Is bridging to transplantation with a left ventricular assist device a risk factor for transplant coronary artery disease?

BACKGROUND: Left ventricular assist device (LVAD) support is associated with coagulopathy, bleeding, increased blood transfusion, and increased anti-HLA antibody production. Increased anti-HLA antibody production is associated with early transplant rejection, transplant coronary artery disease (CAD), and decreased post-transplant survival rates. We asked whether bridging to transplantation with an LVAD increases the risk of transplant CAD. METHODS: We reviewed data for all adults (>18 years old) who underwent heart transplantation at our institution between 1988 and 2000. After exclusion of transplant recipients who survived <3 years, we divided the remaining cohort into 2 groups: those bridged to transplantation with LVADs (mean duration of support, 149 +/- 107 days, n = 29) and those in United Network for Organ Sharing Status 1 bridged to transplantation without LVADs (controls, n = 86). We compared groups in terms of disease cause, age, sex, donor age, panel-reactive antibody testing, crossmatching, pre- and post-transplant cholesterol concentrations, diagnosis of diabetes mellitus or treated hypertension, infections, calcium channel blocker use, transplant rejection, ischemic time, cytomegalovirus infection, pre-transplant transfusion, and incidence of transplant CAD (defined as any coronary lesion identified by coronary angiography). We considered p < 0.05 to be significant. RESULTS: The bridged and control groups were similar in all respects except mean ischemic time (217 +/- 58 minutes vs 179 +/- 67 minutes, p = 0.007), post-transplant cholesterol concentration (212 +/- 55 mg/dl vs 171 +/- 66 mg/dl, p = 0.007), and pre-transplant transfusion incidence (100% vs 22%, p < 0.001). The incidence of transplant CAD was similar in both groups during a 3-year follow-up period (28% vs 17%, p = 0.238) and during total follow-up (34% vs 35%, p = 0.969). Multivariate logistic regression analysis identified cholesterol concentration at 1 year after transplantation as a significant predictor of CAD at 3 years after heart transplantation (p = 0.0029, odds ratio = 0.984). CONCLUSIONS: Bridging to transplantation with an LVAD does not increase the risk of transplant CAD. Nevertheless, aggressive prophylactic therapy to minimize potential risk factors for transplant CAD, such as increased cholesterol concentration, is warranted in all transplant recipients.     

Development of three parallel cytochrome P450 enzyme affinity detection systems coupled on-line to gradient high-performance liquid chromatography.

A high resolution screening (HRS) technology is described, in which gradient high-performance liquid chromatography (HPLC) is connected on-line to three parallel placed bioaffinity detection systems containing mammalian cytochromes P450 (P450s). The three so-called enzyme affinity detection (EAD) systems contained, respectively, liver microsomes from rats induced by beta-naphthoflavone (CYP1A activity), phenobarbital (CYP2B activity), and dexamethasone (CYP3A activity). Each P450-EAD system was optimized for enzyme, substrate, and organic modifier (isopropyl alcohol, methanol, and acetonitrile) in flow injection analysis mode. Characteristic P450 ligands were used to validate the P450-EAD systems. IC(50) values of the ligands were measured and found to be similar to those obtained with conventional microtiter plate reader assays. Detection limits (n = 3; signal-to-noise ratio = 3) of potent inhibitors ranged from 1 to 3 pmol for CYP1A activity, 4 to 17 pmol for CYP2B activity, and 4 to 15 pmol for CYP3A activity. The three optimized P450-EAD systems were subsequently coupled to gradient HPLC and used to screen compound mixtures for individual ligands. Finally, to increase analysis efficiency, a HRS system was constructed in which all three P450-EAD systems were coupled on-line and in parallel to gradient HPLC. The triple parallelized P450-EAD system was shown to enable rapid profiling of individual components in complex mixtures for inhibitory activity to three different P450s.     

Significance of screening in treatment and survival in bronchial carcinoma

In a retrospective study, the influence of the way bronchial carcinoma was detected was evaluated with respect to the possibility of surgery and to survival rates. From the 324 patients detected through mass screening (category I) 69.8% were suitable for surgery, whereas only 41.4% of the 736 patients detected because of pulmonary symptoms (category II) were deemed surgery-eligible. In category I, the type of surgical interventions were 65% (bi)lobectomy and 22.4% pneumonectomy. In category II, these figures were 23.4% and 53.6%, respectively. During the surgery, 10.6% turned out to be unresectable in category I, whereas 22.0% were in category II. There was also a marked difference in survival after 5 and 10 years. For category I, the 5-year survival rate was 23.4%, the 10-year survival 10.9%. In category II, these figures were 8.6% and 4.2%, respectively. The 5-year survival rate of all nonsurgically treated patients was 1% regardless of the method of diagnosis.     

Corticospinal excitability during laughter: implications for cataplexy and the comparison with REM sleep atonia

Cataplexy is usually seen as rapid eye movement (REM) sleep atonia occurring at an inopportune moment. REM sleep atonia is the result of postsynaptic inhibition, i.e. inhibition of alpha motor neurones. Although this may explain the suppression of H-reflexes during REM sleep, cataplexy and laughter, it is not the only explanation. Presynaptic inhibition, in which afferent impulses are prevented from reaching motor neurones, is an alternative. Testing H-reflexes and magnetic-evoked potentials (MEPs) helps to tell them apart: in postsynaptic inhibition MEPs and H-reflexes change in tandem, while H-reflexes may decrease independent of MEPs with other inhibition modes. We studied motor inhibition during laughter, the strongest trigger for cataplexy. H-reflexes were evoked every 2 s in the soleus muscle in 10 healthy subjects watching comical video fragments. MEPs were evoked when H-reflexes decreased during laughter, and, as a control, when subjects did not laugh. Pairs of MEPs and the immediately preceding H-reflexes were studied. Compared with the control condition, laughter caused mean MEP area to increase by 60% (P=0.006) and mean H-reflex amplitude to decrease by 33% (P=0.008). This pattern proves that postsynaptic inhibition cannot have been the sole influence. The findings do not prove which mechanisms are involved; one possibility is that the decrease in H-reflex amplitude was the result of presynaptic inhibition, and that cortical and/or spinal facilitation accounted for increased MEPs. Regardless, the pattern differs fundamentally from the reported mechanism of REM sleep atonia. Existing scanty data on cataplexy suggest a pattern of H-reflexes and MEPs similar to that during laughter, but this needs further study.     

Recirculation in double lumen catheter veno-venous extracorporeal membrane oxygenation measured by an ultrasound dilution technique

Recirculation is a limiting factor for oxygen delivery in double lumen catheter veno-venous extracorporeal membrane oxygenation (DLVV-ECMO). This study compares three different methods for the determination of the recirculation fraction during double lumen catheter veno-venous ECMO at ECMO flow rates of 150, 125, 100, 75, and 50 ml/kg.min in nine lambs: (1) an ultrasound dilution method, in which the change in ultrasound velocity in blood after injection of a saline bolus as a marker is used for determination of recirculation; (2) an SvO2 method using real mixed venous blood oxygen saturation, the gold standard, for determination of recirculation fraction; and (3) the CVL method, in which oxygen saturation of a blood sample of the inferior vena cava is considered to represent mixed venous oxygen saturation. In all methods, the recirculation fraction increased with increasing ECMO flow rate. The correlation coefficient between the ultrasound dilution method and the SvO2 method was 0.68 (p < 0.01); mean difference was -2.4% (p = 0.6). Correlation coefficient between the ultrasound dilution method and the CVL method was 0.48 (p < 0.01); mean difference was -18.1% (p < 0.01). The correlation coefficient between the SvO2 method and the CVL method was 0.51 (p < 0.01); mean difference was -15.7% (p < 0.01). The ultrasound dilution method is a useful method for measurement of the recirculation fraction in DLVV-ECMO and is easier to use than the other methods.     

Role of Toll-like receptor 4 in gram-positive and gram-negative pneumonia in mice

To determine the role of Toll-like receptor 4 (TLR4) in the immune response to pneumonia, C3H/HeJ mice (which display a mutant nonfunctional TLR4) and C3H/HeN wild-type mice were intranasally infected with either Streptococcus pneumoniae (a common gram-positive respiratory pathogen) or Klebsiella pneumoniae (a common gram-negative respiratory pathogen). In cases of pneumococcal pneumonia, TLR4 mutant mice showed a reduced survival only after infection with low-level bacterial doses, which was associated with a higher bacterial burden in their lungs 48 h postinfection. In Klebsiella pneumonia, TLR4 mutant mice demonstrated a shortened survival after infection with either a low- or a high-level bacterial dose together with an enhanced bacterial outgrowth in their lungs. These data suggest that TLR4 contributes to a protective immune response in both pneumococcal and Klebsiella pneumonia and that its role is more important in respiratory tract infection caused by the latter (gram-negative) pathogen.     

Donor genetic variants as risk factors for thrombosis after liver transplantation: A genome-wide association study

Thrombosis after liver transplantation substantially impairs graft- and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome-wide association study (GWAS) and meta-analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis-susceptible polymorphisms. By performing a meta-GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611-T, p = 4.22 × 10⁻⁰⁵) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696-C, p = 2.62 × 10⁻⁰⁵) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia-related variants, are associated with increased risk of thrombosis after liver transplantation.