Raman spectroscopy is a candidate technique for diagnosis applications in medicine due to its high molecular specificity. Optimizing the pre-treatment applied for Raman data is important for ...exploiting Raman signals and ensuring their relevance in medical diagnosis. One of the crucial steps in data pre-processing, normalization, can affect significantly the result interpretation. To select the appropriate normalization method, a strategy based on validity indices (VI) is proposed in this study. VI are based on measuring the quality of data partitioning without involving a full sequence of supervised classification. The approach was tested on Raman data acquired from control and
in vitro
glycated proteins (albumin and collagen). Protein glycation is a process involved in the molecular ageing of tissues that leads to the formation of products altering the functional and structural properties of proteins. Different methods of normalization were applied on the data sets: integrated intensity of the phenylalanine band, integrated intensity of the amide I band, standard normal variate (SNV), multiplicative signal correction (MSC), and extended multiplicative signal correction (EMSC) that performs simultaneously baseline correction and normalization. Following normalization, principal component analysis (PCA) was applied and VI were calculated from PCA scores resulting from each of the normalization methods mentioned. Based on VI quantitative values, our experiments permit to illustrate the effect of normalization on the data separability of control and glycated samples, and to determine the most appropriate normalization and simultaneously the most discriminant principal components to exploit vibrational information associated with glycation-induced modifications. In parallel, principal component analysis - linear discriminant analysis (PCA-LDA) was carried out for positioning the interest of VI in regard to a common chain of data processing.
Vibrational data of biological samples require appropriate pre-processing for ensuring relevant interpretation. Here, mathematical criteria (validity indices) are used to select how to normalize Raman data collected in the protein glycation context.
Protein carbamylation is a hallmark of aging Gorisse, Laëtitia; Pietrement, Christine; Vuiblet, Vincent ...
Proceedings of the National Academy of Sciences - PNAS,
02/2016, Volume:
113, Issue:
5
Journal Article
Peer reviewed
Open access
Aging is a progressive process determined by genetic and acquired factors. Among the latter are the chemical reactions referred to as nonenzymatic posttranslational modifications (NEPTMs), such as ...glycoxidation, which are responsible for protein molecular aging. Carbamylation is a more recently described NEPTM that is caused by the nonenzymatic binding of isocyanate derived from urea dissociation or myeloperoxidase-mediated catabolism of thiocyanate to free amino groups of proteins. This modification is considered an adverse reaction, because it induces alterations of protein and cell properties. It has been shown that carbamylated proteins increase in plasma and tissues during chronic kidney disease and are associated with deleterious clinical outcomes, but nothing is known to date about tissue protein carbamylation during aging. To address this issue, we evaluated homocitrulline rate, the most characteristic carbamylation-derived product (CDP), over time in skin of mammalian species with different life expectancies. Our results show that carbamylation occurs throughout the whole lifespan and leads to tissue accumulation of carbamylated proteins. Because of their remarkably long half-life, matrix proteins, like type I collagen and elastin, are preferential targets. Interestingly, the accumulation rate of CDPs is inversely correlated with longevity, suggesting the occurrence of still unidentified protective mechanisms. In addition, homocitrulline accumulates more intensely than carboxymethyl-lysine, one of the major advanced glycation end products, suggesting the prominent role of carbamylation over glycoxidation reactions in age-related tissue alterations. Thus, protein carbamylation may be considered a hallmark of aging in mammalian species that may significantly contribute in the structural and functional tissue damages encountered during aging.
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IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, frequently leads to end-stage renal disease and kidney transplantation. However, disease recurrence often occurs after ...transplantation. Here we evaluated the predictive value of three markers for IgAN recurrence: the presence of galactose-deficient IgA1, IgG anti-IgA autoantibodies, and IgA-soluble (s) CD89 complexes. This was analyzed in 38 kidney transplant recipients with IgAN recurrence and compared with 22 patients transplanted for IgAN but without recurrence and with 17 healthy controls. Pre-transplantation galactose-deficient IgA1 serum levels were significantly higher in the recurrence compared with the no recurrence or control groups. IgA–IgG complexes were significantly elevated in the recurrence group. Both the recurrence and no recurrence groups had increased values of IgA–sCD89 complexes compared with healthy controls, but values were significantly lower in patients with recurrence compared with no recurrence. Areas under the receiver operating curve of the markers in pre-transplantation sera were 0.86 for galactose-deficient-IgA, 0.82 for IgA–IgG, and 0.78 for sCD89–IgA; all significant. Disease recurrence was associated with decreased serum galactose-deficient IgA1 and appearance of mesangial-galactose-deficient IgA1 deposits, whereas increased serum IgA–sCD89 complexes were associated with mesangial sCD89 deposits. Thus, galactose-deficient-IgA1, IgG autoantibodies, and IgA–sCD89 complexes are valuable biomarkers to predict disease recurrence, highlighting major pathogenic mechanisms in IgAN.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Systemic sclerosis (SSc) is a connective tissue disorder of great clinical heterogeneity. Its pathophysiology remains unclear. Our aim was to evaluate the relative roles of reactive oxygen species ...(ROS) and of the immune system using an original model of SSc. BALB/c and immunodeficient BALB/c SCID mice were injected s.c. with prooxidative agents (hydroxyl radicals, hypochlorous acid, peroxynitrites, superoxide anions), bleomycin, or PBS everyday for 6 wk. Skin and lung fibrosis were assessed by histological and biochemical methods. Autoantibodies were detected by ELISA. The effects of mouse sera on H(2)O(2) production by endothelial cells and on fibroblast proliferation, and serum concentrations in advanced oxidation protein products (AOPP) were compared with sera from patients with limited or diffuse SSc. We observed that s.c. peroxynitrites induced skin fibrosis and serum anti-CENP-B Abs that characterize limited SSc, whereas hypochlorite or hydroxyl radicals induced cutaneous and lung fibrosis and anti-DNA topoisomerase 1 autoantibodies that characterize human diffuse SSc. Sera from hypochlorite- or hydroxyl radical-treated mice and of patients with diffuse SSc contained high levels of AOPP that triggered endothelial production of H(2)O(2) and fibroblast hyperproliferation. Oxidized topoisomerase 1 recapitulated the effects of whole serum AOPP. SCID mice developed an attenuated form of SSc, demonstrating the synergistic role of the immune system with AOPP in disease propagation. We demonstrate a direct role for ROS in SSc and show that the nature of the ROS dictates the form of SSc. Moreover, this demonstration is the first that shows the specific oxidation of an autoantigen directly participates in the pathogenesis of an autoimmune disease.
ObjectiveThe heterogeneity of lupus clinical manifestations makes it difficult to precisely characterize the full spectrum of patient profiles with traditional real-life (claims) data sources. This ...study assesses the ability of the Realli™ solution to characterize patients with lupus attending a reference center in France.MethodsRetrospective longitudinal study with data extracted via the Realli solution, an advanced machine learning-powered platform providing near real time in-depth extraction and analyses of full content structured and unstructured hospital electronic medical records (EMRs), as well as all connected data sources and claims. Upon Ethics Committee approval, eligible adult patients were identified via presence of ICD-10-CM L93.X or M32.X codes in claims and lupus type was characterized by text strings searches in the hospital EMRs.ResultsBetween January 2018 and March 2023, 187 adult patients with lupus (mean age 51.4 years; 88% females) were identified. Overall, 37.4%, 81.8%, 34.2%, 25.7% and 7% of patients presented with lupus erythematous, systemic lupus erythematosus, cutaneous lupus erythematosus (CLE), lupus nephritis (LN), and concomitant CLE with LN, respectively. Biomarkers, such as antinuclear antibodies, C-reactive protein, C4 and CH50 were retrieved in 68.4%, 54.0%, 46.0%, and 45.5% of patients, while SLEDAI disease activity index was reported in 9.6% patients, with an average score of 11.7 (95%CI: 6.36 -17.04). Most prevalent comorbidities and complications were cardiovascular disorders (62.6%), metabolic disorders (39.6%), polyarthritis (39.0%) and high blood pressure (38.5%). Renal impairment was identified in 34.8% of patients (all renal ICD-10 codes + text strings). Lastly, 31.0% and 15.0% of patients presented with antiphospholipid antibody syndrome or Gougerot-Sjögren syndrome, respectively. Patients received cyclophosphamide (4.8%), immunosuppressants (35.8%), glucocorticoids (51.3%), hydroxychloroquine (47.1%), belimumab (15.0%), and/or rituximab (8.6%). Over the study period, patients were hospitalized on average 10.8 times (median 4.0).ConclusionsA digital platform connected to multidata hospital sources is more time efficient in characterizing complex pathologies like lupus than manual chart reviews. This type of solution also provides a breadth and granularity of information not available in traditional RWE claims data sources. Learning from this single-center study will be deployed to multihospital system in France to test the robustness of the approach.
BACKGROUNDThe differential pathogenicity of anti-HLA donor-specific antibodies (DSAs) is not fully understood. The presence of complement-binding DSAs helps in better defining the prognosis of acute ...antibody-mediated rejection (ABMR). The evolution of these antibodies after the treatment of ABMR is unknown.
METHODSWe included patients from the French multicenter RITUX ERAH study diagnosed with acute ABMR within the first year of renal transplantation, with circulating anti-HLA DSAs and treated randomly by rituximab or placebo (and intravenous immunoglobulins, plasma exchange). We centrally analyzed serum samples at the time of ABMR, 3 and 6 months after ABMR, with anti-HLA DSAs specificities and C1q-binding capacity assessment.
RESULTSTwenty-five patients were included68% had C1q-binding DSAs at the time of ABMR. The presence of C1q-binding DSAs was associated with a poorer evolution of chronic glomerulopathy at 6 months (P = 0.036). The persistence of C1q-binding DSAs at 3 and/or 6 months after ABMR was associated with more severe chronic glomerulopathy (P = 0.006), greater C4d score deposition score at 6 months after ABMR (P = 0.008), and graft loss 5 years after ABMR (P = 0.029). C1q-binding capacity was associated with the DSA MFI but 5 C1q-binding DSAs in 4 patients had low MFI values without a prozone effect.
CONCLUSIONThe presence and persistence of anti-HLA C1q-binding DSAs after ABMR is a detrimental marker, leading to transplant glomerulopathy and graft loss. Assessment of the complement-binding capacities of DSAs could help decide treatment intensification.
Bronchiectasis is a chronic airway disease characterized by permanent and irreversible abnormal dilatation of bronchi. Several studies have reported the development of bronchiectasis after renal ...transplantation (RT), but no prospective study specifically assessed bronchiectasis in this population. This study aimed to compare features of patients with bronchiectasis associated with RT to those with idiopathic bronchiectasis.
Nineteen patients with bronchiectasis associated with RT (RT-B group) and 23 patients with idiopathic bronchiectasis (IB group) were prospectively included in this monocentric cross-sectional study. All patients underwent clinical, functional, laboratory, and CT scan assessments. Sputum was collected from 25 patients (n = 11 with RT-B and n = 14 with IB) and airway microbiota was analyzed using an extended microbiological culture.
Dyspnea (≥ 2 on mMRC scale), number of exacerbations, pulmonary function tests, total bronchiectasis score, severity and prognosis scores (FACED and E-FACED), and quality of life scores (SGRQ and MOS SF-36) were similar in the RT-B and IB groups. By contrast, chronic cough was less frequent in the RT-B group than in the IB group (68% vs. 96%, p = 0.03). The prevalence and diversity of the airway microbiota in sputum were similar in the two groups.
Clinical, functional, thoracic CT scan, and microbiological characteristics of bronchiectasis are overall similar in patients with IB and RT-B. These results highlight that in RT patients, chronic respiratory symptoms and/or airway infections should lead to consider the diagnosis of bronchiectasis. Further studies are required to better characterize the pathophysiology of RT-B including airway microbiota, its incidence, and impact on therapeutic management.
Activation of the complement system is involved in the pathogenesis of anti-glomerular basement membrane (anti-GBM) disease. Glomerular deposits of complement 3 (C3) are often detected on kidney ...biopsies. The primary objective of this study was to analyze the prognostic value of the serum C3 level and the presence of C3 glomerular deposits in patients with anti-GBM disease.
We conducted a retrospective cohort study of 150 single-positive patients with anti-GBM disease diagnosed between 1997 and 2017. Patients were categorized according to the serum C3 level (forming a low C3 (C3<1.23 g/L) and a high C3 (C3≥1.23 g/L) groups) and positivity for C3 glomerular staining (forming the C3+ and C3- groups). The main outcomes were kidney survival and patient survival.
Of the 150 patients included, 89 (65%) were men. The median interquartile range (IQR) age was 45 26-64. At diagnosis, kidney involvement was characterized by a median IQR peak serum creatinine (SCr) level of 578 298-977 µmol/L, and 106 (71%) patients required dialysis. Patients in the low C3 group (72 patients) had more severe kidney disease at presentation, as characterized by higher prevalences of oligoanuria, peak SCr ≥500 µmol/L (69%, vs. 53% in the high C3 group; p=0.03), nephrotic syndrome (42%, vs. 24%, respectively; p=0.02) and fibrous forms on the kidney biopsy (21%, vs. 8%, respectively; p=0.04). Similarly, we observed a negative association between the presence of C3 glomerular deposits (in 52 (41%) patients) and the prevalence of cellular forms (83%, vs. 58% in the C3- group; p=0.003) and acute tubulo-interstitial lesions (60%, vs. 36% in the C3- group; p=0.007). When considering patients not on dialysis at diagnosis, the kidney survival rate at 12 months was poorer in the C3+ group (50% 25-76, vs. 91% 78-100 in the C3- group; p=0.01), with a hazard ratio 95% confidence interval of 5.71 1.13-28.85 (p=0.04, after adjusting for SCr).
In patients with anti-GBM disease, a low serum C3 level and the presence of C3 glomerular deposits were associated with more severe disease and histological kidney involvement at diagnosis. In patients not on dialysis at diagnosis, the presence of C3 deposits was associated with worse kidney survival.
The human genome comprises approximately 3% of tandem repeats with variable length (VNTR), a few of which have been linked to human rare diseases. Autosomal dominant tubulointerstitial kidney ...disease—MUC1 (ADTKD-MUC1) is caused by specific frameshift variants in the coding VNTR of the MUC1 gene. Calling variants from VNTR using short-read sequencing (SRS) is challenging due to poor read mappability. We developed a computational pipeline, VNtyper, for reliable detection of MUC1 VNTR pathogenic variants and demonstrated its clinical utility in two distinct cohorts: (1) a historical cohort including 108 families with ADTKD and (2) a replication naive cohort comprising 2,910 patients previously tested on a panel of genes involved in monogenic renal diseases. In the historical cohort all cases known to carry pathogenic MUC1 variants were re-identified, and a new 25bp-frameshift insertion in an additional mislaid family was detected. In the replication cohort, we discovered and validated 30 new patients.
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•Detecting pathogenic variants in VNTRs is challenging due to poor read mappability•VNtyper detects VNTR pathogenic variants in the MUC1 gene using Kestrel algorithm•VNtyper improves ADTKD-MUC1 diagnosis by accurate genotyping of MUC1 coding VNTR•Integration of VNtyper with SRS gene panel testing identified new overlooked patients
Genetics; Genomics; Techniques in genetics; Genotyping
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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