A patient perspective of pharmacist prescribing: 'crossing the specialisms-crossing the illnesses'

Background: The drive for non-medical prescribing has progressed quickly since the late 1990s and involves a range of healthcare professionals including pharmacists. As part of a commissioned research project, this qualitative element of a larger case study focused on the views of patients of pharmacist prescribers. 

Objective: The aim of this study was to explore patients' perspectives of pharmacists as prescribers. 

Methods: Three pharmacists working as independent prescribers in the clinical areas of (i) hypertension, (ii) cardiovascular/diabetes management, (iii) anticoagulation were recruited to three case studies of pharmacist prescribing in Northern Ireland. One hundred and five patients were invited to participate in focus groups after they had been prescribed for by the pharmacist. Focus groups took place between November 2010 and March 2011 (ethical/governance approvals granted) were audio taped, transcribed verbatim, read independently by two authors and analysed using constant comparative analysis. 

Results: Thirty-four patients agreed to participate across seven focus groups. Analysis revealed the emergence of one overarching theme: team approach to patient care. A number of subthemes related to the role of the pharmacist, the role of the doctor and patient benefits. There was an overwhelming lack of awareness of pharmacist prescribing. Patients discussed the importance of a multidisciplinary approach to their care and recognized limitations of the current model of prescribing. 

Conclusion: Patients were positive about pharmacist prescribing and felt that a team approach to their care was the ideal model especially when treating those with more complex conditions. Despite positive attitudes, there was a general lack of awareness of this new mode of practice.

Determining the optimal current direction of transcranial magnetic stimulation to induce motor responses in the tongue: A preliminary study of neurologically healthy individuals

Objective
To determine the optimal transcranial magnetic stimulation (TMS) coil direction for inducing motor responses in the tongue in a group of non-neurologically impaired participants.
Methods
Single-pulse TMS was delivered using a figure-of-eight Magstim 2002 TMS coil. Study 1 investigated the effect of eight different TMS coil directions on the motor-evoked potentials elicited in the tongue in eight adults. Study 2 examined active motor threshold levels at optimal TMS coil direction compared to a customarily-used ventral-caudal direction. Study 3 repeated the procedure of Study 1 at five different sites across the tongue motor cortex in one adult.
Results
Inter-individual variability in optimal direction was observed, with an optimal range of directions determined for the group. Active motor threshold was reduced when a participant's own optimal TMS coil direction was used compared to the ventral-caudal direction. A restricted range of optimal directions was identified across the five cortical positions tested.
Conclusions
There is a need to identify each individual's own optimal TMS coil direction in investigating tongue motor cortex function. A recommended procedure for determining optimal coil direction is described.
Significance
Optimized TMS procedures are needed so that TMS can be utilized in determining the underlying neurophysiological basis of various motor speech disorders.

The vascular targeting agent combretastatin-A4 and a novel cis-Restricted {beta}-Lactam Analogue, CA-432, induce apoptosis in human chronic myeloid leukemia cells and ex vivo patient samples including those displaying multidrug resistance

Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (β-lactam) ring were designed and synthesized with the objective to prevent cis -trans isomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected β-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead β-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G(2)M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-x(L) preceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and β-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells

PURPOSE: The development of multi-drug resistance (MDR) due to the expression of members of the ATP binding cassette (ABC) transporter family is a major obstacle in cancer treatment. The broad range of substrate specificities associated with these transporters leads to the efflux of many anti-cancer drugs from tumour cells. Therefore, the development of new chemotherapeutic agents that are not substrates of these transporters is important. We have recently demonstrated that some members of a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds are microtubule-depolymerising agents that potently induce apoptosis in several cancer cell lines and impair growth of mouse breast tumours. The aim of this current study was to establish whether PBOXs were capable of inducing apoptosis in cancer cells expressing either P-glycoprotein or breast cancer resistance protein (BCRP), two of the main ABC transporters associated with MDR.

METHODS: We performed in vitro studies to assess the effects of PBOXs on cell proliferation, cell cycle and apoptosis in human cancer cell lines and their drug-resistant substrains expressing either P-glycoprotein or BCRP. In addition, we performed a preliminary molecular docking study to examine interactions between PBOXs and P-glycoprotein.

RESULTS: We established that three representative PBOXs, PBOX-6, -15 and -16 were capable of inducing apoptosis in drug-resistant HL60-MDR1 cells (expressing P-glycoprotein) and HL60-ABCG2 cells (expressing BCRP) with similar potencies as in parental human promyelocytic leukaemia HL60 cells. Likewise, resistance to PBOX-6 and -16 was not evident in P-glycoprotein-expressing A2780-ADR cells in comparison with parent human ovarian carcinoma A2780 cells. Finally, we deduced by molecular docking that PBOX-6 is not likely to form favourable interactions with the substrate binding site of P-glycoprotein.

CONCLUSION: Our results suggest that pro-apoptotic PBOX compounds may be potential candidates for the treatment of P-glycoprotein- or BCRP-associated MDR cancers.

Essays on James Clarence Mangan: The Man in the Cloak

This volume explores the extraordinary literary achievement of James Clarence Mangan (1803-1849), increasingly recognised as one of the most important Irish writers of the nineteenth century and a crucial influence on later writers such as W.B. Yeats and James Joyce. It is the first collection of essays to focus on Mangan, and features articles by leading scholars in the field (including Jacques Chuto and David Lloyd) as well as contributions from acclaimed contemporary writers, Paul Muldoon and Ciaran Carson. The collection expands existing fields of debate--translation, the supernatural, intertextuality, nationalism, romanticism-- and introduces new ones: Mangan's afterlife in the English literary canon, cosmopolitanism and Weltliteratur, antiquity and futurity, nineteenth-century spiritualism and magical thinking. 'The man in the cloak', one of Mangan's favourite pseudonyms, is still a a resonant soubriquet for a writer who has eluded sustained critical attention, and this volumes restores him to his proper place in European and British, as well as Irish literary history.

Fish product mislabelling: failings of traceability in the production chain and implications for illegal, unreported and unregulated (IUU) fishing

Increasing consumer demand for seafood, combined with concern over the health of our oceans, has led to many initiatives aimed at tackling destructive fishing practices and promoting the sustainability of fisheries. An important global threat to sustainable fisheries is Illegal, Unreported and Unregulated (IUU) fishing, and there is now an increased emphasis on the use of trade measures to prevent IUU-sourced fish and fish products from entering the international market. Initiatives encompass new legislation in the European Union requiring the inclusion of species names on catch labels throughout the distribution chain. Such certification measures do not, however, guarantee accuracy of species designation. Using two DNA-based methods to compare species descriptions with molecular ID, we examined 386 samples of white fish, or products labelled as primarily containing white fish, from major UK supermarket chains. Species specific real-time PCR probes were used for cod (Gadus morhua) and haddock (Melanogrammus aeglefinus) to provide a highly sensitive and species-specific test for the major species of white fish sold in the UK. Additionally, fish-specific primers were used to sequence the forensically validated barcoding gene, mitochondrial cytochrome oxidase I (COI). Overall levels of congruence between product label and genetic species identification were high, with 94.34% of samples correctly labelled, though a significant proportion in terms of potential volume, were mislabelled. Substitution was usually for a cheaper alternative and, in one case, extended to a tropical species. To our knowledge, this is the first published study encompassing a large-scale assessment of UK retailers, and if representative, indicates a potentially significant incidence of incorrect product designation.

Inbreeding uncovers fundamental differences in the genetic load affecting male and female fertility in a butterfly

Inbreeding depression is most pronounced for traits closely associated with fitness. The traditional explanation is that natural selection eliminates deleterious mutations with additive or dominant effects more effectively than recessive mutations, leading to directional dominance for traits subject to strong directional selection. Here we report the unexpected finding that, in the butterfly Bicyclus anynana, male sterility contributes disproportionately to inbreeding depression for fitness (complete sterility in about half the sons from brother-sister matings), while female fertility is insensitive to inbreeding. The contrast between the sexes for functionally equivalent traits is inconsistent with standard selection arguments, and suggests that trait-specific developmental properties and cryptic selection play crucial roles in shaping genetic architecture. There is evidence that spermatogenesis is less developmentally stable than oogenesis, though the unusually high male fertility load in B. anynana additionally suggests the operation of complex selection maintaining male sterility recessives. Analysis of the precise causes of inbreeding depression will be needed to generate a model that reliably explains variation in directional dominance and reconciles the gap between observed and expected genetic loads carried by populations. This challenging evolutionary puzzle should stimulate work on the occurrence and causes of sex differences in fertility load.

Twenty-two novel microsatellite loci for lumpfish (Cyclopterus lumpus)

Lumpfish (Cyclopterus lumpus L. 1758) are widely distributed on both sides of the North Atlantic. They are a commercially important species, but stock size estimates have declined since the mid-1980s in Canada, Norway and Iceland. Little is known about the biology of this species, in particular the breeding migrations and population structure which are fundamental for effective management. This paper describes the development and characterization of twenty-two polymorphic microsatellite loci using next generation sequencing. The number of alleles per locus ranged from 3 to 27 in two geographically distant North Atlantic populations, with observed and expected heterozygosities ranging between 0. 0625-0. 979 and 0. 0618-0. 946, respectively. These loci are an important resource that will allow assessment of the population genetic structure of this species, and contribute to its appropriate management.

Detection of quantitative trait loci for androstenone, skatole and boar taint in a cross between Large White and Meishan pigs

'Boar taint' is a strong perspiration-like, urine-like unpleasant odour given off upon heating or cooking of meat from some intact (uncastrated) male pigs. Data from the F(2) generation of a Large White (LW) x Meishan (MS) crossbred population were analysed to detect quantitative trait loci (QTL) for traits associated with boar taint. Fat samples from 178 intact male pigs slaughtered at 85 +/- 5 kg were analysed for the major contributors to boar taint (androstenone, indole and skatole). Fat and lean samples from cooked meat were scored for boar, abnormal and pork flavour and odour by a trained sensory panel (SP). A scan with 117 markers covering the whole genome was performed in the F(2) individuals, together with their F(1) parents and purebred grandparents. At the 5% chromosomal significance threshold (approximately equal to the genome-wide suggestive significance threshold), QTL were detected for the laboratory estimate of androstenone on chromosomes 2, 4, 6, 7 and 9. However, only on chromosome 6 were there QTL for boar flavour (BF) traits in the same or adjacent marker intervals as a QTL for the laboratory estimate of androstenone. On chromosome 14, QTL were detected for the laboratory estimates of indole and skatole, the SP score for skatole and the scores for BF in lean and BF in fat. In all five cases, the MS allele generally increased the estimate or score, compared with the LW allele, but it appeared that desirable and undesirable alleles were present in both breeds. This locus on chromosome 14 has considerable potential for use to reduce the incidence of boar taint, especially if further research can identify the causative polymorphism or strongly associated markers.