An immunogenomic exome landscape of triple positive primary antiphospholipid patients.

Primary antiphospholipid syndrome is characterized by thrombosis and autoantibodies directed against phospholipids or associated proteins. The genetic etiology of PAPS remains unknown. We enrolled 21 patients with thromboembolic events associated to lupus anticoagulant, anticardiolipin and anti ß2 glycoprotein1 autoantibodies. We performed whole exome sequencing and a systematic variant-based analysis in genes associated with thrombosis, in candidate genes previously associated with APS or inborn errors of immunity. Data were compared to public databases and to a control cohort of 873 non-autoimmune patients. Variants were identified following a state-of-the-art pipeline. Enrichment analysis was performed by comparing with the control cohort. We found an absence of significant HLA bias and genetic heterogeneity in these patients, including when testing combinations of rare variants in genes encoding for proteins involved in thrombosis and of variants in genes linked with inborn errors of immunity. These results provide evidence of genetic heterogeneity in PAPS, even in a homogenous series of triple positive patients. At the individual scale, a combination of variants may participate to the breakdown of B cell tolerance and to the vessel damage.

Lactobacillus endocarditis: a case report in France and literature review.

Lactobacilli are commensal bacteria in the normal flora of the oral cavity, gastrointestinal and genital tract. However, few cases of lactobacilli-induced bacteremia or endocarditis have been reported, particularly in immunocompromised patients. We reported a rare case of a 57-year-old man with a Lactobacillus rhamnosus endocarditis without immunodeficiency in his medical history. He received a dental scaling one year before. Clinical presentation included weight loss, heart murmur, ankle arthritis and splinter hemorrhage. Echocardiography showed a mitral prolapse and a 16 mm vegetation associated with a valvular perforation. All blood cultures were positive for Lactobacillus rhamnosus. Antibacterial regimen with amoxicillin and gentamicin led to recovery without surgery. We present a literature review of the lactobacillary endocarditis cases published since 1992. Valvulopathy, dental or invasive procedures and probiotics use were the main underlying conditions, in contrary to immunodeficiency. Diagnosis of lactobacillary endocarditis should be more considered and a treatment with penicillin and aminoglycoside should be promptly introduced in life-threatening cases.

Efficacy of anti-TNF alpha in severe and refractory major vessel involvement of Behcet's disease: A multicenter observational study of 18 patients.

OBJECTIVE: To describe the outcome and tolerance in patients treated with anti-TNFα in severe and refractory major vessel disease in Behçet's disease (BD). METHODS: A multicenter study evaluating 18 refractory BD patients with major vessel involvement [pulmonary artery (n = 4), aorta (n = 4) or peripheral artery aneurysm (n = 1) and/or pulmonary artery (n = 7), inferior vena cava (n = 5), or intra-cardiac (n = 3) thrombosis or Budd Chiari Syndrome (n = 2)] treated with anti-TNFα agents. RESULTS: Vascular remission was achieved in 16 (89%) patients. The 9 months risk of relapse was significantly higher with conventional immunosuppressants used prior anti-TNFα agents as compared to anti-TNFα therapy [OR = 8.7 (1.42-62.6), p = 0.03]. The median daily dose of corticosteroids significantly decreased at 12 months. Side effects included infection (n = 4) and pulmonary edema (n = 1). CONCLUSION: TNFα-antagonists are safe and might be associated with a decreased risk of relapse at 9 months compared to conventional immunosuppressants in BD patients with major vessels disease.

[Large vessel vasculitis with myelodysplastic syndrome: A rare association]. / Vascularite des gros vaisseaux et syndrome myélodysplasique : une association rare.

INTRODUCTION: The vasculitis can be the consequence of malignancy: most often hematologic rather than solid tumors. The association between large vessels vasculitis and myelodysplastic syndrome is rare. CASE REPORT: A 55-year-old man experienced asthenia, fever, polyarthritis and inflammatory syndrome. Haematological investigations found a type 2 refractory anemia with excess blasts (RAEB-2) with discovery of severe anemia (Hb: 7,8g/dl) and thrombopenia (platelets: 40,000/mm3). Radiological examinations found thoracic aortitis and carotid vasculitis. Treatment in the form of steroids and azacitidine was instituted. The lack of control of both RAEB-2 and vasculitis was responsible for the death of the patient. CONCLUSION: Myelodysplastic syndrome and large vessels vasculitis is a rare but serious association disease. The lack of efficiency of corticosteroids seems to be common. Prognosis depends on the haematological treatment effectiveness.

Late-onset neutropenia after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the AutoImmunity and Rituximab registry.

OBJECTIVES: To evaluate the prevalence of late-onset neutropenia and its complications in patients treated with rituximab (RTX) for rheumatoid arthritis (RA) and other autoimmune diseases (AIDs) in a prospective registry. METHODS: The AutoImmunity and Rituximab registry is an independent 7-year prospective registry promoted by the French Society of Rheumatology. For each episode of neutropenia, data were validated by the clinician in charge of the patient. RESULTS: Among 2624 patients treated with RTX for refractory AIDs, and at least 1 follow-up visit (a total follow-up of 4179 patient-years in RA and 987 patient-years in AIDs), late-onset neutropenia was observed in 40 patients (25 RA (1.3% of patients with RA, 0.6/100 patient-years), and AIDs in 15 (2.3% of patients with AIDs, 1.5/100 patient-years)). 6 patients (15%) had neutrophils <500/mm(3), 8 (20%) had neutrophils between 500 and 1000/mm(3), and 26 (65%) had neutrophils between 1000 and 1500/mm(3). Neutropenia occurred after a median period of 4.5 (3-6.5) months after the last RTX infusion in patients with RA, and 5 (3-6.5) months in patients with AIDs. 5 patients (12.5%), 4 of them with neutrophils lower than 500/mm(3), developed a non-opportunistic serious infection and required antibiotics and granulocyte colony-stimulating factor injections, with a favourable outcome. After resolution of their RTX-related neutropenia, 19 patients (47.5%) were re-treated, and neutropenia reoccurred in 3 of them. CONCLUSIONS: Late-onset neutropenia might occur after RTX and may result in serious infections. Thus, monitoring of white cell count should be performed after RTX. However, in this large registry of patients with AIDs, the frequency of RTX-induced neutropenia was much lower than that previously reported in patients treated for blood malignancies or AIDs.

[Subcutaneous nodules of the head and neck heralding giant cell arteritis]. / Nodules sous-cutanés cervico-céphaliques précédant l'apparition d'une artérite à cellules géantes.

BACKGROUND: Giant cell arteritis is the most common form of systemic vasculitis affecting individuals aged over 50 years. While its clinical manifestations are numerous, cutaneous involvement is uncommon and rarely constitutes the initial sign. We discuss a case of atypical skin involvement as the initial symptom of giant cell arteritis. OBSERVATION: An 86-year-old woman presented purplish and painful subcutaneous nodules on the scalp and neck. Biological explorations showed systemic inflammation. The skin biopsy was evocative of polyarteritis nodosa. The nodules spontaneously disappeared completely, and asthenia and bitemporal headache gradually appeared. In view of the persistent inflammatory syndrome, a diagnosis of giant cell arteritis was proposed and was later confirmed by the temporal artery biopsy sample, with its typical histological appearance. Systemic corticosteroids resulted in complete regression of symptoms within a few days. DISCUSSION: To our knowledge, inflammatory cervical subcutaneous nodules have never been described in giant cell arteritis. The case we report herein thus raises the issue of differential diagnosis between various forms of vasculitis. While classification of the latter continues to progress thanks to improvements in physiopathological knowledge, the distinction between vasculitis of the large and small vessels remains tenuous on occasion. We discuss the differential diagnoses. CONCLUSION: The dermatological presentation of giant cell arteritis in the present case suggests the existence of a continuum between small-, medium- and large-vessel vasculitis.

A novel phosphorylation-dependent RNase activity of GAP-SH3 binding protein: a potential link between signal transduction and RNA stability.

A potential p120 GTPase-activating protein (RasGAP) effector, G3BP (RasGAP Src homology 3 [SH3] binding protein), was previously identified based on its ability to bind the SH3 domain of RasGAP. Here we show that G3BP colocalizes and physically interacts with RasGAP at the plasma membrane of serum-stimulated but not quiescent Chinese hamster lung fibroblasts. In quiescent cells, G3BP was hyperphosphorylated on serine residues, and this modification was essential for its activity. Indeed, G3BP harbors a phosphorylation-dependent RNase activity which specifically cleaves the 3'-untranslated region of human c-myc mRNA. The endoribonuclease activity of G3BP can initiate mRNA degradation and therefore represents a link between a RasGAP-mediated signaling pathway and RNA turnover.

Sam68 is a Ras-GAP-associated protein in mitosis.

Sam68 is the major tyrosine-phosphorylated and Src-associated protein in mitotic cells. Sam68 stimulates G1/S transition and this effect is dependent on the integrity of its KH domain (hnRNPK Homology) which confers nucleic acid binding properties. During mitosis, Sam68 undergoes tyrosine phosphorylation, which negatively regulates its nucleic acid binding properties and mediates the interaction of Sam68 with critical SH2-containing signaling proteins such as Grb2, PLC gamma 1 and Ras-GAP. However, the interaction of Ras-GAP with Sam68 has been brought into question, based on the lack of co-immunoprecipitation between Sam68 and Ras-GAP in interphase cells. Here we show that the choice of anti-Ras-GAP antibodies is critical for the detection of Ras-GAP/Sam68 complex formation, and that this interaction is specific for G2/M transition in both NIH3T3 and Src-transformed cells. Such data reinforce the importance of the interaction of Ras-GAP with RNA binding proteins during cell proliferation through its SH2 and SH3 domains.

Ras-GTPase activating protein (GAP): a putative effector for Ras.

One attractive candidate for a Ras effector protein, other than the Raf kinases, is Ras-GAP. Indeed, recent literature suggests that besides the Raf/MAP kinase cascade, additional pathways must be stimulated to elicit a full biological response to Ras. Ras binds the COOH terminal domain of Ras-GAP, while the NH2 terminal domain appears to be essential for triggering downstream signals. Since Ras-GAP itself has no obvious enzymatic function that might explain a role in processes associated with proliferation, differentiation or apoptosis, candidates for downstream Ras-GAP effectors that fulfill this role remain to be identified. The newly found GAP-SH3 domain Binding Protein (G3BP) may be one of these. This review will briefly overview the candidates Ras effectors and discuss the results that position Ras-GAP as a critical effector downstream of Ras.

A role for Sam68 in cell cycle progression antagonized by a spliced variant within the KH domain.

Sam68 is the main tyrosine-phosphorylated and Src-associated protein in mitotic cells. Sam68 exhibits a conserved functional KH (hnRNPK homology) RNA binding domain and binds single strand nucleic acids. Tyrosine phosphorylation mediates the interaction of Sam68 with many SH3- and SH2-containing proteins and negatively regulates its nucleic acid binding properties. But the function and the impact of Sam68 on cell signaling and cell proliferation remains elusive. We report here the identification of a natural isoform of Sam68 with a deletion within the KH domain. This isoform, called Sam68DeltaKH, is specifically expressed at growth arrest upon confluency in normal cells. In cells that do not enter quiescence at confluency such as Src-transformed cells, no recruitment of Sam68DeltaKH is observed. Transfected Sam68DeltaKH inhibits serum-induced DNA synthesis and cyclin D1 expression. Sam68 overcomes these effects, suggesting that isoforms of Sam68 are involved, through KH domain signaling, in cell proliferation, and more precisely in G1/S transition.

A Ras-GTPase-activating protein SH3-domain-binding protein.

We report the purification of a Ras-GTPase-activating protein (GAP)-binding protein, G3BP, a ubiquitously expressed cytosolic 68-kDa protein that coimmunoprecipitates with GAP. G3BP physically associates with the SH3 domain of GAP, which previously had been shown to be essential for Ras signaling. The G3BP cDNA revealed that G3BP is a novel 466-amino-acid protein that shares several features with heterogeneous nuclear RNA-binding proteins, including ribonucleoprotein (RNP) motifs RNP1 and RNP2, an RG-rich domain, and acidic sequences. Recombinant G3BP binds effectively to the GAP SH3 domain G3BP coimmunoprecipitates with GAP only when cells are in a proliferating state, suggesting a recruitment of a GAP-G3BP complex when Ras is in its activated conformation.

[Long-term left atrial stimulation by transesophageal approach in complicated biventricular infarction]. / Stimulation auriculaire gauche de longue durée par voie transoesophagienne au cours d'un infarctus biventriculaire compliqué.

The authors report the value of transoesophageal pacing in a 50 year old patient with acute biventricular infarction and cardiogenic shock who developed sinus node dysfunction, junctional rhythm and retrograde atrial activation. This mode of pacing was used permanently for a 48 hour period at a rate of 80/min (atrial capture with a pacing potential of 12 volts and an impulse duration of 12 ms). The clinical results were spectacular and the procedure was well tolerated. This technique can be instituted at the bedside and should be considered in selected cases of sinus node dysfunction when endocavitary pacing is not possible.

[Interauricular communications of the secundum type. Echocardiographic follow-up of the surgical correction]. / Communications interauriculaires de type secundum. Suivi échocardiographique de la correction chirurgicale.

A retrospective study was conducted on the pre- and post-operative electrocardiographic findings in 31 patients aged between 2 and 19 years who were operated for a secundum type of interventricular defect over a period of two years. Immediately after the surgical correction, the left ventricle dilates and returns to a normal size. The right ventricle gradually decreases in size and continues to decrease as the child grows, until a normal size is reached. However, the septum may continue to present abnormal movements despite the return to normal of the ventricular cavities. An alteration in this normal progression involving a RVd/LVd ratio greater than 1 and a RVd/RVd + LVd ratio identical to the pre-operative conditions is suggestive of a persistent shunt, despite the attempted surgical correction.

[Paroxysmal junctional reciprocal tachycardia and fetoplacental anasarca]. / Tachycardie réciproque jonctionnelle paroxystique et anasarque foeto-placentaire.

Foeto-placental anasarca was diagnosed at 34 weeks gestation in a patient with acute hydramnios. Foetal tachycardia at 300 bpm was recorded. This obstetrical problem led to the birth of a premature baby with generalised oedema, for which the only apparent cause was the tachycardia. This was identified as a paroxysmal junctional reciprocating tachycardia, initiating on atrial extrasystolic echos, terminating on R waves, with lengthening of the PR interval at the onset of tachycardia, without acceleration of the sinus rate and P'R = RP'. Paroxysmal junctional reciprocating tachycardia in utero was responsible for congestive cardiac failure and foeto-placental anasarca. The cardiac failure was treated by foetal delivery, artificial respiration and digoxin. The association of digoxin-disopyramide reduces the frequency of attacks of tachycardia and treatment may be stopped after one year's follow-up.