Cardiac xenotransplantation: Recent preclinical progress with 3-month median survival

ObjectivesTransplantation is limited by a lack of human organ donors. Organs derived from animals, most likely the pig, represent a potential solution to this problem. For the heart, 90-day median graft survival of life-supporting pig hearts transplanted to nonhuman primates has been considered a reasonable standard for entry into the clinical arena. Overcoming the immune barrier to successful cardiac xenotransplantation is most appropriately first explored with the non–life-supporting heterotopic model.MethodsWe performed a series of 7 heterotopic heart transplantations from CD46 transgenic pigs to baboons using a combination of therapeutic agents largely targeted at controlling the synthesis of anti-pig antibodies. Rituximab (anti-CD20) and Thymoglobulin (rabbit antithymocyte globulin [ATG]; SangStat Medical Corp, Fremont, Calif) were used as induction therapy. Baseline immunosuppression consisted of splenectomy, tacrolimus, sirolimus, steroids, and TPC (an anti-Gal antibody therapeutic). Rejection events were not treated.ResultsBy using Kaplan-Meier analysis, median graft survival was 96 days (range, 15–137 days; 95% confidence interval, 38–99 days). Only 2 grafts were lost as a result of rejection, as defined by cessation of graft palpation. There was no evidence of a consumptive coagulopathy, infectious complications were treatable, and no posttransplantation lymphoproliferative disorders occurred. No cellular infiltration was observed.ConclusionsThis study reports the longest median survival to date (96 days) of pig hearts transplanted heterotopically into baboons. Duplication of these results in the orthotopic life-supporting position could bring cardiac xenotransplantation to the threshold of clinical application

Nevrological manifestations in patiens with West Nile fever

Гарячка Західного Нілу (ГЗН) є найпоширенішим зооантропонозним трансмісивним «комариним» захворюванням у групі природно осередкових інфекцій. Вірус ГЗН належить до роду Flavivirus родини Flaviviridae, поширений на усіх континентах за винятком Антарктиди. В Європі основним видом комарів, які передають вірус ГЗН людям, є Culex pipiens. Інфікування описане також при вертикальній передачі від матері до дитини та парентеральним шляхом. За філогенетичними властивостями вірусу розрізняють кілька генетичних груп – генотипів, деякі з яких містять підгрупи, що обумовлює нерівномірний територіальний розподіл та тяжкість клінічної маніфестації ГЗН

Thrombus Permeability in Admission Computed Tomographic Imaging Indicates Stroke Pathogenesis Based on Thrombus Histology

Background and Purpose- Intracranial thrombi can be characterized according to their permeability as measured by contrast agent penetration. Thrombus composition and its associated pathogenesis are important factors affecting treatment and secondary prevention. We aimed to explore the histopathologic factors explaining the heterogeneity of thrombus permeability measures and evaluated potential correlations with stroke pathogenesis. Methods- Thrombus densities were measured in thin-slice noncontrast computed tomography and automatically aligned computed tomographic angiography images of 133 patients with large-vessel occlusions of the middle cerebral artery. Change in thrombus attenuation (Deltat) and corrected void fraction (epsilon; attenuation increase corrected for contralateral artery densities) were calculated. First, these thrombus perviousness measures were correlated with histological thrombus components (especially fractions of fibrin-platelet accumulation and red blood cells) and stroke pathogenesis (n=32). For validation, an association between perviousness and pathogenesis was assessed in a second, independent cohort (n=101). Results- Thrombus perviousness estimates were correlated with both fibrin/platelets fractions (Deltat: r=0.43, P=0.016/epsilon: r=0.45, P=0.01) and inversely with red blood cells counts (Deltat: r=-0.46, P=0.01/epsilon: r=-0.49, P=0.006). In the first cohort, Deltat was substantially higher in samples from patients with cardioembolic stroke pathogenesis as compared with noncardioembolic-derived thrombi ( P=0.026). In the validation cohort, thrombus perviousness measures differed significantly between cardioembolic (Deltat: median interquartile range=12.53 8.70-17.90; epsilon: median interquartile range=0.054 0.036-0.082) and noncardioembolic thrombi (Deltat: median interquartile range=3.2 2.17-6.44, P<0.001; epsilon: median interquartile range=0.020 0.011-0.027, P<0.001) and were associated with pathogenesis (Deltat: beta=0.45, P=0.016/epsilon: beta=83.6, P=0.013) in a binary logistic regression model. Conclusions- Permeable thrombi showed a strong correlation with lower fractions of red blood cells counts and more fibrin/platelets conglomerations, concurrent with an association with cardioembolic origin. This novel information about thrombus perviousness may be valuable as a new and simple to acquire imaging marker for identifying stroke pathogenesis using early and readily available imaging

Development of a risk score for outcome after transcatheter aortic valve implantation

Transcatheter aortic valve implantation (TAVI) is an increasingly common procedure in elderly and multimorbid patients with aortic stenosis. We aimed at developing a pre-procedural risk evaluation scheme beyond current surgical risk scores. We developed a risk algorithm for 1-year mortality in two cohorts consisting of 845 patients undergoing routine TAVI procedures by commercially available devices, mean age 80.9 +/- A 6.5, 51 % women. Clinical variables were determined at baseline. Multivariable Cox regression related clinical data to mortality (n = 207 deaths). To account for variability related to age and sex and by enrolment site we forced age, sex, and cohort into the score model. Body mass index, estimated glomerular filtration rate, hemoglobin, pulmonary hypertension, mean transvalvular gradient and left ventricular ejection fraction at baseline were most strongly associated with mortality and entered the risk prediction algorithm [C-statistic 0.66, 95 % confidence interval (CI) 0.61-0.70, calibration chi (2)-statistic = 6.51; P = 0.69]. Net reclassification improvement compared to existing surgical risk predication schemes was positive. The score showed reasonable model fit and calibration in external validation in 333 patients, N = 55 deaths (C-statistic 0.60, 95 % CI 0.52-0.68; calibration chi (2)-statistic = 16.2; P = 0.06). Additional measurement of B-type natriuretic peptide and troponin I did not improve the C-statistic. Frailty increased the C-statistic to 0.71, 95 % CI 0.65-0.76. We present a new risk evaluation tool derived and validated in routine TAVI cohorts that predicts 1-year mortality. Biomarkers only marginally improved risk prediction. Frailty increased the discriminatory ability of the score and needs to be considered. Risk algorithms specific for TAVI may help to guide decision-making when patients are evaluated for TAVI

<i>N</i>,<i>N</i>-Addition of Frustrated Lewis Pairs to Nitric Oxide: An Easy Entry to a Unique Family of Aminoxyl Radicals

The intramolecular cyclohexylene-bridged P/B frustrated Lewis pair [Mes₂PC₆H₁₀B­(C₆F₅)₂] <b>1b</b> reacts rapidly with NO to give the persistent FLP-NO aminoxyl radical <b>2b</b> formed by P/B addition to the nitrogen atom of NO. This species was fully characterized by X-ray diffraction, EPR and UV/vis spectroscopies, C,H,N elemental analysis, and DFT calculations. The reactive oxygen-centered radical <b>2b</b> undergoes a H-atom abstraction (HAA) reaction with 1,4-cyclohexadiene to give the diamagnetic FLP-NOH product <b>3b</b>. FLP-NO <b>2b</b> reacts with toluene at 70 °C in an HAA/radical capture sequence to give a 1:1 mixture of FLP-NOH <b>3b</b> and FLP-NOCH₂Ph <b>4b</b>, both characterized by X-ray diffraction. Structurally related FLPs [Mes₂PCHR¹CHR²B­(C₆F₅)₂] <b>1c</b>, <b>1d</b>, and <b>1e</b> react analogously with NO to give the respective persistent FLP-NO radicals <b>2c</b>, <b>2d</b>, and <b>2e</b>, respectively, which show similar HAA and O-functionalization reactions. The FLP-NOCHMePh <b>6b</b> derived from 1-bromoethylbenzene undergoes NOC bond cleavage at 120 °C with an activation energy of <i>E</i>_a = 35(2) kcal/mol. Species <b>6b</b> induces the controlled nitroxide-mediated radical polymerization (NMP) of styrene at 130 °C to give polystyrene with a polydispersity index of 1.3. The FLP-NO systems represent a new family of aminoxyl radicals that are easily available by <i>N</i>,<i>N</i>-cycloaddition of C₂-bridged intramolecular P/B frustrated Lewis pairs to nitric oxide

<i>N</i>,<i>N</i>-Addition of Frustrated Lewis Pairs to Nitric Oxide: An Easy Entry to a Unique Family of Aminoxyl Radicals

The intramolecular cyclohexylene-bridged P/B frustrated Lewis pair [Mes₂PC₆H₁₀B­(C₆F₅)₂] <b>1b</b> reacts rapidly with NO to give the persistent FLP-NO aminoxyl radical <b>2b</b> formed by P/B addition to the nitrogen atom of NO. This species was fully characterized by X-ray diffraction, EPR and UV/vis spectroscopies, C,H,N elemental analysis, and DFT calculations. The reactive oxygen-centered radical <b>2b</b> undergoes a H-atom abstraction (HAA) reaction with 1,4-cyclohexadiene to give the diamagnetic FLP-NOH product <b>3b</b>. FLP-NO <b>2b</b> reacts with toluene at 70 °C in an HAA/radical capture sequence to give a 1:1 mixture of FLP-NOH <b>3b</b> and FLP-NOCH₂Ph <b>4b</b>, both characterized by X-ray diffraction. Structurally related FLPs [Mes₂PCHR¹CHR²B­(C₆F₅)₂] <b>1c</b>, <b>1d</b>, and <b>1e</b> react analogously with NO to give the respective persistent FLP-NO radicals <b>2c</b>, <b>2d</b>, and <b>2e</b>, respectively, which show similar HAA and O-functionalization reactions. The FLP-NOCHMePh <b>6b</b> derived from 1-bromoethylbenzene undergoes NOC bond cleavage at 120 °C with an activation energy of <i>E</i>_a = 35(2) kcal/mol. Species <b>6b</b> induces the controlled nitroxide-mediated radical polymerization (NMP) of styrene at 130 °C to give polystyrene with a polydispersity index of 1.3. The FLP-NO systems represent a new family of aminoxyl radicals that are easily available by <i>N</i>,<i>N</i>-cycloaddition of C₂-bridged intramolecular P/B frustrated Lewis pairs to nitric oxide