tenascin C, the effects not seen with placebo. No serious adverse events were observed. CONCLUSIONS: An 8-week treatment with the CRTH2-antagonist, OC000459, exerts modest, but significant, anti-eosinophil and beneficial clinical effects in adult patients with active, corticosteroid-dependent or corticosteroid-refractory EoE and is well tolerated.

Unique mixed phenotype and unexpected functional effect revealed by novel compound heterozygosity mutations involving SCN5A.

BACKGROUND Functional characterization of mutations involving the SCN5A-encoded cardiac sodium channel has established the pathogenic mechanisms for type 3 long QT syndrome and type 1 Brugada syndrome and has provided key insights into the physiological importance of essential structure-function domains. OBJECTIVE This study sought to present the clinical and biophysical phenotypes discerned from compound heterozygosity mutations in SCN5A on different alleles in a toddler diagnosed with QT prolongation and fever-induced ventricular arrhythmias. METHODS A 22-month-old boy presented emergently with fever and refractory ventricular tachycardia. Despite restoration of sinus rhythm, the infant sustained profound neurological injury and died. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open-reading frame/splice mutational analysis of the 12 known long QT syndrome susceptibility genes was performed. RESULTS The infant had 2 SCN5A mutations: a maternally inherited N-terminal frame shift/deletion (R34fs/60) and a paternally inherited missense mutation, R1195H. The mutations were engineered by site-directed mutagenesis and heterologously expressed transiently in HEK293 cells. As expected, the frame-shifted and prematurely truncated peptide, SCN5A-R34fs/60, showed no current. SCN5A-R1195H had normal peak and late current but abnormal voltage-dependent gating parameters. Surprisingly, co-expression of SCN5A-R34fs/60 with SCN5A-R1195H elicited a significant increase in late sodium current, whereas co-expression of SCN5A-WT with SCN5A-R34fs/60 did not. CONCLUSIONS A severe clinical phenotype characterized by fever-induced monomorphic ventricular tachycardia and QT interval prolongation emerged in a toddler with compound heterozygosity involving SCN5A: R34fs/60, and R1195H. Unexpectedly, the 94-amino-acid fusion peptide derived from the R34fs/60 mutation accentuated the late sodium current of R1195H-containing Na(V)1.5 channels in vitro.

Follow-up of a group of patients with automatic implantable defibrillator

UNLABELLED The automatic implantable defibrillator (AID) is the treatment of choice for primary and secondary prevention of sudden death. At the Instituto Nacional de Cardiología, since October 1996 until January 2002, 25 patients were implanted with 26 AID. There were 23 men (92%) and the mean age of the whole group, was 51.4 years. Twenty-three patients (92%) presented structural heart disease, the most common was ischemic heart disease in 13 patients (52%), with a mean ejection fraction of 37.8%. One patient without structural heart disease had Brugada Syndrome. The most frequent clinical arrhythmia was ventricular tachycardia in 14 patients (56%). The mean follow-up was of 29.3 months during which a total of 30 events of ventricular arrhythmia were treated through AID; six of them were inappropriate due to paroxismal atrial fibrillation; 10 AID patients (34%) have not applied for therapy. Three patients (12%) of the group died due to congestive heart failure refractory to pharmacologic treatment. CONCLUSION The implant of the AID is a safe and effective measure for primary and secondary prevention of sudden death. World-wide experience evidences, that this kind of device has not modified the mortality rate due to heart failure in these patients, but it has diminished sudden arrhythmic death.

The effectiveness and safety of d,l-sotalol in the ambulatory treatment of atrial fibrillation and flutter

Data on short and long term efficacy and safety of d,l sotalol in patients with atrial fibrillation or atrial flutter is limited. The aims of this study were to (1) assess the antiarrhythmic efficacy of d,l sotalol maintaining normal sinus rhythm in patients with refractory atrial fibrillation or flutter, (2) evaluate the efficacy of d,l sotalol in preventing recurrences of paroxysmal atrial fibrillation or flutter, (3) evaluate the control of ventricular rate in patients with paroxysmal or refractory atrial fibrillation or flutter unsuccessfully treated with other antiarrhythmic agents, (4) determine predictors of efficacy (5) assess the safety of d,l sotalol in this setting. Two hundred patients with chronic or paroxysmal atrial fibrillation or atrial flutter or both, who had failed one to six previous antiarrhythmic drug trials were treated with d,l sotalol 80 to 440 mg/day orally. Fifty four percent was female, age 47 +/- 16 years (range 7-79), follow up period 7 +/- 7 months (range 1 to 14 months), 79% of patients had the arrhythmia for more than one year. The atrial fibrillation in 37.5% of patients was chronic and paroxysmal in 23.5. The atrial flutter was chronic in 31% of patients and paroxysmal in 8%. Eighty two percent of patients was in functional class I (NYHA) and 82% had cardiac heart disease: left atrial (LA) size 44 +/- 10 mm, right atrial (RA) size 37 +/- 7 mm and left ventricular ejection fraction (LVEF) 58 +/- 8%. Total success was achieved in 58% of patients (atrial fibrillation 40% and 18% in atrial flutter), partial success in 38% (atrial fibrillation in 18% and 20% in atrial flutter) and 4% of patients failure. It was p < 0.07 when compared total success vs partial success among atrial fibrillation and atrial flutter groups. Patients with cardiac heart disease responded worst (p = 0.10) to the drug than those without it, specially if the heart was dilated. We concluded that d,l sotalol has moderate efficacy to convert and maintain normal sinus rhythm, as well as it acts controlling paroxysmal relapses and ventricular heart rate.

Irrigated-tip catheter ablation of intraatrial reentrant tachycardia in patients late after surgery of congenital heart disease.

OBJECTIVES The aim of this study was to evaluate irrigated-tip catheter for ablation of intraatrial reentrant tachycardias late after surgical repair of congenital heart disease. BACKGROUND In congenital heart disease patients, the right atrium can be markedly enlarged with areas of low blood flow. Radiofrequency (RF) lesion creation may be hampered by insufficient electrode cooling at sites with low blood flow. METHODS Thirty-six consecutive patients with intraatrial reentrant tachycardia refractory to antiarrhythmic therapy from two centers were included in the study. Entrainment pacing and electroanatomic mapping (CARTO) were used to delineate reentrant circuits and critical isthmus sites. RF ablation was performed using an irrigated-tip catheter (Navistar Thermocool). RESULTS Fifty-two intraatrial reentrant tachycardia circuits were identified, and 48 were targeted with RF ablation. RF ablation was performed using a mean of 13 +/- 11 irrigated RF applications per tachycardia isthmus with a mean power of 36 +/- 8 W. In a historical control group of congenital heart disease patients managed with conventional catheter ablation, the number of lesions per isthmus was higher (23 +/- 11) and mean power was lower (27 +/- 14 W). Acute success was achieved in 45 intraatrial reentrant tachycardias (94% of targeted tachycardias and 87% of all tachycardias). After a mean follow-up of 17 +/- 7 months, 33 (92%) of 36 patients were free of recurrence. Five patients (14%) developed paroxysmal atrial fibrillation. CONCLUSIONS The combination of modern techniques including electroanatomic mapping and catheter irrigation allows safe and highly effective ablation of intraatrial reentrant tachycardia in patients with surgically repaired congenital heart disease.

Difficult to control atopic dermatitis

Difficult to control atopic dermatitis (AD) presents a therapeutic challenge and often requires combinations of topical and systemic treatment. Anti-inflammatory treatment of severe AD most commonly includes topical glucocorticosteroids and topical calcineurin antagonists used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, the topical calcineurin inhibitors tacrolimus and pimecrolimus are preferred in certain locations. Systemic anti-inflammatory treatment is an option for severe refractory cases. Microbial colonization and superinfection contribute to disease exacerbation and thus justify additional antimicrobial / antiseptic treatment. Systemic antihistamines (H1) may relieve pruritus but do not have sufficient effect on eczema. Adjuvant therapy includes UV irradiation preferably of UVA1 wavelength. "Eczema school" educational programs have been proven to be helpful.

Electrode location and clinical outcome in hippocampal electrical stimulation for mesial temporal lobe epilepsy

PURPOSE To study the clinical outcome in hippocampal deep brain stimulation (DBS) for the treatment of patients with refractory mesial temporal lobe epilepsy (MTLE) according to the electrode location. METHODS Eight MTLE patients implanted in the hippocampus and stimulated with high-frequency DBS were included in this study. Five underwent invasive recordings with depth electrodes to localize ictal onset zone prior to chronic DBS. Position of the active contacts of the electrode was calculated on postoperative imaging. The distances to the ictal onset zone were measured as well as atlas-based hippocampus structures impacted by stimulation were identified. Both were correlated with seizure frequency reduction. RESULTS The distances between active electrode location and estimated ictal onset zone were 11±4.3 or 9.1±2.3mm for patients with a >50% or <50% reduction in seizure frequency. In patients (N=6) showing a >50% seizure frequency reduction, 100% had the active contacts located <3mm from the subiculum (p<0.05). The 2 non-responders patients were stimulated on contacts located >3mm to the subiculum. CONCLUSION Decrease of epileptogenic activity induced by hippocampal DBS in refractory MTLE: (1) seems not directly associated with the vicinity of active electrode to the ictal focus determined by invasive recordings; (2) might be obtained through the neuromodulation of the subiculum.

Immunopathogenesis of eosinophilic esophagitis

Background: Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus associated with dysphagia in adults and refractory reflux syndromes in children. Methods: Immunological and genetic approaches have been used to better understand the pathophysiology of the underlying inflammation. Results and Conclusions: Evidence has accumulated that EoE represents a T-helper (Th) 2-type inflammatory disease, in which allergens play a role in triggering the disease. The majority of the patients suffer from concurrent allergic rhinitis, asthma, and eczema, and have a history of atopy. The chronic inflammatory response in EoE is associated with tissue damage and remodeling, both of which lead to esophageal dysfunction and bolus impaction. The new insights into the pathophysiology have resulted in the development of the first pharmacological therapies of EoE.

Estrogen receptor β expression and androgen receptor phosphorylation correlate with a poor clinical outcome in hormone-naive prostate cancer and are elevated in castration-resistant disease

Patients with advanced prostate cancer (PC) are usually treated with androgen withdrawal. While this therapy is initially effective, nearly all PCs become refractory to it. As hormone receptors play a crucial role in this process, we constructed a tissue microarray consisting of PC samples from 107 hormone-naïve (HN) and 101 castration-resistant (CR) PC patients and analyzed the androgen receptor (AR) gene copy number and the protein expression profiles of AR, Serin210-phosphorylated AR (pAR(210)), estrogen receptor (ER)β, ERα and the proliferation marker Ki67. The amplification of the AR gene was virtually restricted to CR PC and was significantly associated with increased AR protein expression (P<0.0001) and higher tumor cell proliferation (P=0.001). Strong AR expression was observed in a subgroup of HN PC patients with an adverse prognosis. In contrast, the absence of AR expression in CR PC was significantly associated with a poor overall survival. While pAR(210) was predominantly found in CR PC patients (P<0.0001), pAR(210) positivity was observed in a subgroup of HN PC patients with a poor survival (P<0.05). Epithelial ERα expression was restricted to CR PC cells (9%). ERβ protein expression was found in 38% of both HN and CR PCs, but was elevated in matched CR PC specimens. Similar to pAR(210), the presence of ERβ in HN patients was significantly associated with an adverse prognosis (P<0.005). Our results strongly suggest a major role for pAR(210) and ERβ in HN PC. The expression of these markers might be directly involved in CR tumor growth.

Thermal release rate studies of nuclear reaction products from polycrystalline metal matrices

The thermal release rate of nuclear reaction products was investigated in offline annealing experiments. This work was motivated by the search for a high melting catcher material for recoiling products from heavy ion induced nuclear fusion reactions. Polycrystalline refractory metal foils of Ni, Y, Zr, Nb, Mo, Hf, W, and Re were investigated as catcher metals. Diffusion data for various tracer/host combinations were deduced from the measured release rates. This work focuses on the diffusion and the release rate of volatile p-elements from row 5 and 6 of the periodic table as lighter homologues of the superheavy elements with Z ≥ 113 to be studied in future experiments. A massive radiation damage enhancement of the diffusion velocity was observed. Diffusion trends have been established along the groups and rows of the periodic table based on the dependence of diffusion velocity on atomic sizes.

REE and Hf distribution among mineral phases in the CV-CK clan : a way to explain present-day Hf isotopic variations in chondrites

Chondrites are among the most primitive objects in the Solar System and constitute the main building blocks of telluric planets. Among the radiochronometers currently used for dating geological events, Sm–Nd and Lu–Hf are both composed of refractory, lithophile element. They are thought to behave similarly as the parent elements (Sm and Lu) are generally less incompatible than the daughter elements (Nd and Hf) during geological processes. As such, their respective average isotopic compositions for the solar system should be well defined by the average of chondrites, called Chondritic Uniform Reservoir (CHUR). However, while the Sm–Nd isotopic system shows an actual spread of less than 4% in the average chondritic record, the Lu–Hf system shows a larger variation range of 28% [Bouvier A., Vervoort J. D. and Patchett P. J. (2008) The Lu–Hf and Sm–Nd isotopic composition of CHUR: Constraints from unequilibrated chondrites and implications for the bulk composition of terrestrial planets. Earth Planet. Sci. Lett.273, 48–57]. To better understand the contrast between Sm–Nd and Lu–Hf systems, the REE and Hf distribution among mineral phases during metamorphism of Karoonda (CK) and Vigarano-type (CV) carbonaceous chondrites has been examined. Mineral modes were determined from elemental mapping on a set of five CK chondrites (from types 3–6) and one CV3 chondrite. Trace-element patterns are obtained for the first time in all the chondrite-forming minerals of a given class (CK chondrites) as well as one CV3 sample. This study reveals that REE are distributed among both phosphates and silicates. Only 30–50% of Sm and Nd are stored in phosphates (at least in chondrites types 3–5); as such, they are not mobilized during early stages of metamorphism. The remaining fraction of Sm and Nd is distributed among the same mineral phases; these elements are therefore not decoupled during metamorphism. Of the whole-rock total of Lu, the fraction held in phosphate decreases significantly as the degree of metamorphism increases (30% for types 3 and 4, less than 5% in type 6). In contrast to Lu, Hf is mainly hosted by silicates with little contribution from phosphates throughout the CK metamorphic sequence. A significant part of Sm and Nd are stored in phosphates in types 3–5, and these elements behave similarly during CK chondrite metamorphism. That explains the robustness of the Sm/Nd ratios in chondrites through metamorphism, and the slight discrepancies observed in the present-day isotopic Nd values in chondrites. On the contrary, Lu and Hf are borne by several different minerals and consequently they are redistributed during metamorphism–induced recrystallization. The Lu/Hf ratios are therefore significantly disturbed during chondrites metamorphism, leading to the high discrepancies observed in present-day Hf isotopic values in chondrites.

Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial

BACKGROUND No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting. METHODS In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095. FINDINGS Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group). INTERPRETATION Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted. FUNDING AstraZeneca.

Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn's disease

BACKGROUND: Influence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn's disease (CD). METHODS: 85 pediatric- and 117 adult-onset CD patients were tested for the three main NOD2 CD-associated variants (p.R702W, p.G908R and p.10007fs) and clinical data of at least two years of follow-up were compared regarding disease behaviour and activity, response to therapy and bone mineral density (BMD). RESULTS: Chronic active and moderate to severe course of CD is associated in patients with pediatric-onset (p=0.0001) and NOD2 variant alleles (p=0.0001). In pediatric-onset CD the average PCDAI-Score was significantly higher in patients carrying NOD2 variants (p=0.0008). In addition, underweight during course of the disease (p=0.012) was associated with NOD2 variants. Interestingly, osteoporosis was found more frequently in patients carrying NOD2 variant alleles (p=0.033), especially in pediatric-onset CD patients with homozygous NOD2 variants (p=0.037). Accordingly, low BMD in pediatric-onset CD is associated with a higher PCDAI (p=0.0092), chronic active disease (p=0.0148), underweight at diagnosis (p=0.0271) and during follow-up (p=0.0109). Furthermore, pediatric-onset CD patients with NOD2 variants are more frequently steroid-dependent or refractory (p=0.048) and need long-term immunosuppressive therapy (p=0.0213). CONCLUSIONS: These data suggests that the presence of any of the main NOD2 variants in CD is associated with osteoporosis and an age of onset dependent influence towards underweight, higher disease activity and a more intensive immunosuppressive therapy. This observation supports the idea for an early intensive treatment strategy in children and adolescent CD patients with NOD2 gene variants.