Anatomy and Neuroscience - Research Publications

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    Kidney omics in hypertension: from statistical associations to biological mechanisms and clinical applications
    Tomaszewski, M ; Morris, AP ; Howson, JMM ; Franceschini, N ; Eales, JM ; Xu, X ; Dikalov, S ; Guzik, TJ ; Humphreys, BD ; Harrap, S ; Charchar, FJ (ELSEVIER SCIENCE INC, 2022-09)
    Hypertension is a major cardiovascular disease risk factor and contributor to premature death globally. Family-based investigations confirmed a significant heritable component of blood pressure (BP), whereas genome-wide association studies revealed >1000 common and rare genetic variants associated with BP and/or hypertension. The kidney is not only an organ of key relevance to BP regulation and the development of hypertension, but it also acts as the tissue mediator of genetic predisposition to hypertension. The identity of kidney genes, pathways, and related mechanisms underlying the genetic associations with BP has started to emerge through integration of genomics with kidney transcriptomics, epigenomics, and other omics as well as through applications of causal inference, such as Mendelian randomization. Single-cell methods further enabled mapping of BP-associated kidney genes to cell types, and in conjunction with other omics, started to illuminate the biological mechanisms underpinning associations of BP-associated genetic variants and kidney genes. Polygenic risk scores derived from genome-wide association studies and refined on kidney omics hold the promise of enhanced diagnostic prediction, whereas kidney omics-informed drug discovery is likely to contribute new therapeutic opportunities for hypertension and hypertension-mediated kidney damage.
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    Renin-Angiotensin System Inhibitors in Patients With COVID-19: A Meta-Analysis of Randomized Controlled Trials Led by the International Society of Hypertension
    Gnanenthiran, SR ; Borghi, C ; Burger, D ; Caramelli, B ; Charchar, F ; Chirinos, JA ; Cohen, JB ; Cremer, A ; Di Tanna, GL ; Duvignaud, A ; Freilich, D ; Gommans, DHF ; Gracia-Ramos, AE ; Murray, TA ; Pelorosso, F ; Poulter, NR ; Puskarich, MA ; Rizas, KD ; Rothlin, R ; Schlaich, MP ; Schreinlecher, M ; Steckelings, UM ; Sharma, A ; Stergiou, GS ; Tignanelli, CJ ; Tomaszewski, M ; Unger, T ; van Kimmenade, RRJ ; Wainford, RD ; Williams, B ; Rodgers, A ; Schutte, AE (WILEY, 2022-09-06)
    Background Published randomized controlled trials are underpowered for binary clinical end points to assess the safety and efficacy of renin-angiotensin system inhibitors (RASi) in adults with COVID-19. We therefore performed a meta-analysis to assess the safety and efficacy of RASi in adults with COVID-19. Methods and Results MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane Controlled Trial Register were searched for randomized controlled trials that randomly assigned patients with COVID-19 to RASi continuation/commencement versus no RASi therapy. The primary outcome was all-cause mortality at ≤30 days. A total of 14 randomized controlled trials met the inclusion criteria and enrolled 1838 participants (aged 59 years, 58% men, mean follow-up 26 days). Of the trials, 11 contributed data. We found no effect of RASi versus control on all-cause mortality (7.2% versus 7.5%; relative risk [RR], 0.95; [95% CI, 0.69-1.30]) either overall or in subgroups defined by COVID-19 severity or trial type. Network meta-analysis identified no difference between angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers. RASi users had a nonsignificant reduction in acute myocardial infarction (2.1% versus 3.6%; RR, 0.59; [95% CI, 0.33-1.06]), but increased risk of acute kidney injury (7.0% versus 3.6%; RR, 1.82; [95% CI, 1.05-3.16]), in trials that initiated and continued RASi. There was no increase in need for dialysis or differences in congestive cardiac failure, cerebrovascular events, venous thromboembolism, hospitalization, intensive care admission, inotropes, or mechanical ventilation. Conclusions This meta-analysis of randomized controlled trials evaluating angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers versus control in patients with COVID-19 found no difference in all-cause mortality, a borderline decrease in myocardial infarction, and an increased risk of acute kidney injury with RASi. Our findings provide strong evidence that RASi can be used safely in patients with COVID-19.
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    Design and rationale of a nationwide screening analysis from the LIPIDOGRAM2015 and LIPIDOGEN2015 studies
    Jozwiak, J ; Kasperczyk, S ; Tomasik, T ; Osadnik, T ; Windak, A ; Studzinski, K ; Mastej, M ; Catapano, A ; Ray, KK ; Mikhailidis, D ; Toth, P ; Howard, G ; Lip, GYH ; Tomaszewski, M ; Charchar, FJ ; Sattar, N ; Williams, B ; MacDonald, TM ; Krzemien, P ; Dobrakowski, M ; Kasperczyk, A ; Nowak, D ; Skowron, L ; Zak, Z ; Lewek, J ; Banach, M (TERMEDIA PUBLISHING HOUSE LTD, 2020-05)
    INTRODUCTION: Cardiovascular disease (CVD) is a major cause of morbidity and mortality throughout the world. The LIPIDOGRAM2015 study was performed to estimate the prevalence of risk factors for atherosclerotic diseases as well as cardiovascular and related disorders in the primary care setting in Poland. The LIPIDOGEN2015 sub-study was designed to include a random cohort of patients in order to analyse parameters related to lipid metabolism, oxidative stress, inflammatory responses, autoimmune disorders, and gene variants that confer susceptibility to cardiometabolic and atherosclerotic diseases. MATERIAL AND METHODS: The recruitment was carried out by 438 primary care physicians in Poland. The expected number of patients recruited for the LIPIDOGRAM2015 study was 13,000-14,000 with 13-15% (1700-2000) also participating in the LIPIDOGEN2015 sub-study. Each patient had to complete a questionnaire concerning medical and family history, concomitant diseases, and pharmacotherapy. Anthropometric measurements were performed at the doctor's office. For the LIPIDOGEN2015 sub-study, saliva samples for DNA isolation and blood samples for measurement of glycated haemoglobin, oxidative stress parameters, autoantibody levels, and inflammatory cytokine profile and apolipoprotein profile were collected. Follow-up data will be obtained from the National Health Fund in Poland. RESULTS: The LIPIDOGRAM2015 and LIPIDOGEN2015 study cohort reflects the prevalence of cardiovascular risk factors and concomitant diseases, markers of oxidative stress, the presence of autoantibodies, inflammatory cytokine profile, and apolipoprotein profile, as well as genetic variants potentially conferring susceptibility to cardiometabolic and atherosclerotic diseases. CONCLUSIONS: This study presents the prevalence of different CV risk factors, with special emphasis on lipid disorders, and it assesses the relationship between inflammation, oxidative stress, and mutations in genes encoding proteins regulating lipid metabolism, as well as genes conferring susceptibility to cardiovascular, cardiometabolic, and related diseases.
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    Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney
    Eales, JM ; Jiang, X ; Xu, X ; Saluja, S ; Akbarov, A ; Cano-Gamez, E ; McNulty, MT ; Finan, C ; Guo, H ; Wystrychowski, W ; Szulinska, M ; Thomas, HB ; Pramanik, S ; Chopade, S ; Prestes, PR ; Wise, I ; Evangelou, E ; Salehi, M ; Shakanti, Y ; Ekholm, M ; Denniff, M ; Nazgiewicz, A ; Eichinger, F ; Godfrey, B ; Antczak, A ; Glyda, M ; Krol, R ; Eyre, S ; Brown, J ; Berzuini, C ; Bowes, J ; Caulfield, M ; Zukowska-Szczechowska, E ; Zywiec, J ; Bogdanski, P ; Kretzler, M ; Woolf, AS ; Talavera, D ; Keavney, B ; Maffia, P ; Guzik, TJ ; O'Keefe, RT ; Trynka, G ; Samani, NJ ; Hingorani, A ; Sampson, MG ; Morris, AP ; Charchar, FJ ; Tomaszewski, M (NATURE PORTFOLIO, 2021-05)
    The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.
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    A Modified MTS Proliferation Assay for Suspended Cells to Avoid the Interference by Hydralazine and β-Mercaptoethanol
    Wang, Y ; Nguyen, DT ; Yang, G ; Anesi, J ; Kelly, J ; Chai, Z ; Ahmady, F ; Charchar, F ; Golledge, J (MARY ANN LIEBERT, INC, 2021-04-01)
    The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay is one of the most commonly used tests of cell proliferation. Hydralazine has been reported to interfere with the performance of the MTS assay when used on adherent cells. This study aimed to investigate whether hydralazine interferes with the performance of the MTS assay on suspended cells. THP-1 (a monocytic leukemia cell line) cells were cultured in the presence or absence of hydralazine (0, 10, 50, 100, and 500 μM) for 2 or 24 h. Cell numbers were analyzed using the MTS, trypan blue exclusion, or microscopic assays. A modified version of the standard MTS assay was established by centrifuging the cells and replacing the test medium with fresh culture medium immediately before the addition of the MTS reagent. Culture of THP-1 cells with hydralazine at concentrations of 50, 100, and 500 μM for 2 h increased absorbance (p < 0.001) in the standard MTS assay, whereas both the trypan blue exclusion assay and microscopy suggested no change in cell numbers. Culture of THP-1 cells with 100 and 500 μm hydralazine for 24 h increased absorbance (p < 0.05) in the standard MTS assay; however, trypan blue exclusion and microscopy suggested a decrease in cell numbers. In a cell-free system, hydralazine (100 and 500 μM) increased absorbance in a time- and concentration-dependent manner. The modified MTS assay produced results consistent with trypan blue exclusion and microscopy using THP-1 cells. In addition, the modified MTS assay produced reliable results when K562 and Jurkat cells were incubated with hydralazine or β-mercaptoethanol (βME). In conclusion, a simple modification of the standard MTS assay overcame the interference of hydralazine and βME when assessing suspended cells.
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    Contributions of obesity to kidney health and disease: insights from Mendelian randomization and the human kidney transcriptomics
    Xu, X ; Eales, JM ; Jiang, X ; Sanderson, E ; Drzal, M ; Saluja, S ; Scannali, D ; Williams, B ; Morris, AP ; Guzik, TJ ; Charchar, FJ ; Holmes, M ; Tomaszewski, M ; Antoniades, C (OXFORD UNIV PRESS, 2022-12-09)
    AIMS: Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. Our objective was to examine if modifiable anthropometric obesity indices show putatively causal association with kidney health and disease and highlight biological mechanisms of potential relevance to the association between obesity and the kidney. METHODS AND RESULTS: We performed observational, one-sample, two-sample Mendelian randomization (MR) and multivariable MR studies in ∼300 000 participants of white-British ancestry from UK Biobank and participants of predominantly European ancestry from genome-wide association studies. The MR analyses revealed that increasing values of genetically predicted body mass index and waist circumference were causally associated with biochemical indices of renal function, kidney health index (a composite renal outcome derived from blood biochemistry, urine analysis, and International Classification of Disease-based kidney disease diagnoses), and both acute and chronic kidney diseases of different aetiologies including hypertensive renal disease and diabetic nephropathy. Approximately 13-16% and 21-26% of the potentially causal effect of obesity indices on kidney health were mediated by blood pressure and type 2 diabetes, respectively. A total of 61 pathways mapping primarily onto transcriptional/translational regulation, innate and adaptive immunity, and extracellular matrix and metabolism were associated with obesity measures in gene set enrichment analysis in up to 467 kidney transcriptomes. CONCLUSIONS: Our data show that a putatively causal association of obesity with renal health is largely independent of blood pressure and type 2 diabetes and uncover the signatures of obesity on the transcriptome of human kidney.
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    Relationship Between Anti-DFS70 Autoantibodies and Oxidative Stress
    Krzemien, P ; Kasperczyk, S ; Banach, M ; Kasperczyk, A ; Dobrakowski, M ; Tomasik, T ; Windak, A ; Mastej, M ; Catapano, A ; Ray, KK ; Mikhailidis, DP ; Toth, PP ; Howard, G ; Lip, GY ; Tomaszewski, M ; Charchar, FJ ; Sattar, N ; Williams, B ; MacDonald, TM ; Penson, PE ; Jozwiak, JJ (SAGE PUBLICATIONS LTD, 2022-01)
    BACKGROUND: The anti-DFS70 autoantibodies are one of the most commonly and widely described agent of unknown clinical significance, frequently detected in healthy individuals. It is not known whether the DFS70 autoantibodies are protective or pathogenic. One of the factors suspected of inducing the formation of anti-DFS70 antibodies is increased oxidative stress. We evaluated the coexistence of anti-DFS70 antibodies with selected markers of oxidative stress and investigated whether these antibodies could be considered as indirect markers of oxidative stress. METHODS: The intensity of oxidative stress was measured in all samples via indices of free-radical damage to lipids and proteins such as total oxidant status (TOS), concentrations of lipid hydroperoxides (LPH), lipofuscin (LPS), and malondialdehyde (MDA). The parameters of the non-enzymatic antioxidant system, such as total antioxidant status (TAS) and uric acid concentration (UA), were also measured, as well as the activity of superoxide dismutase (SOD). Based on TOS and TAS values, the oxidative stress index (OSI) was calculated. All samples were also tested with indirect immunofluorescence assay (IFA) and 357 samples were selected for direct monospecific anti DFS70 enzyme-linked immunosorbent assay (ELISA) testing. RESULTS: The anti-DFS70 antibodies were confirmed by ELISA test in 21.29% of samples. Compared with anti-DFS70 negative samples we observed 23% lower concentration of LPH (P = .038) and 11% lower concentration of UA (P = .005). TOS was 20% lower (P = .014). The activity of SOD was up to 5% higher (P = .037). The Pearson correlation showed weak negative correlation for LPH, UA, and TOS and a weak positive correlation for SOD activity. CONCLUSION: In samples positive for the anti-DFS70 antibody a decreased level of oxidative stress was observed, especially in the case of samples with a high antibody titer. Anti-DFS70 antibodies can be considered as an indirect marker of reduced oxidative stress or a marker indicating the recent intensification of antioxidant processes.
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    The Differences in the Prevalence of Cardiovascular Disease, Its Risk Factors, and Achievement of Therapeutic Goals among Urban and Rural Primary Care Patients in Poland: Results from the LIPIDOGRAM 2015 Study
    Studzinski, K ; Tomasik, T ; Windak, A ; Banach, M ; Wojtowicz, E ; Mastej, M ; Tomaszewski, M ; Mikhailidis, DP ; Toth, PP ; Catapano, A ; Ray, KK ; Howard, G ; Lip, GYH ; Charchar, FJ ; Sattar, N ; Williams, B ; MacDonald, TM ; Penson, PE ; Jozwiak, JJ (MDPI, 2021-12)
    A nationwide cross-sectional study, LIPIDOGRAM2015, was carried out in Poland in the years 2015 and 2016. A total of 438 primary care physicians enrolled 13,724 adult patients that sought medical care in primary health care practices. The prevalence of hypertension, diabetes mellitus, dyslipidaemia, and CVD were similar in urban and rural areas (49.5 vs. 49.4%; 13.7 vs. 13.1%; 84.2 vs. 85.2%; 14.4 vs. 14.2%, respectively). The prevalence of obesity (32.3 vs. 37.5%, p < 0.01) and excessive waist circumference (77.5 vs. 80.7%, p < 0.01), as well as abdominal obesity (43.2 vs. 46.4%, p < 0.01), were higher in rural areas in both genders. Mean levels of LDL-C (128 vs. 130 mg/dL, p = 0.04) and non-HDL-C (147 vs. 148 mg/dL, p = 0.03) were slightly higher in rural populations. Altogether, 14.3% of patients with CVD from urban areas and 11.3% from rural areas reached LDL <70 mg/dL (p = 0.04). There were no important differences in the prevalence of hypertension, diabetes, dyslipidaemia, and CVD, or in mean levels of blood pressure, cholesterol fractions, glucose, and HbA1c between Polish urban and rural primary care patient populations. A high proportion of patients in cities and an even-higher proportion in rural areas did not reach the recommended targets for blood pressure, LDL-C, and HbA1c, indicating the need for novel CVD-prevention programs.
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    Analysis of the impact of sex and age on the variation in the prevalence of antinuclear autoantibodies in Polish population: a nationwide observational, cross-sectional study
    Krzemien, P ; Kasperczyk, S ; Banach, M ; Kasperczyk, A ; Dobrakowski, M ; Tomasik, T ; Windak, A ; Mastej, M ; Catapano, A ; Ray, KK ; Mikhailidis, DP ; Toth, PP ; Howard, G ; Lip, GYH ; Tomaszewski, M ; Charchar, FJ ; Sattar, N ; Williams, B ; MacDonald, TM ; Penson, PE ; Jozwiak, JJ (SPRINGER HEIDELBERG, 2022-02)
    The detection of antinuclear autoantibody (ANA) is dependent on many factors and varies between the populations. The aim of the study was first to assess the prevalence of ANA in the Polish adult population depending on age, sex and the cutoff threshold used for the results obtained. Second, we estimated the occurrence of individual types of ANA-staining patterns. We tested 1731 patient samples using commercially available IIFA using two cutoff thresholds of 1:100 and 1:160. We found ANA in 260 participants (15.0%), but the percentage of positive results strongly depended on the cutoff level. For a cutoff threshold 1:100, the positive population was 19.5% and for the 1:160 cutoff threshold, it was 11.7%. The most prevalent ANA-staining pattern was AC-2 Dense Fine speckled (50%), followed by AC-21 Reticular/AMA (14.38%) ANA more common in women (72%); 64% of ANA-positive patients were over 50 years of age. ANA prevalence in the Polish population is at a level observed in other highly developed countries and is more prevalent in women and elderly individuals. To reduce the number of positive results released, we suggest that Polish laboratories should set 1:160 as the cutoff threshold.
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    Secondary Stroke Prevention in Polish Adults: Results from the LIPIDOGRAM2015 Study
    Labuz-Roszak, B ; Banach, M ; Skrzypek, M ; Windak, A ; Tomasik, T ; Mastej, M ; Tomaszewski, M ; Mikhailidis, DP ; Toth, PP ; Catapano, A ; Ray, KK ; Howard, G ; Lip, GYH ; Charchar, FJ ; Sattar, N ; Williams, B ; MacDonald, TM ; Penson, P ; Jozwiak, JJ (MDPI, 2021-10)
    BACKGROUND: The purpose of the study was to evaluate secondary stroke prevention in Poland and its association with sociodemographic factors, place of residence, and concomitant cardiovascular risk factors. MATERIAL AND METHODS: From all patients in LIPIDOGRAM2015 Study (n = 13,724), 268 subjects had a history of ischaemic stroke and were included. RESULTS: 165 subjects (61.6%) used at least one preventive medication. Oral antiplatelet and anticoagulation agents were used by 116 (43.3%) and 70 (26.1%) patients, respectively. Only 157 (58.6%) participants used lipid-lowering drugs, and 205 (76.5%) were treated with antihypertensive drugs. Coronary heart disease (CHD) and dyslipidaemia were associated with antiplatelet treatment (p = 0.047 and p = 0.012, respectively). A history of atrial fibrillation, CHD, and previous myocardial infarction correlated with anticoagulant treatment (p = 0.001, p = 0.011, and p < 0.0001, respectively). Age, gender, time from stroke onset, place of residence, and level of education were not associated with antiplatelet or anticoagulant treatment. Only 31.7% of patients were engaged in regular physical activity, 62% used appropriate diet, and 13.6% were current smokers. CONCLUSIONS: In Poland drugs and lifestyle modification for secondary stroke prevention are not commonly adhered to. Educational programmes for physicians and patients should be developed to improve application of effective secondary prevention of stroke.