Miracle-dz/UniFAR-FTUs huggingface dataset:
Early Infection Termination Affects Number of CD8+ Memory T Cells and Protective Capacities in Listeria monocytogenes-Infected Mice upon Rechallenge 1

Here, we reevaluate the effects of early termination of infection on primary T cell expansion, subsequent memory cell development, and protective immunity. Using a murine Listeria monocytogenes (LM) infection model, we found the primary expansions of both CD4+ and CD8+ T cells were affected even when ampicillin was given as late as 60 h postinfection (p.i.). Subsequent development of CD8+ memory T cells was also impaired, although to a lesser extent, and only mice that received ampicillin at 24 h p.i. revealed a significant decrease in memory CD8+ T cells. Upon rechallenge with 1 × 105 CFU of LM, all ampicillin-treated mice cleared LM as effectively, and they generated similar amounts of Ag-specific CD8+ T cells as with untreated mice. However, mice that received ampicillin at 24 h p.i. lost their protective abilities when rechallenged with 7.5 × 105 CFU of LM. Ampicillin treatment also revealed early down-regulation of B7.1 and B7.2, but not CD40, on dendritic cells 72 h p.i. Our results have several important implications: 1) they argue against the hypothesis that brief exposure of T cells to an Ag is sufficient for full-fledged primary T cell responses and subsequent memory T cell development in vivo; 2) they suggest the existence of a reservoir of memory T cells, more than the immune system can possibly expand during secondary infection; and 3) they suggest that protective capacity is correlated with the number of preexisting memory T cells and that secondary expanding T cells play a limited role, at least in murine LM infection.
Macrophage Oxygen Sensing Modulates Antigen Presentation and Phagocytic Functions Involving IFN-γ Production through the HIF-1α Transcription Factor1

Low oxygen tension areas are found in inflamed or diseased tissues where hypoxic cells induce survival pathways by regulating the hypoxia-inducible transcription factor (HIF). Macrophages are essential regulators of inflammation and, therefore, we have analyzed their response to hypoxia. Murine peritoneal elicited macrophages cultured under hypoxia produced higher levels of IFN-γ and IL-12 mRNA and protein than those cultured under normoxia. A similar IFN-γ increment was obtained with in vivo models using macrophages from mice exposed to atmospheric hypoxia. Our studies showed that IFN-γ induction was mediated through HIF-1α binding to its promoter on a new functional hypoxia response element. The requirement of HIF-α in the IFN-γ induction was confirmed in RAW264.7 cells, where HIF-1α was knocked down, as well as in resident HIF-1α null macrophages. Moreover, Ag presentation capacity was enhanced in hypoxia through the up-regulation of costimulatory and Ag-presenting receptor expression. Hypoxic macrophages generated productive immune synapses with CD8 T cells that were more efficient for activation of TCR/CD3ε, CD3ζ and linker for activation of T cell phosphorylation, and T cell cytokine production. In addition, hypoxic macrophages bound opsonized particles with a higher efficiency, increasing their phagocytic uptake, through the up-regulated expression of phagocytic receptors. These hypoxia-increased immune responses were markedly reduced in HIF-1α- and in IFN-γ-silenced macrophages, indicating a link between HIF-1α and IFN-γ in the functional responses of macrophages to hypoxia. Our data underscore an important role of hypoxia in the activation of macrophage cytokine production, Ag-presenting activity, and phagocytic activity due to an HIF-1α-mediated increase in IFN-γ levels.
How to avoid trivial mistakes during IPG replacement in patients treated with DBS for movement disorders: technical note from 13-years experience

Purpose: Recent data suggest how adverse events occur more frequently after Implantable Pulse Generator (IPG) replacement than during the deep electrode positioning in patients treated with Deep Brain Stimulation (DBS). For instance, erroneous extension adjustment to change in laterality and inaccurate lead connection represent problems, which strongly affect patients’ outcome. We analyzed our data after 13 years of IPG replacement. Materials and Methods: We treated 107 patients (83 PD and 24 Dystonia) with DBS in 13 years. The Dual Channel IPGs replaced during this period were 91. 25 patients needed more than one replacement, especially among the dystonic population. During surgery, we temporarily marked in all the cases the right extension lead before the disconnection from the exhausted IPG. Good impedances were intraoperatively checked in all the cases. Results: Our surgical technique allowed us to avoid any erroneous change in laterality or abnormal impedances due to a suboptimal connection to the IPG. The mean duration of the operation was 25 min and a quick postoperative restart of DBS was possible in all the cases. Stability of symptoms after IPG replacement was achieved in all the patients, with an accurate clinical management within the first 48–72 postoperative hours. Conclusion: Our surgical and postoperative management demonstrates how to avoid some important adverse events with some easy steps, without any discomfort for the patients in terms of duration of surgery or longer hospitalization. Thus, stability of symptoms after the IPG replacement may be easily guaranteed during the first postoperative period.
The Dual Peroxisome Proliferator-Activated Receptor α/γ Activator Muraglitazar Prevents the Natural Progression of Diabetes in db/db Mice

There are two major defects in type 2 diabetes: 1) insulin resistance and 2) insulin deficiency due to loss of β-cell function. Here we demonstrated that treatment with muraglitazar (a dual peroxisome proliferator-activated receptor α/γ activator), when initiated before or after the onset of diabetes in mice, is effective against both defects. In study 1, prediabetic db/db mice were treated for 12 weeks. The control mice developed diabetes, as evidenced by hyperglycemia, hyperinsulinemia, reduced insulin levels in the pancreas, blunted insulin response to glucose, and impaired glucose tolerance. The muraglitazar-treated mice had normal plasma glucose, and insulin levels, equivalent or higher pancreatic insulin content than normal mice, showed a robust insulin response to glucose and exhibited greater glucose tolerance. In study 2, diabetic db/db mice were treated for 4 weeks. The control mice displayed increased glucose levels, severe loss of islets, and their isolated islets secreted reduced amounts of insulin in response to glucose and exendin-4 compared with baseline. In muraglitazar-treated mice, glucose levels were reduced to normal. These mice showed reduced loss of islets, and their isolated islets secreted insulin at levels comparable to baseline. Thus, muraglitazar treatment decreased both insulin resistance and preserved β-cell function. As a result, muraglitazar treatment, when initiated before the onset of diabetes, prevented development of diabetes and, when initiated after the onset of diabetes, prevented worsening of diabetes in db/db mice.
Fístula Coronária: Causa Rara de Sopro Cardíaco

Coronary arterial fi stula is a rare congenital cardiac anomaly. It accounts for 0.2%-0.4% of all congenital cardiac anomalies. The majority of the patients is asymptomatic and is referred because of a murmur. We describe the case of a 16 month year old girl, asymptomatic, with a continuous murmur. Echocardiographic study revealed a signifi cant right coronary arterial fi stula draining to the right atrium, a fenestrated atrial septal defect and enlarged right atrium and ventricle. The patient underwent percutaneous closure of the fi stula.
Atomoxetine administration combined with intensive speech therapy for post-stroke aphasia: evaluation by a novel SPECT method

Objectives: We clarified the safety, feasibility, and efficacy of atomoxetine administration combined with intensive speech therapy (ST) for patients with post-stroke aphasia. In addition, we investigated the effect of atomoxetine treatment on neural activity of surrounding lesioned brain areas. Materials and Methods: Four adult patients with motor-dominant aphasia and a history of left hemispheric stroke were studied. We have registered on the clinical trials database (ID: JMA-IIA00215). Daily atomoxetine administration of 40 mg was initiated two weeks before admission and raised to 80 mg 1 week before admission. During the subsequent 13-day hospitalization, administration of atomoxetine was raised to 120 mg and daily intensive ST (120 min/day, one-on-one training) was provided. Language function was assessed using the Japanese version of The Western Aphasia Battery (WAB) and the Token test two weeks prior to admission, on the day of admission, and at discharge. At two weeks prior to admission and at discharge, each patient's cortical blood flow was measured using 123I-IMP-single photon emission computed tomography (SPECT). Results: This protocol was successfully completed by all patients without any adverse effects. Four patients showed improved language function with the median of the Token Test increasing from 141 to 149, and the repetition score of WAB increasing from 88 to 99. In addition, cortical blood flow surrounding lesioned brain areas was found to increase following intervention in all patients. Conclusions: Atomoxetine administration and intensive ST were safe and feasible for post-stroke aphasia, suggesting their potential usefulness in the treatment of this patient population.
The Mechanism of Osteoclast Differentiation Induced by IL-11

IL-1 is a potent cytokine that can induce bone erosion in inflammatory sites such as rheumatoid joint regions via activation of osteoclasts. Not only is IL-1 capable of activating osteoclasts, but it is also a key cytokine involved in the differentiation, multinucleation, and survival of osteoclasts. Herein, we show that IL-1 has the potential to drive osteoclast differentiation via a receptor activator of NF-κB ligand (RANKL)/RANK-independent mechanism. Although IL-1 has a synergistic effect on RANKL-induced osteoclast formation, IL-1 alone cannot induce osteoclast differentiation from osteoclast precursors (bone marrow-derived macrophages (BMMs)) due to a lack of IL-1 signaling potential in these cells. However, we demonstrate that overexpression of the IL-1RI receptor in BMMs or induction of IL-1RI by c-Fos overexpression enables IL-1 alone to induce the formation of authentic osteoclasts by a RANKL/RANK-independent mechanism. The expression of IL-1RI is up-regulated by RANKL via c-Fos and NFATc1. Furthermore, the addition of IL-1 to IL-1RI overexpressing BMMs (IL-1/IL-1RI) strongly activates NF-κB, JNK, p38, and ERK which is a hallmark gene activation profile of osteoclastogenesis. Interestingly, IL-1/IL-1RI does not induce expression of c-Fos or NFATc1 during osteoclast differentiation, although basal levels of c-Fos and NFATc1 seem to be required. Rather, IL-1/IL-1RI strongly activates MITF, which subsequently induces osteoclast-specific genes such as osteoclast-associated receptor and tartrate-resistant acid phosphatase. Together, these results reveal that IL-1 has the potential to induce osteoclast differentiation via activation of microphthalmia transcription factor under specific microenvironmental conditions.
The uncounted casualties of war: epigenetics and the intergenerational transference of PTSD symptoms among children and grandchildren of Vietnam veterans in Australia

Knowledge is building about the heritability of Post Traumatic Stress Disorder (PTSD) in the children and grandchildren of Vietnam veterans. These children and grandchildren remain uncounted due to lack of recognition by the medical and social models. This lack of recognition enables them to fall through the gaps in our management systems. Several theorists have made assertions that attempt to explain the heritability of PTSD from genetic, social and environmental perspectives, but simply perpetuate it. Current trends in research are starting to investigate a complex integration of these perspectives that attempt to explain the heritability of a debilitating condition that has plagued humanity for generations past, and, perhaps, generations to come. This issue is discussed in relation to the relatively new perspective of Epigenetics. This paper reviews what we have come to understand as PTSD and debates the dominant paradigms that perpetuate its heritability and enable the existence of gaps in management systems.
Reply: Peptide Receptor Radionuclide Therapy in the United States

investigational new drug (IND) clinical trial (IND 78,256) using 177Lu-octreotate for patients with neuroendocrine cancers. Excel Diagnostics and Nuclear Oncology Center is the first facility in the United States to receive authorization to initiate this therapy. Dr. Ebrahim S. Delpassand is the principle investigator, and the project is in collaboration with St. Luke’s Episcopal Hospital, Baylor College of Medicine, the Radio-Isotope Therapy of America Foundation, Biosynthema Inc., and Advanced Accelerator Application (2,3). So far, we have enrolled and treated 34 patients with 177Lu-octreotate. Our second active peptide receptor radionuclide therapy project under the Food and Drug Administration (IND 72,037) is for treatment of neuroendocrine cancer patients with high-dose 111In-octreotide (4). So far, we have treated more than 110 patients with inoperable metastatic neuroendocrine cancer under this protocol. The results of our treating the first 32 patients with at least 2 cycles of 18,500-MBq (500-mCi) 111In-octreotide were very promising and were published in 2008 (5). A manuscript describing our experience in a larger population is under review for publication. Peptide receptor radionuclide therapy for metastatic neuroendocrine cancer using b-emitters (such as 177Lu or 90Y) is very promising and needs to be brought to routine clinical practice in the United States, just like in Europe (6).
Evaluation of heart rate and rhythm during exercise

Summary Heart rate and rhythm can readily be monitored during exercise. Although there is considerable variation depending on the athletic discipline, exercise can be considered to be one of the most physiologically demanding times for the cardiovascular system. Assessment of heart rate during exercise typically provides information regarding fitness and the intensity of exercise, and on some occasions may provide an early indication of disease. Cardiac causes of poor performance occur relatively infrequently in comparison with disorders of the musculoskeletal and respiratory systems. Nevertheless, exercise induces cardiac hypertrophy, which predisposes athletes to valvular regurgitation and arrhythmias. Consequently cardiac murmurs and arrhythmias are frequently present in equine athletes, whereupon the clinical significance can be difficult to determine. Undertaking an exercise test to identify exercise-induced arrhythmias is important in the assessment of poor athletic performance and the risk of sudden cardiac death during exercise. This paper describes the assessment of heart rate and rhythm during exercise. Most research has been undertaken on racehorses but, where data are available for other disciplines, they have been included. Considerations regarding the choice, type and design of exercise test were detailed in the first paper in this series.
A20 Negatively Regulates T Cell Receptor Signaling to NF-κB by Cleaving Malt1 Ubiquitin Chains1

The Carma1-Bcl10-Malt1 signaling module bridges TCR signaling to the canonical IκB kinase (IKK)/NF-κB pathway. Covalent attachment of regulatory ubiquitin chains to Malt1 paracaspase directs TCR signaling to IKK activation. Further, the ubiquitin-editing enzyme A20 was recently suggested to suppress T cell activation, but molecular targets for A20 remain elusive. In this paper, we show that A20 regulates the strength and duration of the IKK/NF-κB response upon TCR/CD28 costimulation. By catalyzing the removal of K63-linked ubiquitin chains from Malt1, A20 prevents sustained interaction between ubiquitinated Malt1 and the IKK complex and thus serves as a negative regulator of inducible IKK activity. Upon T cell stimulation, A20 is rapidly removed and paracaspase activity of Malt1 has been suggested to cleave A20. Using antagonistic peptides or reconstitution of Malt1−/− T cells, we show that Malt1 paracaspase activity is required for A20 cleavage and optimal IL-2 production, but dispensable for initial IKK/NF-κB signaling in CD4+ T cells. However, proteasomal inhibition impairs A20 degradation and impedes TCR/CD28-induced IKK activation. Taken together, A20 functions as a Malt1 deubiquitinating enzyme and proteasomal degradation and de novo synthesis of A20 contributes to balance TCR/CD28-induced IKK/NF-κB signaling.
Cell-Autonomous Role for NF-κB in Immature Bone Marrow B Cells1

The NF-κB transcription factors have many essential functions in B cells, such as during differentiation and proliferation of Ag-challenged mature B cells, but also during final maturation of developing B cells in the spleen. Among the various specific functions NF-κB factors carry out in these biologic contexts, their ability to assure the survival of mature and maturing B cells in the periphery stands out. Less clear is what if any roles NF-κB factors play during earlier stages of B cell development in the bone marrow. Using mice deficient in both NF-κB1 and NF-κB2, which are thus partially compromised in both the classical and alternative activation pathways, we demonstrate a B cell-autonomous contribution of NF-κB to the survival of immature B cells in the bone marrow. NF-κB1 and NF-κB2 also play a role during the earlier transition from proB to late preB cells; however, in this context these factors do not act in a B cell-autonomous fashion. Although NF-κB1 and NF-κB2 are not absolutely required for survival and progression of immature B cells in the bone marrow, they nevertheless make a significant contribution that marks the beginning of the profound cell-autonomous control these factors exert during all subsequent stages of B cell development. Therefore, the lifelong dependency of B cells on NF-κB-mediated survival functions is set in motion at the time of first expression of a full BCR.
IL-13-Induced Oxidative Stress via Microglial NADPH Oxidase Contributes to Death of Hippocampal Neurons In Vivo1

In the present study, we investigated the effects of IL-13, a well-known anti-inflammatory cytokine, on the thrombin-treated hippocampus in vivo. NeuN immunohistochemistry and Nissl staining revealed significant loss of hippocampal CA1 neurons upon intrahippocampal injection of thrombin. This neurotoxicity was accompanied by substantial microglial activation, as evident from OX-42 immunohistochemistry results. In parallel, Western blot analysis and hydroethidine histochemistry disclosed activation of NADPH oxidase, generation of reactive oxygen species, and oxidative damage in the hippocampal CA1 area showing hippocampal neuron degeneration. Interestingly, immunohistochemical and biochemical experiments showed that intrahippocampal injection of thrombin increased IL-13 immunoreactivity and IL-13 levels as early as 8 h after thrombin, reaching a peak at 7 days, which was maintained up to 14 days. Moreover, double-label immunohistochemistry revealed IL-13 immunoreactivity exclusively in activated microglia. IL-13-neutralizing Abs significantly rescued CA1 hippocampal neurons from thrombin neurotoxicity. In parallel, neutralization of IL-13 inhibited activation of NADPH oxidase, reactive oxygen species production, and oxidative damage. Additionally, IL-13 neutralization suppressed the expression of inducible NO synthase and several proinflammatory cytokines. To our knowledge, the present study is the first to show that IL-13 triggers microglial NADPH oxidase-derived oxidative stress, leading to the degeneration of hippocampal neurons in vivo, as occurs in cases of Alzheimer’s disease.
Tratamiento actual del ataque cerebrovascular isquémico (ACV) agudo

El tratamiento del ataque cerebrovascular isquemico (ACV) agudo cambio desde la publicacion, en 1995, de los resultados del estudio NINDS (National Institute of Neurological Disorders and Stroke Trial) con activador tisular del plasminogeno. En este articulo se hace una revision de la fisiopatologia del ACV isquemico agudo, la generacion del edema, la evaluacion clinica, las pruebas diagnosticas, los estudios clinicos, y los criterios de inclusion y de exclusion para la trombolisis intravenosa al cabo de tres horas del inicio de los sintomas
Chimpanzees Use More Varied Receptors and Ligands Than Humans for Inhibitory Killer Cell Ig-Like Receptor Recognition of the MHC-C1 and MHC-C2 Epitopes1

Humans and chimpanzees have orthologous MHC class I, but few orthologous killer cell Ig-like receptors (KIR). Most divergent are lineage III KIR, which in humans include the inhibitory KIR2DL1 and 2DL2/3 specific for HLA-C. Six lineage III chimpanzee KIR were identified as candidate inhibitory MHC-C receptors and studied using cytolytic assays, to assess the capacity of a defined KIR to function with a defined MHC class I allotype, and direct binding assays with KIR-Fc fusion proteins. Pt-KIR2DL6 and 2DL8 were demonstrated to be inhibitory C1 receptors with a specificity and specificity-determining residue (lysine 44) like KIR2DL3. Analogously, Pt-KIR2DL7 is like KIR2DL1, an inhibitory C2 receptor having methionine 44. Pt-KIR3DL4 and 3DL5 are unusual lineage III KIR with D0 domains, which are also inhibitory C2 receptors with methionine 44. Removal of D0 from KIR3DL, or its addition to KIR2DL, had no effect on KIR function. Pt-KIR2DL9, a fourth inhibitory C2 receptor, has glutamate 44, a previously uncharacterized specificity-determining residue that is absent from human KIR. Reconstruction of the ancestral hominoid KIR sequence shows it encoded lysine 44, indicating that KIR having methionine 44 and glutamate 44 subsequently evolved by independent point substitutions. Thus, MHC-C2-specific KIR have evolved independently on at least two occasions. None of the six chimpanzee KIR studied resembles KIR2DL2, which interacts strongly with C1 and cross-reacts with C2. Whereas human HLA-B allotypes that have functional C1 epitopes are either rare (HLA-B*73) or geographically localized (HLA-B*46), some 25% of Patr-B allotypes have the C1 epitope and are functional KIR ligands.
Investigations into micro-orthogonal cutting and material strengthening

When a scale of metal cutting process reduces to micrometer range, mechanics of material removal are affected by various factors such as workpiece material, cutting tool geometry and cutting conditions. A suitable model of constitutive behaviour of the material is needed to represent properties of the work material at the conditions existing during chip formation. In this paper, a material model based on theory of strain gradient plasticity is proposed for material strengthening in micro cutting, taking into account size effect in micro cutting with a tool having an edge radius. The proposed model effectively combines strain gradient plasticity and basic mechanics of orthogonal cutting. The material model thus developed is validated using results obtained from micro-orthogonal cutting experiments on mild steel (AISI 1019). Micro-orthogonal experiments with varying uncut chip thickness are also carried out to fine-tune the material model and investigate the mechanics of micro cutting considering the minimum uncut chip thickness effect. The results are encouraging and shear strength is predicted with an average absolute error of 11.8%. FE simulations carried out with flow stress obtained from Johnson-Cook relation yield cutting forces that follow the trend in the experimentally obtained force signals, but they are unable to capture the strain gradient and ploughing effects.