Chronic critical limb ischemia: European experiences

Chronic critical limb ischemia still poses a substantial threat to both limb and life of the affected patients since these patients suffer typically also from associated cardiac and cerebrovascular disease and other severe comorbidities. Due to improved secondary prevention strategies and dedicated technical innovation, however, clinical outcomes have improved in the recent years. Purpose of this article is to provide a balanced discussion of contemporary treatment concepts for patients with critical limb ischemia with a focus on arterial revascularization.

Improved dispersive analysis of the scalar form factor of the nucleon

We present a coupled system of integral equations for the pp → ¯NN and ¯K K → ¯N N S-waves derived from Roy–Steiner equations for pion–nucleon scattering. We discuss the solution of the corresponding two-channel Muskhelishvili–Omnès problem and apply the results to a dispersive analysis of the scalar form factor of the nucleon fully including ¯KK intermediate states. In particular, we determine the corrections Ds and DD, which are needed for the extraction of the pion– nucleon s term from pN scattering, and show that the difference DD −Ds = (−1.8±0.2)MeV is insensitive to the input pN parameters.

A field trial of infrared thermography as a non-invasive diagnostic tool for early detection of digital dermatitis in dairy cows

Infrared thermography (IRT) was used to detect digital dermatitis (DD) prior to routine claw trimming. A total of 1192 IRT observations were collected from 149 cows on eight farms. All cows were housed in tie-stalls. The maximal surface temperatures of the coronary band (CB) region and skin (S) of the fore and rear feet (mean value of the maximal surface temperatures of both digits for each foot separately, CBmax and Smax) were assessed. Grouping was performed at the foot level (presence of DD, n=99; absence, n=304), or at the cow level (all four feet healthy, n=24) or where there was at least one DD lesion on the rear feet, n=37). For individual cows (n=61), IRT temperature difference was determined by subtracting the mean sum of CBmax and Smax of the rear feet from that of the fore feet. Feet with DD had higher CBmax and Smax (P<0.001) than healthy feet. Smax was significantly higher in feet with infectious DD lesions (M-stage: M2+M4; n=15) than in those with non-infectious M-lesions (M1+M3; n=84) (P=0.03), but this was not the case for CBmax (P=0.12). At the cow level, an optimal cut-off value for detecting DD of 0.99°C (IRT temperature difference between rear and front feet) yielded a sensitivity of 89.1% and a specificity of 66.6%. The results indicate that IRT may be a useful non-invasive diagnostic tool to screen for the presence of DD in dairy cows by measuring CBmax and Smax.

SUSYFLAVOR v2: A Computational tool for FCNC and CP-violating processes in the MSSM

We present SUSY_FLAVOR version 2 — a Fortran 77 program that calculates low-energy flavor observables in the general R-parity conserving MSSM. For a set of MSSM parameters as input, the code gives predictions for: 1. Electric dipole moments of the leptons and the neutron. 2. Anomalous magnetic moments (i.e. g − 2) of the leptons. 3. Radiative lepton decays (μ → eγ and τ → μγ , eγ ). 4. Rare Kaon decays (K0 L → π0 ¯νν and K+ → π+ ¯νν). 5. Leptonic B decays (Bs,d → l+l−, B → τ ν and B → Dτ ν). 6. Radiative B decays (B → ¯ Xsγ ). 7. ΔF = 2 processes ( ¯ K0–K0, ¯D–D, ¯Bd–Bd and ¯Bs–Bs mixing). Comparing to SUSY_FLAVOR v1, where the matching conditions were calculated strictly at one-loop level, SUSY_FLAVOR v2 performs the resummation of all chirally enhanced corrections, i.e. takes into account the enhanced effects from tan β and/or large trilinear soft mixing terms to all orders in perturbation theory. Also, in SUSY_FLAVOR v2 new routines calculation of B → (D)τ ν, g − 2, radiative lepton decays and Br(l → l′γ ) were added. All calculations are done using exact diagonalization of the sfermion mass matrices. The program can be obtained from http://www.fuw.edu.pl/susy_flavor.

Pyroelectric and piezoelectric scanning microscopy applied to reveal the bipolar state of 4-iodo-4′-nitrobiphenyl (INBP)

Two recent scanning probe techniques were applied to investigate the bipolar twin state of 4-iodo-4′-nitrobiphenyl (INBP) crystals. Solution grown crystals of INBP show typically a morphology which does not express that of a mono-domain polar structure (Fdd2, mm2). From previous X-ray diffraction a twinning volume ratio of [similar]70 : 30 is now explained by two unipolar domains (Flack parameter: 0.075(29)) of opposite orientation of the molecular dipoles, joined by a transition zone showing a width of [similar]140 μm. Scanning pyroelectric microscopy (SPEM) demonstrates a continuous transition of the polarization P from +P into −P across the zone. Application of piezoelectric force microscopy (PFM) confirms unipolar alignment of INBP molecules down to a resolution of [similar]20 nm. A previously proposed real structure for INBP crystals built from lamellae with antiparallel alignment is thus rejected. Anomalous X-ray scattering was used to determine the absolute molecular orientation in the two domains. End faces of the polar axis 2 are thus made up by NO2 groups. Using a previously determined negative pyroelectric coefficient pc leads to a confirmation also by a SPEM analysis. Calculated values for functional group interactions (DA), (AA), (DD) and the stochastic theory of polarity formation allow us to predict that NO2 groups should terminate corresponding faces. Following the present analysis, INBP may represent a first example undergoing dipole reversal upon growth to end up in a bipolar state.

The angiotensin-converting enzyme insertion/deletion polymorphism and its associations with carotid artery wall thickness and coronary heart disease: The atherosclerosis risk in communities study

Coronary heart disease (CHD) is the leading cause of death in the United States. Recently, renin-angiotensin system (RAS) was found associated with atherosclerosis formation, with angiotensin II inducing vascular smooth muscle cell growth and migration, platelet activation and aggregation, and stimulation of plasminogen activator inhibitor-1. Angiotensin II is converted from angiotensin I by angiotensin I-converting enzyme (ACE) and this enzyme is mainly genetically determined. The ACE gene has been assigned to chromosome 17q23 and an insertion/deletion (I/D)polymorphism has been characterized by the presence/absence of a 287 bp fragment in intron 16 of the gene. The two alleles form three genotypes, namely, DD, ID and II and the DD genotype has been linked to higher plasma ACE levels and cell ACE activity.^ In this study, the association between the ACE I/D polymorphism and carotid artery wall thickness measured by B-mode ultrasound was investigated in a biracial sample, and the association between the gene and incident CHD was investigated in whites and if the gene-CHD association in whites, if any, was due to the gene effect on atherosclerosis. The study participants are from the prospective Atherosclerosis Risk in Communities (ARIC) Study, including adults aged 45 to 65 years. The present dissertation used a matched case-control design for studying the associations of the ACE gene with carotid artery atherosclerosis and an unmatched case-control design for the association of the gene with CHD. A significant recessive effect of the D allele on carotid artery thickness was found in blacks (OR = 3.06, 95% C.I: 1.11-8.47, DD vs. ID and II) adjusting for age, gender, cigarette smoking, LDL-cholesterol and diabetes. No similar associations were found in whites. The ACE I/D polymorphism is significantly associated with coronary heart disease in whites, and while stratifying data by carotid artery wall thickness, the significant associations were only observed in thin-walled subgroups. Assuming a recessive effect of the D allele, odds ratio was 2.84 (95% C.I:1.17-6.90, DD vs. ID and II) and it was 2.30 (95% C.I:1.22-4.35, DD vs. ID vs. II) assuming a codominant effect of the D allele. No significant associations were observed while comparing thick-walled CHD cases with thin-walled controls. Following conclusions could be drawn: (1) The ACE I/D polymorphism is unlikely to confer appreciable increase in the risk of carotid atherosclerosis in US whites, but may increases the risk of carotid atherosclerosis in blacks. (2) ACE I/D polymorphism is a genetic risk factor for incident CHD in US whites and this effect is separate from the chronic process of atherosclerosis development. Finally, the associations observed here are not causal, since the I/D polymorphism is in an intron, where no ACE proteins are encoded. ^

Seasonal Deuterium Excess in a Tien Shan Ice Core: Influence of Moisture Transport and Recycling in Central Asia

Stable water isotope (delta(18)O, deltaD) data from a high elevation (5100 masl) ice core recovered from the Tien Shan Mountains, Kyrgyzstan, display a seasonal cycle in deuterium excess (d = deltaD - 8* delta(18)O) related to changes in the regional hydrologic cycle during 1994 - 2000. While there is a strong correlation (r(2) = 0.98) between delta(18)O and dD in the ice core samples, the regression slope (6.9) and mean d value (23.0) are significantly different than the global meteoric water line values. The resulting time-series ice core d profile contains distinct winter maxima and summer minima, with a yearly d amplitude of similar to 15 - 20parts per thousand. Local-scale processes that may affect d values preserved in the ice core are not consistent with the observed seasonal variability. Data from Central Asian monitoring sites in the Global Network of Isotopes in Precipitation (GNIP) have similar seasonal d changes. We suggest that regional-scale hydrological conditions, including seasonal changes in moisture source, transport, and recycling in the Caspian/ Aral Sea region, are responsible for the observed spatial and temporal d variability.

Why Some People Discount More than Others: Baseline Activation in the Dorsal PFC Mediates the Link between COMT Genotype and Impatient Choice

Individuals differ widely in how steeply they discount future rewards. The sources of these stable individual differences in delay discounting (DD) are largely unknown. One candidate is the COMT Val158Met polymorphism, known to modulate prefrontal dopamine levels and affect DD. To identify possible neural mechanisms by which this polymorphism may contribute to stable individual DD differences, we measured 73 participants' neural baseline activation using resting electroencephalogram (EEG). Such neural baseline activation measures are highly heritable and stable over time, thus an ideal endophenotype candidate to explain how genes may influence behavior via individual differences in neural function. After EEG-recording, participants made a series of incentive-compatible intertemporal choices to determine the steepness of their DD. We found that COMT significantly affected DD and that this effect was mediated by baseline activation level in the left dorsal prefrontal cortex (DPFC): (i) COMT had a significant effect on DD such that the number of Val alleles was positively correlated with steeper DD (higher numbers of Val alleles means greater COMT activity and thus lower dopamine levels). (ii) A whole-brain search identified a cluster in left DPFC where baseline activation was correlated with DD; lower activation was associated with steeper DD. (iii) COMT had a significant effect on the baseline activation level in this left DPFC cluster such that a higher number of Val alleles was associated with lower baseline activation. (iv) The effect of COMT on DD was explained by the mediating effect of neural baseline activation in the left DPFC cluster. Our study thus establishes baseline activation level in left DPFC as salient neural signature in the form of an endophenotype that mediates the link between COMT and DD.

Virus-like particle-mediated intracellular delivery of mRNA cap analog with in vivo activity against hepatocellular carcinoma.

UNLABELLED Adenovirus dodecahedron (Dd), a nanoparticulate proteinaceous biodegradable virus-like particle (VLP), was used as a vector for delivery of an oncogene inhibitor to hepatocellular carcinoma (HCC) rat orthotopic model. Initiation factor eIF4E is an oncogene with elevated expression in human cancers. Cell-impermeant eIF4E inhibitor, cap structure analog (cap) and anti-cancer antibiotic doxorubicin (Dox) were delivered as Dd conjugates. Dd-cap and Dd-dox inhibited cancer cell culture proliferation up to 50 and 84%, respectively, while with free Dox similar results could be obtained only at a 5 times higher concentration. In animal HCC model the combination treatment of Dd-cap/Dd-dox caused 40% inhibition of tumor growth. Importantly, the level of two pro-oncogenes, eIF4E and c-myc, was significantly diminished in tumor sections of treated rats. Attachment to Dd, a virus-like particle, permitted the first demonstration of cap analog intracellular delivery and resulted in improved doxorubicin delivery leading to statistically significant inhibition of HCC tumor growth. FROM THE CLINICAL EDITOR Adenovirus dodecahedron, a nanoparticulate proteinaceous biodegradable virus-like particle was used in this study as a vector for the concomitant delivery of cap structure analog and doxorubicine to hepatocellular carcinoma in a rat model, resulting in significant inhibition of tumor growth.

Heterologous expression of equine CYP3A94 and investigation of a tunable system to regulate co-expressed NADPH P450 oxidoreductase levels.

The activity of cytochrome P450 enzymes depends on the enzyme NADPH P450 oxidoreductase (POR). The aim of this study was to investigate the activity of the equine CYP3A94 using a system that allows to regulate the POR protein levels in mammalian cells. CYP3A94 and the equine POR were heterologously expressed in V79 cells. In the system used, the POR protein regulation is based on a destabilizing domain (DD) that transfers its instability to a fused protein. The resulting fusion protein is therefore degraded by the ubiquitin-proteasome system (UPS). Addition of "Shield-1" prevents the DD fusion protein from degradation. The change of POR levels at different Shield-1 concentrations was demonstrated by cytochrome c reduction, Western immunoblot analysis, and immunocytochemistry. The alteration of CYP3A94 activity was investigated using a substrate (BFC) known to detect CYP3A4 activity. Equine CYP3A94 was demonstrated to be metabolically active and its activity could be significantly elevated by co-expression of POR. Cytochrome c reduction was significantly increased in V79-CYP3A94/DD-POR cells compared to V79-CYP3A94 cells. Surprisingly, incubation with different Shield-1 concentrations resulted in a decrease in POR protein shown by Western immunoblot analysis. Cytochrome c reduction did not change significantly, but the CYP3A94 activity decreased more than 4-fold after incubation with 500 nM and 1 µM Shield-1 for 24 hours. No differences were obtained when V79-CYP3A94 POR cells with and without Shield-1 were compared. The basal activity levels of V79-CYP3A94/DD-POR cells were unexpectedly high, indicating that DD/POR is not degraded without Shield-1. Shield-1 decreased POR protein levels and CYP3A94 activity suggesting that Shield-1 might impair POR activity by an unknown mechanism. Although regulation of POR with the pPTuner system could not be obtained, the cell line V79-CYP3A94/DD-POR system can be used for further experiments to characterize the equine CYP3A94 since the CYP activity was significantly enhanced with co-expressed POR.

The influence of absorbed solar radiation by Saharan dust on hurricane genesis

To date, the radiative impact of dust and the Sahar an air layer (SAL) on North Atlantic hurricane activity is not yet known. According to previous studies, dust stabilizes the atmosphere due to absorption of solar radiation but thus shifts convection to regions more conducive for hurricane genesis. Here we analyze differences in hurricane genesis and frequency from ensemble sensitivity simulations with radiatively active and inactive dust in the aerosol-climate model ECHAM6-HAM. We investigate dust burden and other hurricane-related variables and determine their influence on disturbances which develop into hurricanes (developing disturbances, DDs) and those which do not (nondeveloping disturbances, NDDs). Dust and the SAL are found to potentially have both inhibiting and supporting influences on background conditions for hurricane genesis. A slight southward shift of DDs is determined when dust is active as well as a significant warming of the SAL, which leads to a strengthening of the vertical circulation associated with the SAL. The dust burden of DDs is smaller in active dust simulations compared to DDs in simulations with inactive dust, while NDDs contain more dust in active dust simulations. However, no significant influence of radiatively active dust on other variables in DDs and NDDs is found. Furthermore, no substantial change in the DD and NDD frequency due to the radiative effects of dust can be detected.

New associations of classic acute macular neuroretinopathy

PURPOSE: To describe novel underlying associations of classic acute macular neuroretinopathy (AMN). METHODS: Multimodal imaging case series evaluating patients with classic AMN lesions and previously unreported underlying aetiologies. RESULTS: Six patients were included (five women, one man, mean age 30±7 years). Mean distance best corrected visual acuity at initial presentation was 0.21±0.3 logMAR (mean Snellen acuity: 20/30, range 20/15-20/100) and at last follow-up visit 0.09±0.17 logMAR (Snellen acuity: 20/20, range 20/15-20/60). All cases but one had bilateral lesions and showed typical parafoveal hyporeflective lesions on infrared imaging, which corresponded to the hyper-reflectivity in the Henle's layer with attenuation of the external limiting membrane, the ellipsoid zone and interdigitation zone. Underlying diseases included thrombocytopenia and anaemia associated with dengue fever, acute lymphoblastic leukaemia, chronic kidney disease and ulcerative colitis, while Valsalva-like manoeuvre was found to be a potential trigger. Other novel associations included the use of lisdexamphetamine. CONCLUSIONS: Classic AMN may be associated with leukaemia, dengue fever, ulcerative colitis and chronic kidney disease, probably as a result of chorioretinal hypoxia in the setting of thrombocytopenia and anaemia. Adrenergic agonists such as lisdexamphetamine may also contribute to the manifestation of AMN.