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The activity of gatifloxacin, a new fluoroquinolone derivative, was compared with the activities of ciprofloxacin, levofloxacin, amoxicillin, amoxicillin–clavulanate, imipenem, clindamycin and metronidazole against 204 anaerobes isolated from clinical specimens, by MIC determination, using the reference agar dilution method. When determining the overall activity against anaerobes, the MIC50/90 (mg/L) values were amoxicillin 16/>64, amoxicillin–clavulanate 0.125/1, imipenem 0.25/0.5, clindamycin 0.5/>256, metronidazole 1/8, ciprofloxacin 2/32, levofloxacin 1/8 and gatifloxacin 0.5/4. The broad in vitro spectrum of gatifloxacin is promising for the treatment of mixed anaerobic infections, especially those of the respiratory tract, ear, sinus, skin and soft tissues, and bite wounds. These data suggest that gatifloxacin may have a clinical role in the treatment of infections in which anaerobic pathogens are involved. [ABSTRACT FROM AUTHOR]

Abstract Background Meropenem is a carbapenem that has an excellent activity against many gram-positive and gram-negative aerobic, facultative, and anaerobic bacteria. The major objective of the present study was to assess the in vitro activity of meropenem compared to imipenem and piperacillin/tazobactam, against 1071 non-repetitive isolates collected from patients with bacteremia (55%), pneumonia (29%), peritonitis (12%) and wound infections (3%), in 15 French hospitals in 2006. The secondary aim of the study was to compare the results of routinely testings and those obtained by a referent laboratory. Method Susceptibility testing and Minimum Inhibitory Concentrations (MICs) of meropenem, imipenem and piperacillin/tazobactam were determined locally by Etest method. Susceptibility to meropenem was confirmed at a central laboratory by disc diffusion method and MICs determined by agar dilution method for meropenem, imipenem and piperacillin/tazobactam. Results Cumulative susceptibility rates against Escherichia coli were, meropenem and imipenem: 100% and piperacillin/tazobactam: 90%. Against other Enterobacteriaceae, the rates were meropenem: 99%, imipenem: 98% and piperacillin/tazobactam: 90%. All Staphylococci, Streptococci and anaerobes were susceptible to the three antibiotics. Against non fermeters, meropenem was active on 84-94% of the strains, imipenem on 84-98% of the strains and piperacillin/tazobactam on 90-100% of the strains. Conclusions Compared to imipenem, meropenem displays lower MICs against Enterobacteriaceae, Escherichia coli and Pseudomonas aeruginosa. Except for non fermenters, MICs90 of carbapenems were Enterobacteriaceae and Acinetobacter but not P. aeruginosa. Some discrepancies were noted between MICs determined by Etest accross centres and MICs determined by agar dilution method at the central laboratory. Discrepancies were more common for imipenem testing and more frequently related to a few centres. Overall MICs determined by Etest were in general higher (0.5 log to 1 log fold) than MICs by agar dilution.

Uveal melanoma (UM) is the most common cancer of the eye. The loss of chromosome 3 (M3) is associated with a high risk of metastases. M3 tumors are more infiltrated by T-lymphocytes than low-risk disomic-3 (D3) tumors, contrasting with other tumor types in which T cell infiltration correlates with better prognosis. Whether these T cells represent an antitumor response and how these T cells would be primed in the eye are both unknown. Herein, we characterized the T cells infiltrating primary UMs. CD8+ and Treg cells were more abundant in M3 than in D3 tumors. CD39+PD-1+CD8+ T cells were enriched in M3 tumors, suggesting specific responses to tumor antigen (Ag) as confirmed using HLA-A2:Melan-A tetramers. scRNAseq-VDJ analysis of T cells evidenced high numbers of proliferating CD39+PD1+CD8+ clonal expansions, suggesting in situ antitumor Ag responses. TCRseq and tumor-Ag tetramer staining characterized the recirculation pattern of the antitumor responses in M3 and D3 tumors. Thus, tumor-Ag responses occur in localized UMs, raising the question of the priming mechanisms in the absence of known lymphatic drainage., (© 2024 Lucibello et al.)

Background: The mechanisms regulating CD8 + T cell migration to nonlymphoid tissue during inflammation have not been fully elucidated, and the migratory properties of effector memory CD8 + T cells that re-express CD45RA (TEMRA CD8 + T cells) remain unclear, despite their roles in autoimmune diseases and allotransplant rejection., Methods: We used single-cell proteomic profiling and functional testing of CD8 + T cell subsets to characterize their effector functions and migratory properties in healthy volunteers and kidney transplant recipients with stable or humoral rejection., Results: We showed that humoral rejection of a kidney allograft is associated with an accumulation of cytolytic TEMRA CD8 + T cells in blood and kidney graft biopsies. TEMRA CD8 + T cells from kidney transplant recipients exhibited enhanced migratory properties compared with effector memory (EM) CD8 + T cells, with enhanced adhesion to activated endothelium and transmigration in response to the chemokine CXCL12. CXCL12 directly triggers a purinergic P2×4 receptor-dependent proinflammatory response of TEMRA CD8 + T cells from transplant recipients. The stimulation with IL-15 promotes the CXCL12-induced migration of TEMRA and EM CD8 + T cells and promotes the generation of functional PSGL1, which interacts with the cell adhesion molecule P-selectin and adhesion of these cells to activated endothelium. Although disruption of the interaction between functional PSGL1 and P-selectin prevents the adhesion and transmigration of both TEMRA and EM CD8 + T cells, targeting VLA-4 or LFA-1 (integrins involved in T cell migration) specifically inhibited the migration of TEMRA CD8 + T cells from kidney transplant recipients., Conclusions: Our findings highlight the active role of TEMRA CD8 + T cells in humoral transplant rejection and suggest that kidney transplant recipients may benefit from therapeutics targeting these cells., (Copyright © 2022 by the American Society of Nephrology.)

Since the mid-1990s, the biology and functions of natural killer (NK) cells have been deeply investigated in healthy individuals and in people with diseases. These effector cells play a particularly crucial role after allogeneic hematopoietic stem-cell transplantation (HSCT) through their graft-versus-leukemia (GvL) effect, which is mainly mediated through polymorphic killer-cell immunoglobulin-like receptors (KIRs) and their cognates, HLA class I ligands. In this review, we present how KIRs and HLA class I ligands modulate the structural formation and the functional education of NK cells. In particular, we decipher the current knowledge about the extent of KIR and HLA class I gene polymorphisms, as well as their expression, interaction, and functional impact on the KIR + NK cell repertoire in a physiological context and in a leukemic context. In addition, we present the impact of NK cell alloreactivity on the outcomes of HSCT in adult patients with acute leukemia, as well as a description of genetic models of KIRs and NK cell reconstitution, with a focus on emergent T-cell-repleted haplo-identical HSCT using cyclosphosphamide post-grafting (haplo-PTCy). Then, we document how the immunogenetics of KIR/HLA and the immunobiology of NK cells could improve the relapse incidence after haplo-PTCy. Ultimately, we review the emerging NK-cell-based immunotherapies for leukemic patients in addition to HSCT.

The antibody-dependent cellular cytotoxicity (ADCC) effector function of natural killer (NK) cells is one of the known mechanisms of action for rituximab-based anti-cancer immunotherapy. Inhibition of the ADCC function of NK cells through interactions between inhibitory killer cell immunoglobulin-like receptors (KIRs) and HLA class I ligands is associated with resistance of cancers to rituximab. In this study, we deeply investigated the impact of KIR, HLA class I, and CD16 genotypes on rituximab-dependent NK cell responses in both an in vitro cellular model from healthy blood donors and ex vivo rituximab-treated non-Hodgkin lymphoma (NHL) patients. We highlight that an HLA environment with limited KIR ligands is beneficial to promoting a higher frequency of KIR + NK cells including both educated and uneducated NK cells, two NK cell compartments that demonstrate higher rituximab-dependent degranulation than KIR - NK cells. In contrast, a substantial KIR ligand environment favors a higher frequency of poorly effective KIR - NK cells and numerous functional KIR/HLA inhibitions of educated KIR + NK cells. These phenomena explain why NHL patients with limited KIR ligands respond better to rituximab. In this HLA environment, CD16 polymorphism appears to have a collateral effect. Furthermore, we show the synergic effect of KIR2DS1, which strongly potentiates NK cell ADCC from C2 - blood donors against C2 + target cells. Taken together, these results pave the way for stronger prediction of rituximab responses for NHL patients. HLA class I typing and peripheral blood KIR + NK cell frequency could be simple and useful markers for predicting rituximab response., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

BACKGROUND Delayed hemolytic transfusion reactions (DHTR) are life-threatening complications mostly triggered by red blood cell (RBC) transfusions in patients with hemoglobinopathy. CASE REPORT We present a case of DHTR and hyperhemolysis syndrome in a 39-year-old pregnant woman with a history of ß-thalassemia intermediate in whom the hemoglobin (Hb) level fell to 27 g/L after transfusion of 2 units of crossmatch-compatible packed RBCs. No allo- or auto-antibody formation was detected. Administration of intravenous immunoglobulins and methylprednisolone followed by anti-CD20 rituximab was tried, but was unsuccessful. Infusions of eculizumab (900 mg twice at a 7-day interval) followed by another course of intravenous immunoglobulins (2 g/kg/day for 5 days) and combined with repeated erythropoietin injections (darbepoetin alpha 300 µg/week) finally allowed biological and clinical improvement. Blood counts remained controlled until delivery. Despite signs of intrauterine growth retardation, she gave birth by cesarean section at 31 weeks of pregnancy to a 1.15-kg infant. CONCLUSIONS Eculizumab seems to be of benefit in DHTR associated with hyperhemolysis and should be used early in the treatment of this pathology. Despite premature birth, our case report showed an acceptable outcome for the infant when eculizumab treatment was used during pregnancy.

For decades, the term "anti-anaerobic" has been commonly used to refer to antibiotics exhibiting activity against anaerobic bacteria, also designated as anaerobes. This term is used in various situations ranging from infections associated with well-identified pathogens like Clostridioides difficile, or Fusobacterium necrophorum in Lemierre's syndrome, that require specific antibiotic treatments to polymicrobial infections generally resulting from the decreased permeability of anatomical barriers (e.g., intestinal translocation and stercoral peritonitis) or infectious secondary localizations (e.g., brain abscess and infectious pleurisy). In these cases, the causal bacteria generally remain unidentified and the antimicrobial treatment is empirical. However, major progress in the knowledge of human bacterial microbiotas in the last 10 years has shown how diverse are the species involved in these communities. Here, we sought to reappraise the concept of anti-anaerobic spectrum in the light of recent advances in the microbiota field. We first highlight that the term anaerobic itself does not represent the tremendous diversity of the bacteria it spans, and then we stress that the antibiotic susceptibility profiles for most anaerobic bacteria remain unaddressed. Furthermore, we provide examples challenging the relevance of the "anti-anaerobic" spectrum from a clinical and ecological perspective., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We have recently shown a broad disparity of Natural Killer (NK) cell responses against leukemia highlighting good and bad responders resting on the Killer cell Immunoglobulin-like Receptors (KIR) and HLA genetics. In this study, we deeply studied KIR2D allele expression, HLA-C recognition and functional effect on NK cells in 108 blood donors in combining high-resolution KIR allele typing and multicolor flow cytometry. The KIR2DL1*003 allotype is associated with centromeric (cen) AA motif and confers the highest NK cell frequency, expression level and strength of KIR/HLA-C interactions compared to the KIR2DL1*002 and KIR2DL1*004 allotypes respectively associated with cenAB and BB motifs. KIR2DL2*001 and *003 allotypes negatively affect the frequency of KIR2DL1 + and KIR2DL3 + NK cells. Altogether, our data suggest that cenAA individuals display more efficient KIR2DL alleles (L1*003 and L3*001) to mount a consistent frequency of KIR2DL + NK cells and to confer an effective NK cell responsiveness. The transposition of our in vitro observations in the T-replete haplo-identical HSCT context led us to observe that cenAA HSC grafts limit significantly the incidence of relapse in patients with myeloid diseases after T-replete haplo-identical HSCT. As NK cells are crucial in HSCT reconstitution, one could expect that the consideration of KIR2DL1/2/3 allelic polymorphism could help to refine scores used for HSC donor selection.

Natural killer (NK) cells are key cytotoxic effectors against malignant cells. Polygenic and polymorphic Killer cell Immunoglobulin-like Receptor (KIR) and HLA genes participate in the structural and functional formation of the NK cell repertoire. In this study, we extensively investigated the anti-leukemic potential of NK cell subsets, taking into account these genetic parameters and cytomegalovirus (CMV) status. Hierarchical clustering analysis of NK cell subsets based on NKG2A, KIR, CD57 and NKG2C markers from 68 blood donors identified donor clusters characterized by a specific phenotypic NK cell repertoire linked to a particular immunogenetic KIR and HLA profile and CMV status. On the functional side, acute lymphoblastic leukemia (ALL) was better recognized by NK cells than acute myeloid leukemia (AML). However, a broad inter-individual disparity of NK cell responses exists against the same leukemic target, highlighting bad and good NK responders. The most effective NK cell subsets against different ALLs expressed NKG2A and represented the most frequent subset in the NK cell repertoire. In contrast, minority CD57 + or/and KIR + NK cell subsets were more efficient against AML. Overall, our data may help to optimize the selection of hematopoietic stem cell donors on the basis of immunogenetic KIR/HLA for ALL patients and identify the best NK cell candidates in immunotherapy for AML.

Destruction of valuables is a common behavior in human history. Ethnographic data show the polysemic, but fundamentally symbolic, nature of this act. Yet, research aimed at exploring symbolic destruction in prehistoric societies has underlined the difficulties in establishing unambiguous evidence for such behaviour. We present here the analysis of a basalt tool fragment which provides evidence for intentional breakage associated with ritual activity 12,000 years ago. The tool fragment was part of a unique assemblage of grave goods deposited in a burial pit of a woman suggested to have been a shaman (Hilazon Tachtit cave, Southern Levant). The reconstruction of the artefact's life history through morphological, 3D, use wear, residue and contextual analyses suggest that: 1) the fragment was initially part of a shallow bowl used for mixing ash or lime with water; 2) the bowl was subsequently intentionally broken through flaking along multiple axes; 3) The bowl was not used after its breakage but placed in a cache before the interment of the deceased, accompanied with other special items. The broken bowl fragment underlines the ritualistic nature of the act of breakage in the Natufian society. The research presented in this paper provides an important window into Natufian ritual behaviour during the critical period of transformation to agricultural communities. In addition, our results offer new insight into practices related to intentional destruction of valuables associated with death-related ceremonies at the end of the Palaeolithic., Competing Interests: The authors have declared that no competing interests exist.

In recent years, the study of percussive, pounding and grinding tools has provided new insights into human evolution, more particularly regarding the development of technology enabling the processing and exploitation of plant resources. Some of these studies focus on early evidence for flour production, an activity frequently perceived as an important step in the evolution of plant exploitation. The present paper investigates plant food preparation in mobile hunter-gatherer societies from the Southern Levant. The analysis consists of a use-wear study of 18 tools recovered from Ohalo II, a 23 000-year-old site in Israel showing an exceptional level of preservation. Our sample includes a slab previously interpreted as a lower implement used for producing flour, based on the presence of cereal starch residues. The use-wear data we have obtained provide crucial information about the function of this and other percussive tools at Ohalo II, as well as on investment in tool manufacture, discard strategies and evidence for plant processing in the Late Pleistocene. The use-wear analysis indicates that the production of flour was a sporadic activity at Ohalo II, predating by thousands of years the onset of routine processing of plant foods., (© 2015 The Author(s).)

Background: Meropenem is a carbapenem that has an excellent activity against many gram-positive and gram-negative aerobic, facultative, and anaerobic bacteria. The major objective of the present study was to assess the in vitro activity of meropenem compared to imipenem and piperacillin/tazobactam, against 1071 non-repetitive isolates collected from patients with bacteremia (55%), pneumonia (29%), peritonitis (12%) and wound infections (3%), in 15 French hospitals in 2006. The secondary aim of the study was to compare the results of routinely testings and those obtained by a referent laboratory., Method: Susceptibility testing and Minimum Inhibitory Concentrations (MICs) of meropenem, imipenem and piperacillin/tazobactam were determined locally by Etest method. Susceptibility to meropenem was confirmed at a central laboratory by disc diffusion method and MICs determined by agar dilution method for meropenem, imipenem and piperacillin/tazobactam., Results: Cumulative susceptibility rates against Escherichia coli were, meropenem and imipenem: 100% and piperacillin/tazobactam: 90%. Against other Enterobacteriaceae, the rates were meropenem: 99%, imipenem: 98% and piperacillin/tazobactam: 90%. All Staphylococci, Streptococci and anaerobes were susceptible to the three antibiotics. Against non fermeters, meropenem was active on 84-94% of the strains, imipenem on 84-98% of the strains and piperacillin/tazobactam on 90-100% of the strains., Conclusions: Compared to imipenem, meropenem displays lower MICs against Enterobacteriaceae, Escherichia coli and Pseudomonas aeruginosa. Except for non fermenters, MICs90 of carbapenems were <4 mg/L. Piperacillin/tazobactam was less active against Enterobacteriaceae and Acinetobacter but not P. aeruginosa. Some discrepancies were noted between MICs determined by Etest accross centres and MICs determined by agar dilution method at the central laboratory. Discrepancies were more common for imipenem testing and more frequently related to a few centres. Overall MICs determined by Etest were in general higher (0.5 log to 1 log fold) than MICs by agar dilution.

Bacteroides thetaiotaomicron, a bowel anaerobic commensal, seems to release enzymes detoxifying reactive oxygen species according to our recent work. This opportunistic pathogen would be beneficial in the case of an inflammatory process. To explore its role after an oxidative or nutritive stress, six to seven separate experiments were performed. The bacteria were grown on media restricted in growth factors or supplemented with bile. Their viability was checked after surface protein extraction. The extracts underwent 2D electrophoresis. Gel images were statistically analysed to construct "master" gels. Proteins were identified (peptide-mass fingerprinting technique). The effect of each extract on superoxide anions was evaluated (spectrophotometric method). Superoxide dismutase was identified and a major superoxide anion inhibition was shown by extracts obtained after a nutritive and oxidative stress without significant bacterial death. So, a therapeutic antioxidant potential is firmly hoped for. [figure: see text]

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.

Necrotizing soft tissue infections (NSTI) are infrequent but life-threatening, and require prompt empirical antibiotic therapy. Current nosologic classifications have limited value because the criteria used are imprecise and their bacteriological specificity is uncertain. The aim of this study was to describe the bacterial flora and its antibiotic sensitivity in a cohort of patients with NSTI, and to derive guidelines for the choice of antimicrobial chemotherapy. This prospective study involved 120 patients. Aerobic and anaerobic bacteriological samples were taken from infected soft tissues. The species distribution and susceptibility of the isolates to various antibiotic (ATB) combinations were analyzed. The data were analyzed according to the type (cellulitis versus myonecrosis) and anatomical location of NSTI (abdomen and perineum; uterine cervix; limbs). The chi-square test was used to analyze qualitative variables, and Student's t test was used for quantitative variables. A total of 232 samples yielded bacterial isolates (122 aerobic, 110 anaerobic). The species distribution of anaerobes did not differ according to the nature of the involved tissue or the anatomic location. Gram-negative aerobes were more frequently isolated from abdominal, perineal and limb sites than from the cervix (p<0.05), while gram-positive aerobes showed the reverse distribution (p<0.05). Metronidazole was more effective than clindamycin on cervical isolates (95% vs 88%, p=0.0093). Among the broad-spectrum antibiotics tested, imipenem/cilastatin and piperacillin/tazobactam were equally effective against the different groups of bacteria (94% vs 88%, p=0.14), and were clearly more active than the other antibiotics (p<0.05), whatever the site of isolation, the bacterial species, and the type of NSTI. The five antibiotics tested showed similar efficacy against cervical isolates. These results suggest that the choice of antibiotic therapy for NSTI should depend on the anatomical site of involvement rather than the nature of the infection. For abdominal, perineal and limb NSTI, we recommend first-line treatment with a betalactam-inhibitor combination (piperacillin/tazobactam or ticarcillin/clavulanate) plus an agent active on gram-negative species (aminoglycoside or fluoroquinolone). For cervical NSTI, we recommend penicillin G/metronidazole, or amoxicillin/clavulanic acid.

Background: Bacteroides fragilis is a member of normal human flora and well known pathogenic agent. This bacterium produces many virulence factors. In 1984 new virulence factor--enterotoxin was described. The aim of the study was to search for enterotoxin gene in B. fragilis strains isolated from clinical specimens., Material and Methods: Strains isolated in Poland, Great Britain, France and the Netherlands were cultured on BBE medium. For DNA isolation Genomic DNA PREP PLUS isolation kit manufactured by A&A Biotechnology (Poland) was used. In order to detect enterotoxin (fragilysin) gene, polymerase chain reaction (PCR) was applied utilizing the following primers: 404 (GAG CGG AAG ACG GTG TAT GTG ATT TGT) and 407 (TGC TCA GCG CCC AGT ATA TGA CCT AGT). DNA obtained from bacterial cells was amplified in thermocycler Techne. The amplification products were detected by the electrophoresis in 1% agarose gel., Results: Among 65 investigated B. fragilis strains, the enterotoxin gene was detected in DNA isolated from 12 strains., Conclusion: The enterotoxin producing B. fragilis strains were detected among strains isolated from different clinical specimens in Poland, Great Britain, the Netherlands and France.

Low-level vancomycin resistance was observed for 28 clinical Clostridium innocuum isolates and C. innocuum NCIB 10674, whereas teicoplanin was active. DNA from three clinical isolates and the type strain could not be amplified by PCR with primers specific for the genes vanA, vanB, and vanC, suggesting that C. innocuum is intrinsically resistant to vancomycin.