Thrombozytenhemmung und -aktivierung: Mechanismen und klinische Implikationen

Zusammenfassung : Die Empfindlichkeit der Aktivierung von Thrombozyten ist Teil des delikaten Gleichgewichts, welches Hämostase von Thrombose unterscheidet. Unter physiologischen Bedingungen wird es durch die Hemmung der Thrombozytenaktivität und Entfernung von Agonisten erhalten. Unter pathologischen prothrombotischen Bedingungen versucht der Mediziner, das Gleichgewicht mit Hilfe von Arzneimitteln wiederherzustellen. Die Resultate dieser Behandlungen verbessern sich stetig, aber dennoch sind ein besseres Verständnis der Mechanismen und die Suche nach alternativen Inhibitoren nach wie vor wichti

Arsenic detection project: electronics

This project is a collaboration with a team of bioengineers to adapt the functionality of laboratory equipment onto a platform which could be used in the field to determine the concentration levels of toxins in ground water. To this end, using a set of printed electrodes, a device was designed and fabricated with the constraints of field use in mind: low power, low cost, with a mobile user interface. An Android phone served as the mobile user interface, and also as the power supply for the circuit and microcontroller that performed the test. This circuit applied a stimulus voltage across the electrodes and generated an output signal using annodic stripping voltammetry. The microcontroller both generated that stimulus signal, and interpreted the output signal for transmission to the mobile phone where the user then interpreted the data. Testing showed that, in addition to running the expected test for arsenic, the device was able to communicate those results to the mobile phone. Subsequent visual inspection of these results confirmed that control and contaminated samples could be correctly identified from the phone

Postpartum osteoporosis associated with proximal tibial stress fracture

A 33-year-old woman presented with acute nonspecific knee pain, 6months postpartum. MR imaging, computed tomography and radiography were performed and a proximal tibia plateau insufficiency fracture was detected. Bone densitometry demonstrated mild postpartum osteoporosis. To our knowledge these findings have not been described in this location and in this clinical setting. The etiology of the atraumatic fracture of the tibia is presumed to be due to a low bone mineral density. The bone loss was probably due to pregnancy, lactation and postpartum hormonal changes. There were no other inciting causes and the patient was normocalcemic. We discuss the presence of a postpartum stress fracture in a hitherto undescribed site in a patient who had lactated following an uncomplicated pregnancy and had no other identifiable cause for a stress fractur

The State of Children's Dental Health: Making Coverage Matter

Examines states' progress since 2010 in meeting the dental care needs of publicly insured and soon-to-be insured children, including providing fluoridated water to 75 percent of residents and Medicaid reimbursements for preventive care.The state that children call home can make a big difference in the health of their teeth.  In this year's 50-state report card by the Pew Children's Dental Campaign, 27 states earned grades of an A or B, while 23 states and the District of Columbia received a C or lower grade. However, the 2011 grades for 22 states were higher than their 2010 grades, revealing that even in a time of fiscal distress, dental health policies can be improved.More than 16 million U.S. children go without even basic dental care each year. Pew's report card, The State of Children's Dental Health: Making Coverage Matter, assesses states' ability to serve insured and soon-to-be-insured children

G6b-B Inhibits Constitutive and Agonist-induced Signaling by Glycoprotein VI and CLEC-2

Platelets play an essential role in wound healing by forming thrombi that plug holes in the walls of damaged blood vessels. To achieve this, platelets express a diverse array of cell surface receptors and signaling proteins that induce rapid platelet activation. In this study we show that two platelet glycoprotein receptors that signal via an immunoreceptor tyrosine-based activation motif (ITAM) or an ITAM-like domain, namely the collagen receptor complex glycoprotein VI (GPVI)-FcR γ-chain and the C-type lectin-like receptor 2 (CLEC-2), respectively, support constitutive (i.e. agonist-independent) signaling in a cell line model using a nuclear factor of activated T-cells (NFAT) transcriptional reporter assay that can detect low level activation of phospholipase Cγ (PLCγ). Constitutive and agonist signaling by both receptors is dependent on Src and Syk family kinases, and is inhibited by G6b-B, a platelet immunoglobulin receptor that has two immunoreceptor tyrosine-based inhibitory motifs in its cytosolic tail. Mutation of the conserved tyrosines in the two immunoreceptor tyrosine-based inhibitory motifs prevents the inhibitory action of G6b-B. Interestingly, the inhibitory activity of G6b-B is independent of the Src homology 2 (SH2)-domain containing tyrosine phosphatases, SHP1 and SHP2, and the inositol 5′-phosphatase, SHIP. Constitutive signaling via Src and Syk tyrosine kinases is observed in platelets and is associated with tyrosine phosphorylation of GPVI-FcR γ-chain and CLEC-2. We speculate that inhibition of constitutive signaling through Src and Syk tyrosine kinases by G6b-B may help to prevent unwanted platelet activation

Identification of platelet function defects by multi-parameter assessment of thrombus formation.

Assays measuring platelet aggregation (thrombus formation) at arterial shear rate mostly use collagen as only platelet-adhesive surface. Here we report a multi-surface and multi-parameter flow assay to characterize thrombus formation in whole blood from healthy subjects and patients with platelet function deficiencies. A systematic comparison is made of 52 adhesive surfaces with components activating the main platelet-adhesive receptors, and of eight output parameters reflecting distinct stages of thrombus formation. Three types of thrombus formation can be identified with a predicted hierarchy of the following receptors: glycoprotein (GP)VI, C-type lectin-like receptor-2 (CLEC-2)>GPIb>α6β1, αIIbβ3>α2β1>CD36, α5β1, αvβ3. Application with patient blood reveals distinct abnormalities in thrombus formation in patients with severe combined immune deficiency, Glanzmann's thrombasthenia, Hermansky-Pudlak syndrome, May-Hegglin anomaly or grey platelet syndrome. We suggest this test may be useful for the diagnosis of patients with suspected bleeding disorders or a pro-thrombotic tendency.This work was supported by grants from the Center for Translational Molecular Medicine (INCOAG), the Dutch Heart Foundation (2011T6), the Landsteiner Foundation for Blood Transfusion Research (1006) and ZonMW (MKMD 114021004).This is the final published version. It's also available from Nature Communications at http://www.nature.com/ncomms/2014/140716/ncomms5257/full/ncomms5257.html

Effects of Payena dasyphylla (Miq.) on hyaluronidase enzyme activity and metalloproteinases protein expressions in interleukin-1beta stimulated human chondrocytes cells

Background: Hyaluronidases have been found as the target enzymes in the development of osteoarthritis (OA) disease. While there is still no curative treatment for this disease, recent studies on the treatment of OA were focused on the effectiveness of natural products which are expected to improve the symptoms with minimal side effects. The aim of this study was to screen selected Malaysian plants on their anti-hyaluronidase activity as well as to evaluate the active plant and its derived fractions on its potential anti-arthritic and antioxidant activities.Methods: A total of 20 methanolic crude extracts (bark and leaf) from ten different plants were screened using a colorimetric hyaluronidase enzymatic assay. The active plant extract (Payena dasyphylla) was then studied for its hyaluronidase inhibitory activity in the interleukin-1β (IL-1β) stimulated human chondrocytes cell line (NHAC-kn) using zymography method. The Payena dasyphylla methanolic bark extract was then fractionated into several fractions in where the ethyl acetate (EA) fraction was evaluated for its inhibitory effects on the HYAL1 and HYAL2 gene expressions using reverse transcription-polymerase chain reaction (RT-PCR) technique. While the MMP-3 and MMP-13 protein expressions were evaluated using western blot method. The phenolic and flavonoid contents of the three fractions as well as the antioxidant property of the EA fraction were also evaluated.Results: Bark extract of Payena dasyphylla (100 μg/ml) showed the highest inhibitory activity against bovine testicular hyaluronidase with 91.63%. The plant extract also inhibited hyaluronidase expression in the cultured human chondrocyte cells in response to IL-1β (100 ng/ml). Similarly, treatment with Payena dasyphylla ethyl acetate (EA) fraction (100 μg/ml) inhibited the HYAL1 and HYAL2 mRNA gene expressions as well as MMP-3 and MMP-13 protein expression in a dose dependent manner. Payena dasyphylla EA fraction has demonstrated the highest amount of phenolic and flavonoid content with 168.62 ± 10.93 mg GAE/g and 95.96 ± 2.96 mg RE/g respectively as compared to water and hexane fractions. In addition, the Payena dasyphylla EA fraction showed strong antioxidant activity with IC50 value of 11.64 ± 1.69 μg/mL.Conclusion: These findings have shown that Payena dasyphylla might contained potential phenolic compounds that inhibiting the key enzyme in osteoarthritis development, which is the hyaluronidase enzyme through interruption of HYAL1 and HYAL1 gene expressions. The degradation of cartilage could also be inhibited by the plant through suppression of MMP-3 and MMP-13 protein expressions. We also reported that the inhibitory effect of Payena dasyphylla on hyaluronidase activity and expression might be due to its anti-oxidant property