Potential of hydrogel-forming and dissolving microneedles for use in paediatric populations

Development of formulations and drug delivery strategies for paediatric use is challenging, partially due to the age ranges within this population, resulting in varying requirements to achieve optimised patient outcomes. Although the oral route of drug delivery remains the preferred option, there are problematic issues, such as difficulty swallowing and palatability of medicines specific to this population. The parenteral route is not well accepted by children due to needle-related fear and pain. Accordingly, a plethora of alternative routes of drug administration have been investigated. Microneedles (MN) breach the stratum corneum (SC), the outermost layer of skin, increasing the number of drug substances amenable to transdermal delivery. This strategy involves the use of micron-sized needles to painlessly, and without drawing blood, create transient aqueous conduits in the SC. In this study, polymeric dissolving MN and hydrogel-forming MN were fabricated incorporating two model drugs commonly used in paediatric patients (caffeine and lidocaine hydrochloride). The potential efficacy of these MN for paediatric dosing was investigated via in vitro and in vivo studies. Views pertaining to MN technology were sought amongst school children in Northern Ireland, members of the UK general public and UK-based paediatricians, to determine perceived benefits, acceptance, barriers and concerns for adoption of this technology. In this study, polymeric MN were shown to substantially enhance skin permeability of the model therapeutic molecules in vitro and in vivo. In particular, hydrogel-forming MN led to a 6.1-fold increase in caffeine delivery whilst lidocaine HCl delivery was increased by 3.3-fold using dissolving MN in vitro. Application of caffeine-loaded MN led to a caffeine plasma concentration of 23.87μg/mL in rats at 24h. This research also highlighted a strong consensus regarding MN technology amongst schoolchildren, paediatricians and the general public, regarding potential use of MN in the paediatric population. Overall, 93.6% of general public respondents and 85.9% of paediatricians regarded the use of MN as a positive approach.

Microneedle applications in improving skin appearance

Microneedles (MNs) are micron-sized, minimally invasive devices that breach the outermost layer of the skin, the stratum corneum (SC), creating transient, aqueous pores in the skin and facilitating the transport of therapeutic molecules into the epidermis. Following many years of extensive research in the area of MN-mediated trans- and intra-dermal drug delivery, MNs are now being exploited in the cosmeceutical industry as a means of disrupting skin cell architecture, inducing elastin and collagen expression and deposition. They are also being used as vehicles to deliver cosmeceutic molecules across the skin, in addition to their use in combinatorial treatments with topical agents or light sources. This review explores the chronology of microneedling methodologies, which has led to the emergence of MN devices, now extensively used in cosmeceutical applications. Recent developments in therapeutic molecule and peptide delivery to the skin via MN platforms are addressed and some commercially available MN devices are described. Important safety and regulatory considerations relating to MN usage are addressed, as are studies relating to public perception of MN, as these will undoubtedly influence the acceptance of MN products as they progress towards commercialisation.

Parainflammation, chronic inflammation, and age-related macular degeneration

Inflammation is an adaptive response of the immune system to noxious insults to maintain homeostasis and restore functionality. The retina is considered an immune-privileged tissue as a result of its unique anatomic and physiologic properties. During aging, the retina suffers from a low-grade chronic oxidative insult, which sustains for decades and increases in level with advancing age. As a result, the retinal innate-immune system, particularly microglia and the complement system, undergoes low levels of activation (parainflammation). In many cases, this parainflammatory response can maintain homeostasis in the healthy aging eye. However, in patients with age-related macular degeneration, this parainflammatory response becomes dysregulated and contributes to macular damage. Factors contributing to the dysregulation of age-related retinal parainflammation include genetic predisposition, environmental risk factors, and old age. Dysregulated parainflammation (chronic inflammation) in age-related macular degeneration damages the blood retina barrier, resulting in the breach of retinal-immune privilege, leading to the development of retinal lesions. This review discusses the basic principles of retinal innate-immune responses to endogenous chronic insults in normal aging and in age-related macular degeneration and explores the difference between beneficial parainflammation and the detrimental chronic inflammation in the context of age-related macular degeneration.

Domestic Violence as a Human Rights Issue: Rumor v. Italy

The article focuses on the recent developments as regards domestic violence within the context of the Council of Europe. Since 2007 the European Court of Human Rights has issued a series of important judgments in cases involving domestic violence. The most recent of these is Rumor v. Italy, in which the Court issued its judgment on 27 May 2014. The article analyses this case in the context of the Court’s previous jurisprudence on domestic violence. In addition, on 1 August 2014 the Council of Europe Convention on preventing and combating violence against women and domestic violence entered into force, and the article will include a number of reflections on the potential held by this Convention. No violation of the European Convention on Human Rights was found in Rumor, however the question of whether Italy would have been in breach of the provisions of the new Convention, to which it is a party, had this Convention been in force at the time of the relevant events, will be examined.

Contracts for the Sale of Land: Understanding the Impecuniosity Defence

Where either the seller or buyer of landed property fails to complete a contract to sell land the non-breaching party has a right to seek specific performance of the contract. This remedy would compel the party in default to perform the contract on pain of being held in contempt of court if the court's order is not obeyed. The defaulting party would not be able to satisfy its obligations under the law by paying a sum of money as damages for breach of contract. This paper considers the impecuniosity defence to specific performance as recognised by courts in Northern Ireland, the Republic of Ireland, Australia and New Zealand. Where the buyer demonstrates that he or she simply cannot raise the funds to buy the property specific performance will not be decreed and the court will make an award of damages for breach of contract measured by the difference between the contract price and the market price of the property at the time of default. The paper considers the nature and parameters of this defence and how it differs (if at all) from the alternative defence of extreme hardship. The paper addresses the question of whether it might be better to move to a position where sellers of land in all cases no longer enjoy a presumption of specific performance but have to demonstrate that the alternative remedy of damages is clearly inadequate. If this should be so the paper goes on to consider whether abolition of the presumption in favour of specific performance for sellers should lead to abolition of the presumption of specific performance for buyers, as is the position in Canada following the Supreme Court's decision in Semelhago v Paramadevan [1996] 2 SCR 415.

Bouyid v Belgium: The “minimum level of severity” and Human Dignity's Role in Article 3 ECHR

The Grand Chamber of the European Court of Human Rights recently delivered an important judgment on Article 3 ECHR in the case of Bouyid v Belgium. In Bouyid, the Grand Chamber was called upon to consider whether slaps inflicted on a minor and an adult in police custody were in breach of Article 3 ECHR, which provides that ‘No one shall be subjected to torture or to inhuman or degrading treatment or punishment’. Overruling the Chamber judgment in the case, the Grand Chamber ruled by 14 votes to 3 that there had been a substantive violation of Article 3 in that the applicants had been subjected to degrading treatment by members of the Belgian police; it found that there had been a breach of the investigative duty under Article 3 also. In this comment, I focus on the fundamental basis of disagreement between the majority of the Grand Chamber and those who found themselves in dissent, on the question of whether there had been a substantive breach of Article 3. The crux of the disagreement lay in the understanding and application of the test of ‘minimum level of severity’, which the ECtHR has established as decisive of whether a particular form of ill-treatment crosses the Article 3 threshold, seen also in light of Article 3’s absolute character, which makes it non-displaceable – that is, immune to trade-offs of the type applicable in relation to qualified rights such as privacy and freedom of expression. I consider the way the majority of the Grand Chamber unpacked and applied the concept of dignity – or ‘human dignity’ – towards finding a substantive breach of Article 3, and briefly distil some of the principles underpinning the understanding of human dignity emerging in the Court’s analysis.

Transcending epithelial and intracellular biological barriers; a prototype DNA delivery device

Microneedle technology provides the opportunity for the delivery of DNA therapeutics by a non-invasive, patient acceptable route. To deliver DNA successfully requires consideration of both extra and intracellular biological barriers. In this study we present a novel two tier platform; i) a peptide delivery system, termed RALA, that is able to wrap the DNA into nanoparticles, protect the DNA from degradation, enter cells, disrupt endosomes and deliver the DNA to the nucleus of cells ii) a microneedle (MN) patch that will house the nanoparticles within the polymer matrix, breach the skin's stratum corneum barrier and dissolve upon contact with skin interstitial fluid thus releasing the nanoparticles into the skin. Our data demonstrates that the RALA is essential for preventing DNA degradation within the poly(vinylpyrrolidone) (PVP) polymer matrix. In fact the RALA/DNA nanoparticles (NPs) retained functionality when in the MN arrays after 28days and over a range of temperatures. Furthermore the physical strength and structure of the MNs was not compromised when loaded with the NPs. Finally we demonstrated the effectiveness of our MN-NP platform in vitro and in vivo, with systemic gene expression in highly vascularised regions. Taken together this 'smart-system' technology could be applied to a wide range of genetic therapies.

O incumprimento do contrato de crédito ao consumo pelo consumidor

Consumer relations, established between the Consumer and the Creditor, which carry a consequent inequality of contractual positioning between the parties, have been pushing the legislator to adopt more rigid regulations with regard to lending for the purchase of goods or services of consum issues. In this sense, the Decree-Law 359/91 was approved, meanwhile repealed by the Decree-Law 133/2009, which regulates the consumer credit agreement’s regime in the portuguese legal system. Through this contract, the financier makes available to the consumer a certain amount of money, which the consumer must repay, plus the respective remuneration (interest) and other charges, according to a refund plan agreed by the parties. The consumer will be in delay if he breaches this stipulation. In case of default, the creditor, notwithstanding, can choose to wait for the performance by the debtor, promote the loss of benefit of the term or the termination of the contract. From the outset it would seem that, in one way or another, the financier, by imposing a forced shortening of the contract duration initially agreed, will lose the right to remuneration for the provision of capital agreed, but not verified. Nevertheless, unlike presently, the previous regime allowed the parties to rule otherwise, being permitted to agree to the payment of interest of outstanding installments. On the other hand, in the consumer credit contract the principle of freedom of contractual provision of the parties is strongly mitigated by the special legislation, which prevents the waiver of rights by the consumer, and by the regime of general contractual terms, which restricts the freedom of the financier to stipulate the contractual content freely and the freedom of the consumer to negotiate. For all these reasons, associated with the growing need of credit resource to satisfy their needs of consumption, it is confirm the relevance of legislative intervention on consumers protection in the context of hiring credit.

Construção de uma responsabilidade europeia além-fronteiras

The suppression of internal border controls has led the European Union to establish a mechanism for determining the Member State responsible for examining each asylum application, with the main intention of deterring asylum seekers from lodging multiple applications and guaranteeing that it will be assessed by one of the States – the Dublin System. Even though it holds on a variety of criteria, the most commonly used is the country of first entrance in the EU. The growing migrating flows coming mainly from Northern Africa have thus resulted in an incommensurable burden over the border countries. Gradually, countries like Greece, Bulgaria and Italy have lost capability of providing adequate relief to all asylum seekers and the records of fundamental rights violations related to the provision of housing and basic needs or inhuman detention conditions started piling up. To prevent asylum seekers who had already displaced themselves to other Member States from being transferred back to countries where their human dignity is questionable, the European Court of Human Rights and the Court of Justice have developed a solid jurisprudence determining that when there is a risk of serious breach of fundamental rights all transfers to that country must halt, especially when it is identified with systemic deficiencies in the asylum system and procedures. This reflexion will go through the jurisprudence that influenced very recent legislative amendments, in order to identify which elements form part of the obligation not to transfer under the Dublin System. At last, we will critically analyze the new rising obligation, that has clearly proven insufficient in light of the international fundamental rights framework that the Member States and the EU are bound to respect, proposing substantial amendments with a view to reach a future marked by high solidarity and global responsibility from the European Union.

O incumprimento do contrato de crédito ao consumo pelo consumidor

Consumer relations, established between the Consumer and the Creditor, which carry a consequent inequality of contractual positioning between the parties, have been pushing the legislator to adopt more rigid regulations with regard to lending for the purchase of goods or services of consum issues. In this sense, the Decree-Law 359/91 was approved, meanwhile repealed by the Decree-Law 133/2009, which regulates the consumer credit agreement’s regime in the portuguese legal system. Through this contract, the financier makes available to the consumer a certain amount of money, which the consumer must repay, plus the respective remuneration (interest) and other charges, according to a refund plan agreed by the parties. The consumer will be in delay if he breaches this stipulation. In case of default, the creditor, notwithstanding, can choose to wait for the performance by the debtor, promote the loss of benefit of the term or the termination of the contract. From the outset it would seem that, in one way or another, the financier, by imposing a forced shortening of the contract duration initially agreed, will lose the right to remuneration for the provision of capital agreed, but not verified. Nevertheless, unlike presently, the previous regime allowed the parties to rule otherwise, being permitted to agree to the payment of interest of outstanding installments. On the other hand, in the consumer credit contract the principle of freedom of contractual provision of the parties is strongly mitigated by the special legislation, which prevents the waiver of rights by the consumer, and by the regime of general contractual terms, which restricts the freedom of the financier to stipulate the contractual content freely and the freedom of the consumer to negotiate. For all these reasons, associated with the growing need of credit resource to satisfy their needs of consumption, it is confirm the relevance of legislative intervention on consumers protection in the context of hiring credit.

A protecção jurídica do consumidor em Angola

The scope of the present work is to study the legal protection conferred upon the consumer in Angola, especially as regards electronic communication agreements. Its purpose is to promote consumers’ rights and contribute to its defence given the relatively privileged position of professionals in their relationship with consumers. With this in mind, we have made a description of the Consumer Law in Angola based on the Angolan Constitution (as the law that establishes the fundamental rights and guarantees of citizens) and on the Consumer’s Defence Law, which, as the basic law regarding consumers’ rights, provides the framework for this dissertation. We have analysed several aspects relating to consumer relationships, starting from its concept and rights of consumers and covering the legal and contractual mechanisms put in place for their protection. We have also analysed the Advertising Law with a view to better understand consumer’s rights before advertising campaigns carried out by professionals whilst promoting their goods and services and, additionally, to understand the duties and principles that shall be complied with in such campaigns with the purpose to protect the rights and interests of consumers. From a criminal point of view, we have briefly covered the crimes against consumers provided for in the Penal Code and the Law of Infractions against the Economy. In the second part of this work, we have summarised the institutions that protect the rights and interests of consumers, which include the Public Prosecutor Office, the National Institute for the Defence of the Consumers and the Consumers’ Associations. The third and last part of this work covers electronic communications agreements. Given the fact that there is no specific legislation in this matter, our analysis was based on the Civil Code – specifically the part relating to contracts – the Law on General Contractual Terms and Conditions and the Consumer’s Defence Law. We have analysed the formation of contracts, compliance and consumers’ rights resulting from contract breach. We further have appealed to the Angolan legislator to legislate certain aspects of consumer relationships, especially those where breach of consumers’ rights are blatant and facilitated by the lack of specific laws addressing such cases.

Kixikila - um contrato de financiamento informal

The purpose of the present work is to analyse and provide kixikila legal framework under Angolan law. Kixikila, despite being a legally atypical agreement, is a socially typical contract, governed essentially by the practices and customs in Angola and concluded throughout the country. With the above purpose in mind, this thesis is structured in five chapters: the first one aims at better understanding its features and, therefore, it describes the kixikila in accordance with oral research, direct observation and the contributions of scholars that have examined this matter. The second chapter aims at qualifying the kixikila as a legal transaction. For this purpose, we have analysed its requirements, formation stages, content and form, characteristics, rights and obligations of the parties, effects and compliance. We have also covered the reasons that explain why this type of agreement shall be legally protected in line with the protection conferred upon other legal agreements, taking into account its economic and social function. The third chapter covers the vicissitudes which may occur during the term of the kixikila agreement, as well as the enforcement mechanisms in face of breach and its termination. The fourth chapter aims at qualifying this agreement by comparing its most relevant characteristics with those of typical agreements, with a view to determining its legal nature based upon the similarity with other contractual types. This chapter further makes a comparative synthesis between the contracts in analysis. The fifth chapter analyses the legal nature and legal framework applicable to kixikila taking into account mixed-purpose contracts and sui generis contracts. We conclude that practices and customs in Angola take precedence as regards kixikila. Lastly, we attach additional information, such as excerpts of interviews with some individuals intervening in kixikila, the functional structure of kixikila and examples of kixikila, as well as demonstrative lists of countries where this type of agreement takes place and the obligations arising therefrom.

Image guided critical screw placement precision in the cervical spine : important or incidental? : results of a series of 91 consecutive cases using OVEM

Study design: A retrospective study of image guided cervical implant placement precision. Objective: To describe a simple and precise classification of cervical critical screw placement. Summary of Background Data: "Critical" screw placement is defined as implant insertion into a bone corridor which is surrounded circumferentially by neurovascular structures. While the use of image guidance has improved accuracy, there is currently no classification which provides sufficient precision to assess the navigation success of critical cervical screw placement. Methods: Based on postoperative clinical evaluation and CT imaging, the orthogonal view evaluation method (OVEM) is used to classify screw accuracy into grade I (no cortical breach), grade la (screw thread cortical breach), grade II (internal diameter cortical breach) and grade III (major cortical breach causing neural or vascular injury). Grades II and III are considered to be navigation failures, after accounting for bone corridor / screw mismatch (minimal diameter of targeted bone corridor being smaller than an outer screw diameter). Results: A total of 276 screws from 91 patients were classified into grade I (64.9%), grade la (18.1%), and grade II (17.0%). No grade III screw was observed. The overall rate of navigation failure was 13%. Multiple logistic regression indicated that navigational failure was significantly associated with the level of instrumentation and the navigation system used. Navigational failure was rare (1.6%) when the margin around the screw in the bone corridor was larger than 1.5 mm. Conclusions: OVEM evaluation appears to be a useful tool to assess the precision of critical screw placement in the cervical spine. The OVEM validity and reliability need to be addressed. Further correlation with clinical outcomes will be addressed in future studies.

A critical examination of the involvement of Canadian high-performance athletes in the development of anti-doping policy

The use of certain perfonnance enhancing substances and methods has been defined as a major ethical breach by parties involved in the governance of highperfonnance sport. As a result, elite athletes worldwide are subject to rules and regulations set out in international and national anti-doping policies. Existing literature on the development of policies such as the World Anti-Doping Code and The Canadian antiDoping Program suggests a sport system in which athletes are rarely meaningfully involved in policy development (Houlihan, 2004a). Additionally, it is suggested that this lack of involvement is reflective of a similar lack of involvement in other areas of governance concerning athletes' lives. The purpose ofthis thesis is to examine the history and current state of athletes' involvement in the anti-doping policy process in Canada's high-perfonnance sport system. It includes discussion and analysis of recently conducted interviews with those involved in the policy process as well as an analysis of relevant documents, including anti-doping policies. The findings demonstrate that Canadian athletes have not been significantly involved in the creation of recently developed antidoping policies and that a re-evaluation of current policies is necessary to more fully recognize the reality of athletes' lives in Canada's high-perfonnance sport system and their rights within that system.

Monstrum : the vampire in the detective story /

My approach to the vampire detective highlights its connections to the private detective's story and reveals the monstrous investigators' debt to early feminist forms of detection -specifically in their reformation of the' other' and of traditional forms of power and authority. Seen in this light the movement of horror's imaginary 'other' into the rational world of detection can be seen as not an abrupt breach of detection's realist conventions, but an almost seamless transition into symbolic spaces that point to the detective's primary function -- to make sense of the senseless. It is in this light that I explore the monster that is a detective as a symbol that is also a sense-maker, and a quintessential postmodern figure. I argue that the distinctions between monsters and 'others', and between popular narratives and postmodern religion have faded, culminating in a character that can not only model 'otherness' as an exemplary condition, but also provide strategies for modeling the form of active postmodern subjectivity that postmodern theorist Jim Collins' (1989) conceives of as heretical activity.