New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

A multicentre outcome analysis to define global benchmarks for donation after circulatory death liver transplantation

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Highly efficient ex vivo gene transfer to the transplanted heart by means of hypothermic perfusion with a low dose of adenoviral vector.

Background: Hypothermic conditions required for donor heart preservation may reduce gene-transfer efficiency Experiments were designed to determine whether a perfusion technique could improve the efficiency of gene transfer to donor hearts. Methods: An adenoviral vector encoding beta-galactosidase (3.5 x 10(8) plaque-forming units) was infused into explanted rat hearts under 4 conditions teach n = 6): (1) the virus was diluted in 350 mu L of University of Wisconsin solution and infused as a high-pressure bolus into the coronary arteries of donor hearts through the aortic root; (2) the virus was diluted in 5 mL of University of Wisconsin solution and circulated by means of a peristaltic pump (flow, 0.75 mL/min) through the vasculature of the donor heart for 30 minutes; (3) 5 mi of viral solution was circulated as for group 2 for 15 minutes; and (4) 5 mt of viral solution was circulated for 5 minutes at a flow rate of 2.4 mL/min, Transduced hearts were transplanted into the abdomen of syngeneic rats, and transgene expression was assessed by means of immunoassay 4 days later. Results: The median beta-galactosidase content was (1) 45.0 ng/mg protein (25th-75th percentile, 33-73 ng/mg), (2) 6 10 ng/mg protein (25th-75th percentile, 613-878 ng/mg), (3) 493.8 ng/mg protein (25th-75th percentile, 456-527 ng/mg), and (4) 503.3 ng/mg protein (25th-75th percentile, 475-562 ng/mg; P <.01 for group 2 vs group 1, and P <.05 for groups 3 and 4 vs group 1), Transgene expression was predominantly in myocytes and favored the subepicardial region of the right ventricle, Conclusion: Hypothermic perfusion of the donor heart with an adenoviral vector resulted in efficient transgene expression compared with that induced by a single bolus injection

Donor safety and remnant liver volume in living donor liver transplantation

PubMed ID: 18668669Living donor liver transplantation is now a common practice in countries in which the availability of cadaveric organs is limited. The preoperative preparation, intraoperative surgical technique, and postoperative care of donors and recipients have evolved in recent years. We retrospectively compared 67 donors with a remnant liver volume equal to or more than 30% (group 1) with 14 donors who had less than 30% remnant liver volume (group 2) for donor outcomes. All the complications in donors were systematically classified. Donors with less than 30% remnant liver volume showed significantly higher peak aspartate aminotransferase, alanine aminotransferase, international normalized ratio, and bilirubin levels. There were 6 complications in group 1 and 4 complications in group 2. The difference between the 2 groups in terms of donor complications did reach statistical significance (P = 0.043); donors with a remnant liver volume < 30% had a 4 times greater relative risk of morbidity. In conclusion, the use of donors with less than 30% Tmnant liver volume is highly debatable as donor safety should be of utmost importance in living donor liver transplantation. © 2008 AASLD

Gene transfer of endothelial nitric oxide synthase to pulmonary allografts: impact on acute rejection

Experiments were designed to study whether overexpression of nitric oxide (NO) from endothelial nitric oxide synthase (eNOS) affects acute rejection. Allogenic, orthotopic single-lung transplantation was performed after transbronchial adenoviral-mediated gene transfer (3 x 10(8) pfu) of either of eNOS or beta-galactosidase to donor lungs of rats (n = 6 each). No immunosuppression was used. After 4 days, transplanted lungs were prepared for enzyme activity, cGMP and histology. Calcium-dependent NOS activity, reflecting eNOS, was greater in eNOS-transduced lungs (587 +/- 97 vs 2.1 +/- 1.4 pmol/mg protein per h, P <0.001). In contrast, calcium-independent NOS activity, reflecting iNOS, was comparable. Concentrations of cGMP were higher in eNOS-transduced lungs (13.2 +/- 2.3 vs 4.9 +/- 0.5 pmol/mg protein). Positive immunostaining for eNOS was present in pneumocytes only in eNOS-transduced lungs. No difference in histological grade of rejection was observed. eNOS gene transfer to pulmonary allografts results in a functionally active transgene product and increased NO production. Increasing NO from eNOS does not affect histogically identified acute rejection

Baseline clinical characteristics and patient profile of the TURKMI registry: Results of a nation-wide acute myocardial infarction registry in Turkey

Objective: The TURKMI registry is designed to provide insight into the characteristics, management from symptom onset to hospital discharge, and outcome of patients with acute myocardial infarction (MI) in Turkey. We report the baseline and clinical characteristics of the TURKMI population. Methods: The TURKMI study is a nation-wide registry that was conducted in 50 centers capable of percutaneous coronary intervention selected from each EuroStat NUTS region in Turkey according to population sampling weight, prioritized by the number of hospitals in each region. All consecutive patients with acute MI admitted to coronary care units within 48 hours of symptom onset were prospectively enrolled during a predefined 2-week period between November 1, 2018 and November 16, 2018. Results: A total of 1930 consecutive patients (mean age, 62.0±13.2 years; 26.1% female) with a diagnosis of acute MI were prospectively enrolled. More than half of the patients were diagnosed with non-ST elevation MI (61.9%), and 38.1% were diagnosed with ST elevation MI. Coronary angiography was performed in 93.7% and, percutaneous coronary intervention was performed in 73.2% of the study population. Fibrinolytic therapy was administered to 13 patients (0.018%). Aspirin was prescribed in 99.3% of the patients, and 94% were on dual antiplatelet therapy at the time of discharge. Beta blockers were prescribed in 85.0%, anti-lipid drugs in 96.3%, angiotensin converting enzyme inhibitors in 58.4%, and angiotensin receptor blockers in 7.9%. Comparison with European countries revealed that TURKMI patients experienced MI at younger ages compared with patients in France, Switzerland, and the United Kingdom. The most prevalent risk factors in the TURKMI population were hypercholesterolemia (60.2%), hypertension (49.5%), smoking (48.8%), and diabetes (37.9%). Conclusion: The nation-wide TURKMI registry revealed that hypercholesterolemia, hypertension, and smoking were the most prevalent risk factors. TURKMI patients were younger compared with patients in European Countries. The TURKMI registry also confirmed that current treatment guidelines are largely adopted into clinical cardiology practice in Turkey in terms of antiplatelet, anti-ischemic, and anti-lipid therapy. ©Copyright 2020 by Turkish Society of Cardiolog