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We report anisotropic resistivity measurements of the heavy-fermion superconductor CeRh$_2$As$_2$ in magnetic fields up to 16 T and temperatures down to 0.35 K. The measured CeRh$_2$As$_2$ resistivity shows a signature corresponding to the suggested quadrupole density wave order state at $T_0 \sim$ 0.5 K for both measured directions. For a magnetic field applied along the tetragonal $a$ axis, $T_0$ is enhanced with magnetic field reaching $\sim$1.75 K at 16 T. Further, a magnetic field-induced transition occurs at $B_m \sim $ 8.1 T corresponding to a change to a new broken symmetry state. For a magnetic field applied along the $c$ axis, $T_0$ is suppressed below our base temperature $\sim$0.35 K by $B \sim$ 4.5 T, a field close to the previously reported field-induced transition within the superconducting state suggested to be from an even-parity to an odd-parity state. Our results indicate that the multiple superconducting phases in CeRh$_2$As$_2$ are intimately tied to the suppression of the proposed quadrupole-density-wave phase at $T_0$., Comment: 6 pages and 5 figures

The spin-triplet superconductor UTe$_2$ shows spontaneous time-reversal symmetry breaking and multiple superconducting phases in some crystals, implying chiral superconductivity. Here we microscopically image the local magnetic fields and magnetic susceptibility near the surface of UTe$_2$, observing a homogeneous superfluid density $n_s$ and homogeneous pinned vortices. The temperature dependence of $n_s$ is consistent with an anisotropic gap and shows no evidence for an additional kink that would be expected at any second phase transition. Our findings are consistent with a dominant $B_{3u}$ superconducting order parameter in the case of a quasi-2D Fermi surface and provide no evidence for multiple phase transitions in $n_s(T)$ in UTe$_2$., Comment: 12 pages, 13 figures

The proposed topological Kondo insulator SmB$_{6}$ hosts a bulk Kondo hybridization gap that stems from strong electronic correlations and a metallic surface state whose effective mass remains disputed. Thermopower and scanning tunneling spectroscopy measurements argue for heavy surface states that also stem from strong correlations, whereas quantum oscillation and angle-resolved photoemission measurements reveal light effective masses that would be consistent with a Kondo breakdown scenario at the surface. Here we investigate the evolution of the surface state via electrical and thermoelectric transport measurements under hydrostatic pressure, a clean symmetry-preserving tuning parameter that suppresses the Kondo gap and increases the valence of Sm from 2.6+ towards a 3+ magnetic metallic state. Electrical resistivity measurements reveal that the surface carrier density increases with increasing pressure, whereas thermopower measurements show an unchanged Fermi energy under pressure. As a result, the effective mass of the surface state charge carriers linearly increases with pressure as the Sm valence approaches 3+. Our results are consistent with the presence of correlation-driven surface states in SmB$_{6}$ and suggest that the surface Kondo effect persists under pressure to 2 GPa.

Spin-triplet bulk superconductors are a promising route to topological superconductivity, and UTe2 is a recently discovered contender. The superconducting properties of UTe2, however, vary substantially as a function of the synthetic route, and even nonsuperconducting single crystals have been reported. To understand the driving mechanism suppressing superconductivity, we investigate UTe2 single crystals grown close to the nonsuperconducting boundary (growth temperature ∼710 ∘C) through a combination of thermodynamic and x-ray diffraction measurements. Specific heat measurements reveal a sharp decrease in the superconducting volume and a concomitant increase in the residual specific heat coefficient close to the nonsuperconducting boundary. Notably, these crystals are inhomogeneous and show an apparent double transition in specific heat measurements, similar to samples grown at much higher temperatures (∼1000 ∘C). Our single crystal x-ray diffraction measurements reveal that there are two important tuning parameters: uranium vacancies and the atomic displacement along the c axis, which shows a twofold increase in samples with a reduced superconducting volume. Our results highlight the key role of local disorder along the uranium-uranium dimers and suggest that the apparent double superconducting transition is more likely to emerge close to the superconducting limits of UTe2.

We report the electronic and magnetic properties of stoichiometric CeAuBi2 single crystals. At ambient pressure, CeAuBi2 orders antiferromagnetically below a Néel temperature (TN) of 19 K. Neutron diffraction experiments revealed an antiferromagnetic propagation vector τ^=[0,0,1∕2], which doubles the paramagnetic unit cell along the c axis. At low temperatures several metamagnetic transitions are induced by the application of fields parallel to the c axis, suggesting that the magnetic structure of CeAuBi2 changes as a function of field. At low temperatures, a linear positive magnetoresistance may indicate the presence of band crossings near the Fermi level. Finally, the application of external pressure favors the antiferromagnetic state, indicating that the 4f electrons become more localized.

Newly-discovered superconductor UTe$_2$ is a strong contender for a topological spin-triplet state wherein a multi-component order parameter arises from two nearly-degenerate superconducting states. A key issue is whether both of these states intrinsically exist at ambient pressure. Through thermal expansion and calorimetry, we show that UTe$_2$ at ambient conditions exhibits two detectable transitions only in some samples, and the size of the thermal expansion jump at each transition varies when the measurement is performed in different regions of the sample. This result indicates that the two transitions arise from two spatially separated regions that are inhomogeneously mixed throughout the volume of the sample, each with a discrete superconducting transition temperature (T$_c$). Notably, samples with higher T$_c$ only show a single transition at ambient pressure. Above 0.3 GPa, however, two transitions are invariably observed in ac calorimetry. Our results not only point to a nearly vertical line in the pressure-temperature phase diagram but also provide a unified scenario for the sample dependence of UTe$_{2}$., Comment: 6 pages, 4 figures, includes supplemental information, changed conclusion on the origin of double-transition feature observed in some UTe2 samples

The 2017-2018 listeriosis outbreak in South Africa warranted testing forThe study assessed the performance of the commonly used tests in our setting to accurately identifyThe study was conducted in a public health laboratory in South Africa. Cultured isolates from food and environmental samples were tested both prospectively and retrospectively between August 2018 and December 2018. Isolates were phenotypically identified using tests for detecting β-haemolysis, Christie-Atkins-Munch-Peterson, alanine arylamidase (AlaA), mannosidase, and xylose fermentation. Listeria monocytogenes isolates were identified using automated systems, Microscan Walkaway Plus 96, Vitek® MS, Vitekβ-haemolysis and Christie-Atkins-Munch-Peterson tests gave delayed positivity or were negative forNo test was ideal in differentiating

Multicomponent superconductivity in intermediate-valence UTe2 emerges from an antiferromagnetic quantum critical point., UTe2 is a recently discovered unconventional superconductor that has attracted much interest because of its potentially spin-triplet topological superconductivity. Our ac calorimetry, electrical resistivity, and x-ray absorption study of UTe2 under applied pressure reveals key insights on the superconducting and magnetic states surrounding pressure-induced quantum criticality at Pc1 = 1.3 GPa. First, our specific heat data at low pressures, combined with a phenomenological model, show that pressure alters the balance between two closely competing superconducting orders. Second, near 1.5 GPa, we detect two bulk transitions that trigger changes in the resistivity, which are consistent with antiferromagnetic order, rather than ferromagnetism. Third, the emergence of magnetism is accompanied by an increase in valence toward a U4+ (5f2) state, which indicates that UTe2 exhibits intermediate valence at ambient pressure. Our results suggest that antiferromagnetic fluctuations may play a more substantial role on the superconducting state of UTe2 than previously thought.

Aim To investigate the factors influencing uptake of structured education for people with Type 1 diabetes in our local population in order to understand why such uptake is low. Methods We conducted a cross-sectional database study of adults with Type 1 diabetes in two south London boroughs, analysed according to Dose Adjustment For Normal Eating (DAFNE) attendance or non-attendance. Demographics, glycaemic control and service use, with subset analysis by ethnicity, were compared using univariate analysis. An exploratory regression model was used to identify influencing factors. Results The analysis showed that 73% of adults had not attended the DAFNE programme. For non-attenders vs attenders, male gender (59 vs 48%; P = 0.002), older age (39 vs 35 years; P < 0.001), non-white ethnicity (30 vs 20%; P = 0.001) and coming from an area of social deprivation (index of multiple deprivation score 31 vs 28; P < 0.001) were associated with non-attendance. The difference in gender (88% men vs 70% women; P < 0.001) and age (43 vs 34 years) persisted in the non-white group. Regression analysis showed that higher baseline HbA1c level (odds ratio 1.96; P = 0.004), younger age (odds ratio 0.98; P = 0.001) and lower social deprivation (odds ratio 0.52; P = 0.001) was associated with attendance. Conclusion Socio-economic status and factors perceived as indicating greater severity of disease (HbA1c) influence attendance at DAFNE. More work is necessary to understand the demography of non-attenders to aid future service design and alternative engagement strategies for these groups.

SmB_{6} is a candidate topological Kondo insulator that displays surface conduction at low temperatures. Here, we perform torque magnetization measurements as a means to detect de Haas-van Alphen (dHvA) oscillations in SmB_{6} crystals grown by aluminum flux. We find that dHvA oscillations occur in single crystals containing embedded aluminum, originating from the flux used to synthesize SmB_{6}. Measurements on a sample with multiple, unconnected aluminum inclusions show that aluminum crystallizes in a preferred orientation within the SmB_{6} cubic lattice. The presence of aluminum is confirmed through bulk susceptibility measurements, but does not show a signature in transport measurements. We discuss the ramifications of our results.

Visceral artery aneurysms are rare, with a reported incidence of less than 2% in the general population. 1,2 Aneurysms of the left gastric artery are particularly uncommon, accounting for 4% of all visceral aneurysms. 3,4 Although the majority are discovered incidentally and can be managed conservatively, prompt treatment of those ruptured or at risk of rupture is crucial to reduce the associated morbidity. Increasing awareness of visceral artery aneurysms as a cause of spontaneous intraperitoneal haemorrhage will improve early recognition and impact on survival. We present a rare case of spontaneous rupture of a left gastric artery aneurysm.

Keith Clements, Ecumenical Dynamic: Living in More than One Place at Once. Geneva: World Council of Churches, 2013. Pp. 222. $20.00, paper. Together towards Life: Mission and Evangelism in Changing Landscapes, with a Practical Guide. Edited by Jooseop Keum. Geneva: World Council of Churches Publications, 2013. Pp. 81, with DVD. $ 20.00, paper. Michael Kinnamon, Can a Renewal Movement Be Renewed? Questions for the Future of Ecumenism. Grand Rapids, MI, and Cambridge, U.K.: William B. Eerdmans Publishing Co., 2014. Pp. 167. $24.00. After the Spring sparked by the ecumenical dialogues in the 1980's and 1990's, some now describe the ecumenical scene as one of Winter. The ecumenical accords hardly seem to have been noticed by the churches. Cardinal Walter Kasper suggested that the change may be the result of "unfulfilled expectations." But, the dialogues are only part of ecumenism, and two works here reviewed, by Clements and Kinnamon, both with long ecumenical experience, offer suggestions leading to a broader ecumenical vision. Clements, an English Baptist, was active in the Council of Churches for Britain and Ireland and the Conference of European Churches. His Ecumenical Dynamic proposes transcending narrow confines and entering into and identifying oneself with a dynamic that unites people. The central section of the work, "The Dynamic Illustrated," presents movements and individuals who represent this larger approach. Although the 1910 Edinburgh Conference is acknowledged as the beginning of the ecumenical movement, Clements suggests that it was the mutual visits, "the peace exchanges" of the Anglo-German churches in 1908 and 1909, when, as war clouds were rising, the historic voyages of two ships--one from England and the other from Germany, each with hundreds of Christians visiting their brothers and sisters of the other county--laid the foundation for the World Alliance for Promoting International Friendship. Other towering figures of this larger ecumenical vision were J. H. Oldham and "the Moot," a group of British intellectuals founded to explore the role of Christian belief in modern society and the relation between the social environment and the gospel; and George Bell, "the apostle of Unity," dean of Canterbury, for whom ecumenism was grounded in the sovereignty of Christ and expressed in personal relationships. The 1934 Barmen Declaration had ecumenical implications: It was not only a statement of faith but also an invitation to be identified with the Confessing Church. The last section, "The Dynamic Continued," looks to the future, one not dominated by ecclesial structures but with less-clericalized communities such as Taize, the Bruderhof, Focolare, Iona, and Corrymeela. …

Thoracic aortic aneurysms represent a major health problem. Untreated thoracic aortic aneurysms may rupture, which has a dismal outcome. The standard treatment for thoracic aneurysms is open surgical repair, but it is associated with high mortality and morbidity. Endovascular repair provides a less invasive and safer alternative. A systematic review was performed of all published literature on the above subject. Our primary objective was to measure 30-day mortality for nonruptured thoracic aortic aneurysms. Studies describing other pathologies, such as aortic dissection, mycotic aneurysms, penetrating ulcers, traumatic transactions, and pseudoaneurysms, and studies from which independent data for thoracic aortic aneurysm could not be separately extracted were excluded. Case series describing less than 10 patients and all case series describing ruptures or concealed ruptures were excluded as well. Twenty-six case series and one comparative study were identified. This formed a cohort of 1,038 patients. Technical success was possible in more than 97% of patients. The 30-day mortality was calculated to be 5.1% even though the group under study was mostly those who were refused surgery by a surgeon or had a higher surgical risk. The incidence of paraplegia and stroke was 3.1% and 4.7%, respectively. Early endoleak was seen in 16.7% of patients, whereas 11.7% of patients developed late endoleak, but most did not require any additional procedure. The rate of reintervention was 14.9%. The 12-month mortality rate was 14.2%. Endovascular repair shows encouraging short-term results. It is associated with significantly less mortality and morbidity, but long-term results need to be further investigated.

The estimation of a circle’s centre and radius from a set of noisy measurements of its circumference has many applications. It is a problem of fitting a circle to the measurements and the fit can be in algebraic or geometric distances. The former gives linear equations, while the latter yields nonlinear equations. Starting from estimation theory, this paper first proves that the maximum likelihood (ML), i.e., the optimal estimation of the circle parameters, is equivalent to the minimization of the geometric distances. It then derives a pseudolinear set of ML equations whose coefficients are functions of the unknowns. An approximate ML algorithm updates the coefficients from the previous solution and selects the solution that gives the minimum cost. Simulation results show that the ML algorithm attains the Cramer-Rao lower bound (CRLB) for arc sizes as small as 90°. For arc sizes of 15° and 5° the ML algorithm errors are slightly above the CRLB, but lower than those of other linear estimators.

In computer vision and computer aided manufacturing, it is often necessary to fit a circular arc through a number of noisy points. Determining the arc center and radius from a set of points is inherently a nonlinear problem and all estimators will exhibit the so-called threshold phenomenon. A combination of a short arc, small number of points, and large noise magnitude will create a threshold region (THR) whereby the estimation errors are several times larger than those above the THR. The transition into the THR is sudden. It is also difficult to determine the THR for an estimator. This paper presents an estimation scheme for the circle parameters by first computing different centers from all combinations of N data points, taken three at a time. A weighted average of those centers gives the final estimate. The procedure is simple, noniterative and simulation results show that it has a smaller THR than an estimator which is near-optimal when not operating inside the THR.

As a result of intensified globalization of international trade and of substantial travel activities, mosquito-borne exotic pathogens are becoming an increasing threat for Europe. In Germany some 50 different mosquito species are known, several of which have vector competence for pathogens. During the last few years a number of zoonotic arboviruses that are pathogenic for humans have been isolated from mosquitoes in Germany including Usutu, Sindbis and Batai viruses. In addition, filarial worms, such as Dirofilaria repens have been repeatedly detected in mosquitoes from the federal state of Brandenburg. Other pathogens, in particular West Nile virus, are expected to emerge sooner or later in Germany as the virus is already circulating in neighboring countries, e.g. France, Austria and the Czech Republic. In upcoming years the risk for arbovirus transmission might increase in Germany due to increased occurrence of new so-called "invasive" mosquito species, such as the Asian bush mosquito Ochlerotatus japonicus or the Asian tiger mosquito Aedes albopictus. These invasive species are characterized by high vector competence for a broad range of pathogens and a preference for human blood meals. For risk assessment, a number of mosquito and pathogen surveillance projects have been initiated in Germany during the last few years; however, mosquito control strategies and plans of action have to be developed and put into place to allow early and efficient action against possible vector-borne epidemics.

Catheter angiograms have been the standard by which other investigations are judged.Advances in technique and technology have made catheter angiograms safe and minimally invasive.Non-invasive techniques are replacing catheter angiograms in many diagnostic situations.Calibrated catheter imaging is useful when planning endovascular interventions such as stent-grafting.Angiography is an essential part of many endovascular interventional treatments.The future of catheter angiograms lies with its role in intervention rather than diagnosis.

A helicopter's airspeed and sideslip angle is difficult to measure at speeds below 50 knots. This paper describes the application of Artificial Neural Network (ANN) techniques to the helicopter low airspeed problem. Three ANN methods were applied to the problem: a linear network, a Radial Basis Function (RBF) network, and a Multi-Layer Perceptron (MLP), trained using an implementation of the Levenberg-Marquardt (L-M) algorithm. Internally available measurements, such as control positions and body attitudes and rates, were generated using a realistic simulation model of a Lynx helicopter. These measurements formed the inputs to the ANN methods. The MLP was found to be the superior method. Further testing, including a Taguchi analysis, indicated the validity of the method. It is concluded that ANN techniques present a promising solution to the helicopter low airspeed problem.

It is of practical value to estimate the center and radius of a circle from a given set of noisy coordinate measurements. Since the coordinates of the points on a circle relate to its parameters through the nonlinear circle equation, the estimation problem is inherently nonlinear. Additionally, if the measurements are available only along a small arc, the estimation exhibits generally a bias, together with large variances, even at low-noise magnitudes. This paper presents two algorithms, one iterative and another which has a closed-form solution, aiming at the elimination of biases that occur at small arcs. Simulation results show that the two algorithms do provide unbiased and reliable estimates of the circle parameters for noisy measurements on arcs as small as 45°.

Aims—To assess the relation between the grade and the status of follow up cytology, the completeness of loop excision biopsies with cervical intraepithelial neoplasia (CIN), and the findings at follow up cytology, as well as the differences between complete and incomplete exclusion, using the odds ratio. Treatment failure was assessed. Methods—1600 women with CIN (290 CIN1, 304 CIN2, 1006 CIN3) were followed for a minimum of six months and a maximum of 10 years. A database was created and comparisons performed. The mean age of the patients was 37 years. Results—Excision was complete in over 84% of loops. Residual disease and recurrence of high grade dyskaryosis was more common in women with CIN 3 than CIN 2 or 1. No high grade dyskaryosis was seen in the fifth follow up smear in patients with CIN 1 and CIN 2. Residual, recurrent, and persistent disease was most common in patients with incompletely excised CIN at ectocervical and endocervical margins and deep margins of resection than in patients with completely excised CIN. The odds ratios were significantly higher in the women who had incomplete excision of CIN at ectocervical, endocervical, both ecto- and endocervical, and deep margins of resection compared with those with apparent complete excision of CIN lesions. One patient developed invasive squamous cell carcinoma 44 months after loop excision which showed CIN 3 invading endocervical crypts and extending to both ectocervical and endocervical margins of resection. Conclusions—At long term follow up, patients with CIN who have residual disease are at increased risk of persistent disease and should therefore be followed up regularly with cytology and colposcopy. The findings support national policy of returning women with treated CIN of any grade to normal recall after five years except for cases of CIN3 where excision was incomplete or equivocal. In these cases follow up with annual smear for 10 years is recommended. Key Words: cervical cytology • cervical intraepithelial neoplasia

Expanded clays bipillared with [Al(13)O(4)(OH)(24)(H(2)O)(12)](7+) ions and with hexameric Cu complexes such as M[(m-OH)Cu(m-OCH(2)CH(2)NEt(2))](6)(ClO(4))(3), or with M[(m-OH)Cu(m-OCH(2)CH(2)NEt(2))](6)(PF(6))(3) where M = Fe, Al, Ga, form microporous materials whose stability and microporosity depend mainly on the identity of the hexamer central metal atom. In fact, a general decrease in thermal stability, interlamellar heights, surface areas, and pore volumes was noted when, in the (Cu,M) hexamer, M changed from gallium to aluminum to iron. Mossbauer results have indicated that only Fe(3+) in octahedral coordination is present in the iron-containing bi-PILC samples (bi-PILC = bipillared interlayered clays). It is believed that metals such as Fe(3+) and Cu(2+) can interact with the interlamellar Keggin ions thereby decreasing the stability of the alumina pillars. In contrast, the intermediate Al(13)-PILC structure is least affected when the more stable Cr complex is used. Bi-PILC materials containing 2.7-3.4% Cr stable to 500 degrees C have been obtained. The low polarity of the chosen solvent (acetonitrile) appears to inhibit the back-exchange of the intermediate PILC's Keggin ions with the hexameric Cu complexes. Elemental analysis together with XRD results suggests that the primary intercalation pathway was diffusion or ion exchange when Cr[(m-OCH(3))(m-OCH(2)CH(2)NEt(2))CuCl](3) or M[(m-OH)Cu(m-OCH(2)CH(2)NEt(2))](6)(ClO(4))(3), respectively, was used. In all preparations, bi-PILC were produced containing complexes that suffered ligand losses during the synthesis reaction. Molecular scale AFM images have shown that these complexes can be found also outside the clay interlamellar space.

Background The aim was to perform an economic evaluation of the cost-effectiveness of endovascular enhancements to percutaneous transluminal balloon angioplasty (PTA) with bail-out bare metal stents for infrainguinal peripheral arterial disease. Methods The following interventions were considered: PTA with no bail-out stenting, PTA with bail-out drug-eluting stents, drug-coated balloons, primary bare metal stents, primary drug-eluting stents, endovascular brachytherapy, stent-grafts and cryoplasty. A discrete-event simulation model was developed to assess the relative cost-effectiveness of the interventions from a health service perspective over a lifetime. Populations of patients with intermittent claudication (IC) and critical leg ischaemia (CLI) were modelled separately. Univariable and probabilistic sensitivity analyses were undertaken. Effectiveness was measured by quality-adjusted life-years (QALYs). Results For both patient populations, the use of drug-coated balloons dominated all other options by having both lower lifetime costs and greater effectiveness. For willingness-to-pay thresholds between £0 and £100 000 per additional QALY, the probability of drug-coated balloons being cost-effective was at least 58·3 per cent for patients with IC and at least 72·2 per cent for patients with CLI. Sensitivity analyses showed that the results were robust to different assumptions regarding the clinical benefits attributable to the interventions. Conclusion The use of drug-coated balloons represents a cost-effective alternative to the use of PTA with bail-out bare metal stents.

Background There are several additional techniques designed to enhance conventional percutaneous transluminal balloon angioplasty (PTA). This systematic review assessed current evidence on the clinical effectiveness of additional techniques for infrainguinal peripheral arterial occlusive disease (PAD). Methods Relevant electronic databases, including MEDLINE, were searched in May 2011. The population comprised participants with symptomatic PAD undergoing endovascular treatment for disease distal to the inguinal ligament. Interventions were additional techniques compared with conventional PTA. Main outcome measures were restenosis and need for reintervention. Randomized clinical trials (RCTs) of clinical effectiveness were assessed for quality and data were extracted. Where appropriate, meta-analysis was undertaken to produce risk ratios (RRs). Results Forty RCTs were selected. Meta-analysis showed a significant benefit in reducing restenosis rates at 6 months for self-expanding stents (RR 0·49) and drug-coated balloons (RR 0·40), and at 12 months for endovascular brachytherapy (RR 0·63). There was also evidence that use of a stent-graft significantly reduced restenosis compared with PTA, as did drug-eluting stents compared with bare-metal stents. Meta-analysis showed that use of drug-coated balloons was associated with significantly lower reintervention rates than PTA alone at 6 months (RR 0·24) and 24 months (RR 0·27) of follow-up. There was also evidence of significantly lower reintervention rates for self-expanding stents at 6 months. Other techniques did not show significant treatment effects for restenosis or reintervention. Conclusion The conclusions of this review should be tempered by small sample sizes, lack of clinical outcome measures and differing outcome definitions, making direct comparison across trials difficult. However, self-expanding stents, drug-eluting stents and drug-coated balloons appeared to be the most promising technologies worthy of future study.

We assessed the cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for intermittent claudication due to peripheral arterial disease (PAD) in adults whose symptoms continue despite a period of conventional management. A Markov decision model was developed to assess the lifetime costs and benefits of each vasoactive drug compared to no vasoactive drug and with each other. Regression analysis was undertaken to model the relationship between maximum walking distance and utility. Resource use data were sourced from the literature and sensitivity analyses were undertaken. Naftidrofuryl oxalate is more effective and less costly than cilostazol and pentoxifylline and has an estimated cost per quality-adjusted life year gained of around £6070 compared to no vasoactive drug. The analysis uses effectiveness evidence from a network meta-analysis. In contrast to previous guidelines recommending cilostazol, the analysis suggests that naftidrofuryl oxalate is the only vasoactive drug for PAD which is likely to be cost-effective.

Background A systematic review and network meta-analysis was undertaken to consider the evidence for the efficacy and tolerability of placebo, cilostazol, naftidrofuryl oxalate and pentoxifylline in patients with intermittent claudication due to peripheral arterial disease (PAD). Methods MEDLINE, Embase, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings, BIOSIS, National Research Register and MetaRegister databases were searched. Eligible studies were randomized controlled trials (RCTs) and published systematic reviews of patients with intermittent claudication due to PAD and whose symptoms persisted despite a period of conservative management. Study selection was conducted by one reviewer with involvement from a clinician. Data were extracted by one reviewer with no blinding to authors or journal, and checked by a second reviewer. Outcome measures were maximum walking distance (MWD) and pain-free walking distance (PFWD). Results The review identified 1876 citations; 26 RCTs met the inclusion criteria for the systematic review. Eleven trials provided data relevant for the meta-analysis. Naftidrofuryl oxalate was ranked first for both MWD and PFWD (probability of 0·947 and 0·987, respectively, of being the best treatment) followed by cilostazol and pentoxifylline. For naftidrofuryl oxalate, cilostazol and pentoxifylline, MWD increased by 60 (95 per cent credible interval 20 to 114) per cent, 25 (11 to 40) per cent and 11 (−1 to 24) per cent respectively relative to placebo, and PFWD increased by 49, 13 and 9 per cent. Conclusion Naftidrofuryl oxalate and cilostazol are both effective treatments for claudication; naftidrofuryl oxalate is likely to be the most effective, with minimal serious adverse events.

Fungal (Penicillium chrysogenum) and yeast (Saccharomyces cerevisiae) ATP sulfurylases were shown to have very similar kinetic and chemical properties except that the fungal enzyme (a) contains a highly reactive Cys residue (SH-1) whose modification results in sigmoidal velocity curves (Renosto, F., Martin, R. L., and Segel, I. H. (1987) J. Biol. Chem. 262, 16279-16288) and (b) is allosterically inhibited by 3'-phosphoadenosine 5'-phosphosulfate (PAPS), while the yeast enzyme displays neither of these properties. The fungal enzyme subunit (64.3 kDa, 572 amino acids) is also larger than the yeast enzyme subunit (59.3 kDa, 521 amino acids). To correlate the unique allosteric properties of the fungal enzyme with specific structural features, we cloned and sequenced the ATP sulfurylase gene (aps) from P. chrysogenum. The yeast and fungal enzymes are homologous over the first 400 amino acids and contain two regions high in basic residues which are conserved in sulfurylases from Arabidopsis and the Riftia pachyptila (hydrothermal vent tube worm) chemolithotrophic symbiont. These regions may participate in forming the binding sites for MgATP2- and SO4(2-). The fungal enzyme has no sites for MgATP2- and SO4(2-). The fungal enzyme has no significant sequence homology to the yeast enzyme in the C-terminal 172 amino acids. This C-terminal region contains SH-1 (Cys-508) and has homology to MET14 (S. cerevisiae), CYSC (E. coli), and NODQ (Rhizobium meliloti), i.e. adenosine 5'-phosphosulfate (APS) kinase. The cumulative results suggest that (a) the allosteric PAPS binding site of P. chrysogenum ATP sulfurylase is located in the C-terminal domain of the protein and (b) that this domain may have evolved from APS kinase. In spite of the homology, this C-terminal region does not account for the APS kinase activity of P. chrysogenum. Fungal ATP sulfurylase has no significant homology to (or regulatory properties in common with) CYSD or CYSN, proteins reported to comprise E. coli ATP sulfurylase (Leyh, T., Vogt, T. F., and Suo, Y. (1992) J. Biol. Chem. 267, 10405-10410).

In this paper, work that has been carried out on the processing of data derived from interview forms is discussed. Various attempts have been made to process the data using Kohonen self-organising maps. The object of the processing was to identify both local and global trends within the data sets. The difficulty encountered in training the networks and interpreting the results led to the development of a new vector quantisation network, the ‘Euclidean Memory Array’, a network made distinct by the lack of a conventional learning process. This technique provided a valuable insight into the trends within the data, proving effective even on extremely small data sets.

Luria and Delbrück, in a seminal paper, introduced fluctuation analysis primarily as a means to elucidate the timing of mutation in relation to the imposition of selective conditions. Their work, and subsequently that of LEA and COULSON, established also a basis for measuring the frequency of mutational events. The several estimators proposed by these authors differ both in complexity and in efficiency, and the published literature relies mainly on the less efficient but computationally trivial estimators. The estimators as originally proposed assume that all mutants occurring in culture will be counted in the subsequent assay, but a relaxation of this assumption suggests an alternative experimental design and alternative estimators which offer advantages over those currently in common use.

Background Peripheral arterial disease (PAD) is a condition in which there is blockage or narrowing of the arteries that carry blood to the legs and arms. It is estimated to affect around 4.5% of people aged between 55 and 74 years within the UK. The most common symptom of PAD is intermittent claudication (IC), characterised by pain in the legs on walking that is relieved with rest. Objective To assess the effectiveness and cost-effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate, compared with no vasoactive drugs, for IC due to PAD in adults whose symptoms continue despite a period of conventional management. Data source Electronic bibliographic databases were searched during April to June 2010 (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings Citation Index, BIOSIS Previews). Review methods Effectiveness outcomes sought were maximal walking distance (MWD), pain-free walking distance (PFWD), ankle–brachial pressure index, cardiovascular events, mortality, adverse events (AEs) and health-related quality of life (HRQoL). A narrative synthesis was provided for all outcomes and a network meta-analysis was undertaken for the walking distance outcomes. A Markov model was developed to assess the relative cost-effectiveness of the interventions from a NHS perspective over a lifetime. The model has three states: vasoactive drug treatment, no vasoactive drug treatment and death. Each 1-week cycle, patients may continue with the drug, discontinue the drug or die. Regression analysis was undertaken to model the relationship between MWD and utility so that a cost per quality-adjusted life-year (QALY) outcome measure could be presented. Univariate and probabilistic sensitivity analyses were undertaken. All costs and outcomes were discounted at 3.5%. Results Twenty-six randomised controlled trials were identified that met the inclusion criteria for the clinical effectiveness review. There was evidence that walking distance outcomes were significantly improved by both cilostazol and naftidrofuryl oxalate; the 95% credible intervals for the difference from placebo in the logarithm mean change MWD from baseline were 0.108 to 0.337 and 0.181 to 0.762, respectively. It was not possible to include inositol nicotinate within the meta-analysis of MWD and PFWD owing to the lack of 24-month data; however, the shorter-term data did not suggest a significant effect. AEs were minor for all drugs and included headaches and gastrointestinal difficulties. The incidence of serious adverse events (SAEs), including cardiovascular events and mortality, was not increased by the vasoactive drugs compared with placebo; however, most studies had a relatively short follow-up time to address this outcome. HRQoL data were limited. Two studies of limited quality were identified within the review of cost-effectiveness. The de novo model developed suggests that naftidrofuryl oxalate dominates cilostazol and pentoxifylline and has a cost per QALY gained of around £6070 compared with no vasoactive drug. This result is reasonably robust to changes within the key model assumptions. Inositol nicotinate was not included within the main analysis owing to lack of data. However, it is unlikely to be considered to be cost-effective due to its high acquisition cost (£900 vs £100–500 per year for the other drugs). Conclusions Naftidrofuryl oxalate and cilostazol both appear to be effective treatments for this patient population, with minimal SAEs. However, naftidrofuryl oxalate is the only treatment that is likely to be considered cost-effective. The long-term effectiveness is uncertain and hence a trial comparing cilostazol, naftidrofuryl oxalate and placebo beyond 24 weeks would be beneficial. Outcomes associated with naftidrofuryl oxalate could also be compared with those associated with supervised exercise programmes and angioplasty. Source of funding The National Institute for Health Research Health Technology Assessment programme.

The role of indoleamine 2,3-dioxygenase (IDO) in IFN-gamma-mediated inhibition of intracellular parasite growth has been examined previously, although earlier work has been largely correlative. In this study, we defined more completely the role of IDO in the IFN-antimicrobial response. Two mutant cell lines, derived from ME180 cells and exhibiting reduced IDO activity (IR3B6A, IR3B6B) were characterized to determine if they retained the capacity to inhibit intracellular Chlamydia and Toxoplasma growth. Mutant cells treated with IFN-gamma exhibited reduced capacity to suppress pathogen growth. The expression of several IFN-regulated genes also was measured to confirm that the inability to inhibit pathogen growth was because of the lack of IDO. The expression of class II MHC, intracellular adhesion molecule-1, MxA, and P68 kinase genes was induced in the IFN-gamma-treated wild type ME180 cells, but was variable in the mutant cell lines, supporting the hypothesis that IFN-gamma-induced production of IDO is a key IFN-gamma-mediated antimicrobial mechanism.

Alternative transcription factor sigma B of Bacillus subtilis controls a stationary-phase regulon induced under growth conditions that do not favor sporulation. Little is known about the metabolic signals and protein factors regulating the activity of sigma B. The operon containing the sigma B structural gene has the gene order orfV-orfW-sigB-rsbX, and operon expression is autoregulated positively by sigma B and negatively by the rsbX product (rsbX = regulator of sigma B). To establish the roles of the orfV and orfW products, orfV and orfW null and missense mutations were constructed and tested for their effects on expression of the sigma B-dependent genes ctc and csbA. These mutations were tested in two contexts: in the first, the sigB operon was under control of its wild-type, sigma B-dependent promoter, and in the second, the sigB operon promoter was replaced by the inducible Pspac promoter. The principal findings are that (i) the orfV (now called rsbV) product is a positive regulator of sigma B-dependent gene expression; (ii) the orfW (now called rsbW) product is a negative regultor of such expression; (iii) sigma B is inactive during logarithmic growth unless the rsbW product is absent; (iv) the rsbX, rsbV, and rsbW products have a hierarchical order of action; and (v) both the rsbV and rsbW products appear to regulate sigma B activity posttranslationally. There are likely to be at least two routes by which information can enter the system to regulate sigma B: via the rsbX product, and via the rsbV and rsbW products.

The amino-termina, noncatalytic half of Src contains two domains, designated the Src homology 2 (SH2) and Src homology 3 (SH3) domains, that are highly conserved among members of the Src family of tyrosine kinases. The SH2 domain (which can be further divided into the B and C homology boxes) and the SH3 domain (also referred to as the A box) are also found in several proteins otherwise unrelated to protein tyrosine kinases. It is believed that these domains are important for directing specific protein-protein interactions necessary for the proper functioning of Src. To determine the importance of the SH2 and SH3 domains in regulating the functions of c-Src, we evaluated mutants of c-Src lacking the A box (residues 88 to 137), the B box (residues 148 to 187) or the C box (residues 220 to 231). Each of these deletions caused a 14- to 30-fold increase in the in vitro level of kinase activity of c-Src. Chicken embryo fibroblasts expressing the deletion mutants displayed a transformed cell morphology, formed colonies in soft agar, and contained elevated levels of cellular phosphotyrosine-containing proteins. Src substrates p36, p85, p120, p125, the GTPase-activating protein (GAP), and several GAP-associated proteins were phosphorylated on tyrosine in cells expressing the A, B, or C box deletion mutant. p110 was highly phosphorylated in cells expressing the C box mutant, was weakly phosphorylated in cells expressing the B box mutant, and was not phosphorylated in cells expressing the A box mutant. Expression of the mutant proteins caused a reorganization of the actin cytoskeleton similar to that seen in v-Src-transformed cells. In addition, deletion of the A, B, or C box did not diminish the transforming or enzymatic activity of an activated variant of c-Src, E378G. These data indicate that deletion of the A, B, or C homology box causes an activation of the catalytic and transforming potential of c-Src and that while these mutations caused subtle differences in substrate phosphorylation, the homology boxes are not required for many of the phenotypic changes associated with transformation by Src.

The amino-termina, noncatalytic half of Src contains two domains, designated the Src homology 2 (SH2) and Src homology 3 (SH3) domains, that are highly conserved among members of the Src family of tyrosine kinases. The SH2 domain (which can be further divided into the B and C homology boxes) and the SH3 domain (also referred to as the A box) are also found in several proteins otherwise unrelated to protein tyrosine kinases. It is believed that these domains are important for directing specific protein-protein interactions necessary for the proper functioning of Src. To determine the importance of the SH2 and SH3 domains in regulating the functions of c-Src, we evaluated mutants of c-Src lacking the A box (residues 88 to 137), the B box (residues 148 to 187) or the C box (residues 220 to 231). Each of these deletions caused a 14- to 30-fold increase in the in vitro level of kinase activity of c-Src. Chicken embryo fibroblasts expressing the deletion mutants displayed a transformed cell morphology, formed colonies in soft agar, and contained elevated levels of cellular phosphotyrosine-containing proteins. Src substrates p36, p85, p120, p125, the GTPase-activating protein (GAP), and several GAP-associated proteins were phosphorylated on tyrosine in cells expressing the A, B, or C box deletion mutant. p110 was highly phosphorylated in cells expressing the C box mutant, was weakly phosphorylated in cells expressing the B box mutant, and was not phosphorylated in cells expressing the A box mutant. Expression of the mutant proteins caused a reorganization of the actin cytoskeleton similar to that seen in v-Src-transformed cells. In addition, deletion of the A, B, or C box did not diminish the transforming or enzymatic activity of an activated variant of c-Src, E378G. These data indicate that deletion of the A, B, or C homology box causes an activation of the catalytic and transforming potential of c-Src and that while these mutations caused subtle differences in substrate phosphorylation, the homology boxes are not required for many of the phenotypic changes associated with transformation by Src.

The long-term effects of cranial external beam radiotherapy are emerging as survival rates for cerebral tumours improve. Cerebral cavernoma are a recognized consequence of cranial irradiation. Endocrinologists managing the life-long complications of hypopituitarism associated with irradiation need to be aware and vigilant of the risks of cavernoma formation, in particular in the population with a history of childhood irradiation. We present three cases of young patients who were diagnosed with cerebral cavernoma many years after childhood irradiation treatment and review the current literature on this condition. We discuss implications for endocrine practice as rising numbers of patients survive childhood cancer and irradiation and are now attending adult endocrine services for long-term management of secondary hypopituitarism.

Emerging contaminants (ECs) are chemicals that are currently unregulated due to limited understanding of health effects and limited data regarding occurrence. Wastewater treatment plants (WWTP) receive many ECs as components of influent waste and the removal of organic contaminants, such as ECs, occurs primarily by sorption to sludge. Therefore, it is important to develop measures of sorption behavior by ECs to sludge. This study evaluates sorption of three ECs: 3-tert-butyl-4-hydroxyanisole (BHA) a synthetic antioxidant, 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethyl-cyclopenta(g)-2-benzopyrane (HHCB) a polycyclic musk, and chlorpyrifos a organophosphate insecticide. Twenty-four hour laboratory-scale sorption experiments were conducted for each compound individually and then in combination, which allowed the quantification of sorption onto wastewater sludge and the affects of multiple compounds. ECs in both the liquid and solid phases were analyzed using a gas chromatograph with flame ionization detector (GC/FID). Isotherms of individual sorption behavior followed a linear trend (R2>0.9) for individual ECs, while Kd averaged 2,689 L kg−1, 27,786 L kg−1 and 31,402 L kg−1 for BHA, chlorpyrifos and HHCB, respectively. Sorption behavior for BHA was linear during combined studies with Kd of 1,766 L kg−1 or a decrease of 34%, while HHCB and chlorpyrifos followed non-linear isotherm models. Synergistic effects were observed with spike concentrations ≥25 mg L−1 for HHCB and ≥20 mg L−1 for chlorpyrifos. Kd values ranged from 16,984–6,000,000 L kg−1 for HHCB and 19,536–3,000,000 L kg−1 for chlorpyrifos. These distribution coefficients differed substantially from previously published values, mainly because few studies used sludge as the sorption media. Results suggest that HHCB and chlorpyrifos may be contained in the sludge unlike BHA, which is more available in the aqueous phase. Future investigations should evaluate WWTP processes for degrading ECs to harmless products and releases of ECs from sludge.