Protein Kinase C-ß Dictates B Cell Fate by Regulating Mitochondrial Remodeling, Metabolic Reprogramming, and Heme Biosynthesis.

PKCß-null (Prkcb-/-) mice are severely immunodeficient. Here we show that mice whose B cells lack PKCß failed to form germinal centers and plasma cells, which undermined affinity maturation and antibody production in response to immunization. Moreover, these mice failed to develop plasma cells in response to viral infection. At the cellular level, we have shown that Prkcb-/- B cells exhibited defective antigen polarization and mTORC1 signaling. While altered antigen polarization impaired antigen presentation and likely restricted the potential of GC development, defective mTORC1 signaling impaired metabolic reprogramming, mitochondrial remodeling, and heme biosynthesis in these cells, which altogether overwhelmingly opposed plasma cell differentiation. Taken together, our study reveals mechanistic insights into the function of PKCß as a key regulator of B cell polarity and metabolic reprogramming that instructs B cell fate.

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.

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.

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.

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.

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.

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.

Drug Induced Sleep Endoscopy Versus Awake Endoscopy in Retrolingual Obstruction Assessment in Obstructive Sleep Apnea Patients: A Comparative Study.

ABSTRACT: The aim of this study is to evaluate the correlation of retrolingual obstruction determined by drug induced sleep endoscopy (DISE) and awake endoscopy evaluation of Muller maneuver (MM) and lingual tonsil hypertrophy (LTH) in patients with obstructive sleep apnea.A prospective cohort of 100 patients with obstructive sleep apnea who underwent DISE was assessed. The inclusion criteria were age between 18 and 70 years, and apnea-hypopnea index higher than 5. Friedman staging, LTH and MM were determined by awake endoscopy, as other physical findings. The authors evaluated the correlation of retrolingual obstruction determined by DISE using velum oropharynx tongue, epiglottis (VOTE) and nose, oropharynx, hypopharynx, larynx (NOHL) classification.When retrolingual MM was assessed, significant changes between awake and DISE were observed ( P = 0.000). Conversely, Friedman stage had no significant changes to DISE retrolingual findings ( P = 0.868). Analyzing LTH and DISE retrolingual findings according to NOHL and VOTE, if a cutoff value was established at 50%, DISE findings differ from awake: NOHL ( P <0.001) and VOTE ( P = 0.004). Nevertheless, if a restrictive cutoff at 75% was attached, DISE findings were similar to awake: NOHL ( P = 0.124) and VOTE ( P = 0.123).This study demonstrates that awake endoscopy determining LTH and Friedman stage is a mild predictor of collapse at retrolingual level, showing significant correlation to DISE only when severe retrolingual collapse is present. Our findings suggest that in-office awake endoscopy may have certain predictive value to select surgical patients.

Essential function for the GTPase TC21 in homeostatic antigen receptor signaling.

T cell antigen receptors (TCRs) and B cell antigen receptors (BCRs) transmit low-grade signals necessary for the survival and maintenance of mature cell pools. We show here that TC21, a small GTPase encoded by Rras2, interacted constitutively with both kinds of receptors. Expression of a dominant negative TC21 mutant in T cells produced a rapid decrease in cell viability, and Rras2(-/-) mice were lymphopenic, possibly as a result of diminished homeostatic proliferation and impaired T cell and B cell survival. In contrast, TC21 was overexpressed in several human lymphoid malignancies. Finally, the p110delta catalytic subunit of phosphatidylinositol-3-OH kinase (PI(3)K) was recruited to the TCR and BCR in a TC21-dependent way. Consequently, we propose TC21 directly links antigen receptors to PI(3)K-mediated survival pathways.

Ultrasound-guided genicular nerves block: an analgesic alternative to local infiltration analgesia for total knee arthroplasty: A noninferiority, matched cohort study.

BACKGROUND: Standard analgesic strategies for total knee arthroplasty employ local infiltration analgesia. Blockade and radiofrequency ablation of the genicular nerves are effective treatments for patients with chronic pain because of knee osteoarthritis. OBJECTIVE: To test the noninferiority of the analgesic effect of genicular nerves block in comparison with local infiltration analgesia after 24 h of total knee arthroplasty. DESIGN: Prospective cohort study. SETTING: Perioperative setting. PATIENTS: Thirty-five patients scheduled for total knee arthroplasty were prospectively included in the study and compared with 35 patients in a retrospective cohort. INTERVENTION: Genicular nerve blocks in the prospective cohort were compared with local infiltration analgesia in the retrospective cohort. MAIN OUTCOME MEASURES: The pain numeric rating scale and the cumulative opioid consumption in oral morphine equivalents during the first 24 h. RESULTS: We conducted propensity score-matched analyses of patients using acute postoperative pain-related risk covariates. After one-to-one propensity score matching, 21 patients were included in the local infiltration analgesia group and 21 in the genicular nerve block group. The median difference in numeric rating score at rest at 24 h was -0.99 [95% confidence interval (CI), -1.99 to 0.5, P = 0.012] on the unmatched cohort and -1.9 (95% CI, -2 to 0, P = 0.002) on the matched cohort (meeting the noninferiority criteria, Δ=1). The median difference in cumulative opioid consumption was 2.5 mg (95% CI, -13.5 to 2.5, P < 0.001) for the unmatched cohort and 4.99 mg (95% CI, -11.5 to 2.5, P < 0.001) on the matched group (meeting the noninferiority criteria, Δ = 21 mg). CONCLUSION: Local infiltration analgesia and genicular nerve block are comparable in terms of analgesic results. Therefore, genicular nerves block is an alternative to local infiltration analgesia in patients undergoing total knee arthroplasty. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04024319.

Preventing medical adhesive-related skin injury (MARSI).

Medical adhesive-related skin injury (MARSI) is an overlooked and underestimated problem. While awareness of this issue is growing, it is not fully understood by health professionals in a variety of clinical settings. Medical adhesive products are often applied and removed incorrectly, which, albeit unintentionally, causes skin damage. In many cases, MARSI should be considered a preventable injury. Organisations should have processes in place to educate health professionals in acute and community facilities in preventing MARSI; these processes should include the use of products that help to prevent these injuries, including medical adhesive removers. This article will explore this topic and relate it to the most recent consensus document.

T cell receptor internalization from the immunological synapse is mediated by TC21 and RhoG GTPase-dependent phagocytosis.

The immunological synapse (IS) serves a dual role for sustained T cell receptor (TCR) signaling and for TCR downregulation. TC21 (Rras2) is a RRas subfamily GTPase that constitutively associates with the TCR and is implicated in tonic TCR signaling by activating phosphatidylinositol 3-kinase. In this study, we demonstrate that TC21 both cotranslocates with the TCR to the IS and is necessary for TCR internalization from the IS through a mechanism dependent on RhoG, a small GTPase previously associated with phagocytosis. Indeed, we found that the TCR triggers T cells to phagocytose 1-6 µm beads through a TC21- and RhoG-dependent pathway. We further show that TC21 and RhoG are necessary for the TCR-promoted uptake of major histocompatibility complex (MHC) from antigen-presenting cells. Therefore, TC21 and RhoG dependence underlie the existence of a common phagocytic mechanism that drives TCR internalization from the IS together with its peptide-MHC ligand.

Antigen phagocytosis by B cells is required for a potent humoral response.

Successful vaccines rely on activating a functional humoral response that results from promoting a proper germinal center (GC) reaction. Key in this process is the activation of follicular B cells that need to acquire antigens and to present them to cognate CD4 T cells. Here, we report that follicular B cells can phagocytose large antigen-coated particles, a process thought to be exclusive of specialized antigen-presenting cells such as macrophages and dendritic cells. We show that antigen phagocytosis by B cells is BCR-driven and mechanistically dependent on the GTPase RhoG. Using Rhog-/- mice, we show that phagocytosis of antigen by B cells is important for the development of a strong GC response and the generation of high-affinity class-switched antibodies. Importantly, we show that the potentiation effect of alum, a common vaccine adjuvant, requires direct phagocytosis of alum-antigen complexes by B cells. These data suggest a new avenue for vaccination approaches by aiming to deliver 1-3 µm size antigen particles to follicular B cells.

Diffusion Control in Single-Site Zinc Reticular Amination Catalysts.

Zn-containing metal-organic frameworks have been used for the first time as heterogeneous catalysts in the amination of C-Cl bonds. The use of extended bis(pyrazolate) linkers can generate highly porous architectures, which favor the diffusion of amines to the confined spaces with respect to other imidazolate frameworks with narrower pore windows. The N4Zn nodes of the Zn-reticular framework show comparable activity to state-of-the-art homogeneous Zn amination catalysts, avoiding the use of basic conditions, precious metals, or other additives. This is combined with long-term activity and stability upon several reaction cycles, without contamination of the reaction product.

Organic synthesis of high added value molecules with MOF catalysts.

Recent examples of organic synthesis of fine chemicals and pharmaceuticals in confined spaces of MOFs are highlighted and compared with silica-based ordered porous solids, such as zeolites or mesoporous (organo)silica. These heterogeneous catalysts offer the possibility of stabilizing the desired transition states and/or intermediates during organic transformations of functional groups and (C-C/C-N) bond forming steps towards the desired functional high added value molecular scaffolds. A short introduction on zeolites, mesoporous silica and metal-organic frameworks is followed by relevant applications in which confined active sites in the pores promote single or multi-step organic synthesis of industrially relevant molecules. A critical discussion on the catalytic performances of the different types of hybrid inorganic-organic catalysts in the synthesis of O- and N-containing acyclic and heterocyclic molecules has been presented.

Nasal Surgery May Improve Upper Airway Collapse in Patients With Obstructive Sleep Apnea: A Drug-Induced Sleep Endoscopy Study.

OBJECTIVE: The aim of this study is to evaluate the effects of nasal surgery in the upper airway (UA) collapse using drug induced sleep endoscopy (DISE) in a group of patients with obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: Prospective cohort of patients treated with nasal surgery between 2015 and 2016. All patients were diagnosed with mild to severe OSAHS. The inclusion criteria were age between 18 and 70 years, apnea-hypopnea index (AHI) higher than 15, and septal deviation. All patients had a DISE performed before surgery and 3 months after. The DISE findings were evaluated through the NOHL scale. RESULTS: Thirty-four patients were included. Surgical success with subjective and objective improvement in nasal obstructions was achieved in all cases. The pattern of UA obstruction did change significantly following nasal surgery (P < 0.05). Before nasal surgery, 74% of the patients demonstrated multilevel obstruction. After nasal surgery, only 50% patients showed multilevel collapse (P < 0.05). Among patients with single-level collapse, the oropharynx was the most common location of obstruction. It became more frequent after nasal surgery was done (41% vs 21%, P < 0.05). Significant improvement was shown in hypopharyngeal collapse. Postoperative AHI decreased from a mean of 26.7 to 19 events/h, but this change was not significant. CONCLUSION: Nasal surgery may improve hypopharyngeal collapses observed during DISE in patients with OSAHS. Thus, an improvement in nasal obstruction may also modify the surgical plan based on UA functional findings in OSAHS patients.

Making Nanosized CHA Zeolites with Controlled Al Distribution for Optimizing Methanol-to-Olefin Performance.

From theoretical calculations and a rational synthesis methodology, it has been possible to prepare nanocrystalline (60-80 nm) chabazite with an optimized framework Al distribution that has a positive impact on its catalytic properties. This is exemplified for the methanol-to-olefin (MTO) process. The nanosized material with the predicted Al distribution maximizes the formation of the required MTO hydrocarbon pool intermediates, while better precluding excessive diffusion pathways that favor the rapid catalyst deactivation by coke formation.

Fe-Containing Zeolites for NH3 -SCR of NOx : Effect of Structure, Synthesis Procedure, and Chemical Composition on Catalytic Performance and Stability.

The direct preparation of different iron-containing Beta and CHA zeolites has been attempted under diverse synthesis conditions, including in alkaline and fluoride media, to evaluate the influence of their physicochemical properties on the selective catalytic reduction (SCR) of NOx using NH3 as reductant. Of the different Fe-Beta zeolites, the sample prepared in the absence of alkali cations with a Si/Al ratio of around 13 showed high NO conversion values (>90 %). However, this catalyst suffered from severe deactivation when aged at high temperatures in the presence of steam. The preparation of more hydrophobic Fe-Beta zeolites did not improve the resistance of the catalyst against steam. In contrast, Fe-CHA zeolites prepared by a one-pot method under alkaline conditions with a Si/Al ratio of around 13 by using N,N,N-trimethyladamantylammonium as template not only showed excellent catalytic activity but also high hydrothermal stability, especially when sodium cations were selectively removed. Moreover, the Fe-CHA material synthesized by using the less expensive tetraethylammonium template also resulted in an active and hydrothermally stable catalyst.

A multicenter randomized controlled clinical trial using a new resorbable non-cross-linked collagen membrane for guided bone regeneration at dehisced single implant sites: interim results of a bone augmentation procedure.

OBJECTIVE: To compare clinical performance of a new resorbable non-cross-linked collagen membrane, creos xenoprotect (CXP), with a reference membrane (BG) for guided bone regeneration at dehisced implant sites. MATERIALS AND METHODS: This randomized controlled clinical trial enrolled patients with expected dehiscence defects following implant placement to restore single teeth in the maxillary and mandibular esthetic zone and premolar area. Implants were placed using a two-stage surgical protocol with delayed loading. Bone augmentation material placed at the implant surface was immobilized with CXP or BG membrane. Soft tissue health was followed during the healing period, and the defect size was measured at reentry and 6 months after implant placement. RESULTS: Of the 49 included patients, 24 were treated with CXP and 25 with BG. Patient characteristics did not differ between the two arms. In the CXP arm, the defect height at implant insertion was (mean ± SD) 5.1 ± 2.1 mm (n = 24) and reduced at reentry by 81% to 1.0 ± 1.3 mm (n = 23). In the BG arm, the defect height at implant insertion was 4.9 ± 1.9 mm (n = 25) and reduced at reentry by 62% to 1.7 ± 2.1 mm (n = 24). Assuming a margin of non-inferiority of 1 mm, CXP was non-inferior to BG. Membrane exposure rate was highest at week 3 in both arms, reaching 16.7% for BG and 8.7% for CXP. CONCLUSIONS: The new resorbable non-cross-linked collagen membrane facilitates bone gain to support implant placement in expected dehiscence defects. The observed trend toward higher mean bone gain and lower exposure rate with CXP compared to BG should be further investigated.

Chronicity and use of health services: peer education of the School of Patients. / Cronicidad y uso de servicios sanitarios: la formación entre iguales de la Escuela de Pacientes.

OBJECTIVE: To evaluate the impact of the training strategy of the Escuela de Pacientes (School of Patients) on the use of health services among people with chronic diseases. METHOD: Quantitative design study of pretest and posttest evaluation with a population of 3,350 chronic patients of the Escuela de Pacientes (Andalusia, 2013-2015). A questionnaire adapted from the Stanford University was used. It measured the self-perceived health, number of health visits, and level of trust and communication with health personnel. A descriptive and bivariate study, a correlation study and a pretest/posttest net gain analysis were performed. RESULTS: Participation of 964 patients (28.8% of the population), of which 18.8% were men, mean age 56 years. Training increased trust in Primary Care (PC) and Hospital Care (HC) professionals (0.44 and 0.65 points), medical visits decreased by 25%, and hospital admissions fell by 51% with statistically significant differences by sex and disease. The correlation index between trust in professionals and use of health services was -0.215. CONCLUSION: The training strategy had a positive impact on the use of health services and trust in health professionals, and were identified areas of improvement from which recommendations are established.