Preliminary experience with inhaled milrinone in cardiac surgery

Background: Inhaled administration of milrinone reduces pulmonary artery pressure. Pulmonary hypertension (PH) and right heart failure are associated with difficult separation from cardiopulmonary bypass (CPB). Therefore, inhaled milrinone could facilitate separation from CPB. Objective: To determine the impact and timing of administration of inhaled milrinone. Methods: A retrospective analysis of our experience on high-risk patients receiving inhaled milrinone was conducted to evaluate the postoperative course after administration of the drug. Results: Seventy-three patients received inhaled milrinone from June 2002 to February 2005. Mean age was 64 ± 13 years, with a mean preoperative Parsonnet score of 27 ± 14. Inhaled milrinone (5 mg) was administered before (n = 30) or after (n = 40) CPB, three patients had off-pump procedures and were excluded. CPB time was 145 ± 78 min with cross-clamping times of 91 ± 56 min without any significant difference between groups. Fifty-four patients (74%) had difficult separation from CPB, 14 patients (19%) required an intra-aortic balloon pump and 10 patients (14%) needed emergency reinitiation of CPB for hemodynamic instability. Ten patients died in the perioperative period (13.7%). Patients receiving inhaled milrinone prior to CPB initiation had a lowering pulmonary artery pressure after CPB (p < .01) and had less emergency reinitiation of CPB after weaning (3% vs 23%, p = .02) as compared to those with administration after CPB. No detectable side effects were directly linked to the administration of the drug. Conclusion: In this high-risk cohort, use of inhaled milrinone was well tolerated. Administration before initiation of CPB could help weaning from CPB.     

Endovascular management of pseudo-aneurysms after previous surgical repair of congenital aortic coarctation

Objective: Whatever the surgical technique used, false aneurysm formation is one of the long-term complications of repair of aortic coarctation. Conservative management is associated with a 100% rate of rupture. The conventional surgical approach is complex and associated with high morbidity and mortality rates. We report our experience of endovascular management of pseudo-aneurysms after previous surgical repair of congenital aortic coarctation. Methods: Between October 2005 and 2006, stent-grafting of pseudo-aneurysms after previous surgical repair of congenital aortic coarctation was performed in four patients. Median age was 31.5 years (range: 24–38). Two patients had undergone two previous interventions. The last previous surgery consisted of graft interposition (N = 2), subclavian flap aortoplasty (N = 1) and aorto-aortic bypass (N = 1). Median size of the pseudo-aneurysm was 31.5 mm (range: 20–58). Mean time between the last surgery and endovascular treatment was 24 years (range: 3–32). One patient was treated emergently because of hemoptysis in relation with an aorto-bronchial fistula, the three other patients were treated electively. A transfemoral approach was used in all patients. The Zenith TX2^® (Cook) thoracic stent-graft was used in all the patients, one patient underwent previous dilatation at the coarctation level. When present, the ostium of the left subclavian artery was always covered (N = 3). Results: No major complication occurred during the procedure and no patient died during the follow-up. One patient presented a type II endoleak which spontaneously healed during the first month. Another patient with his left subclavian artery covered presented claudication of the left arm requiring a carotid-subclavian bypass. After a median follow-up of 7.5 months (range: 1–12.9), the patients were asymptomatic and CT scans demonstrated complete exclusion of all treated postcoarctation aneurysms without recoarctation and without any stent-graft-related complication. Conclusions: The endovascular management of pseudo-aneurysms after previous surgical repair of congenital aortic coarctation is feasible. This approach was safe and effective. Long-term clinic and imaging follow-up is mandatory.     

Subtraction procedure for powerline interference removing from ECG: improvement for non-multiple sampling

This paper presents an improvement of the subtraction procedure for interference cancellation in ECG. In contrast to the well-known hardware and software filters, the procedure does not affect the signal frequency components around the rated powerline frequency. Originally, the procedure was developed for multiplicity between the sampling rate and the interference frequency. We analysed and improved the procedure structure in cases of non-multiple sampling, introducing a set of specially designed filters. Thus the implementation of the subtraction procedure is extended to almost all possible cases of sampling rate and interference frequency variation. The procedure has been adapted for online implementation. The research was initially carried out in a MATLAB environment. Further, programmes have been written in C^?+?+ language for digital signal processors and personal computers. The results obtained with real ECG signals show high efficiency of the interference cancellation.     

Duration of Antiresorptive Effects of Low‐Dose Zoledronate in Osteopenic Postmenopausal Women: A Randomized,Placebo‐Controlled Trial

Annual intravenous administration of 5 mg zoledronate decreases fracture risk, but the optimal dosing regimen for zoledronate has not been determined. We set out to evaluate the antiresorptive effects of a single administration of lower doses of zoledronate. A total of 180 postmenopausal women with osteopenia enrolled in a double‐blind, randomized, placebo‐controlled trial over 2 years at an academic research center. Participants were randomized to a single baseline administration of intravenous zoledronate in doses of 1 mg, 2.5 mg, or 5 mg, or placebo. The primary endpoint was change in bone mineral density(BMD) at the lumbar spine. Secondary endpoints were change in BMD at the proximal femur and total body, and changes in biochemical markers of bone turnover. After 2 years, the change in spine BMD was greater in each of the zoledronate groups than in the placebo group; values are mean (95% confidence interval [CI]) difference versus placebo: zoledronate 1 mg 4.4% [2.7% to 6.1%]; 2.5 mg 5.5% [3.9% to 7.2%]; 5 mg 5.3% [3.8% to 6.7%], p < 0.001 for each dose). Change in BMD at the total hip was greater in each of the zoledronate groups than the placebo group (mean [95% CI] difference versus placebo: zoledronate 1 mg 2.6% [1.5% to 3.7%]; 2.5 mg 4.4% [3.5% to 5.3%]; 5 mg 4.7% [3.7% to 5.7%], p < 0.001 for each dose). Each of the bone turnover markers, β‐C‐terminal telopeptide of type I collagen (β‐CTX) and procollagen type‐I N‐terminal propeptide (P1NP), was lower in each of the 2.5‐mg and 5‐mg zoledronate groups than the placebo group throughout the trial (p < 0.001 versus placebo for each marker for each dose at each time point). For each endpoint, changes were similar in the 2.5‐mg and 5‐mg zoledronate groups, whereas those in the 1‐mg group were smaller than those in the other zoledronate groups. These data demonstrate that single administrations of zoledronate 1 mg or 2.5 mg produce antiresorptive effects that persist for at least 2 years. Trials assessing the antifracture efficacy of intermittent low doses of zoledronate, in particular the 2.5‐mg dose, are justified. © 2014 American Society for Bone and Mineral Research.     

A Two-Stage Methodology Using K-NN and False-Positive Minimizing ELM for Nominal Data Classification

This paper focuses on the problem of making decisions in the context of nominal data under specific constraints. The underlying goal driving the methodology proposed here is to build a decision-making model capable of classifying as many samples as possible while avoiding false positives at all costs, all within the smallest possible computational time. Under such constraints, one of the best type of model is the cognitive-inspired extreme learning machine (ELM), for the final decision process. A two-stage decision methodology using two types of classifiers, a distance-based one, K-NN, and the cognitive-based one, ELM, provides a fast means of obtaining a classification decision on a sample, keeping false positives as low as possible while classifying as many samples as possible (high coverage). The methodology only has two parameters, which, respectively, set the precision of the distance approximation and the final trade-off between false-positive rate and coverage. Experimental results using a specific dataset provided by F-Secure Corporation show that this methodology provides a rapid decision on new samples, with a direct control over the false positives and thus on the decision capabilities of the model.     

Monitoring glycosidase activity for clustered sugar substrates,a study on β-glucuronidase

Determination of glycosidase hydrolysis kinetics for a monovalent sugar substrate is relatively straightforward and classically achieved by monitoring the fluorescence signal released from the sugar-conjugated probe after enzymatic hydrolysis. Naturally occuring sugar epitopes are, however, often clustered on biopolymers or at biological surfaces, and previous reports have shown that glycosidase hydrolytic rates can differ greatly with multivalent presentation of the sugar epitopes. New probes are needed to make it easier to interpret the importance of substrate clustering towards a specific enzyme activity. In this work, we developed multivalent glucuronide substrates attached to fluorescent amino-coumarines through self-immolative linkers to enable real time-monitoring of the hydrolysing activity of E.coli β-glucuronidases (GUS) towards clustered substrates. GUS are exoglycosidases of considerable therapeutic interest cleaving β-d-glucuronides and are found in the lysosomes, in the tumoral microenvironment, and are expressed by gut microbiota. GUS showed a much lower catalytic efficiency in hydrolysing clustered glucuronides due to a significantly lower enzymatic velocity and affinity for the substrates. GUS was 52-fold less efficient in hydrolysing GlcA substrates presented on an octameric silsequioxane (COSS) compared with a monovalent GlcA of similar chemical structure. Thus, kinetic and thermodynamic data of GUS hydrolysis towards multivalent glucuronides were easily obtained with these new types of enzymatically-triggered probes. More generally, adapting the substrate nature and valency of these new probes, should improve understanding of the impact of multivalency for a specific enzyme.

Enzymatically-triggered probes to determine glucuronidase hydrolysis kinetics for clustered substrates.     

Integrating polyurethane culture substrates into poly(dimethylsiloxane) microdevices

Poly(dimethylsiloxane) (PDMS)-based microdevices have enabled rapid, high-throughput assessment of cellular response to precisely controlled microenvironmental stimuli, including chemical, matrix and mechanical factors. However, the use of PDMS as a culture substrate precludes long-term culture and may significantly impact cell response. Here we describe a method to integrate polyurethane (PU), a well-studied and clinically relevant biomaterial, into the PDMS multilayer microfabrication process, enabling the exploration of long-term cellular response on alternative substrates in microdevices. To demonstrate the utility of these hybrid microdevices for cell culture, we compared initial cell adhesion, cell spreading, and maintenance of protein patterns on PU and PDMS substrates. Initial cell adhesion and cell spreading after three days were comparable between collagen-coated PDMS and PU substrates (with or without collagen coating), but significantly lower on native PDMS substrates. However, for longer culture durations (≥6 days), cell spreading and protein adhesion on PU substrates was significantly better than that on PDMS substrates, and comparable to that on tissue culture-treated polystyrene. Thus, the use of a generic polyurethane substrate in microdevices enables longer-term cell culture than is possible with PDMS substrates. More generally, this technique can improve the impact and applicability of microdevice-based research by facilitating the use of alternate, relevant biomaterials while maintaining the advantages of using PDMS for microdevice fabrication.     

Meriolins, a new class of cell death inducing kinase inhibitors with enhanced selectivity for cyclin-dependent kinases

Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1alpha, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms.