[Clinical characteristics and follow-up of 60 patients with recent diagnosis of giant cell arteritis, NEWTON study]. / Caractéristiques et profils évolutifs des patients avec un diagnostic récent d'artérite à cellules géantes, étude NEWTON.

INTRODUCTION: The management of giant cell arteritis (GCA) has evolved with the arrival of tocilizumab (TCZ) and the use of PET/CT. Our objective is to describe the characteristics and followup of patients with recent diagnosis of GCA in current care. PATIENTS AND METHODS: The NEWTON cohort is a monocentric retrospective cohort based on data collected from 60 GCA patients diagnosed between 2017 and 2022 according to the ACR/EULAR 2022 criteria. RESULTS: The median age at diagnosis was 73 [68.75; 81] years old. At diagnosis, the main manifestations were unusual temporal headaches in 48 (80 %) and an inflammatory syndrome in 50 (83 %) patients. Temporal artery biopsy confirmed the diagnosis in 49/58 (84 %) patients. Doppler of the temporal arteries found a halo in 12/23 (52 %) patients. The PET/CT found hypermetabolism in 19/43 (44 %) patients. Prednisone was stopped in 17.5 [12.75; 24.25] months. During follow-up, 22 (37 %) patients received TCZ. At least one complication of corticosteroid therapy was observed in 22 (37 %) patients. After a median follow-up of 24 [12; 42] months, 25 (42 %) patients relapsed. At the end of the follow-up, 29 (48.3 %) patients were weaned from corticosteroid therapy and 15 (25 %) were on TCZ. CONCLUSION: Despite the increasing use of TCZ in the therapeutic arsenal and of the PET/CT in the imaging tools of GCA patients, relapses and complications of corticosteroid therapy remain frequent, observed in more than a third of patients.

Pharmacophore and binding analysis of known and novel B-RAF kinase inhibitors.

The extensively investigated serine/threonine kinase, B-RAF, is a member of the RAS/RAF/MEK/ERK pathway. It plays important role in the regulation of cell growth, differentiation and survival. The mutation of B-RAF occurs frequently in melanomas and colon tumors; therefore, it is considered as an outstanding therapeutic target. In recent years a great number of B-RAF inhibitors have been reported and this number is expected to increase. The aim of our work was to compare the structures and binding mode of the published B-RAF inhibitors, and then to apply the correlations found for the explanation of our experimental results. In the first part of this paper we describe the main pharmacophore features of the co-crysallized B-RAF inhibitors published in the literature, focusing on the binding modes and common structural elements. In the second part we present and characterize our recently developed B-RAF inhibitor family by application of in silico methods and in vitro kinetic profiling. The inhibitory activity of these compounds was determined in biochemical kinase- and cell-based assays. The docking and assay results support our conclusion that the presented compound family belongs to the type I 1/2 subgroup, they inhibit B-RAF and B-RAF(V600E) mutant in a sub-micromolar range and most of them show selectivity towards B-RAF(V600E) mutant expressing cell lines with equal or even better IC50 values than sorafenib.

Novel mutations of the PRKAR1A gene in patients with acrodysostosis.

Acrodysostosis is characterized by a peripheral dysostosis that is accompanied by short stature, midface hypoplasia, and developmental delay. Recently, it was shown that heterozygous point mutations in the PRKAR1A gene cause acrodysostosis with hormone resistance. By mutational analysis of the PRKAR1A gene we detected four different mutations (p.Arg368Stop, p.Ala213Thr, p.Tyr373Cys, and p.Arg335Cys) in four of seven affected patients with acrodysostosis. The combination of clinical results, endocrinological parameters and in silico mutation analysis gives evidence to suppose a pathogenic effect of each mutation. This assumption is supported by the de novo origin of these mutations. Apart from typical radiological abnormalities of the hand bones, elevated thyroid stimulating hormone and parathyroid hormone values as well as short stature are the most common findings. Less frequent features are characteristic facial dysmorphisms, sensorineural hearing loss and mild intellectual disability. These results lead to the conclusion that mutations of PKRAR1A are the major molecular cause for acrodysostosis with endocrinological abnormalities. In addition, in our cohort of 44 patients affected with brachydactyly type E (BDE) we detected only one sequence variant of PRKAR1A (p.Asp227Asn) with an unclear effect on protein function. Thus, we conclude that PRKAR1A mutations may play no major role in the pathogenesis of BDE.

[Shock, hemoconcentration, and generalized edema in a 47-year-old man]. / Schock, Hämokonzentration und generalisierte Ödeme bei 47-jährigem Patienten.

We report the case of a 47-year-old man who was admitted because of syncope. Upon hospital admission, he rapidly developed circulatory shock with generalized edema and a severe hemoconcentration with a hematocrit of 70%. The condition was stabilized with infusion of 17 l of cristalloid fluids over a period of 24 h. After ruling out possible secondary causes, the diagnosis of a systemic capillary leak syndrome--a severe transient endothelial barrier dysfunction of unknown origin--was made. A triad of hypotension, hemoconcentration (hematocrit >60%) and macromolecular extravasation is the typical finding; furthermore, a strong association with monoclonal gammopathy of unknown significance (MGUS) is described.

Two Adult Patients with Ellis-van Creveld Syndrome Extending the Clinical Spectrum.

Ellis-van Creveld (EvC) syndrome is a rare autosomal recessive malformation syndrome with the main features cardiac defects, postaxial hexadactyly, mesomelic shortening of the limbs, short ribs, dysplastic nails and teeth, oral frenula and various other abnormalities while mental function is normal. We describe 2 adult EvC patients with the cardinal skeletal features of mesomelic short stature and severe, progressive genu valgum deformity, resulting from loss of function mutations in the EVC genes. While the genu valgum was the predominating and disabling feature in patient 1, patient 2 showed acroosteolyses in the distal phalanges and a symmetrical synostosis of metacarpals in his hands. Moreover, patient 2 developed synostoses in the additional fingers in adolescence which had not been present at the age of 12 years, suggesting a further progression of skeletal disease. Joint fusion of phalanges so far has not been reported in EvC syndrome. Our data further expand the phenotypic spectrum of EvC related skeletal malformations and contribute important new information on the clinical course of EvC syndrome with increasing age.

The structure of CDK8/CycC implicates specificity in the CDK/cyclin family and reveals interaction with a deep pocket binder.

Cyclin-dependent kinase (CDK) 8 associates with cyclin C (CycC) and belongs to the CDK module of the Mediator of transcription, together with MED12 and MED13. CDK8 is involved in the regulation of mRNA transcription and was identified as a potent oncogene in colon cancerogenesis. We have solved the 2.2-Å crystal structure of CDK8/CycC in complex with sorafenib, an anti-cancer drug of clinical relevance. The CDK8 structure reveals a unique CycC recognition helix that explains the specificity of the CDK8/CycC pair and discrimination among the highly promiscuous binding in the CDK/cyclin family. In contrast to all CDKs, the CDK8 activation loop appears not to be phosphorylated. Based on the structure, we discuss an alternate mode of CDK8 activation to the general CDK activation by T-loop phosphorylation. Sorafenib binds to the catalytic cleft of CDK8. It displays a deep pocket binding mode and is the first small molecule to induce a DFG-out conformation in the CDK family, which is actually DMG-out in CDK8.

A tale of two cities - the effect of low intensity conflict on prevalence and characteristics of musculoskeletal pain and somatic symptoms associated with chronic stress.

UNLABELLED: Although both acute and chronic stress leads to pain, the precise characteristics of this association have not been well defined. Sderot is an Israeli town exposed to repeated missile attacks. Ofakim, a town of similar demographic and socioeconomic characteristics, had not been targeted, as of the period of our study. We examined the occurrence and characteristics of pain and related somatic symptoms in Sderot and Ofakim. METHODS: One thousand and twenty-four individuals in Sderot and 1006 in Ofakim were interviewed regarding pain, somatic symptoms, mood, trauma-exposure, and general health status. RESULTS: Significantly higher levels of trauma-related symptoms and somatic symptoms were noted in Sderot compared with Ofakim (p<0.001). Chronic widespread pain (CWP) was more common in Sderot (11.1%) than Ofakim (8.3%; OR 1.37, p=0.038). Women were more likely (13.9% vs. 9.3%; OR 1.45, p=0.06) than men (8.9% vs. 7.3%, OR 1.24, p=0.37) to experience CWP in Sderot vs. Ofakim. Amongst males, chronic regional pain (CRP) was more common in Sderot (19.2%) than in Ofakim (14.2%; p=0.036). Pain severity in Sderot was significantly higher than in Ofakim (p<0.001). CONCLUSIONS: Similar to previous studies that have suggested that chronic stress is associated with chronic pain, this study demonstrates significantly increased rates of somatic complaints, including pain, fatigue and IBS-like symptoms, among individuals in Sderot compared with Ofakim, as well as significantly higher rates of trauma-related symptoms. Thus, a fibromyalgia-like symptoms cluster was more likely to be found in Sderot compared with Ofakim. Widespread pain was reported as being significantly more frequent by inhabitants of Sderot compared with Ofakim. These results have relevance to both the general population and for populations enduring chronic stress.

Differences in the personality profile of fibromyalgia patients and their relatives with and without fibromyalgia.

OBJECTIVES: To investigate whether Fibromyalgia (FM) patients differ from their first-degree relatives with and without FM regarding the four personality traits, based on Cloninger's TPQ questionnaire (1). METHODS: The study population was obtained from a genetic study from 2003-2007 and included 129 female FM patients, 27 female relatives with undiagnosed FM and 30 female relatives without FM. All participants completed a socio-demographic questionnaire and the Tridimensional Personality Questionnaire (TPQ) (1) that refers to four personality dimensions: 'novelty seeking', 'harm avoidance', 'reward dependence' and 'persistence'. Non-articular tenderness was evaluated by tender point count and by dolorimetry. RESULTS: FM patients and their relatives with FM had higher scores on 'harm avoidance' than relatives without FM (p<0.001, p=0.017 respectively). Furthermore, the mean point counts of FM patients were significantly higher and their tenderness thresholds were significantly lower than that of their relatives in the other two groups (p<0.001; p<0.001, respectively). CONCLUSIONS: The findings suggest that relatives with FM display personality resemblance to FM patients especially in the personality trait harm avoidance. It appears that there are factors in this personality trait that are hereditary and that may contribute to the development of FM. However, the results could not differentiate between factors from a genetic or a non-genetic origin, due to the study design. In addition, FM's place as an independent component among genetic disorders such as pain, depression and anxiety is still unclear.

[Family screening in patients with retinal angiomatosis]. / Familienuntersuchungen bei Patienten mit Angiomatosis retinae.

BACKGROUND: The aim of this study was to characterise the results of a screening for von Hippel-Lindau disease (VHL), angiomatosis retinae (AR) and further VHL lesions in at-risk relatives of ophthalmological VHL index patients. METHODS: A retrospective analysis of 20 VHL index patients identified by the presence of angiomatosis retinae and a mutation of the VHL gene was carried out. A molecular genetic test for a VHL mutation and funduscopy was offered to all available at-risk relative. In the case of a positive test result, repeated screening for AR and further VHL lesions were suggested. RESULTS: Fifty-one out of 86 first- and second-degree relatives were screened, and 73 % showed a VHL mutation. At first presentation, asymptomatic AR was present in 55 %, at the end of the study in 72 % of gene carriers. In contrast to the index patients, angiomas were small and could be treated without functional loss. During the study 4 eyes of index patients developed blindness, whereas in the affected relatives no such event occurred. Affected relatives developed further VHL lesions to the same number and extent as the index patients. CONCLUSIONS: This study demonstrates the necessity of a screening of at-risk relatives of patients with AR and VHL. Molecular genetic screening allows an early identification of affected relatives. Early and regular screening enables the detection of small retinal angiomas and their treatment without functional loss.

Are psychological distress symptoms different in fibromyalgia patients compared to relatives with and without fibromyalgia?

OBJECTIVES: Investigating psychological distress symptoms in the context of fibromyalgia (FM) is important due to their role in pain perception, and in the development of pain related disability. Although The Symptom Check-List-90-Revised (SCL-90-R) (1) questionnaire was used to evaluate psychological distress symptoms in FM patients, it was not applied in a familial context in families of FM patients. Our aim was to identify possible differences between FM patients and their relatives with and without FM regarding psychological distress symptoms. METHODS: The participants of the current investigation included 127 diagnosed female patients with FM, and 57 of their first degree relatives, 27 of whom had previously undiagnosed FM. Psychological distress was measured using The Symptom Check-List-90-Revised (SCL-90-R), a self report symptom inventory that addresses 9 distress dimensions reflecting various types of psychopathology. RESULTS: FM patients reported significantly higher severity in 6 of the 9 distress symptoms compared to relatives without FM: somatisation, obsessive-compulsive, interpersonal sensitivity, depression, anxiety and psychoticism. Similar results were observed among relatives with FM, compared to the healthy group, except for anxiety. No differences were observed between FM patients and relatives with FM in the report of psychological distress. CONCLUSIONS: FM patients and relatives with FM expressed similar symptoms of psychological distress compared to the healthy group.

The relationship between a common catechol-O-methyltransferase (COMT) polymorphism val(158) met and fibromyalgia.

OBJECTIVES: Fibromyalgia syndrome (FM) is an idiopathic chronic pain syndrome characterised by widespread nonarticular musculoskeletal pain, generalised tender points, in the absence of inflammatory or structural musculoskeletal abnormalities, accompanied by a constellation of symptoms that include fatigue and disturbances of sleep and mood. Catechol-O-methyltransferase (COMT) is the major catecholamine-clearing pathway and involved in the mediation of pain perception in humans, and the hypothesized role of pain perception in FM. The association between Val/Met polymorphism at the COMT gene was evaluated in FM disorder. METHODS: 209 FM female patients were compared with 152 of their non-affected relatives. DNA was obtained from all family members and extracted. We used the logistic based variant of the transmission disequilibrium test to assess association (and linkage) without confounding effect of population stratification. RESULTS: We observed an association between FM and the COMT val(158) met polymorphism in a dose response effect of the COMT genotype and the number of pressure points reported. We also observed that non-affected relatives of FM patients had a reduced percentage of the COMT met allele. CONCLUSIONS: Our results are consistent with carriers of the COMT met/met genotype showing increased sensitivity to pain as one mechanism for the role of this gene in conferring risk for FM. We suggest that the reduced frequency of the met allele in the non-affected relatives acts as a 'protective' allele in this group and prevents the development of clinical FM.

[Ocular manifestations and surgical results in patients with Marfan syndrome]. / Okuläre Manifestationen und chirurgische Ergebnisse beim Marfan-Syndrom.

AIM: This retrospective study should examine and judge the surgical indications and the therapeutic possibilities as well as their complications in patients with ocular manifestations of Marfan syndrome (MFS) diagnosed according to the criteria of the Ghent nosology. PATIENTS AND METHODS: The study included 17 patients. Operative indications were increasing subluxation of the lens, retinal detachments and secondary glaucoma. The operative procedure depended on patient age and findings. Eleven MFS patients were operated in both eyes and six MFS patients in one eye. RESULTS: Stabilization or functional improvement of visual acuity could be achieved in all patients in whom no disorders limiting visual acuity or amblyopia were present preoperatively. In six eyes of five patients, lens insertion was accomplished via a pars plana approach. Lens removal without implantation of an intraocular lens was performed in 16 eyes of 10 patients. Pars plana vitrectomy was accomplished in 12 eyes. Complications were well controlled by pars plana vitrectomy. CONCLUSIONS: Difficult preoperative situations and postoperative complications are not rare in MFS patients. However, they can be controlled well by means of modern vitreous surgery.

[Ultrasound guided implantation of chest port systems via the lateral subclavian vein]. / Die sonographisch gezielte Implantation von Portkathetersystemen über die laterale Vena subclavia.

PURPOSE: Retrospective analysis of the success and complication rates of chest port implantation via the lateral subclavian vein. MATERIALS AND METHODS: Between January 2003 and June 2004, the lateral subclavian vein in 271 patients (186 women, 85 men, mean age 53.2 years) was punctured guided by ultrasound. This access was used to insert a port system, and the catheter tip was placed at the cavoatrial junction. The port reservoir was implanted in a subcutaneous infraclavicular pocket and fixed to the fascia of the pectoralis muscle. Indications for port implantation were chemotherapy (n = 239), total parenteral nutrition (n = 2) and intravenous medication (n = 30). The patient follow-up was mainly performed either by the oncology division of the department of gynecology or by the department of internal medicine. RESULTS: A chest port catheter system was successfully implanted in all patients. The catheter remained in place for a mean duration of 269.4 days (SD 192.3 days). No complications occurred during implantation. In the post-interventional period, 6 catheter dysfunctions were found (thrombotic 0.09 per 1000 catheter days; mechanic 0.05 per 1000 catheter days). While one local infection occurred in the early post-interventional period, 3 local and 15 systemic infections were independent of the port catheter placement (0.39 per 1000 catheter days). The rate of port catheter ex-plantation due to dysfunction or infection was 0.07 per 1000 catheter days. CONCLUSION: Ultrasound-guided puncture of the lateral subclavian vein is a safe procedure for the insertion of central venous port catheter systems and had a very low complication rate in our study. For further evaluation of our port placement technique, prospective studies compared to placement through the internal jugular vein are necessary.

[Magnetic resonance tomogography after cryotherapy of long bones in an animal model]. / Magnetresonanztomographie nach Kryoablation langer Röhrenknochen im Tiermodell.

PURPOSE: To describe the MR findings following cryoablation of long bones. MATERIALS AND METHOD: Cryoablation was performed in femoral and tibial bones of 24 sheep under general anesthesia. MRI of the treated and untreated contralateral bones was performed immediately thereafter and at 2, 4 and 6 months after the cryosurgical procedure. RESULTS: On the MRI performed immediately after cryotherapy, the lesions showed low signal intensities relative to the normal bone marrow on unenhanced T1- and T2-weighted images. At 2, 4 and 6 months after cryoablation, the lesions showed high signal intensities on STIR images, low signal intensities on T1-weighted and heterogeneous enhancement on contrast-enhanced T1-weighted MR images. The femoral lesions decreased in size from 31 +/- 3 mm immediately after the cryotherapy to 13 +/- 4 mm 6 month later and the tibial lesions from 29 +/- 7 mm to 19 +/- 4 mm. CONCLUSION: MRI shows bone marrow lesions immediately after cryotherapy and can easily monitor healing lesions. MR imaging is suitable for following cryotherapy.

Glenothoracic fusion. An adjunct to radical scapulectomy.

We describe a surgical procedure used to achieve glenothoracic fusion after one-stage radical, near total scapulectomy for primary or secondary malignant lesions in six patients. The aim was complete excision of the lesion and preservation of the glenoid to provide a fulcrum for movement of the arm. Post-operative assessment involved determination of the range of movement and the application of the Musculoskeletal Tumour Society score and the Constant score to evaluate function. The results showed that a functional range of movement was attainable despite such radical surgery, although there was a considerable reduction in power and ability to lift.

Autonomic nervous system derangement in fibromyalgia syndrome and related disorders.

Fibromyalgia syndrome is a chronic, painful musculoskeletal disorder of unknown etiology and/or pathophysiology. During the last decade many studies have suggested autonomic nervous system involvement in this syndrome, although contradictory results have been reported. This review focuses on studies of the autonomic nervous system in fibromyalgia syndrome and related disorders, such as chronic fatigue syndrome and irritable bowel syndrome on the one hand and anxiety disorder on the other, and highlights techniques of dynamic assessment of heart rate variability. It raises the potentially important prognostic implications of protracted autonomic dysfunction in patient populations with fibromyalgia and related disorders, especially for cardiovascular morbidity and mortality.

Simultaneous recording of late and ultra-late pain evoked potentials in fibromyalgia.

OBJECTIVE: To characterize laser evoked potentials (LEP), pain psychophysics and local tissue response in fibromyalgia patients. METHODS: LEP were recorded in 14 women with fibromyalgia in response to bilateral stimulation of tender and control points in upper limbs by 4 blocks of 20 stimuli at each point. Subsequently, heat pain thresholds were measured and supra-threshold magnitude estimations of heat pain stimuli were obtained on a visual analogue scale. Finally, the extent of the local tissue response induced by the previous stimuli was evaluated. RESULTS: Laser stimuli elicited two long latency waves: A late wave (mean latency 368.9+/-66.9 ms) in most patients (13/14) from stimuli at all points, and an ultra-late wave (mean latency 917.3+/-91.8 ms) in 78.5% of the patients at the control points and in 71.4% at the tender points. Amplitude of ultra-late waves was higher at the tender points (20.67+/-11.1 microV) than at the control points (10.47+/-4.1 microV) (P=0.016). Pain thresholds were lower in the tender (41.2+/-2.7 degrees C) than the control points (43.9+/-3.2 degrees C) (P=0.008). Local tissue response was significantly more intense at tender than control points (P=0.004). CONCLUSIONS: Ultra-late laser evoked potentials can be recorded simultaneously with late potentials. Our findings are compatible with presence of peripheral C-fiber sensitization, mostly at tender points, probably combined with generalized central sensitization of pain pathways in fibromyalgia.