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.

Stability of Short-span Bridges Subject to Overtopping during Floods: Case Studies from UK and the USA

As a consequence of increased levels of flooding, largely attributable to urbanization of watersheds (and perhaps climate change, more frequent extreme rainfall events are occurring and threatening existing critical infrastructure. Many of which are short-span bridges over relatively small waterways (e.g., small rivers, streams and canals). Whilst these short-span bridges were designed, often many years ago, to pass relatively minor the then standard return-period floods, in recenttimes the failure incidence of such short-span bridges has been noticeably increasing. This is suggestive of insufficient hydraulic capacity or alternative failure mechanism not envisaged at the time of design e.g. foundation scour or undermining. This paper presen ts, and draws lessons, from bridge failures in Ireland and the USA. For example, in November 2009, the UK and Ireland were subjected to extraordinarily severe weather conditions for several days. The resulting flooding led to the collapse of three UK bridges that were generally 19th century masonry arch bridges, withrelatively shallow foundations. Parallel failure events have been observed in the USA. To date, knowledge of the combined effect of waterway erosion, bridge submergence, and geotechnical collapse has not been adequately studied. Recent research carried out considered the hydraulic analysis of short span bridges under flood conditions, but no consideration was given towards the likely damage to these structures due to erosive coupling of hydraulic and geotechnical factors. Some work has been done to predict the discharge downstream of an inundated arch, focusing onpredicting afflux, as opposed to bridge scour, under both pressurized and free-surface flows, but no ! predictive equation for scour under pressurized conditions was ever considered. The case studies this paper presents will be augmented by the initial findings from the laboratory experiments investigating the effects of surcharged flow and subsequent scour within the vicinity of single span arch bridges. Velocities profiles will be shown within the vicinity of the arch, in addition to the depth of consequent scour, for a series of flows and model spans. The data will be presented and correlated to the most recent predictive equations for submerged contraction and abutment scour. The accuracy of these equations is examined, and the findings used as a basis for developing further studies in relation to short span bridges.

Larval development of the pedunculate barnacles Octolasmis angulata Aurivillius 1894 and Octolasmis cor Aurivillius 1892 (Cirripedia: Thoracica: Poecilasmatidae) from the gills of the mud crab, Scylla tranquebarica Fabricius, 1798

Detailed studies of larval development of Octolasmis angulata and Octolasmis cor are pivotal in understanding the larval morphological evolution as well as enhancing the functional ecology. Six planktotrophic naupliar stages and one non-feeding cyprid stage are documented in details for the first time for the two species of Octolasmis. Morphologically, the larvae of O. angulata and O. cor are similar in body size, setation patterns on the naupliar appendages, labrum, dorsal setae-pores, frontal horns, cyprid carapace, fronto-lateral gland pores, and lattice organs. Numbers of peculiarities were observed on the gnathobases of the antennae and mandible throughout the naupliar life-cycle. The setation pattern on the naupliar appendages are classified based on the segmentation on the naupliar appendages. The nauplius VI of both species undergoes a conspicuous change before metamorphosis into cyprid stage. The cyprid structures begin to form and modify beneath the naupliar body towards the end of stage VI. This study emphasises the importance of the pedunculate barnacle larval developmental studies not only to comprehend the larval morphological evolution but also to fill in the gaps in understanding the modification of the naupliar structures to adapt into the cyprid life-style.

Randomized comparison of unfractionated heparin with corticosteroids in severe active inflammatory bowel disease

BACKGROUND: Heparin therapy may be effective in steroid resistant inflammatory bowel disease.

AIM: A randomized pilot study, to compare unfractionated heparin as a first-line therapy with corticosteroids in colonic inflammatory bowel disease.

METHODS: Twenty patients with severe inflammatory bowel disease (ulcerative colitis, n=17; Crohn's colitis, n=3) were randomized to either intravenous heparin for 5 days, followed by subcutaneous heparin for 5 weeks (n=8), or high-dose intravenous hydrocortisone for 5 days followed by oral prednisolone 40 mg daily, reducing by 5 mg per day each week (n=12). After 5 days, non-responders in each treatment group were commenced on combination therapy. Response to therapy was monitored by: clinical disease activity (ulcerative colitis: Truelove and Witt Index; Crohn's colitis: Harvey and Bradshaw Index), stool frequency, serum C-reactive protein and alpha1 acid glycoprotein, endoscopic and histopathological grading.

RESULTS: The response rates were similar in both treatment groups: clinical activity index (heparin vs. steroid; 75% vs. 67%; P=0.23), stool frequency (75% vs. 67%; P=0.61), endoscopic (75% vs. 67%; P=0.4) and histopathological grading (63% vs. 50%; P=0.67). Both treatments were well-tolerated with no serious adverse events.

CONCLUSION: Heparin as a first line therapy is as effective as corticosteroids in the treatment of colonic inflammatory bowel disease. Large multicentre randomized comparative studies are required to determine the role of heparin in the management of inflammatory bowel disease.

Androgen-regulated metabolism and biosynthesis in prostate cancer

Metabolic changes are a well-described hallmark of cancer and are responses to changes in the activity of diverse oncogenes and tumour suppressors. For example, steroid hormone biosynthesis is intimately associated with changes in lipid metabolism and represents a therapeutic intervention point in the treatment of prostate cancer (PCa). Both prostate gland development and tumorigenesis rely on the activity of a steroid hormone receptor family member, the androgen receptor (AR). Recent studies have sought to define the biological effect of the AR on PCa by defining the whole-genome binding sites and gene networks that are regulated by the AR. These studies have provided the first systematic evidence that the AR influences metabolism and biosynthesis at key regulatory steps within pathways that have also been defined as points of influence for other oncogenes, including c-Myc, p53 and hypoxia-inducible factor 1α, in other cancers. The success of interfering with these pathways in a therapeutic setting will, however, hinge on our ability to manage the concomitant stress and survival responses induced by such treatments and to define appropriate therapeutic windows.

Adiposity as a cause of cardiovascular disease: a Mendelian randomization study

Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods.

Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes.

Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12–1.28, P = 1.9·10−7), heart failure (HR = 1.47, 95% CI, 1.35–1.60, P = 9·10−19) and ischaemic stroke (HR = 1.15, 95% CI, 1.06–1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028–0.033, P = 3·10−107). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12–3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05–3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD.

Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.

Temperament test for re-homed dogs validated through direct behavioral observation in shelter and home environment

This study was the first attempt to carry out a validation of a temperament test (TT) for shelter dogs that addressed the topics of inter- and intra-raters agreements, test-retest reliability, and validity. The TT consisted of 22 subtests. Each dog was approached and handled by an unfamiliar person and made to interact with a same- and an opposite-gender conspecific. Dogs were tested twice in the shelter and once in their new homes 4 months after adoption to evaluate consistency in behavioral assessment. Playfulness, trainability, problem solving abilities, food possessiveness, and reactivity to sudden stimuli were also evaluated. Testers scored dogs' responses in terms of confidence, fearfulness, and aggressiveness. Results highlighted strengths and limits of this TT that was devised to help shelter staff in matching dogs' personality and owners' expectations. Methodological constraints when working with sheltered dogs are unavoidable; however, the test proved to be overall feasible, reliable, and valid although further studies are needed to address the critical issues that emerged. © 2011 Elsevier Inc.

Peripheral Iridotomy for Angle-Closure Glaucoma

This chapter covers the indications, contraindications, techniques, outcomes, and complications of LPI. Its role is well defined in most of the areas, but no conclusion can be drawn at present regarding prophylactic use for glaucoma suspects. More studies are needed to define its safety and efficacy. Overall, LPI is a relatively safe procedure and the majority of complications can be avoided if it is performed properly.

Production of extended-spectrum β-lactamases and the potential indirect pathogenic role of Prevotella isolates from the cystic fibrosis respiratory microbiota

Extended-spectrum β-lactamase (ESBL) production and the prevalence of the β-lactamase-encoding gene blaTEM were determined in Prevotella isolates (n=50) cultured from the respiratory tract of adults and young people with cystic fibrosis (CF). Time-kill studies were used to investigate the concept of passive antibiotic resistance and to ascertain whether a β-lactamase-positive Prevotella isolate can protect a recognised CF pathogen from the action of ceftazidime in vitro. The results indicated that approximately three-quarters (38/50; 76%) of Prevotella isolates produced ESBLs. Isolates positive for ESBL production had higher minimum inhibitory concentrations (MICs) of β-lactam antibiotics compared with isolates negative for production of ESBLs (P<0.001). The blaTEM gene was detected more frequently in CF Prevotella isolates from paediatric patients compared with isolates from adults (P=0.002), with sequence analysis demonstrating that 21/22 (95%) partial blaTEM genes detected were identical to blaTEM-116. Furthermore, a β-lactamase-positive Prevotella isolate protected Pseudomonas aeruginosa from the antimicrobial effects of ceftazidime (P=0.03). Prevotella isolated from the CF respiratory microbiota produce ESBLs and may influence the pathogenesis of chronic lung infection via indirect methods, including shielding recognised pathogens from the action of ceftazidime.

Psychological interventions for children and young people affected by armed conflict or political violence: a systematic literature review.

Youths exposed to armed conflict have a higher prevalence of mental health and psychosocial difficulties. Diverse interventions exist that aim to ameliorate the effect of armed conflict on the psychological and psychosocial wellbeing of conflict affected youths. However, the evidence base for the effectiveness of these interventions is limited. Using standard review methodology, this review aims to address the effectiveness of psychological interventions employed among this population. The search was performed across four databases and grey literature. Article quality was assessed using the Downs and Black Quality Checklist (1998). Where possible, studies were subjected to meta-analyses. The remaining studies were included in a narrative synthesis. Eight studies concerned non clinical populations, while nine concerned clinical populations. Review findings conclude that Group Trauma Focused-Cognitive Behavioural Therapy is effective for reducing symptoms of posttraumatic stress disorder, anxiety, depression and improving prosocial behaviour among clinical cohorts. The evidence does not suggest that interventions aimed at non clinical groups within this population are effective. Despite high quality studies, further robust trials are required to strengthen the evidence base, as a lack of replication has resulted in a limited evidence base to inform practice.