Modifications in cellular viability, DNA damage and stress responses inflicted in cancer cells by copper-64 ions.

Due to combined therapeutical emissions, a high linear energy transfer Auger-electrons with the longer ranged ß- particles, 64Cu-based radiopharmaceuticals raise particular theragnostic interest in cancer, by joined therapeutic and real-time PET imaging properties. The in vitro study aimed to investigate the biological and molecular background of 64CuCl2 therapy by analyzing the damages and stress responses inflicted in various human normal and tumor cell lines. Colon (HT29 and HCT116) and prostate carcinoma (DU145) cell lines, as well as human normal BJ fibroblasts, were treated up to 72 h with 2-40 MBq/mL 64CuCl2. Radioisotope uptake and retention were assessed, and cell viability/death, DNA damage, oxidative stress, and the expression of 84 stress genes were investigated at various time points after [64Cu]CuCl2 addition. All the investigated cells incorporated 64Cu ions similarly, independent of their tumoral or normal status, but their fate after exposure to [64Cu]CuCl2 was cell-dependent. The most striking cytotoxic effects of the radioisotope were registered in colon carcinoma HCT116 cells, for which a substantial decrease in the number of metabolically active cells, and an increased DNA damage and oxidative stress were registered. The stress gene expression study highlighted the activation of both death and repair mechanisms in these cells, related to extrinsic apoptosis, necrosis/necroptosis or autophagy, and cell cycle arrest, nucleotide excision repair, antioxidant, and hypoxic responses, respectively. The in vitro study indicated that 40 MBq/mL [64Cu]CuCl2 delivers a therapeutic effect in human colon carcinoma, but its use is limited by harmful, yet lower effects on normal fibroblasts. The exposure of tumor cells to 20 MBq/mL [64Cu]CuCl2, might be used for a softer approach aiming for a lower radiotoxicity in normal fibroblasts as compared to tumor cells. This radioactive concentration was able to induce a persistent decrease in the number of metabolically active cells, accompanied by DNA damage and oxidative stress, associated with significant changes in stress gene expression in HCT116 colon cancer cells.

Preclinical Evaluation of NHS-Activated Gold Nanoparticles Functionalized with Bombesin or Neurotensin-Like Peptides for Targeting Colon and Prostate Tumours.

Recent advances and large-scale use of hybrid imaging modalities like PET-CT have led to the necessity of improving nano-drug carriers that can facilitate both functional and metabolic screening in nuclear medicine applications. In this study, we focused on the evaluation of four potential imaging nanoparticle structures labelled with the 68Ga positron emitter. For this purpose, we functionalized NHS-activated PEG-gold nanoparticles with 68Ga-DOTA-Neuromedin B, 68Ga-DOTA-PEG(4)-BBN(7-14), 68Ga-DOTA-NT and 68Ga-DOTA-Neuromedin N. In vitro binding kinetics and specific binding to human HT-29 colon carcinoma cells and DU-145 prostate carcinoma cells respectively were assessed, over 75% retention being obtained in the case of 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP in prostate tumour cells and over 50% in colon carcinoma cells. Biodistribution in NU/J mice highlighted a three-fold uptake increase in tumours at 30 min post-injection of 68Ga-DOTA-NT-AuNP and 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP compared to 68Ga-DOTA-NT and 68Ga-DOTA-PEG(4)-BBN(7-14) respectively, therewith fast distribution in prostate and colon tumours and minimum accumulation in non-targeted tissues.

Unusual Presentation Of Kawasaki Disease With Gastrointestinal And Renal Manifestations.

Diagnosis of Kawasaki disease (KD) is based on well-established clinical criteria. In incomplete or atypical KD, the diagnosis is challenging, because of the paucity of clinical signs or because of the presence of clinical manifestations that generally are not seen in KD. We describe the case of a 3-year-old female patient with persistent high fever, vomiting, watery diarrhea, metabolic acidosis and severe hypopotassemia. On the fourth day of fever, bilateral conjunctivitis, mucous and extremity changes were registered. Urine changes as glycosuria and proteinuria were also noticed. Echocardiography revealed ectasia of the left anterior descending coronary artery, and diagnosis of KD was established. The treatment consisted of intravenous immunoglobulin (IVIG) and oral aspirin. Recurrence of disease was recorded on the 23rd day of the disease, with favorable evolution after the second dose of IVIG was infused.

Bruising as the first sign of exocrine pancreatic insufficiency in infancy.

Exocrine pancreatic insufficiency is an important cause of chronic malnutrition, secondary to maldigestion-malabsorption, which can be caused in children especially by cystic fibrosis, but also by other much rarer diseases. The case of a 6 months and 3 weeks old male pediatric patient is reported, who was admitted to the clinic for head and forearms bruising. Laboratory findings identified vitamin K deficiency as the cause of the cutaneous hemorrhagic syndrome. Further investigations revealed association of steatorrhea (which is a marker of fat malabsorption), iron-deficiency anemia and hypovitaminosis D, which had been produced by nutritional deficiencies caused by malabsorption syndrome. From the numerous disorders that could be associated with pancreatic insufficiency in children, the following conditions had been excluded: cystic fibrosis (mucoviscidosis), cow's milk protein intolerance, gluten-sensitive enteropathy (coeliac disease), Shwachman-Diamond syndrome, abetalipoproteinemia, etc. Based upon decreased levels of stool pancreatic elastase in repeated measurements, together with low serum lipase, the final diagnosis of exocrine pancreatic insufficiency was established. Treatment of this case consisted mainly in pancreatic enzyme replacement therapy, but also oral iron supplementation and dietary supplements with fat-soluble vitamins (A, D, E, K). The outcome was favorable, characterized by normalization of intestinal passage, ascending growth curve and normalization of the majority of laboratory tests values that were modified between the time of patient admission to our clinic and initiation of specific therapy (serum level of vitamin K, vitamin D and lipase, coagulation profile, hemoglobin and red blood cell indexes), as well as higher value of fecal pancreatic elastase.

Photon-pixel coupling: A method for parallel acquisition of electrical signals in scientific investigations.

Here we describe a novel prototype method for parallel sampling of electrical signals from 200 sensors. The amplified signal from each sensor was remotely converted into a luminous signal on a LED matrix. A digital camera supported by a duralumin skeleton, was installed at 15 cm above an LED matrix inside an opaque box. Images were sampled at discrete time intervals of 5 s. A total of 25,920 images of the LED matrix have been recorded. Thus, 5.2 million measurements have been recorded as light intensities from the LED matrix. Light intensities of individual LEDs from the images were converted into 1 pixel value/LED. Each pixel value was then converted into percentages for evaluation. We used this methodology to measure the temporal variation of the electrical current on the skin of the torso on human volunteers, to assess the presence of a correlation between the electrical activity and diabetes (Ionescu-Tirgoviste et al., 2018). This method also allowed us to compile the first high resolution map of the electrical activity generated by the human skin (Ionescu-Tirgoviste et al., 2018). •A novel method for a parallel acquisition of electrical signals which can be applied in any related field.•It provides the ability to retrieve a large number of electrical channels simultaneously.•It provides for an inexpensive and reliable way to digitize hundreds to thousands of channels at video rate frequencies.

Compliant contact versus rigid contact: A comparison in the context of granular dynamics.

We summarize and numerically compare two approaches for modeling and simulating the dynamics of dry granular matter. The first one, the discrete-element method via penalty (DEM-P), is commonly used in the soft matter physics and geomechanics communities; it can be traced back to the work of Cundall and Strack [P. Cundall, Proc. Symp. ISRM, Nancy, France 1, 129 (1971); P. Cundall and O. Strack, Geotechnique 29, 47 (1979)GTNQA80016-850510.1680/geot.1979.29.1.47]. The second approach, the discrete-element method via complementarity (DEM-C), considers the grains perfectly rigid and enforces nonpenetration via complementarity conditions; it is commonly used in robotics and computer graphics applications and had two strong promoters in Moreau and Jean [J. J. Moreau, in Nonsmooth Mechanics and Applications, edited by J. J. Moreau and P. D. Panagiotopoulos (Springer, Berlin, 1988), pp. 1-82; J. J. Moreau and M. Jean, Proceedings of the Third Biennial Joint Conference on Engineering Systems and Analysis, Montpellier, France, 1996, pp. 201-208]. The DEM-P and DEM-C are manifestly unlike each other: They use different (i) approaches to model the frictional contact problem, (ii) sets of model parameters to capture the physics of interest, and (iii) classes of numerical methods to solve the differential equations that govern the dynamics of the granular material. Herein, we report numerical results for five experiments: shock wave propagation, cone penetration, direct shear, triaxial loading, and hopper flow, which we use to compare the DEM-P and DEM-C solutions. This exercise helps us reach two conclusions. First, both the DEM-P and DEM-C are predictive, i.e., they predict well the macroscale emergent behavior by capturing the dynamics at the microscale. Second, there are classes of problems for which one of the methods has an advantage. Unlike the DEM-P, the DEM-C cannot capture shock-wave propagation through granular media. However, the DEM-C is proficient at handling arbitrary grain geometries and solves, at large integration step sizes, smaller problems, i.e., containing thousands of elements, very effectively. The DEM-P vs DEM-C comparison is carried out using a public-domain, open-source software package; the models used are available online.

Using model checking for critiquing based on clinical guidelines.

OBJECTIVE: Medical critiquing systems compare clinical actions performed by a physician with a predefined set of actions. In order to provide useful feedback, an important task is to find differences between the actual actions and a set of 'ideal' actions as described by a clinical guideline. In case differences exist, the critiquing system provides insight into the extent to which they are compatible. METHODS AND MATERIAL: We propose a computational method for such critiquing, where the ideal actions are given by a formal model of a clinical guideline, and where the actual actions are derived from real world patient data. We employ model checking to investigate whether a part of the actual treatment is consistent with the guideline. RESULTS: We show how critiquing can be cast in terms of temporal logic, and what can be achieved by using model checking. Furthermore, a method is introduced for off-line computing relevant information which can be exploited during critiquing. The method has been applied to a clinical guideline of breast cancer in conjunction with breast cancer patient data.

Extraction and use of linguistic patterns for modelling medical guidelines.

OBJECTIVE: The quality of knowledge updates in evidence-based medical guidelines can be improved and the effort spent for updating can be reduced if the knowledge underlying the guideline text is explicitly modelled using the so-called linguistic guideline patterns, mappings between a text fragment and a formal representation of its corresponding medical knowledge. METHODS AND MATERIAL: Ontology-driven extraction of linguistic patterns is a method to automatically reconstruct the control knowledge captured in guidelines, which facilitates a more effective modelling and authoring of medical guidelines. We illustrate by examples the use of this method for generating and instantiating linguistic patterns in the text of a guideline for treatment of breast cancer, and evaluate the usefulness of these patterns in the modelling of this guideline. RESULTS: We developed a methodology for extracting and using linguistic patterns in guideline formalization, to aid the human modellers in guideline formalization and reduce the human modelling effort. Using automatic transformation rules for simple linguistic patterns, a good recall (between 72% and 80%) is obtained in selecting the procedural knowledge relevant for the guideline model, even though the precision of the guideline model generated automatically covers only between 20% and 35% of the human-generated guideline model. These results indicate the suitability of our method as a pre-processing step in medical guideline formalization. CONCLUSIONS: Modelling and authoring of medical texts can benefit from our proposed method. As pre-requisites for generating automatically a skeleton of the guideline model from the procedural part of the guideline text, to aid the human modeller, the medical terminology used by the guideline must have a good overlap with existing medical thesauri and its procedural knowledge must obey linguistic regularities that can be mapped into the control constructs of the target guideline modelling language.

Helicobacter pylori gastritis in children: endoscopical and histological aspects.

UNLABELLED: Helicobacter pylori (Hp) infection is involved in both digestive and extradigestive diseases. Endoscopically, antral location of gastritis, as well as antral nodularity, a consequence of the development of lymphoid follicles in the mucosa of this area, are considered by some authors specific for gastritis in children. Histologically, lymphoid follicles, noticed usually in children, are considered pathognomonic. AIMS: To establish prevalence of gastritis in children and the correlation between of endoscopical and histological findings. PATIENTS AND METHODS: The study group included 267 children in whom upper digestive endoscopy was performed for digestive symptoms. The diagnosis of Hp infection was based on the concordance between the positive urease test and the histological examination (documenting the presence of Hp in the gastric mucosa). RESULTS: Endoscopical aspect of antral nodular gastritis was mainly found in children infected with Hp. Follicular gastritis, considered the histological marker of nodular gastritis, was also revealed in congestive gastritis. Patients infected with Hp most often displayed chronic gastritis and noninfected patients acute gastritis. Hp was not found in gastric mucosa without histological changes. CONCLUSIONS: Nodular pattern of antral mucosa might be considered specific for Hp infection in childhood. In patients infected with Hp chronic gastritis was mainly found while in noninfected children acute gastritis was usually revealed. Hp was not found in gastric mucosa without histological changes.