[Cushing's syndrome with subsequent tertiary adrenocortical insufficiency after simultaneous multiple intra-articular local glucocorticoid treatment : Keep an eye on hormone deficiency conditions requiring treatment after multiple administrations of local steroids]. / Cushing-Syndrom mit konsekutiver tertiärer Nebennierenrindeninsuffizienz nach simultaner multipler intraartikulärer Lokaltherapie mit Glukokortikoiden : Bei Mehrfachgabe von lokalen Steroiden behandlungsbedürftige Hormonmangelzustände im Blick behalten.

After simultaneous multiple local treatment with glucocorticoids at 46 sites a 4­year-old female patient with newly diagnosed polyarticular juvenile idiopathic arthritis (JIA) initially developed Cushing's syndrome followed by a gradual worsening of her condition and finally an acute high fever urinary tract infection. Iatrogenic adrenocortical insufficiency after multiple intra-articular glucocorticoid administration was diagnosed. The possibility of severe systemic glucocorticoid side effects after extensive local treatment should be included in the regular management of JIA patients.

[Still's disease as biphasic disorder : Current knowledge on pathogenesis and novel treatment approaches]. / Das Still-Syndrom als biphasische Erkrankung : Aktuelle Erkenntnisse zur Pathogenese und neue therapeutische Ansätze.

Still's disease covers a range of disorders from systemic juvenile idiopathic arthritis (SJIA) up to adult onset Still's disease (AOSD). The overlapping clinical features suggest that SJIA and AOSD are different manifestations of a phenotypic continuum in different age stages. Still's disease is clinically characterized by fever, rash, joint involvement, lymphadenopathy and serositis. In this review the more recent pathogenetic model of a biphasic disease course is presented. The initial autoinflammation with predominant dysregulation of innate immunity is the basis of the "window of opportunity" hypothesis for the early use of a cytokine blockade. If the disease is not stopped in this phase, a phenotype change to a disease with destructive arthritis regularly occurs, in which dysregulation of the mechanisms of adaptive immunity plays a special role. The understanding of Still's disease as a biphasic disease enables the monitoring of molecular signatures. At the same time, this opens up perspectives for phase-specific targeted treatment using modern treat-to-target strategies.

Update of the evidence based, interdisciplinary guideline for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis.

BACKGROUND: Uveitis in juvenile idiopathic arthritis (JIAU) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first line therapy, and disease modifying anti-rheumatic drugs (DMARDs) are commonly used. However, treatment has not been standardized. METHODS: Interdisciplinary guideline were developed with representatives from the German Ophthalmological Society, Society for Paediatric Rheumatology, Professional Association of Ophthalmologists, German Society for Rheumatology, parents' group, moderated by the Association of the Scientific Medical Societies in Germany. A systematic literature analysis in MEDLINE was performed, evidence and recommendations were graded, an algorithm for anti-inflammatory treatment and final statements were discussed in a consensus meeting (Nominal Group Technique), a preliminary draft was fine-tuned and discussed thereafter by all participants (Delphi procedure). RESULTS: Consensus was reached on recommendations, including a standardized treatment strategy according to uveitis severity in the individual patient. Thus, methotrexate shall be introduced for uveitis not responding to low-dose (≤ 2 applications/day) topical corticosteroids, and a TNFalpha antibody (preferably adalimumab) used, if uveitis inactivity is not achieved. In very severe active uveitis with uveitis-related deterioration of vision, systemic corticosteroids should be considered for bridging until DMARDs take effect. If TNFalpha antibodies fail to take effect or lose effect, another biological should be selected (tocilizumab, abatacept or rituximab). De-escalation of DMARDs should be preceded by a period of  ≥ 2 years of uveitis inactivity. CONCLUSIONS: An interdisciplinary, evidence-based treatment guideline for JIAU is presented.

Differentiation of vestibular schwannomas from meningiomas of the internal auditory canal using perilymphatic signal evaluation on T2-weighted gradient-echo fast imaging employing steady state acquisition at 3T.

BACKGROUND: Our aim was to confirm the usefulness of the perilymphatic signal changes on T2-weighted (T2W) gradient-echo sequence to differentiate vestibular schwannomas from internal auditory canal (IAC) meningiomas, through a compartmental analysis of inner ear fluids signal intensity. METHODS: A total of 203 patients with all criteria for typical vestibular schwannoma on T1-weighted contrast-enhanced sequences were retrospectively enrolled (190 schwannomas and 13 meningiomas). All patients underwent a T2W gradient-echo steady state free precession (SSFP) acquisition at 3T. Two radiologists analysed the signal intensity of the perilymph (cistern and cochlea) and endolymph (saccule and utricle) using a region of interest-based method for obtaining ratios between the analysed structures and the cerebrospinal fluid (CSF). RESULTS: Obstructive vestibular schwannomas showed a markedly decreased perilymphatic signal in both cistern and cochlea; the cistern/CSF ratio (Ci/CSF) was 0.62. The decrease was more moderate in IAC meningiomas (Ci/CSF = 0.81). For Ci/CSF > 0.70, the tumour was more likely a meningioma, with a 92% sensitivity and 83% specificity. No endolymphatic signal changes were observed. CONCLUSION: The pronounced decrease in perilymphatic signal on a T2W SSFP sequence in obstructive vestibular schwannoma provides a new tool to differentiate schwannomas from IAC meningiomas, which may be useful to overcome the insufficiencies of morphological analysis.

The learning curve effect on embolization of cerebral dural arteriovenous fistula single-center experience in 48 consecutive patients.

BACKGROUND: Cerebral dural arteriovenous fistulas (DAVFs) are rare intracranial vascular lesions but can cause significant morbidity and mortality. OBJECTIVES: To analyze the effect of the center's experience on DAVF embolization efficacy and safety. METHODS: From May 2008 to October 2014, 57 embolization procedures were attempted on 48 patients (37 men and 11 women; median age: 63.9 years) for DAVF in a single center. DAVF presented with cortical venous reflux in 44/48 cases (91.7%) and hemorrhagic manifestation in 21/48 cases (43.75%). Angiographic occlusion quality, whether complete or incomplete (efficacy), and neurological complications (safety) were recorded. The patient population was divided into four consecutive quartiles during the inclusion period to assess the progress profile. Efficacy and safety outcomes were compared with Fisher's test. RESULTS: A logistic regression was performed to explore a learning curve phenomenon, showing a significant association between the chronological rank in the cohort and embolization efficacy (P=0.007). Significant differences were found between first and last quarter (P=0.036). The endovascular technique involved an arterial injection of Onyx® in 36/48 cases (75%), administered via the middle meningeal artery in 25/36 cases (69.5%). The complete occlusion rate improved significantly from 33.3% for the first quartile of the population, to 75.0% for the 2nd and 3rd quartiles and 83.3% for the last quartile. Neurological complications were found in 7/48 patients (14.6%), the rate decreased by 41.7% to 16.7%, without statistically difference. CONCLUSION: The efficacy and safety of DAVF embolization improved with the experience gained at the center, suggesting the existence of a learning curve.

[Biomarkers for chronic inflammatory diseases]. / Biomarker für chronisch-entzündliche Erkrankungen.

Inflammatory disorders of childhood, such as juvenile idiopathic arthritis (JIA) and inflammatory bowel disease (IBD) are a challenge for laboratory diagnostics. Firstly, the classical inflammatory markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) often inadequately reflect disease activity but on the other hand there are few specific biomarkers that can be helpful in managing these diseases. Acute phase proteins reflect the systemic inflammatory response insufficiently as their increase is only the indirect result of local inflammatory processes. Modern inflammation diagnostics aim to reflect these local processes and to allow precise monitoring of disease activity. Experimental biomarkers, such as S100 proteins can detect subclinical inflammatory activity. In addition, established laboratory parameters exist for JIA [antinuclear antibodies (ANA), rheumatoid factor (RF), antibodies against cyclic citrullinated peptide (anti-CCP)] and for chronic IBD (fecal calprotectin) that are useful in the treatment of these diseases.

Genotype-phenotype and genotype-origin correlations in children with mediterranean fever in Germany - an AID-net study.

Familial Mediterranean fever (FMF) is the most inherited common autoinflammatory disease (AID) with mutations in the MEFV (MEditerraneanFeVer) gene.The Mor- and Pras-Score modified for children and C-reactive protein (CRP) were used to assess FMF disease severity in Germany. We evaluate the applicability of the 2 severity scores and the correlations between ethnic origin, phenotype, and genotype.Among 242 children (median 5 age at diagnosis), we detected 431 pyrin mutations and 22 different sequence variants, including one new mutation (p.Gly488Asp). The 5 most -frequent alterations were p.Met694Val (55.2%), p.Met680lle (11.8%), p.Val726Ala (10%), p.Glu148Gln (7.9%) and p.Met694IIe (2.3%). The prevailing ancestries of 223 cases were Turkish (82.5%) and Lebanese (8.1%). Homozygous p.Met694Val substitution (30.2%) was associated with a more severe disease activity by Mor-Score, as well as with a higher mean CRP (74 mg/l) compared to patients with other mutations. Indeed, Mor- and Pras-Score were inconsistent with each other. A typical distribution of mutations in different ethnic populations was obvious, but not statistically verifiable due to the low number of cases.The homozygous p.Met694Val substitution was associated with a more severe disease activity in our German cohort. The common severity scores were inconsistent in -children.

[Genetic fever syndromes. Hereditary recurrent (periodic) fever syndromes]. / Genetische Fiebersyndrome. Hereditäre rekurrierende (periodische) Fiebersyndrome.

Genetic fever syndromes or hereditary recurrent fever syndromes (HRF) are considered to be part of the autoinflammatory diseases (AID) which result from errors in the innate immune system. Patients typically have self-limiting episodes of fever and high levels of inflammation markers. The mode of inheritance is autosomal recessive or autosomal dominant. The diseases of the HRF include familial Mediterranean fever, tumor necrosis factor receptor 1-associated periodic syndrome, hyper-IgD syndrome and cryopyrin-associated periodic fever syndromes. The disease known as deficiency of interleukin 1 (IL1) receptor antagonist does not fully belong to this group because fever is not a typical symptom. The therapy depends on the type and severity of the disease. Effective prophylaxis is possible for FMF. Biologicals, especially IL1 blocking agents are highly effective in very severe fever syndromes. In order to collect more information on AID, to establish a biobank and coordinate research in this field the AID-Net project was founded. Currently 606 patients with AID are registered of whom 381 have HRF.

Closing the gap: discrimination of the expression profile of HLA questionable alleles by a cytokine-induced secretion approach using HLA-A*32:11Q.

Matching of human leukocyte antigen (HLA) alleles between donors and recipients plays a major role in hematopoietic stem cell transplantation (HSCT). Null or questionably expressed HLA allelic variants are a major issue in HLA matching, because the aberrant expression of such alleles can have a major impact on the outcome of HSCT and/or its complications such as graft-versus-host disease. The goal of this study was to investigate the potential of a recently developed cytokine-induced secretion assay to differentiate the expression levels of HLA-A*32:11Q (questionable) into a null (N) or low (L) expression variant. An amino acid mutation at position 164 of HLA-A*32:11Q disrupts the disulfide bridge in the α2 domain. HLA-A*32:11Q is not detectable by standard microlymphocytotoxicity assay. To this end, we cloned soluble HLA-A*32:11Q and a reference allele (HLA-A*32:01) into expression vectors and transfected/transduced HEK293 and K562 cells. Allele-expressing K562 cells were simultaneously transfected/transduced with a ß2-microglobulin (B2M)-encoding vector to ensure the intact HLA structure with B2M. After treatment with proinflammatory cytokines, secreted soluble HLA molecules were determined by enzyme-linked immunosorbent assay in the supernatant and intracellular accumulation of the recombinant proteins by flow cytometry. HLA-A*32:11Q was nearly undetectable in untreated transfectants. Cytokine treatment increased the secretion of HLA-A*32:11Q to detectable levels and resulted in intracellular accumulation of the allele. There was no difference in mRNA transcription between the A*32 alleles. On the basis of these results, we recommend reclassification of HLA-A*32:11Q as a low expression (L) variant.

Magnetic resonance tissue phase mapping: analysis of age-related and pathologically altered left ventricular radial and long-axis dyssynchrony.

PURPOSE: To employ magnetic resonance tissue phase mapping (TPM) for the assessment of age-related left ventricular (LV) synchrony of radial and long-axis motion in healthy volunteers and in hypertensive heart disease, dilated cardiomyopathy (DCM), and left bundle branch block (LBBB). MATERIALS AND METHODS: TPM (spatial/temporal resolution = 1.3 × 2.6 mm(2)/13.8 msec) was employed to measure radial and long-axis myocardial velocities in 58 healthy volunteers of three age groups and 37 patients (hypertensive, n = 18; DCM, n = 12; DCM and LBBB n = 7). Regional times-to-peak velocities (TTP) in systole and diastole were derived for all LV segments. Four measures of dyssynchrony were defined as the standard deviation of systolic and diastolic TTP for radial and long-axis motion. RESULTS: Systolic radial and diastolic long-axis dyssynchrony was increased (P < 0.01) in all patient groups compared to controls. Multiple regressions revealed a significant relationship of dyssynchrony with LV ejection fraction and mass for systolic radial (P < 0.001 resp. P = 0.02), diastolic radial (P < 0.001 resp. P < 0.05), and long-axis (P < 0.001 resp. P = 0.001) motion. Diastolic dyssynchrony correlated with the LV remodeling index (P < 0.05) and increased with age (P < 0.03). Systolic long-axis dyssynchrony was not influenced by disease or LV function. CONCLUSION: Radial systolic and long-axis diastolic dyssynchrony were the most sensitive markers for altered dyssynchrony in hypertensive heart disease or DCM. Future studies are needed to evaluate the diagnostic value of TPM-derived dyssynchrony parameters.

[Methotrexate in the therapy of juvenile idiopathic arthritis]. / Methotrexat bei der Therapie der juvenilen idiopathischen Arthritis.

Treatment with low-dose methotrexate (MTX) is an important element in the therapy of juvenile idiopathic arthritis (JIA). It could be demonstrated in placebo-controlled trials that MTX is a safe and effective drug which is generally well tolerated by children and adolescents. MTX is usually used at a dose of 10-15 mg/m(2)/week, whereby oral administration is preferred for children. Side effects occur mainly in the form of gastro-intestinal discomfort such as nausea and vomiting or raised transaminases, which can be effectively treated with folic-acid supplementation.There are no general recommendations to date regarding in particular duration and discontinuation of MTX treatment or combination treatment with other disease-modifying antirheumatic drugs or biologics. These unresolved questions are the subject of current trials in which biomarkers have an increasingly important role.

[Updated statement by the German Society for Pediatric and Adolescent Rheumatology (GKJR) on the FDA's report regarding malignancies in anti-TNF-treated patients from Aug. 4, 2009]. / Aktualisierte Stellungnahme der GKJR zur Meldung der FDA über Fälle von Malignomen bei Anti-TNF-behandelten Patienten vom 04.08.2009.

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.

[Acute upper gastrointestinal bleeding as initial manifestation of a gastrointestinal stromal tumor]. / Akute obere gastrointestinale Blutung als Erstmanifestation eines gastrointestinalen Stromatumors.

HISTORY: An 80-years-old man was admitted to our clinic because of upper gastrointestinal bleeding with tarry stool for 3 days after taking non steroidal antiinflammatory drugs (NSAID) for back pain. The history was otherwise unremarkable. INVESTIGATIONS: Laboratory results showed anaemia. Initial endoscopy revealed acute bleeding from an elevated ulcer in the pars inferior of the duodenum. The bleeding was successfully treated by epinephrine and fibrin injection. Biopsies showed inflammatory changes without presence of malignant cells. In the CT scan of the abdomen there was a mass near the ligament of Treitz of 6.3 cm in diameter adjacent to the duodenum. CLINICAL COURSE: The abdominal tumor was not suitable for ultrasound-guided biopsy. Therefore, laparotomy and surgical resection of the tumor were performed. Histology showed a gastrointestinal stromal tumor (GIST) with infiltration of the muscle layer of the duodenal wall with one small local metastasis. No lymph node metastases were present. The tumor was surgically completely removed and the regular follow-up examinations have fo far shown no evidence for tumor recurrence or metastases. CONCLUSIONS: In upper gastrointestinal bleeding from unusual sites, GIST has to be considered as an underlying disease even if endoscopic biopsies are negative for neoplastic changes.

Effects of a wheelchair ergometer training programme on spinal cord-injured persons.

STUDY DESIGN: Before and after investigation of the effects of a wheelchair ergometer Training programme. OBJECTIVE: To investigate the effects of an original interval-training programme on work capacity and cardiorespiratory variables with spinal cord-injured persons (SCIP's) on a wheelchair-specific ergometer. SETTING: BESANCON, FRANCE. METHODS: Seven SCIP's (male) performed 45 min of wheelchair ergometry three times per week, for 6 weeks. Training effects on maximal dynamic performance and endurance capacity were studied by comparison of performance and cardiorespiratory responses observed during both a maximal progressive test (10 W/2 min) and the same training session performed before and after training. RESULTS: Training induced significant improvements in maximal tolerated power (+19.6%), in peak oxygen consumption (VO2,+16%), and in oxygen pulse (O2p,+18.7%). At ventilatory threshold, significant improvements were also observed in power output (+63%), VO2VT(+ 34.1), ventilation VEVT(+ 37.1%), and V2pVT(+ 19.9% ). Heart rate and ventilation were significantly lower (-11 and -14.6%, respectively) after training at the same work rate, while VO2 was unchanged. Between the first and the last training session, the total physical work was improved by 24.7%, whereas heart rate was unchanged. CONCLUSION: An interval-training programme individualised to each paraplegic subject using a wheelchair ergometer can significantly improve the fitness level and endurance capacity.

[Life-threatening theophylline intoxication: a variant of Munchhausen syndrome by proxy]. / Lebensbedrohliche Theophyllin-Intoxikation im Rahmen eines Münchhausen-by-proxy-Syndroms.

We report of a prematurely born infant, who was admitted to hospital at the age of 6 months due to seizures. The seizures continued despite of an improved electroencephalogram due to varying medications. The boy had episodes of hypokaliaemia, diarrhea, and tachycardia which were treated in critical care unit. Not before 3 months of continued treatment and diagnostic work up in three different hospitals had passed the underlying poisoning with theophylline by the mother was proved. The toxicity of theophylline is well known. Adverse reactions occur frequently during theophylline therapy. There are numerous reports of suicidal intoxications with theophylline. Non-accidental poisoning with theophylline has not yet been reported in the context of Munchausen syndrome by proxy.

Classical conditioning of the electrically elicited blink reflex in humans: a new method of data analysis.

The eyeblink conditioning paradigm is a well-established model to study learning processes in humans and animals. Especially results from animal studies have supplied new insight into physiological pathways and brain structures involved in associative motor learning and memory. An important role of the cerebellum and its afferent fiber systems could be shown. Recent studies in humans have given evidence that results of animal experiments can be applied directly to the human condition. A high variation of baseline EMG activity and/or spontaneous blinks may influence the analysis of classical conditioning of the electrically elicited blink reflex in humans. To optimize differentiation between real conditioned responses and stimulus-independent EMG activity, we developed an algorithm which is fully automated and independent of a possible bias of an examiner. In a first step the algorithm decides whether a subject fulfills the criteria of a successful learning process or not. The second step quantifies the learning process. For quantification of the learning process, the following parameters were calculated: number of conditioned responses, onset of conditioning, time and amount of maximal conditioning, speed of conditioning and speed of habituation. According to our criteria, 80% of the healthy volunteers acquired conditioned responses. There is an age-related decline in eyeblink classical conditioning. Analysis of patient groups with different types of lesions will further improve our knowledge and understanding of pathways involved in learning processes in humans. The proposed new algorithm of data analysis takes less than 10 s on a standard computer, is more sensitive and more specific in detecting conditioned responses and, therefore, may further improve the value and reliability of the eyeblink conditioning paradigm in clinical research.

[Dislocated hips in cerebral palsy (author's transl)]. / Les défauts de centrage de la tête fémorale chez l'infirme moteur d'origine cérébrale.

The authors have observed 119 excentrated hips in 81 spastic children. Most of the cases were noted in non walking children under the age of ten. However some excentrated hips were seen in older patients eventually able to walk. The importance of a three dimensional approach of the problem is pointed out. The results of the surgical procedures are analysed. It appeared that it was important to restore a muscle balance before any pelvic or femoral osteotomy. Triple pelvic osteotomy was indicated of obtaining a better orientation of the acetabulum in younger children. Its complications were infrequent. Chiari's osteotomy was indicated in older children. The authors point out the importance of an early diagnosis in cases of lack of muscles balance which can be corrected by minor surgical procedures on soft tissues.