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| 2. |
- Danesh, John, et al.
(author)
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Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis
- 2005
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In: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 294:14, s. 1799-1809
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Research review (peer-reviewed)abstract
- CONTEXT: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data. DATA SOURCES: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators. STUDY SELECTION: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded. DATA EXTRACTION: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias. DATA SYNTHESIS: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design. CONCLUSIONS: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.
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| 3. |
- Emerging Risk Factors, Collaboration, et al.
(author)
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The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases
- 2007
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In: Eur J Epidemiol. - 0393-2990. ; 22:12, s. 839-69
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Journal article (peer-reviewed)abstract
- Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.
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| 6. |
- Kaptoge, S., et al.
(author)
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C-Reactive Protein, Fibrinogen, and Cardiovascular Disease Prediction
- 2012
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 367:14, s. 1310-1320
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Journal article (peer-reviewed)abstract
- Background There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. Methods We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. Results The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P < 0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (< 10%), " intermediate" (10% to < 20%), and "high" (>= 20%) (P < 0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of >= 20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years. Conclusions In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.)
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- Liu, Z. G., et al.
(author)
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Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features
- 2023
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In: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 32:20, s. 2981-2995
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Journal article (peer-reviewed)abstract
- Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.
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- Wormser, David, et al.
(author)
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Adult height and the risk of cause-specific death and vascular morbidity in 1 million people : individual participant meta-analysis
- 2012
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In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 41:5, s. 1419-1433
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Journal article (peer-reviewed)abstract
- BackgroundThe extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.MethodsWe calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.ResultsFor people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.ConclusionAdult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
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| 14. |
- Joseph, A, et al.
(author)
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Metabolic features of cancer cells impact immunosurveillance
- 2021
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In: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 9:6
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Journal article (peer-reviewed)abstract
- Tumors rewire their metabolism to achieve robust anabolism and resistance against therapeutic interventions like cisplatin treatment. For example, a prolonged exposure to cisplatin causes downregulation of pyridoxal kinase (PDXK), the enzyme that generates the active vitamin B6, and upregulation of poly ADP-ribose (PAR) polymerase-1 (PARP1) activity that requires a supply of nicotinamide (vitamin B3) adenine dinucleotide. We investigated the impact of the levels of PDXK and PAR on the local immunosurveillance (ie, density of the antigen presenting cells and adaptive immune response by CD8 T lymphocytes) in two different tumor types.MethodsTumors from patients with locally advanced cervical carcinoma (LACC) and non-small cell lung cancer (NSCLC) were stained for PAR, PDXK, dendritic cell lysosomal associated membrane glycoprotein (DC-LAMP) and CD8 T cell infiltration. Their correlations and prognostic impact were assessed. Cisplatin-resistant NSCLC cell clones isolated from Lewis-lung cancer (LLC) cells were evaluated for PAR levels by immunoblot. Parental (PARlow) and cisplatin-resistant (PARhigh) clones were subcutaneously injected into the flank of C57BL/6 mice. Tumors were harvested to evaluate their immune infiltration by flow cytometry.ResultsThe infiltration of tumors by CD8 T and DC-LAMP+ cells was associated with a favorable overall survival in patients with LACC (p=0.006 and p=0.008, respectively) and NSCLC (p<0.001 for both CD8 T and DC-LAMP cells). We observed a positive correlation between PDXK expression and the infiltration by DC-LAMP (R=0.44, p=0.02 in LACC, R=0.14, p=0.057 in NSCLC), and a negative correlation between PAR levels and CD8 T lymphocytes (R=−0.39, p=0.034 in LACC, R=−0.18, p=0.017 in NSCLC). PARP1 is constitutively hyperactivated in cisplatin-resistant LLC cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PARhigh). Tumors formed by such cancer cells injected into immunocompetent mice were scarcely infiltrated by CD8 T (p=0.028) and antigen presenting cells (p=0.086).ConclusionsOncometabolic features can impact local immunosurveillance, providing new functional links between cisplatin resistance and therapeutic failure.
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| 16. |
- Albshesh, Ahmad, et al.
(author)
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Effectiveness of Third-Class Biologic Treatment in Crohn's Disease : A Multi-Center Retrospective Cohort Study
- 2021
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In: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 10:13
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Journal article (peer-reviewed)abstract
- Background: Multiple studies have described the effectiveness of ustekinumab (UST) and vedolizumab (VDZ) in patients with Crohn's disease (CD) failing anti- Tumor necrosis factors (TNFs); however, the effectiveness of VDZ or UST as a third-class biologic has not yet been described.Aims and Methods: In this retrospective multicenter cohort study, we aimed to investigate the effectiveness of VDZ and UST as a third-class biologic in patients with CD.Results: Two-hundred and four patients were included; 156/204 (76%) patients received VDZ as a second- and UST as a third-class therapy (group A); the remaining 48/204 (24%) patients received UST as a second- and VDZ as a third-class therapy (group B). At week 16-22, 87/156 (55.5%) patients and 27/48 (56.2%) in groups A and B, respectively, responded to treatment (p = 0.9); 41/156 (26.2%) and 15/48 (31.2%) were in clinical remission (p = 0.5). At week 52; 89/103 (86%) patients and 25/29 (86.2%) of the patients with available data had responded to third-class treatment in groups A and B, respectively (p = 0.9); 31/103 (30%) and 47/29 (24.1%) were in clinical remission (p = 0.5).Conclusion: Third-class biological therapy was effective in more than half of the patients with CD. No differences in effectiveness were detected between the use of VDZ and UST as a third-class agent.
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| 17. |
- Aw, S T, et al.
(author)
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Individual semicircular canal function in superior and inferior vestibular neuritis
- 2001
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In: Neurology. - 1526-632X. ; 57:5, s. 768-774
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To examine the concept of selective superior and inferior vestibular nerve involvement in vestibular neuritis by studying the distribution of semicircular canal (SCC) involvement in such patients. BACKGROUND: Vestibular neuritis was traditionally thought to involve the superior and inferior vestibular nerves. Recent work suggests that in some patients, only the superior nerve is involved. So far there are no reported cases of selective involvement of the inferior vestibular nerve. METHODS: The authors measured the vestibuloocular reflex from individual SCC at natural head accelerations using the head impulse test. The authors studied 33 patients with acute unilateral peripheral vestibulopathy, including 29 with classic vestibular neuritis and 4 with simultaneous ipsilateral hearing loss, 18 healthy subjects and 15 surgical unilateral vestibular deafferented patients. RESULTS: In patients with preserved hearing, eight had deficits in all three SCC, suggesting involvement of the superior and inferior vestibular nerves. Twenty-one had a lateral SCC deficit or a combined lateral and anterior SCC deficit consistent with selective involvement of the superior vestibular nerve. Two patients with ipsilateral hearing loss had normal caloric responses and an isolated posterior SCC deficit on impulsive testing. The authors propose that these two patients had a selective loss of inferior vestibular nerve function. CONCLUSION: Vestibular neuritis can affect the superior and inferior vestibular nerves together or can selectively affect the superior vestibular nerve.
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| 22. |
- Kraka, Elfi, et al.
(author)
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Trimesitylsilylium cation verification of a free silylium cation in solution by NMR chemical shift calculations
- 1997
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In: Chemical Physics Letters. - 0009-2614. ; 279, s. 9-16
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Journal article (peer-reviewed)abstract
- NMR chemical shift calculations at the SOS-DFPT/PW91/[7s6p2d/5s4p1d/3s]//B3LYP/6-31G(d) level of theory were used to describe the trimesitylsilylium cation 1, recently synthesized in benzene solution and investigated by NMR spectroscopy. The conformation of cation 1 is characterized by mesityl rings rotated by 47° in a propeller-like form. Contrary to other silylium cations investigated, cation 1 forms a weak Van der Waals complex 3 with benzene rather than a Wheland σ-complex. The calculated 29 Si NMR chemical shifts for 1 and 3 are 226 and 227 ppm, compared to the experimental value of 225.5 ppm. The agreement between calculated and measured NMR chemical shifts provides evidence that cation 1 presents the first free silylium cation synthesized. © 1997 Elsevier Science B.V.
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| 23. |
- Mahajna, H., et al.
(author)
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Idiopathic Thrombocytopenic Purpura associated with Inflammatory Bowel Disease : a multi-centre ECCO CONFER case series
- 2022
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In: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 16:Suppl. 1, s. I561-I561
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Journal article (other academic/artistic)abstract
- Background: Idiopathic Thrombocytopenic Purpura (ITP) is an acquired haematological disorder with an incidence of 1 to 6 per 100.000, with reported comorbidity in patients with Inflammatory Bowel Disease (IBD). The current study aimed to evaluate the clinical presentation and outcome of ITP in IBD patients.Methods: This multicenter retrospective case series was performed as part of the ECCO Collaborative Network of Exceptionally Rare case reports (CONFER) project. Cases of patients with ITP and IBD were collected by participating investigators. Clinical data were recorded in a standardised collection form.Results: This report includes 20 patients with concurrent ITP and IBD: 15 were males, median age was 34 [Interquartile range (IQR) 25–56]. 12 subjects had a diagnosis of ulcerative colitis and 8 of Crohn’s disease. The diagnosis of IBD preceded the ITP diagnosis in 17 patients (median time between diagnosis was 7 years [IQR 1–14 years]). Among those, 10 patients were in IBD clinical remission at ITP diagnosis. Nine were treated with mesalamine, one with thiopurine, 4 with tumor necrosis factor-alpha (TNF) blockers, and 3 with no treatment. The mean platelet count at the presentation of ITP was 41.7±38.6 × 109/L. 6 patients had rectal bleeding, 8 had purpura, 6 had mucosal petechia, 2 had epistaxis, and 6 patients were asymptomatic. Regarding ITP treatment, 11 were treated with corticosteroids, 1 with Anti-RhD immunoglobulin, 7 with intravenous immunoglobulins (IVIG), 2 with rituximab and 2 patients eventually required splenectomy. All patients whose first presentation of ITP was rectal bleeding were treated medically with successful control of the ITP and IBD, None of them required splenectomy. 3 patients required colectomy with long-term follow-up, indicated by the IBD and not due to massive bleeding as a complication of ITP. With long-term follow-up, all patients had thrombocytes count above 50 × 109/L, and 18 were in IBD clinical remission.Conclusion: Most ITP cases in this case series occurred after the IBD diagnosis and responded well to regular ITP treatment. The course of the ITP in the IBD patients follows a regular course, including response to medical therapy and low rates of splenectomy.
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| 26. |
- Wilke, T., et al.
(author)
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Deep drilling reveals massive shifts in evolutionary dynamics after formation of ancient ecosystem
- 2020
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In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 6:40
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Journal article (peer-reviewed)abstract
- The scarcity of high-resolution empirical data directly tracking diversity over time limits our understanding of speciation and extinction dynamics and the drivers of rate changes. Here, we analyze a continuous species-level fossil record of endemic diatoms from ancient Lake Ohrid, along with environmental and climate indicator time series since lake formation 1.36 million years (Ma) ago. We show that speciation and extinction rates nearly simultaneously decreased in the environmentally dynamic phase after ecosystem formation and stabilized after deep-water conditions established in Lake Ohrid. As the lake deepens, we also see a switch in the macroevolutionary trade-off, resulting in a transition from a volatile assemblage of short-lived endemic species to a stable community of long- lived species. Our results emphasize the importance of the interplay between environmental/climate change, ecosystem stability, and environmental limits to diversity for diversification processes. The study also provides a new understanding of evolutionary dynamics in long-lived ecosystems.
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