Leicester Royal Infirmary

About: Leicester Royal Infirmary is a healthcare organization based out in Leicester, United Kingdom. It is known for research contribution in the topics: Population & Carotid endarterectomy. The organization has 5300 authors who have published 6204 publications receiving 208464 citations.

Functional plasticity of the N/OFQ‐NOP receptor system determines analgesic properties of NOP receptor agonists

Abstract: Despite high sequence similarity between NOP (nociceptin/orphanin FQ opioid peptide) and opioid receptors, marked differences in endogenous ligand selectivity, signal transduction, phosphorylation, desensitization, internalization and trafficking have been identified; underscoring the evolutionary difference between NOP and opioid receptors. Activation of NOP receptors affects nociceptive transmission in a site-specific manner, with antinociceptive effects prevailing after peripheral and spinal activation, and pronociceptive effects after supraspinal activation in rodents. The net effect of systemically administered NOP receptor agonists on nociception is proposed to depend on the relative contribution of peripheral, spinal and supraspinal activation, and this may depend on experimental conditions. Functional expression and regulation of NOP receptors at peripheral and central sites of the nociceptive pathway exhibits a high degree of plasticity under conditions of neuropathic and inflammatory pain. In rodents, systemically administered NOP receptor agonists exerted antihypersensitive effects in models of neuropathic and inflammatory pain. However, they were largely ineffective in acute pain while concomitantly evoking severe motor side effects. In contrast, systemic administration of NOP receptor agonists to non-human primates (NHPs) exerted potent and efficacious antinociception in the absence of motor and sedative side effects. The reason for this species difference with respect to antinociceptive efficacy and tolerability is not clear. Moreover, co-activation of NOP and μ-opioid peptide (MOP) receptors synergistically produced antinociception in NHPs. Hence, both selective NOP receptor as well as NOP/MOP receptor agonists may hold potential for clinical use as analgesics effective in conditions of acute and chronic pain.

The Townes-Brocks syndrome.

Abstract: The Townes-Brocks syndrome derives its eponymous title from the names of the two authors who, in 1972, described variable anal, hand, foot, and ear anomalies in a father and five of his seven children.' Shortly afterwards, similar abnormalities were documented in 19 subjects from four generations of a large Australian family.2 Subsequent reports of both familial3-6 and isolated6-9 cases have established the Townes-Brocks syndrome as a discrete entity and enabled fuller delineation of the phenotype of what appears to be a relatively rare disorder. Individual patients or families or both have been reported from North America, 3 6 8 Australia,2 4 Belgium,5 Brazil,7 and Portugal.9

Diagnosis of heart failure using urinary natriuretic peptides.

Abstract: In the present study, we assessed the use of urinary natriuretic peptides [N-terminal proatrial natriuretic peptide (N-ANP) and N-terminal pro-brain natriuretic peptide (N-BNP) and C-type natriuretic peptide (CNP)] in the diagnosis of heart failure. Thirty-four consecutive hospitalized heart failure patients (median age, 75.5 years; 14 female) were compared with 82 age- and gender-matched echocardiographically normal controls. All subjects provided plasma and urine specimens. Plasma was assayed for N-BNP, and urine was assayed for N-ANP, N-BNP and CNP. The diagnostic efficiency of peptides was assessed using receiver operating characteristic (ROC) curve analysis. All three urinary natriuretic peptides were significantly elevated in heart failure patients ( P <0.001). Urine N-BNP was correlated with plasma N-BNP ( r (s)=0.53, P <0.0005). Areas under the ROC curves for urinary N-ANP, N-BNP and CNP were 0.86, 0.93 and 0.70 and for plasma N-BNP was 0.96. Correcting urinary peptide levels using urine creatinine produced ROC areas of 0.89, 0.93 and 0.76 respectively. A urine N-BNP level cut-off point of 11.6 fmol/ml had a sensitivity and specificity for heart failure detection of 97% and 78% respectively, with positive and negative predictive values of 64.7 and 98%. In conclusion, although all three natriuretic peptides were elevated in urine in heart failure, urinary N-BNP had diagnostic accuracy comparable with plasma N-BNP. Use of urinary N-BNP for heart failure diagnosis may be suitable for high-throughput screening, especially in subjects reluctant to provide blood samples.

Primary breast myoepithelial cells exert an invasion-suppressor effect on breast cancer cells via paracrine down-regulation of MMP expression in fibroblasts and tumour cells

Abstract: In normal breast and ductal carcinoma in situ, myoepithelial cells form an incomplete layer separating the epithelial compartment from the stromal environment Transition to invasive disease is marked by penetration of the myoepithelial-basement membrane (BM) interface One mechanism involved in tumour invasion is breakdown of extracellular matrices by matrix metalloproteinases (MMPs) It was hypothesized that myoepithelial cells may modulate tumour invasion by controlling MMP gene expression, both in tumour cells and in peri-ductal fibroblasts To investigate this, myoepithelial cells from normal breast were purified and characterized and their effect on tumour cell invasive potential was assessed The effect on MMP gene expression of breast cancer cells cultured alone or in combination with primary normal breast fibroblasts was also analysed using RT-PCR with ELISA quantitation, with zymographic analysis to measure enzyme activity Normal breast myoepithelial cells significantly reduced invasion by the breast cancer cell lines MCF-7, T47D, MDA-MB 231, and MDA-MB 468 when they were cultured alone or in the presence of a fibroblast population Reduced invasion was associated with changes in MMP gene expression In those tumour cells expressing MMP, there was a significant down-regulation of MMP-2 (MDA-MB 468, p<0001), MMP-9 (MDA-MB 231, p=005; MDA-MB 468, p<0001), and MT1-MMP (p<0001 for both MDA-MB 231 and MDA-MB 468) Myoepithelial cells also caused a significant decrease in MMP gene expression in co-cultured fibroblasts Furthermore, this was associated with reduced gelatinolytic activity as identified by zymography This study demonstrates for the first time that primary myoepithelial cells from normal breast reduce breast cancer cell invasion and that this is mediated via modulation of both tumour cell and fibroblast function This emphasizes the importance of the myoepithelial cell in controlling the breast microenvironment and focuses on the potential significance of the loss of this population with disease progression

Rechallenge with clozapine following leucopenia or neutropenia during previous therapy.

Abstract: Background Further treatment with clozapine is contraindicated in any patient who has previously experienced leucopenia or neutropenia during clozapine therapy. Aims To investigate the results of such a rechallenge in 53 patients. Method An analysis was made of the demographic, haematological and outcome data of patients in the UK and Ireland who were rechallenged with clozapine following leucopenia or neutropenia during previous clozapine therapy. Results Of 53 patients who were rechallenged, 20 (38%) experienced a further blood dyscrasia. In 17 of these 20 patients (85%) the second blood dyscrasia was more severe ( P <0.001), in 12 (60%) it lasted longer ( P =0.0368) and in 17 (85%) it occurred more quickly on rechallenge ( P <0.001). Of the original 53 patients, 55% (29 patients) are still receiving clozapine. Conclusions No clear risk factor for repeat blood dyscrasias was identified. Despite this, after risks and benefits have been considered, rechallenge may well be justified in some patients.