Systemic juvenile idiopathic arthritis: The Great Ormond Street Hospital experience (2005-2021).

Systemic juvenile idiopathic arthritis (sJIA) is a complex, systemic inflammatory disorder driven by both innate and adaptive immunity. Improved understanding of sJIA pathophysiology has led to recent therapeutic advances including a growing evidence base for the earlier use of IL-1 or IL-6 blockade as first-line treatment. We conducted a retrospective case notes review of patients diagnosed with sJIA over a 16-year period (October 2005-October 2021) at Great Ormond Street Hospital for Children. We describe the clinical presentation, therapeutic interventions, complications, and remission rates at different timepoints over the disease course. We examined our data, which spanned a period of changing therapeutic landscape, to try and identify potential therapeutic signals in patients who received biologic treatment early in the disease course compared to those who did not. A total of 76-children (female n = 40, 53%) were diagnosed with sJIA, median age 4.5 years (range 0.6-14.1); 36% (27/76) presented with suspected or confirmed macrophage activation syndrome. A biologic disease-modifying anti-rheumatic drug (bDMARD) alone was commenced as first-line treatment in 28% (n = 21/76) of the cohort; however, at last review, 84% (n = 64/76) had received treatment with a bDMARD. Clinically inactive disease (CID) was achieved by 88% (n = 67/76) of the cohort at last review; however, only 32% (24/76) achieved treatment-free CID. At 1-year follow-up, CID was achieved in a significantly greater proportion of children who received treatment with a bDMARD within 3 months of diagnosis compared to those who did not (90% vs. 53%, p = 0.002). Based on an ever-increasing evidence base for the earlier use of bDMARD in sJIA and our experience of the largest UK single-centre case series described to date, we now propose a new therapeutic pathway for children diagnosed with sJIA in the UK based on early use of bDMARDs. Reappraisal of the current National Health Service commissioning pathway for sJIA is now urgently required.

Synchronized beamline at FLASH2 based on high-order harmonic generation for two-color dynamics studies.

We present the design, integration, and operation of the novel vacuum ultraviolet (VUV) beamline installed at the free-electron laser (FEL) FLASH. The VUV source is based on high-order harmonic generation (HHG) in gas and is driven by an optical laser system synchronized with the timing structure of the FEL. Ultrashort pulses in the spectral range from 10 to 40 eV are coupled with the FEL in the beamline FL26, which features a reaction microscope (REMI) permanent endstation for time-resolved studies of ultrafast dynamics in atomic and molecular targets. The connection of the high-pressure gas HHG source to the ultra-high vacuum FEL beamline requires a compact and reliable system, able to encounter the challenging vacuum requirements and coupling conditions. First commissioning results show the successful operation of the beamline, reaching a VUV focused beam size of about 20 µm at the REMI endstation. Proof-of-principle photo-electron momentum measurements in argon indicate the source capabilities for future two-color pump-probe experiments.

Monogenic mimics of Behçet's disease in the young.

OBJECTIVES: Monogenic autoinflammatory disorders (AID) and primary immunodeficiencies can present early in life with features that may be mistaken for Behçet's disease (BD). We aimed to retrospectively describe the clinical and laboratory features of 11 paediatric cases referred for suspected BD who turned out to have an alternative, monogenic disease mimicking BD. METHODS: Retrospective, paediatric BD specialist multicentre case series. Next generation sequencing (NGS) or conventional candidate gene screening approaches were utilized, facilitated in some cases by functional assays. RESULTS: Eleven children referred with suspected BD underwent genetic screening because of atypical BD features, and/or presentation before age 5 years. Eight patients (73%) were Caucasian, two were Pakistani and one was Turkish; 55% were female. A positive family history of BD was reported in 54% cases. The median age of disease onset was 0.6 (range 0.2-2.3) years. All had systemic inflammation and oral ulceration; 5/11 had genital ulceration; 3/11 had ocular involvement; and 9/11 had cutaneous manifestations. Nine/11 had known disease-causing genetic mutations in: TNFAIP3 (n = 2), WDR1 (n = 2), NCF1, AP1S3, LYN, MEFV and GLA. The remaining two cases each had novel variants in STAT1 and TNFRSF1A. CONCLUSION: Rare monogenic diseases can mimic BD, particularly when presenting early in life. These observations are now informing a strategy to explore screening for genetic mimics of BD in a UK cohort of children and adults to better understand the proportion of UK BD patients who may in fact have an underlying monogenetic diagnosis.

[Treatment Options for Basal Cell Carcinomas of the Medial Canthus]. / Therapieoptionen bei Basalzellkarzinomen des medialen Lidwinkels.

Basal cell carcinoma is the most common skin cancer of the eyelid. It most frequently occurs on the lower eyelid and the medial canthus. Although metastases appear only very rarely, basal cell carcinoma is locally destructive if left untreated. Nowadays several surgical and nonsurgical treatments can be used to remove or destroy basal cell carcinomas. The selection of optimal treatment depends on the initial individual situation as well as the age and the general condition of the patient. The "gold standard" method for the treatment of basal cell carcinomas is surgical removal with subsequent histological examination. Because of the complex anatomical characteristics of the medial canthus and the lateral nasal root region, basal cell carcinomas of this area present great challenges for any treatment method. These characteristics also explain the higher rates of incomplete removal and greater risk of recurrence, with in depth extension of the tumor. Additionally, surgical removal of the tumor from the medial canthus area often results in extended tissue defects. The plastic covering of these defects can be achieved by various reconstruction procedures.

Probing the dynamics of highly excited toluene on the fs timescale.

Investigation of the dynamics of toluene-h8 (C6H5CH3), toluene-d8 (C6D5CD3) and toluene-α,α,α-d3 (C6H5CD3) has been performed utilizing the VUV pump-IR probe technique on the fs timescale. Using the 5th harmonic (∼160 nm) of a Ti:sapphire laser as the pump beam, two superimposed electronic states, the valence S3 and the Rydberg 4p, were excited by one-photon absorption, followed by ionization and dissociation induced by the probe beam (800 nm). Analysis of the transient signal of the parent (P(+)) and fragment ions ([P-H](+) or [P-D](+)) implies the existence of two different relaxation processes: (i) from the Rydberg and (ii) from the S3 valence state. Using a rate equation model, the decay times have been determined and comparison between the different isotopologues has been made. Conclusions on the relaxation path, the relative displacements of the potential energy surfaces and the activation energies needed have been drawn from the decay times. The signals corresponding to the fragment ions present a small in amplitude, but nonetheless, unambiguous periodical modulation, which is attributed to out-of-plane bending oscillation, involving also the methyl group. The dynamics of the H- and D-loss channels has been investigated. Especially for the case of toluene-α,α,α-d3, where both channels are in operation, it was found that the ratio of the abundance of H/D-loss dissociation reactions decreases as the pump-probe delay time increases.

Phospholipase activity after ß-endorphin exposure discriminates Malassezia strains isolated from healthy and seborrhoeic dermatitis skin.

BACKGROUND: Phospholipase activity and its induction by ß-endorphin have been associated with pathogenic Malassezia pachydermatis animal isolates. OBJECTIVE: To evaluate Malassezia phosholipase activity in human isolates from seborrhoeic dermatitis (SD) and healthy controls before and after ß-endorphin exposure. METHODS: Eighty-four volunteers with or without SD (N = 41) were sampled. Isolated Malassezia strains were incubated in Dixon's medium with and without 100 nmol/L ß-endorphin. Subsequently, phospholipase activity was assessed in egg-yolk agar and the results were compared employing Wilcoxon sign test for paired data, chi-squared test and multinomial logistic regression analysis. RESULTS: A total of 64 Malassezia strains were isolated. SD strains tended to have decreased phospholipase activity before (P = 0.057) and increased after exposure to ß-endorphin (P = 0.061) compared to isolates from healthy skin. Phospholipase activity after ß-endorphin exposure related to basal enzyme activity as a measure of per strain phospholipase inducibility by ß-endorphin did not depend on Malassezia species (P = 0.652). However, this latter biochemical trait discriminates strains isolated from SD lesional and healthy skin (P = 0.036). CONCLUSION: ß-endorphin exposure modifies the in vitro phosholipase activity in Malassezia species isolated from SD lesional skin. This is in accordance with emerging evidence that enhanced local lipase activity is involved in the pathogenesis of SD.

Is birth weight associated with childhood lymphoma? A meta-analysis.

Several risk factors have been identified for childhood lymphomas. The purpose of this meta-analysis was to synthesize current evidence regarding the association between birth weight with primarily the risk for non-Hodgkin lymphoma (NHL), given its similarity to acute lymphoblastic leukemia, Hodgkin lymphoma (HL) and any category of lymphoma. Two cohort (278,751 children) and seven case-control studies (2,660 cases and 69,274 controls) were included. Effects estimates regarding NHL, HL and any lymphoma were appropriately pooled using fixed or random effects model in two separate analyses: specifically, high was compared to normal or any birth weight. Similarly, low was compared to normal or any birth weight. No statistically significant association was found between high birth weight, as compared to normal birth weight, and risk for NHL plus Burkitt lymphoma (OR = 1.17, 95% CI = 0.76-1.80, random effects), HL (OR = 0.94, 95% CI = 0.64-1.38, fixed effects) or any plus Burkitt lymphoma (OR = 1.09, 95% CI = 0.76-1.56, fixed effects). A null association emerged when low was compared with normal birth weight for NHL plus Burkitt lymphoma (OR = 1.07, 95% CI = 0.71-1.62, random effects), HL (OR = 0.94, 95% CI = 0.54-1.65, fixed effects) or any plus Burkitt lymphoma (OR = 1.02, 95% CI = 0.79-1.33, fixed effects). Accordingly, no association was found when high or low birth weight was compared to any birth weight. Although current evidence suggests no association, birth weight might be a too crude indicator to reveal a genuine association of fetal growth with specific lymphoma categories; hence, there is an emerging need for use of more elaborate proxies, at least those accounting for gestational week.

Maternal smoking during pregnancy and childhood lymphoma: a meta-analysis.

Results from epidemiological studies exploring the association between childhood lymphoma and maternal smoking during pregnancy have been contradictory. This meta-analysis included all published cohort (n = 2) and case-control (n = 10) articles; among the latter, the data of the Greek Nationwide Registry for Childhood Hematological Malignancies study were updated to include all recently available cases (-2008). Odds ratios (ORs), relative risks and hazard ratios were appropriately pooled in three separate analyses concerning non-Hodgkin lymphoma (NHL, n = 1,072 cases), Hodgkin lymphoma (HL, n = 538 cases) and any lymphoma (n = 1,591 cases), according to data availability in the included studies. An additional metaregression analysis was conducted to explore dose-response relationships. A statistically significant association between maternal smoking (any vs. no) during pregnancy and risk for childhood NHL was observed (OR = 1.22, 95% confidence interval, CI: 1.03-1.45, fixed effects model), whereas the risk for childhood HL was not statistically significant (OR = 0.90, 95% CI: 0.66-1.21, fixed effects model). The analysis on any lymphoma did not reach statistical significance (OR = 1.10, 95% CI = 0.96-1.27, fixed effects model), possibly because of the case-mix of NHL to HL. No dose-response association was revealed in the metaregression analysis. In conclusion, this meta-analysis points to a modest increase in the risk for childhood NHL, but not HL, among children born by mothers smoking during pregnancy. Further investigation of dose-response phenomena in the NHL association, however, warrants accumulation of additional data.

Estimation of Salmonella prevalence in UK egg-laying holdings.

As part of an EU-wide programme to reduce the prevalence of Salmonella in commercial egg-laying holdings, the EU has set for the UK an annual target of 10% reduction in the prevalence of Salmonella Enteritidis and Salmonella Typhimurium in commercial egg-laying holdings. To assist in demonstrating such a reduction, it is very important to obtain an accurate as possible baseline prevalence for Salmonella. The objective of this study was to provide a baseline estimate of the Salmonella prevalence in egg-laying holdings in the UK. Data from an EU baseline survey for Salmonella in UK commercial egg-laying flocks were therefore analysed using Bayesian methods, taking into account the sampling of only 1 flock per holding and estimates of the test sensitivity of the methods used in the EU baseline survey. In addition, in the UK the majority of the eggs come from farms which have participated in voluntary monitoring programmes for Salmonella since the early 1990s, and this data was also used, along with a prior estimate of the test sensitivity of voluntary surveillance. Results indicated that a true prevalence 14% for Salmonella Enteriditis and Typhimurium, and 18% for all serovars, both of these estimates being higher than has previously been reported from the EU baseline survey data. It is also shown that the sensitivity of voluntary surveillance is low, and it will therefore be important to compare results from "official" and "non-official" samples to check that the sampling performed in the National Control Plan is as sensitive as expected.

Salmonella infection in cattle in Great Britain, 2003 to 2008.

Surveillance data for clinical disease in cattle in Great Britain due to Salmonella infections were analysed for the period 2003 to 2008 in order to describe seasonality and to investigate possible associations between Salmonella diagnoses and other variables such as region, climate, age and production type. A clear seasonal pattern was shown for Salmonella infection, coinciding with the second half of the year. The incidence of Salmonella Dublin and Salmonella Typhimurium was highest in the west of the country, which has the greatest cattle density, but this was not a feature of diagnoses with other serovars. Abortion was a more common clinical sign of S Dublin infections, but was relatively unusual in the case of S Typhimurium. The observed clinical picture and age of affected animals were largely determined by the seasonality of dairy cattle calving in Great Britain.

Retrospective analysis of Salmonella isolates recovered from animal feed in Great Britain.

To examine feed contamination rates with Salmonella, the diversity of serovars and the antimicrobial resistance of isolates from animal feedingstuffs in Great Britain, and to compare Salmonella strains found in animal feed and in livestock, data collected under voluntary and statutory Salmonella surveillance during the period 1987 to 2006 were analysed retrospectively. The feed contamination rate decreased from 3.8 per cent in 1993 to 1.1 per cent in 2006. A total of 263 Salmonella serovars were recovered: S Mbandaka (11.2 per cent), S Tennessee (10.4 per cent), S Senftenberg (8.4 per cent), S Agona (6.4 per cent), S Montevideo (6.4 per cent) and S Ohio (3.1 per cent) were the most prevalent. S Typhimurium was recovered at a proportion of 1.6 per cent from raw ingredients and 2.4 per cent from finished feed, while S Enteritidis was recovered at a proportion of 0.5 per cent from raw ingredients and 0.6 per cent from finished feed; 14.1 per cent of the isolates were resistant to at least one antimicrobial, and 1.9 per cent were multiresistant. There was no evidence of a statistical association (P<0.05) between the top 10 serovars recovered from feed and from livestock.

Salmonella serovars and their antimicrobial resistance in British turkey flocks in 1995 to 2006.

Serovar and antimicrobial resistance data from the scanning surveillance of British turkey flocks for Salmonella between 1995 and 2006 were analysed and compared with prevalence data from other livestock and animal feed. A total of 2753 incidents of 57 different serovars were reported. The five most prevalent serovars were Salmonella Typhimurium (20.8%), Salmonella Newport (14.7%), Salmonella Derby (10.6%), Salmonella Indiana (8.3%) and Salmonella Agona (6.4%). S. Typhimurium reports peaked in the mid- to late 1990s; this occurred in parallel with the S. Typhimurium DT104 epidemic in other livestock species. S. Enteritidis reports peaked in mid- to late 1990s, followed by a considerable decrease after 2000, which was also noted in flocks of domestic fowl. S. Newport, Salmonella Montevideo, Salmonella Senftenberg and Salmonella Binza occurred in marked clusters, indicating that they were introduced into one or more flocks at a certain time (i.e. via contaminated feed or infected 1-day-old chicks). A proportion of 43.1% of the reported Salmonella isolates were resistant to at least one antimicrobial, while 17.7% were multi-resistant. No isolates were resistant to ciprofloxacin or to the third-generation cephalosporins ceftazidime and cefotaxime. Resistance to ampicillin, chloramphenicol, streptomycin, sulphonamide compounds and tetracycline was common, and it was mainly a characteristic of S. Typhimurium DT104 compared with S. Typhimurium non-DT104 and non-S. Typhimurium isolates (P<0.001). Resistance to nalidixic acid decreased from 16.9% in 1995 to 11.8% in 2006. Nalidixic acid resistance was most frequently found in Salonella Hadar (71.4%), S. Typhimurium DT104 (30.0%), S. Newport (17.9%) and S. Typhimurium non-DT104 (11.1%).

Trends in phage types and antimicrobial resistance of Salmonella enterica serovar Enteritidis isolated from animals in Great Britain from 1990 to 2005.

Surveillance data for Salmonella enterica serovar Enteritidis incidents and isolations from food animals in Great Britain from 1990 to 2005 were analysed to detect any trends and provide the basis for a comparison between phage types (pt) and antimicrobial sensitivity patterns in human beings and animals. During 2001 to 2005 there was a decrease in incidents involving most species except ducks. Only the numbers of incidents involving pts 6, 6a, 9b and 14b (in ducks) and pts 6a and 13a (in mammals) increased significantly during this period, whereas there were 93 per cent fewer incidents involving pt 4 than in 1990 to 2000. After adjustment for pt, the isolates from ducks were more resistant to nalidixic acid, tetracyclines and sulfonamides, and were more likely to be multiresistant than isolates from chickens. Isolates from turkeys tended to be more resistant to sulfonamides than isolates from chickens. pts 1, 5a, 6, 6a and 35 had the highest level of resistance after adjusting for species. During 2001 to 2005 there was an increase in resistance among pts 1, 6 and 7, in most cases involving nalidixic acid.

Survey of the histamine content in fish samples randomly selected from the Greek retail market.

The histamine content of fish sold in the Greek retail market was surveyed and the performance of high-performance liquid chromatography (HPLC) and enzyme-linked immunoabsorbant assay (ELISA) methods for the determination of histamine were compared. A total of 125 samples of fresh and canned tuna, fresh and canned sardines, deep frozen swordfish, smoked and deep frozen mackerel, anchovies, salted and smoked herring were analysed by HPLC (55 samples), ELISA (106 samples) and both methods (36 samples). Histamine levels as determined by HPLC, ranged from 2.7 mg kg(-1) to 220 mg kg(-1). The highest histamine concentrations obtained by HPLC were found in herring and anchovy samples. Eight out of the 55 samples (14.5%) analysed by HPLC, exceeded the US Food and Drug Administration (USFDA) limit (50 mg kg(-1)), while 16 out of the 106 samples (15%) analysed by ELISA exceeded the limit. The results show that for histamine concentrations below 50 mg kg(-1), there is good agreement between the ELISA and HPLC but above 50 mg kg(-1) big differences were found.

Diarrheic shellfish poisoning due to toxic mussel consumption: the first recorded outbreak in Greece.

During the week of 14-20 January 2000, 120 people visited the Emergency Departments of hospitals in Thessaloniki, northern Greece, complaining of acute gastrointestinal illness after eating mussels (Mytilus galloprovincialis). The symptoms indicated diarrhoeic shellfish poisoning, and the toxicity of mussels harvested from Thermaikos Gulf in Thessaloniki during the outbreak was investigated using mouse bioassays. The bioassays revealed toxicity to mice by the mussel samples; while high numbers of toxic algae Dinophysis acuminata were identified in water samples from Thermaikos Gulf. The harvesting of mussels was immediately suspended and a monitoring programme for algal blooms was established from then onwards. During a follow-up of the mussels' toxicity from January 2000 to January 2005, two more mussel samples were found positive for diarrheic shellfish poisoning: one harvested in March 2001 from the area of the outbreak (Thermaikos Gulf) and the other harvested in January 2001 from Amvrakikos Gulf in north-western Greece. However, no sporadic cases or outbreaks were reported during this period.

Intravitreal dirofilariasis: a rare ocular infection.

Human ocular dirofilariasis is a zoonotic disease, rare in Europe, caused by filarial nematodes. The parasite is either encysted in a subcutaneous nodule or located under the bulbar conjunctiva. We report the case of a 62-year-old man with intravitreal dirofilariasis, which is a rare site of presentation of the nematode in the human eye. It was located in the fundus area and was surgically removed. The nematode was identified as Dirofilaria repens (D. conjuctiva) by two different Microbiology Departments, making this the fifth report of identified intravitreal dirofilariasis caused by D. repens in the relative literature.

The effect of short-time microwave exposures on Escherichia coli O157:H7 inoculated onto chicken meat portions and whole chickens.

Small portions of fresh chicken breasts weighting 20 g each and fresh whole chickens, weighting on average 1310 g each, were inoculated with Escherichia coli O157:H7 (10(5)-10(6) cfu/g) and cooked, using two different domestic microwave ovens at full power. The chicken portions were heated for 5, 10, 15, 20, 25, 30, and 35 s and the whole chickens for 22 min. Following exposures, viable counts and temperature measurements were performed. Although the chicken breast portions looked well-cooked after 30 s of MW heating at a mean end-point surface temperature of 69.8 degrees C, a mean concentration of 83 cfu/g E. coli O157:H7 cells was recovered. Elimination of E. coli O157:H7 cells occurred only after 35 s of MW exposure at 73.7 degrees C. When whole chickens were thoroughly cooked by MW heating, the final subsurface temperatures, measured in the thighs and wings, ranged from 60.2 degrees C to 92 degrees C and viable cells of E. coli O157:H7 were recovered from all samples of whole chicken. The results indicate that short time exposures of chicken portions to microwave heating do not eliminate E. coli O157:H7.

Lack of the appropriate natural killer cell inhibitory receptors in women with spontaneous abortion.

Previous studies have revealed that women with unexplained recurrent spontaneous abortions have a limited repertoire of inhibitory KI receptors (inhKIRs) and that the inhKIRs they possess do not have specificity for the human leukocyte antigen (HLA)-Cw molecules that would be expressed on trophoblast. We sought to confirm these findings by direct definition of maternal inhKIR and trophoblastic HLA-Cw allotypes on the placental material of spontaneously missed pregnancies. The study included 30 women undergoing vacuum uterine curettage for first-trimester missed pregnancy (group A; n = 15) or for elective termination of normal pregnancy (group C, n = 15). DNA extracted from isolated decidual and trophoblastic cells was used for molecular detection of maternal inhKIRs (2DL1, 2DL2, 2DL3) and fetal HLA-Cw alleles, respectively. The results revealed that in the group of women who experienced abortion, 60% did not have the full repertoire of three inhKIRs (group A vs group C; p = 0.006); that in five of 15 patients (none in the controls), no epitope matching existed between maternal inhKIRs and trophoblastic HLA-Cw alleles (group A vs group C; p = 0.01); and that more cases were found with limited epitope matching (less than three inhKIRs with specificity for fetal HLA-Cw alleles). The results provide additional evidence that in some cases of spontaneous abortions, the women lack the appropriate inhKIRs to interact with the HLA-Cw molecules on trophoblasts and to deliver signals to inhibit natural killer cell activation and protect the embryo.

Human and canine leishmaniasis in asymptomatic and symptomatic population in Northwestern Greece.

The occurrence of human and canine Mediterranean visceral leishmaniasis (MVL) in Northwestern Greece was investigated during an 8-year survey (1994-2001). A total of 1200 blood sera samples, collected from asymptomatic human population, and 1200 blood sera samples from asymptomatic dogs were screened for Leishmania infantum antibodies using the indirect immunofluorescence test (IFA). Also during the survey 111 human subjects and 350 canines were referred as clinically suspect cases for MVL. Significant differences (p = 0.001) were found between the prevalence of MVL in symptomatic and asymptomatic human populations (12.6 and 0.5%, respectively), but a more modest difference was observed between symptomatic and asymptomatic canines (45.4 and 24.4%, respectively). From the results, it appears that Greece has a high background of canine leishmaniasis, which is likely to be a risk factor for the emergence of human MVL.