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1.
Inflammasome Genetic Variants, Macrophage Function, and Clinical Outcomes in Cystic Fibrosis.
Graustein, AD, Berrington, WR, Buckingham, KJ, Nguyen, FK, Joudeh, LL, Rosenfeld, M, Bamshad, MJ, Gibson, RL, Hawn, TR, Emond, MJ
American journal of respiratory cell and molecular biology. 2021;(2):157-166
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Abstract
Cystic fibrosis (CF) is characterized by chronic airway infection, inflammation, and tissue damage that lead to progressive respiratory failure. NLRP3 and NLRC4 are cytoplasmic pattern recognition receptors that activate the inflammasome, initiating a caspase-1-mediated response. We hypothesized that gain-of-function inflammasome responses are associated with worse outcomes in children with CF. We genotyped nonsynonymous variants in NLRP3 and the NLRC4 pathway from individuals in the EPIC (Early Pseudomonas Infection Control) Observational Study cohort and tested for association with CF outcomes. We generated knockouts of NLRP3 and NLRC4 in human macrophage-like cells and rescued knockouts with wild-type or variant forms of NLRP3 and NLRC4. We identified a SNP in NLRP3, p.(Q705K), that was associated with a higher rate of P. aeruginosa colonization (N = 609; P = 0.01; hazard ratio, 2.3 [Cox model]) and worsened lung function over time as measured by forced expiratory volume in 1 second (N = 445; P = 0.001 [generalized estimating equation]). We identified a SNP in NLRC4, p.(A929S), that was associated with a lower rate of P. aeruginosa colonization as part of a composite of rare variants (N = 405; P = 0.045; hazard ratio, 0.68 [Cox model]) and that was individually associated with protection from lung function decline (P < 0.001 [generalized estimating equation]). Rescue of the NLRP3 knockout with the p.(Q705K) variant produced significantly more IL-1β in response to NLRP3 stimulation than rescue with the wild type (P = 0.020 [Student's t test]). We identified a subset of children with CF at higher risk of early lung disease progression. Knowledge of these genetic modifiers could guide therapies targeting inflammasome pathways.
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2.
A novel biomarker for predicting sepsis mortality: SCUBE-1.
Erdoğan, M, Findikli, HA, Okuducu Teran, İ
Medicine. 2021;(6):e24671
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Abstract
The mortality rate of patients diagnosed with sepsis is high. To date, many markers in sepsis patients have been studied to diagnose, determine their prognosis, and contribute to treatment. These studies were conducted in both experimental and clinical settings, but clinical trials remain limited. Therefore, more well-planned clinical studies are needed in patients with sepsis.The current study aimed to examine the prognostic role of signal peptide-CUB-epidermal growth factor-like domain-containing protein 1 (SCUBE-1) in sepsis and sepsis-related mortality. We also wanted to study its relationship with inflammatory markers and scoring systems.This prospective, cross-sectional, observational study included a total of 187 sepsis cases treated in the intensive care unit. Venous samples were obtained after diagnosis. The patients were separated into 2 groups: (1) the survivor group who were discharged or transferred within 28 days of the first diagnosis and (2) the nonsurvivor group who died within 28 days of the first diagnosis.The SCUBE-1, C-reactive protein, procalcitonin, creatinine, lactate values, acute physiology and chronic health evaluation 2, sequential organ failure assessment scores were significantly higher in the survivor group, and platelets were higher in the survivor group. In addition, SCUBE-1 positively correlated with the inflammatory markers C-reactive protein, lactate, sequential organ failure assessment, and acute physiology and chronic health evaluation 2. Additionally, the SCUBE-1 value predicts 28-day mortality, and the optimal cutoff value for predicting mortality is 4,73 pg/mL.Sepsis is a disease with high mortality. SCUBE-1 can be used as a new prognostic factor for sepsis patients.
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Progressive sector retinitis pigmentosa due to c.440G>T mutation in SAG in an Australian family.
Pappalardo, J, Heath Jeffery, RC, Thompson, JA, Charng, J, Chelva, ES, Constable, IJ, McLaren, TL, Lamey, TM, De Roach, JN, Chen, FK
Ophthalmic genetics. 2021;(1):62-70
Abstract
BACKGROUND Heterozygous c.440 G > T mutation in the S-antigen visual arrestin (SAG) gene has been described as a cause of autosomal dominant retinitis pigmentosa (adRP) in a series of patients of Hispanic origin. This study presents the early and late clinical features and disease progression rates in an Australian family with SAG adRP. MATERIALS AND METHODS An observational case series of four family members with adRP. They were examined clinically, with multi-modal retinal imaging and electroretinography (ERG) to ascertain phenotype. Disease progression rate was measured using optical coherence tomography (OCT) and fundus autofluorescence (FAF). A retinal dystrophy panel was used for the proband and cascade testing with targeted Sanger sequencing was conducted in other available family members. RESULTS The proband presented at 36 years of age with profoundly reduced full-field ERG responses despite a sector RP phenotype. This progressed to a classic RP pattern over several decades leaving a small residual island of central visual field. The horizontal span of the residual outer nuclear layer and the area of hyperautofluorescent ring contracted at a rate of 8-11% and 9-14% per year, respectively. DNA sequencing confirmed the segregation of SAG c.440 G > T mutation with disease. CONCLUSION SAG adRP presents with a reduced full-field ERG response consistent with a rod-cone dystrophy in mid-life despite a sector RP phenotype. Centripetal progression of the disease into the macula can be tracked by OCT and FAF imaging.
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Circulating EGFL7 distinguishes between IUGR and PE: an observational case-control study.
Massimiani, M, Salvi, S, Tiralongo, GM, Moresi, S, Stuhlmann, H, Valensise, H, Lanzone, A, Campagnolo, L
Scientific reports. 2021;(1):17919
Abstract
Isolated intrauterine growth restriction (IUGR) and preeclampsia (PE) share common placental pathogenesis. Differently from IUGR, PE is a systemic disorder which may also affect liver and brain. Early diagnosis of these conditions may optimize maternal and fetal management. Aim of this study was to assess whether Epidermal Growth Factor-Like domain 7 (EGFL7) dosage in maternal blood discriminates between isolated IUGR and PE. A total of 116 women were enrolled in this case-control study: 12 non-pregnant women, 34 healthy pregnant women, 34 women presenting with isolated IUGR and 36 presenting with PE. Levels of circulating EGFL7 and other known pro- and anti-angiogenic factors were measured by ELISA at different gestational ages (GA). Between 22-25 weeks of gestation, EGFL7 levels in early-onset PE (e-PE) plasma samples were significantly higher than those measured in controls or isolated IUGR samples (69.86 ± 6.17 vs. 19.8 ± 2.5 or 18.8 ± 2.8 µg/ml, respectively). Between 26-34 weeks, EGFL7 levels remained significantly higher in e-PE compared to IUGR. At term, circulating and placental EGFL7 levels were comparable between IUGR and late-onset PE (l-PE). In contrast, circulating levels of PlGF were decreased in both IUGR- and PE- complicated pregnancies, while levels of both sFLT-1 and sENDOGLIN were increased in both conditions. In conclusion, EGFL7 significantly discriminates between isolated IUGR and PE.
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Vitamin K2 Status and Arterial Stiffness Among Untreated Migraine Patients: A Case-Control Study.
Mansour, AG, Ahdab, R, Daaboul, Y, Korjian, S, Morrison, DA, Hariri, E, Salem, M, El Khoury, C, Riachi, N, Aoun Bahous, S
Headache. 2020;(3):589-599
Abstract
OBJECTIVE We aimed to examine arterial stiffness and vitamin K2 status in migraine subjects by comparison to controls. BACKGROUND Migraine is a primary headache disorder that has been associated with an increased risk of cardiovascular events. Mechanisms underlying this increased risk, however, remain unclear. Vitamin K2 deficiency emerged as a cardiovascular risk factor, but vitamin K2 status has never been explored in migraine subjects. DESIGN AND METHODS This is a case-control, single-center, observational study that includes a cohort of subjects with migraine and their age- and sex-matched controls. Arterial stiffness was measured using carotid-femoral pulse wave velocity (cfPWV). Dephosphorylated-uncarboxylated matrix-Gla-protein (dp-ucMGP) was used as a marker for vitamin K2 status. A propensity-matched scoring method was used. RESULTS A total of 146 patients (73 matched pairs) were included in this study, of whom 89% were women with a mean age of 31.9 ± 8.4 years. Compared with controls, migraine patients had statistically significantly higher mean cfPWV (7.2 ± 1.1 vs 6.4 ± 0.8 m/s, 95% confidence interval (CI) of mean difference [0.45, 1.08], P < .001), as well as higher dp-ucMGP (454.3 ± 116.7 pmol/L vs 379.8 ± 126.6 pmol/L, 95% CI of mean difference [34.63, 114.31], P < .001). Higher cfPWV was associated with higher dp-ucMGP concentrations only in the migraine with aura (MWA) group. Moreover, migraine subjects had a higher frequency of vitamin K2 deficiency (dp-ucMGP ≥ 500 pmol/L) compared to controls, but this association was not statistically significant (23/73 [31.5%] vs 16/73 [21.9%], P = .193). CONCLUSIONS Individuals with migraine have worse indices of arterial stiffness as compared with their age- and sex-matched control subjects. This increase in arterial stiffness is associated with an increase in markers of vitamin K2 deficiency in the MWA group.
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Plasma dephosphorylated-uncarboxylated Matrix Gla-Protein (dp-ucMGP): reference intervals in Caucasian adults and diabetic kidney disease biomarker potential.
Griffin, TP, Islam, MN, Wall, D, Ferguson, J, Griffin, DG, Griffin, MD, O'Shea, PM
Scientific reports. 2019;(1):18452
Abstract
Recent studies suggest a possible association between dephosphorylated-uncarboxylated MGP (dp-ucMGP) and glomerular filtration rate (GFR). This study aimed to establish normative data in an adult Caucasian population and to explore the potential utility of dp-ucMGP in patients with diabetes mellitus (DM) with and without diabetic kidney disease (DKD). Healthy volunteers (HVs) (cross-sectional study) and participants with DM (prospective cohort study) were recruited. Plasma dp-ucMGP was measured using the IDS®-iSYS Ina Ktif (dp-ucMGP) assay. Of the HVs recruited (n = 208), 67(32.2%) were excluded leaving a reference population of 141(67.8%) metabolically healthy participants with normal kidney function. Plasma dp-ucMGP RIs were <300-532 pmol/L. There were 100 eligible participants with DKD and 92 with DM without DKD. For the identification of participants with DKD, the area under the receiver operating characteristic curve (AUC) for dp-ucMGP was 0.842 (95%CI:0.799-0.880; p < 0.001). Plasma dp-ucMGP demonstrated similar ability to urine albumin:creatinine ratio (uACR) to detect participants with DM and renal function decline. Among patients with DM, there was a negative correlation between natural log (LN) dp-ucMGP and eGFR (r = -0.7041; p < 0.001) and rate of change in renal function [%change (r = -0.4509; p < 0.001)] and a positive correlation between LN dp-ucMGP and LN uACR (r = 0.3392; p < 0.001). These results suggest the potential for plasma dp-ucMGP with well-defined RIs to identify adults at high risk for vascular disease in the context of progressive DKD.
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The relation of serum nesfatin-1 level with anthropometric and metabolic parameters in children and adolescents: A prospective observational study.
Kim, SH, Ahn, MB, Cho, WK, Cho, KS, Jung, MH, Suh, BK
Medicine. 2019;(19):e15460
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Abstract
Nesfatin-1, a recently discovered anorexigenic neuropeptide, seems to play an important role in hypothalamic pathways regulating food intake and energy homeostasis. The aim of this study was to evaluate the relation of serum nesfatin-1 level with metabolic and anthropometric parameters in children and adolescents.This study prospectively included 78 Korean children and adolescents (42 obese/overweight group and 36 healthy control group). Fasting serum nesfatin-1 was quantitatively assayed by ELISA. Lipid profile, fasting blood glucose, fasting insulin, and the homeostasis model assessment of insulin resistance (HOMA-IR) were measured as metabolic parameters.Serum nesfatin-1 levels were significantly lower in obese/overweight group than in control group (median 1.4 vs 2.0 ng/mL; P = .003). Pubertal subjects have the lower serum nesfatin-1 level than pre-pubertal subjects (median 1.5 vs 2.6 ng/mL; P = .02). Nesfatin-1 levels negatively correlated with chronological age (r = -0.37; P = .001), BMI (r = -0.33; P = .003), and BMI SDS (r = -0.26; P = .02).In conclusion, our results suggest that serum nesfatin-1 negatively correlated with BMI in children and adolescents. It suggests that nesfatin-1 might have an important role in regulation of food intake in obese children and adolescents.
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Associations of Serum S100B and S100P With the Presence and Classification of Diabetic Peripheral Neuropathy in Adults With Type 2 Diabetes: A Case-Cohort Study.
Afarideh, M, Zaker Esteghamati, V, Ganji, M, Heidari, B, Esteghamati, S, Lavasani, S, Ahmadi, M, Tafakhori, A, Nakhjavani, M, Esteghamati, A
Canadian journal of diabetes. 2019;(5):336-344.e2
Abstract
OBJECTIVES Novel biomarkers of diabetic peripheral neuropathy provide potentially useful information for early identification and treatment of diabetic neuropathy, ultimately serving to reduce the burden of disease. This study was designed to investigate the potential associations of serum S100B and S100P (calcium-modulated proteins) with the presence and classification of diabetic peripheral neuropathy in adults with type 2 diabetes. METHODS In a case-cohort setting, the data of 44 participants diagnosed with diabetic peripheral neuropathy, 44 control participants with type 2 diabetes but free of peripheral neuropathy and 87 healthy control individuals were collected and analyzed. RESULTS Serum S100P concentrations were elevated in participants with diabetic peripheral neuropathy compared with their controls with type 2 diabetes (median [IQR]: 2,235 pg/mL [1,497.5 to 2,680] vs. 1,200 pg/mL [975 to 1,350)], respectively; p<0.001). Conversely, serum S100B values were comparable in these 2 groups (p=0.570). Those with the typical diabetic peripheral neuropathy had significantly higher serum S100P levels compared to their counterparts with the atypical group of diabetic peripheral neuropathies (p=0.048). The independent significant association between serum S100P and diabetic peripheral neuropathy persisted into the multivariable adjusted logistic regression model (OR for S100P: 1.004 [95% CI 1.002 to 1.006]; p<0.001). CONCLUSIONS The present study's findings demonstrated that serum S100P is a more significant indicator of peripheral neuropathy in type 2 diabetes than is serum S100B. Prospective longitudinal studies are required to confirm the prognostic value of baseline serum S100P to predict incident peripheral neuropathy in people with diabetes.
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The Association between Serum Matricellular Protein: Secreted Protein Acidic and Rich in Cysteine-Like 1 Levels and Ischemic Stroke Severity.
Ambrosius, W, Michalak, S, Kazmierski, R, Lukasik, M, Andrzejewska, N, Kozubski, W
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2018;(3):682-685
Abstract
BACKGROUND The role of matricellular proteins like secreted protein acidic and rich in cysteine-like 1 (SC1) has been shown in important functions in the central nervous system, including the regulation of synaptic stability with upregulation throughout axonal regeneration. The aim of this study was to determine whether SC1 is related to ischemic stroke severity. METHODS A total of 132 consecutively recruited patients admitted for acute ischemic stroke were included in this observational prospective study. Stroke severity was evaluated in the National Institutes of Health (NIHSS) scale on hospital admission. RESULTS There was a positive correlation between SC1 levels and NIHSS score (r = .22, P = .009). Compared with patients with NIHSS scores lower than 5 at admission, patients with moderate and severe stroke (NIHSS ≥ 6) had significantly higher SC1 levels: 4.84 (2.53-11.58) ng/mL versus 3.31 (1.67-8.95) ng/mL (P = .01). SC1 was an independent predictor of stroke severity at admission (adjusted odds ratio =1.25; 95% confidence interval, 1.03-1.97; P = .04). CONCLUSION SC1 levels were independently associated with ischemic stroke severity evaluated by the NIHSS.
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Desphospho-Uncarboxylated Matrix-Gla Protein Is Increased Postoperatively in Cardiovascular Risk Patients.
Dahlberg, S, Ede, J, Schurgers, L, Vermeer, C, Kander, T, Klarin, B, Schött, U
Nutrients. 2018;(1)
Abstract
BACKGROUND Matrix Gla protein (MGP) is an extrahepatic protein that is dependent on glutamate carboxylation, a vitamin K-dependent process. Its dysfunctional form, desphospho-uncarboxylated-MGP, has been associated with increased arterial calcification and stiffness. The aim of this study was to measure the degree of postoperative carboxylation of MGP and two other Gla proteins in patients scheduled for abdominal or orthopaedic surgery. METHODS Forty patients undergoing abdominal or orthopaedic surgery were included. Blood samples were collected preoperatively and four days after the surgery. Desphospho-carboxylated MGP (dp-cMGP), desphospho-uncarboxylated MGP (dp-ucMGP), carboxylated osteocalcin (OC) (cOC), uncarboxylated OC (ucOC), and uncarboxylated prothrombin (PIVKA-II) were analysed. RESULTS Preoperatively, 29 patients had dp-ucMGP levels above the reference values. Patients with pre-existing cardiovascular comorbidities had higher dp-ucMGP preoperatively compared with patients with no record of cardiovascular disease. Postoperatively, this number increased to 36 patients, and median dp-ucMGP levels increased (p < 0.0001) and correlated to a PIVKA-II increase (r = 0.44). On the other hand, dp-cMGP levels did not significantly alter. Decreased levels of ucOC and cOC were seen after surgery (p = 0.017 and p = 0.0033, respectively). Comorbidities, possible nutritional defects, and complications affecting Gla protein activity and function were identified. CONCLUSIONS Dp-ucMGP was high preoperatively, and had further increased postoperatively. This pattern was linked to several comorbidities, possible nutritional defects, and postoperative complications, which motivates further research about potential interactions between perioperative corrective treatments with vitamin K supplements, cardiovascular biomarkers, and incidents of stroke and myocardial infarction events.