Synthesis and coordination ability of a partially silicon based crown ether.

The first hybrid crown ether with two adjacent disilane fragments was synthesized through reaction of O(Si2Me4Cl)2 (3) with O(C2H4OH)2. By means of DFT calculations, the complexation ability of 1,2,4,5-tetrasila[12]crown-4 (7) towards Li+ was determined to be considerably higher compared to [12]crown-4.

Platelet inhibition by abciximab bolus-only administration and oral ADP receptor antagonist loading in acute coronary syndrome patients: the blocking and bridging strategy.

INTRODUCTION: Current guidelines still recommend the bolus and infusion administration of glycoprotein IIbIIIa inhibitors in patients with high-risk acute coronary syndrome undergoing percutaneous coronary intervention. We sought to evaluate the extent of platelet inhibition by a blocking and bridging strategy with intracoronary abciximab bolus-only administration and oral loading of adenosine diphosphate receptor antagonists. PATIENTS AND METHODS: Fifty-six consecutive high-risk acute coronary syndrome patients with bolus-only abciximab administration (0.25 mg/kg i.c.) and loading with 600 mg clopidogrel (55%) or 60 mg prasugrel (45%) were included in this study. Platelet aggregation induced by thrombin receptor-activating peptide and adenosine diphosphate was measured by multiple electrode aggregometry up to 7 days. RESULTS: Thrombin receptor-activating peptide induced platelet aggregation was significantly suppressed for a minimum of 48 h (45±17U) and returned to a normal range (>84 U) after 6 days (90±26U; p<0.001). Co-medication with prasugrel significantly reduced adenosine diphosphate-induced (p=0.002) and thrombin receptor-activating peptide-induced (p=0.02) platelet aggregation compared with clopidogrel throughout the observation period. No stent thrombosis or repeat myocardial infarction occurred at 30-day follow-up. CONCLUSIONS: Immediate blocking of platelet aggregation in high-risk acute coronary syndrome patients by intracoronary abciximab bolus-only administration and bridging to prolonged inhibition via oral blockade of ADP receptors effectively inhibited overall platelet reactivity for at least 48 h, questioning the value of continuous abciximab infusion. Co-medication with prasugrel vs. clopidogrel synergistically augmented platelet inhibition.

High LRRK2 levels fail to induce or exacerbate neuronal alpha-synucleinopathy in mouse brain.

The G2019S mutation in the multidomain protein leucine-rich repeat kinase 2 (LRRK2) is one of the most frequently identified genetic causes of Parkinson's disease (PD). Clinically, LRRK2(G2019S) carriers with PD and idiopathic PD patients have a very similar disease with brainstem and cortical Lewy pathology (α-synucleinopathy) as histopathological hallmarks. Some patients have Tau pathology. Enhanced kinase function of the LRRK2(G2019S) mutant protein is a prime suspect mechanism for carriers to develop PD but observations in LRRK2 knock-out, G2019S knock-in and kinase-dead mutant mice suggest that LRRK2 steady-state abundance of the protein also plays a determining role. One critical question concerning the molecular pathogenesis in LRRK2(G2019S) PD patients is whether α-synuclein (aSN) has a contributory role. To this end we generated mice with high expression of either wildtype or G2019S mutant LRRK2 in brainstem and cortical neurons. High levels of these LRRK2 variants left endogenous aSN and Tau levels unaltered and did not exacerbate or otherwise modify α-synucleinopathy in mice that co-expressed high levels of LRRK2 and aSN in brain neurons. On the contrary, in some lines high LRRK2 levels improved motor skills in the presence and absence of aSN-transgene-induced disease. Therefore, in many neurons high LRRK2 levels are well tolerated and not sufficient to drive or exacerbate neuronal α-synucleinopathy.

LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice.

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset Parkinson's disease (PD), but the underlying pathophysiological mechanisms and the normal function of this large multidomain protein remain speculative. To address the role of this protein in vivo, we generated three different LRRK2 mutant mouse lines. Mice completely lacking the LRRK2 protein (knock-out, KO) showed an early-onset (age 6 weeks) marked increase in number and size of secondary lysosomes in kidney proximal tubule cells and lamellar bodies in lung type II cells. Mice expressing a LRRK2 kinase-dead (KD) mutant from the endogenous locus displayed similar early-onset pathophysiological changes in kidney but not lung. KD mutants had dramatically reduced full-length LRRK2 protein levels in the kidney and this genetic effect was mimicked pharmacologically in wild-type mice treated with a LRRK2-selective kinase inhibitor. Knock-in (KI) mice expressing the G2019S PD-associated mutation that increases LRRK2 kinase activity showed none of the LRRK2 protein level and histopathological changes observed in KD and KO mice. The autophagy marker LC3 remained unchanged but kidney mTOR and TCS2 protein levels decreased in KD and increased in KO and KI mice. Unexpectedly, KO and KI mice suffered from diastolic hypertension opposed to normal blood pressure in KD mice. Our findings demonstrate a role for LRRK2 in kidney and lung physiology and further show that LRRK2 kinase function affects LRRK2 protein steady-state levels thereby altering putative scaffold/GTPase activity. These novel aspects of peripheral LRRK2 biology critically impact ongoing attempts to develop LRRK2 selective kinase inhibitors as therapeutics for PD.

Influence of low-dose oral contraception on peripheral blood lymphocyte subsets at particular phases of the hormonal cycle.

OBJECTIVE: To investigate the effects of low-dose oral hormonal contraception on the immune system during certain phases of the hormonal cycle. DESIGN: Prospective, nonrandomized, controlled study. SETTING: Academic research setting. PATIENT(S): Women with regular menstrual cycle using hormonal oral contraception (OC; Cileste, 250 microg of norgestimat and 35 microg of ethinylestradiol, or Marvelon, 150 microg of desogestrel and 30 microg of ethinylestradiol) and women not using hormonal or other forms of contraception. INTERVENTION(S): Peripheral blood lymphocyte subsets were determined by flow cytometry on the first day of menstruation (day 1), in the follicular phase (day 8), midcycle (day 15), and in the luteal phase (day 22). MAIN OUTCOME MEASURE(S): Levels of lymphocyte subpopulations. RESULT(S): Women using OC had significantly higher levels of CD3+ CD8+ cells throughout their pill cycle compared to controls. Furthermore, women taking Cileste had lower levels of natural killer (NK) cells during their cycle and also women taking Marvelon but only from days 8-15. Within the pill cycle of Cileste we observed an increase in CD20+ and CD20+ CD5+ cells from days 1-8. CONCLUSION(S): Cytotoxic lymphocytes, which are responsible for first-line immune defense, and B cells, which are involved in autoimmune disorders, are affected by OC.