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1.
Background
The genetic basis of amyotrophic lateral sclerosis (ALS) is not entirely clear. While there are families with rare highly penetrant mutations in Cu/Zn superoxide dismutase 1 and several other genes that cause apparent Mendelian inheritance of the disease, most ALS occurs in families without another affected individual. However, twin studies suggest that all ALS has a substantial genetic basis. Herein, we estimate the genetic contribution to ALS in a clinically ascertained case series from the United States.Methodology/Principal Findings
We used the database of the Emory ALS Center to ascertain individuals with ALS along with their family histories to determine the concordance among parents and offspring for the disease. We found that concordance for all parent–offspring pairs was low (<2%). With this concordance we found that ALS heritability, or the proportion of the disease explained by genetic factors, is between 40 and 45% for all likely estimates of ALS lifetime prevalence.Conclusions/Significance
We found the lifetime risk of ALS is 1.1% in first-degree relatives of those with ALS. Environmental and genetic factors appear nearly equally important for the development of ALS. 相似文献2.
Oeckl P Steinacker P Lehnert S Jesse S Kretzschmar HA Ludolph AC Otto M Ferger B 《PloS one》2012,7(3):e32664
Background
The cyclic nucleotides cyclic adenosine-3′,5′-monophosphate (cAMP) and cyclic guanosine-3′,5′-monophosphate (cGMP) are important second messengers and are potential biomarkers for Parkinson''s disease (PD), amyotrophic lateral sclerosis (ALS) and Creutzfeldt-Jakob disease (CJD).Methodology/Principal Findings
Here, we investigated by liquid chromatography/tandem mass spectrometry (LC-MS/MS) the cerebrospinal fluid (CSF) concentrations of cAMP and cGMP of 82 patients and evaluated their diagnostic potency as biomarkers. For comparison with a well-accepted biomarker, we measured tau concentrations in CSF of CJD and control patients. CJD patients (n = 15) had lower cAMP (−70%) and cGMP (−55%) concentrations in CSF compared with controls (n = 11). There was no difference in PD, PD dementia (PDD) and ALS cases. Receiver operating characteristic (ROC) curve analyses confirmed cAMP and cGMP as valuable diagnostic markers for CJD indicated by the area under the curve (AUC) of 0.86 (cAMP) and 0.85 (cGMP). We calculated a sensitivity of 100% and specificity of 64% for cAMP and a sensitivity of 67% and specificity of 100% for cGMP. The combination of both nucleotides increased the sensitivity to 80% and specificity to 91% for the term cAMPxcGMP (AUC 0.92) and to 93% and 100% for the ratio tau/cAMP (AUC 0.99).Conclusions/Significance
We conclude that the CSF determination of cAMP and cGMP may easily be included in the diagnosis of CJD and could be helpful in monitoring disease progression as well as in therapy control. 相似文献3.
Blasco H Corcia P Moreau C Veau S Fournier C Vourc'h P Emond P Gordon P Pradat PF Praline J Devos D Nadal-Desbarats L Andres CR 《PloS one》2010,5(10):e13223
Background
Pathophysiological mechanisms involved in amyotrophic lateral sclerosis (ALS) are complex and none has identified reliable markers useful in routine patient evaluation. The aim of this study was to analyze the CSF of patients with ALS by 1H NMR (Nuclear Magnetic Resonance) spectroscopy in order to identify biomarkers in the early stages of the disease, and to evaluate the biochemical factors involved in ALS.Methodology
CSF samples were collected from patients with ALS at the time of diagnosis and from patients without neurodegenerative diseases. One and two-dimensional 1H NMR analyses were performed and metabolites were quantified by the ERETIC method. We compared the concentrations of CSF metabolites between both groups. Finally, we performed principal component (PCA) and discriminant analyses.Principal Findings
Fifty CSF samples from ALS patients and 44 from controls were analyzed. We quantified 17 metabolites including amino-acids, organic acids, and ketone bodies. Quantitative analysis revealed significantly lower acetate concentrations (p = 0.0002) in ALS patients compared to controls. Concentration of acetone trended higher (p = 0.015), and those of pyruvate (p = 0.002) and ascorbate (p = 0.003) were higher in the ALS group. PCA demonstrated that the pattern of analyzed metabolites discriminated between groups. Discriminant analysis using an algorithm of 17 metabolites revealed that patients were accurately classified 81.6% of the time.Conclusion/Significance
CSF screening by NMR spectroscopy could be a useful, simple and low cost tool to improve the early diagnosis of ALS. The results indicate a perturbation of glucose metabolism, and the need to further explore cerebral energetic metabolism. 相似文献4.
Fang F Chen H Wirdefeldt K Ronnevi LO Al-Chalabi A Peters TL Kamel F Ye W 《PloS one》2011,6(12):e29749
Background
Severe infections may lead to chronic inflammation in the central nervous system (CNS) which may in turn play a role in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). The relentless progression and invasive supportive treatments of ALS may on the other hand induce severe infections among ALS patients.Methodology and Principal Findings
The present study included 4,004 ALS patients identified from the Swedish Patient Register during 1991–2007 and 20,020 age and sex matched general population controls. Conditional logistic regression was used to estimate the odds ratios (ORs) of ALS given a previous hospitalization for CNS infection or sepsis. Cox models were used to estimate the hazard ratios (HRs) of hospitalization for CNS infection or sepsis after ALS diagnosis. Overall, previous CNS infection (OR: 1.3, 95% confidence interval [CI]: 0.8, 2.4) or sepsis (OR: 1.2, 95% CI: 0.9, 1.6) was not associated with ALS risk. However, compared to ALS free individuals, ALS cases were more likely to be hospitalized for sepsis after diagnosis (HR: 2.6, 95% CI: 1.9, 3.5). We did not observe a higher risk of CNS infection after ALS diagnosis.Conclusions/Significance
Our results suggest that acute and severe infections unlikely contribute to the development of ALS; however, ALS patients are at a higher risk of sepsis after diagnosis, compared to ALS free individuals. 相似文献5.
Rekha RS Kamal SM Andersen P Rahim Z Hoq MI Ara G Andersson J Sack D Raqib R 《PloS one》2011,6(1):e16425
Background
We have earlier shown that Bacille Calmette-Guérin (BCG) vaccine-specific IgG Antibodies in Lymphocyte Supernatant (ALS) can be used for diagnosis of active tuberculosis (TB) in adults and children.Methodology/Principal Findings
The ALS method was validated in a larger cohort (n = 212) of patients with suspicion of pulmonary TB using multiple antigens (BCG, LAM, TB15.3, TB51A, CFP10-ESAT6-A, CFP, CW) from Mycobacterium tuberculosis. The sensitivity and specificity of the ALS assay was calculated using non-TB patients as controls. The sensitivity and the specificity were highest with BCG vaccine (90% and 88% respectively) followed by LAM (89% and 87% respectively). Simultaneous assessment of multiple antigen-specific antibodies increased sensitivity (91%) and specificity (88%). Using higher lymphocyte count in smaller volume of culture media increased detection and reduced the assay duration to ∼30 hrs. Twenty one patients with clinical findings strongly suggestive of TB finally diagnosed as non-TB patients were positive by the ALS assay, of which 9 (43%) were positive for 7 antigens and 19 (90%) for at least 3 antigens.Conclusions/Significance
Our findings show that simultaneous detection of antigens improves the diagnostic potential of the ALS assay; the modified method increases sensitivity and can provide results in <48 hours, and enable detection of some cases of pulmonary TB that are not detectable by standard methods. 相似文献6.
Castillo-Trivino T Mowry EM Gajofatto A Chabas D Crabtree-Hartman E Cree BA Goodin DS Green AJ Okuda DT Pelletier D Zamvil SS Vittinghoff E Waubant E 《PloS one》2011,6(2):e16664
Background
Multiple sclerosis (MS) patients with breakthrough disease on immunomodulatory drugs are frequently offered to switch to natalizumab or immunosuppressants. The effect of natalizumab monotherapy in patients with breakthrough disease is unknown.Methods
This is an open-label retrospective cohort study of 993 patients seen at least four times at the University of California San Francisco MS Center, 95 had breakthrough disease on first-line therapy (60 patients switched to natalizumab, 22 to immunosuppressants and 13 declined the switch [non-switchers]). We used Poisson regression adjusted for potential confounders to compare the relapse rate within and across groups before and after the switch.Results
In the within-group analyses, the relapse rate decreased by 70% (95% CI 50,82%; p<0.001) in switchers to natalizumab and by 77% (95% CI 59,87%; p<0.001) in switchers to immunosuppressants; relapse rate in non-switchers did not decrease (6%, p = 0.87). Relative to the reduction among non-switchers, the relapse rate was reduced by 68% among natalizumab switchers (95% CI 19,87%; p = 0.017) and by 76% among the immunosuppressant switchers (95% CI 36,91%; p = 0.004).Conclusions
Switching to natalizumab or immunosuppressants in patients with breakthrough disease is effective in reducing clinical activity of relapsing MS. The magnitude of the effect and the risk-benefit ratio should be evaluated in randomized clinical trials and prospective cohort studies. 相似文献7.
Dupuis L Spreux-Varoquaux O Bensimon G Jullien P Lacomblez L Salachas F Bruneteau G Pradat PF Loeffler JP Meininger V 《PloS one》2010,5(10):e13346
Background
Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease involving upper and lower motor neurons loss. Clinical features are highly variable among patients and there are currently few known disease-modifying factors underlying this heterogeneity. Serotonin is involved in a range of functions altered in ALS, including motor neuron excitability and energy metabolism. However, whether serotoninergic activity represents a disease modifier of ALS natural history remains unknown.Methodology
Platelet and plasma unconjugated concentrations of serotonin and plasma 5-HIAA, the major serotonin metabolite, levels were measured using HPLC with coulometric detection in a cohort of 85 patients with ALS all followed-up until death and compared to a control group of 29 subjects.Principal Findings
Platelet serotonin levels were significantly decreased in ALS patients. Platelet serotonin levels did not correlate with disease duration but were positively correlated with survival of the patients. Univariate Cox model analysis showed a 57% decreased risk of death for patients with platelet serotonin levels in the normal range relative to patients with abnormally low platelet serotonin (p = 0.0195). This protective effect remained significant after adjustment with age, gender or site of onset in multivariate analysis. Plasma unconjugated serotonin and 5-HIAA levels were unchanged in ALS patients compared to controls and did not correlate with clinical parameters.Conclusions/Significance
The positive correlation between platelet serotonin levels and survival strongly suggests that serotonin influences the course of ALS disease. 相似文献8.
9.
Lesnick TG Sorenson EJ Ahlskog JE Henley JR Shehadeh L Papapetropoulos S Maraganore DM 《PloS one》2008,3(1):e1449
Background
We recently described a genomic pathway approach to study complex diseases. We demonstrated that models constructed using single nucleotide polymorphisms (SNPs) within axon guidance pathway genes were highly predictive of Parkinson disease (PD) susceptibility, survival free of PD, and age at onset of PD within two independent whole-genome association datasets. We also demonstrated that several axon guidance pathway genes represented by SNPs within our final models were differentially expressed in PD.Methodology/Principal Findings
Here we employed our genomic pathway approach to analyze data from a whole-genome association dataset of amyotrophic lateral sclerosis (ALS); and demonstrated that models constructed using SNPs within axon guidance pathway genes were highly predictive of ALS susceptibility (odds ratio = 1739.73, p = 2.92×10−60), survival free of ALS (hazards ratio = 149.80, p = 1.25×10−74), and age at onset of ALS (R2 = 0.86, p = 5.96×10−66). We also extended our analyses of a whole-genome association dataset of PD, which shared 320,202 genomic SNPs in common with the whole-genome association dataset of ALS. We compared for ALS and PD the genes represented by SNPs in the final models for susceptibility, survival free of disease, and age at onset of disease and noted that 52.2%, 37.8%, and 34.9% of the genes were shared respectively.Conclusions/Significance
Our findings for the axon guidance pathway and ALS have prior biological plausibility, overlap partially with PD, and may provide important insight into the causes of these and related neurodegenerative disorders. 相似文献10.
Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by motor neuron death in the central nervous system. Vitamin D supplementation increases antioxidant activity, reduces inflammation and improves motor neuron survival. We have previously demonstrated that vitamin D3 supplementation at 10× the adequate intake improves functional outcomes in a mouse model of ALS.
Objective
To determine whether vitamin D deficiency influences functional and disease outcomes in a mouse model of ALS.Methods
At age 25 d, 102 G93A mice (56 M, 46 F) were divided into two vitamin D3 groups: 1) adequate (AI; 1 IU D3/g feed) and 2) deficient (DEF; 0.025 IU D3/g feed). At age 113 d, tibialis anterior (TA), quadriceps (quads) and brain were harvested from 42 mice (22 M and 20 F), whereas the remaining 60 mice (34 M and 26 F) were followed to endpoint.Results
During disease progression, DEF mice had 25% (P = 0.022) lower paw grip endurance AUC and 19% (P = 0.017) lower motor performance AUC vs. AI mice. Prior to disease onset (CS 2), DEF mice had 36% (P = 0.016) lower clinical score (CS) vs. AI mice. DEF mice reached CS 2 six days later vs. AI mice (P = 0.004), confirmed by a logrank test which revealed that DEF mice reached CS 2 at a 43% slower rate vs. AI mice (HR = 0.57; 95% CI: 0.38, 1.74; P = 0.002). Body weight-adjusted TA (AI: r = 0.662, P = 0.001; DEF: r = 0.622, P = 0.006) and quads (AI: r = 0.661, P = 0.001; DEF: r = 0.768; P<0.001) weights were strongly correlated with age at CS 2.Conclusion
Vitamin D3 deficiency improves early disease severity and delays disease onset, but reduces performance in functional outcomes following disease onset, in the high-copy G93A mouse. 相似文献11.
N von Neuhoff T Oumeraci T Wolf K Kollewe P Bewerunge B Neumann B Brors J Bufler U Wurster B Schlegelberger R Dengler M Zapatka S Petri 《PloS one》2012,7(9):e44401
Background
Amyotrophic lateral sclerosis (ALS) is a fatal disorder of the motor neuron system with poor prognosis and marginal therapeutic options. Current clinical diagnostic criteria are based on electrophysiological examination and exclusion of other ALS-mimicking conditions. Neuroprotective treatments are, however, most promising in early disease stages. Identification of disease-specific CSF biomarkers and associated biochemical pathways is therefore most relevant to monitor disease progression, response to neuroprotective agents and to enable early inclusion of patients into clinical trials.Methods and Findings
CSF from 35 patients with ALS diagnosed according to the revised El Escorial criteria and 23 age-matched controls was processed using paramagnetic bead chromatography for protein isolation and subsequently analyzed by MALDI-TOF mass spectrometry. CSF protein profiles were integrated into a Random Forest model constructed from 153 mass peaks. After reducing this peak set to the top 25%, a classifier was built which enabled prediction of ALS with high accuracy, sensitivity and specificity. Further analysis of the identified peptides resulted in a panel of five highly sensitive ALS biomarkers. Upregulation of secreted phosphoprotein 1 in ALS-CSF samples was confirmed by univariate analysis of ELISA and mass spectrometry data. Further quantitative validation of the five biomarkers was achieved in an 80-plex Multiple Reaction Monitoring mass spectrometry assay.Conclusions
ALS classification based on the CSF biomarker panel proposed in this study could become a valuable predictive tool for early clinical risk stratification. Of the numerous CSF proteins identified, many have putative roles in ALS-related metabolic processes, particularly in chromogranin-mediated secretion signaling pathways. While a stand-alone clinical application of this classifier will only be possible after further validation and a multicenter trial, it could be readily used to complement current ALS diagnostics and might also provide new insights into the pathomechanisms of this disease in the future. 相似文献12.
Ledwaba L Tavel JA Khabo P Maja P Qin J Sangweni P Liu X Follmann D Metcalf JA Orsega S Baseler B Neaton JD Lane HC;Project Phidisa Biomarkers Team 《PloS one》2012,7(3):e24243
Background
Levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer predict mortality in HIV patients on antiretroviral therapy (ART) with relatively preserved CD4+ T cell counts. We hypothesized that elevated pre-ART levels of these markers among patients with advanced HIV would be associated with an increased risk of death following the initiation of ART.Methods
Pre-ART plasma from patients with advanced HIV in South Africa was used to measure hsCRP, IL-6 and D-dimer. Using a nested case-control study design, the biomarkers were measured for 187 deaths and two controls matched on age, sex, clinical site, follow-up time and CD4+ cell counts. Odds ratios were estimated using conditional logistic regression. In addition, for a random sample of 100 patients, biomarkers were measured at baseline and 6 months following randomization to determine whether ART altered their levels.Results
Median baseline biomarkers levels for cases and controls, respectively, were 11.25 vs. 3.6 mg/L for hsCRP, 1.41 vs. 0.98 mg/L for D-dimer, and 9.02 vs. 4.20 pg/mL for IL-6 (all p<0.0001). Adjusted odds ratios for the highest versus lowest quartile of baseline biomarker levels were 3.5 (95% CI: 1.9–6.7) for hsCRP, 2.6 (95%CI 1.4–4.9) for D-dimer, and 3.8 (95% CI: 1.8–7.8) for IL-6. These associations were stronger for deaths that occurred more proximal to the biomarker measurements. Levels of D-dimer and IL-6, but not hsCRP, were significantly lower at month 6 after commencing ART compared to baseline (p<0.0001).Conclusions
Among patients with advanced HIV disease, elevated pre-ART levels of hsCRP, IL-6 and D-dimer are strongly associated with early mortality after commencing ART. Elevated levels of inflammatory and coagulation biomarkers may identify patients who may benefit from aggressive clinical monitoring after commencing ART. Further investigation of strategies to reduce biomarkers of inflammation and coagulation in patients with advanced HIV disease is warranted.Trial Registration
Parent Study: ClinicalTrials.gov NCT00342355相似文献13.
Tripathi SC Matta A Kaur J Grigull J Chauhan SS Thakar A Shukla NK Duggal R Choudhary AR Dattagupta S Sharma MC Ralhan R Siu KW 《PloS one》2011,6(5):e19213
Background
In our recent study, tissue proteomic analysis of oral pre-malignant lesions (OPLs) and normal oral mucosa led to the identification of a panel of biomarkers, including prothymosin alpha (PTMA), to distinguish OPLs from histologically normal oral tissues. This study aimed to determine the clinical significance of PTMA overexpression in oral squamous cell hyperplasia, dysplasia and head and neck squamous cell carcinoma (HNSCC).Methodology
Immunohistochemistry of PTMA protein was performed in HNSCCs (n = 100), squamous cell hyperplasia (n = 116), dysplasia (n = 50) and histologically normal oral tissues (n = 100). Statistical analysis was carried out to determine the association of PTMA overexpression with clinicopathological parameters and disease prognosis over 7 years for HNSCC patients.Results
Our immunohistochemical analysis demonstrated significant overexpression of nuclear PTMA in squamous cell hyperplasia (63.8%), dysplasia (50%) and HNSCC (61%) in comparison with oral normal mucosa (ptrend<0.001). Chi-square analysis showed significant association of nuclear PTMA with advanced tumor stages (III+IV). Kaplan Meier survival analysis indicated reduced disease free survival (DFS) in HNSCC patients (p<0.001; median survival 11 months). Notably, Cox-multivariate analysis revealed nuclear PTMA as an independent predictor of poor prognosis of HNSCC patients (p<0.001, Hazard''s ratio, HR = 5.2, 95% CI = 2.3–11.8) in comparison with the histological grade, T-stage, nodal status and tumor stage.Conclusions
Nuclear PTMA may serve as prognostic marker in HNSCC to determine the subset of patients that are likely to show recurrence of the disease. 相似文献14.
Ponce J Calvet X Gallach M Ponce M;Esophagitis Study Group of the Asociación Española de Gastroenterología 《PloS one》2011,6(10):e25051
Background
Few data are available on the prevalence of erosive and severe esophagitis in Western countries.Objective
To retrospectively determine the prevalence and the factors predicting erosive esophagitis and severe esophagitis in a large series of endoscopies in Spain.Design
Retrospective observational study. A multivariate analysis was performed to determine variables predicting severe esophagitis.Setting
Databases of 29 Spanish endoscopy units.Patients
Patients submitted to a diagnostic endoscopy during the year 2005.Interventions
Retrospective review of the databases.Main Outcome Measurements
Esophagitis severity (graded according to the Los Angeles classification) and associated endoscopic findings.Results
Esophagitis was observed in 8.7% of the 93,699 endoscopies reviewed. Severe esophagitis (LA grade C or D) accounted for 22.5% of cases of the disease and was found in 1.9% of all endoscopies. Incidences of esophagitis and those of severe esophagitis were 86.2 and 18.7 cases per 100,000 inhabitants per year respectively. Male sex (OR 1.89) and advanced age (OR 4.2 for patients in the fourth age quartile) were the only variables associated with severe esophagitis. Associated peptic ulcer was present in 8.8% of cases.Limitations
Retrospective study, no data on individual proton pump inhibitors use.Conclusions
Severe esophagitis is an infrequent finding in Spain. It occurs predominantly in males and in older individuals. Peptic ulcer disease is frequently associated with erosive esophagitis. 相似文献15.
16.
Background
Knowledge of sedentary behaviour associations with health has relied mainly on television-viewing as a proxy and studies with other measures are less common. To clarify whether sedentary behaviour is associated with disease-risk, we examined associations for television-viewing and sitting at work.Methods
Using the 1958 British birth cohort (n = 7660), we analysed cross-sectional associations between television-viewing and work sitting (four categories, 0–1 to ≥3 h/d) with total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL)-cholesterol, triglycerides, blood pressure, glycated haemoglobin, fibrinogen, C-reactive protein, hypertension and metabolic syndrome at 45 y. We adjusted for lifestyle and socio-demographic factors and assessed mediation of associations by body mass index (BMI) and diet. We also assessed whether the sedentary indicators are related similarly to factors linked to disease-risk.Results
There was a general trend of adverse socio-demographic and lifestyle characteristics with higher h/d television-viewing, but trends in the opposite direction for work sitting. Television-viewing was associated with most biomarkers and associations were mediated by BMI: e.g. for each category increase in television-viewing, HDL-cholesterol in men was lower by 2.3% (95% CI: 1.5%, 3.2%) and, in BMI and diet adjusted analyses, by 1.6% (0.8%, 2.4%); for women, by 2.0% (1.2%, 2.9%) and 0.9% (0.1%, 1.6%) respectively. Few, weaker associations for work sitting were found, in men only: e.g. corresponding values for HDL-cholesterol were 1.2% (0.5%, 1.9%) and 0.9% (0.3%, 1.5%). Odds for metabolic syndrome were elevated by 82% and 33% respectively for men watching television or work sitting for ≥3 vs. 0–1 h/d.Conclusions
Associations with cardiovascular disease and diabetes biomarkers in mid-adulthood differed for television-viewing and work sitting. The role of sedentary behaviour may vary by leisure and work domains or the two indicators reflect differing associations with other disease-related influences. 相似文献17.
Jahn H Wittke S Zürbig P Raedler TJ Arlt S Kellmann M Mullen W Eichenlaub M Mischak H Wiedemann K 《PloS one》2011,6(10):e26540
Background
Today, dementias are diagnosed late in the course of disease. Future treatments have to start earlier in the disease process to avoid disability requiring new diagnostic tools. The objective of this study is to develop a new method for the differential diagnosis and identification of new biomarkers of Alzheimer''s disease (AD) using capillary-electrophoresis coupled to mass-spectrometry (CE-MS) and to assess the potential of early diagnosis of AD.Methods and Findings
Cerebrospinal fluid (CSF) of 159 out-patients of a memory-clinic at a University Hospital suffering from neurodegenerative disorders and 17 cognitively-healthy controls was used to create differential peptide pattern for dementias and prospective blinded-comparison of sensitivity and specificity for AD diagnosis against the Criterion standard in a naturalistic prospective sample of patients. Sensitivity and specificity of the new method compared to standard diagnostic procedures and identification of new putative biomarkers for AD was the main outcome measure. CE-MS was used to reliably detect 1104 low-molecular-weight peptides in CSF. Training-sets of patients with clinically secured sporadic Alzheimer''s disease, frontotemporal dementia, and cognitively healthy controls allowed establishing discriminative biomarker pattern for diagnosis of AD. This pattern was already detectable in patients with mild cognitive impairment (MCI). The AD-pattern was tested in a prospective sample of patients (n = 100) and AD was diagnosed with a sensitivity of 87% and a specificity of 83%. Using CSF measurements of beta-amyloid1-42, total-tau, and phospho181-tau, AD-diagnosis had a sensitivity of 88% and a specificity of 67% in the same sample. Sequence analysis of the discriminating biomarkers identified fragments of synaptic proteins like proSAAS, apolipoprotein J, neurosecretory protein VGF, phospholemman, and chromogranin A.Conclusions
The method may allow early differential diagnosis of various dementias using specific peptide fingerprints and identification of incipient AD in patients suffering from MCI. Identified biomarkers facilitate face validity for the use in AD diagnosis. 相似文献18.
Wan XB Zhao Y Fan XJ Cai HM Zhang Y Chen MY Xu J Wu XY Li HB Zeng YX Hong MH Liu Q 《PloS one》2012,7(3):e31989
Background
Accurate prognostication of locally advanced nasopharyngeal carcinoma (NPC) will benefit patients for tailored therapy. Here, we addressed this issue by developing a mathematical algorithm based on support vector machine (SVM) through integrating the expression levels of multi-biomarkers.Methodology/Principal Findings
Ninety-seven locally advanced NPC patients in a randomized controlled trial (RCT), consisting of 48 cases serving as training set and 49 cases as testing set of SVM models, with 5-year follow-up were studied. We designed SVM models by selecting the variables from 38 tissue molecular biomarkers, which represent 6 tumorigenesis signaling pathways, and 3 EBV-related serological biomarkers. We designed 3 SVM models to refine prognosis of NPC with 5-year follow-up. The SVM1 displayed highly predictive sensitivity (sensitivity, specificity were 88.0% and 81.9%, respectively) by integrating the expression of 7 molecular biomarkers. The SVM2 model showed highly predictive specificity (sensitivity, specificity were 84.0% and 94.5%, respectively) by grouping the expression level of 12 molecular biomarkers and 3 EBV-related serological biomarkers. The SVM3 model, constructed by combination SVM1 with SVM2, displayed a high predictive capacity (sensitivity, specificity were 88.0% and 90.3%, respectively). We found that 3 SVM models had strong power in classification of prognosis. Moreover, Cox multivariate regression analysis confirmed these 3 SVM models were all the significant independent prognostic model for overall survival in testing set and overall patients.Conclusions/Significance
Our SVM prognostic models designed in the RCT displayed strong power in refining patient prognosis for locally advanced NPC, potentially directing future target therapy against the related signaling pathways. 相似文献19.
Introduction
In experimental models of West Nile virus (WNV) infection, animals develop chronic kidney infection with histopathological changes in the kidney up to 8-months post-infection. However, the long term pathologic effects of acute infection in humans are largely unknown. The purpose of this study was to assess renal outcomes following WNV infection, specifically the development of chronic kidney disease (CKD).Methods
In a cohort of 139 study participants with a previous diagnosis of WNV infection, we investigated the prevalence of CKD using the Kidney Disease Outcomes Quality Initiative (KDOQI) criteria based on the Modification of Diet in Renal Disease (MDRD) formula and urinary abnormalities, and assessed various risk factors and biomarkers.Results
Study participants were primarily male (60%) and non-Hispanic white (86%) with a mean age of 57 years. Most (83%) were four to nine years post-infection at the time of this study. Based on the KDOQI definition, 40% of participants had evidence of CKD, with 10% having Stage III or greater and 30% having Stage I–II. By urinary dipstick testing, 26% of patients had proteinuria and 23% had hematuria. Plasma NGAL levels were elevated in 14% of participants while MCP-1 levels were increased in 12%. Over 1.5 years, the average change in eGFR was −3.71 mL/min/1.73 m2. Only a history of Neuroinvasive WNV disease was independently associated with CKD following multivariate analysis.Discussion
We found a high prevalence of CKD after long term follow-up in a cohort of participants previously infected with WNV. The majority of those with CKD are in Stage I-II indicating early stages of renal disease. Traditional risk factors were not associated with the presence of CKD in this population. Therefore, clinicians should regularly evaluate all patients with a history of WNV for evidence of CKD. 相似文献20.
Edmond K Scott S Korczak V Ward C Sanderson C Theodoratou E Clark A Griffiths U Rudan I Campbell H 《PloS one》2012,7(2):e31239