Nitroglycerin-induced migraine type headache: bilaterally visible temporal arteries

A 37-year-old man presented to the emergency department suffering from headache, nausea and vomiting, which had started 1 h previously. He had been diagnosed with coronary artery disease and had been taking isosorbid-5-mononitrate, aspirin and metoprolol for 3 days. His vital signs and physical and detailed neurological examinations were normal except for a new onset of bilaterally visible, palpable and pulsatile temporal arteries. We discuss how nitrates can increase the cerebral and also temporal blood flow, which can rarely be seen with the naked eye, as was observed in this patient

Fatigue analysis-based numerical design of stamping tools made of cast iron

This work concerns stress and fatigue analysis of stamping tools made of cast iron with an essentially pearlitic matrix and containing foundry defects. Our approach consists at first, in coupling the stamping numerical processing simulations and structure analysis in order to improve the tool stiffness geometry for minimizing the stress state and optimizing their fatigue lifetime. The method consists in simulating the stamping process by considering the tool as a perfect rigid body. The estimated contact pressure is then used as boundary condition for FEM structure loading analysis of the tool. The result of this analysis is compared with the critical stress limit depending on the automotive model. The acceptance of this test allows calculating the fatigue lifetime of the critical zone by using the S–N curve of corresponding load ratio. If the prescribed tool life requirements are not satisfied, then the critical region of the tool is redesigned and the whole simulation procedures are reactivated. This method is applied for a cast iron EN-GJS-600-3. The stress-failure (S–N) curves for this material is determined at room temperature under push pull loading with different load ratios R0σmin/σmax0−2, R0−1 and R00.1. The effects of the foundry defects are determined by SEM observations of crack initiation sites. Their presence in tested specimens is associated with a reduction of fatigue lifetime by a factor of 2. However, the effect of the load ratio is more important

The Devil is in the Errors: Leveraging Large Language Models for Fine-grained Machine Translation Evaluation

Automatic evaluation of machine translation (MT) is a critical tool driving the rapid iterative development of MT systems. While considerable progress has been made on estimating a single scalar quality score, current metrics lack the informativeness of more detailed schemes that annotate individual errors, such as Multidimensional Quality Metrics (MQM). In this paper, we help fill this gap by proposing AutoMQM, a prompting technique which leverages the reasoning and in-context learning capabilities of large language models (LLMs) and asks them to identify and categorize errors in translations. We start by evaluating recent LLMs, such as PaLM and PaLM-2, through simple score prediction prompting, and we study the impact of labeled data through in-context learning and finetuning. We then evaluate AutoMQM with PaLM-2 models, and we find that it improves performance compared to just prompting for scores (with particularly large gains for larger models) while providing interpretability through error spans that align with human annotations.Comment: 19 page

In vivo study of the GC90/IRIV vaccine for immune response and autoimmunity into a novel humanised transgenic mouse

Parathyroid hormone-related protein (PTH-rP), a secreted protein produced by prostate carcinoma and other epithelial cancers, is considered a key agent for the development of bone metastases. We investigated the construct GC90/IRIV, composed of immunopotentiating reconstituted influenza virosomes (IRIV) containing PTH-rP gene plasmids (GC90), as a potential tool for human anticancer immunotherapy into humanised mice transgenic for HLA-A(*)02.01, the human-β2 microglobulin, and the human CD8α molecule. Intranasal administration of GC90/IRIV resulted in the induction of a PTH-rP-specific multiepitope cytotoxic T-cell (CTL) response. Cytotoxic T cells derived from vaccinated mice were capable of lysing in vitro syngenic murine PTH-rP transfectants and human HLA-A(*)02.01+/PTH-rP+ prostate carcinoma LNCaP cells as well. The immune response capacity and the absence of any sign of toxicity and/or autoimmunity in vivo suggest the GC90/IRIV vaccine as a valid tool for active specific immunotherapy of human cancers and metastases overexpressing PTH-rP

Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6)

Aims Short QT syndrome (SQTS) is a genetically determined ion-channel disorder, which may cause malignant tachyarrhythmias and sudden cardiac death. Thus far, mutations in five different genes encoding potassium and calcium channel subunits have been reported. We present, for the first time, a novel loss-of-function mutation coding for an L-type calcium channel subunit. Methods and results The electrocardiogram of the affected member of a single family revealed a QT interval of 317 ms (QTc 329 ms) with tall, narrow, and symmetrical T-waves. Invasive electrophysiological testing showed short ventricular refractory periods and increased vulnerability to induce ventricular fibrillation. DNA screening of the patient identified no mutation in previously known SQTS genes; however, a new variant at a heterozygous state was identified in the CACNA2D1 gene (nucleotide c.2264G > C; amino acid p.Ser755Thr), coding for the Cavα2δ-1 subunit of the L-type calcium channel. The pathogenic role of the p.Ser755Thr variant of the CACNA2D1 gene was analysed by using co-expression of the two other L-type calcium channel subunits, Cav1.2α1 and Cavβ2b, in HEK-293 cells. Barium currents (IBa) were recorded in these cells under voltage-clamp conditions using the whole-cell configuration. Co-expression of the p.Ser755Thr Cavα2δ-1 subunit strongly reduced the IBa by more than 70% when compared with the co-expression of the wild-type (WT) variant. Protein expression of the three subunits was verified by performing western blots of total lysates and cell membrane fractions of HEK-293 cells. The p.Ser755Thr variant of the Cavα2δ-1 subunit was expressed at a similar level compared with the WT subunit in both fractions. Since the mutant Cavα2δ-1 subunit did not modify the expression of the pore-forming subunit of the L-type calcium channel, Cav1.2α1, it suggests that single channel biophysical properties of the L-type channel are altered by this variant. Conclusion In the present study, we report the first pathogenic mutation in the CACNA2D1 gene in humans, which causes a new variant of SQTS. It remains to be determined whether mutations in this gene lead to other manifestations of the J-wave syndrom

Non-Invasive In Vivo Imaging of Tumor-Associated CD133/Prominin

detection of cancer stem cells is of great importance. detection of CD133/prominin, a cancer stem cell surface marker for a variety of tumor entities. The CD133-specific monoclonal antibody AC133.1 was used for quantitative fluorescence-based optical imaging of mouse xenograft models based on isogenic pairs of CD133 positive and negative cell lines. A first set consisted of wild-type U251 glioblastoma cells, which do not express CD133, and lentivirally transduced CD133-overexpressing U251 cells. A second set made use of HCT116 colon carcinoma cells, which uniformly express CD133 at levels comparable to primary glioblastoma stem cells, and a CD133-negative HCT116 derivative. Not surprisingly, visualization and quantification of CD133 in overexpressing U251 xenografts was successful; more importantly, however, significant differences were also found in matched HCT116 xenograft pairs, despite the lower CD133 expression levels. The binding of i.v.-injected AC133.1 antibodies to CD133 positive, but not negative, tumor cells isolated from xenografts was confirmed by flow cytometry. imaging of tumor-associated CD133 is feasible and that CD133 antibody-based tumor targeting is efficient. This should facilitate developing clinically applicable cancer stem cell imaging methods and CD133 antibody-based therapeutics

Coxiella burnetii Phagocytosis Is Regulated by GTPases of the Rho Family and the RhoA Effectors mDia1 and ROCK

The GTPases belonging to the Rho family control the actin cytoskeleton rearrangements needed for particle internalization during phagocytosis. ROCK and mDia1 are downstream effectors of RhoA, a GTPase involved in that process. Coxiella burnetii, the etiologic agent of Q fever, is internalized by the host´s cells in an actin-dependent manner. Nevertheless, the molecular mechanism involved in this process has been poorly characterized. This work analyzes the role of different GTPases of the Rho family and some downstream effectors in the internalization of C. burnetii by phagocytic and non-phagocytic cells. The internalization of C. burnetii into HeLa and RAW cells was significantly inhibited when the cells were treated with Clostridium difficile Toxin B which irreversibly inactivates members of the Rho family. In addition, the internalization was reduced in HeLa cells that overexpressed the dominant negative mutants of RhoA, Rac1 or Cdc42 or that were knocked down for the Rho GTPases. The pharmacological inhibition or the knocking down of ROCK diminished bacterium internalization. Moreover, C. burnetii was less efficiently internalized in HeLa cells overexpressing mDia1-N1, a dominant negative mutant of mDia1, while the overexpression of the constitutively active mutant mDia1-ΔN3 increased bacteria uptake. Interestingly, when HeLa and RAW cells were infected, RhoA, Rac1 and mDia1 were recruited to membrane cell fractions. Our results suggest that the GTPases of the Rho family play an important role in C. burnetii phagocytosis in both HeLa and RAW cells. Additionally, we present evidence that ROCK and mDia1, which are downstream effectors of RhoA, are involved in that processFil: Salinas Ojeda, Romina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ortiz Flores, Rodolfo Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Distel, Jesús Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Aguilera, Milton Osmar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Colombo, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Beron, Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin