Preoperative transarterial embolization of vertebral metastases

The aim of this study was to evaluate the impact of preoperative devascularization of spinal metastases in relation to the preembolization tumor vascularization degree and in relation to the intraoperative blood loss. Twenty-four patients underwent preoperative transarterial embolization of hypervascular spinal metastases. Each tumor was assigned a vascularization grade (I-III) according to tumor blush after contrast agent injection in the main feeding artery. Embolization was performed with polyvinyl alcohol particles in all patients. Surgical reports were reviewed in terms of estimated blood loss. A mild hypervascularization was found in three patients (group I), medium in six patients (group II) and extensive in 15 patients (group III). In 22 out of 24 patients embolization could be performed with a complete devascularization. In two patients, only partial embolization could be performed, due to the main feeding artery arising from the artery of Adamkiewicz. In patients with complete devascularization the mean intraoperative blood loss was 1,900ml, whereas in the two patients who were not embolized it was 5,500ml. Intraoperative blood loss was not correlated to the vascularization grade. Angiography and embolization could be performed in all patients without causing permanent neurologic deficit, skin or muscle necrosis. The surgeons concluded that radical tumor resection after embolization was facilitated. Intraoperative blood loss is not correlated with the pre-interventional vascularization degree, if complete devascularization can be achieved with embolization. Preoperative embolization of vertebral hypervascular tumors is safe, effective and facilitates tumor resectio

Identification of Small Molecule Inhibitors of Tau Aggregation by Targeting Monomeric Tau As a Potential Therapeutic Approach for Tauopathies.

A potential strategy to alleviate the aggregation of intrinsically disordered proteins (IDPs) is to maintain the native functional state of the protein by small molecule binding. However, the targeting of the native state of IDPs by small molecules has been challenging due to their heterogeneous conformational ensembles. To tackle this challenge, we applied a high-throughput chemical microarray surface plasmon resonance imaging screen to detect the binding between small molecules and monomeric full-length Tau, a protein linked with the onset of a range of Tauopathies. The screen identified a novel set of drug-like fragment and lead-like compounds that bound to Tau. We verified that the majority of these hit compounds reduced the aggregation of different Tau constructs in vitro and in N2a cells. These results demonstrate that Tau is a viable receptor of drug-like small molecules. The drug discovery approach that we present can be applied to other IDPs linked to other misfolding diseases such as Alzheimer's and Parkinson's diseases.We thank the Wellcome Trust (UK), Medical Research Council (UK), Elan Pharmaceuticals (USA), the Canadian Institutes of Health Research (Canada) and the Alzheimer Society of Ontario (Canada), and Hungarian Brain Research Program (KTIA_NAP_13-2014-0009) for funding.This is the author accepted manuscript. The final version is available from Bentham Science via http://dx.doi.org/10.2174/15672050120915101910495

Häufige Magen-Darm-Beschwerden: Management der funktionellen Dyspepsie und des Reizdarm-Syndroms in der Praxis

Funktionelle Dyspepsie (FD) und Reizdarm-Syndrom (RDS), zwei häufige gastro-intestinale Entitäten mit überlappenden Symptomen, sollten nach den Rom-IV-Kriterien diagnostiziert werden. Dabei handelt es sich um eines oder mehrere der folgenden Symptome: bei FD um postprandiales Völlegefühl, frühes Sättigungsgefühl, Schmerzen oder Brennen epigastral; bei RDS um rezidivierende abdominale Schmerzen jeweils assoziiert mit Defäkation, Veränderungen der Stuhlfrequenz oder der Stuhlform. Zum Ausschluss struktureller Krankheiten ist auf Alarmsymptome zu achten. Für die Therapie bewährt sich bei beiden Krankheiten ein Stufenschema. Stufe 1: Arzt-Patienten-Gespräch mit Erläuterung von Diagnose und Prognose sowie Klärung der Therapieziele; Optimierung des Lebensstils; Einsatz von Phytotherapeutika; Stufe 2: Symptomorientierte Medikamente: bei FD Protonenpumpenhemmer bzw. Prokinetika; bei RDS Spasmolytika, Sekretagoga, Laxanzien, Gallensäurebinder, Antidiarrhoika, Antibiotika, Probiotika; Stufe. 3: viszerale Analgetika (Antidepressiva). // Frequent Gastro-Intestinal Disorders: Management of Functional Dyspepsia and Irritable Bowel Syndrome in Clinical Practice Abstract: Functional dyspepsia (FD) and irritable bowel syndrome (IBS), two common gastrointestinal entities with overlapping symptoms, should be diagnosed according to Rome IV criteria. This includes one or more of the following symptoms: in FD, postprandial fullness, early satiation, epigastric pain or burning; in IBS, recurrent abdominal pain associated with defecation, change in frequency of stool or form of stool. To exclude structural diseases, attention should be paid to alarm symptoms. As far as treatment is concerned, a stepwise scheme proves to be effective for both diseases. Step 1: doctor-patient discussion with explanation of diagnosis and prognosis as well as clarification of therapy goals; lifestyle adaptations; use of phytotherapeutics; step 2: symptom-oriented medication: for FD, PPIs or prokinetics; for IBS, antispasmodics, secretagogues, laxatives, bile acid sequestrants, antidiarrheals, antibiotics, probiotics; step 3: visceral analgesics (antidepressants)

Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of a-Synuclein Protect Against Diverse a-Synuclein Mediated Dysfunctions

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease

Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions

Funder: Howard Hughes Medical Institute (HHMI); doi: https://doi.org/10.13039/100000011Abstract: The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease

Lead optimization studies on E-selectin antagonists

The interaction of E-, P- and L-selectin with their natural carbohydrate ligands has been shown to mediate the initial step of the recruitment of leukocytes and to play a crucial role in many physiological processes and disease states. Therefore, control of the leukocyte-endothelial cell adhesion process may be useful in cases where excessive recruitment of leukocytes can contribute to acute or chronic diseases such as stroke, reperfusion injury, psoriasis or rheumatoid arthritis. The tetrasaccharide mimetic CGP69669 (41) was early recognized as a lead structure for the inhibition of E-selectin. In order to improve the lead compound’s pharmacodynamic profile, two different optimization strategies were envisaged. On the one hand, an unoccupied hydrophobic patch on the lectin’s surface was targeted with hydrophobic fragments, attached to the galactose moiety of the lead compound (193, 194, 195/196, 197/198). On the other hand, the ligand’s entropic costs upon binding were minimized by modifying the cyclohexane moiety (226a-c, 226e-h, 244, 255)

Biographies

The real-time monitoring of an industrial ball bonding process is reported using a new type of test chips with custom-made integrated sensors (microsensors). These sensors were fabricated using a commercial double-metal CMOS process [1]

Häufige Magen-Darm-Beschwerden: Management der funktionellen Dyspepsie und des Reizdarm-Syndroms in der Praxis

Frequent Gastro-Intestinal Disorders: Management of Functional Dyspepsia and Irritable Bowel Syndrome in Clinical Practic