Blood Levels Of Protein Research Articles

Proteome-wide assessment of diabetes mellitus in Qatari identifies IGFBP-2 as a risk factor already with early glycaemic disturbances

BackgroundProteomics is expected to provide novel insights in the underlying pathophysiology of type 2 diabetes mellitus. In the present study, we aimed to identify and biochemically characterize proteins associated with diabetes mellitus in a Qatari population. MethodsIn a diabetes case-control study (175 cases, 164 controls; Arab, South Asian and Philippine ethnicities), we conducted a discovery study to screen 1141 blood protein levels for associations with diabetes mellitus. Additional analyses were done in controls in relation to Hb1Ac, and biochemical characterization of the main findings was performed with metabolomics (501 metabolites). We performed two-sample Mendelian Randomization to provide evidence of potential causality using data from European descent of the DIAGRAM consortium (74,124 cases of diabetes mellitus and 824,006 controls) for the identified proteins for T2D and Hb1Ac. ResultsAfter accounting for multiple testing, 30 protein levels were different (p-values<8.6e−5) between cases and controls. Of these, a higher Hb1Ac in controls was associated with a lower IGFBP-2 level (p-value = 4.1e−6). IGFBP-2 protein level was found lower among cases compared with controls across all ethnicities. In controls, IGFBP-2 was associated with 21 metabolite levels, but specifically connected to the metabolite citrulline in network analyses. We observed no evidence, however, that the association between IGFBP-2 and diabetes mellitus was causal. ConclusionsWe specifically identified IGFBP-2 to be associated with diabetes mellitus, although with no evidence for causality, which was specifically connected to citrulline metabolism.

Guanidinoacetic acid supplementation improves feed conversion in broilers subjected to heat stress associated with muscle creatine loading and arginine sparing

It was hypothesized that dietary guanidinoacetic acid (GAA), the precursor of creatine (Cr), would be beneficial to heat-stressed finisher broilers owing to improved cellular energy status and arginine sparing effects. A total of 720 one-day-old male Ross 308 broilers were allocated to 3 treatments, 0 (control), 0.6, or 1.2 g/kg of GAA added to complete corn–soybean meal diets, and were fed for 39 D, with 12 replicates (20 birds each) per treatment. A chronic cyclic heat stress model (at a temperature of 34°C and 50 to 60% relative humidity for 7 h daily) was applied in the finisher phase (day 25–39). Samples were taken on day 26 and 39 to determine thrombocyte, white blood cell, corticosterone, protein and amino acid levels in blood and Cr, phosphocreatine (PCr), and adenosine triphosphate levels in the breast muscle. Meat quality was assessed on day 40 after overnight fasting. Guanidinoacetic acid at a dose of 1.2 g/kg decreased feed-to-gain ratio compared with the control in the grower phase (1.32 vs. 1.35, respectively; P <0.05). In the finisher period, the supplementation of 1.2 g/kg of GAA reduced feed intake compared with the control (–3.3%, P <0.05), whereas both GAA supplementation levels improved feed efficiency markedly (1.76, 1.66, and 1.67 for 0 [control], 0.6, and 1.2 g/kg of GAA, respectively, P <0.05). Mortality outcomes highlight that GAA feeding improved survival during heat stress, supported by lower panting frequency (linear effect, P <0.05). Plasma arginine was higher with increase in dietary GAA concentration on day 26 (+18.3 and + 30.8% for 0.6 and 1.2 g/kg of GAA, respectively; P <0.05). This suggests enhanced availability of arginine for other metabolic purposes than de novo GAA formation. In the breast muscle, PCr (day 39, P <0.05), free Cr (day 39, P <0.05), total Cr (both days, P <0.05), and PCr-to-adenosine triphosphate ratio (day 39, P <0.05) levels were increased with higher GAA content in diet. Guanidinoacetic acid supplementation improved feed conversion and survival during chronic cyclic heat stress, which may be associated with enhanced breast muscle energy status and arginine sparing effect.

The prognostic value of high-sensitivity C-reactive protein blood level after coronary stenting for the development of stent restenosis

Aim To analyze the relationship between serum concentrations of high-sensitivity C-reactive protein (hsCRP) in dynamics and development of restenosis at 12 months following elective coronary stent placement (CSP).Material and methods The key role in atherogenesis, neointimal proliferation and restenosis belongs to inflammation. This study included 91 patients (median age, 60 [56; 66] years) with stable exertional angina after an elective CSP using second-generation stents. Follow-up coronarography was performed for 60 patients at 12 months. Concentration of hsCRP was measured immediately prior to CSP and at 1, 3, 6, and 12 months after CSP. Restenosis of the stented segment (50% or more narrowing of the stented segment or a 5-mm vessel segment proximally or distally adjacent to the stented segment) was observed in 8 patients.Results According to results of the ROC analysis, the increase in hsCRP concentration &gt;0.9 mg/l (&gt;25%) at one month after CSP had the highest predictive significance with respect of restenosis (area under the ROC curve, 0.89 at 95 % confidence interval (CI) from 0.79 to 0.99; sensitivity, 87.5 %; specificity, 82.8 %; р=0.0005), which was superior to the absolute value of hsCRP concentration &gt;3.0 mg/l (area under the ROC curve, 0.82 at 95 % CI from 0.68 to 0.96; р=0.0007).Conclusion Increased concentration of hsCRP ≥0.9 mg /l (≥25 %) at a month after CSP was associated with restenosis of the coronary artery stented segment.

Potential of peel extracts of Punica granatum and Citrus aurantifolia on alloxan-induced diabetic rats

BackgroundPeel is one of the major by-products in fruit processing industry. Fruit products (non-edible parts) are also considered as waste products and often discarded in the environment. Fruit peels are now serving as one of the primary sources for isolation and extraction of secondary metabolites in pharmaceutical industry. The present investigation was carried out to screen the phytochemical constituents and HPTLC analysis of peel extracts of Punica granatum and Citrus aurantifolia and their antidiabetic potential in alloxan-induced diabetic rats.ResultsAmong the different solvent extracts, methanol solvent extract was found to possess more amounts of secondary metabolites. In addition, HPTLC analysis of the plant samples revealed the presence of 13 peaks in both the plants by using gallic acid as marker. Different biochemical parameters such as blood glucose, cholesterol, protein, urea, creatinine, and triglycerides level were subjected for estimation by collecting the blood samples from the treated diabetic rats after 21 days. A sharp decline in blood glucose, cholesterol, triglycerides, creatinine, and urea level was noticed when methanolic extracts of Punica granatum and Citrus aurantifolia were given to experimental animals when compared with negative control. However, protein and weight of the animal were found to be enhanced when treated with methanolic extracts of both the plants.ConclusionIt can be concluded that fruit peels of both the plants exhibited antidiabetic potential on alloxan-induced diabetic rats which can be attributed to wide range of active pool of secondary metabolites. Further, screening and isolation of secondary metabolites along with their mode of action is required for effective use of plant-based drugs as antihyperglycemic agent.Graphical abstract

Searching for autoimmune encephalitis: Beware of normal CSF

ObjectiveTo determine the prevalence of cerebrospinal fluid (CSF) markers associated with inflammation (i.e., elevated white blood cell count, protein concentration, and CSF-specific oligoclonal bands) in patients with early active autoimmune encephalitis (AE). MethodsCSF characteristics, including WBC count, protein concentration, and oligoclonal banding, were analyzed in patients diagnosed with AE at two tertiary care centers. ResultsNinety-five patients were included in the study. CSF white blood cell counts and protein levels were within normal limits for 27% (CI95%: 19–37) of patients with AE. When results of oligoclonal banding were added, 14% (CI95%: 6–16) of patients with AE had “normal” CSF. The median CSF white blood cell count was 8 cells/mm3 (range: 0–544) and the median CSF protein concentration was 0.42 g/L (range: 0.15–3.92). ConclusionsWhite blood cell counts and protein levels were within normal limits in the CSF of a substantial proportion of patients with early active AE. Inclusion of CSF oligoclonal banding identified a higher proportion of patients with an inflammatory CSF profile, especially when CSF was sampled early in the disease process.

P0758THE CORRELATION BETWEEN THE MANAGEMENT OF COMORBIDITIES AND THE PROGRESSION OF THE RENAL DYSFUNCTION OR ADVERSE EVENTS OF CHRONIC KIDNEY DISEASE

Abstract Background and Aims Several factors, such as anemia, hypertension, hyperuricemia, metabolic acidosis, and chronic kidney disease (CKD)-mineral and bone disorder (MBD), are associated with the progression of CKD or adverse events in CKD patients. However, the significant factors associated with the progression of CKD or adverse events in patients under the condition of appropriate control according to guidelines have not been clarified. Method The study was a 3-year observational study conducted in a single center. In 88 patients with various stages of CKD (not on renal replacement therapy (RRT)) who were treated by nephrologists, blood levels of Hb, ferritin, iron, total iron-binding capacity, and albumin were measured every 3 months, and high-sensitivity C reactive protein (hCRP), β2-microglobulin (MG), HCO3-, and intact-parathyroid hormone (int-PTH), in addition to urinary sodium, potassium, calcium, phosphorus, protein, and β2-MG levels, were measured every 6 months. We also evaluated the doses of iron, erythropoiesis-stimulating agent (ESA), vitamin D, phosphate binder, anti-hypertensive agents, and anti-hyperuricemic agents. All patients were treated according to the clinical practice guidelines for CKD (Japanese Society of Nephrology 2013). A time-dependent Cox hazard model was applied to evaluate the associations between clinical parameters and adverse events (initiation of RRT and hospitalization resulting in cardiovascular disease or infection). Results Unexpectedly, under the condition of appropriate control by nephrologists, hypertension, hyperuricemia, metabolic acidosis, iron metabolism, and inflammation were not selected as significant predictors of the progression of renal dysfunction or adverse events. (Factors associated with the progression of renal dysfunction) In multiple regression analysis, lower baseline blood levels of Hb (β=0.497, P&amp;lt;0.001) and vitamin D 125 (β=0.258, P=0.006) and higher baseline blood levels of int-PTH (β=-0.334, P=0.001), urinary phosphorus (β=0.328, P=0.001), urinary β2-MG (β=-0.225, P=0.031) and urinary protein (β=0.280, P=0.02) were selected as significant predictors of reduced estimated glomerular filtration rate (eGFR) or 1/creatinine (Cr) at the end of the study. (Factors associated with the initiation of RRT and adverse events) In the Cox hazard model, low calcium (HR: 0.37, P=0.026), high phosphate (HR: 5.90, P&amp;lt;0.001), low 1,25-vitamin D (HR: 0.94, P=0.013), high int-PTH (HR: 1.02, P&amp;lt;0.001), use of a phosphate binder (HR: 4.95, P=0.012), and use of vitamin D analogs (HR: 3.75, P=0.014) were selected as risks for adverse events, including the initiation of RRT. Conclusion In this study, we found that among several factors, anemia and CKD-MBD-related factors (phosphate, calcium, vitamin D, int-PTH) were selected as significant predictors of the progression of renal dysfunction. Furthermore, although phosphate binders or vitamin D analogs were administered appropriately, CKD-MBD-related factors (phosphate, calcium, vitamin D, and int-PTH) were associated with RRT initiation or adverse events in these patients. From these results, we presumed that early intervention or strict control of CKD-MBD factors might attenuate the risk for adverse events in CKD patients.

P1264LOW PHOSPHATE AND LOW CALCIUM LEVELS PREDICT A HIGHER RISK FOR CARDIOVASCULAR EVENTS OF MAINTENANCE HEMODIALYSIS PATIENTS

Abstract Background and Aims It has been reported that higher serum levels of phosphate (P) and calcium (Ca) are associated with a higher risk of cardiovascular disease (CVD) and premature death of maintenance hemodialysis (MHD) patients. Thus, several clinical guidelines recommend that serum P and Ca levels in MHD patients be maintained within the optimal range. However, in the current situation in which the guidelines have penetrated widely, there are few reports that have investigated the association between chronic kidney disease (CKD)-mineral and bone disorder (MBD)-related factors and adverse events in MHD patients. Method The study design was a 3-year multicenter, observational study. A total of 989 MHD patients were enrolled in this study. The blood levels of Hb, ferritin, iron, total iron-binding capacity, β2-microglobulin, creatinine, total protein, albumin, total cholesterol, Ca and P were measured every 3 months. The blood levels of high-sensitivity C-reactive protein (hCRP) and intact parathyroid hormone (int-PTH) were also measured every six months. The correlation between CKD-MBD factors and adverse events was evaluated by the time-dependent Cox hazard model. Results In 82% of patients, 83% of patients, and 78% of patients, serum P levels, serum Ca levels, and int-PTH levels, respectively, were maintained in the target ranges (3.5≤P≤6.0 mg/dL, 8.4≤Ca≤10.0 mg/dL, 60≤int-PTH≤240 pg/mL) that were recommended by the 2012 guidelines of the Japanese Society for Dialysis Therapy. After correcting for age, sex, past history of CVD, Hb, albumin, and hCRP, compared with the patients with target levels of P, patients with low P levels (&amp;lt;3.5 mg/dL) had a significantly higher risk for CVD (P=0.042, HR: 2.27), hospitalization (P=0.034, HR: 2.44), and all-cause mortality (P=0.03, HR: 2.29). On the other hand, there was no association between higher serum P levels and adverse events. Compared with the patients who maintained target int-PTH levels, patients with lower (&amp;lt;60) (P=0.025, HR: 1.46) and higher (&amp;gt;240 pg/mL) (P=0.04, HR: 1.44) int-PTH levels had a significantly higher risk for hospitalization. There was no significant correlation between serum Ca and adverse events. Furthermore, compared with the patients who maintained the target levels of both Ca and P, the patients with target Ca and low P levels (P=0.042, HR: 2.75) had a significantly higher risk for CVD. Compared with the patients who maintained the target levels of both Ca and P, the patients with low Ca and low P levels (P&amp;lt;0.001, HR: 4.4) and target Ca and low P levels (P=0.22, HR: 2.0) had a significantly higher risk for hospitalization. Conclusion After correcting for several clinical factors, we found that patients who maintained low serum P levels had a significantly higher risk for CVD and all-cause mortality than patients who maintained higher Ca and P levels. Undoubtedly, extremely high serum P, Ca, and int-PTH levels should be treated according to the guidelines. However, in the current situation in which the guidelines have penetrated widely, CKD-MBD management, in which the clinical conditions of low P, Ca, and int-PTH are considered, is needed.

Obesity induces limited changes to systemic and local immune profiles in treatment-naive human clear cell renal cell carcinoma.

Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" ≥ 30 kg/m2) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1+CD8+ T cells, CD14+CD16neg classical monocytes, and Foxp3+ regulatory T cells (Tregs). Only CD14+CD16neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ+ CD8 T cells or IFNγ+, IL-4+, or IL-17A+ CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1β, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI ≥ 35 kg/m2 versus 18.5-24.9 kg/m2, respectively) subjects. Intratumoral PLGF and VEGF-A proteins were elevated in ccRCC subjects with obesity. Thus, in ccRCC patients with localized disease, obesity is not associated with widespread detrimental alterations in systemic or intratumoral immune profiles. The effects of combined obesity and immunotherapy administration on immune parameters remains to be determined.

Evaluation of cysteamine supplementation in red tilapia (Oreochromis sp.) diet: Serum insulin and somatostatin, IGF-1 and GLUT4 genes expression, growth performance, and robustness against stress

The present study evaluated the effects of cysteamine supplementation on the serum insulin and somatostatin, IGF-1 and GLUT4 genes expression, growth performance and robustness against stress in red tilapia (Oreochromis sp.). This study tested five cysteamine dietary levels (quadruplicate), i.e. treatments consisted of control (N = 0 g/kg of cysteamine), A1 (0.25 g/kg cysteamine), A2 (0.50 g/kg of cysteamine), A3 (0.75 g/kg of cysteamine) and A4 (1.00 g/kg of cysteamine). All male red tilapia juvenile, with an average body weight of 6.98 ± 0.06 g, were kept in an aquarium (100 cm × 50 cm × 50 cm) previously filled with 175 L filtered water at the density of 12 fish/aquarium. Experimental diet was fed to the fish to satiation 3 times a day for 56 days rearing period. Stress challenge test was carried out by using air exposure technique. The results showed that final body weight, feed conversion ratio (FCR), protein retention and muscle protein significantly increased (P < .05) in response to cysteamine supplementation. Polynomial orthogonal contrast analysis demonstrated that the quadratic model regression of cysteamine supplementation level for specific growth rate (SGR) is y = 58.67 × 2 + 6.9317× + 3.7973 (P = .01) with an optimum level of 0.59 g/kg of cysteamine in the diet. Optimum cysteamine supplementation resulted in reduced blood glucose, protein and triglyceride blood levels (P < .05), indicating non protein energy utilization. Plasma somatostatin levels decreased along with the increase of cysteamine supplementation. IGF-1 and Glut4 genes expression in the liver significantly upregulated (P < .05) with cysteamine supplementation. In addition, cysteamine supplementation improved the fish robustness against stress, as indicated by increased superoxide dismutase (SOD), higher post-challenge survival and lower plasma cortisol, malondialdehyde (MDA) and glucose levels (P < .05). In conclusion, optimum cysteamine supplementation (0.59 g/kg) improved growth performance and robustness against stress in red tilapia.

1118 Examining the Role of Serum and Exosomal Biomarkers in Symptoms of Fatigue and Daytime Sleepiness Following Traumatic Brain Injury

Abstract Introduction Fatigue and daytime sleepiness are two of the most common chronic symptoms reported after traumatic brain injury (TBI). However, there is limited understanding of the pathophysiological mechanisms following TBI that result in these symptoms. Previous research has observed elevations in peripheral blood levels of proteins in TBI patients versus controls, including neurofilament light chain (NFL)—predominantly expressed in long myelinated subcortical axons—and glial fibrillary acidic protein (GFAP)—predominantly expressed in reactive astrocytes responding to central nervous system injuries. This study examines the relationship between serum and exosomal NFL and GFAP, and symptoms of fatigue and daytime sleepiness in TBI patients 1-year after injury. Methods Sixty-seven patients with TBIs ranging from mild to severe were included in this study. Blood samples were collected from all participants 1-year post TBI, with concentrations of GFAP and NFL measured in serum and exosomes using Single Molecule Array technology (Simoa), an ultrasensitive assay. Participants reported fatigue using the Fatigue Severity Scale (FSS), and daytime sleepiness using the Epworth Sleepiness Scale (ESS). Results A linear regression model of fatigue symptoms and exosomal NFL controlling for age revealed that fatigue was negatively associated with exosomal NFL concentrations (β = -.317, p = .041, ηp2 = -.343) and accounted for 20.2% of the change in NFL. Serum NFL concentrations were not associated with fatigue, nor were GFAP serum or exosomes. No significant associations were found between NFL, GFAP, and daytime sleepiness. Conclusion Our findings suggest that exosomal NFL may be related to mechanisms underlying TBI-related fatigue and the potential of NFL as a biomarker of fatigue. To our knowledge, this study is the first to examine the relationship between post-TBI NFL levels and fatigue symptoms. Further investigation into serum and exosome biomarkers of TBI-related fatigue and daytime sleepiness is warranted. Support National Institutes of Health and Center for Neuroscience and Regenerative Medicine

Systems Genetics in Human Endothelial Cells Identifies Non-coding Variants Modifying Enhancers, Expression, and Complex Disease Traits

The identification of causal variants and mechanisms underlying complex disease traits in humans is important for the progress of human disease genetics; this requires finding strategies to detect functional regulatory variants in disease-relevant cell types. To achieve this, we collected genetic and transcriptomic data from the aortic endothelial cells of up to 157 donors and four epigenomic phenotypes in up to 44 human donors representing individuals of both sexes and three major ancestries. We found thousands of expression quantitative trait loci (eQTLs) at all ranges of effect sizes not detected by the Gene-Tissue Expression Project (GTEx) in human tissues, showing that novel biological relationships unique to endothelial cells (ECs) are enriched in this dataset. Epigenetic profiling enabled discovery of over 3,000 regulatory elements whose activity is modulated by genetic variants that most frequently mutated ETS, AP-1, and NF-kB binding motifs, implicating these motifs as governors of EC regulation. Using CRISPR interference (CRISPRi), allele-specific reporter assays, and chromatin conformation capture, we validated candidate enhancer variants located up to 750 kb from their target genes, VEGFC, FGD6, and KIF26B. Regulatory SNPs identified were enriched in coronary artery disease (CAD) loci, and this result has specific implications for PECAM-1, FES, and AXL. We also found significant roles for EC regulatory variants in modifying the traits pulse pressure, blood protein levels, and monocyte count. Lastly, we present two unlinked SNPs in the promoter of MFAP2 that exhibit pleiotropic effects on human disease traits. Together, this supports the possibility that genetic predisposition for complex disease is manifested through the endothelium.

D-dimer and C-reactive Protein Blood Levels Over Time Used to Predict Pulmonary Embolism in Two COVID-19 Patients.

The diagnosis of pulmonary embolism is challenging in symptomatic COVID-19 patients since shortness of breath, chest pain, tachycardia, tachypnoea, fever, oxygen desaturation and high D-dimer blood levels might be features of both diseases. We present two COVID-19 patients in whom pulmonary embolism was suspected (and diagnosed) due to a discrepancy between an increase in D-dimer blood levels and a decrease in C-reactive protein blood levels over time. We believe that an opposite change in the blood levels of both biomarkers over time may be used as a novel method to predict pulmonary embolism in COVID-19 patients.LEARNING POINTSThe diagnosis of pulmonary embolism is challenging in COVID-19 patients since symptoms, signs and high D-dimer blood levels might be similar in both diseases.An increase in D-dimer blood levels and a decrease in C-reactive protein blood levels over time may be used as a novel method to predict pulmonary embolism in COVID-19 patients.

CDH6 and HAGH protein levels in plasma associate with Alzheimer\u2019s disease in APOE \u03b54 carriers

Many Alzheimer’s disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (Aβ) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N = 441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (β = 0.638, P = 3.33 × 10−4) and HAGH (β = 0.481, P = 7.20 × 10−4), were significantly elevated in APOE ε4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (β = 1.365, P = 3.97 × 10−3) and HAGH proteins (β = 0.506, P = 9.31 × 10−7) when comparing cases and controls in APOE ε4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ε4 stratum (P < 1 × 10−3). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 × 10−9). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers.

Prospective Randomized Study on the Effects of Improved Sleep Quality After Craniotomy on Melatonin Concentrations and Inflammatory Response in Neurosurgical Intensive Care Patients

Sleep disorders in intensive care units after a craniotomy can decrease melatonin secretion and increase the inflammatory stress response. The aim of this study was to investigate the influence of improving sleep quality via eye patches and earplugs on melatonin secretion and inflammatory mediator release. The study enrolled 41 patients who underwent craniotomy. Patients were randomized into 2 groups. "Group Intervention" received a sleep-promoting intervention with eye patches and earplugs to provide light and noise isolation, while "Group Control" received standard care. Blood levels of C-reactive protein and interleukin 1 and interleukin 6 along with urine levels of 6-sulphatoxymelatonin (aMT6) were measured preoperatively (baseline) and on postoperative days 1 and 3. Sleep quality was assessed with the Richards-Campbell Sleep Questionnaire. Sleep quality was higher in the intervention group (Richards-Campbell score:80.61 ± 11.96 vs. 33.50 ±16.32; P < 0.001). Urine aMT6 levels increased significantly in the intervention group in spot urine samples from 10.15 (5.38-14.40) ng/mL at baseline to 14.52 (6.24-29.11) and 11.51 (7.88-29.05) ng/mL on postoperative days 1 and 3. They also increased in 24-hour urine samples from 25.73 (8.24-52.73) ng/mL at baseline to 35.38 (11.48-95.65) and 39.18 (2.36-125.23) ng/mL on postoperative days 1 and 3 (P= 0.001 and P= 0.005, respectively). The aMT6 concentration did not change significantly in the control group. The C-reactive protein concentrations increased postoperatively compared with baseline concentrations in both groups (P= 0.001 and P < 0.001). Melatonin secretion significantly increased as a result of improving postoperative sleep quality by noise and light isolation in neurosurgical intensive care unit patients after craniotomy.

Anti-inflammatory and anti-arthritic properties of aqueous extract of Nauclea diderrichii (Rubiaceae) stem bark in rats

Nauclea diderrichii, is a common woody plant in Africa where it is traditionally used for the relief and treatment of multiple pain-related conditions. The aim was to evaluate the inflammatory and anti-arthritic properties of the aqueous extract of N. diderrichii stem bark. Carrageenan and formalin were used to induce inflammation while zymosan A was used to induce monoarthritis in rats. The extract was given orally at doses of 100, 200 and 400 mg/kg. The extract significantly reduced carrageenan-induced edema up to 6 h, with 61.94% (6th hour). The extract induces a significant inhibition of the formalin-induced edema from the 2nd to the 8th hour with 61.50% (2nd hour). In continuous treatment, the activity of the extract remains significant from the 2nd to the 10th day of treatment with 63.85% (9th day). The extract (400 mg/kg) induces a significant decrease of the organ weight while the body weight increases significantly. At 400 mg/kg, the extract significantly increases the levels of red blood cells, hemoglobin and proteins, as well as the catalase and SOD activities, then a significant decrease of the levels of white blood cells, lymphocytes, hematocrit, MDA and NO. Furthermore, the extract significantly inhibited zymosan A-induced edema from the 1st to the 5th day with 60.99% (5th day). The joints of the treated animals show a close to normal architecture compared to that of the untreated animals. These results demonstrate the anti-inflammatory and anti-arthritic properties of N. diderrichii and confirm its traditional use to relieve pain and inflammation.

Fatty acid metabolism in newborns with sepsis; Report 1 — New clinical outcome prediction scale

The aim of our study was to develop a new scale for predicting clinical outcome in newborns with sepsis, taking into account the information about depth of metabolic disorders.Methods. Design of study — retrospective observational single-center study. Medical cards data of 163 newborns with sepsis were included in analysis. To measure the predictive value of the analyzed clinical and laboratory signs we used the Kullback measure. The clinical outcome of the disease was determined as the response function: survived or died.Results. An analysis of the predictive value of the clinical and laboratory parameters of in newborns with sepsis was made, the threshold values of the most informative indicators were developed, which were: the number of blood platelets, the level of total blood protein, body weight and the number of blood neutrophils. The Clinical and Laboratory Condition Index for Newborns scale has been developed, which takes into account the depth of metabolic disorders. ROC analysis (Area Under Curve — 0,723) and the information method (information coefficient 0.992) showed that the Clinical and Laboratory Condition Index score can be used in the intensive care unit to predict the risk negative clinical outcome and evaluate the effectiveness of treatment in infants with organ dysfunction caused by systemic infection.Conclusion. New Clinical and Laboratory Condition Index score scale allows to predict the development of negative outcome of sepsis in newborns taking into account the depth of metabolic disorders in newborns with sepsis.

Метаболизм жирных кислот у новорожденных с сепсисом; Сообщение 2 — Нарушение метаболизма жирных кислот

The aim of our study was to develop a new scale for predicting clinical outcome in newborns with sepsis, taking into account the information about depth of metabolic disorders.Methods. Design of study — retrospective observational single-center study. Medical cards data of 163 newborns with sepsis were included in analysis. To measure the predictive value of the analyzed clinical and laboratory signs we used the Kullback measure. The clinical outcome of the disease was determined as the response function: survived or died.Results. An analysis of the predictive value of the clinical and laboratory parameters of in newborns with sepsis was made, the threshold values of the most informative indicators were developed, which were: the number of blood platelets, the level of total blood protein, body weight and the number of blood neutrophils. The Clinical and Laboratory Condition Index for Newborns scale has been developed, which takes into account the depth of metabolic disorders. ROC analysis (Area Under Curve — 0,723) and the information method (information coefficient 0.992) showed that the Clinical and Laboratory Condition Index score can be used in the intensive care unit to predict the risk negative clinical outcome and evaluate the effectiveness of treatment in infants with organ dysfunction caused by systemic infection.Conclusion. New Clinical and Laboratory Condition Index score scale allows to predict the development of negative outcome of sepsis in newborns taking into account the depth of metabolic disorders in newborns with sepsis.

Plasma Levels of Protein Z in Ischemic Stroke: A Systematic Review and Meta-Analysis.

The association between blood levels of protein Z (PZ) and risk of ischemic stroke remains poorly understood. We aimed to assess this potential relationship through a meta-analysis of case-control studies. PubMed, Scopus, Web of Science Core Collection, and the Cochrane Library were searched from April 1984 to April 2019. We selected case-control studies comparing PZ levels in adult patients with ischemic stroke and controls without ischemic stroke. Six case-control studies, with a total of 1,011 ischemic stroke patients and 1,128 controls, were included. Patients in the acute phase of ischemic stroke showed significantly higher levels of PZ compared with patients in the convalescent phase (standardized mean difference [SMD]: 0.289 mg/L; 95% confidence interval [CI]: 0.010, 0.569; p = 0.043). No significant differences in PZ levels were found between patients and controls in the acute phase (SMD: -0.059 mg/L; 95% CI: -0.570, 0.452; p = 0.821) or in the convalescent phase of ischemic stroke (SMD: -0.341 mg/L; 95% CI: -0.736, 0.055; p = 0.091). Subgroup analysis indicated that older patients (≥ 50 years old) had lower PZ levels than similarly aged controls. In contrast, when the study groups came from the United States and Australia or Europe no significant differences in PZ levels existed between patients and controls. No association between PZ and ischemic stroke was identified in this meta-analysis. The acute phase of ischemic stroke was associated with higher levels of PZ.

Tumor Fibroblast Growth Factor Receptor 4 Level Predicts the Efficacy of Lenvatinib in Patients With Advanced Hepatocellular Carcinoma.

OBJECTIVES:Biomarkers for optimizing the outcome of treatment with lenvatinib in patients with advanced hepatocellular carcinoma remain to be established despite intensive and comprehensive genomic research. Lenvatinib is characterized by its prominent inhibitory potency for fibroblast growth factor receptor (FGFR) 4 compared with earlier tyrosine kinase inhibitors. Thus, in this study, we focused on simplified quantification of FGFR4 in tumors as a potential predictive indicator.METHODS:According to The Cancer Genome Atlas data set curation, FGFR4 messenger RNA is broadly overexpressed in hepatocellular carcinoma in the absence of gene alteration. Gene set enrichment analysis revealed that the aggressiveness of the tumor was closely related to the FGFR4 level. To confirm the relationship between the benefits of lenvatinib and tumor addiction to the FGFR4 pathway, we analyzed protein levels in tumors and peripheral blood obtained from 57 prospectively registered patients treated with lenvatinib.RESULTS:Positive immunohistochemistry (>10% of tumor cells) for FGFR4 in biopsy samples before treatment was associated with a longer progression-free survival (2.5 vs 5.5 months, P = 0.01) and a favorable objective response rate (31% vs 81%, P = 0.006). By contrast, the concentration of soluble FGFR4 in peripheral blood as measured by an enzyme-linked immunosorbent assay was not associated with survival outcomes, because its fluctuations reflect hepatic fibrosis. Additional RNA sequencing analysis using archival surgical specimens (n = 90) suggested that alternative RNA splicing of FGFR4 in cancer may also explain this discrepancy.DISCUSSION:The tumor FGFR4 level was an independent predictor of response to lenvatinib.

Nausea and Vomiting of Pregnancy and HG Risk Genes Associated With Blood Levels, Sleep, Stomach Pain, and Other Traits [23N

INTRODUCTION: Our genome-wide association study (GWAS) and replication study of nausea and vomiting of pregnancy (NVP) and Hyperemesis Gravidarum (HG) implicates the placenta and appetite hormone gene GDF15, its receptor GFRAL, PGR, and IGFBP7. The purpose of this study was to determine whether these genes and summary statistics overlap with other traits. METHODS: The GWAS catalog was searched for risk genes. The database and web interface platform, LD Hub, was used for genetic correlation analysis of summary statistics. RESULTS: Among 4220 GWASes, the HG risk locus GDF15 was associated with GDF15 protein levels, periodontitis, and lupus. GFRAL was associated with glomerular filtration rate, blood urea nitrogen levels, insomnia, body mass index, periodontal inflammation, blood protein levels, osteoporosis, and HIV-1 infection. IGFBP7 was associated with IGFBP7 protein levels, IgG glycosylation, diastolic blood pressure, brain volume in infants, heel bone mineral density, alcohol consumption, itch intensity from mosquitoes, and cotinine glucuronidation. PGR was associated with diastolic blood pressure, endometriosis/endometrial cancer, menstrual cycle length, lung adenocarcinoma, height, and adolescent idiopathic scoliosis. Among 855 pairs of traits, the leading findings showed variants increasing HG also increase stomach pain (P=.0004) and variants increasing NVP also increase sleeplessness/insomnia (P=1.37E-14). CONCLUSION: The finding that variants in GDF15 and IGFBP7 are associated with blood protein levels supports our study showing abnormal levels of GDF15 and IGFBP7 in women with HG. Overlap of the genes with other conditions provides biological insight. Associations with poor sleep and stomach pain may have implications for treatment strategies for NVP/HG.