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| 2. |
- Satizabal, Claudia L., et al.
(author)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Journal article (peer-reviewed)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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| 3. |
- Ademuyiwa, Adesoji O., et al.
(author)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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In: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Journal article (peer-reviewed)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 4. |
- Brown, Russell D., et al.
(author)
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Tubuloglomerular feedback response in the prenatal and postnatal ovine kidney
- 2011
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In: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1522-1466 .- 1931-857X. ; 300:6, s. F1368-F1374
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Journal article (peer-reviewed)abstract
- Brown RD, Turner AJ, Carlstrom M, Persson AE, Gibson KJ. Tubuloglomerular feedback response in the prenatal and postnatal ovine kidney. Am J Physiol Renal Physiol 300: F1368-F1374, 2011. First published March 30, 2011; doi:10.1152/ajprenal. 00019.2011.-The tubuloglomerular feedback mechanism (TGF) plays an important role in regulating single-nephron glomerular filtration rate (GFR) by coupling distal tubular flow to arteriolar tone. It is not known whether TGF is active in the developing kidney or whether it can regulate renal vascular tone and thus GFR during intrauterine life. TGF characteristics were examined in late-gestation ovine fetuses and lambs under normovolemic and volume-expanded (VE) conditions. Lambs and pregnant ewes were anesthetized and the fetuses were delivered via a caesarean incision into a heated water bath, with the umbilical cord intact. Under normovolemic conditions, mean arterial pressure of the fetuses was lower than lambs (51 +/- 1 vs. 64 +/- 3 mmHg). The maximum TGF response (Delta P(SFmax)) was found to be lower in fetuses than lambs when tubular perfusion was increased from 0 to 40 nl/min (5.4 +/- 0.7 vs. 10.6 +/- 0.4 mmHg). Furthermore, the flow rate eliciting half-maximal response [turning point (TP)] was 15.7 +/- 0.9 nl/min in fetuses compared with 19.3 +/- 1.0 nl/min in lambs, indicating a greater TGF sensitivity of the prenatal kidney. VE decreased Delta P(SFmax) (4.2 +/- 0.4 mmHg) and increased TP to 23.7 +/- 1.3 nl/min in lambs. In fetuses, VE increased stop-flow pressure from 26.6 +/- 1.5 to 30.3 +/- 0.8 mmHg, and reset TGF sensitivity so that TP increased to 21.3 +/- 0.7 nl/min, but it had no effect on Delta P(SFmax). This study provides direct evidence that the TGF mechanism is active during fetal life and responds to physiological stimuli. Moreover, reductions in TGF sensitivity may contribute to the increase in GFR at birth.
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| 5. |
- Köttgen, Anna, et al.
(author)
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New loci associated with kidney function and chronic kidney disease
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:5, s. 376-384
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Journal article (peer-reviewed)abstract
- Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide–significant loci (P < 5 × 10−8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
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| 6. |
- Petrov, Dmitry, et al.
(author)
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Machine Learning for Large-Scale Quality Control of 3D Shape Models in Neuroimaging
- 2017
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In: Machine learning in medical imaging. MLMI (Workshop). - Cham : Springer International Publishing. ; 10541, s. 371-378
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Journal article (peer-reviewed)abstract
- As very large studies of complex neuroimaging phenotypes become more common, human quality assessment of MRI-derived data remains one of the last major bottlenecks. Few attempts have so far been made to address this issue with machine learning. In this work, we optimize predictive models of quality for meshes representing deep brain structure shapes. We use standard vertex-wise and global shape features computed homologously across 19 cohorts and over 7500 human-rated subjects, training kernelized Support Vector Machine and Gradient Boosted Decision Trees classifiers to detect meshes of failing quality. Our models generalize across datasets and diseases, reducing human workload by 30-70%, or equivalently hundreds of human rater hours for datasets of comparable size, with recall rates approaching inter-rater reliability.
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| 7. |
- Turner, Anita J., et al.
(author)
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Fetal tubuloglomerular feedback in an ovine model of mild maternal renal disease
- 2015
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In: Physiological Reports. - : WILEY. - 2051-817X. ; 3:7
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Journal article (peer-reviewed)abstract
- Fetuses of pregnant ewes, which were subtotally nephrectomized prior to mating, were studied to assess whether mild maternal renal impairment would affect fetal tubuloglomerular feedback (TGF) under control conditions and after the inhibition of macula densa-derived nitric oxide (NO). Based on previous observations we hypothesized that, the TGF curve of fetuses of subtotally nephrectomized (STNx) ewes would resemble that of a volume expanded fetus with a high production rate of NO and that inhibition of neuronal nitric oxide synthase (nNOS) would increase the sensitivity of the TGF system in these fetuses. Renal function studies were performed on anaesthetized fetal sheep (133-140 days gestation; term similar to 150 days; Isoflurane 2-4% in oxygen). Fetuses were removed from the uterus and placed in a water bath (39.5 degrees C) while maintaining umbilical blood flow. Glomerular filtration rate (GFR) and urine flow rate were markedly increased in fetuses of STNx ewes compared to fetuses of untreated ewes. Interestingly, and contrary to our hypothesis, the fetuses of STNx ewes exhibited no difference in TGF sensitivity in the presence or absence of 7-nitroindazole (7NI; nNOS inhibitor), compared to fetuses of untreated ewes, although sensitivity and reactivity increased in both groups after 7NI. There was however, a decrease in the stop flow pressure and net filtration pressure with an increase in the filtration coefficient (K-f). These factors suggest that maternal renal impairment drives the glomerular hypertrophy which has previously been found to be present in the neonatal period. Thus, we conclude that at similar to 138 days gestation, the fetal kidney has matured functionally and fetuses of STNx ewes are able to maintain fluid and electrolyte homeostasis even in the presence of increased transplacental flux.
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| 8. |
- Turner, Anita J, et al.
(author)
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Mechanisms of neonatal increase in glomerular filtration rate
- 2008
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In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 295:3, s. R916-21
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Journal article (peer-reviewed)abstract
- To investigate the mechanisms responsible for the neonatal increase in glomerular filtration rate (GFR), renal function studies (whole kidney and micropuncture) were carried out in anesthesized fetal sheep (133-140 days gestation; term = 150 days) and lambs (12-18 days). Fetuses were delivered and placed in a water bath (39.5 degrees C), keeping the umbilical cord moist and intact. Lambs were studied on a thermostatically controlled heating pad. Animals were prepared for either blood flow studies or micropuncture measurements. Expected differences in blood composition and cardiovascular and renal function were observed between fetuses and lambs, and values obtained for most variables were similar to those measured in chronically catheterized unanesthetized animals. Fetal GFR was much lower than that of lambs (0.20 vs. 0.62 ml.min(-1).g kidney(-1), P < 0.001). Free-flow, stop-flow, and net filtration pressures (NFP) were lower in the fetuses than the lambs (NFP 20.8 vs. 23.8 mmHg, P < 0.001), as was the calculated ultrafiltration coefficient (0.014 vs. 0.022 ml.min(-1).g(-1).mmHg(-1), P < 0.001). Thus, we conclude that rises in both net filtration pressure and the ultrafiltration coefficient contribute to the large increase in GFR between fetal life and approximately 2 wk after birth.
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| 9. |
- Turner, Anita J., et al.
(author)
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Tubuloglomerular feedback responses in offspring of dexamethasone-treated ewes
- 2017
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In: American Journal of Physiology - Renal Physiology. - : AMER PHYSIOLOGICAL SOC. - 0363-6127 .- 1522-1466 .- 1931-857X. ; 313:4, s. F864-F873
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Journal article (peer-reviewed)abstract
- Via developmental programming, prenatal perturbations, such as exposure to glucocorticoids and maternal malnutrition alter kidney development and contribute to the development of hypertension. To examine the possibility that alterations in tubuloglomerular feedback (TGF) contribute to the development of hypertension in offspring following maternal dexamethasone treatment (Dex) in early gestation, studies were conducted in fetal sheep and lambs. Pregnant ewes were infused with dexamethasone (0.48 mg/h) at 26-28 days gestation. No differences were observed in mean arterial pressure, glomcrular.filtration rate. or electrolyte excretion rates between the.Dex and Untreated fetuses or lambs. Gestational exposure to Dex markedly enhanced TGF sensitivity, as the turning point in Dex treatedfetuses was significantly lower (12.9 +/- 0.9 nl/min; P < 0.05) compared with Untreated fetuses (17.0 +/- 1.0 til/min). This resetting of TOE sensitivity persisted after birth (P < 0.01). TGF reactivity did not differ between the groups in fetuses or lambs. In response to nitric oxide inhibition, TOE sensitivity increased (the turning point decreased) and reactivity increased in Untreated fetuses and lambs, but these effects were blunted in the Dex-treated fetuses and lambs. Our data suggest that an altered TOE response may be an underlying renal mechanism contributing to the development of hypertension in the Dex model of fetal programming. The lower tonic level of NO production in these dexamethasone-exposed offspring may contribute to the development of hypertension as adults.
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| 10. |
- Benatar, Michael, et al.
(author)
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The Miami Framework for ALS and related neurodegenerative disorders : an integrated view of phenotype and biology
- 2024
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In: Nature Reviews Neurology. - : Springer Nature. - 1759-4758 .- 1759-4766. ; 20:6, s. 364-376
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Research review (peer-reviewed)abstract
- Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.
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