Chemotherapy for a secondary malignancy nearly restores complete chimerism in an SCID-patient after HSCT.

For patients with inborn errors of immunity (IEI) and other inborn diseases, mixed donor chimerism is a well-accepted outcome of hematopoietic stem cell transplantation (HSCT). Cytoreductive chemotherapy for a secondary malignancy is a potential challenge for the stability of the graft function after HSCT. We report on a boy with X-SCID who developed Ewing sarcoma ten years after HSCT which was successfully treated with cytoreductive chemotherapy, surgery and local radiation. Surprisingly, this treatment had a positive impact on mixed chimerism with an increase of donor-cell proportions from 40% for neutrophils and 75% for non-T-mononuclear cells (MNCs) to >90% for both. T-cell counts remained stable with 100% of donor origin. This is -to our knowledge- the first report on the impact of cytoreductive chemotherapy on post-HSCT mixed chimerism and provides an important first impression for future patients.

Spin-Orbit-Lattice Entangled State in A_{2}MgReO_{6} (A=Ca, Sr, Ba) Revealed by Resonant Inelastic X-Ray Scattering.

The 5d^{1} ordered double perovskites present an exotic playground for studying novel multipolar physics due to large spin-orbit coupling. We present Re L_{3} edge resonant inelastic x-ray scattering (RIXS) results that reveal the presence of the dynamic Jahn-Teller effect in the A_{2}MgReO_{6} (A=Ca, Sr, Ba) family of 5d^{1} double perovskites. The spin-orbit excitations in these materials show a strongly asymmetric line shape and exhibit substantial temperature dependence, indicating that they are dressed with lattice vibrations. Our experimental results are explained quantitatively through a RIXS calculation based on a spin-orbit-lattice entangled electronic ground state with the dynamic Jahn-Teller effect taken into consideration. We find that the spin-orbit-lattice entangled state is robust against magnetic and structural phase transitions as well as against significant static Jahn-Teller distortions. Our results illustrate the importance of including vibronic coupling for a complete description of the ground state physics of 5d^{1} double perovskites.

Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis.

Chronic inflammatory diseases like rheumatoid arthritis are characterized by a deficit in fully functional regulatory T cells. DNA-methylation inhibitors have previously been shown to promote regulatory T cell responses and, in the present study, we evaluated their potential to ameliorate chronic and acute animal models of rheumatoid arthritis. Of the drugs tested, decitabine was the most effective, producing a sustained therapeutic effect that was dependent on indoleamine 2,3-dioxygenase (IDO) and was associated with expansion of induced regulatory T cells, particularly at the site of disease activity. Treatment with decitabine also caused apoptosis of Th1 and Th17 cells in active arthritis in a highly selective manner. The molecular basis for this selectivity was shown to be ENT1, a nucleoside transporter, which facilitates intracellular entry of the drug and is up-regulated on effector T cells during active arthritis. It was further shown that short-term treatment with decitabine resulted in the generation of a population of regulatory T cells that were able to suppress arthritis upon adoptive transfer. In summary, a therapeutic approach using an approved drug is described that treats active inflammatory disease effectively and generates robust regulatory T cells with the IDO-dependent capacity to maintain remission.

Lattice thermal conductivity of 2D nanomaterials: a simple semi-empirical approach.

Extracting reliable information on certain physical properties of materials, such as thermal transport, can be computationally very demanding. Aiming to overcome such difficulties in the particular case of lattice thermal conductivity (LTC) of 2D nanomaterials, we propose a simple, fast, and accurate semi-empirical approach for LTC calculation. The approach is based on parameterized thermochemical equations and Arrhenius-like fitting procedures, thus avoiding molecular dynamics or ab initio protocols, which frequently require computationally expensive simulations. As a proof of concept, we obtain the LTC of some prototypical physical systems, such as graphene (and other 2D carbon allotropes), hexagonal boron nitride (hBN), silicene, germanene, binary, and ternary BNC lattices and two examples of the fullerene network family. Our obtained values are in good agreement with other theoretical and experimental estimations, nonetheless, being derived in a rather straightforward way, at a fraction of the usual computational cost.

Nfkb2 deficiency and its impact on plasma cells and immunoglobulin expression in murine small intestinal mucosa.

The alternative (noncanonical) nuclear factor-κB (NF-κB) signaling pathway predominantly regulates the function of the p52/RelB heterodimer. Germline Nfkb2 deficiency in mice leads to loss of p100/p52 protein and offers protection against a variety of gastrointestinal conditions, including azoxymethane/dextran sulfate sodium (DSS)-induced colitis-associated cancer and lipopolysaccharide (LPS)-induced small intestinal epithelial apoptosis. However, the common underlying protective mechanisms have not yet been fully elucidated. We applied high-throughput RNA-Seq and proteomic analyses to characterize the transcriptional and protein signatures of the small intestinal mucosa of naïve adult Nfkb2-/- mice. Those data were validated by immunohistochemistry and quantitative ELISA using both small intestinal tissue lysates and serum. We identified a B-lymphocyte defect as a major transcriptional signature in the small intestinal mucosa and immunoglobulin A as the most downregulated protein by proteomic analysis in Nfkb2-/- mice. Small intestinal immunoglobulins were dramatically dysregulated, with undetectable levels of immunoglobulin A and greatly increased amounts of immunoglobulin M being detected. The numbers of IgA-producing, cluster of differentiation (CD)138-positive plasma cells were also reduced in the lamina propria of the small intestinal villi of Nfkb2-/- mice. This phenotype was even more striking in the small intestinal mucosa of RelB-/- mice, although these mice were equally sensitive to LPS-induced intestinal apoptosis as their RelB+/+ wild-type counterparts. NF-κB2/p52 deficiency confers resistance to LPS-induced small intestinal apoptosis and also appears to regulate the plasma cell population and immunoglobulin levels within the gut.NEW & NOTEWORTHY Novel transcriptomic analysis of murine proximal intestinal mucosa revealed an unexpected B cell signature in Nfkb2-/- mice. In-depth analysis revealed a defect in the CD38+ B cell population and a gut-specific dysregulation of immunoglobulin levels.

Disease status in human and experimental arthritis, and response to TNF blockade, is associated with MHC class II invariant chain (CD74) isoform expression.

Splice variants of CD74 differentially modulate the activity of cathepsin L (CTSL). As CD74 and CTSL participate in the pathogenesis of inflammatory diseases such as rheumatoid arthritis (RA), we determined whether splice variants of CD74 could be biomarkers of disease activity. Gene expression was measured in mice with collagen-induced arthritis using quantitative PCR (qPCR). In vitro studies using murine macrophage/DC-lineage cells determined the relative influence of macrophage phenotype on isoform expression and the potential to produce CTSL in response to TNF. CD74 splice variants were measured in human RA synovium and RA patients' monocytes. In arthritic mice, the expression of the p41 CD74 isoform was significantly higher in severely affected paws compared with unaffected paws or the paws of naïve mice; the p41 isoform significantly correlated with the expression of TNF in arthritic paws. Compared with M2-like macrophages, M1-like macrophages expressed increased levels of CD74 and had higher expression, secretion and activity of CTSL. RA patients that responded to TNF blockade had significantly higher expression levels of CD74 in circulating monocytes after treatment, compared with non-responders. The expression of the human CD74 isoform a was significantly higher in RA synovia, compared with osteoarthritis synovia, and was associated with CSTL enzymatic activity. This study is the first to demonstrate differential expression of the CD74 p41 isoform in an auto-immune disorder and in response to therapy. The differential expression of CD74 splice variants indicates an association, and potentially a mechanistic role, in the pathogenesis of RA.

Targeting hydrogen sulfide and nitric oxide to repair cardiovascular injury after trauma.

The systemic cardiovascular effects of major trauma, especially neurotrauma, contribute to death and permanent disability in trauma patients and treatments are needed to improve outcomes. In some trauma patients, dysfunction of the autonomic nervous system produces a state of adrenergic overstimulation, causing either a sustained elevation in catecholamines (sympathetic storm) or oscillating bursts of paroxysmal sympathetic hyperactivity. Trauma can also activate innate immune responses that release cytokines and damage-associated molecular patterns into the circulation. This combination of altered autonomic nervous system function and widespread systemic inflammation produces secondary cardiovascular injury, including hypertension, damage to cardiac tissue, vascular endothelial dysfunction, coagulopathy and multiorgan failure. The gasotransmitters nitric oxide (NO) and hydrogen sulfide (H2S) are small gaseous molecules with potent effects on vascular tone regulation. Exogenous NO (inhaled) has potential therapeutic benefit in cardio-cerebrovascular diseases, but limited data suggests potential efficacy in traumatic brain injury (TBI). H2S is a modulator of NO signaling and autonomic nervous system function that has also been used as a drug for cardio-cerebrovascular diseases. The inhaled gases NO and H2S are potential treatments to restore cardio-cerebrovascular function in the post-trauma period.

National survey regarding the timing of endoscopic procedures during the COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic, several questions have arisen about which endoscopic procedures (EPs) must be performed and which ones can be postponed. The aim of this study was to conduct a nationwide survey regarding the appropriate timing of EPs during the COVID-19 pandemic. METHODS: This prospective study was performed through a nationwide electronic survey. The survey consisted of 15 questions divided into three sections. The first evaluated the agreement for EPs classified as "time sensitive" and "not time sensitive". Two other sections assessed "high-priority" and "low-priority" scenarios. Agreement was considered when > 75% of respondents answered a question in the same direction. RESULTS: The response rate was 27.2% (214/784). Among the respondents, agreement for the need to perform EP in < 72 h was only reached for variceal bleeding (93.4%). Dysphagia with alarm symptoms was the scenario in which the highest percentage of physicians (95.9%) agreed that an EP needed to be performed within a month. Less than 30% of endoscopists would perform an EP within the first 72 h for patients with mild cholangitis, non-variceal upper gastrointestinal bleeding without hemodynamic instability, or severe anaemia without overt bleeding. In time-sensitive clinical scenarios suggestive of benign disease, none of the scenarios reached agreement in any sense. Among the time-sensitive clinical scenarios suggestive of malignancy, > 90% of the surveyed respondents considered that EP could not be postponed for > 8 weeks. CONCLUSIONS: There was no consensus among endoscopists about the timing of EPs in patients with pathologies considered time sensitive or in those with high-priority pathologies. Agreement was only reached in five (17%) of the evaluated clinical scenarios.

Biodiversity of wild Lactococcus lactis and their geo-spatial relationship with the environment.

Lactic acid bacteria are distributed in nature, isolating themselves from diverse ecosystems and presenting a wide metabolic biodiversity. In Corrientes (Argentina), artisanal cheeses and their specific environment are an important source of autochthonous lactic acid bacteria. The objective of this work was to establish associations between the phenotypic characteristics of strains of Lactococcus lactis subsp. lactis native from Corrientes with climatological data of the Province and the characteristics of the soil and the landscapes. Physiological and biochemical characterization data of Lactococcus lactis subsp. lactis isolated from the dairy environment and from different localities of Corrientes will be used. The strains were space-located through Google Earth, flood and drought events were evaluated using Standardized Precipitation Evapotranspiration Index, and soil composition data (A and Bt horizons) in the study areas were obtained from the experimental station National Institute of Agricultural Technology - Corrientes. A statistical analysis was applied to these results (Infostat Software, Di Rienzo et al. 2008). The resulting consists in three conglomerates, differentiating strains from soils coming from "flooded landscapes" and those from "sandy hills landscape". The analysis by main components highlighted the preference of strains from flooded landscapes by a saline-alkaline environment, affecting during periods of drought, and strains from sandy hills landscape by a low medium in salts and acid soil, directly during period of high humidity resulting from previous floods.

TLR expression profiles are a function of disease status in rheumatoid arthritis and experimental arthritis.

The role of the innate immune system has been established in the initiation and perpetuation of inflammatory disease, but less attention has been paid to its role in the resolution of inflammation and return to homeostasis. Toll-like receptor (TLR) expression profiles were analysed in tissues with differing disease status in rheumatoid arthritis (RA), ankylosing spondylitis (AS), and in experimental arthritis. TLR gene expression was measured in whole blood and monocytes, before and after TNF blockade. In RA and osteoarthritis synovia, the expression of TLRs was quantified by standard curve qPCR. In addition, four distinct stages of disease were defined and validated in collagen-induced arthritis (CIA), the gold standard animal model for RA - pre-onset, early disease, late disease and immunised mice that were resistant to the development of disease. TLR expression was measured in spleens, lymph nodes, blood cells, liver and the paws (inflamed and unaffected). In RA whole blood, the expression of TLR1, 4 and 6 was significantly reduced by TNF blockade but the differences in TLR expression profiles between responders and non-responders were less pronounced than the differences between RA and AS patients. In RA non-responders, monocytes had greater TLR2 expression prior to therapy compared to responders. The expression of TLR1, 2, 4 and 8 was higher in RA synovium compared to control OA synovium. Circulating cytokine levels in CIA resistant mice were similar to naïve mice, but anti-collagen antibodies were similar to arthritic mice. Distinct profiles of inflammatory gene expression were mapped in paws and organs with differing disease status. TLR expression in arthritic paws tended to be similar in early and late disease, with TLR1 and 2 moderately higher in late disease. TLR expression in unaffected paws varied according to gene and disease status but was generally lower in resistant paws. Disease status-specific profiles of TLR expression were observed in spleens, lymph nodes, blood cells and the liver. Notably, TLR2 expression rose then fell in the transition from naïve to pre-onset to early arthritis. TLR gene expression profiles are strongly associated with disease status. In particular, increased expression in the blood precedes clinical manifestation.

EUS-guided biliary drainage in patients with distal malignant biliary obstruction requires fewer interventions and has a lower cost compared to ERCP biliary drainage.

INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP) biliary drainage is considered the reference standard in patients with biliary obstruction, but it is not free of complications. EUS-guided biliary drainage (EUS-BD) is considered an alternative in patients with failed ERCP; however, data are scarce as to whether EUS-BD could be considered a first option. OBJECTIVE: The aim of our study was to compare the need for reintervention and cost between ERCP biliary drainage vs. EUS-BD. MATERIAL AND METHODS: We conducted a retrospective and comparative study of patients with distal malignant biliary obstruction with biliary drainage with ERCP + plastic stent (ERCP-PS) vs. ERCP + metal stent (ERCP-MS) vs. EUS-BD. RESULTS: 124 patients were included, divided into three groups: ERCP-PS, 60 (48.3%) patients; ERCP-MS, 40 (32.2%) patients; and EUS-BD, 24 (19.3%) patients. The need for reinterventions (67 vs. 37 vs. 4%, respectively), the number of procedures [3 (1-10) vs. 2 (1-7) vs. 1 (1-2)], and the costs (4550 ± 3130 vs. 5555 ± 3210 vs. 2375 ± 1020 USD) were lower in the EUS-BD group. No differences in terms of complications were detected. CONCLUSION: EUS-BD requires fewer reinterventions and has a lower cost compared to drainage by ERCP with metal or plastic stents.

A low-residue diet before colonoscopy tends to improve tolerability by patients with no differences in preparation quality: a randomized trial.

BACKGROUND: The pre-colonoscopy diet traditionally involves 24 h of a clear liquid diet (CLD) in combination with a lavage solution; however, this preparation is poorly tolerated. AIM: To compare the impact on the quality of bowel cleansing and tolerability of a CLD versus a low-residue diet (LRD). METHODS: We performed a randomized trial. Subjects were randomized to CLD or LRD the day before of elective colonoscopy. All subjects received a 4-L preparation of single-dose PEG beginning 16 h prior to colonoscopy. The Boston bowel preparation scale was used to evaluate bowel cleansing; an adequate-quality preparation was defined as a score ≥ 2 per segment. RESULTS: A total of 205 subjects were included with a mean age (SD) of 55.6 (12.6) years; 133 (64.9%) of them were female. A total of 105 subjects were randomized to receive CLD and 100 to LRD. No significant differences in bowel preparation quality were observed between groups according to the section of colon: right colon (70% vs. 73%, p = 0.08), transverse colon (82% vs. 79%, p = 0.062), or left colon (80% vs. 78.7%, p = 0.28). There was a tendency toward less-frequent nausea (p = 0.08) and vomiting (p = 0.07) in patients with LRD. No differences between groups regarding ADR (12% vs. 10%) were noted. CONCLUSIONS: An LRD before colonoscopy resulted in a tendency toward improved tolerability by patients, with no differences in the quality of bowel preparation.

Functional and phenotypic heterogeneity of Th17 cells in health and disease.

BACKGROUND: Th17 cells have nonredundant roles in maintaining immunity, particularly at mucosal surfaces. These roles are achieved principally through the production of cytokines and the recruitment of other immune cells to maintain the integrity of mucosal barriers and prevent the dissemination of microorganisms. Th17 cells are heterogeneous and exhibit a considerable degree of plasticity. This allows these cells to respond to changing environmental challenges. However, Th17 cells also play pro-inflammatory roles in chronic autoimmune diseases. The trigger(s) that initiate these Th17 responses in chronic autoimmune diseases remain unclear. DESIGN: In this report, we provide an overview of studies involving animal models, patient data, genome wide association studies and clinical trials targeting IL-17 for treatment of patients to gain a better understanding of the pathogenic roles of Th17 cells play in a range of autoimmune diseases. RESULTS: The report sheds light on likely triggers that initiate or perpetuate Th17 responses that promote chronic inflammation and autoimmunity. The divergent effects of tumour necrosis factor alpha blockade on Th17 cells in patients, is explored. Furthermore, we highlight the role of Th17 cells in inducing autoreactive B cells, leading to autoantibody production. Pathogenic bacterial species can change Th17 cell phenotype and responses. These findings provide insights into how Th17 cells could be induced to promoting autoimmune disease pathogenesis. CONCLUSION: This article provides an overview of the distinct roles Th17 cells play in maintaining immunity at mucosal surfaces and in skin mucosa and how their functional flexibility could be linked with chronic inflammation in autoimmune rheumatic diseases.

T cell activation Rho GTPase activating protein (TAGAP) is upregulated in clinical and experimental arthritis.

Genome-wide association studies have identified various susceptibility variants and loci associated with incidence of rheumatoid arthritis (RA) in different populations. One of these is T cell activation Rho GTPase activating protein (TAGAP). The present study sought to measure the expression of TAGAP in RA patients, CD4+ T cells subsets from healthy humans and in mice with collagen-induced arthritis. Peripheral blood mononuclear cells (PBMC) from RA patients and tissues of arthritic mice at different stages of the disease were used for the evaluation of TAGAP mRNA expression. Increased TAGAP expression was observed in RA patients compared to healthy controls, and there were differences in the expression level of TAGAP in the tissues of mice with experimental arthritis. Gene expression in CD4+ T cells from healthy humans was greatest 4 h after activation and protein expression was greatest after 24 h. The expression of TAGAP was not correlated with CD4+ lymphocyte subsets which were enriched for functionally defined subsets (Th17, Treg, Th1), further indicating its utility as an indicator of lymphocyte activation. These findings indicate that increased TAGAP expression is a distinguishing feature of inflammatory disease and further highlight the role of TAGAP in RA susceptibility.

Permanent Indwelling Transmural Stents for Endoscopic Treatment of Patients With Disconnected Pancreatic Duct Syndrome: Long-term Results.

INTRODUCTION: Disconnected pancreatic duct syndrome (DPDS) is defined as the complete disruption of the main pancreatic duct, the result are peripancreatic fluid collections or pancreatic leaks. The aim of this study was to report the results of derivative endoscopic treatment of DPDS in a long-term follow-up period. PATIENTS AND METHODS: We performed a retrospective analysis of prospectively collected data. Endoscopic treatment consisted of transmural drainage with 2 double pigtail plastic stents (7 F and 4 cm) deployed under endoscopic ultrasound guidance. RESULTS: In total, 21 patients were included in our study. There were 15 (71%) men and the median age was 36 years (range, 23 to 86 y). The principal etiology of DPDS was acute pancreatitis. A total of 20 (95.2%) patients were diagnosed with DPDS by endoscopic pancreatography and only 1 (4.8%) patient by magnetic resonance cholangiopancreatography (MRCP). The median follow-up time was 28 months (range, 7 to 76 mo). Technique success was 100% and initial clinical success was 80.9% (17/21). Three (17.6%) of these patients required a new endoscopic procedure with success in all cases. During follow-up, 11 (52%) patients developed diabetes mellitus and 3 patients (14%) developed exocrine pancreatic insufficiency. There were 5 (15%) patients with complications. CONCLUSION: According to our data, endoscopic treatment with the placement of a permanent indwelling transmural stents is a useful and safe tool for the treatment of DPDS.

Evidence-Based Program Service Deserts: A Geographic Information Systems (GIS) Approach to Identifying Service Gaps for State-Level Implementation Planning.

The long term effects of untreated mental health need for individuals, families and society has prompted a number of federal policy statements encouraging the use of evidence-based programs (EBP) in children's healthcare. However, among other challenges of evidence-based practice implementation, states often do not know where to make investments based on population need. In this paper we present the use of a Geographic Information System approach to undertake a mental health needs assessment for Washington State. Our study found that this technology can be beneficially applied to conducting needs assessment for EBP implementation, and we provide recommendations for future applications.

Uncovering dental implants using a new thermo-optically powered (TOP) technology with tissue air-cooling.

BACKGROUND AND OBJECTIVES: Uncovering implants with lasers, while bloodless, has been associated with a risk of implant and bone overheating. The present study evaluated the effect of using a new generation of high-power diode lasers on the temperature of a dental implant and the surrounding tissues using an in vitro model. STUDY DESIGN/MATERIALS AND METHODS: The implant temperature was measured at three locations using micro thermocouples. Collateral thermal damage of uncovered soft tissues was evaluated using NTBC stain. Implant temperature rise during and collateral thermal soft-tissue damage following implant uncovering with and without tissue air-cooling was studied using both the classic operational mode and the new thermo-optically powered (TOP) technology. RESULTS: For the classic surgical mode using a cork-initiated tip and constant laser power set at 3.4 W, the maximum temperature rise in the coronal and apical parts of the implant was 23.2 ± 4.1°Ð¡ and 9.5 ± 1.8°Ð¡, respectively, while 1.5 ± 0.5 mm of collateral thermal damage of the soft tissue surrounding the implant model occurred. Using the TOP surgical tip with constant laser power reduced implant overheating by 30%; collateral thermal soft-tissue damage was 0.8 ± 0.2 mm. Using the TOP surgical mode with a tip temperature setting of 800°C and air-cooling reduced the implant temperature rise by more than 300%, and only 0.2 ± 0.1 mm of collateral thermal soft-tissue damage occurred, typical for optimized CO2 laser surgery. Furthermore, use of the new generation diode technology (TOP surgical mode) appeared to reduce the time required for implant uncovering by a factor of two, compared to the standard surgical mode. CONCLUSIONS: Use of the new generation diode technology (TOP surgical mode) may significantly reduce overheating of dental implants during uncovering and seems to be safer for the adjacent soft and hard tissues. Use of such diode lasers with air-cooling can radically reduce the rise in implant temperatures (by more than three times), potentially making this technology safe and effective for implant uncovering.

Harnessing the Therapeutic Potential of Th17 Cells.

Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORγt while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon γ (IFNγ). In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORγt is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases.