Group A Streptococcus (GAS) has acquired an arsenal of virulence factors, promoting life-threatening invasive infections such as necrotizing fasciitis. Current therapeutic regimens for necrotizing fasciitis include surgical debridement and treatment with cell wall-active antibiotics. Addition of clindamycin (CLI) is recommended, although clinical evidence is lacking. Reflecting the current clinical dilemma, an observational study showed that only 63% of the patients with severe invasive GAS infection received CLI. This work thus aimed to address whether CLI improves necrotizing fasciitis outcome by modulating virulence factors of CLI-susceptible and CLI-resistant GAS in vitro and in vivo. Treatment with CLI reduced extracellular DNase Sda1 and streptolysin O (SLO) activity in vivo, whereas subinhibitory CLI concentrations induced expression and activity of SLO, DNase, and Streptococcus pyogenes cell envelope protease in vitro. Our in vivo results suggest that CLI should be administered as soon as possible to patients with necrotizing fasciitis, while our in vitro studies emphasize that a high dosage of CLI is essential.

Background: Natalizumab, a humanized monoclonal antibody raised against ␣ 4 integrins, is approved for treatment of active relapsing-remitting multiple sclerosis (RRMS) in adult patients. Objective: To determine the safety, effectiveness, and tolerability of natalizumab use in pediatric patients with MS.

Group A Streptococcus (GAS) is a human pathogen causing a wide range of mild to severe and life-threatening diseases. The GAS M1 protein is a major virulence factor promoting GAS invasiveness and resistance to host innate immune clearance. M1 displays an irregular coiled-coil structure, including the B-repeats that bind fibrinogen. Previously, we found that B-repeat stabilisation generates an idealised version of M1 (M1*) characterised by decreased fibrinogen binding in vitro. To extend these findings based on a soluble truncated version of M1, we now studied the importance of the B-repeat coiled-coil irregularities in full length M1 and M1* expressed in live GAS and tested whether the modulation of M1–fibrinogen interactions would open up novel therapeutic approaches. We found that altering either the M1 structure on the GAS cell surface or removing its target host protein fibrinogen blunted GAS virulence. GAS expressing M1* showed an impaired ability to adhere to and to invade human endothelial cells, was more readily killed by whole blood or neutrophils and most importantly was less virulent in a murine necrotising fasciitis model. M1-mediated virulence of wild-type GAS was strictly dependent on the presence and concentration of fibrinogen complementing our finding that M1–fibrinogen interactions are crucial for GAS virulence. Consistently blocking M1–fibrinogen interactions by fragment D reduced GAS virulence in vitro and in vivo. This supports our conclusion that M1–fibrinogen interactions are crucial for GAS virulence and that interference may open up novel complementary treatment options for GAS infections caused by the leading invasive GAS strain M1.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-013-1012-6) contains supplementary material, which is available to authorized users.

Antithrombotic activity, necessary doses and effects on coagulation and lipid variables of the low molecular weight heparin derivative Fragmin were compared to unfractionated (UF) heparin in long-term multicentre trials. Results of more than 10,000 dialyses are reported. On the basis of preliminary studies, UF heparin and Fragmin doses were used that lead to anti-Xa activities of more than 0.5 U/ml. With this dose, sufficient antithrombotic activity was achieved with both heparins. Bleeding complications were not noticed. Partial thromboplastin time (PTT) and thrombin time were only marginally increased by Fragmin (5–8 s) in contrast to UF heparin (PTT 90–120 s, thrombin time 230–260 s). Surprisingly, the elevated levels of factor VIII strongly decreased during the 6-month treatment period with Fragmin and increased again during the following 6-month treatment period with UF heparin. Creatinine, urea, haemoglobin and transaminases did not change in both heparin groups: this excluded reduced dialysis efficiency or occult blood loss. Additionally, 15 patients with acute renal failure and high bleeding risk were dialysed with low doses of Fragmin (anti-FXa: 0.2–0.3 U/ml). No severe bleeding occurred. A continuous ambulant peritoneal dialysis patient with deep vein thrombosis was treated effectively with intraperitoneal application of Fragmin for 6 months without any problems.

The clear reduction in disease severity in IVIG-treated mice and inhibition of virulence factor activity in mouse and human sera suggest that IVIG may be beneficial in invasive group A Streptococcus infections such as NF in addition to streptococcal toxic shock syndrome.

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The incidence of spontaneously occurring tumors of the cervix and vagina was unusually high in an inbred strain of Brown Norway rats (BN/Bi). Fifty-four tumors were diagnosed in the cervixes or vaginas of 252 rats. Of the tumors, 7 were squamous cell carcinomas, 4 were leiomyomas, and the rest were sarcomas. These tumors were found in nearly 20% of all female rats that died naturally.