We evaluated the influence of transit-time flow measurement with epicardial and epiaortic high-frequency ultrasound in patients undergoing coronary artery bypass grafting procedure.
The Registry for ...Quality Assessment with Ultrasound Imaging and Transit-time Flow Measurement in Cardiac Bypass Surgery study is a multicenter, prospective study among 7 international centers performing coronary artery bypass grafting procedures. The primary end point was any change in the planned surgical procedure. Major secondary end points consisted of the rate and reason for surgical changes related to the aorta, in situ conduits, coronary targets, and completed grafts, and the rate of in-hospital mortality and major morbidity.
Between April 2015 and December 2017, 1046 patients were enrolled. Of those, 1016 were included in the final analyses. Mean age was 65.9 years, 14.0% were women, and diabetes was present in 39.6%. Off-pump procedures were performed in 39.6% and bilateral internal thoracic arteries in 30.5%. The primary end point occurred in 25.2% of patients (n = 256) and in 77% (197 out of 256) this was based on transit-time flow measurement and/or high-frequency ultrasound. Surgical changes were related to the aorta in 9.9%, to in situ conduits in 2.7%, and the coronary targets in 22.6%. Graft revision occurred in 7.8%, including revisions of the proximal and/or distal anastomosis in 6.6%. In-hospital adverse event rates were 0.6% for mortality, 1.0% for cerebrovascular events, and 0.3% for myocardial infarction.
Surgical changes related to the aorta, conduits, coronary targets, and anastomosis were made in 25% of patients. This was associated with low operative mortality and low major morbidity. Transit-time flow measurement and high-frequency ultrasound may improve the quality, safety, and efficacy of coronary artery bypass grafting procedures and should be considered as a routine procedural aspect.
Changes to the planned surgical strategy were made in 25.2% of cases with few complications. Display omitted
Achondroplasia (ACH), the most common form of human dwarfism, is caused by an activating autosomal dominant mutation in the fibroblast growth factor receptor-3 gene. Genetic overexpression of C-type ...natriuretic peptide (CNP), a positive regulator of endochondral bone growth, prevents dwarfism in mouse models of ACH. However, administration of exogenous CNP is compromised by its rapid clearance in vivo through receptor-mediated and proteolytic pathways. Using in vitro approaches, we developed modified variants of human CNP, resistant to proteolytic degradation by neutral endopeptidase, that retain the ability to stimulate signaling downstream of the CNP receptor, natriuretic peptide receptor B. The variants tested in vivo demonstrated significantly longer serum half-lives than native CNP. Subcutaneous administration of one of these CNP variants (BMN 111) resulted in correction of the dwarfism phenotype in a mouse model of ACH and overgrowth of the axial and appendicular skeletons in wild-type mice without observable changes in trabecular and cortical bone architecture. Moreover, significant growth plate widening that translated into accelerated bone growth, at hemodynamically tolerable doses, was observed in juvenile cynomolgus monkeys that had received daily subcutaneous administrations of BMN 111. BMN 111 was well tolerated and represents a promising new approach for treatment of patients with ACH.
Prioritizing genes for translation to therapeutics for common diseases has been challenging. Here, we propose an approach to identify drug targets with high probability of success by focusing on ...genes with both gain of function (GoF) and loss of function (LoF) mutations associated with opposing effects on phenotype (Bidirectional Effect Selected Targets, BEST). We find 98 BEST genes for a variety of indications. Drugs targeting those genes are 3.8-fold more likely to be approved than non-BEST genes. We focus on five genes (IGF1R, NPPC, NPR2, FGFR3, and SHOX) with evidence for bidirectional effects on stature. Rare protein-altering variants in those genes result in significantly increased risk for idiopathic short stature (ISS) (OR = 2.75, p = 3.99 × 10
). Finally, using functional experiments, we demonstrate that adding an exogenous CNP analog (encoded by NPPC) rescues the phenotype, thus validating its potential as a therapeutic treatment for ISS. Our results show the value of looking for bidirectional effects to identify and validate drug targets.
The chemokine system represents a diverse group of G protein-coupled receptors responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions. Chemokine receptor 9 ...(CCR9) is a chemokine receptor known to be central for migration of immune cells into the intestine. Its only ligand, CCL25, is expressed at the mucosal surface of the intestine and is known to be elevated in intestinal inflammation. To date, there are no reports of small-molecule antagonists targeting CCR9. We report, for the first time, the discovery of a small molecule, CCX282-B, which is an orally bioavailable, selective, and potent antagonist of human CCR9. CCX282-B inhibited CCR9-mediated Ca(2+) mobilization and chemotaxis on Molt-4 cells with IC(50) values of 5.4 and 3.4 nM, respectively. In the presence of 100% human serum, CCX282-B inhibited CCR9-mediated chemotaxis with an IC(50) of 33 nM, and the addition of α1-acid glycoprotein did not affect its potency. CCX282-B inhibited chemotaxis of primary CCR9-expressing cells to CCL25 with an IC(50) of 6.8 nM. CCX282-B was an equipotent inhibitor of CCL25-directed chemotaxis of both splice forms of CCR9 (CCR9A and CCR9B) with IC(50) values of 2.8 and 2.6 nM, respectively. CCX282-B also inhibited mouse and rat CCR9-mediated chemotaxis. Inhibition of CCR9 with CCX282-B results in normalization of Crohn's disease such as histopathology associated with the TNF(ΔARE) mice. Analysis of the plasma level of drug associated with this improvement provides an understanding of the pharmacokinetic/pharmacodynamic relationship for CCR9 antagonists in the treatment of intestinal inflammation.
Summary
Despite there being numerous studies of intraoperative graft flow assessment by transit-time flow measurement (TTFM) on outcomes after coronary artery bypass grafting (CABG), the adoption of ...contemporary TTFM is low. Therefore, on 31 January 2018, a systematic literature search was performed to identify articles that reported (i) the amount of grafts classified as abnormal or which were revised or (ii) an association between TTFM and outcomes during follow-up. Random-effects models were used to create pooled estimates with 95% confidence intervals (CI) of (i) the rate of graft revision per patient, (ii) the rate of graft revision per graft and (iii) the rate of graft revision among grafts deemed abnormal based on TTFM parameters. The search yielded 242 articles, and 66 original articles were included in the systematic review. Of those articles, 35 studies reported on abnormal grafts or graft revisions (8943 patients, 15 673 grafts) and were included in the meta-analysis. In 4.3% of patients (95% CI 3.3–5.7%, I2 = 73.9) a revision was required and 2.0% of grafts (95% CI 1.5–2.5%; I2 = 66.0) were revised. The pooled rate of graft revisions among abnormal grafts was 25.1% (95% CI 15.5–37.9%; I2 = 80.2). Studies reported sensitivity ranging from 0.250 to 0.457 and the specificity from 0.939 to 0.984. Reported negative predictive values ranged from 0.719 to 0.980 and reported positive predictive values ranged from 0.100 to 0.840. This systematic review and meta-analysis showed that TTFM could improve CABG procedures. However, due to heterogeneous data, drawing uniform conclusions appeared challenging. Future studies should focus on determining the optimal use of TTFM and assessing its diagnostic accuracy.
Objective: A transcranial magnetic stimulation system with programmable stimulus pulses and patterns is presented. The stimulus pulses of the implemented system expand beyond conventional damped ...cosine or near-rectangular pulses and approach an arbitrary waveform. Methods: The desired stimulus waveform shape is defined as a reference signal. This signal controls the semiconductor switches of an H-bridge inverter to generate a high-power imitation of the reference. The design uses a new paradigm for TMS, applying pulse-width modulation with a non-resonant, high-frequency switching architecture to synthesize waveforms that leverages the low-pass filtering properties of neuronal cells. The modulation technique enables control of the waveform, frequency, pattern, and intensity of the stimulus. Results: A system prototype was developed to demonstrate the technique. The experimental measurements demonstrate that the system is capable of generating stimuli up to 4 kHz with peak voltage and current values of ±1000 V and ±3600 A, respectively. The maximum transferred energy measured in the experimental validation was 100.4 Joules. To characterize repetitive TMS modalities, the efficiency of generating consecutive pulse triplets and quadruplets with interstimulus intervals of 1 ms was tested and verified. Conclusion: The implemented TMS device can generate consecutive rectangular pulses with a predetermined time interval, widths and polarities, enables the synthesis of a wide range of magnetic stimuli. Significance: New waveforms promise functional advantages over the waveforms generated by current-generation TMS systems for clinical neuroscience research.
Intraoperative graft assessment with tools like Transit Time Flow Measurement (TTFM) is imperative for quality control in coronary surgery. We investigated the variation of TTFM parameters before and ...after protamine administration to identify new benchmark parameters for graft quality assessment.
The database of the REQUEST ("REgistry for QUality AssESsmenT with Ultrasound Imaging and TTFM in Cardiac Bypass Surgery") study was retrospectively reviewed. A per graft analysis was performed. Only single grafts (i.e., no sequential nor composite grafts) where both pre- and post-protamine TTFM values were recorded with an acoustical coupling index > 30% were included. Grafts with incomplete data and mixed grafts (arterio-venous) were excluded. A second analysis was performed including single grafts only in the same MAP range pre- and post- protamine administration.
After adjusting for MAP, we found a small increase in MGF (29 mL/min to 30 mL/min, p = 0.009) and decrease in PI (2.3 to 2.2, p < 0.001) were observed after the administration of protamine. These changes were especially notable for venous conduits and for CABG procedures performed on-pump.
The small changes in TTFM parameters observed before and after protamine administration seem to be clinically irrelevant, despite being statistically significant in aggregate. Our data do not support a need to perform TTFM measurements both before and after protamine administration. A single TTFM measurement taken either before or after protamine may suffice to achieve reliable data on each graft's performance. Depending on the specific clinical situation and intraoperative changes, more measurements may be informative.
Clinical Trials Number: NCT02385344 , registered February 17th, 2015.
Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder caused by N-sulfoglucosamine sulfohydrolase (SGSH) deficiency. SGSH removes the sulfate from N-sulfoglucosamine residues on ...the nonreducing end of heparan sulfate (HS-NRE) within lysosomes. Enzyme deficiency results in accumulation of partially degraded HS within lysosomes throughout the body, leading to a progressive severe neurological disease. Enzyme replacement therapy has been proposed, but further evaluation of the treatment strategy is needed. Here, we used Chinese hamster ovary cells to produce a highly soluble and fully active recombinant human sulfamidase (rhSGSH). We discovered that rhSGSH utilizes both the CI-MPR and LRP1 receptors for uptake into patient fibroblasts. A single intracerebroventricular (ICV) injection of rhSGSH in MPS IIIA mice resulted in a tissue half-life of 9 days and widespread distribution throughout the brain. Following a single ICV dose, both total HS and the MPS IIIA disease-specific HS-NRE were dramatically reduced, reaching a nadir 2 weeks post dose. The durability of effect for reduction of both substrate and protein markers of lysosomal dysfunction and a neuroimmune response lasted through the 56 days tested. Furthermore, seven weekly 148 μg doses ICV reduced those markers to near normal and produced a 99.5% reduction in HS-NRE levels. A pilot study utilizing every other week dosing in two animals supports further evaluation of less frequent dosing. Finally, our dose–response study also suggests lower doses may be efficacious. Our findings show that rhSGSH can normalize lysosomal HS storage and markers of a neuroimmune response when delivered ICV.
Significance Mucopolysaccharidosis type IIIB (MPS IIIB) is a devastating and currently untreatable disease affecting mainly the brain. The cause is lack of the lysosomal enzyme, α– N ...-acetylglucosaminidase (NAGLU), and storage of heparan sulfate. Using a mouse model of MPS IIIB, we administered a modified NAGLU by injection into the left ventricle of the brain, bypassing the blood–brain barrier. The modification consisted of a fragment of IGFII, which allows receptor-mediated uptake and delivery to lysosomes. The modified enzyme was taken up avidly by cells in both brain and liver, where it reduced pathological accumulation of heparan sulfate and other metabolites to normal or near-normal levels. The results suggest the possibility of treatment for MPS IIIB.
Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disease characterized by profound intellectual disability, dementia, and a lifespan of about two decades. The cause is mutation in the gene encoding α– N -acetylglucosaminidase (NAGLU), deficiency of NAGLU, and accumulation of heparan sulfate. Impediments to enzyme replacement therapy are the absence of mannose 6-phosphate on recombinant human NAGLU and the blood–brain barrier. To overcome the first impediment, a fusion protein of recombinant NAGLU and a fragment of insulin-like growth factor II (IGFII) was prepared for endocytosis by the mannose 6-phosphate/IGFII receptor. To bypass the blood–brain barrier, the fusion protein (“enzyme”) in artificial cerebrospinal fluid (“vehicle”) was administered intracerebroventricularly to the brain of adult MPS IIIB mice, four times over 2 wk. The brains were analyzed 1–28 d later and compared with brains of MPS IIIB mice that received vehicle alone or control (heterozygous) mice that received vehicle. There was marked uptake of the administered enzyme in many parts of the brain, where it persisted with a half-life of approximately 10 d. Heparan sulfate, and especially disease-specific heparan sulfate, was reduced to control level. A number of secondary accumulations in neurons β-hexosaminidase, LAMP1(lysosome-associated membrane protein 1), SCMAS (subunit c of mitochondrial ATP synthase), glypican 5, β-amyloid, P-tau were reduced almost to control level. CD68, a microglial protein, was reduced halfway. A large amount of enzyme also appeared in liver cells, where it reduced heparan sulfate and β-hexosaminidase accumulation to control levels. These results suggest the feasibility of enzyme replacement therapy for MPS IIIB.
A cascaded H-bridge based pulse generator for transcranial magnetic stimulation is introduced. The system demonstrates complete flexibility for producing different shape, duration, direction, and ...rate of repetition of stimulus pulses within its electrical limits, and can emulate all commercial and research systems available to-date in this application space. An offline model predictive control algorithm, used to generate pulses and sequences, shows superior performance compared to conventional carrier-based pulse width modulation. A fully functioning laboratory prototype delivers up to 1.5 kV, 6 kA pulses, and is ready to be used as a research tool for the exploration of transcranial magnetic stimulation therapies by leveraging the many degrees-of-freedom offered by the design.
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