Metformin in cancer: translational challenges

The anti-diabetic drug metformin is rapidly emerging as a potential anti-cancer agent. Metformin, effective in treating type 2 diabetes and the insulin resistance syndromes, improves insulin resistance by reducing hepatic gluconeogenesis and by enhancing glucose uptake by skeletal muscle. Epidemiological studies have consistently associated metformin use with decreased cancer incidence and cancer-related mortality. Furthermore, numerous preclinical and clinical studies have demonstrated anti-cancer effects of metformin, leading to an explosion of interest in evaluating this agent in human cancer. The effects of metformin on circulating insulin levels indicate a potential efficacy towards cancers associated with hyperinsulinaemia; however, metformin may also directly inhibit tumour growth. In this review, we describe the mechanism of action of metformin and summarise the epidemiological, clinical and preclinical evidence supporting a role for metformin in the treatment of cancer. In addition, the challenges associated with translating preclinical results into therapeutic benefit in the clinical setting will be discussed.     

Who can inspect your dental practice?

There are several government agencies that may inspect your dental practice. The majority of inspections are carried out by the National Employment Rights Authority, the Health and Safety Authority, the Revenue Commissioners and the Radiological Protection Institute of Ireland. Below is a summary of the minimum requirements that should be in place to ensure compliance with the relevant legislation. You should always seek appropriate advice for your own particular circumstances.     

Comparison of microsurgery and endovascular treatment on clinical outcome following poor-grade subarachnoid hemorrhage

Poor-grade (World Federation of Neurological Surgeons [WFNS] clinical grading scale grades IV and V) subarachnoid hemorrhage (SAH) is associated with significant morbidity and mortality. However, the correlation between the timing, modality of intervention (clipping or coiling) and the clinical outcome is not clear. This study aims to examine this correlation. Patients presenting with WFNS grades IV and V aneurysmal SAH between 1997 and 2008 to a single centre were studied. An aggressive policy of early intervention was followed, and the selection of endovascular versus microsurgical intervention was made according to angiographic rather than clinical features. Clinical outcomes were graded using the modified Rankin scale (mRS) at 6 month follow-up. One hundred and forty-three poor-grade patients (23.9% of all 598 aneurysmal SAH patients) were studied. Treatment was microsurgical in 83 (58.0%) and endovascular in 60 (42%) patients. Twenty patients (14.0%) were lost to follow-up. Good outcome (mRS 0-2) at 6 months was found in 45 microsurgical patients (63.3%) and 24 endovascular patients (46.1%). This trend towards better clinical outcomes in the microsurgical group was not statistically significant. With an aggressive early treatment policy more than half of the poor-grade SAH patients demonstrated a good clinical outcome. Microsurgery and endovascular treatment, when selected primarily according to angiographic features, were equally likely to achieve good outcome.     

Promoting social inclusion through Unified Sports for youth with intellectual disabilities: a five‐nation study

Background Although the promotion of social inclusion through sports has received increased attention with other disadvantaged groups, this is not the case for children and adults with intellectual disability who experience marked social isolation. The study evaluated the outcomes from one sports programme with particular reference to the processes that were perceived to enhance social inclusion. Method The Youth Unified Sports programme of Special Olympics combines players with intellectual disabilities (called athletes) and those without intellectual disabilities (called partners) of similar skill level in the same sports teams for training and competition. Alongside the development of sporting skills, the programme offers athletes a platform to socialise with peers and to take part in the life of their community. Unified football and basketball teams from five countries – Germany, Hungary, Poland, Serbia and Ukraine – participated. Individual and group interviews were held with athletes, partners, coaches, parents and community leaders: totalling around 40 informants per country. Results Qualitative data analysis identified four thematic processes that were perceived by informants across all countries and the two sports to facilitate social inclusion of athletes. These were: (1) the personal development of athletes and partners; (2) the creation of inclusive and equal bonds; (3) the promotion of positive perceptions of athletes; and (4) building alliances within local communities. Conclusions Unified Sports does provide a vehicle for promoting the social inclusion of people with intellectual disabilities that is theoretically credible in terms of social capital scholarship and which contains lessons for advancing social inclusion in other contexts. Nonetheless, certain limitations are identified that require further consideration to enhance athletes' social inclusion in the wider community.     

The crushing truth about glass ionomer restoratives: exposing the standard of the standard

ObjectivesThe compressive fracture strength (CFS) test is the only strength test for glass ionomers (GIs) in ISO 9917-1: 2003. The CFS test was the subject of much controversy in 1990 and has been challenged over its appropriateness and reproducibility and the study aimed to revisit the suitability of the CFS test for GIs.MethodsGroups of 20 (four batches of n = 5) cylinders (6.0 ± 0.1 mm height, 4.0 ± 0.1 mm diameter) of three encapsulated GIs were prepared for CFS testing using two mechanical mixing regimes and two operators. The CFS data for each GI restorative were pooled, three-, two- and one-way analyses of variance (ANOVAs) were conducted (p = 0.05) for operator, mixing regime and batch to assess reliability. The data was also analysed according to ISO 9917-1: 2003.ResultsThe three-way ANOVAs showed a significant interaction of operator × mixing regime × batch (p < 0.017) for two of the three encapsulated GIs. However, no significant effects of operator × mixing regime (p > 0.042), operator × batch (p > 0.332), mixing regime × batch (p > 0.056), operator (p > 0.094), mixing regime (p > 0.118) or batch (p > 0.054) were evident. When examined in batches of five (or ten where appropriate) as specified in ISO 9917-1: 2003, inter- and intra-operator variability were evident.ConclusionsThe use of batch-censoring in accordance with ISO 9917-1: 2003 is unsafe when the data scatter reflects a homogenous flaw distribution as it misidentifies operative variability. Despite demonstrating that the CFS test can be performed reliably, the validity of the CFS test for GIs remains under scrutiny.     

Using Little's Irregularity Index in orthodontics: Outdated and inaccurate?

Objectives

Little's Irregularity Index (LII) was devised to objectively score mandibular incisor alignment for epidemiological studies but has been extended to assess the relative performance of orthodontic brackets, retainer or treatment modalities. Our aim was to examine the repeatability and precision of LII measurements of four independent examiners on the maxillary arch of orthodontic patients. The hypothesis was that the reproducibility of individual contact point displacement measurements, used to calculate the LII score, are inappropriate.

Methods

The displacement of the anterior contact points, of the six upper labial segment teeth of the maxillary arch on each of ten casts, were randomly assessed by four examiners at three time-points using LII.

Results

Significant correlations were evident between the six examiner-pairs (r > 0.413; p < 0.001) for contact point displacements of >0.5 mm. The coefficients of variation showed that 516 of the 600 individual contact point displacement measurements differed by >20% of the mean. Analyses of variance revealed significant differences (p < 0.047) between examiners for 46% of the contact point displacement measurements.

Conclusion

The reproducibility of individual contact point displacement measurements, used to calculate the LII score, is poor such that using LII to assess the performance of orthodontic brackets, retainers or treatment modalities must emphatically be discouraged.

Clinical significance

The use of LII by the orthodontic community to predictably determine the outcome of orthodontic treatment modalities in clinical practice cannot be advocated due to the limited accuracy and precision of the technique.     

The effects of ageing on the distribution of vesicular acetylcholine transporter immunoreactive inputs to pelvic motoneurons of male Wistar rats

Age-related changes in the number and size of large cholinergic terminals immunoreactive for vesicular acetylcholine transporter (VAChT), were documented for the dorsolateral nucleus (DLN), retrodorsolateral nucleus (RDLN) and spinal nucleus of the bulbospongiosus (SNB) of the lumbosacral spinal cord of male rats. The most significant changes were a large increase in the number and size of cholinergic terminals within the DLN of aged animals, together with a small decrease in terminal number within the RDLN. No significant age-associated differences in VAChT labeling were seen within the SNB. In both age groups, SNB motoneurons projecting to the levator ani muscle received about 9 to 10 contacts from large cholinergic terminals. Ultrastructural examination of the terminals revealed structures likely to be postsynaptic subsurface cisterns that are characteristic of type C terminal boutons. Since both the DLN and SNB contain motoneurons innervating pelvic muscles and sphincters, these findings provide further evidence for a central cholinergic influence on micturition and sexual reflexes and suggest that this may remain robust in the face of ageing.     

Supporting parents caring for a child with a learning disability

Parenting a child with a learning disability is a unique and often demanding experience. The learning disability nurse can play a key role in supporting parents and families by communicating effectively, providing information and working in partnership.