Modifications in Upper Airway Collapsibility during Sleep Endoscopy with a Mandibular Positioner: Study in Snorers and Obstructive Sleep Apnea Patients.

BACKGROUND: Mandibular advancement devices (MADs) are an effective treatment for patients with sleep-related breathing disorders, with variable response. Increasingly more research points to the predictive value of Drug-Induced Sleep Endoscopy (DISE) in patient selection. This study aims to analyze the changes in upper airway collapsibility using a titratable MAD simulator during DISE. METHODS: This study included 104 patients with simple snoring and obstructive sleep apnea (OSA). The VOTE scale was used to assess the presence of collapses during the DISE both without and with the MAD simulator. RESULTS: In snorers, there was a decrease in collapses at the level of the soft palate and oropharynx when the advancement was achieved. Patients with mild OSA also showed a decrease in collapses at the base of the tongue. Patients with moderate/severe OSA exhibited significant amelioration at all levels. The levels at which there were residual collapses despite the maneuver were, in order, the velopharynx, oropharynx, epiglottis, and tongue. CONCLUSIONS: The MAD simulator reduces collapsibility at all levels and in all severity groups. Residual collapses suitable for combined treatments were able to be identified. This highlights the need for individualized patient selection, as upper airway collapsibility exhibits variable improvement or worsening with the MAD simulator regardless of the severity of the condition.

DISE with CPAP: a useful procedure to evaluate upper airway collapsibility.

PURPOSE: Drug-induced sleep endoscopy (DISE) is commonly performed in patients suffering obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) intolerance. We aimed to evaluate the effects of adding CPAP to DISE to provide understanding of the reason of its failure and better guidance in future therapeutic decisions. METHODS: A retrospective observational descriptive study was conducted on CPAP-intolerant patients with moderate-severe OSA. DISE was used to evaluate upper airway collapsibility, and CPAP was tested to better describe anatomical sites of obstruction and to measure the opening pharyngeal pressure. RESULTS: Sample size consisted of 38 patients with a mean age of 49 ± 9 years. Mean BMI was 28.4 ± 2.4 kg/m2, mean apnea-hypopnea index (AHI) was 35.4 events per hour ± 20.1, and mean saturation under 90% (TSat90) was 14.5%. In DISE we found a collapse at Velum in 92% of patients, at Oropharyngeal level in 89%, at tongue in 42%, and at epiglottis in 36%. In the subgroup of patients with clinical failure with CPAP, we observed 100% of epiglottic collapse and 50% of tongue obstruction. In this specific population, we recommended personalized surgery and myofunctional therapy. CONCLUSION: DISE-CPAP is a useful tool to select the treatment that better fits to each patient taking care all information available. It improves our ability to prescribe a multilevel treatment with an exhaustive topographic evaluation of upper airway collapsibility that complements CPAP classic titration, and it can be helpful to distinguish better candidates for surgery, myofunctional therapy or CPAP.

Defective mitochondria remodelling in B cells leads to an aged immune response.

The B cell response in the germinal centre (GC) reaction requires a unique bioenergetic supply. Although mitochondria are remodelled upon antigen-mediated B cell receptor stimulation, mitochondrial function in B cells is still poorly understood. To gain a better understanding of the role of mitochondria in B cell function, here we generate mice with B cell-specific deficiency in Tfam, a transcription factor necessary for mitochondrial biogenesis. Tfam conditional knock-out (KO) mice display a blockage of the GC reaction and a bias of B cell differentiation towards memory B cells and aged-related B cells, hallmarks of an aged immune response. Unexpectedly, blocked GC reaction in Tfam KO mice is not caused by defects in the bioenergetic supply but is associated with a defect in the remodelling of the lysosomal compartment in B cells. Our results may thus describe a mitochondrial function for lysosome regulation and the downstream antigen presentation in B cells during the GC reaction, the dysruption of which is manifested as an aged immune response.

Tuning Ni-Pyrazolate Frameworks by Post-Synthetic Fe-Incorporation for Oxidase-Mimicking H2 O2 Activation.

The introduction of iron ionic sites by metal exchange of defective homometallic nickel pyrazolate frameworks generates non-precious, Earth-abundant, first-row heterometallic Fe/Ni-pyrazolate frameworks. The Fe incorporation at the Ni nodes of the framework allows to control the hydrogen peroxide activation, minimizing its decomposition and O2 liberation, occurring at the homometallic Ni nodes. The generation of Fe-OH reactive oxygen species at the heterometallic Fe/Ni nodes is demonstrated by the higher activity in the proof-of-concept oxidation of 1-phenylethanol to acetophenone in an aqueous medium.

Physiological and therapeutic relevance of T cell receptor-mediated antigen trogocytosis.

Trogocytosis is an active process whereby fragments of plasma membrane proteins and cytoplasm are transferred from one cell to another in a cell-cell contact-dependent manner. T cells trogocytose pieces of the cells presenting antigen to them at the site of the immunological synapse. Fragments of the antigen-presenting cell membrane rich in antigen/major histocompatibility (MHC) complexes are internalized by the T cell. Those complexes are redirected to the plasma membrane of the T cell, which becomes an antigen-presenting cell to other T cells. Removing antigen/MHC complexes from professional and tumoral cells has consequences for the intensity and duration of the immune response. However, the acquired capacity of T cells to present the acquired cognate antigen/MHC complexes also affects the properties of the antigen-presenting trogocytotic T cells. Acting as antigen-presenting cells, trogocytotic CD4 T cells influence the differentiation of cytotoxic T cells and the differentiation of other CD4 T cells into pro-inflammatory effector T cells. Furthermore, trogocytosis of antigen/MHC complexes promotes the differentiation of the trogocytotic CD4 T cells towards regulatory T cells and Th2 effector cells. Trogoctyosis is, therefore, a parallel mechanism to signal transduction by membrane receptors, including the T cell antigen receptor, at the plane of the plasma membrane.

Growth hormone remodels the 3D-structure of the mitochondria of inflammatory macrophages and promotes metabolic reprogramming.

Introduction: Macrophages are a heterogeneous population of innate immune cells that support tissue homeostasis through their involvement in tissue development and repair, and pathogen defense. Emerging data reveal that metabolism may control macrophage polarization and function and, conversely, phenotypic polarization may drive metabolic reprogramming. Methods: Here we use biochemical analysis, correlative cryogenic fluorescence microscopy and cryo-focused ion-beam scanning electron microscopy. Results: We demonstrate that growth hormone (GH) reprograms inflammatory GM-CSF-primed monocyte-derived macrophages (GM-MØ) by functioning as a metabolic modulator. We found that exogenous treatment of GM-MØ with recombinant human GH reduced glycolysis and lactate production to levels similar to those found in anti-inflammatory M-MØ. Moreover, GH treatment of GM-MØ augmented mitochondrial volume and altered mitochondrial dynamics, including the remodeling of the inner membrane to increase the density of cristae. Conclusions: Our data demonstrate that GH likely serves a modulatory role in the metabolism of inflammatory macrophages and suggest that metabolic reprogramming of macrophages should be considered as a new target to intervene in inflammatory diseases.

Ag2(0) dimers within a thioether-functionalized MOF catalyze the CO2 to CH4 hydrogenation reaction.

Ultrasmall silver clusters in reduced state are difficult to synthesize since silver atoms tend to rapidly aggregate into bigger entities. Here, we show that dimers of reduced silver (Ag2) are formed within the framework of a metal-organic framework provided with thioether arms in their walls (methioMOF), after reduction with NaBH4 of the corresponding Ag+-methioMOF precursor. The resulting Ag2-methioMOF catalyzes the methanation reaction of carbon dioxide (CO2 to CH4 hydrogenation reaction) under mild reaction conditions (1 atm CO2, 4 atm H2, 140 °C), with production rates much higher than Ag on alumina and even comparable to the state-of-the-art Ru on alumina catalyst (Ru-Al2O3) under these reaction conditions, according to literature results.

Epigenetic age deacceleration in youth at familial risk for schizophrenia and bipolar disorder.

Epigenetic modifications occur sequentially during the lifespan, but their pace can be altered by external stimuli. The onset of schizophrenia and bipolar disorder is critically modulated by stressors that may alter the epigenetic pattern, a putative signature marker of exposure to environmental risk factors. In this study, we estimated the age-related epigenetic modifications to assess the differences between young individuals at familial high risk (FHR) and controls and their association with environmental stressors. The sample included 117 individuals (6-17 years) at FHR (45%) and a control group (55%). Blood and saliva samples were used estimate the epigenetic age with six epigenetic clocks through methylation data. Environmental risk was measured with obstetric complications, socioeconomic statuses and recent stressful life events data. Epigenetic age was correlated with chronological age. FHR individuals showed epigenetic age deacceleration of Horvath and Hannum epigenetic clocks compared to controls. No effect of the environmental risk factors on the epigenetic age acceleration could be detected. Epigenetic age acceleration adjusted by cell counts showed that the FHR group was deaccelerated also with the PedBE epigenetic clock. Epigenetic age asynchronicities were found in the young at high risk, suggesting that offspring of affected parents follow a slower pace of biological aging than the control group. It still remains unclear which environmental stressors orchestrate the changes in the methylation pattern. Further studies are needed to better characterize the molecular impact of environmental stressors before illness onset, which could be critical in the development of tools for personalized psychiatry.

Quantification of Intracellular ATP Content in Ex Vivo GC B Cells.

The study of immunometabolism is an important and emerging field in immunology. B-cell activation upon antigen recognition induces profound metabolic changes in the cell, leading to an increase in ATP production to sustain cell proliferation and differentiation. Current methods available to determine the amount of ATP are time-consuming, require extensive sample processing, and need a large amount of starting material. We set up an easy follow-up protocol to determine the relative amount of ATP in living cells, combining cell surface staining with quinacrine. This acridine dye emits a green fluorescent signal in the presence of intracellular ATP. This protocol allows us to determine ATP in small populations of cells using flow cytometry, such as the germinal center.

Bacteria-instructed B cells cross-prime naïve CD8+ T cells triggering effective cytotoxic responses.

In addition to triggering humoral responses, conventional B cells have been described in vitro to cross-present exogenous antigens activating naïve CD8+ T cells. Nevertheless, the way B cells capture these exogenous antigens and the physiological roles of B cell-mediated cross-presentation remain poorly explored. Here, we show that B cells capture bacteria by trans-phagocytosis from previously infected dendritic cells (DC) when they are in close contact. Bacterial encounter "instructs" the B cells to acquire antigen cross-presentation abilities, in a process that involves autophagy. Bacteria-instructed B cells, henceforth referred to as BacB cells, rapidly degrade phagocytosed bacteria, process bacterial antigens and cross-prime naïve CD8+ T cells which differentiate into specific cytotoxic cells that efficiently control bacterial infections. Moreover, a proof-of-concept experiment shows that BacB cells that have captured bacteria expressing tumor antigens could be useful as novel cellular immunotherapies against cancer.

MOF-Triggered Synthesis of Subnanometer Ag02 Clusters and Fe3+ Single Atoms: Heterogenization Led to Efficient and Synergetic One-Pot Catalytic Reactions.

The combination of well-defined Fe3+ isolated single-metal atoms and Ag2 subnanometer metal clusters within the channels of a metal-organic framework (MOF) is reported and characterized by single-crystal X-ray diffraction for the first time. The resulting hybrid material, with the formula [Ag02(Ag0)1.34FeIII0.66]@NaI2{NiII4[CuII2(Me3mpba)2]3}·63H2O (Fe3+Ag02@MOF), is capable of catalyzing the unprecedented direct conversion of styrene to phenylacetylene in one pot. In particular, Fe3+Ag02@MOF─which can easily be obtained in a gram scale─exhibits superior catalytic activity for the TEMPO-free oxidative cross-coupling of styrenes with phenyl sulfone to give vinyl sulfones in yields up to >99%, which are ultimately transformed, in situ, to the corresponding phenylacetylene product. The results presented here constitute a paradigmatic example of how the synthesis of different metal species in well-defined solid catalysts, combined with speciation of the true metal catalyst of an organic reaction in solution, allows the design of a new challenging reaction.

Palatopharyngeal Arch Staging System (PASS): Consensus about Oropharyngeal Evaluation.

Intraoral examinations are essential in the evaluation of the upper airway in patients with obstructive sleep apnea (OSA). The morphology of the anatomic structures of the soft palate, the tonsillar fossae, and the palatoglossus and palatopharyngeal muscles is an important determinant of the size and collapsibility of the velum and oropharynx. The Palatopharyngeal Arch Staging System (PASS) is a systematic way to explore the oropharynx and report anatomic variations in the visible part of the palatopharyngeal muscle. In this prospective study, 30 sleep surgeons evaluated the reliability of the PASS using a selection of 23 videos of oropharyngeal examinations of healthy patients. The corresponding score on the PASS scale was graded for each examination. For internal structure and internal agreement, the Cronbach and Krippendorff alpha values were 0.96 and 0.46, which corresponded to a nearly perfect interrelationship and a moderate agreement, respectively. These findings suggest that the PASS is a valuable tool for evaluating the position of the palatopharyngeus muscle during oropharyngeal examinations and may be useful for creating a common language for sleep surgeons when evaluating the palatopharyngeal muscle.

Coagulation Alterations in Major Burn Patients: A Narrative Review.

Major burn patients (MBP) can present multifactorial coagulation alterations induced by trauma and endothelial damage, fluid replacement therapy, hypothermia, hypoperfusion, acidosis, and activation of the inflammatory cascade. However, the multiple coagulation alterations that occur are still poorly defined. The aim of this review is to combine the results of the different coagulation tests currently used to study coagulation changes in these patients. The PubMed database was searched for articles reporting factor levels or coagulation tests using the keywords "Burns" and "Blood Coagulation". Of the 720 articles retrieved from the search, 20 were finally included in the review. Coagulopathy in the MBP differs from that of the trauma patient, insofar as the former present with an increase in factors VIII, IX, and vW on admission accompanied by an increase in fibrin and thrombin production. This is followed by activation of fibrinolysis and prolonged prothrombin (PT) and thromboplastin (aPTT) times in the first 24 hours, increased fibrinogen after 48 hours, and thrombocytosis between the second and third week. Viscoelastic testing shows a pattern that shifts from normal coagulation to a hypercoagulable state with no evidence of hyperfibrinolysis. Alterations in PT and aPTT together with elevated Factor VIII have been associated with mortality, while normalization of antithrombin, and protein C and S levels are associated with a good prognosis. Although standard coagulation tests initially show alterations, the MBP does not appear to be hypocoagulable, and viscoelastic testing shows a trend toward hypercoagulability over time. Coagulation disorders affect prognosis in the MBP.

Cognitive reserve and its correlates in child and adolescent offspring of patients diagnosed with schizophrenia or bipolar disorder.

AIM: To analyze cognitive reserve (CR) in child and adolescent offspring of patients diagnosed with schizophrenia (SZ-off) or bipolar disorder (BD-off) and compare them with a group of community controls (CC-off). We also aimed to investigate whether there was an association between CR and clinical and neuropsychological variables according to group. METHODS: The study included 46 SZ-off, 105 BD-off and 102 CC-off. All participants completed assessments regarding CR and clinical, neuropsychological and psychosocial functioning. CR was measured with a proxy based on premorbid intelligence, parental occupational level, educational attainment, developmental milestones and sociability. The clinical assessment included the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime, the Semi-structured Interview for Prodromal Syndromes, and the Global Assessment Functioning scale. The neuropsychological assessment included measures of executive functioning, attention, verbal memory, working memory and processing speed. RESULTS: SZ-off showed a lower level of CR compared to BD-off and CC-off, while BD-off showed an intermediate level of CR between SZ-off and CC-off. Moreover, an association between higher CR and less lifetime psychopathology, fewer prodromal psychotic symptoms, higher psychosocial functioning, and a higher working memory score was observed in all groups, but it was stronger in SZ-off. CONCLUSIONS: CR seemed to be associated with psychopathology, clinical symptoms, psychosocial functioning, and some cognitive functions. SZ-off appeared to benefit more from a higher CR, therefore it could be considered a protective factor against the development of clinical symptomatology and cognitive impairment.

In vitro antibacterial activity of antiretroviral drugs on key commensal bacteria from the human microbiota.

Introduction: Antiretroviral therapy has improved life expectancy in HIV-infected patients. However, people living with HIV under antiretroviral therapy are at higher risks of developing chronic complications and acquiring multidrug resistant bacteria than healthy population. These factors have been associated with shifts in gut microbiome composition and immune activation. It is unclear how antiretroviral drugs affect gut microbiota composition, but it has been observed that antiretroviral treatment is not able to fully restore gut health after HIV infection. Additionally, some antiretroviral drugs have shown antibacterial activity suggesting that these drugs could have a direct impact on the human microbiome composition. Methods: We determined the in vitro antibacterial activity of 16 antiretroviral drugs against a set of key clinically relevant and human commensal bacterial strains. Results: Our results demonstrate that 5 antiretroviral drugs have in vitro antibacterial activity against gut and vaginal human commensal bacteria. Zidovudine has antibacterial activity against Escherichia coli, Klebsiella pneumoniae and Prevotella bivia, abacavir against Gardnerella vaginalis, efavirenz against G. vaginalis and P. bivia and bictegravir against Enterococcus spp. and G. vaginalis. Moreover, we describe for the first time that elvitegravir has antibacterial activity against G. vaginalis and P. bivia and, most importantly, against vancomycin-resistant Enterococcus spp. and methicillin-resistant Staphylococcus aureus strains with MIC values of 4-16 and 4 µg/mL, respectively showing high level of effectiveness against the tested multidrug-resistant bacteria. Discussion: Our results underscore that some antiretroviral drugs may influence the human microbiota composition. In addition, we report the potential use of elvitegravir to treat multidrug-resistant Gram-positive bacteria warranting the need of clinical studies to repurpose this antiretroviral drug.

Recovery of hypothalamic-pituitary-gonadal function with low dose testosterone treatment in a male with congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare disease caused by deficiency or action of gonadotropin-releasing hormone. While generally considered a long-life condition, CHH can be reversible in about 5%-20% of cases, but mechanisms of reversibility are unknown. We report the case of a male with CHH who began treatment with low dose (20 mg/day) transdermal testosterone to induce pubertal development at age 17. Following the start of treatment, he experienced testicular growth and his serum testosterone concentrations increased beyond the expectations in relation to the dose. Treatment was withdrawn, but this led to the reappearance of symptoms of hypogonadism and a drop in testosterone levels. Testosterone was again prescribed at the same dose and, for the subsequent years, he completed full puberty, including attainment of 20 cc testicular volume, mature secondary sexual characteristics, normal levels of testosterone and only partially arrested germinal function, as demonstrated by inhibin B levels and spermogram. Testosterone treatment was withdrawn three more times, but hypogonadism resumed on each occasion. This case suggests that low-dose testosterone treatment can induce reversal of CHH through the activation, albeit non-permanent, of the hypothalamic-pituitary-gonadal axis, indicating that testosterone administration might be a reliable therapeutic option for reverting GnRH deficiency.

Depression and Suicide Risk in Mild Cognitive Impairment: The Role of Alzheimer's Disease Biomarkers.

BACKGROUND: Patients with depression and mild cognitive impairment (MCI) are at greater risk of developing dementia. Depression involves a higher risk of suicidal ideation (SI) and suicide attempts (SA). Biomarkers of Alzheimer's Disease (AD) could help to clarify the role of depression and SI in AD. METHOD: Fifty-nine participants aged > 50 with criteria of MCI positive (MCI-AD) (n=22) and negative (MCI-Non AD) (n=24) AD and healthy controls (HC) (n=13) were evaluated. We used the Geriatric Depression Scale (GDS-30) and the GDS-SI factor to measure depression and indirect risk for suicide, respectively. Additionally, AD biomarkers such as amyloid-ß (Aß), hyperphosphorilated tau (P-tau), and total tau (T-tau) in cerebrospinal fluid (CSF) were analyzed. RESULTS: No significant differences between the groups were found in depression. However, in the MCI-AD group, lower P-tau and T-tau levels were related to higher GDS-SI scores, suggesting that MCI-AD patients with lower AD pathology are at a higher risk of suicide. CONCLUSIONS: The result highlights the importance of considering SI in the initial phases of AD, and the potential role of AD biomarkers in early detection of symptoms.

Highly Efficient MOF-Driven Silver Subnanometer Clusters for the Catalytic Buchner Ring Expansion Reaction.

The preparation of novel efficient catalysts─that could be applicable in industrially important chemical processes─has attracted great interest. Small subnanometer metal clusters can exhibit outstanding catalytic capabilities, and thus, research efforts have been devoted, recently, to synthesize novel catalysts bearing such active sites. Here, we report the gram-scale preparation of Ag20 subnanometer clusters within the channels of a highly crystalline three-dimensional anionic metal-organic framework, with the formula [Ag20]@AgI2NaI2{NiII4[CuII2(Me3mpba)2]3}·48H2O [Me3mpba4- = N,N'-2,4,6-trimethyl-1,3-phenylenebis(oxamate)]. The resulting crystalline solid catalyst─fully characterized with the help of single-crystal X-ray diffraction─exhibits high catalytic activity for the catalytic Buchner ring expansion reaction.

Depression and Suicide Risk in Mild Cognitive Impairment: The Role of Alzheimer’s Disease Biomarkers / Depresión y Riesgo de Suicidio en el Deterioro Cognitivo Leve: el Rol de los Biomarcadores de la Enfermedad de Alzheimer

Background: Patients with depression and mild cognitive impairment (MCI) are at greater risk of developing dementia. Depression involves a higher risk of suicidal ideation (SI) and suicide attempts (SA). Biomarkers of Alzheimer’s Disease (AD) could help to clarify the role of depression and SI in AD. Method: Fifty-nine participants aged > 50 with criteria of MCI positive (MCI-AD) (n=22) and negative (MCI-Non AD) (n=24) AD and healthy controls (HC) (n=13) were evaluated. We used the Geriatric Depression Scale (GDS-30) and the GDS-SI factor to measure depression and indirect risk for suicide, respectively. Additionally, AD biomarkers such as amyloid-ß (Aß), hyperphosphorilated tau (P-tau), and total tau (T-tau) in cerebrospinal fluid (CSF) were analyzed. Results: No significant differences between the groups were found in depression. However, in the MCI-AD group, lower P-tau and T-tau levels were related to higher GDS-SI scores, suggesting that MCI-AD patients with lower AD pathology are at a higher risk of suicide. Conclusions: The result highlights the importance of considering SI in the initial phases of AD, and the potential role of AD biomarkers in early detection of symptoms.(AU)

Antecedentes: Los pacientes con depresión y deterioro cognitivo leve (DCL) tienen un alto riesgo de desarrollar demencia. La depresión implica un alto riesgo de ideación suicida (IS) e intentos de suicidio (AS). Los biomarcadores de la enfermedad de Alzheimer (EA) pueden clarificar el papel de la depresión e IS en la EA. Método: Cincuenta y nueve participantes >50 años con criterios de DCL-EA positivo (DCL-EA; 22) y negativo (DCL-NoEA; 24) y 13 controles sanos. La depresión fue evaluada con la Escala Geriátrica de Depresión (GDS-30) y la IS con el factor GDS-IS. Además, se midieron los siguientes biomarcadores en el líquido cefalorraquídeo: ß-amiloide (ß-A), tau hiperfosforilada (H-tau) y total (T-tau). Resultados: No se encontraron diferencias significativas entre los tres grupos de participantes en depresión o en IS. Sin embargo, en el grupo DCL-EA, niveles más bajos de H-tau y T-tau, indicadores de menor patología EA, se relacionaron significativamente con mayor riesgo de suicidio indirecto. Conclusiones: Este resultado subraya la importancia de considerar la IS en fases iniciales de EA, y el potencial papel de los biomarcadores de EA para detectar sus síntomas.(AU)