A pilot multicentre randomised controlled trial of lidocaine infusion in women undergoing breast cancer surgery.

Chronic postoperative pain is common after breast cancer surgery. Peri-operative lidocaine infusion may prevent the development of chronic postoperative pain, but a large-scale trial is required to test this hypothesis. It is unclear whether a pragmatic, multicentre trial design that is consistent with expert guidance, addresses the limitations of previous studies, and overcomes existing translational barriers is safe, effective and feasible. We conducted a double-blind, randomised controlled pilot study in 150 patients undergoing breast cancer surgery across three hospitals in Western Australia. Patients received lidocaine, or equivalent volumes of saline, as an intravenous bolus (1.5 mg.kg-1 ) and infusion (2 mg.kg-1 .h-1 ) intra-operatively, and a subcutaneous infusion (1.33 mg.kg-1 .h-1 ) postoperatively for up to 12 h on a standard surgical ward, with novel safety monitoring tools in place. The co-primary outcomes were: in-hospital safety events; serum levels of lidocaine during intravenous and subcutaneous infusion; and annualised enrolment rates per site with long-term data capture. In-hospital safety events were rare, and similar in the placebo and lidocaine arms (3% vs. 1%). Median (IQR [range]) serum lidocaine levels during intravenous (2.16 (1.74-2.83 [1.12-6.06]) µg.ml-1 , n = 41) and subcutaneous (1.52 (1.28-1.83 [0.64-2.85]) µg.ml-1 , n = 48) infusion were comparable with previous trials reporting improved pain outcomes. Annualised enrolment approximated 50 patients per site per year, with high levels of protocol adherence and ≥ 99% capture of outcomes at 3 and 6 months. The adjusted odds ratio (95%CI) for postoperative pain at 6 months in the lidocaine arm was 0.790 (0.370-1.684). We conclude that this trial, as designed, is safe, effective and feasible in patients undergoing breast cancer surgery, and a larger-scale trial is planned.

Dronabinol increases pain threshold in patients with functional chest pain: a pilot double-blind placebo-controlled trial.

Noncardiac chest pain is associated with poor quality of life and high care expenditure. The majority of noncardiac chest pain is either gastresophageal reflux disease related or due to esophageal motility disorders, and the rest are considered functional chest pain (FCP) due to central and peripheral hypersensitivity. Current treatment of FCP improves 40-50% of patients. Cannabinoid receptors 1 (CB1) and 2 (CB2) modulate release of neurotransmitters; CB1 is located in the esophageal epithelium and reduces excitatory enteric transmission and potentially could reduce esophageal hypersensitivity. We performed a prospective study to evaluate its effects on pain threshold, frequency, and intensity in FCP. Subjects with FCP received dronabinol (5 mg, twice daily; n = 7; average age, 44 years; mean body mass index, 26.7) or placebo (n = 6; average age, 42 years; mean body mass index, 25.9) for 28 days (4 weeks). Chest pain, general health, and anxiety/depression questionnaires were assessed at baseline and at 4 weeks. Subjects underwent an esophageal balloon distention test prior to treatment and on last day of the study. Dronabinol increased pain thresholds significantly (3.0 vs. 1.0; P = 0.03) and reduced pain intensity and odynophagia compared to placebo (0.18 vs. 0.01 and 0.12 vs. 0.01, respectively, P = 0.04). Depression and anxiety scores did not differ between the groups at baseline or after treatment. No significant adverse effects were observed. In this novel study, dronabinol increased pain threshold and reduced frequency and intensity of pain in FCP. Further, large scale studies are needed to substantiate these findings.

Baroreflex impairment and morbidity after major surgery.

BACKGROUND: Baroreflex dysfunction is a common feature of established cardiometabolic diseases that are most frequently associated with the development of critical illness. Laboratory models show that baroreflex dysfunction impairs cardiac contractility and cardiovascular performance, thereby increasing the risk of morbidity after trauma and sepsis. We hypothesized that baroreflex dysfunction contributes to excess postoperative morbidity after major surgery as a consequence of the inability to achieve adequate perioperative tissue oxygen delivery. METHODS: In a randomized controlled trial of goal-directed haemodynamic therapy (GDT) in higher-risk surgical patients, baroreflex function was assessed using the spontaneous baroreflex sensitivity (BRS) method via an arterial line placed before surgery, using a validated sequence method technique (one beat lag). The BRS was calculated during the 6 h postoperative GDT intervention. Analyses of BRS were done by investigators blinded to clinical outcomes. The primary outcome was the association between postoperative baroreflex dysfunction (BRS <6 mm Hg s(-1), a negative prognostic threshold in cardiovascular pathology) and early postoperative morbidity. The relationship between baroreflex dysfunction and postoperative attainment of preoperative indexed oxygen delivery was also assessed. RESULTS: Patients with postoperative baroreflex dysfunction were more likely to sustain infectious {relative risk (RR) 1.75 [95% confidence interval (CI): 1.07-2.85], P=0.02} and cardiovascular morbidity [RR 2.39 (95% CI: 1.22-4.71), P=0.008]. Prolonged hospital stay was more likely in patients with baroreflex dysfunction [unadjusted hazard ratio 1.62 (95% CI: 1.14-2.32), log-rank P=0.004]. Postoperative O2 delivery was 36% (95% CI: 7-65) lower in patients with baroreflex dysfunction in those not randomly assigned to GDT (P=0.02). CONCLUSIONS: Baroreflex dysfunction is associated with excess morbidity, impaired cardiovascular performance, and delayed hospital discharge, suggesting a mechanistic role for autonomic dysfunction in determining perioperative outcome. CLINICAL TRIAL REGISTRATION: ISCRTN76894700.

The novel toluidine sulphonamide EL102 shows pre-clinical in vitro and in vivo activity against prostate cancer and circumvents MDR1 resistance.

BACKGROUND: Taxanes are routinely used for the treatment of prostate cancer, however the majority of patients eventually develop resistance. We investigated the potential efficacy of EL102, a novel toluidine sulphonamide, in pre-clinical models of prostate cancer. METHODS: The effect of EL102 and/or docetaxel on PC-3, DU145, 22Rv1 and CWR22 prostate cancer cells was assessed using cell viability, cell cycle analysis and PARP cleavage assays. Tubulin polymerisation and immunofluorescence assays were used to assess tubulin dynamics. CWR22 xenograft murine model was used to assess effects on tumour proliferation. Multidrug-resistant lung cancer DLKPA was used to assess EL102 in a MDR1-mediated drug resistance background. RESULTS: EL102 has in vitro activity against prostate cancer, characterised by accumulation in G2/M, induction of apoptosis, inhibition of Hif1α, and inhibition of tubulin polymerisation and decreased microtubule stability. In vivo, a combination of EL102 and docetaxel exhibits superior tumour inhibition. The DLKP cell line and multidrug-resistant DLKPA variant (which exhibits 205 to 691-fold greater resistance to docetaxel, paclitaxel, vincristine and doxorubicin) are equally sensitive to EL102. CONCLUSION: EL102 shows potential as both a single agent and within combination regimens for the treatment of prostate cancer, particularly in the chemoresistance setting.

Troponin in critically ill patients.

Assays of cardiac troponin have become a cornerstone in the diagnosis of myocardial infarction across a broad range of clinical settings. In critically ill patients, cardiac troponin is detectable in the plasma in up to 60% of cases, and this incidence may increase further as assays become more sensitive. Troponin rises in critical care are commonly unrelated to pathology in the coronary arteries, but are frequently associated with conditions such as sepsis and respiratory failure. Such non-coronary troponin release is a significant, independent predictor of poor patient outcomes, and can be incorporated into risk scoring systems. Despite adding prognostic value, treatment for non-coronary troponin rises remains limited to management of the underlying cause, and restoration of a favourable balance between myocardial oxygen demand and supply. Conversely, troponin rises secondary to myocardial infarctions are amenable to the same interventions as in any other setting, albeit with additional diagnostic and therapeutic challenges. In this review, we will explore the utility of troponin as a biomarker in critical care, and we will outline a pragmatic management strategy for this patient population.

Low vision service delivery: an audit of newly developed outreach clinics in Northern Ireland.

Recent publications recommend that low vision services are multi-professional; easily accessible; freely available to all those with visual impairment; monitored by professional and patient groups, and responsive to user feedback. These standards were applied when developing low vision outreach services in Northern Ireland in 1999/2000. Results are reported of the complete clinical audit cycle, coupled with a patient satisfaction telephone questionnaire, which was used to evaluate the service. Of the 48 patients randomly selected from the list of clinic attendees, 28 (58%) were female, 27 (56%) over 80 years of age and 38 (78%) had a primary ocular diagnosis of age related macular degeneration (AMD). Of the 46 low vision aids issued at patients' first appointments, 30 (67%) were illuminated stand magnifiers and 29 (63%) had magnification levels of x5 or less. A total of 46 (96%) patients reported that they had benefited from low vision services.

Preparation and characterization of ruthenium(II) monophosphaferrocene complexes. Reactivity, dynamic solution behavior, and X-ray structure of [RuH(2)(eta(2)-H(2))(PCy(3))2(2-phenyl-3,4-dimethylphosphaferrocene)].

The bis(dihydrogen) complex RuH(2)(H(2))(2)(PCy(3))(2) (1) reacts with 2-phenyl-3,4-dimethylphosphaferrocene (L(1)) to give RuH(2)(H(2))(PCy(3))(2)(L(1)) (2). This dihydride-dihydrogen complex has been characterized by X-ray crystallography and variable-temperature (1)H and (31)P NMR spectroscopy. The exchange between the dihydrogen ligand and the two hydrides is characterized by a DeltaG() of 46.2 kJ/mol at 263 K. H/D exchange is readily observed when heating a C(7)D(8) solution of 2 (J(H-D) = 30 Hz). The H(2) ligand in 2 can be displaced by ethylene or carbon monoxide leading to the corresponding ethylene or carbonyl complexes. The reaction of 1 with 2 equiv of 3,4-dimethylphosphaferrocene (L(2)) yields the dihydride complex RuH(2)(PCy(3))(2)(L(2))(2) (5).

Contributions to somatic and germline lineages of chicken blastodermal cells maintained in culture.

Chicken blastodermal cells were cultured for 48 hr as explanted intact embryos, as dispersed cells in a monolayer, or with a confluent layer of mouse fibroblasts. The cells were then dispersed and injected into stage X (E-G&K) recipient embryos that were exposed to 600 rads of irradiation from a 60Co source. Regardless of the conditions in which the cells were cultured, chimeras with contributions to both somatic tissues and the germline were observed. When blastodermal cells were co-cultured with mouse embryonic fibroblasts, significantly more somatic chimeras were observed and the proportion of feather follicles derived from donor cells was increased relative to that observed following the injection of cells derived from explanted embryos or monolayer cultures. Culture of blastodermal cells in any of the systems, however, yielded fewer chimeras that exhibited reduced contributions to somatic tissues in comparison to the frequency and extent of somatic chimerism observed following injection of freshly prepared cells. Contributions to the germline were observed at an equal frequency regardless of the conditions of culture, but were significantly reduced in comparison to the frequency and rate of germline transmission following injection of cells obtained directly from stage X (E-G&K) embryos. These data demonstrate that some cells retain the ability to contribute to germline and somatic tissues after 48 hr in culture and that the ability to contribute to the somatic and germline lineages is not retained equally.

Chimeric chickens and their use in manipulation of the chicken genome.

Germline chimeric chickens can be made by injecting dispersed cells from Stage X blastoderms into recipient embryos at an equivalent stage of development. Colonization of the chimera by donor-derived cells is facilitated when the recipient embryo is compromised by exposure to irradiation prior to injection of the donor cells. Donor cells can be genetically manipulated by lipofection-mediated gene transfer before they are introduced into the recipient. The genetic modification is expressed in the ectoderm, mesoderm, and endoderm of the chimera after incubation for 96 h. Donor cells can also be cultured as dispersed cells in a monolayer or as whole-embryo explants for at least 48 h before transfer into recipients and retain the ability to enter both somatic and germline tissues in the resulting chimera. A strategy is proposed for the production of transgenic chickens using lipofection-mediated gene transfer to blastoderm cells isolated from Stage X embryos, which are subsequently injected into compromised recipients to yield a germline chimera.