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The treatment of juvenile idiopathic arthritis (JIA) has made substantial progress within the last 25 years. Modern medicinal treatment enables inflammatory activity of the disease to be controlled in most of the cases. Mutilating courses of disease, which were formerly the rule have now become the exception. Today remission of disease is the aim of pediatric rheumatological treatment. Apart from effective control of inflammation this includes complete restoration of functional abilities of affected joints and the surrounding structures also affected. To achieve this goal a holistic and foresighted view of each patient's course is required. Therefore, even in an apparently uncomplicated course of disease in some cases of JIA it is advisable to plan an early interdisciplinary consultation including the pediatric rheumatologist and the orthopedic surgeon, in order to discuss an early surgical intervention, which can then be carried out in a timely manner, if necessary. This article provides an overview of the orthopedic rheumatological indications and options.Die Behandlung der juvenilen idiopathischen Arthritis (JIA) hat in den vergangenen 25 Jahren dramatische Fortschritte gemacht. Durch moderne medikamentöse Therapie lässt sich die Entzündungsaktivität in den meisten Fällen erfolgreich kontrollieren. Mutilierende Verläufe, wie sie früher regelhaft zu sehen waren, sind die Ausnahme geworden. Ziel einer kinderrheumatologischen Therapie ist heute die Remission. Dazu gehört neben einer erfolgreichen Kontrolle der entzündlichen Aktivität auch die vollständige funktionelle Wiederherstellung der betroffenen Gelenke und der gelenknahen, mitbetroffenen Strukturen. Dies erfordert eine ganzheitliche, vorausschauende Betrachtung des Erkrankungsverlaufes. Daher ist es auch bei scheinbar unkompliziertem Verlauf in einigen Fällen einer JIA ratsam, frühzeitig ein interdisziplinäres Konsil zwischen Kinderrheumatologen und orthopädischem Rheumatologen zu planen, um frühzeitig chirurgische Interventionen zu erörtern, die dann erforderlichenfalls rechtzeitig angegangen werden können. Die vorliegende Arbeit gibt eine Übersicht über die orthopädisch-rheumatologischen Indikationen und Möglichkeiten.

Juvenile Idiopathic Arthritis (JIA) patients living in areas with high prevalence of tick-borne-encephalitis-virus-(TBEV)-infection are recommended for administration of inactivated TBE-vaccination. However, there are serious concerns regarding protective vaccine-induced immune responses against TBEV in immunocompromised patients. The present study aimed to analyze the humoral and cellular immune response to TBE-vaccination in previously TBE-vaccinated JIA patients compared to healthy controls (HC) including investigation of IgG-anti-TBEV avidity, neutralization capacity, cellular reactivity by IFNgamma-ELISPOT and cytokine secretion assays. Similar IgG-anti-TBEV antibody concentrations, neutralization titers and cellular reactivity were found between JIA and HC. The number and the early timing of booster vaccinations after primary vaccination had the most prominent effect on neutralizing antibodies in JIA and on IgG-anti-TBEV concentrations in both JIA and HC. Administration of booster vaccinations made it more likely for JIA patients to have IgG-anti-TBEV concentrations ≥165 VIEU/ml and avidities >60%. TNF-alpha inhibitors had a positive and MTX administration a negative effect on humoral immune responses. In conclusion, irrespective of having JIA or not, vaccinated children showed similar humoral and cellular immunity against TBEV several years after primary TBE-vaccination. However, in JIA, booster vaccinations mounted a significantly higher humoral immune response than in JIA without boosters. Our results highlight the need for timely administration of boosters particularly in JIA. Although immunosuppressive treatment at vaccinations in diagnosed JIA had a negative effect mainly on TBEV-specific cellular immunity, most JIA patients mounted a favorable humoral immune response which was maintained over time. Thus, successful TBE-vaccination seems highly feasible in JIA patients with immunosuppressive regimens.

Rheumatic diseases, such as juvenile idiopathic arthritis (JIA), are typically associated with acute pain mainly caused by inflammation. Chronic pain is described as pain lasting at least 3 months. In JIA patients chronic pain may occur despite successful treatment. Chronic pain and pain disorders frequently occur during the course of the disease despite successful control of inflammation.Possible interrelations between JIA and pain disorders are presented.Besides a review of the available literature, a retrospective cohort study was conducted, including 906 patients with a chronic pain disorder with somatic and psychological factors (CPD) and/or a complex regional pain syndrome type I (CRPS I). The frequency of pre-existing rheumatic illnesses was analyzed.The JIA is a risk factor for the development of a CPD. Especially polyarticular, extended oligoarticular, enthesitis-associated JIA and psoriatic arthropathy were found to be significantly associated with an increased risk for developing CPD. In contrast, an increased risk for development of CRPS I was not observed.Our study demonstrates JIA to be a risk factor for the development of chronic pain not only as a result from malpositioning or arthrosis but also as a chronic pain disorder (CPD). Further studies are necessary to clarify the relevance of disease activity and duration and also of psychological factors for the pathogenesis.HINTERGRUND: Bei rheumatischen Erkrankungen wie der juvenilen idiopathischen Arthritis (JIA) tritt klassischerweise ein entzündungsbedingter Akutschmerz auf. Von chronischen Schmerzen spricht man ab einem Zeitraum von 3 Monaten. Schmerzen können sich trotz erfolgreicher Therapie als Schmerzerkrankung zu einem eigenständigen Krankheitsbild entwickeln. Chronische Schmerzen und Schmerzerkrankungen können trotz guter Kontrolle der entzündlichen Aktivität auch im Verlauf einer JIA entstehen.Es erfolgt die Darstellung möglicher Zusammenhänge zwischen einer JIA und Schmerzerkrankungen.Neben einem Review der vorhandenen Literatur wurde eine retrospektive Kohortenstudie mit 906 Patienten mit chronischer Schmerzstörung mit somatischen und psychischen Faktoren (CSSPF) und/oder einem komplexen regionalen Schmerzsyndrom Typ I (CRPS I) durchgeführt und die Häufigkeit rheumatologischer Vorerkrankungen untersucht.Die JIA ist ein Risikofaktor für die Entwicklung einer CSSPF. Vor allem die polyartikuläre, die „extended“ oligoartikuläre JIA, die Enthesitis-assoziierte JIA und die Psoriasisarthritis haben ein signifikant erhöhtes Risiko. Dagegen finden sich die persistierende oligoartikuläre und die systemische JIA nicht gehäuft in der Vorgeschichte von Patienten mit einer CSSPF. Im Gegensatz dazu wurde kein nennenswert erhöhtes Risiko für die Entwicklung eines CRPS I beobachtet.Unsere Untersuchung zeigt, dass das Vorliegen einer JIA einen Risikofaktor nicht nur für die Entstehung chronischer durch Fehlstellungen bzw. Arthrose bedingter Schmerzen, sondern auch einer chronischen Schmerzstörung darstellt. Weitere Untersuchungen sind notwendig, um zu klären, welche Relevanz Krankheitsaktivität und -dauer, aber auch psychologische Faktoren auf die Entstehung haben.

Inflammatory rheumatic diseases in childhood and adolescence are a special challenge in the treatment of acute trauma. The pharmaceutical treatment strategies for children and adolescents have been modified.Which special aspects must be considered in young patients suffering from rheumatism when a trauma necessitates an operative procedure?A literature search was carried out to elaborate recommendations for the practice.The joint-related alterations in young patients suffering from rheumatism differ with respect to the differently altered inflammatory rheumatic destruction. The extent of these inflammatory destructive alterations dictates the operative approach. Consequences arise in paying attention to the concurrent medication with respect to avoidance of events triggering an exacerbation and tissue infections. The bone strength necessitates an individualized selection of implants and sometimes influences the duration of follow-up treatment. In the early stages of the inflammatory process the approach in cases of trauma is no different to that for healthy patients but in later stages (Larsen stage III) it does differ.An interdisciplinary concept can help to avoid disadvantages in the treatment of the underlying disease. Due to the special dysplastic anatomy and tissue alterations, trauma in these patients is a particular challenge.

Adalimumab (ADA) has become a valuable treatment option for juvenile idiopathic arthritis (JIA). The importance of combination with methotrexate (MTX) is unclear.Data from the German Biologics in Paediatric Rheumatology (BIKER) registry are reported. Response to treatment was analysed using JIA American College of Rheumatology (ACR) scores, 10-joint Juvenile Arthritis Disease Activity Score (JADAS10), and improvement of functional status and ACR inactive disease criteria. Compa-risons between rates of adverse events (AEs) and serious adverse events (SAEs) provided data for the safety assessment.Overall, 584 patients with non-systemic JIA started ADA therapy, 61% of whom received concomitant MTX treatment at baseline. The latter patients were younger (p 0.001), with shorter disease duration (p = 0.001), more frequently had antinuclear antibodies (p = 0.04), and had higher baseline JADAS10 scores (p = 0.03). In patients with ADA monotherapy, enthesitis-related arthritis (p = 0.004) and presence of human leucocyte antigen-B27 (p = 0.008) were documented more often. Mean treatment duration in both cohorts was 15 months. Comparable last follow-up rates for JIA ACR 30/50/70/90% response, JADAS minimal disease activity, JADAS remission, and ACR inactive disease were, respectively, 75/72/64/49%, 66%, 46%, and 58% for ADA monotherapy, and 77/72/61/45%, 64%, 48%, and 55%, for ADA + MTX. During 1082 patient-years (PY) of ADA exposure, 725 AEs (67/100 PY), including 57 SAEs (5.3/100 PY), were reported. Serious infections were reported in 10 patients (0.9/100 PY) and 11 (1.0/100 PY) had varicella infections/zoster reactivation. Rates of AEs, SAEs, infectious events, and serious infections did not differ between the cohorts. Elevated transaminases (p = 0.005) and gastrointestinal events (p 0.0001) were reported more often in the combination cohort. Two pregnancies and no deaths were reported.ADA demonstrated an acceptable risk profile and high percentages of patients in both cohorts showed sufficient treatment response. No differences in treatment response or adherence to treatment were found.

The treatment of children and adolescents with juvenile idiopathic arthritis (JIA) has progressed substantially during recent years. Multiple different factors have played a role in this advancement: improved medical treatment due to the introduction of new drugs, structural improvements with provision of units specializing in childhood rheumatology, multidisciplinary treatment concepts, structured educational programs for patients and parents, improved functional treatment including sports therapy, and selective surgical and orthopedic interventions improving functional capacities. Current treatment strategies in JIA are aimed at achieving disease remission, i.e., control of disease activity and re-establishment of age-appropriate functional capacities. This review summarizes important developments in the conservative treatment of JIA. Part 2 deals with orthopedic and surgical treatment strategies.

In most cases of juvenile idiopathic arthritis (JIA), disease remission can be achieved by a multidisciplinary approach using modern medication. However, JIA is currently incurable An interdisciplinary concept is therefore needed for long-term development of affected joints and tendons. Only early interdisciplinary treatment strategies can improve long-term outcomes in patients with a complicated disease course or persistent disease activity, thereby delaying or even avoiding joint replacement. An early interdisciplinary assessment and treatment planning according to surgical orthopedic rheumatology aspects is now state of the art and will continue to be in the future, especially in treatment-refractory disease courses.

Taking part in physical education is an important element of social participation for children with chronic diseases. Nevertheless, children suffering from rheumatism mostly receive recommendations to stop sport activities either completely or partially, without underlying scientific guidelines.The aim was the development of an IT-tool based on scientific data in order to create individualized recommendations for sport activities plus verification of its practical feasibility.An interdisciplinary group of experts developed and approved a prototype of the rheumatism and sports compass (Rheuma und Sport Kompass, RSK) based on the literature and own experience. They considered individual health factors and biomechanics of sports functions. The prototype was tested, revised and reconsidered in an interim evaluation. The resulting RSKv1 was evaluated in a clinical observation phase with 61 patients. The results were subsequently incorporated into the final version of RSK during an interdisciplinary decision-making process. This was verified in a feasibility study with a follow-up survey of rheumatic patients with a RSK partial participation certification for physical education including: clinical assessment during 8 lessons of physical education and after 8 lessons of physical education. Teachers rated the RSK online after 8 lessons. The evaluation was descriptive and differences in mean values were tested.In this study 50 patients and 31 teachers were evaluated. The affliction of pain decreased in terms of frequency, amount and duration after physical education with RSK. No worsening in health was reported after participation in sports. The teachers rated the RSK as understandable, practicable and they felt confident to allow the patients to participate in classes. The RSK was rated significantly better than a standard certification text. With the RSK, patients can be advised to safely take part in physical education.

Background Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with an autoinflammatory component of unknown etiology related to the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines like interleukin-6 (IL-6), and effective drugs inhibiting their signaling are being developed. This study evaluates sJIA patients treated with the IL-6 inhibitor tocilizumab (TCZ) concerning clinical response rate, disease course and adverse effects in a real-life clinical setting. Methods In 2009 a clinical and research consortium was established, including an online registry for autoinflammatory diseases (AID) (https://aid-register.de). Data for this retrospective TCZ study were documented by 13 centers. Results From 7/2009 to 4/2014, 200 patients with sJIA were recorded in the AID-registry. Out of these, 46 (19 m, 27 f, age 1–18 years) received therapy with TCZ. Long term treatment (median 23 months) has been documented in 24/46 patients who were evaluated according to Wallace criteria (active disease 6/24, inactive disease 5/24, remission 13/24 cases). Under observation co-medication were used in 40/46 cases. Adverse events were reported in 11/46 patients. The clinical response rate (no clinical manifestation, no increased inflammation parameters) within the first 12 weeks of treatment was calculated to be 35%. Conclusion Out of 200 sJIA children reported in the German AID-registry, 46 were treated with TCZ, showing a clinical response rate of 35% during the first 12 weeks, and inactive disease and/or remission under medication in 75% after one year. Adverse events were seen in 24% and severe adverse events in 4%. Trial registration The AID-Registry is funded by the BMBF (01GM08104, 01GM1112D, 01GM1512D).

OBJECTIVE: To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date. METHODS: Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available. RESULTS: We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10(-4) ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]). CONCLUSION: In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.

Congenital anomalies of the kidneys and urinary tract (CAKUT) are among the most common anomalies in newborn infants, and may cause chronic renal disease in newborns. We investigated the sensitivity and specificity of different ultrasound-based screening strategies for CAKUT.Newborns (n = 4331) were analyzed for CAKUT in at least one ultrasound examination as a part of the Survey of Neonates in Pomerania (SNiP), a 7-year population-based study on neonates in Western Pomerania (Germany). Intrauterine ultrasound examinations were compared with early postnatal ultrasound findings (from days 3 - 7 of life) and pathological findings within the first 6 months of postnatal life.Cases of CAKUT were detected in 309 (3.7 %) kidneys in one ultrasound examination at the following points of time at least: (i) prenatally in 56 newborns (18.2 %), (ii) 3 - 7 days postnatally in 201 newborns (65.2 %) and (iii) in 52 newborns (17 %) during the 6-month follow-up. The prevalence was significantly higher in male infants, and hydronephrosis was found to be the most frequent obstructive nephropathy (83.3 %). Significant co-morbidity was observed with CNS malformations. The diagnostic sensitivity was significantly higher in postnatal ultrasound screening (79.6 vs. 18.2 % prenatally), while the specificity was above 99 % at all time points.This study demonstrates a high prevalence of CAKUT and demonstrates the importance of combined prenatal and postnatal ultrasound examinations for early CAKUT diagnosis.ZIEL:: Angeborene Fehlbildungen der Nieren und ableitenden Harnwege (CAKUT) gehören zu den häufigsten neonatalen Anomalien und können zur Entstehung chronischer Nierenerkrankungen und Niereninsuffizienz führen. In dieser Studie haben wir Sensitivität und Spezifität der verschiedenen ultraschallbasierten Screening-Ansätze untersucht.Im Rahmen des über 6 Jahre durchgeführten Survey of Neonates in Pomerania (SNiP) erhielten Neugeborene (n = 4331) mindestens eine Ultraschalluntersuchung der Nieren und ableitenden Harnwege im Rahmen der zweiten Vorsorgeuntersuchung (U2) zwischen dem 4.–7. Lebenstag. Intrauterine Ultraschallergebnisse wurden mit den postnatalen Ergebnissen und eventuellen weiteren Auffälligkeiten in den ersten 6 Lebensmonaten verglichen.Bei 309 (3,7 %) Nieren wurde in einer der folgenden Ultraschalluntersuchungen eine CAKUT diagnostiziert, (i) pränatal bei 56 Neugeborenen (18,2 %), (ii) 4 – 7 Tage postnatal bei 201 (65,2 %) und (iii) während der ersten 6 Lebensmonate bei weiteren 52 (17 %) Neugeborenen. Es zeigte sich eine signifikant höhere Prävalenz bei männlichen Neugeborenen. Eine angeborene Hydronephrose war die am häufigsten gefundene obstruktive Nephropathie (83,3 %). Eine signifikante Komorbidität zeigte sich mit Auffälligkeiten des ZNS. Die diagnostische Sensitivität des postnatalen Screenings war signifikant höher (79,6 vs. 18,2 % pränatal), die Spezifität war zu allen Screeningzeitpunkten über 99 %.Diese Studie zeigt eine hohe CAKUT-Prävalenz und demonstriert die Wichtigkeit eines Ultraschallscreenings zur Früherkennung einer angeborenen Fehlbildung der ableitenden Harnwege.

Juvenile idiopathic arthritis (JIA) summarizes a group of inflammatory diseases of childhood. The etiology remains still unclear. In JIA, T cells have been demonstrated to play key roles in the pathogenesis. T-cell proliferation in JIA may be different in the peripheral blood (PB) and the synovial fluid (SF). The aim of this study is to demonstrate the turnover of T cells in the PB and SF of patients with persistent oligoarticular JIA (oJIA) compared to controls. Matched pairs of samples were investigated derived from PB and SF of nine patients with persistent oJIA. The cells from PB and SF were determined by flow cytometry. The majority of the PBMC and IAMC were in phase G0/G1, with fewer than 1% in S phase. In the SF, the percentage of cells in the S phase are higher than in the PB. The percentage of cells in the S phase in SF are equal to the result in the control group. In conclusion, the turnover of synovial T cells in persistent oJIA is higher than in the PB.

Neonatal health is of major concern to parents, midwives, physicians and society as a whole, yet a prospective population-based birth cohort to collect comprehensive data on multiple issues including medical, social, environmental and genetic aspects remains to be established in Germany. The survey of newborns in Pomerania (SNiP) described in this paper attempts to take up this goal. The objectives of SNiP are to establish (a) a population-based birth cohort providing detailed information about neonatal health, morbidity and mortality, (b) a biobank with newborn DNA and serum from cord blood, placenta tissue samples and DNA obtained from oral mucosal swabs of the mothers, (c) a prospective study design by re-examination of the SNiP population prior to attendance at primary school. From March 2003 until November 2008 all childbearing mothers in a well-defined region in North-Eastern Germany were asked to participate with their newborns. Detailed data on health status of the newborn, pregnancy, medical and family history, socio-economic status and maternal life style were obtained via face-to-face interview, standardised questionnaires and medical records. Placental tissue samples, cord blood plasma and DNA were continuously collected; sampling of maternal DNA from mouth swabs started in 2007. As a result, during the study period n = 6747 births and n = 6828 babies were enrolled. A population coverage of 95% was achieved. The active participation rate was 75%. A non-responder analysis revealed no meaningful selection bias. Thus, SNiP is a population-based, representative study in Germany that is able to describe the health and living conditions of newborns and their families comprehensively. It can contribute to existing knowledge and to similar cohort studies since data are accessible by researchers.

Chronic pain syndromes in children and adolescents are defined as continuous or recurrent pain without an underlying causative diagnosis and lasting for more than 3 months. It is estimated that every fourth child in Germany suffers from chronic pain with every twentieth suffering from extreme recurrent pain. The incidence of chronic pain in children and adolescents is increasing with headache, abdominal pain and musculoskeletal pain being the most frequent. The quality of life declines not only due to the pain but to relieving postural and psychological factors, such as fear and sadness. School attendance, social activities and hobbies are mostly affected. This review summarizes the background of chronic pain syndromes and introduces a multimodal therapeutic approach.

Chronic anterior uveitis is a serious complication of juvenile idiopathic arthritis (JIA); disease flares are highly associated with loss of vision. Leflunomide (LEF) is used successfully for JIA joint disease but its effectiveness in uveitis has not been determined. The aim of this study was to determine whether LEF improves flare rates of uveitis in JIA patients compared to preceding methotrexate (MTX) therapy.A single-centre retrospective study of consecutive children with JIA and chronic anterior uveitis was performed. All children initially received MTX and were then switched to LEF. Demographic, clinical, and laboratory data, dose and duration of MTX and LEF therapy, concomitant medications and rate of anterior uveitis flares, as determined by an expert ophthalmologist, were obtained. Flare rates were compared using a generalized linear mixed model with a negative binomial distribution.A total of 15 children were included (80% females, all antinuclear antibody positive). The median duration of MTX therapy was 51 (range 26-167) months; LEF was given for a median of 12 (range 4-47) months. Anti-tumour necrosis factor (anti-TNF-α) co-medication was given to four children while on MTX. By contrast, LEF was combined with anti-TNF-α treatment in six children. On MTX, JIA patients showed a uveitis flare rate of 0.0247 flares/month, while LEF treatment was associated with a significantly higher flare rate of 0.0607 flares/month (p = 0.008).Children with JIA had significantly more uveitis flares on LEF compared to MTX despite receiving anti-TNF-α co-medication more frequently. Therefore, LEF may need to be considered less effective in controlling chronic anterior uveitis.

The diagnostic biochemical hallmarks of Smith-Lemli-Opitz syndrome (SLOS) are elevated concentrations of the cholesterol precursors 7- and 8-dehydrocholesterol (7- and 8-DHC). We describe a patient with classical SLOS phenotype and oesophageal achalasia, which has not been reported in SLOS patients before. Plasma 7-DHC and 8-DHC were only marginally elevated. The diagnosis was confirmed by sterol analysis in cultured skin fibroblasts and mutation analysis.

Growth factor deprivation-induced apoptosis plays an important role in several cellular systems. However, knowledge of the molecular mechanisms involved are restricted to a few murine models or tumor cell lines. Therefore, we aimed studying signaling pathways leading to apoptosis in activated human peripheral T cells after IL-2 withdrawal. Lymphoblasts from patients with CD 95 (Fas/APO-1)-deficiency revealed that functional CD95 was not required to induce apoptosis after IL-2 withdrawal. Moreover, apoptosis induction in response to various cytotoxic stimuli was found to be mediated in the absence of functional CD95 but was affirmatorily influenced by IL-2 signaling. Immunoblots showed no downregulation of Bcl-2 or Bcl-xL and no upregulation of Bax, whereas decreased mitochondrial membrane potential was readily measurable 24 h after cytokine deprivation. Tetrapeptide inhibitors showed limited efficacy in preventing apoptosis whereas the caspase inhibitor zVAD-FMK potently blocked induction of apoptosis. Cleavage of different fluorogenic substrates revealed multiple caspase enzyme activities in lymphoblasts, which were not negatively affected by the fas mutation. Starting at 8 h after IL-2 withdrawal, upregulation of active caspase-3 but not of caspase-8 could be detected. Taken together, our data argue for molecular mechanisms of cytokine deprivation-induced apoptosis in activated human lymphocytes independent of CD95.

Determination of the efficacy of an early ultrasound examination followed by immediate treatment of hip joint dysplasia as well as measuring the therapeutic success in a population-based cohort study of neonates.The Survey of Neonates in Pomerania (SNiP) study included 4,093 neonates which represents 95.1 % of the total neonatal population. Of these children 2,534 (61.9 %) underwent ultrasound examination of the hip joint during the U2 stage (3-10 days after birth). The mean gestational age was 38.9 weeks. The sonographic classification was performed according to Graf.Initially (U2 stage) 42 (1.66 %) children were reported to be in need of therapy (stage IIc or higher according to Graf). The analysis showed a significantly higher incidence in girls (32 girls vs. 10 boys, p 0.023, χ(2) test) and in children who had a breech birth (116, 4.6 %). A genetic predisposition was ascertained in 180 (7.1 %) children. The children could be subdivided into two groups: 1) children who underwent hip joint ultrasound during both U2 and U3 and 2) children who were first screened at the U3 stage. Of the 49 out of 54 neonates where the ultrasound findings were positive at the U2 examination the hip joint was matured in 32 children at U3 (4-8 weeks), 11 children had to be treated for 8-12 weeks 5 children were treated for over 3 months and1 child needed surgical correction.The early diagnosis of hip maturation disorders and joint dysplasia facilitates early implementation of effective treatment. At our clinic over 60 % of the infants underwent the U2 check up and, given a pathological finding, could undergo early treatment. It was possible to successfully treat 78 % of these children with a Tübingen hip flexion splint in just 4-8 weeks. In contrast, infants who were first examined at the U3 stage needed treatment for 4-12 months. In our opinion, early diagnosis at the age of 3-10 days should be carried out for all newborns.

The increasing use of combination therapies, including disease-modifying antirheumatic drugs (DMARD) and biologicals has improved the outcome for children and adolescents in several rheumatic diseases. However, this strategy has increased the risk of drug-specific side-effects, such as an increased risk of infections. Furthermore, the underlying rheumatic disease itself often includes an increased risk of infections and some patients additionally present with immunological or organic comorbidities (e.g. complement deficiency and interstitial pulmonary disease) further increasing the susceptibility to infections. The presented review is based on an analysis of the currently available literature proposing a checklist of diagnostic procedures and immunological laboratory tests specific for the detection of patients prone to infections. The combined stratification of the underlying disease, comorbidities and the immunological mechanisms of the medication enables (1) an individual risk stratification of planned immunosuppressive therapy and (2) a prediction of the risks of infection for the patient.

Early-onset pauciarticular juvenile chronic arthritis (EOPA-JCA) has associations with different alleles of the MHC region (HLA-A2, DR5, 6, 8, DQA 1*0401, *0501, *0601 and DPB1*0201). All susceptible DQA1 alleles carry an exclusive sequence motif. MHC-class II gene expression is controlled by 5′ flanking upstream regulatory regions (URR). A hypervariable region in the promoter region of the HLA-DQA1 gene (-240 and-200 base pairs upstream) defines ten different QAP (DQA1-Promoter) alleles, which are associated with certain DQA1-alleles. The Y-Box in the DQA1 promoter (YC-Box-125 to-115 upstream from the ATG) differs from the consensus sequence (-123 A for G) of all other MHC class II Y-Boxes, resulting in a lower affinity to the NF-Y transcription factor and in a reduced expression of DQA1. A second substitution in the Y-Box of QAP 4.1 and 4.2 (-119 A for G) is found in the promoter alleles of the DQA 1-alleles (DQA 1*0401, *0501, *0601) and is strongly associated with susceptibility to EOPA-JCA.

Control of disease activity and recovery of function are major issues in the treatment of children and adolescents suffering from juvenile idiopathic arthritis (JIA). Functional therapies including physiotherapy are important components in the multidisciplinary teamwork and each phase of the disease requires different strategies. While in the active phase of the disease pain alleviation is the main focus, the inactive phase requires strategies for improving motility and function. During remission the aim is to regain general fitness by sports activities. These phase adapted strategies must be individually designed and usually require a combination of different measures including physiotherapy, occupational therapy, massage as well as other physical procedures and sport therapy. There are only few controlled studies investigating the effectiveness of physical therapies in JIA and many strategies are derived from long-standing experience. New results from physiology and sport sciences have contributed to the development in recent years. This report summarizes the basics and main strategies of physical therapy in JIA.

A total of 94 patients with juvenile chronic arthritis (JCA) was tested for HLA class I by serology and for class II by RFLP typing. Early onset JCA (EOPA) is associated with HLA-A2, DR5 and DR8 in both males and females. The combination (joint occurrence) of these JCA associated alleles (A2, DR5, DR8) is frequently seen in patients with chronic iridocyclitis. Late onset pauciarticular disease has an increased frequency of HLA-B27, especially in males. Our data confirm that polyarticular JCA with early childhood onset (or = 4 years) is associated with DR5 and DR8 and has a different immunogenetic background from polyarticular JCA with later childhood (4 years) onset (associated with DR4).

Several genetic factors have recently been observed as having an influence on susceptibility, course and prognosis of juvenile idiopathic arthritis (JIA): 1. Affected sib pairs were observed to have a low concordance in terms of disease incidence, but significant concordance in terms of subtype and course of disease. 2. Each subtype of JIA was observed to have a distinct genetic background. 3. Some JIA patients do not carry any of the defined risk genes. 4. Most subtypes of JIA have a distinct different genetic background to rheumatoid arthritis in adults. 5. Multiple factors have been observed to be involved in pathogenesis implying genetic and environmental factors. 6. Systemic JIA differs from all other subtypes in terms of genetic background and treatment options. It is currently assumed to be an autoinflammatory disease. 7. Genetic factors not only affect the course of the disease, but also response and complication rate. Increasing knowledge on the factors involved in the pathogenesis of JIA as well as analysis of large patient cohorts in consortiums cooperating on an international level have helped define many important polymorphisms; these are currently the subject of further investigation.

It has recently been shown that an increased plasma level of the tryptophan catabolite kynurenine is an early indicator for the development of sepsis in major trauma patients. We examined the predictive value of kynurenine pathway activity for ongoing sepsis in patients being admitted to a surgical intensive care unit for different reasons. In addition, we asked whether an accumulation of kynurenines in patients’ plasma depends on reduced renal clearance. We conducted a prospective observational study including 100 consecutive patients and monitored laboratory variables, physiological and adverse events, sepsis and outcome. Using tandem mass spectrometry, we quantified the five indoleamines tryptophan, serotonin (5-HT), kynurenine, quinolinic acid and kynurenic acid at baseline and twice a week during the intensive care unit stay. Among the patients enrolled, 50 did not develop sepsis in the intensive care unit (non-septic), 18 patients did not have sepsis at baseline but developed sepsis later on (preseptic) and 32 patients already fulfilled the criteria of severe sepsis and septic shock at baseline (septic). In general, non-septic critically ill patients showed activation of the kynurenine pathway, but septic shock coincided with an exacerbation of kynurenine pathway activity even in the absence of renal failure. Importantly, plasma concentrations of quinolinic acid (area under the curve 0.832 [95% confidence interval 0.710 to 0.954]) and the Quin/Trp ratio (area under the curve 0.835 [95% confidence interval; 0.719 to 0.952]) showed the best discrimination between non-septic and pre-septic patients at baseline. These findings open new avenues for further investigations on the pathophysiology of sepsis.

TNF inhibitors and other biologicals have greatly expanded the therapeutic options for juvenile idiopathic arthritis (JIA). While the efficacy of etanercept and adalimumab has been proven in randomized controlled clinical trials, their long-term safety remains the subject of ongoing investigations. Reports of leukaemia and tumours in children and adolescents treated with etanercept, infliximab and adalimumab have raised questions about an increased risk for malignancies, with lymphoma accounting for the largest group at 50% of all 48 malignancies reported by the FDA.Consequently, TNF inhibitors should be indicated under careful consideration of individual risk factors, such as increased family occurrence of malignancies, or pre-treatment with carcinogenic substances such as cyclophosphamide. This is particularly true for non-approved substances, and non-approved indications, and for combination therapy of TNF inhibitors with immunosuppressive drugs. On the other hand, however, treatment should not be stopped or started in any patient in whom treatment is necessary due to the current knowledge. Adequate patient information, surveillance and documentation of treatment in the registry of the GKJR is strongly recommended.

The official birth statistics are regarded as a reliable data source on births and birth rate in the German population. However, they show methodological limitations with respect to the identification of first-time mothers and the number of children per mother. The mothers' social and economical background is not assessed. The goal of the present analysis was (a) to describe demographic and socio-economic variables of all births in a defined region over a fixed time-frame and (b) to make a comparison on the basis of parity and gravidity.From 2004-2007 4,982 children were born in the region and data from n=4,788 children were assessed (96%); n=3,505 (73%) of these mothers consented to a more detailed assessment.The fertility rate in the SniP region is low. There are fewer children per 1,000 women and born per women in general. The average age of primiparae was 25 and 26 years. As can be expected there is a significant difference between primiparae and multiparae with respect to age. There is also a difference in occupational status. 17% of the primiparae have been multigravidae.For the first time in Germany, the SNiP collected comprehensive population-based data on the age and socio-demographic variables of children and their mothers in a defined geographical region. A significant discrepancy for average age of primiparae between the study results and the official statistics is discussed in the light of methodological and regional issues. Our results require the continuation of comprehensive population-based data assessment. Furthermore, the SniP region could serve as a model region for future research. In international comparisons Germany's reproductive behaviour has proved to be unfavourable, which is accentuated in the region under examination.

Changes in reproductive behaviour and decreasing fertility rates have recently led to policy actions that attempt to counteract these developments. Evidence on the efficacy of such policy interventions, however, is limited. The present analysis examines fertility rates and demographic variables of a population in Germany in response to new maternity leave regulations, which were introduced in January 2007. As part of a population-based survey of neonates in Pomerania (SNiP), all births in the study region from the period 23 months prior to January 1st, 2007 until 23 months afterwards were examined. Crude Birth Rates (CBR) per month, General Fertility Rates (GFR) per month, parity and sociodemographic variables were compared using bivariate techniques. Logistic regression analysis was performed. No statistically significant difference in the CBR or GFR after Jan. 1st, 2007 was found. There were statistically significant differences in other demographic variables, however. The proportion of mothers who (a) were employed full-time before pregnancy; (b) came from a higher socioeconomic status; and (c) had higher income levels all increased after January 1st, 2007. The magnitude of these effects was higher in multigravid women. Forward stepwise logistic regression found an odds ratio of 1.79 for women with a family income of more than 3000 euro to give birth after the new law was introduced. This is the first analysis of population-based data that examines fertility rates and sociodemographic variables in response to new legal regulations. No short-term effects on birth rates were detected, but there was a differential effect on the subgroup of multigravidae. The focus of this policy was to provide financial support, which is certainly important, but the complexity of having a child suggests that attitudinal and motivational aspects also need to be taken into account. Furthermore, these analyses were only able to evaluate the short-term consequences of the policy; further studies are needed to assess for different, long-term effects.

Polymorphisms in the upstream regulatory region of the HLA class II DQA1 gene are currently defined by 10 different alleles. Two of them carrying a Y-box mutation are associated with susceptibility to oligoarticular juvenile idiopathic arthritis (OA-JIA). We investigated allele-dependent differences in HLA-DQA1 gene expression in OA-JIA patients. In cells from affected joints compared to peripheral blood, gene expression of HLA-DRA as well as total HLA-DQA1 was significantly upregulated. Differential analyses of HLA-DQA1 allelic expression showed DQA1*02 and *04 to be comparatively increased. Intra-articular upregulation of HLA-DQA1 was predominantly observed for the OA-JIA associated allele HLA-DQA1*04. Nevertheless, the Y-box mutation of the disease-associated allele DQA1*0401 was not a common denominator for expression behaviour.

Population-based data on smoking behavior in Germany of women before or during pregnancy have been lacking. Smoking rates of these women have now been recorded over a period of 3 years against the background of growing tobacco control activities in Germany.The study was conducted between 4/2003 and 3/2006 in the context of a prospective population-based survey about perinatal morbidity and mortality (Survey of Neonates in Pomerania - SNiP). This survey registers all newborns and their mothers in one defined region. Of the women eligible for the study 2 297 (68.1%) participated after delivery by giving data about their smoking behavior before and during pregnancy.61.2% of the women had smoked at some time, 46.6% had smoked before, 24.2% into the 4. month and 20.5% into the last 4 weeks of pregnancy. Smoking rates remained unchanged over the 3 years that were studied. The rates of smokers who had quit by the time of delivery varied according to the length of school education: (10 years: 30%; 10 y: 59%;10 y: 84%) and age (24 years: 45%; 25-30 y: 65%;30 y: 77%).This study for the first time provides population-based data about the prevalence of smoking before and during pregnancy among women in Germany. The data show extremely high numbers of smokers, especially younger women and women of only 10 years or less of school education. Despite growing tobacco control activities no changes in smoking rates were observed over three years. These findings underline the need to develop effective interventions to prevent smoking of women before and during pregnancy.

Vaccinations represent a special problem in children and adolescents with inflammatory rheumatic diseases. There are very limited data on the safety and efficacy of vaccines in these patients, and guidelines for immunization are missing. The immunosuppressive therapy often necessary for these patients gives rise to additional uncertainty. In addition, many colleagues consider vaccination to increase the risk of relapse of the rheumatic illness. As a consequence, there are substantial variations in practicing vaccination in these patients, resulting in insufficient vaccination coverage rates. For example, every third patient with juvenile idiopathic arthritis is incompletely vaccinated; this even includes toxoid vaccines for tetanus and diphtheria. The benefit of vaccinations, which far outweighs their potential risks, is well recognized even in patients with autoimmune diseases. These patients in particular require a special protection from infections due to their immunosuppressive therapies. Therefore, children and adolescents with rheumatic diseases should be immunized according to the Standing Immunization Commission of the Robert Koch Institute recommendations whenever possible. However, the time of vaccination must be carefully selected, taking disease activity and treatment into account.

To correlate findings of hip ultrasound on day 4-10 of life with sex, intrauterine position and a positive family history for congenital hip anomalies.The SNiP-study ( Survey of Neonates In Pommerania) registered 2256 neonates (2030 term, 226 preterm) between May 2002 and March 2004. Hip ultrasound results of 1043 term and since October 2003 33 preterm neonates were analysed. Time of ultrasound was day 4-10 after birth. Preterm neonates were examined when reaching their corrected term gestational age. Ultrasound was applied with a 7.5 MHz linear scanner and results were classified according to Graf. Chi-square and Fishers exact test were used for statistical analysis.4.9 % of the screened hips were classified as IIc or higher, 3.1 % were unilateral and 1.7 % bilateral. Incidence was significantly higher (p0.023) in females (6.6 %) than in males (3.2 %). There was no significant difference in intrauterine position or positive family history for hip anomalies with 3.7 % for mothers, 1.2 % of fathers and 2.4 % of siblings positive. There was a higher incidence for congenital hip dysplasia in preterms with 6.1 %, which is not significant due to the limited number.Current screening methods miss up to 18 % of newborns with severe hip dysplasia. We were able to demonstrate that screening for congenital hip dysplasia with ultrasound is a diagnostic tool even during the first days of life. There is a significantly higher incidence of congenital hip dysplasia in females, but in contrast to other studies we found no significant difference in intrauterine position or familial history. Earlier diagnosis and therapy on the base of relevant risk factors might correspond with an improved prognosis and outcome. Further studies are warranted to evaluate the significance in preterm neonates.

Severe pancytopenia due to azathioprine (AZA) toxicity in patients with autoimmune diseases is not uncommon. We describe a 14-year-old girl with HLA-B27+ spondylarthritis who was treated with AZA 3 mg/kg/day and who suddenly developed severe pancytopenia in the seventh week of treatment. Analysis of the catabolic pathway of AZA revealed a homozygous deficiency of thiopurine methyltransferase (TPMT) on the basis of a combined 2-point mutation at nucleotide positions 460 and 719 in the gene for TPMT, causing a toxic level of the metabolic active 6-thioguanine nucleotides (6-TGN) (2,394 pmoles/8 x 10(8) red blood cells). The patient was transfusion dependent and finally recovered 8 weeks after the development of the pancytopenia. At that time, 6-TGN had already returned to normal therapeutic levels. Family studies revealed another homozygous deficiency in the mother, while the other family members were heterozygous.

Polymorphism in the upstream regulatory region (URR) of the MHC class II DQA1 gene defines 10 different alleles named QAP (DQA1 promoter). In vitro studies have suggested that allelic polymorphism in the HLA-DQA promoter region may result in differences in HLA-DQA1 gene expression. In the present study, we used real-time reverse transcriptase-polymerase chain reaction (RT-PCR) to quantify differences in HLA-DQA1 gene expression. After the isolation of total mRNA, reverse transcription into cDNA was carried out using random hexamer priming and moloney murine leukaemia virus (MMLV) reverse transcriptase. Quantification of DQA1 mRNA species using a set of six group-specific primer pairs for the detection of HLA-DQA1*01, *02, *03, *04, *05 and *06 was carried out on an ABI PRISM GeneAmp 7700 Sequence Detection System (Perkin Elmer, Foster City, CA) with real-time detection and quantification taking advantage of the fluorescence TaqMan technology (Perkin Elmer, Foster City, CA). Normalization of cDNA templates was achieved by glyceraldehyde-3-phosphate dehydrogenase (GAPDH) quantification. In addition, the total amount of mRNA produced by HLA-DQA1 and HLA-DRA1 expression was quantified for comparison. Subsequently, this approach was validated using Raji and HUT-78 cell lines and tested with peripheral mononuclear cells (PBMC) of 45 samples taken from healthy volunteers. The sensitivity was determined withor = 10(2) copies. Comparison of the allele-specific DQA1 expression with the total expression of DQA1 and DRA1 mRNA indicated that DQA1*04 expression was increased compared with the expression of other alleles of the DQA1 gene. Thus, allele-specific quantification of DQA1 gene products could be achieved by real-time RT-PCR suitable for the analysis of differential expression of DQA1 mRNAs in homozygote and heterozygote combinations.

Unless treated with haematopoetic stem cell transplantation, Omenn’s syndrome, a rare variant of severe combined immunodeficiency, is associated with a fatal outcome. We describe a male infant showing all the typical features of Omenn’s syndrome, who was successfully treated with cyclosporin A to improve clinical condition prior to haematopoetic stem cell transplantation.

We report a female who was diagnosed with Wegener's granulomatosis at 4 years of age with life-threatening intracranial bleeding. The patient's serum was positive for c-antineutrophilic cytoplasmic antibodies, and histologic analysis of the lung biopsy revealed evidence of granulomatous vasculitis. Initial treatment with steroids and cyclophosphamide was successfully converted to a long-term medication regimen consisting of azathioprine, trimethoprim, and sulfamethoxazole. Thereafter the patient showed no signs of disease activity for more than 3 years and manifested only a low-grade neurologic handicap. In February 2001, 5 years after the initial diagnosis, she presented with altered consciousness and myoclonic multifocal seizures. Subsequent diagnostic studies confirmed the diagnosis of disseminated cerebral vasculitis unresponsive to steroid treatment. Acute neurologic symptoms relented immediately after cyclophosphamide pulse therapy. Magnetic resonance imaging of the brain demonstrated complete remission within 8 weeks. Her current treatment includes steroids and monthly pulses of cyclophosphamide.

T cell activation was analysed in peripheral CD4/ T cells from both systemic lupus erythematosus (SLE) patients with active and inactive disease as well as in normal healthy donors (NHD) to investigate the involvement of CD4/ T cells in the etiopathogenesis of SLE. CD4/ T cell receptor (TCR) b-chain transcripts, containing the complementarity determining region 3 (CDR3), were amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) and analysed by highresolution polyacrylamide gel electrophoresis. In addition the CDR3 of both clonally activated as well as heterogeneous Vb families from SLE patients were analysed at the molecular level. We observed a restricted CDR3 length polymorphism in peripheral CD4/ T cells from SLE patients compared with NHD, more pronounced in patients with high disease activity. Furthermore, in some Vb families single peaks in the histogram indicated nearly monoclonal T cell expansion. Sequencing of selected TCR b-chains revealed a increased content of acidic amino acids in the CDR3 encoded by either proximal Jb elements or N nucleotides. We conclude that CD4/ T cells from peripheral blood of SLE patients display features of a secondary antigen driven immune response. The bias of the CDR3 towards acidic amino acids suggests the involvement of positively charged antigens.

Dominant T cells in idiopathic nephrotic syndrome of childhood. Background Because of several studies, idiopathic nephrotic syndrome (INS) of childhood is suspected to have an immunologic pathogenesis with T cells playing a major role. To investigate this hypothesis further, we studied the diversity of the CDR3 region of the T-cell receptor (TCR) β;-chain from peripheral T cells isolated from patients with INS. Methods The study was performed over a three-year period to obtain longitudinal data on the repertoire of peripheral T cells. mRNA from peripheral mononuclear cells (PBMCs) of seven INS patients and two healthy controls (NHD) was prepared and analyzed for CDR3 length polymorphism of TCR β;-chain by spectratyping. Results All INS patients presented individually skewed spectratype histograms in at least one Vβ;-family. Patients suffering from a frequent relapsing course of INS or a focal global sclerosis showed some alterations to persist in all samples isolated in the observation period (up to 3 years). In addition, sequence analyses of the β;-chain of the TCR CDR3 region confirmed clonal expansion of peripheral T cells in those patients who had displayed spectratype alterations. Conclusions The data give strong evidence for an direct involvement of CD8+ T cells in the complicated course of INS.

The expression of m-fas/apo1 (CD95) and its soluble form (s-fas) was studied in patients with early onset pauciarticular (n = 23) and systemic juvenile chronic arthritis (n = 7). RNA was prepared from peripheral blood of patients and 22 healthy controls and from 23 samples derived from the synovial fluid of JCA patients. The ratio of m-fas/s-fas transcripts was calculated by densitometry of fas-specific RT-PCR products. An inverted ratio of m-fas/s-fas transcripts was found in PBMC and mononuclear cells from the joints of early onset pauciarticular JCA patients. The m-fas/s-fas ratios were similar in PBMC and mononuclear cells from synovial fluid. PBMC from patients with a systemic JCA showed the same m-fas/s-fas ratio as healthy controls, with an inverted ratio of both transcripts in cells from the synovial fluid. The data indicate a role of Fas/Apo1 regulated apoptosis in EOPA-JCA which is not limited to the affected joints.

The tragic death of a 26-year old hobby soccer player is described, who had a collision with the opposing goalie and suffered from a fracture of the left lateral process of the atlas, an extensive subarachnoid haemorrhage, tamponade of the third and fourth cerebral ventricles, bleeding into both lateral cerebral ventricles, infratentorial and supratentorial cerebral oedema. Furthermore, a survey of the literature concerning acute death in soccer is presented.

Polymorphism in the URR of the MHC class II DQA1 gene defines ten different alleles named QAP. Oligotyping for the alleles of DRB1, QAP, DQA1, and DQB1 have been performed in 210 unrelated healthy controls from Germany. Moreover, 83 HTCs from the Tenth IHWS have been tested. Four point loci haplotypes (DRB1, QAP, DQA1, and DQB1) have been analyzed in the unrelated healthy population sample. Computer analysis of the linkage disequilibria leads to the conclusion that QAP alleles are in strong linkage disequilibrium with alleles either the DQA1 or the DRB1 locus. One typical (“common”) haplotype was found to be associated with each DRB1 allele in the majority (86%) of the tested persons. Apart from that, 25 other less frequent (“unusual”) haplotypes, with an overall frequency of 14% have been defined. Some of these “unusual” MHC class II haplotypes were found to differ only in the regulatory alleles of DQA1 (QAP alleles) while they are identical for the alleles coding for structural elements (DRB1, DQA1, and DQB1). Most of the “unusual” haplotypes were found to carry HLA-DQ6. Assuming that “unusual” (= rare) haplotypes have arisen from “common” (= frequent) haplotypes by point mutation and recombination, we propose the existence of three recombination sites in the MHC DR-DQ region: one between DRB1 and QAP, the second between QAP and DQA1, and the third between DQA1 and DQB1.

Restriction fragment length polymorphism (RFLP) typing of MHC-class II loci DRB, DQA1, DQB1, DQA2 and DPB1 was performed in 94 patients with seronegative juvenile chronic arthritis (JCA) and 184 random controls. Analysis of allele frequencies and MHC-class II 4-loci haplotypes indicate: (1) Susceptibility to JCA is more strongly associated with the HLA-DQ subregion than with the HLA-DR subregion, especially in early onset pauciarticular JCA (EOPA-JCA). (2) Haplotype and sequence analysis show two independent MHC-class II associations for susceptibility to EOPA-JCA, one located in DQA1, the other in DPB1. (3) Two RFLP defined patterns of the DQA1 locus, DQA1.5 (DQA1*0501) and DQA1.8 (DQA1*0401, *0601) are strongly associated with the disease. (4) Analysis of amino-acid (AA) sequences coded in exon 2 of DQA1 reveals an AA sequence of six AAs common to all three associated DQA1 alleles. This suggests a model that includes a functional role for HLA-DQ molecules in the pathogenesis of JCA.

A validation was made of various published methods of computer processing of radionuclide angiography studies of the brain: qualitative and quantitative evaluation of count-rate curves from regular and irregular regions of interest, evaluation of images of the arterial, capillary and venous phase of the tracer transit and the evaluation of function images of the slope, the height of the maximum and the time of the maximum of the regional countrate curves. By logical combination of results from various methods, an attempt was made to improve the final diagnosis in terms of higher sensitivity and simultaneously higher overall accuracy. It was found that the logical "OR" combination of slope function images, qualitative comparison of curves from irregular ROIs and quotient of the maxima of these curves is an "acceptable" processing method for clinicians with average experience in nuclear medicine. This was demonstrated by a comparison of ROC curves.

A method for quantifying the function of the salivary glands using the dynamic scintigraphy with 99mTc is presented. After a special back-ground subtraction, the net-time-activity curves of the glands are characterized by 4 quantitative parameters, describing the ability of the glands to accumulate and to excrete the tracer. As a basis for clinical application, normal values are determined and their reproducibility is discussed. To demonstrate also regional functional differences within a single gland, phase-and gradient images are suggested.

A special background subtraction in dynamic scintigraphy of the salivary glands enables the production of net-time-activity-curves and the calculation of quantitative parameters of each gland. Regional functional differences within a single gland are shown by phase and gradient images. The physiological kinetics of the tracer and its modifications in different diseases of the glands (acute and chronic inflammation, tumours, Sjögrens-Syndrome) are analyzed in 367 patients.

The detailed evaluation of anatomy and pathology of the temporal bone requires imaging modalities that are superior to plain x-ray films. Conventional polytomography has today largely been replaced by high-resolution CT. High-resolution CT provides excellent demonstration of the delicate bony structures and provides superior information about the soft tissues. The axial 1 mm scans of a complete temporal bone examination can be reformated in any number of planes. These reconstructions display the temporal bone in various projections. This theoretically well-founded procedure of individual processing has proven to be highly practical in more than 1000 examinations of the skull base. High-resolution CT with image reconstruction is the diagnostic method of choice for the evaluation of the skull base and especially the temporal bone, as the complex anatomy is best demonstrated by this technique. Six axial computed tomographic scans are demonstrated in detail. The special value of multiplanar reconstructions is illustrated by reconstructions in the coronal, sagittal and longitudinal plane.