North Atlantic climate far more predictable than models imply.

Quantifying signals and uncertainties in climate models is essential for the detection, attribution, prediction and projection of climate change1-3. Although inter-model agreement is high for large-scale temperature signals, dynamical changes in atmospheric circulation are very uncertain4. This leads to low confidence in regional projections, especially for precipitation, over the coming decades5,6. The chaotic nature of the climate system7-9 may also mean that signal uncertainties are largely irreducible. However, climate projections are difficult to verify until further observations become available. Here we assess retrospective climate model predictions of the past six decades and show that decadal variations in North Atlantic winter climate are highly predictable, despite a lack of agreement between individual model simulations and the poor predictive ability of raw model outputs. Crucially, current models underestimate the predictable signal (the predictable fraction of the total variability) of the North Atlantic Oscillation (the leading mode of variability in North Atlantic atmospheric circulation) by an order of magnitude. Consequently, compared to perfect models, 100 times as many ensemble members are needed in current models to extract this signal, and its effects on the climate are underestimated relative to other factors. To address these limitations, we implement a two-stage post-processing technique. We first adjust the variance of the ensemble-mean North Atlantic Oscillation forecast to match the observed variance of the predictable signal. We then select and use only the ensemble members with a North Atlantic Oscillation sufficiently close to the variance-adjusted ensemble-mean forecast North Atlantic Oscillation. This approach greatly improves decadal predictions of winter climate for Europe and eastern North America. Predictions of Atlantic multidecadal variability are also improved, suggesting that the North Atlantic Oscillation is not driven solely by Atlantic multidecadal variability. Our results highlight the need to understand why the signal-to-noise ratio is too small in current climate models10, and the extent to which correcting this model error would reduce uncertainties in regional climate change projections on timescales beyond a decade.

How does a beef × dairy calving affect the dairy cow's following lactation?

For beef semen usage on dairy cows, much of the research has focused on the performance of the crossbred calves, yet little focus has been given to the subsequent performance of the cow herself. This study aimed to evaluate the performance of dairy cows for milk yield, fertility, and survival traits after giving birth to beef × dairy crossbred calves and compare this with the performance after giving birth to purebred dairy calves. Further, we aimed to study if the effect of a difficult calving was the same regardless of whether the calf was purebred dairy or beef × dairy crossbred. Phenotypic records from 587,288 calving events from 1997 to 2020 were collected from the Swedish milk recording system from cows of the dairy breeds Swedish Red (SR) and Swedish Holstein. The sire beef breeds studied were Aberdeen Angus, Hereford (combined in category LHT), Charolais, Limousin, and Simmental (category HVY). Sixteen traits were defined and grouped in 3 categories: cumulative and 305-d milk, fat, and protein yield, daily milk yield, and 75-d milk yield as yield traits; calving to first insemination interval, calving to last insemination interval, first to last insemination interval, calving interval, and number of inseminations as fertility traits; and survival to 75 d or to next calving and lactation length as measures of survival. The data were analyzed for all traits for first and second parities separately using mixed linear models, with a focus on the estimates of cow breed by service sire breed combinations. All traits in parity 2 were adjusted for previous 305-d milk yield based on the expectation that low-yielding cows would more likely to be inseminated with beef semen. Overall, milk yield was lower after beef × dairy calvings compared with the purebred dairy calvings. The largest effects were found on cumulative yields and in second parity, with lower effects for yields early in lactation and yields in first parity. The largest decrease was 13 to 14 kg (0.12 phenotypic SD) for cumulative fat yield when breeding beef breed sires with purebred SR dams. For fertility traits, for most breed combinations, the effects were not large enough to be significant. Conversely, all beef × dairy crossbred combinations showed significantly lower results for survival to the next lactation, and mostly also for lactation length. There was some indication that dairy cows with beef × dairy calvings in parity 2 that were the result of maximum 2 inseminations in parity 1, had lower survival than corresponding calvings resulting from more than 2 inseminations. This could indicate that the former cows were marked for culling already when inseminated. There was generally an unfavorable effect of a difficult calving on all traits, however, there were almost no significant interactions between calving performance and dam by sire breed combination, and these interactions were never significant in first parity.

[Burden and management of severe asthma in Russia: results from international observational study].

AIM: To assess clinical and demographic characteristics of severe asthma (SA) patients and their management in Russian Federation. MATERIALS AND METHODS: This publication provides data for Russian part of population of the international observational study. In Phase I, retrospective analysis of medical records of patients with SA was performed with assessment of clinical and demographic data, medical history, comorbidities, treatment approaches and healthcare utilization. Phase II was a cross-sectional collection of patient-reported outcomes: level of asthma control assessed by ACT (Asthma Control Test) and health-related quality of life (HRQoL) measured using the EQ-5D-5L questionnaire. Phase I patients were enrolled into Phase II if they signed a written consent form. RESULTS: A total of 315 patients were included in Phase I of the study, 106 (33.6%) of them entered Phase II. Majority of study participants were either obese (n=103; 39.8%) or overweight (n=94; 36.3%). The most common comorbidities were cardiovascular diseases (n=217; 71.4%), followed by chronic respiratory diseases (n=198; 68.8%). There were 268 (85.1%) patients who had at least one exacerbation during last 12 months. Data for blood eosinophil count were available in 176 patients; 81.3% of them (n=143) had only one test in the last 12 months. The mean (SD) last available blood eosinophil count was 161.2 (181.2) cells/mm3. Serum Immunoglobulin E (IgE) value was known for 88 patients, and the mean (SD) last measured IgE value was 254.3 (249.7) ng/mL. Only 4.7% of Phase II participants had ACT scores indicative of controlled asthma (>20). As much as 74.5% had scores ≤15 suggesting uncontrolled disease. Most patients also had impaired HRQoL. CONCLUSION: Most SA patients had poor disease control with frequent exacerbations and high number of comorbidities. Blood eosinophils and IgE level measurements were not evaluated routinely which might be a barrier for appropriate phenotyping and treatment selection.

Short-Term Local Expression of a PD-L1 Blocking Antibody from a Self-Replicating RNA Vector Induces Potent Antitumor Responses.

Immune checkpoint blockade has shown anti-cancer efficacy, but requires systemic administration of monoclonal antibodies (mAbs), often leading to adverse effects. To avoid toxicity, mAbs could be expressed locally in tumors. We developed adeno-associated virus (AAV) and Semliki Forest virus (SFV) vectors expressing anti-programmed death ligand 1 (aPDL1) mAb. When injected intratumorally in MC38 tumors, both viral vectors led to similar local mAb expression at 24 h, diminishing quickly in SFV-aPDL1-treated tumors. However, SFV-aPDL1 induced >40% complete regressions and was superior to AAV-aPDL1, as well as to aPDL1 mAb given systemically or locally. SFV-aPDL1 induced abscopal effects and was also efficacious against B16-ovalbumin (OVA). The higher SFV-aPDL1 antitumor activity could be related to local upregulation of interferon-stimulated genes because of SFV RNA replication. This was confirmed by combining local SFV-LacZ administration and systemic aPDL1 mAb, which provided higher antitumor effects than each separated agent. SFV-aPDL1 promoted tumor-specific CD8 T cells infiltration in both tumor models. In MC38, SFV-aPDL1 upregulated co-stimulatory markers (CD137/OX40) in tumor CD8 T cells, and its combination with anti-CD137 mAb showed more pronounced antitumor effects than each single agent. These results indicate that local transient expression of immunomodulatory mAbs using non-propagative RNA vectors inducing type I interferon (IFN-I) responses represents a potent and safe approach for cancer treatment.

Intratumoral Delivery of Immunotherapy-Act Locally, Think Globally.

Immune mechanisms have evolved to cope with local entry of microbes acting in a confined fashion but eventually inducing systemic immune memory. Indeed, in situ delivery of a number of agents into tumors can mimic in the malignant tissue the phenomena that control intracellular infection leading to the killing of infected cells. Vascular endothelium activation and lymphocyte attraction, together with dendritic cell-mediated cross-priming, are the key elements. Intratumoral therapy with pathogen-associated molecular patterns or recombinant viruses is being tested in the clinic. Cell therapies can be also delivered intratumorally, including infusion of autologous dendritic cells and even tumor-reactive T lymphocytes. Intralesional virotherapy with an HSV vector expressing GM-CSF has been recently approved by the Food and Drug Administration for the treatment of unresectable melanoma. Immunomodulatory monoclonal Abs have also been successfully applied intratumorally in animal models. Local delivery means less systemic toxicity while focusing the immune response on the malignancy and the affected draining lymph nodes.

Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy.

CD137 (4-1BB, TNF-receptor superfamily 9) is a surface glycoprotein of the TNFR family which can be induced on a variety of leukocyte subsets. On T and NK cells, CD137 is expressed following activation and, if ligated by its natural ligand (CD137L), conveys polyubiquitination-mediated signals via TNF receptor associated factor 2 that inhibit apoptosis, while enhancing proliferation and effector functions. CD137 thus behaves as a bona fide inducible costimulatory molecule. These functional properties of CD137 can be exploited in cancer immunotherapy by systemic administration of agonist monoclonal antibodies, which increase anticancer CTLs and enhance NK-cell-mediated antibody-dependent cell-mediated cytotoxicity. Reportedly, anti-CD137 mAb and adoptive T-cell therapy strongly synergize, since (i) CD137 expression can be used to select the T cells endowed with the best activities against the tumor, (ii) costimulation of the lymphocyte cultures to be used in adoptive T-cell therapy can be done with CD137 agonist antibodies or CD137L, and (iii) synergistic effects upon coadministration of T cells and antibodies are readily observed in mouse models. Furthermore, the signaling cytoplasmic tail of CD137 is a key component of anti-CD19 chimeric antigen receptors that are used to redirect T cells against leukemia and lymphoma in the clinic. Ongoing phase II clinical trials with agonist antibodies and the presence of CD137 sequence in these successful chimeric antigen receptors highlight the importance of CD137 in oncoimmunology.

Blastocystis in Côte d'Ivoire: molecular identification and epidemiological data.

Blastocystis is an enteric protozoan infecting humans and animals in both developed and developing countries at all latitudes. Despite this, data on Blastocystis infection are not available for several geographical areas, including many African countries. In this study, a survey was conducted on Blastocystis among humans and domestic animals in rural and urban localities in Côte d'Ivoire, in order to investigate the prevalence, the subtype distribution, and the zoonotic potential in association with sociodemographic factors, seasonality, symptoms, and co-infections. A total of 110 fecal samples were collected from patients living in four localities. Molecular and phylogenetic analyses were conducted for Blastocystis detection and subtyping. Positive samples from symptomatic patients were tested by Luminex xTAG® Gastrointestinal Pathogen Panel (GPP) to evidence the presence of other common intestinal pathogens. Overall, a prevalence of 58.2% was observed in humans and subtypes ST1(50.0%), ST2 (22.0%) and ST3 (28.1%) were identified. The prevalence values varied significantly among the sites but not in relation to the subtype. The seasonal rains significantly increase the infection rate in all localities. No significant differences in the ST distribution between asymptomatic and symptomatic subjects were observed. As regard the zoonotic transmission, an additional sampling was conducted in another village where fecal samples were simultaneously collected from humans and animals. Blastocystis STs 1-3 and ST7 were identified in eight humans and four chickens, respectively. This study provides the first exhaustive data on the prevalence and molecular epidemiology of Blastocystis in Côte d'Ivoire.

The Association of Intracranial Vascular Calcification and Stenosis With Acute Ischemic Cerebrovascular Events.

OBJECTIVE: The aim of this article was to evaluate the association of intracranial artery calcification (IAC) with acute downstream ischemic stroke (dAIS)/transient ischemic attack while considering stenosis. METHODS: Consecutive stroke computed tomography angiography head/neck examinations from January 2010 to April 2010 were reviewed. Per-vessel IAC and stenosis of greater than or equal to 30% were documented by 2 neuroradiologists. Associations between calcification and dAIS were assessed using multivariate logistic regression, controlling for traditional risk factors and stenosis. RESULTS: A total of 1287 arterial segments from 99 patients were reviewed. Intracranial artery calcification was significantly associated with dAIS (odds ratio [OR], 2.2; P = 0.009). This association persisted among nonstenotic arteries, with significantly higher likelihood of dAIS for arteries with IAC than those without (OR, 2.5; P = 0.009). However, among stenotic arteries, calcified stenoses had a lower association of dAIS than noncalcified stenoses (OR, 0.55; 95% confidence interval, 0.17-1.8; P = 0.33). CONCLUSIONS: Without concurrent stenosis, IAC is a significant risk factor for dAIS. When stenosis is present, IAC does not increase the association with dAIS. Stenotic and nonstenotic calcifications may represent different disease processes, as represented in the histology literature.

Social determinants associated with Giardia duodenalis infection in southern Côte d'Ivoire.

The purpose of this investigation was to analyze the association between different social determinants of health at the local scale and Giardia duodenalis infection in diverse settlements in southern Côte d'Ivoire. Stool samples from 306 individuals aged 1-16 years were collected from six rural villages and a small town. Five variables were categorized to classify the increasing risk levels of acquiring intestinal parasites. Giardia prevalences (%) and odds ratios (ORs) were evaluated. Correlation and regression analyses were conducted to determine the correlation coefficients and to propose predictive models based on social determinants to forecast the risk of giardiasis. The overall observed prevalence of Giardia was 21.6 %. When the analysis was conducted at the local level, the percentage of infected people varied from a minimum of 12.7 up to 36.4 %. A significant association (p < 0.001) was found between the selected social determinants and G. duodenalis prevalence in the different localities. Correlation and regression analyses allowed us to describe two predictive models to estimate the OR of Giardia transmission. This study helps to clarify the possible impact of different social determinants of health on the risk of giardiasis at the local scale. Both predictive models could be suitable in order to assess the likelihood of the transmission of intestinal parasitic infection in developing countries.

Exercise improves load bearing bone structural properties in female secreted protein acidic and rich in cysteine (SPARC) null mice but not in males.

Secreted protein acidic and rich in cysteine (SPARC) is the most abundant glycoprotein in bone and is thought to play a critical role in bone remodeling and homeostasis. However, the effect of SPARC in relation to gender and exercise on bone quality is not well understood. The purpose of this study was to quantify differences in the structural and biomechanical properties between calvarial and femoral bone from male and female wild-type (WT) and SPARC null (SPARC(-/-)) mice as well as the ability of exercise to rescue bone health. Male and female WT and transgenic SPARC(-/-) mice were given either a fixed or rotating running wheel for exercise. Bone structural, biomechanical, and morphological parameters were quantified using micro computed tomography, push out testing for the calvaria, three-point flexural testing for the femurs, histological and immunofluorescent staining. Similar reductions in structural and biomechanical strength were observed in both male and female SPARC(-/-) calvaria, most of which were not significantly affected by exercise. In femurs, SPARC(-/-) had a significant effect on structural parameters in both sexes, but was more pronounced in females with some properties being rescued with running. Interestingly, the effect of SPARC(-/-) on bone mineral density was only detected in female SPARC(-/-) mice, not males, and was subsequently rescued with exercise. This study emphasizes the differences between sexes in WT and SPARC(-/-) mice in regard to structural parameters and biomechanical properties. Research into gender differences can help inform and personalize treatment options to more accurately meet patient needs.

Prevalence and metabolic risk factors of chronic kidney disease among a Mexican adult population: a cross-sectional study in primary healthcare medical units.

Introduction: The intricate relationship between obesity and chronic kidney disease (CKD) progression underscores a significant public health challenge. Obesity is strongly linked to the onset of several health conditions, including arterial hypertension (AHTN), metabolic syndrome, diabetes, dyslipidemia, and hyperuricemia. Understanding the connection between CKD and obesity is crucial for addressing their complex interplay in public health strategies. Objective: This research aimed to determine the prevalence of CKD in a population with high obesity rates and evaluate the associated metabolic risk factors. Material and Methods: In this cross-sectional study conducted from January 2017 to December 2019 we included 3,901 participants of both sexes aged ≥20 years who were selected from primary healthcare medical units of the Mexican Social Security Institute (IMSS) in Michoacan, Mexico. We measured the participants' weight, height, systolic and diastolic blood pressure, glucose, creatinine, total cholesterol, triglycerides, HDL-c, LDL-c, and uric acid. We estimated the glomerular filtration rate using the Collaborative Chronic Kidney Disease Epidemiology (CKD-EPI) equation. Results: Among the population studied, 50.6% were women and 49.4% were men, with a mean age of 49 years (range: 23-90). The prevalence of CKD was 21.9%. Factors significantly associated with an increased risk of CKD included age ≥60 years (OR = 11.70, 95% CI [9.83-15.93]), overweight (OR = 4.19, 95% CI [2.88-6.11]), obesity (OR = 13.31, 95% CI [11.12-15.93]), abdominal obesity (OR = 9.25, 95% CI [7.13-11.99]), AHTN (OR = 20.63, 95% CI [17.02-25.02]), impaired fasting glucose (IFG) (OR = 2.73, 95% CI [2.31-3.23]), type 2 diabetes (T2D) (OR = 14.30, 95% CI [11.14-18.37]), total cholesterol (TC) ≥200 mg/dL (OR = 6.04, 95% CI [5.11-7.14]), triglycerides (TG) ≥150 mg/dL (OR = 5.63, 95% CI 4.76-6.66), HDL-c <40 mg/dL (OR = 4.458, 95% CI [3.74-5.31]), LDL-c ≥130 mg/dL (OR = 6.06, 95% CI [5.12-7.18]), and serum uric acid levels ≥6 mg/dL in women and ≥7 mg/dL in men (OR = 8.18, 95% CI [6.92-9.68]), (p < 0.0001). These factors independently contribute to the development of CKD. Conclusions: This study underscores the intricate relationship between obesity and CKD, revealing a high prevalence of CKD. Obesity, including overweight, abdominal obesity, AHTN, IFG, T2D, dyslipidemia, and hyperuricemia emerged as significant metabolic risk factors for CKD. Early identification of these risk factors is crucial for effective intervention strategies. Public health policies should integrate both pharmacological and non-pharmacological approaches to address obesity-related conditions and prevent kidney damage directly.

Class I Myosins, molecular motors involved in cell migration and cancer.

Class I Myosins are a subfamily of motor proteins with ATPase activity and a characteristic structure conserved in all myosins: A N-Terminal Motor Domain, a central Neck and a C terminal Tail domain. Humans have eight genes for these myosins. Class I Myosins have different functions: regulate membrane tension, participate in endocytosis, exocytosis, intracellular trafficking and cell migration. Cell migration is influenced by many cellular components including motor proteins, like myosins. Recently has been reported that changes in myosin expression have an impact on the migration of cancer cells, the formation of infiltrates and metastasis. We propose that class I myosins might be potential markers for future diagnostic, prognostic or even as therapeutic targets in leukemia and other cancers.Abbreviations: Myo1g: Myosin 1g; ALL: Acute Lymphoblastic Leukemia, TH1: Tail Homology 1; TH2: Tail Homology 2; TH3: Tail Homology 3.

Impact of synchronous atrioventricular delay optimization on left ventricle flow force angle evaluated by echocardiographic particle image velocimetry.

PURPOSE: To evaluate the improvement in electrical synchrony and left ventricle (LV) hemodynamics provided by combining the dynamic atrioventricular delay (AVD) of SyncAVTM CRT and the multiple LV pacing sites of MultiPoint pacing (MPP). METHODS: Patients with LBBB and QRS duration (QRSd) > 140 ms implanted with a CRT-D or CRT-P device and quadripolar LV lead were enrolled in this prospective study. During a post-implant follow-up visit, QRSd was measured from 12-lead surface electrograms by experts blinded to pacing configurations. QRSd reduction relative to intrinsic rhythm was evaluated during biventricular pacing (BiV) and MPP for two AVDs: nominal (140/110 ms paced/sensed) and SyncAV (patient-optimized SyncAV offset [10-60 ms] minimizing QRSd). Echocardiography particle imaging velocimetry (Echo-PIV) analysis was performed for each configuration. The resulting hemodynamic force LV flow angle (φ) was analyzed, which ranges from 0o (predominantly base-apex forces) to 90o (predominantly transverse forces). Higher angles indicate more energy dissipation at lateral walls due to transverse flow; lower angles indicate healthier flow aligned with the longitudinal base-apex path of the pressure gradient. RESULTS: Twelve patients (58% male, 17% ischemic, 32±7% ejection fraction, 165 ± 18 ms intrinsic QRSd) completed QRSd and Echo-PIV assessment. Relative to intrinsic rhythm, BiV and MPP with nominal AVD reduced QRSd by 10 ± 9% and 12 ± 9%, respectively. BiV+SyncAV and MPP+SyncAV further reduced QRSd by 19 ± 8%, (p < 0.05 vs. BiV with nominal AVD) and 23 ± 9% (p < 0.05 vs BiV+SyncAV), respectively. Echo-PIV showed similar sequential hemodynamic improvements. LV flow angular orientation during intrinsic activation (46 ± 3o) reduced with BiV+SyncAV (37 ± 4o, p < 0.05 vs intrinsic) and further with MPP+SyncAV (34 ± 4o, p < 0.05 vs BiV+SyncAV). CONCLUSION: These results suggest that SyncAV may improve electrical synchrony and influence LV flow patterns in patients suffering from heart failure compared to conventional CRT with a fixed AVD, with further improvement observed by combining with MPP.

Targeting Macrophages with CAR T Cells Delays Solid Tumor Progression and Enhances Antitumor Immunity.

Tumor-associated macrophages (TAM) are one of the most abundant cell types in many solid tumors and typically exert protumor effects. This has led to an interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials. Here, we report the development of a strategy for TAM depletion in mouse solid tumor models using chimeric antigen receptor (CAR) T cells targeting the macrophage marker F4/80 (F4.CAR-T). F4.CAR-T cells effectively killed macrophages in vitro and in vivo without toxicity. When injected into mice bearing orthotopic lung tumors, F4.CAR-T cells infiltrated tumor lesions and delayed tumor growth comparably with PD-1 blockade, and significantly extended mouse survival. Antitumor effects were mediated by F4.CAR-T-produced IFNγ, which promoted upregulation of MHC molecules on cancer cells and tumor-infiltrating myeloid cells. Notably, F4.CAR-T promoted expansion of endogenous CD8 T cells specific for tumor-associated antigen and led to immune editing of highly antigenic tumor cell clones. Antitumor impact was also observed in mouse models of ovarian and pancreatic cancer. These studies provide proof of principle to support CAR T-cell targeting of TAMs as a means to enhance antitumor immunity.

Importance of receptor flexibility in binding of cyclam compounds to the chemokine receptor CXCR4.

We have elucidated the binding sites of four moncyclam and one bicyclam antagonist AMD3100, in the human chemokine receptor CXCR4. Using the predicted structural models of CXCR4, we have further predicted the binding sites of these cyclam compounds. We used the computational method LITiCon to map the differences in receptor structure stabilized by the mono and bicyclam compounds. Accounting for the receptor flexibility lead to a single binding mode for the cyclam compounds, that has not been possible previously using a single receptor structural model and fixed receptor docking algorithms. There are several notable differences in the receptor conformations stabilized by monocyclam antagonist compared to a bicylam antagonist. The loading of the Cu(2+) ions in the cyclam compounds, shrinks the size of the cyclam rings and the residue D262(6.58) plays an important role in bonding to the copper ion in the monocylam compounds while residue E288(7.39) is important for the bicyclam compound.

[Clinical signs and changes in serum and tissue chemistry in rats treated with vitamin D3 (calciferol)]. / Manifestaciones clínicas y cambios en la química sérica y tisular en ratas tratadas con vitamina D3 (calciferol).

In the present work the effect of subcutaneous administration of 250, 500 and 750 microg (10.000, 20.000 and 30.000 IU, respectively) of vitamin D3 (calciferol) daily for eight days, on serum concentrations of vitamin D3 and 25-hydroxyvitamin D3 (25-OH-D3) and on serum and tissue concentrations of Ca, Zn, Cu and Fe in 45 white male Wistar rats, aged 12 weeks and weighing 180-200 g, have been studied. The group control was integrated by 15 healthy rats with similar characteristics (strain, gender, age and weight) that treated animals. Administration of high doses of calciferol produced a hypervitaminosis D characterized by a significant (p < 0.05) increase in serum vitamin D3 and 25-OH-D3, diverse clinical signs (such as, anorexia, marked loss of body weight, bloody diarrhea, bilateral conjunctivitis, and death), hypercalcemia, hypozincaemia, hypercupremia, hypoferraemia and an alteration in the tissue distribution of Ca, Zn, Cu and Fe as compared with untreated controls. Hypercalcemia and inflammation are prominent findings in hypervitaminosis D. Inflammation or infection induce systemic changes, collectively known as the acute phase response. Among the varied alterations that together produce this response are hypoferraemia, hypozincaemia and hypercupremia. It is likely that these responses are mediated, in part, by production and release of cytokines such as interleukin 1, interferons (IFN-alpha), interleukin 6 (11-6) and tumor necrosis factor (TNF). The development of hypoferraemia during inflammation requires hepcidin, an iron regulatory hormone, a disulfide-rich peptide, produced in the liver in response to the release of I1-6 during inflammation/infection. In conclusion, our results provide evidence that short-term administration of high doses of vitamin D determined diverse clinical signs and produced a marked increase of serum vitamin D3 and 25-OH-D3 and a marked alteration in the serum and tissue concentrations of Ca, Zn, Cu, and Fe. These changes depend on the doses given of vitamin D.

Computed tomography angiography findings predictive of post-intervention vasospasm in patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVE: To evaluate the association of CT/CT angiography (CTA) findings and clinical characteristics with subsequent vasospasm in patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS-: Consecutive presentation CTA head exams in patients with aSAH between January 2005 and June 2015 were retrospectively evaluated for intracranial arterial calcification, undulation and non-calcified stenosis. Additional variables including modified Fisher Scale (mFS), Glasgow Coma Scale (GCS) and neurological exam status were reviewed. Associations of CTA findings with the incidence of angiographic vasospasm were assessed with multivariate logistic regression models using the least absolute shrinkage and selection operator machine-learning algorithm. Model performance was summarized using c-index with bootstrap optimism-adjustment. RESULTS: Intracranial arterial calcification, seen in 51.7% of 195 total patients, was protective against vasospasm (OR-0.6; 95% CI-0.52-0.67; p = 0.009), while arterial undulation (24%) was associated with subsequent vasospasm (OR-2.6; 95% CI-1.3-5.1; p = 0.007). Non-calcified intracranial arterial stenosis (5%) was associated with subsequent vasospasm, (OR-4.7; 95% CI-1.0-22.8; p = 0.054). Least absolute shrinkage and selection operator selected all three CTA findings as predictors in a multivariate model for vasospasm in addition to clinical factors, which demonstrated superior predictive performance (c-index-0.74; 95% CI-0.69-0.82) compared to a model based on mFS and clinical factors only (c-index-0.66; 95% CI-0.57-0.75; p = 0.010 for the difference). CONCLUSION: Presentation CTA findings combined with clinical factors may better predict the development of vasospasm in patients with aSAH compared to current prognostic models alone. ADVANCES IN KNOWLEDGE: The combination of initial CT/CTA and clinical findings better predict development of vasospasm after aSAH. This can lead to better markers for use in future clinical trials to develop vasospasm preventative treatments and potentially provide better targets for early aggressive treatment.

DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells.

BACKGROUND: Conventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet. METHODS: B16 and MC38 tumor cell lines were inoculated subcutaneously into wild-type (WT) and DNGR-1-deficient mice. To overexpress Flt3L systemically, we performed gene therapy through the hydrodynamic injection of an Flt3L-encoding plasmid. To characterize the immune response, we performed flow cytometry and RNA-Seq of tumor-infiltrating cDC1s. RESULTS: Here, we found that cross-presentation of tumor antigens in the steady state was DNGR-1-independent. However, on Flt3L systemic overexpression, tumor growth was delayed in DNGR-1-deficient mice compared with WT mice. Of note, this protection was recapitulated by anti-DNGR-1-blocking antibodies in mice following Flt3L gene therapy. This improved antitumor immunity was associated with Batf3-dependent enhanced accumulation of CD8+ T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including Ccl5 expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5/CCR5 chemoattraction. Moreover, FLT3LG and CCL5 or CCR5 gene expression signatures correlate with an enhanced cDC1 signature and a favorable overall survival in patients with cancer. Notably, cyclophosphamide elevated serum Flt3L levels and, in combination with the absence of DNGR-1, synergized against tumor growth. CONCLUSION: DNGR-1 limits the accumulation of tumor-infiltrating cDC1s promoted by Flt3L. Thus, DNGR-1 blockade may improve antitumor immunity in tumor therapy settings associated to high Flt3L expression.

High expression of Myosin 1g in pediatric acute lymphoblastic leukemia.

Acute Lymphoblastic Leukemia (ALL) is the most frequent cancer in pediatric population. Although the treatment has improved and almost 85% of the children are cured about 20% suffer relapse, therefore finding molecules that participate in the pathogenesis of the disease for the identification of relapse and patients at risk is an urgent unmet need. Class I myosins are molecular motors involved in membrane tension, endocytosis, phagocytosis and cell migration and recently they have been shown important for development and aggressiveness of diverse cancer types, however Myo1g an hematopoietic specific myosin has not been studied in cancer so far. We evaluated the expression of Myo1g by qRT-PCR, Immunocytochemistry and Immunofluorescence in a cohort of 133 ALL patients and correlated the expression at diagnosis and after treatment with clinical features and treatment outcomes. We found high expression levels of Myo1g in Peripheral Blood Mononuclear Cells (PBMCs) from patients with ALL at diagnosis and those levels decreased after complete remission; furthermore, we found an increase in Myo1g expression on patients with 9:22 translocation and those who relapse. This study show that Myo1g is over expressed in ALL and that may participate in the pathogenesis of the disease specially in high-risk patients.

Pulmonary involvement in patients with juvenile systemic sclerosis.

Background: Pulmonary involvement in juvenile systemic sclerosis (JSSc) is rare in children and contributes to morbimortality. This study aimed to describe the pulmonary function and clinical, radiologic, and tomographic findings in JSSc. Methods: Patients with JSSc between 5-14 years of age were included. Clinical, functional, and imaging characteristics were assessed. Patients were excluded if they showed lung disease not associated with JSSc: mixed connective tissue disease, overlap syndrome, or acute cardiopulmonary failure at the time of the study. All patients underwent physical examination, electrocardiogram, spirometry, chest X-ray, high-resolution computed tomography (HRCT) of the chest, echocardiography, lung function tests, and the 6-minute walk test (6-MWT). Descriptive statistics were employed for data analysis. Results: We studied 15 patients with the following characteristics: median age, 11 years; median since symptoms onset, 6 years; median since JSSc diagnosis and the finding of pulmonary involvement, 2 years. Lung disease was detected in 73%, interstitial lung disease (ILD) the most common affection (67%); pulmonary hypertension was found in 6.6%. 6-MWT was positive in 26.6%, forced vital capacity (FVC) was abnormal in 26.6%. No pulmonary involvement was found in four patients. Conclusions: The most frequent pulmonary affection in JSSc was ILD. Thus, early JSSc detection and periodic lung monitoring are mandatory to avoid further complications once JSSc is diagnosed.

Introducción: La afección pulmonar en la esclerosis sistémica juvenil (ESJ) es rara en niños y contribuye a la morbimortalidad. El objetivo de este estudio fue describir los hallazgos de función pulmonar, clínicos, radiológicos y tomográficos en la ESJ. Métodos: Se incluyeron pacientes con ESJ de 5-14 años de edad. Se evaluaron las características clínicas, funcionales y de imagen. No se incluyeron pacientes con enfermedades pulmonares no asociadas con ESJ en el momento del estudio: enfermedad mixta del tejido conectivo, síndrome de superposición o insuficiencia cardiopulmonar aguda. Se realizaron exploración física, electrocardiograma, espirometría, radiografía de tórax, tomografía computarizada de alta resolución de tórax, ecocardiografía, pruebas de función pulmonar y prueba de caminata de 6 minutos (PC6M). Se utilizó estadística descriptiva para el análisis de los datos. Resultados: Se estudiaron 15 pacientes con las siguientes características: mediana de edad, 11 años; mediana desde el inicio de los síntomas, 6 años; y mediana desde el diagnóstico de ESJ y hallazgo de afección pulmonar, 2 años. Se detectó enfermedad pulmonar en el 73%. La enfermedad pulmonar intersticial (EPI) fue la afección más común (67%) y se encontró hipertensión pulmonar en el 6.6%. La PC6M fue positiva en el 26.6%, y la capacidad vital forzada resultó anormal en el 26.6%. Cuatro pacientes no presentaron afección pulmonar. Conclusiones: La afección pulmonar más frecuente en la ESJ fue la EPI. La detección temprana de ESJ y la monitorización pulmonar periódica son obligatorias para evitar más complicaciones una vez diagnosticada la ESJ.