Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo

Fragment-based design was used to guide derivatization of a lead series of β-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a K_i of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with β-lactamase-expressing Escherichia coli, 65% were cleared of infection when treated with a cefotaxime:5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome β-lactamase-based resistance, a key clinical challenge.     

Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey

Data on the clinical spectrum and therapeutic management of noninfectious mixed cryoglobulinemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. We analyzed data from 242 patients with noninfectious mixed CryoVas included in the French multicenter CryoVas survey. Baseline manifestations were purpura (75%), peripheral neuropathy (52%), arthralgia or arthritis (44%), glomerulonephritis (35%), cutaneous ulcers (16%), and cutaneous necrosis (14%). A connective tissue disease was diagnosed in 30% and B-cell non-Hodgkin lymphoma in 22%, whereas the CryoVas was considered to be essential in 48%. With the use of Cox-marginal structural models, rituximab plus corticosteroids showed the greater therapeutic efficacy compared with corticosteroids alone and alkylating agents plus corticosteroids to achieve complete clinical, renal, and immunologic responses and a prednisone dosage < 10 mg/d at 6 months. However, this regimen was also associated with severe infections, particularly when high doses of corticosteroids were used, whereas death rates did not differ between the therapeutic regimens. The role of each of these strategies remains to be defined in well-designed randomized controlled trials.     

Autophagy is required for CSF-1-induced macrophagic differentiation and acquisition of phagocytic functions

Autophagy is the process by which superfluous or damaged macromolecules or organelles are degraded by the lysosome. Pharmacologic and genetic evidence indicates that autophagy plays pleiotropic functions in cellular homeostasis, development, survival, and differentiation. The differentiation of human blood monocytes into macrophages is a caspase-dependent process when triggered ex vivo by colony stimulating factor-1. We show here, using pharmacologic inhibitors, siRNA approaches, and Atg7-/- mice, that autophagy initiated by ULK1 is required for proper colony stimulating factor-1-driven differentiation of human and murine monocytes. We also unravel a role for autophagy in macrophage acquisition of phagocytic functions. Collectively, these findings highlight an unexpected and essential role of autophagy during monocyte differentiation and acquisition of macrophage functions.     

Effects of growth on maxillary distraction osteogenesis in cleft lip and palate

PurposeThe objective was to analyze the effects of growth on the long-term result of maxillary distraction osteogenesis (DO) in cleft lip and palate (CLP).Patients and methodsRetrospective study of 24 CLP cases with long-term follow-up operated for maxillary DO using the Polley and Figueroa technique: 10 patients were distracted during growth, while 14 patients were operated after their growth spurt. Preoperative (T0), 6–12 months postoperative (T1), and ≥4 years postoperative (T2) cephalometric radiographs were evaluated. A classical cephalometric analysis was used to assess the treatment stability, and a Procrustes superimposition method was performed to assess local changes in the maxilla and the mandible.ResultsAt T0, the mean age was of 11.9 ± 1.4 years for growing patient, and 17.9 ± 3.5 years for patient treated after their growth spurt (P < 0.001). Between T0 and T1, a greater increase of the SNA was shown in growing patients (P = 0.036), but the relapse was more important between T1 and T2, with a significant decrease of the SNA (P = 0.002) and ANB (P = 0.032) compared to the patients treated after their growth spurt. Although not significant, growing patients showed greater rotations of their palatal plane and mandibular plane.ConclusionsMaxillary DO in CLP does not correct the growth deficit inherent to the pathology. Overcorrection of at least 20% is advised during growth.     

Hypoxaemic rescue therapies in acute respiratory distress syndrome: Why,when, what and which one?

Acute respiratory distress syndrome (ARDS) is an inflammatory condition of the lungs which can result in refractory and life-threatening hypoxaemic respiratory failure. The risk factors for the development of ARDS are many but include trauma, multiple blood transfusions, burns and major surgery, therefore this condition is not uncommon in the severely injured patient. When ARDS is severe, high-inspired oxygen concentrations are frequently required to minimise hypoxaemia. In these situations clinicians commonly utilise interventions termed ‘hypoxaemic rescue therapies’ in an attempt to improve oxygenation, as without these, conventional mechanical ventilation can be associated with high mortality. However, their lack of efficacy on mortality when used prophylactically in generalised ARDS cohorts has resulted in their use being confined to clinical trials and the subset of ARDS patients with refractory hypoxaemia.