European Academy of Bolzano Bozen EURAC

Bolzano, Italy

European Academy of Bolzano Bozen EURAC

Bolzano, Italy

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Jing J.,Albert Ludwigs University of Freiburg | Pattaro C.,European Academy of Bolzano Bozen EURAC | Hoppmann A.,Albert Ludwigs University of Freiburg | Okada Y.,Tokyo Medical and Dental University | And 4 more authors.
Kidney International | Year: 2016

Genomewide association studies have identified numerous chronic kidney disease–associated genetic variants, but often do not pinpoint causal genes. This limitation was addressed by combining Mouse Genome Informatics with human genomewide association studies of kidney function. Genes for which mouse models showed abnormal renal physiology, morphology, glomerular filtration rate (GFR), or urinary albumin-to-creatinine ratio were identified from Mouse Genome Informatics. The corresponding human orthologs were then evaluated for GFR-associated single-nucleotide polymorphisms in 133,814 individuals and urinary albumin-to-creatinine ratio-associated SNPs in 54,451 individuals in genome-wide association studies meta-analysis of the CKDGen Consortium. After multiple testing corrections, significant associations with estimated GFR in humans were identified for single-nucleotide polymorphisms in 2, 7, and 17 genes causing abnormal GFR, abnormal physiology, and abnormal morphology in mice, respectively. Genes identified for abnormal kidney morphology showed significant enrichment for estimated GFR–associated single-nucleotide polymorphisms. In total, 19 genes contained variants associated with estimated GFR or the urinary albumin-to-creatinine ratio of which 16 mapped into previously reported genomewide significant loci. CYP26A1 and BMP4 emerged as novel signals subsequently validated in a large, independent study. An additional gene, CYP24A1, was discovered after conditioning on a published nearby association signal. Thus, our novel approach to combine comprehensive mouse phenotype information with human genomewide association studies data resulted in the identification of candidate genes for kidney disease pathogenesis. © 2016 International Society of Nephrology


Pattaro C.,European Academy of Bolzano Bozen EURAC | Riegler P.,Hospital of Merano | Stifter G.,Hospital of Brunico | Modenese M.,European Academy of Bolzano Bozen EURAC | And 4 more authors.
Nephron - Clinical Practice | Year: 2013

Background/Aims: Several formulas for glomerular filtration rate (GFR) estimation, based on serum creatinine or cystatin C, have been proposed. We assessed the impact of some of these equations on estimated GFR (eGFR) and chronic kidney disease (CKD) prevalence, and on the association with cardiovascular risk factors, in a general population sample characterized by a young mean age. Methods: We studied 1,199 individuals from three Alpine villages enrolled into the MICROS study. eGFR was obtained with the 4- and 6-parameter MDRD study equations, the Virga equation, and with the three CKD-EPI formulas for creatinine, cystatin C, and the combination of creatinine and cystatin C. We assessed the concordance between quantitative eGFR levels, CKD prevalence, and in terms of association with total, LDL, and HDL cholesterol. Results: The highest and lowest eGFR levels corresponded to the cystatin C-based and MDRD-4 equations, respectively. CKD prevalence varied from 1.8% (Virga) to 5.8% (MDRD-4). The CKD-EPI based on creatinine showed the highest agreement with all other equations. Agreement between methods was higher at lower eGFR levels, older age, and in the presence of diabetes and hypertension. Creatinine-based estimates of eGFR were associated with total and low-density lipoprotein but not high-density lipoprotein cholesterol. The opposite was observed for the cystatin C-based GFR. Conclusion: GFR estimation is strongly affected by the chosen equation. Differences are more pronounced in healthy and younger individuals. To identify CKD risk factors, the choice of the equation is of secondary importance to the choice of the biomarker used in the formula. If eGFR is not calibrated to a gold standard GFR in the general population, reports about CKD prevalence should be considered with caution. © 2013 S. Karger AG, Basel.


PubMed | European Academy of Bolzano Bozen EURAC and Sandro Pertini Hospital
Type: Clinical Trial | Journal: Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association | Year: 2015

The purpose of this study was to assess our experience of carotid surgery habitually performed under general anesthesia without intraoperative intracerebral monitoring, and following a pre-established perioperative protocol, which includes extensive use of an intraoperative shunt (IOS).This study included 311 consecutive carotid operations performed over 32 months. This patient cohort represents 14% of our total experience in carotid surgery (2219 operations, major stroke/mortality rate: 1.4%). The IOS was inserted routinely in the presence of intraoperative blood pressure instability during cross-clamping and when the predictable clamping time might have exceeded 20 minutes. A moderate and stable hypertension was maintained throughout surgery without IOS.Overall, 120 (38.6%) endarterectomies were performed with primary closure, 73 (23.5%) with eversion technique, 113 (36.3%) with patch angioplasty, and 5 (1.6%) with other techniques. Out of 113 patch angioplasties, 111 (98.2%) were performed with an IOS. This was utilized in only 3 cases of direct carotid reconstructions or other carotid endarterectomy techniques (1.5%). Overall, the IOS placement rate was 36.7%. Postoperatively, 2 major strokes (.64%), 2 minor strokes (.64%), 4 hyperperfusion syndromes (1.3%), and no mortality were recorded. No cases of cross-clamp ischemia/shunt-related perioperative strokes were observed.The low perioperative stroke rate reported in this prospective study proves the advantages of wide use of IOS during carotid surgery. This coupled with a large experience in carotid surgery and close monitoring and support of blood pressure, are the major determinants of these results that demonstrate the low risk of shunt-related complications for surgeons who regularly utilize an IOS.


PubMed | Al - Azhar University of Egypt, University of California at Irvine, Newport Diagnostic Center, Mission Heritage Medical Group and 12 more.
Type: Comparative Study | Journal: Global heart | Year: 2015

Although atherosclerosis is usually thought of as a disease of modernity, the Horus Team has previously reported atherosclerotic vascular calcifications on computed tomographic (CT) scans in ancient Egyptians.The purpose of this study was to compare patterns and demographic characteristics of this disease among Egyptians from ancient and modern eras.We compared the presence and extent of vascular calcifications from whole-body CT scans performed on 178 modern Egyptians from Cairo undergoing positron emission tomography (PET)/CT for cancer staging to CT scans of 76 Egyptian mummies (3100 bce to 364 ce).The mean age of the modern Egyptian group was 52.3 15 years (range 14 to 84) versus estimated age at death of ancient Egyptian mummies 36.5 13 years (range 4 to 60); p < 0.0001. Vascular calcification was detected in 108 of 178 (60.7%) of modern patients versus 26 of 76 (38.2%) of mummies, p < 0.001. Vascular calcifications on CT strongly correlated to age in both groups. In addition, the severity of disease by number of involved arterial beds also correlated to age, and there was a very similar pattern between the 2 groups. Calcifications in both modern and ancient Egyptians were seen peripherally in aortoiliac beds almost a decade earlier than in event-related beds (coronary and carotid).The presence and severity of atherosclerotic vascular disease correlates strongly to age in both ancient and modern Egyptians. There is a striking correlation in the distribution of the number of vascular beds involved. Atherosclerotic calcifications are seen in the aortoiliac beds almost a decade earlier than in the coronary and carotid beds.


PubMed | Johns Hopkins University, European Academy of Bolzano Bozen EURAC, Tokyo Medical and Dental University, Albert Ludwigs University of Freiburg and Harvard University
Type: Journal Article | Journal: Kidney international | Year: 2016

Genomewide association studies have identified numerous chronic kidney disease-associated genetic variants, but often do not pinpoint causal genes. This limitation was addressed by combining Mouse Genome Informatics withhuman genomewide association studies of kidney function. Genes for which mouse models showed abnormal renal physiology, morphology, glomerular filtration rate (GFR), or urinary albumin-to-creatinine ratio were identified from Mouse Genome Informatics. The corresponding human orthologs were then evaluated for GFR-associated single-nucleotide polymorphisms in 133,814 individuals and urinary albumin-to-creatinine ratio-associated SNPs in 54,451 individuals in genome-wide association studies meta-analysis of the CKDGen Consortium. After multiple testing corrections, significant associations with estimated GFR in humans were identified for single-nucleotide polymorphisms in 2, 7, and 17 genes causing abnormal GFR, abnormal physiology, and abnormal morphology in mice, respectively. Genes identified for abnormal kidney morphology showed significant enrichment for estimated GFR-associated single-nucleotide polymorphisms. In total, 19 genes contained variants associated with estimated GFR or the urinary albumin-to-creatinine ratio of which 16 mapped into previously reported genomewide significant loci. CYP26A1 and BMP4 emerged as novel signals subsequently validated in a large, independent study. An additional gene, CYP24A1, was discovered after conditioning on apublished nearby association signal. Thus, our novel approach to combine comprehensive mouse phenotype information with human genomewide association studies data resulted in the identification of candidate genes for kidney disease pathogenesis.


PubMed | Al - Azhar University of Egypt, University of California at Irvine, Newport Diagnostic Center, University of Pennsylvania and 11 more.
Type: Journal Article | Journal: Global heart | Year: 2015

Although atherosclerosis is widely thought to be a disease of modernity, computed tomographic evidence of atherosclerosis has been found in the bodies of a large number of mummies. This article reviews the findings of atherosclerotic calcifications in the remains of ancient people-humans who lived across a very wide span of human history and over most of the inhabited globe. These people had a wide range of diets and lifestyles and traditional modern risk factors do not thoroughly explain the presence and easy detectability of this disease. Nontraditional risk factors such as the inhalation of cooking fire smoke and chronic infection or inflammation might have been important atherogenic factors in ancient times. Study of the genetic and environmental risk factors for atherosclerosis in ancient people may offer insights into this common modern disease.


PubMed | Al - Azhar University of Egypt, University of California at Irvine, Newport Diagnostic Center, Mission Heritage Medical Group and 14 more.
Type: Journal Article | Journal: Global heart | Year: 2015

Paleogenetics offers a unique opportunity to study human evolution, population dynamics, and disease evolution in situ. Although histologic and computed x-ray tomographic investigations of ancient mummies have clearly shown that atherosclerosis has been present in humans for more than 5,000 years, limited data are available on the presence of genetic predisposition for cardiovascular disease in ancient human populations. In a previous whole-genome study of the Tyrolean Iceman, a 5,300-year-old glacier mummy from the Alps, an increased risk for coronary heart disease was detected. The Icemans genome revealed several single nucleotide polymorphisms that are linked with cardiovascular disease in genome-wide association studies. Future genetic studies of ancient humans from various geographic origins and time periods have the potential to provide more insights into the presence and possible changes of genetic risk factors in our ancestors. The study of ancient humans and a better understanding of the interaction between environmental and genetic influences on the development of heart diseases may lead to a more effective prevention and treatment of the most common cause of death in the modern world.


Quaglio G.,University of Verona | Pattaro C.,European Academy of Bolzano Bozen EURAC | Gerra G.,Health and Human Development Section | Mathewson S.,University of Verona | And 3 more authors.
Psychiatry Research | Year: 2012

The withdrawal syndrome from benzodiazepine (BZD) can be severe and in some cases may impede cessation of the use of the drug. We present here a case series of benzodiazepine detoxification by flumazenil infusion, stabilised with clonazepam. Patients were treated with flumazenil 1.35. mg/day for a median of 7. days. Self-reported physical withdrawal symptoms were recorded daily. In addition to flumazenil, antidepressants were given before treatment commenced and clonazepam was administered nightly with both being continued after discharge. Twenty-nine patients were treated. No patients dropped out from the treatment programme. Nine patients (31%) required a temporary reduction/cessation of the infusion. The linear trend in the reduction of the daily withdrawal scores in the overall study population was significant. The linear trends were also significant in the group of patients for whom a temporary reduction/suspension of the flumazenil was required. Six months after treatment, 15 patients (53%) were abstinent from clonazepam and other BZDs. For five (21%) the BZD dependence were reinstated. More than two-thirds of the subjects tolerated the procedure well and about half had a good long term response. Slow flumazenil infusion appears to merit consideration as a possible future treatment. Suggestions for future research are examined. © 2012 Elsevier Ltd.


Pattaro C.,European Academy of Bolzano Bozen EURAC | Saint-Pierre A.,European Academy of Bolzano Bozen EURAC
Kidney International | Year: 2013

Contrary to the apparent impossibility of replicating linkage results across studies on renal outcomes, and denying the general difficulty of identifying meaningful association signals under previously identified linkage peaks, a new study on an isolated Mongolian population could replicate two previously reported linkage peaks and corroborate them by significant associations at multiple single-nucleotide polymorphisms. Although the two genetic loci are not novel, the study sheds light on key aspects of the genetic analysis of kidney function in the general population. © 2012 International Society of Nephrology.


Taliun D.,European Academy of Bolzano Bozen EURAC | Taliun D.,Free University of Bozen Bolzano | Gamper J.,Free University of Bozen Bolzano | Pattaro C.,European Academy of Bolzano Bozen EURAC
BMC Bioinformatics | Year: 2014

Background: The new sequencing technologies enable to scan very long and dense genetic sequences, obtaining datasets of genetic markers that are an order of magnitude larger than previously available. Such genetic sequences are characterized by common alleles interspersed with multiple rarer alleles. This situation has renewed the interest for the identification of haplotypes carrying the rare risk alleles. However, large scale explorations of the linkage-disequilibrium (LD) pattern to identify haplotype blocks are not easy to perform, because traditional algorithms have at least Θ(n2) time and memory complexity.Results: We derived three incremental optimizations of the widely used haplotype block recognition algorithm proposed by Gabriel et al. in 2002. Our most efficient solution, called MIG ++, has only Θ(n) memory complexity and, on a genome-wide scale, it omits >80% of the calculations, which makes it an order of magnitude faster than the original algorithm. Differently from the existing software, the MIG ++ analyzes the LD between SNPs at any distance, avoiding restrictions on the maximal block length. The haplotype block partition of the entire HapMap II CEPH dataset was obtained in 457 hours. By replacing the standard likelihood-based D′ variance estimator with an approximated estimator, the runtime was further improved. While producing a coarser partition, the approximate method allowed to obtain the full-genome haplotype block partition of the entire 1000 Genomes Project CEPH dataset in 44 hours, with no restrictions on allele frequency or long-range correlations. These experiments showed that LD-based haplotype blocks can span more than one million base-pairs in both HapMap II and 1000 Genomes datasets. An application to the North American Rheumatoid Arthritis Consortium (NARAC) dataset shows how the MIG ++ can support genome-wide haplotype association studies.Conclusions: The MIG ++ enables to perform LD-based haplotype block recognition on genetic sequences of any length and density. In the new generation sequencing era, this can help identify haplotypes that carry rare variants of interest. The low computational requirements open the possibility to include the haplotype block structure into genome-wide association scans, downstream analyses, and visual interfaces for online genome browsers. © 2014 Taliun et al.; licensee BioMed Central Ltd.

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