Early administration of umbilical cord blood cells following brief high tidal volume ventilation in preterm sheep: a cautionary tale.

BACKGROUND: Umbilical cord blood (UCB) cells are a promising treatment for preterm brain injury. Access to allogeneic sources of UCB cells offer the potential for early administration to optimise their therapeutic capacities. As preterm infants often require ventilatory support, which can contribute to preterm brain injury, we investigated the efficacy of early UCB cell administration following ventilation to reduce white matter inflammation and injury. METHODS: Preterm fetal sheep (0.85 gestation) were randomly allocated to no ventilation (SHAM; n = 5) or 15 min ex utero high tidal volume ventilation. One hour following ventilation, fetuses were randomly allocated to i.v. administration of saline (VENT; n = 7) or allogeneic term-derived UCB cells (24.5 ± 5.0 million cells/kg; VENT + UCB; n = 7). Twenty-four hours after ventilation, lambs were delivered for magnetic resonance imaging and post-mortem brain tissue collected. Arterial plasma was collected throughout the experiment for cytokine analyses. To further investigate the results from the in vivo study, mononuclear cells (MNCs) isolated from human UCB were subjected to in vitro cytokine-spiked culture medium (TNFα and/or IFNγ; 10 ng/mL; n = 3/group) for 16 h then supernatant and cells collected for protein and mRNA assessments respectively. RESULTS: In VENT + UCB lambs, systemic IFNγ levels increased and by 24 h, there was white matter neuroglial activation, vascular damage, reduced oligodendrocytes, and increased average, radial and mean diffusivity compared to VENT and SHAM. No evidence of white matter inflammation or injury was present in VENT lambs, except for mRNA downregulation of OCLN and CLDN1 compared to SHAM. In vitro, MNCs subjected to TNFα and/or IFNγ displayed both pro- and anti-inflammatory characteristics indicated by changes in cytokine (IL-18 & IL-10) and growth factor (BDNF & VEGF) gene and protein expression compared to controls. CONCLUSIONS: UCB cells administered early after brief high tidal volume ventilation in preterm fetal sheep causes white matter injury, and the mechanisms underlying these changes are likely dysregulated responses of the UCB cells to the degree of injury/inflammation already present. If immunomodulatory therapies such as UCB cells are to become a therapeutic strategy for preterm brain injury, especially after ventilation, our study suggests that the inflammatory state of the preterm infant should be considered when timing UCB cells administration.

Postnatal steroids as lung protective and anti-inflammatory in preterm lambs exposed to antenatal inflammation.

BACKGROUND: Lung inflammation and impaired alveolarization precede bronchopulmonary dysplasia (BPD). Glucocorticoids are anti-inflammatory and reduce ventilator requirements in preterm infants. However, high-dose glucocorticoids inhibit alveolarization. The effect of glucocorticoids on lung function and structure in preterm newborns exposed to antenatal inflammation is unknown. We hypothesise that postnatal low-dose dexamethasone reduces ventilator requirements, prevents inflammation and BPD-like lung pathology, following antenatal inflammation. METHODS: Pregnant ewes received intra-amniotic LPS (E.coli, 4 mg/mL) or saline at 126 days gestation; preterm lambs were delivered 48 h later. Lambs were randomised to receive either tapered intravenous dexamethasone (LPS/Dex, n = 9) or saline (LPS/Sal, n = 10; Sal/Sal, n = 9) commencing <3 h after birth. Respiratory support was gradually de-escalated, using a standardised protocol aimed at weaning from ventilation towards unassisted respiration. Tissues were collected at day 7. RESULTS: Lung morphology and mRNA levels for inflammatory mediators were measured. Respiratory support requirements were not different between groups. Histological analyses revealed higher tissue content and unchanged alveolarization in LPS/Sal compared to other groups. LPS/Dex lambs exhibited decreased markers of pulmonary inflammation compared to LPS/Sal. CONCLUSION: Tapered low-dose dexamethasone reduces the impact of antenatal LPS on ventilation requirements throughout the first week of life and reduces inflammation and pathological thickening of the preterm lung IMPACT: We are the first to investigate the combination of antenatal inflammation and postnatal dexamethasone therapy in a pragmatic study design, akin to contemporary neonatal care. We show that antenatal inflammation with postnatal dexamethasone therapy does not reduce ventilator requirements, but has beneficial maturational impacts on the lungs of preterm lambs at 7 days of life. Appropriate tapered postnatal dexamethasone dosing should be explored for extuabtion of oxygen-dependant neonates.

Influenza A virus causes maternal and fetal pathology via innate and adaptive vascular inflammation in mice.

Influenza A virus (IAV) infection during pregnancy causes severe maternal and perinatal complications, despite a lack of vertical transmission of IAV across the placenta. Here, we demonstrate a significant alteration in the maternal vascular landscape that underpins the maternal and downstream fetal pathology to IAV infection in mice. In IAV infection of nonpregnant mice, the local lung inflammatory response was contained to the lungs and was self-resolving, whereas in pregnant mice, virus dissemination to major maternal blood vessels, including the aorta, resulted in a peripheral "vascular storm," with elevated proinflammatory and antiviral mediators and the influx of Ly6Clow and Ly6Chigh monocytes, plus neutrophils and T cells. This vascular storm was associated with elevated levels of the adhesion molecules ICAM and VCAM and the pattern-recognition receptors TLR7 and TLR9 in the vascular wall, resulting in profound vascular dysfunction. The sequalae of this IAV-driven vascular storm included placental growth retardation and intrauterine growth restriction, evidence of placental and fetal brain hypoxia, and increased circulating cell free fetal DNA and soluble Flt1. In contrast, IAV infection in nonpregnant mice caused no obvious alterations in endothelial function or vascular inflammation. Therefore, IAV infection during pregnancy drives a significant systemic vascular alteration in pregnant dams, which likely suppresses critical blood flow to the placenta and fetus. This study in mice provides a fundamental mechanistic insight and a paradigm into how an immune response to a respiratory virus, such as IAV, is likely to specifically drive maternal and fetal pathologies during pregnancy.

Synthesis and Characterization of Solvated Lanthanide Tris(trimethylsilyl)siloxides.

In an effort to develop precursors for the production of lanthanide silicate (LnSiOx) materials, the reactions of [Ln(NR2)3] (R = SiMe3) with three equivalents of tris(trimethylsilyl)silanol (H-OSi(SiMe3)3) or H-SST) in tetrahydrofuran (THF) were undertaken. The products were crystallographically characterized as [Ln(SST)3(THF)2] (where Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu). In general, these compounds are similar to the previously reported [Gd(SST)3(THF)2] complex, where each metal center of the monomeric species is found to adopt a trigonal bipyramidal (TBP; τ = av 0.95) geometry; however, the crystallographic structure solutions for these crystals invoke a much larger unit cell that reveals the complex disorder of the axial THF ligands. Using incompletely washed H-SST, the tetrahedrally (T-4) bound [Ln(SST)3(NEt3)] (Ln-NEt3 = Pr-NEt3, Ho-NEt3; NEt3 = triethylamine) compounds were isolated from the same reaction run in toluene. Rational syntheses of amine derivatives were realized by performing the same reaction with pure H-SST in toluene containing the appropriate amine and [Ln(NR2)3] with the final products identified as [Tm(SST)3(NEt3)] (Tm-NEt3) or [Tm(SST)3(NHPr2i)] (NHPr2i = di-iso-propylamine; Tm-NHPr2i). The products isolated from reactions undertaken in pyridine (py) were identified as [Ln(SST)3(py)2] (Ln-py = Ce-py, Eu-py, and Tm-py). The Ln-py structures exhibit the larger unit cell noted for the THF derivatives with each Ln adopting a TBP (τ = av 0.98) metal center possessing equatorial SST and axial py ligands. The same reaction run in toluene led to the isolation of [(η6-tol)Tm(SST)3] (Tm-tol). Multinuclear NMR (1H and 29Si) data support the retention of the solid-state structures of all of these compounds in solution. Photoluminescent measurements of Tb, Sm, Dy, and Eu were found to display emission and lifetime profiles in the visible range due to f-f transitions, consistent with trivalent lanthanide metal centers.

Bronchopulmonary dysplasia: Pathophysiology and potential anti-inflammatory therapies.

Inflammation of the preterm lungs is key to the pathogenesis of bronchopulmonary dysplasia (BPD), whether it arises as a consequence of intrauterine inflammation or postnatal respiratory management. This review explores steroidal and non-steroidal therapies for reducing neonatal pulmonary inflammation, aimed at treating or preventing BPD.

Stochastic descriptors to study the fate and potential of naive T cell clonotypes in the periphery.

The population of naive T cells in the periphery is best described by determining both its T cell receptor diversity, or number of clonotypes, and the sizes of its clonal subsets. In this paper, we make use of a previously introduced mathematical model of naive T cell homeostasis, to study the fate and potential of naive T cell clonotypes in the periphery. This is achieved by the introduction of several new stochastic descriptors for a given naive T cell clonotype, such as its maximum clonal size, the time to reach this maximum, the number of proliferation events required to reach this maximum, the rate of contraction of the clonotype during its way to extinction, as well as the time to a given number of proliferation events. Our results show that two fates can be identified for the dynamics of the clonotype: extinction in the short-term if the clonotype experiences too hostile a peripheral environment, or establishment in the periphery in the long-term. In this second case the probability mass function for the maximum clonal size is bimodal, with one mode near one and the other mode far away from it. Our model also indicates that the fate of a recent thymic emigrant (RTE) during its journey in the periphery has a clear stochastic component, where the probability of extinction cannot be neglected, even in a friendly but competitive environment. On the other hand, a greater deterministic behaviour can be expected in the potential size of the clonotype seeded by the RTE in the long-term, once it escapes extinction.

RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.

Pontocerebellar hypoplasias (PCH) are characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. We report five patients referred for PCH, showing atypical clinical and magnetic resonance imaging (MRI) features suggestive of defects in the Reelin pathway. We screened for mutations in RELN or VLDLR and compared the phenotype of these patients with that of previously reported patients. All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities. Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation. The four other patients had a milder phenotype consistent with CARMQ1 (cerebellar ataxia and mental retardation with or without quadrupedal locomotion). These patients showed mild simplification or thickening of cortical gyration and had VLDLR mutations. Reelin signaling regulates neuronal migration in the developing mammalian brain. VLDLR is a key component of the Reelin pathway. Our patients had a very small and dysplatic cerebellar vermis that should suggest the involvement of these genes. Moreover, differences in clinical severity, involvement of the cerebellar hemispheres, together with the severity of the neocortical defect, enables RELN-mutated patients to be distinguished from VLDLR-mutated patients.

First evidence of occupational asthma to argan powder in a cosmetic factory.

BACKGROUND: Argan is used worldwide in numerous cosmetic products, as this fruit is supposed to have many beneficial properties on health. New cases of allergy can be expected with the growing use of argan. We investigated all workers (9) employed by a cosmetic factory and exposed to argan powder to identify possible allergies related to exposure to argan powder. METHODS: Patients were investigated in the occupational disease department and, according to their symptoms, underwent pulmonary function testing, methacholine challenge, specific inhalation challenge to argan powder, skin prick tests, and immunoblotting analysis. RESULTS: We report three cases of occupational asthma to argan powder and a probable case of rhinitis. Fifteen argan proteins were recognized by the patients' IgE. Identification of proteins, cross-reactions to nuts, and ELISA inhibition tests suggested that some argan allergens can cross-react in vitro with hazelnut allergens, including 11S globulin and vicilin. CONCLUSION: High-level exposure to argan powder should be considered to be a potential cause of IgE-mediated allergy, and workers handling argan powder should be carefully investigated.

[Intravenous thrombolysis in ischemic stroke: Therapeutic perspectives]. / Thrombolyse intraveineuse des infarctus cérébraux: perspectives thérapeutiques.

New therapeutic strategies are under evaluation to improve the treatment of acute ischemic stroke (AIS). Approaches combining intravenous (IV) thrombolysis with recombinant tissue plasminogen activator (rt-PA) and antithrombotic agents are currently evaluated. The combination of IV rt-PA and aspirin showed a high rate of intracranial hemorrhage whereas the association of rt-PA and eptifibatide seems more promising. The results of recent studies evaluating the administration of eptifibatide or argatroban in conjunction with conventional IV thrombolysis with rt-PA are expected to clarify the safety and efficacy of these treatments. More fibrin-specific plasminogen activators, tenecteplase and desmoteplase, are also investigated. These fibrinolytic agents showed a favorable safety profile but their efficacy in AIS remains uncertain. While phase III studies, DIAS-3 and DIAS-4, evaluating IV desmoteplase up to nine hours after stroke onset did not meet the primary endpoint, the results of studies comparing IV tenecteplase and IV rt-PA are expected.

Occupational allergic contact dermatitis and major allergens in France: temporal trends for the period 2001-2010.

BACKGROUND: Occupational allergic contact dermatitis (OACD) is one of the most common occupational skin diseases in developed countries, but data about its temporal trends in incidence remain sparse. OBJECTIVES: The aim of this study is to describe OACD trends in terms of industrial activities and main causal agents in France over the period 2001-2010. MATERIALS AND METHODS: Data were collected from the French National Network of Occupational Disease Vigilance and Prevention (RNV3P, Réseau National de Vigilance et de Prévention des Pathologies Professionnelles). All OACD considered probably or certainly associated with an occupational exposure were included in the study. Trends were examined (i) on annual crude numbers of OACD and (ii) on reported odds ratios of OACD calculated using logistic regression models. RESULTS: Overall, 3738 cases of OACD were reported and the mean age of OACD cases was 35 years, 52% being women. The most frequent occupations were hairdressers, health care workers, cleaning staff and masons. The total number of OACD cases remained stable over the study period, but increases in OACD related to isothiazolinones (P = 0·002), epoxy resins (P = 0·012) and fragrances (P = 0·005) were observed. Conversely, decreases were noted for cement compounds (P = 0·002) and plant products (P = 0·031). These trends highlight specific sectors and exposures at risk of OACD. CONCLUSIONS: Trends in OACD depend on the nature of exposure. Observed decreases were consistent with prevention measures taken during the study period, and the increases observed serve to highlight those areas where preventative efforts need to be made to reduce skin allergies in the workplace.

Infection prevention for immunocompromised patients: A cross-translational multicentric survey of current organization in France.

OBJECTIVES: To evaluate current organization of infection prevention for immunocompromised patients (ICP) at a countrywide level. METHODS: Nationwide cross-sectional multicenter study based on an online survey disseminated in 2022 to physicians invested with preventive healthcare missions. RESULTS: A total of 341 physicians (96% graduates, 32% infectious disease specialists), participated in the survey, with a median age of 40 [35-51] years. On-site access to infection prevention consultations for ICP was reported by 30%, dedicated pre-travel consultations for ICPs by 29%, consultations for infection prevention in solid organ transplant candidates by 16% and return-to-work consultations for ICPs by 6%. Most participants (73%) were aware of nationwide vaccination guidelines for ICP, while 50% felt comfortable using them. Tools for infection prevention advice and ICP vaccination had been developed by 10%, while 89% would have appreciated access to tools developed by others. CONCLUSIONS: Infection prevention for ICPs remains neglected. Guidelines covering all fields of prevention for ICPs would be more than welcome.

Genome sequencing identify chromosome 9 inversions disrupting ENG in 2 unrelated HHT families.

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the ENG and ACVRL1 genes are responsible for most cases of HHT. Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine. Structural variations were confirmed by standard molecular cytogenetic analysis (FISH). In two families with a definite diagnosis of HHT, we identified two different paracentric inversions of chromosome 9, both disrupting the ENG gene. These inversions are considered as pathogenic and causative for the HHT phenotype of the patients. This is the first time structural variations are reported to cause HHT. As such balanced events are often missed by exon-based sequencing (panel, exome), structural variations may be an under-recognized cause of HHT. Genome sequencing for the detection of these events could be suggested for patients with a definite diagnosis of HHT and in whom no causative pathogenic variant was identified.

Detecting larval export from marine reserves.

Marine reserve theory suggests that where large, productive populations are protected within no-take marine reserves, fished areas outside reserves will benefit through the spillover of larvae produced in the reserves. However, empirical evidence for larval export has been sparse. Here we use a simple idealized coastline model to estimate the expected magnitude and spatial scale of larval export from no-take marine reserves across a range of reserve sizes and larval dispersal scales. Results suggest that, given the magnitude of increased production typically found in marine reserves, benefits from larval export are nearly always large enough to offset increased mortality outside marine reserves due to displaced fishing effort. However, the proportional increase in recruitment at sites outside reserves is typically small, particularly for species with long-distance (on the order of hundreds of kilometers) larval dispersal distances, making it very difficult to detect in field studies. Enhanced recruitment due to export may be detected by sampling several sites at an appropriate range of distances from reserves or at sites downcurrent of reserves in systems with directional dispersal. A review of existing empirical evidence confirms the model's suggestion that detecting export may be difficult without an exceptionally large differential in production, short-distance larval dispersal relative to reserve size, directional dispersal, or a sampling scheme that encompasses a broad range of distances from the reserves.

Effect of oxygen on the biosynthesis of flavor compound 3-methylbutanal from leucine catabolism during batch culture in Carnobacterium maltaromaticum LMA 28.

In this study, we demonstrated the effect of different dissolved oxygen concentrations (DOC) on cell growth and intracellular biosynthesis of 3-methylbutanal from leucine catabolism in Carnobacterium maltaromaticum LMA 28 during batch culture. The maximum specific growth rate was obtained in culture when DOC was controlled at 50% of air saturation. The specific consumption rates of glucose and specific production rates of lactate were higher at a DOC at 50 or 90% of air saturation. Carnobacterium maltaromaticum LMA 28 produced high quantities of 3-methylbutanal and 3-methylbutanol during culture with DOC maintained at 90%, suggesting that oxygen had a significant effect of the formation of these flavor compounds. This high formation of flavor compounds in an oxygen-rich environment was attributed to the simultaneous activation and stimulation of both α-ketoacid decarboxylase (KADC) and α-ketoacid dehydrogenase (KADH) pathways. Thus, intracellular biosynthesis of 3-methylbutanal can be controlled by modifying the DOC of the culture or food product during fermentation.

[Compensation for occupational diseases after tomodensitometry screening for benign pleuro-pulmonary disease in a multiregional post-occupational medical surveillance program of asbestos-exposed retired workers]. / Déclaration et reconnaissance en maladie professionnelle après dépistage tomodensitométrique de maladies pleuropulmonaires bénignes dans le programme multirégional de surveillance postprofessionnelle de personnes exposées à l'amiante.

BACKGROUND: Underreporting of occupational diseases related to asbestos exposure remains a matter of concern in France. The aim of this study was to evaluate the number of claims for compensation for asbestos-related non-malignant pulmonary or pleural occupational disease in subjects having undergone a chest CT-scan in a multiregional screening programme. METHODS: Among the 5444 voluntary retired asbestos-exposed subjects recruited in four regions between 2003 and 2005 who had undergone a chest CT-scan, the number of claims for compensation for an asbestos-related pulmonary or pleural benign disease was analysed in 2006 and 2010. RESULTS: Following CT-scan screening, 17.2% of participants were acknowledged as presenting with an asbestos-related non-malignant occupational disease, essentially pleural plaques, by the French National Health Insurance fund. Underreporting decreased as duration of follow-up after CT-scan increased. Nevertheless, 4 years after CT-scan, underreporting was still as high as 36% for subjects identified as presenting with pleural plaques. Mean duration between the date of CT-scan and the date of recognition as occupational disease was 7.4 months, shorter in cases where screening was coordinated by specialized centres. CONCLUSION: A plan of action for an easier claiming process for compensation of asbestos-related diseases is desired. This could probably be obtained through improved sensitization of physicians engaged in the follow-up of asbestos-exposed subjects, and by standardization of the interpretation and reporting of asbestos-related abnormalities observed on chest CT-scans.

Long-term follow-up of patients with extensive segmental infantile hemangioma of the cervical or facial region: A French single-center prospective study.

BACKGROUND: Infantile hemangiomas (IHs) can be part of PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, eye anomalies) syndrome when they are segmental, extensive, and located on the face or neck. The initial assessment is codified and well known, but there are no recommendations for the follow-up of these patients. The aim of this study was to assess the long-term prevalence of different associated abnormalities. METHODS: Patients with a history of large segmental IHs of the face or neck. diagnosed between 2011 and 2016 were included in the study. Each patient underwent an ophthalmological, dental, ENT (ear, nose, and throat), dermatological, neuro-pediatric, and radiological assessment at inclusion. Eight patients including five with PHACE syndrome were prospectively evaluated. RESULTS: After a mean follow-up of 8.5 years, three patients presented with an angiomatous aspect of the oral mucosa, two with hearing loss, and two with otoscopic abnormalities. No patients developed ophthalmological abnormalities. The neurological examination was altered in three cases. Brain magnetic resonance imaging follow-up was unchanged in three out four patients and revealed atrophy of the cerebellar vermis in 1 patient. Neurodevelopmental disorders were found in five of the patients and learning difficulties were observed in five patients. The S1 location appears to be associated with a higher risk of neurodevelopmental disorders and cerebellar malformations, while the S3 location was associated with more progressive complications, including neurovascular, cardiovascular, and ENT abnormalities. CONCLUSION: Our study reported late complications in patients with a large segmental IH of the face or neck, whether associated with PHACE syndrome or not, and we proposed an algorithm to optimize the long-term follow-up.

Occupational risk factors have to be considered in the definition of high-risk lung cancer populations.

BACKGROUND: The aim of this study was to compute attributable fractions (AF) to occupational factors in an area in North-Eastern France with high lung cancer rates and a past of mining and steel industry. METHODS: A population-based case-control study among males aged 40-79 was conducted, including confirmed primary lung cancer cases from all hospitals of the study region. Controls were stratified by broad age-classes, district and socioeconomic classes. Detailed occupational and personal risk factors were obtained in face-to-face interviews. Cumulative occupational exposure indices were obtained from the questionnaires. Attributable fractions were computed from multiple unconditional logistic regression models. RESULTS: A total of 246 cases and 531 controls were included. The odds ratios (ORs) adjusted on cumulative smoking and family history of lung cancer increased significantly with the cumulative exposure indices to asbestos, polycyclic aromatic hydrocarbons and crystalline silica, and with exposure to diesel motor exhaust. The AF for occupational factors exceeded 50%, the most important contributor being crystalline silica and asbestos. CONCLUSION: These AFs are higher than most published figures. This can be because of the highly industrialised area or methods for exposure assessments. Occupational factors are important risk factors and should not be forgotten when defining high-risk lung cancer populations.

[Clinical case of the month. A complicated infective endocarditis, diagnosis, treatment and prophylaxis]. / Une endocardite infectieuse compliquée: diagnostic, traitement et prophylaxie.

The case of a 60-year-old male presenting fever of recent onset is reported. He had undergone a Bentall operation seven yeasr previously. An infective endocarditis caused by Entercoccus Faecalis was detected on his prosthetic valve. After a favorable evolution under antibiotic treatment, the patient developed a perivalvular abscess requiring surgical treatment. The patient's evolution was satisfactory. Diagnosis, with the specific role of echocardiography; treatment, with a recall of surgical indications; particularities of the specific complication and prevention of this pathology are discussed.