A modified perfusion protocol for pulmonary endarterectomy in a patient with a hematologic malignancy treated with a tyrosine kinase inhibitor.

Tyrosine kinase inhibitors (TKI) are known to be highly effective in the treatment of various cancers with kinase-domain mutations such as chronic myelogenous leukemia. However, they have important side effects such as increased vascular permeability and pulmonary hypertension. In patients undergoing pulmonary endarterectomy with deep hypothermic circulatory arrest, these side effects may exacerbate postoperative complications such as reperfusion edema and persistent pulmonary hypertension. We report on a simple modification of the perfusion strategy to increase intravascular oncotic pressure by retrograde autologous priming and the addition of packed cells and albumin in a patient treated with a TKI.

Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition.

The intestinal microbiota has been implicated in insulin resistance, although evidence regarding causality in humans is scarce. We therefore studied the effect of lean donor (allogenic) versus own (autologous) fecal microbiota transplantation (FMT) to male recipients with the metabolic syndrome. Whereas we did not observe metabolic changes at 18 weeks after FMT, insulin sensitivity at 6 weeks after allogenic FMT was significantly improved, accompanied by altered microbiota composition. We also observed changes in plasma metabolites such as γ-aminobutyric acid and show that metabolic response upon allogenic FMT (defined as improved insulin sensitivity 6 weeks after FMT) is dependent on decreased fecal microbial diversity at baseline. In conclusion, the beneficial effects of lean donor FMT on glucose metabolism are associated with changes in intestinal microbiota and plasma metabolites and can be predicted based on baseline fecal microbiota composition.

High speed e-beam lithography for gold nanoarray fabrication and use in nanotechnology.

E-beam lithography has been used for reliable and versatile fabrication of sub-15 nm single-crystal gold nanoarrays and led to convincing applications in nanotechnology. However, so far this technique was either too slow for centimeter to wafer-scale writing or fast enough with the so-called dot on the fly (DOTF) technique but not optimized for sub-15 nm dots dimension. This prevents use of this technology for some applications and characterization techniques. Here, we show that the DOTF technique can be used without degradation in dots dimension. In addition, we propose two other techniques. The first one is an advanced conventional technique that goes five times faster than the conventional one. The second one relies on sequences defined before writing which enable versatility in e-beam patterns compared to the DOTF technique with same writing speed. By comparing the four different techniques, we evidence the limiting parameters for the writing speed. Wafer-scale fabrication of such arrays with 50 nm pitch allowed XPS analysis of a ferrocenylalkyl thiol self-assembled monolayer coated gold nanoarray.

High-fat diets rich in medium- versus long-chain fatty acids induce distinct patterns of tissue specific insulin resistance.

Excess dietary long-chain fatty acid (LCFA) intake results in ectopic lipid accumulation and insulin resistance. Since medium-chain fatty acids (MCFA) are preferentially oxidized over LCFA, we hypothesized that diets rich in MCFA result in a lower ectopic lipid accumulation and insulin resistance compared to diets rich in LCFA. Feeding mice high-fat (HF) (45% kcal fat) diets for 8 weeks rich in triacylglycerols composed of MCFA (HFMCT) or LCFA (HFLCT) revealed a lower body weight gain in the HFMCT-fed mice. Indirect calorimetry revealed higher fat oxidation on HFMCT compared to HFLCT (0.011.0±0.0007 vs. 0.0096±0.0015 kcal/g body weight per hour, P<.05). In line with this, neutral lipid immunohistochemistry revealed significantly lower lipid storage in skeletal muscle (0.05±0.08 vs. 0.30±0.23 area%, P <.05) and in liver (0.9±0.4 vs. 6.4±0.8 area%, P<.05) after HFMCT vs. HFLCT, while ectopic fat storage in low fat (LF) was very low. Hyperinsulinemic euglycemic clamps revealed that the HFMCT and HFLCT resulted in severe whole body insulin resistance (glucose infusion rate: 53.1±6.8, 50.8±15.3 vs. 124.6±25.4 µmol min(-1) kg(-1), P<.001 in HFMCT, HFLCT and LF-fed mice, respectively). However, under hyperinsulinemic conditions, HFMCT revealed a lower endogenous glucose output (22.6±8.0 vs. 34.7±8.5 µmol min(-1) kg(-1), P<.05) and a lower peripheral glucose disappearance (75.7±7.8 vs. 93.4±12.4 µmol min(-1) kg(-1), P<.03) compared to HFLCT-fed mice. In conclusion, both HF diets induced whole body insulin resistance compared to LF. However, the HFMCT gained less weight, had less ectopic lipid accumulation, while peripheral insulin resistance was more pronounced compared to HFLCT. This suggests that HF-diets rich in medium- versus long-chain triacylglycerols induce insulin resistance via distinct mechanisms.

Two time-point assessment of bile acid kinetics in humans using stable isotopes.

The stable isotope dilution measurement of bile acid pool sizes and turnover rates in humans has involved the collection of nine blood samples over four days. This precludes widespread application to larger population studies. This study describes a two time-point approach for blood sampling without loss of statistical power. Isotopic decay curves of cholic acid, chenodeoxycholic acid and deoxycholic acid acquired in three recent human studies were analysed. The optimal combination of two time-points was determined. Time-points around 12 and 72 h after administration allowed for the most accurate description of the decay curves and prediction of kinetic parameters. Analyses of 39 statistical comparisons of kinetic parameters based upon the two time-points and all time-points approaches exhibited only one slightly discrepant result. In conclusion, for group comparison of bile acid kinetics in humans, a two time-point blood collection approach at time-points near 12 and 72 h provides statistically reliable data.

Attenuated renal and intestinal injury after use of a mini-cardiopulmonary bypass system.

BACKGROUND: Transient, subclinical myocardial, renal, intestinal, and hepatic tissue injury and impaired homeostasis is detectable even in low-risk patients undergoing conventional cardiopulmonary bypass (CPB). Small extracorporeal closed circuits with low priming volumes and optimized perfusion have been developed to reduce deleterious effects of CPB. METHODS: A prospective, randomized trial was conducted in 49 patients undergoing elective coronary artery bypass graft surgery either with the use of a standard or mini-CPB system (Synergy). We determined early postoperative inflammatory response (leukocytosis, C-reactive protein, urine interleukin-6), platelet consumption and activation (urine thromboxane B2), proximal renal tubular injury (urine N-acetyl-glucosaminidase), and intestinal injury (intestinal fatty acid binding protein). RESULTS: In patients undergoing coronary artery bypass grafting with a mini-CPB system, we observed decreased priming volumes with subsequent attenuation of on-pump hemodilution, improved hemostatic status with reduced platelet consumption and platelet activation, decreased postoperative bleeding and minimized transfusion requirements. We also found reduced leukocytosis and decreased urinary interleukin-6. Levels of urine N-acetyl-glucosaminidase were on average threefold lower, and urinary intestinal fatty acid binding protein was 40% decreased in the patients on the mini-CPB system, as compared with standard CPB. CONCLUSIONS: The use of the mini-CPB system during myocardial revascularization represents a viable nonpharmacologic strategy that can attenuate the alterations in the hemostatic system, reduce bleeding and transfusion requirements, decrease systemic inflammatory response, and reduce immediate postoperative renal and intestinal tissue injury.

Evaluation of proinflammatory cytokines and inflammation markers as biomarkers for the action of thiazolidinediones in Type 2 diabetes mellitus patients and healthy volunteers.

AIMS: Thiazolidinediones (TZDs) not only enhance cellular glucose transport but are reported to have potent anti-inflammatory effects. These effects may play an important role in the insulin sensitizing mechanism, and possibly precede the effects on parameters of glucoregulation. We sought to investigate whether these anti-inflammatory effects could yield early responding biomarkers for TZD action in Type 2 diabetes mellitus (T2DM) patients and healthy volunteers (HV) to expedite early clinical development of novel compounds. METHODS: We investigated the timing of treatment effects on several proinflammatory cytokines and markers of inflammation in comparison with effects on typical measures of glucoregulation in T2DM patients and HV receiving rosiglitazone 4 mg or placebo twice daily for 6 weeks. RESULTS: We found a significant reduction in interleukin (IL)-6 [-39.4%, confidence interval (CI) - 60.0, - 8.2] and white blood cell count (-18.4%, CI - 30.2, - 4.5) after 4 weeks of treatment in the T2DM group. These anti-inflammatory effects did not precede the effects on typical parameters of glucoregulation in the T2DM group and there was no significant anti-inflammatory response in the HV group. CONCLUSION: We could not identify biomarkers that precede the effects of rosiglitazone on parameters of glucoregulation in T2DM or that have a significant response in HV. However, the IL-6 response observed in this study indicates a potential role for this cytokine as complementary biomarker in clinical 'proof of concept' studies with novel TZDs.

Dietary flavonoids and iodine metabolism.

Flavonoids have inhibiting effects on the proliferation of cancer cells, including thyroidal ones. In the treatment of thyroid cancer the uptake of iodide is essential. Flavonoids are known to interfere with iodide organification in vitro, and to cause goiter. The influence of flavonoids on iodine metabolism was studied in a human thyroid cancer cell line (FTC-133) transfected with the human sodium/iodide transporter (NIS). All flavonoids inhibited growth, and iodide uptake was decreased in most cells. NIS mRNA expression was affected during the early hours after treatment, indicating that these flavonoids can act on NIS. Pendrin mRNA expression did not change after treatment. Only myricetin increased iodide uptake. Apeginin, luteolin, kaempferol and F21388 increased the efflux of iodide, leading to a decreased retention of iodide. Instead myricetin increased the retention of iodide; this could be of use in the radioiodide treatment of thyroid cancer.