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1.
Rev. cir. (Impr.) ; 74(6)dic. 2022.
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1441439

ABSTRACT

Introducción: El trauma penetrante de la arteria vertebral es extremadamente infrecuente. Objetivo: Aportar evidencia clínica mediante la revisión de una serie de casos. Materiales y Método: Se analizan cuatro casos de trauma penetrante con compromiso de la arteria vertebral entre los años 2020 y 2021, manejados en la unidad de trauma y urgencias del Complejo Asistencial Dr. Sótero del Río. Resultados: Se presentan cuatro casos clínicos relatando su proceso diagnóstico y manejo. Discusión: La evidencia de compromiso traumático de arteria vertebral es escasa. Reconocer su compleja anatomía y variada clínica resultan trascendentales para su adecuado manejo. Ante sospecha de este tipo de lesión, la angiografía por tomografía computada es el estudio de elección cuando se presentan hemodinámicamente estables. El abanico de opciones terapéuticas incluyen: observación, terapia antitrombótica o con antiagregantes, terapia endovascular o cirugía abierta. Conclusión: El trauma penetrante de arteria vertebral es una condición infrecuente, sin embargo, su diagnóstico y manejo deben ser conocidos por el cirujano.


Introduction: Traumatic involvement of the vertebral artery is extremely rare and difficult to diagnose. Objective: To provide clinical evidence by reviewing a case series. Materials and Method: We analyze four cases of penetrating trauma with involvement of the vertebral artery between 2020 and 2021, managed in the trauma and emergency unit of the Dr. Sótero del Río Care Complex. Results: Four clinical cases are presented describing diagnosis and management process. Discussion: There is little evidence of traumatic involvement of the vertebral artery. Recognizing its complex anatomy and varied clinic are transcendental for its proper management. When this type of lesion is suspected, computed tomography angiography is the choice study when hemodynamically stable. The range of therapeutic options include observation, antithrombotic or antiplatelet therapy, endovascular therapy or open surgery. Conclusion: Penetrating trauma of the vertebral artery is an uncommon condition, however, its diagnosis and management should be known to the surgeon.

2.
Andes Pediatr ; 93(4): 591-598, 2022 Aug.
Article in Spanish | MEDLINE | ID: mdl-37906860

ABSTRACT

Serendipity has played a crucial role in the history of many different areas of science, including modern medicine. This corresponds to the ability to make a discovery, which occurs accidentally or by chance, in combination with the sagacity of the observer. Many of the most important and revolutio nary findings in medical science, specifically pharmacology, involved serendipitous events of a natu re. Some examples related to drug discovery and pharmacological research are briefly reviewed, such as the history of benzodiazepines, chloral hydrate, clonidine, warfarin, Ringer's solution, valproic acid, barbiturates, penicillin and insulin, in which there were events related to serendipity. All these drugs or their derivatives are currently in frequent use in Intensive Care Units.


Subject(s)
Chloral Hydrate , Valproic Acid , Child , Humans , Penicillins , Critical Care
3.
Front Psychiatry ; 10: 762, 2019.
Article in English | MEDLINE | ID: mdl-31736795

ABSTRACT

Violent behavior in correctional facilities is common and differs substantially in type, target, implication, and trigger. Research on frequency and characteristics of violent behavior in correctional facilities and psychiatric hospitals is limited. Results from recent research suggest that comorbidity of severe mental disorder, personality disorder, and diagnosis of substance abuse is related to a higher risk of violent behavior. In the Berlin prison hospital, a database was created to collect data from all violent incidences (n=210) between 1997 and 2006 and between 2010 and 2016. In a retrospective, case-control study, we analyzed specific socioeconomic data and psychiatric diagnosis and compared the group of prisoners with violent behavior with randomly selected prisoners of the same department without violent behavior (n = 210). Diagnosis of schizophrenia, non-German nationality, no use of an interpreter, no children, and no previous sentence remained significantly associated with the dependent variable violent behavior. There were no significant differences regarding age and legal statuses. Practical implications for clinical work are discussed.

4.
Sci Rep ; 9(1): 8830, 2019 06 20.
Article in English | MEDLINE | ID: mdl-31222008

ABSTRACT

Pulmonary vein isolation (PVI) as interventional treatment for atrial fibrillation (AF) aims to eliminate arrhythmogenic triggers from the PVs. Improved signal detection facilitating a more robust electrical isolation might be associated with a better outcome. This retrospective cohort study compared PVI procedures using a novel high-density mapping system (HDM) with improved signal detection vs. age- and sex-matched PVIs using a conventional 3D mapping system (COM). Endpoints comprised freedom from AF and procedural parameters. In total, 108 patients (mean age 63.9 ± 11.2 years, 56.5% male, 50.9% paroxysmal AF) were included (n = 54 patients/group). Our analysis revealed that HDM was not superior regarding freedom from AF (mean follow-up of 494.7 ± 26.2 days), with one- and two-year AF recurrence rates of 38.9%/46.5% (HDM) and 38.9%/42.2% (COM), respectively. HDM was associated with reduction in fluoroscopy times (18.8 ± 10.6 vs. 29.8 ± 13.4 min; p < 0.01) and total radiation dose (866.0 ± 1003.3 vs. 1731.2 ± 1978.4 cGy; p < 0.01) compared to the COM group. HDM was equivalent but not superior to COM with respect to clinical outcome after PVI and resulted in reduced fluoroscopy time and radiation exposure. These results suggest that HDM-guided PVI is effective and safe for AF ablation. Potential benefits in comparison to conventional mapping systems, e.g. arrhythmia recurrence rates, have to be addressed in randomized trials.


Subject(s)
Atrial Fibrillation/therapy , Pulmonary Veins/surgery , Aged , Catheter Ablation , Epicardial Mapping/methods , Female , Fluoroscopy/methods , Humans , Male , Middle Aged , Pulmonary Veins/physiopathology , Radiation Exposure , Recurrence , Retrospective Studies , Treatment Outcome
5.
Internist (Berl) ; 60(7): 690-700, 2019 Jul.
Article in German | MEDLINE | ID: mdl-31093686

ABSTRACT

Treatments in oncology, transplantation medicine and immunology frequently lead to immunodeficiency. This review presents the most important opportunistic neurologic infections, mostly of the central nervous system (CNS). Signs and symptoms, diagnostic procedures and therapeutic options are presented. The most frequent infections are due to varicella zoster virus (VZV), Cryptococcus neoformans and Toxoplasma gondii; JC virus (JCV) and cytomegalovirus (CMV) are rare causes of encephalitis. Differential diagnoses include infection by non-opportunistic causatives, therapy associated neurotoxicity, Epstein-Barr virus (EBV) associated CNS lymphoma, recurrence of the malignancy, as well as non-infectious diseases like intracranial bleeding, ischemic stroke, autoimmune diseases and posterior reversible leukencephalopathy syndrome. Treatment of these patients, moreover, needs to consider all previous therapies and to involve a neurologist.


Subject(s)
Central Nervous System/physiopathology , Cryptococcosis , Immunocompromised Host , Opportunistic Infections/complications , Toxoplasmosis , Varicella Zoster Virus Infection , Central Nervous System Diseases/etiology , Cryptococcosis/diagnosis , Cryptococcosis/etiology , Cryptococcus neoformans/isolation & purification , Encephalitis/etiology , Herpes Simplex/etiology , Herpesvirus 3, Human/isolation & purification , Humans , Leukoencephalopathy, Progressive Multifocal/etiology , Opportunistic Infections/diagnosis , Opportunistic Infections/virology , Toxoplasma , Toxoplasmosis/diagnosis , Toxoplasmosis/etiology , Varicella Zoster Virus Infection/diagnosis , Varicella Zoster Virus Infection/virology
6.
Front Psychiatry ; 10: 961, 2019.
Article in English | MEDLINE | ID: mdl-32009992

ABSTRACT

[This corrects the article DOI: 10.3389/fpsyt.2019.00762.].

7.
J Mater Sci Mater Med ; 29(6): 83, 2018 Jun 11.
Article in English | MEDLINE | ID: mdl-29892952

ABSTRACT

Following percutaneous coronary intervention, vascular closure devices (VCDs) are increasingly used to reduce time to ambulation, enhance patient comfort, and reduce potential complications compared with traditional manual compression. Newer techniques include complicated, more or less automated suture devices, local application of pads or the use of metal clips and staples. These techniques often have the disadvantage of being time consuming, expensive or not efficient enough. The VCD failure rate in association with vascular complications of 2.0-9.5%, depending on the type of VCD, is still not acceptable. Therefore, the aim of this study is to develop a self-expanding quick vascular closure device (QVCD) made from a bioabsorbable elastic polymer that can be easily applied through the placed introducer sheath. Bioabsorbable block-co-polymers were synthesized and the chemical and mechanical degradation were determined by in vitro tests. The best fitting polymer was selected for further investigation and for microinjection moulding. After comprehensive haemocompatibility analyses in vitro, QVCDs were implanted in arterial vessels following arteriotomy for different time points in sheep to investigate the healing process. The in vivo tests proved that the new QVCD can be safely placed in the arteriotomy hole through the existing sheath instantly sealing the vessel. The degradation time of 14 days found in vitro was sufficient for vessel healing. After 4 weeks, the remaining QVCD material was covered by neointima. Overall, our experiments showed the safety and feasibility of applying this novel QVCD through an existing arterial sheath and hence encourage future work with larger calibers.


Subject(s)
Arteries/diagnostic imaging , Catheterization/methods , Radiography , Vascular Closure Devices , Anesthesia , Animals , Biocompatible Materials/chemistry , Equipment Design , Female , Femoral Artery , Hemostasis , Humans , Inflammation , Male , Microscopy, Electron, Scanning , Polymers/chemistry , Pressure , Sheep , Stress, Mechanical
8.
Rev Chil Pediatr ; 89(2): 270-277, 2018 Apr.
Article in Spanish | MEDLINE | ID: mdl-29799898

ABSTRACT

Eponyms reflect the history of medicine, diseases, and doctors in their time. Their use is controversial, presenting supporters and detractors. However, the use of eponyms persist in the modern medical language in the Intensive Care Units and includes some frequently used ones such as Foley, Seldinger, Down, Macintosh, Magill, Ringer, Yankauer, Doppler, and French. The objective of this review is to promote biographical knowledge and the historical period in which its medical use took place, in order to deepen aspects of medicine history.


Subject(s)
Critical Care/history , Eponyms , Intensive Care Units/history , Critical Care/methods , Europe , History, 19th Century , History, 20th Century , New Zealand , United States
9.
Rev. chil. pediatr ; 89(2): 270-277, abr. 2018. graf
Article in Spanish | LILACS | ID: biblio-900098

ABSTRACT

Los epónimos reflejan la historia de la medicina, las enfermedades y los médicos en su época. Su uso es controversial, presentando partidarios y detractores. No obstante, el empleo de epónimos persiste en el lenguaje médico contemporáneo en las Unidades de Cuidados Intensivos e incluyen a algunos de frecuente uso como: Foley, Seldinger, Down, Macintosh, Magill, Ringer, Yankauer, Doppler y French. El objetivo de la presente revisión es fomentar el conocimiento biográfico y la época histórica en la cual tomó lugar su quehacer médico o laboral, para así profundizar aspectos de la historia de la medicina.


Eponyms reflect the history of medicine, diseases, and doctors in their time. Their use is controversial, presenting supporters and detractors. However, the use of eponyms persist in the modern medical language in the Intensive Care Units and includes some frequently used ones such as Foley, Seldinger, Down, Macintosh, Magill, Ringer, Yankauer, Doppler, and French. The objective of this review is to promote biographical knowledge and the historical period in which its medical use took place, in order to deepen aspects of medicine history.


Subject(s)
History, 19th Century , History, 20th Century , Critical Care/history , Eponyms , Intensive Care Units/history , United States , Critical Care/methods , Europe , New Zealand
10.
Talanta ; 178: 166-171, 2018 Feb 01.
Article in English | MEDLINE | ID: mdl-29136808

ABSTRACT

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been revealed as a convenient technique for trace elemental imaging in tissue sections, providing elemental 2D distribution at a quantitative level. For quantification purposes, in the last years several approaches have been proposed in the literature such as the use of CRMs or matrix matched standards. The use of Isotope Dilution (ID) for quantification by LA-ICP-MS has been also described, being mainly useful for bulk analysis but not feasible for spatial measurements so far. In this work, a quantification method based on ID analysis was developed by printing isotope-enriched inks onto kidney slices from rats treated with antitumoral Pt-based drugs using a commercial ink-jet device, in order to perform an elemental quantification in different areas from bio-images. For the ID experiments 194Pt enriched platinum was used. The methodology was validated by deposition of natural Pt standard droplets with a known amount of Pt onto the surface of a control tissue, where could be quantified even 50pg of Pt, with recoveries higher than 90%. The amount of Pt present in the whole kidney slices was quantified for cisplatin, carboplatin and oxaliplatin-treated rats. The results obtained were in accordance with those previously reported. The amount of Pt distributed between the medullar and cortical areas was also quantified, observing different behavior for the three drugs.


Subject(s)
Mass Spectrometry , Molecular Imaging , Platinum/metabolism , Animals , Kidney/metabolism , Rats , Reproducibility of Results
11.
Rev Chil Pediatr ; 88(5): 668-676, 2017.
Article in Spanish | MEDLINE | ID: mdl-29546955

ABSTRACT

Down syndrome is the most common chromosomal abnormality in newborns, with a high incidence in Chile. This condition presents unique physiological aspects that should be known, which can affect the child during their stay in an Intensive Care Unit, beyond the neonatal period This review is focused on the respiratory, cardiovascular, infectious and neurological disorders. Anesthetic management and postoperative analgesia considerations, weaning from mechanical ventilation, cervical spine instability and prognosis of the critically ill child with Down syndrome are also analyzed. The evaluation of these conditions should be performed when the patient is admitted to the intensive care unit. The purpose of this update is to update the knowledge of the diagnosis and treatment of potential complications of children with Down syndrome during their stay in the unit of critical patient.


Subject(s)
Critical Care/methods , Down Syndrome/complications , Child , Critical Illness , Down Syndrome/physiopathology , Humans , Intensive Care Units , Perioperative Care/methods
12.
Rev. chil. pediatr ; 88(5): 668-676, 2017. ilus, tab
Article in Spanish | LILACS | ID: biblio-900034

ABSTRACT

El síndrome de Down es la alteración cromosómica más frecuente en los recién nacidos, con una alta incidencia en Chile. Esta condición presenta aspectos fisiológicos únicos, los cuales pueden afectar al niño durante su estadía en una Unidad de Cuidados Intensivos, posterior al período neonatal. En esta revisión abordamos aspectos actuales de la patología respiratoria, cardiovascular, infecciosa y neurológica, así como también consideraciones anestésicas y de analgesia postoperatoria, destete de la ventilación mecánica, inestabilidad columna cervical y pronóstico del niño críticamente enfermo portador de síndrome de Down. La evaluación de todas estas condiciones debe ser realizada cuando el paciente es ingresado a la Unidad de Cuidados Intensivos. El objetivo de la presente actualización es profundizar el conocimiento del diagnóstico y tratamiento de las potenciales complicaciones del niño con síndrome de Down durante su estadía en la unidad de paciente crítico.


Down syndrome is the most common chromosomal abnormality in newborns, with a high incidence in Chile. This condition presents unique physiological aspects that should be known, which can affect the child during their stay in an Intensive Care Unit, beyond the neonatal period This review is focused on the respiratory, cardiovascular, infectious and neurological disorders. Anesthetic management and postoperative analgesia considerations, weaning from mechanical ventilation, cervical spine instability and prognosis of the critically ill child with Down syndrome are also analyzed. The evaluation of these conditions should be performed when the patient is admitted to the intensive care unit. The purpose of this update is to update the knowledge of the diagnosis and treatment of potential complications of children with Down syndrome during their stay in the unit of critical patient.


Subject(s)
Humans , Child , Down Syndrome/complications , Critical Care/methods , Critical Illness , Down Syndrome/physiopathology , Perioperative Care/methods , Intensive Care Units
13.
Br J Anaesth ; 114(6): 973-8, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25835025

ABSTRACT

BACKGROUND: Neurosurgical procedures requiring a sitting position may put the patient at risk of a potentially life-threatening air embolism. Transient manual jugular venous compression limits further air entry in this situation. This study presents an alternative technique aimed at reducing the risk of air embolism. METHODS: In an in vitro model, an intrajugular balloon catheter was inserted to demonstrate that this device prevents air embolism. In an in vivo study, this device was bilaterally placed into jugular vessels in pigs. Using an ultrasound technique, blood flow was monitored and jugular venous pressure was recorded before and during cuff inflation. Air was applied proximally to the inflated cuffs to test the hypothesis that this novel device blocks air passage. RESULTS: In vitro, the intrajugular balloon catheter reliably prevented further air entry (n=10). Additionally, accumulated air could be aspirated from an orifice of the catheter (n=10). In vivo, inflation of the catheter balloon completely obstructed venous blood flow (n=8). Bilateral inflation of the cuff significantly increased the proximal jugular venous pressure from 9.8 (2.4) mm Hg to 14.5 (2.5) mm Hg (n=8, P<0.05). Under conditions mimicking an air embolism, air passage across the inflated cuffs was prevented and 78 (20%) (n=6) of the air dose could be aspirated by the proximal orifice of the catheter. CONCLUSIONS: These findings may serve as a starting point for the development of intrajugular balloon catheters designed to reduce the risk of air embolism in patients undergoing neurosurgery in a sitting position.


Subject(s)
Balloon Occlusion/methods , Catheterization, Peripheral/methods , Embolism, Air/prevention & control , Jugular Veins , Animals , Jugular Veins/diagnostic imaging , Neurosurgical Procedures/methods , Patient Positioning , Swine , Ultrasonography
14.
AJNR Am J Neuroradiol ; 36(1): 133-9, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25258364

ABSTRACT

BACKGROUND AND PURPOSE: Stent-assisted coiling is routinely used for the endovascular treatment of complex or wide-neck intracranial aneurysms. However, in-stent thrombosis, thromboembolic events, and ischemic complications remain a major concern associated with stent implants. Therefore, a novel low-profile neurovascular stent with a bare metal surface was investigated with regard to thrombogenicity and endothelialization and compared with the same stent coated with albumin or heparin. MATERIALS AND METHODS: The bare metal and heparin- or albumin-coated stents were loaded in heparin-coated tubing, which was then filled with heparinized human blood (n = 5) and circulated at 150 mL/min and 37°C for 60 minutes. Before and after circulation, measurement of various inflammation and coagulation markers and scanning electron microscopy were performed. Endothelialization of the stents was investigated in an in vitro model including human umbilical vascular endothelial cells. RESULTS: Our results showed that platelet loss and platelet activation and activation of the coagulation cascade, which are induced by the bare metal stents, were significantly reduced by heparin or albumin coating. Adverse effects on erythrocytes, leukocytes, and the complement cascade were not induced by the bare metal or coated stents. Moreover, the bare metal and albumin-coated stents showed good endothelialization properties. CONCLUSIONS: Albumin and heparin coatings clearly improve the thrombogenicity of the stents and thus may represent fundamental progress in the treatment of intracranial aneurysms. Moreover, preclinical evaluation of neurovascular stents under physiologic conditions supports and accelerates the development of more biocompatible neurovascular stents.


Subject(s)
Endovascular Procedures/instrumentation , Materials Testing , Stents , Albumins , Endovascular Procedures/adverse effects , Heparin , Humans , In Vitro Techniques , Metals , Platelet Activation , Stents/adverse effects , Thrombosis/etiology
15.
Int J Comput Biol Drug Des ; 7(2-3): 259-77, 2014.
Article in English | MEDLINE | ID: mdl-24878733

ABSTRACT

This paper presents a method of separating cells that are connected to each other forming clusters. The difference to many other publications covering similar topics is that the cell types we are dealing with form clusters of highly varying morphology. An advantage of our method is that it can be universally used for different cell types. The segmentation method is based on a growth simulation starting from the nuclei areas. To start the evaluation, the cells need to be made visible with a histological stain, in our case with the May-Grünwald solution. After the staining process has been completed, the nuclei areas can be distinguished from the other cell areas by a histogram backprojection algorithm. The presented method can, in addition to histological stained cells, also be applied to fluorescent-stained cells.


Subject(s)
Cell Separation/methods , Animals , Mice
16.
Chem Commun (Camb) ; 50(47): 6204-6, 2014 Jun 14.
Article in English | MEDLINE | ID: mdl-24764020

ABSTRACT

Addition of NHC→SiCl4 to the highly Lewis acidic bis(pentafluoroethyl)silane ((C2F5)2SiH2) afforded the salt [(NHC)2SiCl2H][(C2F5)2SiCl3] with pentacoordinate silicon in the cation and the anion. The anion represents the first example of a chlorosilicate structurally characterized in the solid state. In this reaction, the long sought pentacoordinate NHC-adduct of silicochloroform was identified as an intermediate and its crystal structure is presented.

17.
Mycoses ; 57(3): 147-52, 2014 Mar.
Article in English | MEDLINE | ID: mdl-23952012

ABSTRACT

In superficial tinea and pityriasis versicolor, the causative fungi are for the most part confined to the stratum corneum which is barely reached by leukocytes. Therefore, a role of non-cellular components in the epidermal antifungal defence was suggested. To investigate the presence of such factors in these infections, the expression of human beta defensins 2 and 3 (hBD-2, hBD-3), RNase 7, psoriasin, toll-like receptors 2, 4 and 9 (TLR2, TLR4 and TLR9) and dectin 2 was analysed by use of immunostainings in skin biopsies. We found that hBD2, hBD3, psoriasin, RNase7, TLR2 and TLR4 were significantly more often expressed in distinct layers of lesional epidermis as compared with uninfected epidermis. In both infections but not in normal skin, hBD2 and hBD3 were commonly expressed within the stratum corneum and in the stratum granulosum. Similarly, psoriasin was seen more often in the upper skin layers of both infections as compared with normal skin. No significant differences between normal and infected skin were found for the expression of TLR9 and dectin 2. Our findings clearly show the expression of specific antimicrobial proteins and defence-related ligands in superficial tinea as well as in pityriasis versicolor, suggesting that these factors contribute to fungal containment.


Subject(s)
Ribonucleases/metabolism , S100 Proteins/metabolism , Tinea Versicolor/metabolism , Tinea/metabolism , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 4/metabolism , beta-Defensins/metabolism , Humans , Lectins, C-Type/genetics , Lectins, C-Type/metabolism , Retrospective Studies , Ribonucleases/genetics , S100 Calcium Binding Protein A7 , S100 Proteins/genetics , Skin/microbiology , Skin/pathology , Toll-Like Receptor 2/genetics , Toll-Like Receptor 4/genetics , Toll-Like Receptor 9/genetics , Toll-Like Receptor 9/metabolism , Trichophyton/isolation & purification , beta-Defensins/genetics
18.
Anal Chem ; 84(12): 5268-75, 2012 Jun 19.
Article in English | MEDLINE | ID: mdl-22659083

ABSTRACT

As the quantification of peptides and proteins extends from comparative analyses to the determination of actual amounts, methodologies for absolute protein quantification are desirable. Metal-coded affinity tags (MeCAT) are chemical labels for peptides and proteins with a lanthanide-bearing chelator as a core. This modification of analytes with non-naturally occurring heteroelements adds the analytical possibilities of inductively coupled plasma mass spectrometry (ICPMS) to quantitative proteomics. We here present the absolute quantification of recombinantly expressed aprotinin out of its host cell protein background using two independent MeCAT methodologies. A bottom-up strategy employs labeling of primary amino groups on peptide level. Synthetic peptides with a MeCAT label which are externally quantified by flow injection analysis (FIA)-ICPMS serve as internal standard in nanoHPLC-ESI-MS/MS. In the top-down approach, protein is labeled on cysteine residues and separated by two-dimensional gel electrophoresis. Flow injection analysis of dissolved gel spots by ICPMS yields the individual protein amount via its lanthanide label content. The enzymatic determination of the fusion protein via its ß-galactosidase activity found 8.3 and 9.8 ng/µg (nanogram fusion protein per microgram sample) for batches 1 and 2, respectively. Using MeCAT values of 4.0 and 5.4 ng/µg are obtained for top-down analysis, while 14.5 and 15.9 ng/µg were found in the bottom-up analysis.


Subject(s)
Affinity Labels/chemistry , Aprotinin/analysis , Aprotinin/chemistry , Chelating Agents/chemistry , Lanthanoid Series Elements/chemistry , beta-Galactosidase/analysis , beta-Galactosidase/chemistry , Amino Acid Sequence , Mass Spectrometry , Models, Molecular , Molecular Sequence Data , Peptide Fragments/analysis , Peptide Fragments/chemistry , Protein Conformation , Proteome , Recombinant Fusion Proteins/analysis , Recombinant Fusion Proteins/chemistry
19.
Br J Anaesth ; 108(6): 912-21, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22369765

ABSTRACT

BACKGROUND: Extracorporeal circulation (ECC) and hypothermia are routinely used in cardiac surgery to maintain stable circulatory parameters and to increase the ischaemic tolerance of the patient. However, ECC and hypothermia cause platelet activation and dysfunction possibly followed by a devastating coagulopathy. Stimulation of the adenosinediphosphate (ADP) receptor P(2)Y(12) plays a pivotal role in platelet activation. This experimental study tested P(2)Y(12) receptor blockade as an approach to protect platelets during ECC. METHODS: Human blood was treated with the short-acting P(2)Y(12) blocker cangrelor (1 µM, t(1/2)<5 min) or the P(2)Y(12) inhibitor 2-MeSAMP (100 µM) and circulated in an ex vivo ECC model at normothermia (37°C) and hypothermia (28°C). Before and after circulation, markers of platelet activation and of coagulation (thrombin-antithrombin complex generation) were analysed. During hypothermic ECC in pigs, the effect of reversible P(2)Y(12) blockade on platelet function was evaluated by cangrelor infusion (0.075 µg kg(-1) min(-1)). RESULTS: During ex vivo hypothermic ECC, P(2)Y(12) blockade inhibited platelet granule release (P<0.01), platelet-granulocyte binding (P<0.05), and platelet loss (P<0.001), whereas no effects on platelet-ECC binding, platelet CD42bα expression, glycoprotein IIb/IIIa activation, or thrombin-antithrombin complex generation were observed. During hypothermic ECC in pigs, cangrelor inhibited platelet-fibrinogen binding (P<0.05) and ADP-induced platelet aggregation (P<0.001). Platelet function was rapidly restored after termination of cangrelor infusion. CONCLUSIONS: P(2)Y(12) blockade by cangrelor prevents platelet activation during ECC and hypothermia. Owing to its short half-life, platelet inhibition can be well controlled, thus potentially reducing bleeding complications. This novel pharmacological strategy has the potential to reduce complications associated with ECC and hypothermia.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Blood Coagulation Disorders/prevention & control , Blood Platelets/drug effects , Extracorporeal Circulation , Hypothermia, Induced , Purinergic P2Y Receptor Antagonists/pharmacology , Adenosine Diphosphate/blood , Adenosine Monophosphate/pharmacology , Animals , Antithrombin III/metabolism , Blood Platelets/physiology , Cardiopulmonary Bypass , Cytoplasmic Granules/drug effects , Humans , Peptide Hydrolases/metabolism , Platelet Glycoprotein GPIIb-IIIa Complex/drug effects , Platelet Glycoprotein GPIIb-IIIa Complex/physiology , Platelet Glycoprotein GPIb-IX Complex/analysis , Swine
20.
Cell Death Differ ; 19(5): 798-807, 2012 May.
Article in English | MEDLINE | ID: mdl-22075984

ABSTRACT

53BP1 is a mediator of DNA damage response (DDR) and a tumor suppressor whose accumulation on damaged chromatin promotes DNA repair and enhances DDR signaling. Using foci formation of 53BP1 as a readout in two human cell lines, we performed an siRNA-based functional high-content microscopy screen for modulators of cellular response to ionizing radiation (IR). Here, we provide the complete results of this screen as an information resource, and validate and functionally characterize one of the identified 'hits': a nuclear pore component NUP153 as a novel factor specifically required for 53BP1 nuclear import. Using a range of cell and molecular biology approaches including live-cell imaging, we show that knockdown of NUP153 prevents 53BP1, but not several other DDR factors, from entering the nuclei in the newly forming daughter cells. This translates into decreased IR-induced 53BP1 focus formation, delayed DNA repair and impaired cell survival after IR. In addition, NUP153 depletion exacerbates DNA damage caused by replication stress. Finally, we show that the C-terminal part of NUP153 is required for effective 53BP1 nuclear import, and that 53BP1 is imported to the nucleus through the NUP153-importin-ß interplay. Our data define the structure-function relationships within this emerging 53BP1-NUP153/importin-ß pathway and implicate this mechanism in the maintenance of genome integrity.


Subject(s)
Cell Nucleus/metabolism , Genome, Human/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Nuclear Pore Complex Proteins/metabolism , Cell Line, Tumor , HeLa Cells , Humans , Immunoblotting , Immunoprecipitation , Intracellular Signaling Peptides and Proteins/genetics , Nuclear Pore Complex Proteins/genetics , Protein Binding/genetics , RNA Interference/physiology , Tumor Suppressor p53-Binding Protein 1
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