On the intersystem crossing rate in a Platinum(II) donor-bridge-acceptor triad.

The rates of ultrafast intersystem crossing in acceptor-bridge-donor molecules centered on Pt(II) acetylides are investigated. Specifically, a Pt(II) trans-acetylide triad NAP--Pt--Ph-CH2-PTZ [1], with acceptor 4-ethynyl-N-octyl-1,8-naphthalimide (NAP) and donor phenothiazine (PTZ), is examined in detail. We have previously shown that optical excitation in [1] leads to a manifold of singlet charge-transfer states, S*, which evolve via a triplet charge-transfer manifold into a triplet state 3NAP centered on the acceptor ligand and partly to a charge-separated state 3CSS (NAP--Pt-PTZ+). A complex cascade of electron transfer processes was observed, but intersystem crossing (ISC) rates were not explicitly resolved due to lack of spin selectivity of most ultrafast spectroscopies. Here we revisit the question of ISC with a combination and complementary analysis of (i) transient absorption, (ii) ultrafast broadband fluorescence upconversion, FLUP, which is only sensitive to emissive states, and (iii) femtosecond stimulated Raman spectroscopy, FSR. Raman resonance conditions allow us to observe S* and 3NAP exclusively by FSR, through vibrations which are pertinent only to these two states. This combination of methods enabled us to extract the intersystem crossing rates that were not previously accessible. Multiple timescales (1.6 ps to ∼20 ps) are associated with the rise of triplet species, which can now be assigned conclusively to multiple ISC pathways from a manifold of hot charge-transfer singlet states. The analysis is consistent with previous transient infrared spectroscopy data. A similar rate of ISC, up to 20 ps, is observed in the trans-acetylide NAP--Pt--Ph [2] which maintains two acetylide groups across the platinum center but lacks a donor unit, whilst removal of one acetylide group in mono-acetylide NAP--Pt-Cl [3] leads to >10-fold deceleration of the intersystem crossing process. Our work provides insight on the intersystem crossing dynamics of the organo-metallic complexes, and identifies a general method based on complementary ultrafast spectroscopies to disentangle complex spin, electronic and vibrational processes following photoexcitation.

The effect of an ultrasound-activated needle tip tracker needle on the performance of sciatic nerve block on a soft embalmed Thiel cadaver.

In this study, we measured the performance of medical students and anaesthetists using a new tracker needle during simulated sciatic nerve block on soft embalmed cadavers. The tracker needle incorporates a piezo element near its tip that generates an electrical signal in response to insonation. A circle, superimposed on the ultrasound image surrounding the needle tip, changes size and colour according to the position of the piezo element within the ultrasound beam. Our primary objective was to compare sciatic block performance with the tracker switched on and off. Our secondary objectives were to record psychometrics, procedure efficiency, participant self-regulation and focused attention using eye-tracking technology. Our primary outcome measures were the number of steps successfully performed and the number of errors committed during each block. Videos were scored by trained experts using validated checklists. Sequential tracker activation and deactivation was randomised equally within subjects. With needle activation, steps improved in 10 (25%) subjects and errors reduced in six (15%) subjects. The most important steps were: needle tip identification before injection, OR (95%CI) 2.12 (1.61-2.80; p < 0.001); and needle tip identification before advance of the needle, 1.80 (1.36-2.39; p < 0.001). The most important errors were: failure to identify the needle tip before injection, 2.40 (1.78-3.24; p < 0.001); and failure to quickly regain needle tip position when tip visibility was lost, 2.03 (1.5-2.75; p < 0.001). In conclusion, needle-tracking technology improved performance in a quarter of subjects.

An initial evaluation of the effect of a novel regional block needle with tip-tracking technology on the novice performance of cadaveric ultrasound-guided sciatic nerve block.

Visibility of the needle tip is difficult to maintain during ultrasound-guided nerve block. A new needle has been developed that incorporates a piezo element 2-2.3 mm from the tip, activated by ultrasound. The electrical signal manifests as a coloured circle surrounding the needle tip, and allows real-time tracking. We hypothesised that novice regional anaesthetists would perform nerve block better with the tracker turned on rather than off. Our primary objective was to evaluate the new needle by measuring the performance of novice anaesthetists conducting simulated sciatic block on the soft embalmed Thiel cadaver. Training consisted of a lecture, scanning in volunteers and practice on cadavers. Testing entailed scanning the sciatic nerve of a cadaver and conducting 20 in-plane sciatic blocks in the mid-to-upper thigh region. Subjects were randomised equally, in groups of five, according to the sequence: tracker on/off/on/off; or tracker off/on/off/on. Video recordings were assessed by six raters for steps performed correctly and errors committed. Eight subjects were recruited and 160 videos were analysed. Using the tracking needle, five correct steps improved and one error reduced. The benefits included: better identification of the needle tip before advancing the needle, OR (95%CI) 3.4 (1.6-7.7; p < 0.001); better alignment of the needle to the transducer, 3.1 (1.3-8.7; p = 0.009); and better visibility of the needle tip 3.0 (1.4-7.3; p = 0.005). In conclusion, use of the tracker needle improved the sciatic block performance of novices on the soft embalmed cadaver.

Defining sepsis on the wards: results of a multi-centre point-prevalence study comparing two sepsis definitions.

Our aim was to prospectively determine the predictive capabilities of SEPSIS-1 and SEPSIS-3 definitions in the emergency departments and general wards. Patients with National Early Warning Score (NEWS) of 3 or above and suspected or proven infection were enrolled over a 24-h period in 13 Welsh hospitals. The primary outcome measure was mortality within 30 days. Out of the 5422 patients screened, 431 fulfilled inclusion criteria and 380 (88%) were recruited. Using the SEPSIS-1 definition, 212 patients had sepsis. When using the SEPSIS-3 definitions with Sequential Organ Failure Assessment (SOFA) score ≥ 2, there were 272 septic patients, whereas with quickSOFA score ≥ 2, 50 patients were identified. For the prediction of primary outcome, SEPSIS-1 criteria had a sensitivity (95%CI) of 65% (54-75%) and specificity of 47% (41-53%); SEPSIS-3 criteria had a sensitivity of 86% (76-92%) and specificity of 32% (27-38%). SEPSIS-3 and SEPSIS-1 definitions were associated with a hazard ratio (95%CI) 2.7 (1.5-5.6) and 1.6 (1.3-2.5), respectively. Scoring system discrimination evaluated by receiver operating characteristic curves was highest for Sequential Organ Failure Assessment score (0.69 (95%CI 0.63-0.76)), followed by NEWS (0.58 (0.51-0.66)) (p < 0.001). Systemic inflammatory response syndrome criteria (0.55 (0.49-0.61)) and quickSOFA score (0.56 (0.49-0.64)) could not predict outcome. The SEPSIS-3 definition identified patients with the highest risk. Sequential Organ Failure Assessment score and NEWS were better predictors of poor outcome. The Sequential Organ Failure Assessment score appeared to be the best tool for identifying patients with high risk of death and sepsis-induced organ dysfunction.

Brominated flame retardants in Canadian chicken egg yolks.

Chicken eggs categorised as conventional, omega-3 enriched, free range and organic were collected at grading stations in three regions of Canada between 2005 and 2006. Free run eggs, which were only available for collection from two regions, were also sampled during this time frame. Egg yolks from each of these egg types (n = 162) were analysed to determine brominated flame retardant levels, specifically polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD). PBDEs were detected in 100% of the 162 samples tested, while HBCD was observed in 85% of the egg yolks. Total PBDE concentrations in egg yolks ranged from 0.018 to 20.9 ng g(-1) lipid (median = 3.03 ng g(-1) lipid), with PBDE 209 identified as being the major contributor to ΣPBDE concentrations. In addition to PBDE 209, PBDE 99, 47, 100, 183 and 153 were important contributors to ΣPBDE concentrations. Total HBCD concentrations ranged from below the limit of detection to a maximum concentration of 71.9 ng g(-1) lipid (median = 0.053 ng g(-1) lipid). The α-isomer was the dominant contributor to ΣHBCD levels in Canadian egg yolks and was the most frequently detected HBCD isomer. ΣPBDE levels exhibited large differences in variability between combinations of region and type. ΣHBCD concentrations were not significantly different among regions, although differences were observed between the different types of egg yolks analysed in the present study.

Use of global gene expression patterns in mechanistic studies of oestrogen action in MCF7 human breast cancer cells.

Over the years, the MCF7 human breast cancer cell line has provided a model system for the study of cellular and molecular mechanisms in oestrogen regulation of cell proliferation and in progression to oestrogen and antioestrogen independent growth. Global gene expression profiling has shown that oestrogen action in MCF7 cells involves the coordinated regulation of hundreds of genes across a wide range of functional groupings and that more genes are downregulated than upregulated. Adaptation to long-term oestrogen deprivation, which results in loss of oestrogen-responsive growth, involves alterations to gene patterns not only at early time points (0-4 weeks) but continuing through to later times (20-55 weeks), and even involves alterations to patterns of oestrogen-regulated gene expression. Only 48% of the genes which were regulated > or =2-fold by oestradiol in oestrogen-responsive cells retained this responsiveness after long-term oestrogen deprivation but other genes developed de novo oestrogen regulation. Long-term exposure to fulvestrant, which resulted in loss of growth inhibition by the antioestrogen, resulted in some very large fold changes in gene expression up to 10,000-fold. Comparison of gene profiles produced by environmental chemicals with oestrogenic properties showed that each ligand gave its own unique expression profile which suggests that environmental oestrogens entering the human breast may give rise to a more complex web of interference in cell function than simply mimicking oestrogen action at inappropriate times.

Structure and function of the protein kinase R.

The protein kinase R (PKR) is an intracellular sensor of stress, exemplified by viral infection. Double-stranded (ds) RNA produced during viral replication activates PKR, which in turn arrests protein synthesis by phosphorylating the alpha subunit of the translation initiation factor eIF2. As well as dsRNA, two additional ligands, PACT and heparin, directly activate the kinase. These mediate the response of PKR to additional indirect stimuli, including bacterial lipopolysaccharides, ceramide and polyanionic molecules. This responsiveness to multiple stimuli advocates a broader role for PKR as a signalling molecule for diverse physiological stresses. Appropriately, a number of other protein substrates have been reported for PKR. These substrates support additional roles for PKR in the regulation of transcription and signal transduction in infected cells, as well as uninfected but diseased tissues, such as in tumorigenesis and neurodegenerative diseases. Finally, PKR plays a role in normal cell differentiation in platelet-derived growth factor signalling and in osteoblast-mediated calcification.

Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells.

Since the alkyl esters of p-hydroxybenzoic acid (parabens) can be measured intact in the human breast and possess oestrogenic properties, it has been suggested that they could contribute to an aberrant burden of oestrogen signalling in the human breast and so play a role in the rising incidence of breast cancer. However, although parabens have been shown to regulate a few single genes (reporter genes, pS2, progesterone receptor) in a manner similar to that of 17beta-oestradiol, the question remains as to the full extent of the similarity in the overall gene profile induced in response to parabens compared with 17beta-oestradiol. The GE-Amersham CodeLink 20 K human expression microarray system was used to profile the expression of 19881 genes in MCF7 human breast cancer cells following a 7-day exposure to 5 x 10(-4) M methylparaben, 10(-5) M n-butylparaben and 10(-8) M 17beta-oestradiol. At these concentrations, the parabens gave growth responses in MCF7 cells of similar magnitude to 17beta-oestradiol. The study identified genes which are upregulated or downregulated to a similar extent by methylparaben, n-butylparaben and 17beta-oestradiol. However, the majority of genes were not regulated in the same way by all three treatments. Some genes responded differently to parabens from 17beta-oestradiol, and furthermore, differences in expression of some genes could be detected even between the two individual parabens. Therefore, although parabens possess oestrogenic properties, their mimicry in terms of global gene expression patterns is not perfect and differences in gene expression profiles could result in consequences to the cells that are not identical to those following exposure to 17beta-oestradiol.

Changes in oestrogen receptor-alpha and -beta during progression to acquired resistance to tamoxifen and fulvestrant (Faslodex, ICI 182,780) in MCF7 human breast cancer cells.

Cell culture models of antioestrogen resistance often involve applying selective pressures of oestrogen deprivation simultaneously with addition of tamoxifen or fulvestrant (Faslodex, ICI 182,780) which makes it difficult to distinguish events in development of antioestrogen resistance from those in loss of response to oestrogen or other components. We describe here time courses of loss of antioestrogen response using either oestrogen-maintained or oestrogen-deprived MCF7 cells in which the only alteration to the culture medium was addition of 10(-6) M tamoxifen or 10(-7) M fulvestrant. In both oestrogen-maintained and oestrogen-deprived models, loss of growth response to tamoxifen was not associated with loss of response to fulvestrant. However, loss of growth response to fulvestrant was associated in both models with concomitant loss of growth response to tamoxifen. Measurement of oestrogen receptor alpha (ERalpha) and oestrogen receptor beta (ERbeta) mRNA by real-time RT-PCR together with ERalpha and ERbeta protein by Western immunoblotting revealed substantial changes to ERalpha levels but very little alteration to ERbeta levels following development of antioestrogen resistance. In oestrogen-maintained cells, tamoxifen resistance was associated with raised levels of ERalpha mRNA/protein. However by contrast, in oestrogen-deprived MCF7 cells, where oestrogen deprivation alone had already resulted in increased levels of ERalpha mRNA/protein, long-term tamoxifen exposure now reduced ERalpha levels. Whilst long-term exposure to fulvestrant reduced ERalpha mRNA/protein levels in the oestrogen-maintained cells to a level barely detectable by Western immunoblotting and non-functional in inducing gene expression (ERE-LUC reporter or pS2), in oestrogen-deprived cells the reduction was much less substantial and these cells retained an oestrogen-induction of both the ERE-LUC reporter gene and the endogenous pS2 gene which could still be inhibited by antioestrogen. This demonstrates that whilst ERalpha can be abrogated by fulvestrant and increased by tamoxifen in some circumstances, this does not always hold true and mechanisms other than alteration to ER must be involved in the development of antioestrogen resistant growth.

The military environment: risk factors for women's non-fatal assaults.

Little is known regarding environmental exposures for non-fatal violence toward women in the workplace. We sought to identify factors associated with non-fatal physical assault occurring to women during military service. A cross-sectional telephone survey of a national sample of 558 women veterans who served in Vietnam and subsequent eras of military service was conducted; 537 women were interviewed. Twenty-three percent experienced non-fatal physical assault during military service. Rates of assault were consistent across eras of service. Military environmental exposures, including sexual harassment allowed by officers (P < 0.0001) and unwanted sexual advances while on duty (P < .0001) and in sleeping quarters (P < 0.0001), were independent risk factors for assault. Environmental factors in the military workplace, including leadership behavior, appeared to promote violence toward military women. Such occupational factors can be identified and should be eliminated.

Health-related consequences of physical and sexual violence: women in the military.

OBJECTIVES: To identify differences in health-related quality of life among women veterans who were raped, physically assaulted (not in the context of rape or domestic violence), both, or neither during military service. METHODS: We did a cross-sectional telephone survey of a national sample of 558 women veterans who served in Vietnam and subsequent eras of military service. A stratified survey design selected subjects according to era of service and location. The interview included socioeconomic information, lifetime violence history, the Women's Military Environment Survey to assess women's military experiences, and the Medical Outcomes Study Short Form-36 to assess health-related quality of life. RESULTS: Five hundred thirty-seven women completed the interview. Half (48%) experienced violence during military service, including rape (30%), physical assault (35%), or both (16%). Women who were raped or dually victimized were more likely to report chronic health problems, prescription medication use for emotional problems, failure to complete college, and annual incomes less than $25,000 (P <.05). Women who were physically assaulted or raped reported significantly lower health-related quality of life (P <.05). Those who had both traumas reported the most severe impairment, comparable to women with chronic illnesses. CONCLUSION: This study suggests that the sequelae of violence against women are an important public health concern. More than a decade after rape or physical assault during military service, women reported severely decreased health-related quality of life, with limitations of physical and emotional health, educational and financial attainment, and severe, recurrent problems with work and social activities.

Cerebral asymmetries in inspection time?

Recent studies have suggested that there are low-level processing asymmetries across the cerebral hemispheres, with a right visual field-left hemisphere advantage in tasks involving temporal resolution. In the present report, one such task, inspection time, was measured separately for each cerebral hemisphere in 10 right-handed male subjects over 5 days. A number of methodological improvements were made on previous studies in which a general right visual field-left hemisphere advantage had been found relative to the left visual field-right hemisphere in inspection time performance. The present results suggest that there is no general left hemisphere advantage in inspection time, although there might be asymmetries in practice effects across the hemispheres. The findings also suggest the existence of individual differences in the extent and direction of hemispheric specialisation for this task (ranging from left hemisphere dominance to marked right hemisphere dominance for some subjects) even in right-handed subjects.

Personality and stress in consultant psychiatrists.

A randomly selected group of consultant psychiatrists (n = 39) working within the NHS in Scotland was compared with a combined group of physicians and surgeons (n = 149) on several variables related to the stress process, including personality traits, coping strategies, psychological distress, burnout, job stress and work demands. Psychiatrists reported fewer clinical work demands (p < .001), and their mean personality scores were significantly different from physicians and surgeons by being high in neuroticism (p = .009), openness (p = .003) and agreeableness (p = .002), and low in conscientiousness (p = .04). Psychiatrists reported higher work-related emotional exhaustion (p = .03) and severe depression (p = .02). However, psychiatrists did not report more work-related stress than physicians and surgeons. Many stress-related variables were highly correlated within the group of psychiatrists, suggesting that there is a very general disposition to experience negative emotion (including job-related stress) in some individuals. Organisational and personal contributions to stress in the practice of psychiatry are considered. There are personality characteristics that might dispose some people toward psychiatry as a career and toward stress. However, there is no evidence to suggest that screening for admission to psychiatry in terms of personality or other psychological factors would be useful or advisable.

Retrograde femoral nailing between an ankylosed hip and a stiff knee.

We describe a case of retrograde nailing of a comminuted infraisthmal femur fracture between an ankylosed hip and a stiff knee stemming from heterotopic bone and soft-tissue contracture. A tibial nail directed through the medial femoral condyle was used. At 1 year follow-up the fracture has united anatomically, and the patient has been rehabilitated to his preinjury functional status.

Microvascular free flaps in head and neck surgery.

This study is a retrospective review of 60 patients who had microvascular free flap reconstructions in the head and neck region. They were all performed over a 10-year period by a single surgeon. The series includes a wide range of flap types and analyses pre-operative risk factors for flap failure as well as complications and outcome. Smoking and advanced age did not appear to prejudice flap survival but peripheral vascular disease, cardiac disease and alcohol withdrawal were found to increase the likelihood of flap failure. The most frequent complications encountered were thrombosis of one of the anastomosis and haematoma. The most successful flap in terms of survival and function was the fasciocutaneous radial forearm flap. The literature is reviewed in relation to the general principles of microvascular free flap surgery and the results of this series are placed in context.