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Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank.

Wed, 10/11/2017 - 14:11

Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank.

Wellcome Open Res. 2017;2:61

Authors: Howard DM, Adams MJ, Clarke TK, Wigmore EM, Zeng Y, Hagenaars SP, Lyall DM, Thomson PA, Evans KL, Porteous DJ, Nagy R, Hayward C, Haley CS, Smith BH, Murray AD, Batty GD, Deary IJ, McIntosh AM

Abstract
BACKGROUND: Cognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants.
METHODS: In the present analysis, three cohort studies (n total = 48,002) were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS), the English Longitudinal Study of Ageing (ELSA), and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions.
RESULTS: None of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed P-value overlapped with the D-amino acid oxidase activator ( DAOA) gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer's disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: P = 4.09 x 10 (-7)), was the butyrylcholinesterase ( BCHE) gene coding region. The protein encoded by BCHE has been shown to influence the progression of Alzheimer's disease and its role in cognitive ability merits further investigation.
CONCLUSIONS: Although no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect.

PMID: 28989979 [PubMed]

Banking brain tissue for research.

Wed, 10/11/2017 - 14:11

Banking brain tissue for research.

Handb Clin Neurol. 2017;145:9-12

Authors: Klioueva N, Bovenberg J, Huitinga I

Abstract
Well-characterized human brain tissue is crucial for scientific breakthroughs in research of the human brain and brain diseases. However, the collection, characterization, management, and accessibility of brain human tissue are rather complex. Well-characterized human brain tissue is often provided from private, sometimes small, brain tissue collections by (neuro)pathologic experts. However, to meet the increasing demand for human brain tissue from the scientific community, many professional brain-banking activities aiming at both neurologic and psychiatric diseases as well as healthy controls are currently being initiated worldwide. Professional biobanks are open-access and in many cases run donor programs. They are therefore costly and need effective business plans to guarantee long-term sustainability. Here we discuss the ethical, legal, managerial, and financial aspects of professional brain banks.

PMID: 28987198 [PubMed - in process]

Cyclosporine A in addition to standard ART during primary HIV-1 infection: pilot randomized clinical trial.

Wed, 10/11/2017 - 14:11
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Cyclosporine A in addition to standard ART during primary HIV-1 infection: pilot randomized clinical trial.

J Antimicrob Chemother. 2017 Mar 01;72(3):829-836

Authors: Nicolás D, Ambrosioni J, Sued O, Brunet M, López-Diéguez M, Manzardo C, Agüero F, Tuset M, Plana M, Guardo AC, Mosquera MM, Muñoz-Fernández MÁ, Caballero M, Marcos MÁ, Gatell JM, de Lazzari E, Gallart T, Miró JM

Abstract
Background: Initiating ART during acute/recent HIV-1 infection reduces viral reservoir formation. It has been proposed that, during this phase, the size of the viral reservoir could be further reduced by the association of immunomodulatory therapy with ART. Contradictory results have emerged, however, from two trials evaluating the impact on immune recovery and the viral reservoir of adding cyclosporine A to ART during primary HIV-1 infection.
Patients and methods: Twenty patients with acute/recent HIV-1 infection were randomized to receive ART alone (tenofovir, emtricitabine and lopinavir/ritonavir) or associated with 8 weeks of cyclosporine A (0.3-0.6 mg/kg twice daily). The impact on viral load, immune response and integrated and non-integrated DNA viral reservoir at 0, 8 and 36 weeks of treatment was evaluated.
Results: The estimated median time from HIV-1 infection to ART onset was 63 days (IQR 53; 79.5) with 90% of patients at Fiebig V stage. No significant differences were observed in viral load decay, CD4 T cell recovery, immune response markers or the evolution of integrated DNA at week 8 (end of cyclosporine A) and week 36 between groups. However, non-integrated DNA significantly increased in the cyclosporine A arm between weeks 0 and 36. Cyclosporine A was well tolerated.
Conclusions: Adding cyclosporine A to ART during acute/recent infection did not improve immune recovery. However, unintegrated DNA increased in the cyclosporine A group, suggesting an anti-integration effect, a point warranting further research (ClinicalTrials.gov Identifier: NCT00979706).

PMID: 27999018 [PubMed - indexed for MEDLINE]

Fish consumption and risk of stroke: a second prospective case-control study from northern Sweden.

Wed, 10/11/2017 - 14:11
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Fish consumption and risk of stroke: a second prospective case-control study from northern Sweden.

Nutr J. 2016 Nov 16;15(1):98

Authors: Wennberg M, Jansson JH, Norberg M, Skerfving S, Strömberg U, Wiklund PG, Bergdahl IA

Abstract
BACKGROUND: Fish consumption has been concluded to be associated with decreased risk of stroke in several reviews. However, among men, but not women, an increased risk of stroke was previously found at high fish consumption (>3 meals/week) in northern Sweden. This study investigates if previous results on elevated stroke risk with high fish consumption in men in northern Sweden can be confirmed in a larger study with new cases in the same population.
METHODS: A prospective nested case-control study was performed within the population-based Northern Sweden Health and Disease Study cohort. Information on fish consumption, other lifestyle and medical data was collected at baseline. Incident stroke cases (1987-2007, n = 735) were identified and 2698 controls matched for gender, age, year of baseline and geographical region.
RESULTS: There were no associations between total fish or fatty fish consumption and stroke risk; thus the previous finding of increased risk of stroke with high fish consumption in men could not be repeated. High intake of lean fish (>twice/week compared to < once/month) was associated with increased stroke risk in men [OR 1.80 (95% CI 1.00, 3.21), but not in women [OR 0.50 (95% CI 0.24, 1.10)]. The association was driven by men living alone.
CONCLUSIONS: The previous association between high total fish consumption and risk of stroke in men could not be repeated. The increased risk found in men with high intake of lean fish may be due to chance or confounding specific for this group.

PMID: 27852254 [PubMed - indexed for MEDLINE]

Glial degeneration with oxidative damage drives neuronal demise in MPSII disease.

Wed, 10/11/2017 - 14:11
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Glial degeneration with oxidative damage drives neuronal demise in MPSII disease.

Cell Death Dis. 2016 Aug 11;7(8):e2331

Authors: Zalfa C, Verpelli C, D'Avanzo F, Tomanin R, Vicidomini C, Cajola L, Manara R, Sala C, Scarpa M, Vescovi AL, De Filippis L

Abstract
Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiating IDS-ko NSCs and in the aging IDS-ko mouse brain, glial degeneration precedes neuronal degeneration. Here we show that pure IDS-ko NSC-derived astrocytes are selectively able to drive neuronal degeneration when cocultured with healthy neurons. This phenotype suggests concurrent oxidative damage with metabolic dysfunction. Similar patterns were observed in murine IDS-ko animals and in human MPSII brains. Most importantly, the mutant phenotype of IDS-ko astrocytes was reversed by low oxygen conditions and treatment with vitamin E, which also reversed the toxic effect on cocultured neurons. Moreover, at very early stages of disease we detected in vivo the development of a neuroinflammatory background that precedes astroglial degeneration, thus suggesting a novel model of MPSII pathogenesis, with neuroinflammation preceding glial degeneration, which is finally followed by neuronal death. This hypothesis is also consistent with the progression of white matter abnormalities in MPSII patients. Our study represents a novel breakthrough in the elucidation of MPSII brain pathogenesis and suggests the antioxidant molecules as potential therapeutic tools to delay MPSII onset and progression.

PMID: 27512952 [PubMed - indexed for MEDLINE]

Associations Between Diabetes and Both Cardiovascular Disease and All-Cause Mortality Are Modified by Grip Strength: Evidence From UK Biobank, a Prospective Population-Based Cohort Study.

Sun, 10/08/2017 - 13:00

Associations Between Diabetes and Both Cardiovascular Disease and All-Cause Mortality Are Modified by Grip Strength: Evidence From UK Biobank, a Prospective Population-Based Cohort Study.

Diabetes Care. 2017 Oct 06;:

Authors: Celis-Morales CA, Petermann F, Hui L, Lyall DM, Iliodromiti S, McLaren J, Anderson J, Welsh P, Mackay DF, Pell JP, Sattar N, Gill JMR, Gray SR

Abstract
OBJECTIVE: Grip strength and diabetes are predictors of mortality and cardiovascular disease (CVD), but whether these risk factors interact to predispose to adverse health outcomes is unknown. This study determined the interactions between diabetes and grip strength and their association with health outcomes.
RESEARCH DESIGN AND METHODS: We undertook a prospective, general population cohort study by using UK Biobank. Cox proportional hazards models were used to explore the associations between both grip strength and diabetes and the outcomes of all-cause mortality and CVD incidence/mortality as well as to test for interactions between diabetes and grip strength.
RESULTS: 347,130 UK Biobank participants with full data available (mean age 55.9 years, BMI 27.2 kg/m(2), 54.2% women) were included in the analysis, of which 13,373 (4.0%) had diabetes. Over a median follow-up of 4.9 years (range 3.3-7.8 years), 6,209 died (594 as a result of CVD), and 4,301 developed CVD. Participants with diabetes were at higher risk of all-cause and CVD mortality and CVD incidence. Significant interactions (P < 0.05) existed whereby the risk of CVD mortality was higher in participants with diabetes with low (hazard ratio [HR] 4.05 [95% CI 2.72, 5.80]) versus high (HR 1.46 [0.87, 2.46]) grip strength. Similar results were observed for all-cause mortality and CVD incidence.
CONCLUSIONS: Risk of adverse health outcomes among people with diabetes is lower in those with high grip strength. Low grip strength may be useful to identify a higher-risk subgroup of patients with diabetes. Intervention studies are required to determine whether resistance exercise can reduce risk.

PMID: 28986505 [PubMed - as supplied by publisher]

Validation of Polygenic Scores for QT Interval in Clinical Populations.

Sun, 10/08/2017 - 13:00

Validation of Polygenic Scores for QT Interval in Clinical Populations.

Circ Cardiovasc Genet. 2017 Oct;10(5):

Authors: Rosenberg MA, Lubitz SA, Lin H, Kosova G, Castro VM, Huang P, Ellinor PT, Perlis RH, Newton-Cheh C

Abstract
BACKGROUND: Polygenic risk scores (PGS) enable rapid estimation of genome-wide susceptibility for traits, which may be useful in clinical settings, such as prediction of QT interval. In this study, we sought to validate PGS for QT interval in 2 real-world cohorts of European ancestry (EA) and African ancestry (AA).
METHODS AND RESULTS: Two thousand nine hundred and fifteen participants of EA and 366 of AA in the MGH CAMP study (Cardiology and Metabolic Patient) were genotyped on a genome-wide array and imputed to the 1000 Genomes reference panel. An additional 820 EA and 57 AA participants in the Partners Biobank were genotyped and used for validation. PGS were created for each individual using effect estimates from association tests with QT interval obtained from prior genome-wide association studies, with variants selected based from multiple significance thresholds in the original study. In regression models, clinical variables explained ≈9% to 10% of total variation in resting QTc in EA individuals and ≈12% to 18% in AA individuals. The PGS significantly increased variation explained at most significance thresholds (P<0.001), with a trend toward increased variation explained at more stringent P value cut points in the CAMP EA cohort (P<0.05). In AA individuals, PGS provided no improvement in variation explained at any significance threshold.
CONCLUSIONS: For individuals of European descent, PGS provided a significant increase in variation in QT interval explained compared with a model with only nongenetic factors at nearly every significance level. There was no apparent benefit gained by relaxing the significance threshold from conventional genome-wide significance (P<5×10(-)(8)).

PMID: 28986454 [PubMed - in process]

Trans-generational changes and rural-urban inequality in household fuel use and cookstove ventilation in China: A multi-region study of 0.5 million adults.

Sun, 10/08/2017 - 13:00

Trans-generational changes and rural-urban inequality in household fuel use and cookstove ventilation in China: A multi-region study of 0.5 million adults.

Int J Hyg Environ Health. 2017 Sep 28;:

Authors: Chan KH, Lam KBH, Kurmi OP, Guo Y, Bennett D, Bian Z, Sherliker P, Chen J, Li L, Chen Z, China Kadoorie Biobank collaborative group

Abstract
BACKGROUND: Disease burden estimates related to household air pollution (HAP) relied on cross-sectional data on cooking fuel, overlooking other important sources (e.g. heating) and temporal-regional variations of exposure in geographically diverse settings. We aimed to examine the trends and variations of for cooking and heating fuel use and ventilation in 500,000 adults recruited from 10 diverse localities of China.
METHODS: At baseline (2004-08) and two subsequent resurveys (2008-14), participants of China Kadoorie Biobank, aged 30-79, reported their past and current fuel use for cooking and heating and the availability of cookstove ventilation. These were compared across regions, time periods, birth cohorts, and socio-demographic factors.
RESULTS: During 1968-2014, the proportion of self-reported solid fuel use for cooking or heating decreased by two-thirds (from 84% to 27%), whereas those having complete kitchen ventilation tripled (from 19% to 66%). By 2014, despite a continuing downward trend, many in rural areas still used solid fuels for cooking (48%) and heating (72%), often without adequate ventilation (51%), in contrast to urban residents (all <5%). The large urban-rural inequalities in solid fuel use persisted across multiple generations and also varied by socioeconomic status, especially in rural areas.
CONCLUSIONS: Despite marked progress in fuel modernization in the last 50 years, substantial rural-urban inequalities remain in the study population, especially those who were older or of lower socioeconomic status. Uptake of cleaner heating fuel and ventilation has been slow. More proactive and targeted strategies are needed to expedite universal access to clean energy for both cooking and heating.

PMID: 28986011 [PubMed - as supplied by publisher]

The Contribution of Neanderthals to Phenotypic Variation in Modern Humans.

Sat, 10/07/2017 - 12:01

The Contribution of Neanderthals to Phenotypic Variation in Modern Humans.

Am J Hum Genet. 2017 Oct 05;101(4):578-589

Authors: Dannemann M, Kelso J

Abstract
Assessing the genetic contribution of Neanderthals to non-disease phenotypes in modern humans has been difficult because of the absence of large cohorts for which common phenotype information is available. Using baseline phenotypes collected for 112,000 individuals by the UK Biobank, we can now elaborate on previous findings that identified associations between signatures of positive selection on Neanderthal DNA and various modern human traits but not any specific phenotypic consequences. Here, we show that Neanderthal DNA affects skin tone and hair color, height, sleeping patterns, mood, and smoking status in present-day Europeans. Interestingly, multiple Neanderthal alleles at different loci contribute to skin and hair color in present-day Europeans, and these Neanderthal alleles contribute to both lighter and darker skin tones and hair color, suggesting that Neanderthals themselves were most likely variable in these traits.

PMID: 28985494 [PubMed - in process]

Relation of Odor Identification with Alzheimer's Disease Markers in Cerebrospinal Fluid and Cognition.

Sat, 10/07/2017 - 12:01

Relation of Odor Identification with Alzheimer's Disease Markers in Cerebrospinal Fluid and Cognition.

J Alzheimers Dis. 2017;60(3):1025-1034

Authors: Reijs BLR, Ramakers IHGB, Elias-Sonnenschein L, Teunissen CE, Koel-Simmelink M, Tsolaki M, Wahlund LO, Waldemar G, Hausner L, Johannsen P, Vanderstichele H, Verhey F, Devanand DP, Visser PJ

Abstract
BACKGROUND: Impaired olfactory function is an early characteristic of Alzheimer's disease (AD), but it remains unclear if odor identification also relates to early markers of AD in cerebrospinal fluid (CSF).
OBJECTIVE: To investigate the association between odor identification and amyloid-β 1-42 (Aβ42) and total tau (t-tau) concentrations in CSF. In addition, to examine the relation between odor identification and cognitive function at baseline and at follow-up, and whether these associations are moderated by CSF Aβ42 and t-tau and apolipoprotein E (APOE) genotype.
METHODS: We included 160 individuals (40 with normal cognition, 45 with mild cognitive impairment (MCI), 42 with AD-type dementia, and 26 individuals with non-AD dementia) from the EDAR study. Individuals were recruited from six memory clinics across Europe. Odor identification was tested with the brief University of Pennsylvania Smell Identification Test. CSF Aβ42 and t-tau were assessed with INNO-BIA AlzBio3 Luminex assay. Neuropsychological assessment included tests for verbal memory, verbal fluency, attention, executive function, and visuoconstruction. Follow-up was performed within 3 years after baseline.
RESULTS: Lower odor identification scores correlated with increased CSF t-tau concentrations and with lower scores on all cognitive measures at baseline independent of diagnostic group. Lower odor identification scores predicted decline on the MMSE in the total group, and decline on wordlist learning and delayed recall in APOE ɛ4 carriers and in individuals with abnormal Aβ42.
CONCLUSION: Odor identification impairment may be an indicator of neuronal injury rather than amyloid pathology.

PMID: 28984603 [PubMed - in process]

Memory Correlates of Alzheimer's Disease Cerebrospinal Fluid Markers: A Longitudinal Cohort Study.

Sat, 10/07/2017 - 12:01

Memory Correlates of Alzheimer's Disease Cerebrospinal Fluid Markers: A Longitudinal Cohort Study.

J Alzheimers Dis. 2017;60(3):1119-1128

Authors: Reijs BLR, Ramakers IHGB, Köhler S, Teunissen CE, Koel-Simmelink M, Nathan PJ, Tsolaki M, Wahlund LO, Waldemar G, Hausner L, Vandenberghe R, Johannsen P, Blackwell A, Vanderstichele H, Verhey F, Visser PJ

Abstract
BACKGROUND: Performance on episodic, semantic, and working memory tests is impaired in Alzheimer's disease (AD)-type dementia, but it is unclear which type of memory test is most strongly associated with early AD biomarkers in cerebrospinal fluid (CSF), and most useful for monitoring disease progression.
OBJECTIVE: To examine the association between amyloid-β 1-42 (Aβ42) and tau in CSF with performance on different memory domains at baseline, and how these CSF markers are related with memory decline.
METHODS: We included 263 individuals with normal cognition, mild cognitive impairment, AD-type dementia, and non-AD dementia from the European EDAR study. Assessment included CSF Aβ42 and t-tau analyses with INNO-BIA AlzBio3 Luminex assay, the CERAD wordlist learning and delayed recall, animal fluency test, and the CANTAB Paired Associates Learning (PAL) and Spatial Working Memory tasks. Follow-up assessments were performed within 3 years after baseline.
RESULTS: At baseline, decreased CSF Aβ42 correlated most strongly with the PAL total errors adjusted and the wordlist delayed recall and increased CSF t-tau with the wordlist delayed recall. Over time, decreased CSF Aβ42 was associated with decline on the wordlist learning, whereas increased CSF t-tau were associated with decline in scores on the wordlist learning, wordlist delayed recall, and animal fluency. Associations were independent of baseline diagnosis.
CONCLUSION: Tests assessing episodic verbal and visuospatial memory are most useful for detection of AD pathology. Tests for episodic verbal memory and semantic memory are most useful for tracking memory decline.

PMID: 28984585 [PubMed - in process]

Fluid biomarkers for disease activity in multiple sclerosis.

Sat, 10/07/2017 - 12:01

Fluid biomarkers for disease activity in multiple sclerosis.

Mult Scler. 2017 Oct 01;:1352458517736151

Authors: Zetterberg H, Teunissen C

PMID: 28984535 [PubMed - as supplied by publisher]

Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling.

Sat, 10/07/2017 - 12:01

Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling.

Circulation. 2017 Oct 05;:

Authors: Emdin CA, Khera AV, Klarin D, Natarajan P, Zekavat SM, Nomura A, Haas ME, Aragam K, Ardissino D, Wilson JG, Schunkert H, McPherson R, Watkins H, Elosua R, Bown MJ, Samani NJ, Baber U, Erdmann J, Gormley P, Palotie A, Stitziel N, Gupta N, Danesh JN, Saleheen D, Gabriel SB, Kathiresan S

Abstract
Background -Nitric oxide signaling plays a key role in regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacologic stimulation of the nitric oxide pathway as a therapeutic strategy. Methods -We analyzed the association of common and rare genetic variants in two genes that mediate nitric oxide signaling [Nitric Oxide Synthase 3 (NOS3) and Guanylate Cyclase 1, Soluble, Alpha 3 (GUCY1A3)] with a range of human phenotypes. We selected two common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335,464 participants in the UK Biobank and summary association results from seven large-scale genome wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27,815). Results -A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease [OR 0.37 95% CI 0.31, 0.45; p=5.5*10(-26)], peripheral arterial disease (OR 0.42 CI 0.26, 0.68; p=0.0005) and stroke (OR 0.53 CI 0.37, 0.76; p=0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (CI 12, 34 mm Hg; p=5.6*10(-5)) and a three-fold higher risk of coronary heart disease (OR 3.03 CI 1.29, 7.12, p=0.01). Conclusions -A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease and stroke. Pharmacologic stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease.

PMID: 28982690 [PubMed - as supplied by publisher]

The Impact of Ethnicity and Country of Birth on Inflammatory Bowel Disease Phenotype: a Prospective Cohort Study.

Fri, 10/06/2017 - 13:41

The Impact of Ethnicity and Country of Birth on Inflammatory Bowel Disease Phenotype: a Prospective Cohort Study.

J Crohns Colitis. 2017 Jul 22;:

Authors: Spekhorst LM, Severs M, de Boer NKH, Festen EAM, Fidder HH, Hoentjen F, Imhann F, de Jong DJ, van der Meulen-de Jong AE, Pierik MJ, van der Woude CJ, Dijkstra G, Ponsioen CY, Löwenberg M, Oldenburg B, Weersma RK, Parelsnoer Institute and the Dutch Initiative on Crohn and Colitis

Abstract
Background: The number of patients with inflammatory bowel disease [IBD], of non-Caucasian descent in Western Europe, is increasing. We aimed to explore the impact of ethnicity and country of birth on IBD phenotype.
Methods: IBD patients treated in the eight University Medical Centers in The Netherlands [Dutch IBD Biobank] were divided into two groups according to their ethnicity: 1] Caucasian patients of Western and Central European descent [CEU]; and 2] patients of non-Caucasian descent [non-CEU]. The non-CEU group was subdivided according to country of birth, into: born in The Netherlands or Western Europe [non-CEU European born]; or born outside Western-Europe who migrated to The Netherlands [non-CEU non-European born]. Both comparisons were analysed for phenotype differences [by chi-square test].
Results: The Dutch IBD Biobank included 2921 CEU patients and 233 non-CEU patients. Non-CEU Crohn's disease [CD] patients more often had upper gastro-intestinal disease [16% vs 8%, p = 0.001] and anal stenosis [10% vs 4%, p = 0.002] than CEU CD patients. The use of anti-tumour necrosis factor [TNF] agents and immunomodulators was higher in non-CEU IBD patients than in CEU IBD patients [45% vs 38%, p = 0.042] and [77% vs 66%, p = 0.001], respectively. Non-CEU IBD patients born in Europe [n = 116] were diagnosed at a lower age than non-CEU IBD patients born outside Europe [n = 115] [at 22.7 vs 28.9 years old, p < 0.001].
Conclusion: Non-Caucasians had more severe disease behaviour than Caucasians. Non-CEU patients born in Europe were diagnosed at a lower age with IBD than those born outside Europe who migrated to The Netherlands.

PMID: 28981621 [PubMed - as supplied by publisher]

Oocyte Cryopreservation Based in Sheep: The Current Status and Future Perspective.

Fri, 10/06/2017 - 13:41

Oocyte Cryopreservation Based in Sheep: The Current Status and Future Perspective.

Biopreserv Biobank. 2017 Oct 05;:

Authors: Quan G, Wu G, Hong Q

Abstract
The establishment of a cryopreservation procedure for sheep oocytes will enhance the development of long-term conservation of sheep female genetic resources and the advancement of sheep embryonic biotechnology. However, higher cytoplasmic lipid content and complex subcellular structures affect the relatively higher sensitivity of oocytes to chilling and freezing stresses. Currently, the reports related to sheep oocyte cryopreservation lag behind bovine or pig studies. A standardized freezing procedure has not been established. The present mainstream viewpoint favors the superiority of vitrification over conventional slow-freezing methods. The combination of permeable and impermeable cryoprotectants plus vitrification at a fast cooling/warming velocity benefits the cryosurvival of sheep oocytes. In this review, the research status and the cryoinjury mechanism of sheep oocyte cryopreservation will be reviewed in detail. Moreover, some technological highlights potentially influencing survival of cryopreserved sheep oocytes, such as delipidation, high hydrostatic pressure, or loading trehalose into cytoplasm, are summarized. Meanwhile, the future perspectives in the field of sheep oocyte cryopreservation will be discussed.

PMID: 28981320 [PubMed - as supplied by publisher]

A machine-learning heuristic to improve gene score prediction of polygenic traits.

Fri, 10/06/2017 - 13:41

A machine-learning heuristic to improve gene score prediction of polygenic traits.

Sci Rep. 2017 Oct 04;7(1):12665

Authors: Paré G, Mao S, Deng WQ

Abstract
Machine-learning techniques have helped solve a broad range of prediction problems, yet are not widely used to build polygenic risk scores for the prediction of complex traits. We propose a novel heuristic based on machine-learning techniques (GraBLD) to boost the predictive performance of polygenic risk scores. Gradient boosted regression trees were first used to optimize the weights of SNPs included in the score, followed by a novel regional adjustment for linkage disequilibrium. A calibration set with sample size of ~200 individuals was sufficient for optimal performance. GraBLD yielded prediction R (2) of 0.239 and 0.082 using GIANT summary association statistics for height and BMI in the UK Biobank study (N = 130 K; 1.98 M SNPs), explaining 46.9% and 32.7% of the overall polygenic variance, respectively. For diabetes status, the area under the receiver operating characteristic curve was 0.602 in the UK Biobank study using summary-level association statistics from the DIAGRAM consortium. GraBLD outperformed other polygenic score heuristics for the prediction of height (p < 2.2 × 10(-16)) and BMI (p < 1.57 × 10(-4)), and was equivalent to LDpred for diabetes. Results were independently validated in the Health and Retirement Study (N = 8,292; 688,398 SNPs). Our report demonstrates the use of machine-learning techniques, coupled with summary-level data from large genome-wide meta-analyses to improve the prediction of polygenic traits.

PMID: 28979001 [PubMed - in process]

Polyanionic carbosilane dendrimers prevent hepatitis C virus infection in cell culture.

Fri, 10/06/2017 - 13:41
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Polyanionic carbosilane dendrimers prevent hepatitis C virus infection in cell culture.

Nanomedicine. 2017 Jan;13(1):49-58

Authors: Sepúlveda-Crespo D, Jiménez JL, Gómez R, De La Mata FJ, Majano PL, Muñoz-Fernández MÁ, Gastaminza P

Abstract
Hepatitis C virus (HCV) infection is a major biomedical problem worldwide. Although new direct antiviral agents (DAAs) have been developed for the treatment of chronic HCV infection, the potential emergence of resistant virus variants and the difficulties to implement their administration worldwide make the development of novel antiviral agents an urgent need. Moreover, no effective vaccine is available against HCV and transmission of the virus still occurs particularly when prophylactic measures are not taken. We used a cell-based system to screen a battery of polyanionic carbosilane dendrimers (PCDs) to identify compounds with antiviral activity against HCV and show that they inhibit effective virus adsorption of major HCV genotypes. Interestingly, one of the PCDs irreversibly destabilized infectious virions. This compound displays additive effect in combination with a clinically relevant DAA, sofosbuvir. Our results support further characterization of these molecules as nanotools for the control of hepatitis C virus spread.

PMID: 27562210 [PubMed - indexed for MEDLINE]

HSP90 inhibitors potentiate PGF2α-induced IL-6 synthesis via p38 MAP kinase in osteoblasts.

Thu, 10/05/2017 - 12:27
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HSP90 inhibitors potentiate PGF2α-induced IL-6 synthesis via p38 MAP kinase in osteoblasts.

PLoS One. 2017;12(5):e0177878

Authors: Fujita K, Tokuda H, Kuroyanagi G, Yamamoto N, Kainuma S, Kawabata T, Sakai G, Matsushima-Nishiwaki R, Kozawa O, Otsuka T

Abstract
Heat shock protein 90 (HSP90) that is ubiquitously expressed in various tissues, is recognized to be a major molecular chaperone. We have previously reported that prostaglandin F2α (PGF2α), a potent bone remodeling mediator, stimulates the synthesis of interleukin-6 (IL-6) through p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells, and that Rho-kinase acts at a point upstream of p38 MAP kinase. In the present study, we investigated the involvement of HSP90 in the PGF2α-stimulated IL-6 synthesis and the underlying mechanism in MC3T3-E1 cells. Geldanamycin, an inhibitor of HSP90, significantly amplified both the PGF2α-stimulated IL-6 release and the mRNA expression levels. In addition, other HSP90 inhibitors, 17-allylamino-17demethoxy-geldanamycin (17-AAG) and 17-dimethylamino-ethylamino-17-demethoxy-geldanamycin (17-DMAG) and onalespib, enhanced the PGF2α-stimulated IL-6 release. Geldanamycin, 17-AAG and onalespib markedly strengthened the PGF2α-induced phosphorylation of p38 MAP kinase. Geldanamycin and 17-AAG did not affect the PGF2α-induced phosphorylation of p44/p42 MAP kinase and myosin phosphatase targeting subunit (MYPT-1), a substrate of Rho-kinase, and the protein levels of RhoA and Rho-kinase. In addition, HSP90-siRNA enhanced the PGF2α-induced phosphorylation of p38 MAP kinase. Furthermore, SB203580, an inhibitor of p38 MAP kinase, significantly suppressed the amplification by geldanamycin, 17-AAG or 17-DMAG of the PGF2α-stimulated IL-6 release. Our results strongly suggest that HSP90 negatively regulates the PGF2α-stimulated IL-6 synthesis in osteoblasts, and that the effect of HSP90 is exerted through regulating p38 MAP kinase activation.

PMID: 28542188 [PubMed - indexed for MEDLINE]

Mechanistic Studies of Viral Entry: An Overview of Dendrimer-Based Microbicides As Entry Inhibitors Against Both HIV and HSV-2 Overlapped Infections.

Thu, 10/05/2017 - 12:27
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Mechanistic Studies of Viral Entry: An Overview of Dendrimer-Based Microbicides As Entry Inhibitors Against Both HIV and HSV-2 Overlapped Infections.

Med Res Rev. 2017 Jan;37(1):149-179

Authors: Sepúlveda-Crespo D, Ceña-Díez R, Jiménez JL, Ángeles Muñoz-Fernández M

Abstract
This review provides an overview of the development of different dendrimers, mainly polyanionic, against human immunodeficiency virus (HIV) and genital herpes (HSV-2) as topical microbicides targeting the viral entry process. Vaginal topical microbicides to prevent sexually transmitted infections such as HIV and HSV-2 are urgently needed. To inhibit HIV/HSV-2 entry processes, new preventive targets have been established to maximize the current therapies against wild-type and drug-resistant viruses. The entry of HIV/HSV-2 into target cells is a multistep process that triggers a cascade of molecular interactions between viral envelope proteins and cell surface receptors. Polyanionic dendrimers are highly branched nanocompounds with potent activity against HIV/HSV-2. Inhibitors of each entry step have been identified with regard to generations and surface groups, and possible roles for these agents in anti-HIV/HSV-2 therapies have also been discussed. Four potential binding sites for impeding HIV infection (HSPG, DC-SIGN, GSL, and CD4/gp120 inhibitors) and HSV-2 infection (HS, gB, gD, and gH/gL inhibitors) exist according to their mechanisms of action and structures. This review clarifies that inhibition of HIV/HSV-2 entry continues to be a promising target for drug development because nanotechnology can transform the field of HIV/HSV-2 prevention by improving the efficacy of the currently available antiviral treatments.

PMID: 27518199 [PubMed - indexed for MEDLINE]

Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.

Wed, 10/04/2017 - 13:55

Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.

Hum Mol Genet. 2017 Aug 24;:

Authors: Dand N, Mucha S, Tsoi LC, Mahil SK, Stuart PE, Arnold A, Baurecht H, Burden AD, Duffin KC, Chandran V, Curtis CJ, Das S, Ellinghaus D, Ellinghaus E, Enerback C, Esko T, Gladman DD, Griffiths CEM, Gudjonsson JE, Hoffman P, Homuth G, Hüffmeier U, Krueger GG, Laudes M, Lee SH, Lieb W, Lim HW, Löhr S, Mrowietz U, Müller-Nurayid M, Nöthen M, Peters A, Rahman P, Reis A, Reynolds NJ, Rodriguez E, Schmidt CO, Spain SL, Strauch K, Tejasvi T, Voorhees JJ, Warren RB, Weichenthal M, Weidinger S, Zawistowski M, Nair RP, Capon F, Smith CH, Trembath RC, Abecasis GR, Elder JT, Franke A, Simpson MA, Barker JN

Abstract
Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11,861 psoriasis cases and 28,610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; p = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.

PMID: 28973304 [PubMed - as supplied by publisher]