Crystalline silica exposure in patients with rheumatoid arthritis and systemic sclerosis: a nationwide cross-sectional survey.

OBJECTIVES: Develop and validate a thorough exposure questionnaire to comprehensively explore crystalline silica (SiO2) exposure in the general population (gender-specific, occupational and non-occupational) and in patients with autoimmune diseases (rheumatoid arthritis (RA), systemic sclerosis (SSc)). METHODS: Lifetime exposures to SiO2 in occupational and non-occupational settings were assessed using a thorough exposure questionnaire. The questionnaire was applied to a general population panel (n = 2911) sampled from the French rolling census, and to unselected patients with SSc (n = 100) and RA (n = 97). Global (GES), occupational (OES) and non-occupational (NOES) exposure scores were assessed in SSc and RA patients, and compared with up to four controls from the general population, matched by age group, sex and tobacco consumption. RESULTS: Patients had higher GES than their matched controls (SSc: P = 0.001; RA: P < 0.0001) due to higher OES (P < 0.0001 for SSc and RA). Men had higher GES than women (SSc: P < 0.0001; RA: P = 0.002) due to higher OES (P < 0.0001 for SSc and RA). The NOES did not differ between men and women. In SSc patients: Men had higher GES than controls (P < 0.0001). Men and women with SSc had higher OES than controls (P < 0.0001). In RA patients: GES and OES were higher in both men (P = 0.00521; P < 0.0001) and women (P < 0.0001; P < 0.0001) than in their respective controls. Women had higher NOES than controls (P = 0.045). CONCLUSION: The lifetime SiO2 exposure gap between RA and SSc patients and controls was substantially due to occupational exposure. In both diseases, men had higher exposure scores than women.

Exposure to inorganic particles in paediatric sarcoidosis: the PEDIASARC study.

Inorganic antigens may contribute to paediatric sarcoidosis. Thirty-six patients matched with 36 healthy controls as well as a group of 21 sickle-cell disease (SCD) controls answered an environmental questionnaire. Patients' indirect exposure to inorganic particles, through coresidents' occupations, was higher than in healthy and SCD controls (median score: 2.5 (0.5-7) vs 0.5 (0-2), p=0.003 and 1 (0-2), p=0.012, respectively), especially for construction, exposures to metal dust, talc, abrasive reagents and scouring products. Wood or fossil energies heating were also linked to paediatric sarcoidosis. This study supports a link between mineral environmental exposure due to adult coresident occupations and paediatric sarcoidosis.

Drivers of Rift Valley fever epidemics in Madagascar.

Rift Valley fever (RVF) is a vector-borne viral disease widespread in Africa. The primary cycle involves mosquitoes and wild and domestic ruminant hosts. Humans are usually contaminated after contact with infected ruminants. As many environmental, agricultural, epidemiological, and anthropogenic factors are implicated in RVF spread, the multidisciplinary One Health approach was needed to identify the drivers of RVF epidemics in Madagascar. We examined the environmental patterns associated with these epidemics, comparing human and ruminant serological data with environmental and cattle-trade data. In contrast to East Africa, environmental drivers did not trigger the epidemics: They only modulated local Rift Valley fever virus (RVFV) transmission in ruminants. Instead, RVFV was introduced through ruminant trade and subsequent movement of cattle between trade hubs caused its long-distance spread within the country. Contact with cattle brought in from infected districts was associated with higher infection risk in slaughterhouse workers. The finding that anthropogenic rather than environmental factors are the main drivers of RVF infection in humans can be used to design better prevention and early detection in the case of RVF resurgence in the region.

Association between lung cancer somatic mutations and occupational exposure in never-smokers.

Occupational exposure constitutes a common risk factor for lung cancer. We observed molecular alterations in 73% of never-smokers, 35% of men and 8% of women were exposed to at least one occupational carcinogen. We report herein associations between molecular patterns and occupational exposure.BioCAST was a cohort study of lung cancer in never-smokers that reported risk factor exposure and molecular patterns. Occupational exposure was assessed via a validated 71-item questionnaire. Patients were categorised into groups that were unexposed and exposed to polycyclic aromatic hydrocarbons (PAH), asbestos, silica, diesel exhaust fumes (DEF), chrome and paints. Test results were recorded for EGFR, KRAS, HER2, BRAF and PIK3 mutations, and ALK alterations.Overall, 313 out of 384 patients included in BioCAST were analysed. Asbestos-exposed patients displayed a significantly lower rate of EGFR mutations (20% versus 44%, p=0.033), and a higher rate of HER2 mutations (18% versus 4%, p=0.084). ALK alterations were not associated with any occupational carcinogens. The DEF-exposed patients were diagnosed with a BRAF mutation in 25% of all cases. Chrome-exposed patients exhibited enhanced HER2 and PIK3 mutation frequency.Given its minimal effects in the subgroups, we conclude that occupational exposure slightly affects the molecular pattern of lung cancers in never-smokers. In particular, asbestos-exposed patients have a lower chance of EGFR mutations.

Structure, Dynamics, and Interaction of p54(nrb)/NonO RRM1 with 5' Splice Site RNA Sequence.

p54(nrb)/NonO is a nuclear RNA-binding protein involved in many cellular events such as pre-mRNA processing, transcription, and nuclear retention of hyper-edited RNAs. In particular, it participates in the splicing process by directly binding the 5' splice site of pre-mRNAs. The protein also concentrates in a nuclear body called paraspeckle by binding a G-rich segment of the ncRNA NEAT1. The N-terminal section of p54(nrb)/NonO contains tandem RNA recognition motifs (RRMs) preceded by an HQ-rich region including a threonine residue (Thr15) whose phosphorylation inhibits its RNA binding ability, except for G-rich RNAs. In this work, our goal was to understand the rules that characterize the binding of the p54(nrb)/NonO RRMs to their RNA target. We have done in vitro RNA binding experiments which revealed that only the first RRM of p54(nrb)/NonO binds to the 5' splice site RNA. We have then determined the structure of the p54(nrb)/NonO RRM1 by liquid-state NMR which revealed the presence of a canonical fold (ß1α1ß2ß3α2ß4) and the conservation of aromatic amino acids at the protein surface. We also investigated the dynamics of this domain by NMR. The p54(nrb)/NonO RRM1 displays some motional properties that are typical of a well-folded protein with some regions exhibiting more flexibility (loops and ß-strands). Furthermore, we determined the affinity of p54(nrb)/NonO RRM1 interaction to the 5' splice site RNA by NMR and fluorescence quenching and mapped its binding interface by NMR, concluding in a classical nucleic acid interaction. This study provides an improved understanding of the molecular basis (structure and dynamics) that governs the binding of the p54(nrb)/NonO RRM1 to one of its target RNAs.

BioCAST/IFCT-1002: epidemiological and molecular features of lung cancer in never-smokers.

Lung cancer in never-smokers (LCINS) (fewer than 100 cigarettes in lifetime) is considered as a distinct entity and harbours an original molecular profile. However, the epidemiological and molecular features of LCINS in Europe remain poorly understood. All consecutive newly diagnosed LCINS patients were included in this prospective observational study by 75 participating centres during a 14-month period. Each patient completed a detailed questionnaire about risk factor exposure. Biomarker and pathological analyses were also collected. We report the main descriptive overall results with a focus on sex differences. 384 patients were included: 65 men and 319 women. 66% had been exposed to passive smoking (significantly higher among women). Definite exposure to main occupational carcinogens was significantly higher in men (35% versus 8% in women). A targetable molecular alteration was found in 73% of patients (without any significant sex difference): EGFR in 51%, ALK in 8%, KRAS in 6%, HER2 in 3%, BRAF in 3%, PI3KCA in less than 1%, and multiple in 2%. We present the largest and most comprehensive LCINS analysis in a European population. Physicians should track occupational exposure in men (35%), and a somatic molecular alteration in both sexes (73%).

From the definition of silicosis at the 1930 Johannesburg conference to the blurred boundaries between pneumoconioses, sarcoidosis, and pulmonary alveolar proteinosis (PAP).

The 1930 International Labour Office Conference on silicosis in Johannesburg identified silicosis by setting a medicolegal framework to its nosology: as with other occupational illnesses, its medical content was fixed under economic pressure. This article follows a reading of all the proceedings of this conference (debates and reports of experts) to examine their potential impact on the etiology and nosology of other diseases, specifically sarcoidosis and pulmonary alveolar proteinosis (PAP), "idiopathic" diseases in which inorganic particles may be involved. We propose renewed study of the role of inorganic particles in these diseases. To do this, we propose to mobilize detection means such as mineralogical analysis and electron microscopy and in depth interviewing that are currently seldom used in France, in order to establish diagnosis and the potential occupational and environmental origin of these diseases.

PARP activation regulates the RNA-binding protein NONO in the DNA damage response to DNA double-strand breaks.

After the generation of DNA double-strand breaks (DSBs), poly(ADP-ribose) polymerase-1 (PARP-1) is one of the first proteins to be recruited and activated through its binding to the free DNA ends. Upon activation, PARP-1 uses NAD+ to generate large amounts of poly(ADP-ribose) (PAR), which facilitates the recruitment of DNA repair factors. Here, we identify the RNA-binding protein NONO, a partner protein of SFPQ, as a novel PAR-binding protein. The protein motif being primarily responsible for PAR-binding is the RNA recognition motif 1 (RRM1), which is also crucial for RNA-binding, highlighting a competition between RNA and PAR as they share the same binding site. Strikingly, the in vivo recruitment of NONO to DNA damage sites completely depends on PAR, generated by activated PARP-1. Furthermore, we show that upon PAR-dependent recruitment, NONO stimulates nonhomologous end joining (NHEJ) and represses homologous recombination (HR) in vivo. Our results therefore place NONO after PARP activation in the context of DNA DSB repair pathway decision. Understanding the mechanism of action of proteins that act in the same pathway as PARP-1 is crucial to shed more light onto the effect of interference on PAR-mediated pathways with PARP inhibitors, which have already reached phase III clinical trials but are until date poorly understood.

Predisposing factors, clinical and microbiological insights of bacterial keratitis: analysis of 354 cases from a leading French academic centre.

AIMS: To report an epidemiological update of bacterial keratitis (BK) in a tertiary ophthalmology centre over 20 months compared with a previous study on the same timeframe from 1998 to 1999. METHODS: 354 patients with BK documented by microbiological corneal scraping or resolutive under antibiotics treatment from January 2020 to September 2021 were analysed retrospectively. RESULTS: One or several risk factors were found in 95.2% of patients: contact lens wear (45.2%), ocular surface disease (25.0%), systemic disease (21.8%), ocular trauma (11.9%) and ocular surgery (8.8%). The positivity rate of corneal scrapings was 82.5%, with 18.2% polybacterial. One hundred seventy-five (59.9%) bacteria were Gram-negative, and 117 (40.1%) were Gram-positive. The most common bacteria were Pseudomonas aeruginosa (32.5%), Moraxella spp (18.1%) and Staphylococcus aureus (8.2%). Final visual acuity (logarithm of the minimum angle of resolution) was associated with age (r=+0.48; p=0.0001), infiltrate size (r=+0.32; p<0.0001), ocular surface disease (r=+0.13; p=0.03), ocular trauma (r=-0.14; p=0.02) and contact lens wear (r=-0.26; p<0.0001). Gram-negative bacteria were responsible for deeper (r=+0.18; p=0.004) and more extensive infiltrates (r=+0.18; p=0.004) in younger patients (r=-0.19; p=0.003). Compared with the previous period, the positivity rate of corneal scrapings and the proportion of Gram-negative bacteria, especially Moraxella spp, increased. All P. aeruginosa and Moraxella spp were sensitive to quinolones, and all S. aureus were sensitive to both quinolones and methicillin. CONCLUSION: Contact lens wear remained the leading risk factor. The bacteria distribution was reversed, with a predominance of Gram-negative bacteria and increased Moraxella spp.

Towards a better understanding of Rift Valley fever epidemiology in the south-west of the Indian Ocean.

Rift Valley fever virus (Phlebovirus, Bunyaviridae) is an arbovirus causing intermittent epizootics and sporadic epidemics primarily in East Africa. Infection causes severe and often fatal illness in young sheep, goats and cattle. Domestic animals and humans can be contaminated by close contact with infectious tissues or through mosquito infectious bites. Rift Valley fever virus was historically restricted to sub-Saharan countries. The probability of Rift Valley fever emerging in virgin areas is likely to be increasing. Its geographical range has extended over the past years. As a recent example, autochthonous cases of Rift Valley fever were recorded in 2007-2008 in Mayotte in the Indian Ocean. It has been proposed that a single infected animal that enters a naive country is sufficient to initiate a major outbreak before Rift Valley fever virus would ever be detected. Unless vaccines are available and widely used to limit its expansion, Rift Valley fever will continue to be a critical issue for human and animal health in the region of the Indian Ocean.

Long-term outcomes of deep anterior lamellar versus penetrating keratoplasty for keratoconus.

AIMS: To compare the long-term outcomes of deep anterior lamellar keratoplasty (DALK) with penetrating keratoplasty (PK) in keratoconus. METHODS: Retrospective comparative case series (228 DALKs and 274 PKs). A biphasic linear model was used to describe the postoperative outcome of the endothelial cell density (ECD). Visual acuity, specular microscopy, corneal topography and optical coherence tomography findings were recorded. RESULTS: Graft survival of the 502 keratoconus eyes was 96.7 at 10 years and 95.6% at 20 years. Visual acuity improved from 20/378±5.1 lines preoperatively to 20/32±2.1 lines at 30 months. The corneal ECD decreased from 2494±382 cells/mm2 to 1521±659 cells/mm2 at 10 years. The mean simulated keratometry increased from 44.88±2.54 D at 1 year to 46.60±3.0 D at 3 years. The mean follow-up was 103.4 months for DALKs and 106.1 months for PKs. The cumulated incidence of postoperative ocular hypertension requiring treatment was significantly higher in PKs than in DALKs. The early- and late-phase rates of ECD loss were significantly lower in DALKs than in PKs. These figures in DALKs were 50% of those observed in PKs. The simulated mean keratometry was significantly higher in DALKs than in PKs in the mid but not in the long term. No significant differences in visual acuity were observed between both groups. Manual dissection-DALK featured slower visual recovery than PK and big bubble-DALK, whereas big bubble-DALK and PK featured similar visual recovery. CONCLUSIONS: DALK featuring higher endothelial survival and lower risk of postoperative ocular hypertension may be superior to PK when indicated for keratoconus.

Interaction with membrane mimics of transmembrane fragments 16 and 17 from the human multidrug resistance ABC transporter 1 (hMRP1/ABCC1) and two of their tryptophan variants.

The human multidrug resistance-associated protein 1 (hMRP1/ABCC1) belongs to the ATP-binding cassette transporter superfamily. Together with P-glycoprotein (ABCB1) and the breast cancer resistance protein (BCRP/ABCG2), hMRP1 confers resistance to a large number of structurally diverse drugs. The current topological model of hMRP1 includes two cytosolic nucleotide-binding domains and 17 putative transmembrane (TM) helices forming three membrane-spanning domains. Mutagenesis and labeling studies have shown TM16 and TM17 to be important for function. We characterized the insertion of the TM16 fragment into dodecylphosphocholine (DPC) or n-dodecyl-beta-d-maltoside (DM) micelles as membrane mimics and extended our previous work on TM17 (Vincent et al., 2007, Biochim. Biophys. Acta 1768, 538). We synthesized TM16 and TM17, with the Trp residues, W1198 in TM16 and W1246 in TM17, acting as an intrinsic fluorescent probe, and TM16 and TM17 Trp variants, to probe different positions in the peptide sequence. We assessed the interaction of peptides with membrane mimics by evaluating the increase in fluorescence intensity resulting from such interactions. In all micelle-bound peptides, the tryptophan residue appeared to be located, on average, in the head group micelle region, as shown by its fluorescence spectrum. Each tryptophan residue was partially accessible to both acrylamide and the brominated acyl chains of two DM analogs, as shown by fluorescence quenching. Tryptophan fluorescence lifetimes were found to depend on the position of the tryptophan residue in the various peptides, probably reflecting differences in local structures. Far UV CD spectra showed that TM16 contained significant beta-strand structures. Together with the high Trp correlation times, the presence of these structures suggests that TM16 self-association may occur at the interface. In conclusion, this experimental study suggests an interfacial location for both TM16 and TM17 in membrane mimics. In terms of overall hMRP1 structure, the experimentally demonstrated amphipathic properties of these TM are consistent with a role in the lining of an at least partly hydrophilic transport pore, as suggested by the currently accepted structural model, the final structure being modified by interaction with other TM helices.

The mitotic phosphorylation of p54(nrb) modulates its RNA binding activity.

The RNA-binding protein p54(nrb) is involved in many nuclear processes including transcription, RNA processing, and retention of hyperedited RNAs. In interphase cells, p54(nrb) localizes to the nucleoplasm and concentrates with protein partners in the paraspeckles via an interaction with the non-coding RNA Neat1. During mitosis, p54(nrb) becomes multiphosphorylated and the effects of this modification are not known. In the present study, we show that p54(nrb) phosphorylation does not affect the interactions with its protein partners but rather diminishes its general RNA-binding ability. Biochemical assays indicate that in vitro phosphorylation of a GST-p54(nrb) construct by CDK1 abolishes the interaction with 5' splice site RNA sequence. Site-directed mutagenesis shows that the threonine 15 residue, located N-terminal to the RRM tandem domains of p54(nrb), is involved in this inhibition. In vivo analysis reveals that Neat1 ncRNA co-immunoprecipitates with p54(nrb) in either interphase or mitotic cells, suggesting that p54(nrb)-Neat1 interaction is not modulated by phosphorylation. Accordingly, in vitro phosphorylated GST-p54(nrb) still interacts with PIR-1 RNA, a G-rich Neat1 sequence known to interact with p54(nrb). In vitro RNA binding assays show that CDK1-phosphorylation of a GST-p54(nrb) construct abolishes its interaction with homoribopolymers poly(A), poly(C), and poly(U) but not with poly(G). These data suggest that p54(nrb) interaction with RNA could be selectively modulated by phosphorylation during mitosis.

Transverse and tangential orientation of predicted transmembrane fragments 4 and 10 from the human multidrug resistance protein (hMRP1/ABCC1) in membrane mimics.

The human multidrug-resistance-associated protein 1 (hMRP1/ABCC1) belongs to the large ATP-binding cassette transporter superfamily. In normal tissues, hMRP1 is involved in tissue defense, whereas, in cancer cells, it is overproduced and contributes to resistance to chemotherapy. We previously investigated the folding properties of the predicted transmembrane fragments (TM) TM16, and TM17 from membrane-spanning domain 2 (MSD2). These TMs folded only partially as an α-helix and were located in the polar headgroup region of detergent micelles used as membrane mimics (Vincent et al. in Biochim Biophys Acta 1768:538-552, 2007; de Foresta et al. in Biochim Biophys Acta 1798:401-414, 2010). We have now extended these studies to TM4 and TM10, from MSD0 and MSD1, respectively. TM10 may be involved in the substrate translocation pathway whereas the role of TM4 is less predictable, because few studies have focused on MSD0, a domain present in some hMRP1 homologs only. Each TM contained a single Trp residue (W142 or W553) acting as an intrinsic fluorescent probe. The location and dynamics of the TMs in dodecylphosphocholine (DPC) or n-dodecyl-ß-D: -maltoside (DDM) micelles were studied by Trp steady-state and time-resolved fluorescence, including quenching experiments. Overall TM structure was analyzed by far-UV circular dichroism studies in detergent micelles and TFE. TM10 behaved similarly to TM16 and TM17, with an interfacial location in micelles consistent with a possible role in lining the transport pore. By contrast, TM4 behaved like a classical TM fragment with a high α-helical content, and its transmembrane insertion did not require its interaction with other TMs.

Transitin is required for the differentiation of avian QM7 myoblasts into myotubes.

Transitin is a nestin-like intermediate filament protein co-expressed with vimentin in the precursor cells of the myogenic and neurogenic lineages of the avian embryo. To understand its role in myogenesis, stable cell lines expressing transitin-targeted siRNAs were derived from the quail muscle cell line QM7. When cells were cultured in differentiation medium, we found that transitin knockdown prevented myoblast fusion and myotube formation. MyoD mRNA could be detected in transitin siRNA-transfected cells, but upregulation of myogenin and desmin expression was impaired compared to control cells. In addition, transitin siRNA cells maintain high levels of Pax7 expression suggesting that QM7 myoblasts into which transitin expression has been attenuated display a muscle progenitor cell phenotype (Pax7(+)/MyoD(+)/myogenin(-)/desmin(-)). These observations indicate that transitin plays an important role in the initiation of the myogenic program in avian muscle progenitor cells in acting downstream of MyoD and upstream of myogenin during the lineage progression.

Structural and dynamic properties of juxta-membrane segments of caveolin-1 and caveolin-2 at the membrane interface.

Caveolins (cav1-3) are essential membrane proteins found in caveolae. The caveolin scaffolding domain of cav-1 includes a short sequence containing a CRAC motif (V94TKYWFYR101) at its C-terminal end. To investigate the role of this motif in the caveolin-membrane interaction at the atomic level, we performed a detailed structural and dynamics characterization of a cav-1(V94-L102) nonapeptide encompassing this motif and including the first residue of cav-1 hydrophobic domain (L102), in dodecylmaltoside (DM) or dodecylphosphocholine (DPC) micelles, as membrane mimics. Cav-1(V94-L102) partitioned better in DPC and in DM/anionic lipid micelles than in DM micelles, as shown by fluorescence titration and CD. NMR data revealed that this peptide folded as an amphipathic helix located in the polar head group region of DPC micelles. The two tyrosine side-chains, flanked by arginine and lysine residues, are situated on one face of this helix, whereas the phenylalanine and tryptophan side-chains are located on the opposite face. Fluorescence studies showed significant Trp subnanosecond rotations, the presence of several rotamers, and a heterogeneous location within the water/micelle interface. NMR studies of the shorter cav-1(V94-R101) peptide and of the homologous sequence of cav-2(I79SKYVMYKF87) allowed the description of the effect of L102 and of the amino acid variations occurring in cav-2 on the structure and localization in DPC micelles. Based on the topological model of caveolins, our results suggest that the cav-1 and cav-2 nonapeptides studied form interfacial alpha-helix membrane anchors in which the K/RhhhYK/Rh motif, also found in cav-3, may play a significant role.

Metal-Metal Hip Prosthesis and Kidney Cancer: Assumed Role of Chromium and Cobalt Overload.

BACKGROUND The case of a patient with bilateral renal cancers diagnosed at 94 and 120 months after metal-on-metal hip placement may serve as a warning. It suggests that there may be a need for kidney echography observation of patients with similar types of prostheses. CASE REPORT A 61-year-old woman received a metal-on-metal hip prosthesis for degenerative arthritis in January 2007. In November 2014, after bleeding from the renal tract, she was diagnosed with clear cell carcinoma of the right kidney. When she returned to her orthopaedic surgeon 1 year later, a blood test showed a serum cobalt level that exceeded the French medical agency recommendation. After the patient's metallic acetabulum was replaced in September 2015, her blood cobalt level fell. However, in February 2017, she was diagnosed with adenocarcinoma of the left kidney. Laser-induced breakdown spectroscopy (LIBS) showed cobalt, chromium, and silica overload in both the patient's kidneys despite the drop in serum levels. CONCLUSIONS In this case, exposure to a cobalt-chromium implant with high particulate wear, LIBS results showing chromium overload of the kidneys, diagnosis of renal cancer at 7 years, 10 months and 10 years in a patient with a metal-on-metal hip prosthesis suggests that there may be a causal relationship between the implant, carcinogenic chromium intoxication, and development of renal cancer.

Desquamative interstitial pneumonia induced by metal exposure. A case report and literature review.

BACKGROUND: Forms of interstitial pneumonia secondary to exposure to an air-contaminant are varied and so far, insufficiently described. OBJECTIVES/METHODS: We report here a case of a 57-year-old patient managed in our department for the exploration of MRC grade 2 dyspnoea and interstitial pneumonia. He mentioned multiple occupational and domestic exposures such as hens' excrements, asbestos and metal particles; he also had a previous history of smoking. RESULTS: High-resolution computed tomography showed ground glass opacities predominating in posterior territories and surrounding cystic lesions or emphysematous destruction. The entire etiological assessment revealed only macrophagic alveolitis with giant multinucleated cells on the bronchoalveolar lavage. A surgical lung biopsy allowed us to refine the diagnosis with evidence of desquamative interstitial pneumonia and pulmonary granulomatosis. Finally, the analysis of the mineral particles in the biopsy revealed abnormally high rates of Zirconium and Aluminium. We were therefore able to conclude to a desquamative interstitial pneumonia associated with pulmonary granulomatosis linked to metal exposure (Aluminium and Zirconium). The clinical, functional and radiological evolution was favorable after a systemic corticosteroid treatment with progressive decay over one year. CONCLUSION: This presentation reports the first case to our knowledge of desquamative interstitial pneumonitis related to exposure to Zirconium and the third one in the context of Aluminium exposure. The detailed analysis of the mineral particles present on the surgical lung biopsy allows for the identification of the relevant particle to refine the etiological diagnosis, to guide the therapeutic management and to give access to recognition as an occupational disease. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 79-84).

Identification of inorganic particles resulting from degradation of ESSURE® implants: Study of 10 cases.

OBJECTIVE: Approximately 750,000 women worldwide have undergone ESSURE hysteroscopic sterilization since 2002. In 2015, an increase in adverse effects was noted, with gynaecological and systemic symptoms reported. Scanning electron microscopy (SEM) analysis of fallopian tube and uterine horn tissues and implants, after hysterectomy or salpingectomy, revealed the presence of inorganic particles resulting from implant degradation. STUDY DESIGN: Ten patients (age 42-53 years) were included in this study. Of these, eight patients had undergone hysterectomy and two patients had undergone salpingectomy. Mean exposure time was 85.5 months (standard deviation 26.8 months, range 34-105 months). Mineralogical analyses were performed on 13 tissue biopsies and four implants by SEM coupled with energy dispersive x-ray spectrometry. RESULTS: In five of the 10 patients, tin particles were observed in fallopian tube or uterine horn tissues with inflammatory cell reactions. In the other five cases, iron, chromium, nickel or platinum particles were observed. For implants, major deterioration of the weld zone was observed with either destroyed appearance or the presence of an organic coating containing numerous particles. DISCUSSION AND CONCLUSION: Analysis of the preclinical studies performed by the manufacturer suggests that degradation of the tin weld plays a major role in these adverse events, with increasing leaching and corrosion between 3 and 6 months for an intratubal insert that si designed to remain in an woman's body for her entire life. For patients with gynaecological symptoms (e.g. pain, metrorragies) needing explantation, these findings raise the question of a causal relationship between tin particles from implant degradation and the inflammatory tissue response. For patients with systemic symptoms (e.g. blurred vision, headache, asthenia, myalgia), the hypothesis that these symptoms may be related to the formation of organotin (chemical compounds based on tin with hydrocarbon substituents) in the body has yet to be proven. Tin levels in blood have to be measured before and after explantation. To the authors' knowledge, this is the first study to report significant degradation of the ESSURE implant weld, evidenced by the detection of tin particles in the uterine tissue of patients and comparison of the welding zone between unused and used implants.

Specific interactions of clausin, a new lantibiotic, with lipid precursors of the bacterial cell wall.

We investigated the specificity of interaction of a new type A lantibiotic, clausin, isolated from Bacillus clausii, with lipid intermediates of bacterial envelope biosynthesis pathways. Isothermal calorimetry and steady-state fluorescence anisotropy (with dansylated derivatives) identified peptidoglycan lipids I and II, embedded in dodecylphosphocholine micelles, as potential targets. Complex formation with dissociation constants of approximately 0.3 muM and stoichiometry of approximately 2:1 peptides/lipid intermediate was observed. The interaction is enthalpy-driven. For the first time, to our knowledge, we evidenced the interaction between a lantibiotic and C(55)-PP-GlcNAc, a lipid intermediate in the biosynthesis of other bacterial cell wall polymers, including teichoic acids. The pyrophosphate moiety of these lipid intermediates was crucial for the interaction because a strong binding with undecaprenyl pyrophosphate, accounting for 80% of the free energy of binding, was observed. No binding occurred with the undecaprenyl phosphate derivative. The pentapeptide and the N-acetylated sugar moieties strengthened the interaction, but their contributions were weaker than that of the pyrophosphate group. The lantibiotic decreased the mobility of the pentapeptide. Clausin did not interact with the water-soluble UDP-MurNAc- and pyrophosphoryl-MurNAc-pentapeptides, pointing out the importance of the hydrocarbon chain of the lipid target.