A single localized dose of enzyme-responsive hydrogel improves long-term survival of a vascularized composite allograft

Currently, systemic immunosuppression is used in vascularized composite allotransplantation (VCA). This treatment has considerable side effects and reduces the quality of life of VCA recipients. We loaded the immunosuppressive drug tacrolimus into a self-assembled hydrogel, which releases the drug in response to proteolytic enzymes that are overexpressed during inflammation. A one-time local injection of the tacrolimus-laden hydrogel significantly prolonged graft survival in a Brown Norway-to-Lewis rat hindlimb transplantation model, leading to a median graft survival of >100 days compared to 33.5 days in tacrolimus only-treated recipients. Control groups with no treatment or hydrogel only showed a graft survival of 11 days. Histopathological evaluation, including anti-graft antibodies and complement C3, revealed significantly reduced immune responses in the tacrolimus-hydrogel group compared with tacrolimus only. In conclusion, a single-dose local injection of an enzyme-responsive tacrolimus-hydrogel is capable of preventing VCA rejection for >100 days in a rat model and may offer a new approach for immunosuppression in VCA.

A comprehensive discussion of HMBC pulse sequences. III. Solving the problem of missing and weakly observed long-range correlations

The intensity of long-range correlations observed with the classical HMBC pulse sequence using static optimization of the long-range coupling delay is directly related to the size of the coupling constant and is often set as a compromise. As such, some long-range correlations might appear with a reduced intensity or might even be completely absent from the spectra. After a short introduction, this third manuscript will give a detailed review of some selected HMBC variants dedicated to improve the detection of long-range correlations, such as the ACCORD-HMBC, CIGAR-HMBC, and Broadband HMBC experiments. Practical details about the accordion optimization, which affords a substantial improvement in both the number and intensity of the long-range correlations observed, but introduces a modulation in F1, will be discussed. The incorporation of the so-called constant time variable delay in the CIGAR-HMBC experiment, which can trigger or even completely suppress 1H–1H coupling modulation inherent to the utilization of the accordion principle, will be also discussed. The broadband HMBC scheme, which consists of recording a series of HMBC spectra with different delays set as a function of the long-range heteronuclear coupling constant ranges and transverse relaxation times T2, is also examined.

Activation of metabotropic glutamate 5 and NMDA receptors underlies the induction of persistent bursting and associated long-lasting changes in CA3 recurrent connections.

The aim of this study was to describe the induction and expression mechanisms of a persistent bursting activity in a horizontal slice preparation of the rat limbic system that includes the ventral part of the hippocampus and the entorhinal cortex. Disinhibition of this preparation by bicuculline led to interictal-like bursts in the CA3 region that triggered synchronous activity in the entorhinal cortex. Washout of bicuculline after a 1 hr application resulted in a maintained production of hippocampal bursts that continued to spread to the entorhinal cortex. Separation of CA3 from the entorhinal cortex caused the activity in the latter to become asynchronous with CA3 activity in the presence of bicuculline and disappear after washout; however, in CA3, neither the induction of bursting nor its persistence were affected. Associated with the CA3 persistent bursting, a strengthening of recurrent collateral excitatory input to CA3 pyramidal cells and a decreased input to CA3 interneurons was found. Both the induction of the persistent bursting and the changes in synaptic strength were prevented by antagonists of metabotropic glutamate 5 (mGlu5) or NMDA receptors or protein synthesis inhibitors and did not occur in slices from mGlu5 receptor knock-out mice. The above findings suggest potential synaptic mechanisms by which the hippocampus switches to a persistent interictal bursting mode that may support a spread of interictal-like bursting to surrounding temporal lobe regions.

Impact of body mass index on long-term clinical outcomes after second-generation drug eluting stent implantation: Insights from the international global RESOLUTE program

BACKGROUND An increased body mass index (BMI) is associated with a high risk of cardiovascular disease and reduction in life expectancy. However, several studies reported improved clinical outcomes in obese patients treated for cardiovascular diseases. The aim of the present study is to investigate the impact of BMI on long-term clinical outcomes after implantation of zotarolimus eluting stents. METHODS Individual patient data were pooled from the RESOLUTE Clinical Program comprising five trials worldwide. The study population was sorted according to BMI tertiles and clinical outcomes were evaluated at 2-year follow-up. RESULTS Data from a total of 5,127 patients receiving the R-ZES were included in the present study. BMI tertiles were as follow: I tertile (≤ 25.95 kg/m(2) -Low or normal weight) 1,727 patients; II tertile (>25.95 ≤ 29.74 kg/m(2) -overweight) 1,695 patients, and III tertile (>29.74 kg/m(2) -obese) 1,705 patients. At 2-years follow-up no difference was found for patients with high BMI (III tertile) compared with patients with normal or low BMI (I tertile) in terms of target lesion failure (I-III tertile, HR [95% CI] = 0.89 [0.69, 1.14], P = 0.341; major adverse cardiac events (I-III tertile, HR [95% CI] = 0.90 [0.72, 1.14], P = 0.389; cardiac death (I-III tertile, HR [95% CI] = 1.20 [0.73, 1.99], P = 0.476); myocardial infarction (I-III tertile, HR [95% CI] = 0.86 [0.55, 1.35], P = 0.509; clinically-driven target lesion revascularization (I-III tertile, HR [95% CI] = 0.75 [0.53, 1.08], P = 0.123; definite or probable stent thrombosis (I-III tertile, HR [95% CI] = 0.98 [0.49, 1.99], P = 0.964. CONCLUSIONS In the present study, the patients' body mass index was found to have no impact on long-term clinical outcomes after coronary artery interventions.

The role of sensory neuron outgrowth in long-term sensitization of the tail-elicited tail-siphon withdrawal reflex of Aplysia

Neuronal outgrowth has been proposed in many systems as a mechanism underlying memory storage. For example, sensory neuron outgrowth is widely accepted as an underlying mechanism of long-term sensitization of defensive withdrawal reflexes in Aplysia. The hypothesis is that learning leads to outgrowth and consequently to the formation of new synapses, which in turn strengthen the neural circuit underlying the behavior. However, key experiments to test this hypothesis have never been performed. ^ Four days of sensitization training leads to outgrowth of siphon sensory neurons mediating the siphon-gill withdrawal response in Aplysia . We found that a similar training protocol produced robust outgrowth in tail sensory neurons mediating the tail siphon withdrawal reflex. In contrast, 1 day of training, which effectively induces long-term behavioral sensitization and synaptic facilitation, was not associated with neuronal outgrowth. Further examination of the effect of behavioral training protocols on sensory neuron outgrowth indicated that this structural modification is associated only with the most persistent forms of sensitization, and that the induction of these changes is dependent on the spacing of the training trials over multiple days. Therefore, we suggest that neuronal outgrowth is not a universal mechanism underlying long-term sensitization, but is involved only in the most persistent forms of the memory. ^ Sensory neuron outgrowth presumably contributes to long-term sensitization through formation of new synapses with follower motor neurons, but this hypothesis has never been directly tested. The contribution of outgrowth to long-term sensitization was assessed using confocal microscopy to examine sites of contact between physiologically connected pairs of sensory and motor neurons. Following 4 days of training, the strength of both the behavior and sensorimotor synapse and the number of appositions with follower neurons was enhanced only on the trained side of the animal. In contrast, outgrowth was induced on both sides of the animal, indicating that although sensory neuron outgrowth does appear to contribute to sensitization through the formation of new synapses, outgrowth alone is not sufficient to account for the effects of sensitization. This indicates that key regulatory steps are downstream from outgrowth, possibly in the targeting of new processes and activation of new synapses. ^

Cultural competence in an HIV dedicated dental clinic: Application of the National Standards for Culturally and Linguistically Appropriate Services in Health Care (CLAS)

This dissertation investigated perspectives on cultural competence among African-American women patients, staff, and the administrator of a dental clinic serving people living with HIV/AIDS; and evaluated the role of the National Standards for Culturally and Linguistically Appropriate Services in Health Care (CLAS) in advancing the provision of culturally competent care in the clinic. ^ The study was qualitative with data collection via focus groups and individual interviews with a sample of African-American women patients, and individual interviews with a sample of staff and the clinic administrator. Transcripts were coded and themes identified using the software program ATLAS.ti. A cultural audit template was developed and applied to evaluate cultural competency. ^ Among attitudes and behaviors that contributed to the provision of culturally competent care at the clinic were respect and empathic communication. Formal cultural competency was not featured strongly in the methods by which the staff learned to work with diverse populations. Instead cultural competence among the staff was based on thoughtful hiring practices, natural aptitude and a climate that encouraged learning through informal sharing of experiences. The staff and administrator felt that an African-American dentist would be an asset in improving culturally competent care at the clinic. Previous research and national policy also promote the provider-patient racial/ethnic concordance to improve care. In this study, however, the patients were happy with the care provided regardless of the race/ethnicity of the staff, probably reflecting the well developed cultural competence skills of clinic staff overall. ^ The clinic administrator was unaware of the CLAS standards although the clinic was implicitly operated under their mandates. This occurred because the clinic is supported by federal funding and the CLAS standards were incorporated into the requirements. Incorporation into and monitoring of the CLAS standards in federally funded programs therefore appears to be an effective means for ensuring that they are implemented. ^ This study illustrates that cultural competence, though not universally understood, can be systematically investigated to identify what constitutes appropriate care and the factors that support or inhibit it. Among important elements of culturally competent care are respect and empathic communication. ^

A topical outline for the teaching of family health : a life-cycle approach (nursing and midwifery) /

"Project no. AID-PHA/CM/C-73-33"--T.p. verso.

Responsiveness summary : United States Army Corps of Engineers : Waukegan Harbor, Lake County, Illinois : Section 401 water quality certification for dredging of the Waukegan Harbor approach channel and advanced maintenance area.

The approved project allows the Corps to dredge the Waukegan Harbor approach channel and advanced maintenance area. The area to be dredged lies immediately east of the north breakwater. It is approximately a rectangle 650 feet north and south and 1,400 feet east and west. The advanced maintenance area is a band along the north side of the channel. The approved project is for a 10-year certification, under which the Corps may remove 22,000 to 75,000 cubic yards of sediment per dredging event. The dredging depth is 22 feet and the amount to be dredged is about one foot of sediment. As a condition of the certification, disposal of the dredged sediment in Lake Michigan or the waters of the state cannot occur until the conditions of the certification are met. These conditions, which have been placed on the certification by Illinois EPA, ensure that the project meets state water quality standards and is consistent with the determinations of the Illinois Attorney General's Task Force on asbestos contamination at Illinois Beach State Park.

Spring Phenology of Butterflies : The role of seasonal variation in life-cycle regulation

Animals and plants in temperate regions must adapt their life cycle to pronounced seasonal variation. The research effort that has gone into studying these cyclical life history events, or phenological traits, has increased greatly in recent decades. As phenological traits are often correlated to temperature, they are relevant to study in terms of understanding the effect of short term environmental variation as well as long term climate change. Because of this, changes in phenology are the most obvious and among the most commonly reported responses to climate change. Moreover, phenological traits are important for fitness as they determine the biotic and abiotic environment an individual encounters. Fine-tuning of phenology allows for synchronisation at a local scale to mates, food resources and appropriate weather conditions. On a between-population scale, variation in phenology may reflect regional variation in climate. Such differences can not only give insights to life cycle adaptation, but also to how populations may respond to environmental change through time. This applies both on an ecological scale through phenotypic plasticity as well as an evolutionary scale through genetic adaptation. In this thesis I have used statistical and experimental methods to investigate both the larger geographical patterns as well as mechanisms of fine-tuning of phenology of several butterfly species. The main focus, however, is on the orange tip butterfly, Anthocharis cardamines, in Sweden and the United Kingdom. I show a contrasting effect of spring temperature and winter condition on spring phenology for three out of the five studied butterfly species. For A. cardamines there are population differences in traits responding to these environmental factors between and within Sweden and the UK that suggest adaptation to local environmental conditions. All populations show a strong negative plastic relationship between spring temperature and spring phenology, while the opposite is true for winter cold duration. Spring phenology is shifted earlier with increasing cold duration. The environmental variables show correlations, for example, during a warm year a short winter delays phenology while a warm spring speeds phenology up. Correlations between the environmental variables also occur through space, as the locations that have long winters also have cold springs. The combined effects of these two environmental variables cause a complex geographical pattern of phenology across the UK and Sweden. When predicting phenology with future climate change or interpreting larger geographical patterns one must therefore have a good enough understanding of how the phenology is controlled and take the relevant environmental factors in to account. In terms of the effect of phenological change, it should be discussed with regards to change in life cycle timing among interacting species. For example, the phenology of the host plants is important for A. cardamines fitness, and it is also the main determining factor for oviposition. In summary, this thesis shows that the broad geographical pattern of phenology of the butterflies is formed by counteracting environmental variables, but that there also are significant population differences that enable fine-tuning of phenology according to the seasonal progression and variation at the local scale.

Description and training of neural network dynamics

Attractor properties of a popular discrete-time neural network model are illustrated through numerical simulations. The most complex dynamics is found to occur within particular ranges of parameters controlling the symmetry and magnitude of the weight matrix. A small network model is observed to produce fixed points, limit cycles, mode-locking, the Ruelle-Takens route to chaos, and the period-doubling route to chaos. Training algorithms for tuning this dynamical behaviour are discussed. Training can be an easy or difficult task, depending whether the problem requires the use of temporal information distributed over long time intervals. Such problems require training algorithms which can handle hidden nodes. The most prominent of these algorithms, back propagation through time, solves the temporal credit assignment problem in a way which can work only if the relevant information is distributed locally in time. The Moving Targets algorithm works for the more general case, but is computationally intensive, and prone to local minima.

Learning for life:educational provision at Cadbury, 1831-1981

Cadbury showed concern for the welfare of its labour force in a variety of ways and not least in the provision of educational and educative-recreational facilities. The firm regarded the education of employees as having a positive effect on the efficiency of the business at the same time as being of benefit to the individual, the local community and the nation. The life-long education of people was seen as essential for personal fulfilament, social improvement, economic competitiveness and the proper functioning of democratic procedures. The educational system built up at Cadbury, and the philosophy on which it was founded, acquired both a domestic and international reputation. Its main components were the day continuation education of juniors; the Bournville Works Evening Institute; vocational and non-vocational scholarships; emphasis on the primary importance of general education as a basis for life, work and technical training; stress on equality of educational opportunity for females; and leisure and sporting amenities which the firm felt to be educative in the sense that they contributed to personal psychological and physical development and social skills. The system was primarily shaped and constructed in the first three decades of the twentieth century and went into decline and eventual demise in the 1960's and 1970's as a result of economic pressures, social changes, enhanced state arrangements for education, shifts in Cadbury management thinking and the merger with Schweppes in 1969.

Results of the IEA round Robin on viscosity and aging of fast pyrolysis bio-oils:long-term tests and repeatability

An international round robin study of the viscosity measurements and aging of fast pyrolysis bio-oil has been undertaken recently, and this work is an outgrowth from that effort. Two bio-oil samples were distributed to two laboratories for accelerated aging tests and to three laboratories of long-term aging studies. The accelerated aging test was defined as the change in viscosity of a sealed sample of bio-oil held for 24 h at 80 °C. The test was repeated 10 times over consecutive days to determine the intra-laboratory repeatability of the method. Other bio-oil samples were placed in storage at three temperatures, 21, 5, and -17 °C, for a period of up to 1 year to evaluate the change in viscosity. The variation in the results of the accelerated aging test was shown to be low within a given laboratory. The long-term aging studies showed that storage of a filtered bio-oil under refrigeration can minimize the amount of change in viscosity. The accelerated aging test gave a measure of change similar to that of 6-12 months of storage at room temperature for a filtered bio-oil. Filtration of solids was identified as a key contributor to improving the stability of the bio-oil as expressed by the viscosity based on results of the accelerated aging tests as well as long-term aging studies. Only the filtered bio-oil consistently gave useful results in the accelerated aging and long-term aging studies. The inconsistency suggests that better protocols need to be developed for sampling bio-oils. These results can be helpful in setting standards for use of bio-oil, which is just coming into the marketplace. © 2012 American Chemical Society.

Some Aspects of the Theme "Information Platform" in the Training of Students in Economic Majors

Information Platform has a major impact on the core activities and development of businesses. In this connection it is necessary for students of economics (the future leaders of such entities) to submit any problems related to the Information Platform, the risks they may pose, and exemplary approach to solve part or all of the problems and minimizing risks. The current issue examines the adaptation of the above problems when presenting them to students in economic majors. To the students are presented generalizations based on long observation of the occurrence and development of Information Platforms to the businesses in Bulgaria in a growing market economy.

Politics and protestant Lordship in North East Scotland during the reign of James VI: The life of George Keith, fourth Earl Marischal, 1554-1623

George Keith, fourth Earl Marischal is a case study of long-term, quietly successful and stable lordship through the reign of James VI. Marischal’s life provides a wholly underrepresented perspective on this era, where the study of rebellious and notorious characters has dominated. He is also a counter-example to the notion of a general crisis among the European nobility, at least in the Scottish context, as well as to the notion of a ‘conservative’ or ‘Catholic’ north east. In 1580 George inherited the richest earldom in Scotland, with a geographical extent stretching along the east coast from Caithness to East Lothian. His family came to be this wealthy as a long term consequence of the Battle of Flodden (1513) where a branch of the family, the Inverugie Keiths had been killed. The heiress of this branch was married to the third earl and this had concentrated a large number of lands, and consequently wealth, in the hands of the earls. This had, however, also significantly decreased the number of members and hence power of the Keith kindred. The third earl’s conversion to Protestantism in 1544 and later his adherence to the King’s Party during the Marian Civil War forced the Keiths into direct confrontation with their neighbours in the north east, the Gordons (led by the Earls of Huntly), a Catholic family and supporters of the Queen’s Party. Although this feud was settled for a time at the end of the war, the political turmoil caused by a succession of short-lived factional regimes in the early part of the personal reign of James VI (c.1578-1585) led the new (fourth) Earl Marischal into direct confrontation with the new (sixth) Earl of Huntly. Marischal was outclassed, outmanoeuvred and outgunned at both court and in the locality in this feud, suffering considerably. However, Huntly’s over-ambition in wider court politics meant that Marischal was able to join various coalitions against his rival, until Huntly was exiled in 1595. Marischal also came into conflict briefly with Chancellor John Maitland of Thirlestane as a consequence of Marischal’s diplomatic mission to Denmark in 1589-1590, but was again outmatched politically and briefly imprisoned. Both of these feuds reveal Marischal to be relatively cautious and reactionary, and both reveal the limitations of his power. Elsewhere, the study of Marischal’s activities in the centre of Scottish politics reveal him to be unambitious. He was ready to serve King James, the two men having a healthy working relationship, but Marischal showed no ambition as a courtier, to woo the king’s favour or patronage, instead delegating interaction with the monarch to his kinsmen. Likewise, in government, Marischal rarely attended any of the committees he was entitled to attend, such as the Privy Council, although he did keep a keen eye on the land market and the business conducted under the Great Seal. Although personally devout and a committed Protestant, the study of Marischal’s interaction with the national Kirk and the parishes of which he was patron reveal that he was at times a negligent patron and exercised his right of ministerial presentation as lordly, not godly patronage. The notion of a ‘conservative North East’ is, however, rejected. Where Marischal was politically weak at court and weak in terms of force in the locality, we see him pursuing sideways approaches to dealing with this. Thus he was keen to build up his general influence in the north and in particular with the burgh of Aberdeen (one result of this being the creation of Marischal College in 1593), pursued disputes through increasing use of legal methods rather than bloodfeud (thus exploiting his wealth and compensating for his relative lack of force) and developed a sophisticated system of maritime infrastructure, ultimately expressed through the creating of the burghs of Peterhead and Stonehaven. Although his close family caused him a number of problems over his lifetime, he was able to pass on a stable and enlarged lordship to his son in 1623.

Objective evaluation of surgical competency for minimally invasive surgery with a collection of simple tests

Objective: This study aims at determining if a collection of 16 motor tests on a physical simulator can objectively discriminate and evaluate practitioners' competency level, i.e. novice, resident, and expert. Methods: An experimental design with three study groups (novice, resident, and expert) was developed to test the evaluation power of each of the 16 simple tests. An ANOVA and a Student Newman-Keuls (SNK) test were used to analyze results of each test to determine which of them can discriminate participants' competency level. Results: Four of the 16 tests used discriminated all of the three competency levels and 15 discriminated at least two of the three groups (α= 0.05). Moreover, other two tests differentiate beginners\' level from intermediate, and other seven tests differentiate intermediate level from expert. Conclusion: The competency level of a practitioner of minimally invasive surgery can be evaluated by a specific collection of basic tests in a physical surgical simulator. Reduction of the number of tests needed to discriminate the competency level of surgeons can be the aim of future research.