Characterization of carrier behavior in photonically excited 6H silicon carbide exhibiting fast, high voltage, bulk transconductance properties.

Unabated, worldwide trends in CO2 production project growth to > 43-BMT per year over the next two decades. Efficient power electronics are crucial to fully realizing the CO2 mitigating benefits of a worldwide smart grid (~ 18% reduction for the United States alone). Even state-of-the-art SiC high voltage junction devices are inefficient because of slow transition times (~ 0.5-µs) and limited switching rates at high voltage (~ 20-kHz at ≥ 15-kV) resulting from the intrinsically limited charge carrier drift speed (< 2 × 107-cm-s-1). Slow transition times and limited switch rates waste energy through transition loss and hysteresis loss in external magnetic components. Bulk conduction devices, where carriers are generated and controlled nearly simultaneously throughout the device volume, minimize this loss. Such devices are possible using below bandgap excitation of semi-insulating (SI) SiC single crystals. We explored carrier dynamics with a 75-fs single wavelength pump/supercontinuum probe and a modified transient spectroscopy technique and also demonstrated a new class of efficient, high-speed, high-gain, bi-directional, optically-controlled transistor-like power device. At a performance level six times that of existing devices, for the first time we demonstrated prototype operation at multi-10s of kW and 20-kV, 125-kHz in a bulk conduction transistor-like device using direct photon-carrier excitation with below bandgap light.

Accessing cancer services in North West England: the Chinese population.

Relatively few Chinese patients access tertiary cancer services in North West England. We investigated the reasons behind this using a culturally sensitive questionnaire. The questionnaire, completed by 214 Chinese people in English, Cantonese or Mandarin, evaluated the Chinese population's access and satisfaction with primary care, understanding of cancer and awareness of local cancer services. Ninety-five per cent of respondents were registered with a general practitioner (GP) and 75% had accessed primary care in the last year. Satisfaction with GP consultations was high but a third of respondents reported a lack of confidence in local National Health Service (NHS) services. Only 57% of eligible women had attended cervical screening programmes. The overall understanding of the causes and treatment of cancer and cancer services in the North West was poor. Despite registration with primary healthcare, the Chinese population under-utilise cancer prevention programmes and tertiary cancer services because of a lack of awareness and understanding of cancer services in the North West. A significant proportion of the population is dissatisfied with the perceived slow service and lack confidence in services, with 41% considering using healthcare abroad. These data highlight the critical need to engage with, educate and support the Chinese population if they are to access NHS cancer services.

First-year results of a national abdominal aortic aneurysm screening programme in a single centre.

BACKGROUND: The UK Multicentre Aneurysm Screening Study (MASS) demonstrated reduced mortality from screening for abdominal aortic aneurysm (AAA). As a result, the National Health Service AAA Screening Programme was introduced in England. This study reports the results from an early-implementation screening centre. METHODS: Men aged 65 years were invited to attend an ultrasound assessment. Data were analysed for 15 months from the onset of the screening programme. RESULTS: A total of 6091 men aged 65 years were invited between April 2009 and June 2010, of whom 2037 (33·4 per cent) failed to attend. There were 162 self-referrals (median age 71·3 years) so that 4216 men were screened. Of those scanned, 4146 (98·3 per cent) had an aortic diameter of less than 3·0 cm, 65 (1·5 per cent) had an aneurysm measuring 3·0-5·4 cm, and five (0·1 per cent) had an aneurysm with a diameter of 5·5 cm and above. The presence of an aneurysm was more common in those who self-referred than in the invited group (P < 0·001). All 70 screen-detected aneurysms were found in white men. CONCLUSION: The prevalence of AAA was lower than expected. This reflects the younger age of this cohort compared with those in published large multicentre studies and the diverse ethnic background of the local population.

Patient-reported symptoms are independent of disease severity in patients with primary varicose veins.

The objective of this paper is to explore patterns of incompetence and disease distribution in patients with chronic venous disorders and to correlate this with CEAP (Clinical, Etiologic, Anatomic and Pathologic) classification and presenting symptoms to determine which features of chronic venous disorder (CVD) could be used to guide a patient pathway for referral and treatment. Consecutive patients attending a one-stop venous clinic at a university teaching hospital were recruited over a 12-month period. Patients were clinically assessed, assigned CEAP scores, duplex-scanned and categorized. Data were analyzed to identify associations between symptomatology and disease. Four hundred twenty-four limbs were divided into groups A (C2-3) (339) and B (C4-6) (85). The number of men, mean patient age, varicose vein diameter and quality-of-life score (Aberdeen Varicose Vein Questionnaire - AVVS) were significantly higher in group B (P < 0.01). Ache occurred more commonly in group A and in women (P < 0.01). Ache and pain were seen more frequently with saphenofemoral junction reflux (P < 0.05). Group A women were more likely to be offered surgical intervention while men were managed conservatively (P < 0.05). In conclusion, CVD symptoms are independent of disease severity assessed by CEAP score. Advanced disease is associated with larger venous diameters, older age and corresponds to a poorer quality of life. Objective markers such as CEAP, Venous Clinical Severity Score and AVVS should be used in determining a patient pathway for referral and treatment of CVD.

Supralevator fistula-in-ano in tuberculosis.

AIM: Perianal Mycobacterium tuberculosis is rare, but tuberculosis (TB) is now endemic in many areas of the world. It is essential to recognize TB to institute appropriate management. We report three cases of TB presenting with supralevator abscess. METHOD: We analysed the outcomes of three patients who presented to our unit, from 2004 to 2009, with supralevator abscess caused by TB. RESULTS: The patients presented as emergencies with symptoms of per-anal sepsis. All required multiple drainage procedures. Supralevator extension was confirmed clinically and radiologically (by magnetic resonance imaging in two patients and by computed tomography scanning in one patient). One patient was diagnosed by perianal biopsy, the second by culture of pus and the third by sputum culture. Following drainage, all three patients were given anti-TB medication for 6 months. In all patients, the fistulae had high communication with the anal canal. In one patient, local drainage and medical therapy led to sepsis resolution, the second patient has residual complex fistulae and the third patient has recently commenced antimicrobial therapy. CONCLUSION: As TB is endemic in many parts of Europe, TB should be suspected in patients with complex and/or recurrent perianal sepsis. Samples for histological and bacteriological analyses should be obtained from these patients. Recurrent perianal drainage procedures are likely to be required, and sepsis may persist after anti-TB therapy.

Regulation of myosin light chain phosphorylation by RhoB in neuronal cells.

The phosphorylation of myosin light chain (MLC) is a key regulatory point in the control of cellular morphology. Evidence suggests that RhoA-a member of the Rho GTPase family-regulates MLC phosphorylation via Rho kinase (ROK). Neurones display subtle alterations in their cytoarchitecture during the synaptic plasticity following high-frequency stimulation. We have recently demonstrated that RhoB, and not RhoA, is activated in neurones by high-frequency stimulation. However, the downstream consequences of RhoB activation in cells are unclear. In this study, we tested the hypothesis that RhoB might stimulate neuronal MLC phosphorylation. Transfection of PC12 cells with constitutively active RhoB increased MLC phosphorylation. Conversely, dominant-negative RhoB vectors reduced MLC phosphorylation. The effect of RhoB was attenuated by pretreatment with a selective ROK inhibitor. This confirms that Rho GTPases are important regulators of MLC phosphorylation, but suggests that, in neuronal cells, the control is exerted via RhoB rather than RhoA.

The clinical relevance of an isolated increase in the number of circulating hyperchromic red blood cells.

AIMS: To search for laboratory evidence of hereditary spherocytosis (HS) among apparently healthy children with the chance finding of an isolated increase in hyperchromic red cells (cells with intracellular haemoglobin concentration > 410 g/litre). METHODS: Blood and reticulocyte counts and Pink tests were performed on successive children found on routine counts to have > 4% hyperchromic red cells, and compared with age and mean cell haemoglobin concentration (MCHC) matched controls and children known to have HS. RESULTS: Thirty four patients with > 4% hyperchromic red cells had significantly higher absolute numbers of such cells (p < 0.0001) and higher reticulocyte counts (p < 0.01) than age matched controls, together with higher MCHC (p < 0.0001) and haemoglobin distribution width (p < 0.0001) values and lower mean cell volume (p < 0.02) values. Significant differences were also found among hyperchromic red blood cell, reticulocyte, and haemoglobin distribution width values when subjects were compared with MCHC matched controls. Pink test values were higher in children with increased hyperchromic red blood cells, but not significantly so. In patients with HS, most variables measured were significantly different both from those of children with > 4% hyperchromic cells and controls. Despite the differences found, few MCHC, HDW, reticulocyte, or Pink test values were outside of the normal limits, and only one child with increased hyperchromic cells had both a mild reticulocytosis and a slightly raised Pink test value. CONCLUSIONS: Subjects with an isolated increase in hyperchromic red blood cells have a profile of red blood cell changes similar to that of patients with HS, but to a lesser degree. They may carry a recessive form of the disease but lack the laboratory features of clinically manifest HS.

Assessment of the extracellular and intracellular actions of sphingosine 1-phosphate by using the p42/p44 mitogen-activated protein kinase cascade as a model.

We have investigated the extracellular and intracellular actions of sphingosine 1-phosphate (S1P) by using cultured airway smooth muscle cells. We have demonstrated that exogenous S1P elicited an activation of mitogen-activated protein kinase (p42/p44 MAPK) that was abolished by pertussis toxin (0.1 microg/mL, 24 h), which was used to inactivate Gi. The effect of exogenous S1P might therefore be attributed to an action at a putative Gi-coupled receptor. The regulation of the p42/p44 MAPK cascade by S1P was also shown to include a protein kinase C (PKC)-dependent intermediate step. Platelet-derived growth factor (PDGF) stimulates intracellular S1P formation and was therefore used to evaluate the intracellular action of S1P. This has previously been investigated by others using the sphingosine kinase inhibitors D,L-threo-dihydrosphingosine and N,N-dimethylsphingosine. We have demonstrated here that both inhibitors block the PDGF-dependent activation of p42/p44 MAPK. However, both are also PKC inhibitors, which might account for their effect because PDGF utilises PKC as an intermediate in the regulation of the p42/p44 MAPK cascade. Significantly, sphingosine, which is the substrate of sphingosine kinase and a PKC inhibitor, blocked the activation of p42/p44 MAPK by PDGF with an almost identical concentration dependence compared with D,L-threo-dihydrosphingosine and N,N-dimethylsphingosine. Therefore, the use of so-called sphingosine kinase inhibitors might lead to misleading interpretations because of their additional effect on PKC. Other approaches, such as oligodeoxynucleotide anti-sense against sphingosine kinase, are required to address the intracellular role of S1P.

Sphingosine 1-phosphate stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle. Role of endothelial differentiation gene 1, c-Src tyrosine kinase and phosphoinositide 3-kinase.

We report here that cultured airway smooth muscle cells contain transcripts of endothelial differentiation gene 1 (EDG-1), a prototypical orphan Gi-coupled receptor whose natural ligand is sphingosine 1-phosphate (S1P). This is consistent with data that showed that S1P activated both c-Src and p42/p44 mitogen-activated protein kinase (p42/p44 MAPK) in a pertussis toxin (PTX)-sensitive manner in these cells. An essential role for c-Src was confirmed by using the c-Src inhibitor, PP1, which markedly decreased p42/p44 MAPK activation. We have also shown that phosphoinositide 3-kinase (PI-3K) inhibitors (wortmannin and LY294002) decreased p42/p44 MAPK activation. An essential role for PI-3K was supported by experiments that showed that PI-3K activity was increased in Grb-2 immunoprecipitates from S1P-stimulated cells. Significantly, Grb-2 associated PI-3K activity was decreased by pretreatment of cells with PTX. Finally, we have shown that the co-stimulation of cells with platelet-derived growth factor (PDGF) and S1P (which failed to stimulate DNA synthesis) elicited a larger p42/p44 MAPK activation over a 30 min stimulation compared with each agonist alone. This was associated with a S1P-dependent increase in PDGF-stimulated DNA synthesis. These results demonstrate that S1P activates c-Src and Grb-2-PI-3K (intermediates in the p42/p44 MAPK cascade) via a PTX-sensitive mechanism. This action of S1P is consistent with the stimulation of EDG-1 receptors. S1P might also function as a co-mitogen with PDGF, producing a more robust activation of a common permissive signal transduction pathway linked to DNA synthesis.

Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle: role of pertussis-toxin-sensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase.

The mechanism used by the platelet-derived growth factor receptor (PDGFR) to activate the mitogen-activated- protein-kinase (p42/p44 MAPK) pathway was investigated in cultured airway smooth muscle (ASM) cells. We have found that pertussis toxin (PTX, which was used to inactivate the heterotrimeric G-protein Gi) induced an approx. 40-50% decrease in the activation of c-Src and p42/p44 MAPK by PDGF. An essential role for c-Src was confirmed using the c-Src inhibitor, PP1, which abolished p42/p44 MAPK activation (PP1 and PTX were without effect on PDGFR tyrosine phosphorylation). Furthermore, the PTX-dependent decrease in c-Src and p42/p44 MAPK activation appeared correlated. These findings suggest that the PDGFR can utilize the PTX-sensitive G-protein, Gi, to regulate c-Src and subsequent p42/p44 MAPK activation. Phosphoinositide 3-kinase (PI3K) has been shown by others to be involved in p42/p44 MAPK activation. This is confirmed here by experiments which showed that PI3K inhibitors (wortmannin and LY294002) reduced the activation of p42/p44 MAPK by PDGF. PI3K activity was increased in Grb-2 immunoprecipitates from PDGF-stimulated cells and was decreased by pretreating these cells with PTX. These findings show that Gi might also promote Grb-2-PI3K complex formation and that Grb-2 may be a site at which PI3K is integrated into the p42/p44 MAPK cascade. In conclusion, our results demonstrate that Gi enables the PDGFR to signal more efficiently to p42/p44 MAPK, and this appears to be achieved through the regulation of c-Src and Grb-2/PI3K, which are intermediates in the p42/p44 MAPK cascade.

Measurement of haemoglobin using single drops of skin puncture blood: is precision acceptable?

The study aimed to investigate local concerns about clinically important discrepancies between repeat HemoCue haemoglobin measurements from single drops of blood. Two biomedical scientists and two health visitors each obtained a series of paired haemoglobin values by fingerprick sampling from healthy volunteers. Seven of 20 paired values obtained by health visitors and three of 20 obtained by scientists from the first drop of blood forming at the puncture site differed by > or = 10 g/l; 11 of 20 paired values obtained by health visitors and one of 20 by the scientists from the fourth drop of blood differed by > or = 10 g/l. After collecting and mixing a number of drops in EDTA tubes before analysis, seven of 40 paired values differed by > 5 g/l, and none by > 10 g/l. Pooling drops of blood before analysis improves precision of HemoCue haemoglobin measurement and allows users to achieve results comparable to those obtained by experienced laboratory staff. Measurement of haemoglobin from single drops of skin puncture blood should be discontinued.

Sphingosine prevents diacylglycerol signaling to mitogen-activated protein kinase in airway smooth muscle.

Because many agonists utilize diacylglycerol (DAG) to initiate nuclear transcriptional activity via protein kinase C (PKC), we have investigated whether sphingosine might counter DAG. Sphingosine inhibited PKC activity in an isolated airway smooth muscle cell lysate and prevented the activation of mitogen-activated protein kinase (MAPK) by platelet-derived growth factor, bradykinin, and phorbol 12-myristate 13-acetate in intact cells. MAPK activation in response to all the agonists involves PKC. The stimulation of [3H]palmitate-labeled cells with sphingosine, in the presence of butan-1-ol (0.3%, vol/vol), induced an increase in [3H]phosphatidate (PtdOH) but was without effect on [3H]DAG. [3H]PtdOH synthesis was inhibited, whereas [3H]DAG levels were increased in the presence of the DAG kinase inhibitor R-59949, indicating that sphingosine stimulates phospholipase C/DAG kinase. Recycling of DAG from PtdOH was prevented by a sphingosine-dependent inhibition of PtdOH phosphohydrolase-2 activity. In conclusion, the sphingosine-induced conversion of DAG to PtdOH may serve to optimize the effect of sphingosine on MAPK. This may account for the antiproliferative action of sphingosine.

The identification of DL-threo dihydrosphingosine and sphingosine as novel inhibitors of extracellular signal-regulated kinase signalling in airway smooth muscle.

We present entirely novel evidence that DL-threo dihydrosphingosine and sphingosine are inhibitors of the extracellular signal-regulated kinase (ERK) signalling cassette in mammalian cells. We show that DL-threo dihydrosphingosine is effective against both growth factor- and G-protein-dependent activation of ERK. We conclude that DL-threo dihydrosphingosine may represent an important pharmacological cell-permeable agent that may be usefully employed to block smooth muscle cell proliferation.

Synthetic peptides as substrates for processing enzymes in the bovine pituitary.

Synthetic peptides, based on sequences of proopiomelanocortin (POMC) cleaved in both the bovine anterior and intermediate pituitaries (-Phe-Pro-Leu-Gly-Phe-Lys-Arg-Glu-Leu-Thr-Gly-) and only in the intermediate lobe (-Gly-Lys-Pro-Val-Gly-Lys-Lys-Arg-Arg-Pro-Val-), were used as substrates for the enzymes that process POMC to active hormones in the anterior and intermediate lobes of the pituitary. Cleavage of these peptides at the dibasic pair of residues, the expected cleavage site, was observed with a lysate from bovine pituitary secretory granules. Cleavage occurred optimally at a pH between 4 and 5 and was inhibited with sulfhydryl reagents, pepstatin, and leupeptin. Little specificity for the nature of the basic residues at the cleavage site was observed. An additional cleavage, following glutamic acid residues, was also seen.