Real-time and non-invasive acute lung rejection diagnosis using confocal LASER Endomicroscopy in lung transplant recipients: Results from the CELTICS study.

BACKGROUND AND OBJECTIVE: Traditionally, the diagnosis of acute rejection (AR) relies on invasive transbronchial biopsies (TBBs) to obtain histopathological samples. We aimed to evaluate the diagnostic yield of probe-based confocal laser endomicroscopy (pCLE) as a complementary and non-invasive tool for ACR screening, comparing its results with those obtained from TBBs. METHODS: Between January 2015 and April 2022, we conducted a retrospective study of all lung transplant recipients aged over 18 years at Toulouse University Hospital (France). All patients who underwent bronchoscopies with both TBBs and pCLE imaging were included. Two experienced interpreters (TV and MS) reviewed the pCLE images independently, blinded to all clinical information and pathology results. RESULTS: From 120 procedures in 85 patients, 34 abnormal histological samples were identified. Probe-based confocal laser endomicroscopy revealed significant associations between both alveolar (ALC) and perivascular (PVC) cellularities and abnormal histological samples (p<0.0001 and 0.003 respectively). Alveolar cellularity demonstrated a sensitivity (Se) of 85.3 %, specificity (Spe) of 43 %, positive predictive value (PPV) of 37.2 % and negative predictive value (NPV) of 88.1 %. For PVC, Se was 70.6 %, Spe 80.2 %, PPV 58.5 % and NPV 87.3 %. Intra-interpreter correlation (TV) was 88.3 % for the number of vessels (+/-1), 98.3 % for ALC and 90 % for PVC. Inter-interpreter correlation (TV and MS) was 80 % for vessels (+/-1), 97.5 % for ALC and 83.3 % for PVC. CONCLUSION: Our study demonstrates the feasibility of incorporating pCLE into clinical practice, demonstrating good diagnostic yield and reproducible outcomes in the screening of AR in lung transplant recipients.

Cytopathological analysis of salivary gland cancer: REFCOR recommendations by the formal consensus method.

OBJECTIVE: To determine the indications for fine-needle cytology and the modalities of frozen section pathological analysis in the management of salivary gland cancer. MATERIAL AND METHODS: The French Network of Rare Head and Neck Tumors (REFCOR) formed a steering group who drafted a narrative review of the literature published on Medline and proposed recommendations. The level of adherence to the recommendations was then assessed by a rating group according to the formal consensus method. RESULTS: Fine-needle cytology is recommended as part of the diagnostic work-up for a major salivary gland tumor suspicious for malignancy. Fine-needle cytology should be performed after MRI to avoid artifacts. Frozen section analysis is recommended to confirm the malignant nature of the tumor, to adapt the extent of resection and to indicate neck dissection. Whenever possible, the entire tumor and adjacent salivary or periglandular tissue should be sent for frozen section analysis. CONCLUSION: Fine-needle cytology and frozen section analysis play an essential role in the management of salivary gland cancers.

Artifacts and main lesions in fetal ocular histology.

Histological artifacts in fetal eyes can involve different tissues and can be related to mechanical or autolytic lesions, fixation, the cause of death or the cutting technique. Knowing the causes, effects and appearance of artifacts allow the minimization of the risk of avoidable artifacts and help distinguish them from "true" pathological lesions. We describe these different types of artifacts and specifically analyze their involvement in different tissue structures of the eye. We compare them with primary fetal ocular lesions. Given the wide variety of artifacts, the identification of lesions in fetal eyes must be done with caution, since differentiating true lesions from artifacts requires some experience and relies on both macroscopic examination and microscopic analyses, with ideally comparisons with references' images of normal tissues of the same gestational age.

Common and Exclusive Features of Intestinal Intraepithelial γδ T Cells and Other γδ T Cell Subsets.

Murine peripheral lymph node TCR γδ T cells have been divided into type 1 and type 17 functional categories based on phenotypic and functional markers. Localized in the gut epithelial barrier, intestinal intraepithelial lymphocytes (iIEL) γδ T cells constitute a peculiar subset of T lymphocytes involved in intestinal homeostasis. However, whether iIEL γδ T cells obey the type 1/type 17 dichotomy is unclear. Using both global transcriptional signatures and expression of cell surface markers, we reveal that murine iIEL γδ T cells compose a distinct population, expressing ∼1000 specific genes, in particular genes that are responsible for cytotoxicity and regulatory functions. The expression of the transcription factor Helios is a feature of iIEL γδ T cells, distinguishing them from the other TCR γδ T subsets, including those present in the epithelia of other tissues. The marked expression of Helios is also shared by the other iIELs, TCRαßCD8αα lymphocytes present within the intestinal epithelium. Finally, we show that Helios expression depends in part on TGF-ß signaling but not on the microbiota. Thus, our study proposes iIEL γδ T cells as a distinct subset and identifies novel markers to differentiate them from their peripheral counterparts.

SMAD4 TGF-ß-independent function preconditions naive CD8+ T cells to prevent severe chronic intestinal inflammation.

SMAD4, a mediator of TGF-ß signaling, plays an important role in T cells to prevent inflammatory bowel disease (IBD). However, the precise mechanisms underlying this control remain elusive. Using both genetic and epigenetic approaches, we revealed an unexpected mechanism by which SMAD4 prevents naive CD8+ T cells from becoming pathogenic for the gut. Prior to the engagement of the TGF-ß receptor, SMAD4 restrains the epigenetic, transcriptional, and functional landscape of the TGF-ß signature in naive CD8+ T cells. Mechanistically, prior to TGF-ß signaling, SMAD4 binds to promoters and enhancers of several TGF-ß target genes, and by regulating histone deacetylation, suppresses their expression. Consequently, regardless of a TGF-ß signal, SMAD4 limits the expression of TGF-ß negative feedback loop genes, such as Smad7 and Ski, and likely conditions CD8+ T cells for the immunoregulatory effects of TGF-ß. In addition, SMAD4 ablation conferred naive CD8+ T cells with both a superior survival capacity, by enhancing their response to IL-7, as well as an enhanced capacity to be retained within the intestinal epithelium, by promoting the expression of Itgae, which encodes the integrin CD103. Accumulation, epithelial retention, and escape from TGF-ß control elicited chronic microbiota-driven CD8+ T cell activation in the gut. Hence, in a TGF-ß-independent manner, SMAD4 imprints a program that preconditions naive CD8+ T cell fate, preventing IBD.

Epidemiology of multiple sclerosis in West bank of Palestine.

BACKGROUND: Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, and the major neurologic cause of disability in young adults. Its incidence and prevalence vary significantly between different ethnic groups and geographical regions. It is thought that MS is more frequent as we go further from the equator. In Palestine, there is yet no published data concerning its incidence and prevalence. So, in this article, we aim to study the epidemiological and clinical characteristics of MS in the West Bank of Palestine. METHODS: A retrospective observational study was conducted from year 2010 to 2019 among MS patients in West Bank. Demographic and clinical records of concerned patients were collected from the database of the Palestinian Ministry of Health. Age, sex, onset of symptoms, first symptom, year of diagnosis, family history, and smoking were noted. The crude 2019 prevalence and incidence rate were calculated. RESULTS: We identified 1652 MS patients with 1074 (65.01%) females and 578 (34.99%) males. In 2010, the crude incidence rate was 1.96 cases per 100,000. Peaked in 2017 to 6.08, and then dropped unexpectedly in 2018 to 2.91 before it re-rose again to 3.54 in 2019. The incidence rates among females were higher than in males from 2010 to 2019. 802 and 730 patients were diagnosed at age groups (below 30) year and (30-45) year respectively, which comprises 92.74% of all patients. Males were slightly more affected at a later age group (30-45), whereas females were more affected at age group below 30. The most common symptom at disease onset was motor presentation (16.04%) followed by blurring of vision (15.74%). CONCLUSION: This is the first epidemiological study regarding MS disease in the West Bank of Palestine. Our results showed that crude incidence rate is increasing from 2010 to 2017. This is in part due to increasing awareness of the disease as well as the availability of diagnostic tools. Further researches will be necessary to closely monitor this increasing trend of the disease amongst Palestinian population in the coming future. Clinical features of the disease were similar to those described in the literature.

Forced to move on: An interview study with survivors who have lost a relative to suicide.

PURPOSE: To explore the loss of a relative due to suicide. DESIGN AND METHODS: Ten survivors of relatives who had taken their lives were interviewed. Data was analyzed from a phenomenological perspective. FINDINGS: The survivors described how they witnessed the darkness that took over their relative's lifeworld. During the time before and after the suicide, the survivor felt barred from having a role in the relative's care. PRACTICE IMPLICATIONS: Understanding and exploring implicit dynamics, such as "a feeling of darkness taking over," "a sense of relief," or "putting on a mask" could be important for developing person-centered suicide care.

A T cell-intrinsic function for NF-κB RelB in experimental autoimmune encephalomyelitis.

NF-kappaB (NF-κB) is a family of transcription factors with pleiotropic functions in immune responses. The alternative NF-κB pathway that leads to the activation of RelB and NF-κB2, was previously associated with the activation and function of T cells, though the exact contribution of these NF-κB subunits remains unclear. Here, using mice carrying conditional ablation of RelB in T cells, we evaluated its role in the development of conventional CD4+ T (Tconv) cells and their function in autoimmune diseases. RelB was largely dispensable for Tconv cell homeostasis, activation and proliferation, and for their polarization toward different flavors of Thelper cells in vitro. Moreover, ablation of RelB had no impact on the capacity of Tconv cells to induce autoimmune colitis. Conversely, clinical severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS) was significantly reduced in mice with RelB-deficient T cells. This was associated with impaired expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) specifically in the central nervous system. Our data reveal a discrete role for RelB in the pathogenic function of Tconv cells during EAE, and highlight this transcription factor as a putative therapeutic target in MS.

Guidelines of the French Society of Otorhinolaryngology-Head and Neck Surgery (SFORL), part II: Management of recurrent pleomorphic adenoma of the parotid gland.

INTRODUCTION: The authors present the guidelines of the French Society of Otorhinolaryngology-Head and Neck Surgery (SFORL) for the management of recurrent pleomorphic adenoma (RPA) of the parotid gland. METHOD: A review of the literature was performed by a multidisciplinary task force. Guidelines were drafted, based on the articles retrieved and the work group members' individual experience. There were then read and re-edited by an independent reading group. The proposed recommendations were graded A, B or C on decreasing levels of evidence. RESULTS: Complete resection under neuromonitoring is recommended in case of RPA. The risks of progression and malignant transformation, which are higher the younger the patient, have to be taken into consideration. The risk of functional sequelae must be explained to the patient. MRI is recommended ahead of any surgery for parotid RPA, to determine extension and detect subclinical lesions. Radiotherapy should be considered in case of multi-recurrent pleomorphic adenoma after macroscopically complete revision surgery at high risk of new recurrence (microscopic residual disease), in case of RPA after incomplete resection, and in non-operable RPA.

Guidelines of the French Society of Otorhinolaryngology-Head and Neck Surgery (SFORL), part I: Primary treatment of pleomorphic adenoma.

INTRODUCTION: The authors present the guidelines of the French Society of Otorhinolaryngology-Head and Neck Surgery (SFORL) for the diagnosis and treatment of pleomorphic adenoma (PA) of the salivary glands. METHOD: A review of the literature was performed by a multidisciplinary task force. Guidelines were drafted based on the articles retrieved and the workgroup members' individual experience. Guidelines were graded A, B, C or expert opinion by decreasing level of evidence. RESULTS: In clinically suspected salivary gland PA, MRI should be performed, including head and neck lymph node levels. Fine needle aspiration cytology is particularly recommended for tumours difficult to characterise by MRI. Frozen section biopsy should be performed to confirm diagnosis and adapt the surgical procedure in case of intraoperative findings of malignancy. Complete resection of the parotid PA should be performed en bloc, including margins, when feasible according to tumour location, while respecting the facial nerve. Enucleation (resection only in contact with the tumour) is not recommended. For the accessory salivary and submandibular glands, complete en bloc resection should be performed.

Epidemiology of breast cancer in women based on diagnosis data from oncologists and senologists in Algeria.

BACKGROUND: Breast cancer (BC) is a major health issue threatening women's life. No reliable epidemiological data on BC diagnosed by oncologists/senologists are available in Algeria. METHODS: The BreCaReAl study, a non-interventional prospective cohort study, included adult women with confirmed BC in Algeria. Disease incidence, patients and disease characteristics, treatment patterns, and mortality rate were recorded up to 12 months of follow-up. RESULTS: Overall, 1,437 patients were analysed: median age was 48 [41;57] years and 337 (23.5%) women had a family history of BC. BC incidence was 22.3 (95% CI: 21.5; 23.2) cases per 100,000 inhabitants over 8 months. Delayed diagnosis was reported in 400 (29.2%) patients. First line of treatments were mainly chemotherapy and surgery. Twenty-eight serious adverse events were reported including 10 (37.0%) events which led to death. Mortality rate reached 3.2% at 12 months CONCLUSION: A delayed diagnosis highlights the importance of implementing more effective screening strategies.

Improved tribological properties, thermal and colloidal stability of poly-α-olefins based lubricants with hydrophobic MoS2 submicron additives.

HYPOTHESIS: Newtonian liquids, usually used as base oil lubricants, exhibit low viscosity under extreme thermal conditions, needed for the functioning of wind turbines. This is directly affecting the colloidal stability and the tribological properties of the formulations containing additives, such as MoS2. Here, it was hypothesized that the surface hydrophobization of MoS2 particles will allow for an increased colloidal stability of the resulting formulations, for temperatures as high as 80 °C. EXPERIMENTS: The antifriction properties and the thermal stability of the designed formulations were determined on submicron MoS2 particles dispersed in poly-α-olefins (PAO) base oils of different dynamic viscosities (from 32 to 1650 mPa·s at 25 °C). The submicron particles of MoS2 (300-500 nm in diameter) were synthesised by a simple one-pot solvothermal method under mild conditions. The resulting particles were hydrophobized in situ in PAO base oils using alkyltrichlorosilane grafting agents with two chain lengths (C8 and C18). FINDINGS: The covalent grafting of alkylsilanes through Mo-O-Si bonds was confirmed by DFT calculations and FT-IR measurements. Turbiscan optical analysis revealed that thermal and colloidal stabilities can be significantly improved depending on oil viscosity and chain length of the grafting agent. The formulations in the PAO65 oil remained highly stable (TSI < 1), even at 80 °C. Herein, we demonstrate the impact of hydrophobization degree on the tribological properties of the lubricants, which, importantly, could reach ultra-low friction coefficients, less than 0.02.

Transforming Growth Factor-beta signaling in αß thymocytes promotes negative selection.

In the thymus, the T lymphocyte repertoire is purged of a substantial portion of highly self-reactive cells. This negative selection process relies on the strength of TCR-signaling in response to self-peptide-MHC complexes, both in the cortex and medulla regions. However, whether cytokine-signaling contributes to negative selection remains unclear. Here, we report that, in the absence of Transforming Growth Factor beta (TGF-ß) signaling in thymocytes, negative selection is significantly impaired. Highly autoreactive thymocytes first escape cortical negative selection and acquire a Th1-like-phenotype. They express high levels of CXCR3, aberrantly accumulate at the cortico-medullary junction and subsequently fail to sustain AIRE expression in the medulla, escaping medullary negative selection. Highly autoreactive thymocytes undergo an atypical maturation program, substantially accumulate in the periphery and induce multiple organ-autoimmune-lesions. Thus, these findings reveal TGF-ß in thymocytes as crucial for negative selection with implications for understanding T cell self-tolerance mechanisms.

An innovative in vitro device providing continuous low doses of γ-rays mimicking exposure to the space environment: A dosimetric study.

Astronauts are exposed to microgravity and chronic irradiation but experimental conditions combining these two factors are difficult to reproduce on earth. We have created an experimental device able to combine chronic irradiation and altered gravity that may be used for cell cultures or plant models in a ground based facility. Irradiation was provided by thorium nitrate powder, conditioned so as to constitute a sealed source that could be placed in an incubator. Cell plates or plant seedlings could be placed in direct contact with the source or at various distances above it. Moreover, a random positioning machine (RPM) could be positioned on the source to simulate microgravity. The activity of the source was established using the Bateman formula. The spectrum of the source, calculated according to the natural decrease of radioactivity and the gamma spectrometry, showed very good adequacy. The experimental fluence was close to the theoretical fluence evaluation, attesting its uniform distribution. A Monte Carlo model of the irradiation device was processed by GATE code. Dosimetry was performed with radiophotoluminescent dosimeters exposed for one month at different locations (x and y axes) in various cell culture conditions. Using the RPM placed on the source, we reached a mean absorbed dose of gamma rays of (0.33 ± 0.17) mSv per day. In conclusion, we have elaborated an innovative device allowing chronic radiation exposure to be combined with altered gravity. Given the limited access to the International Space Station, this device could be useful to researchers interested in the field of space biology.

Ultrasound-guided fine-needle capillary cytology of parotid gland masses coupled with a rapid-on-site evaluation improves results.

OBJECTIVE OF THE STUDY: To test whether a direct-on-site microscopic examination of fresh, unstained puncture slides by the radiologist decreases the rate of false-negative cases on ultrasound-guided fine-needle cytology of parotid gland masses. PATIENTS: Thirty parotid gland masses from 28 patients were punctured under ultrasound guidance. The same group was used as its control group. METHODS: After one or two passes, the material was spread on slides and air-dried (control group, without microscopic examination). For the study group, it was thus analyzed unstained under the microscope. A sample was considered adequate if at least six clusters of parotid cells were found per slide on at least two slides. For the study group, new punctures were obtained and slides prepared until this condition was fulfilled. RESULTS: Of the 30 evaluated masses, 100% benefited from a cytological diagnosis after microscopy. Twenty-four were adequate in the control group, while 30 were adequate in the study group. The maximum number of punctures to obtain an adequate sample was six. On-site direct microscopy significantly increased the number of adequate specimens by 20% (P=0.03, CI [1.63-20%]). CONCLUSION: Direct and systematic examination of slides by a radiologist avoided the risk of false-negative results caused by having insufficient sample material.

Fully-coupled mathematical modeling of actomyosin-cytosolic two-phase flow in a highly deformable moving Keratocyte cell.

Interaction between intracellular dynamics and extracellular matrix (ECM) generally occurred into very thin fragment of moving cell, namely lamellipodia, enables all movable cells to crawl on ECM. In fast-moving cells such as fish Keratocytes, Lamellipodia including most cell area finds a fan-like shape during migration, with a variety of aspect ratio function of fish type. In this work, our purpose is to present a novel and more complete two-dimensional continuum mathematical model of actomyosin-cytosolic two-phase flow of a self-deforming Keratocyte with circular spreaded to steady fan-like shape. In the new approach, in addition to the two-phase flow of the F-actin and cytosol, the G-actin transport was spatiotemporally modeled. We also for the first time modeled the effect of variable volume fraction of the moving F-actin porous network on solute transport in the cytosolic fluid. Our novel fully-coupled mathematical model provides a better understanding of intracellular dynamics of fast-migrating Keratocytes; such as the F-actin centripetal and cytosolic fountain-like flows, free-active myosin distribution, distribution sequence of the G-actin, F-actin, and myosin, and myosin-induced pressure flied of cytoplasm as well as the map of intracellular forces like myosin contraction and adhesion traction. All these results are qualitatively and quantitatively in good agreement with experimental observations. According to a range of value of parameters used in this model, our steady state of moving Keratocyte finds fan-like shape with the same aspect ratio as wide category of fish Keratocytes. This new model can predict shape of Keratocytes in other range of parameter values.

Synthetic nanocomposite MgH2/5 wt. % TiMn2 powders for solid-hydrogen storage tank integrated with PEM fuel cell.

Storing hydrogen gas into cylinders under high pressure of 350 bar is not safe and still needs many intensive studies dedic ated for tank's manufacturing. Liquid hydrogen faces also severe practical difficulties due to its very low density, leading to larger fuel tanks three times larger than traditional gasoline tank. Moreover, converting hydrogen gas into liquid phase is not an economic process since it consumes high energy needed to cool down the gas temperature to -252.8 °C. One practical solution is storing hydrogen gas in metal lattice such as Mg powder and its nanocomposites in the form of MgH2. There are two major issues should be solved first. One related to MgH2 in which its inherent poor hydrogenation/dehydrogenation kinetics and high thermal stability must be improved. Secondly, related to providing a safe tank. Here we have succeeded to prepare a new binary system of MgH2/5 wt. % TiMn2 nanocomposite powder that show excellent hydrogenation/dehydrogenation behavior at relatively low temperature (250 °C) with long cycle-life-time (1400 h). Moreover, a simple hydrogen storage tank filled with our synthetic nanocomposite powders was designed and tested in electrical charging a battery of a cell phone device at 180 °C through a commercial fuel cell.

Use of fluorescent in-situ hybridisation in salivary gland cytology: A powerful diagnostic tool.

OBJECTIVE: Salivary gland cytology is challenging because it includes a diversity of lesions and a wide spectra of tumours. Recently, it has been reported that many types of salivary gland tumours have specific molecular diagnostic signatures that could be identified by fluorescent in-situ hybridisation (FISH). The aim of the present study was to demonstrate the feasibility and efficiency of FISH on routine cytological salivary gland smears. METHODS: FISH was conducted on 37 cytological salivary gland smears from 34 patients. According to the cytological diagnosis suspected, MECT1/MAML2 gene fusion and rearrangements of PLAG1, MYB, or ETV6 were analysed. The presence and percentages of cells that had gene rearrangements were evaluated. Results were compared with the histological surgical samples, available from 26 patients. RESULTS: The PLAG1 rearrangement was observed in 12/20 (60%) cases of pleomorphic adenoma. MECT1/MAML2 gene fusion was observed in 1:2 mucoepidermoid carcinomas but was not observed in five other tumours (two pleomorphic adenomas, one Warthin's tumour, one mammary analogue secretory carcinoma [MASC] and one cystic tumour). MYB rearrangement was observed in 4/4 adenoid cystic carcinomas. ETV6-gene splitting identified one MASC. CONCLUSION: Overall, FISH had a specificity of 100% and a sensitivity of 66.7%. When FISH and cytological analyses were combined, the overall sensitivity was increased to 93.3%. It can thus be concluded that when the FISH analysis is positive, the extent of surgery could be determined with confidence pre-operatively without needing a diagnosis from a frozen section.

Theoretical modeling of actin-retrograde-flow passing clusters of confined T cell receptors.

Through the activation process of T cells, actin filaments move from the cell periphery toward the cell center. The moving filaments engage with T cell receptors and thus contribute to transportation of the signaling molecules. To study the connection between the moving actin filaments and T cell receptors, an experiment available in the literature has measured filaments flow velocity passing over a region of confined clusters of receptors. It shows that flow velocity decreases in the proximity of the receptors, and then regains its normal value after traversing the region, suggesting a dissipative friction-like connection. In this work, we develop a minimal theoretical model to re-examine this experiment. The model brings the insight that, in contrast to the first impression that the experiment gives, the direct necessity of having a minimum in the velocity profile is not the locally high friction region, but a combined driving force of push from upstream and pull from within and downstream of the system. The predicted driving force integrates our current understanding of the spatially dependent role of the myosin motor proteins and the actin-polymerization-machinery, which make the pulling and pushing forces, respectively.