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Background Mesenchymal stromal cells (MSC) have been proposed as a promising complement to standard immunosuppression in solid organ transplantation because of their immunomodulatory properties. The present work addresses the role of adipose-derived MSC (Ad-MSC) in an experimental model of acute rejection in small bowel transplantation (SBT). Material/methods heterotopic allogeneic SBT was performed. A single dose of 1.5x106 Ad-MSC was intra-arterially delivered just before graft reperfusion. Animals were divided into CONTROL (CTRL), CONTROL+Ad-MSC (CTRL_MSC), tacrolimus (TAC), and TAC+Ad-MSC (TAC_MSC) groups. Each Ad-MSC groups was subdivided in autologous and allogeneic third-party groups. Results Rejection rate and severity were similar in MSC-treated and untreated animals. CTRL_MSC animals showed a decrease in macrophages, T cell (CD4, CD8 and Foxp3 subsets) and B cell counts in the graft compared with CTRL, this decrease was attenuated in TAC_MSC animals. Pro- and anti-inflammatory cytokines and some chemokines and growth factors increased in CTRL_MSC animals, especially in the allogeneic group, whereas milder changes were seen in the TAC groups. Conclusion Ad-MSC did not prevent rejection when administered just before reperfusion. However, they showed immunomodulatory effects that could be relevant for a longer-term outcome. Interference between tacrolimus and the MSC effects should be addressed in further studies.

The balance between NLRP3 inflammasome activation and mitophagy is essential for homeostasis and cellular health, but this relationship remains poorly understood. Here we found that interleukin-1α (IL-1α)–deficient macrophages have reduced caspase-1 activity and diminished IL-1β release, concurrent with reduced mitochondrial damage, suggesting a role for IL-1α in regulating this balance. LPS priming of macrophages induced pro-IL-1α translocation to mitochondria, where it directly interacted with mitochondrial cardiolipin (CL). Computational modeling revealed a likely CL binding motif in pro-IL-1α, similar to that found in LC3b. Thus, binding of pro-IL-1α to CL in activated macrophages may interrupt CL-LC3b–dependent mitophagy, leading to enhanced Nlrp3 inflammasome activation and more robust IL-1β production. Mutation of pro-IL-1α residues predicted to be involved in CL binding resulted in reduced pro-IL-1α–CL interaction, a reduction in NLRP3 inflammasome activity, and increased mitophagy. These data identify a function for pro-IL-1α in regulating mitophagy and the potency of NLRP3 inflammasome activation.

During hematopoiesis, stem and progenitor cells become progressively restricted in their differentiation potential. This process is driven by lineage-specific transcription factors and is accompanied by dynamic changes in chromatin structure. The chromatin assembly factor complex CAF-1 is a key regulator of cellular plasticity in various cell lineages in different organisms. However, whether CAF-1 sustains lineage identity during normal homeostasis is unclear. To address this question, we investigated the role of CAF-1 in myeloid progenitor cells. CAF-1 suppression in myeloid progenitors triggered their rapid commitment but incomplete differentiation toward granulocyte, megakaryocyte, and erythrocyte lineages, resulting in a mixed cellular state. Through comparison with a canonical paradigm of directed terminal myeloid differentiation, we define changes in chromatin accessibility that underlie a unique transcriptome of the aberrantly matured CAF-1 deficient cells. We further identify C/EBPα and ELF1 as key transcription factors whose control of myeloid lineage commitment is kept in check by CAF-1. These findings shed new light on molecular underpinnings of hematopoiesis and suggest that manipulation of chromatin accessibility through modulating CAF-1 levels may provide a powerful strategy for controlled differentiation of blood cells.

Background Epidemiological and animal studies have associated systemic inflammation with blood pressure (BP). However, the mechanistic factors linking inflammation and BP remain unknown. Fatty acid–derived eicosanoids serve as mediators of inflammation and have been suggested to regulate renal vascular tone, peripheral resistance, renin‐angiotensin system, and endothelial function. We hypothesize that specific proinflammatory and anti‐inflammatory eicosanoids are linked with BP. Methods and Results We studied a population sample of 8099 FINRISK 2002 participants randomly drawn from the Finnish population register (53% women; mean age, 48±13 years) and, for external validation, a sample of 2859 FHS (Framingham Heart Study) Offspring study participants (55% women; mean age, 66±9 years). Using nontargeted liquid chromatography–mass spectrometry, we profiled 545 distinct high‐quality eicosanoids and related oxylipin mediators in plasma. Adjusting for conventional hypertension risk factors, we observed 187 (34%) metabolites that were significantly associated with systolic BP ( P Conclusions Plasma eicosanoids demonstrate strong associations with BP in the general population. As eicosanoid compounds affect numerous physiological processes that are central to BP regulation, they may offer new insights about the pathogenesis of hypertension, as well as serve as potential targets for therapeutic intervention.

Omega-3 (n-3) treatment may lower cardiovascular risk, yet its effects on the circulating lipidome and relation to cardiovascular risk biomarkers are unclear. We hypothesized that n-3 treatment is associated with favorable changes in downstream fatty acids (FAs), oxylipins, bioactive lipids, clinical lipid and inflammatory biomarkers. We examined these VITAL200, a nested substudy of 200 subjects balanced on demographics and treatment and randomly selected from the Vitamin D and Omega-3 Trial (VITAL). VITAL is a randomized double-blind trial of 840 mg/d eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) vs. placebo among 25,871 individuals. Small polar bioactive lipid features, oxylipins and FAs from plasma and red blood cells were measured using three independent assaying techniques at baseline and one year. The Women&rsquo, s Health Study (WHS) was used for replication with dietary n-3 intake. Randomized n-3 treatment led to changes in 143 FAs, oxylipins and bioactive lipids (False Discovery Rate (FDR) &lt, 0.05 in VITAL200, validated (p-values &lt, 0.05)) in WHS with increases in 95 including EPA, DHA, n-3 docosapentaenoic acid (DPA-n3), and decreases in 48 including DPA-n6, dihomo gamma linolenic (DGLA), adrenic and arachidonic acids. N-3 related changes in the bioactive lipidome were heterogeneously associated with changes in clinical lipid and inflammatory biomarkers. N-3 treatment significantly modulates the bioactive lipidome, which may contribute to its clinical benefits.

BackgroundHealth systems need evidence about how best to deliver home-based palliative care (HBPC) to meet the growing needs of seriously ill patients. We hypothesised that a tech-supported model that aimed to promote timely inter-professional team coordination using video consultation with a remote physician while a nurse is in the patient’s home would be non-inferior compared with a standard model that includes routine home visits by nurses and physicians.MethodsWe conducted a pragmatic, cluster randomised non-inferiority trial across 14 sites (HomePal Study). Registered nurses (n=111) were randomised to the two models so that approximately half of the patients with any serious illness admitted to HBPC and their caregivers were enrolled in each study arm. Process measures (video and home visits and satisfaction) were tracked. The primary outcomes for patients and caregivers were symptom burden and caregiving preparedness at 1–2 months.ResultsThe study was stopped early after 12 months of enrolment (patients=3533; caregivers=463) due to a combination of low video visit uptake (31%), limited substitution of video for home visits, and the health system’s decision to expand telehealth use in response to changes in telehealth payment policies, the latter of which was incompatible with the randomised design. Implementation barriers included persistent workforce shortages and inadequate systems that contributed to scheduling and coordination challenges and unreliable technology and connectivity.ConclusionsWe encountered multiple challenges to feasibility, relevance and value of conducting large, multiyear pragmatic randomised trials with seriously ill patients in the real-world settings where care delivery, regulatory and payment policies are constantly shifting.

Coronavirus disease 2019 (COVID-19) pandemic has become one of the most challenging episodes in the history of modern public health, with particular emphasis in high-risk population. However, the evidence regarding their response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent responsible for COVID-19 is scant. Herein, we present the clinical and therapeutic course of a SARS-CoV-2 infection in a patient with multivisceral transplant and a recent tuberculosis infection., Instituto de Estudios Inmunológicos y Fisiopatológicos

The concerted actions of the CNS and the immune system are essential to coordinating the outcome of neuroinflammatory responses. Yet, the precise mechanisms involved in this crosstalk and their contribution to the pathophysiology of neuroinflammatory diseases largely elude us. Here, we show that the CNS-endogenous hedgehog pathway, a signal triggered as part of the host response during the inflammatory phase of multiple sclerosis and experimental autoimmune encephalomyelitis, attenuates the pathogenicity of human and mouse effector CD4 T cells by regulating their production of inflammatory cytokines. Using a murine genetic model, in which the hedgehog signalling is compromised in CD4 T cells, we show that the hedgehog pathway acts on CD4 T cells to suppress the pathogenic hallmarks of autoimmune neuroinflammation, including demyelination and axonal damage, and thus mitigates the development of experimental autoimmune encephalomyelitis. Impairment of hedgehog signalling in CD4 T cells exacerbates brain-brainstem-cerebellum inflammation and leads to the development of atypical disease. Moreover, we present evidence that hedgehog signalling regulates the pathogenic profile of CD4 T cells by limiting their production of the inflammatory cytokines granulocyte-macrophage colony-stimulating factor and interferon-γ and by antagonizing their inflammatory program at the transcriptome level. Likewise, hedgehog signalling attenuates the inflammatory phenotype of human CD4 memory T cells. From a therapeutic point of view, our study underlines the potential of harnessing the hedgehog pathway to counteract ongoing excessive CNS inflammation, as systemic administration of a hedgehog agonist after disease onset effectively halts disease progression and significantly reduces neuroinflammation and the underlying neuropathology. We thus unveil a previously unrecognized role for the hedgehog pathway in regulating pathogenic inflammation within the CNS and propose to exploit its ability to modulate this neuroimmune network as a strategy to limit the progression of ongoing neuroinflammation.

Given that adverse remodeling is the leading cause of heart failure and death in the USA, there is an urgent unmet need to develop new methods in dealing with this devastating disease. Here we evaluated the efficacy of a short-course glucagon-like peptide-1 receptor agonist therapy—specifically 2-quinoxalinamine, 6,7-dichloro-N-(1,1-dimethylethyl)-3-(methylsulfonyl)-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB; aka Compound 2) – in attenuating adverse LV remodeling. We also examined the role, if any, of mitochondrial turnover in this process. Wild-type, Parkin knockout and MitoTimer-expressing mice were subjected to permanent coronary artery ligation, then treated briefly with DMB. LV remodeling and cardiac function were assessed by histology and echocardiography. Autophagy and mitophagy markers were examined by western blot and mitochondrial biogenesis was inferred from MitoTimer protein fluorescence and qPCR. We found that DMB given post-infarction significantly reduced adverse LV remodeling and the decline of cardiac function. This paralleled an increase in autophagy, mitophagy and mitochondrial biogenesis. The salutary effects of the drug were lost in Parkin knockout mice, implicating Parkin-mediated mitophagy as part of its mechanism of action. Our findings suggest that enhancing Parkin-associated mitophagy and mitochondrial biogenesis after infarction is a viable target for therapeutic mitigation of adverse remodeling.

Introduction There is a lack of an agreed Hirschsprung-associated enterocolitis (HAEC) definition. In 2009, a HAEC score was proposed for the diagnosis of HAEC episodes. Our aim was to apply the HAEC score on HAEC episodes to determine its diagnostic efficiency and whether it correlated to its severity. Methods Retrospective study of patients with HAEC admitted between 2000 and 2016. Episodes of HAEC were identified and the HAEC score was calculated. A cut-off of ≥ 10 according to Pastor et al and ≥ 4 according to Frykman et al were used. A Pearson's correlation coefficient was performed for outcome variable: length-of-stay (LOS). Results Note that 21/93 (22.6%) patients with Hirschsprung's disease presented 50 HAEC episodes with a median of 2 (1–5) episodes during an 8.3-year (2–15.6) follow-up. The most common symptoms were foul-smelling (86% [43/50]) and explosive (60% [30/50]) diarrhea. Physical findings showed a distended abdomen (76% [38/50]) and fever (60% [30/50]) with dilated bowel (82% [41/50]) and rectosigmoid cut-off (80% [40/50]) identified on X-rays. Only 34% (17/50) showed abnormal laboratory findings. Patients were admitted with a median LOS of 7 days (1–28). A HAEC score of 9 (2–16) was found, and only 50% (25/50) of patients met the initial criteria (score of 10 points). However, the use of a 4-point cut-off would have allowed the diagnosis of 98% (49/50) of the patients. A positive linear correlation was found for LOS and HAEC score (r = 0.3, p = 0.014). Conclusion There is no standardized definition for HAEC. The initial HAEC score cut-off is restrictive and might fail to identify milder episodes. The positive correlation with LOS and thus HAEC severity might aid in patient information and anticipation of treatment.

Coxsackievirus B (CVB) is a common human enterovirus that causes systemic infection but specifically replicates to high titers in the pancreas. It was reported that certain viruses induce mitochondrial fission to support infection. We documented that CVB triggers mitochondrial fission and blocking mitochondrial fission limits infection. The transient receptor potential channels have been implicated in regulating mitochondrial dynamics, namely, the heat and capsaicin receptor transient receptor potential cation channel subfamily V member 1 (TRPV1) contributes to mitochondrial depolarization and fission. When we transiently warmed HeLa cells to 39 &deg, C prior to CVB exposure, infection was heightened, whereas cooling cells to 25 &deg, C reduced infection. Inducing &ldquo, cold&rdquo, by stimulating transient receptor potential cation channel subfamily M member 8 (TRPM8) with menthol led to reduced infection and also resulted in lower levels of mitochondrial fission during infection. Additionally, menthol stabilized levels of mitochondrial antiviral signaling (MAVS) which is known to be tied to mitochondrial dynamics. Taken together, this highlights a novel pathway wherein CVB relies on TRPV1 to initiate proviral mitochondrial fission, which may contribute to the disruption of antiviral immunity. TRPM8 has been shown to antagonize TRPV1, and thus we hypothesize that stimulating TRPM8 blocks TRPV1-mediated mitochondrial fragmentation following CVB exposure and attenuates infection.

BackgroundThe Covid-19 pandemic has meant a modification of the patterns of the doctor-patient relationship, favoring online visits and reducing face-to-face visits. Likewise, the implementation of Patient-Reported Outcomes (PROs) that do not require the intervention of the doctor in our clinical practice and that given their close relationship with the clinical activity of chronic inflammatory joint diseases (CIJD) has favored an empowerment of patients and can allow the development of the online visit.ObjectivesKnow the use and acceptance of patients with CIJD: rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthropathies (SpA) of a non-face-to-face online visit, through a digital environment.MethodsPatients were included in a platform called Rheumanet for access by username and passwords (https://www.laconsultacercadeti.com/). At the time of inclusion, demographic variables were collected: date of birth, sex, level of education (primary education, secondary education, vocational training, further education and higher education), distance from the hospital to the patient’s home, and clinical variables such as diagnosis: RA, PsA or SpA, as well as the duration of the disease. Prior to the appointment, patients were encouraged to complete a PRO survey to assess their clinical situation: Routine Assessment of Patient Index Data 3 (RAPID3) for RA, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for SpA and RAPID3 and / or BASDAI for the PsA. Both the RAPID3 and BASDAI were scored for the patient’s knowledge and assigned to a color scale based on disease activity in green (remission or low activity), orange (moderate activity) or red (severe activity). Likewise, they were ordered to express through a free text what they would tell us as if they were in a face-to-face consultation. Complementary tests (analytical, radiological studies and others) are obtained simultaneously from the medical records and a joint assessment of the visit is carried out.ResultsBetween September 1, 2020 and January 31, 2022, a total of 248 patients (113 RA, 53 SpA and 82 PsA) were included in the platform. 172 (69.3%) patients used the digital platform and made at least one non-face-to-face visit during follow-up. The number of online visits made by each patient ranged from 1 to a maximum of 13 visits. 80 patients (70.7%) suffered from RA, 40 (75.4%) from SpA and 52 (63.4%) from PsA. The number of patients who made non-face-to-face visits was 38 (72.3%) for a disease duration of 5 years. When the ages of the patients were analyzed, the number of patients who made visits was 75 (73.5%) between 18 and 30 years old, 50 (67.7%) between 30 and 50 and 47 (66.4 %) from 50 years. According to the degree of activity of the disease, 75 patients were in remission or low activity at some point during the visits, 63 patients with moderate activity and 34 with severe activity. The distribution according to level of education was: 11 (6.3%) primary education, 21 (12.2%) secondary education, 37 (21.5%) vocational training, 63 (36.6%) further education and 40 (23.2%)higher education. The number of online visits was higher in patients who lived at a distance of 50 km or more from the hospital, reaching 100% of the visits in this subgroup of patients.ConclusionThe online visit through a digital platform through PROs is well accepted by our population with CIJD, especially in the young population, with a higher cultural level and whose home is far from the hospital. The online visit was made by patients regardless of the severity of their disease activity. Speed and ease of use using PROs already known to the patient and clinician is an important consideration for rheumatologists working in healthcare systems where patient contact time is limited. It would be interesting to obtain this information in non-pandemic situations such as COVID-19, which would make it possible to assess actual acceptance and its use in this type of patient in circumstances in which fear of contagion is not a variable to consider.Disclosure of InterestsNone declared

Aim Hepatoblastoma is the most frequent hepatic tumor in children, and its initial presentation will affect treatment and prognosis. The aim of this study is to evaluate long-term results of liver transplantation in children with unresectable hepatoblastoma. Patients and Methods This is a retrospective review of patients with hepatoblastoma who underwent liver transplantation, analyzing risk factors, tumor presentation, treatment, and long-term survival to identify prognostic factors. Results Thirty-one patients underwent liver transplantation in the context of unresectable hepatoblastoma, mainly males (67%) and with risk factors such as prematurity (12.9%), maternal smoking (6.5%), and familial adenomatous polyposis (3.2%). Most frequent presentation was multifocal PRETEXT III (51.6%) and PRETEXT IV (45.2%), with metastasis at diagnosis in 12.9% and vascular involvement in 54.8%.Twenty-one patients received a living-donor (67.7%) and 10 a cadaveric graft (32.2%), at 31.7 months of age (5–125). Most transplants were primary, and only two were performed as rescue therapy after an attempt of surgical resection of the tumor.Overall survival 1 and 5 years after transplantation were 93.3% ± 4.6% and 86.4% ± 6.3%, respectively. We could not find any statistically significant differences between risk factors, tumor presentation, type of graft, or type of transplant. Conclusion Liver transplantation has increased hepatoblastoma survival in unresectable tumors. Probably due to these good results, we have not been able to find significant prognostic factors in this cohort.

The occupation of the Iberian Peninsula during the Upper Palaeolithic is mainly known from archaeological sites located in the Cantabrian and Mediterranean regions. Numerous sites have been excavated in these two regions when few sites are found in the interior of the peninsula. Several authors explain this scarcity of sites, in the inner region during the Upper Palaeolithic, by a decrease of human population resulting from a low capacity of human groups to adapt to the cold conditions of the Marine Isotopic Stage 2 (MIS 2), i.e. the effect of cold climate on human populations might have been stronger in the interior of the peninsula than in coastal areas. Recent studies underline the evidence of prehistoric occupation during this period in that region. It has been suggested that these occupations are isolated events limited to the warmest phases of the end of the MIS 2. The present study focuses on zooarchaeological and taphonomic aspects of the Magdalenian site of La Peña de Estebanvela (Segovia, Spain). Our results show that this site was recurrently occupied during the Magdalenian period, including warm and cold phases, which provide a new evidence of sustainable presence of human populations in the interior of the Iberian Peninsula at the end of the Upper Palaeolithic.We further propose hypotheses on the subsistence strategies (e.g. availability of hunting resources) developed at La Peña de Estebanvela and in a larger context including other Magdalenian sites of the inner region of the Peninsula.

Summary Genetic deficiency of dystrophin leads to disability and premature death in Duchenne muscular dystrophy (DMD), affecting the heart as well as skeletal muscle. Here, we report that clinical-stage cardiac progenitor cells, known as cardiosphere-derived cells (CDCs), improve cardiac and skeletal myopathy in the mdx mouse model of DMD. Injection of CDCs into the hearts of mdx mice augments cardiac function, ambulatory capacity, and survival. Exosomes secreted by human CDCs reproduce the benefits of CDCs in mdx mice and in human induced pluripotent stem cell-derived Duchenne cardiomyocytes. Surprisingly, CDCs and their exosomes also transiently restored partial expression of full-length dystrophin in mdx mice. The findings further motivate the testing of CDCs in Duchenne patients, while identifying exosomes as next-generation therapeutic candidates., Graphical Abstract, Highlights • CDCs improve cardiac and skeletal myopathy in the mdx mouse model of DMD • CDC exosomes reproduce the benefits of CDCs • CDCs and their exosomes transiently restored partial expression of dystrophin, In this article, Marbán and colleagues show that exosomes mediate benefits of cell therapy in mouse and human models of Duchenne muscular dystrophy.

TPS8 Background: PSqCC is a rare tumor with poor prognosis and limited therapeutic options. The current standard of care for advanced disease has been palliative platinum-based chemotherapy, with only marginal survival benefit. Recent data has shown that the majority of PSqCC patients present high levels of programmed death-ligand 1 (PD-L1). The ORPHEUS trial is evaluating the efficacy and safety of INCMGA00012 –a programmed cell death 1 (PD-1) antagonist– in patients with unresectable, locally advanced or metastatic PSqCC. Methods: ORPHEUS is an international, multicenter, open-label, single-arm, phase 2 clinical trial. Eligible patients are male aged ≥18 years with locally advanced or metastatic PSqCC, ECOG performance status of 0-1, adequate organ function, a life expectancy of ≥12 weeks, and with no prior treatment with PD-1 or PD-L1/2 agents. A total of 18 patients will be enrolled to receive INCMGA00012 500 mg administered intravenously on day 1 of each 28-day cycle. Treatment will continue until progressive disease or unacceptable toxicity. Tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune-related RECIST will be performed approximately every 8 weeks for the first 6 months and every 12 weeks thereafter until progressive disease. The primary endpoint is objective response rate. Secondary objectives include additional efficacy outcomes (clinical benefit rate, progression-free survival (PFS), 6-month PFS, duration of response, time to progression, overall survival, and maximum tumor shrinkage) and safety evaluated as per NCI-CTCAE 5.0. Exploratory objectives will evaluate efficacy based on immune-related RECIST; predictive and prognostic biomarkers; impact of INCMGA00012 on human immunodeficiency virus (HIV) control in patients known to be HIV-positive. The sample size calculation is based on an exact binomial test. At least 4 responders (22.2%) among 18 patients will be adequate to justify further investigation of this strategy. The analyses were designed to attain an 80% power, with a 10% dropout rate assumption, at a nominal one-sided α level of 5%. The response probabilities for null (H0) and alternative hypotheses (H1) were H0: ≤ 5% and H1: ≥ 25%, respectively. All 18 planned patients have been enrolled since the trial began in March 2020. Clinical trial information: NCT04231981.

Language impairment (LI) is highly heritable and aggregates in families. Genetic investigation of LI has revealed many chromosomal regions and genes of interest, though very few studies have focused on rare variant analysis in non-English speaking or non-European samples. We selected four candidate genes (TM4SF20, NFXL1, CNTNAP2 and ATP2C2) strongly suggested for specific language impairment (SLI), a subtype of LI, and investigated rare protein coding variants through Sanger sequencing of probands with LI ascertained from Pakistan. The probands and their family members completed a speech and language family history questionnaire and a vocabulary measure, the Peabody Picture Vocabulary Test-fourth edition (PPVT-4), translated to Urdu, the national language of Pakistan. Our study aimed to determine the significance of rare variants in these SLI candidate genes through segregation analysis in a novel population with a high rate of consanguinity. In total, we identified 16 rare variants (according to the rare MAF in the global population in gnomAD v2.1.1 database exomes), including eight variants with a MAF C in CNTNAP2) co-segregated in a small family (PKSLI-64) and another (c.2465C>T in ATP2C2) co-segregated in the proband branch (PKSLI-27). The lack of complete co-segregation of most of the identified rare variants indicates that while these genes could be involved in overall risk for LI, other genes are likely involved in LI in this population. Future investigation of these consanguineous families has the potential to expand our understanding of gene function related to language acquisition and impairment.

Tuberculosis in childhood is clinically challenging, but it is a preventable and treatable disease. Risk factors depend on age and immunity status. The most common form of pediatric tuberculosis is pulmonary disease, which comprises more than half of the cases. Other forms make up the extrapulmonary tuberculosis that involves infection of the lymph nodes, central nervous system, gastrointestinal system, hepatobiliary tree, and renal and musculoskeletal systems. Knowledge of the imaging characteristics of pediatric tuberculosis provides clues to diagnosis. This article aims to review the imaging characteristics of common sites for extrapulmonary tuberculous involvement in children.

Asparagine synthetase (ASNS) is a gene on the long arm of chromosome 7 that is copy-number amplified in the majority of glioblastomas. ASNS copy-number amplification is associated with a significantly decreased survival. Using patient-derived glioma stem cells (GSC), we showed that significant metabolic alterations occur in gliomas when perturbing the expression of ASNS, which is not merely restricted to amino acid homeostasis. ASNS-high GSCs maintained a slower basal metabolic profile yet readily shifted to a greatly increased capacity for glycolysis and oxidative phosphorylation when needed. This led ASNS-high cells to a greater ability to proliferate and spread into brain tissue. Finally, we demonstrate that these changes confer resistance to cellular stress, notably oxidative stress, through adaptive redox homeostasis that led to radiotherapy resistance. Furthermore, ASNS overexpression led to modifications of the one-carbon metabolism to promote a more antioxidant tumor environment revealing a metabolic vulnerability that may be therapeutically exploited. Implications: This study reveals a new role for ASNS in metabolic control and redox homeostasis in glioma stem cells and proposes a new treatment strategy that attempts to exploit one vulnerable metabolic node within the larger multilayered tumor network.

The Interior Exploration using Seismic Investigations, Geodesy and Heat Transport (InSight) spacecraft landed successfully on Mars and imaged the surface to characterize the surficial geology. Here we report on the geology and subsurface structure of the landing site to aid in situ geophysical investigations. InSight landed in a degraded impact crater in Elysium Planitia on a smooth sandy, granule- and pebble-rich surface with few rocks. Superposed impact craters are common and eolian bedforms are sparse. During landing, pulsed retrorockets modified the surface to reveal a near surface stratigraphy of surficial dust, over thin unconsolidated sand, underlain by a variable thickness duricrust, with poorly sorted, unconsolidated sand with rocks beneath. Impact, eolian, and mass wasting processes have dominantly modified the surface. Surface observations are consistent with expectations made from remote sensing data prior to landing indicating a surface composed of an impact-fragmented regolith overlying basaltic lava flows., The InSight spacecraft landed on Mars on November 2018. Here, the authors characterize the surficial geology of the landing site and compare with observations and models derived from remote sensing data prior to landing and from ongoing in situ geophysical investigations of the subsurface.

[EN] In this study, three tannins from different sources have been used (from white peel grape (W), red peel grape (R) and from oak bark (O)) to obtain active films based on proteins (caseinate and gelatin) on the basis of their natural origin and potential antioxidant and antimicrobial activity. Films were obtained in two different ways: monolayer films, by homogeneously blending the tannins with the proteins and bilayer films, by coating the previously obtained protein film with the different tannin solutions. The microstructural, physicochemical characterisation as well as the antioxidant and antimicrobial activities of the films were analysed. The interactions developed between tannins and protein matrices determined the physico-chemical properties of the films. Significant changes were only observed in tannin-caseinate films, due to the establishment of hydrogen bonding and hydrophobic interactions, especially when using the tannin with the greatest phenolic content (W). Thus, the W tannin caseinate based films turned thicker, with markedly improved (p < 0.05) water solubility and WVP values and became mechanically stiffer and less stretchable. All of the films incorporating tannins exhibited remarkable antioxidant and antimicrobial activities against E.Coli and L. innocua, being the bilayer films containing W tannin the ones exhibiting the best antioxidant and antimicrobial activity against both bacteria (5 log of reduction), due to the greater availability of the active component when incorporated as a bilayer., The authors acknowledge the financial support from the Spanish Ministerio de Economia y Competitividad through the project AGL2016-76699-R.

Mitophagy plays a major role in heart physiology. Impairment of Parkin-dependent mitophagy in heart is known to be deleterious. Obesity is a known cardiovascular risk factor. Impaired autophagy has been reported in models of obesity or hyperlipidemia/hypercholesterolemia; however less is known regarding obesity and mitophagy. The aim of this study was to evaluate the regulation of Parkin expression in hearts of mice fed a high fat diet. Interestingly, we found a significant decrease in Parkin protein in hearts of HFD mice compared those fed a low-fat diet. This was associated with mitochondrial dysfunction in the context of ischemia/reperfusion (I/R). This downregulation was not associated with a decrease in Parkin mRNA expression. We did not detect any change in the degradation rate of Parkin and only a slight decrease in its translation. The reduction of Parkin protein abundance in HFD hearts remains a mystery and will need further studies. However, Parkin depletion in the setting of obesity may contribute to cardiovascular risk.

An aging worldwide population demands that anesthesiologists consider geriatrics a unique subset of patients requiring customization of practice. This article reviews the current literature investigating physiologic changes of the elderly that affect pharmacokinetics and pharmacodynamics. Changes in drug absorption, distribution, metabolism, and excretion are discussed as well as the ultimate effects of medications. Implications for practice regarding specific anesthetic and analgesic drugs are addressed. Despite the immense body of research that contributes to understanding of geriatric pharmacology, elderly patients often are excluded from rigorous research trials, and further scientific investigation to inform best practices for this group of patients is needed.