Donor to recipient age matching in lung transplantation: A European experience.

BACKGROUND: The age profile of organ donors and patients on lung transplantation (LT) waiting lists have changed over time. In Europe, the donor population has aged much more rapidly than the recipient population, making allocation decisions on lungs from older donors common. In this study we assessed the impact of donor and recipient age discrepancy on LT outcomes in the UK and France. METHODS: A retrospective analysis of all adult single or bilateral LT in France and the UK between 2010 and 2021. Recipients were stratified into 3 age author groups: young (≤30 years), middle-aged (30-60) and older (≥60). Their donors were also stratified into 2 groups <60, ≥60. Primary graft dysfunction (PGD) rates and recipient survival was compared between matched and mismatched donor and recipient age groups. Propensity matching was employed to minimize covariate imbalances and to improve the internal validity of our results. RESULTS: Our study cohort was 4,696 lung transplant recipients (LTRs). In young and older LTRs, there was no significant difference in 1 and 5-year post-transplant survival dependent on the age category of the donor. Young LTRs who received older donor grafts had a higher risk of severe grade 3 PGD. CONCLUSION: Our findings show that clinically usable organs from older donors can be utilized safely in LT, even for younger recipients. Further research is needed to assess if the higher rate of PGD3 associated with use of older donors has an effect on long-term outcomes.

[Chronic lung allograft dysfunction in 2022, past and updates]. / La dysfonction chronique du greffon pulmonaire en 2022 : une entité mieux comprise et un défi thérapeutique.

INTRODUCTION: While short-term results of lung transplantation have improved considerably, long-term survival remains below that achieved for other solid organ transplants. CURRENT KNOWLEDGE: The main cause of late mortality is chronic lung allograft dysfunction (CLAD), which affects nearly half of the recipients 5 years after transplantation. Immunological and non-immune risk factors have been identified. These factors activate the innate and adaptive immune system, leading to lesional and altered wound-healing processes, which result in fibrosis affecting the small airways or interstitial tissue. Several phenotypes of CLAD have been identified based on respiratory function and imaging pattern. Aside from retransplantation, which is possible for only small number of patients, no treatment can reverse the CLAD process. PERSPECTIVES: Current therapeutic research is focused on anti-fibrotic treatments and photopheresis. Basic research has identified numerous biomarkers that could prove to be relevant as therapeutic targets. CONCLUSION: While the pathophysiological mechanisms of CLAD are better understood than before, a major therapeutic challenge remains.

[Updated indications and contraindications in 2022 for lung transplantation in France]. / Transplantation pulmonaire en France : actualisation des indications et contre-indications en 2022.

Lung transplantation (LTx) is the last-resort treatment for end-stage respiratory insufficiency, whatever its origin, and represents a steadily expanding field of endeavor. Major developments have been impelled over the years by painstaking efforts at LTx centers to improve donor and recipient selection, and multifaceted attempts have been made to meet the challenges raised by surgical management, perioperative care, and long-term medical complications. The number of procedures has increased, leading to improved post-LTx prognosis. One consequence of these multiple developments has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. With these considerations in mind, the Francophone Pulmonology Society (Société de Pneumology de Langue Française [SPLF]) has set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force has examined the most recent literature and evaluated the risk factors that continue to limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

TLR3 promotes MMP-9 production in primary human airway epithelial cells through Wnt/ß-catenin signaling.

BACKGROUND: Airway epithelial cells (AEC) act as the first line of defence in case of lung infections. They constitute a physical barrier against pathogens and they participate in the initiation of the immune response. Yet, the modalities of pathogen recognition by AEC and the consequences on the epithelial barrier remain poorly documented. METHOD: We investigated the response of primary human AEC to viral (polyinosinic-polycytidylic acid, poly(I:C)) and bacterial (lipopolysaccharide, LPS) stimulations in combination with the lung remodeling factor Transforming Growth Factor-ß (TGF-ß). RESULTS: We showed a strong production of pro-inflammatory cytokines (Interleukin (IL)-6, Tumor Necrosis Factor α, TNFα) or chemokines (CCL2, CCL3, CCL4, CXCL10, CXCL11) by AEC stimulated with poly(I:C). Cytokine and chemokine production, except CXCL10, was Toll Like Receptor (TLR)-3 dependent and although they express TLR4, we found no cytokine production after LPS stimulation. Poly(I:C), but not LPS, synergised with TGF-ß for the production of matrix metalloproteinase-9 (MMP-9) and fibronectin. Mechanistic analyses suggest the secretion of Wnt ligands by AEC along with a degradation of the cellular junctions after poly(I:C) exposure, leading to the release of ß-catenin from the cell membrane and stimulation of the Wnt/ß-catenin pathway. CONCLUSION: Our results highlight the cross talk between TGF-ß and TLR signaling in bronchial epithelium and its impact on the remodeling process.

T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction.

Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-ß. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-ß-induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD.

Nanocrystals of Fe(phen)2(NCS)2 and the size-dependent spin-crossover characteristics.

We report on the size reduction of the neutral Fe(phen)2(NCS)2 prototypical compound exhibiting a cooperative spin-crossover associated with a first-order phase transition (at ca. 176 K). We use the [Fe(phen)3](NCS)2 ionic precursor and the solvent-assisted precipitation technique to prepare an array of crystalline objects with sizes varying over two orders of magnitude (from 15 up to 1400 nm). TEM, X-ray diffraction and IR measurements provide evidences for the formation of particles of neutral and ionic species, which results from the interplay between the relevant chemical equilibrium and the reaction kinetics (ligand extraction, complex precipitation), and the modulation of the latter by physico-chemical parameters. A thermal transformation of diamagnetic nanocrystals of [Fe(phen)3](NCS)2 leads to spin-crossover particles of Fe(phen)2(NCS)2 of a comparable size. Powders of nano-, micro- and polycrystals of Fe(phen)2(NCS)2 present X-ray diffractograms typical of the so-called polymorph II. The importance of size effects on the cooperative spin-crossover process was probed with magnetic, Mössbauer, Raman and IR spectroscopic measurements. Each sample exhibits spin-state switching of the Fe(ii) ions. The salient features are: a cooperativity preserved at the micrometric scale, a very limited downshift of the transition temperature and an asymmetric spreading of the thermal process (over ca. 100 K) with the size reduction. At temperatures close to room temperature, the process appears to be quasi complete whatever the size of the samples. This result, extracted from Raman data, was confirmed by Mössbauer measurements in the case of the largest objects (LS residue <5-10% for bulk and microparticles). Below 150 K, a very efficient low-spin to high-spin photoexcitation was induced by the Raman laser beam in all the samples which prevents the extraction of the high-spin fraction in this temperature range. However variable temperature IR spectra of the 29 nm particles indicate that the HS residue, that is close to zero in the case of microparticles, does not drastically increase (<30%) for the smallest particles. The processing of a number of related spin-crossover compounds in the form of nanoparticles may be achieved with this general approach.

[Quality standards for ultrasonographic assessment of peripheral vascular malformations and vascular tumors. Report of the French Society for Vascular Medicine]. / Standards de qualité pour la pratique de l'examen écho-doppler dans l'étude des malformations et tumeurs vasculaires. Rapport de la Société française de médecine vasculaire (SFMV).

THE QUALITY STANDARDS OF THE FRENCH SOCIETY OF VASCULAR MEDICINE FOR THE ULTRASONOGRAPHIC ASSESSMENT OF VASCULAR MALFORMATIONS ARE BASED ON THE TWO FOLLOWING REQUIREMENTS: Technical know-how: mastering the use of ultrasound devices and the method of examination. Medical know-how: ability to adapt the methods and scope of the examination to its clinical indication and purpose, and to rationally analyze and interpret its results. AIMS OF THE QUALITY STANDARDS: To describe an optimal method of examination in relation to the clinical question and hypothesis. To achieve consistent practice, methods, glossary, and reporting. To provide good practice reference points, and promote a high-quality process. ITEMS OF THE QUALITY STANDARDS: The three levels of examination; their clinical indications and goals. The reference standard examination (level 2), its variants according to clinical needs. The minimal content of the examination report; the letter to the referring physician (synthesis, conclusion and proposal for further investigation and/or therapeutic management). Commented glossary (anatomy, hemodynamics, semiology). Technical bases. Settings and use of ultrasound devices. Here, we discuss the methods of using ultrasonography for the assessment of peripheral vascular malformations and tumors.

Neuropsychological functioning in girls with premature adrenarche.

Contemporary research indicates that brain development occurs during childhood and into early adulthood, particularly in certain regions. A critical question is whether premature or atypical hormone exposures impact brain development (e.g., structure) or function (e.g., neuropsychological functioning). The current study enrolled 40 girls (aged 6-8 years) diagnosed with premature adrenarche (PA) and a comparison group of 36 girls with on-time maturation. It was hypothesized that girls with PA would demonstrate lower IQ and performance on several neuropsychological tasks. The potential for a sexually dimorphic neuropsychological profile in PA was also explored. No significant univariate or multivariate group differences emerged for any neuropsychological instrument. However, effect size confidence intervals contained medium-sized group differences at the subscale level. On-time girls performed better on verbal, working memory, and visuospatial tasks. Girls with PA showed improved attention, but not a sexually dimorphic profile. These results, though preliminary, suggest that premature maturation may influence neuropsychological functioning.

Ligand-driven light-induced spin change activity and bidirectional photomagnetism of styrylpyridine iron(II) complexes in polymeric media.

Two pseudo-octahedral iron(II) complexes, Fe(stpy)(4)(NCSe)(2), containing photoresponsive ligands (cis <--> trans isomerization of -CHCH-) were prepared with trans- or cis-styrylpyridine (stpy) isomers. The magnetic behavior of the polycrystalline solids was previously shown to depend on the configuration of the stpy ligand. The crystal X-ray structures were determined at 293 and 104 K for both isomers. The all-trans and all-cis compounds crystallize in the orthorhombic (Pna2(1)) and the monoclinic space groups (C2/c), respectively. No symmetry change occurs upon cooling to 104 K. The Fe(II) centers lie in axially compressed octahedra with NCSe anions in the apical position and the four pyridinic nitrogens in the meridional plane. The variation of metal-ligand bond lengths as a function of temperature reflects the thermal S = 0 <--> S = 2 crossover of all-trans complexes and the S = 2 ground state of all-cis complexes. The unit-cell volumes per metal ion also change accordingly, and the relative variation due to the spin-crossover compares those associated with the formal change of configuration of the four stpy isomers. The photomagnetic responses were investigated at 130 K with doped polymer thin films containing all-cis (high-spin) or all-trans species (partly low-spin). The 130 K illumination of these doped poly(methyl methacrylate) (PMMA) films leads to the UV-vis absorption features typical for the cis <--> trans photoisomerization of the stilbenoid moiety. The direct magnetic measurements have unambiguously established the photomagnetic effect named ligand-driven light-induced spin change (LD-LISC). The 355 nm excitation of doped thin films produces very long lifetime states that are manifested by high-spin to low-spin (all-cis complex) and low-spin to high-spin (all-trans complex) changes of the Fe(II) magnetic behavior; the process is bidirectional. A structural analysis based on the single-crystal X-ray diffraction data has been proposed to rationalize the LD-LISC activity detected here for doped PMMA thin films.

Structure and magnetic properties of the hybrid system copper(II) mu2-2,2'-bipyridine-3-carboxylate-N,N':O-mu2-phosphate-O,O'.

The title compound [Cu(PO4H2)(C11H7N2O2)]n presents antiferromagnetic behavior. It has a polymeric one-dimensional structure in which the elemental links are tetranuclear units and the doubly protonated phosphates and the bipyridinemonocarboxylates act in a bridging mode. The magnetic behavior is described using an alternating chain model, with J = -3.32 cm (-1), alpha = 0.7, and g = 2.05.

Acceptability of human papillomavirus self testing in female adolescents.

OBJECTIVES: To develop scales assessing acceptability of human papillomavirus (HPV) testing in adolescents, to compare acceptability of self to clinician testing, and to identify adolescent characteristics associated with acceptability. METHODS: Female adolescents 14-21 years of age attending a hospital based teen health centre self collected vaginal samples and a clinician, using a speculum, collected cervicovaginal samples for HPV DNA. Acceptability of and preferences for self and clinician testing were assessed at baseline and 2 week visits. RESULTS: The mean age of the 121 participants was 17.8 years and 82% were black. The acceptability scales demonstrated good internal consistency, reliability, test-retest reliability, and factorial validity. Scores were significantly lower for self testing than clinician testing on the acceptability scale and three subscales measuring trust of the test result, confidence in one's ability to collect a specimen, and perceived effects of testing (p < 0.01). Of those who reported a preference, 73% preferred clinician to self testing. Acceptability scores for both self and clinician testing increased significantly pre-examination to post-examination (p < 0.01). Multivariable analyses demonstrated that race was independently associated with pre-examination and post-examination acceptability of self testing, and that sexual behaviours and gynaecological experiences were associated with specific acceptability subscales. CONCLUSIONS: This sample of adolescents found clinician testing for HPV to be more acceptable than self testing and preferred clinician to self testing. If self testing for HPV is offered in the future, clinicians should not assume that adolescent patients will prefer self testing. Instead, they should educate adolescents about available testing options and discuss any concerns regarding self collection technique or accuracy of test results.

Zooming in on the hydrophobic ridge of H-2D(b): implications for the conformational variability of bound peptides.

Class I major histocompatibility complex (MHC) molecules, which display intracellularly processed peptides on the cell surface for scanning by T-cell receptors (TCRs), are extraordinarily polymorphic. MHC polymorphism is believed to result from natural selection, since individuals heterozygous at the corresponding loci can cope with a larger number of pathogens. Here, we present the crystal structures of the murine MHC molecule H-2D(b) in complex with the peptides gp276 and np396 from the lymphocytic choriomeningitis virus (LCMV), solved at 2.18 A and 2.20 A resolution, respectively. The most prominent feature of H-2D(b) is a hydrophobic ridge that cuts across its antigen-binding site, which is conserved in the L(d)-like family of class I MHC molecules. The comparison with previously solved crystal structures of peptide/H-2D(b) complexes shows that the hydrophobic ridge focuses the conformational variability of the bound peptides in a "hot-spot", which could allow optimal TCR interaction and discrimination. This finding suggests a functional reason for the conservation of this structural element.

Viral escape at the molecular level explained by quantitative T-cell receptor/peptide/MHC interactions and the crystal structure of a peptide/MHC complex.

Viral escape, first characterized for the lymphocytic choriomeningitis virus (LCMV) in a mouse transgenic for the P14 T cell-receptor (TCR), can be due to mutations in T-cell epitopes. We have measured the affinity between the H-2D(b) containing the wild-type and two of its "viral escape" epitopes, as well as other altered peptide ligands (APL), by using BIACORE analysis, and solved the crystal structure of H-2D(b) in complex with the wild-type peptide at 2.75 A resolution. We show that viral escape is due to a 50 to 100-fold reduction in the level of affinity between the P14 TCR and the binary complexes of the MHC molecule with the different peptides. Structurally, one of the mutations alters a TCR contact residue, while the effect of the other on the binding of the TCR must be indirect through structural rearrangements. The former is a null ligand, while the latter still leads to some central tolerance. This work defines the structural and energetic threshold for viral escape.

Giant aneurysm of the splenic artery--a case report.

Giant aneurysms of the splenic artery larger than 10 cm are rare. The size of splenic aneurysms rarely exceeds 3 cm. Aneurysms that are often symptomatic because of their size must be treated rapidly before rupture. An etiologic and diagnostic evaluation with computed tomography and selective angiography of the visceral arteries is essential before treatment. Operative indication is imperative for these aneurysms. Their mass with portal compression and dense adhesions to adjacent organs allow only aneurysmal exclusion by proximal and distal ligation with preservation of the spleen. The control of the proximal splenic artery is often difficult, justifying the choice of the surgical access. A case of surgically treated giant splenic artery aneurysm associated with right benign renal lesion is presented with a review of the literature on this subject.

Characterizing the functionality of recombinant T-cell receptors in vitro: a pMHC tetramer based approach.

The very low affinity of the T-cell receptor (TCR) for the peptide-major histocompatibility complex (pMHC) has made it very challenging to design assays for testing the functionality of these molecules on small scales, which in turn has severely hampered the progress in developing expression and refolding methodologies for the TCR. We have now developed an ELISA assay for detecting pMHC binding to functional recombinant TCRs. It uses tetramers of biotinylated pMHCs bound to a neutravidin-horseradish peroxidase conjugate and detects the presence of functional TCR, bound in a productive orientation to an immobilized anti-Cbeta antibody. Specificity can be stringently demonstrated by inhibition with monomeric pMHCs. The assay is very sensitive and specific, and requires only very small amounts of protein. It has allowed us to study the unstable recombinant TCR P14, which we expressed and refolded from Escherichia coli. The TCR P14 is directed against the most abundant epitope of LCMV. We have confirmed the specificity of the interaction by BIAcore, and were able to determine the dissociation constant of the interaction of the P14 TCR and of the gp33-pMHC as 6 microM. This affinity ranks it among the tighter ones of TCR-pMHC interactions, and unusually low affinity thus does not seem to be the cause of the modest protective power of these T-cells, compared to others elicited in the anti-LCMV response. This strategy of multimerizing one partner and immobilizing the other in both a native form and productive orientation should be generally useful for characterizing the weak interactions of cell-surface molecules.

Folding, heterodimeric association and specific peptide recognition of a murine alphabeta T-cell receptor expressed in Escherichia coli.

In a systematic study of the murine T-cell receptor UZ3-4, expressed and refolded from inclusion bodies in Escherichia coli, it was found that functional molecules can be obtained only under a very narrow set of conditions. The refolded T-cell receptor UZ3-4 specifically recognizes its cognate peptide (from mycobacterial Hsp60) in the context of H-2Db, but not another peptide bound to H-2Db, and the dissociation constant was determined by BIAcore as 10(-4) M. Using T-cell receptor constructs comprising all extracellular domains (ValphaCalpha and VbetaCbeta), found to be necessary for stability of the final product, significant amounts of native molecules were obtained only if the intermolecular Calpha-Cbeta disulfide bridge bond was deleted, even though the interaction between the complete alpha and beta-chain was determined to be very weak and fully reversible (KD approximately 10(-7) to 10(-6) M). Fusion of Jun and Fos to the constant domains also decreased the folding yield, because of premature association of intermediates leading to aggregation. Furthermore, only in a very narrow set of concentrations of oxidized and reduced glutathione, native disulfide bonds dominated. This shows that T-cell receptor domains are very prone to aggregation and misassociation during folding, compounded by incorrect disulfide bond formation. Once folded, however, the heterodimeric molecule is very stable and could be concentrated to millimolar concentration.

Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes.

This study describes the construction of soluble major histocompatibility complexes consisting of the mouse class I molecule, H-2Db, chemically biotinylated beta2 microglobulin and a peptide epitope derived from the glycoprotein (GP; amino acids 33-41) of lymphocytic choriomeningitis virus (LCMV). Tetrameric class I complexes, which were produced by mixing the class I complexes with phycoerythrin-labeled neutravidin, permitted direct analysis of virus-specific cytotoxic T lymphocytes (CTLs) by flow cytometry. This technique was validated by (a) staining CD8+ cells in the spleens of transgenic mice that express a T cell receptor (TCR) specific for H-2Db in association with peptide GP33-41, and (b) by staining virus-specific CTLs in the cerebrospinal fluid of C57BL/6 (B6) mice that had been infected intracranially with LCMV-DOCILE. Staining of spleen cells isolated from B6 mice revealed that up to 40% of CD8(+) T cells were GP33 tetramer+ during the initial phase of LCMV infection. In contrast, GP33 tetramers did not stain CD8+ T cells isolated from the spleens of B6 mice that had been infected 2 mo previously with LCMV above the background levels found in naive mice. The fate of virus-specific CTLs was analyzed during the acute phase of infection in mice challenged both intracranially and intravenously with a high or low dose of LCMV-DOCILE. The results of the study show that the outcome of infection by LCMV is determined by antigen load alone. Furthermore, the data indicate that deletion of virus-specific CTLs in the presence of excessive antigen is preceded by TCR downregulation and is dependent upon perforin.