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Background. Assessment of the ratio between tumour volume and breast volume in therapeutic mammoplasty is paramount. Traditionally based on clinical assessment and conventional breast imaging, the role of breast magnetic resonance imaging (MRI) in this context has not been established. Methods. Data was collected from all women undergoing therapeutic mammoplasty (TM) between 2006 and 2011. Each case was discussed at an MDT where MRI was considered to facilitate surgical planning. The contribution of MRI to disease assessment and surgical outcome was then reviewed. Results. 35 women underwent TM, 15 of whom had additional MRI. 33% of patients within the MRI subgroup had abnormalities not seen on either mammography or USS. Of those undergoing MRI, 1/15 patients required completion mastectomy versus 3 patients requiring completion mastectomy and 1 patient requiring further wide local excision (4/20) in the conventional imaging group. No statistical difference was seen between size on MRI and size on mammography versus final histological size, but a general trend for greater correlation between size on MRI and final histological size was seen. Conclusion. MRI should be considered in selected patients undergoing therapeutic mammoplasty. Careful planning can identify those who are most likely to benefit from MRI, potentially reducing the need for further surgery. [ABSTRACT FROM AUTHOR]

Abstract: Clinically, inflammatory pain is far more persistent than that typically modelled pre-clinically, with the majority of animal models focussing on short-term effects of the inflammatory pain response. The large attrition rate of compounds in the clinic which show pre-clinical efficacy suggests the need for novel models of, or approaches to, chronic inflammatory pain if novel mechanisms are to make it to the market. A model in which a more chronic inflammatory hypersensitivity phenotype is profiled may allow for a more clinically predictive tool. The aims of these studies were to characterise and validate a chronic model of inflammatory pain. We have shown that injection of a large volume of adjuvant to the intra-articular space of the rat knee results in a prolonged inflammatory pain response, compared to the response in an acute adjuvant model. Additionally, this model also results in a hypersensitive state in the presence and absence of inflammation. A range of clinically effective analgesics demonstrate activity in this chronic model, including morphine (3mg/kg, t.i.d.), dexamethasone (1mg/kg, b.i.d.), ibuprofen (30mg/kg, t.i.d.), etoricoxib (5mg/kg, b.i.d.) and rofecoxib (0.3–10mg/kg, b.i.d.). A further aim was to exemplify the utility of this chronic model over the more acute intra-plantar adjuvant model using two novel therapeutic approaches; NR2B selective NMDA receptor antagonism and iNOS inhibition. Our data shows that different effects were observed with these therapies when comparing the acute model with the model of chronic inflammatory joint pain. These data suggest that the chronic model may be more relevant to identifying mechanisms for the treatment of chronic inflammatory pain states in the clinic. [Copyright &y& Elsevier]

Large conductance calcium-activated potassium (BKCa) channels are regulated by a number of different protein kinases and phosphatases. The close association of enzymes and channel have been shown to underlie many examples of modulation. However, only the association of protein kinase A with the BKCa channel has been detailed [ Tian et al. (2003) J. Biol. Chem., 278, 8669–8677]. We have found using reciprocal immunoprecipitations that the BKCa channel associates with the calcium/calmodulin-dependent phosphatase calcineurin, in Wistar rat brain. A HA-tagged construct of the carboxyl terminus of rSlo27, a variant of the BKCa channel that is abundant in the hippocampus [ Ha et al. (2000) Eur. J. Biochem., 267, 910–9218], was found to associate only with the B subunit of calcineurin. This data suggests that the majority of the interaction of the BKCa channel with calcineurin is mediated by the B subunit of the phosphatase. This was confirmed by using glutathione- S-transferase (GST) fusion proteins of the linker regions between the S7–S10 hydrophobic domains in the carboxyl terminus of rSlo27, where only the B subunit of calcineurin interacted with regions between S7 and S9 of the channel. Addition of a constitutively active calcineurin (CaN420) to inside-out membrane patches excised from cultured hippocampal neurons resulted in a dramatic reduction in BKCa channel open probability, with only very short-duration events being apparent. These data suggest that BKCa channel activity is inhibited by calcineurin, an effect mediated by the association of the calcineurin B subunit with the carboxyl terminus of the channel. [ABSTRACT FROM AUTHOR]

Lumbar splanchnic (LSN) and sacral pelvic (PN) nerves convey different mechanosensory information from the colon to the spinal cord. Here we determined whether these pathways also differ in their chemosensitivity and receptor expression. Using an in vitro mouse colon preparation, individual primary afferents were tested with selective P2X and transient receptor potential vanilloid receptor 1 (TRPV1) receptor ligands. Afferent cell bodies in thoracolumbar and lumbosacral dorsal root ganglia (DRG) were retrogradely labelled from the colon and analysed for P2X3- and TRPV1-like immunoreactivity (LI). Forty per cent of LSN afferents responded to α,β-methylene adenosine 5′-triphosphate (α,β-meATP; 1 m m), an effect that was concentration dependent and reversed by the P2X antagonist pyridoxyl5-phosphate 6-azophenyl-2′,4′-disulphonic acid (PPADS) (100 μ m). Significantly fewer PN afferents (7%) responded to α,β-meATP. Correspondingly, 36% of colonic thoracolumbar DRG neurones exhibited P2X3-LI compared with only 19% of colonic lumbosacral neurones. Capsaicin (3 μ m) excited 61% of LSN afferents and 47% of PN afferents; 82% of thoracolumbar and 50% of lumbosacral colonic DRG neurones displayed TRPV1-LI. Mechanically insensitive afferents were recruited by α,β-meATP or capsaicin, and were almost exclusive to the LSN. Capsaicin-responsive LSN afferents displayed marked mechanical desensitization after responding to capsaicin, which did not occur in capsaicin-responsive PN afferents. Therefore, colonic LSN and PN pathways differ in their chemosensitivity to known noxious stimuli and their corresponding receptor expression. As these pathways relay information that may relate to symptoms in functional gastrointestinal disease, these results may have implications for the efficacy of therapies targeting receptor modulation. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the contribution of the TRPV1 receptor to jejunal afferent sensitivity in the murine intestine. Multiunit activity was recorded in vitro from mesenteric afferents supplying segments of mouse jejunum taken from wild-type (WT) and TRPV1 knockout (TRPV1-/-) animals. In WT preparations, ramp distension of the gut (up to 60 mmHg) produced biphasic changes in afferent activity so the pressure-response curve had an initial rapid increase in afferent discharge followed by a second phase of slower increase in activity. Afferent response to distension was significantly lower in TRPV1-/- than in WT mice. Single-unit analysis revealed three functional types of afferent fibres: (1) low-threshold fibres (2) wide dynamic range fibres and (3) high-threshold fibres. There was a marked downward shift of the pressure-response curve for wide dynamic range fibres in the TRPV1-/- mice as compared to the WT controls. The afferent response to intraluminal hydrochloric acid (20 mM) was also attenuated in the TRPV1-/- mice. In contrast, the response to bath application of bradykinin (1 µM, 3 ml) was not significantly different between the two groups. The TRPV1 antagonist capsazepine (10 µM) significantly attenuated the nerve responses to distension, intraluminal acid and bradykinin, as well as the spontaneous discharge in WT mice. The WT jejunal afferents responded to capsaicin with rapid increases in afferent activity, whereas TRPV1-/- afferents were not at all sensitive to capsaicin. Previous evidence indicates that TRPV1 is not mechanosensitive, so the results of the present study suggest that activation of TRPV1 may sensitize small intestinal afferent neurones. [ABSTRACT FROM AUTHOR]