IL-13 enhances agonist-evoked calcium signals and contractile responses in airway smooth muscle

Growing evidence suggests that interleukin (IL)-13, a Th2-type cytokine, plays a critical role in the development of bronchial hyper-responsiveness (BHR), an essential feature of asthma, although the underlying mechanisms remain unknown. In the present study, we investigated whether IL-13 directly affects airway smooth muscle (ASM) function. In murine tracheal rings, IL-13 (100 ng ml-1, 24 h) significantly increased both the carbachol- and KCl-induced maximal force generation without affecting ASM sensitivity. In cultured human ASM cells, IL-13 (50 ng ml-1, 24 h) also augmented cytosolic calcium levels to bradykinin, histamine and carbachol by 60, 35 and 26%, respectively. The present study demonstrates that IL-13 may promote BHR by directly modulating ASM contractility, an effect that may be due to enhanced G protein-coupled receptor (GPCR)-associated calcium signaling.     

Treatment of ruptured intracranial aneurysms since the International Subarachnoid Aneurysm Trial: practice utilizing clip ligation and coil embolization as individual or complementary therapies

OBJECT: The aim of this study was to analyze the therapeutic decision-making process and outcome in 100 consecutive patients with aneurysmal subarachnoid hemorrhage (SAH) treated since the completion of the International Subarachnoid Aneurysm Trial (ISAT). All patients were evaluated and treated by a neurosurgeon with subspecialty training in both cerebrovascular and neuroendovascular surgery. METHODS: One hundred consecutive patients with aneurysmal SAH who had been admitted within 1 week posthemorrhage and who had been treated using either surgical clip application or endovascular coil embolization were included in this analysis. All patients underwent a uniform perioperative protocol. All surviving patients were given a questionnaire to assess their modified Rankin Scale score (mRS) and to grade themselves at 6 months and 1 year postintervention. The cohort consisted of 73 women and 27 men with a mean age of 57.27 years (range 27-87 years). Twenty-nine percent of the patients had a World Federation of Neurosurgical Societies (WFNS) Grade IV or V SAH. Forty-seven patients underwent direct surgical clip application, 41 endovascular embolization, and 12 a combination of the two procedures. Good functional outcome--indicated by mRS scores of 0 to 2 after at least 6 months--was achieved in 71% of patients. CONCLUSIONS: Data from the ISAT demonstrated a better functional outcome following endovascular embolization in a selected group of patients with aneurysmal SAH. In routine clinical practice, however, a significant number of patients still benefit from direct surgical clip ligation. Excellent functional results can be realized in a complementary clip ligation and coil occlusion practice in which each patient and aneurysm is evaluated and the two treatment modalities are used individually or, when needed, in combination.     

Evolution of a fatal septic arthritis caused by a Panton-Valentine leukocidin (PVL)-producing Staphylococcus aureus strain

We report the observation of a septic arthritis of the knee complicated within first 36 hours by multiorgan failure including acute respiratory distress syndrome (ARDS), heart failure, acute renal failure and disseminated intravascular coagulation (DIC). A diagnosis of staphylococcal arthritis was suspected confirmed by direct examination, and culture showed a Staphylococcus aureus sensitive to methicillin. The sample sent to the National Reference Centre for Staphylococci (Lyon, France) for genetic analysis confirmed the isolate positive for the PVL gene expression. The fulminating evolution of a septic S. aureus arthritis in an otherwise healthy man should probably evoke the possibility of LPV strain. Anti-PLV antibiotics with anti-staphylococcal activity, such as clindamycin and linezolid should be started without waiting for typing of the S. aureus strain.     

Fludarabine and melphalan-based conditioning for patients with advanced hematological malignancies relapsing after a previous hematopoietic stem cell transplant

Severe regimen-related toxicity often complicates second transplant procedures performed in patients with hematological malignancies that have relapsed after an initial hematopoietic stem cell (HSC) transplant. Therefore, we studied the safety and efficacy of a reduced-intensity fludarabine and melphalan based conditioning regimen in 11 patients who had relapsed following an autologous (n = 7) or allogeneic (n = 4) HSC transplant. All patients received allogeneic peripheral blood HSC from either an HLA-identical (n = 7) or an HLA-mismatched (n = 4) relative. Diagnoses included AML (n = 9), ALL (n = 1), or Hodgkin's disease (n = 1). Only one patient was in complete remission at the time of second transplant. The median interval between first transplant and relapse was 163 days (range 58-1885). Recipients of HLA-mismatched transplants received antithymocyte globulin in addition to fludarabine and melphalan as part of the conditioning regimen. All 11 patients received acute GVHD prophylaxis consisting of tacrolimus and methotrexate. Ten of 11 patients achieved hematopoietic engraftment with a median time to absolute neutrophil count >0.5 x 10(9)/l and to platelet count of >20 x 10(9)/l of 14 and 19 days, respectively. All engrafting patients achieved 100% donor chimerism on initial analysis, except for one with persistent leukemia at day +19. Two patients experienced grade 3 regimen-related toxicity, manifesting as acute renal failure. Acute GVHD grades 2-4 occurred in two recipients and chronic GVHD in four. The 100-day mortality from all causes was 36%. Ten of 11 patients (91%) died a median of 140 days (range 9-996) after the second transplant. The causes of death included relapse (n = 5), sepsis (n = 4), and idiopathic pneumonia syndrome (n = 1). One patient with AML survives in remission at 880 days post-transplant. We conclude that fludarabine- and melphalan-based conditioning promotes full donor chimerism, even following HLA-mismatched transplants. However, the regimen may be more beneficial when applied to patients undergoing allogeneic HSC transplantation earlier in their disease course.