Potential Disease Markers Research Articles

Discovery of IgG4 Anti-Gliadin Autoantibody as a Potential Biomarker of Psoriasis Using an Autoantigen Array.

Psoriasis is a complex immunological skin disease. However, whether humoral autoimmunity is involved in the pathogenesis of psoriasis remains unclear. The aim is to determine if there are autoantibodies associated with disease activity of psoriasis. A novel autoantigen array harboring 75 antigens is developed to discover autoantibodies in the serum of psoriasis patients (N=12) compared to healthy controls (N=12). Validation studies are performed in a larger cohort of psoriasis patients (N=73) and healthy controls (N=75) together with atopic dermatitis as disease controls (N=10). The screening results demonstrate that immunoglobulin G4 (IgG4) anti-gliadin autoantibodies are significantly elevated in the serum of psoriasis patients, compared to healthy controls. Receiver operating characteristic (ROC) analysis indicates that IgG4 anti-gliadin autoantibody levels can clearly discriminate psoriasis patients from healthy controls with an AUC of 0.98 (p<0.001). Also, IgG4 anti-gliadin autoantibody can reflect disease severity with the psoriasis area severity index score in a subpopulation of psoriasis patients. These results suggest that IgG4 anti-gliadin autoantibody may be a disease marker of psoriasis, and it may be useful in clinical diagnostics and disease monitoring of psoriasis. This work represents a relatively comprehensive screening of autoantibodies, that is, IgG4 autoantibodies in psoriasis using an in-house autoantigen array. This novel proteomic platform may be useful in clinical screening of IgG type or IgG4 subtype autoantibodies in psoriasis patients for disease monitoring or drug responses. Particularly, IgG4 anti-gliadin autoantibody, as a new potential disease marker of psoriasis, may be useful in clinical diagnostics or prognostics of related immunological disorders.

Spectroscopy goes viral: Diagnosis of hepatitis B and C virus infection from human sera using ATR-FTIR spectroscopy

The development of a new fast, portable and reagent-free diagnostic technique for hepatitis B (HBV) and hepatitis C (HCV) viruses would be an enormous benefit to society. Here, we evalulate the ability of Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectroscopy combined with multivariate data analysis to classify human serum samples based on the presence of HBV and HCV infection. Sera samples were prepared using three different methodologies: i) Sera depsoited onto glass cover slips, airdried and placed onto the ATR crystal. ii) Whole serum dried directly onto the ATR crystal. iii) Serum separated into high and low molecular weight compounds using a filtration approach and the high molecular weight fraction placed directly onto the ATR-FTIR diamond window and dried. For methodology i) the Partial Least Squares Discriminate Analysis (PLS-DA) calibration set included 313 (70 %) samples and the validation set 93 (30 %) samples. For HBV vs control the sensitivity and specificity was found to be 69.4 % and 73.7 % (10 latent variables (LV)), respectively. For HCV vs control the sensitivity and specificity was 51.3 % and 90.9 % (LV 11), respectively. In the second set of experiments the serum samples were dried directly onto the ATR diamond. PLS-DA models were constructed using 144 (70 %) samples for the calibration set and tested using an independent test set containing 62 (30 %) samples. For HBV versus control the sensitivity and the specificity was 84.4 % and 93.1 %, respectively (LV 8). For HCV versus control the sensitivity and specificity was 80.0 % and 97.2 %, respectively (LV 9). For HBV versus HCV the sensitivity and the specificity was 77.4 % and 83.3 %, respectively (LV 5). To increase the sensitivity and specificity serum sample was fractionated into high and low molecular weight components. In PLS-DA cross validated model (LV 8) the sensitivity and specificity was 87.5 % and 94.9 %, respectively for HBV vs control (high molecular concentrate). The PLS-DA cross-validated model (LV 8) for HCV vs control high molecular fraction produced a sensitivity and specificity of 81.6 % and 89.6 %, respectively. No linear correlation was observed for sera samples spiked with known viral loads using Partial Least Squares Regression (PLS-R) modelling.Spectra of positive serum (HBV and HCV) showed a strong band observed at 1631 cm−1, which was absent in the spectra of controls and assigned to the β-pleated sheet protein marker of immunoglobulin (Ig). A band at 1093 cm−1, observed in spectra of HBV infected sera, was assigned to CC and COmodes of polysaccharide N-glycan from hepatitis B surface antigen (HBsAg). The assignment was confirmed by atomic force microsocpy infrared (AFM-IR) spectroscopy of the isolated protein. This band represents a unique marker for HBV infection. In summary, ATR-FTIR spectroscopy is a powerful tool to study blood composition and identify potential disease markers but care must be taken to ensure that the modelling is not biased by inflammation markers, which may confound diagnosis.

Hyperventilation-induced heart rate response as a potential marker for cardiovascular disease

An increase of heart rate to physical or mental stress reflects the ability of the autonomous nervous system and the heart to respond adequately. Hyperventilation is a user-controlled breathing maneuver that has a significant impact on coronary function and hemodynamics. Thus, we aimed to investigate if the heart rate response to hyperventilation (HRRHV) can provide clinically useful information. A pooled analysis of the HRRHV after 60 s of hyperventilation was conducted in 282 participants including healthy controls; patients with heart failure (HF); coronary artery disease (CAD); a combination of both; or patients suspected of CAD but with a normal angiogram. Hyperventilation significantly increased heart rate in all groups, although healthy controls aged 55 years and older (15 ± 9 bpm) had a larger HRRHV than each of the disease groups (HF: 6 ± 6, CAD: 8 ± 8, CAD+/HF+: 6 ± 4, and CAD−/HF−: 8 ± 6 bpm, p < 0.001). No significant differences were found between disease groups. The HRRHV may serve as an easily measurable additional marker of cardiovascular health. Future studies should test its diagnostic potential as a simple, inexpensive pre-screening test to improve patient selection for other diagnostic exams.

α-Galactosidase A/lysoGb3 ratio as a potential marker for Fabry disease in females

Fabry disease (FD [MIM:301500]) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene. Deficient activity of its product, lysosomal enzyme α-galactosidase A (α-Gal A), leads to excessive accumulation of glycosphingolipids in cells of multiple organs.The establishing of the diagnosis is challenge in female patients because of milder clinical manifestation and normal α-Gal A activity.The globotriaosylsphingosine (lysoGb3) is described as a more sensitive diagnostic biomarker for females with pathogenic mutation in the GLA gene.Thus, the aim of this study is to improve the biochemical diagnostic efficiency for FD in females.Here we report the α-Gal A/lysoGb3 ratio as the novel biochemical criteria for diagnosis of female patients with FD, using dried blood spots (DBS) as test samples. It showed 100% sensitivity in distinguishing our group of 35 female patients from control (n = 140). Whereas measurement of α-Gal A and lysoGb3 alone showed 8.6% and 74.4% respectively.A new approach of using the ratio of α-Gal A activity to lysoGb3 concentration in DBS may provide a more accurate screening tool for identification of FD females.

Clinical-Grade Whole Genome Sequencing Reproduces FISH Cytogenetics and Provides Actionable Data in Newly Diagnosed Myeloma - a Pilot Study from the UK 100,000 Genomes Project

Background Treatment decisions in Multiple Myeloma (MM) have been driven by a patient's age or ability to tolerate therapy, but as yet, not by their tumour genetics, even though understanding of the prognostic utility of genetic features continues to develop. The ability to identify genetic prognostic markers and potential therapeutic targets in a timely fashion within a health service is a vital step in delivering precision medicine to patients. The aims of this study were to assess the implementation of clinical grade whole genome sequencing (WGS) data at diagnosis to replicate, and ultimately replace, standard-of-care Fluorescence In Situ Hybridisation (FISH) cytogenetics; to provide markers for prognostication or MRD; and to identify actionable targets for clinical trials in precision therapy of MM. Methods Bone marrow aspirates from patients with newly-diagnosed myeloma were collected between June 2017 and April 2018 in a single tertiary hospital in the United Kingdom. The population comprised seven male and seven female patients with a mean age of 78 years. From the first-draw of bone marrow aspirate, standard-of-care FISH cytogenetic analyses were performed locally according to criteria from the International Myeloma Working Group (IMWG). From the remnant aspirate samples, CD138-positive plasma cells were enriched by magnetic bead-sorting and genomic DNA was extracted locally for WGS with a success rate of approximately 70%. Fourteen samples underwent successful plasma cell purification (78 - 99% morphological purity) with a yield of at least 0.5 μg DNA. To identify germline genomic variants, DNA was extracted from peripheral blood samples obtained simultaneously. WGS was performed at a centralised facility and mean coverage for germline samples was 35.1x and for plasma cell-enriched samples was 100.9x. Conventional cytogenetic FISH data were compared with genomic data for chromosome-level alterations. Identified somatic variants were automatically cross-referenced against publicly available databases that describe somatic mutations in cancer as well as a virtual panel of potentially actionable therapeutic targets including : NRAS, KRAS, BRAF, CDKN2C, FGFR3 and IDH2. Results In paired samples, WGS replicated all 13 translocation and chromosomal loss/gain events identified by FISH (Figure 1). Furthermore, three translocations involving the IGH locus suggested by FISH analysis were characterised by WGS. Using samples derived from surplus material, fast-track turnaround of 14 days was attainable. Five patients had no identifiable marker by FISH cytogenetics. In these patients, WGS found all five to possess somatic variants could be used as prognostic or potential Measurable Residual Disease (MRD) markers. Nine patients exhibited somatic variants in genes that may be subject to targetable therapy as determined by trials available on ClinicalTrials.gov: five NRAS, two KRAS, one BRAF and one FGFR3 mutation as of July 2019. Conclusion WGS assessment of newly diagnosed myeloma provides accurate, timely and actionable information beyond what is available from standard-of-care FISH. The application of WGS to myeloma diagnostics presents a number of advantages. Firstly, WGS can replicate and exceed existing myeloma FISH assessment of translocation and loss/gain events in a prompt turnaround time. Secondly, germline variants are deducted from tumour variants to provide a gold standard description of the somatic mutational landscape in the patient's disease. Thirdly, virtual panels of known somatic variants can be applied to the data as knowledge accumulates about the role of specific mutations on prognosis or therapeutic response. We demonstrate that centrally provided WGS and its analysis can be incorporated into routine local assessment of newly diagnosed myeloma. Therefore, these observations show that such technology has the potential to be rapidly scalable across existing hospital networks. Disclosures Gooding: Celgene Corporation: Research Funding. Ramasamy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research Grants; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research Grants; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research Grants; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Cardiac-Related Pulsatility in the Insula Is Directly Associated With Middle Cerebral Artery Pulsatility Index.

Arterial stiffness in large arteries is a risk factor for cerebral small vessel disease and neurodegeneration. The challenge of accessing intracranial pulsatility noninvasively is one reason few studies provide empirical insight on the relationship between large artery and tissue pulsatility in the human brain. To investigate the association between the functional magnetic resonance imaging (fMRI)-derived cardiac-related pulsatility in the insular cortex and the ultrasound-derived pulsatility index in the middle cerebral artery (MCA-PI). Cross-sectional. Younger adults (11; 25 ± 4 years) and older adults with and without cardiovascular risk factors (44; 70 ± 6 years). T1 -weighted, fluid attenuated inversion recovery, and T2 *-weighted blood oxygenation level-dependent (BOLD) sequences at 3T. MCA-PI and cardiac-related pulsatility were assessed at rest by transcranial Doppler ultrasound and BOLD fMRI, respectively. Multivariate analyses of covariance between MCA-PI and cardiac-related pulsatility. Analysis of variance was used to assess regional differences. MCA-PI was associated with cardiac-related insular pulsatility (P = 0.037), but not whole-brain pulsatility (P = 0.81). Left insular pulsatility was higher than right insular pulsatility (P < 0.01) and was associated with diastolic blood pressure (P = 0.028). We show a correlation between ultrasound and fMRI measures of cerebrovascular pulsatility. This association provides insight into the transmission of pulsatile energy from large basal arteries at the Circle of Willis to downstream cerebrovascular beds and has implications for the utility of cardiac-related pulsatility as a potential marker for cerebral small vessel disease. 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:1454-1462.

Rapid profiling method for the analysis of lipids in human plasma using ion mobility enabled-reversed phase-ultra high performance liquid chromatography/mass spectrometry

The incorporation of ion mobility (IM) into LC–MS analysis has been demonstrated to result in the generation of superior quality MS and MS/MS spectral data as well as providing enhanced resolution in the IM dimension based on lipid class. Here a sub 4 min microbore LC-ion mobility-accurate mass MS (LC-IM-MS) method has been developed for the rapid, profiling of lipids in biological fluids. The method was scaled directly from a conventional, 12 min, LC-MS analysis maintaining the chromatographic performance and lipid separation observed in the longer methodology giving a 75% saving in mobile phase consumption and analysis time. Because of the additional dimension of separation provided by IM, improvements in mass spectral quality from the increased resolution of co-eluting species were also seen when compared to the same separation without IM, thus aiding the identification of target lipids. When applied to human plasma samples some 5037 (positive ESI) and 2020 (negative ESI) mass/retention time features were detected following adduct deconvolution and, of these, 3727 and 800 of those present in the pooled plasma QC samples had a CV of below 30% for positive and negative ESI modes respectively. The method was applied to the analysis of a pilot set of commercially sourced breast cancer plasma samples enabling the differentiation of samples from healthy controls and patients based on their lipid phenotypes. Analysis of the resulting data showed that phosphatidylcholines, triglycerides and diglycerides exhibited lower expression and phosphatidylserine showed increased expression in the breast cancer samples compared to those of healthy subjects. The coefficients of variation, determined by reference to the QC data, for all of the features identified as potential markers of disease, were 6% or less.

Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography.

Chronic pain is a common and severely disabling disease whose treatment is often unsatisfactory. Insights into the brain mechanisms of chronic pain promise to advance the understanding of the underlying pathophysiology and might help to develop disease markers and novel treatments. Here, we systematically exploited the potential of electroencephalography to determine abnormalities of brain function during the resting state in chronic pain. To this end, we performed state-of-the-art analyses of oscillatory brain activity, brain connectivity, and brain networks in 101 patients of either sex suffering from chronic pain. The results show that global and local measures of brain activity did not differ between chronic pain patients and a healthy control group. However, we observed significantly increased connectivity at theta (4-8 Hz) and gamma (>60 Hz) frequencies in frontal brain areas as well as global network reorganization at gamma frequencies in chronic pain patients. Furthermore, a machine learning algorithm could differentiate between patients and healthy controls with an above-chance accuracy of 57%, mostly based on frontal connectivity. These results suggest that increased theta and gamma synchrony in frontal brain areas are involved in the pathophysiology of chronic pain. Although substantial challenges concerning the reproducibility of the findings and the accuracy, specificity, and validity of potential electroencephalography-based disease markers remain to be overcome, our study indicates that abnormal frontal synchrony at theta and gamma frequencies might be promising targets for noninvasive brain stimulation and/or neurofeedback approaches.

Nanodiamond for Sample Preparation in Proteomics

Protein analysis of potential disease markers in blood is complicated by the fact that proteins in plasma show very different abundances. As a result, high-abundance proteins dominate the analysis, which often render the analysis of low-abundance proteins impossible. Depleting high-abundance proteins is one strategy to solve this problem. Here, we present, for the first time, a very simple approach based on selective binding of serum proteins to the surface of nanodiamonds. In our first proof-of-principle experiments, we were able to detect, on average, eight proteins that are present at a concentration of 1 ng/mL (instead of 0.5 ng/mL in the control without sample preparation). Remarkably, we detect proteins down to a concentration of 400 pg/mL after only one simple depletion step. Among the proteins we could analyze are also numerous disease biomarkers, including markers for multiple cancer forms, cardiovascular diseases, or Alzheimer’s disease. Remarkably, many of the biomarkers we find also could not be detected with a state-of-the-art ultrahigh-performance liquid chromatography column (which depletes the 64 most-abundant serum proteins).

Characterization of circulating plasma proteins in dairy cows with cytological endometritis

Early diagnosis of endometritis in dairy cattle is currently requires invasive techniques and specialist expertise. The goal of this study is to utilize a gel-free mass-spectrometry based proteomics approach to compare the plasma proteome of dairy cattle with cytological endometritis to those without. Blood samples were collected from cows (N = 112) seven days postpartum (DPP). Plasma samples from a cohort of 20 animals with cytological endometritis (n = 10) and without (n = 10) as classified 21 DPP were selected for proteomic analysis. Differential abundances of proteins between the two animal groups were determined using both fold change (≥1.5 fold change) and statistical significance threshold (p < .05). A total of 181 non-redundant proteins were quantified, and 25 proteins were found with differential abundance. These include 4 binding protein alpha and mannose binding lectin 2 involved in immune responses. Differentially abundant proteins between the animals were then processed using PANTHER for gene ontology. Gene ontology included associations with innate immune processes, acute phase responses and immune regulation. A potential marker for disease identified here is the “uncharacterized protein G5E513,” a protein previously defined by RNA-transcripts.These proteins may form the basis for endometritis prognosis, the development of which is proceeded by systemic changes in immune function. SignificanceEndometritis is a costly reproductive disease of lactating dairy cows that warrants timely diagnosis. We utilized a gel-free mass-spectrometry based proteomics approach to compare the plasma proteome of dairy cattle with cytological endometritis to those without, for the characterization of changes in the proteomic profile associated with uterine disease postpartum. Furthermore, we compared the plasma proteome of healthy and affected cows in the same physiological status of production to better understand the relationship between changes in expression of circulating proteins and to unravel essential biological mechanisms involved in bovine cytological endometritis.

The levels of matrix metalloproteinase-9 and neutrophil gelatinase-associated lipocalin in different stages of endometriosis

This study was designed to explore matrix metalloproteinase-9 (MMP-9), neutrophil gelatinase-associated lipocalin (NGAL) levels and MMP-9/NGAL ratio in women with and without endometriosis diagnosed surgically and/or histopathologically. The correlation between biomarkers and the severity of the disease is analysed. The revised American Fertility Society classification system was used to determine the severity of endometriosis. Serum MMP-9 and Ca125, urine NGAL levels were measured in all participants. Serum MMP-9 levels were significantly higher in the study group (n = 60) compared to controls (n = 31) (15.0 pg/mL (6.0–143.0) vs. 12.0 (4.0–18.0), respectively; p=.002). MMP-9 levels were significantly higher in severe endometriosis compared to mild endometriosis subgroups (p<.001). No significant difference was found between NGAL levels in study and control groups (p>.05). The diagnostic value of MMP-9 and NGAL is not superior than CA-125 for endometriosis. Nevertheless, MMP-9 might be a potential predictive marker for advanced stage of the disease.Impact StatementWhat is already known on this subject? The gold standard diagnostic test for diagnosis of endometriosis is laparoscopy combined with histopathological confirmation of eutopic endometrial glands and/or stroma. Both invasiveness and possible accompanying complications limit the preference regarding the surgical approach. Among non-invasive markers none has been accepted as gold standard neither for diagnosis nor for determining the severity of the disease. MMPs are extracellular endopeptidases, which have a significant role in degradation and remodelling of extracellular matrix for cellular migration and invasion. Among these, MMP-9 has been shown to be higher in eutopic/ectopic endometrial tissue in women with endometriosis and has been suggested to have a role in pathogenesis of endometriosis by promoting invasion of the endometriotic lesions. NGAL is an acute phase protein, which is involved in a variety of physiological and pathophysiological processes. The molecule has also been revealed to correlate with endometriosis pathophysiology through the epithelial–mesenchymal transition process which is the basis for the onset of endometriosis. But also, NGAL which composes a complex with MMP-9 (MMP-9 and NGAL complex), has been shown to protect MMP-9 from autodegradation in vitro which might be a contributing factor for endometriosis pathophysiology.What the results of this study add? MMP-9 cut-off level for prediction of severe endometriosis is a novel finding obtained from this study with acceptable sensitivity and specificity. On the other hand, NGAL seems to have no significant value either for diagnosis of for determining severity of the disease. After all, MMP-9 might be an easy use acceptable biomarker for endometriosis but further studies on larger populations are needed.What the implications are of these findings for clinical practice and/or further research? MMP might be a potential non-invasive predictive marker for advanced stage disease.

Histological growth pattern as a potential marker of oligometastatic disease in patients operated for colorectal liver metastases.

e15093 Background: The identification of oligometastatic profile in patients with resectable colorectal liver metastases (CRLM) would represent a major progress to improve selection for surgery. Currently, in the absence of biomarkers, the most reliable method to identify oligometastatic (OLM) and non-oligometastatic (NOLM) tumors relies on the oncological outcome after metastases-targeted surgery. The histological growth pattern (HGP) of CRLM, defined as desmoplastic (dHGP) or replacement (rHGP), has recently been shown to have prognostic value. We analyzed HGP in a series of patients operated for CRLM, characterized as OLM in case of prolonged postoperative recurrence-free survival (RFS) or NOLM in case of rapid postoperative relapse. Methods: In 357 patients operated for CRLM, we identified OLM patients as those with RFS≥5 years (N = 64), and NOLM patients as those with RFS &lt; 1 year (N = 77). Clinicopathologic and surgical parameters were analyzed. In each CRLM, HGP was assessed in archival H&amp;E stained tissue sections, according to international consensus guidelines. Proportions of rHGP and dHGP were determined in each metastasis. In case of multiple metastases, the mean HGP was calculated in each patient. Patients were categorized as pure (&gt; 95% rHGP or dHGP) or dominant phenotypes (&gt; 50% rHGP or dHGP, of the entire tumor-liver interface). Results: Preoperative characteristics of primary tumor and CRLM, and surgical data were identical in OLM and NOLM groups. In a first set of analyses, HGP was determined in 39 OLM and 52 NOLM patients. Pure dHGP was observed in 54.3% of OLM and 17.3% of NOLM patients (p = 0.001). Pure rHGP was similarly distributed among OLM and NOLM groups. Sixty-nine% of the OLM patients displayed a dHGP-dominant phenotype, whereas 57.7% of the NOLM patients presented with a rHGP-dominant phenotype (p = 0.02). Conclusions: These results confirm the potential prognostic value of HGP in patients operated for CRLM. dHGP, associated with angiogenesis and inflammation, could represent a (surrogate) marker for oligometastatic progression, whereas rHGP appears strongly associated with rapid postoperative relapse.

Expression of long intergenic non-coding RNA, regulator of reprogramming, and its prognostic value in patients with glioblastoma.

Long intergenic non-coding RNA, regulator of reprogramming ( LINC-ROR) is a newly identified cytoplasmic long non-coding RNA (lncRNA), which has been found to be dysregulated in different cancers. The present work aimed to quantify LINC-ROR expression profile and assess the tumor proteins p53 and caspase 3 expressions in glioblastoma tissue specimens compared to non-cancer tissues, and to correlate these expression levels with the available clinicopathological and survival data. LINC-ROR relative expression in 57 glioblastoma cancer tissues and 10 non-cancer tissues was quantified by real-time polymerase chain reaction (qPCR). In addition, methylation-specific PCR of O-6-methylguanine-DNA methyltransferase ( MGMT) promoter and immunohistochemical expression of apoptosis related proteins: p53 and caspase 3 were performed. The up-regulation of LINC-ROR was encountered in 89.5% of patients. The higher expression of LINC-ROR was associated with poor disease progression-free and overall survival as well as a younger age of patients ( P=0.036). p53 protein was expressed only in glioblastoma but not in non-cancer tissues while caspase 3 was weakly expressed in most non-cancer tissues and in varying degrees in glioblastoma (24% weak, 30% moderate, and 16% strong expression). The Kaplan-Meier survival plot illustrated poor survival in glioblastoma patients with over-expressed LINC-ROR ( P=0.010) and down-regulated p53 ( P=0.002). Multivariate analysis showed that glioblastoma patients were clustered into two distinct groups based on LINC-ROR expression profile, p53 staining levels and patients' overall survival. LINC-ROR up-regulation may have a role in glioblastoma tumorigenesis and could be a potential prognostic marker for this fatal disease.

Prenatal cadmium exposure is associated with shorter leukocyte telomere length in Chinese newborns

BackgroundNewborn telomere length (TL) is considered a potential marker for future disease and lifelong health, but few epidemiological studies have examined the determinants of TL in early life. The study aim was to investigate whether there is an association between prenatal cadmium exposure and relative cord blood TL in Chinese newborns.MethodsParticipants were 410 mother–newborn pairs drawn from a prospective birth cohort study conducted in Wuhan, China, between November 2013 and March 2015. Urine samples were collected from pregnant women during their period of institutional delivery. Urinary cadmium concentrations were measured by inductively coupled plasma mass spectrometry. The real-time quantitative polymerase chain reaction detection was used to measure relative TL using genomic DNA isolated from umbilical cord blood leukocytes. Multivariate linear regression models were used to estimate the effect of prenatal urinary cadmium concentration on relative cord blood TL.ResultsThe geometric mean of maternal urinary cadmium concentration was 0.68 μg/g creatinine. In the multivariate-adjusted linear regression model, per doubling of maternal urinary cadmium concentration was associated with 6.83% (95% CI − 11.44%, − 1.97%; P = 0.006) shorter relative cord blood TL. Stratified analyses indicated that the inverse association between prenatal urinary cadmium and newborn relative TL was more pronounced among female infants and mothers < 29 years, while there were no significant effect modification according to infant sex (P for interaction = 0.907) and maternal age (P for interaction = 0.797).ConclusionsThe findings indicated that increased maternal urinary cadmium was associated with shortened relative cord blood TL. The results provide more evidence of the negative effects of environmental cadmium exposure and suggest that accelerated aging or cadmium-related diseases may begin in early life.

Eating peptides: biomarkers of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia.

ObjectivePhysiological changes potentially influence disease progression and survival along the Amyotrophic Lateral Sclerosis (ALS)‐Frontotemporal dementia (FTD) spectrum. The peripheral peptides that regulate eating and metabolism may provide diagnostic, metabolic, and progression biomarkers. The current study aimed to examine the relationships and biomarker potential of hormonal peptides.MethodsOne hundred and twenty‐seven participants (36 ALS, 26 ALS‐ cognitive, patients with additional cognitive behavioral features, and 35 behavioral variant FTD (bvFTD) and 30 controls) underwent fasting blood analyses of leptin, ghrelin, neuropeptide Y (NPY), peptide YY (PYY), and insulin levels. Relationships between endocrine measures, cognition, eating behaviors, and body mass index (BMI) were investigated. Biomarker potential was evaluated using multinomial logistic regression for diagnosis and correlation to disease duration.ResultsCompared to controls, ALS and ALS‐cognitive had higher NPY levels and bvFTD had lower NPY levels, while leptin levels were increased in all patient groups. All groups had increased insulin levels and a state of insulin resistance compared to controls. Lower NPY levels correlated with increasing eating behavioral change and BMI, while leptin levels correlated with BMI. On multinomial logistic regression, NPY and leptin levels were found to differentiate between diagnosis. Reduced Neuropeptide Y levels correlated with increasing disease duration, suggesting it may be useful as a potential marker of disease progression.Interpretation ALS‐FTD is characterized by changes in NPY and leptin levels that may impact on the underlying regional neurodegeneration as they were predictive of diagnosis and disease duration, offering the potential as biomarkers and for the development of interventional treatments.

Analysis of O-Acetylated Sialic Acids in Dried Blood Spots.

Sialic acid is a family of N- and O-substitutions of neuraminic acid. Plasma or serum sialic acid has been established as a potential disease marker. For example, the presence of 9- O-acetyl on the sialic acid of some glycans and glycoconjugates (e.g., 9- O-acetyl GD3 ganglioside) could be related to cancer occurrence. A variety of assays are available to measure serum or plasma sialic acid; however, sample preparation and storage can alter the O-acetylation profile due to the loss of O-acetyl groups and/or the migration of O-acetyl groups. Herein, we report dried blood spot (DBS) sampling, in combination with diamino-4,5-methylenedioxybenzene derivatization, for profiling sialic acids in blood samples with minimal alteration in O-acetylation patterns. The feasibility of the method was first evaluated by analyzing sialic acids in crucian carp blood and comparing with traditional blood/plasma sample preparation procedures. A total of 19 different sialic acids were identified by using liquid chromatography-Orbitrap mass spectrometry, including four mono-O-acetylated N-acetylneuraminic acids, four mono-O-acetylated N-glycolylneuraminic acids, six di-O-acetylated N-acetylneuraminic acids, and three tri-O-acetylated N-acetylneuraminic acids. The long-term storage study indicated that DBS sampling could effectively preserve the O-acetylation information for at least 6 weeks. Thus, it is demonstrated that this method is a valuable tool for the study of sialic acid diversity, especially for the characterization of isomeric structures.

Hypertensive and Metabolic Issues in Nephrolithiasis with Pregnancy

Background: Renal stones are correlated clinically with forthcoming development of hypertension, diabetes, and the metabolic syndrome. Objective of the study: To evaluate and investigate whether stone formation before pregnancy is correlated with metabolic and hypertensive medical development emergence in gestation. The research team hypothesis was based on that stone development is considered a potential marker of metabolic disease and will be linked with greater risk for maternal complications in pregnancy. Methodology: We conducted a two-group cohort study of women who delivered infants at El Sahel teaching Hospital 2015to 20118. Women with abdominal imaging investigate (computed tomography or sonography) before pregnancy were incorporated in the analysis. 923 cases were assessed for eligibility for the study 817 cases were eligible consequently they were categorized into stone formers (126 cases) and non-stone formers (691 cases .finally 110 cases were enrolled for each arm of the study 8 cases were lost during follow up in the stone former research group and 6 cases were lost during follow up in non-stone former research group. Gestational outcomes in women with documented renal stones by imaging were compared with those of women without stones on imaging. Females with preexisting chronic kidney disease, hypertension, and diabetes were excluded. Results: Stone former research group had statistically significantly more frequent hypertension, gestational hypertension, preeclampsia and preterm (p values=0.005,0.035,0.034,0.017, consecutively) as well as higher Maximum systolic blood pressure, diastolic blood pressure and glucose tolerance test (p values&lt;0.001,0.030,0.039, consecutively). Conclusions: In women without preexisting diabetes, hypertension, and CKD, a history of nephrolithiasis was associated with gestational diabetes and hypertensive disorders of pregnancy, especially in women with high first trimester body mass index.

Circulating angiopoietin-like protein 2 levels are associated with decreased renal function in HIV+ subjects on cART: A potential marker of kidney disease.

Chronic kidney disease (CKD) is an important cause of morbidity and mortality in HIV-infected individuals, even in the antiretroviral therapy (ART) era. Inflammatory cytokines and adipokines have been suggested to play a role in the development of CKD. The aim of the present study was to examine the circulating levels of a novel proinflammatory cytokine, angiopoietin-like protein 2 (ANGPTL2), in a cohort of 72 HIV-positive subjects on ART. HIV-positive patients were on cART for at least one year. Urine and blood samples were collected. Various factors were analyzed including body mass index (BMI), smoking, and presence/treatment for comorbidities such as diabetes. The estimated glomerular filtration rate was calculated by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Plasma samples obtained were stored and used to measure sCD14 and ANGPTL2 levels. Data were presented as mean (± standard deviation) or median (interquartile range) for continuous variables. Categorical variables were expressed as number (%). Variables were compared using Student's t-test, Mann-Whitney test, or χ2 test. The results showed an independent negative association between plasma ANGPTL2 and CKD-EPI values. Further prospective studies on larger cohorts are needed to evaluate the pathogenetic role of ANGPTL2 as well as its use as a diagnostic marker of renal dysfunction.

Correlations between Interleukin-33 and -1α Levels in Gingival Crevicular Fluid and Plasma in Patients with Chronic or Aggressive Periodontitis and Disease-free Subjects.

Interleukin (IL)-33 is a dual-function protein that may play important roles as both a cytokine and intracellular nuclear factor. It may also function similarly to prototypical alarmin IL-1α, as an endogenous danger signal to alert innate immune system cells to tissue damage during trauma or infection, as it can be released in the extracellular space after endothelial cell damage or mechanical injury. The aim of this study was to determine possible correlations between concentrations of IL-33 and IL-1α in gingival crevicular fluid (GCF) and plasma obtained from healthy patients, those with chronic periodontitis (CP), and those with generalized aggressive periodontitis (GAP) patients. Forty-five patients with an age range of 20-60 years were enrolled and divided into 3 groups: Group H, 30 samples (15 GCF and 15 plasma) from 15 patients with healthy periodontium; Group CP, 30 samples from 15 patients with CP; and Group GAP, 30 samples from 15 patients with GAP. The clinical periodontal parameters investigated in all groups comprised the gingival index score, probing pocket depth, and clinical attachment level. The GCF and plasma levels of IL-33 and IL-1α were quantitated using enzyme linked immunosorbent assay. The mean IL-33 concentrations in GCF and plasma were highest in Group GAP, followed by Group CP, with the lowest in Group H; the difference among them was statistically significant (p<0.05). Concentration of IL-1α followed the same trend as that of IL-33 in GCF, but was lower than detection levels in plasma. The GCF and plasma concentrations of IL-33 correlated with IL-1α concentrations in GCF. Concentrations of IL-33 and IL-1α in GCF varied significantly between healthy patients and those with disease, allowing healthy patients to be distinguished from those with GAP or CP. The results of this study suggest that IL-33 offers a potential inflammatory marker of periodontal disease, similar to IL-1α.

Evaluation of bone disease in patients with cystic fibrosis and end-stage lung disease.

ABSTRACTObjective:Bone disease is a common comorbidity in patients with cystic fibrosis (CF). We sought to determine risk factors and identify potential biochemical markers for CF-related bone disease (CFBD) in a unique cohort of CF patients with end-stage lung disease undergoing lung transplantation (LTx) evaluation. Methods:All of the CF patients who were evaluated for LTx at our center between November of 1992 and December of 2010 were included in the study. Clinical data and biochemical markers of bone turnover, as well as bone mineral density (BMD) at the lumbar spine and femoral neck, were evaluated. Spearman’s rho and multivariate logistic regression analysis were used. Results:A total of 102 adult CF patients were evaluated. The mean age was 28.1 years (95% CI: 26.7-29.5), and the mean body mass index was 17.5 kg/m2 (95% CI: 17.2-18.2). Mean T-scores were −2.3 and −1.9 at the lumbar spine and femoral neck, respectively, being lower in males than in females (−2.7 vs. −2.0 at the lumbar spine and −2.2 vs. −1.7 at the femoral neck). Overall, 52% had a T-score of < −2.5 at either skeletal site. The homozygous Phe508del genotype was found in 57% of patients without osteoporosis and in 60% of those with low BMD. Mean T-scores were not particularly low in patients with severe CFTR mutations. Although the BMI correlated with T-scores at the femoral neck and lumbar spine, serum 25-hydroxyvitamin D and parathyroid hormone levels did not. Conclusions:CFBD is common in CF patients with end-stage lung disease, particularly in males and patients with a low BMI. It appears that CF mutation status does not correlate with CFBD. In addition, it appears that low BMD does not correlate with other risk factors or biochemical parameters. The prevalence of CFBD appears to have recently decreased, most likely reflecting increased efforts at earlier diagnosis and treatment.