Composition and Conformation of Hetero- versus Homo-Fluorinated Triazolamers Influence their Activity on Islet Amyloid Polypeptide Aggregation.

Novel fluorinated foldamers based on aminomethyl-1,4-triazolyl-difluoroacetic acid (1,4-Tz-CF2) units were synthesized and their conformational behaviour was studied by NMR and molecular dynamics. Their activity on the aggregation of the human islet amyloid polypeptide (hIAPP) amyloid protein was evaluated by fluorescence spectroscopy and mass spectrometry. The fluorine labelling of these foldamers allowed the analysis of their interaction with the target protein. We demonstrated that the preferred extended conformation of homotriazolamers of 1,4-Tz-CF2 unit increases the aggregation of hIAPP, while the hairpin-like conformation of more flexible heterotriazolamers containing two 1,4-Tz-CF2 units mixed with natural amino acids from the hIAPP sequence reduces it, and more efficiently than the parent natural peptide. The longer heterotriazolamers having three 1,4-Tz-CF2 units adopting more folded hairpin-like and ladder-like structures similar to short multi-stranded ß-sheets have no effect. This work demonstrates that a good balance between the structuring and flexibility of these foldamers is necessary to allow efficient interaction with the target protein.

Online reaction monitoring by single-scan 2D NMR under flow conditions.

Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for reaction monitoring. Several devices have been recently developed for online monitoring, using flow NMR, of batch reactions carried out under realistic experimental conditions in terms of, e.g., agitation and temperature. Here we show that time series of single-scan ultrafast 2D NMR (UF2DNMR) spectra can be collected to monitor solution mixtures that circulate in a flow unit. Fast multidimensional NMR methods have the demonstrated potential to provide kinetic and mechanistic information on reactions. UF2DNMR makes it possible to collect 2D data sets in less than one second, but relies on spatial encoding (SPEN) that is sensitive to sample motion, thus making online monitoring challenging. We characterize the interference between flow and spatial encoding and provide pulse-sequence- and hardware-based solutions. The resulting method is illustrated with the monitoring of a saponification reaction. UF2DNMR with a flow unit is a promising tool for the online monitoring of organic chemical reactions.

Hematopoietic stem cell transplantation in children with sickle cell anemia: The parents' experience.

Genoidentical HSCT is currently the only curative treatment for SCA, preventing further vascular complications in high-risk children. Studies on the psychological implications of HSCT for recipient, sibling donor, and the rest of the family have been limited in SCA. This study enrolled ten families and used semi-structured interviews to explore the parents' experience at three time points: first before transplantation, then 3 months later, and 1 year later. Three themes emerged from the results: (a) the presence of anxiety, experienced throughout the process, and alleviated by coping strategies (positive thinking, family support, praying); (b) the ability to remain parents to recipient and other family members, despite apprehension and feelings of helplessness, reinforced by the mobilization of important resources at the individual/family levels; (c) the ability to acknowledge the opportunity for their child to be cured of the disease, despite feelings of guilt toward families without a donor, or their own families back home. Overall, the parental experience with HSCT is complex, involving intra-psychic, familial, cultural, religious, and existential factors. Thus, it is important for medical teams to be cognizant of these issues in order to provide the best support to families during the HSCT process.

Familial Transmission of emm12 Group A Streptococcus.

Incidence and severity of invasive group A Streptococcus infections are of increasing concern in France and worldwide. The risk for secondary infection of close contacts is known but rarely described. We report a case of intrafamilial and life-threatening transmission of emm12 group A Streptococcus.

Exploration of the dynamic interplay between lipids and membrane proteins by hydrostatic pressure.

Cell membranes represent a complex and variable medium in time and space of lipids and proteins. Their physico-chemical properties are determined by lipid components which can in turn influence the biological function of membranes. Here, we used hydrostatic pressure to study the close dynamic relationships between lipids and membrane proteins. Experiments on the ß-barrel OmpX and the α-helical BLT2 G Protein-Coupled Receptor in nanodiscs of different lipid compositions reveal conformational landscapes intimately linked to pressure and lipids. Pressure can modify the conformational landscape of the membrane protein per se, but also increases the gelation of lipids, both being monitored simultaneously at high atomic resolution by NMR. Our study also clearly shows that a membrane protein can modulate, at least locally, the fluidity of the bilayer. The strategy proposed herein opens new perspectives to scrutinize the dynamic interplay between membrane proteins and their surrounding lipids.

Fluorinated Triazole Foldamers: Folded or Extended Conformational Preferences.

The Ministère de l'Enseignement Supérieur et de la Recherche (MESR) is thanked for financial support for José Laxio Arenas. The China Scholarship Council is thanked for financial support for Yaochun Xu. The authors thank Pr. Vadim Soloshonok and TOSOH F-TECH, Inc. for the kind gift of N-terbutyl-sulfinylimine.

NMR Characterization of the Influence of Zinc(II) Ions on the Structural and Dynamic Behavior of the New Delhi Metallo-ß-Lactamase-1 and on the Binding with Flavonols as Inhibitors.

New Delhi metallo-ß-lactamase-1 (NDM-1) has recently emerged as a global threat because of its ability to confer resistance to all common ß-lactam antibiotics. Understanding the molecular basis of ß-lactam hydrolysis by NDM is crucial for designing NDM inhibitors or ß-lactams resistant to their hydrolysis. In this study, for the first time, NMR was used to study the influence of Zn(II) ions on the dynamic behavior of NDM-1. Our results highlighted that the binding of Zn(II) in the NDM-1 active site induced several structural and dynamic changes on active site loop 2 (ASL2) and L9 loops and on helix α2. We subsequently studied the interaction of several flavonols: morin, quercetin, and myricetin were identified as natural and specific inhibitors of NDM-1. Quercetin conjugates were also synthesized in an attempt to increase the solubility and bioavailability. Our NMR investigations on NDM-1/flavonol interactions highlighted that both Zn(II) ions and the residues of the NDM-1 ASL1, ASL2, and ASL4 loops are involved in the binding of flavonols. This is the first NMR interaction study of NDM-1/inhibitors, and the models generated using HADDOCK will be useful for the rational design of more active inhibitors, directed against NDM-1.

Under-Age Children Returning From Jihadist Group Operation Areas: How Can We Make a Diagnosis and Construct a Narrative With a Fragmentary Anamnesis?

INTRODUCTION: Since 2011, the French government estimates that about 500 French children have been born in or taken by their parents to areas where terrorist operations prevail. Since May 2017, 75 children who returned to France have benefited from a dedicated health care system. METHOD: This article is the result of clinical interviews conducted with 53 patients evaluated and taken care of at Avicenne Hospital in Bobigny. To our knowledge, no studies have been published on this subject. RESULTS: A total of 32 evaluations have been completed, all of which indicated the need for care for these children. Of these children, 64% are under 5 years old, and 59% were born in France. Their clinical profiles are heterogeneous and fluctuate with time. DISCUSSION: The multiple adverse events experienced by these children and the uniqueness of children born to families suspected by authorities of having participated in activities related to terrorism make this situation unprecedented. How can we make a diagnosis of PTSD without the help of a precise anamnesis? How can we help these children form a structuring narrative that avoids the pitfalls inherent to generalized fascination?

Effect of Cyclosporine in Nonshockable Out-of-Hospital Cardiac Arrest: The CYRUS Randomized Clinical Trial.

IMPORTANCE: Experimental evidence suggests that cyclosporine prevents postcardiac arrest syndrome by attenuating the systemic ischemia reperfusion response. OBJECTIVE: To determine whether early administration of cyclosporine at the time of resuscitation in patients with out-of-hospital cardiac arrest (OHCA) would prevent multiple organ failure. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, single-blind, randomized clinical trial was conducted from June 22, 2010, to March 13, 2013 (Cyclosporine A in Out-of-Hospital Cardiac Arrest Resuscitation [CYRUS]). Sixteen intensive care units in 7 university-affiliated hospitals and 9 general hospitals in France participated. A total of 6758 patients who experienced nonshockable OHCA (ie, asystole or pulseless electrical activity) were assessed for eligibility. Analyses were performed according to the intention-to-treat analysis. INTERVENTIONS: Patients received an intravenous bolus injection of cyclosporine, 2.5 mg/kg, at the onset of advanced cardiovascular life support (cyclosporine group) or no additional intervention (control group). MAIN OUTCOMES AND MEASURES: The primary end point was the Sequential Organ Failure Assessment (SOFA) score, assessed 24 hours after hospital admission, which ranges from 0 to 24 (with higher scores indicating more severe organ failure). Secondary end points included survival at 24 hours, hospital discharge, and favorable neurologic outcome at discharge. RESULTS: Of the 6758 patients screened, 794 were included in intention-to-treat analysis (cyclosporine, 400; control, 394). The median (interquartile range [IQR]) ages were 63.0 (54.0-71.8) years for the cyclosporine group and 66.0 (57.0-74.0) years for the control group. The cohorts included 293 men (73.3%) in the treatment group and 288 men (73.1%) in the control group. At 24 hours after hospital admission, the SOFA score was not significantly different between the cyclosporine (median, 10.0; IQR, 7.0-13.0) and the control (median, 11.0; IQR, 7.0-15.0) groups. Survival was not significantly different between the 98 (24.5%) cyclosporine vs 101 (25.6%) control patients at hospital admission (adjusted odds ratio [aOR], 0.94; 95% CI, 0.66-1.34), at 24 hours for 67 (16.8%) vs 62 (15.7%) patients (aOR, 1.08; 95% CI, 0.71-1.63), and at hospital discharge for 10 (2.5%) vs 5 (1.3%) patients (aOR, 2.00; 95% CI, 0.61-6.52). Favorable neurologic outcome at discharge was comparable between the cyclosporine and control groups: 7 (1.8%) vs 5 (1.3%) patients (aOR, 1.39; 95% CI, 0.39-4.91). CONCLUSION AND RELEVANCE: In patients presenting with nonshockable cardiac rhythm after OHCA, cyclosporine does not prevent early multiple organ failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01595958; EudraCT Identifier: 2009-015725-37.

Results with Kudo elbow prostheses in non-traumatic indications : a study of 36 cases.

With a mean follow-up of 62 months, we reviewed 13 Kudo type 4 and 23 Kudo type 5 elbow prostheses implanted for non-traumatic indications in 30 patients. Clinical results were assessed with the Mayo Clinic Performance Index (MCPI) taking into account pain, mobility, stability and daily activities. Postoperatively, pain disappeared or decreased, ulnar nerve dysfunction was improved and the functional status was significantly improved. The average range of motion increased by 7.8 degrees in extension and by 11.5 degrees in flexion; pronation and supination remained unchanged. Clinically, 89% of patients scored poorly on the MCPI preoperatively, whereas 61% had excellent or good scores postoperatively. Twenty-two patients out of 30 were satisfied. There were two early prosthetic dislocations, and prosthetic instability, assessed clinically, was found in 6 cases (17%). The rate of loosening was 28% (10/36) and seven elbows were revised. Metallosis, loosening and instability were significantly correlated. The survival rate of 82% at 54 months (SD = 7) is lower than that reported for non-constrained and semi-constrained prostheses in the literature.

Improved aero-anaerobe recovery from infected prosthetic joint samples taken from 72 patients and collected intraoperatively in Rosenow's broth.

INTRODUCTION: Recovery of the bacteria responsible for prosthetic joint infections is a major problem, which is due in part to the alteration of their ability to grow by storage during transportation to the laboratory. METHODS: In this prospective study, we assessed the benefit of inoculating an enriched liquid medium (Rosenow's broth) with intraoperative samples from 72 patients with prosthetic joint revision due to infection. We compared the results of culture of specimens collected in a standard receptacle with the results for specimens collected in Rosenow's broth. RESULTS AND INTERPRETATION: 144 samples were taken by each of the 2 collection methods for subsequent culture. Concordance between standard and Rosenow samples was observed for 52 of the 58 strains cultured on agar and for 42 of the 97 strains (p < 0.001) which grew only in liquid medium. Infection would not have been diagnosed in 26 patients (almost one-third of all patients) without combining sample collection in Rosenow's broth with standard collection. The bacteria that were not recovered from standard samples but which were recovered from those collected in Rosenow's broth included not only strict anaerobes, in particular Propionibacterium acnes, but also coagulase-negative staphylococci and streptococci.

Long-term survivorship of hip shelf arthroplasty and Chiari osteotomy in adults.

The current authors retrospectively assessed 56 hip shelf arthroplasties (48 patients) with a mean followup of 17 years (range, 15-30 years) and 89 Chiari osteotomies (82 patients) with a mean followup of 13 years (range, 6-25 years) done in adults with painful hip dysplasia. Preoperative joint space narrowing was observed in 32 of 56 shelf arthroplasties and in 67 of 89 Chiari osteotomies. Survival rates, using hip replacement as the end point, were 37% (20% to 54%) at 20 years for shelf arthroplasty and 68% (54% to 81%) at 18 years for Chiari osteotomy. The severity of preoperative arthrosis was the main factor that impaired the survivorship of shelf arthroplasty and Chiari osteotomy. With arthritic changes without joint space narrowing, the 18-year survival rates were 83% (69% to 97%) for shelf arthroplasty and 94% (89% to 99%) for Chiari osteotomy. Shelf arthroplasty is best indicated for moderate dysplasia (center edge angle >0 degrees) without severe arthrosis. Chiari osteotomy is best suited for severe dysplasia (center edge angle <0 degrees) especially without or with slight arthrosis. Chiari osteotomy also can be a salvage procedure when marked joint space narrowing is present but only if it is related to severe dysplasia (center edge angle <0 degrees).

Cementless metal-on-metal hip arthroplasty in patients less than 50 years of age: comparison with a matched control group using ceramic-on-polyethylene after a minimum 5-year follow-up.

Thirty-nine cementless hip arthroplasties using metal-on-metal articulation were consecutively implanted in 30 patients less than 50 years of age and compared with a matched control group (by age, diagnosis, Devane activity, and Harris hip scores) of cementless arthroplasties using ceramic-on-polyethylene articulation. The Harris hip score at follow-up (minimum 5 years) for the metal-on-metal was 94.9 (range, 74-100). After the same follow-up, the results of the ceramic-on-polyethylene were significantly worse: 9 osteolyses and 7 surgical revisions related to wear (none in the metal-on-metal). Five-year survival rates were 97% +/-2% for the ceramic-on-polyethylene and 100% for the metal-on-metal. The metal-on-metal may be recommended to prevent wear problems in younger and more active patients; however, a longer follow-up is required to confirm this encouraging data.

Risk factors for anaemia in patients on prolonged linezolid therapy for chronic osteomyelitis: a case-control study.

OBJECTIVES: The intrinsic properties of the new antibiotic linezolid make it an attractive candidate for the treatment of chronic osteomyelitis. However, data regarding the tolerance of long-term linezolid administration are still lacking. METHODS: The medical charts of patients given linezolid for >4 weeks were retrospectively analysed, especially their haematology. In a case-control study, we compared the respective characteristics of patients who developed anaemia during linezolid therapy and those who did not. RESULTS: Forty-five adults with chronic osteomyelitis received 600 mg linezolid intravenously twice daily for 7 days, and then orally, for a mean total duration of 15.9 weeks (range, 6-36). Anaemia episodes requiring blood transfusion occurred in 13/45 patients (28.9%). Median time from treatment initiation to anaemia onset was 7.4 weeks (range, 4-16). Anaemia was significantly associated with premature linezolid therapy cessation (P = 0.0012). No linezolid-related thrombocytopenia was observed. By univariate analysis, four variables were associated with the occurrence of anaemia: age >58 years, alcohol abuse, diabetes mellitus and low haemoglobin before linezolid treatment. Logistic regression analysis revealed two independent risk factors for anaemia: age >58 years (OR = 20.5, 95% CI 0.69-599; P = 0.0001) and pre-treatment haemoglobin <10.5 g/dL (OR = 16.49, 95% CI 1.06-255; P = 0.04). CONCLUSIONS: Profound anaemia may occur in adult patients with chronic osteomyelitis on prolonged linezolid therapy, and often necessitates linezolid cessation. These patients are likely to be aged >58 years and to have low pre-treatment haemoglobin. The results for the present series might help physicians to identify patients who should not be given long-term linezolid treatment for chronic osteomyelitis.