Among 367 subjects, the authors analyzed 167 patients with essential tremor, sporadic progressive cerebellar ataxia, multiple-system atrophy, and atypical parkinsonism and 200 healthy control ...subjects for FMR1 premutation alleles. None of the subjects carried alleles within the premutation range. These findings suggest that in the absence of other supportive clinical or imaging features, the cost-effectiveness of routine fragile X tremor/ataxia syndrome screening in this Asian cohort with movement disorders was low.
The dispersion of vapour of liquefied natural gas (LNG) is generally assumed to be from a liquid spill on the ground in hazard and risk analysis. However, this cold vapour could be discharged at ...height through cold venting. While there is similarity to the situation where a heavier-than-air gas, e.g., CO2, is discharged through tall vent stacks, LNG vapour is cold and induces phase change of ambient moisture leading to changes in the thermodynamics as the vapour disperses. A recent unplanned cold venting of LNG vapour event due to failure of a pilot, provided valuable data for further analysis. This event was studied using CFD under steady-state conditions and incorporating the effect of thermodynamics due to phase change of atmospheric moisture. As the vast majority of processing plants do not reside on flat planes, the effect of surrounding topography was also investigated. This case study highlighted that integral dispersion model was not applicable as key assumptions used to derive the models were violated and suggested guidance and methodologies appropriate for modelling cold vent and flame out situations for elevated vents.
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Non-cystic fibrosis bronchiectasis (NCFB) characterized by permanent bronchial dilatation and recurrent infections has been clinically managed by long-term intermittent inhaled ...antibiotic therapy among other treatments. Herein we investigated dry powder inhaler (DPI) formulation of ciprofloxacin (CIP) nanoplex with mannitol/lactose as the excipient for NCFB therapy. The DPI of CIP nanoplex was evaluated against DPI of native CIP in terms of their (1) dissolution characteristics in artificial sputum medium, (2) ex vivo mucus permeability in sputum from NCFB and healthy individuals, (3) antibacterial efficacy in the presence of sputum against clinical Pseudomonas aeruginosa strains (planktonic and biofilm), and (4) cytotoxicity towards human lung epithelial cells. Despite their similarly fast dissolution rates in sputum, the DPI of CIP nanoplex exhibited superior mucus permeability to the native CIP (5–7 times higher) attributed to its built-in ability to generate highly supersaturated CIP concentration in the sputum. The superior mucus permeability led to the CIP nanoplex’s higher antibacterial efficacy (>3 log10 CFU/mL). The DPI of CIP nanoplex exhibited similar cytotoxicity towards the lung epithelial cells as the native CIP indicating its low risk of toxicity. These results established the promising potential of DPI of CIP nanoplex as a new therapeutic avenue for NCFB.
The advent of novel therapeutics in recent years has urged the need for a safe, non-immunogenic drug delivery vector capable of delivering therapeutic payloads specifically to diseased cells, thereby ...increasing therapeutic efficacy and reducing side effects. Extracellular vesicles (EVs) have garnered attention in recent years as a potentially ideal vector for drug delivery, taking into account their intrinsic ability to transfer bioactive cargo to recipient cells and their biocompatible nature. However, natural EVs are limited in their therapeutic potential and many challenges need to be overcome before engineered EVs satisfy the levels of efficiency, stability, safety and biocompatibility required for therapeutic use. Here, we demonstrate that an enzyme-mediated surface functionalization method in combination with streptavidin-mediated conjugation results in efficient surface functionalization of EVs. Surface functionalization using the above methods permits the stable and biocompatible conjugation of peptides, single domain antibodies and monoclonal antibodies at high copy number on the EV surface. Functionalized EVs demonstrated increased accumulation in target cells expressing common cancer associated markers such as CXCR4, EGFR and EpCAM both
and
. The functionality of this approach was further highlighted by the ability of targeting EVs to specifically deliver therapeutic antisense oligonucleotides to a metastatic breast tumor model, resulting in increased knockdown of a targeted oncogenic microRNA and improved metastasis suppression. The method was also used to equip EVs with a bifunctional peptide that targets EVs to leukemia cells and induces apoptosis, leading to leukemia suppression. Moreover, we conducted extensive testing to verify the biocompatibility, and safety of engineered EVs for therapeutic use, suggesting that surface modified EVs can be used for repeated dose treatment with no detectable adverse effects. This modular, biocompatible method of EV engineering offers a promising avenue for the targeted delivery of a range of therapeutics while addressing some of the safety concerns associated with EV-based drug delivery.
The growth response, non‐specific immune activities and disease resistance were measured in sea cucumber, Apostichopus japonicus Selenka (initial average weight 6.80 ± 0.10 g), when fed diets ...supplemented with graded levels of guanosine from the guanosine‐5’‐monophosphate disodium (GMP) at 0 (control), 0.3, 0.6 and 1.2 g/kg for 8 weeks. The results showed that GMP supplemented at 0.6 and 1.2 g/kg significantly enhanced the growth of sea cucumber. Sea cucumber fed a diet with 0.6 g/kg of GMP had significantly higher intracellular superoxide anion production, nitric oxide synthase activity, lysozyme activity and the total superoxide dismutase (T‐SOD) activity than those in control group (p < .05). Increased lysozyme activity and T‐SOD activity were also found in sea cucumber fed GMP at 1.2 g/kg. Moreover, there was significantly lower cumulative mortality after the disease challenge in sea cucumber fed the diets with 0.6 and 1.2 g/kg GMP than that in control and 0.3 g/kg GMP groups (p < .05), and no significant difference was observed between 0.6 and 1.2 g/kg GMP groups. These results suggested that feeding GMP at a dose of 0.6 g/kg could enhance growth, non‐specific immunity of sea cucumber as well as its resistance against Vibrio splendidus.
During the last decade, evolutionary methods such as genetic algorithms have been used extensively for the optimal design and operation of water distribution systems. More recently, ant colony ...optimization algorithms (ACOAs), which are evolutionary methods based on the foraging behavior of ants, have been successfully applied to a number of benchmark combinatorial optimization problems. In this paper, a formulation is developed which enables ACOAs to be used for the optimal design of water distribution systems. This formulation is applied to two benchmark water distribution system optimization problems and the results are compared with those obtained using genetic algorithms (GAs). The findings of this study indicate that ACOAs are an attractive alternative to GAs for the optimal design of water distribution systems, as they outperformed GAs for the two case studies considered both in terms of computational efficiency and their ability to find near global optimal solutions.
The appropriate combination between bones and implants is an important issue for the long-term stability of biomaterials. Hence, a Ti implant alloy with stable osteointegration and simultaneously low ...modulus is extremely desirable. Ca possesses superb bioactivity and biodegradability in orthopedic applications. Cu is not only favorable for angiogenesis but also exhibits prolonged antibacterial effects. In our present work, Cu and Ca are thus selected as alloying elements to develop a multifunctional Ti-2Cu-4Ca biomaterial with controllable pore structure through spark plasma sintering (SPS). The developed porous Ti-2Cu-4Ca alloy with interconnected pores, a porosity of 43% ± 5% and an average pore size of 460 μm, exhibits bone-like mechanical properties and enhanced cellular affinity (ROS1728 cells). The favorable cell viability and growth inside the pores of the alloy arise from the rough porous surface and the release of bioactive Ca and Cu ions into the biological environment. Our work provides a strategy to design multifunctional biomaterials and, specifically, the porous Ti-2Cu-4Ca alloy is expected to be a promising bone-implant biomaterial.
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•A multifunctional Ti-2Cu-4Ca porous biomaterial was designed.•The alloy exhibits high strength and favorable cellular affinity.•Experiments revealed excellent cell growth on the surface and inside the pores.
There is increased platelet activation in many cardiovascular diseases. This observation may explain the presence of increased levels of platelet microparticles (PMP) in these diseases. However, ...whether or not levels of PMPs inter-relate with other markers of platelet activation, such as soluble P-selectin, or with disease severity, is unknown. We therefore hypothesized raised PMP levels in stable peripheral artery disease (PAD) intermittent claudication (IC), with an additional increase in severe PAD critical limb ischaemia (CLI). Furthermore, we tested the hypothesis that PMP levels are correlated with other markers of platelet activation, such as soluble P-selectin, membrane bound P-selectin (CD62P) and 63.
Patients with PAD were recruited from the vascular outpatient and inpatient facilities at a teaching hospital. Age- and sex-matched controls were also recruited from healthy volunteers. Venous blood was obtained from 23 patients with severe disease (CLI), 36 with moderate disease (IC), and from 30 healthy controls. The percentage of platelets positive for CD62P and CD63, as well as the numbers of PMPs were defined by flow cytometry. Plasma soluble P selectin was measured by enzyme-linked immunosorbent assay (ELISA).
PMPs were increased relative to healthy controls in patients with IC, with a further increase in CLI (P<0.001). Soluble P selectin and CD62+ve platelets were raised in both patient groups, but there was no difference amongst the two patient groups. CD63+ve cells were raised only in CLI compared to healthy controls. In multivariate analysis, only PMP and soluble P selectin independently predicted disease severity, and the two markers correlated modestly (r=0.345, P<0.001).
Increased PMP and soluble P selectin are both related to the severity of symptomatic PAD. However, it is uncertain if this relationship is a cause or effect of atherosclerosis. This finding may have clinical implications as PMPs have the potential to influence the progression of atheroma as well as promote thrombosis.
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