The influence of intercalating perfluorohexane into lipid shells on nano and microbubble stability

Microbubbles are potential diagnostic and therapeutic agents. In vivo stability is important as the bubbles are required to survive multiple passages through the heart and lungs to allow targeting and delivery. Here we have systematically varied key parameters affecting microbubble lifetime to significantly increase in vivo stability. Whilst shell and core composition are found to have an important role in improving microbubble stability, we show that inclusion of small quantities of C6F14 in the microbubble bolus significantly improves microbubble lifetime. Our results indicate that C6F14 inserts into the lipid shell, decreasing surface tension to 19 mN m-1, and increasing shell resistance, in addition to saturating the surrounding medium. Surface area isotherms suggest that C6F14 incorporates into the acyl chain region of the lipid at a high molar ratio, indicating ∼2 perfluorocarbon molecules per 5 lipid molecules. The resulting microbubble boluses exhibit a higher in vivo image intensity compared to commercial compositions, as well as longer lifetimes

Evidence for distinct coastal and offshore communities of bottlenose dolphins in the north east Atlantic.

Bottlenose dolphin stock structure in the northeast Atlantic remains poorly understood. However, fine scale photo-id data have shown that populations can comprise multiple overlapping social communities. These social communities form structural elements of bottlenose dolphin (Tursiops truncatus) [corrected] populations, reflecting specific ecological and behavioural adaptations to local habitats. We investigated the social structure of bottlenose dolphins in the waters of northwest Ireland and present evidence for distinct inshore and offshore social communities. Individuals of the inshore community had a coastal distribution restricted to waters within 3 km from shore. These animals exhibited a cohesive, fission-fusion social organisation, with repeated resightings within the research area, within a larger coastal home range. The offshore community comprised one or more distinct groups, found significantly further offshore (>4 km) than the inshore animals. In addition, dorsal fin scarring patterns differed significantly between inshore and offshore communities with individuals of the offshore community having more distinctly marked dorsal fins. Specifically, almost half of the individuals in the offshore community (48%) had characteristic stereotyped damage to the tip of the dorsal fin, rarely recorded in the inshore community (7%). We propose that this characteristic is likely due to interactions with pelagic fisheries. Social segregation and scarring differences found here indicate that the distinct communities are likely to be spatially and behaviourally segregated. Together with recent genetic evidence of distinct offshore and coastal population structures, this provides evidence for bottlenose dolphin inshore/offshore community differentiation in the northeast Atlantic. We recommend that social communities should be considered as fundamental units for the management and conservation of bottlenose dolphins and their habitat specialisations

Sustainable development of production in Russia: an informative aspect

This paper is devoted to the study of the problems of introduction of the concept of sustainable development of production at modern enterprises. The paper substantiates the necessity of application of this concept at enterprises, gives reasons hindering this process. In addition, the analysis of the notion of sustainable development of production, wherein this process is represented as development of production by means of rational and economical use of resources oriented to provision of a long-term competitive advantage, was conducted in the paper. Moreover, the paper presents the basic principles of successful introduction of the concept of sustainable development of production. By the example of Toyota Company the benefits, which can be derived by an enterprise from application of this concept, were shown

The statistics of natural hand movements.

Humans constantly use their hands to interact with the environment and they engage spontaneously in a wide variety of manual activities during everyday life. In contrast, laboratory-based studies of hand function have used a limited range of predefined tasks. The natural movements made by the hand during everyday life have thus received little attention. Here, we developed a portable recording device that can be worn by subjects to track movements of their right hand as they go about their daily routine outside of a laboratory setting. We analyse the kinematic data using various statistical methods. Principal component analysis of the joint angular velocities showed that the first two components were highly conserved across subjects, explained 60% of the variance and were qualitatively similar to those reported in previous studies of reach-to-grasp movements. To examine the independence of the digits, we developed a measure based on the degree to which the movements of each digit could be linearly predicted from the movements of the other four digits. Our independence measure was highly correlated with results from previous studies of the hand, including the estimated size of the digit representations in primary motor cortex and other laboratory measures of digit individuation. Specifically, the thumb was found to be the most independent of the digits and the index finger was the most independent of the fingers. These results support and extend laboratory-based studies of the human hand

Why Can't Rodents Vomit? A Comparative Behavioral, Anatomical, and Physiological Study

The vomiting (emetic) reflex is documented in numerous mammalian species, including primates and carnivores, yet laboratory rats and mice appear to lack this response. It is unclear whether these rodents do not vomit because of anatomical constraints (e.g., a relatively long abdominal esophagus) or lack of key neural circuits. Moreover, it is unknown whether laboratory rodents are representative of Rodentia with regards to this reflex. Here we conducted behavioral testing of members of all three major groups of Rodentia; mouse-related (rat, mouse, vole, beaver), Ctenohystrica (guinea pig, nutria), and squirrel-related (mountain beaver) species. Prototypical emetic agents, apomorphine (sc), veratrine (sc), and copper sulfate (ig), failed to produce either retching or vomiting in these species (although other behavioral effects, e.g., locomotion, were noted). These rodents also had anatomical constraints, which could limit the efficiency of vomiting should it be attempted, including reduced muscularity of the diaphragm and stomach geometry that is not well structured for moving contents towards the esophagus compared to species that can vomit (cat, ferret, and musk shrew). Lastly, an in situ brainstem preparation was used to make sensitive measures of mouth, esophagus, and shoulder muscular movements, and phrenic nerve activity-key features of emetic episodes. Laboratory mice and rats failed to display any of the common coordinated actions of these indices after typical emetic stimulation (resiniferatoxin and vagal afferent stimulation) compared to musk shrews. Overall the results suggest that the inability to vomit is a general property of Rodentia and that an absent brainstem neurological component is the most likely cause. The implications of these findings for the utility of rodents as models in the area of emesis research are discussed. © 2013 Horn et al

Age, extent and carbon storage of the central Congo Basin peatland complex

Peatlands are carbon-rich ecosystems that cover just three per cent of Earth's land surface, but store one-third of soil carbon. Peat soils are formed by the build-up of partially decomposed organic matter under waterlogged anoxic conditions. Most peat is found in cool climatic regions where unimpeded decomposition is slower, but deposits are also found under some tropical swamp forests. Here we present field measurements from one of the world's most extensive regions of swamp forest, the Cuvette Centrale depression in the central Congo Basin. We find extensive peat deposits beneath the swamp forest vegetation (peat defined as material with an organic matter content of at least 65 per cent to a depth of at least 0.3 metres). Radiocarbon dates indicate that peat began accumulating from about 10,600 years ago, coincident with the onset of more humid conditions in central Africa at the beginning of the Holocene. The peatlands occupy large interfluvial basins, and seem to be largely rain-fed and ombrotrophic-like (of low nutrient status) systems. Although the peat layer is relatively shallow (with a maximum depth of 5.9 metres and a median depth of 2.0 metres), by combining in situ and remotely sensed data, we estimate the area of peat to be approximately 145,500 square kilometres (95 per cent confidence interval of 131,900-156,400 square kilometres), making the Cuvette Centrale the most extensive peatland complex in the tropics. This area is more than five times the maximum possible area reported for the Congo Basin in a recent synthesis of pantropical peat extent. We estimate that the peatlands store approximately 30.6 petagrams (30.6 × 10(15) grams) of carbon belowground (95 per cent confidence interval of 6.3-46.8 petagrams of carbon)-a quantity that is similar to the above-ground carbon stocks of the tropical forests of the entire Congo Basin. Our result for the Cuvette Centrale increases the best estimate of global tropical peatland carbon stocks by 36 per cent, to 104.7 petagrams of carbon (minimum estimate of 69.6 petagrams of carbon; maximum estimate of 129.8 petagrams of carbon). This stored carbon is vulnerable to land-use change and any future reduction in precipitation

Mediastinal extension of a complicated pancreatic pseudocyst; a case report and literature review

BACKGROUND: Mediastinal pancreatic pseudocyst is a rare complication of acute or chronic pancreatitis. CASE PRESENTATION: This case report describes the management of a difficult case of pancreatic pseudocyst with a mediastinal extension in a patient having chronic pancreatitis. Different management strategies were used until complete resolution of this complex pseudocyst occurred using open surgical cystogastrostomy. CONCLUSION: Despite the availablity of different minimally invasive techniques to treat pancreatic pseudocysts, management of complex mediastinal pseudocyst may still require open surgical drainage procedures

The role of leadership in salespeople’s price negotiation behavior

Salespeople assume a key role in defending firms’ price levels in price negotiations with customers. The degree to which salespeople defend prices should critically depend upon their leaders’ influence. However, the influence of leadership on salespeople’s price defense behavior is barely understood, conceptually or empirically. Therefore, building on social learning theory, the authors propose that salespeople might adopt their leaders’ price defense behavior given a transformational leadership style. Furthermore, drawing on the contingency leadership perspective, the authors argue that this adoption fundamentally depends on three variables deduced from the motivation–ability–opportunity (MAO) framework, that is, salespeople’s learning motivation, negotiation efficacy, and perceived customer lenience. Results of a multi-level model using data from 92 salespeople and 264 salesperson–customer interactions confirm these predictions. The first to explore contingencies of salespeople’s adoption of their transformational leaders’ price negotiation behaviors, this study extends marketing theory and provides actionable guidance to practitioners

Freeze-Dried Therapeutic Microbubbles: Stability and Gas Exchange

Microbubbles (MBs) are widely used as contrast enhancement agents for ultrasound imaging and have the potential to enhance therapeutic delivery to diseases such as cancer. Yet, they are only stable in solution for a few hours to days after production, which limits their potential application. Freeze-drying provides long-term storage, ease of transport, and consistency in structure and composition, thereby facilitating their use in clinical settings. Therapeutic microbubbles (thMBs) consisting of MBs with attached therapeutic payload potentially face even greater issues for production, stability, and well-defined drug delivery. The ability to freeze-dry thMBs represents an important step for their translation to the clinic. Here, we show that it is possible to freeze-dry and reconstitute thMBs that consist of lipid-coated MBs with an attached liposomal payload. The thMBs were produced microfluidically, and the liposomes contained either calcein, as a model drug, or gemcitabine. The results show that drug-loaded thMBs can be freeze-dried and stored for at least 6 months. Upon reconstitution, they maintain their structural integrity and drug loading. Furthermore, we show that their in vivo echogenicity is maintained post-freeze-drying. Depending on the gas used in the original bubbles, we also demonstrate that the approach provides a method to exchange the gas core to allow the formulation of thMBs with different gases for combination therapies or improved drug efficacy. Importantly, this work provides an important route for the facile off-site production of thMBs that can be reformulated at the point of care

Ultrasound-triggered therapeutic microbubbles enhance the efficacy of cytotoxic drugs by increasing circulation and tumor drug accumulation and limiting bioavailability and toxicity in normal tissues

Most cancer patients receive chemotherapy at some stage of their treatment which makes improving the efficacy of cytotoxic drugs an ongoing and important goal. Despite large numbers of potent anti-cancer agents being developed, a major obstacle to clinical translation remains the inability to deliver therapeutic doses to a tumor without causing intolerable side effects. To address this problem, there has been intense interest in nanoformulations and targeted delivery to improve cancer outcomes. The aim of this work was to demonstrate how vascular endothelial growth factor receptor 2 (VEGFR2)-targeted, ultrasound-triggered delivery with therapeutic microbubbles (thMBs) could improve the therapeutic range of cytotoxic drugs. Methods: Using a microfluidic microbubble production platform, we generated thMBs comprising VEGFR2-targeted microbubbles with attached liposomal payloads for localised ultrasound-triggered delivery of irinotecan and SN38 in mouse models of colorectal cancer. Intravenous injection into tumor-bearing mice was used to examine targeting efficiency and tumor pharmacodynamics. High-frequency ultrasound and bioluminescent imaging were used to visualise microbubbles in real-time. Tandem mass spectrometry (LC-MS/MS) was used to quantitate intratumoral drug delivery and tissue biodistribution. Finally, 89Zr PET radiotracing was used to compare biodistribution and tumor accumulation of ultrasound-triggered SN38 thMBs with VEGFR2-targeted SN38 liposomes alone. Results: ThMBs specifically bound VEGFR2 in vitro and significantly improved tumor responses to low dose irinotecan and SN38 in human colorectal cancer xenografts. An ultrasound trigger was essential to achieve the selective effects of thMBs as without it, thMBs failed to extend intratumoral drug delivery or demonstrate enhanced tumor responses. Sensitive LC-MS/MS quantification of drugs and their metabolites demonstrated that thMBs extended drug exposure in tumors but limited exposure in healthy tissues, not exposed to ultrasound, by persistent encapsulation of drug prior to elimination. 89Zr PET radiotracing showed that the percentage injected dose in tumors achieved with thMBs was twice that of VEGFR2-targeted SN38 liposomes alone. Conclusions: thMBs provide a generic platform for the targeted, ultrasound-triggered delivery of cytotoxic drugs by enhancing tumor responses to low dose drug delivery via combined effects on circulation, tumor drug accumulation and exposure and altered metabolism in normal tissues