The cholesterol-raising diterpenes from coffee beans increase serum lipid transfer protein activity levels in humans

Cafestol and kahweol–diterpenes present in unfiltered coffee— strongly raise serum VLDL and LDL cholesterol and slightly reduce HDL cholesterol in humans. The mechanism of action is unknown. We determined whether the coffee diterpenes may affect lipoprotein metabolism via effects on lipid transfer proteins and lecithin:cholesterol acyltransferase in a randomized, double-blind cross-over study with 10 healthy male volunteers. Either cafestol (61–64 mg/day) or a mixture of cafestol (60 mg/day) and kahweol (48–54 mg/day) was given for 28 days. Serum activity levels of cholesterylester transfer protein, phospholipid transfer protein and lecithin:cholesterol acyltransferase were measured using exogenous substrate assays. Relative to baseline values, cafestol raised the mean (±S.D.) activity of cholesterylester transfer protein by 18±12% and of phospholipid transfer protein by 21±14% (both P<0.001). Relative to cafestol alone, kahweol had no significant additional effects. Lecithin:cholesterol acyltransferase activity was reduced by 11±12% by cafestol plus kahweol (P=0.02). It is concluded that the effects of coffee diterpenes on plasma lipoproteins may be connected with changes in serum activity levels of lipid transfer proteins

Complications in subfascial endoscopic perforating vein surgery: A report of two cases

AbstractSubfascial endoscopic perforating vein surgery is a safe method for the division of incompetent perforating veins. Nevertheless, we report two cases with unfortunate complications: the posterior tibial artery and tibial nerve were damaged during the procedures. In one patient this resulted in a reintervention, but in both patients it resulted in permanent discomfort. We then present a guideline that may prevent damage to these critical structures. (J Vasc Surg 2001;33:1108-10.

ViroSpot microneutralization assay for antigenic characterization of human influenza viruses

The hemagglutination inhibition (HI) assay has been used for the antigenic characterization of influenza viruses for decades. However, the majority of recent seasonal influenza A viruses of the H3N2 subtype has lost the capacity to agglutinate erythrocytes of various species. The hemagglutination (HA) activity of other A(H3N2) strains is generally sensitive to the action of the neuraminidase inhibitor oseltamivir, which indicates that the neuraminidase and not the hemagglutinin is responsible for the HA activity. These findings complicate the antigenic characterization and selection of A(H3N2) vaccine strains, calling for alternative antigenic characterization assays. Here we describe the development and use of the ViroSpot microneutralization (MN) assay as a reliable and robust alternative for the HI assay. Serum neutralization of influenza A(H3N2) reference virus strains and epidemic isolates was determined by automated readout of immunostained cell monolayers, in a format designed to minimize the influence of infectious virus doses on serum neutralization titers. Neutralization of infection was largely independent from rates of viral replication and cell-to-cell transmission, facilitating the comparison of different virus isolates. Other advantages of the ViroSpot MN assay include its relative insensitivity to variation in test dose of infectious virus, automated capture and analyses of residual infection patterns, and compatibility with standardized large scale analyses. Using this assay, a number of epidemic influenza A(H3N2) strains that failed to agglutinate erythrocytes, were readily characterized antigenically

Galactose inhibition of the constitutive transport of hexoses in Saccharomyces cerevisiae

The relationship between the pathways of glucose and galactose utilization in Saccharomyces cerevisiae has been studied. Galactose (which is transported and phosphorylated by inducible systems) is a strong inhibitor of the utilization of glucose, fructose and mannose (which have the same constitutive transport and phosphorylation systems). Conversely, all these three hexoses inhibit the utilization of galactose, though with poor efficiency. These cross-inhibitions only occur in yeast adapted to galactose or in galactose-constitutive mutants. The efficiency of galactose as inhibitor is even greater than the efficiencies of each of the other three hexoses to inhibit the utilization of each other. Phosphorylation is not involved in the inhibition and transport of sugars is the affected step. The cross-inhibitions between galactose and either glucose, fructose or mannose do not implicate utilization of one hexose at the expense of the other, as it occurs in the mutual interactions between the latter three sugars. it seems that, by growing the yeast in galactose, a protein component is synthesized, or alternatively modified, that once bound to either galactose or any one of the other three hexoses (glucose, fructose or mannose), cross-interacts respectively with the constitutive or the inducible transport systems, impairing their function.This work was supported by a grant (PB87-0206) from the DGICYT, Promoción General del Conocimiento.Peer Reviewe

Optimization by Quantum Annealing: Lessons from hard 3-SAT cases

The Path Integral Monte Carlo simulated Quantum Annealing algorithm is applied to the optimization of a large hard instance of the Random 3-SAT Problem (N=10000). The dynamical behavior of the quantum and the classical annealing are compared, showing important qualitative differences in the way of exploring the complex energy landscape of the combinatorial optimization problem. At variance with the results obtained for the Ising spin glass and for the Traveling Salesman Problem, in the present case the linear-schedule Quantum Annealing performance is definitely worse than Classical Annealing. Nevertheless, a quantum cooling protocol based on field-cycling and able to outperform standard classical simulated annealing over short time scales is introduced.Comment: 10 pages, 6 figures, submitted to PR

Spitzer Space Telescope observations of magnetic cataclysmic variables: possibilities for the presence of dust in polars

We present Spitzer Space Telescope photometry of six short-period polars, EF Eri, V347 Pav, VV Pup, V834 Cen, GG Leo, and MR Ser. We have combined the Spitzer Infrared Array Camera (3.6 -8.0 microns) data with the 2MASS J, H, K_s photometry to construct the spectral energy distributions of these systems from the near- to mid-IR (1.235 - 8 microns). We find that five out of the six polars have flux densities in the mid-IR that are substantially in excess of the values expected from the stellar components alone. We have modeled the observed SEDs with a combination of contributions from the white dwarf, secondary star, and either cyclotron emission or a cool, circumbinary dust disk to fill in the long-wavelength excess. We find that a circumbinary dust disk is the most likely cause of the 8 micron excess in all cases, but we have been unable to rule out the specific (but unlikely) case of completely optically thin cyclotron emission as the source of the observed 8 micron flux density. While both model components can generate enough flux at 8 microns, neither dust nor cyclotron emission alone can match the excess above the stellar components at all wavelengths. A model combining both cyclotron and dust contributions, possibly with some accretion-generated flux in the near-IR, is probably required, but our observed SEDs are not sufficiently well-sampled to constrain such a complicated model. If the 8 micron flux density is caused by the presence of a circumbinary dust disk, then our estimates of the masses of these disks are many orders of magnitude below the mass required to affect CV evolution.Comment: 58 pages, 14 figures, ApJ accepte

Healthy living the the Amsterdam region:Housing market, environmental quality, health and inequality in the metropolitan region

De centrale vraag was in hoeverre veranderde planning in de Amsterdamse regionale woningmarkt bijdraagt aan verschillen in de mate van blootstelling aan omgevingseffecten voor kopers en huurders, en in hoeverre omgevingskwaliteit en vervuiling te koppelen is aan gezondheidsuitkomsten.Het onderzoek bracht hierom unieke, grootschalige kwantitatieve datasets over woonomgeving, individuele bewoners en medische gesteldheid bij elkaar. Hierdoor kon de blootstelling aan luchtvervuiling, geluidoverlast, groenvoorzieningen en hittestress vergeleken worden, en konden de effecten van blootstelling op psychische en lichamelijke gezondheid geschat worden. Het onderzoek laat verschillen zien zijn tussen kopers en huurders in blootstelling. In de meest recente nieuwbouw is dit verschil met name groter voor particuliere huurders. Dit lijkt een gevolg van recente verstedelijking langs infrastructuur en in bevolkte gebieden (verdichting in de stad). Ondanks aanzienlijke blootstellings- en gezondheidsverschillen tussen huurders en kopers, is het verband tussen verschillen in blootstelling en gezondheidsuitkomsten echter zwak, en behoeft verder onderzoek.De uitkomsten dragen bij aan academische debatten over milieurechtvaardigheid, ruimtelijke gezondheid, en het cumulatieve karakter van ongelijkheden. Daarnaast biedt het inzicht in de opeenstapeling van verschillende dimensies van ongelijkheid en kunnen de bevindingen bijdragen aan de ontwikkeling van interventies en beleid voor een duurzame, gezondere, en rechtvaardigere ruimtelijke ordening, buurtontwikkeling en woningmarkt. Om beleid en interventies te helpen zijn samen met maatschappelijke partners vijf beleidsdilemma’s opgesteld.Het twee jaar durende onderzoek is uitgevoerd door een interdisciplinair team van geografen, planologen en medisch onderzoekers van Amsterdam Institute for Social Science Research (AISSR) en van Amsterdam UMC, onder leiding van dr. Wouter van Gent (Urban Geographies, UvA). Maatschappelijke partners zijn GGD Amsterdam, Amsterdamse Federatie Woningcorporaties, Stichting de Gezonde Stad, en de Gemeente Amsterdam. Het project is gefinancierd door Kenniscentrum Ongelijkheid

Cardiac safety of adjuvant pegylated liposomal doxorubicin with concurrent trastuzumab: a randomized phase II trial

Background The cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) in an adjuvant breast cancer treatment regimen is unknown. Patients and methods Women with resected node-positive or intermediate-risk node-negative HER2 overexpressing breast cancer and baseline left ventricular ejection fraction (LVEF) ≥55% were randomized (1:2) to doxorubicin 60 mg/m2 (A)+cyclophosphamide 600 mg/m2 (C) every 21 days (q21d) for four cycles or PLD 35 mg/m2+C q21d+trastuzumab 2 mg/kg weekly (H) for 12 weeks. Both groups then received paclitaxel (Taxol, T) 80 mg/m2 with H for 12 weeks followed by H to complete 1 year. The primary end point was cardiac event rate or inability to administer 1 year of trastuzumab. Results Of 181 randomized patients, 179 underwent cardiac analysis. The incidence of cardiac toxicity or inability to administer trastuzumab due to cardiotoxicity was 18.6% [n=11; 95% confidence interval (CI) 9.7% to 30.9%] with A+C → T+H and 4.2% (n=5; 95% CI 1.4% to 9.5%) with PLD+C+H → T+H (P=0.0036). All events, except one, were asymptomatic systolic dysfunction or mildly symptomatic heart failure. Mean absolute LVEF reduction at cycle 8 was greater with doxorubicin (5.6% versus 2.1%; P=0.0014). Conclusion PLD+C+H → T+H is feasible and results in lower early cardiotoxicity rates compared with A+C → T+

Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets.

<div><p>Background</p><p>Pulmonary first pass filtration of particles marginally exceeding ∼7 µm (the size of a red blood cell) is used routinely in diagnostics, and allows cellular aggregates forming or entering the circulation in the preceding cardiac cycle to lodge safely in pulmonary capillaries/arterioles. Pulmonary arteriovenous malformations compromise capillary bed filtration, and are commonly associated with ischaemic stroke. Cohorts with CT-scan evident malformations associated with the highest contrast echocardiographic shunt grades are known to be at higher stroke risk. Our goal was to identify within this broad grouping, which patients were at higher risk of stroke.</p><p>Methodology</p><p>497 consecutive patients with CT-proven pulmonary arteriovenous malformations due to hereditary haemorrhagic telangiectasia were studied. Relationships with radiologically-confirmed clinical ischaemic stroke were examined using logistic regression, receiver operating characteristic analyses, and platelet studies.</p><p>Principal Findings</p><p>Sixty-one individuals (12.3%) had acute, non-iatrogenic ischaemic clinical strokes at a median age of 52 (IQR 41–63) years. In crude and age-adjusted logistic regression, stroke risk was associated not with venous thromboemboli or conventional neurovascular risk factors, but with low serum iron (adjusted odds ratio 0.96 [95% confidence intervals 0.92, 1.00]), and more weakly with low oxygen saturations reflecting a larger right-to-left shunt (adjusted OR 0.96 [0.92, 1.01]). For the same pulmonary arteriovenous malformations, the stroke risk would approximately double with serum iron 6 µmol/L compared to mid-normal range (7–27 µmol/L). Platelet studies confirmed overlooked data that iron deficiency is associated with exuberant platelet aggregation to serotonin (5HT), correcting following iron treatment. By MANOVA, adjusting for participant and 5HT, iron or ferritin explained 14% of the variance in log-transformed aggregation-rate (p = 0.039/p = 0.021).</p><p>Significance</p><p>These data suggest that patients with compromised pulmonary capillary filtration due to pulmonary arteriovenous malformations are at increased risk of ischaemic stroke if they are iron deficient, and that mechanisms are likely to include enhanced aggregation of circulating platelets.</p></div

Heat-induced BRCA2 degradation in human tumours provides rationale for hyperthermia-PARP-inhibitor combination therapies

Purpose: Hyperthermia (40–44 °C) effectively sensitises tumours to radiotherapy by locally altering tumour biology. One of the effects of heat at the cellular level is inhibition of DNA repair by homologous recombination via degradation of the BRCA2-protein. This suggests that hyperthermia can expand the group of patients that benefit from PARP-inhibitors, a drug exploiting homologous recombination deficiency. Here, we explore whether the molecular mechanisms that cause heat-mediated degradation of BRCA2 are conserved in cell lines from various origins and, most importantly, whether, BRCA2 protein levels can be attenuated by heat in freshly biopted human tumours. Experimental design: Cells from four established cell lines and from freshly biopsied material of cervical (15), head- and neck (9) or bladder tumours (27) were heated to 42 °C for 60 min ex vivo. In vivo hyperthermia was studied by taking two biopsies of the same breast or cervical tumour: one before and one after treatment. BRCA2 protein levels were measured by immunoblotting. Results: We found decreased BRCA2-levels after hyperthermia in all established cell lines and in 91% of all tumours treated ex vivo. For tumours treated with hyperthermia in vivo, technical issues and intra-tumour heterogeneity prevented obtaining interpretable results. Conclusions: This study demonstrates that heat-mediated degradation of BRCA2 occurs in tumour material directly derived from patients. Although BRCA2-degradation may not be a practical biomarker for heat deposition in situ, it does suggest that application of hyperthermia could be an effective method to expand the patient group that could benefit from PARP-inhibitors