Antigen-positive platelet transfusion in neonatal alloimmune thrombocytopenia (NAIT)

Neonatal alloimmune thrombocytopenia (NAIT) is a fetomaternal incompatibility most commonly induced by maternal anti-HPA-1a, IgG alloantibodies against a polymorphic epitope of the glycoprotein IIb/IIIa complex in approximately 97.5% of white patients. Current guidelines recommend transfusion of immunologically compatible platelets to prevent cerebral hemorrhage, the most severe complication in affected newborns. Such platelet concentrates, however, are often not readily available. In a retrospective analysis in German and Canadian centers, 27 newborns with NAIT were identified who received platelets from random donors. Unexpectedly, 24 of 27 newborns showed an increase above a threshold of 40 x 10(9) platelets per liter, with moderate (n = 8) or significant (n = 16) platelet count increments (more than 80 x 10(9)/L). We conclude that transfusion of platelet concentrates from random donors is an appropriate strategy in the management of unexpected, severe NAIT predominantly in first pregnancies, pending the availability of compatible platelets.     

Activation of p38 MAPK is a key step in tumor necrosis factor-mediated inflammatory bone destruction

OBJECTIVE: To investigate whether activation of p38 MAPK is a crucial signaling factor in inflammatory bone destruction mediated by tumor necrosis factor (TNF). Mice overexpressing TNF were treated with 2 different inhibitors of p38 MAPK, and the effect of this treatment on joint inflammation and structural damage was assessed. METHODS: Human TNF-transgenic mice received systemic treatment with 2 different p38 MAPK inhibitors (RO4399247 and AVE8677). Treatment was started at the time of symptom onset and lasted for 6 weeks. Mice were assessed for clinical signs of arthritis, bone erosion, and cartilage damage. In addition, the effect of these inhibitors on osteoclast generation in vitro and in vivo was assessed. RESULTS: Both p38 MAPK inhibitors significantly reduced clinical signs of TNF-mediated arthritis. This was attributable to reducing synovial inflammation by 50% without affecting the cellular composition of the infiltrate. Synovial expression of interleukin-1 and RANKL was reduced upon p38 MAPK blockade, and activation of the molecular target MAPK-activated protein kinase 2 (MAPKAP-2) was also inhibited. Proteoglycan loss of articular cartilage was reduced by 50%, although p38 MAPK inhibition did not change matrix molecule synthesis by cultivated chondrocytes. Importantly, bone loss was almost completely prevented by p38 MAPK inhibition. The numbers of synovial osteoclasts and precursors were dramatically reduced, and both p38 MAPK inhibitors also inhibited in vitro osteoclastogenesis at micromolar concentrations and blocked activation of MAPKAP-2 as well as differentiation markers in cultured osteoclast precursors. CONCLUSION: These results suggest the major importance of p38 MAPK for TNF-mediated inflammatory bone destruction in arthritis and suggest that inhibition of p38 MAPK might be an important tool for reducing structural damage in rheumatoid arthritis.     

Cachexia in chronic heart failure: Prognostic implications and novel therapeutic approaches

Cachexia in patients with chronic heart failure (CHF) has been recognized for a long time; however, it has not received much attention until recently. Cardiac cachexia, a common and serious complication of CHF, is associated with very poor prognosis. Several studies have demonstrated that increased neurohormonal and immune abnormalities may play a crucial role in the pathophysiology of cardiac cachexia. Hormonal and catabolic/anabolic imbalances of the body are likely to be responsible for the development of cachexia in CHF. Recently, ghrelin, a novel growth hormone-releasing peptide, has been widely noticed to have potential in the treatment of severe CHF and cardiac cachexia. However, further research will be necessary to identify the exact pathways involved and to find the best therapeutic strategies of using ghrelin to fight the wasting process.     

Fosmidomycin-clindamycin for Plasmodium falciparum Infections in African children

BACKGROUND: Fosmidomycin is a new antimalarial drug with a novel mechanism of action. Studies in Africa that have evaluated fosmidomycin as monotherapeutic agent demonstrated its excellent tolerance, but 3-times-daily treatment regimens of >or=4 days were required to achieve radical cure, prompting further research to identify and validate a suitable combination partner to enhance its efficacy. METHODS: We conducted a randomized, controlled, open-label study to evaluate the efficacy and safety of fosmidomycin combined with clindamycin (n=12; 30 and 5 mg/kg body weight every 12 h for 5 days, respectively), compared with fosmidomycin alone (n=12; 30 mg/kg body weight every 12 h for 5 days) and clindamycin alone (n=12; 5 mg/kg body weight every 12 h for 5 days) for the clearance of asymptomatic Plasmodium falciparum infections in schoolchildren in Gabon aged 7-14 years. RESULTS: Asexual parasites were rapidly cleared in children treated with fosmidomycin-clindamycin (median time, 18 h) and fosmidomycin alone (25 h) but slowly in children treated with clindamycin alone (71 h; P=.004). However, only treatment with fosmidomycin-clindamycin or clindamycin alone led to the radical elimination of asexual parasites as measured by day 14 and 28 cure rates of 100%. Asexual parasites reappeared by day 28 in 7 children who received fosmidomycin (day 14 cure rate, 92% [11/12; day 28 cure rate, 42% [5/12]). All regimens were well tolerated, and no serious adverse events occurred. CONCLUSION: The combination of fosmidomycin and clindamycin is well tolerated and superior to either agent on its own with respect to the rapid and radical clearance of P. falciparum infections in African children.     

RETRACTED ARTICLE: Noninvasive assessment of cardiac output using thoracic electrical bioimpedance in hemodynamically stable and unstable patients after cardiac surgery: a comparison with pulmonary artery thermodilution

Objective To compare noninvasive cardiac output (CO)measurement obtained with a new thoracic electrical bioimpedance (TEB) device, using a proprietary modification of the impedance equation, with invasive measurement obtained via pulmonary artery thermodilution.Design Prospective, observational study.Setting Surgical intensive care unit (ICU) of a university-affiliated community hospital.Patients and participants Seventy-four adult patients undergoing elective cardiac surgery with routine pulmonary artery catheter placement.Interventions None.Measurements and results Simultaneous paired CO and cardiac index (CI) measurements by TEB and thermodilution were obtained in mechanically ventilated patients upon admission to the ICU. For analysis of CI data the patients were subdivided into a hemodynamically stable group and a hemodynamically unstable group. The groups were analyzed using linear regression and tests of bias and precision. We found a significant correlation between thermodilution and TEB (r = 0.83; n< 0.001), accompanied by a bias of –0.01 l/min/m² and a precision of ±0.57 l/min/m² for all CI data pairs. Correlation, bias, and precision were not influenced by stratification of the data. The correlation coefficient, bias, and precision for CI were 0.86 (n< 0.001), 0.03 l/min/m², and ±0.47 l/min/m² in hemodynamically stable patients and 0.79 (n< 0.001), 0.06 l/min/m², and ±0.68 l/min/m² in hemodynamically unstable patients.Conclusions Our results demonstrate a close correlation and clinically acceptable agreement and precision between CO measurements obtained with impedance cardiography using a new algorithm to calculate CO from variations in TEB, and those obtained with the clinical standard of care, pulmonary artery thermodilution, in hemodynamically stable and unstable patients after cardiac surgery.     

Rosuvastatin regulates vascular smooth muscle cell phenotypic modulation in vascular remodeling: role for the urokinase receptor

The urokinase (uPA)/urokinase receptor (uPAR) multifunctional system is an important mediator of migration and proliferation of vascular smooth muscle cells (VSMC). However, whether uPA/uPAR-directed mechanisms are involved in the beneficial effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on vascular remodeling remains unexplored. In this study, we have investigated the effect of the hydrophilic statin rosuvastatin on neointimal remodeling, and the role of uPAR. Using an ex vivo organ and in vitro cell culture models we demonstrate that rosuvastatin decreases injury-induced neointima formation and proliferation of medial VSMC in porcine coronary arteries, as well as migration and proliferation of human coronary VSMC. Studies on the underlying mechanisms show that rosuvastatin impairs VSMC transition from their physiological contractile to the pathophysiological synthetic phenotype. These effects are mediated, at least in part, via uPAR, as confirmed by means of rosuvastatin-directed uPAR expression and uPAR silencing in both models. Our findings provide evidence that rosuvastatin modulates VSMC phenotypic changes and subsequently their proliferation and migration, and indicate the important role for uPAR in these processes. This mechanism contributes to the beneficial non-lipid lowering effect of rosuvastatin on negative vascular remodeling.     

Evaluation of the MLH1 I219V alteration in DNA mismatch repair activity and ulcerative colitis

BACKGROUND: Inflammatory bowel diseases (IBDs; ulcerative colitis, UC, and Crohn's disease, CD) show familial clustering suggestive of a genetic background. A linkage susceptibility region for these diseases (IBD9) lies on chromosome 3p and includes the DNA mismatch repair gene MLH1. Loss of MLH1 confers the characteristic microsatellite instability (MSI) phenotype which is also frequently found in the mucosa of IBD patients. A common germline alteration of MLH1 (655A>G) results in the amino acid exchange MLH1 I219V. Conflicting data exist on its effect on the function of the protein and it has recently been reported to cosegregate with refractory UC, suggesting that this alteration may impair mismatch repair activity and thereby contribute to certain forms of UC. METHODS: We analyzed the MLH1 I219V alteration using in silico and biochemical analyses and assessed its appearance in 67 well-classified UC patients in comparison to 40 healthy individuals. RESULTS: The analyses showed that I219 is a conserved, buried hydrophobic residue, and that I219V is unlikely to abolish MLH1 function but may modulate it. Quantitative biochemical evaluation showed identical stability and activity of the protein. Furthermore, the alteration occurred equally frequently in analyzed patients and healthy volunteers. CONCLUSIONS: The MLH1 I219V alteration does not directly contribute to the etiology of UC through an impairment of mismatch repair. A putative linkage disequilibrium of MLH1 I219V with the causative gene(s) of the IBD9 locus is rather distant.     

Prognostic relevance of dic(9;20)(p11;q13) in childhood B‐cell precursor acute lymphoblastic leukaemia treated with Berlin‐Frankfurt‐Münster (BFM) protocols containing an intensive induction and post‐induction consolidation therapy

The presence of a dicentric chromosome dic(9;20) has been reported to have an unfavourable prognosis in children with B‐cell precursor acute lymphoblastic leukaemia (BCP‐ALL). As outcome may be influenced by type and composition of treatment, we analyzed 19 BCP‐ALL patients with dic(9;20) who have been treated with ALL‐BFM (Berlin‐Frankfurt‐Münster) protocols that included a 4‐drug induction and subsequent consolidation therapy. All patients were good responders to prednisone and in complete remission after induction therapy. Eight patients had no molecular disease after induction and another eight patients had levels ≤10^?4 after consolidation therapy. After a median follow‐up of 3·4 years, probabilities of 5‐year event‐free and overall survival were 75 ± 11% and 94 ± 6%, respectively. Of note, there was a tendency for extramedullary disease in case of relapse (two of three relapses with central nervous system involvement). In conclusion, in the context of ALL‐BFM protocols dic(9;20)‐positivity appeared to have a favourable prognosis, which could be due to a dose‐ and time‐intensified induction and induction consolidation therapy. Given that in vitro studies have shown high cellular sensitivity of dic(9;20)‐positive leukemic blasts to l ‐asparaginase and cytarabine, it is reasonable to speculate that both drugs, as given early during BFM‐like induction and consolidation therapy, may have contributed to this good outcome.