Whole Exome Analysis of Early Onset Alzheimer’s Disease

DTIC Science & Technology

2016-04-01

Early Onset Alzheimer’s Disease 5a. CONTRACT NUMBER W81XWH-12-1-0013 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR( S ) Margaret A. Pericak...relationship between SORL1, AD, and Parkinsonism . 16 Appendix V: ABCA7 Frameshift Deletion Associated with Alzheimer’s Disease in African Americans...onset Alzheimer disease identified using whole-exome sequencing G. W. Beecham1, B. W. Kunkle1, B. Vardarajan2, P. L. Whitehead1, S . Rolati1, E. R

Converging approaches to understanding early onset familial Alzheimer disease: A First Nation study

PubMed Central

Cabrera, Laura Y; Beattie, B Lynn; Dwosh, Emily; Illes, Judy

2015-01-01

Objectives: In 2007, a novel pathogenic genetic mutation associated with early onset familial Alzheimer disease was identified in a large First Nation family living in communities across British Columbia, Canada. Building on a community-based participatory study with members of the Nation, we sought to explore the impact and interplay of medicalization with the Nation’s knowledge and approaches to wellness in relation to early onset familial Alzheimer disease. Methods: We performed a secondary content analysis of focus group discussions and interviews with 48 members of the Nation between 2012 and 2013. The analysis focused specifically on geneticization, medicalization, and traditional knowledge of early onset familial Alzheimer disease, as these themes were prominent in the primary analysis. Results: We found that while biomedical explanations of disease permeate the knowledge and understanding of early onset familial Alzheimer disease, traditional concepts about wellness are upheld simultaneously. Conclusion: The analysis brings the theoretical framework of “two-eyed seeing” to the case of early onset familial Alzheimer disease for which the contributions of different ways of knowing are embraced, and in which traditional and western ways complement each other on the path of maintaining wellness in the face of progressive neurologic disease. PMID:27092264

Early Menopause Predicts Future Coronary Heart Disease and Stroke: The Multi-Ethnic Study of Atherosclerosis (MESA)

PubMed Central

Wellons, Melissa; Ouyang, Pamela; Schreiner, Pamela J; Herrington, David M; Vaidya, Dhananjay

2012-01-01

Objective Cardiovascular disease is the number one killer of women. Identifying women at risk of cardiovascular disease has tremendous public health importance. Early menopause is associated with increased cardiovascular disease events in some predominantly white populations, but not consistently. Our objective was to determine if a self-reported early menopause (menopause at an age <46) identifies women as at risk for future coronary heart disease or stroke. Methods The study population came from the Multi-Ethnic Study of Atherosclerosis, a longitudinal, ethnically diverse cohort study of US men and women aged 45 to 84 years enrolled in 2000–2002 and followed up until 2008. The association between a personal history of early menopause (either natural menopause or surgical removal of ovaries at an age <46) and future coronary heart disease and stroke was assessed in 2509 women (ages 45–84, 987 White, 331 Chinese, 641 Black, 550 Hispanic) from the Multi-Ethnic Study Atherosclerosis, who were free of cardiovascular disease at baseline. Results 693/2509 (28%) of women reported either surgical or natural early menopause. In survival curves, women with early menopause had worse coronary heart disease and stroke-free survival (log rank p=<0.008 and 0.0158). In models adjusted for age, race/ethnicity, Multi-Ethnic Study Atherosclerosis site and traditional cardiovascular disease risk factors, this risk for coronary heart disease and stroke remained (HR 2.08, 95% CI 1.17, 3.70 and 2.19, 95% CI 1.11, 4.32, respectively). Conclusions Early menopause is positively associated with coronary heart disease and stroke in a multiethnic cohort, independent of traditional cardiovascular disease risk factors. PMID:22692332

Identifying Future Disease Hot Spots: Infectious Disease Vulnerability Index.

PubMed

Moore, Melinda; Gelfeld, Bill; Okunogbe, Adeyemi; Paul, Christopher

2017-06-01

Recent high-profile outbreaks, such as Ebola and Zika, have illustrated the transnational nature of infectious diseases. Countries that are most vulnerable to such outbreaks might be higher priorities for technical support. RAND created the Infectious Disease Vulnerability Index to help U.S. government and international agencies identify these countries and thereby inform programming to preemptively help mitigate the spread and effects of potential transnational outbreaks. The authors employed a rigorous methodology to identify the countries most vulnerable to disease outbreaks. They conducted a comprehensive review of relevant literature to identify factors influencing infectious disease vulnerability. Using widely available data, the authors created an index for identifying potentially vulnerable countries and then ranked countries by overall vulnerability score. Policymakers should focus on the 25 most-vulnerable countries with an eye toward a potential "disease belt" in the Sahel region of Africa. The infectious disease vulnerability scores for several countries were better than what would have been predicted on the basis of economic status alone. This suggests that low-income countries can overcome economic challenges and become more resilient to public health challenges, such as infectious disease outbreaks.

Disease evolution in late-onset and early-onset systemic lupus erythematosus.

PubMed

Aljohani, R; Gladman, D D; Su, J; Urowitz, M B

2017-10-01

Objective The objective of this study was to compare clinical features, disease activity, and outcome in late-onset versus early-onset systemic lupus erythematosus (SLE) over 5 years of follow up Method Patients with SLE since 1970 were followed prospectively according to standard protocol and tracked on a computerized database. Patients entering the cohort within one year of diagnosis constitute the inception cohort. Patients with late-onset (age at diagnosis ≥50) disease were identified and matched 1:2 based on gender and first clinic visit (±5) years with patients with early-onset disease (age at diagnosis 18-40 years). Results A total of 86 patients with late-onset disease (84.9% female, 81.4% Caucasian, mean age at SLE diagnosis ± SD 58.05 ± 7.30) and 169 patients with early-onset disease (86.4% female, 71% Caucasian, mean age at SLE diagnosis ± SD 27.80 ± 5.90) were identified. At enrollment, late-onset SLE patients had a lower total number of American College of Rheumatology (ACR) criteria, with less renal and neurologic manifestations. Mean SLE Disease Activity Index 2000 (SLEDAI-2K) scores were lower in late-onset SLE, especially renal features and anti-dsDNA positivity. Over 5 years, mean SLEDAI-2K scores decreased in both groups, while mean Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI) scores increased more significantly in the late-onset group; they developed more cardiovascular, renal, and ocular damage, and had higher prevalence of cardiovascular risk factors. Conclusion Although the late-onset SLE group had a milder presentation and less active disease, with the evolution of disease, they developed more organ damage likely as a consequence of cardiovascular risk factors and aging.

Multi-Domain Transfer Learning for Early Diagnosis of Alzheimer's Disease.

PubMed

Cheng, Bo; Liu, Mingxia; Shen, Dinggang; Li, Zuoyong; Zhang, Daoqiang

2017-04-01

Recently, transfer learning has been successfully applied in early diagnosis of Alzheimer's Disease (AD) based on multi-domain data. However, most of existing methods only use data from a single auxiliary domain, and thus cannot utilize the intrinsic useful correlation information from multiple domains. Accordingly, in this paper, we consider the joint learning of tasks in multi-auxiliary domains and the target domain, and propose a novel Multi-Domain Transfer Learning (MDTL) framework for early diagnosis of AD. Specifically, the proposed MDTL framework consists of two key components: 1) a multi-domain transfer feature selection (MDTFS) model that selects the most informative feature subset from multi-domain data, and 2) a multi-domain transfer classification (MDTC) model that can identify disease status for early AD detection. We evaluate our method on 807 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database using baseline magnetic resonance imaging (MRI) data. The experimental results show that the proposed MDTL method can effectively utilize multi-auxiliary domain data for improving the learning performance in the target domain, compared with several state-of-the-art methods.

Identifying Candidate Chemical-Disease Linkages ...

EPA Pesticide Factsheets

Presentation at meeting on Environmental and Epigenetic Determinants of IBD in New York, NY on identifying candidate chemical-disease linkages by using AOPs to identify molecular initiating events and using relevant high throughput assays to screen for candidate chemicals. This hazard information is combined with exposure models to inform risk assessment. Presentation at meeting on Environmental and Epigenetic Determinants of IBD in New York, NY on identifying candidate chemical-disease linkages by using AOPs to identify molecular initiating events and using relevant high throughput assays to screen for candidate chemicals. This hazard information is combined with exposure models to inform risk assessment.

Early detection of Alzheimer disease: methods, markers, and misgivings.

PubMed

Green, R C; Clarke, V C; Thompson, N J; Woodard, J L; Letz, R

1997-01-01

There is at present no reliable predictive test for most forms of Alzheimer disease (AD). Although some information about future risk for disease is available in theory through ApoE genotyping, it is of limited accuracy and utility. Once neuroprotective treatments are available for AD, reliable early detection will become a key component of the treatment strategy. We recently conducted a pilot survey eliciting attitudes and beliefs toward an unspecified and hypothetical predictive test for AD. The survey was completed by a convenience sample of 176 individuals, aged 22-77, which was 75% female, 30% African-American, and of which 33% had a family member with AD. The survey revealed that 69% of this sample would elect to obtain predictive testing for AD if the test were 100% accurate. Individuals were more likely to desire predictive testing if they had an a priori belief that they would develop AD (p = 0.0001), had a lower educational level (p = 0.003), were worried that they would develop AD (p = 0.02), had a self-defined history of depression (p = 0.04), and had a family member with AD (p = 0.04). However, the desire for predictive testing was not significantly associated with age, gender, ethnicity, or income. The desire to obtain predictive testing for AD decreased as the assumed accuracy of the hypothetical test decreased. A better short-term strategy for early detection of AD may be computer-based neuropsychological screening of at-risk (older aged) individuals to identify very early cognitive impairment. Individuals identified in this manner could be referred for diagnostic evaluation and early cases of AD could be identified and treated. A new self-administered, touch-screen, computer-based, neuropsychological screening instrument called Neurobehavioral Evaluation System-3 is described, which may facilitate this type of screening.

Kidney Disease: Early Detection and Treatment

MedlinePlus

... Bar Home Current Issue Past Issues Special Section Kidney Disease: Early Detection and Treatment Past Issues / Winter ... called a "urine albumin-to-creatinine ratio." Treating Kidney Disease Kidney disease is usually a progressive disease, ...

SU-F-R-24: Identifying Prognostic Imaging Biomarkers in Early Stage Lung Cancer Using Radiomics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zeng, X; Wu, J; Cui, Y

2016-06-15

Purpose: Patients diagnosed with early stage lung cancer have favorable outcomes when treated with surgery or stereotactic radiotherapy. However, a significant proportion (∼20%) of patients will develop metastatic disease and eventually die of the disease. The purpose of this work is to identify quantitative imaging biomarkers from CT for predicting overall survival in early stage lung cancer. Methods: In this institutional review board-approved HIPPA-compliant retrospective study, we retrospectively analyzed the diagnostic CT scans of 110 patients with early stage lung cancer. Data from 70 patients were used for training/discovery purposes, while those of remaining 40 patients were used for independentmore » validation. We extracted 191 radiomic features, including statistical, histogram, morphological, and texture features. Cox proportional hazard regression model, coupled with the least absolute shrinkage and selection operator (LASSO), was used to predict overall survival based on the radiomic features. Results: The optimal prognostic model included three image features from the Law’s feature and wavelet texture. In the discovery cohort, this model achieved a concordance index or CI=0.67, and it separated the low-risk from high-risk groups in predicting overall survival (hazard ratio=2.72, log-rank p=0.007). In the independent validation cohort, this radiomic signature achieved a CI=0.62, and significantly stratified the low-risk and high-risk groups in terms of overall survival (hazard ratio=2.20, log-rank p=0.042). Conclusion: We identified CT imaging characteristics associated with overall survival in early stage lung cancer. If prospectively validated, this could potentially help identify high-risk patients who might benefit from adjuvant systemic therapy.« less

Development of a Multiantigen Panel for Improved Detection of Borrelia burgdorferi Infection in Early Lyme Disease

PubMed Central

Panas, Michael W.; Mao, Rong; Delanoy, Michelle; Flanagan, John J.; Binder, Steven R.; Rebman, Alison W.; Montoya, Jose G.; Soloski, Mark J.; Steere, Allen C.; Dattwyler, Raymond J.; Arnaboldi, Paul M.; Aucott, John N.

2015-01-01

The current standard for laboratory diagnosis of Lyme disease in the United States is serologic detection of antibodies against Borrelia burgdorferi. The Centers for Disease Control and Prevention recommends a two-tiered testing algorithm; however, this scheme has limited sensitivity for detecting early Lyme disease. Thus, there is a need to improve diagnostics for Lyme disease at the early stage, when antibiotic treatment is highly efficacious. We examined novel and established antigen markers to develop a multiplex panel that identifies early infection using the combined sensitivity of multiple markers while simultaneously maintaining high specificity by requiring positive results for two markers to designate a positive test. Ten markers were selected from our initial analysis of 62 B. burgdorferi surface proteins and synthetic peptides by assessing binding of IgG and IgM to each in a training set of Lyme disease patient samples and controls. In a validation set, this 10-antigen panel identified a higher proportion of early-Lyme-disease patients as positive at the baseline or posttreatment visit than two-tiered testing (87.5% and 67.5%, respectively; P < 0.05). Equivalent specificities of 100% were observed in 26 healthy controls. Upon further analysis, positivity on the novel 10-antigen panel was associated with longer illness duration and multiple erythema migrans. The improved sensitivity and comparable specificity of our 10-antigen panel compared to two-tiered testing in detecting early B. burgdorferi infection indicates that multiplex analysis, featuring the next generation of markers, could advance diagnostic technology to better aid clinicians in diagnosing and treating early Lyme disease. PMID:26447113

Identifying Unstable Regions of Proteins Involved in Misfolding Diseases

NASA Astrophysics Data System (ADS)

Guest, Will; Cashman, Neil; Plotkin, Steven

2009-05-01

Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and all-atoms molecular dynamics. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

[Mutations of amyloid precursor protein in early-onset familial Alzheimer's disease].

PubMed

Naruse, S; Tsuji, S; Miyatake, T

1992-09-01

Genetic linkage studies of familial Alzheimer's disease (FAD) have suggested that some form of early-onset FAD is linked to proximal long arm of chromosome 21. It has been also suggested that some form of late-onset FAD is linked to long arm of chromosome 19. Goate et al have identified a mis-sense mutation (Val to Ile) in exon 17 of the amyloid precursor protein (APP) gene in 2 of 16 early-onset FAD families, and have shown that the FAD locus in an FAD family is tightly linked to the mis-sense mutation. To determine if the mis-sense mutation is observed in different ethnic origine, we have studied some early-onset FAD families. Two early-onset FAD families showed the existence of the mutation. As the mutation has been identified in different ethnic origine and the mutation has not been observed in normal individuals, it strengthen hypothesis that the mutation is pathogenic. Recently, Val to Phe and Val to Gly mutations have been also identified at the same codon (Codon 717) of the APP gene.

Spatiotemporal proteomic analyses during pancreas cancer progression identifies serine/threonine stress kinase 4 (STK4) as a novel candidate biomarker for early stage disease.

PubMed

Mirus, Justin E; Zhang, Yuzheng; Hollingsworth, Michael A; Solan, Joell L; Lampe, Paul D; Hingorani, Sunil R

2014-12-01

Pancreas cancer, or pancreatic ductal adenocarcinoma, is the deadliest of solid tumors, with a five-year survival rate of <5%. Detection of resectable disease improves survival rates, but access to tissue and other biospecimens that could be used to develop early detection markers is confounded by the insidious nature of pancreas cancer. Mouse models that accurately recapitulate the human condition allow disease tracking from inception to invasion and can therefore be useful for studying early disease stages in which surgical resection is possible. Using a highly faithful mouse model of pancreas cancer in conjunction with a high-density antibody microarray containing ∼2500 antibodies, we interrogated the pancreatic tissue proteome at preinvasive and invasive stages of disease. The goal was to discover early stage tissue markers of pancreas cancer and follow them through histologically defined stages of disease using cohorts of mice lacking overt clinical signs and symptoms and those with end-stage metastatic disease, respectively. A panel of seven up-regulated proteins distinguishing pancreas cancer from normal pancreas was validated, and their levels were assessed in tissues collected at preinvasive, early invasive, and moribund stages of disease. Six of the seven markers also differentiated pancreas cancer from an experimental model of chronic pancreatitis. The levels of serine/threonine stress kinase 4 (STK4) increased between preinvasive and invasive stages, suggesting its potential as a tissue biomarker, and perhaps its involvement in progression from precursor pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma. Immunohistochemistry of STK4 at different stages of disease revealed a dynamic expression pattern further implicating it in early tumorigenic events. Immunohistochemistry of a panel of human pancreas cancers confirmed that STK4 levels were increased in tumor epithelia relative to normal tissue. Overall, this integrated approach

Byler disease: early natural history.

PubMed

Morris, Amy L; Bukauskas, Kathryn; Sada, Rachel E; Shneider, Benjamin L

2015-04-01

Byler disease, originally described in Amish kindred, results from mutations in ATPase Class I Type 8b Member 1 (ATP8b1). Specific clinical reports of Amish Byler disease were last published 40 years ago. These investigations were directed at the present detailed clinical understanding of the early course of hepatic manifestations of Byler disease. This study analyzed routine clinical practice and outcomes of children with Byler disease (defined by homozygous c.923G>T mutation in ATP8b1), who initially presented to Children's Hospital of Pittsburgh of UPMC between January 2007 and October 2014. Data were analyzed to the earlier of 24 months of age or partial external biliary diversion. Six children presented between 1 and 135 days of life: 2 presented with newborn direct hyperbilirubinemia, 2 had complications of coagulopathy, 1 had failure to thrive and rickets, and 1 sibling was identified by newborn genetic testing. Intensive fat-soluble vitamin supplementation was required to prevent insufficiencies in vitamins D, E, and K. Hyperbilirubinemia was variable both over time and between children. Serum bile acid levels were elevated, whereas γ-glutamyltranspeptidase levels were low normal. Scratching behavior (pruritus) was intractable in 4 of 6 children with onset between 6 and 12 months of age. Features of portal hypertension were not observed. Partial external biliary diversion was used during the second year of life in 4 children. Detailed analysis of Byler disease revealed varied disease presentation and course. Nutritional issues and pruritus dominated the clinical picture in the first 2 years of life.

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease.

PubMed

Chaudhury, Sultan; Patel, Tulsi; Barber, Imelda S; Guetta-Baranes, Tamar; Brookes, Keeley J; Chappell, Sally; Turton, James; Guerreiro, Rita; Bras, Jose; Hernandez, Dena; Singleton, Andrew; Hardy, John; Mann, David; Morgan, Kevin

2018-02-01

Sporadic early-onset Alzheimer's disease (sEOAD) exhibits the symptoms of late-onset Alzheimer's disease but lacks the familial aspect of the early-onset familial form. The genetics of Alzheimer's disease (AD) identifies APOEε4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRSs) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases was genotyped on the NeuroX array, and PRSs were generated using PRSice. The target data set consisted of 408 sEOAD cases and 436 controls. The base data set was collated by the International Genomics of Alzheimer's Project consortium, with association data from 17,008 late-onset Alzheimer's disease cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRSs were generated using all common single nucleotide polymorphisms between the base and target data set, PRS were also generated using only single nucleotide polymorphisms within a 500 kb region surrounding the APOE gene. Sex and number of APOE ε2 or ε4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap among the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy. Copyright © 2017 Elsevier Inc. All rights reserved.

Endoscopic fluorescence imaging for early assessment of anastomotic recurrence of Crohn's disease

NASA Astrophysics Data System (ADS)

Mordon, Serge R.; Maunoury, Vincent; Geboes, K.; Klein, Olivier; Desreumaux, P.; Debaert, A.; Colombel, Jean-Frederic

1999-02-01

Crohn's disease is an inflammatory bowel disease of unknown etiology. The mechanism of the initial mucosal alterations is still unclear: ulcerations overlying lymphoid follicles and/or vasculitis have been proposed as the early lesions. We have developed a new and original method combining endoscopy of fluorescence angiography for identifying the early pathological lesions, occurring in the neo-terminal ileum after right ileocolonic resection. The patient population consisted of 10 subjects enrolled in a prospective protocol of endoscopic follow-up at 3 and 12 months after surgery. Fluorescence imaging showed small spots giving a bright fluorescence distributed singly in mucosa which appeared normal in routine endoscopy. Histopathological examination demonstrated that the fluorescence of small spots originated from small, usually superficial, erosive lesions. In several cases, these erosive lesions occurred over lymphoid follicles. Endoscopic fluorescence imaging provides a suitable means of investigating the initial aspect of the Crohn's disease process in displaying some correlative findings between fluorescent aspects and early pathological mucosal alterations.

The reorganization of functional architecture in the early-stages of Parkinson's disease.

PubMed

Tuovinen, Noora; Seppi, Klaus; de Pasquale, Francesco; Müller, Christoph; Nocker, Michael; Schocke, Michael; Gizewski, Elke R; Kremser, Christian; Wenning, Gregor K; Poewe, Werner; Djamshidian, Atbin; Scherfler, Christoph; Seki, Morinobu

2018-05-01

The study aim was to identify longitudinal abnormalities of functional connectivity and its relation with motor disability in early to moderately advanced stages of Parkinson's disease patients. 3.0T structural and resting-state functional MRI was performed in healthy subjects (n = 16) and Parkinson's disease patients (n = 16) with mean disease duration of 2.2 ± 1.2 years at baseline with a clinical follow-up of 1.5 ± 0.3 years. Resting-state fMRI analysis included region-to-region connectivity in correlation with UPDRS-III scores and computation of Global Efficiency and Degree Centrality. At baseline, patients' connectivity increased between the cerebellum and somatomotor network, and decreased between motor regions (Rolandic operculum, precentral gyrus, supplementary motor area, postcentral gyrus) and cingulate connectivity. At 1.5 years follow-up, connectivity remained altered in the same regions identified at baseline. The cerebellum showed additional hyperconnectivity within itself and to the caudate nucleus, thalamus and amygdala compared to controls. These differences correlated with UPDRS-III scores. Seed-based connectivity revealed increased involvement of the default mode network with precentral gyrus in patients at follow-up investigation. Resting-state fMRI identified marked disturbances of the overall architecture of connectivity in Parkinson's disease. The noted alterations in cortical motor areas were associated with cerebellar hyperconnectivity in early to moderately advanced stages of Parkinson's disease suggesting ongoing attempts of recovery and compensatory mechanism for affected functions. The potential to identify connectivity alterations in regions related to both motor and attentional functions requires further evaluation as an objective marker to monitor disease progression, and medical, as well as surgical interventions. Copyright © 2018 Elsevier Ltd. All rights reserved.

Proteomic profiling in MPTP monkey model for early Parkinson disease biomarker discovery

PubMed Central

Lin, Xiangmin; Shi, Min; Gunasingh Masilamoni, Jeyaraj; Dator, Romel; Movius, James; Aro, Patrick; Smith, Yoland; Zhang, Jing

2015-01-01

Identification of reliable and robust biomarkers is crucial to enable early diagnosis of Parkinson disease (PD) and monitoring disease progression. While imperfect, the slow, chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced non-human primate animal model system of parkinsonism is an abundant source of pre-motor or early stage PD biomarker discovery. Here, we present a study of a MPTP rhesus monkey model of PD that utilizes complementary quantitative iTRAQ-based proteomic, glycoproteomics and phosphoproteomics approaches. We compared the glycoprotein, non-glycoprotein, and phosphoprotein profiles in the putamen of asymptomatic and symptomatic MPTP-treated monkeys as well as saline injected controls. We identified 86 glycoproteins, 163 non-glycoproteins, and 71 phosphoproteins differentially expressed in the MPTP-treated groups. Functional analysis of the data sets inferred the biological processes and pathways that link to neurodegeneration in PD and related disorders. Several potential biomarkers identified in this study have already been translated for their usefulness in PD diagnosis in human subjects and further validation investigations are currently under way. In addition to providing potential early PD biomarkers, this comprehensive quantitative proteomic study may also shed insights regarding the mechanisms underlying early PD development. This article is part of a Special Issue entitled: Neuroproteomics: Applications in neuroscience and neurology. PMID:25617661

Unusual early-onset Huntingtons disease.

PubMed

Vargas, Antonio P; Carod-Artal, Francisco J; Bomfim, Denise; Vázquez-Cabrera, Carolina; Dantas-Barbosa, Carmela

2003-06-01

Huntington's disease is an autosomal dominant progressive neurodegenerative disorder characterized by involuntary movements, cognitive decline, and behavioral disorders leading to functional disability. In contrast to patients with adult onset, in which chorea is the major motor abnormality, children often present with spasticity, rigidity, and significant intellectual decline associated with a more rapidly progressive course. An unusual early-onset Huntington's disease case of an 11-year-old boy with severe hypokinetic/rigid syndrome appearing at the age of 2.5 years is presented. Clinical diagnosis was confirmed by polymerase chain reaction study of the expanded IT-15 allele with a compatible size of 102 cytosine-adenosine-guanosine repeats L-Dopa mildly ameliorated rigidity, bradykinesia, and dystonia. We conclude that Huntington's disease should be included in the differential diagnoses of regressive syndromes of early childhood.

Gene-environment interaction in atopic diseases: a population-based twin study of early-life exposures.

PubMed

Kahr, Niklas; Naeser, Vibeke; Stensballe, Lone Graff; Kyvik, Kirsten Ohm; Skytthe, Axel; Backer, Vibeke; Bønnelykke, Klaus; Thomsen, Simon Francis

2015-01-01

The development of atopic diseases early in life suggests an important role of perinatal risk factors. To study whether early-life exposures modify the genetic influence on atopic diseases in a twin population. Questionnaire data on atopic diseases from 850 monozygotic and 2279 like-sex dizygotic twin pairs, 3-9 years of age, from the Danish Twin Registry were cross-linked with data on prematurity, Cesarean section, maternal age at birth, parental cohabitation, season of birth and maternal smoking during pregnancy, from the Danish National Birth Registry. Significant predictors of atopic diseases were identified with logistic regression and subsequently tested for genetic effect modification using variance components analysis. After multivariable adjustment, prematurity (gestational age below 32 weeks) [odds ratio (OR) = 1.93, confidence interval (CI) = 1.45-2.56], Cesarean section (OR = 1.25, CI = 1.05-1.49) and maternal smoking during pregnancy (OR = 1.70, CI = 1.42-2.04) significantly influenced the risk of asthma, whereas none of the factors were significantly associated with atopic dermatitis and hay fever. Variance components analysis stratified by exposure status showed no significant change in the heritability of asthma according to the identified risk factors. In this population-based study of children, there was no evidence of genetic effect modification of atopic diseases by several identified early-life risk factors. The causal relationship between these risk factors and atopic diseases may therefore be mediated via mechanisms different from gene-environment interaction. © 2014 John Wiley & Sons Ltd.

Psychometric evaluation of a new instrument to measure disease self-management of the early stage chronic kidney disease patients.

PubMed

Lin, Chiu-Chu; Wu, Chia-Chen; Wu, Li-Min; Chen, Hsing-Mei; Chang, Shu-Chen

2013-04-01

This study aims to develop a valid and reliable chronic kidney disease self-management instrument (CKD-SM) for assessing early stage chronic kidney disease patients' self-management behaviours. Enhancing early stage chronic kidney disease patients' self-management plays a key role in delaying the progression of chronic kidney disease. Healthcare provider understanding of early stage chronic kidney disease patients' self-management behaviours can help develop effective interventions. A valid and reliable instrument for measuring chronic kidney disease patients' self-management behaviours is needed. A cross-sectional descriptive study collected data for principal components analysis with oblique rotation. Mandarin- or Taiwanese-speaking adults with chronic kidney disease (n=252) from two medical centres and one regional hospital in Southern Taiwan completed the CKD-SM. Construct validity was evaluated by exploratory factor analysis. Internal consistency and test-retest reliability were estimated by Cronbach's alpha and Pearson correlation coefficients. Four factors were extracted and labelled self-integration, problem-solving, seeking social support and adherence to recommended regimen. The four factors accounted for 60.51% of the total variance. Each factor showed acceptable internal reliability with Cronbach's alpha from 0.77-0.92. The test-retest correlations for the CKD-SM was 0.72. The psychometric quality of the CKD-SM instrument was satisfactory. Research to conduct a confirmatory factor analysis to further validate this new instrument's construct validity is recommended. The CKD-SM instrument is useful for clinicians who wish to identify the problems with self-management among chronic kidney disease patients early. Self-management assessment will be helpful to develop intervention tailored to the needs of the chronic kidney disease population. © 2013 Blackwell Publishing Ltd.

Early vitrectomy effective for Norrie disease.

PubMed

Walsh, Mark K; Drenser, Kimberly A; Capone, Antonio; Trese, Michael T

2010-04-01

To review our experience with Norrie disease to determine if early vitrectomy abrogates the natural history of this rare disease; namely, bilateral no light perception visual acuity and phthisis bulbi. We retrospectively reviewed the medical records of all patients seen in our tertiary care pediatric retinal clinical practice from 1988 through 2008 with a potential diagnosis of Norrie disease. Inclusion required not only clinical findings consistent with Norrie disease but also genetics and/or a family history consistent with Norrie disease. Medical record review revealed 14 boys with clinically diagnosed Norrie disease and either Norrie disease gene (NDP) mutations noted on genetic testing (13 patients) and/or a clear family history consistent with Norrie disease (4 patients). All 14 boys with definite Norrie disease had vitrectomy with or without lensectomy in at least 1 eye prior to 12 months of age. Of the 14 boys with definite Norrie disease, 7 maintained at least light perception visual acuity in 1 eye and 3 had no light perception visual acuity bilaterally; visual acuity data were not available for 4 patients. Only 2 of 24 (8%) eyes became phthisical. Historically, no treatment has been offered to mitigate the dismal natural history of Norrie disease. We recommend consideration of early vitrectomy in Norrie disease.

Multi-Domain Transfer Learning for Early Diagnosis of Alzheimer’s Disease

PubMed Central

Cheng, Bo; Liu, Mingxia; Li, Zuoyong

2017-01-01

Recently, transfer learning has been successfully applied in early diagnosis of Alzheimer’s Disease (AD) based on multi-domain data. However, most of existing methods only use data from a single auxiliary domain, and thus cannot utilize the intrinsic useful correlation information from multiple domains. Accordingly, in this paper, we consider the joint learning of tasks in multi-auxiliary domains and the target domain, and propose a novel Multi-Domain Transfer Learning (MDTL) framework for early diagnosis of AD. Specifically, the proposed MDTL framework consists of two key components: 1) a multi-domain transfer feature selection (MDTFS) model that selects the most informative feature subset from multi-domain data, and 2) a multidomain transfer classification (MDTC) model that can identify disease status for early AD detection. We evaluate our method on 807 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database using baseline magnetic resonance imaging (MRI) data. The experimental results show that the proposed MDTL method can effectively utilize multi-auxiliary domain data for improving the learning performance in the target domain, compared with several state-of-the-art methods. PMID:27928657

Loss of corticospinal tract integrity in early MS disease stages

PubMed Central

Neumann, Jens; Kaufmann, Jörn; Heidel, Jan; Stadler, Erhard; Sweeney-Reed, Catherine; Sailer, Michael; Schreiber, Stefanie

2017-01-01

Objective: We investigated corticospinal tract (CST) integrity in the absence of white matter (WM) lesions using diffusion tensor imaging (DTI) in early MS disease stages. Methods: Our study comprised 19 patients with clinically isolated syndrome (CIS), 11 patients with relapsing-remitting MS (RRMS), and 32 age- and sex-matched healthy controls, for whom MRI measures of CST integrity (fractional anisotropy [FA], mean diffusivity [MD]), T1- and T2-based lesion load, and brain volumes were available. The mean (SD) disease duration was 3.5 (2.1) months, and disability score was low (median Expanded Disability Status Scale 1.5) at the time of the study. Results: Patients with CIS and RRMS had significantly lower CST FA and higher CST MD values compared with controls. These findings were present, irrespective of whether WM lesions affected the CST. However, no group differences in the overall gray or WM volume were identified. Conclusions: In early MS disease stages, CST integrity is already affected in the absence of WM lesions or brain atrophy. PMID:28959706

Can early host responses to mycobacterial infection predict eventual disease outcomes?

PubMed

de Silva, Kumudika; Begg, Douglas J; Plain, Karren M; Purdie, Auriol C; Kawaji, Satoko; Dhand, Navneet K; Whittington, Richard J

2013-11-01

Diagnostic tests used for Johne's disease in sheep either have poor sensitivity and specificity or only detect disease in later stages of infection. Predicting which of the infected sheep are likely to become infectious later in life is currently not feasible and continues to be a major hindrance in disease control. We conducted this longitudinal study to investigate if a suite of diagnostic tests conducted in Mycobacterium avium subspecies paratuberculosis (MAP) exposed lambs at 4 months post infection can accurately predict their clinical status at 12 months post infection. We tracked cellular and humoral responses and quantity of MAP shedding for up to 12 months post challenge in 20 controls and 37 exposed sheep. Infection was defined at necropsy by tissue culture and disease spectrum by lesion type. Data were analysed using univariable and multivariable logistic regression models and a subset of variables from the earliest period post inoculation (4 months) was selected for predicting disease outcomes later on (12 months). Sensitivity and specificity of tests and their combinations in series and parallel were determined. Early elevation in faecal MAP DNA quantity and a lower interferon gamma (IFNγ) response were significantly associated with sheep becoming infectious as well as progressing to severe disease. Conversely, early low faecal MAP DNA and higher interleukin-10 responses were significantly associated with an exposed animal developing protective immunity. Combination of early elevated faecal MAP DNA or lower IFNγ response had the highest sensitivity (75%) and specificity (81%) for identifying sheep that would become infectious. Collectively, these results highlight the potential for combined test interpretation to aid in the early prediction of sheep susceptibility to MAP infection. Copyright © 2013 Elsevier B.V. All rights reserved.

Evidence for early disease-modifying drugs in rheumatoid arthritis

PubMed Central

Scott, David L

2004-01-01

Some research evidence supports early aggressive treatment of rheumatoid arthritis (RA) using combination therapy with two or more disease modifying anti-rheumatic drugs (DMARDs) plus steroids, or even DMARDs plus an anti-TNF. By contrast, conservatively delayed DMARD monotherapy, given after non-steroidal anti-inflammatory drugs have failed, has been criticised. However, recent long-term studies highlight the complexities in evaluating whether to abandon pyramidal treatment in favour of early DMARDs. Although patients given early DMARD therapy show short-term benefits, longer-term results show no prolonged clinical advantages from early DMARDs. By 5 years patients receiving early DMARDs had similar disease activity and comparable health assessment questionnaire scores to patients who received DMARDs later in their disease course. X-ray progression was persistent and virtually identical in both groups. These negative findings do not invalidate the case for early DMARD therapy, as it is gives sustained reductions in disease activity in the early years of treatment without excessive risks from adverse effects. However, early DMARDs alone do not adequately control RA in the longer term. This may require starting with very aggressive therapy or treating patients more aggressively after early DMARD therapy has been initiated. PMID:14979927

Common variants at five new loci associated with early-onset inflammatory bowel disease.

PubMed

Imielinski, Marcin; Baldassano, Robert N; Griffiths, Anne; Russell, Richard K; Annese, Vito; Dubinsky, Marla; Kugathasan, Subra; Bradfield, Jonathan P; Walters, Thomas D; Sleiman, Patrick; Kim, Cecilia E; Muise, Aleixo; Wang, Kai; Glessner, Joseph T; Saeed, Shehzad; Zhang, Haitao; Frackelton, Edward C; Hou, Cuiping; Flory, James H; Otieno, George; Chiavacci, Rosetta M; Grundmeier, Robert; Castro, Massimo; Latiano, Anna; Dallapiccola, Bruno; Stempak, Joanne; Abrams, Debra J; Taylor, Kent; McGovern, Dermot; Silber, Gary; Wrobel, Iwona; Quiros, Antonio; Barrett, Jeffrey C; Hansoul, Sarah; Nicolae, Dan L; Cho, Judy H; Duerr, Richard H; Rioux, John D; Brant, Steven R; Silverberg, Mark S; Taylor, Kent D; Barmuda, M Michael; Bitton, Alain; Dassopoulos, Themistocles; Datta, Lisa Wu; Green, Todd; Griffiths, Anne M; Kistner, Emily O; Murtha, Michael T; Regueiro, Miguel D; Rotter, Jerome I; Schumm, L Philip; Steinhart, A Hillary; Targan, Stephen R; Xavier, Ramnik J; Libioulle, Cécile; Sandor, Cynthia; Lathrop, Mark; Belaiche, Jacques; Dewit, Olivier; Gut, Ivo; Heath, Simon; Laukens, Debby; Mni, Myriam; Rutgeerts, Paul; Van Gossum, André; Zelenika, Diana; Franchimont, Denis; Hugot, J P; de Vos, Martine; Vermeire, Severine; Louis, Edouard; Cardon, Lon R; Anderson, Carl A; Drummond, Hazel; Nimmo, Elaine; Ahmad, Tariq; Prescott, Natalie J; Onnie, Clive M; Fisher, Sheila A; Marchini, Jonathan; Ghori, Jilur; Bumpstead, Suzannah; Gwillam, Rhian; Tremelling, Mark; Delukas, Panos; Mansfield, John; Jewell, Derek; Satsangi, Jack; Mathew, Christopher G; Parkes, Miles; Georges, Michel; Daly, Mark J; Heyman, Melvin B; Ferry, George D; Kirschner, Barbara; Lee, Jessica; Essers, Jonah; Grand, Richard; Stephens, Michael; Levine, Arie; Piccoli, David; Van Limbergen, John; Cucchiara, Salvatore; Monos, Dimitri S; Guthery, Stephen L; Denson, Lee; Wilson, David C; Grant, Straun F A; Daly, Mark; Silverberg, Mark S; Satsangi, Jack; Hakonarson, Hakon

2009-12-01

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

The Intestinal Microbiome in Early Life: Health and Disease

PubMed Central

Arrieta, Marie-Claire; Stiemsma, Leah T.; Amenyogbe, Nelly; Brown, Eric M.; Finlay, Brett

2014-01-01

Human microbial colonization begins at birth and continues to develop and modulate in species abundance for about 3 years, until the microbiota becomes adult-like. During the same time period, children experience significant developmental changes that influence their health status as well as their immune system. An ever-expanding number of articles associate several diseases with early-life imbalances of the gut microbiota, also referred to as gut microbial dysbiosis. Whether early-life dysbiosis precedes and plays a role in disease pathogenesis, or simply originates from the disease process itself is a question that is beginning to be answered in a few diseases, including IBD, obesity, and asthma. This review describes the gut microbiome structure and function during the formative first years of life, as well as the environmental factors that determine its composition. It also aims to discuss the recent advances in understanding the role of the early-life gut microbiota in the development of immune-mediated, metabolic, and neurological diseases. A greater understanding of how the early-life gut microbiota impacts our immune development could potentially lead to novel microbial-derived therapies that target disease prevention at an early age. PMID:25250028

High-throughput sequencing of the T cell receptor β gene identifies aggressive early-stage mycosis fungoides.

PubMed

de Masson, Adele; O'Malley, John T; Elco, Christopher P; Garcia, Sarah S; Divito, Sherrie J; Lowry, Elizabeth L; Tawa, Marianne; Fisher, David C; Devlin, Phillip M; Teague, Jessica E; Leboeuf, Nicole R; Kirsch, Ilan R; Robins, Harlan; Clark, Rachael A; Kupper, Thomas S

2018-05-09

Mycosis fungoides (MF), the most common cutaneous T cell lymphoma (CTCL) is a malignancy of skin-tropic memory T cells. Most MF cases present as early stage (stage I A/B, limited to the skin), and these patients typically have a chronic, indolent clinical course. However, a small subset of early-stage cases develop progressive and fatal disease. Because outcomes can be so different, early identification of this high-risk population is an urgent unmet clinical need. We evaluated the use of next-generation high-throughput DNA sequencing of the T cell receptor β gene ( TCRB ) in lesional skin biopsies to predict progression and survival in a discovery cohort of 208 patients with CTCL (177 with MF) from a 15-year longitudinal observational clinical study. We compared these data to the results in an independent validation cohort of 101 CTCL patients (87 with MF). The tumor clone frequency (TCF) in lesional skin, measured by high-throughput sequencing of the TCRB gene, was an independent prognostic factor of both progression-free and overall survival in patients with CTCL and MF in particular. In early-stage patients, a TCF of >25% in the skin was a stronger predictor of progression than any other established prognostic factor (stage IB versus IA, presence of plaques, high blood lactate dehydrogenase concentration, large-cell transformation, or age). The TCF therefore may accurately predict disease progression in early-stage MF. Early identification of patients at high risk for progression could help identify candidates who may benefit from allogeneic hematopoietic stem cell transplantation before their disease becomes treatment-refractory. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Coronary artery disease: new insights into the pathophysiology, prevalence and early detection of a monster menace.

PubMed

Slater, James; Rill, Velisar

2003-04-01

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the United States and industrialized countries. In the undeveloped world a similar epidemic is brewing. A new pathophysiologic paradigm has emerged, which assigns the mediators of inflammation a much larger role in the disease process. This paradigm has helped explain the unpredictable nature of many adverse consequences of CAD. The long latent phase of the disease and often sudden initial presentation make efforts at early detection extremely important. Considerable work has been devoted to identify as well as influence predisposing risk factors for developing arteriosclerosis. Novel markers of inflammation, like C-reactive protein, have been identified and compared to traditional risk factors. In addition, new imaging modalities introduce the possibility of screening for sub-clinical disease. Electron-beam and spiral CT scanners, as well as other techniques, are emerging as powerful tools to detect early disease presence and allow intervention to take place before major clinical events occur. Advances in our understanding of the pathophysiology and our ability to image the stages of silent disease will go hand in hand to revolutionize our approach to prevention and treatment of this deadly disease.

Early diagnosis of mild cognitive impairment and Alzheimer's disease based on salivary lactoferrin.

PubMed

Carro, Eva; Bartolomé, Fernando; Bermejo-Pareja, Félix; Villarejo-Galende, Alberto; Molina, José Antonio; Ortiz, Pablo; Calero, Miguel; Rabano, Alberto; Cantero, José Luis; Orive, Gorka

2017-01-01

The Alzheimer's disease (AD) process is likely initiated many years before clinical onset. Biomarkers of preclinical disease are critical for the development of disease-modifying or even preventative therapies. Current biomarkers for early disease, including cerebrospinal fluid tau and amyloid β (Aβ) levels, structural and functional magnetic resonance imaging, and the use of brain amyloid imaging, are limited because they are very invasive or expensive. Noninvasive biomarkers may be a more accessible alternative, but none can currently detect preclinical AD with the required sensitivity and specificity. Here, we show a novel, straight-forward, and noninvasive approach for assessment of early stages of cognitive decline. Salivary samples from cases of amnestic mild cognitive impairment (aMCI) and AD, and neurology controls were analyzed. We have discovered and validated a new single saliva biomarker, lactoferrin, which in our cross-sectional investigation perfectly discriminates clinically diagnosed aMCI and AD patients from a cognitively healthy control group. The accuracy for AD diagnosis shown by salivary lactoferrin was greater than that obtained from core cerebrospinal fluid (CSF) biomarkers, including total tau and CSF Aβ 42 . Furthermore, salivary lactoferrin can be used for population screening and for identifying those underdiagnosed subjects with very early stages of mild cognitive impairment and AD. This biomarker may offer new insights in the early diagnostics for AD.

First hundred cases of variant Creutzfeldt-Jakob disease: retrospective case note review of early psychiatric and neurological features

PubMed Central

Spencer, Michael D; Knight, Richard S G; Will, Robert G

2002-01-01

Objective To describe the early psychiatric and neurological features of variant Creutzfeldt-Jakob disease. Design Cohort study. Setting National surveillance system for Creutzfeldt-Jakob disease in the United Kingdom. Participants The first 100 cases of variant Creutzfeldt-Jakob disease identified in the United Kingdom. Main outcome measures The timing and nature of early psychiatric and neurological symptoms in variant Creutzfeldt-Jakob disease. Results The early stages of variant Creutzfeldt-Jakob disease are dominated by psychiatric symptoms, but neurological symptoms precede psychiatric symptoms in 15% of cases and are present in combination with psychiatric symptoms in 22% of cases from the onset of disease. Common early psychiatric features include dysphoria, withdrawal, anxiety, insomnia, and loss of interest. No common early neurological features exist, but a significant proportion of patients do exhibit neurological symptoms within 4 months of clinical onset, including poor memory, pain, sensory symptoms, unsteadiness of gait, and dysarthria. Conclusions Although the diagnosis of variant Creutzfeldt-Jakob disease may be impossible in the early stages of the illness, particular combinations of psychiatric and neurological features may allow early diagnosis in an appreciable proportion of patients. What is already known on this topicThe early stages of variant Creutzfeldt-Jakob disease are dominated by psychiatric symptomatologySome patients have early neurological features that might suggest the presence of an underlying neurological disorderWhat this study addsThis study provides a comprehensive description of the evolution of psychiatric and neurological features in variant Creutzfeldt-Jakob diseaseAn appreciable proportion of patients have early neurological symptomsA high proportion of patients have a combination of psychiatric and neurological features within four months of clinical onset that suggest the diagnosis of variant Creutzfeldt-Jakob disease

Coronary artery disease: new insights into the pathophysiology, prevalence, and early detection of a monster menace.

PubMed

Slater, James; Rill, Velisar

2004-04-01

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the United States and other industrialized countries. In the undeveloped world a similar epidemic is brewing. A new pathophysiologic paradigm has emerged, which assigns the mediators of inflammation a much larger role in the disease process. This paradigm has helped explain the unpredictable nature of many adverse consequences of CAD. The long latent phase of the disease, and often sudden initial presentation, make efforts at early detection extremely important. Considerable work has been devoted to identify, as well as influence, predisposing risk factors for developing arteriosclerosis. Novel markers of inflammation, like C-reactive protein, have been identified and compared to traditional risk factors. In addition, new imaging modalities introduce the possibility of screening for subclinical disease. Electron beam and multidetector computed tomography (CT) scanners, as well as other techniques, are emerging as powerful tools to detect early disease presence and allow intervention to take place before major clinical events occur. Advances in our understanding of the pathophysiology of CAD, and our ability to image the stages of silent disease will go hand in hand to revolutionize our approach to prevention and treatment of this deadly malady.

Development of a Metabolic Biosignature for Detection of Early Lyme Disease

PubMed Central

Molins, Claudia R.; Ashton, Laura V.; Wormser, Gary P.; Hess, Ann M.; Delorey, Mark J.; Mahapatra, Sebabrata; Schriefer, Martin E.; Belisle, John T.

2015-01-01

Background. Early Lyme disease patients often present to the clinic prior to developing a detectable antibody response to Borrelia burgdorferi, the etiologic agent. Thus, existing 2-tier serology-based assays yield low sensitivities (29%–40%) for early infection. The lack of an accurate laboratory test for early Lyme disease contributes to misconceptions about diagnosis and treatment, and underscores the need for new diagnostic approaches. Methods. Retrospective serum samples from patients with early Lyme disease, other diseases, and healthy controls were analyzed for small molecule metabolites by liquid chromatography-mass spectrometry (LC-MS). A metabolomics data workflow was applied to select a biosignature for classifying early Lyme disease and non-Lyme disease patients. A statistical model of the biosignature was trained using the patients' LC-MS data, and subsequently applied as an experimental diagnostic tool with LC-MS data from additional patient sera. The accuracy of this method was compared with standard 2-tier serology. Results. Metabolic biosignature development selected 95 molecular features that distinguished early Lyme disease patients from healthy controls. Statistical modeling reduced the biosignature to 44 molecular features, and correctly classified early Lyme disease patients and healthy controls with a sensitivity of 88% (84%–95%), and a specificity of 95% (90%–100%). Importantly, the metabolic biosignature correctly classified 77%–95% of the of serology negative Lyme disease patients. Conclusions. The data provide proof-of-concept that metabolic profiling for early Lyme disease can achieve significantly greater (P < .0001) diagnostic sensitivity than current 2-tier serology, while retaining high specificity. PMID:25761869

Methods for Surgical Targeting of the STN in Early-Stage Parkinson’s Disease

PubMed Central

Camalier, Corrie R.; Konrad, Peter E.; Gill, Chandler E.; Kao, Chris; Remple, Michael R.; Nasr, Hana M.; Davis, Thomas L.; Hedera, Peter; Phibbs, Fenna T.; Molinari, Anna L.; Neimat, Joseph S.; Charles, David

2013-01-01

Patients with Parkinson’s disease (PD) experience progressive neurological decline, and future interventional therapies are thought to show most promise in early stages of the disease. There is much interest in therapies that target the subthalamic nucleus (STN) with surgical access. While locating STN in advanced disease patients (Hoehn–Yahr Stage III or IV) is well understood and routinely performed at many centers in the context of deep brain stimulation surgery, the ability to identify this nucleus in early-stage patients has not previously been explored in a sizeable cohort. We report surgical methods used to target the STN in 15 patients with early PD (Hoehn–Yahr Stage II), using a combination of image guided surgery, microelectrode recordings, and clinical responses to macrostimulation of the region surrounding the STN. Measures of electrophysiology (firing rates and root mean squared activity) have previously been found to be lower than in later-stage patients, however, the patterns of electrophysiology seen and dopamimetic macrostimulation effects are qualitatively similar to those seen in advanced stages. Our experience with surgical implantation of Parkinson’s patients with minimal motor symptoms suggest that it remains possible to accurately target the STN in early-stage PD using traditional methods. PMID:24678307

Development of a metabolic biosignature for detection of early Lyme disease.

PubMed

Molins, Claudia R; Ashton, Laura V; Wormser, Gary P; Hess, Ann M; Delorey, Mark J; Mahapatra, Sebabrata; Schriefer, Martin E; Belisle, John T

2015-06-15

Early Lyme disease patients often present to the clinic prior to developing a detectable antibody response to Borrelia burgdorferi, the etiologic agent. Thus, existing 2-tier serology-based assays yield low sensitivities (29%-40%) for early infection. The lack of an accurate laboratory test for early Lyme disease contributes to misconceptions about diagnosis and treatment, and underscores the need for new diagnostic approaches. Retrospective serum samples from patients with early Lyme disease, other diseases, and healthy controls were analyzed for small molecule metabolites by liquid chromatography-mass spectrometry (LC-MS). A metabolomics data workflow was applied to select a biosignature for classifying early Lyme disease and non-Lyme disease patients. A statistical model of the biosignature was trained using the patients' LC-MS data, and subsequently applied as an experimental diagnostic tool with LC-MS data from additional patient sera. The accuracy of this method was compared with standard 2-tier serology. Metabolic biosignature development selected 95 molecular features that distinguished early Lyme disease patients from healthy controls. Statistical modeling reduced the biosignature to 44 molecular features, and correctly classified early Lyme disease patients and healthy controls with a sensitivity of 88% (84%-95%), and a specificity of 95% (90%-100%). Importantly, the metabolic biosignature correctly classified 77%-95% of the of serology negative Lyme disease patients. The data provide proof-of-concept that metabolic profiling for early Lyme disease can achieve significantly greater (P < .0001) diagnostic sensitivity than current 2-tier serology, while retaining high specificity. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Early detection of contagious diseases

DOEpatents

Colston, Jr., Billy W.; Milanovich, Fred P [Lafayette, CA; Estacio, Pedro [Mission San Jose, CA; Chang, John [Walnut Creek, CA

2011-08-09

This invention provides an electronic proximity apparatus and a surveillance method using such an apparatus for alerting individuals that are exposed to a contagious disease. When a person becomes symptomatic and is diagnosed as positive for a given contagious agent, individuals that have recently maintained a threshold proximity with respect to an infected individual are notified and advised to seek immediate medial care. Treatment of individuals in the very early phases of infection (pre-symptomatic) significantly reduces contagiousness of the infected population first exposed to the contagious disease, thus preventing spread of the disease throughout the general population.

Identifying Disease Associated miRNAs Based on Protein Domains.

PubMed

Qin, Gui-Min; Li, Rui-Yi; Zhao, Xing-Ming

2016-01-01

MicroRNAs (miRNAs) are a class of small endogenous non-coding genes, acting as regulators in the post-transcriptional processes. Recently, the miRNAs are found to be widely involved in different types of diseases. Therefore, the identification of disease associated miRNAs can help understand the mechanisms that underlie the disease and identify new biomarkers. However, it is not easy to identify the miRNAs related to diseases due to its extensive involvements in various biological processes. In this work, we present a new approach to identify disease associated miRNAs based on domains, the functional and structural blocks of proteins. The results on real datasets demonstrate that our method can effectively identify disease related miRNAs with high precision.

The cost-effectiveness of using chronic kidney disease risk scores to screen for early-stage chronic kidney disease.

PubMed

Yarnoff, Benjamin O; Hoerger, Thomas J; Simpson, Siobhan K; Leib, Alyssa; Burrows, Nilka R; Shrestha, Sundar S; Pavkov, Meda E

2017-03-13

Better treatment during early stages of chronic kidney disease (CKD) may slow progression to end-stage renal disease and decrease associated complications and medical costs. Achieving early treatment of CKD is challenging, however, because a large fraction of persons with CKD are unaware of having this disease. Screening for CKD is one important method for increasing awareness. We examined the cost-effectiveness of identifying persons for early-stage CKD screening (i.e., screening for moderate albuminuria) using published CKD risk scores. We used the CKD Health Policy Model, a micro-simulation model, to simulate the cost-effectiveness of using CKD two published risk scores by Bang et al. and Kshirsagar et al. to identify persons in the US for CKD screening with testing for albuminuria. Alternative risk score thresholds were tested (0.20, 0.15, 0.10, 0.05, and 0.02) above which persons were assigned to receive screening at alternative intervals (1-, 2-, and 5-year) for follow-up screening if the first screening was negative. We examined incremental cost-effectiveness ratios (ICERs), incremental lifetime costs divided by incremental lifetime QALYs, relative to the next higher screening threshold to assess cost-effectiveness. Cost-effective scenarios were determined as those with ICERs less than $50,000 per QALY. Among the cost-effective scenarios, the optimal scenario was determined as the one that resulted in the highest lifetime QALYs. ICERs ranged from $8,823 per QALY to $124,626 per QALY for the Bang et al. risk score and $6,342 per QALY to $405,861 per QALY for the Kshirsagar et al. risk score. The Bang et al. risk score with a threshold of 0.02 and 2-year follow-up screening was found to be optimal because it had an ICER less than $50,000 per QALY and resulted in the highest lifetime QALYs. This study indicates that using these CKD risk scores may allow clinicians to cost-effectively identify a broader population for CKD screening with testing for albuminuria

Brain metabolite alterations and cognitive dysfunction in early Huntington’s Disease

PubMed Central

Unschuld, Paul G.; Edden, Richard A. E.; Carass, Aaron; Liu, Xinyang; Shanahan, Megan; Wang, Xin; Oishi, Kenichi; Brandt, Jason; Bassett, Susan S.; Redgrave, Graham W.; Margolis, Russell L.; van Zijl, Peter C. M.; Barker, Peter B.; Ross, Christopher A.

2012-01-01

Background Huntington’s Disease (HD) is a neurodegenerative disorder characterized by early cognitive decline, which progresses at later stages to dementia and severe movement disorder. HD is caused by a cytosine-adenine-guanine triplet-repeat expansion mutation in the Huntingtin gene, allowing early diagnosis by genetic testing. This study aims to identify the relationship of N-acetylaspartate and other brain metabolites to cognitive function in HD-mutation carriers by using high field strength magnetic-resonance-spectroscopy at 7-Tesla. Methods Twelve individuals with the HD-mutation in premanifest or early stage of disease versus twelve healthy controls underwent 1H magnetic-resonance-spectroscopy (7.2ml voxel in the posterior cingulate cortex) at 7-Tesla, and also T1-weighted structural magnetic-resonance-imaging. All participants received standardized tests of cognitive functioning including the Montreal Cognitive Assessment and standardized quantified neurological examination within an hour before scanning. Results Individuals with the HD mutation had significantly lower posterior cingulate cortex N-acetylaspartate (−9.6%, p=0.02) and glutamate levels (−10.1%, p=0.02) than controls. By contrast, in this small group, measures of brain morphology including striatal and ventricle volumes did not differ significantly. Linear regression with Montreal Cognitive Assessment scores revealed significant correlations with N-acetylaspartate (r2=0.50, p=0.01) and glutamate (r2=0.64, p=0.002) in HD subjects. Conclusions Our data suggest a relationship between reduced N-acetylaspartate and glutamate levels in the posterior cingulate cortex with cognitive decline in early stages of HD. N-acetylaspartate and glutamate magnetic-resonance-spectroscopy signals of the posterior cingulate cortex region may serve as potential biomarkers of disease progression or treatment outcome in HD and other neurodegenerative disorders with early cognitive dysfunction, when structural

Nanomedicine for Early Disease Detection and Treatment

DTIC Science & Technology

2013-09-01

AD_________________ Award Number: W81XWH-11-1-0442 TITLE: Nanomedicine for early disease ...been developed to report and cure diseases . ESNM is prepared with multiple layers of polyelectrolytes, sequentially assembled on an inert gold...molecular characteristics of the patient and his/her specific diseased tissues with the treatment. In order to maximize therapeutic effects and

Early Environmental Origins of Neurodegenerative Disease in Later Life

PubMed Central

Landrigan, Philip J.; Sonawane, Babasaheb; Butler, Robert N.; Trasande, Leonardo; Callan, Richard; Droller, Daniel

2005-01-01

Parkinson disease (PD) and Alzheimer disease (AD), the two most common neurodegenerative disorders in American adults, are of purely genetic origin in a minority of cases and appear in most instances to arise through interactions among genetic and environmental factors. In this article we hypothesize that environmental exposures in early life may be of particular etiologic importance and review evidence for the early environmental origins of neurodegeneration. For PD the first recognized environmental cause, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), was identified in epidemiologic studies of drug abusers. Chemicals experimentally linked to PD include the insecticide rotenone and the herbicides paraquat and maneb; interaction has been observed between paraquat and maneb. In epidemiologic studies, manganese has been linked to parkinsonism. In dementia, lead is associated with increased risk in chronically exposed workers. Exposures of children in early life to lead, polychlorinated biphenyls, and methylmercury have been followed by persistent decrements in intelligence that may presage dementia. To discover new environmental causes of AD and PD, and to characterize relevant gene–environment interactions, we recommend that a large, prospective genetic and epidemiologic study be undertaken that will follow thousands of children from conception (or before) to old age. Additional approaches to etiologic discovery include establishing incidence registries for AD and PD, conducting targeted investigations in high-risk populations, and improving testing of the potential neurologic toxicity of chemicals. PMID:16140633

Early brain connectivity alterations and cognitive impairment in a rat model of Alzheimer's disease.

PubMed

Muñoz-Moreno, Emma; Tudela, Raúl; López-Gil, Xavier; Soria, Guadalupe

2018-02-07

Animal models of Alzheimer's disease (AD) are essential to understanding the disease progression and to development of early biomarkers. Because AD has been described as a disconnection syndrome, magnetic resonance imaging (MRI)-based connectomics provides a highly translational approach to characterizing the disruption in connectivity associated with the disease. In this study, a transgenic rat model of AD (TgF344-AD) was analyzed to describe both cognitive performance and brain connectivity at an early stage (5 months of age) before a significant concentration of β-amyloid plaques is present. Cognitive abilities were assessed by a delayed nonmatch-to-sample (DNMS) task preceded by a training phase where the animals learned the task. The number of training sessions required to achieve a learning criterion was recorded and evaluated. After DNMS, MRI acquisition was performed, including diffusion-weighted MRI and resting-state functional MRI, which were processed to obtain the structural and functional connectomes, respectively. Global and regional graph metrics were computed to evaluate network organization in both transgenic and control rats. The results pointed to a delay in learning the working memory-related task in the AD rats, which also completed a lower number of trials in the DNMS task. Regarding connectivity properties, less efficient organization of the structural brain networks of the transgenic rats with respect to controls was observed. Specific regional differences in connectivity were identified in both structural and functional networks. In addition, a strong correlation was observed between cognitive performance and brain networks, including whole-brain structural connectivity as well as functional and structural network metrics of regions related to memory and reward processes. In this study, connectivity and neurocognitive impairments were identified in TgF344-AD rats at a very early stage of the disease when most of the pathological hallmarks

Early neurovascular dysfunction in a transgenic rat model of Alzheimer's disease.

PubMed

Joo, Illsung L; Lai, Aaron Y; Bazzigaluppi, Paolo; Koletar, Margaret M; Dorr, Adrienne; Brown, Mary E; Thomason, Lynsie A M; Sled, John G; McLaurin, JoAnne; Stefanovic, Bojana

2017-04-12

Alzheimer's disease (AD), pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aβ-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans.

Early childhood poverty, immune-mediated disease processes, and adult productivity.

PubMed

Ziol-Guest, Kathleen M; Duncan, Greg J; Kalil, Ariel; Boyce, W Thomas

2012-10-16

This study seeks to understand whether poverty very early in life is associated with early-onset adult conditions related to immune-mediated chronic diseases. It also tests the role that these immune-mediated chronic diseases may play in accounting for the associations between early poverty and adult productivity. Data (n = 1,070) come from the US Panel Study of Income Dynamics and include economic conditions in utero and throughout childhood and adolescence coupled with adult (age 30-41 y) self-reports of health and economic productivity. Results show that low income, particularly in very early childhood (between the prenatal and second year of life), is associated with increases in early-adult hypertension, arthritis, and limitations on activities of daily living. Moreover, these relationships and particularly arthritis partially account for the associations between early childhood poverty and adult productivity as measured by adult work hours and earnings. The results suggest that the associations between early childhood poverty and these adult disease states may be immune-mediated.

Ultra-Early Phase pathologies of Alzheimer's disease and other neurodegenerative diseases.

PubMed

Okazawa, Hitoshi

2017-01-01

The concept of neurodegenerative diseases and the therapeutics targeting these intractable diseases are changing rapidly. Protein aggregation as the top of pathological cascade is now challenged, and many alternative ideas are proposed. Early molecular pathologies before microscopic detection of diseases protein aggregates, which I propose to call "Ultra-Early Phase pathologies or phase 0 pathologies", are the focus of research that might explain the failures of clinical trials with anti-Aβ antibodies against Alzheimer's disease. In this review article, I summarize the critical issues that should be successfully and consistently answered by a new concept of neurodegeneration. For reevaluating old concepts and reconstructing a new concept of neurodegeneration that will replace the old ones, non-biased comprehensive approaches including proteome combined with systems biology analyses will be a powerful tool. I introduce our recent efforts in this orientation that have reached to the stage of non-clinical proof of concept applicable to clinical trials.

Glaucoma as an early complication of Hurler's disease.

PubMed Central

Nowaczyk, M J; Clarke, J T; Morin, J D

1988-01-01

We report three cases of Hurler's disease in which glaucoma developed in early childhood. We draw attention to the fact that glaucoma may be a commonly unrecognised early complication of this condition. PMID:3140740

Pathologic features of early inflammatory bowel disease.

PubMed

Finkelstein, Sydney D; Sasatomi, Eizaburo; Regueiro, Miguel

2002-03-01

Often the pathologic changes of IBD are subtle and may not be present in a proportion of biopsy specimens. In cases of early disease, the changes may be missed, and additional specimens should be taken after a period of time. Modifying factors, such as prebiopsy treatment and coexisting disease, should be considered. A forum to review cases and allow for communication between gastroenterologists and pathologists is especially useful for clinicopathologic correlation and assignment of a working diagnosis to each case. Careful attention to the pathologic features of early UC and CD would be most useful when evaluating new therapies for IBD.

Whole Exome Analysis of Early Onset Alzheimer’s Disease

DTIC Science & Technology

2015-04-01

autosomal recessive early-onset Parkinson’s disease and juvenile Parkinson disease , Parkin has been shown to promote intracellular Abeta1–42 clearance [15... Parkinsonism . Conclusions Mutations were found in 6/50 families. The presence of an APOE-4 allele may account for disease status in one affected non...AD_________________ Award Number: W81XWH-12-1-0013 TITLE: Whole Exome Analysis of Early Onset Alzheimer’s Disease PRINCIPAL INVESTIGATOR

Development and Operation of Space-Based Disease Early Warning Models

NASA Astrophysics Data System (ADS)

John, M. M.

2010-12-01

Millions of people die every year from preventable diseases such as malaria and cholera. Pandemics put the entire world population at risk and have the potential to kill thousands and cripple the global economy. In light of these dangers, it is fortunate that the data and imagery gathered by remote sensing satellites can be used to develop models that predict areas at risk for outbreaks. These warnings can help decision makers to distribute preventative medicine and other forms of aid to save lives. There are already many Earth observing satellites in orbit with the ability to provide data and imagery. Researchers have created a number of models based on this information, and some are being used in real-life situations. These capabilities should be further developed and supported by governments and international organizations to benefit as many people as possible. To understand the benefits and challenges of disease early warning models, it is useful to understand how they are developed. A number of steps must occur for satellite data and imagery to be used to prevent disease outbreaks; each requires a variety of inputs and may include a range of experts and stakeholders. This paper discusses the inputs, outputs, and basic processes involved in each of six main steps to developing models, including: identifying and validating links between a disease and environmental factors, creating and validating a software model to predict outbreaks, transitioning a model to operational use, using a model operationally, and taking action on the data provided by the model. The paper briefly overviews past research regarding the link between remote sensing data and disease, and identifies ongoing research in academic centers around the world. The activities of three currently operational models are discussed, including the U.S. Department of Defense Global Emerging Infections Surveillance and Response System (DoD-GEIS), NASA carries out its Malaria Modeling and Surveillance

Biomarker for early renal microvascular and diabetic kidney diseases.

PubMed

Futrakul, Narisa; Futrakul, Prasit

2017-11-01

Recognition of early stage of diabetic kidney disease, under common practice using biomarkers, namely microalbuminuria, serum creatinine level above 1 mg/dL and accepted definition of diabetic kidney disease associated with creatinine clearance value below 60 mL/min/1.73 m 2 , is unlikely. This would lead to delay treatment associated with therapeutic resistance to vasodilator due to a defective vascular homoeostasis. Other alternative biomarkers related to the state of microalbuminuria is not sensitive to screen for early diabetic kidney disease (stages I, II). In this regard, a better diagnostic markers to serve for this purpose are creatinine clearance, fractional excretion of magnesium (FE Mg), cystatin C. Recently, renal microvascular disease and renal ischemia have been demonstrated to correlate indirectly with the development of diabetic kidney disease and its function. Among these are angiogenic and anti-angiogenic factors, namely VEGF, VEGF receptors, angiopoietins and endostatin. With respect to therapeutic prevention, implementation of treatment at early stage of diabetic and nondiabetic kidney disease is able to restore renal perfusion and function.

Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis.

PubMed

Conrado, Daniela J; Nicholas, Timothy; Tsai, Kuenhi; Macha, Sreeraj; Sinha, Vikram; Stone, Julie; Corrigan, Brian; Bani, Massimo; Muglia, Pierandrea; Watson, Ian A; Kern, Volker D; Sheveleva, Elena; Marek, Kenneth; Stephenson, Diane T; Romero, Klaus

2018-01-01

Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was -3.16 (90% confidence interval [CI] = -0.96 to -5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Lexical and semantic fluency discrepancy scores in aMCI and early Alzheimer's disease.

PubMed

Lonie, Jane A; Herrmann, Lucie L; Tierney, Kevin M; Donaghey, Claire; O'Carroll, Ronan; Lee, Andrew; Ebmeier, Klaus P

2009-03-01

Episodic memory is compromised in amnestic mild cognitive impairment (aMCI), but lesser deficits in other cognitive domains are also commonly observed and may be helpful in identifying this group. The relative difference in performance on lexical and semantic fluency tasks may be a sensitive and specific measure in aMCI and early Alzheimer's disease (AD). We compared four groups of participants, 35 early AD, 47 aMCI, 24 healthy controls, and 18 depressive out-patient controls, on semantic and lexical fluency as well as other neuropsychological tests. Early AD and aMCI patients showed a distinct pattern of semantic impairment in the two fluency measures compared with the healthy and depressive controls. The findings implicate early failure of the semantic memory system in aMCI and AD and suggest that consideration of the discrepancy in performance on semantic and lexical fluency measures may help in the early identification of AD.

Early-onset Alzheimer's Disease Phenotypes: Neuropsychology and Neural Networks

ClinicalTrials.gov

2017-05-11

Alzheimer Disease, Early Onset; Alzheimer Disease; Alzheimer Disease, Late Onset; Dementia, Alzheimer Type; Logopenic Progressive Aphasia; Primary Progressive Aphasia; Visuospatial/Perceptual Abilities; Posterior Cortical Atrophy; Executive Dysfunction; Corticobasal Degeneration; Ideomotor Apraxia

Magnetic Resonance Imaging to Detect Early Molecular and Cellular Changes in Alzheimer's Disease.

PubMed

Knight, Michael J; McCann, Bryony; Kauppinen, Risto A; Coulthard, Elizabeth J

2016-01-01

Recent pharmaceutical trials have demonstrated that slowing or reversing pathology in Alzheimer's disease is likely to be possible only in the earliest stages of disease, perhaps even before significant symptoms develop. Pathology in Alzheimer's disease accumulates for well over a decade before symptoms are detected giving a large potential window of opportunity for intervention. It is therefore important that imaging techniques detect subtle changes in brain tissue before significant macroscopic brain atrophy. Current diagnostic techniques often do not permit early diagnosis or are too expensive for routine clinical use. Magnetic Resonance Imaging (MRI) is the most versatile, affordable, and powerful imaging modality currently available, being able to deliver detailed analyses of anatomy, tissue volumes, and tissue state. In this mini-review, we consider how MRI might detect patients at risk of future dementia in the early stages of pathological change when symptoms are mild. We consider the contributions made by the various modalities of MRI (structural, diffusion, perfusion, relaxometry) in identifying not just atrophy (a late-stage AD symptom) but more subtle changes reflective of early dementia pathology. The sensitivity of MRI not just to gross anatomy but to the underlying "health" at the cellular (and even molecular) scales, makes it very well suited to this task.

Early life programming and the risk of non-alcoholic fatty liver disease.

PubMed

Lynch, C; Chan, C S; Drake, A J

2017-06-01

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, type 2 diabetes and cardiovascular disease and can be considered the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of disease, from the relatively benign simple steatosis to the more serious non-alcoholic steatohepatitis, which can progress to liver cirrhosis, hepatocellular carcinoma and end-stage liver failure, necessitating liver transplantation. Although the increasing prevalence of NAFLD in developed countries has substantial implications for public health, many of the precise mechanisms accounting for the development and progression of NAFLD are unclear. The environment in early life is an important determinant of cardiovascular disease risk in later life and studies suggest this also extends to NAFLD. Here we review data from animal models and human studies which suggest that fetal and early life exposure to maternal under- and overnutrition, excess glucocorticoids and environmental pollutants may confer an increased susceptibility to NAFLD development and progression in offspring and that such effects may be sex-specific. We also consider studies aimed at identifying potential dietary and pharmacological interventions aimed at reducing this risk. We suggest that further human epidemiological studies are needed to ensure that data from animal models are relevant to human health.

Similarities and differences between infantile and early childhood onset vanishing white matter disease.

PubMed

Zhou, Ling; Zhang, Haihua; Chen, Na; Zhang, Zhongbin; Liu, Ming; Dai, Lifang; Wang, Jingmin; Jiang, Yuwu; Wu, Ye

2018-06-01

Vanishing white matter disease (VWM) is one of the most prevalent inherited leukoencephalopathies in childhood. Infantile VWM is more severe but less understood than the classic early childhood type. We performed a follow-up study on 14 infantile and 26 childhood patients to delineate the natural history and neuroimaging features of VWM. Infantile and childhood patients shared similarities in the incidence of epileptic seizure (35.7 vs. 38.5%) and episodic aggravation (92.9 vs. 84.6%). Developmental delay before disease onset was more common in infantile patients. Motor disability was earlier and more severe in infantile VWM. In survivors with disease durations of 1-3 years, the Gross Motor Function Classification System (GMFCS) was classified as IV-V in 66.7% of infantile and only 29.4% of childhood patients. Kaplan-Meier survival curve analysis indicated that the 5-year survival rates were 21.6 and 91.3% in infantile and childhood VWM, respectively. In terms of MRI, infantile patients showed more extensive involvement and earlier rarefaction, with more common involvement of subcortical white matter, internal capsule, brain stem and dentate nuclei of the cerebellum. Restricted diffusion was more diffuse or extensive in infantile patients. In addition, four novel mutations were identified. In conclusion, we identified some similarities and differences in the natural history and neuroimaging features between infantile and early childhood VWM.

Transcriptional signature associated with early rheumatoid arthritis and healthy individuals at high risk to develop the disease

PubMed Central

Macías-Segura, N.; Bastian, Y.; Santiago-Algarra, D.; Castillo-Ortiz, J. D.; Alemán-Navarro, A. L.; Jaime-Sánchez, E.; Gomez-Moreno, M.; Saucedo-Toral, C. A.; Lara-Ramírez, Edgar E.; Zapata-Zuñiga, M.; Enciso-Moreno, L.; González-Amaro, R.; Ramos-Remus, C.; Enciso-Moreno, J. A.

2018-01-01

Background Little is known regarding the mechanisms underlying the loss of tolerance in the early and preclinical stages of autoimmune diseases. The aim of this work was to identify the transcriptional profile and signaling pathways associated to non-treated early rheumatoid arthritis (RA) and subjects at high risk. Several biomarker candidates for early RA are proposed. Methods Whole blood total RNA was obtained from non-treated early RA patients with <1 year of evolution as well as from healthy first-degree relatives of patients with RA (FDR) classified as ACCP+ and ACCP- according to their antibodies serum levels against cyclic citrullinated peptides. Complementary RNA (cRNA) was synthetized and hybridized to high-density microarrays. Data was analyzed in Genespring Software and functional categories were assigned to a specific transcriptome identified in subjects with RA and FDR ACCP positive. Specific signaling pathways for genes associated to RA were identified. Gene expression was evaluated by qPCR. Receiver operating characteristic (ROC) analysis was used to evaluate these genes as biomarkers. Results A characteristic transcriptome of 551 induced genes and 4,402 repressed genes were identified in early RA patients. Bioinformatics analysis of the data identified a specific transcriptome in RA patients. Moreover, some overlapped transcriptional profiles between patients with RA and ACCP+ were identified, suggesting an up-regulated distinctive transcriptome from the preclinical stages up to progression to an early RA state. A total of 203 pathways have up-regulated genes that are shared between RA and ACCP+. Some of these genes show potential to be used as progression biomarkers for early RA with area under the curve of ROC > 0.92. These genes come from several functional categories associated to inflammation, Wnt signaling and type I interferon pathways. Conclusion The presence of a specific transcriptome in whole blood of RA patients suggests the activation

Chronic granulomatous disease mimicking early-onset Crohn's disease with cutaneous manifestations.

PubMed

Barbato, Maria; Ragusa, Giovanni; Civitelli, Fortunata; Marcheggiano, Adriana; Di Nardo, Giovanni; Iacobini, Metello; Melengu, Taulant; Cucchiara, Salvatore; Duse, Marzia

2014-06-20

Chronic granulomatous disease is a rare inherited disorder of the innate immune system. In patients with a clinical history of recurrent or persistent infections, especially infections caused by uncommon species, chronic granulomatous disease should be considered. We report the case of a 5-year-old boy with a presumptive diagnosis of Crohn's disease with extraintestinal manifestations. Chronic granulomatous disease was suspected in this case after Serratia marcescens was isolated from a skin ulcer culture. Granulomas were confirmed on histology and chronic granulomatous disease was diagnosed. This case emphasizes the importance of high clinical suspicion of an alternative diagnosis of immune deficiency in patients with presumed inflammatory bowel disease and opportunistic infections, especially when disease occurs in early life.

The construction of a panel of serum amino acids for the identification of early chronic kidney disease patients.

PubMed

Li, Rui; Dai, Jinna; Kang, Hui

2018-03-01

Serum creatinine, urea, and cystatin-c are standardly used for the evaluation of renal function in the clinic. However, some patients have chronic kidney disease but still retain kidney function; a conventional serum index in these patients can be completely normal. Serum amino acid levels can reflect subtle changes in metabolism and are closely related to renal function. Here, we investigated how amino acids change as renal impairment increases. Subjects were divided into three groups by renal function glomerular filtration rate: healthy controls, patients with chronic kidney disease with normal kidney function, and patients with chronic kidney disease with decreased kidney function group. We identified 11 amino acids of interest using LC-MS/MS on MRM (+) mode. Statistical analysis indicated that alanine (ALA), valine (VAL), and tyrosine (TYR) decrease with renal function impairment, whereas phenylalanine (PHE) and citrulline (CIT) increase. We tried to construct a diagnostic model utilizing a combination of amino acids capable of identifying early chronic kidney disease patients. The accuracy, specificity, and sensitivity of the combining predictors were 86.9%, 84.6%, and 90.9%, respectively, which is superior to the reported values for serum creatinine, urea, and cystatin-c. Our data suggest that serum amino acid levels may supply important information for the early detection of chronic kidney disease. We are the first to establish a diagnostic model utilizing serum levels of multiple amino acids for the diagnosis of patients with early-stage chronic kidney disease. © 2017 Wiley Periodicals, Inc.

PGC-1α, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease

PubMed Central

Zheng, Bin; Liao, Zhixiang; Locascio, Joseph J.; Lesniak, Kristen A.; Roderick, Sarah S.; Watt, Marla L.; Eklund, Aron C.; Zhang-James, Yanli; Kim, Peter D.; Hauser, Michael A.; Grünblatt, Edna; Moran, Linda B.; Mandel, Silvia A.; Riederer, Peter; Miller, Renee M.; Federoff, Howard J.; Wüllner, Ullrich; Papapetropoulos, Spyridon; Youdim, Moussa B.; Cantuti-Castelvetri, Ippolita; Young, Anne B.; Vance, Jeffery M.; Davis, Richard L.; Hedreen, John C.; Adler, Charles H.; Beach, Thomas G.; Graeber, Manuel B.; Middleton, Frank A.; Rochet, Jean-Christophe; Scherzer, Clemens R.

2011-01-01

Parkinson’s disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson’s and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson’s disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson’s disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson’s disease identifies PGC-1α as a potential therapeutic target for early intervention. PMID:20926834

Proteomics analysis identified peroxiredoxin 2 involved in early-phase left ventricular impairment in hamsters with cardiomyopathy.

PubMed

Kuzuya, Kentaro; Ichihara, Sahoko; Suzuki, Yuka; Inoue, Chisa; Ichihara, Gaku; Kurimoto, Syota; Oikawa, Shinji

2018-01-01

Given the hypothesis that inflammation plays a critical role in the progression of cardiovascular diseases, the aim of the present study was to identify new diagnostic and prognostic biomarkers of myocardial proteins involved in early-phase cardiac impairment, using proteomics analysis. Using the two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with MALDI-TOF/TOF tandem mass spectrometry, we compared differences in the expression of proteins in the whole left ventricles between control hamsters, dilated cardiomyopathic hamsters (TO-2), and hypertrophy cardiomyopathic hamsters (Bio14.6) at 6 weeks of age (n = 6, each group). Proteomic analysis identified 10 protein spots with significant alterations, with 7 up-regulated and 3 down-regulated proteins in the left ventricles of both TO-2 and Bio 14.6 hamsters, compared with control hamsters. Of the total alterations, peroxiredoxin 2 (PRDX2) showed significant upregulation in the left ventricles of TO-2 and Bio 14.6 hamsters. Our data suggest that PRDX2, a redox regulating molecule, is involved in early-phase left ventricular impairment in hamsters with cardiomyopathy.

Early neurovascular dysfunction in a transgenic rat model of Alzheimer’s disease

PubMed Central

Joo, Illsung L.; Lai, Aaron Y.; Bazzigaluppi, Paolo; Koletar, Margaret M.; Dorr, Adrienne; Brown, Mary E.; Thomason, Lynsie A. M.; Sled, John G.; McLaurin, JoAnne; Stefanovic, Bojana

2017-01-01

Alzheimer’s disease (AD), pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aβ-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans. PMID:28401931

Rodent Models of Experimental Endometriosis: Identifying Mechanisms of Disease and Therapeutic Targets

PubMed Central

Bruner-Tran, Kaylon L.; Mokshagundam, Shilpa; Herington, Jennifer L.; Ding, Tianbing; Osteen, Kevin G.

2018-01-01

Background: Although it has been more than a century since endometriosis was initially described in the literature, understanding the etiology and natural history of the disease has been challenging. However, the broad utility of murine and rat models of experimental endometriosis has enabled the elucidation of a number of potentially targetable processes which may otherwise promote this disease. Objective: To review a variety of studies utilizing rodent models of endometriosis to illustrate their utility in examining mechanisms associated with development and progression of this disease. Results: Use of rodent models of endometriosis has provided a much broader understanding of the risk factors for the initial development of endometriosis, the cellular pathology of the disease and the identification of potential therapeutic targets. Conclusion: Although there are limitations with any animal model, the variety of experimental endometriosis models that have been developed has enabled investigation into numerous aspects of this disease. Thanks to these models, our under-standing of the early processes of disease development, the role of steroid responsiveness, inflammatory processes and the peritoneal environment has been advanced. More recent models have begun to shed light on how epigenetic alterations con-tribute to the molecular basis of this disease as well as the multiple comorbidities which plague many patients. Continued de-velopments of animal models which aid in unraveling the mechanisms of endometriosis development provide the best oppor-tunity to identify therapeutic strategies to prevent or regress this enigmatic disease.

R6/2 Huntington's disease mice develop early and progressive abnormal brain metabolism and seizures.

PubMed

Cepeda-Prado, Efrain; Popp, Susanna; Khan, Usman; Stefanov, Dimitre; Rodríguez, Jorge; Menalled, Liliana B; Dow-Edwards, Diana; Small, Scott A; Moreno, Herman

2012-05-09

A hallmark feature of Huntington's disease pathology is the atrophy of brain regions including, but not limited to, the striatum. Though MRI studies have identified structural CNS changes in several Huntington's disease (HD) mouse models, the functional consequences of HD pathology during the progression of the disease have yet to be investigated using in vivo functional MRI (fMRI). To address this issue, we first established the structural and functional MRI phenotype of juvenile HD mouse model R6/2 at early and advanced stages of disease. Significantly higher fMRI signals [relative cerebral blood volumes (rCBVs)] and atrophy were observed in both age groups in specific brain regions. Next, fMRI results were correlated with electrophysiological analysis, which showed abnormal increases in neuronal activity in affected brain regions, thus identifying a mechanism accounting for the abnormal fMRI findings. [(14)C] 2-deoxyglucose maps to investigate patterns of glucose utilization were also generated. An interesting mismatch between increases in rCBV and decreases in glucose uptake was observed. Finally, we evaluated the sensitivity of this mouse line to audiogenic seizures early in the disease course. We found that R6/2 mice had an increased susceptibility to develop seizures. Together, these findings identified seizure activity in R6/2 mice and show that neuroimaging measures sensitive to oxygen metabolism can be used as in vivo biomarkers, preceding the onset of an overt behavioral phenotype. Since fMRI-rCBV can also be obtained in patients, we propose that it may serve as a translational tool to evaluate therapeutic responses in humans and HD mouse models.

Glypican1 identifies cancer exosomes and facilitates early detection of cancer

PubMed Central

Melo, Sonia A.; Luecke, Linda B.; Kahlert, Christoph; Fernandez, Agustin F.; Gammon, Seth T.; Kaye, Judith; LeBleu, Valerie S.; Mittendorf, Elizabeth A.; Weitz, Juergen; Rahbari, Nuh; Reissfelder, Christoph; Pilarsky, Christian; Fraga, Mario F.; Piwnica-Worms, David; Kalluri, Raghu

2016-01-01

Summary Exosomes are lipid bilayer-enclosed extracellular vesicles (EVs) that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer cell-derived exosomes in circulation is currently lacking. Using mass spectrometry analyses, we identified a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer cell-derived exosomes. GPC1+ circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of cancer patients and mice with cancer. GPC1+ crExos were detected in the serum of patients with pancreas cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreas disease from patients with early and late stage pancreas cancer. Levels of GPC1+ crExos correlate with tumor burden and survival in patients pre- and post-surgical tumor resection. GPC1+ crExos from patients and from mice with spontaneous pancreas tumors driven by oncogenic KRAS contained RNA with specific KRAS mutation, and it emerges as a reliable biomarker for the detection of PanIN lesions despite negative signal by MRI in mice. GPC1+ crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreas cancer to facilitate possible curative surgical therapy. PMID:26106858

Metabolic Differentiation of Early Lyme Disease from Southern Tick-Associated Rash Illness (STARI)

PubMed Central

Molins, C. R.; Ashton, L. V.; Wormser, G. P.; Andre, B. G.; Hess, A. M.; Delorey, M. J.; Pilgard, M. A.; Johnson, B. J.; Webb, K.; Islam, M. N.; Pegalajar-Jurado, A; Molla, I.; Jewett, M. W.; Belisle, J. T.

2017-01-01

Lyme disease, the most commonly reported vector-borne disease in the United States, results from infection with Borrelia burgdorferi. Early clinical diagnosis of this disease is largely based on the presence of an erythematous skin lesion for individuals in high-risk regions. This, however, can be confused with other illnesses including southern tick-associated rash illness (STARI), an illness that lacks a defined etiological agent or laboratory diagnostic test, and is co-prevalent with Lyme disease in portions of the Eastern United States. By applying an unbiased metabolomics approach with sera retrospectively obtained from well-characterized patients we defined biochemical and diagnostic differences between early Lyme disease and STARI. Specifically, a metabolic biosignature consisting of 261 molecular features (MFs) revealed that altered N-acyl ethanolamine and primary fatty acid amide metabolism discriminated early Lyme disease from STARI. More importantly, development of classification models with the 261 MF biosignature and testing against validation samples differentiated early Lyme disease from STARI with an accuracy of 85 to 98%. These findings revealed metabolic dissimilarity between early Lyme disease and STARI, and provide a powerful and new approach to objectively distinguish early Lyme disease from an illness with nearly identical symptoms. PMID:28814545

Early recognition of Cushing's disease: a case study.

PubMed

Iuliano, Sherry L; Laws, Edward R

2013-08-01

To present a case study of a 34-year-old woman with Cushing's disease and provide nurse practitioners (NPs) with the understanding of the clinical presentation needed for early recognition and treatment of the disease. A comprehensive review of published literature on Cushing's disease. Findings from history, physical examination, and diagnostic studies of a woman presenting to primary care NPs, physicians and other healthcare providers with multiple symptoms of Cushing's disease. Cushing's disease is the result of the pituitary gland producing excess amounts of adrenocorticotropic hormone (ACTH) causing the overproduction of cortisol. The disease is fairly rare and is seen mostly in women. Common chief complaints include increased facial hair, weight gain, amenorrhea, changes in the face, neck, and abdomen, with muscle wasting of the lower extremities. Untreated, diabetes mellitus and hypertension can occur and increase the patient's morbidity and mortality. Early recognition and appropriate referral can reverse the signs and symptoms over time and lead to a significantly improved quality of life. This case presented the challenges faced by NPs and physicians in diagnosing patients with Cushing's disease. ©2013 The Author(s) ©2013 American Association of Nurse Practitioners.

Early-Life Toxic Insults and Onset of Sporadic Neurodegenerative Diseases-an Overview of Experimental Studies.

PubMed

Tartaglione, Anna Maria; Venerosi, Aldina; Calamandrei, Gemma

2016-01-01

The developmental origin of health and disease hypothesis states that adverse fetal and early childhood exposures can predispose to obesity, cardiovascular, and neurodegenerative diseases (NDDs) in adult life. Early exposure to environmental chemicals interferes with developmental programming and induces subclinical alterations that may hesitate in pathophysiology and behavioral deficits at a later life stage. The mechanisms by which perinatal insults lead to altered programming and to disease later in life are still undefined. The long latency between exposure and onset of disease, the difficulty of reconstructing early exposures, and the wealth of factors which the individual is exposed to during the life course make extremely difficult to prove the developmental origin of NDDs in clinical and epidemiological studies. An overview of animal studies assessing the long-term effects of perinatal exposure to different chemicals (heavy metals and pesticides) supports the link between exposure and hallmarks of neurodegeneration at the adult stage. Furthermore, models of maternal immune activation show that brain inflammation in early life may enhance adult vulnerability to environmental toxins, thus supporting the multiple hit hypothesis for NDDs' etiology. The study of prospective animal cohorts may help to unraveling the complex pathophysiology of sporadic NDDs. In vivo models could be a powerful tool to clarify the mechanisms through which different kinds of insults predispose to cell loss in the adult age, to establish a cause-effect relationship between "omic" signatures and disease/dysfunction later in life, and to identify peripheral biomarkers of exposure, effects, and susceptibility, for translation to prospective epidemiological studies.

Measuring Disease Progression in Early Parkinson Disease: the National Institutes of Health Exploratory Trials in Parkinson Disease (NET-PD) Experience

PubMed Central

Parashos, Sotirios A.; Luo, Sheng; Biglan, Kevin M.; -Wollner, Ivan Bodis; He, Bo; Liang, Grace S.; Ross, G. Webster; Tilley, Barbara C.; Shulman, Lisa M.

2014-01-01

associated with earlier need for symptomatic therapy. Conclusions and Relevance In early PD, UPDRS II and III, and S&E can be used to measure disease progression, while the PDQ39 ADL, PDQ39 SI, TFC, SF12 PH, and SF12 MH are not sensitive to change. Trial Registration clinicaltrials.gov identifiers NCT00063193 and NCT00076492 PMID:24711047

Putaminal volume and diffusion in early familial Creutzfeldt-Jakob disease.

PubMed

Seror, Ilana; Lee, Hedok; Cohen, Oren S; Hoffmann, Chen; Prohovnik, Isak

2010-01-15

The putamen is centrally implicated in the pathophysiology of Creutzfeldt-Jakob Disease (CJD). To our knowledge, its volume has never been measured in this disease. We investigated whether gross putaminal atrophy can be detected by MRI in early stages, when the diffusion is already reduced. Twelve familial CJD patients with the E200K mutation and 22 healthy controls underwent structural and diffusion MRI scans. The putamen was identified in anatomical scans by two methods: manual tracing by a blinded investigator, and automatic parcellation by a computerized segmentation procedure (FSL FIRST). For each method, volume and mean Apparent Diffusion Coefficient (ADC) were calculated. ADC was significantly lower in CJD patients (697+/-64 microm(2)/s vs. 750+/-31 microm(2)/s, p<0.005), as expected, but the volume was not reduced. The computerized FIRST delineation yielded comparable ADC values to the manual method, but computerized volumes were smaller than manual tracing values. We conclude that significant diffusion reduction in the putamen can be detected by delineating the structure manually or with a computerized algorithm. Our findings confirm and extend previous voxel-based and observational studies. Putaminal volume was not reduced in our early-stage patients, thus confirming that diffusion abnormalities precede detectible atrophy in this structure.

Early bronchopulmonary involvement in Crohn disease: a case report

PubMed Central

Valletta, Enrico; Bertini, Marina; Sette, Luciano; Braggion, Cesare; Pradal, Ugo; Zannoni, Marina

2001-01-01

Background Bronchopulmonary manifestations of Crohn disease have been rarely described in children, including both subclinical pulmonary involvement and severe lung disease. Case presentation A 6.5-year-old girl is described with early recurrent bronchopulmonary symptoms both at presentation and in the quiescent phase of Crohn disease. Pulmonary function tests (lung volumes and flows, bronchial reactivity and carbon monoxide diffusing capacity) were normal. Bronchoalveolar cytology showed increased (30%) lymphocyte counts and bronchial biopsy revealed thickening of basal membrane and active chronic inflammation. Conclusions Clinical and histological findings in our young patient suggest involvement of both distal and central airways in an early phase of lung disease. The pathogenesis of Crohn disease-associated lung disorders is discussed with reference to the available literature. A low threshold for pulmonary evaluation seems to be advisable in all children with CD. PMID:11734067

Early-Onset Autoimmune Disease as a Manifestation of Primary Immunodeficiency

PubMed Central

Carneiro-Sampaio, Magda; Coutinho, Antonio

2015-01-01

Autoimmune disorders (AID) have been increasingly observed in association with primary immunodeficiencies (PIDs). Here, we discuss the interface between PID and AID, focusing on autoimmune manifestations early in life, which can be diagnostic clues for underlying PIDs. Inflammatory bowel disease in infants and children has been associated with IL-10 and IL-10R deficiencies, chronic granulomatous disease, immunedysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (IPEX), autoinflammatory disorders, and others. Some PIDs have been identified as underlying defects in juvenile systemic lupus erythematosus: C1q-, IgA-, IgM deficiencies, alterations of the IFN-α pathway (in Aicardi–Goutières syndrome due to TREX1 mutation). IPEX (due to FOXP3 mutation leading to Treg cell deficiency), usually appearing in the first months of life, was recently observed in miscarried fetuses with hydrops who presented with CD3+ infiltrating lymphocytes in the pancreas. Hemophagocytic lymphohistiocytosis due to perforin deficiency was also identified as a cause of fetal hydrops. In conclusion, PID should be suspected in any infant with signs of autoimmunity after excluding transferred maternal effects, or in children with multiple and/or severe AID. PMID:25999944

Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn's disease.

PubMed

Lakatos, Peter Laszlo; Czegledi, Zsofia; Szamosi, Tamas; Banai, Janos; David, Gyula; Zsigmond, Ferenc; Pandur, Tunde; Erdelyi, Zsuzsanna; Gemela, Orsolya; Papp, Janos; Lakatos, Laszlo

2009-07-28

To assess the combined effect of disease phenotype, smoking and medical therapy [steroid, azathioprine (AZA), AZA/biological therapy] on the probability of disease behavior change in a Caucasian cohort of patients with Crohn's disease (CD). Three hundred and forty well-characterized, unrelated, consecutive CD patients were analyzed (M/F: 155/185, duration: 9.4 +/- 7.5 years) with a complete clinical follow-up. Medical records including disease phenotype according to the Montreal classification, extraintestinal manifestations, use of medications and surgical events were analyzed retrospectively. Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits. A change in disease behavior was observed in 30.8% of patients with an initially non-stricturing, non-penetrating disease behavior after a mean disease duration of 9.0 +/- 7.2 years. In a logistic regression analysis corrected for disease duration, perianal disease, smoking, steroid use, early AZA or AZA/biological therapy use were independent predictors of disease behavior change. In a subsequent Kaplan-Meier survival analysis and a proportional Cox regression analysis, disease location (P = 0.001), presence of perianal disease (P < 0.001), prior steroid use (P = 0.006), early AZA (P = 0.005) or AZA/biological therapy (P = 0.002), or smoking (P = 0.032) were independent predictors of disease behavior change. Our data suggest that perianal disease, small bowel disease, smoking, prior steroid use, early AZA or AZA/biological therapy are all predictors of disease behavior change in CD patients.

Urine biomarkers in the early stages of diseases: current status and perspective.

PubMed

Jing, Jian; Gao, Youhe

2018-02-01

As a noninvasive and easily available biological fluid, the urine is becoming an important source for disease biomarker study. Change is essential for the usefulness of a biomarker. Without homeostasis mechanisms, urine can accommodate more changes, especially in the early stages of diseases. In this review, we summarize current status and discuss perspectives on the discovery of urine biomarkers in the early stages of diseases. We emphasize the advantages of urine biomarkers compared to plasma biomarkers for the diagnosis of diseases at early stages, propose a urine biomarker research roadmap, and highlight a novel membrane storage technique that enables large-scale urine sample collection and storage efficiently and economically. It is anticipated that urine biomarker studies will greatly promote early diagnosis, prevention, treatment, and prognosis of a variety of diseases, and provide strong support for translational and precision medicine.

Identifying Early Target Cells of Nipah Virus Infection in Syrian Hamsters

PubMed Central

Baseler, Laura; Scott, Dana P.; Saturday, Greg; Horne, Eva; Rosenke, Rebecca; Thomas, Tina; Meade-White, Kimberly; Haddock, Elaine; Feldmann, Heinz

2016-01-01

Background Nipah virus causes respiratory and neurologic disease with case fatality rates up to 100% in individual outbreaks. End stage lesions have been described in the respiratory and nervous systems, vasculature and often lymphoid organs in fatal human cases; however, the initial target organs of Nipah virus infection have not been identified. Here, we detected the initial target tissues and cells of Nipah virus and tracked virus dissemination during the early phase of infection in Syrian hamsters inoculated with a Nipah virus isolate from Malaysia (NiV-M) or Bangladesh (NiV-B). Methodology/Principal Findings Syrian hamsters were euthanized between 4 and 48 hours post intranasal inoculation and tissues were collected and analyzed for the presence of viral RNA, viral antigen and infectious virus. Virus replication was first detected at 8 hours post inoculation (hpi). Nipah virus initially targeted type I pneumocytes, bronchiolar respiratory epithelium and alveolar macrophages in the lung and respiratory and olfactory epithelium lining the nasal turbinates. By 16 hpi, virus disseminated to epithelial cells lining the larynx and trachea. Although the pattern of viral dissemination was similar for both virus isolates, the rate of spread was slower for NiV-B. Infectious virus was not detected in the nervous system or blood and widespread vascular infection and lesions within lymphoid organs were not observed, even at 48 hpi. Conclusions/Significance Nipah virus initially targets the respiratory system. Virus replication in the brain and infection of blood vessels in non-respiratory tissues does not occur during the early phase of infection. However, virus replicates early in olfactory epithelium and may serve as the first step towards nervous system dissemination, suggesting that development of vaccines that block virus dissemination or treatments that can access the brain and spinal cord and directly inhibit virus replication may be necessary for preventing central

Identifying Early Target Cells of Nipah Virus Infection in Syrian Hamsters.

PubMed

Baseler, Laura; Scott, Dana P; Saturday, Greg; Horne, Eva; Rosenke, Rebecca; Thomas, Tina; Meade-White, Kimberly; Haddock, Elaine; Feldmann, Heinz; de Wit, Emmie

2016-11-01

Nipah virus causes respiratory and neurologic disease with case fatality rates up to 100% in individual outbreaks. End stage lesions have been described in the respiratory and nervous systems, vasculature and often lymphoid organs in fatal human cases; however, the initial target organs of Nipah virus infection have not been identified. Here, we detected the initial target tissues and cells of Nipah virus and tracked virus dissemination during the early phase of infection in Syrian hamsters inoculated with a Nipah virus isolate from Malaysia (NiV-M) or Bangladesh (NiV-B). Syrian hamsters were euthanized between 4 and 48 hours post intranasal inoculation and tissues were collected and analyzed for the presence of viral RNA, viral antigen and infectious virus. Virus replication was first detected at 8 hours post inoculation (hpi). Nipah virus initially targeted type I pneumocytes, bronchiolar respiratory epithelium and alveolar macrophages in the lung and respiratory and olfactory epithelium lining the nasal turbinates. By 16 hpi, virus disseminated to epithelial cells lining the larynx and trachea. Although the pattern of viral dissemination was similar for both virus isolates, the rate of spread was slower for NiV-B. Infectious virus was not detected in the nervous system or blood and widespread vascular infection and lesions within lymphoid organs were not observed, even at 48 hpi. Nipah virus initially targets the respiratory system. Virus replication in the brain and infection of blood vessels in non-respiratory tissues does not occur during the early phase of infection. However, virus replicates early in olfactory epithelium and may serve as the first step towards nervous system dissemination, suggesting that development of vaccines that block virus dissemination or treatments that can access the brain and spinal cord and directly inhibit virus replication may be necessary for preventing central nervous system pathology.

Metabolic differentiation of early Lyme disease from southern tick-associated rash illness (STARI).

PubMed

Molins, Claudia R; Ashton, Laura V; Wormser, Gary P; Andre, Barbara G; Hess, Ann M; Delorey, Mark J; Pilgard, Mark A; Johnson, Barbara J; Webb, Kristofor; Islam, M Nurul; Pegalajar-Jurado, Adoracion; Molla, Irida; Jewett, Mollie W; Belisle, John T

2017-08-16

Lyme disease, the most commonly reported vector-borne disease in the United States, results from infection with Borrelia burgdorferi. Early clinical diagnosis of this disease is largely based on the presence of an erythematous skin lesion for individuals in high-risk regions. This, however, can be confused with other illnesses including southern tick-associated rash illness (STARI), an illness that lacks a defined etiological agent or laboratory diagnostic test, and is coprevalent with Lyme disease in portions of the eastern United States. By applying an unbiased metabolomics approach with sera retrospectively obtained from well-characterized patients, we defined biochemical and diagnostic differences between early Lyme disease and STARI. Specifically, a metabolic biosignature consisting of 261 molecular features (MFs) revealed that altered N -acyl ethanolamine and primary fatty acid amide metabolism discriminated early Lyme disease from STARI. Development of classification models with the 261-MF biosignature and testing against validation samples differentiated early Lyme disease from STARI with an accuracy of 85 to 98%. These findings revealed metabolic dissimilarity between early Lyme disease and STARI, and provide a powerful and new approach to inform patient management by objectively distinguishing early Lyme disease from an illness with nearly identical symptoms. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Urinary Biomarkers at Early ADPKD Disease Stage

PubMed Central

Petzold, Katja; Poster, Diane; Krauer, Fabienne; Spanaus, Katharina; Andreisek, Gustav; Nguyen-Kim, Thi Dan Linh; Pavik, Ivana; Ho, Thien Anh; Serra, Andreas L.; Rotar, Laura

2015-01-01

Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by a decline in renal function at late disease stage when the majority of functional renal parenchyma is replaced by cystic tissue. Thus, kidney function, assessed by estimated glomerular filtration rate (eGFR) does not well represent disease burden in early disease. Here, we investigated various urinary markers for tubular injury and their association with disease burden in ADPKD patients at early disease course. Methods ADPKD patients between 18 and 40 years with an eGFR greater or equal to 70 ml per min per 1.73m2 were eligible for this cross-sectional study. Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL), Kidney Injury Molecule-1 (KIM-1), and Uromodulin (UMOD) were investigated by Enzyme-Linked Immunosorbent Assay. Clara Cell Protein 16 (CC16) was investigated by Latex Immuno Assay. Cryoscopy was performed to assess urine osmolality and Urinary Albumin-to-Creatinine Ratio (UACR) was calculated. The association and the predictive properties of the markers on eGFR and height adjusted total kidney volume (htTKV) was evaluated using multiple regression analysis, incorporating different control variables for adjustment. Internal bootstrapping validated the obtained results. Results In 139 ADPKD patients (age 31 ±7 years, mean eGFR of 93 ± 19 ml per min per 1.73 m2) the total kidney volume was negatively correlated with eGFR and UMOD and positive associated with age, UACR, KIM-1 and urine osmolality after adjustment for possible confounders. Urine osmolality and htTKV were also associated with eGFR, whereas no association of CC16, NGAL and UMOD with eGFR or htTKV was found. Conclusion UACR and urinary KIM-1 are independently associated with kidney size but not with renal function in our study population. Urine osmolality was associated with eGFR and kidney volume following adjustment for multiple confounders. Despite statistical significance, the clinical value of our

Confidence interval estimation of the difference between two sensitivities to the early disease stage.

PubMed

Dong, Tuochuan; Kang, Le; Hutson, Alan; Xiong, Chengjie; Tian, Lili

2014-03-01

Although most of the statistical methods for diagnostic studies focus on disease processes with binary disease status, many diseases can be naturally classified into three ordinal diagnostic categories, that is normal, early stage, and fully diseased. For such diseases, the volume under the ROC surface (VUS) is the most commonly used index of diagnostic accuracy. Because the early disease stage is most likely the optimal time window for therapeutic intervention, the sensitivity to the early diseased stage has been suggested as another diagnostic measure. For the purpose of comparing the diagnostic abilities on early disease detection between two markers, it is of interest to estimate the confidence interval of the difference between sensitivities to the early diseased stage. In this paper, we present both parametric and non-parametric methods for this purpose. An extensive simulation study is carried out for a variety of settings for the purpose of evaluating and comparing the performance of the proposed methods. A real example of Alzheimer's disease (AD) is analyzed using the proposed approaches. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A critical review: early life nutrition and prenatal programming for adult disease.

PubMed

Carolan-Olah, Mary; Duarte-Gardea, Maria; Lechuga, Julia

2015-12-01

To present the evidence in relation to early life nutrition and foetal programming for adult disease. Epigenetics is a new and growing area of study investigating the impact of the intrauterine environment on the lifelong health of individuals. Discursive paper. Searches were conducted in a range of electronic health databases. Hand searches located additional articles for review. Maternal search terms included: pregnancy; nutrition; diet; obesity; over nutrition; under nutrition. Offspring related search terms included: macrosomia; intrauterine growth restriction; epigenetics; foetal programming; childhood obesity; adolescent obesity; adolescent type 2 diabetes. Results indicate that foetal programming for adult disease occurs in response to particular insults during vulnerable developmental periods. Four main areas of foetal exposure were identified in this review: (1) under nutrition; (2) over nutrition; (3) gestational diabetes mellitus; and (4) infant catch-up growth. Numerous studies also described the trans-generational nature of foetal programming. Overall, foetal exposure to excess or insufficient nutrition during vulnerable developmental periods appears to result in a lifelong predisposition to obesity and adult disease, such as type 2 diabetes and cardiac disease. For the infant who has been undernourished during early life, a predisposition to renal disease also occurs. Pregnancy is a time when women are engaged in health systems and are receptive to health messages. These factors suggest that pregnancy may be an optimal time for dietary education and intervention. There is a particular need for education on healthy diet and for interventions which aim to limit over consumption of calories. © 2015 John Wiley & Sons Ltd.

Limbic grey matter changes in early Parkinson's disease.

PubMed

Li, Xingfeng; Xing, Yue; Schwarz, Stefan T; Auer, Dorothee P

2017-05-02

The purpose of this study was to investigate local and network-related changes of limbic grey matter in early Parkinson's disease (PD) and their inter-relation with non-motor symptom severity. We applied voxel-based morphometric methods in 538 T1 MRI images retrieved from the Parkinson's Progression Markers Initiative website. Grey matter densities and cross-sectional estimates of age-related grey matter change were compared between subjects with early PD (n = 366) and age-matched healthy controls (n = 172) within a regression model, and associations of grey matter density with symptoms were investigated. Structural brain networks were obtained using covariance analysis seeded in regions showing grey matter abnormalities in PD subject group. Patients displayed focally reduced grey matter density in the right amygdala, which was present from the earliest stages of the disease without further advance in mild-moderate disease stages. Right amygdala grey matter density showed negative correlation with autonomic dysfunction and positive with cognitive performance in patients, but no significant interrelations were found with anxiety scores. Patients with PD also demonstrated right amygdala structural disconnection with less structural connectivity of the right amygdala with the cerebellum and thalamus but increased covariance with bilateral temporal cortices compared with controls. Age-related grey matter change was also increased in PD preferentially in the limbic system. In conclusion, detailed brain morphometry in a large group of early PD highlights predominant limbic grey matter deficits with stronger age associations compared with controls and associated altered structural connectivity pattern. This provides in vivo evidence for early limbic grey matter pathology and structural network changes that may reflect extranigral disease spread in PD. Hum Brain Mapp, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. © 2017 The

Measuring disease progression in early Parkinson disease: the National Institutes of Health Exploratory Trials in Parkinson Disease (NET-PD) experience.

PubMed

Parashos, Sotirios A; Luo, Sheng; Biglan, Kevin M; Bodis-Wollner, Ivan; He, Bo; Liang, Grace S; Ross, G Webster; Tilley, Barbara C; Shulman, Lisa M

2014-06-01

% CI, 1.06-1.13] for 1 scale unit change per 6 months), and the Schwab and England Independence Scale score (hazard ratio, 1.29 [95% CI, 1.12-1.48] for 5 percentage point change per 6 months) was associated with earlier need for symptomatic therapy. AND RELEVANCE In early PD, the UPDRS Part II score and Part III score and the Schwab and England Independence Scale score can be used to measure disease progression, whereas the 39-item Parkinson's Disease Questionnaire and summary index, Total Functional Capacity scale, and the 12-item Short Form Health Survey Physical Summary and Mental Summary are not sensitive to change. clinicaltrials.gov Identifiers: NCT00063193 and NCT00076492.

Early-Life Nutritional Programming of Health and Disease in The Gambia.

PubMed

Moore, Sophie E

2017-01-01

Exposures during early life are increasingly being recognised as factors that play an important role in the aetiology of chronic non-communicable diseases (NCDs). The "Developmental Origins of Health and Disease" (DOHaD) hypothesis asserts that adverse early-life exposures - most notably unbalanced nutrition - leads to an increased risk for a range of NCDs and that disease risk is highest when there is a "mismatch" between the early- and later-life environments. Thus, the DOHaD hypothesis would predict highest risk in settings undergoing a rapid nutrition transition. We investigated the link between early-life nutritional exposures and long-term health in rural Gambia, West Africa. Using demographic data dating back to the 1940s, the follow-up of randomised controlled trials of nutritional supplementation in pregnancy, and the "experiment of nature" that seasonality in this region provides, we investigated the DOHaD hypothesis in a population with high rates of maternal and infant under-nutrition, a high burden from infectious disease, and an emerging risk of NCDs. Key Messages: Our work in rural Gambia suggests that in populations with high rates of under-nutrition in early life, the immune system may be sensitive to nutritional deficiencies early in life, resulting in a greater susceptibility to infection-related morbidity and mortality. © 2017 S. Karger AG, Basel.

Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications

PubMed Central

Pohl, Calvin S.; Medland, Julia E.

2015-01-01

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted. PMID:26451004

The design of composite monitoring scheme for multilevel information in crop early diseases

NASA Astrophysics Data System (ADS)

Zhang, Yan; Meng, Qinglong; Shang, Jing

2018-02-01

It is difficult to monitor and predict the crops early diseases in that the crop disease monitoring is usually monitored by visible light images and the availabilities in early warning are poor at present. The features of common nondestructive testing technology applied to the crop diseases were analyzed in this paper. Based on the changeable characteristics of the virus from the incubation period to the onset period of crop activities, the multilevel composite information monitoring scheme were designed by applying infrared thermal imaging, visible near infrared hyperspectral imaging, micro-imaging technology to the monitoring of multilevel information of crop disease infection comprehensively. The early warning process and key monitoring parameters of compound monitoring scheme are given by taking the temperature, color, structure and texture of crops as the key monitoring characteristics of disease. With overcoming the deficiency that the conventional monitoring scheme is only suitable for the observation of diseases with naked eyes, the monitoring and early warning of the incubation and early onset of the infection crops can be realized by the composite monitoring program as mentioned in this paper.

Characteristics of seroconversion and implications for diagnosis of post-treatment Lyme disease syndrome: acute and convalescent serology among a prospective cohort of early Lyme disease patients.

PubMed

Rebman, Alison W; Crowder, Lauren A; Kirkpatrick, Allison; Aucott, John N

2015-03-01

Two-tier serology is often used to confirm a diagnosis of Lyme disease. One hundred and four patients with physician diagnosed erythema migrans rashes had blood samples taken before and after 3 weeks of doxycycline treatment for early Lyme disease. Acute and convalescent serologies for Borrelia burgdorferi were interpreted according to the 2-tier antibody testing criteria proposed by the Centers for Disease Control and Prevention. Serostatus was compared across several clinical and demographic variables both pre- and post-treatment. Forty-one patients (39.4%) were seronegative both before and after treatment. The majority of seropositive individuals on both acute and convalescent serology had a positive IgM western blot and a negative IgG western blot. IgG seroconversion on western blot was infrequent. Among the baseline variables included in the analysis, disseminated lesions (p < 0.0001), a longer duration of illness (p < 0.0001), and a higher number of reported symptoms (p = 0.004) were highly significantly associated with positive final serostatus, while male sex (p = 0.05) was borderline significant. This variability, and the lack of seroconversion in a subset of patients, highlights the limitations of using serology alone in identifying early Lyme disease. Furthermore, these findings underline the difficulty for rheumatologists in identifying a prior exposure to Lyme disease in caring for patients with medically unexplained symptoms or fibromyalgia-like syndromes.

Destructive bone disease in early syphilis.

PubMed

Dismukes, W E; Delgado, D G; Mallernee, S V; Myers, T C

1976-12-06

Although destructive bone disease is a well-known complication of tertiary syphilis, osteitis or osteomyelitis are not commonly recognized as complications of early (primary or secondary) syphillis. A patient with secondary syphilis characterized by generalized lymphadenopathy, perianal condyloma lata, and positive rapid plasma reagin (RPR) and fluorescent treponemal antibody-absorption (FTA-ABS) tests also complained of headache, right should pain, and right anterior chest pain and swelling. Roentgenograms showed mottled osteolytic lesions consistent with previously described luetic bone disease. Biopsy confirmed the diagnosis of syphilitic osteomyelitis, and treatment with penicillin resulted in prompt resolution of symptoms.

Speech acoustic markers of early stage and prodromal Huntington's disease: a marker of disease onset?

PubMed

Vogel, Adam P; Shirbin, Christopher; Churchyard, Andrew J; Stout, Julie C

2012-12-01

Speech disturbances (e.g., altered prosody) have been described in symptomatic Huntington's Disease (HD) individuals, however, the extent to which speech changes in gene positive pre-manifest (PreHD) individuals is largely unknown. The speech of individuals carrying the mutant HTT gene is a behavioural/motor/cognitive marker demonstrating some potential as an objective indicator of early HD onset and disease progression. Speech samples were acquired from 30 individuals carrying the mutant HTT gene (13 PreHD, 17 early stage HD) and 15 matched controls. Participants read a passage, produced a monologue and said the days of the week. Data were analysed acoustically for measures of timing, frequency and intensity. There was a clear effect of group across most acoustic measures, so that speech performance differed in-line with disease progression. Comparisons across groups revealed significant differences between the control and the early stage HD group on measures of timing (e.g., speech rate). Participants carrying the mutant HTT gene presented with slower rates of speech, took longer to say words and produced greater silences between and within words compared to healthy controls. Importantly, speech rate showed a significant correlation to burden of disease scores. The speech of early stage HD differed significantly from controls. The speech of PreHD, although not reaching significance, tended to lie between the performance of controls and early stage HD. This suggests that changes in speech production appear to be developing prior to diagnosis. Copyright © 2012 Elsevier Ltd. All rights reserved.

Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Research Trends and Scientific Gaps

PubMed Central

Bailey, Kathryn A.; Smith, Allan H.; Tokar, Erik J.; Graziano, Joseph H.; Kim, Kyoung-Woong; Navasumrit, Panida; Ruchirawat, Mathuros; Thiantanawat, Apinya; Suk, William A.; Fry, Rebecca C.

2015-01-01

Background Millions of individuals worldwide, particularly those living in rural and developing areas, are exposed to harmful levels of inorganic arsenic (iAs) in their drinking water. Inorganic As exposure during key developmental periods is associated with a variety of adverse health effects, including those that are evident in adulthood. There is considerable interest in identifying the molecular mechanisms that relate early-life iAs exposure to the development of these latent diseases, particularly in relationship to cancer. Objectives This work summarizes research on the molecular mechanisms that underlie the increased risk of cancer development in adulthood that is associated with early-life iAs exposure. Discussion Epigenetic reprogramming that imparts functional changes in gene expression, the development of cancer stem cells, and immunomodulation are plausible underlying mechanisms by which early-life iAs exposure elicits latent carcinogenic effects. Conclusions Evidence is mounting that relates early-life iAs exposure and cancer development later in life. Future research should include animal studies that address mechanistic hypotheses and studies of human populations that integrate early-life exposure, molecular alterations, and latent disease outcomes. Citation Bailey KA, Smith AH, Tokar EJ, Graziano JH, Kim KW, Navasumrit P, Ruchirawat M, Thiantanawat A, Suk WA, Fry RC. 2016. Mechanisms underlying latent disease risk associated with early-life arsenic exposure: current research trends and scientific gaps. Environ Health Perspect 124:170–175; http://dx.doi.org/10.1289/ehp.1409360 PMID:26115410

Quantitative structural MRI for early detection of Alzheimer’s disease

PubMed Central

McEvoy, Linda K; Brewer, James B

2011-01-01

Alzheimer’s disease (AD) is a common progressive neurodegenerative disorder that is not currently diagnosed until a patient reaches the stage of dementia. There is a pressing need to identify AD at an earlier stage, so that treatment, when available, can begin early. Quantitative structural MRI is sensitive to the neurodegeneration that occurs in mild and preclinical AD, and is predictive of decline to dementia in individuals with mild cognitive impairment. Objective evidence of ongoing brain atrophy will be critical for risk/benefit decisions once potentially aggressive, disease-modifying treatments become available. Recent advances have paved the way for the use of quantitative structural MRI in clinical practice, and initial clinical use has been promising. However, further experience with these measures in the relatively unselected patient populations seen in clinical practice is needed to complete translation of the recent enormous advances in scientific knowledge of AD into the clinical realm. PMID:20977326

Magnetic resonance imaging for diagnosis of early Alzheimer's disease.

PubMed

Colliot, O; Hamelin, L; Sarazin, M

2013-10-01

A major challenge for neuroimaging is to contribute to the early diagnosis of Alzheimer's disease (AD). In particular, magnetic resonance imaging (MRI) allows detecting different types of structural and functional abnormalities at an early stage of the disease. Anatomical MRI is the most widely used technique and provides local and global measures of atrophy. The recent diagnostic criteria of "mild cognitive impairment due to AD" include hippocampal atrophy, which is considered a marker of neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in the hippocampus and throughout the whole brain. Recent modalities such as diffusion-tensor imaging and resting-state functional MRI provide additional measures that could contribute to the early diagnosis but require further validation. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Functional neuroanatomical associations of working memory in early-onset Alzheimer's disease.

PubMed

Kobylecki, Christopher; Haense, Cathleen; Harris, Jennifer M; Stopford, Cheryl L; Segobin, Shailendra H; Jones, Matthew; Richardson, Anna M T; Gerhard, Alexander; Anton-Rodriguez, José; Thompson, Jennifer C; Herholz, Karl; Snowden, Julie S

2018-01-01

To characterize metabolic correlates of working memory impairment in clinically defined subtypes of early-onset Alzheimer's disease. Established models of working memory suggest a key role for frontal lobe function, yet the association in Alzheimer's disease between working memory impairment and visuospatial and language symptoms suggests that temporoparietal neocortical dysfunction may be responsible. Twenty-four patients with predominantly early-onset Alzheimer's disease were clinically classified into groups with predominantly amnestic, multidomain or visual deficits. Patients underwent neuropsychological evaluation focused on the domains of episodic and working memory, T1-weighted magnetic resonance imaging and brain fluorodeoxyglucose positron emission tomography. Fluorodeoxyglucose positron emission tomography data were analysed by using a region-of-interest approach. Patients with multidomain and visual presentations performed more poorly on tests of working memory compared with amnestic Alzheimer's disease. Working memory performance correlated with glucose metabolism in left-sided temporoparietal, but not frontal neocortex. Carriers of the apolipoprotein E4 gene showed poorer episodic memory and better working memory performance compared with noncarriers. Our findings support the hypothesis that working memory changes in early-onset Alzheimer's disease are related to temporoparietal rather than frontal hypometabolism and show dissociation from episodic memory performance. They further support the concept of subtypes of Alzheimer's disease with distinct cognitive profiles due to prominent neocortical dysfunction early in the disease course. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

A vector space model approach to identify genetically related diseases.

PubMed

Sarkar, Indra Neil

2012-01-01

The relationship between diseases and their causative genes can be complex, especially in the case of polygenic diseases. Further exacerbating the challenges in their study is that many genes may be causally related to multiple diseases. This study explored the relationship between diseases through the adaptation of an approach pioneered in the context of information retrieval: vector space models. A vector space model approach was developed that bridges gene disease knowledge inferred across three knowledge bases: Online Mendelian Inheritance in Man, GenBank, and Medline. The approach was then used to identify potentially related diseases for two target diseases: Alzheimer disease and Prader-Willi Syndrome. In the case of both Alzheimer Disease and Prader-Willi Syndrome, a set of plausible diseases were identified that may warrant further exploration. This study furthers seminal work by Swanson, et al. that demonstrated the potential for mining literature for putative correlations. Using a vector space modeling approach, information from both biomedical literature and genomic resources (like GenBank) can be combined towards identification of putative correlations of interest. To this end, the relevance of the predicted diseases of interest in this study using the vector space modeling approach were validated based on supporting literature. The results of this study suggest that a vector space model approach may be a useful means to identify potential relationships between complex diseases, and thereby enable the coordination of gene-based findings across multiple complex diseases.

Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn’s disease

PubMed Central

Lakatos, Peter Laszlo; Czegledi, Zsofia; Szamosi, Tamas; Banai, Janos; David, Gyula; Zsigmond, Ferenc; Pandur, Tunde; Erdelyi, Zsuzsanna; Gemela, Orsolya; Papp, Janos; Lakatos, Laszlo

2009-01-01

AIM: To assess the combined effect of disease phenotype, smoking and medical therapy [steroid, azathioprine (AZA), AZA/biological therapy] on the probability of disease behavior change in a Caucasian cohort of patients with Crohn’s disease (CD). METHODS: Three hundred and forty well-characterized, unrelated, consecutive CD patients were analyzed (M/F: 155/185, duration: 9.4 ± 7.5 years) with a complete clinical follow-up. Medical records including disease phenotype according to the Montreal classification, extraintestinal manifestations, use of medications and surgical events were analyzed retrospectively. Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits. RESULTS: A change in disease behavior was observed in 30.8% of patients with an initially non-stricturing, non-penetrating disease behavior after a mean disease duration of 9.0 ± 7.2 years. In a logistic regression analysis corrected for disease duration, perianal disease, smoking, steroid use, early AZA or AZA/biological therapy use were independent predictors of disease behavior change. In a subsequent Kaplan-Meier survival analysis and a proportional Cox regression analysis, disease location (P = 0.001), presence of perianal disease (P < 0.001), prior steroid use (P = 0.006), early AZA (P = 0.005) or AZA/biological therapy (P = 0.002), or smoking (P = 0.032) were independent predictors of disease behavior change. CONCLUSION: Our data suggest that perianal disease, small bowel disease, smoking, prior steroid use, early AZA or AZA/biological therapy are all predictors of disease behavior change in CD patients. PMID:19630105

Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications.

PubMed

Pohl, Calvin S; Medland, Julia E; Moeser, Adam J

2015-12-15

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted. Copyright © 2015 the American Physiological Society.

Treponemal disease in the middle Archaic to early Woodland periods of the western Tennessee River Valley.

PubMed

Smith, Maria Ostendorf

2006-10-01

The high frequency of late prehistoric New World treponemal disease is attributable to the demographic changes concomitant with the adoption of agriculture. However, these demographic changes in group mobility and site density episodically preceded intensive plant domestication, suggesting possible staggered temporal change in observed treponemal disease case frequency. Thirteen convincing and an additional two probable (N = 581) cases of treponemal disease were identified in an eight-site skeletal sample spanning the Middle (6,000-3,000 BCE) to Late (2,500-ca. 1,000 to 500 BCE) Archaic and Early Woodland (500 BCE-0 CE) periods from the western Tennessee River Valley. Treponemal disease cases are infrequent in both the Middle (3/115, 2.6%) and Late (2 to 4 cases, Early Woodland horizon. As the subsistence economy across the Archaic-Woodland temporal boundary in the western Tennessee River Valley remained, as elsewhere, based on intensive hunting and collecting, the demographic corollaries of treponemal disease would apparently not be met. However, the traditional horizon marker of the Woodland period is the adoption of pottery, an activity associated with sedentism.

Predictors of weight loss in early treated Parkinson's disease from the NET-PD LS-1 cohort.

PubMed

Wills, Anne-Marie; Li, Ruosha; Pérez, Adriana; Ren, Xuehan; Boyd, James

2017-08-01

Weight loss is a common symptom of Parkinson's disease and is associated with impaired quality of life. Predictors of weight loss have not been studied in large clinical cohorts. We previously observed an association between change in body mass index and change in Unified Parkinson's Disease Rating Scale (UPDRS) motor and total scores. In this study, we performed a secondary analysis of longitudinal data (1-6 years) from 1619 participants in the NINDS Exploratory Trials in PD Long-term Study-1 (NET-PD LS1) to explore predictors of weight loss in a large prospective clinical trial cohort of early treated Parkinson's disease. The NET-PD LS1 study was a double-blind randomized placebo controlled clinical trial of creatine monohydrate 10 gm/day in early treated PD (within 5 years of diagnosis and within 2 years of starting dopaminergic medications). Linear mixed models were used to estimate the effect of baseline clinical covariates on weight change over time. On average, participants lost only 0.6 kg per year. Higher age, baseline weight, female gender, higher baseline UPDRS scores, greater postural instability, difficulty eating and drinking, lower cognitive scores and baseline levodopa use (compared to dopamine agonists) were all associated with weight loss. Surprisingly baseline difficulty swallowing, dyskinesia, depression, intestinal hypomotility (constipation) and self-reported nausea/vomiting/anorexia were not significantly associated with weight loss in this cohort of early treated Parkinson's disease patients. On average, participants with Parkinson's disease experience little weight loss during the first 1-6 years after starting dopaminergic replacement therapy, however levodopa use and postural instability were both predictors of early weight loss. Trial Registration clinicaltrials.gov identifier# NCT00449865.

Determining the optimal approach to identifying individuals with chronic obstructive pulmonary disease: The DOC study.

PubMed

Ronaldson, Sarah J; Dyson, Lisa; Clark, Laura; Hewitt, Catherine E; Torgerson, David J; Cooper, Brendan G; Kearney, Matt; Laughey, William; Raghunath, Raghu; Steele, Lisa; Rhodes, Rebecca; Adamson, Joy

2018-06-01

Early identification of chronic obstructive pulmonary disease (COPD) results in patients receiving appropriate management for their condition at an earlier stage in their disease. The determining the optimal approach to identifying individuals with chronic obstructive pulmonary disease (DOC) study was a case-finding study to enhance early identification of COPD in primary care, which evaluated the diagnostic accuracy of a series of simple lung function tests and symptom-based case-finding questionnaires. Current smokers aged 35 or more were invited to undertake a series of case-finding tools, which comprised lung function tests (specifically, spirometry, microspirometry, peak flow meter, and WheezoMeter) and several case-finding questionnaires. The effectiveness of these tests, individually or in combination, to identify small airways obstruction was evaluated against the gold standard of spirometry, with the quality of spirometry tests assessed by independent overreaders. The study was conducted with general practices in the Yorkshire and Humberside area, in the UK. Six hundred eighty-one individuals met the inclusion criteria, with 444 participants completing their study appointments. A total of 216 (49%) with good-quality spirometry readings were included in the analysis. The most effective case-finding tools were found to be the peak flow meter alone, the peak flow meter plus WheezoMeter, and microspirometry alone. In addition to the main analysis, where the severity of airflow obstruction was based on fixed ratios and percent of predicted values, sensitivity analyses were conducted by using lower limit of normal values. This research informs the choice of test for COPD identification; case-finding by use of the peak flow meter or microspirometer could be used routinely in primary care for suspected COPD patients. Only those testing positive to these tests would move on to full spirometry, thereby reducing unnecessary spirometric testing. © 2018 John Wiley

Digitized Spiral Drawing: A Possible Biomarker for Early Parkinson's Disease.

PubMed

San Luciano, Marta; Wang, Cuiling; Ortega, Roberto A; Yu, Qiping; Boschung, Sarah; Soto-Valencia, Jeannie; Bressman, Susan B; Lipton, Richard B; Pullman, Seth; Saunders-Pullman, Rachel

2016-01-01

Pre-clinical markers of Parkinson's Disease (PD) are needed, and to be relevant in pre-clinical disease, they should be quantifiably abnormal in early disease as well. Handwriting is impaired early in PD and can be evaluated using computerized analysis of drawn spirals, capturing kinematic, dynamic, and spatial abnormalities and calculating indices that quantify motor performance and disability. Digitized spiral drawing correlates with motor scores and may be more sensitive in detecting early changes than subjective ratings. However, whether changes in spiral drawing are abnormal compared with controls and whether changes are detected in early PD are unknown. 138 PD subjects (50 with early PD) and 150 controls drew spirals on a digitizing tablet, generating x, y, z (pressure) data-coordinates and time. Derived indices corresponded to overall spiral execution (severity), shape and kinematic irregularity (second order smoothness, first order zero-crossing), tightness, mean speed and variability of spiral width. Linear mixed effect adjusted models comparing these indices and cross-validation were performed. Receiver operating characteristic analysis was applied to examine discriminative validity of combined indices. All indices were significantly different between PD cases and controls, except for zero-crossing. A model using all indices had high discriminative validity (sensitivity = 0.86, specificity = 0.81). Discriminative validity was maintained in patients with early PD. Spiral analysis accurately discriminates subjects with PD and early PD from controls supporting a role as a promising quantitative biomarker. Further assessment is needed to determine whether spiral changes are PD specific compared with other disorders and if present in pre-clinical PD.

Using bacterial biomarkers to identify early indicators of cystic fibrosis pulmonary exacerbation onset

PubMed Central

Rogers, Geraint B; Hoffman, Lucas R; Johnson, Matt W; Mayer-Hamblett, Nicole; Schwarze, Jürgen; Carroll, Mary P; Bruce, Kenneth D

2011-01-01

Acute periods of pulmonary exacerbation are the single most important cause of morbidity in cystic fibrosis patients, and may be associated with a loss of lung function. Intervening prior to the onset of a substantially increased inflammatory response may limit the associated damage to the airways. While a number of biomarker assays based on inflammatory markers have been developed, providing useful and important measures of disease during these periods, such factors are typically only elevated once the process of exacerbation has been initiated. Identifying biomarkers that can predict the onset of pulmonary exacerbation at an early stage would provide an opportunity to intervene before the establishment of a substantial immune response, with major implications for the advancement of cystic fibrosis care. The precise triggers of pulmonary exacerbation remain to be determined; however, the majority of models relate to the activity of microbes present in the patient's lower airways of cystic fibrosis. Advances in diagnostic microbiology now allow for the examination of these complex systems at a level likely to identify factors on which biomarker assays can be based. In this article, we discuss key considerations in the design and testing of assays that could predict pulmonary exacerbations. PMID:21405970

Orthostatic hypotension predicts motor decline in early Parkinson disease.

PubMed

Kotagal, Vikas; Lineback, Christina; Bohnen, Nicolaas I; Albin, Roger L

2016-11-01

Orthostatic hypotension is increasingly reported as a risk factor for development of late-stage disease features in Parkinson disease (PD). Less is known about its significance in individuals with early PD who are often targeted for neuroprotective trials. Using data from the CALM-PD trial (n = 275), we explored whether early orthostatic hypotension predicts a decline in the Unified Parkinson's Disease Rating Scale (UPDRS) II (activities of daily living) or UDPRS III (motor) score after 102 weeks. We also explored risk factors for worsening orthostatic hypotension over a nearly 2-year period. After controlling for age, disease duration, gender, study drug, change in mini-mental status exam score, levodopa equivalent dose, and baseline UPDRS II or III score respectively, the degree of orthostatic hypotension at enrollment associated with a worsening in UPDRS motor score (t = 2.40, p = 0.017) at week 102 but not with UPDRS ADL score (t = 0.83, p = 0.409). Worsening in orthostatic hypotension during the study associated with longer disease duration (t = 2.37, p = 0.019) and lower body mass index (BMI) (t = -2.96, p = 0.003). Baseline orthostatic hypotension is a predictor of UPDRS motor decline in individuals with early PD and should be accounted for in clinical trial design. Low BMI may predict orthostatic hypotension in PD. Copyright © 2016 Elsevier Ltd. All rights reserved.

The die is cast - Arsenic exposure in early life and disease susceptibility

EPA Science Inventory

Abstract Early life exposure to arsenic in humans and mice produces similar patterns of disease in later life. Given the long interval between exposure and effect, epigenetic effects of early life exposure to arsenic may account for development and progression of disease in bo...

[Implementation of an early rheumatoid athritis unit for the early recognition and treatment of the disease].

PubMed

Espinoza, Francisco; Monckeberg, Gustavo; Hassi, Isabel; Queirolo, Alejandra; Chicao, Fernando; Sandoval, Ximena; Jorquera, Evelyn; Badilla, Alejandro

2018-01-01

Early recognition of rheumatoid arthritis (RA) provides clinical benefits in terms of remission induction, reduced disease progression, and eventually treatment free remission. To describe the setting of a Unit devoted exclusively to the recognition and treatment of early RA in patients referred from primary healthcare centers (PHC) in Chile. Patients were referred from nine participating PHC from 2014 through 2016. PHC physicians received a formal training to enhance criteria recognition and program adherence. Mandatory referral criteria were an age above 17 years, and arthralgia of less than 1-year duration, plus at least one of the following: morning stiffness of more than 30 minutes, swelling involving more than 3 joints for more than 1 month, a positive squeeze test or abnormal inflammatory serum markers. One hundred twenty patients aged 45 ± 12 years (90% women) were assessed at the early rheumatoid arthritis unit. Median time to referral from PHC to the Unit was 14.6 days. The median duration of symptoms for the overall sample of patients was 10.8 months. RA was identified in 43 patients (36%), with a delay between onset of symptoms and diagnosis of 8.3 months. Regarding the performance of referral criteria, the most sensitive was morning stiffness (80%, sensitivity 95% confidence intervals (CI) 64-89%) and synovitis was the most specific (specificity 83%, 95% CI 72-90%). The positive predictive value of the three clinical criteria altogether was 68.1% (95% CI 47-83%). Institution of an early RA unit was feasible within the Chilean healthcare system enabling the identification of early RA in one-third of patients.

Mutation screening of patients with Alzheimer disease identifies APP locus duplication in a Swedish patient

PubMed Central

2011-01-01

Background Missense mutations in three different genes encoding amyloid-β precursor protein, presenilin 1 and presenilin 2 are recognized to cause familial early-onset Alzheimer disease. Also duplications of the amyloid precursor protein gene have been shown to cause the disease. At the Dept. of Geriatric Medicine, Karolinska University Hospital, Sweden, patients are referred for mutation screening for the identification of nucleotide variations and for determining copy-number of the APP locus. Methods We combined the method of microsatellite marker genotyping with a quantitative real-time PCR analysis to detect duplications in patients with Alzheimer disease. Results In 22 DNA samples from individuals diagnosed with clinical Alzheimer disease, we identified one patient carrying a duplication on chromosome 21 which included the APP locus. Further mapping of the chromosomal region by array-comparative genome hybridization showed that the duplication spanned a maximal region of 1.09 Mb. Conclusions This is the first report of an APP duplication in a Swedish Alzheimer patient and describes the use of quantitative real-time PCR as a tool for determining copy-number of the APP locus. PMID:22044463

Mutation screening of patients with Alzheimer disease identifies APP locus duplication in a Swedish patient.

PubMed

Thonberg, Håkan; Fallström, Marie; Björkström, Jenny; Schoumans, Jacqueline; Nennesmo, Inger; Graff, Caroline

2011-11-01

Missense mutations in three different genes encoding amyloid-β precursor protein, presenilin 1 and presenilin 2 are recognized to cause familial early-onset Alzheimer disease. Also duplications of the amyloid precursor protein gene have been shown to cause the disease. At the Dept. of Geriatric Medicine, Karolinska University Hospital, Sweden, patients are referred for mutation screening for the identification of nucleotide variations and for determining copy-number of the APP locus. We combined the method of microsatellite marker genotyping with a quantitative real-time PCR analysis to detect duplications in patients with Alzheimer disease. In 22 DNA samples from individuals diagnosed with clinical Alzheimer disease, we identified one patient carrying a duplication on chromosome 21 which included the APP locus. Further mapping of the chromosomal region by array-comparative genome hybridization showed that the duplication spanned a maximal region of 1.09 Mb. This is the first report of an APP duplication in a Swedish Alzheimer patient and describes the use of quantitative real-time PCR as a tool for determining copy-number of the APP locus.

Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease

NASA Astrophysics Data System (ADS)

Viola, Kirsten L.; Sbarboro, James; Sureka, Ruchi; de, Mrinmoy; Bicca, Maíra A.; Wang, Jane; Vasavada, Shaleen; Satpathy, Sreyesh; Wu, Summer; Joshi, Hrushikesh; Velasco, Pauline T.; Macrenaris, Keith; Waters, E. Alex; Lu, Chang; Phan, Joseph; Lacor, Pascale; Prasad, Pottumarthi; Dravid, Vinayak P.; Klein, William L.

2015-01-01

One way to image the molecular pathology in Alzheimer's disease is by positron emission tomography using probes that target amyloid fibrils. However, these fibrils are not closely linked to the development of the disease. It is now thought that early-stage biomarkers that instigate memory loss are composed of Aβ oligomers. Here, we report a sensitive molecular magnetic resonance imaging contrast probe that is specific for Aβ oligomers. We attach oligomer-specific antibodies onto magnetic nanostructures and show that the complex is stable and binds to Aβ oligomers on cells and brain tissues to give a magnetic resonance imaging signal. When intranasally administered to an Alzheimer's disease mouse model, the probe readily reached hippocampal Aβ oligomers. In isolated samples of human brain tissue, we observed a magnetic resonance imaging signal that distinguished Alzheimer's disease from controls. Such nanostructures that target neurotoxic Aβ oligomers are potentially useful for evaluating the efficacy of new drugs and ultimately for early-stage Alzheimer's disease diagnosis and disease management.

Computer keyboard interaction as an indicator of early Parkinson's disease.

PubMed

Giancardo, L; Sánchez-Ferro, A; Arroyo-Gallego, T; Butterworth, I; Mendoza, C S; Montero, P; Matarazzo, M; Obeso, J A; Gray, M L; Estépar, R San José

2016-10-05

Parkinson's disease (PD) is a slowly progressing neurodegenerative disease with early manifestation of motor signs. Objective measurements of motor signs are of vital importance for diagnosing, monitoring and developing disease modifying therapies, particularly for the early stages of the disease when putative neuroprotective treatments could stop neurodegeneration. Current medical practice has limited tools to routinely monitor PD motor signs with enough frequency and without undue burden for patients and the healthcare system. In this paper, we present data indicating that the routine interaction with computer keyboards can be used to detect motor signs in the early stages of PD. We explore a solution that measures the key hold times (the time required to press and release a key) during the normal use of a computer without any change in hardware and converts it to a PD motor index. This is achieved by the automatic discovery of patterns in the time series of key hold times using an ensemble regression algorithm. This new approach discriminated early PD groups from controls with an AUC = 0.81 (n = 42/43; mean age = 59.0/60.1; women = 43%/60%;PD/controls). The performance was comparable or better than two other quantitative motor performance tests used clinically: alternating finger tapping (AUC = 0.75) and single key tapping (AUC = 0.61).

Restless legs syndrome: an early clinical feature of Parkinson disease in men.

PubMed

Wong, Janice C; Li, Yanping; Schwarzschild, Michael A; Ascherio, Alberto; Gao, Xiang

2014-02-01

The association between restless legs syndrome (RLS) and Parkinson disease has been extensively studied, but the temporal relationship between the two remains unclear. We thus conduct the first prospective study to examine the risk of developing Parkinson disease in RLS. Prospective study from 2002-2010. United States. There were 22,999 US male health professionals age 40-75 y enrolled in the Health Professionals Follow-up Study without Parkinson disease, arthritis, or diabetes mellitus at baseline. RLS was assessed in 2002 using a set of standardized questions recommended by the International RLS Study Group. Incident Parkinson disease was identified by biennial questionnaires and then confirmed by review of participants' medical records by a movement disorder specialist. We documented 200 incident Parkinson disease cases during 8 y of follow-up. Compared to men without RLS, men with RLS symptoms who had symptoms greater than 15 times/mo had higher risk of Parkinson disease development (adjusted relative risk = 1.47; 95% confidence interval: 0.59, 3.65; P = 0.41). This was statistically significant only for cases diagnosed within 4 y of follow-up (adjusted relative risk = 2.77; 95% confidence interval: 1.08, 7.11; P = 0.03). Severe restless legs syndrome may be an early feature of Parkinson disease.

How to select a proper early warning threshold to detect infectious disease outbreaks based on the China infectious disease automated alert and response system (CIDARS).

PubMed

Wang, Ruiping; Jiang, Yonggen; Michael, Engelgau; Zhao, Genming

2017-06-12

China Centre for Diseases Control and Prevention (CDC) developed the China Infectious Disease Automated Alert and Response System (CIDARS) in 2005. The CIDARS was used to strengthen infectious disease surveillance and aid in the early warning of outbreak. The CIDARS has been integrated into the routine outbreak monitoring efforts of the CDC at all levels in China. Early warning threshold is crucial for outbreak detection in the CIDARS, but CDCs at all level are currently using thresholds recommended by the China CDC, and these recommended thresholds have recognized limitations. Our study therefore seeks to explore an operational method to select the proper early warning threshold according to the epidemic features of local infectious diseases. The data used in this study were extracted from the web-based Nationwide Notifiable Infectious Diseases Reporting Information System (NIDRIS), and data for infectious disease cases were organized by calendar week (1-52) and year (2009-2015) in Excel format; Px was calculated using a percentile-based moving window (moving window [5 week*5 year], x), where x represents one of 12 centiles (0.40, 0.45, 0.50….0.95). Outbreak signals for the 12 Px were calculated using the moving percentile method (MPM) based on data from the CIDARS. When the outbreak signals generated by the 'mean + 2SD' gold standard were in line with a Px generated outbreak signal for each week during the year of 2014, this Px was then defined as the proper threshold for the infectious disease. Finally, the performance of new selected thresholds for each infectious disease was evaluated by simulated outbreak signals based on 2015 data. Six infectious diseases were selected in this study (chickenpox, mumps, hand foot and mouth diseases (HFMD), scarlet fever, influenza and rubella). Proper thresholds for chickenpox (P75), mumps (P80), influenza (P75), rubella (P45), HFMD (P75), and scarlet fever (P80) were identified. The selected proper thresholds for these

Identification of sero-reactive antigens for the early diagnosis of Johne’s disease in cattle

PubMed Central

Randall, Arlo; Grohn, Yrjo T.; Katani, Robab; Schilling, Megan; Radzio-Basu, Jessica

2017-01-01

Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of Johne’s disease (JD), a chronic intestinal inflammatory disease of cattle and other ruminants. JD has a high herd prevalence and causes serious animal health problems and significant economic loss in domesticated ruminants throughout the world. Since serological detection of MAP infected animals during the early stages of infection remains challenging due to the low sensitivity of extant assays, we screened 180 well-characterized serum samples using a whole proteome microarray from Mycobacterium tuberculosis (MTB), a close relative of MAP. Based on extensive testing of serum and milk samples, fecal culture and qPCR for direct detection of MAP, the samples were previously assigned to one of 4 groups: negative low exposure (n = 30, NL); negative high exposure (n = 30, NH); fecal positive, ELISA negative (n = 60, F+E-); and fecal positive, ELISA positive (n = 60, F+E+). Of the 740 reactive proteins, several antigens were serologically recognized early but not late in infection, suggesting a complex and dynamic evolution of the MAP humoral immune response during disease progression. Ordinal logistic regression models identified a subset of 47 candidate proteins with significantly different normalized intensity values (p<0.05), including 12 in the NH and 23 in F+E- groups, suggesting potential utility for the early detection of MAP infected animals. Next, the diagnostic utility of four MAP orthologs (MAP1569, MAP2942c, MAP2609, and MAP1272c) was assessed and reveal moderate to high diagnostic sensitivities (range 48.3% to 76.7%) and specificity (range 96.7% to 100%), with a combined 88.3% sensitivity and 96.7% specificity. Taken together, the results of our analyses have identified several candidate MAP proteins of potential utility for the early detection of MAP infection, as well individual MAP proteins that may serve as the foundation for the next generation of well-defined serological

Early life nutritional programming of health and disease in The Gambia.

PubMed

Moore, S E

2016-04-01

Exposures during the early life (periconceptional, prenatal and early postnatal) period are increasingly recognized as playing an important role in the aetiology of chronic non-communicable diseases (NCD), including coronary heart disease, stroke, hypertension, Type 2 diabetes and osteoporosis. The 'Developmental Origins of Health and Disease' (DOHaD) hypothesis states that these disorders originate through unbalanced nutrition early in life and risk is highest when there is a 'mismatch' between the early- and later-life environments. Thus, the DOHaD hypothesis would predict highest risk in countries where an excess of infants are born with low birth weight and where there is a rapid transition to nutritional adequacy or excess in adulthood. Here, I will review data from work conducted in rural Gambia, West Africa. Using demographic data dating back to the 1940s, the follow-up of randomized controlled trials of nutritional supplementation in pregnancy and the 'experiment of nature' that seasonality in this region provides, we have investigated the DOHaD hypothesis in a population with high rates of maternal and infant under-nutrition, a high burden from infectious disease, and an emerging risk of NCDs.

Developmental Origins of Chronic Kidney Disease: Should We Focus on Early Life?

PubMed Central

Tain, You-Lin; Hsu, Chien-Ning

2017-01-01

Chronic kidney disease (CKD) is becoming a global burden, despite recent advances in management. CKD can begin in early life by so-called “developmental programming” or “developmental origins of health and disease” (DOHaD). Early-life insults cause structural and functional changes in the developing kidney, which is called renal programming. Epidemiological and experimental evidence supports the proposition that early-life adverse events lead to renal programming and make subjects vulnerable to developing CKD and its comorbidities in later life. In addition to low nephron endowment, several mechanisms have been proposed for renal programming. The DOHaD concept opens a new window to offset the programming process in early life to prevent the development of adult kidney disease, namely reprogramming. Here, we review the key themes on the developmental origins of CKD. We have particularly focused on the following areas: evidence from human studies support fetal programming of kidney disease; insight from animal models of renal programming; hypothetical mechanisms of renal programming; alterations of renal transcriptome in response to early-life insults; and the application of reprogramming interventions to prevent the programming of kidney disease. PMID:28208659

Identifying early indicators in bipolar disorder: a qualitative study.

PubMed

Benti, Liliane; Manicavasagar, Vijaya; Proudfoot, Judy; Parker, Gordon

2014-06-01

The identification of early markers has become a focus for early intervention in bipolar disorder. Using a retrospective, qualitative methodology, the present study compares the early experiences of participants with bipolar disorder to those with unipolar depression up until their first diagnosed episode. The study focuses on differences in early home and school environments as well as putative differences in personality characteristics between the two groups. Finally we a compare and contrast prodromal symptoms in these two populations. Thirty-nine participants, 20 diagnosed with unipolar depression and 19 diagnosed with bipolar disorder, took part in the study. A semi-structured interview was developed to elicit information about participants' experiences prior to their first episode. Participants with bipolar disorder reported disruptive home environments, driven personality features, greater emotion dysregulation and adverse experiences during the school years, whereas participants with depression tended to describe more supportive home environments, and more compliant and introvert personality traits. Retrospective data collection and no corroborative evidence from other family members. No distinction was made between bipolar I and bipolar II disorder nor between melancholic and non-melancholic depression in the sample. Finally the study spanned over a 12-month period which does not allow for the possibility of diagnostic reassignment of some of the bipolar participants to the unipolar condition. These findings indicate that there may be benefits in combining both proximal and distal indicators in identifying a bipolar disorder phenotype which, in turn, may be relevant to the development of early intervention programs for young people with bipolar disorder.

Lipoxins Regulate the Early Growth Response-1 Network and Reverse Diabetic Kidney Disease.

PubMed

Brennan, Eoin P; Mohan, Muthukumar; McClelland, Aaron; Tikellis, Christos; Ziemann, Mark; Kaspi, Antony; Gray, Stephen P; Pickering, Raelene; Tan, Sih Min; Ali-Shah, Syed Tasadaque; Guiry, Patrick J; El-Osta, Assam; Jandeleit-Dahm, Karin; Cooper, Mark E; Godson, Catherine; Kantharidis, Phillip

2018-05-01

Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation. Methods We investigated the potential of LXA 4 and a synthetic LX analog (Benzo-LXA 4 ) as therapeutics in a murine model of diabetic kidney disease, ApoE -/- mice treated with streptozotocin. Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10 weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P ≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renal proinflammatory/profibrotic signals (TNF- α , IL-1 β , NF- κ B). In diabetic mice, we identified 20 and 51 transcripts regulated by LXA 4 and Benzo-LXA 4 , respectively, and pathway analysis identified established (TGF- β 1, PDGF, TNF- α , NF- κ B) and novel (early growth response-1 [EGR-1]) networks activated in diabetes and regulated by LXs. In cultured human renal epithelial cells, treatment with LXs attenuated TNF- α -driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF- β 1 and TNF- α Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation. Copyright © 2018 by the American Society of Nephrology.

Cyclooxygenase inhibition targets neurons to prevent early behavioural decline in Alzheimer’s disease model mice

PubMed Central

Woodling, Nathaniel S.; Colas, Damien; Wang, Qian; Minhas, Paras; Panchal, Maharshi; Liang, Xibin; Mhatre, Siddhita D.; Brown, Holden; Ko, Novie; Zagol-Ikapitte, Irene; van der Hart, Marieke; Khroyan, Taline V.; Chuluun, Bayarsaikhan; Priyam, Prachi G.; Milne, Ginger L.; Rassoulpour, Arash; Boutaud, Olivier; Manning-Boğ, Amy B.; Heller, H. Craig

2016-01-01

Abstract Identifying preventive targets for Alzheimer’s disease is a central challenge of modern medicine. Non-steroidal anti-inflammatory drugs, which inhibit the cyclooxygenase enzymes COX-1 and COX-2, reduce the risk of developing Alzheimer’s disease in normal ageing populations. This preventive effect coincides with an extended preclinical phase that spans years to decades before onset of cognitive decline. In the brain, COX-2 is induced in neurons in response to excitatory synaptic activity and in glial cells in response to inflammation. To identify mechanisms underlying prevention of cognitive decline by anti-inflammatory drugs, we first identified an early object memory deficit in APP Swe -PS1 ΔE9 mice that preceded previously identified spatial memory deficits in this model. We modelled prevention of this memory deficit with ibuprofen, and found that ibuprofen prevented memory impairment without producing any measurable changes in amyloid-β accumulation or glial inflammation. Instead, ibuprofen modulated hippocampal gene expression in pathways involved in neuronal plasticity and increased levels of norepinephrine and dopamine. The gene most highly downregulated by ibuprofen was neuronal tryptophan 2,3-dioxygenase ( Tdo2 ), which encodes an enzyme that metabolizes tryptophan to kynurenine. TDO2 expression was increased by neuronal COX-2 activity, and overexpression of hippocampal TDO2 produced behavioural deficits. Moreover, pharmacological TDO2 inhibition prevented behavioural deficits in APP Swe -PS1 ΔE9 mice. Taken together, these data demonstrate broad effects of cyclooxygenase inhibition on multiple neuronal pathways that counteract the neurotoxic effects of early accumulating amyloid-β oligomers. PMID:27190010

Diagnostic challenges of early Lyme disease: Lessons from a community case series

PubMed Central

2009-01-01

Background Lyme disease, the most common vector-borne infection in North America, is increasingly reported. When the characteristic rash, erythema migrans, is not recognized and treated, delayed manifestations of disseminated infection may occur. The accuracy of diagnosis and treatment of early Lyme disease in the community is unknown. Methods A retrospective, consecutive case series of 165 patients presenting for possible early Lyme disease between August 1, 2002 and August 1, 2007 to a community-based Lyme referral practice in Maryland. All patients had acute symptoms of less than or equal to 12 weeks duration. Patients were categorized according to the Centers for Disease Control and Prevention criteria and data were collected on presenting history, physical findings, laboratory serology, prior diagnoses and prior treatments. Results The majority (61%) of patients in this case series were diagnosed with early Lyme disease. Of those diagnosed with early Lyme disease, 13% did not present with erythema migrans; of those not presenting with a rash, 54% had been previously misdiagnosed. Among those with a rash, the diagnosis of erythema migrans was initially missed in 23% of patients whose rash was subsequently confirmed. Of all patients previously misdiagnosed, 41% had received initial antibiotics likely to be ineffective against Lyme disease. Conclusion For community physicians practicing in high-risk geographic areas, the diagnosis of Lyme disease remains a challenge. Failure to recognize erythema migrans or alternatively, viral-like presentations without a rash, can lead to missed or delayed diagnosis of Lyme disease, ineffective antibiotic treatment, and the potential for late manifestations. PMID:19486523

Molecular Diagnostics of Copper-Transporting Protein Mutations Allows Early Onset Individual Therapy of Menkes Disease.

PubMed

Králík, L; Flachsová, E; Hansíková, H; Saudek, V; Zeman, J; Martásek, P

2017-01-01

Menkes disease is a severe X-linked recessive disorder caused by a defect in the ATP7A gene, which encodes a membrane copper-transporting ATPase. Deficient activity of the ATP7A protein results in decreased intestinal absorption of copper, low copper level in serum and defective distribution of copper in tissues. The clinical symptoms are caused by decreased activities of copper-dependent enzymes and include neurodegeneration, connective tissue disorders, arterial changes and hair abnormalities. Without therapy, the disease is fatal in early infancy. Rapid diagnosis of Menkes disease and early start of copper therapy is critical for the effectiveness of treatment. We report a molecular biology-based strategy that allows early diagnosis of copper transport defects and implementation of individual therapies before the full development of pathological symptoms. Low serum copper and decreased activity of copperdependent mitochondrial cytochrome c oxidase in isolated platelets found in three patients indicated a possibility of functional defects in copper-transporting proteins, especially in the ATPA7 protein, a copper- transporting P-type ATPase. Rapid mutational screening of the ATP7A gene using high-resolution melting analysis of DNA indicated presence of mutations in the patients. Molecular investigation for mutations in the ATP7A gene revealed three nonsense mutations: c.2170C>T (p.Gln724Ter); c.3745G>T (p.Glu1249Ter); and c.3862C>T (p.Gln1288Ter). The mutation c.3745G>T (p.Glu1249Ter) has not been identified previously. Molecular analysis of the ATOX1 gene as a possible modulating factor of Menkes disease did not reveal presence of pathogenic mutations. Molecular diagnostics allowed early onset of individual therapies, adequate genetic counselling and prenatal diagnosis in the affected families.

Operational Thought in Alzheimer's Disease Early Onset and SDAT.

ERIC Educational Resources Information Center

Emery, Olga B.; Breslau, Lawrence D.

For more than a decade it has been convention to assume that senile dementia Alzheimer's type (SDAT) and Alzheimer's disease early onset represent a unitary disease process with only an onset difference. This assumption has been neither confirmed nor disconfirmed. To address this issue, a study was conducted which analyzed the dissolution of…

Impact of DNA testing for early-onset familial Alzheimer disease and frontotemporal dementia.

PubMed

Steinbart, E J; Smith, C O; Poorkaj, P; Bird, T D

2001-11-01

DNA testing of persons at risk for hereditary, degenerative neurologic diseases is relatively new. Only anecdotal reports of such testing in familial Alzheimer disease (FAD) exist, and little is know about the personal and social impact of such testing. In a descriptive, observational study, individuals at 50% risk for autosomal dominant, early-onset FAD or frontotemporal dementia with parkinsonism linked to chromosome 17 underwent DNA testing for the genetic mutations previously identified in affected family members. Individuals were followed up for (1/2) to 3 years and were interviewed regarding attitudes toward the testing process and the impact of the results. Twenty-one (8.4%) of 251 persons at risk for FAD or frontotemporal dementia requested genetic testing. The most common reasons for requesting testing were concern about early symptoms of dementia, financial or family planning, and relief from anxiety. Twelve individuals had positive DNA test results, and 6 of these had early symptoms of dementia; 8 had negative results; and 1 has not yet received results. Of 14 asymptomatic individuals completing testing, 13 believed the testing was beneficial. Two persons reported moderate anxiety and 1 reported moderate depression. As expected, persons with negative test results had happier experiences overall, but even they had to deal with ongoing anxiety and depression. Thus far, there have been no psychiatric hospitalizations, suicide attempts, or denials of insurance. Genetic testing in early-onset FAD and frontotemporal dementia can be completed successfully. Most individuals demonstrate effective coping skills and find the testing to be beneficial, but long-term effects remain unknown.

Development of the Paris definition of early Crohn's disease for disease-modification trials: results of an international expert opinion process.

PubMed

Peyrin-Biroulet, Laurent; Billioud, Vincent; D'Haens, Geert; Panaccione, Remo; Feagan, Brian; Panés, Julian; Danese, Silvio; Schreiber, Stefan; Ogata, Haruhiko; Hibi, Toshifumi; Higgins, Peter D R; Beaugerie, Laurent; Chowers, Yehuda; Louis, Edouard; Steinwurz, Flávio; Reinisch, Walter; Rutgeerts, Paul; Colombel, Jean-Frédéric; Travis, Simon; Sandborn, William J

2012-12-01

We report the findings and outputs of an international expert opinion process to develop a definition of early Crohn's disease (CD) that could be used in future disease-modification trials. Nineteen experts on inflammatory bowel diseases held an international expert opinion meeting to discuss and agree on a definition for early CD to be used in disease-modification trials. The process included literature searches for the relevant basic-science and clinical evidence. A published preliminary definition of early CD was used as the basis for development of a proposed definition that was discussed at the expert opinion meeting. The participants then derived a final definition, based on best current knowledge, that it is hoped will be of practical use in disease-modification trials in CD.

Gene expression profiling combined with bioinformatics analysis identify biomarkers for Parkinson disease.

PubMed

Diao, Hongyu; Li, Xinxing; Hu, Sheng; Liu, Yunhui

2012-01-01

Parkinson disease (PD) progresses relentlessly and affects approximately 4% of the population aged over 80 years old. It is difficult to diagnose in its early stages. The purpose of our study is to identify molecular biomarkers for PD initiation using a computational bioinformatics analysis of gene expression. We downloaded the gene expression profile of PD from Gene Expression Omnibus and identified differentially coexpressed genes (DCGs) and dysfunctional pathways in PD patients compared to controls. Besides, we built a regulatory network by mapping the DCGs to known regulatory data between transcription factors (TFs) and target genes and calculated the regulatory impact factor of each transcription factor. As the results, a total of 1004 genes associated with PD initiation were identified. Pathway enrichment of these genes suggests that biological processes of protein turnover were impaired in PD. In the regulatory network, HLF, E2F1 and STAT4 were found have altered expression levels in PD patients. The expression levels of other transcription factors, NKX3-1, TAL1, RFX1 and EGR3, were not found altered. However, they regulated differentially expressed genes. In conclusion, we suggest that HLF, E2F1 and STAT4 may be used as molecular biomarkers for PD; however, more work is needed to validate our result.

Gene Expression Profiling Combined with Bioinformatics Analysis Identify Biomarkers for Parkinson Disease

PubMed Central

Diao, Hongyu; Li, Xinxing; Hu, Sheng; Liu, Yunhui

2012-01-01

Parkinson disease (PD) progresses relentlessly and affects approximately 4% of the population aged over 80 years old. It is difficult to diagnose in its early stages. The purpose of our study is to identify molecular biomarkers for PD initiation using a computational bioinformatics analysis of gene expression. We downloaded the gene expression profile of PD from Gene Expression Omnibus and identified differentially coexpressed genes (DCGs) and dysfunctional pathways in PD patients compared to controls. Besides, we built a regulatory network by mapping the DCGs to known regulatory data between transcription factors (TFs) and target genes and calculated the regulatory impact factor of each transcription factor. As the results, a total of 1004 genes associated with PD initiation were identified. Pathway enrichment of these genes suggests that biological processes of protein turnover were impaired in PD. In the regulatory network, HLF, E2F1 and STAT4 were found have altered expression levels in PD patients. The expression levels of other transcription factors, NKX3-1, TAL1, RFX1 and EGR3, were not found altered. However, they regulated differentially expressed genes. In conclusion, we suggest that HLF, E2F1 and STAT4 may be used as molecular biomarkers for PD; however, more work is needed to validate our result. PMID:23284986

Developmental origins of cardiovascular disease: Impact of early life stress in humans and rodents.

PubMed

Murphy, M O; Cohn, D M; Loria, A S

2017-03-01

The Developmental Origins of Health and Disease (DOHaD) hypothesizes that environmental insults during childhood programs the individual to develop chronic disease in adulthood. Emerging epidemiological data strongly supports that early life stress (ELS) given by the exposure to adverse childhood experiences is regarded as an independent risk factor capable of predicting future risk of cardiovascular disease. Experimental animal models utilizing chronic behavioral stress during postnatal life, specifically maternal separation (MatSep) provides a suitable tool to elucidate molecular mechanisms by which ELS increases the risk to develop cardiovascular disease, including hypertension. The purpose of this review is to highlight current epidemiological studies linking ELS to the development of cardiovascular disease and to discuss the potential molecular mechanisms identified from animal studies. Overall, this review reveals the need for future investigations to further clarify the molecular mechanisms of ELS in order to develop more personalized therapeutics to mitigate the long-term consequences of chronic behavioral stress including cardiovascular and heart disease in adulthood. Copyright © 2016 Elsevier Ltd. All rights reserved.

Identifying Local Hotspots of Pediatric Chronic Diseases Using Emergency Department Surveillance

PubMed Central

Lee, David C.; Yi, Stella S.; Fong, Hiu-Fai; Athens, Jessica K.; Ravenell, Joseph E.; Sevick, Mary Ann; Wall, Stephen P.; Elbel, Brian

2016-01-01

Objective To use novel geographic methods and large-scale claims data to identify the local distribution of pediatric chronic diseases in New York City. Methods Using a 2009 all-payer emergency claims database, we identified the proportion of unique children aged 0 to 17 with diagnosis codes for specific medical and psychiatric conditions. As a proof of concept, we compared these prevalence estimates to traditional health surveys and registry data using the most geographically granular data available. In addition, we used home addresses to map local variation in pediatric disease burden. Results We identified 549,547 New York City children who visited an emergency department at least once in 2009. Though our sample included more publicly insured and uninsured children, we found moderate to strong correlations of prevalence estimates when compared to health surveys and registry data at pre-specified geographic levels. Strongest correlations were found for asthma and mental health conditions by county among younger children (0.88, p=0.05 and 0.99, p<0.01, respectively). Moderate correlations by neighborhood were identified for obesity and cancer (0.53 and 0.54, p<0.01). Among adolescents, correlations by health districts were strong for obesity (0.95, p=0.05), and depression estimates had a non-significant, but strong negative correlation with suicide attempts (−0.88, p=0.12). Using SaTScan, we also identified local hotspots of pediatric chronic disease. Conclusions For conditions easily identified in claims data, emergency department surveillance may help estimate pediatric chronic disease prevalence with higher geographic resolution. More studies are needed to investigate limitations of these methods and assess reliability of local disease estimates. What’s New This study demonstrated how emergency department surveillance may improve estimates of pediatric disease prevalence with higher geographic resolution. We identified 29% of New York City children with a

Association of rheumatic diseases with early exit from paid employment in Portugal.

PubMed

Laires, Pedro A; Gouveia, Miguel

2014-04-01

To examine the association between rheumatic diseases (RD) and other chronic morbidity with early exit from paid employment in the Portuguese population. The study population consisted of all people between 50 and 64 years of age (3,762 men and 4,241 women) who participated in the Portuguese National Health Survey, conducted in 2005/2006. Data were collected on demographics, ill-health, lifestyle, and socioeconomic factors. Logistic regression was used to estimate the isolated effect of rheumatic diseases and other chronic diseases on the likelihood of exit from paid employment. At the time of the survey, 45.1 % of the Portuguese population with ages between 50 and 64 years old were not employed. In the nonemployed population, 31.6 % self-reported "poor" to "very poor" health, whereas 16.4 % did so in the employed population. A larger average number of major chronic diseases per capita were also found in those not employed (1.9 vs. 1.4, p < 0.001). In the multivariate models, chronic diseases were associated with early exit from paid employment. In particular, rheumatic diseases were more prevalent (43.4 vs. 32.1 %) and associated with early exit from work (OR 1.31; CI 1.12-1.52, p = 0.001). This study suggests an association between RD and other major chronic diseases with early exit from paid employment in Portugal. Thus, health and social protection policies should target these chronic disorders in order to better address sustainability issues and social protection effectiveness.

Informativeness of Early Huntington Disease Signs about Gene Status.

PubMed

Oster, Emily; Eberly, Shirley W; Dorsey, E Ray; Kayson-Rubin, Elise; Oakes, David; Shoulson, Ira

2015-01-01

The cohort-level risk of Huntington disease (HD) is related to the age and symptom level of the cohort, but this relationship has not been made precise. To predict the evolving likelihood of carrying the Huntington disease (HD) gene for at-risk adults using age and sign level. Using data from adults with early signs and symptoms of HD linked to information on genetic status, we use Bayes' theorem to calculate the probability that an undiagnosed individual of a certain age and sign level has an expanded CAG repeat. Both age and sign levels have substantial influence on the likelihood of HD onset, and the probability of eventual diagnosis changes as those at risk age and exhibit (or fail to exhibit) symptoms. For example, our data suggest that in a cohort of individuals age 26 with a Unified Huntington's Disease Rating Scale (UHDRS) motor score of 7-10 70% of them will carry the HD mutation. For individuals age 56, the same motor score suggests only a 40% chance of carrying the mutation. Early motor signs of HD, overall and the chorea subscore, were highly predictive of disease onset at any age. However, body mass index (BMI) and cognitive performance scores were not as highly predictive. These results suggest that if researchers or clinicians are looking for early clues of HD, it may be more foretelling to look at motor rather than cognitive signs. Application of similar approaches could be used with other adult-onset genetic conditions.

An Early Mathematical Patterning Assessment: identifying young Australian Indigenous children's patterning skills

NASA Astrophysics Data System (ADS)

Papic, Marina

2015-12-01

This paper presents an Early Mathematical Patterning Assessment (EMPA) tool that provides early childhood educators with a valuable opportunity to identify young children's mathematical thinking and patterning skills through a series of hands-on and drawing tasks. EMPA was administered through one-to-one assessment interviews to children aged 4 to 5 years in the year prior to formal school. Two hundred and seventeen assessments indicated that the young low socioeconomic and predominantly Australian Indigenous children in the study group had varied patterning and counting skills. Three percent of the study group was able to consistently copy and draw an ABABAB pattern made with coloured blocks. Fifty percent could count to six by ones and count out six items with 4 % of the total group able to identify six items presented in regular formations without counting. The integration of patterning into early mathematics learning is critical to the abstraction of mathematical ideas and relationships and to the development of mathematical reasoning in young children. By using the insights into the children's thinking that the EMPA tool provides, early childhood educators can better inform mathematics teaching and learning and so help close the persistent gap in numeracy between Indigenous and non-Indigenous children.

Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study.

PubMed

Adler, Charles H; Beach, Thomas G; Hentz, Joseph G; Shill, Holly A; Caviness, John N; Driver-Dunckley, Erika; Sabbagh, Marwan N; Sue, Lucia I; Jacobson, Sandra A; Belden, Christine M; Dugger, Brittany N

2014-07-29

Determine diagnostic accuracy of a clinical diagnosis of Parkinson disease (PD) using neuropathologic diagnosis as the gold standard. Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to determine the predictive value of a clinical PD diagnosis, using 2 clinical diagnostic confidence levels, PossPD (never treated or not clearly responsive) and ProbPD (responsive to medications). Neuropathologic diagnosis was the gold standard. Based on first visit, 9 of 34 (26%) PossPD cases had neuropathologically confirmed PD while 80 of 97 (82%) ProbPD cases had confirmed PD. PD was confirmed in 8 of 15 (53%) ProbPD cases with <5 years of disease duration and 72 of 82 (88%) with ≥5 years of disease duration. Using final diagnosis at time of death, 91 of 107 (85%) ProbPD cases had confirmed PD. Clinical variables that improved diagnostic accuracy were medication response, motor fluctuations, dyskinesias, and hyposmia. Using neuropathologic findings of PD as the gold standard, this study establishes the novel findings of only 26% accuracy for a clinical diagnosis of PD in untreated or not clearly responsive subjects, 53% accuracy in early PD responsive to medication (<5 years' duration), and >85% diagnostic accuracy of longer duration, medication-responsive PD. Caution is needed when interpreting clinical studies of PD, especially studies of early disease that do not have autopsy confirmation. The need for a tissue or other diagnostic biomarker is reinforced. This study provides Class II evidence that a clinical diagnosis of PD identifies patients who will have pathologically confirmed PD with a sensitivity of 88% and specificity of 68%. © 2014 American Academy of Neurology.

Neuropsychiatric and cognitive profile of early Richardson's syndrome, Progressive Supranuclear Palsy-parkinsonism and Parkinson's disease.

PubMed

Pellicano, Clelia; Assogna, Francesca; Cellupica, Nystya; Piras, Federica; Pierantozzi, Mariangela; Stefani, Alessandro; Cerroni, Rocco; Mercuri, Bruno; Caltagirone, Carlo; Pontieri, Francesco E; Spalletta, Gianfranco

2017-12-01

The two main variants of Progressive Supranuclear Palsy (PSP), Richardson's syndrome (PSP-RS) and PSP-parkinsonism (PSP-P), share motor and non-motor features with Parkinson's disease (PD) particularly in the early stages. This makes the precocious diagnosis more challenging. We aimed at defining qualitative and quantitative differences of neuropsychiatric and neuropsychological profiles between PSP-P, PSP-RS and PD patients recruited within 24 months after the onset of symptoms, in order to clarify if the identification of peculiar cognitive and psychiatric symptoms is of help for early PSP diagnosis. PD (n = 155), PSP-P (n = 11) and PSP-RS (n = 14) patients were identified. All patients were submitted to clinical, neurological, neuropsychiatric diagnostic evaluation and to a comprehensive neuropsychiatric and neuropsychological battery. Predictors of PSP-P and PSP-RS diagnosis were identified by multivariate logistic regressions including neuropsychiatric and neuropsychological features that differed significantly among groups. The three groups differed significantly at the Apathy Rating Scale score and at several neuropsychological domains. The multivariate logistic regressions indicated that the diagnosis of PSP-RS was predicted by phonological verbal fluency deficit whereas the presence of apathy significantly predicted the PSP-P diagnosis. Peculiar neuropsychiatric and neuropsychological symptoms are identifiable very precociously in PSP-P, PSP-RS and PD patients. Early phonological verbal fluency deficit identifies patients with PSP-RS whereas apathy supports the diagnosis of PSP-P. Copyright © 2017 Elsevier Ltd. All rights reserved.

Using hyperspectral imaging technology to identify diseased tomato leaves

NASA Astrophysics Data System (ADS)

Li, Cuiling; Wang, Xiu; Zhao, Xueguan; Meng, Zhijun; Zou, Wei

2016-11-01

In the process of tomato plants growth, due to the effect of plants genetic factors, poor environment factors, or disoperation of parasites, there will generate a series of unusual symptoms on tomato plants from physiology, organization structure and external form, as a result, they cannot grow normally, and further to influence the tomato yield and economic benefits. Hyperspectral image usually has high spectral resolution, not only contains spectral information, but also contains the image information, so this study adopted hyperspectral imaging technology to identify diseased tomato leaves, and developed a simple hyperspectral imaging system, including a halogen lamp light source unit, a hyperspectral image acquisition unit and a data processing unit. Spectrometer detection wavelength ranged from 400nm to 1000nm. After hyperspectral images of tomato leaves being captured, it was needed to calibrate hyperspectral images. This research used spectrum angle matching method and spectral red edge parameters discriminant method respectively to identify diseased tomato leaves. Using spectral red edge parameters discriminant method produced higher recognition accuracy, the accuracy was higher than 90%. Research results have shown that using hyperspectral imaging technology to identify diseased tomato leaves is feasible, and provides the discriminant basis for subsequent disease control of tomato plants.

Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis

PubMed Central

Nicholas, Timothy; Tsai, Kuenhi; Macha, Sreeraj; Sinha, Vikram; Stone, Julie; Corrigan, Brian; Bani, Massimo; Muglia, Pierandrea; Watson, Ian A.; Kern, Volker D.; Sheveleva, Elena; Marek, Kenneth; Stephenson, Diane T.; Romero, Klaus

2017-01-01

Abstract Given the recognition that disease‐modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient‐level longitudinal data of 672 subjects with early‐stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP‐1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed‐effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was –3.16 (90% confidence interval [CI] = –0.96 to –5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size. PMID:28749580

Bone density and brain atrophy in early Alzheimer's disease.

PubMed

Loskutova, Natalia; Honea, Robyn A; Vidoni, Eric D; Brooks, William M; Burns, Jeffrey M

2009-01-01

Studies suggest a link between bone loss and Alzheimer's disease. To examine bone mineral density (BMD) in early Alzheimer's disease (AD) and its relationship to brain structure and cognition, we evaluated 71 patients with early stage AD (Clinical Dementia Rating (CDR) 0.5 and 1) and 69 non-demented elderly control participants (CDR 0). Measures included whole body BMD by dual energy x-ray absorptiometry (DXA) and normalized whole brain volumes computed from structural MRI scans. Cognition was assessed with a standard neuropsychological test battery. Mean BMD was lower in the early AD group (1.11 +/- 0.13) compared to the non-demented control group (1.16 +/- 0.12, p = 0.02), independent of age, gender, habitual physical activity, smoking, depression, estrogen replacement, and apolipoprotein E4 carrier status. In the early AD group, BMD was related to whole brain volume (b = 0.18, p = 0.03). BMD was also associated with cognitive performance, primarily in tests of memory (logical memory [b = 0.15, p = 0.04], delayed logical memory [b = 0.16, p = 0.02], and the selective reminding task - free recall [b = 0.18, p = 0.009]). BMD is reduced in the earliest clinical stages of AD and associated with brain atrophy and memory decline, suggesting that central mechanisms may contribute to bone loss in early AD.

Cortical atrophy patterns in early Parkinson's disease patients using hierarchical cluster analysis.

PubMed

Uribe, Carme; Segura, Barbara; Baggio, Hugo Cesar; Abos, Alexandra; Garcia-Diaz, Anna Isabel; Campabadal, Anna; Marti, Maria Jose; Valldeoriola, Francesc; Compta, Yaroslau; Tolosa, Eduard; Junque, Carme

2018-05-01

Cortical brain atrophy detectable with MRI in non-demented advanced Parkinson's disease (PD) is well characterized, but its presence in early disease stages is still under debate. We aimed to investigate cortical atrophy patterns in a large sample of early untreated PD patients using a hypothesis-free data-driven approach. Seventy-seven de novo PD patients and 50 controls from the Parkinson's Progression Marker Initiative database with T1-weighted images in a 3-tesla Siemens scanner were included in this study. Mean cortical thickness was extracted from 360 cortical areas defined by the Human Connectome Project Multi-Modal Parcellation version 1.0, and a hierarchical cluster analysis was performed using Ward's linkage method. A general linear model with cortical thickness data was then used to compare clustering groups using FreeSurfer software. We identified two patterns of cortical atrophy. Compared with controls, patients grouped in pattern 1 (n = 33) were characterized by cortical thinning in bilateral orbitofrontal, anterior cingulate, and lateral and medial anterior temporal gyri. Patients in pattern 2 (n = 44) showed cortical thinning in bilateral occipital gyrus, cuneus, superior parietal gyrus, and left postcentral gyrus, and they showed neuropsychological impairment in memory and other cognitive domains. Even in the early stages of PD, there is evidence of cortical brain atrophy. Neuroimaging clustering analysis is able to detect two subgroups of cortical thinning, one with mainly anterior atrophy, and the other with posterior predominance and worse cognitive performance. Copyright © 2018 Elsevier Ltd. All rights reserved.

The Prevention of Early-Onset Neonatal Group B Streptococcal Disease.

PubMed

Money, Deborah; Allen, Victoria M

2016-12-01

To review the evidence in the literature and to provide recommendations on the management of pregnant women in labour for the prevention of early-onset neonatal group B streptococcal disease. The key revisions in this updated guideline include changed recommendations for regimens for antibiotic prophylaxis, susceptibility testing, and management of women with pre-labour rupture of membranes. Maternal outcomes evaluated included exposure to antibiotics in pregnancy and labour and complications related to antibiotic use. Neonatal outcomes of rates of early-onset group B streptococcal infections are evaluated. Published literature was retrieved through searches of MEDLINE, CINAHL, and The Cochrane Library from January 1980 to July 2012 using appropriate controlled vocabulary and key words (group B streptococcus, antibiotic therapy, infection, prevention). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to May 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). The recommendations in this guideline are designed to help clinicians identify and manage pregnancies at risk for neonatal group B streptococcal disease to optimize maternal and perinatal outcomes. No cost-benefit analysis is provided. There is good evidence based on randomized control trial data that in women with pre-labour rupture of membranes at term who are colonized with group B streptococcus, rates of neonatal infection are

Computer keyboard interaction as an indicator of early Parkinson’s disease

PubMed Central

Giancardo, L.; Sánchez-Ferro, A.; Arroyo-Gallego, T.; Butterworth, I.; Mendoza, C. S.; Montero, P.; Matarazzo, M.; Obeso, J. A.; Gray, M. L.; Estépar, R. San José

2016-01-01

Parkinson’s disease (PD) is a slowly progressing neurodegenerative disease with early manifestation of motor signs. Objective measurements of motor signs are of vital importance for diagnosing, monitoring and developing disease modifying therapies, particularly for the early stages of the disease when putative neuroprotective treatments could stop neurodegeneration. Current medical practice has limited tools to routinely monitor PD motor signs with enough frequency and without undue burden for patients and the healthcare system. In this paper, we present data indicating that the routine interaction with computer keyboards can be used to detect motor signs in the early stages of PD. We explore a solution that measures the key hold times (the time required to press and release a key) during the normal use of a computer without any change in hardware and converts it to a PD motor index. This is achieved by the automatic discovery of patterns in the time series of key hold times using an ensemble regression algorithm. This new approach discriminated early PD groups from controls with an AUC = 0.81 (n = 42/43; mean age = 59.0/60.1; women = 43%/60%;PD/controls). The performance was comparable or better than two other quantitative motor performance tests used clinically: alternating finger tapping (AUC = 0.75) and single key tapping (AUC = 0.61). PMID:27703257

Computer keyboard interaction as an indicator of early Parkinson’s disease

NASA Astrophysics Data System (ADS)

Giancardo, L.; Sánchez-Ferro, A.; Arroyo-Gallego, T.; Butterworth, I.; Mendoza, C. S.; Montero, P.; Matarazzo, M.; Obeso, J. A.; Gray, M. L.; Estépar, R. San José

2016-10-01

Parkinson’s disease (PD) is a slowly progressing neurodegenerative disease with early manifestation of motor signs. Objective measurements of motor signs are of vital importance for diagnosing, monitoring and developing disease modifying therapies, particularly for the early stages of the disease when putative neuroprotective treatments could stop neurodegeneration. Current medical practice has limited tools to routinely monitor PD motor signs with enough frequency and without undue burden for patients and the healthcare system. In this paper, we present data indicating that the routine interaction with computer keyboards can be used to detect motor signs in the early stages of PD. We explore a solution that measures the key hold times (the time required to press and release a key) during the normal use of a computer without any change in hardware and converts it to a PD motor index. This is achieved by the automatic discovery of patterns in the time series of key hold times using an ensemble regression algorithm. This new approach discriminated early PD groups from controls with an AUC = 0.81 (n = 42/43 mean age = 59.0/60.1 women = 43%/60%PD/controls). The performance was comparable or better than two other quantitative motor performance tests used clinically: alternating finger tapping (AUC = 0.75) and single key tapping (AUC = 0.61).

Classification of Rhinoentomophthoromycosis into Atypical, Early, Intermediate, and Late Disease: A Proposal

PubMed Central

Blumentrath, Christian G.; Grobusch, Martin P.; Matsiégui, Pierre-Blaise; Pahlke, Friedrich; Zoleko-Manego, Rella; Nzenze-Aféne, Solange; Mabicka, Barthélemy; Sanguinetti, Maurizio; Kremsner, Peter G.; Schaumburg, Frieder

2015-01-01

Background Rhinoentomophthoromycosis, or rhino-facial conidiobolomycosis, is a rare, grossly disfiguring disease due to an infection with entomophthoralean fungi. We report a case of rhinoentomophthoromycosis from Gabon and suggest a staging system, which provides information on the prognosis and duration of antifungal therapy. Methods We present a case of rhinoentomophthoromycosis including the histopathology, mycology, and course of disease. For the suggested staging system, all cases on confirmed rhinoentomophthoromycosis published in the literature without language restriction were eligible. Exclusion criteria were missing data on (i) duration of disease before correct diagnosis, (ii) outcome, and (iii) confirmation of entomophthoralean fungus infection by histopathology and/or mycology. We classified cases into atypical (orbital cellulitis, severe pain, fever, dissemination), early, intermediate, and late disease based on the duration of symptoms before diagnosis. The outcome was evaluated for each stage of disease. Findings The literature search of the Medpilot database was conducted on January 13, 2014, (updated on January 18, 2015). The search yielded 8,333 results including 198 cases from 117 papers; of these, 145 met our inclusion criteria and were included in the final analysis. Median duration of treatment was 4, 3, 4, and 5 months in atypical, early, intermediate, and late disease, respectively. Cure rates were clearly associated with stage of disease and were 57%, 100%, 82%, and 43% in atypical, early, intermediate, and late disease, respectively. Conclusion We suggest a clinical staging system that underlines the benefit of early case detection and may guide the duration of antifungal treatment. The scientific value of this classification is its capacity to structure and harmonize the clinical and research approach towards rhinoentomophthoromycosis. PMID:26426120

CTNNB1 (beta-catenin) mutation identifies low grade, early stage endometrial cancer patients at increased risk of recurrence.

PubMed

Kurnit, Katherine C; Kim, Grace N; Fellman, Bryan M; Urbauer, Diana L; Mills, Gordon B; Zhang, Wei; Broaddus, Russell R

2017-07-01

Although the majority of low grade, early stage endometrial cancer patients will have good survival outcomes with surgery alone, those patients who do recur tend to do poorly. Optimal identification of the subset of patients who are at high risk of recurrence and would benefit from adjuvant treatment has been difficult. The purpose of this study was to evaluate the impact of somatic tumor mutation on survival outcomes in this patient population. For this study, low grade was defined as endometrioid FIGO grades 1 or 2, while early stage was defined as endometrioid stages I or II (disease confined to the uterus). Next-generation sequencing was performed using panels comprised of 46-200 genes. Recurrence-free and overall survival was compared across gene mutational status in both univariate and multivariate analyses. In all, 342 patients were identified, 245 of which had endometrioid histology. For grades 1-2, stages I-II endometrioid endometrial cancer patients, age (HR 1.07, 95% CI 1.03-1.10), CTNNB1 mutation (HR 5.97, 95% CI 2.69-13.21), and TP53 mutation (HR 4.07, 95% CI 1.57-10.54) were associated with worse recurrence-free survival on multivariate analysis. When considering endometrioid tumors of all grades and stages, CTNNB1 mutant tumors were associated with significantly higher rates of grades 1-2 disease, lower rates of deep myometrial invasion, and lower rates of lymphatic/vascular space invasion. When both TP53 and CTNNB1 mutations were considered, presence of either TP53 mutation or CTNNB1 mutation remained a statistically significant predictor of recurrence-free survival on multivariate analysis and was associated with a more precise confidence interval (HR 4.69, 95% CI 2.38-9.24). Thus, mutational analysis of a 2 gene panel of CTNNB1 and TP53 can help to identify a subset of low grade, early stage endometrial cancer patients who are at high risk of recurrence.

Clinical features that identify children with primary immunodeficiency diseases.

PubMed

Subbarayan, Anbezhil; Colarusso, Gloria; Hughes, Stephen M; Gennery, Andrew R; Slatter, Mary; Cant, Andrew J; Arkwright, Peter D

2011-05-01

The 10 warning signs of primary immunodeficiency diseases (PID) have been promoted by various organizations in Europe and the United States to predict PID. However, the ability of these warning signs to identify children with PID has not been rigorously tested. The main goal of this study was to determine the effectiveness of these 10 warning signs in predicting defined PID among children who presented to 2 tertiary pediatric immunodeficiency centers in the north of England. A retrospective survey of 563 children who presented to 2 pediatric immunodeficiency centers was undertaken. The clinical records of 430 patients with a defined PID and 133 patients for whom detailed investigations failed to establish a specific PID were reviewed. Overall, 96% of the children with PID were referred by hospital clinicians. The strongest identifiers of PID were a family history of immunodeficiency disease in addition to use of intravenous antibiotics for sepsis in children with neutrophil PID and failure to thrive in children with T-lymphocyte PID. With these 3 signs, 96% of patients with neutrophil and complement deficiencies and 89% of children with T-lymphocyte immunodeficiencies could be identified correctly. Family history was the only warning sign that identified children with B-lymphocyte PID. PID awareness initiatives should be targeted at hospital pediatricians and families with a history of PID rather than the general public. Our results provide the general pediatrician with a simple refinement of 10 warning signs for identifying children with underlying immunodeficiency diseases.

An Overview of Inflammatory Bowel Disease: General Consideration and Genetic Screening Approach in Diagnosis of Early Onset Subsets

PubMed Central

Nemati, Shahram; Teimourian, Shahram

2017-01-01

Inflammatory bowel disease (IBD) is the consequence of an aberrant hemostasis of the immune cells at the gut mucosal border. Based on clinical manifestation, laboratory tests, radiological studies, endoscopic and histological features, this disease is divided into three main types including Crohn’s disease (CD), Ulcerative colitis (UC), and IBDunclassified (IBD-U). IBD is frequently presented in adults, but about 20% of IBD cases are diagnosed during childhood called pediatric IBD (PIBD). Some patients in the latter group emerge the first symptoms during infancy or under 5 years of age named infantile and very early onset IBD (VEO-IBD), respectively. These subtypes make a small fraction of PIBD, but they have exclusive phenotypic and genetic characteristics such that they are accompanied by severe disease course and resistance to conventional therapy. In this context, understanding the underlying molecular pathology opens a promising field for individualized and effective treatment. Here, we describe current hypotheses on IBD pathophysiology then explain the new idea about genetic screening technology as a good potential approach to identify the causal variants early in the disease manifestation, which is especially important for the fast and accurate treatment of VEO-IBD. PMID:28638582

Early Life Stress, Air Pollution, Inflammation, and Disease: An Integrative Review and Immunologic Model of Social-Environmental Adversity and Lifespan Health.

PubMed

Olvera Alvarez, Hector A; Kubzansky, Laura D; Campen, Matthew J; Slavich, George M

2018-06-03

Socially disadvantaged individuals are at greater risk for simultaneously being exposed to adverse social and environmental conditions. Although the mechanisms underlying joint effects remain unclear, one hypothesis is that toxic social and environmental exposures have synergistic effects on inflammatory processes that underlie the development of chronic diseases, including cardiovascular disease, diabetes, depression, and certain types of cancer. In the present review, we examine how exposure to two risk factors that commonly occur with social disadvantage-early life stress and air pollution-affect health. Specifically, we identify neuroimmunologic pathways that could link early life stress, inflammation, air pollution, and poor health, and use this information to propose an integrated, multi-level model that describes how these factors may interact and cause health disparity across individuals based on social disadvantage. This model highlights the importance of interdisciplinary research considering multiple exposures across domains and the potential for synergistic, cross-domain effects on health, and may help identify factors that could potentially be targeted to reduce disease risk and improve lifespan health. Copyright © 2018. Published by Elsevier Ltd.

Network for Early Onset Cystic Kidney Diseases-A Comprehensive Multidisciplinary Approach to Hereditary Cystic Kidney Diseases in Childhood.

PubMed

König, Jens Christian; Titieni, Andrea; Konrad, Martin

2018-01-01

Hereditary cystic kidney diseases comprise a complex group of genetic disorders representing one of the most common causes of end-stage renal failure in childhood. The main representatives are autosomal recessive polycystic kidney disease, nephronophthisis, Bardet-Biedl syndrome, and hepatocyte nuclear factor-1beta nephropathy. Within the last years, genetic efforts have brought tremendous progress for the molecular understanding of hereditary cystic kidney diseases identifying more than 70 genes. Yet, genetic heterogeneity, phenotypic variability, a lack of reliable genotype-phenotype correlations and the absence of disease-specific biomarkers remain major challenges for physicians treating children with cystic kidney diseases. To tackle these challenges comprehensive scientific approaches are urgently needed that match the ongoing "revolution" in genetics and molecular biology with an improved efficacy of clinical data collection. Network for early onset cystic kidney diseases (NEOCYST) is a multidisciplinary, multicenter collaborative combining a detailed collection of clinical data with translational scientific approaches addressing the genetic, molecular, and functional background of hereditary cystic kidney diseases. Consisting of seven work packages, including an international registry as well as a biobank, NEOCYST is not only dedicated to current scientific questions, but also provides a platform for longitudinal clinical surveillance and provides precious sources for high-quality research projects and future clinical trials. Funded by the German Federal Government, the NEOCYST collaborative started in February 2016. Here, we would like to introduce the rationale, design, and objectives of the network followed by a short overview on the current state of progress.

[Early diagnosis of Hansen disease: study of the health services in Recife (Pernambuco), Brazil].

PubMed

Feliciano, K V; Kovacs, M H; Alzate, A

1998-07-01

This paper presents the results of a descriptive study carried out in the city of Recife, state of Pernambuco, Brazil, between March and September 1994. The study aimed at health services available for performing early diagnosis of Hansen's disease with emphasis on accessibility and quality of the services provided. The sample consisted of 32 health clinics visited for diagnostic purposes by 183 patients with Hansen's disease. Information on organizational infrastructures was collected by means of interviews with health clinic managers. Information regarding routine procedures in the 32 clinics was collected by observation, with special attention given to archival and inspection activities. A total of 1,998 patients were interviewed to determine accessibility of services. Time spent in consultation with the physician was determined for 1,000 patients who were seen by 123 physicians at the clinics during the interviews. To explore physicians' attitude and knowledge regarding Hansen's disease, 133 were randomly selected from a list of names. The following factors were identified as hindering early diagnosis of Hansen's disease: the large number of people seeking service who could not be seen by a physician on the same day; the long time elapsed between appointment scheduling and the actual visit (for those not seen on the same day); the long wait for the consultation; the brevity of the consultation; the low availability of trained personnel; the low proportion of physicians who examined all body surfaces; difficulties in the clinical recognition of the disease; and physicians not prepared to make a differential diagnosis. These obstacles can precipitate the physical deterioration of Hansen's disease patients and stimulate the persistence of transmissibility; therefore, they need to be overcome if Hansen's disease is to be eliminated.

The HEART Pathway randomized trial: identifying emergency department patients with acute chest pain for early discharge.

PubMed

Mahler, Simon A; Riley, Robert F; Hiestand, Brian C; Russell, Gregory B; Hoekstra, James W; Lefebvre, Cedric W; Nicks, Bret A; Cline, David M; Askew, Kim L; Elliott, Stephanie B; Herrington, David M; Burke, Gregory L; Miller, Chadwick D

2015-03-01

The HEART Pathway is a decision aid designed to identify emergency department patients with acute chest pain for early discharge. No randomized trials have compared the HEART Pathway with usual care. Adult emergency department patients with symptoms related to acute coronary syndrome without ST-elevation on ECG (n=282) were randomized to the HEART Pathway or usual care. In the HEART Pathway arm, emergency department providers used the HEART score, a validated decision aid, and troponin measures at 0 and 3 hours to identify patients for early discharge. Usual care was based on American College of Cardiology/American Heart Association guidelines. The primary outcome, objective cardiac testing (stress testing or angiography), and secondary outcomes, index length of stay, early discharge, and major adverse cardiac events (death, myocardial infarction, or coronary revascularization), were assessed at 30 days by phone interview and record review. Participants had a mean age of 53 years, 16% had previous myocardial infarction, and 6% (95% confidence interval, 3.6%-9.5%) had major adverse cardiac events within 30 days of randomization. Compared with usual care, use of the HEART Pathway decreased objective cardiac testing at 30 days by 12.1% (68.8% versus 56.7%; P=0.048) and length of stay by 12 hours (9.9 versus 21.9 hours; P=0.013) and increased early discharges by 21.3% (39.7% versus 18.4%; P<0.001). No patients identified for early discharge had major adverse cardiac events within 30 days. The HEART Pathway reduces objective cardiac testing during 30 days, shortens length of stay, and increases early discharges. These important efficiency gains occurred without any patients identified for early discharge suffering MACE at 30 days. URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01665521. © 2015 American Heart Association, Inc.

Digitized Spiral Drawing: A Possible Biomarker for Early Parkinson’s Disease

PubMed Central

San Luciano, Marta; Wang, Cuiling; Ortega, Roberto A.; Yu, Qiping; Boschung, Sarah; Soto-Valencia, Jeannie; Bressman, Susan B.; Lipton, Richard B.; Pullman, Seth; Saunders-Pullman, Rachel

2016-01-01

Introduction Pre-clinical markers of Parkinson’s Disease (PD) are needed, and to be relevant in pre-clinical disease, they should be quantifiably abnormal in early disease as well. Handwriting is impaired early in PD and can be evaluated using computerized analysis of drawn spirals, capturing kinematic, dynamic, and spatial abnormalities and calculating indices that quantify motor performance and disability. Digitized spiral drawing correlates with motor scores and may be more sensitive in detecting early changes than subjective ratings. However, whether changes in spiral drawing are abnormal compared with controls and whether changes are detected in early PD are unknown. Methods 138 PD subjects (50 with early PD) and 150 controls drew spirals on a digitizing tablet, generating x, y, z (pressure) data-coordinates and time. Derived indices corresponded to overall spiral execution (severity), shape and kinematic irregularity (second order smoothness, first order zero-crossing), tightness, mean speed and variability of spiral width. Linear mixed effect adjusted models comparing these indices and cross-validation were performed. Receiver operating characteristic analysis was applied to examine discriminative validity of combined indices. Results All indices were significantly different between PD cases and controls, except for zero-crossing. A model using all indices had high discriminative validity (sensitivity = 0.86, specificity = 0.81). Discriminative validity was maintained in patients with early PD. Conclusion Spiral analysis accurately discriminates subjects with PD and early PD from controls supporting a role as a promising quantitative biomarker. Further assessment is needed to determine whether spiral changes are PD specific compared with other disorders and if present in pre-clinical PD. PMID:27732597

Fungal infections in children in the early postoperative period after cardiac surgery for congenital heart disease: a single-centre experience.

PubMed

Jaworski, Radoslaw; Haponiuk, Ireneusz; Irga-Jaworska, Ninela; Chojnicki, Maciej; Steffens, Mariusz; Paczkowski, Konrad; Zielinski, Jacek

2016-09-01

Postoperative infections are still an important problem in cardiac surgery, especially in the paediatric population, and may influence the final outcome of congenital heart disease treatment. Postoperative infections with fungi are uncommon. The aetiology is poorly understood, and the proper diagnosis and treatment is unclear. In this single-centre study, the frequency of invasive fungal disease in children who underwent surgical management of congenital heart diseases was determined along with the risk factors for infection, treatment options and outcomes. All consecutive paediatric patients (<18 years of age) who underwent cardiac surgery for congenital heart disease between September 2008 and December 2015 in a paediatric cardiac centre in Poland were identified. Those who developed invasive fungal disease in the early postoperative period (30 days) were identified. Of the 1540 cardiosurgical procedures for congenital heart disease, 6 were complicated by fungal infection (0.39%). One patient had a high probability of fungal infection, but the diagnosis was unproved. Nevertheless, the patient was successfully treated with antifungal treatment. Five had proven invasive fungal disease. Of these, 3 were diagnosed with candidaemia. All had undergone cardiopulmonary bypass. Of the remaining 2 patients, 1 was a preterm newborn with complete atrioventricular septal defect who developed rib fungal invasion. The remaining patient had pulmonary atresia with ventricular septal defect and developed Fournier's gangrene after surgery. None of the patients died due to infection in the early postoperative period. However, the child with rib fungal invasion died 39 days after surgery as a result of multiorgan failure. Fungal infections in paediatric patients after cardiac surgery may markedly influence morbidity and mortality. Fungal infection prophylaxis in this specific group of children may reduce morbidity, whereas early empirical treatment followed by a targeted approach may

Targeting early PKCθ-dependent T-cell infiltration of dystrophic muscle reduces disease severity in a mouse model of muscular dystrophy.

PubMed

Lozanoska-Ochser, Biliana; Benedetti, Anna; Rizzo, Giuseppe; Marrocco, Valeria; Di Maggio, Rosanna; Fiore, Piera; Bouche, Marina

2018-03-01

Chronic muscle inflammation is a critical feature of Duchenne muscular dystrophy and contributes to muscle fibre injury and disease progression. Although previous studies have implicated T cells in the development of muscle fibrosis, little is known about their role during the early stages of muscular dystrophy. Here, we show that T cells are among the first cells to infiltrate mdx mouse dystrophic muscle, prior to the onset of necrosis, suggesting an important role in early disease pathogenesis. Based on our comprehensive analysis of the kinetics of the immune response, we further identify the early pre-necrotic stage of muscular dystrophy as the relevant time frame for T-cell-based interventions. We focused on protein kinase C θ (PKCθ, encoded by Prkcq), a critical regulator of effector T-cell activation, as a potential target to inhibit T-cell activity in dystrophic muscle. Lack of PKCθ not only reduced the frequency and number of infiltrating T cells but also led to quantitative and qualitative changes in the innate immune cell infiltrate in mdx/Prkcq -/- muscle. These changes were due to the inhibition of T cells, since PKCθ was necessary for T-cell but not for myeloid cell infiltration of acutely injured muscle. Targeting T cells with a PKCθ inhibitor early in the disease process markedly diminished the size of the inflammatory cell infiltrate and resulted in reduced muscle damage. Moreover, diaphragm necrosis and fibrosis were also reduced following treatment. Overall, our findings identify the early T-cell infiltrate as a therapeutic target and highlight the potential of PKCθ inhibition as a therapeutic approach to muscular dystrophy. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Prototype early warning system for heart disease detection using Android Application.

PubMed

Zennifa, Fadilla; Fitrilina; Kamil, Husnil; Iramina, Keiji

2014-01-01

Heart Disease affects approximately 70 million people worldwide where most people do not even know the symptoms. This research examines the prototype of early warning system for heart disease by android application. It aims to facilitate users to early detect heart disease which can be used independently. To build the application in android phone, variable centered intelligence rule system (VCIRS) as decision makers and pulse sensor - Arduino as heart rate detector were applied in this study. Moreover, in Arduino, the heart rate will become an input for symptoms in Android Application. The output of this system is the conclusion statement of users diagnosed with either coronary heart disease, hypertension heart disease, rheumatic heart disease or do not get any kind of heart disease. The result of diagnosis followed by analysis of the value of usage variable rate (VUR) rule usage rate (RUR) and node usage rate (NUR) that shows the value of the rule that will increase when the symptoms frequently appear. This application was compared with the medical analysis from 35 cases of heart disease and it showed concordance between diagnosis from android application and expert diagnosis of the doctors.

Factors influencing speech and language outcomes of children with early identified severe/profound hearing loss: Clinician-identified facilitators and barriers.

PubMed

Fulcher, Anne Nivelles; Purcell, Alison; Baker, Elise; Munro, Natalie

2015-06-01

Early identification of severe/profound childhood hearing loss (HL) gives these children access to hearing devices and early intervention to facilitate improved speech and language outcomes. Predicting which infants will go on to achieve such outcomes remains difficult. This study describes clinician identified malleable and non-malleable factors that may influence speech and language outcomes for children with severe/profound HL. Semi-structured interviews were conducted with six experienced auditory verbal clinicians. A collective case study design was implemented. The interviews were transcribed and coded into themes using constant comparative analysis. Clinicians identified that, for children with severe/profound HL, early identification, early amplification and commencing auditory-verbal intervention under 6 months of age may facilitate child progress. Possible barriers were living in rural/remote areas, the clinicians' lack of experience and confidence in providing intervention for infants under age 6-months and belonging to a family with a culturally and linguistically diverse (CALD) background. The results indicate that multiple factors need to be considered by clinicians working with children with HL and their families to determine how each child functions within their own environment and personal contexts, consistent with the International Classification of Functioning, Disability and Health (ICF) framework. Such an approach is likely to empower clinicians to carefully balance potential barriers to, and facilitators of, optimal speech and language outcomes for all children with HL.

Novel ZBTB24 Mutation Associated with Immunodeficiency, Centromere Instability, and Facial Anomalies Type-2 Syndrome Identified in a Patient with Very Early Onset Inflammatory Bowel Disease.

PubMed

Conrad, Máire A; Dawany, Noor; Sullivan, Kathleen E; Devoto, Marcella; Kelsen, Judith R

2017-12-01

Very early onset inflammatory bowel disease, diagnosed in children ≤5 years old, can be the initial presentation of some primary immunodeficiencies. In this study, we describe a 17-month-old boy with recurrent infections, growth failure, facial anomalies, and inflammatory bowel disease. Immune evaluation, whole-exome sequencing, karyotyping, and methylation array were performed to evaluate the child's constellation of symptoms and examination findings. Whole-exome sequencing revealed that the child was homozygous for a novel variant in ZBTB24, the gene associated with immunodeficiency, centromere instability, and facial anomalies type-2 syndrome. This describes the first case of inflammatory bowel disease associated with immunodeficiency, centromere instability, and facial anomalies type-2 syndrome in a child with a novel disease-causing mutation in ZBTB24 found on whole-exome sequencing.

Changes in neural circuitry associated with depression at pre-clinical, pre-motor and early motor phases of Parkinson's disease.

PubMed

Borgonovo, Janina; Allende-Castro, Camilo; Laliena, Almudena; Guerrero, Néstor; Silva, Hernán; Concha, Miguel L

2017-02-01

Although Parkinson's Disease (PD) is mostly considered a motor disorder, it can present at early stages as a non-motor pathology. Among the non-motor clinical manifestations, depression shows a high prevalence and can be one of the first clinical signs to appear, even a decade before the onset of motor symptoms. Here, we review the evidence of early dysfunction in neural circuitry associated with depression in the context of PD, focusing on pre-clinical, pre-motor and early motor phases of the disease. In the pre-clinical phase, structural and functional changes in the substantia nigra, basal ganglia and limbic structures are already observed. Some of these changes are linked to motor compensation mechanisms while others correspond to pathological processes common to PD and depression and thus could underlie the appearance of depressive symptoms during the pre-motor phase. Studies of the early motor phase (less than five years post diagnosis) reveal an association between the extent of damage in different monoaminergic systems and the appearance of emotional disorders. We propose that the limbic loop of the basal ganglia and the lateral habenula play key roles in the early genesis of depression in PD. Alterations in the neural circuitry linked with emotional control might be sensitive markers of the ongoing neurodegenerative process and thus may serve to facilitate an early diagnosis of this disease. To take advantage of this, we need to improve the clinical criteria and develop biomarkers to identify depression, which could be used to determine individuals at risk to develop PD. Copyright © 2016 Elsevier Ltd. All rights reserved.

CSF N-glycoproteomics for early diagnosis in Alzheimer's disease.

PubMed

Palmigiano, Angelo; Barone, Rita; Sturiale, Luisa; Sanfilippo, Cristina; Bua, Rosaria Ornella; Romeo, Donata Agata; Messina, Angela; Capuana, Maria Luisa; Maci, Tiziana; Le Pira, Francesco; Zappia, Mario; Garozzo, Domenico

2016-01-10

This work aims at exploring the human CSF (Cerebrospinal fluid) N-glycome by MALDI MS techniques, in order to assess specific glycosylation pattern(s) in patients with Alzheimer's disease (n:24) and in subjects with mild cognitive impairment (MCI) (n:11), these last as potential AD patients at a pre-dementia stage. For comparison, 21 healthy controls were studied. We identified a group of AD and MCI subjects (about 40-50% of the studied sample) showing significant alteration of CSF N-glycome profiling, consisting of a decrease in the overall sialylation degree and an increase in species bearing bisecting GlcNAc. Noteworthy, all the MCI patients that converted to AD within the clinical follow-up, had an abnormal CSF glycosylation profile. Based on the studied cohort, CSF glycosylation changes may occur before an AD clinical onset. Previous studies specifically focused on the key role of glycosyltransferase GnT-III on AD-pathogenesis, addressing the patho-mechanism to specific sugar modification of BACE-1 glycoprotein with bisecting GlcNAc. Our patients addressed protein N-glycosylation changes at an early phase of the whole biomolecular misregulation on AD, pointing to CSF N-glycome analyses as promising tool to enhance early detection of AD and also suggesting alternative therapeutics target molecules, such as specific glyco-enzymes. Copyright © 2015 Elsevier B.V. All rights reserved.

Standardized Symptom Measurement of Individuals with Early Lyme Disease Over Time.

PubMed

Bechtold, Kathleen T; Rebman, Alison W; Crowder, Lauren A; Johnson-Greene, Doug; Aucott, John N

2017-03-01

Understanding the Lyme disease (LD) literature is challenging given the lack of consistent methodology and standardized measurement of symptoms and the impact on functioning. This prospective study incorporates well-validated measures to capture the symptom picture of individuals with early LD from time of diagnosis through 6-months post-treatment. One hundred seven patients with confirmed early LD and 26 healthy controls were evaluated using standardized instruments for pain, fatigue, depressive symptoms, functional impact, and cognitive functioning. Prior to antibiotic treatment, patients experience notable symptoms of fatigue and pain statistically higher than controls. After treatment, there are no group differences, suggesting that symptoms resolve and that there are no residual cognitive impairments at the level of group analysis. However, using subgroup analyses, some individuals experience persistent symptoms that lead to functional decline and these individuals can be identified immediately post-completion of standard antibiotic treatment using well-validated symptom measures. Overall, the findings suggest that ideally-treated early LD patients recover well and experience symptom resolution over time, though a small subgroup continue to suffer with symptoms that lead to functional decline. The authors discuss use of standardized instruments for identification of individuals who warrant further clinical follow-up. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Regional variation in identified cancer care needs of early-career oncologists in China, India, and Pakistan.

PubMed

Lyerly, H Kim; Fawzy, Maria R; Aziz, Zeba; Nair, Reena; Pramesh, C S; Parmar, Vani; Parikh, Purvish M; Jamal, Rozmin; Irumnaz, Azizunissa; Ren, Jun; Stockler, Martin R; Abernethy, Amy P

2015-05-01

Cancer incidence and mortality is increasing in the developing world. Inequities between low-, middle-, and high-income countries affect disease burden and the infrastructure needs in response to cancer. We surveyed early-career oncologists attending workshops in clinical research in three countries with emerging economies about their perception of the evolving cancer burden. A cross-sectional survey questionnaire was distributed at clinical trial concept development workshops held in Beijing, Lahore, Karachi, and Mumbai at major hospitals to acquire information regarding home-country health conditions and needs. A total of 100 respondents participated in the workshops held at major hospitals in the region (India = 29, China = 25, Pakistan = 42, and other = 4). Expected consensus on many issues (e.g., emergence of cancer as a significant health issue) was balanced with significant variation in priorities, opportunities, and challenges. Chinese respondents prioritized improvements in cancer-specific care and palliative care, Indian respondents favored improved cancer detection and advancing research in cancer care, and Pakistani respondents prioritized awareness of cancer and improvements in disease detection and cancer care research. For all, the most frequently cited opportunity was help in improving professional cancer education and training. Predominantly early-career oncologists attending clinical research workshops (in China, India, and Pakistan) identified needs for increasing clinical cancer research, professional education, and public awareness of cancer. Decision makers supporting efforts to reduce the burden of cancer worldwide will need to factor the specific needs and aspirations of health care providers in their country in prioritizing health policies and budgets. ©AlphaMed Press.

Identifying Nodes of Transmission in Disease Diffusion Through Social Media

NASA Astrophysics Data System (ADS)

Lamb, David Sebastian

The spread of infectious diseases can be described in terms of three interrelated components: interaction, movement, and scale. Transmission between individuals requires some form of interaction, which is dependent on the pathogen, to occur. Diseases spread through the movement of their hosts; they spread across many spatial scales from local neighborhoods to countries, or temporal scales from days to years, or periodic intervals. Prior research into the spread of disease have examined diffusion processes retrospectively at regional or country levels, or developed differential equation or simulation models of the dynamics of disease transmission. While some of the more recent models incorporate all three components, they are limited in the way they understand where interactions occur. The focus has been on home or work, including contact with family or coworkers. The models reflect a lack of knowledge about how transmissions are made at specific locations in time, so-called nodes of transmission. That is, how individuals' intersections in time and space function in disease transmission. This project sought to use the three factors of interaction, movement, and scale to better understand the spread of disease in terms of the place of interaction called the node of transmission. The overarching objective of this research was: how can nodes of transmission be identified through individual activity spaces incorporating the three factors of infectious disease spread: interaction, movement, and scale?. This objective fed into three main sub-objectives: defining nodes of transmission, developing an appropriate methodology to identifying nodes of transmission, and applying it using geotagged social media data from Twitter. To develop an appropriate framework, this research relied on time geography, and traditional disease. This particularly relied on the idea of bundling to create the nodes, and a nesting effect that integrated scale. The data source used to identify nodes

Malaria: An Early Indicator of Later Disease and Work Level

PubMed Central

Hong, Sok Chul

2014-01-01

This study investigates the effect of early-life exposure to malaria on disease and work level in old age over the past one and a half centuries. Using longitudinal lifetime records of Union Army veterans, I first estimate that exposure to a malarial environment in early life (c.1840) substantially increased the likelihood of having various chronic diseases and not working in old age (c.1900). Second, from data on US cohorts born between 1891 and 1960, I find that those exposed to a higher level of the anti-malaria campaign, which began in 1921, had lower levels of work disability in old age. Third, I seek the same implications for the modern period by linking WHO's country statistics on DALYs among older populations in 2004 to country-level malaria risk in pre-eradication era. In the paper, I discuss possible mechanisms and propose the significance of malaria eradication and early-life conditions from a long-term perspective. PMID:23584052

Best practices in the treatment of early cystic fibrosis lung disease.

PubMed

Proesmans, Marijke

2017-02-01

For many years, management of cystic fibrosis (CF) lung disease was focused on symptomatic treatment of chronic lung infection, which is characterized by cough and sputum production, leading to progressive lung damage. With increasing survival and better knowledge of the pathogenesis of CF lung disease, it has become clear that treatment has to start very early because lung damage occurs in young patients, often before obvious symptoms appear. The arrival of new cystic fibrosis transmembrane conductance-regulator (CFTR)-correcting therapies will bring more opportunities to prevent the disease, apart from only treating chronic lung infection. In this review, a summary of the current knowledge of early CF lung disease is provided, based on animal model studies, as well as on data obtained from well structured follow-up programs after newborn screening (NBS). The most important clinical guidelines for treating young CF patients are also summarized.

Basal ganglia dysfunction in idiopathic REM sleep behaviour disorder parallels that in early Parkinson's disease.

PubMed

Rolinski, Michal; Griffanti, Ludovica; Piccini, Paola; Roussakis, Andreas A; Szewczyk-Krolikowski, Konrad; Menke, Ricarda A; Quinnell, Timothy; Zaiwalla, Zenobia; Klein, Johannes C; Mackay, Clare E; Hu, Michele T M

2016-08-01

behaviour disorder and Parkinson's disease relative to each other and to controls. Connectivity measures of basal ganglia network dysfunction differentiated both rapid eye movement sleep behaviour disorder and Parkinson's disease from controls with high sensitivity (96%) and specificity (74% for rapid eye movement sleep behaviour disorder, 78% for Parkinson's disease), indicating its potential as an indicator of early basal ganglia dysfunction. Rapid eye movement sleep behaviour disorder was indistinguishable from Parkinson's disease on resting state functional magnetic resonance imaging despite obvious differences on dopamine transported single photon emission computerized tomography. Basal ganglia connectivity is a promising biomarker for the detection of early basal ganglia network dysfunction, and may help to identify patients at risk of developing Parkinson's disease in the future. Future risk stratification using a polymodal approach could combine basal ganglia network connectivity with clinical and other imaging measures, with important implications for future neuroprotective trials in rapid eye movement sleep behaviour disorder. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

The die is cast: arsenic exposure in early life and disease susceptibility.

PubMed

Thomas, David J

2013-12-16

Early life exposure to arsenic in humans and mice produces similar patterns of disease in later life. Given the long interval between exposure and effect, epigenetic effects of early life exposure to arsenic may account for the development and progression of disease in both species. Mode of action and dosimetric studies in the mouse may help assess the role of age at exposure as a factor in susceptibility to the toxic and carcinogenic effects of arsenic in humans.

Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer's disease.

PubMed

Schöll, Michael; Ossenkoppele, Rik; Strandberg, Olof; Palmqvist, Sebastian; Jögi, Jonas; Ohlsson, Tomas; Smith, Ruben; Hansson, Oskar

2017-09-01

Patients with Alzheimer's disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer's disease (>65 years) typically present with medial temporal lobe neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer's disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer's disease, 21 with late-onset Alzheimer's disease, three with prodromal early-onset Alzheimer's disease and 13 with prodromal late-onset Alzheimer's disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer's disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F-AV-1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early-onset Alzheimer's disease with controls resulted in significantly higher 18F-AV-1451 retention throughout the neocortex, while comparing healthy controls with late-onset Alzheimer's disease patients yielded a distinct pattern of higher 18F-AV-1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early-onset Alzheimer's disease group exhibited greater uptake than the late-onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimer's disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimer's disease. © The Author (2017). Published by Oxford

[Early episodic memory impairments in Alzheimer's disease].

PubMed

Ergis, A-M; Eusop-Roussel, E

2008-05-01

Patients with Alzheimer's disease (AD) show early episodic memory impairments. Such deficits reflect specific impairments affecting one or several stages of encoding, storage and retrieval processes. However, AD patients not only have great difficulty retrieving memories and information but also suffer from distortions of memory, as intrusions and false recognitions. Intrusions can be defined as the unintentional recall of inappropriate information in a laboratory-learning tasks such as word-list recall and story recall. False recognition refers to the erroneous recognition of information that was not previously presented. The first objective of this review is to present studies from the literature that allowed a better understanding of the nature of episodic memory deficits in AD, and to examine recent research on false memories. The second part of this review is aimed at presenting recent research conducted on prospective memory (PM) in Alzheimer's disease. Prospective memory situations involve forming intentions and then realizing those intentions at some appropriate time in the future. Everyday examples of prospective memory include remembering to buy bread on the way home from work, remembering to give friends a message upon next encountering them, and remembering to take medication. Patients suffering from AD show difficulties in performing prospective tasks in daily life, according to the complaints of their care givers, and these difficulties are massively present at the first stages of the disease. Nevertheless, very few studies have been dedicated to this subject, although the evaluation of PM could be helpful for the early diagnosis of AD.

Surveillance and early warning systems of infectious disease in China: From 2012 to 2014.

PubMed

Zhang, Honglong; Wang, Liping; Lai, Shengjie; Li, Zhongjie; Sun, Qiao; Zhang, Peng

2017-07-01

Appropriate surveillance and early warning of infectious diseases have very useful roles in disease control and prevention. In 2004, China established the National Notifiable Infectious Disease Surveillance System and the Public Health Emergency Event Surveillance System to report disease surveillance and events on the basis of data sources from the National Notifiable Infectious Disease Surveillance System, China Infectious Disease Automated-alert and Response System in this country. This study provided a descriptive summary and a data analysis, from 2012 to 2014, of these 3 key surveillance and early warning systems of infectious disease in China with the intent to provide suggestions for system improvement and perfection. Copyright © 2017 John Wiley & Sons, Ltd.

Identifying Insomnia in Early Pregnancy: Validation of the Insomnia Symptoms Questionnaire (ISQ) in Pregnant Women.

PubMed

Okun, Michele L; Buysse, Daniel J; Hall, Martica H

2015-06-15

Although a substantial number of pregnant women report symptoms of insomnia, few studies have used a validated instrument to determine the prevalence in early gestation. Identification of insomnia in pregnancy is vital given the strong connection between insomnia and the incidence of depression, cardiovascular disease, or immune dysregulation. The goal of this paper is to provide additional psychometric evaluation and validation of the Insomnia Symptom Questionnaire (ISQ) and to establish prevalence rates of insomnia among a cohort of pregnant women during early gestation. The ISQ was evaluated in 143 pregnant women at 12 weeks gestation. The internal consistency and criterion validity of the dichotomized ISQ were compared to traditional measures of sleep from sleep diaries, actigraphy, and the Pittsburgh Sleep Quality Index using indices of sensitivity, specificity, positive and negative predictive value (PPV, NPV), and likelihood ratio (LR) tests. The ISQ identified 12.6% of the sample as meeting a case definition of insomnia, consistent with established diagnostic criteria. Good reliability was established with Cronbach α = 0.86. The ISQ had high specificity (most > 85%), but sensitivity, PPV, NPV, and LRs varied according to which sleep measure was used as the validating criterion. Insomnia is a health problem for many pregnant women at all stages in pregnancy. These data support the validity and reliability of the ISQ to identify insomnia in pregnant women. The ISQ is a short and cost-effective tool that can be quickly employed in large observational studies or in clinical practice where perinatal women are seen. A commentary on this article appears in this issue on page 593. © 2015 American Academy of Sleep Medicine.

Early Detection of Amyloid Plaque in Alzheimer’s Disease via X-ray Phase CT

DTIC Science & Technology

2016-08-01

AWARD NUMBER: W81XWH-12-1-0138 TITLE: Early Detection of Amyloid Plaque in Alzheimer’s Disease via X-ray Phase CT PRINCIPAL INVESTIGATOR...NUMBER W81XWH-12-1-0138 Early Detection of Amyloid Plaque in Alzheimer’s Disease via X-ray Phase CT 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6...method for early detection of amyloid plaque in Alzheimer’s disease , with three Specific Aims: #1 Develop and optimize an x-ray PCCT to explore the

[Early coronary heart disease together with tyoe II diabetes mellitus in persons of Hindustani origin].

PubMed

Bongers, I; Westendorp, R G; Stolk, B; Huysmans, H A; Vandenbroucke, J P

1995-01-07

To investigate the association between early coronary heart disease and non insulin dependent diabetes mellitus in South Asian patients in the Netherlands, a homogeneous population which descends from Indian immigrants to Surinam in the late nineteenth century. Case control study. University hospital Leiden. South Asian patients (n = 38) and control patients (n = 76) were identified in an automated data base comprising all patients who had aortocoronary surgery in the period January 1st 1990 to January 1st 1993. Control patients were from the general population and matched for calendar time. Patients' characteristics such as the onset of coronary heart disease and the presence of non insulin dependent diabetes mellitus were obtained from the medical records at the time of surgery. The onset of coronary heart disease in South Asian patients occurred about eight years earlier than in control patients (49.8 versus 58.2 years; 95% confidence interval of the difference: 4.3-12.5). Non insulin dependent diabetes mellitus was about four times more frequent in South Asian patients (50% versus 13%; 19-54). This difference was the same after correction for differences in sex, age, and body mass index. Diabetes mellitus caused by insulin resistance significantly contributes to early coronary heart disease in South Asian immigrant patients, in accordance with the literature on the present population of India. These findings strengthen the belief that genetic factor are important in the development of insulin resistance and atherosclerosis.

Early, asymptomatic stage of degenerative joint disease in canine hip joints.

PubMed

Lust, G; Summers, B A

1981-11-01

The early stages of degenerative joint disease were investigated in coxofemoral joints from dogs with a hereditary predisposition to hip dysplasia. Alterations observed included mild nonsuppurative synovitis, increased volume of both synovial fluid and the ligamentum teres, and focal degenerative articular cartilage lesions. On radiologic examination, subluxation of the femoral head was seen, but only in the most severely affected joints. Synovial inflammation with increased synovial fluid and ligament volumes were indicators of early degenerative joint disease in dogs. These changes seemed to coincide with, or perhaps to precede, microscopic evidence for articular cartilage degeneration and occurred before radiologic abnormalities were detected.

Children's, parents' and other stakeholders' perspectives on early dietary self-management to delay disease progression of chronic disease in children: a protocol for a mixed studies systematic review with a narrative synthesis.

PubMed

Pugh, Pearl; Hemingway, Pippa; Christian, Martin; Higginbottom, Gina

2018-01-25

Chronic disease of childhood may be delayed by early dietary intervention. The purpose of this systematic review is to provide decision-makers with a perspective on the role of early dietary intervention, as a form of self-management, to delay disease progression in children with early chronic disease, as described by children, parents and other stakeholders. The study will systematically review empirical research (qualitative, quantitative and mixed method designs), including grey literature, using a narrative synthesis. A four-stage search process will be conducted involving a scoping search, the Scottish Intercollegiate Guidelines Network (SIGN) Patient Issues search filter on MEDLINE, the search of seven databases using a chronic disease and chronic kidney disease (CKD) search strategy, and hand searching the reference lists of identified papers for additional studies. All studies retrieved during the search process will undergo a screening and selection process against the inclusion/exclusion criteria. Methodological quality of relevant studies will be assessed using a validated Mixed Studies Review scoring system, before inclusion in the review. Relevant grey literature will be assessed for methodological quality and relative importance using McGrath et al.'s framework and the Academy Health advisory committee categories, respectively. Data extraction will be guided by the Centre for Review and Dissemination guidance and Popay et al.'s work. The narrative synthesis of the findings will use elements of Popay et al.'s methodology of narrative synthesis, applying recognised tools for each of the four elements: (1) developing a theory of how the intervention works, why and for whom; (2) developing a preliminary synthesis of findings of included studies; (3) exploring relationships in the data; and (4) assessing the robustness of the synthesis. This mixed studies systematic review with a narrative synthesis seeks to elucidate the gaps in current knowledge and

Cooperative Genome-Wide Analysis Shows Increased Homozygosity in Early Onset Parkinson's Disease

PubMed Central

Nalls, Michael A.; Martinez, Maria; Schulte, Claudia; Holmans, Peter; Gasser, Thomas; Hardy, John; Singleton, Andrew B.; Wood, Nicholas W.; Brice, Alexis; Heutink, Peter; Williams, Nigel; Morris, Huw R.

2012-01-01

Parkinson's disease (PD) occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD) is particularly associated with autosomal recessive (AR) mutations, and three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading to AR disease. Since mutations in these genes account for less than 10% of EOPD patients, we hypothesized that further recessive genetic factors are involved in this disorder, which may appear in extended runs of homozygosity. We carried out genome wide SNP genotyping to look for extended runs of homozygosity (ROHs) in 1,445 EOPD cases and 6,987 controls. Logistic regression analyses showed an increased level of genomic homozygosity in EOPD cases compared to controls. These differences are larger for ROH of 9 Mb and above, where there is a more than three-fold increase in the proportion of cases carrying a ROH. These differences are not explained by occult recessive mutations at existing loci. Controlling for genome wide homozygosity in logistic regression analyses increased the differences between cases and controls, indicating that in EOPD cases ROHs do not simply relate to genome wide measures of inbreeding. Homozygosity at a locus on chromosome19p13.3 was identified as being more common in EOPD cases as compared to controls. Sequencing analysis of genes and predicted transcripts within this locus failed to identify a novel mutation causing EOPD in our cohort. There is an increased rate of genome wide homozygosity in EOPD, as measured by an increase in ROHs. These ROHs are a signature of inbreeding and do not necessarily harbour disease-causing genetic variants. Although there might be other regions of interest apart from chromosome 19p13.3, we lack the power to detect them with this analysis. PMID:22427796

Content validation of the infant malnutrition and feeding checklist for congenital heart disease: a tool to identify risk of malnutrition and feeding difficulties in infants with congenital heart disease.

PubMed

St Pierre, Astrid; Khattra, Parveen; Johnson, Mandy; Cender, Laurie; Manzano, Sandra; Holsti, Liisa

2010-10-01

Infants with congenital heart disease (CHD) have a high prevalence of feeding difficulties and malnutrition. Early intervention decreases morbidity and long-term developmental deficits. The purpose of this study was to develop and establish the content validity of a screening checklist to identify infants with CHD at risk of feeding difficulties or inadequate nutritional intake for timely referral to a feeding specialist or dietitian. The Delphi method was used, and expert participants reached consensus on 24 risk indicators. This study is the first step in establishing the validity and reliability of a screening tool for early intervention of feeding difficulties and inadequate nutritional intake in infants with CHD. Copyright © 2010 Elsevier Inc. All rights reserved.

Cognitive Development in Infantile-Onset Pompe Disease Under Very Early Enzyme Replacement Therapy.

PubMed

Lai, Chih-Jou; Hsu, Ting-Rong; Yang, Chia-Feng; Chen, Shyi-Jou; Chuang, Ya-Chin; Niu, Dau-Ming

2016-12-01

Most patients with infantile-onset Pompe disease die in early infancy before beginning enzyme replacement therapy, which has made it difficult to evaluate the impact of Pompe disease on cognitive development. Patients with infantile-onset Pompe disease can survive with enzyme replacement therapy, and physicians can evaluate cognitive development in these patients. We established an effective newborn screening program with quick clinical diagnostic criteria. Cognitive and motor development were evaluated using the Bayley Scales of Infant and Toddler Development-Third Edition at 6, 12, and 24 months of age. The patients who were treated very early demonstrate normal cognitive development with no significant change in cognition during this period (P = .18 > .05). The cognitive development was positively correlated with motor development (r = 0.533, P = .011). The results indicated that very early enzyme replacement therapy could protect cognitive development in patients with infantile-onset Pompe disease up to 24 months of age. © The Author(s) 2016.

Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins.

PubMed

Toro, Camilo; Olivé, Montse; Dalakas, Marinos C; Sivakumar, Kumaraswami; Bilbao, Juan M; Tyndel, Felix; Vidal, Noemí; Farrero, Eva; Sambuughin, Nyamkhishig; Goldfarb, Lev G

2013-03-20

Hereditary myopathy with early respiratory failure (HMERF) was described in several North European families and recently linked to a titin gene (TTN) mutation. We independently studied HMERF-like diseases with the purpose to identify the cause, refine diagnostic criteria, and estimate the frequency of this disease among myopathy patients of various ethnic origins. Whole exome sequencing analysis was carried out in a large U.S. family that included seven members suffering from skeletal muscle weakness and respiratory failure. Subsequent mutation screening was performed in further 45 unrelated probands with similar phenotypes. Studies included muscle strength evaluation, nerve conduction studies and concentric needle EMG, respiratory function test, cardiologic examination, and muscle biopsy. A novel TTN p.Gly30150Asp mutation was identified in the highly conserved A-band of titin that co-segregated with the disease in the U.S. family. Screening of 45 probands initially diagnosed as myofibrillar myopathy (MFM) but excluded based on molecular screening for the known MFM genes led to the identification of a previously reported TTN p.Cys30071Arg mutation in one patient. This same mutation was also identified in a patient with suspected HMERF. The p.Gly30150Asp and p.Cys30071Arg mutations are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin. Missense mutations in TTN are the cause of HMERF in families of diverse origins. A comparison of phenotypic features of HMERF caused by the three known TTN mutations in various populations allowed to emphasize distinct clinical/pathological features that can serve as the basis for diagnosis. The newly identified p.Gly30150Asp and the p.Cys30071Arg mutation are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin.

Rare Disease Mechanisms Identified by Genealogical Proteomics of Copper Homeostasis Mutant Pedigrees.

PubMed

Zlatic, Stephanie A; Vrailas-Mortimer, Alysia; Gokhale, Avanti; Carey, Lucas J; Scott, Elizabeth; Burch, Reid; McCall, Morgan M; Rudin-Rush, Samantha; Davis, John Bowen; Hartwig, Cortnie; Werner, Erica; Li, Lian; Petris, Michael; Faundez, Victor

2018-03-28

Rare neurological diseases shed light onto universal neurobiological processes. However, molecular mechanisms connecting genetic defects to their disease phenotypes are elusive. Here, we obtain mechanistic information by comparing proteomes of cells from individuals with rare disorders with proteomes from their disease-free consanguineous relatives. We use triple-SILAC mass spectrometry to quantify proteomes from human pedigrees affected by mutations in ATP7A, which cause Menkes disease, a rare neurodegenerative and neurodevelopmental disorder stemming from systemic copper depletion. We identified 214 proteins whose expression was altered in ATP7A -/y fibroblasts. Bioinformatic analysis of ATP7A-mutant proteomes identified known phenotypes and processes affected in rare genetic diseases causing copper dyshomeostasis, including altered mitochondrial function. We found connections between copper dyshomeostasis and the UCHL1/PARK5 pathway of Parkinson disease, which we validated with mitochondrial respiration and Drosophila genetics assays. We propose that our genealogical "omics" strategy can be broadly applied to identify mechanisms linking a genomic locus to its phenotypes. Copyright © 2018 Elsevier Inc. All rights reserved.

Identifying patterns of immune-related disease: use in disease prevention and management.

PubMed

Dietert, Rodney R; Zelikoff, Judith T

2010-05-01

Childhood susceptibility to diseases linked with immune dysfunction affects over a quarter of the pediatric population in some countries. While this alone is a significant health issue, the actual impact of immune-related diseases extends over a lifetime and involves additional secondary conditions. Some comorbidities are well known (e.g., allergic rhinitis and asthma). However, no systematic approach has been used to identify life-long patterns of immune-based disease where the primary condition arises in childhood. Such information is useful for both disease prevention and treatment approaches. Recent primary research papers as well as review articles were obtained from PubMed, Chem Abstracts, Biosis and from the personal files of the authors. Search words used were: the diseases and conditions shown Figs. 1 and 2 in conjunction with comorbid, comorbidities, pediatric, childhood, adult, immune, immune dysfunction, allergy, autoimmune, inflammatory, infectious, health risks, environment, risk factors. Childhood diseases such as asthma, type-1 diabetes, inflammatory bowel disease, respiratory infections /rhinitis, recurrent otitis media, pediatric celiac, juvenile arthritis and Kawasaki disease are examples of significant childhood health problems where immune dysfunction plays a significant role. Each of these pediatric diseases is associated with increased risk of several secondary conditions, many of which appear only later in life. To illustrate, four prototypes of immune-related disease patterns (i.e., allergy, autoimmunity, inflammation and infectious disease) are shown as tools for: 1) enhanced disease prevention; 2) improved management of immune-based pediatric diseases; and 3) better recognition of underlying pediatric immune dysfunction. Identification of immune-related disease patterns beginning in childhood provides the framework for examining the underlying immune dysfunctions that can contribute to additional diseases in later life. Many pediatric

Favorable outcome of early treatment of new onset child and adolescent migraine-implications for disease modification.

PubMed

Charles, James A; Peterlin, B L; Rapoport, Alan M; Linder, Steven L; Kabbouche, Marielle A; Sheftell, Fred D

2009-08-01

There is evidence that the prevalence of migraine in children and adolescents may be increasing. Current theories of migraine pathophysiology in adults suggest activation of central cortical and brainstem pathways in conjunction with the peripheral trigeminovascular system, which ultimately results in release of neuropeptides, facilitation of central pain pathways, neurogenic inflammation surrounding peripheral vessels, and vasodilatation. Although several risk factors for frequent episodic, chronic, and refractory migraine have been identified, the causes of migraine progression are not known. Migraine pathophysiology has not been fully evaluated in children. In this review, we will first discuss the evidence that early therapeutic interventions in the child or adolescent new onset migraineur, may halt or limit progression and disability. We will then review the evidence suggesting that many adults with chronic or refractory migraine developed their migraine as children or adolescents and may not have been treated adequately with migraine-specific therapy. Finally, we will show that early, appropriate and optimal treatment of migraine during childhood and adolescence may result in disease modification and prevent progression of this disease.

78 FR 9396 - Draft Guidance for Industry on Alzheimer's Disease: Developing Drugs for the Treatment of Early...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-08

...] Draft Guidance for Industry on Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage Disease; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and... ``Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage Disease.'' This guidance outlines FDA...

Determinants of Objectively Measured Physical Functional Performance in Early to Mid-stage Parkinson Disease

PubMed Central

Kluger, Benzi M.; Brown, R. Preston; Aerts, Shanae; Schenkman, Margaret

2014-01-01

Background Parkinson disease (PD) may lead to functional limitations through both motor and non-motor symptoms. While patients with advanced disease have well-documented and profound functional limitations, less is known about the determinants of function in early to mid-stage disease where interventions may be more likely to benefit and preserve function. Objective The objective of the current study was to identify motor, cognitive and gait determinants of physical functional performance in patients with early to mid-stage PD. Design Secondary analysis of cross-sectional baseline data from a randomized clinical trial of exercise. Setting Tertiary academic medical center. Participants 121 patients with early to mid-stage PD. Methods Our functional performance outcomes included: 1) the Continuous Scale Functional Performance Test (CS-PFP; primary outcome); 2) the timed up and go (TUG) tests; and Section 2 (Activities of Daily Living) of the Unified Parkinson's Disease Rating Scale (UPDRS). Explanatory variables included measures of disease severity, motor function, cognitive function, balance and gait. Step-wise linear regression models were used to determine correlations between explanatory variables and outcome measures. Results In our regression models the CS-PFP significantly correlated with walking endurance (six minute walk; r2 = 0.12, p < .0001), turning ability (360 degree turn; r2 = .03, p = .002), attention (brief test of attention; r2 = .01, p = .03), overall cognitive status (Mini-mental State Examination; r2 = .01, p = .04) and bradykinesia (timed tapping; r2 = .02, p = .02). The TUG significantly correlated with walking speed (5 meter walk; r2 = 0.33, p <.0001), stride length (r2 = 0.25, p <.0001), turning ability (360 turn r2 = .05, p = .0003) and attention (r2 = .016, p = .03). Section 2 of the UPDRS was significantly correlated with endurance (r2 = .09, p < .0001), turning ability (r2 = .03, p = .001) and attention (r2 = .01, p = .03). Conclusions

Early retirement and income loss in patients with early and advanced Parkinson's disease.

PubMed

Johnson, Scott; Davis, Matthew; Kaltenboeck, Anna; Birnbaum, Howard; Grubb, Elizabeth; Tarrants, Marcy; Siderowf, Andrew

2011-11-01

The indirect costs of Parkinson's disease (PD) may be larger than direct healthcare costs, and the largest component of indirect costs is income loss related to early retirement. No recent retrospective analysis details PD-related early retirement and income loss in the US. We used an observational, matched cohort to study wages and labour force participation over 4 years and to simulate lifetime income losses conditional on being newly diagnosed with PD (naive) or having evidence of increasing disability. Actively employed primary beneficiaries of private insurance policies aged 18-64 years with more than two PD diagnoses (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]: 332.x) or one diagnosis and a prescription of an antiparkinsonian drug were selected from a privately insured claims database. Continuous health coverage during analysis periods was required. Naive patients were defined as having no claims history indicative of PD during the year prior to first diagnosis or prescription use. A PD with ambulatory assistance devices (PDAAD) cohort was also followed from the date of first evidence of a wheelchair or walker. Controls without PD were matched on age, sex and region. Survival analysis and Wilcoxon rank sum tests were used to compare rates of early retirement and income loss. A simulation of projected economic loss was conducted for PD cohorts diagnosed at different ages using Bureau of Labor Statistics labour force participation and income data. Naive PD patients (n = 278) and PDAAD patients (n = 28) were on average aged 53 years and had significantly higher rates of co-morbidities at baseline versus controls. Conditional on being employed, there was no statistical difference in earnings. However, the hazard of early retirement associated with PD was 2.08 (p < 0.001) for the naive cohort and 5.01 (p < 0.001) for the PDAAD cohort. From age 40 to 79 years, earnings losses in year 2009 values were

Linguistic ability in early life and the neuropathology of Alzheimer's disease and cerebrovascular disease. Findings from the Nun Study.

PubMed

Snowdon, D A; Greiner, L H; Markesbery, W R

2000-04-01

Findings from the Nun Study indicate that low linguistic ability in early life has a strong association with dementia and premature death in late life. In the present study, we investigated the relationship of linguistic ability in early life to the neuropathology of Alzheimer's disease and cerebrovascular disease. The analyses were done on a subset of 74 participants in the Nun Study for whom we had handwritten autobiographies completed some time between the ages of 19 and 37 (mean = 23 years). An average of 62 years after writing the autobiographies, when the participants were 78 to 97 years old, they died and their brains were removed for our neuropathologic studies. Linguistic ability in early life was measured by the idea (proposition) density of the autobiographies, i.e., a standard measure of the content of ideas in text samples. Idea density scores from early life had strong inverse correlations with the severity of Alzheimer's disease pathology in the neocortex: Correlations between idea density scores and neurofibrillary tangle counts were -0.59 for the frontal lobe, -0.48 for the temporal lobe, and -0.49 for the parietal lobe (all p values < 0.0001). Idea density scores were unrelated to the severity of atherosclerosis of the major arteries at the base of the brain and to the presence of lacunar and large brain infarcts. Low linguistic ability in early life may reflect suboptimal neurological and cognitive development, which might increase susceptibility to the development of Alzheimer's disease pathology in late life.

The AIMAR recommendations for early diagnosis of chronic obstructive respiratory disease based on the WHO/GARD model*

PubMed Central

2014-01-01

Respiratory diseases in Italy already now represent an emergency (they are the 3rd ranking cause of death in the world, and the 2nd if Lung cancer is included). In countries similar to our own, they result as the principal cause for a visit to the general practitioner (GP) and the second main cause after injury for recourse to Emergency Care. Their frequency is probably higher than estimated (given that respiratory diseases are currently underdiagnosed). The trend is towards a further increase due to epidemiologic and demographic factors (foremost amongst which are the widespread diffusion of cigarette smoking, the increasing mean age of the general population, immigration, and pollution). Within the more general problem of chronic disease care, chronic respiratory diseases (CRDs) constitute one of the four national priorities in that they represent an important burden for society in terms of mortality, invalidity, and direct healthcare costs. The strategy suggested by the World Health Organization (WHO) is an integrated approach consisting of three goals: inform about health, reduce risk exposure, improve patient care. The three goals are translated into practice in the three areas of prevention (1-primary, 2-secondary, 3-tertiary) as: 1) actions of primary (universal) prevention targeted at the general population with the aim to control the causes of disease, and actions of Predictive Medicine - again addressing the general population but aimed at measuring the individual’s risk for disease insurgence; 2) actions of early diagnosis targeted at groups or - more precisely - subgroups identified as at risk; 3) continuous improvement and integration of care and rehabilitation support - destined at the greatest possible number of patients, at all stages of disease severity. In Italy, COPD care is generally still inadequate. Existing guidelines, institutional and non-institutional, are inadequately implemented: the international guidelines are not always adaptable to

The AIMAR recommendations for early diagnosis of chronic obstructive respiratory disease based on the WHO/GARD model*.

PubMed

Nardini, Stefano; Annesi-Maesano, Isabella; Del Donno, Mario; Delucchi, Maurizio; Bettoncelli, Germano; Lamberti, Vincenzo; Patera, Carlo; Polverino, Mario; Russo, Antonio; Santoriello, Carlo; Soverina, Patrizio

2014-01-01

Respiratory diseases in Italy already now represent an emergency (they are the 3(rd) ranking cause of death in the world, and the 2(nd) if Lung cancer is included). In countries similar to our own, they result as the principal cause for a visit to the general practitioner (GP) and the second main cause after injury for recourse to Emergency Care. Their frequency is probably higher than estimated (given that respiratory diseases are currently underdiagnosed). The trend is towards a further increase due to epidemiologic and demographic factors (foremost amongst which are the widespread diffusion of cigarette smoking, the increasing mean age of the general population, immigration, and pollution). Within the more general problem of chronic disease care, chronic respiratory diseases (CRDs) constitute one of the four national priorities in that they represent an important burden for society in terms of mortality, invalidity, and direct healthcare costs. The strategy suggested by the World Health Organization (WHO) is an integrated approach consisting of three goals: inform about health, reduce risk exposure, improve patient care. The three goals are translated into practice in the three areas of prevention (1-primary, 2-secondary, 3-tertiary) as: 1) actions of primary (universal) prevention targeted at the general population with the aim to control the causes of disease, and actions of Predictive Medicine - again addressing the general population but aimed at measuring the individual's risk for disease insurgence; 2) actions of early diagnosis targeted at groups or - more precisely - subgroups identified as at risk; 3) continuous improvement and integration of care and rehabilitation support - destined at the greatest possible number of patients, at all stages of disease severity. In Italy, COPD care is generally still inadequate. Existing guidelines, institutional and non-institutional, are inadequately implemented: the international guidelines are not always adaptable

Prognostic capability of different liver disease scoring systems for prediction of early mortality after transjugular intrahepatic portosystemic shunt creation.

PubMed

Gaba, Ron C; Couture, Patrick M; Bui, James T; Knuttinen, M Grace; Walzer, Natasha M; Kallwitz, Eric R; Berkes, Jamie L; Cotler, Scott J

2013-03-01

To compare the performance of various liver disease scoring systems in predicting early mortality after transjugular intrahepatic portosystemic shunt (TIPS) creation. In this single-institution retrospective study, eight scoring systems were used to grade liver disease in 211 patients (male-to-female ratio = 131:80; mean age, 54 y) before TIPS creation from 1999-2011. Scoring systems included bilirubin level, Child-Pugh (CP) score, Model for End-Stage Liver Disease (MELD) and Model for End-Stage Liver Disease sodium (MELD-Na) score, Emory score, prognostic index (PI), Acute Physiology and Chronic Health Evaluation (APACHE) 2 score, and Bonn TIPS early mortality (BOTEM) score. Medical record review was used to identify 30-day and 90-day clinical outcomes. The relationship of scoring parameters with mortality outcomes was assessed with multivariate analysis, and the relative ability of systems to predict mortality after TIPS creation was evaluated by comparing area under receiver operating characteristic (AUROC) curves. TIPS were successfully created for variceal hemorrhage (n = 121), ascites (n = 72), hepatic hydrothorax (n = 15), and portal vein thrombosis (n = 3). All scoring systems had a significant association with 30-day and 90-day mortality (P<.050 in each case) on multivariate analysis. Based on 30-day and 90-day AUROC, MELD (0.878, 0.816) and MELD-Na (0.863, 0.823) scores had the best capability to predict early mortality compared with bilirubin (0.786, 0.749), CP (0.822, 0.771), Emory (0.786, 0.681), PI (0.854, 0.760), APACHE 2 (0.836, 0.735), and BOTEM (0.798, 0.698), with statistical superiority over bilirubin, Emory, and BOTEM scores. Several liver disease scoring systems have prognostic value for early mortality after TIPS creation. MELD and MELD-Na scores most effectively predict survival after TIPS creation. Copyright © 2013. Published by Elsevier Inc.

Identifying patients with gastroesophageal reflux disease in a managed care organization.

PubMed

Ofman, J J; Ryu, S; Borenstein, J; Kania, S; Lee, J; Grogg, A; Farup, C; Weingarten, S

2001-09-01

The ability of various strategies to identify patients with gastroesophageal reflux disease (GERD) and the relative economic impact on disease management programs for GERD were studied. A telephone interview was conducted of a random sample of patients enrolled in any of three health plans in a 100,000-member managed care organization who had either a pharmacy claim or an encounter claim during 1997. The telephone interview identified patients with GERD and served as the standard by which the sensitivity, specificity, and predictive values of the following patient-identification strategies were compared: (1) telephone interview, (2) chart review, (3) use of encounter claims, (4) use of pharmacy claims, (5) use of both encounter claims, and pharmacy claims, and (6) use of encounter claims or pharmacy claims. Conservative estimates of costs and projected savings were then used to model the potential return on investment of the strategies. A total of 1186 patients completed the telephone interview, of whom 390 (33%) met the case definition of GERD. The most sensitive method for identifying patients with GERD was using either pharmacy or encounter claims (26%). The most specific strategy with the highest positive predictive value (PPV) (87%) was using both pharmacy and encounter claims, but this approach had a case-detection rate of only 3%. Encounter claims were significantly more sensitive than pharmacy claims and yielded a higher estimate of prevalence. The telephone interview identified the most subjects who could have benefited from a disease management program and cost 84% less than chart review. While use of administrative data (pharmacy and encounter claims) was the least costly strategy, it identified 74% fewer patients expected to benefit from disease management. The efficiency of disease management programs for GERD may depend on the method of patient identification, which in turn may depend on whether PPV or negative predictive value (NPV) should be

QIL1 mutation causes MICOS disassembly and early onset fatal mitochondrial encephalopathy with liver disease

PubMed Central

Guarani, Virginia; Jardel, Claude; Chrétien, Dominique; Lombès, Anne; Bénit, Paule; Labasse, Clémence; Lacène, Emmanuelle; Bourillon, Agnès; Imbard, Apolline; Benoist, Jean-François; Dorboz, Imen; Gilleron, Mylène; Goetzman, Eric S; Gaignard, Pauline; Slama, Abdelhamid; Elmaleh-Bergès, Monique; Romero, Norma B; Rustin, Pierre; Ogier de Baulny, Hélène; Paulo, Joao A; Harper, J Wade; Schiff, Manuel

2016-01-01

Previously, we identified QIL1 as a subunit of mitochondrial contact site (MICOS) complex and demonstrated a role for QIL1 in MICOS assembly, mitochondrial respiration, and cristae formation critical for mitochondrial architecture (Guarani et al., 2015). Here, we identify QIL1 null alleles in two siblings displaying multiple clinical symptoms of early-onset fatal mitochondrial encephalopathy with liver disease, including defects in respiratory chain function in patient muscle. QIL1 absence in patients’ fibroblasts was associated with MICOS disassembly, abnormal cristae, mild cytochrome c oxidase defect, and sensitivity to glucose withdrawal. QIL1 expression rescued cristae defects, and promoted re-accumulation of MICOS subunits to facilitate MICOS assembly. MICOS assembly and cristae morphology were not efficiently rescued by over-expression of other MICOS subunits in patient fibroblasts. Taken together, these data provide the first evidence of altered MICOS assembly linked with a human mitochondrial disease and confirm a central role for QIL1 in stable MICOS complex formation. DOI: http://dx.doi.org/10.7554/eLife.17163.001 PMID:27623147

Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies.

PubMed

Pimpin, Laura; Cortez-Pinto, Helena; Negro, Francesco; Corbould, Emily; Lazarus, Jeffrey V; Webber, Laura; Sheron, Nick

2018-05-16

The burden of liver disease in Europe continues to grow. We aimed to describe the epidemiology of liver diseases and their risk factors in European countries, and identify public health interventions that could impact on these risk factors to reduce the burden of liver disease. As part of the HEPAHEALTH project, commissioned by EASL, we extracted information on historical and current prevalence and mortality from national and international literature and databases on liver disease in 35 countries in the WHO European region, as well as historical and recent prevalence data on their main determinants; alcohol consumption, obesity and hepatitis B and C virus infections. We extracted information from peer-reviewed and grey literature to identify public health interventions targeting these risk factors. The epidemiology of liver disease is diverse and countries cluster with similar pictures, although the exact composition of diseases and the trends in risk factors which drive them is varied. Prevalence and mortality data indicate that increasing cirrhosis and liver cancer may be linked to dramatic increases in harmful alcohol consumption in Northern European countries, and viral hepatitis epidemics in Eastern and Southern European countries. Countries with historically low levels of liver disease may experience an increase in non-alcoholic fatty liver disease in the future, given the rise of obesity across the majority of European countries. Interventions exist for curbing harmful alcohol use, reducing obesity, preventing or treating viral hepatitis, and screening for liver disease at an early stage. Liver disease in Europe is a serious issue, with increasing cirrhosis and liver cancer. The public health and hepatology communities are uniquely placed to implement measures aimed at reducing their causes: harmful alcohol consumption, child and adult obesity prevalence and chronic infection with hepatitis viruses, which will in turn reduce the burden of liver disease. The

Walking the interactome to identify human miRNA-disease associations through the functional link between miRNA targets and disease genes

PubMed Central

2013-01-01

Background MicroRNAs (miRNAs) are important post-transcriptional regulators that have been demonstrated to play an important role in human diseases. Elucidating the associations between miRNAs and diseases at the systematic level will deepen our understanding of the molecular mechanisms of diseases. However, miRNA-disease associations identified by previous computational methods are far from completeness and more effort is needed. Results We developed a computational framework to identify miRNA-disease associations by performing random walk analysis, and focused on the functional link between miRNA targets and disease genes in protein-protein interaction (PPI) networks. Furthermore, a bipartite miRNA-disease network was constructed, from which several miRNA-disease co-regulated modules were identified by hierarchical clustering analysis. Our approach achieved satisfactory performance in identifying known cancer-related miRNAs for nine human cancers with an area under the ROC curve (AUC) ranging from 71.3% to 91.3%. By systematically analyzing the global properties of the miRNA-disease network, we found that only a small number of miRNAs regulated genes involved in various diseases, genes associated with neurological diseases were preferentially regulated by miRNAs and some immunological diseases were associated with several specific miRNAs. We also observed that most diseases in the same co-regulated module tended to belong to the same disease category, indicating that these diseases might share similar miRNA regulatory mechanisms. Conclusions In this study, we present a computational framework to identify miRNA-disease associations, and further construct a bipartite miRNA-disease network for systematically analyzing the global properties of miRNA regulation of disease genes. Our findings provide a broad perspective on the relationships between miRNAs and diseases and could potentially aid future research efforts concerning miRNA involvement in disease pathogenesis

Basal ganglia dysfunction in idiopathic REM sleep behaviour disorder parallels that in early Parkinson’s disease

PubMed Central

Rolinski, Michal; Griffanti, Ludovica; Piccini, Paola; Roussakis, Andreas A.; Szewczyk-Krolikowski, Konrad; Menke, Ricarda A.; Quinnell, Timothy; Zaiwalla, Zenobia; Klein, Johannes C.; Mackay, Clare E.

2016-01-01

movement sleep behaviour disorder and Parkinson’s disease relative to each other and to controls. Connectivity measures of basal ganglia network dysfunction differentiated both rapid eye movement sleep behaviour disorder and Parkinson’s disease from controls with high sensitivity (96%) and specificity (74% for rapid eye movement sleep behaviour disorder, 78% for Parkinson’s disease), indicating its potential as an indicator of early basal ganglia dysfunction. Rapid eye movement sleep behaviour disorder was indistinguishable from Parkinson’s disease on resting state functional magnetic resonance imaging despite obvious differences on dopamine transported single photon emission computerized tomography. Basal ganglia connectivity is a promising biomarker for the detection of early basal ganglia network dysfunction, and may help to identify patients at risk of developing Parkinson’s disease in the future. Future risk stratification using a polymodal approach could combine basal ganglia network connectivity with clinical and other imaging measures, with important implications for future neuroprotective trials in rapid eye movement sleep behaviour disorder. PMID:27297241

Prototype early warning systems for vector-borne diseases in Europe.

PubMed

Semenza, Jan C

2015-06-02

Globalization and environmental change, social and demographic determinants and health system capacity are significant drivers of infectious diseases which can also act as epidemic precursors. Thus, monitoring changes in these drivers can help anticipate, or even forecast, an upsurge of infectious diseases. The European Environment and Epidemiology (E3) Network has been built for this purpose and applied to three early warning case studies: (1) The environmental suitability of malaria transmission in Greece was mapped in order to target epidemiological and entomological surveillance and vector control activities. Malaria transmission in these areas was interrupted in 2013 through such integrated preparedness and response activities. (2) Since 2010, recurrent West Nile fever outbreaks have ensued in South/eastern Europe. Temperature deviations from a thirty year average proved to be associated with the 2010 outbreak. Drivers of subsequent outbreaks were computed through multivariate logistic regression models and included monthly temperature anomalies for July and a normalized water index. (3) Dengue is a tropical disease but sustained transmission has recently emerged in Madeira. Autochthonous transmission has also occurred repeatedly in France and in Croatia mainly due to travel importation. The risk of dengue importation into Europe in 2010 was computed with the volume of international travelers from dengue affected areas worldwide.These prototype early warning systems indicate that monitoring drivers of infectious diseases can help predict vector-borne disease threats.

Prototype Early Warning Systems for Vector-Borne Diseases in Europe

PubMed Central

Semenza, Jan C.

2015-01-01

Globalization and environmental change, social and demographic determinants and health system capacity are significant drivers of infectious diseases which can also act as epidemic precursors. Thus, monitoring changes in these drivers can help anticipate, or even forecast, an upsurge of infectious diseases. The European Environment and Epidemiology (E3) Network has been built for this purpose and applied to three early warning case studies: (1) The environmental suitability of malaria transmission in Greece was mapped in order to target epidemiological and entomological surveillance and vector control activities. Malaria transmission in these areas was interrupted in 2013 through such integrated preparedness and response activities. (2) Since 2010, recurrent West Nile fever outbreaks have ensued in South/eastern Europe. Temperature deviations from a thirty year average proved to be associated with the 2010 outbreak. Drivers of subsequent outbreaks were computed through multivariate logistic regression models and included monthly temperature anomalies for July and a normalized water index. (3) Dengue is a tropical disease but sustained transmission has recently emerged in Madeira. Autochthonous transmission has also occurred repeatedly in France and in Croatia mainly due to travel importation. The risk of dengue importation into Europe in 2010 was computed with the volume of international travelers from dengue affected areas worldwide.These prototype early warning systems indicate that monitoring drivers of infectious diseases can help predict vector-borne disease threats. PMID:26042370

Alzheimer's disease prevention: from risk factors to early intervention.

PubMed

Crous-Bou, Marta; Minguillón, Carolina; Gramunt, Nina; Molinuevo, José Luis

2017-09-12

Due to the progressive aging of the population, Alzheimer's disease (AD) is becoming a healthcare burden of epidemic proportions for which there is currently no cure. Disappointing results from clinical trials performed in mild-moderate AD dementia combined with clear epidemiological evidence on AD risk factors are contributing to the development of primary prevention initiatives. In addition, the characterization of the long asymptomatic stage of AD is allowing the development of intervention studies and secondary prevention programmes on asymptomatic at-risk individuals, before substantial irreversible neuronal dysfunction and loss have occurred, an approach that emerges as highly relevant.In this manuscript, we review current strategies for AD prevention, from primary prevention strategies based on identifying risk factors and risk reduction, to secondary prevention initiatives based on the early detection of the pathophysiological hallmarks and intervention at the preclinical stage of the disease. Firstly, we summarize the evidence on several AD risk factors, which are the rationale for the establishment of primary prevention programmes as well as revising current primary prevention strategies. Secondly, we review the development of public-private partnerships for disease prevention that aim to characterize the AD continuum as well as serving as platforms for secondary prevention trials. Finally, we summarize currently ongoing clinical trials recruiting participants with preclinical AD or a higher risk for the onset of AD-related cognitive impairment.The growing body of research on the risk factors for AD and its preclinical stage is favouring the development of AD prevention programmes that, by delaying the onset of Alzheimer's dementia for only a few years, would have a huge impact on public health.

Multiplexed Immunoassay Panel Identifies Novel CSF Biomarkers for Alzheimer's Disease Diagnosis and Prognosis

PubMed Central

Craig-Schapiro, Rebecca; Kuhn, Max; Xiong, Chengjie; Pickering, Eve H.; Liu, Jingxia; Misko, Thomas P.; Perrin, Richard J.; Bales, Kelly R.; Soares, Holly; Fagan, Anne M.; Holtzman, David M.

2011-01-01

Background Clinicopathological studies suggest that Alzheimer's disease (AD) pathology begins ∼10–15 years before the resulting cognitive impairment draws medical attention. Biomarkers that can detect AD pathology in its early stages and predict dementia onset would, therefore, be invaluable for patient care and efficient clinical trial design. We utilized a targeted proteomics approach to discover novel cerebrospinal fluid (CSF) biomarkers that can augment the diagnostic and prognostic accuracy of current leading CSF biomarkers (Aβ42, tau, p-tau181). Methods and Findings Using a multiplexed Luminex platform, 190 analytes were measured in 333 CSF samples from cognitively normal (Clinical Dementia Rating [CDR] 0), very mildly demented (CDR 0.5), and mildly demented (CDR 1) individuals. Mean levels of 37 analytes (12 after Bonferroni correction) were found to differ between CDR 0 and CDR>0 groups. Receiver-operating characteristic curve analyses revealed that small combinations of a subset of these markers (cystatin C, VEGF, TRAIL-R3, PAI-1, PP, NT-proBNP, MMP-10, MIF, GRO-α, fibrinogen, FAS, eotaxin-3) enhanced the ability of the best-performing established CSF biomarker, the tau/Aβ42 ratio, to discriminate CDR>0 from CDR 0 individuals. Multiple machine learning algorithms likewise showed that the novel biomarker panels improved the diagnostic performance of the current leading biomarkers. Importantly, most of the markers that best discriminated CDR 0 from CDR>0 individuals in the more targeted ROC analyses were also identified as top predictors in the machine learning models, reconfirming their potential as biomarkers for early-stage AD. Cox proportional hazards models demonstrated that an optimal panel of markers for predicting risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) consisted of calbindin, Aβ42, and age. Conclusions/Significance Using a targeted proteomic screen, we identified novel candidate biomarkers that complement the best

A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families.

PubMed

Athan, E S; Williamson, J; Ciappa, A; Santana, V; Romas, S N; Lee, J H; Rondon, H; Lantigua, R A; Medrano, M; Torres, M; Arawaka, S; Rogaeva, E; Song, Y Q; Sato, C; Kawarai, T; Fafel, K C; Boss, M A; Seltzer, W K; Stern, Y; St George-Hyslop, P; Tycko, B; Mayeux, R

2001-11-14

Genetic determinants of Alzheimer disease (AD) have not been comprehensively examined in Caribbean Hispanics, a population in the United States in whom the frequency of AD is higher compared with non-Hispanic whites. To identify variant alleles in genes related to familial early-onset AD among Caribbean Hispanics. Family-based case series conducted in 1998-2001 at an AD research center in New York, NY, and clinics in the Dominican Republic. Among 206 Caribbean Hispanic families with 2 or more living members with AD who were identified, 19 (9.2%) had at least 1 individual with onset of AD before the age of 55 years. The entire coding region of the presenilin 1 gene and exons 16 and 17 of the amyloid precursor protein gene were sequenced in probands from the 19 families and their living relatives. A G-to-C nucleotide change resulting in a glycine-alanine amino acid substitution at codon 206 (Gly206Ala) in exon 7 of presenilin 1 was observed in 23 individuals from 8 (42%) of the 19 families. A Caribbean Hispanic individual with the Gly206Ala mutation and early-onset familial disease was also found by sequencing the corresponding genes of 319 unrelated individuals in New York City. The Gly206Ala mutation was not found in public genetic databases but was reported in 5 individuals from 4 Hispanic families with AD referred for genetic testing. None of the members of these families were related to one another, yet all carriers of the Gly206Ala mutation tested shared a variant allele at 2 nearby microsatellite polymorphisms, indicating a common ancestor. No mutations were found in the amyloid precursor protein gene. The Gly206Ala mutation was found in 8 of 19 unrelated Caribbean Hispanic families with early-onset familial AD. This genetic change may be a prevalent cause of early-onset familial AD in the Caribbean Hispanic population.

Identifying key features of early stressful experiences that produce stress vulnerability and resilience in primates

PubMed Central

Parker, Karen J.; Maestripieri, Dario

2010-01-01

This article examines the complex role of early stressful experiences in producing both vulnerability and resilience to later stress-related psychopathology in a variety of primate models of human development. Two types of models are reviewed: Parental Separation Models (e.g., isolate-rearing, peer-rearing, parental separations, and stress inoculation) and Maternal Behavior Models (e.g., foraging demands, variation in maternal style, and maternal abuse). Based on empirical evidence, it is argued that early life stress exposure does not increase adult vulnerability to stress-related psychopathology as a linear function, as is generally believed, but instead reflects a quadratic function. Features of early stress exposure including the type, duration, frequency, ecological validity, sensory modality, and developmental timing, within and between species, are identified to better understand how early stressful experiences alter neurobiological systems to produce such diverse developmental outcomes. This article concludes by identifying gaps in our current knowledge, providing directions for future research, and discussing the translational implications of these primate models for human development and psychopathology. PMID:20851145

Early changes in cytokine expression in peste des petits ruminants disease.

PubMed

Baron, Jana; Bin-Tarif, Abdelghani; Herbert, Rebecca; Frost, Lorraine; Taylor, Geraldine; Baron, Michael D

2014-02-22

Peste des petits ruminants is a viral disease of sheep and goats that has spread through most of Africa as well as the Middle East and the Indian subcontinent. Although, the spread of the disease and its economic impact has made it a focus of international concern, relatively little is known about the nature of the disease itself. We have studied the early stages of pathogenesis in goats infected with six different isolates of Peste des petits ruminants virus representing all four known lineages of the virus. No lineage-specific difference in the pathogenicity of the virus isolates was observed, although there was evidence that even small numbers of cell culture passages could affect the degree of pathogenicity of an isolate. A consistent reduction in CD4+ T cells was observed at 4 days post infection (dpi). Measurement of the expression of various cytokines showed elements of a classic inflammatory response but also a relatively early induction of interleukin 10, which may be contributing to the observed disease.

The role of monogenic disease in children with very early onset inflammatory bowel disease.

PubMed

Kelsen, Judith R; Baldassano, Robert N

2017-10-01

Inflammatory bowel disease (IBD) is a multifactorial disease caused by dysregulated immune responses to commensal or pathogenic intestinal microbes, resulting in chronic intestinal inflammation. Patients diagnosed with IBD occurring before the age of 5 are a unique population, known as very early onset (VEO)-IBD and can be phenotypically and genetically distinct from older-onset IBD. We aim to review the clinical presentation of children with VEO-IBD and recent discoveries that point to genomic drivers of disease that may impact our therapeutic decisions. VEO-IBD is increasing in incidence and is associated with more severe disease, aggressive progression and poor response to most conventional therapies. This article will review the advances in sequencing technology that have led to identification of novel gene variants associated with disease and potentially new targeted therapeutic options. Children with VEO-IBD may present with a different phenotype and more severe disease than older children and adults. Identification of the causal gene or pathways, these children may allow for true precision medicine with targeted therapy and improved disease course.

Identifying Trajectories of Adolescents' Depressive Phenomena: An Examination of Early Risk Factors

ERIC Educational Resources Information Center

Mazza, James J.; Fleming, Charles B.; Abbott, Robert D.; Haggerty, Kevin P.; Catalano, Richard F.

2010-01-01

Few studies have examined risk factors of childhood and early adolescent depressive symptomatology trajectories. This study examined self-report depressive symptomatology across a 6-year time period from 2nd to 8th grade to identify latent groups of individuals with similar patterns of depressive phenomena in a sample of 951 children (440 girls,…

Extracellular matrix disruption is an early event in the pathogenesis of skeletal disease in mucopolysaccharidosis I.

PubMed

Heppner, Jonathan M; Zaucke, Frank; Clarke, Lorne A

2015-02-01

Progressive skeletal and connective tissue disease represents a significant clinical burden in all of the mucopolysaccharidoses. Despite the introduction of enzyme replacement strategies for many of the mucopolysaccharidoses, symptomatology related to bone and joint disease appears to be recalcitrant to current therapies. In order to address these unmet medical needs a clearer understanding of skeletal and connective tissue disease pathogenesis is required. Historically the pathogenesis of the mucopolysaccharidoses has been assumed to directly relate to progressive storage of glycosaminoglycans. It is now apparent for many lysosomal storage disorders that more complex pathogenic mechanisms underlie patients' clinical symptoms. We have used proteomic and genome wide expression studies in the murine mucopolysaccharidosis I model to identify early pathogenic events occurring in micro-dissected growth plate tissue. Studies were conducted using 3 and 5-week-old mice thus representing a time at which no obvious morphological changes of bone or joints have taken place. An unbiased iTRAQ differential proteomic approach was used to identify candidates followed by validation with multiple reaction monitoring mass spectrometry and immunohistochemistry. These studies reveal significant decreases in six key structural and signaling extracellular matrix proteins; biglycan, fibromodulin, PRELP, type I collagen, lactotransferrin, and SERPINF1. Genome-wide expression studies in embryonic day 13.5 limb cartilage and 5 week growth plate cartilage followed by specific gene candidate qPCR studies in the 5week growth plate identified fourteen significantly deregulated mRNAs (Adamts12, Aspn, Chad, Col2a1, Col9a1, Hapln4, Lum, Matn1, Mmp3, Ogn, Omd, P4ha2, Prelp, and Rab32). The involvement of biglycan, PRELP and fibromodulin; all members of the small leucine repeat proteoglycan family is intriguing, as this protein family is implicated in the pathogenesis of late onset osteoarthritis

Gender's Effects to the Early Symptoms of Alzheimer's Disease in 5 Asian Countries.

PubMed

Yang, Yuan-Han; Meguro, Kenichi; Dominguez, Jacqueline; Chen, Christopher Li-Hsian; Wang, Huali; Ong, Paulus Anam

2017-06-01

Asia has the greatest population and more patients with dementia in the world. Early recognition of clinical symptoms of Alzheimer's disease (AD) is crucial for dementia care. In order to foster collaboration in AD care, a uniformed manner to report the early clinical symptoms of AD is necessary. We have recruited clinically diagnosed patients with AD at their very mild stage with Clinical Dementia Rating (CDR) 0.5 in Taiwan, Japan, China, Philippines, and Singapore. Demographic characteristics and psychometrics including Ascertain of Dementia-8 (AD8) questionnaire were administrated to collect and report the clinical presentation in these countries. In total, 713 clinically diagnosed patients with AD at very mild stage, CDR 0.5, have been recruited from these 5 countries. "Repeats questions, stories, or statements" were consistently the frequently reported symptom across these countries. Taiwan, China, and Singapore have the higher AD8 total score compared to that in Japan and Philippines. Japan and Philippines have the gender-related differences in clinical presentation of early AD. Difficulties in using small trouble appliance and in handling complicated financial affairs were frequently reported in Japan female, compared to male, patients with AD. Identifying the clinical symptom of AD and the gender-related issues would be crucial in the dementia care in Asia.

Understanding the management of early-stage chronic kidney disease in primary care: a qualitative study.

PubMed

Blakeman, Tom; Protheroe, Joanne; Chew-Graham, Carolyn; Rogers, Anne; Kennedy, Anne

2012-04-01

Primary care is recognised to have an important role in the delivery of care for people with chronic kidney disease (CKD). However, there is evidence that CKD management is currently suboptimal, with a range of practitioner concerns about its management. To explore processes underpinning the implementation of CKD management in primary care. Qualitative study in general practices participating in a chronic kidney disease collaborative undertaken as part of the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for Greater Manchester. Semi-structured interviews were conducted with GPs and practice nurses (n = 21). Normalisation Process Theory provided a framework for generation and analysis of the data. A predominant theme was anxiety about the disclosure of early-stage CKD with patients. The tensions experienced related to identifying and discussing CKD in older people and patients with stage 3A, embedding early-stage CKD within vascular care, and the distribution of work within the practice team. Participants provided accounts of work undertaken to resolve the difficulties encountered, with efforts having tended to focus on reassuring patients. Analysis also highlighted how anxiety surrounding disclosure influenced, and was shaped by, the organisation of care for people with CKD and associated long-term conditions. Offering reassurance alone may be of limited benefit, and current management of early-stage CKD in primary care may miss opportunities to address susceptibility to kidney injury, improve self-management of vascular conditions, and improve the management of multimorbidity.

The airway microbiota in early cystic fibrosis lung disease.

PubMed

Frayman, Katherine B; Armstrong, David S; Grimwood, Keith; Ranganathan, Sarath C

2017-11-01

Infection plays a critical role in the pathogenesis of cystic fibrosis (CF) lung disease. Over the past two decades, the application of molecular and extended culture-based techniques to microbial analysis has changed our understanding of the lungs in both health and disease. CF lung disease is a polymicrobial disorder, with obligate and facultative anaerobes recovered alongside traditional pathogens in varying proportions, with some differences observed to correlate with disease stage. While healthy lungs are not sterile, differences between the lower airway microbiota of individuals with CF and disease-controls are already apparent in childhood. Understanding the evolution of the CF airway microbiota, and its relationship with clinical treatments and outcome at each disease stage, will improve our understanding of the pathogenesis of CF lung disease and potentially inform clinical management. This review summarizes current knowledge of the early development of the respiratory microbiota in healthy children and then discusses what is known about the airway microbiota in individuals with CF, including how it evolves over time and where future research priorities lie. © 2017 Wiley Periodicals, Inc.

Ancestry-based stratified analysis of Immunochip data identifies novel associations with celiac disease.

PubMed

Garcia-Etxebarria, Koldo; Jauregi-Miguel, Amaia; Romero-Garmendia, Irati; Plaza-Izurieta, Leticia; Legarda, Maria; Irastorza, Iñaki; Bilbao, Jose Ramon

2016-12-01

To identify candidate genes in celiac disease (CD), we reanalyzed the whole Immunochip CD cohort using a different approach that clusters individuals based on immunoancestry prior to disease association analysis, rather than by geographical origin. We detected 636 new associated SNPs (P<7.02 × 10 -07 ) and identified 5 novel genomic regions, extended 8 others previously identified and also detected 18 isolated signals defined by one or very few significant SNPs. To test whether we could identify putative candidate genes, we performed expression analyses of several genes from the top novel region (chr2:134533564-136169524), from a previously identified locus that is now extended, and a gene marked by an isolated SNP, in duodenum biopsies of active and treated CD patients, and non-celiac controls. In the largest novel region, CCNT2 and R3HDM1 were constitutively underexpressed in disease, even after gluten removal. Moreover, several genes within this region were coexpressed in patients, but not in controls. Other novel genes like KIF21B, REL and SORD also showed altered expression in active disease. Apart from the identification of novel CD loci, these results suggest that ancestry-based stratified analysis is an efficient strategy for association studies in complex diseases.

Accumulation of murine amyloid-β mimics early Alzheimer's disease.

PubMed

Krohn, Markus; Bracke, Alexander; Avchalumov, Yosef; Schumacher, Toni; Hofrichter, Jacqueline; Paarmann, Kristin; Fröhlich, Christina; Lange, Cathleen; Brüning, Thomas; von Bohlen Und Halbach, Oliver; Pahnke, Jens

2015-08-01

Amyloidosis mouse models of Alzheimer's disease are generally established by transgenic approaches leading to an overexpression of mutated human genes that are known to be involved in the generation of amyloid-β in Alzheimer's families. Although these models made substantial contributions to the current knowledge about the 'amyloid hypothesis' of Alzheimer's disease, the overproduction of amyloid-β peptides mimics only inherited (familiar) Alzheimer's disease, which accounts for <1% of all patients with Alzheimer's disease. The inherited form is even regarded a 'rare' disease according to the regulations for funding of the European Union (www.erare.eu). Here, we show that mice that are double-deficient for neprilysin (encoded by Mme), one major amyloid-β-degrading enzyme, and the ABC transporter ABCC1, a major contributor to amyloid-β clearance from the brain, develop various aspects of sporadic Alzheimer's disease mimicking the clinical stage of mild cognitive impairment. Using behavioural tests, electrophysiology and morphological analyses, we compared different ABC transporter-deficient animals and found that alterations are most prominent in neprilysin × ABCC1 double-deficient mice. We show that these mice have a reduced probability to survive, show increased anxiety in new environments, and have a reduced working memory performance. Furthermore, we detected morphological changes in the hippocampus and amygdala, e.g. astrogliosis and reduced numbers of synapses, leading to defective long-term potentiation in functional measurements. Compared to human, murine amyloid-β is poorly aggregating, due to changes in three amino acids at N-terminal positions 5, 10, and 13. Interestingly, our findings account for the action of early occurring amyloid-β species/aggregates, i.e. monomers and small amyloid-β oligomers. Thus, neprilysin × ABCC1 double-deficient mice present a new model for early effects of amyloid-β-related mild cognitive impairment that allows

Early Huntington's Disease Affects Movements in Transformed Sensorimotor Mappings

ERIC Educational Resources Information Center

Boulet, C.; Lemay, M.; Bedard, M.A.; Chouinard, M.J.; Chouinard, S.; Richer, F.

2005-01-01

This study examined the effect of transformed visual feedback on movement control in Huntington's disease (HD). Patients in the early stages of HD and controls performed aiming movements towards peripheral targets on a digitizing tablet and emphasizing precision. In a baseline condition, HD patients were slower but showed few precision problems in…

Pathways of Prion Spread during Early Chronic Wasting Disease in Deer.

PubMed

Hoover, Clare E; Davenport, Kristen A; Henderson, Davin M; Denkers, Nathaniel D; Mathiason, Candace K; Soto, Claudio; Zabel, Mark D; Hoover, Edward A

2017-05-15

Among prion infections, two scenarios of prion spread are generally observed: (i) early lymphoid tissue replication or (ii) direct neuroinvasion without substantial antecedent lymphoid amplification. In nature, cervids are infected with chronic wasting disease (CWD) prions by oral and nasal mucosal exposure, and studies of early CWD pathogenesis have implicated pharyngeal lymphoid tissue as the earliest sites of prion accumulation. However, knowledge of chronological events in prion spread during early infection remains incomplete. To investigate this knowledge gap in early CWD pathogenesis, we exposed white-tailed deer to CWD prions by mucosal routes and performed serial necropsies to assess PrP CWD tissue distribution by real-time quaking-induced conversion (RT-QuIC) and tyramide signal amplification immunohistochemistry (TSA-IHC). Although PrP CWD was not detected by either method in the initial days (1 and 3) postexposure, we observed PrP CWD seeding activity and follicular immunoreactivity in oropharyngeal lymphoid tissues at 1 and 2 months postexposure (MPE). At 3 MPE, PrP CWD replication had expanded to all systemic lymphoid tissues. By 4 MPE, the PrP CWD burden in all lymphoid tissues had increased and approached levels observed in terminal disease, yet there was no evidence of nervous system invasion. These results indicate the first site of CWD prion entry is in the oropharynx, and the initial phase of prion amplification occurs in the oropharyngeal lymphoid tissues followed by rapid dissemination to systemic lymphoid tissues. This lymphoid replication phase appears to precede neuroinvasion. IMPORTANCE Chronic wasting disease (CWD) is a universally fatal transmissible spongiform encephalopathy affecting cervids, and natural infection occurs through oral and nasal mucosal exposure to infectious prions. Terminal disease is characterized by PrP CWD accumulation in the brain and lymphoid tissues of affected animals. However, the initial sites of prion

Pathways of Prion Spread during Early Chronic Wasting Disease in Deer

PubMed Central

Hoover, Clare E.; Davenport, Kristen A.; Henderson, Davin M.; Denkers, Nathaniel D.; Mathiason, Candace K.; Soto, Claudio; Zabel, Mark D.

2017-01-01

ABSTRACT Among prion infections, two scenarios of prion spread are generally observed: (i) early lymphoid tissue replication or (ii) direct neuroinvasion without substantial antecedent lymphoid amplification. In nature, cervids are infected with chronic wasting disease (CWD) prions by oral and nasal mucosal exposure, and studies of early CWD pathogenesis have implicated pharyngeal lymphoid tissue as the earliest sites of prion accumulation. However, knowledge of chronological events in prion spread during early infection remains incomplete. To investigate this knowledge gap in early CWD pathogenesis, we exposed white-tailed deer to CWD prions by mucosal routes and performed serial necropsies to assess PrPCWD tissue distribution by real-time quaking-induced conversion (RT-QuIC) and tyramide signal amplification immunohistochemistry (TSA-IHC). Although PrPCWD was not detected by either method in the initial days (1 and 3) postexposure, we observed PrPCWD seeding activity and follicular immunoreactivity in oropharyngeal lymphoid tissues at 1 and 2 months postexposure (MPE). At 3 MPE, PrPCWD replication had expanded to all systemic lymphoid tissues. By 4 MPE, the PrPCWD burden in all lymphoid tissues had increased and approached levels observed in terminal disease, yet there was no evidence of nervous system invasion. These results indicate the first site of CWD prion entry is in the oropharynx, and the initial phase of prion amplification occurs in the oropharyngeal lymphoid tissues followed by rapid dissemination to systemic lymphoid tissues. This lymphoid replication phase appears to precede neuroinvasion. IMPORTANCE Chronic wasting disease (CWD) is a universally fatal transmissible spongiform encephalopathy affecting cervids, and natural infection occurs through oral and nasal mucosal exposure to infectious prions. Terminal disease is characterized by PrPCWD accumulation in the brain and lymphoid tissues of affected animals. However, the initial sites of prion

Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

PubMed

Jun, Gyungah R; Chung, Jaeyoon; Mez, Jesse; Barber, Robert; Beecham, Gary W; Bennett, David A; Buxbaum, Joseph D; Byrd, Goldie S; Carrasquillo, Minerva M; Crane, Paul K; Cruchaga, Carlos; De Jager, Philip; Ertekin-Taner, Nilufer; Evans, Denis; Fallin, M Danielle; Foroud, Tatiana M; Friedland, Robert P; Goate, Alison M; Graff-Radford, Neill R; Hendrie, Hugh; Hall, Kathleen S; Hamilton-Nelson, Kara L; Inzelberg, Rivka; Kamboh, M Ilyas; Kauwe, John S K; Kukull, Walter A; Kunkle, Brian W; Kuwano, Ryozo; Larson, Eric B; Logue, Mark W; Manly, Jennifer J; Martin, Eden R; Montine, Thomas J; Mukherjee, Shubhabrata; Naj, Adam; Reiman, Eric M; Reitz, Christiane; Sherva, Richard; St George-Hyslop, Peter H; Thornton, Timothy; Younkin, Steven G; Vardarajan, Badri N; Wang, Li-San; Wendlund, Jens R; Winslow, Ashley R; Haines, Jonathan; Mayeux, Richard; Pericak-Vance, Margaret A; Schellenberg, Gerard; Lunetta, Kathryn L; Farrer, Lindsay A

2017-07-01

Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10 -8 ) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10 -6 ) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10 -6 ). Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Early Disseminated Lyme Disease Masquerading as Mononucleosis: A Case Report.

PubMed

Tumminello, Richard; Glaspey, Lindsey; Bhamidipati, Anita; Sheehan, Patrick; Patel, Sundip

2017-12-01

Disseminated Lyme disease can be difficult to diagnose, as it begins with nonspecific signs and symptoms, which, if not treated correctly, can lead to atrioventricular conduction blocks and meningitis. In addition, the diagnosis can be further complicated by potentially false-positive test results. We report a case of early-disseminated Lyme disease presenting with Borrelia meningitis and concomitant Lyme carditis, which was misdiagnosed as mononucleosis. A young, previously healthy patient had been hiking in the woods of upstate New York and 4 weeks later developed fever, night sweats, and myalgias. He was diagnosed with mononucleosis via a positive rapid heterophile agglutination antibody test to the Epstein-Barr virus at a walk-in clinic and was started on medications, but then subsequently developed left hip pain, a facial droop, and a very long first-degree atrioventricular conduction block. He went to the Emergency Department, where he had testing that confirmed disseminated Lyme disease. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case highlights the difficulty in early diagnosis of disseminated Lyme disease and how a potentially false-positive laboratory test can lead to the complications of Borrelia meningitis and Lyme carditis in untreated young healthy patients. Emergency physicians need to consider Lyme disease in patients with nonspecific signs and symptoms, especially if they have been outdoors for prolonged periods of time in Lyme-endemic areas. Copyright © 2017 Elsevier Inc. All rights reserved.

Identifying Candidate Chemical-Disease Linkages (Environmental and Epigenetic Determinants of IBD)

EPA Science Inventory

Presentation at meeting on Environmental and Epigenetic Determinants of IBD in New York, NY on identifying candidate chemical-disease linkages by using AOPs to identify molecular initiating events and using relevant high throughput assays to screen for candidate chemicals. This h...

[Evaluation and analysis of monitoring and early warning functions of the occupational disease reporting system in China].

PubMed

Zhu, Xiaojun; Li, Tao; Liu, Mengxuan

2015-06-01

To evaluate the monitoring and early warning functions of the occupational disease reporting system right now in China, and to analyze their influencing factors. An improved audit tool (ODIT) was used to score the monitoring and early warning functions with a total score of 10. The nine indices were completeness of information on the reporting form, coverage of the reporting system, accessibility of criteria or guidelines for diagnosis, education and training for physicians, completeness of the reporting system, statistical methods, investigation of special cases, release of monitoring information, and release of early warning information. According to the evaluation, the occupational disease reporting system in China had a score of 5.5 in monitoring existing occupational diseases with a low score for release of monitoring information; the reporting system had a score of 6.5 in early warning of newly occurring occupational diseases with low scores for education and training for physicians as well as completeness of the reporting system. The occupational disease reporting system in China still does not have full function in monitoring and early warning. It is the education and participation of physicians from general hospitals in the diagnosis and treatment of occupational diseases and suspected occupational diseases that need to be enhanced. In addition, the problem of monitoring the incidence of occupational diseases needs to be solved as soon as possible.

Investigations into Retinal Pathology in the Early Stages of a Mouse Model of Alzheimer’s Disease

PubMed Central

Chidlow, Glyn; Wood, John P.M.; Manavis, Jim; Finnie, John; Casson, Robert J.

2016-01-01

There is increasing recognition that visual performance is impaired in early stages of Alzheimer’s disease (AD); however, no consensus exists as to the mechanisms underlying this visual dysfunction, in particular regarding the timing, nature, and extent of retinal versus cortical pathology. If retinal pathology presents sufficiently early, it offers great potential as a source of novel biomarkers for disease diagnosis. The current project utilized an array of immunochemical and molecular tools to perform a characterization of retinal pathology in the early stages of disease progression using a well-validated mouse model of AD (APPSWE/PS1ΔE9). Analytical endpoints included examination of aberrant amyloid and tau in the retina, quantification of any neuronal degeneration, delineation of cellular stress responses of neurons and particularly glial cells, and investigation of oxidative stress. Brain, eyes, and optic nerves were taken from transgenic and wild-type mice of 3 to 12 months of age and processed for immunohistochemistry, qPCR, or western immunoblotting. The results revealed robust expression of the human APP transgene in the retinas of transgenic mice, but a lack of identifiable retinal pathology during the period when amyloid deposits were dramatically escalating in the brain. We were unable to demonstrate the presence of amyloid plaques, dystrophic neurites, neuronal loss, macro- or micro-gliosis, aberrant cell cycle re-entry, oxidative stress, tau hyperphosphorylation, or upregulations of proinflammatory cytokines or stress signaling molecules in the retina. The overall results do not support the hypothesis that detectable retinal pathology occurs concurrently with escalating amyloid deposition in the brains of APPSWE/PS1ΔE9 mice. PMID:28035930

Early-Life State-of-Residence Characteristics and Later Life Hypertension, Diabetes, and Ischemic Heart Disease.

PubMed

Rehkopf, David H; Eisen, Ellen A; Modrek, Sepideh; Mokyr Horner, Elizabeth; Goldstein, Benjamin; Costello, Sadie; Cantley, Linda F; Slade, Martin D; Cullen, Mark R

2015-08-01

We examined how state characteristics in early life are associated with individual chronic disease later in life. We assessed early-life state of residence using the first 3 digits of social security numbers from blue- and white-collar workers from a US manufacturing company. Longitudinal data were available from 1997 to 2012, with 305 936 person-years of observation. Disease was assessed using medical claims. We modeled associations using pooled logistic regression with inverse probability of censoring weights. We found small but statistically significant associations between early-state-of-residence characteristics and later life hypertension, diabetes, and ischemic heart disease. The most consistent associations were with income inequality, percentage non-White, and education. These associations were similar after statistically controlling for individual socioeconomic and demographic characteristics and current state characteristics. Characteristics of the state in which an individual lives early in life are associated with prevalence of chronic disease later in life, with a strength of association equivalent to genetic associations found for these same health outcomes.

Gut Microbiota Dysfunction as Reliable Non-invasive Early Diagnostic Biomarkers in the Pathophysiology of Parkinson’s Disease: A Critical Review

PubMed Central

Nair, Arun T; Ramachandran, Vadivelan; Joghee, Nanjan M; Antony, Shanish; Ramalingam, Gopalakrishnan

2018-01-01

Recent investigations suggest that gut microbiota affects the brain activity through the microbiota-gut-brain axis under both physiological and pathological disease conditions like Parkinson’s disease. Further dopamine synthesis in the brain is induced by dopamine producing enzymes that are controlled by gut microbiota via the microbiota-gut-brain axis. Also alpha synuclein deposition and the associated neurodegeneration in the enteric nervous system that increase intestinal permeability, oxidative stress, and local inflammation, accounts for constipation in Parkinson’s disease patients. The trigger that causes blood brain barrier leakage, immune cell activation and inflammation, and ultimately neuroinflammation in the central nervous system is believed to be due to the chronic low-grade inflammation in the gut. The non-motor symptoms that appear years before motor symptoms could be reliable early biomarkers, if they could be correlated with the established and reliable neuroimaging techniques or behavioral indices. The future directions should therefore, focus on the exploration of newer investigational techniques to identify these reliable early biomarkers and define the specific gut microbes that contribute to the development of Parkinson’s disease. This ultimately should pave the way to safer and novel therapeutic approaches that avoid the complications of the drugs delivered today to the brain of Parkinson’s disease patients. PMID:29291606

Body weight and dysautonomia in early Parkinson's disease.

PubMed

Umehara, T; Nakahara, A; Matsuno, H; Toyoda, C; Oka, H

2017-05-01

Patients with Parkinson's disease (PD) begin to lose weight several years before diagnosis, which suggests weight variation is associated with some factor(s) that precede the onset of motor symptoms. This study aimed to investigate the association of autonomic nervous system with body weight in patients with PD. The subjects were 90 patients with early de novo PD. We examined the associations of body mass index (BMI) with sympathetic nervous activity reflected in orthostatic intolerance or cardiac uptake of 123 I-metaiodobenzylguanidine and parasympathetic nervous activity reflected in constipation or heart rate variability (HRV). Twelve patients (13.3%) were overweight (BMI>25 kg/m 2 ), 62 patients (68.9%) were normal-weight (18.5≦BMI<25 kg/m 2 ), and 16 patients (17.8%) were underweight (BMI<18.5 kg/m 2 ). Underweight patients had greater disease severity and decrease in blood pressure on head-up tilt-table testing, higher cardiac washout ratio of 123 I-metaiodobenzylguanidine, and lower HRV and complained of constipation more often than those with normal-weight or overweight patients. On multiple regression analyses, the correlation of these variables with BMI maintained statistical significance after adjustment for age, sex, symptom duration, and motor subtype. Dysautonomia and disease severity are closely related to body weight independently of age, sex, symptom duration, and motor subtype. Dysautonomia may play a partial role on weight variation in the early stage of PD. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Blood biomarker for Parkinson disease: peptoids

PubMed Central

Yazdani, Umar; Zaman, Sayed; Hynan, Linda S; Brown, L Steven; Dewey, Richard B; Karp, David; German, Dwight C

2016-01-01

Parkinson disease (PD) is the second most common neurodegenerative disease. Because dopaminergic neuronal loss begins years before motor symptoms appear, a biomarker for the early identification of the disease is critical for the study of putative neuroprotective therapies. Brain imaging of the nigrostriatal dopamine system has been used as a biomarker for early disease along with cerebrospinal fluid analysis of α-synuclein, but a less costly and relatively non-invasive biomarker would be optimal. We sought to identify an antibody biomarker in the blood of PD patients using a combinatorial peptoid library approach. We examined serum samples from 75 PD patients, 25 de novo PD patients, and 104 normal control subjects in the NINDS Parkinson’s Disease Biomarker Program. We identified a peptoid, PD2, which binds significantly higher levels of IgG3 antibody in PD versus control subjects (P<0.0001) and is 68% accurate in identifying PD. The PD2 peptoid is 84% accurate in identifying de novo PD. Also, IgG3 levels are significantly higher in PD versus control serum (P<0.001). Finally, PD2 levels are positively correlated with the United Parkinson’s Disease Rating Scale score (r=0.457, P<0001), a marker of disease severity. The PD2 peptoid may be useful for the early-stage identification of PD, and serve as an indicator of disease severity. Additional studies are needed to validate this PD biomarker. PMID:27812535

Dental Hygienist-Led Chronic Disease Management System to Control Early Childhood Caries.

PubMed

Ng, Man Wai; Fida, Zameera

2016-06-01

Management of the complex chronic disease of early childhood caries requires a system of coordinated health care interventions which can be led by a dental hygienist and where patient self-care efforts are paramount. Even after receiving costly surgical treatment under general anesthesia in the operating room, many children develop new and recurrent caries after only 6-12 months, a sequela that can be prevented. This article describes the chronic disease management (CDM) of dental caries, a science-based approach that can prevent and control caries. In this article, we (1) introduce the concept of CDM of dental caries, (2) provide evidence that CDM improves oral health outcomes, and (3) propose a dental hygienist-led team-based oral health care approach to CDM. Although we will be describing the CDM approach for early childhood caries, CDM of caries is applicable in children, adolescents, and adults. Early childhood caries disease control requires meaningful engagement of patients and parents by the oral health care team to assist them with making behavioral changes in the unique context of their families and communities. The traditional dentist/hygienist/assistant model needs to evolve to a collaborative partnership between care providers and patients/families. This partnership will be focused on systematic risk assessment and behaviorally based management of the disease itself, with sensitivity toward the familial environment. Early pilot study results demonstrate reductions in the rates of new caries, dental pain, and referral to the operating room compared with baseline rates. Dental hygienists are the appropriate team members to lead this approach because of their expertise in behavior change and prevention. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Opportunity cost for early treatment of Chagas disease in Mexico.

PubMed

Ramsey, Janine M; Elizondo-Cano, Miguel; Sanchez-González, Gilberto; Peña-Nieves, Adriana; Figueroa-Lara, Alejandro

2014-04-01

Given current neglect for Chagas disease in public health programs in Mexico, future healthcare and economic development policies will need a more robust model to analyze costs and impacts of timely clinical attention of infected populations. A Markov decision model was constructed to simulate the natural history of a Chagas disease cohort in Mexico and to project the associated short and long-term clinical outcomes and corresponding costs. The lifetime cost for a timely diagnosed and treated Chagas disease patient is US$ 10,160, while the cost for an undiagnosed individual is US$ 11,877. The cost of a diagnosed and treated case increases 24-fold from early acute to indeterminate stage. The major cost component for lifetime cost was working days lost, between 44% and 75%, depending on the program scenario for timely diagnosis and treatment. In the long term, it is cheaper to diagnose and treat chagasic patients early, instead of doing nothing. This finding by itself argues for the need to shift current policy, in order to prioritize and attend this neglected disease for the benefit of social and economic development, which implies including treatment drugs in the national formularies. Present results are even more relevant, if one considers that timely diagnosis and treatment can arrest clinical progression and enhance a chronic patient's quality of life.

Opportunity Cost for Early Treatment of Chagas Disease in Mexico

PubMed Central

Ramsey, Janine M.; Elizondo-Cano, Miguel; Sanchez-González, Gilberto; Peña-Nieves, Adriana; Figueroa-Lara, Alejandro

2014-01-01

Background Given current neglect for Chagas disease in public health programs in Mexico, future healthcare and economic development policies will need a more robust model to analyze costs and impacts of timely clinical attention of infected populations. Methodology/Principal Findings A Markov decision model was constructed to simulate the natural history of a Chagas disease cohort in Mexico and to project the associated short and long-term clinical outcomes and corresponding costs. The lifetime cost for a timely diagnosed and treated Chagas disease patient is US$ 10,160, while the cost for an undiagnosed individual is US$ 11,877. The cost of a diagnosed and treated case increases 24-fold from early acute to indeterminate stage. The major cost component for lifetime cost was working days lost, between 44% and 75%, depending on the program scenario for timely diagnosis and treatment. Conclusions/Significance In the long term, it is cheaper to diagnose and treat chagasic patients early, instead of doing nothing. This finding by itself argues for the need to shift current policy, in order to prioritize and attend this neglected disease for the benefit of social and economic development, which implies including treatment drugs in the national formularies. Present results are even more relevant, if one considers that timely diagnosis and treatment can arrest clinical progression and enhance a chronic patient's quality of life. PMID:24743112

Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci.

PubMed

Raelson, John V; Little, Randall D; Ruether, Andreas; Fournier, Hélène; Paquin, Bruno; Van Eerdewegh, Paul; Bradley, W E C; Croteau, Pascal; Nguyen-Huu, Quynh; Segal, Jonathan; Debrus, Sophie; Allard, René; Rosenstiel, Philip; Franke, Andre; Jacobs, Gunnar; Nikolaus, Susanna; Vidal, Jean-Michel; Szego, Peter; Laplante, Nathalie; Clark, Hilary F; Paulussen, René J; Hooper, John W; Keith, Tim P; Belouchi, Abdelmajid; Schreiber, Stefan

2007-09-11

Genome-wide association (GWA) studies offer a powerful unbiased method for the identification of multiple susceptibility genes for complex diseases. Here we report the results of a GWA study for Crohn's disease (CD) using family trios from the Quebec Founder Population (QFP). Haplotype-based association analyses identified multiple regions associated with the disease that met the criteria for genome-wide significance, with many containing a gene whose function appears relevant to CD. A proportion of these were replicated in two independent German Caucasian samples, including the established CD loci NOD2 and IBD5. The recently described IL23R locus was also identified and replicated. For this region, multiple individuals with all major haplotypes in the QFP were sequenced and extensive fine mapping performed to identify risk and protective alleles. Several additional loci, including a region on 3p21 containing several plausible candidate genes, a region near JAKMIP1 on 4p16.1, and two larger regions on chromosome 17 were replicated. Together with previously published loci, the spectrum of CD genes identified to date involves biochemical networks that affect epithelial defense mechanisms, innate and adaptive immune response, and the repair or remodeling of tissue.

Changes in spontaneous brain activity in early Parkinson's disease.

PubMed

Yang, Hong; Zhou, Xiaohong Joe; Zhang, Min-Ming; Zheng, Xu-Ning; Zhao, Yi-Lei; Wang, Jue

2013-08-09

Resting state brain activity can provide valuable insights into the pathophysiology of Parkinson's disease (PD). The purpose of the present study was (a) to investigate abnormal spontaneous neuronal activity in early PD patients using resting-state functional MRI (fMRI) with a regional homogeneity (ReHo) method and (b) to demonstrate the potential of using changes in abnormal spontaneous neuronal activity for monitoring the progression of PD during its early stages. Seventeen early PD patients were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS), the Hoehn and Yahr disability scale and the Mini-mental State Examination (MMSE) were compared with seventeen gender- and age-matched healthy controls. All subjects underwent MRI scans using a 1.5T General Electric Signa Excite II scanner. The MRI scan protocol included whole-brain volumetric imaging using a 3D inversion recovery prepared (IR-Prep) fast spoiled gradient-echo pulse sequence and 2D multi-slice (22 axial slices covering the whole brain) resting-state fMRI using an echo planar imaging (EPI) sequence. Images were analyzed in SPM5 together with a ReHo algorithm using the in-house software program REST. A corrected threshold of p<0.05 was determined by AlphaSim and used in statistical analysis. Compared with the healthy controls, the early PD group showed significantly increased ReHo in a number of brain regions, including the left cerebellum, left parietal lobe, right middle temporal lobe, right sub-thalamic nucleus areas, right superior frontal gyrus, middle frontal gyrus (MFG), right inferior parietal lobe (IPL), right precuneus lobe, left MFG and left IPL. Additionally, significantly reduced ReHo was also observed in the early PD patients in the following brain regions: the left putamen, left inferior frontal gyrus, right hippocampus, right anterior cingulum, and bilateral lingual gyrus. Moreover, in PD patients, ReHo in the left putamen was negatively correlated with the UPDRS scores (r=-0

Is early limited surgery associated with a more benign disease course in Crohn’s disease?

PubMed Central

Golovics, Petra Anna; Lakatos, Laszlo; Nagy, Attila; Pandur, Tunde; Szita, Istvan; Balogh, Mihaly; Molnar, Csaba; Komaromi, Erzsebet; Lovasz, Barbara Dorottya; Mandel, Michael; Veres, Gabor; Kiss, Lajos S; Vegh, Zsuzsanna; Lakatos, Peter Laszlo

2013-01-01

AIM: To analyze the difference in disease course and need for surgery in patients with Crohn’s disease (CD). METHODS: Data of 506 patients with incident CD were analyzed (age at diagnosis: 31.5 ± 13.8 years). Both hospital and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database, which includes incident CD patients diagnosed between January 1, 1977 and December 31, 2008. Follow-up data were collected until December 31, 2009. All patients included had at least 1 year of follow-up available. Patients with indeterminate colitis at diagnosis were excluded from the analysis. RESULTS: Overall, 73 patients (14.4%) required resective surgery within 1 year of diagnosis. Steroid exposure and need for biological therapy were lower in patients with early limited surgery (P < 0.001 and P = 0.09). In addition, surgery rates during follow-up in patients with and without early surgery differed significantly after matching on propensity scores (P < 0.001, HR = 0.23). The need for reoperation was also lower in patients with early limited resective surgery (P = 0.038, HR = 0.42) in a Kaplan-Meier and multivariate Cox regression (P = 0.04) analysis. However, this advantage was not observed after matching on propensity scores (PLogrank = 0.656, PBreslow = 0.498). CONCLUSION: Long-term surgery rates and overall exposure to steroids and biological agents were lower in patients with early limited resective surgery, but reoperation rates did not differ. PMID:24282358

Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology.

PubMed

Wilson, Gabrielle R; Sim, Joe C H; McLean, Catriona; Giannandrea, Maila; Galea, Charles A; Riseley, Jessica R; Stephenson, Sarah E M; Fitzpatrick, Elizabeth; Haas, Stefan A; Pope, Kate; Hogan, Kirk J; Gregg, Ronald G; Bromhead, Catherine J; Wargowski, David S; Lawrence, Christopher H; James, Paul A; Churchyard, Andrew; Gao, Yujing; Phelan, Dean G; Gillies, Greta; Salce, Nicholas; Stanford, Lynn; Marsh, Ashley P L; Mignogna, Maria L; Hayflick, Susan J; Leventer, Richard J; Delatycki, Martin B; Mellick, George D; Kalscheuer, Vera M; D'Adamo, Patrizia; Bahlo, Melanie; Amor, David J; Lockhart, Paul J

2014-12-04

Advances in understanding the etiology of Parkinson disease have been driven by the identification of causative mutations in families. Genetic analysis of an Australian family with three males displaying clinical features of early-onset parkinsonism and intellectual disability identified a ∼45 kb deletion resulting in the complete loss of RAB39B. We subsequently identified a missense mutation (c.503C>A [p.Thr168Lys]) in RAB39B in an unrelated Wisconsin kindred affected by a similar clinical phenotype. In silico and in vitro studies demonstrated that the mutation destabilized the protein, consistent with loss of function. In vitro small-hairpin-RNA-mediated knockdown of Rab39b resulted in a reduction in the density of α-synuclein immunoreactive puncta in dendritic processes of cultured neurons. In addition, in multiple cell models, we demonstrated that knockdown of Rab39b was associated with reduced steady-state levels of α-synuclein. Post mortem studies demonstrated that loss of RAB39B resulted in pathologically confirmed Parkinson disease. There was extensive dopaminergic neuron loss in the substantia nigra and widespread classic Lewy body pathology. Additional pathological features included cortical Lewy bodies, brain iron accumulation, tau immunoreactivity, and axonal spheroids. Overall, we have shown that loss-of-function mutations in RAB39B cause intellectual disability and pathologically confirmed early-onset Parkinson disease. The loss of RAB39B results in dysregulation of α-synuclein homeostasis and a spectrum of neuropathological features that implicate RAB39B in the pathogenesis of Parkinson disease and potentially other neurodegenerative disorders. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

The march from early life food sensitization to allergic disease: a systematic review and meta-analyses of birth cohort studies.

PubMed

Alduraywish, S A; Lodge, C J; Campbell, B; Allen, K J; Erbas, B; Lowe, A J; Dharmage, S C

2016-01-01

There is growing evidence for an increase in food allergies. The question of whether early life food sensitization, a primary step in food allergies, leads to other allergic disease is a controversial but important issue. Birth cohorts are an ideal design to answer this question. We aimed to systematically investigate and meta-analyse the evidence for associations between early food sensitization and allergic disease in birth cohorts. MEDLINE and SCOPUS databases were searched for birth cohorts that have investigated the association between food sensitization in the first 2 years and subsequent wheeze/asthma, eczema and/or allergic rhinitis. We performed meta-analyses using random-effects models to obtain pooled estimates, stratified by age group. The search yielded fifteen original articles representing thirteen cohorts. Early life food sensitization was associated with an increased risk of infantile eczema, childhood wheeze/asthma, eczema and allergic rhinitis and young adult asthma. Meta-analyses demonstrated that early life food sensitization is related to an increased risk of wheeze/asthma (pooled OR 2.9; 95% CI 2.0-4.0), eczema (pooled OR 2.7; 95% CI 1.7-4.4) and allergic rhinitis (pooled OR 3.1; 95% CI 1.9-4.9) from 4 to 8 years. Food sensitization in the first 2 years of life can identify children at high risk of subsequent allergic disease who may benefit from early life preventive strategies. However, due to potential residual confounding in the majority of studies combined with lack of follow-up into adolescence and adulthood, further research is needed. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Identifying Common Practice Elements to Improve Social, Emotional, and Behavioral Outcomes of Young Children in Early Childhood Classrooms.

PubMed

McLeod, Bryce D; Sutherland, Kevin S; Martinez, Ruben G; Conroy, Maureen A; Snyder, Patricia A; Southam-Gerow, Michael A

2017-02-01

Educators are increasingly being encouraged to implement evidence-based interventions and practices to address the social, emotional, and behavioral needs of young children who exhibit problem behavior in early childhood settings. Given the nature of social-emotional learning during the early childhood years and the lack of a common set of core evidence-based practices within the early childhood literature, selection of instructional practices that foster positive social, emotional, and behavioral outcomes for children in early childhood settings can be difficult. The purpose of this paper is to report findings from a study designed to identify common practice elements found in comprehensive intervention models (i.e., manualized interventions that include a number of components) or discrete practices (i.e., a specific behavior or action) designed to target social, emotional, and behavioral learning of young children who exhibit problem behavior. We conducted a systematic review of early childhood classroom interventions that had been evaluated in randomized group designs, quasi-experimental designs, and single-case experimental designs. A total of 49 published articles were identified, and an iterative process was used to identify common practice elements. The practice elements were subsequently reviewed by experts in social-emotional and behavioral interventions for young children. Twenty-four practice elements were identified and classified into content (the goal or general principle that guides a practice element) and delivery (the way in which a teacher provides instruction to the child) categories. We discuss implications that the identification of these practice elements found in the early childhood literature has for efforts to implement models and practices.

Understanding the management of early-stage chronic kidney disease in primary care: a qualitative study

PubMed Central

Blakeman, Tom; Protheroe, Joanne; Chew-Graham, Carolyn; Rogers, Anne; Kennedy, Anne

2012-01-01

Background Primary care is recognised to have an important role in the delivery of care for people with chronic kidney disease (CKD). However, there is evidence that CKD management is currently suboptimal, with a range of practitioner concerns about its management. Aim To explore processes underpinning the implementation of CKD management in primary care. Design and setting Qualitative study in general practices participating in a chronic kidney disease collaborative undertaken as part of the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for Greater Manchester. Method Semi-structured interviews were conducted with GPs and practice nurses (n = 21). Normalisation Process Theory provided a framework for generation and analysis of the data. Results A predominant theme was anxiety about the disclosure of early-stage CKD with patients. The tensions experienced related to identifying and discussing CKD in older people and patients with stage 3A, embedding early-stage CKD within vascular care, and the distribution of work within the practice team. Participants provided accounts of work undertaken to resolve the difficulties encountered, with efforts having tended to focus on reassuring patients. Analysis also highlighted how anxiety surrounding disclosure influenced, and was shaped by, the organisation of care for people with CKD and associated long-term conditions. Conclusion Offering reassurance alone may be of limited benefit, and current management of early-stage CKD in primary care may miss opportunities to address susceptibility to kidney injury, improve self-management of vascular conditions, and improve the management of multimorbidity. PMID:22520910

Nocturnal hypoglycemia identified by a continuous glucose monitoring system in patients with primary adrenal insufficiency (Addison's Disease).

PubMed

Meyer, Gesine; Hackemann, Annika; Reusch, Juergen; Badenhoop, Klaus

2012-05-01

Hypoglycemia can be a symptom in patients with Addison's disease. The common regimen of replacement therapy with oral glucocorticoids results in unphysiological low cortisol levels in the early morning, the time of highest insulin sensitivity. Therefore patients with Addison's disease are at risk for unrecognized and potentially severe nocturnal hypoglycemia also because of a disturbed counterregulatory function. Use of a continuous glucose monitoring system (CGMS) could help to adjust hydrocortisone treatment and to avoid nocturnal hypoglycemia in these patients. Thirteen patients with Addison's disease were screened for hypoglycemia wearing a CGMS for 3-5 days. In one patient we identified a hypoglycemic episode at 3:45 a.m. with a blood glucose level of 46 mg/dL, clearly beneath the 95% tolerance interval of minimal glucose levels between 2 and 4 a.m. (53.84 mg/dL). After the hydrocortisone replacement scheme was changed, the minimum blood glucose level between 2 and 4 a.m. normalized to 87 mg/dL. Continuous glucose monitoring can detect nocturnal hypoglycemia in patients with primary adrenal insufficiency and hence prevent in these patients an impaired quality of life and even serious adverse effects.

Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease.

PubMed

Okou, David T; Mondal, Kajari; Faubion, William A; Kobrynski, Lisa J; Denson, Lee A; Mulle, Jennifer G; Ramachandran, Dhanya; Xiong, Yuning; Svingen, Phyllis; Patel, Viren; Bose, Promita; Waters, Jon P; Prahalad, Sampath; Cutler, David J; Zwick, Michael E; Kugathasan, Subra

2014-05-01

Inflammatory bowel disease (IBD) is heritable, but a total of 163 variants commonly implicated in IBD pathogenesis account for only 25% of the heritability. Rare, highly penetrant genetic variants may also explain mendelian forms of IBD and some of the missing heritability. To test the hypothesis that rare loss-of-function mutations can be causative, we performed whole exome sequencing (WES) on 5 members of a 2-generation family of European ancestry presenting with an early-onset and atypical form of IBD. WES was performed for all of the 5 family members; the mother and 3 male offspring were affected, whereas the father was unaffected. Mapping, annotation, and filtering criteria were used to reduce candidate variants. For functional testing we performed forkhead box P3 (FOXP3) staining and a T-cell suppression assay. We identified a novel missense variant in exon 6 of the X-linked FOXP3 gene. The c.694A>C substitution in FOXP3 results in a cysteine-to-glycine change at the protein position 232 that is completely conserved among all vertebrates. This variant (heterozygous in the mother and hemizygous in all 3 affected sons) did not impair FOXP3 protein expression, but significantly reduced the ability of the host's T regulatory cells to suppress an inappropriate autoimmune response. The variant results in a milder immune dysregulation, polyendocrinopathy, enteropathy, and X-linked phenotype with early-onset IBD. Our study illustrates the successful application of WES for making a definitive molecular diagnosis in a case of multiply affected families, with atypical IBD-like phenotype. Our results also have important implications for disease biology and disease-directed therapeutic development.

Hereditary myopathies with early respiratory insufficiency in adults.

PubMed

Naddaf, Elie; Milone, Margherita

2017-11-01

Hereditary myopathies with early respiratory insufficiency as a predominant feature of the clinical phenotype are uncommon and underestimated in adults. We reviewed the clinical and laboratory data of patients with hereditary myopathies who demonstrated early respiratory insufficiency before the need for ambulatory assistance. Only patients with disease-causing mutations or a specific histopathological diagnosis were included. Patients with cardiomyopathy were excluded. We identified 22 patients; half had isolated respiratory symptoms at onset. The diagnosis of the myopathy was often delayed, resulting in delayed ventilatory support. The most common myopathies were adult-onset Pompe disease, myofibrillar myopathy, multi-minicore disease, and myotonic dystrophy type 1. Single cases of laminopathy, MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike events), centronuclear myopathy, and cytoplasmic body myopathy were identified. We highlighted the most common hereditary myopathies associated with early respiratory insufficiency as the predominant clinical feature, and underscored the importance of a timely diagnosis for patient care. Muscle Nerve 56: 881-886, 2017. © 2017 Wiley Periodicals, Inc.

Chagas disease vector blood meal sources identified by protein mass spectrometry

PubMed Central

Keller, Judith I.; Ballif, Bryan A.; St. Clair, Riley M.; Vincent, James J.; Monroy, M. Carlota

2017-01-01

Chagas disease is a complex vector borne parasitic disease involving blood feeding Triatominae (Hemiptera: Reduviidae) insects, also known as kissing bugs, and the vertebrates they feed on. This disease has tremendous impacts on millions of people and is a global health problem. The etiological agent of Chagas disease, Trypanosoma cruzi (Kinetoplastea: Trypanosomatida: Trypanosomatidae), is deposited on the mammalian host in the insect’s feces during a blood meal, and enters the host’s blood stream through mucous membranes or a break in the skin. Identifying the blood meal sources of triatomine vectors is critical in understanding Chagas disease transmission dynamics, can lead to identification of other vertebrates important in the transmission cycle, and aids management decisions. The latter is particularly important as there is little in the way of effective therapeutics for Chagas disease. Several techniques, mostly DNA-based, are available for blood meal identification. However, further methods are needed, particularly when sample conditions lead to low-quality DNA or to assess the risk of human cross-contamination. We demonstrate a proteomics-based approach, using liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify host-specific hemoglobin peptides for blood meal identification in mouse blood control samples and apply LC-MS/MS for the first time to Triatoma dimidiata insect vectors, tracing blood sources to species. In contrast to most proteins, hemoglobin, stabilized by iron, is incredibly stable even being preserved through geologic time. We compared blood stored with and without an anticoagulant and examined field-collected insect specimens stored in suboptimal conditions such as at room temperature for long periods of time. To our knowledge, this is the first study using LC-MS/MS on field-collected arthropod disease vectors to identify blood meal composition, and where blood meal identification was confirmed with more traditional DNA

Varenicline improves motor and cognitive symptoms in early Huntington’s disease

PubMed Central

McGregor, Ailsa L; Dysart, Jo; Tingle, Malcolm D; Russell, Bruce R; Kydd, Rob R; Finucane, Gregory

2016-01-01

The aim of this study was to describe the effects of varenicline, a smoking cessation aid that acts as a nicotinic agonist, on cognitive function in patients with early clinical Huntington’s disease (HD) who were current smokers. Three gene-positive patients transitioning to symptomatic HD were evaluated using the Unified Huntington’s Disease Rating Scale part I and III (motor and behavioral subscales) at baseline and after 4 weeks of treatment. Cognitive function was assessed using a touch screen computer-based neurocognitive test battery (IntegNeuro®). Varenicline (1 mg twice daily) significantly improved performance in executive function and emotional recognition tasks. Our case reports describe no clinically significant adverse effects and suggest that varenicline improves aspects of cognitive function in patients with early HD. A randomized controlled study is now underway. PMID:27695336

Early events of citrus greening (Huanglongbing) disease development at the ultrastructural level.

PubMed

Folimonova, Svetlana Y; Achor, Diann S

2010-09-01

Citrus greening (Huanglongbing [HLB]) is one of the most destructive diseases of citrus worldwide. The causal agent of HLB in Florida is thought to be 'Candidatus Liberibacter asiaticus'. Understanding of the early events in HLB infection is critical for the development of effective measures to control the disease. In this work, we conducted cytopathological studies by following the development of the disease in citrus trees graft inoculated with 'Ca. L. asiaticus'-containing material under greenhouse conditions to examine the correlation between ultrastructural changes and symptom production, with the main objective of characterizing the early events of infection. Based on our observations, one of the first degenerative changes induced upon invasion of the pathogen appears to be swelling of middle lamella between cell walls surrounding sieve elements. This anatomical aberration was often observed in samples from newly growing flushes in inoculated sweet orange and grapefruit trees at the early "presymptomatic" stage of HLB infection. Development of symptoms and their progression correlated with an increasing degree of microscopic aberrations. Remarkably, the ability to observe the bacterium in the infected tissue also correlated with the degree of the disease progression. Large numbers of bacterial cells were found in phloem sieve tubes in tissue samples from presymptomatic young flushes. In contrast, we did not observe the bacteria in highly symptomatic leaf samples, suggesting a possibility that, at more advanced stages of the disease, a major proportion of 'Ca. L. asiaticus' is present in a nonviable state. We trust that observations reported here advance our understanding of how 'Ca. L. asiaticus' causes disease. Furthermore, they may be an important aid in answering a question: when and where within an infected tree the tissue serves as a better inoculum source for acquisition and transmission of the bacterium by its psyllid vector.

Forecasting Alzheimer's Disease.

ERIC Educational Resources Information Center

Fackelmann, Kathleen

1996-01-01

Suggests that doctors may one day be able to identify healthy people who will develop Alzheimer's disease. Discusses recent studies in which characteristics of a person's writing early in life appear to predict the disease, and brain scans can highlight changes that may precede dementia. (CCM)

Major Alterations of Phosphatidylcholine and Lysophosphotidylcholine Lipids in the Substantia Nigra Using an Early Stage Model of Parkinson’s Disease

PubMed Central

Farmer, Kyle; Smith, Catherine A.; Hayley, Shawn; Smith, Jeffrey

2015-01-01

Parkinson’s disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal pathway, where patients do not manifest motor symptoms until >50% of neurons are lost. Thus, it is of great importance to determine early neuronal changes that may contribute to disease progression. Recent attention has focused on lipids and their role in pro- and anti-apoptotic processes. However, information regarding the lipid alterations in animal models of PD is lacking. In this study, we utilized high performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) and novel HPLC solvent methodology to profile phosphatidylcholines and sphingolipids within the substantia nigra. The ipsilateral substantia nigra pars compacta was collected from rats 21 days after an infusion of 6-hydroxydopamine (6-OHDA), or vehicle into the anterior dorsal striatum. We identified 115 lipid species from their mass/charge ratio using the LMAPS Lipid MS Predict Database. Of these, 19 lipid species (from phosphatidylcholine and lysophosphotidylcholine lipid classes) were significantly altered by 6-OHDA, with most being down-regulated. The two lipid species that were up-regulated were LPC (16:0) and LPC (18:1), which are important for neuroinflammatory signalling. These findings provide a first step in the characterization of lipid changes in early stages of PD-like pathology and could provide novel targets for early interventions in PD. PMID:26274953

Hyperspectral remote sensing for advanced detection of early blight (Alternaria solani) disease in potato (Solanum tuberosum) plants

NASA Astrophysics Data System (ADS)

Atherton, Daniel

Early detection of disease and insect infestation within crops and precise application of pesticides can help reduce potential production losses, reduce environmental risk, and reduce the cost of farming. The goal of this study was the advanced detection of early blight (Alternaria solani) in potato (Solanum tuberosum) plants using hyperspectral remote sensing data captured with a handheld spectroradiometer. Hyperspectral reflectance spectra were captured 10 times over five weeks from plants grown to the vegetative and tuber bulking growth stages. The spectra were analyzed using principal component analysis (PCA), spectral change (ratio) analysis, partial least squares (PLS), cluster analysis, and vegetative indices. PCA successfully distinguished more heavily diseased plants from healthy and minimally diseased plants using two principal components. Spectral change (ratio) analysis provided wavelengths (490-510, 640, 665-670, 690, 740-750, and 935 nm) most sensitive to early blight infection followed by ANOVA results indicating a highly significant difference (p < 0.0001) between disease rating group means. In the majority of the experiments, comparisons of diseased plants with healthy plants using Fisher's LSD revealed more heavily diseased plants were significantly different from healthy plants. PLS analysis demonstrated the feasibility of detecting early blight infected plants, finding four optimal factors for raw spectra with the predictor variation explained ranging from 93.4% to 94.6% and the response variation explained ranging from 42.7% to 64.7%. Cluster analysis successfully distinguished healthy plants from all diseased plants except for the most mildly diseased plants, showing clustering analysis was an effective method for detection of early blight. Analysis of the reflectance spectra using the simple ratio (SR) and the normalized difference vegetative index (NDVI) was effective at differentiating all diseased plants from healthy plants, except for the

A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease.

PubMed

2004-04-01

Treatment with rasagiline mesylate, an irreversible monoamine oxidase type B inhibitor, improves symptoms of early Parkinson disease (PD). Preclinical studies suggest that this compound may also modify the progression of PD. To compare the effects of early and later initiation of rasagiline on progression of disability in patients with PD. Double-blind, parallel-group, randomized, delayed-start clinical trial. Four hundred four subjects with early PD, not requiring dopaminergic therapy, enrolled at 32 sites in the United States and Canada. Subjects were randomized to receive rasagiline, 1 or 2 mg/d, for 1 year or placebo for 6 months followed by rasagiline, 2 mg/d, for 6 months. Change in total Unified Parkinson's Disease Rating Scale score from baseline to 12 months. Three hundred seventy-one subjects were included in the 1-year efficacy analysis. Subjects treated with rasagiline, 2 mg/d, for 1 year had a 2.29-unit smaller increase in mean adjusted total Unified Parkinson's Disease Rating Scale score compared with subjects treated with placebo for 6 months followed by rasagiline, 2 mg/d, for 6 months (P =.01). The mean adjusted difference between the placebo/rasagiline, 2 mg/d, group and those receiving rasagiline, 1 mg/d, for 1 year was -1.82 unit on the Unified Parkinson's Disease Rating Scale score (P =.05). Subjects treated with rasagiline, 2 and 1 mg/d, for 12 months showed less functional decline than subjects whose treatment was delayed for 6 months.

Investigations of remote sensing techniques for early detection of Dutch elm disease

NASA Technical Reports Server (NTRS)

Hammerschlag, R. S.; Sopstyle, W. J.

1975-01-01

Several forms of aerial photography were pursued in quest of a technique which could provide early detection of Dutch elm disease. The two most promising techniques tested were multispectral photography with object enhancement and biband ratioing coupled with scanning microdensitometry. For practical purposes the multispectral system has the advantage of providing a readily interpretable image in a relatively short time. Laboratory studies indicated that less emphasis should be placed on the use of a red filter or the near infrared beyond 750 mm for early detection of stress within a single plant species. Color infrared film would be optimal when used for a long term detection of loss of plant vigor which results in a physical change in a plant canopy, but should find minimal practicality for early detection of specific sources of plant stress such as Dutch elm disease. Considerable discretion should be used when interpreting imagery on copy film because of loss of resolution and color definition.

Early Motor Unit Disease Masquerading as Psychogenic Breathy Dysphonia: A Clinical Case Presentation

ERIC Educational Resources Information Center

Aronson, Arnold E.

1971-01-01

Presented is a study of a 20-year-old girl with mild, breathy dysphonia, previously diagnosed as psychogenic. In actuality, her voice change was a sign of early myasthenia gravis. It is pointed out that voice changes can be a first and only sign of early neurologic disease. (Author/KW)

Subthalamic nucleus deep brain stimulation in early stage Parkinson's disease.

PubMed

Charles, David; Konrad, Peter E; Neimat, Joseph S; Molinari, Anna L; Tramontana, Michael G; Finder, Stuart G; Gill, Chandler E; Bliton, Mark J; Kao, Chris; Phibbs, Fenna T; Hedera, Peter; Salomon, Ronald M; Cannard, Kevin R; Wang, Lily; Song, Yanna; Davis, Thomas L

2014-07-01

Deep brain stimulation (DBS) is an effective and approved therapy for advanced Parkinson's disease (PD), and a recent study suggests efficacy in mid-stage disease. This manuscript reports the results of a pilot trial investigating preliminary safety and tolerability of DBS in early PD. Thirty subjects with idiopathic PD (Hoehn & Yahr Stage II off medication), age 50-75, on medication ≥6 months but ≤4 years, and without motor fluctuations or dyskinesias were randomized to optimal drug therapy (ODT) (n = 15) or DBS + ODT (n = 15). Co-primary endpoints were the time to reach a 4-point worsening from baseline in the UPDRS-III off therapy and the change in levodopa equivalent daily dose from baseline to 24 months. As hypothesized, the mean UPDRS total and part III scores were not significantly different on or off therapy at 24 months. Medication requirements in the DBS + ODT group were lower at all time points with a maximal difference at 18 months. With a few exceptions, differences in neuropsychological functioning were not significant. Two subjects in the DBS + ODT group suffered serious adverse events; remaining adverse events were mild or transient. This study demonstrates that subjects with early stage PD will enroll in and complete trials testing invasive therapies and provides preliminary evidence that DBS is well tolerated in early PD. The results of this trial provide the data necessary to design a large, phase III, double-blind, multicenter trial investigating the safety and efficacy of DBS in early PD. Copyright © 2014 Elsevier Ltd. All rights reserved.

Identifying Mendelian disease genes with the Variant Effect Scoring Tool

PubMed Central

2013-01-01

Background Whole exome sequencing studies identify hundreds to thousands of rare protein coding variants of ambiguous significance for human health. Computational tools are needed to accelerate the identification of specific variants and genes that contribute to human disease. Results We have developed the Variant Effect Scoring Tool (VEST), a supervised machine learning-based classifier, to prioritize rare missense variants with likely involvement in human disease. The VEST classifier training set comprised ~ 45,000 disease mutations from the latest Human Gene Mutation Database release and another ~45,000 high frequency (allele frequency >1%) putatively neutral missense variants from the Exome Sequencing Project. VEST outperforms some of the most popular methods for prioritizing missense variants in carefully designed holdout benchmarking experiments (VEST ROC AUC = 0.91, PolyPhen2 ROC AUC = 0.86, SIFT4.0 ROC AUC = 0.84). VEST estimates variant score p-values against a null distribution of VEST scores for neutral variants not included in the VEST training set. These p-values can be aggregated at the gene level across multiple disease exomes to rank genes for probable disease involvement. We tested the ability of an aggregate VEST gene score to identify candidate Mendelian disease genes, based on whole-exome sequencing of a small number of disease cases. We used whole-exome data for two Mendelian disorders for which the causal gene is known. Considering only genes that contained variants in all cases, the VEST gene score ranked dihydroorotate dehydrogenase (DHODH) number 2 of 2253 genes in four cases of Miller syndrome, and myosin-3 (MYH3) number 2 of 2313 genes in three cases of Freeman Sheldon syndrome. Conclusions Our results demonstrate the potential power gain of aggregating bioinformatics variant scores into gene-level scores and the general utility of bioinformatics in assisting the search for disease genes in large-scale exome sequencing studies. VEST is

Early cystic fibrosis lung disease: Role of airway surface dehydration and lessons from preventive rehydration therapies in mice.

PubMed

Mall, Marcus A; Graeber, Simon Y; Stahl, Mirjam; Zhou-Suckow, Zhe

2014-07-01

Cystic fibrosis (CF) lung disease starts in the first months of life and remains one of the most common fatal hereditary diseases. Early therapeutic interventions may provide an opportunity to prevent irreversible lung damage and improve outcome. Airway surface dehydration is a key disease mechanism in CF, however, its role in the in vivo pathogenesis and as therapeutic target in early lung disease remains poorly understood. Mice with airway-specific overexpression of the epithelial Na(+) channel (βENaC-Tg) recapitulate airway surface dehydration and phenocopy CF lung disease. Recent studies in neonatal βENaC-Tg mice demonstrated that airway surface dehydration produces early mucus plugging in the absence of mucus hypersecretion, which triggers airway inflammation, promotes bacterial infection and causes early mortality. Preventive rehydration therapy with hypertonic saline or amiloride effectively reduced mucus plugging and mortality in neonatal βENaC-Tg mice. These results support clinical testing of preventive/early rehydration strategies in infants and young children with CF. Copyright © 2014 Elsevier Ltd. All rights reserved.

Changes in insomnia subtypes in early Parkinson disease.

PubMed

Tholfsen, Lena K; Larsen, Jan P; Schulz, Jörn; Tysnes, Ole-Bjørn; Gjerstad, Michaela D

2017-01-24

To examine the development of factors associated with insomnia in a cohort of originally drug-naive patients with incident Parkinson disease (PD) during the first 5 years after diagnosis. One hundred eighty-two drug-naive patients with PD derived from a population-based incident cohort and 202 control participants were assessed for insomnia before treatment initiation and were repeatedly examined after 1, 3, and 5 years. Insomnia was diagnosed according to the Stavanger Sleepiness Questionnaire. The Parkinson's Disease Sleep Scale was used to differentiate sleep initiation problems from problems of sleep maintenance. Generalized estimating equation models were applied for statistical measures. The prevalence of insomnia in general was not higher in patients with PD compared to controls at the 5-year follow-up. There were changes in the prevalence of the different insomnia subtypes over the 5-year follow-up. The prevalence of solitary problems in sleep maintenance increased from 31% (n = 18) in the drug-naive patients at baseline to 49% (n = 29) after 1 year and were associated with the use of dopamine agonists and higher Montgomery-Åsberg Depression Rating Scale scores. The prevalence of solitary sleep initiation problems decreased continuously from 21% (n = 12) at baseline to 7.4% (n = 4) after 5 years; these were associated with less daytime sleepiness. The prevalence rates of the different insomnia subtypes changed notably in patients with early PD. The frequency of sleep maintenance problems increased, and these problems were associated with dopamine agonist use and depressive symptoms, while the total number of patients with insomnia remained stable. Our findings reflect the need for early individual assessments of insomnia subtypes and raise the possibility of intervention to reduce these symptoms in patients with early PD. © 2016 American Academy of Neurology.

Early childhood caries: risk-based disease prevention and management.

PubMed

Ng, Man Wai; Chase, Isabelle

2013-01-01

Early childhood caries (ECC), common in preschoolers, can lead to pain and infection if left untreated. Yet, ECC is largely preventable, and if it is identified early and the responsible risk factors are addressed, its progression can be halted or slowed. This article reviews the rationale for a first dental visit by age 1 year, caries risk assessment, and risk-based prevention and management of ECC and discusses strategies for providers to implement these contemporary evidence-based concepts into clinical practice. Copyright © 2013 Elsevier Inc. All rights reserved.

Subjective experiences of an art museum engagement activity for persons with early-stage Alzheimer's disease and their family caregivers.

PubMed

Flatt, Jason D; Liptak, Amy; Oakley, Mary Ann; Gogan, Jessica; Varner, Tresa; Lingler, Jennifer H

2015-06-01

To describe the subjective experiences of older adults with early-stage Alzheimer's disease or related cognitive disorders (ADRDs) and their family caregivers who participated in an art museum engagement activity. Four focus groups were conducted with 10 persons with ADRD and 10 family caregivers following the completion of a 1-time, 3-hour engagement activity. Participants also completed a brief satisfaction survey, and associations were examined using nonparametric statistics. Three key themes were identified: cognitive stimulation, social connections, and self-esteem. In addition, we identified programmatic issues such as activity-specific concerns and program logistics that could help improve future art program offerings. Past experience with art and perceived social cohesion were correlated with participants' overall satisfaction with the program. Efforts aimed at improving the quality of life of those with Alzheimer's disease and their family caregivers should consider the potential role of art museums. © The Author(s) 2014.

An extended set of yeast-based functional assays accurately identifies human disease mutations

PubMed Central

Sun, Song; Yang, Fan; Tan, Guihong; Costanzo, Michael; Oughtred, Rose; Hirschman, Jodi; Theesfeld, Chandra L.; Bansal, Pritpal; Sahni, Nidhi; Yi, Song; Yu, Analyn; Tyagi, Tanya; Tie, Cathy; Hill, David E.; Vidal, Marc; Andrews, Brenda J.; Boone, Charles; Dolinski, Kara; Roth, Frederick P.

2016-01-01

We can now routinely identify coding variants within individual human genomes. A pressing challenge is to determine which variants disrupt the function of disease-associated genes. Both experimental and computational methods exist to predict pathogenicity of human genetic variation. However, a systematic performance comparison between them has been lacking. Therefore, we developed and exploited a panel of 26 yeast-based functional complementation assays to measure the impact of 179 variants (101 disease- and 78 non-disease-associated variants) from 22 human disease genes. Using the resulting reference standard, we show that experimental functional assays in a 1-billion-year diverged model organism can identify pathogenic alleles with significantly higher precision and specificity than current computational methods. PMID:26975778

Exome Sequencing Frequently Reveals the Cause of Early-Onset Chronic Kidney Disease

PubMed Central

Vivante, Asaf; Hildebrandt, Friedhelm

2016-01-01

The primary causes of chronic kidney disease (CKD) in children differ from those of adult onset CKD. In the United States the most common diagnostic groups of CKD that manifests before 25 years of age are: i) congenital anomalies of the kidneys and urinary tract (CAKUT) (49.1%), ii) steroid-resistant nephrotic syndrome (SRNS) (10.4%), iii) chronic glomerulonephritis (8.1%), and iv) renal cystic ciliopathies (5.3 %), encompassing >70% of CKD together. Recent findings suggest that early-onset CKD is caused by mutations in any one of over 200 different monogenic genes. High-throughput sequencing has very recently rendered identification of causative mutations in this high number of genes feasible. Molecular genetic diagnostics in early onset-CKD (before the age of 25 years) will, i) provide patients and families with a molecular genetic diagnosis, ii) generate new insights into diseases mechanisms, iii) allow etiology-based classification of patient cohorts for clinical studies and, iv) may have consequences for personalized treatment and prevention of CKD. In this review, we will discuss the implications of next-generation sequencing for clinical genetic diagnostics and discovery of novel genes in early-onset CKD. We also delineate the resulting opportunities for deciphering disease mechanisms and therapeutic implications. PMID:26750453

Biomechanical and morphological multi-parameter photoacoustic endoscope for identification of early esophageal disease

NASA Astrophysics Data System (ADS)

Jin, Dayang; Yang, Fen; Chen, Zhongjiang; Yang, Sihua; Xing, Da

2017-09-01

The combination of phase-sensitive photoacoustic (PA) imaging of tissue viscoelasticity with the esophagus-adaptive PA endoscope (PAE) technique allows the characterization of the biomechanical and morphological changes in the early stage of esophageal disease with high accuracy. In this system, the tissue biomechanics and morphology are obtained by detecting the PA phase and PA amplitude information, respectively. The PAE has a transverse resolution of approximately 37 μm and an outer diameter of 1.2 mm, which is suitable for detecting rabbit esophagus. Here, an in-situ biomechanical and morphological study of normal and diseased rabbit esophagus (tumors of esophagus and reflux esophagitis) was performed. The in-situ findings were highly consistent with those observed by histology. In summary, we demonstrated the potential application of PAE for early clinical detection of esophageal diseases.

Method for early detection of infectious mononucleosis by identifying inmono proteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Willard, K. E.

1984-10-02

Early detection of infectious mononucleosis is carried out using a sample of human blood by isolating and identifying the presence of Inmono proteins in the sample from a two-dimensional protein map with the proteins being characterized by having isoelectric banding as measured in urea of about -16 to -17 with respect to certain isoelectric point standards and molecular mass of about 70 to 75 K daltons as measured in the presence of sodium dodecylsulfate containing polyacrylamide gels, the presence of the Inmono proteins being correlated with the existence of infectious mononucleosis.

Method for early detection of infectious mononucleosis by identifying Inmono proteins

DOEpatents

Willard, Karen E.

1984-01-01

Early detection of infectious mononucleosis is carried out using a sample of human blood by isolating and identifying the presence of Inmono proteins in the sample from a two-dimensional protein map with the proteins being characterized by having isoelectric banding as measured in urea of about -16 to -17 with respect to certain isoelectric point standards and molecular mass of about 70 to 75 K daltons as measured in the presence of sodium dodecylsulfate containing polyacrylamide gels, the presence of the Inmono proteins being correlated with the existence of infectious mononucleosis.

Subcortical grey matter changes in untreated, early stage Parkinson's disease without dementia.

PubMed

Lee, Hye Mi; Kwon, Kyum-Yil; Kim, Min-Jik; Jang, Ji-Wan; Suh, Sang-Il; Koh, Seong-Beom; Kim, Ji Hyun

2014-06-01

Previous MRI studies have investigated cortical or subcortical grey matter changes in patients with Parkinson's disease (PD), yielding inconsistent findings between the studies. We therefore sought to determine whether focal cortical or subcortical grey matter changes may be present from the early disease stage. We recruited 49 untreated, early stage PD patients without dementia and 53 control subjects. Voxel-based morphometry was used to evaluate cortical grey matter changes, and automated volumetry and shape analysis were used to assess volume changes and shape deformation of the subcortical grey matter structures, respectively. Voxel-based morphometry showed neither reductions nor increases in grey matter volume in patients compared to controls. Compared to controls, PD patients had significant reductions in adjusted volumes of putamen, nucleus accumbens, and hippocampus (corrected p < 0.05). Vertex-based shape analysis showed regionally contracted area on the posterolateral and ventromedial putamen bilaterally in PD patients (corrected p < 0.05). No correlations were found between cortical and subcortical grey matter and clinical variables representing disease duration and severity. Our results suggest that untreated, early stage PD without dementia is associated with volume reduction and shape deformation of subcortical grey matter, but not with cortical grey matter reduction. Our findings of structural changes in the posterolateral putamen and ventromedial putamen/nucleus accumbens could provide neuroanatomical basis for the involvement of motor and limbic striatum, further implicating motor and non-motor symptoms in PD, respectively. Early hippocampal involvement might be related to the risk for developing dementia in PD patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

Early versus delayed erythropoietin for the anaemia of end-stage kidney disease.

PubMed

Coronado Daza, Jorge; Martí-Carvajal, Arturo J; Ariza García, Amaury; Rodelo Ceballos, Joaquín; Yomayusa González, Nancy; Páez-Canro, Carol; Loza Munárriz, César; Urrútia, Gerard

2015-12-16

Anaemia is a common complication in people with chronic kidney disease (CKD) and mainly develops as a consequence of relative erythropoietin (EPO) deficiency. Anaemia develops early in the course of disease and peaks among people with end-stage kidney disease (ESKD). Many types of EPO - also called erythropoiesis-stimulating agents (ESAs) - are used to treat anaemia in people with ESKD.ESAs have changed treatment of severe anaemia among people with CKD by relieving symptoms and avoiding complications associated with blood transfusion. However, no benefits have been found in relation to mortality rates and non-cardiac fatal events, except quality of life. Moreover, a relationship between ESA use and increased cardiovascular morbidity and mortality in patients with CKD has been reported in studies with fully correcting anaemia comparing with partial anaemia correction. Until 2012, guidelines recommended commencing ESA treatment when haemoglobin was less than 11 g/dL; the current recommendation is EPO commencement when haemoglobin is between 9 and 10 g/dL. However, advantages in commencing therapy when haemoglobin levels are greater than 10 g/dL but less than 11 g/dL remain unknown, especially among older people whose life expectancy is limited, but in whom EPO therapy may improve quality of life. To assess the clinical benefits and harms of early versus delayed EPO for anaemia in patients with ESKD undergoing haemodialysis or peritoneal dialysis We searched the Cochrane Kidney and Transplant Specialised Register to 8 July 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. We planned to include randomised controlled trials (RCTs) and quasi-RCTs evaluating at the clinical benefits and harms of early versus delayed EPO for anaemia in patients with ESKD undergoing haemodialysis or peritoneal dialysis. Studies comparing EPO with another EPO, placebo or no treatment were eligible for inclusion. It was planned that two

Identifiability and estimation of multiple transmission pathways in cholera and waterborne disease.

PubMed

Eisenberg, Marisa C; Robertson, Suzanne L; Tien, Joseph H

2013-05-07

Cholera and many waterborne diseases exhibit multiple characteristic timescales or pathways of infection, which can be modeled as direct and indirect transmission. A major public health issue for waterborne diseases involves understanding the modes of transmission in order to improve control and prevention strategies. An important epidemiological question is: given data for an outbreak, can we determine the role and relative importance of direct vs. environmental/waterborne routes of transmission? We examine whether parameters for a differential equation model of waterborne disease transmission dynamics can be identified, both in the ideal setting of noise-free data (structural identifiability) and in the more realistic setting in the presence of noise (practical identifiability). We used a differential algebra approach together with several numerical approaches, with a particular emphasis on identifiability of the transmission rates. To examine these issues in a practical public health context, we apply the model to a recent cholera outbreak in Angola (2006). Our results show that the model parameters-including both water and person-to-person transmission routes-are globally structurally identifiable, although they become unidentifiable when the environmental transmission timescale is fast. Even for water dynamics within the identifiable range, when noisy data are considered, only a combination of the water transmission parameters can practically be estimated. This makes the waterborne transmission parameters difficult to estimate, leading to inaccurate estimates of important epidemiological parameters such as the basic reproduction number (R0). However, measurements of pathogen persistence time in environmental water sources or measurements of pathogen concentration in the water can improve model identifiability and allow for more accurate estimation of waterborne transmission pathway parameters as well as R0. Parameter estimates for the Angola outbreak suggest

RED Alert – Early warning or detection of global re-emerging infectious disease (RED)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deshpande, Alina

This is the PDF of a presentation for a webinar given by Los Alamos National Laboratory (LANL) on the early warning or detection of global re-emerging infectious disease (RED). First, there is an overview of LANL biosurveillance tools. Then, information is given about RED Alert. Next, a demonstration is given of a component prototype. RED Alert is an analysis tool that can provide early warning or detection of the re-emergence of an infectious disease at the global level, but through a local lens.

A de novo whole gene deletion of XIAP detected by exome sequencing analysis in very early onset inflammatory bowel disease: a case report.

PubMed

Kelsen, Judith R; Dawany, Noor; Martinez, Alejandro; Martinez, Alejuandro; Grochowski, Christopher M; Maurer, Kelly; Rappaport, Eric; Piccoli, David A; Baldassano, Robert N; Mamula, Petar; Sullivan, Kathleen E; Devoto, Marcella

2015-11-18

Children with very early-onset inflammatory bowel disease (VEO-IBD), those diagnosed at less than 5 years of age, are a unique population. A subset of these patients present with a distinct phenotype and more severe disease than older children and adults. Host genetics is thought to play a more prominent role in this young population, and monogenic defects in genes related to primary immunodeficiencies are responsible for the disease in a small subset of patients with VEO-IBD. We report a child who presented at 3 weeks of life with very early-onset inflammatory bowel disease (VEO-IBD). He had a complicated disease course and remained unresponsive to medical and surgical therapy. The refractory nature of his disease, together with his young age of presentation, prompted utilization of whole exome sequencing (WES) to detect an underlying monogenic primary immunodeficiency and potentially target therapy to the identified defect. Copy number variation analysis (CNV) was performed using the eXome-Hidden Markov Model. Whole exome sequencing revealed 1,380 nonsense and missense variants in the patient. Plausible candidate variants were not detected following analysis of filtered variants, therefore, we performed CNV analysis of the WES data, which led us to identify a de novo whole gene deletion in XIAP. This is the first reported whole gene deletion in XIAP, the causal gene responsible for XLP2 (X-linked lymphoproliferative Disease 2). XLP2 is a syndrome resulting in VEO-IBD and can increase susceptibility to hemophagocytic lymphohistocytosis (HLH). This identification allowed the patient to be referred for bone marrow transplantation, potentially curative for his disease and critical to prevent the catastrophic sequela of HLH. This illustrates the unique etiology of VEO-IBD, and the subsequent effects on therapeutic options. This cohort requires careful and thorough evaluation for monogenic defects and primary immunodeficiencies.

Major Depressive Disorder and Bipolar Disorder Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease: A Scientific Statement From the American Heart Association.

PubMed

Goldstein, Benjamin I; Carnethon, Mercedes R; Matthews, Karen A; McIntyre, Roger S; Miller, Gregory E; Raghuveer, Geetha; Stoney, Catherine M; Wasiak, Hank; McCrindle, Brian W

2015-09-08

In the 2011 "Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents," several medical conditions among youth were identified that predispose to accelerated atherosclerosis and early cardiovascular disease (CVD), and risk stratification and management strategies for youth with these conditions were elaborated. Major depressive disorder (MDD) and bipolar disorder (BD) among youth satisfy the criteria set for, and therefore merit inclusion among, Expert Panel tier II moderate-risk conditions. The combined prevalence of MDD and BD among adolescents in the United States is ≈10%, at least 10 times greater than the prevalence of the existing moderate-risk conditions combined. The high prevalence of MDD and BD underscores the importance of positioning these diseases alongside other pediatric diseases previously identified as moderate risk for CVD. The overall objective of this statement is to increase awareness and recognition of MDD and BD among youth as moderate-risk conditions for early CVD. To achieve this objective, the primary specific aims of this statement are to (1) summarize evidence that MDD and BD are tier II moderate-risk conditions associated with accelerated atherosclerosis and early CVD and (2) position MDD and BD as tier II moderate-risk conditions that require the application of risk stratification and management strategies in accordance with Expert Panel recommendations. In this scientific statement, there is an integration of the various factors that putatively underlie the association of MDD and BD with CVD, including pathophysiological mechanisms, traditional CVD risk factors, behavioral and environmental factors, and psychiatric medications. © 2015 American Heart Association, Inc.

Early Developmental Conditioning of Later Health and Disease: Physiology or Pathophysiology?

PubMed Central

Hanson, M. A.; Gluckman, P. D.

2014-01-01

Extensive experimental animal studies and epidemiological observations have shown that environmental influences during early development affect the risk of later pathophysiological processes associated with chronic, especially noncommunicable, disease (NCD). This field is recognized as the developmental origins of health and disease (DOHaD). We discuss the extent to which DOHaD represents the result of the physiological processes of developmental plasticity, which may have potential adverse consequences in terms of NCD risk later, or whether it is the manifestation of pathophysiological processes acting in early life but only becoming apparent as disease later. We argue that the evidence suggests the former, through the operation of conditioning processes induced across the normal range of developmental environments, and we summarize current knowledge of the physiological processes involved. The adaptive pathway to later risk accords with current concepts in evolutionary developmental biology, especially those concerning parental effects. Outside the normal range, effects on development can result in nonadaptive processes, and we review their underlying mechanisms and consequences. New concepts concerning the underlying epigenetic and other mechanisms involved in both disruptive and nondisruptive pathways to disease are reviewed, including the evidence for transgenerational passage of risk from both maternal and paternal lines. These concepts have wider implications for understanding the causes and possible prevention of NCDs such as type 2 diabetes and cardiovascular disease, for broader social policy and for the increasing attention paid in public health to the lifecourse approach to NCD prevention. PMID:25287859

microRNA expression profiling on individual breast cancer patients identifies novel panel of circulating microRNA for early detection.

PubMed

Hamam, Rimi; Ali, Arwa M; Alsaleh, Khalid A; Kassem, Moustapha; Alfayez, Musaed; Aldahmash, Abdullah; Alajez, Nehad M

2016-05-16

Breast cancer (BC) is the most common cancer type and the second cause of cancer-related death among women. Therefore, better understanding of breast cancer tumor biology and the identification of novel biomarkers is essential for the early diagnosis and for better disease stratification and management choices. Herein we developed a novel approach which relies on the isolation of circulating microRNAs through an enrichment step using speed-vacuum concentration which resulted in 5-fold increase in microRNA abundance. Global miRNA microarray expression profiling performed on individual samples from 23 BC and 9 normals identified 18 up-regulated miRNAs in BC patients (p(corr) < 0.05). Nine miRNAs (hsa-miR-4270, hsa-miR-1225-5p, hsa-miR-188-5p, hsa-miR-1202, hsa-miR-4281, hsa-miR-1207-5p, hsa-miR-642b-3p, hsa-miR-1290, and hsa-miR-3141) were subsequently validated using qRT-PCR in a cohort of 46 BC and 14 controls. The expression of those microRNAs was overall higher in patients with stage I, II, and III, compared to stage IV, with potential utilization for early detection. The expression of this microRNA panel was slightly higher in the HER2 and TN compared to patients with luminal subtype. Therefore, we developed a novel approach which led to the identification of a novel microRNA panel which was upregulated in BC patients with potential utilization in disease diagnosis and stratification.

Recent advances in the diagnosis and treatment of niemann-pick disease type C in children: a guide to early diagnosis for the general pediatrician.

PubMed

Alobaidy, Hanna

2015-01-01

Niemann-Pick disease (NP-C) is a lysosomal storage disease in which impaired intracellular lipid transport leads to accumulation of cholesterol and glycosphingolipids in various neurovisceral tissues. It is an autosomal recessive disorder, caused by mutations in the NPC1 or NPC2 genes. The clinical spectrum is grouped by the age of onset and onset of neurological manifestation: pre/perinatal; early infantile; late infantile; and juvenile periods. The NP-C Suspicion Index (SI) screening tool was developed to identify suspected patients with this disease. It is especially good at recognizing the disease in patients older than four years of age. Biochemical tests involving genetic markers and Filipin staining of skin fibroblast are being employed to assist diagnosis. Therapy is mostly supportive and since 2009, the first specific therapy approved for use was Miglustat (Zavesca) aimed at stabilizing the rate of progression of neurological manifestation. The prognosis correlates with age at onset of neurological signs; patients with early onset form progress faster. The NP-C disease has heterogeneous neurovisceral manifestations. A SI is a screening tool that helps in diagnostic process. Filipin staining test is a specific biomarker diagnostic test. Miglustat is the first disease-specific therapy.

The management of patients with early Parkinson's disease.

PubMed

Rascol, O; Payoux, P; Ferreira, J; Brefel-Courbon, C

2002-10-01

A major problem in the management of early Parkinson's disease is to choose the first medication to prescribe. This decision should rely on the level of available clinical evidence, largely based, at least for efficacy, on the results of randomised clinical trials. Safety and costs are also crucial to consider. Other factors like for example pathophysiological concepts, individual experience, marketing pressure, socio-economical environment, patients needs and expectations have, however, also their own influence. Levodopa is efficacious and cheap, but induces long-term motor complications. The early use of dopamine agonists is more and more frequently promoted, because large prospective L-dopa-controlled trials demonstrated that this strategy reduces the risk of such long-term complications. Integrating individual clinical expertise to the best available external clinical evidence (evidence-based medicine) is the best strategy in making decisions about the care of individual patients. Copyright 2002 Elsevier Science Ltd.

Lung Cancer Workshop XI: Tobacco-Induced Disease: Advances in Policy, Early Detection and Management.

PubMed

Mulshine, James L; Avila, Rick; Yankelevitz, David; Baer, Thomas M; Estépar, Raul San Jose; Ambrose, Laurie Fenton; Aldigé, Carolyn R

2015-05-01

The Prevent Cancer Foundation Lung Cancer Workshop XI: Tobacco-Induced Disease: Advances in Policy, Early Detection and Management was held in New York, NY on May 16 and 17, 2014. The two goals of the Workshop were to define strategies to drive innovation in precompetitive quantitative research on the use of imaging to assess new therapies for management of early lung cancer and to discuss a process to implement a national program to provide high quality computed tomography imaging for lung cancer and other tobacco-induced disease. With the central importance of computed tomography imaging for both early detection and volumetric lung cancer assessment, strategic issues around the development of imaging and ensuring its quality are critical to ensure continued progress against this most lethal cancer.

MicroRNAs and Target Genes As Biomarkers for the Diagnosis of Early Onset of Parkinson Disease

PubMed Central

Arshad, Ahmad R.; Sulaiman, Siti A.; Saperi, Amalia A.; Jamal, Rahman; Mohamed Ibrahim, Norlinah; Abdul Murad, Nor Azian

2017-01-01

Among the neurodegenerative disorders, Parkinson's disease (PD) ranks as the second most common disorder with a higher prevalence in individuals aged over 60 years old. Younger individuals may also be affected with PD which is known as early onset PD (EOPD). Despite similarities between the characteristics of EOPD and late onset PD (LODP), EOPD patients experience much longer disease manifestations and poorer quality of life. Although some individuals are more prone to have EOPD due to certain genetic alterations, the molecular mechanisms that differentiate between EOPD and LOPD remains unclear. Recent findings in PD patients revealed that there were differences in the genetic profiles of PD patients compared to healthy controls, as well as between EOPD and LOPD patients. There were variants identified that correlated with the decline of cognitive and motor symptoms as well as non-motor symptoms in PD. There were also specific microRNAs that correlated with PD progression, and since microRNAs have been shown to be involved in the maintenance of neuronal development, mitochondrial dysfunction and oxidative stress, there is a strong possibility that these microRNAs can be potentially used to differentiate between subsets of PD patients. PD is mainly diagnosed at the late stage, when almost majority of the dopaminergic neurons are lost. Therefore, identification of molecular biomarkers for early detection of PD is important. Given that miRNAs are crucial in controlling the gene expression, these regulatory microRNAs and their target genes could be used as biomarkers for early diagnosis of PD. In this article, we discussed the genes involved and their regulatory miRNAs, regarding their roles in PD progression, based on the findings of significantly altered microRNAs in EOPD studies. We also discussed the potential of these miRNAs as molecular biomarkers for early diagnosis. PMID:29163029

Meta-analytic framework for sparse K-means to identify disease subtypes in multiple transcriptomic studies

PubMed Central

Huo, Zhiguang; Ding, Ying; Liu, Silvia; Oesterreich, Steffi; Tseng, George

2016-01-01

Disease phenotyping by omics data has become a popular approach that potentially can lead to better personalized treatment. Identifying disease subtypes via unsupervised machine learning is the first step towards this goal. In this paper, we extend a sparse K-means method towards a meta-analytic framework to identify novel disease subtypes when expression profiles of multiple cohorts are available. The lasso regularization and meta-analysis identify a unique set of gene features for subtype characterization. An additional pattern matching reward function guarantees consistent subtype signatures across studies. The method was evaluated by simulations and leukemia and breast cancer data sets. The identified disease subtypes from meta-analysis were characterized with improved accuracy and stability compared to single study analysis. The breast cancer model was applied to an independent METABRIC dataset and generated improved survival difference between subtypes. These results provide a basis for diagnosis and development of targeted treatments for disease subgroups. PMID:27330233

Meta-analytic framework for sparse K-means to identify disease subtypes in multiple transcriptomic studies.

PubMed

Huo, Zhiguang; Ding, Ying; Liu, Silvia; Oesterreich, Steffi; Tseng, George

Disease phenotyping by omics data has become a popular approach that potentially can lead to better personalized treatment. Identifying disease subtypes via unsupervised machine learning is the first step towards this goal. In this paper, we extend a sparse K -means method towards a meta-analytic framework to identify novel disease subtypes when expression profiles of multiple cohorts are available. The lasso regularization and meta-analysis identify a unique set of gene features for subtype characterization. An additional pattern matching reward function guarantees consistent subtype signatures across studies. The method was evaluated by simulations and leukemia and breast cancer data sets. The identified disease subtypes from meta-analysis were characterized with improved accuracy and stability compared to single study analysis. The breast cancer model was applied to an independent METABRIC dataset and generated improved survival difference between subtypes. These results provide a basis for diagnosis and development of targeted treatments for disease subgroups.

Voluntary pulmonary function screening identifies high rates of undiagnosed asymptomatic chronic obstructive pulmonary disease.

PubMed

Wang, Shengyu; Gong, Wei; Tian, Yao

2016-05-01

Chronic obstructive pulmonary disease (COPD) is projected to be the third leading cause of death by 2020. Early detection and screening may alter the course and prognosis associated with lung disease. We investigated the effectiveness of a voluntary public lung function screening program and factors that had a predictive value for asymptomatic COPD in Xi'an, China. Pulmonary function testing (PFT) was conducted on volunteers recruited from four community centers in Xi'an, China, between July and August 2012. Participants underwent three forced vital capacity maneuvers. The maneuver with the best forced expiratory volume in first second was retained. Participants filled out a medical history and environmental exposure survey before undergoing the PFT. Patients who self-reported lung disease on the health survey were excluded from the analysis. Logistical regression was used to determine associations with airway obstruction. A total of 803 volunteers participated in this study, and 33 subjects were excluded as the participants did not meet the requirements of PFT. Of the 770 volunteers, 44 participants had been diagnosed with chronic respiratory diseases previously, and 144 participants (18.7%) met COPD criteria. Four hundred forty-four participants did not self-report any respiratory symptoms, and the remaining 282 participants self-reported respiratory symptoms. Of the asymptomatic participants, 98 volunteers had PFT results that were consistent with COPD and 68.1% of asymptomatic participants were undiagnosed. A greater percentage of women than men had moderate or severe airway obstruction (p = 0.004).Only smoking status (odds ratio = 2.64, 95% confidence interval 1.20-6.04) was associated with asymptomatic COPD. Voluntary public lung function screening programs in China are likely to identify a large number of undiagnosed, asymptomatic COPD. Smoking status is associated with airway obstruction and a greater percentage of women than men had moderate or severe

PREDICT-PD: An online approach to prospectively identify risk indicators of Parkinson's disease.

PubMed

Noyce, Alastair J; R'Bibo, Lea; Peress, Luisa; Bestwick, Jonathan P; Adams-Carr, Kerala L; Mencacci, Niccolo E; Hawkes, Christopher H; Masters, Joseph M; Wood, Nicholas; Hardy, John; Giovannoni, Gavin; Lees, Andrew J; Schrag, Anette

2017-02-01

A number of early features can precede the diagnosis of Parkinson's disease (PD). To test an online, evidence-based algorithm to identify risk indicators of PD in the UK population. Participants aged 60 to 80 years without PD completed an online survey and keyboard-tapping task annually over 3 years, and underwent smell tests and genotyping for glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) mutations. Risk scores were calculated based on the results of a systematic review of risk factors and early features of PD, and individuals were grouped into higher (above 15th centile), medium, and lower risk groups (below 85th centile). Previously defined indicators of increased risk of PD ("intermediate markers"), including smell loss, rapid eye movement-sleep behavior disorder, and finger-tapping speed, and incident PD were used as outcomes. The correlation of risk scores with intermediate markers and movement of individuals between risk groups was assessed each year and prospectively. Exploratory Cox regression analyses with incident PD as the dependent variable were performed. A total of 1323 participants were recruited at baseline and >79% completed assessments each year. Annual risk scores were correlated with intermediate markers of PD each year and baseline scores were correlated with intermediate markers during follow-up (all P values < 0.001). Incident PD diagnoses during follow-up were significantly associated with baseline risk score (hazard ratio = 4.39, P = .045). GBA variants or G2019S LRRK2 mutations were found in 47 participants, and the predictive power for incident PD was improved by the addition of genetic variants to risk scores. The online PREDICT-PD algorithm is a unique and simple method to identify indicators of PD risk. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder

Gene expression profiling to identify the toxicities and potentially relevant human disease outcomes associated with environmental heavy metal exposure.

PubMed

Korashy, Hesham M; Attafi, Ibraheem M; Famulski, Konrad S; Bakheet, Saleh A; Hafez, Mohammed M; Alsaad, Abdulaziz M S; Al-Ghadeer, Abdul Rahman M

2017-02-01

Heavy metals are the most commonly encountered toxic substances that increase susceptibility to various diseases after prolonged exposure. We have previously shown that healthy volunteers living near a mining area had significant contamination with heavy metals associated with significant changes in the expression of some detoxifying genes, xenobiotic metabolizing enzymes, and DNA repair genes. However, alterations of most of the molecular target genes associated with diseases are still unknown. Thus, the aims of this study were to (a) evaluate the gene expression profile and (b) identify the toxicities and potentially relevant human disease outcomes associated with long-term human exposure to environmental heavy metals in mining area using microarray analysis. For this purpose, 40 healthy male volunteers who were residents of a heavy metal-polluted area (Mahd Al-Dhahab city, Saudi Arabia) and 20 healthy male volunteers who were residents of a non-heavy metal-polluted area were included in the study. Total RNA was isolated from whole blood using PAXgene Blood RNA tubes and then reversed transcribed and hybridized to the gene array using the Affymetrix U219 GeneChip. Microarray analysis showed about 2129 genes were identified and differentially altered, among which a shared set of 425 genes was differentially expressed in the heavy metal-exposed groups. Ingenuity pathway analysis revealed that the most altered gene-regulated diseases in heavy metal-exposed groups included hematological and developmental disorders and mostly renal and urological diseases. Quantitative real-time polymerase chain reaction closely matched the microarray data for some genes tested. Importantly, changes in gene-related diseases were attributed to alterations in the genes encoded for protein synthesis. Renal and urological diseases were the diseases that were most frequently associated with the heavy metal-exposed group. Therefore, there is a need for further studies to validate these

Serum Metabolomics to Identify the Liver Disease-Specific Biomarkers for the Progression of Hepatitis to Hepatocellular Carcinoma

NASA Astrophysics Data System (ADS)

Gao, Rong; Cheng, Jianhua; Fan, Chunlei; Shi, Xiaofeng; Cao, Yuan; Sun, Bo; Ding, Huiguo; Hu, Chengjin; Dong, Fangting; Yan, Xianzhong

2015-12-01

Hepatocellular carcinoma (HCC) is a common malignancy that has region specific etiologies. Unfortunately, 85% of cases of HCC are diagnosed at an advanced stage. Reliable biomarkers for the early diagnosis of HCC are urgently required to reduced mortality and therapeutic expenditure. We established a non-targeted gas chromatography-time of flight-mass spectrometry (GC-TOFMS) metabolomics method in conjunction with Random Forests (RF) analysis based on 201 serum samples from healthy controls (NC), hepatitis B virus (HBV), liver cirrhosis (LC) and HCC patients to explore the metabolic characteristics in the progression of hepatocellular carcinogenesis. Ultimately, 15 metabolites were identified intimately associated with the process. Phenylalanine, malic acid and 5-methoxytryptamine for HBV vs. NC, palmitic acid for LC vs. HBV, and asparagine and β-glutamate for HCC vs. LC were screened as the liver disease-specific potential biomarkers with an excellent discriminant performance. All the metabolic perturbations in these liver diseases are associated with pathways for energy metabolism, macromolecular synthesis, and maintaining the redox balance to protect tumor cells from oxidative stress.

Microbiome Networks: A Systems Framework for Identifying Candidate Microbial Assemblages for Disease Management.

PubMed

Poudel, R; Jumpponen, A; Schlatter, D C; Paulitz, T C; Gardener, B B McSpadden; Kinkel, L L; Garrett, K A

2016-10-01

Network models of soil and plant microbiomes provide new opportunities for enhancing disease management, but also challenges for interpretation. We present a framework for interpreting microbiome networks, illustrating how observed network structures can be used to generate testable hypotheses about candidate microbes affecting plant health. The framework includes four types of network analyses. "General network analysis" identifies candidate taxa for maintaining an existing microbial community. "Host-focused analysis" includes a node representing a plant response such as yield, identifying taxa with direct or indirect associations with that node. "Pathogen-focused analysis" identifies taxa with direct or indirect associations with taxa known a priori as pathogens. "Disease-focused analysis" identifies taxa associated with disease. Positive direct or indirect associations with desirable outcomes, or negative associations with undesirable outcomes, indicate candidate taxa. Network analysis provides characterization not only of taxa with direct associations with important outcomes such as disease suppression, biofertilization, or expression of plant host resistance, but also taxa with indirect associations via their association with other key taxa. We illustrate the interpretation of network structure with analyses of microbiomes in the oak phyllosphere, and in wheat rhizosphere and bulk soil associated with the presence or absence of infection by Rhizoctonia solani.

Pathological conformations involving the amino terminus of tau occur early in Alzheimer’s disease and are differentially detected by monoclonal antibodies

PubMed Central

Combs, Benjamin; Hamel, Chelsey; Kanaan, Nicholas M.

2016-01-01

Conformational changes involving the amino terminus of the tau protein are among the earliest alterations associated with tau pathology in Alzheimer’s disease and other tauopathies. This region of tau contains a phosphatase-activating domain (PAD) that is aberrantly exposed in pathological forms of the protein, an event that is associated with disruptions in anterograde fast axonal transport. We utilized four antibodies that recognize the amino terminus of tau, TNT1, TNT2 (a novel antibody), Tau12, and Tau13, to further study this important region. Using scanning alanine mutations in recombinant tau proteins, we refined the epitopes of each antibody. We examined the antibodies’ relative abilities to specifically label pathological tau in non-denaturing and denaturing assays to gain insight into some of the mechanistic details of PAD exposure. We then determined the pattern of tau pathology labeled by each antibody in human hippocampal sections at various disease stages in order to characterize PAD exposure in the context of disease progression. The characteristics of reactivity for the antibodies fell into two groups. TNT1 and TNT2 recognized epitopes within amino acids 7–12 and specifically identified recombinant tau aggregates and pathological tau from Alzheimer’s disease brains in a conformation-dependent manner. These antibodies labeled early pre-tangle pathology from neurons in early Braak stages and colocalized with thiazine red, a marker of fibrillar pathology, in classic neurofibrillary tangles. However, late tangles were negative for TNT1 and TNT2 indicating a loss of the epitope in later stages of tangle evolution. In contrast, Tau12 and Tau13 both identified discontinuous epitopes in the amino terminus and were unable to differentiate between normal and pathological tau in biochemical and tissue immunohistological assays. Despite the close proximity of these epitopes, the antibodies demonstrated remarkably different abilities to identify

Verbal and visual memory in patients with early Parkinson's disease: effect of levodopa.

PubMed

Singh, Sumit; Behari, Madhuri

2006-03-01

The effect of initiation of levodopa therapy on the memory functions in patients with Parkinson's disease remains poorly understood. To evaluate the effect of initiation of levodopa therapy on memory, in patients with early Parkinson's disease. Prospective case control study. Seventeen patients with early Parkinson's disease were evaluated for verbal memory using Rey's auditory verbal learning test, and visual memory using the Benton's visual retention test and Form sequence learning test. UPDRS scores, Hoehn and Yahr's Staging and Schwab and England scores of Activities of daily living. Hamilton's depression rating scale and MMSE were also evaluated. Six controls were also evaluated according to similar study protocol. Levodopa was then prescribed to the cases. Same tests were repeated on all the subjects after 12 weeks. The mean age of the patients was 59.8 (+ 12.9 yrs); mean disease duration of 3.26 (+ 2.06 yrs). The mean UPDRS scores of patients were 36.52 (+ 15.84). Controls were of a similar age and sex distribution. A statistically significant improvement in the scores on the UPDRS, Hamilton's depression scale, Schwab and England scale, and a statistically significant deterioration in the scores of visual memory was observed in patients with PD after starting levodopa, as compared to their baseline scores. There was no correlation between degree of deterioration and the dose of levodopa. Initiation of levodopa therapy in patients with early and stable Parkinson's disease is associated with deterioration in visual memory functions, with relative preservation of the verbal memory.

Nocturnal Hypoglycemia Identified by a Continuous Glucose Monitoring System in Patients with Primary Adrenal Insufficiency (Addison's Disease)

PubMed Central

Hackemann, Annika; Reusch, Juergen; Badenhoop, Klaus

2012-01-01

Abstract Background Hypoglycemia can be a symptom in patients with Addison's disease. The common regimen of replacement therapy with oral glucocorticoids results in unphysiological low cortisol levels in the early morning, the time of highest insulin sensitivity. Therefore patients with Addison's disease are at risk for unrecognized and potentially severe nocturnal hypoglycemia also because of a disturbed counterregulatory function. Use of a continuous glucose monitoring system (CGMS) could help to adjust hydrocortisone treatment and to avoid nocturnal hypoglycemia in these patients. Methods Thirteen patients with Addison's disease were screened for hypoglycemia wearing a CGMS for 3–5 days. Results In one patient we identified a hypoglycemic episode at 3:45 a.m. with a blood glucose level of 46 mg/dL, clearly beneath the 95% tolerance interval of minimal glucose levels between 2 and 4 a.m. (53.84 mg/dL). After the hydrocortisone replacement scheme was changed, the minimum blood glucose level between 2 and 4 a.m. normalized to 87 mg/dL. Conclusions Continuous glucose monitoring can detect nocturnal hypoglycemia in patients with primary adrenal insufficiency and hence prevent in these patients an impaired quality of life and even serious adverse effects. PMID:22242902

Quantitative acoustic measurements for characterization of speech and voice disorders in early untreated Parkinson's disease.

PubMed

Rusz, J; Cmejla, R; Ruzickova, H; Ruzicka, E

2011-01-01

An assessment of vocal impairment is presented for separating healthy people from persons with early untreated Parkinson's disease (PD). This study's main purpose was to (a) determine whether voice and speech disorder are present from early stages of PD before starting dopaminergic pharmacotherapy, (b) ascertain the specific characteristics of the PD-related vocal impairment, (c) identify PD-related acoustic signatures for the major part of traditional clinically used measurement methods with respect to their automatic assessment, and (d) design new automatic measurement methods of articulation. The varied speech data were collected from 46 Czech native speakers, 23 with PD. Subsequently, 19 representative measurements were pre-selected, and Wald sequential analysis was then applied to assess the efficiency of each measure and the extent of vocal impairment of each subject. It was found that measurement of the fundamental frequency variations applied to two selected tasks was the best method for separating healthy from PD subjects. On the basis of objective acoustic measures, statistical decision-making theory, and validation from practicing speech therapists, it has been demonstrated that 78% of early untreated PD subjects indicate some form of vocal impairment. The speech defects thus uncovered differ individually in various characteristics including phonation, articulation, and prosody.

Implementation of Nearest Neighbor using HSV to Identify Skin Disease

NASA Astrophysics Data System (ADS)

Gerhana, Y. A.; Zulfikar, W. B.; Ramdani, A. H.; Ramdhani, M. A.

2018-01-01

Today, Android is one of the most widely used operating system in the world. Most of android device has a camera that could capture an image, this feature could be optimized to identify skin disease. The disease is one of health problem caused by bacterium, fungi, and virus. The symptoms of skin disease usually visible. In this work, the symptoms that captured as image contains HSV in every pixel of the image. HSV can extracted and then calculate to earn euclidean value. The value compared using nearest neighbor algorithm to discover closer value between image testing and image training to get highest value that decide class label or type of skin disease. The testing result show that 166 of 200 or about 80% is accurate. There are some reasons that influence the result of classification model like number of image training and quality of android device’s camera.

Exome Sequencing Identified a Recessive RDH12 Mutation in a Family with Severe Early-Onset Retinitis Pigmentosa

PubMed Central

Gong, Bo; Wei, Bo; Huang, Lulin; Hao, Jilong; Li, Xiulan; Yang, Yin; Zhou, Yu; Hao, Fang; Cui, Zhihua; Zhang, Dingding; Wang, Le

2015-01-01

Retinitis pigmentosa (RP) is the most important hereditary retinal disease caused by progressive degeneration of the photoreceptor cells. This study is to identify gene mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in a Chinese family using next-generation sequencing technology. A Chinese family with 7 members including two individuals affected with severe early-onset RP was studied. All patients underwent a complete ophthalmic examination. Exome sequencing was performed on a single RP patient (the proband of this family) and direct Sanger sequencing on other family members and normal controls was followed to confirm the causal mutations. A homozygous mutation c.437Tidentified as being related to the phenotype of this arRP family. This homozygous mutation was detected in the two affected patients, but not present in other family members and 600 normal controls. Another three normal members in the family were found to carry this heterozygous missense mutation. Our results emphasize the importance of c.437T

Are Upper-Body Axial Symptoms a Feature of Early Parkinson’s Disease?

PubMed Central

Moreau, Caroline; Baille, Guillaume; Delval, Arnaud; Tard, Céline; Perez, Thierry; Danel-Buhl, Nicolas; Seguy, David; Labreuche, Julien; Duhamel, Alain; Delliaux, Marie; Dujardin, Kathy; Defebvre, Luc

2016-01-01

Background Axial disorders are considered to appear late in the course of Parkinson’s disease (PD). The associated impact on quality of life (QoL) and survival and the lack of an effective treatment mean that understanding and treating axial disorders is a key challenge. However, upper-body axial disorders (namely dysarthria, swallowing and breathing disorders) have never been prospectively assessed in early-stage PD patients. Objectives To characterize upper-body axial symptoms and QoL in consecutive patients with early-stage PD. Methods We prospectively enrolled 66 consecutive patients with early-stage PD (less than 3 years of disease progression) and assessed dysarthria, dysphagia and respiratory function (relative to 36 controls) using both objective and patient-reported outcomes. Results The mean disease duration was 1.26 years and the mean UPDRS motor score was 19.4 out of 108. 74% of the patients presented slight dysarthria (primarily dysprosodia). Men appeared to be more severely affected (i.e. dysphonia). This dysfunction was strongly correlated with low swallowing speed (despite the absence of complaints about dysphagia), respiratory insufficiency and poor QoL. Videofluorography showed that oral-phase swallowing disorders affected 60% of the 31 tested patients and that pharyngeal-phase disorders affected 21%. 24% of the patients reported occasional dyspnea, which was correlated with anxiety in women but not in men. Marked diaphragmatic dysfunction was suspected in 42% of the patients (predominantly in men). Conclusion Upper body axial symptoms were frequent in men with early-stage PD, whereas women presented worst non-motor impairments. New assessment methods are required because currently available tools do not reliably detect these upper-body axial disorders. PMID:27654040

YAC128 Huntington's disease transgenic mice show enhanced short-term hippocampal synaptic plasticity early in the course of the disease.

PubMed

Ghilan, Mohamed; Bostrom, Crystal A; Hryciw, Brett N; Simpson, Jessica M; Christie, Brian R; Gil-Mohapel, Joana

2014-09-18

Huntington's disease (HD) is a progressive and fatal neurodegenerative disorder caused by a polyglutamine expansion in the gene encoding the protein huntingtin. The disease progresses over decades, but often patients develop cognitive impairments that precede the onset of the classical motor symptoms. Similar to the disease progression in humans, the yeast artificial chromosome (YAC) 128 HD mouse model also exhibits cognitive dysfunction that precedes the onset of the neuropathological and motor impairments characteristic of HD. Thus, the purpose of this study was to evaluate whether short- and long-term synaptic plasticity in the hippocampus, two related biological models of learning and memory processes, were altered in YAC128 mice in early stages of disease progression. We show that the YAC128 hippocampal dentate gyrus (DG) displays marked reductions in paired-pulse depression both at 3 and 6 months of age. In addition, significantly enhanced post-tetanic and short-term potentiation are apparent in YAC128 mice after high-frequency stimulation at this time. Early and late forms of long-term plasticity were not altered at this stage. Together these findings indicate that there may be elevated neurotransmitter release in response to synaptic stimulation in YAC128 mice during the initial phase of disease progression. These abnormalities in short-term plasticity detected at this stage in YAC128 HD transgenic mice indicate that aberrant information processing at the level of the synapses may contribute, at least in part, to the early onset of cognitive deficits that are characteristic of this devastating neurodegenerative disorder. Copyright © 2014 Elsevier B.V. All rights reserved.

Nurses' knowledge to identify early acute kidney injury.

PubMed

Nascimento, Roseli Aparecida Matheus do; Assunção, Murillo Santucci Cesar; Silva, João Manoel; Amendola, Cristina Prata; Carvalho, Taysa Martindo de; Lima, Emerson Quintino; Lobo, Suzana Margareth Ajeje

2016-01-01

To evaluate the knowledgeof nurses on early identification of acute kidney injury (AKI) in intensive care, emergency and hospitalization units. A prospective multi-center study was conducted with 216 nurses, using a questionnaire with 10 questions related to AKI prevention, diagnosis, and treatment. 57.2% of nurses were unable to identify AKI clinical manifestations, 54.6% did not have knowledge of AKI incidence in patients admitted to the ICU, 87.0% of the nurses did not know how to answer as regards the AKI mortality rate in patients admitted to the ICU, 67.1% answered incorrectly that slight increases in serum creatinine do not have an impact on mortality, 66.8% answered incorrectly to the question on AKI prevention measures, 60.4% answered correctly that loop diuretics for preventing AKI is not recommended, 77.6% answered correctly that AKI does not characterize the need for hemodialysis, and 92.5% said they had no knowledge of the Acute Kidney Injury Networkclassification. Nurses do not have enough knowledge to identify early AKI, demonstrating the importance of qualification programs in this field of knowledge. Avaliar o conhecimento do enfermeiro na identificação precoce da Injúria Renal Aguda (IRA) em Unidade de Terapia Intensiva, Unidade de Internação e Emergência. Estudo multicêntrico, prospectivo.Participaram do estudo 216 enfermeiros,por meio de questionário com 10 questões relacionadas à prevenção, ao diagnóstico e ao tratamento da IRA. 57,2% não souberam identificar as manifestações clínicas da IRA, 54,6% não têm conhecimento da incidência de IRA em pacientes internados na UTI, 87,0% dos enfermeiros não souberam responder ao índice de mortalidade de IRA em pacientes internados na UTI, 67,1% responderam incorretamente que aumentos discretos da creatinina sérica não têm impacto na mortalidade, 66,8% responderam incorretamente à questão sobre as medidas de prevenção da IRA, 60,4% acertaram quando responderam que não �

Mortality of New York children with sickle cell disease identified through newborn screening.

PubMed

Wang, Ying; Liu, Gang; Caggana, Michele; Kennedy, Joseph; Zimmerman, Regina; Oyeku, Suzette O; Werner, Ellen M; Grant, Althea M; Green, Nancy S; Grosse, Scott D

2015-06-01

Long-term follow-up of newborn screening for conditions such as sickle cell disease can be conducted using linkages to population-based data. We sought to estimate childhood sickle cell disease mortality and risk factors among a statewide birth cohort with sickle cell disease identified through newborn screening. Children with sickle cell disease identified by newborn screening and born to New York residents in 2000-2008 were matched to birth and death certificates. Mortality rates were calculated (using numbers of deaths and observed person-years at risk) and compared with mortality rates for all New York children by maternal race/ethnicity. Stratified analyses were conducted to examine associations between selected factors and mortality. Among 1,911 infants with sickle cell disease matched to birth certificates, 21 deaths were identified. All-cause mortality following diagnosis was 3.8 per 1,000 person-years in the first 2 years of life and 1.0 per 1,000 person-years at ages 2-9 years. The mortality rate was significantly lower among children of foreign-born mothers and was significantly higher among preterm infants with low birth weight. The mortality rates were not significantly higher for infants after 28 days with sickle cell disease than for all New York births, but they were 2.7-8.4 times higher for children 1 through 9 years old with homozygous sickle cell disease than for those of all non-Hispanic black or Hispanic children born to New York residents. Estimated mortality risk in children with homozygous sickle cell disease remains elevated even after adjustment for maternal race/ethnicity. These results provide evidence regarding the current burden of child mortality among children with sickle cell disease despite newborn screening.Genet Med 17 6, 452-459.

Clinical features of early onset, familial Alzheimer`s disease linked to chromosome 14

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mullan, M.; Bennett, C.; Figueredo, C.

1995-02-27

Early onset familial Alzheimer`s disease (AD) has an autosomal dominant mode of inheritance. Two genes are responsible for the majority of cases of this subtype of AD. Mutations in the {beta}-amyloid precursor protein ({beta}APP) gene on chromosome 21 have been shown to completely cosegregate with the disease. We and others have previously described the clinical features of families with {beta}APP mutations at the codon 717 locus in an attempt to define the phenotype associated with a valine to isoleucine (Val {r_arrow} Ile) or a valine to glycine (Val {r_arrow} Gly) change. More recently, a second locus for very early onsetmore » disease has been localized to chromosome 14. The results of linkage studies in some families suggesting linkage to both chromosomes have been explained by the suggestion of a second (centromeric) locus on chromosome 21. Here we report the clinical features and genetic analysis of a British pedigree (F74) with early onset AD in which neither the {beta}APP locus nor any other chromosome 21 locus segregates with the disease, but in which good evidence is seen for linkage on the long arm of chromosome 14. In particular we report marker data suggesting that the chromosome 14 disease locus is close to D14S43 and D14S77. Given the likelihood that F74 represents a chromosome 14 linked family, we describe the clinical features and make a limited clinical comparison with the {beta}APP717 Val {r_arrow} Ile and {beta}APP717 Val {r_arrow} Gly encoded families that have been previously described. We conclude that although several previously reported clinical features occur to excess in early onset familial AD, no single clinical feature demarcates either the chromosome 14 or {beta}APP codon 717 mutated families except mean age of onset. 52 refs., 2 figs., 5 tabs.« less

Central Pain Processing in Early-Stage Parkinson's Disease: A Laser Pain fMRI Study

PubMed Central

Petschow, Christine; Scheef, Lukas; Paus, Sebastian; Zimmermann, Nadine; Schild, Hans H.; Klockgether, Thomas; Boecker, Henning

2016-01-01

Background & Objective Pain is a common non-motor symptom in Parkinson’s disease. As dopaminergic dysfunction is suggested to affect intrinsic nociceptive processing, this study was designed to characterize laser-induced pain processing in early-stage Parkinson’s disease patients in the dopaminergic OFF state, using a multimodal experimental approach at behavioral, autonomic, imaging levels. Methods 13 right-handed early-stage Parkinson’s disease patients without cognitive or sensory impairment were investigated OFF medication, along with 13 age-matched healthy control subjects. Measurements included warmth perception thresholds, heat pain thresholds, and central pain processing with event-related functional magnetic resonance imaging (erfMRI) during laser-induced pain stimulation at lower (E = 440 mJ) and higher (E = 640 mJ) target energies. Additionally, electrodermal activity was characterized during delivery of 60 randomized pain stimuli ranging from 440 mJ to 640 mJ, along with evaluation of subjective pain ratings on a visual analogue scale. Results No significant differences in warmth perception thresholds, heat pain thresholds, electrodermal activity and subjective pain ratings were found between Parkinson’s disease patients and controls, and erfMRI revealed a generally comparable activation pattern induced by laser-pain stimuli in brain areas belonging to the central pain matrix. However, relatively reduced deactivation was found in Parkinson’s disease patients in posterior regions of the default mode network, notably the precuneus and the posterior cingulate cortex. Conclusion Our data during pain processing extend previous findings suggesting default mode network dysfunction in Parkinson’s disease. On the other hand, they argue against a genuine pain-specific processing abnormality in early-stage Parkinson’s disease. Future studies are now required using similar multimodal experimental designs to examine pain processing in more advanced

Novel Biomarkers of Abdominal Aortic Aneurysm Disease: Identifying Gaps and Dispelling Misperceptions

PubMed Central

Moris, Demetrios; Avgerinos, Efthymios; Makris, Marinos; Bakoyiannis, Chris; Pikoulis, Emmanuel; Georgopoulos, Sotirios

2014-01-01

Abdominal aortic aneurysm (AAA) is a prevalent and potentially life-threatening disease. Early detection by screening programs and subsequent surveillance has been shown to be effective at reducing the risk of mortality due to aneurysm rupture. The aim of this review is to summarize the developments in the literature concerning the latest biomarkers (from 2008 to date) and their potential screening and therapeutic values. Our search included human studies in English and found numerous novel biomarkers under research, which were categorized in 6 groups. Most of these studies are either experimental or hampered by their low numbers of patients. We concluded that currently no specific laboratory markers allow screeing for the disease and monitoring its progression or the results of treatment. Further studies and studies in larger patient groups are required in order to validate biomarkers as cost-effective tools in the AAA disease. PMID:24967416

Ptau-Aβ42 ratio as a continuous trait for biomarker discovery for early stage Alzheimer’s disease in multiplex immunoassay panels of Cerebrospinal fluid

PubMed Central

Harari, Oscar; Cruchaga, Carlos; Kauwe, John S.K.; Ainscough, Benjamin J.; Bales, Kelly; Pickering, Eve H.; Bertelsen, Sarah; Fagan, Anne M.; Holtzman, David M.; Morris, John C.; Goate, Alison M.

2014-01-01

Background Identification of the physiological changes that occur during the early stages of Alzheimer’s disease (AD) may provide critical insights for the diagnosis, prognosis and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome. Methods We applied a novel approach to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay and detected common associations in the Knight- Alzheimer’s Disease Research Center (ADRC;N=311) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI;N=293) cohorts. CSF ptau181-Aβ42 ratio was used as a continuous trait, rather than case control status in these analyses. Results We demonstrate the ptau181-Aβ42 ratio has more statistical power than traditional modeling approaches and that the levels of CSF Fatty Acid Binding Protein (H-FABP) and 12 other correlated analytes increase as the disease progresses. These results were validated using the traditional case control status model. Stratification of our dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in non-demented individuals with AD pathology (low ptau181, low Aβ42) compared to pathology-negative elderly control subjects (low ptau181, high Aβ42). FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor Conclusions Our results clearly indicate that the approach presented here can be employed to correctly identify novel biomarkers for AD, and that CSF H-FABP levels start to increase at very early stages of the disease. PMID:24548642

Renocardiovascular Biomarkers: from the Perspective of Managing Chronic Kidney Disease and Cardiovascular Disease

PubMed Central

Niizuma, Shinichiro; Iwanaga, Yoshitaka; Yahata, Takaharu; Miyazaki, Shunichi

2017-01-01

Mortality among the patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) remains high because of the very high incidence of cardiovascular disease (CVD) such as coronary artery disease, cardiac hypertrophy, and heart failure. Identifying CVD in patients with CKD/ESRD remains a significant hurdle and the early diagnosis and therapy for CVD is crucial in these patients. Therefore, it is necessary for the better management to identify and utilize cardiovascular (CV) biomarkers in profiling CVD risk and enabling stratification of early mortality. This review summarizes current evidence about renocardiovascular biomarkers: CV biomarkers in patients with CKD as well as with ESRD, emphasizing on the emerging biomarkers: B-type natriuretic peptide, cardiac troponins, copeptin, the biomarker of renal injury (neutrophil gelatinase-associated lipocalin), and the mineral and bone disorder hormone/marker (fibroblast growth factor-23). Furthermore, it discusses their potential roles especially in ESRD and in future diagnostic and therapeutic strategies for CVD in the context of managing cardiorenal syndrome. PMID:28321399

Injection of celiac disease patient sera or immunoglobulins to mice reproduces a condition mimicking early developing celiac disease.

PubMed

Kalliokoski, Suvi; Caja, Sergio; Frias, Rafael; Laurila, Kaija; Koskinen, Outi; Niemelä, Onni; Mäki, Markku; Kaukinen, Katri; Korponay-Szabó, Ilma R; Lindfors, Katri

2015-01-01

Typical features of celiac disease are small-bowel villus atrophy, crypt hyperplasia, and inflammation which develop gradually concomitant with ingestion of gluten. In addition, patients have anti-transglutaminase 2 (TG2) autoantibodies in their serum and tissues. The aim of this study was to establish whether celiac disease can be passively transferred to mice by serum or immunoglobulins. Serum aliquots or purified immunoglobulins (Ig) were intraperitoneally injected into Hsd:Athymic Nude-Foxn1nu mice for 8 or 27 days. As mice do not have proper IgA transport from peritoneum to blood, sera with a high content of IgG class anti-TG2 antibodies from untreated IgA-deficient celiac patients were used. Mouse sera were tested for celiac disease-specific autoantibodies, and several tissues were analyzed for autoantibody deposits targeted to TG2. Morphological assessment was made of the murine small intestinal mucosa. Injection of celiac disease patient sera or total IgG led to a significant delay in weight gain and mild diarrhea in a subset of mice. The mice injected with celiac patient sera or IgG had significantly decreased villus height crypt depth (Vh/CrD) ratios and celiac disease-specific autoantibody deposits targeted to TG2 in several tissues, including the small intestine. None of these features were observed in control mice. We conclude that administration of IgA-deficient celiac disease patient serum or total IgG induces both deterioration of the intestinal mucosa and clinical features of celiac disease in mice. The experimentally induced condition in the mice injected with patient serum or IgG resembles early developing celiac disease in humans. Celiac disease patient sera or total IgG was injected into athymic mice. A significant delay in weight gain and mild diarrhea was observed. Mice evinced significantly decreased villus height crypt depth ratios. Celiac disease-specific autoantibody deposits were present in several tissues. The condition in mice

Identifying economic hurdles to early adoption of trunk disease preventative practices in California winegrape vineyards

USDA-ARS?s Scientific Manuscript database

Trunk diseases poses a serious threat to winegrape growers. Despite high prevalence and substantial consequences, growers routinely wait to adopt field-tested, preventative practices (delayed pruning, double pruning, or application of pruning wound protectant) until symptomatic vines appear (~10 yea...

[Immune system aging rate in patients with early forms of chronic cerebrovascular diseases].

PubMed

Kochetkova, N G; Al'tman, D Sh; Teplova, S N

2009-01-01

Using the Bioage and Snake software the immune and cardiovascular system aging rate was diagnosed in patients having early forms of chronic cerebrovascular diseases (CCVD). The indicators of biological, cardiopulmonary and immunological age were studied in patients showing early symptoms of cerebrovascular insufficiency and dyscirculatory encephalopathy of the 1st stage. The rate of age-dependent physiological changes was diagnosed compared to general body aging rate. Some specific patterns of immune system aging were found in patients with early forms of CCVDs, the cardinal aging symptoms (heterotropia, heterochronia) were verified.

Identifying management and disease priorities of Canadian dairy industry stakeholders.

PubMed

Bauman, C A; Barkema, H W; Dubuc, J; Keefe, G P; Kelton, D F

2016-12-01

The objective of this study was to identify the key management and disease issues affecting the Canadian dairy industry. An online questionnaire (FluidSurveys, http://fluidsurveys.com/) was conducted between March 1 and May 31, 2014. A total of 1,025 responses were received from across Canada of which 68% (n=698) of respondents were dairy producers, and the remaining respondents represented veterinarians, university researchers, government personnel, and other allied industries. Participants were asked to identify their top 3 management and disease priorities from 2 lists offered. Topics were subsequently ranked from highest to lowest using 3 different ranking methods based on points: 5-3-1 (5 points for first priority, 3 for second, and 1 for first), 3-2-1, and 1-1-1 (equal ranking). The 5-3-1 point system was selected because it minimized the number of duplicate point scores. Stakeholder groups showed general agreement with the top management issue identified as animal welfare and the number one health concern as lameness. Other areas identified as priorities were reproductive health, antibiotic use, bovine viral diarrhea, and Staphylococcus aureus mastitis with these rankings influenced by region, herd size, and stakeholder group. This is the first national comprehensive assessment of priorities undertaken in the Canadian dairy industry and will assist researchers, policymakers, program developers, and funding agencies make future decisions based on direct industry feedback. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Childhood developmental vulnerabilities associated with early life exposure to infectious and noninfectious diseases and maternal mental illness.

PubMed

Green, Melissa J; Kariuki, Maina; Dean, Kimberlie; Laurens, Kristin R; Tzoumakis, Stacy; Harris, Felicity; Carr, Vaughan J

2017-12-26

Fetal exposure to infectious and noninfectious diseases may influence early childhood developmental functioning, on the path to later mental illness. Here, we investigated the effects of in utero exposure to maternal infection and noninfectious diseases during pregnancy on offspring developmental vulnerabilities at age 5 years, in the context of estimated effects for early childhood exposures to infectious and noninfectious diseases and maternal mental illness. We used population data for 66,045 children from an intergenerational record linkage study (the New South Wales Child Development Study), for whom a cross-sectional assessment of five developmental competencies (physical, social, emotional, cognitive, and communication) was obtained at school entry, using the Australian Early Development Census (AEDC). Child and maternal exposures to infectious or noninfectious diseases were determined from the NSW Ministry of Health Admitted Patients Data Collection (APDC) and maternal mental illness exposure was derived from both APDC and Mental Health Ambulatory Data collections. Multinomial logistic regression analyses were used to examine unadjusted and adjusted associations between these physical and mental health exposures and child developmental vulnerabilities at age 5 years. Among the physical disease exposures, maternal infectious diseases during pregnancy and early childhood infection conferred the largest associations with developmental vulnerabilities at age 5 years; maternal noninfectious illness during pregnancy also retained small but significant associations with developmental vulnerabilities even when adjusted for other physical and mental illness exposures and covariates known to be associated with early childhood development (e.g., child's sex, socioeconomic disadvantage, young maternal age, prenatal smoking). Among all exposures examined, maternal mental illness first diagnosed prior to childbirth conferred the greatest odds of developmental

Risk Matrix for Prediction of Disease Progression in a Referral Cohort of Patients with Crohn's Disease.

PubMed

Lakatos, Peter L; Sipeki, Nora; Kovacs, Gyorgy; Palyu, Eszter; Norman, Gary L; Shums, Zakera; Golovics, Petra A; Lovasz, Barbara D; Antal-Szalmas, Peter; Papp, Maria

2015-10-01

Early identification of patients with Crohn's disease (CD) at risk of subsequent complications is essential for adapting the treatment strategy. We aimed to develop a prediction model including clinical and serological markers for assessing the probability of developing advanced disease in a prospective referral CD cohort. Two hundred and seventy-one consecutive CD patients (42.4% males, median follow-up 108 months) were included and followed up prospectively. Anti-Saccharomyces cerevisiae antibodies (ASCA IgA/IgG) were determined by enzyme-linked immunosorbent assay. The final analysis was limited to patients with inflammatory disease behaviour at diagnosis. The final definition of advanced disease outcome was having intestinal resection or disease behaviour progression. Antibody (ASCA IgA and/or IgG) status, disease location and need for early azathioprine were included in a 3-, 5- and 7-year prediction matrix. The probability of advanced disease after 5 years varied from 6.2 to 55% depending on the combination of predictors. Similar findings were obtained in Kaplan-Meier analysis; the combination of ASCA, location and early use of azathioprine was associated with the probability of developing advanced disease (p < 0.001, log rank test). Our prediction models identified substantial differences in the probability of developing advanced disease in the early disease course of CD. Markers identified in this referral cohort were different from those previously published in a population-based cohort, suggesting that different prediction models should be used in the referral setting. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Cardiovascular Disease Outcomes Related to Early Stage Renal Impairment Following Liver Transplantation.

PubMed

VanWagner, Lisa B; Montag, Samantha; Zhao, Lihui; Allen, Norrina B; Lloyd-Jones, Donald M; Das, Arighno; Skaro, Anton I; Hohmann, Samuel; Friedewald, John J; Levitsky, Josh

2018-03-20

In the general population, even mild renal disease is associated with increased cardiovascular (CV) complications. Whether this is true in liver transplant recipients (LTR) is unknown. This was a retrospective cohort study of 671 LTR (2002-2012) from a large urban tertiary care center and 37,322 LTR using Vizient hospitalization data linked to the United Network for Organ Sharing. The MDRD4 equation estimated GFR (eGFR). Outcomes were 1-year CV complications (death/hospitalization from myocardial infarction, heart failure, atrial fibrillation, cardiac arrest, pulmonary embolism or stroke) and mortality. Latent mixture modeling identified trajectories in eGFR in the first LT year in the 671 patients. Mean(SD) eGFR was 72.1(45.7) ml/min/1.73m. Six distinct eGFR trajectories were identified in the local cohort (n=671): qualitatively Normal-Slow Decrease (4% of cohort), Normal-Rapid Decrease (4%), Mild-Stable (18%), Mild-Slow Decrease (35%), Moderate-Stable (30%), and Severe-Stable (9%). In multivariable analyses adjusted for confounders and baseline eGFR, the greatest odds of 1-year CV complications were in the Normal-Rapid Decrease group (OR, 95% CI: 10.6, 3.0-36.9). Among the national cohort, each 5-unit lower eGFR at LT was associated with a 2% and 5% higher hazard of all-cause and CV-mortality, respectively (p<0.0001) independent of multiple confounders. Even mild renal disease at the time of LT is a risk factor for posttransplant all-cause and CV mortality. More rapid declines in eGFR soon after LT correlate with risk of adverse CV outcomes, highlighting the need to study whether early renal preservation interventions also reduce CV complications.

A Systems Biology Framework Identifies Molecular Underpinnings of Coronary Heart Disease

PubMed Central

Huan, Tianxiao; Zhang, Bin; Wang, Zhi; Joehanes, Roby; Zhu, Jun; Johnson, Andrew D.; Ying, Saixia; Munson, Peter J.; Raghavachari, Nalini; Wang, Richard; Liu, Poching; Courchesne, Paul; Hwang, Shih-Jen; Assimes, Themistocles L.; McPherson, Ruth; Samani, Nilesh J.; Schunkert, Heribert; Meng, Qingying; Suver, Christine; O'Donnell, Christopher J.; Derry, Jonathan; Yang, Xia; Levy, Daniel

2013-01-01

Objective Genetic approaches have identified numerous loci associated with coronary heart disease (CHD). The molecular mechanisms underlying CHD gene-disease associations, however, remain unclear. We hypothesized that genetic variants with both strong and subtle effects drive gene subnetworks that in turn affect CHD. Approach and Results We surveyed CHD-associated molecular interactions by constructing coexpression networks using whole blood gene expression profiles from 188 CHD cases and 188 age- and sex-matched controls. 24 coexpression modules were identified including one case-specific and one control-specific differential module (DM). The DMs were enriched for genes involved in B-cell activation, immune response, and ion transport. By integrating the DMs with altered gene expression associated SNPs (eSNPs) and with results of GWAS of CHD and its risk factors, the control-specific DM was implicated as CHD-causal based on its significant enrichment for both CHD and lipid eSNPs. This causal DM was further integrated with tissue-specific Bayesian networks and protein-protein interaction networks to identify regulatory key driver (KD) genes. Multi-tissue KDs (SPIB and TNFRSF13C) and tissue-specific KDs (e.g. EBF1) were identified. Conclusions Our network-driven integrative analysis not only identified CHD-related genes, but also defined network structure that sheds light on the molecular interactions of genes associated with CHD risk. PMID:23539213

Allergic Diseases and Internalizing Behaviors in Early Childhood

PubMed Central

LeMasters, Grace K.; Levin, Linda; Rothenberg, Marc E.; Assa'ad, Amal H.; Newman, Nicholas; Bernstein, David; Khurana-Hershey, Gurjit; Lockey, James E.; Ryan, Patrick H.

2016-01-01

BACKGROUND AND OBJECTIVES: The relationship between allergic diseases and internalizing disorders has not been well characterized with regard to multiple allergic diseases or longitudinal study. The objective of this study was to examine the association between multiple allergic diseases in early childhood with validated measures of internalizing disorders in the school-age years. METHODS: Children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study underwent skin testing and examinations at ages 1, 2, 3, 4, and 7 years. At age 7, parents completed the Behavior Assessment System for Children, Second Edition (BASC-2), a validated measure of childhood behavior and emotion. The association between allergic diseases at age 4, including allergic rhinitis, allergic persistent wheezing, atopic dermatitis, and allergic sensitization, and BASC-2 internalizing, anxiety, and depression T scores at age 7 was examined by logistic and linear regression, adjusting for covariates. RESULTS: The cohort included 546 children with complete information on allergic disease and BASC-2 outcomes. Allergic rhinitis at age 4 was significantly associated with elevated internalizing (adjusted odds ratio [aOR]: 3.2; 95% confidence interval [CI]: 1.8–5.8), anxiety (aOR: 2.0; 95% CI: 1.2–3.6), and depressive scores (aOR: 3.2; 95% CI: 1.7–6.5) at age 7. Allergic persistent wheezing was significantly associated with elevated internalizing scores (aOR: 2.7; 95% CI: 1.2–6.3). The presence of >1 allergic disease (aOR: 3.6; 95% CI: 1.7–7.6) and allergic rhinitis with comorbid allergic disease(s) (aOR: 4.3; 95% CI: 2.0–9.2) at age 4 had dose-dependent associations with internalizing scores. CONCLUSIONS: Children with allergic rhinitis and allergic persistent wheezing at age 4 are at increased risk of internalizing behaviors at age 7. Furthermore, multiple allergic diseases had a dose-dependent association with elevated internalizing scores. PMID:26715608

Allergic Diseases and Internalizing Behaviors in Early Childhood.

PubMed

Nanda, Maya K; LeMasters, Grace K; Levin, Linda; Rothenberg, Marc E; Assa'ad, Amal H; Newman, Nicholas; Bernstein, David; Khurana-Hershey, Gurjit; Lockey, James E; Ryan, Patrick H

2016-01-01

The relationship between allergic diseases and internalizing disorders has not been well characterized with regard to multiple allergic diseases or longitudinal study. The objective of this study was to examine the association between multiple allergic diseases in early childhood with validated measures of internalizing disorders in the school-age years. Children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study underwent skin testing and examinations at ages 1, 2, 3, 4, and 7 years. At age 7, parents completed the Behavior Assessment System for Children, Second Edition (BASC-2), a validated measure of childhood behavior and emotion. The association between allergic diseases at age 4, including allergic rhinitis, allergic persistent wheezing, atopic dermatitis, and allergic sensitization, and BASC-2 internalizing, anxiety, and depression T scores at age 7 was examined by logistic and linear regression, adjusting for covariates. The cohort included 546 children with complete information on allergic disease and BASC-2 outcomes. Allergic rhinitis at age 4 was significantly associated with elevated internalizing (adjusted odds ratio [aOR]: 3.2; 95% confidence interval [CI]: 1.8-5.8), anxiety (aOR: 2.0; 95% CI: 1.2-3.6), and depressive scores (aOR: 3.2; 95% CI: 1.7-6.5) at age 7. Allergic persistent wheezing was significantly associated with elevated internalizing scores (aOR: 2.7; 95% CI: 1.2-6.3). The presence of >1 allergic disease (aOR: 3.6; 95% CI: 1.7-7.6) and allergic rhinitis with comorbid allergic disease(s) (aOR: 4.3; 95% CI: 2.0-9.2) at age 4 had dose-dependent associations with internalizing scores. Children with allergic rhinitis and allergic persistent wheezing at age 4 are at increased risk of internalizing behaviors at age 7. Furthermore, multiple allergic diseases had a dose-dependent association with elevated internalizing scores. Copyright © 2016 by the American Academy of Pediatrics.

Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson’s Disease

PubMed Central

Charles, David; Konrad, Peter E.; Neimat, Joseph S.; Molinari, Anna L.; Tramontana, Michael G.; Finder, Stuart G.; Gill, Chandler E.; Bliton, Mark J.; Kao, Chris C.; Phibbs, Fenna T.; Hedera, Peter; Salomon, Ronald M.; Cannard, Kevin R.; Wang, Lily; Song, Yanna; Davis, Thomas L.

2014-01-01

Background Deep brain stimulation (DBS) is an effective and approved therapy for advanced Parkinson’s disease (PD), and a recent study suggests efficacy in mid-stage disease. This manuscript reports the results of a pilot trial investigating preliminary safety and tolerability of DBS in early PD. Methods Thirty subjects with idiopathic PD (Hoehn & Yahr Stage II off medication), age 50–75, on medication ≥ 6 months but < 4 years, and without motor fluctuations or dyskinesias were randomized to optimal drug therapy (ODT) (n=15) or DBS+ODT (n=15). Co-primary endpoints were the time to reach a 4-point worsening from baseline in the UPDRS-III off therapy and the change in levodopa equivalent daily dose from baseline to 24 months. Results As hypothesized, the mean UPDRS total and part III scores were not significantly different on or off therapy at 24 months. The DBS+ODT group took less medication at all time points, and this reached maximum difference at 18 months. With a few exceptions, differences in neuropsychological functioning were not significant. Two subjects in the DBS+ODT group suffered serious adverse events; remaining adverse events were mild or transient. Conclusions This study demonstrates that subjects with early stage PD will enroll in and complete trials testing invasive therapies and provides preliminary evidence that DBS is well tolerated in early PD. The results of this trial provide the data necessary to design a large, phase III, double-blind, multicenter trial investigating the safety and efficacy of DBS in early PD. PMID:24768120

Cimetidine as a novel adjunctive treatment for early stage Lyme disease.

PubMed

Shemenski, Justin

2016-04-09

Lyme disease, caused by the spirochete Borrelia burgdorferi (Bb), is the most common vector-borne illness in the United States. It is a complex disease which may affect the skin, joints, heart, eyes, and central nervous system. Prompt diagnosis and treatment is curative in most instances. However, a significant percentage of patients experience ongoing symptoms after treatment. Currently, there is much controversy regarding the diagnosis, pathophysiology, and treatment of Lyme disease. Pathogen persistence despite treatment lies at the heart of this debate. Many believe that the ongoing symptoms are due to factors such as autoimmunity or permanent damage that is incurred during the active infection. However, there is an emerging school of thought that states that ongoing symptoms are due to a persistent infection that is able to survive both the immune response and antibiotic therapy. Numerous studies have shown that Bb can indeed persist within the host despite treatment and several mechanisms have been proposed to explain Bb's persistence capabilities. These include: polymorphism, antigenic variance, biofilm formation, persister cells, and immunomodulation. There is evidence that Bb is able to alter cytokine profiles within the host which may allow the organism to survive the immune response. This immunomodulation follows a pattern of T-helper 1 (TH1) suppression in favor of T-helper 2 (TH2) processes. In contrast, it has been shown that the optimal immune response to Bb infection involves an early, robust TH1 response and a later conversion to TH2 dominance once the infection is controlled or cleared. It has been proposed that a reconstitution of proper immune-competency in the infected host may improve clinical outcomes in Lyme disease. Cimetidine (CIM) is an over-the-counter histamine-2 (H2) antagonist that is primarily used to lower acid secretions in the stomach. T-regulatory (Treg) cells also possess the H2 receptor, which has spurred interest in CIM as a

A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study.

PubMed

2002-12-01

Monotherapy with rasagiline mesylate may be useful in early Parkinson disease (PD). To evaluate the safety and efficacy of the selective monoamine oxidase type B inhibitor rasagiline. Multicenter, 26-week, parallel-group, randomized, double-blind, placebo-controlled clinical trial. Academically based movement disorders clinics. Patients with early PD not requiring dopaminergic therapy (n = 404). Research participants were randomized to rasagiline mesylate at dosages of 1 mg or 2 mg per day or matching placebo. A 1-week escalation period was followed by a 25-week maintenance period. The primary prespecified measure of efficacy was the change in the total Unified Parkinson's Disease Rating Scal score between baseline and 26 weeks of treatment, comparing each active treatment group with the placebo group. Monotherapy with rasagiline was effective in this 26-week study. The adjusted effect size for the total Unified Parkinson's Disease Rating Scale was -4.20 units comparing 1 mg of rasagiline and placebo (95% confidence interval, -5.66 to -2.73 units; P<.001) and -3.56 units comparing a 2-mg dosage and placebo (95% confidence interval, -5.04 to -2.08 units; P<.001). There were no meaningful differences in the frequency of adverse events or premature withdrawals among the treatment groups. Rasagiline is effective as monotherapy for patients with early PD. The 2 dosages in this trial were both effective relative to placebo. Further study is warranted to evaluate the longer-term effects of rasagiline in PD.

[Assessment of an algorithm to identify paediatric-onset celiac disease cases through administrative healthcare databases].

PubMed

Pitter, Gisella; Gnavi, Roberto; Romor, Pierantonio; Zanotti, Renzo; Simonato, Lorenzo; Canova, Cristina

2017-01-01

to assess the role of four administrative healthcare databases (pathology reports, copayment exemptions, hospital discharge records, gluten-free food prescriptions) for the identification of possible paediatric cases of celiac disease. population-based observational study with record linkage of administrative healthcare databases. SETTING AND PARTICIPANT S: children born alive in the Friuli Venezia Giulia Region (Northern Italy) to resident mothers in the years 1989-2012, identified using the regional Medical Birth Register. we defined possible celiac disease as having at least one of the following, from 2002 onward: 1. a pathology report of intestinal villous atrophy; 2. a copayment exemption for celiac disease; 3. a hospital discharge record with ICD-9-CM code of celiac disease; 4. a gluten-free food prescription. We evaluated the proportion of subjects identified by each archive and by combinations of archives, and examined the temporal relationship of the different sources in cases identified by more than one source. RESULT S: out of 962 possible cases of celiac disease, 660 (68.6%) had a pathology report, 714 (74.2%) a copayment exemption, 667 (69.3%) a hospital discharge record, and 636 (66.1%) a gluten-free food prescription. The four sources coexisted in 42.2% of subjects, whereas 30.2% were identified by two or three sources and 27.6% by a single source (16.9% by pathology reports, 4.2% by hospital discharge records, 3.9% by copayment exemptions, and 2.6% by gluten-free food prescriptions). Excluding pathology reports, 70.6% of cases were identified by at least two sources. A definition based on copayment exemptions and discharge records traced 80.5% of the 962 possible cases of celiac disease; whereas a definition based on copayment exemptions, discharge records, and gluten-free food prescriptions traced 83.1% of those cases. The temporal relationship of the different sources was compatible with the typical diagnostic pathway of subjects with celiac

'Outbreak Gold Standard' selection to provide optimized threshold for infectious diseases early-alert based on China Infectious Disease Automated-alert and Response System.

PubMed

Wang, Rui-Ping; Jiang, Yong-Gen; Zhao, Gen-Ming; Guo, Xiao-Qin; Michael, Engelgau

2017-12-01

The China Infectious Disease Automated-alert and Response System (CIDARS) was successfully implemented and became operational nationwide in 2008. The CIDARS plays an important role in and has been integrated into the routine outbreak monitoring efforts of the Center for Disease Control (CDC) at all levels in China. In the CIDARS, thresholds are determined using the "Mean+2SD‟ in the early stage which have limitations. This study compared the performance of optimized thresholds defined using the "Mean +2SD‟ method to the performance of 5 novel algorithms to select optimal "Outbreak Gold Standard (OGS)‟ and corresponding thresholds for outbreak detection. Data for infectious disease were organized by calendar week and year. The "Mean+2SD‟, C1, C2, moving average (MA), seasonal model (SM), and cumulative sum (CUSUM) algorithms were applied. Outbreak signals for the predicted value (Px) were calculated using a percentile-based moving window. When the outbreak signals generated by an algorithm were in line with a Px generated outbreak signal for each week, this Px was then defined as the optimized threshold for that algorithm. In this study, six infectious diseases were selected and classified into TYPE A (chickenpox and mumps), TYPE B (influenza and rubella) and TYPE C [hand foot and mouth disease (HFMD) and scarlet fever]. Optimized thresholds for chickenpox (P 55 ), mumps (P 50 ), influenza (P 40 , P 55 , and P 75 ), rubella (P 45 and P 75 ), HFMD (P 65 and P 70 ), and scarlet fever (P 75 and P 80 ) were identified. The C1, C2, CUSUM, SM, and MA algorithms were appropriate for TYPE A. All 6 algorithms were appropriate for TYPE B. C1 and CUSUM algorithms were appropriate for TYPE C. It is critical to incorporate more flexible algorithms as OGS into the CIDRAS and to identify the proper OGS and corresponding recommended optimized threshold by different infectious disease types.

Early intranasal insulin therapy halts progression of neurodegeneration: progress in Alzheimer's disease therapeutics.

PubMed

de la Monte, Suzanne M

Evaluation of Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial. Arch Neurol . 2011 Sep 12. Alzheimer's disease is associated with brain insulin deficiency and insulin resistance, similar to the problems in diabetes. If insulin could be supplied to the brain in the early stages of Alzheimer's, subsequent neurodegeneration might be prevented. Administering systemic insulin to elderly non-diabetics poses unacceptable risks of inadvertant hypoglycemia. However, intranasal delivery directs the insulin into the brain, avoiding systemic side-effects. This pilot study demonstrates both efficacy and safety of using intranasal insulin to treat early Alzheimer's and mild cognitive impairment, i.e. the precursor to Alzheimer's. Significant improvements in learning, memory, and cognition occured within a few months, but without intranasal insulin, brain function continued to deteriorate in measurable degrees. Intranasal insulin therapy holds promise for halting progression of Alzheimer's disease.

Multidisciplinary strategies in the management of early chronic kidney disease.

PubMed

Martínez-Ramírez, Héctor R; Cortés-Sanabria, Laura; Rojas-Campos, Enrique; Hernández-Herrera, Aurora; Cueto-Manzano, Alfonso M

2013-11-01

Chronic kidney disease (CKD) is a worldwide epidemic especially in developing countries, with clear deficiencies in identification and treatment. Better care of CKD requires more than only economic resources, utilization of health research in policy-making and health systems changes that produce better outcomes. A multidisciplinary approach may facilitate and improve management of patients from early CKD in the primary health-care setting. This approach is a strategy for improving comprehensive care, initiating and maintaining healthy behaviors, promoting teamwork, eliminating barriers to achieve goals and improving the processes of care. A multidisciplinary intervention may include educational processes guided by health professional, use of self-help groups and the development of a CKD management plan. The complex and fragmented care management of patients with CKD, associated with poor outcome, enhances the importance of implementing a multidisciplinary approach in the management of this disease from the early stages. Multidisciplinary strategies should focus on the needs of patients (to increase their empowerment) and should be adapted to the resources and health systems prevailing in each country; its systematic implementation can help to improve patient care and slow the progression of CKD. Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.

Is epigenetics an important link between early life events and adult disease?

USDA-ARS?s Scientific Manuscript database

Epigenetic mechanisms provide one potential explanation for how environmental influences in early life cause long-term changes in chronic disease susceptibility. Whereas epigenetic dysregulation is increasingly implicated in various rare developmental syndromes and cancer, the role of epigenetics in...

Early Alzheimer's Disease Neuropathology Detected by Proton MR Spectroscopy

PubMed Central

Murray, Melissa E.; Przybelski, Scott A.; Lesnick, Timothy G.; Liesinger, Amanda M.; Spychalla, Anthony; Zhang, Bing; Gunter, Jeffrey L.; Parisi, Joseph E.; Boeve, Bradley F.; Knopman, David S.; Petersen, Ronald C.; Jack, Clifford R.; Dickson, Dennis W.

2014-01-01

Proton magnetic resonance spectroscopy (1H-MRS) is sensitive to early neurodegenerative processes associated with Alzheimer's disease (AD). Although 1H-MRS metabolite ratios of N-acetyl aspartate (NAA)/creatine (Cr), NAA/myoinositol (mI), and mI/Cr measured in the posterior cingulate gyrus reveal evidence of disease progression in AD, pathologic underpinnings of the 1H-MRS metabolite changes in AD are unknown. Pathologically diagnosed human cases ranging from no likelihood to high likelihood AD (n = 41, 16 females and 25 males) who underwent antemortem 1H-MRS of the posterior cingulate gyrus at 3 tesla were included in this study. Immunohistochemical evaluation was performed on the posterior cingulate gyrus using antibodies to synaptic vesicles, hyperphosphorylated tau (pTau), neurofibrillary tangle conformational-epitope (cNFT), amyloid-β, astrocytes, and microglia. The slides were digitally analyzed using Aperio software, which allows neuropathologic quantification in the posterior cingulate gray matter. MRS and pathology associations were adjusted for time from scan to death. Significant associations across AD and control subjects were found between reduced synaptic immunoreactivity and both NAA/Cr and NAA/mI in the posterior cingulate gyrus. Higher pTau burden was associated with lower NAA/Cr and NAA/mI. Higher amyloid-β burden was associated with elevated mI/Cr and lower NAA/mI ratios, but not with NAA/Cr. 1H-MRS metabolite levels reveal early neurodegenerative changes associated with AD pathology. Our findings support the hypothesis that a decrease in NAA/Cr is associated with loss of synapses and early pTau pathology, but not with amyloid-β or later accumulation of cNFT pathology in the posterior cingulate gyrus. In addition, elevation of mI/Cr is associated with the occurrence of amyloid-β plaques in AD. PMID:25471565

Mutations, associated with early-onset Alzheimer’s disease, discovered in Asian countries

PubMed Central

Bagyinszky, Eva; Youn, Young Chul; An, Seong Soo A; Kim, SangYun

2016-01-01

Alzheimer’s disease (AD), the most common form of senile dementia, is a genetically complex disorder. In most Asian countries, the population and the number of AD patients are growing rapidly, and the genetics of AD has been extensively studied, except in Japan. However, recent studies have been started to investigate the genes and mutations associated with AD in Korea, the People’s Republic of China, and Malaysia. This review describes all of the known mutations in three early-onset AD (EOAD) causative genes (APP, PSEN1, and PSEN2) that were discovered in Asian countries. Most of the EOAD-associated mutations have been detected in PSEN1, and several novel PSEN1 mutations were recently identified in patients from various parts of the world, including Asia. Until 2014, no PSEN2 mutations were found in Asian patients; however, emerging studies from Korea and the People’s Republic of China discovered probably pathogenic PSEN2 mutations. Since several novel mutations were discovered in these three genes, we also discuss the predictions on their pathogenic nature. This review briefly summarizes genome-wide association studies of late-onset AD and the genes that might be associated with AD in Asian countries. Standard sequencing is a widely used method, but it has limitations in terms of time, cost, and efficacy. Next-generation sequencing strategies could facilitate genetic analysis and association studies. Genetic testing is important for the accurate diagnosis and for understanding disease-associated pathways and might also improve disease therapy and prevention. PMID:27799753

Early disease progression in patients with localized natural killer/T-cell lymphoma treated with concurrent chemoradiotherapy.

PubMed

Yamaguchi, Motoko; Suzuki, Ritsuro; Kim, Seok Jin; Ko, Young Hyeh; Oguchi, Masahiko; Asano, Naoko; Miyazaki, Kana; Terui, Yasuhiko; Kubota, Nobuko; Maeda, Takeshi; Kobayashi, Yukio; Amaki, Jun; Soejima, Toshinori; Saito, Bungo; Shimoda, Emiko; Fukuhara, Noriko; Tsukamoto, Norifumi; Shimada, Kazuyuki; Choi, Ilseung; Utsumi, Takahiko; Ejima, Yasuo; Kim, Won Seog; Katayama, Naoyuki

2018-03-30

Prognosis of patients with localized nasal extranodal natural killer/T-cell lymphoma, nasal type (ENKL) has been improved by non-anthracycline-containing treatments such as concurrent chemoradiotherapy (CCRT). However, some patients experience early disease progression. To clarify the clinical features and outcomes of these patients, data from 165 patients with localized nasal ENKL who were diagnosed between 2000 and 2013 at 31 institutes in Japan and who received radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) were retrospectively analyzed. Progression of disease within 2 years after diagnosis (POD24) was used as the definition of early progression. An independent dataset of 60 patients with localized nasal ENKL who received CCRT at Samsung Medical Center was used in the validation analysis. POD24 was documented in 23% of patients who received RT-DeVIC and in 25% of patients in the validation cohort. Overall survival (OS) from risk-defining events of the POD24 group was inferior to that of the reference group in both cohorts (P < .00001). In the RT-DeVIC cohort, pretreatment elevated levels of serum soluble interleukin-2 receptor (sIL-2R), lactate dehydrogenase, C-reactive protein, and detectable Epstein-Barr virus DNA in peripheral blood were associated with POD24. In the validation cohort, no pretreatment clinical factor associated with POD24 was identified. Our study indicates that POD24 is a strong indicator of survival in localized ENKL, despite the different CCRT regimens adopted. In the treatment of localized nasal ENKL, POD24 is useful for identifying patients who have unmet medical needs. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Low-grade disease activity in early life precedes childhood asthma and allergy.

PubMed

Chawes, Bo Lund Krogsgaard

2016-08-01

Asthma and allergies are today the most common chronic diseases in children and the leading causes of school absences, chronic medication usage, emergency department visits and hospitalizations, which affect all members of the family and represent a significant societal and scientific challenge. These highly prevalent disorders are thought to originate from immune distortion in early childhood, but the etiology and heterogeneity of the disease mechanisms are not understood, which hampers preventive initiatives and makes treatment inadequate. The objective of this thesis is to investigate the presence of an early life disease activity prior to clinical symptoms to understand the anteceding pathophysiological steps towards childhood asthma and allergy. The thesis is built on seven studies from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2000) birth cohort examining biomarkers of disease activity in 411 asymptomatic neonates in cord blood (I-II), urine (III), exhaled breath (IV-V) and infant lung function (VI-VII) in relation to the subsequent development of asthma and allergy during the first seven years of life. In papers I-II, we studied cord blood chemokines and 25(OH)-vitamin D, which represent a proxy of the inborn immature immune system, the intrauterine milieu, and the maternal immune health during pregnancy. High levels of the Th2-related chemokine CCL22 and high CCL22/CXCL11 ratio were positively correlated with total IgE level during preschool age (II). This suggests an inborn Th2 skewing of the immune system in healthy newborns subsequently developing elevated total IgE antibodies, which is considered to increase the risk of asthma and allergies later in life. Additionally, deficient cord blood 25(OH)-vitamin D levels were associated with a 2.7-fold increased risk of recurrent wheeze at age 0-7 years (I). Together, these findings support the concept that early life immune programming in the pre-symptomatic era plays an essential role

Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study.

PubMed

Snowdon, D A; Kemper, S J; Mortimer, J A; Greiner, L H; Wekstein, D R; Markesbery, W R

1996-02-21

To determine if linguistic ability in early life is associated with cognitive function and Alzheimer's disease in late life. Two measures of linguistic ability in early life, idea density and grammatical complexity, were derived from autobiographies written at a mean age of 22 years. Approximately 58 years later, the women who wrote these autobiographies participated in an assessment of cognitive function, and those who subsequently died were evaluated neuropathologically. Convents in the United States participating in the Nun Study; primarily convents in the Milwaukee, Wis, area. Cognitive function was investigated in 93 participants who were aged 75 to 95 years at the time of their assessments, and Alzheimer's disease was investigated in the 14 participants who died at 79 to 96 years of age. Seven neuropsychological tests and neuropathologically confirmed Alzheimer's disease. Low idea density and low grammatical complexity in autobiographies written in early life were associated with low cognitive test scores in late life. Low idea density in early life had stronger and more consistent associations with poor cognitive function than did low grammatical complexity. Among the 14 sisters who died, neuropathologically confirmed Alzheimer's disease was present in all of those with low idea density in early life and in none of those with high idea density. Low linguistic ability in early life was a strong predictor of poor cognitive function and Alzheimer's disease in late life.

Molecular genetics of early-onset Alzheimer's disease revisited.

PubMed

Cacace, Rita; Sleegers, Kristel; Van Broeckhoven, Christine

2016-06-01

As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (APOE) risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Multimodal and Multiscale Deep Neural Networks for the Early Diagnosis of Alzheimer's Disease using structural MR and FDG-PET images.

PubMed

Lu, Donghuan; Popuri, Karteek; Ding, Gavin Weiguang; Balachandar, Rakesh; Beg, Mirza Faisal

2018-04-09

Alzheimer's Disease (AD) is a progressive neurodegenerative disease where biomarkers for disease based on pathophysiology may be able to provide objective measures for disease diagnosis and staging. Neuroimaging scans acquired from MRI and metabolism images obtained by FDG-PET provide in-vivo measurements of structure and function (glucose metabolism) in a living brain. It is hypothesized that combining multiple different image modalities providing complementary information could help improve early diagnosis of AD. In this paper, we propose a novel deep-learning-based framework to discriminate individuals with AD utilizing a multimodal and multiscale deep neural network. Our method delivers 82.4% accuracy in identifying the individuals with mild cognitive impairment (MCI) who will convert to AD at 3 years prior to conversion (86.4% combined accuracy for conversion within 1-3 years), a 94.23% sensitivity in classifying individuals with clinical diagnosis of probable AD, and a 86.3% specificity in classifying non-demented controls improving upon results in published literature.

Deep Brain Stimulation for Early Stage Parkinson's Disease: An Illustrative Case

PubMed Central

Gill, Chandler E.; Allen, Laura A.; Konrad, Peter E.; Davis, Thomas L.; Bliton, Mark J.; Finder, Stuart G.; Tramontana, Michael G.; Kao, C. Chris; Remple, Michael S.; Bradenham, Courtney H.; Charles, P. David

2011-01-01

Objectives Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective intervention in advanced Parkinson's Disease (PD), but its efficacy and safety in early PD are unknown. Our team is conducting a randomized pilot trial investigating DBS in early PD. This report describes one participant who received bilateral STN-DBS. Materials/Methods Thirty subjects have been randomized to either optimal drug therapy (ODT) or DBS + ODT. Microelectrode recordings from the STN and substantia nigra (SN) are collected at implantation. The Unified Parkinson's Disease Rating Scale Motor Subscale (UPDRS-III) is administered in the ON and OFF states semi-annually and neuropsychological function and quality of life are assessed annually. We describe a 54-year-old man with a two-year history of PD who was randomized to DBS + ODT and followed for two years. Results The subject showed a lower STN to SN ratio of neuronal activity than advanced PD patients, and higher firing rate than non-PD patients. The subject's ON total UPDRS and UPDRS-III scores improved during the two-year follow-up, while his OFF UPDRS-III score and levodopa equivalent daily dose (LEDD) increased. Quality of life, verbal fluency and verbal learning improved. He did not experience any serious adverse events. Conclusions This report details the first successful application of bilateral STN DBS for early stage PD during a clinical trial. PMID:21939467

Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci

PubMed Central

Ellinghaus, David; Jostins, Luke; Spain, Sarah L; Cortes, Adrian; Bethune, Jörn; Han, Buhm; Park, Yu Rang; Raychaudhuri, Soumya; Pouget, Jennie G; Hübenthal, Matthias; Folseraas, Trine; Wang, Yunpeng; Esko, Tonu; Metspalu, Andres; Westra, Harm-Jan; Franke, Lude; Pers, Tune H; Weersma, Rinse K; Collij, Valerie; D'Amato, Mauro; Halfvarson, Jonas; Jensen, Anders Boeck; Lieb, Wolfgang; Degenhardt, Franziska; Forstner, Andreas J; Hofmann, Andrea; Schreiber, Stefan; Mrowietz, Ulrich; Juran, Brian D; Lazaridis, Konstantinos N; Brunak, Søren; Dale, Anders M; Trembath, Richard C; Weidinger, Stephan; Weichenthal, Michael; Ellinghaus, Eva; Elder, James T; Barker, Jonathan NWN; Andreassen, Ole A; McGovern, Dermot P; Karlsen, Tom H; Barrett, Jeffrey C; Parkes, Miles; Brown, Matthew A; Franke, Andre

2016-01-01

We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European-ancestry we identified 244 independent multi-disease signals including 27 novel genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multi-disease signals with expression data sets from human, rat and mouse, and epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases that is genetically identical to another disease, possibly due to diagnostic misclassification, molecular subtypes, or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes. PMID:26974007

Antibiotic Use in Early Life, Rural Residence, and Allergic Diseases in Argentinean Children.

PubMed

Han, Yueh-Ying; Forno, Erick; Badellino, Héctor A; Celedón, Juan C

Little is known about differential effects of antibiotic use on allergic diseases in rural versus urban environments. To examine whether area of residence in the first year of life modifies the relation between antibiotic use in early life and allergic diseases during childhood. Cross-sectional study of allergic diseases in 1517 children (ages 6-7 years) attending 101 schools in urban and rural areas of San Francisco (Córdoba, Argentina). Current asthma, wheeze, and allergic rhinoconjunctivitis were defined on the basis of responses to a validated questionnaire from the International Study of Asthma and Allergies in Childhood. Multivariate logistic regression was used for the analysis of antibiotic use and allergic diseases. After adjustment for paracetamol use, bronchiolitis, and other covariates, antibiotic use in the first year of life was associated with increased odds of current wheeze (odds ratio [OR], 1.8; 95% CI, 1.3-2.6) and allergic rhinoconjunctivitis (OR, 1.9; 95% CI, 1.3-2.7). After stratification by area of residence, antibiotic use was associated with current wheeze (OR, 2.4; 95% CI, 1.5-4.0) and allergic rhinoconjunctivitis (OR, 2.1; 95% CI, 1.3-3.4) among children who lived in an urban area in their first year of life, but not among those who lived in a rural area in their first year of life. Early-life antibiotic use is associated with current wheeze and allergic rhinoconjunctivitis in Argentinean children who lived in urban areas during their first year of life. Exposure to a rural environment early in life may protect against the adverse effects of antibiotics on atopic diseases in children. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Oral-Fluid Thiol-Detection Test Identifies Underlying Active Periodontal Disease Not Detected by the Visual Awake Examination.

PubMed

Queck, Katherine E; Chapman, Angela; Herzog, Leslie J; Shell-Martin, Tamara; Burgess-Cassler, Anthony; McClure, George David

Periodontal disease in dogs is highly prevalent but can only be accurately diagnosed by performing an anesthetized oral examination with periodontal probing and dental radiography. In this study, 114 dogs had a visual awake examination of the oral cavity and were administered an oral-fluid thiol-detection test prior to undergoing a a full-mouth anesthetized oral examination and digital dental radiographs. The results show the visual awake examination underestimated the presence and severity of active periodontal disease. The thiol-detection test was superior to the visual awake examination at detecting the presence and severity of active periodontal disease and was an indicator of progression toward alveolar bone loss. The thiol-detection test detected active periodontal disease at early stages of development, before any visual cues were present, indicating the need for intervention to prevent periodontal bone loss. Early detection is important because without intervention, dogs with gingivitis (active periodontal disease) progress to irreversible periodontal bone loss (stage 2+). As suggested in the current AAHA guidelines, a thiol-detection test administered in conjunction with the visual awake examination during routine wellness examinations facilitates veterinarian-client communication and mitigates under-diagnosis of periodontal disease and underutilization of dental services. The thiol-detection test can be used to monitor the periodontal health status of the conscious patient during follow-up examinations based on disease severity.

Identifying improvements to complex pathways: evidence synthesis and stakeholder engagement in infant congenital heart disease

PubMed Central

Crowe, Sonya; Knowles, Rachel; Wray, Jo; Tregay, Jenifer; Ridout, Deborah A; Utley, Martin; Franklin, Rodney; Bull, Catherine L; Brown, Katherine L

2016-01-01

Objectives Many infants die in the year following discharge from hospital after surgical or catheter intervention for congenital heart disease (3–5% of discharged infants). There is considerable variability in the provision of care and support in this period, and some families experience barriers to care. We aimed to identify ways to improve discharge and postdischarge care for this patient group. Design A systematic evidence synthesis aligned with a process of eliciting the perspectives of families and professionals from community, primary, secondary and tertiary care. Setting UK. Results A set of evidence-informed recommendations for improving the discharge and postdischarge care of infants following intervention for congenital heart disease was produced. These address known challenges with current care processes and, recognising current resource constraints, are targeted at patient groups based on the number of patients affected and the level and nature of their risk of adverse 1-year outcome. The recommendations include: structured discharge documentation, discharging certain high-risk patients via their local hospital, enhanced surveillance for patients with certain (high-risk) cardiac diagnoses and an early warning tool for parents and community health professionals. Conclusions Our recommendations set out a comprehensive, system-wide approach for improving discharge and postdischarge services. This approach could be used to address challenges in delivering care for other patient populations that can fall through gaps between sectors and organisations. PMID:27266768

Phospholipase A2 activation as a therapeutic approach for cognitive enhancement in early-stage Alzheimer disease.

PubMed

Schaeffer, Evelin L; Forlenza, Orestes V; Gattaz, Wagner F

2009-01-01

Alzheimer disease (AD) is the leading cause of dementia in the elderly and has no known cure. Evidence suggests that reduced activity of specific subtypes of intracellular phospholipases A2 (cPLA2 and iPLA2) is an early event in AD and may contribute to memory impairment and neuropathology in the disease. The objective of this study was to review the literature focusing on the therapeutic role of PLA2 stimulation by cognitive training and positive modulators, or of supplementation with arachidonic acid (PLA2 product) in facilitating memory function and synaptic transmission and plasticity in either research animals or human subjects. MEDLINE database was searched (no date restrictions) for published articles using the keywords Alzheimer disease (mild, moderate, severe), mild cognitive impairment, healthy elderly, rats, mice, phospholipase A(2), phospholipid metabolism, phosphatidylcholine, arachidonic acid, cognitive training, learning, memory, long-term potentiation, protein kinases, dietary lipid compounds, cell proliferation, neurogenesis, and neuritogenesis. Reference lists of the identified articles were checked to select additional studies of interest. Overall, the data suggest that PLA2 activation is induced in the healthy brain during learning and memory. Furthermore, learning seems to regulate endogenous neurogenesis, which has been observed in AD brains. Finally, PLA2 appears to be implicated in homeostatic processes related to neurite outgrowth and differentiation in both neurodevelopmental processes and response to neuronal injury. The use of positive modulators of PLA2 (especially of cPLA2 and iPLA2) or supplementation with dietary lipid compounds (e.g., arachidonic acid) in combination with cognitive training could be a valuable therapeutic strategy for cognitive enhancement in early-stage AD.

EVALUATION OF SYMMETRIC DIMETHYLARGININE AS AN EARLY BIOMARKER OF CHRONIC KIDNEY DISEASE IN CAPTIVE CHEETAHS (ACINONYX JUBATUS).

PubMed

Lamglait, Benjamin; Vandenbunder-Beltrame, Marielle

2017-09-01

Symmetric dimethylarginine (SDMA) has been shown to be a valuable biomarker for early detection of chronic kidney disease (CKD) in canine and feline patients. Recognition of early (subclinical) kidney disease would be of value in cheetahs (Acinonyx jubatus) as prevalence of CKD is relatively high in this species in captivity. Fifty-eight banked serum and plasma samples from seven adult cheetahs that died of CKD were analyzed for creatinine, urea, and SDMA. A marked increase in SDMA was noted on five of the tested cheetahs earlier than the rise of serum creatinine and urea (estimated 8-35 mo; mean 21.4 mo; median 22 mo). SDMA appears as an early biomarker to evaluate renal function for the diagnosis of CKD in cheetahs regardless of the cause of this disease.

Early Nutrition as a Major Determinant of 'Immune Health': Implications for Allergy, Obesity and Other Noncommunicable Diseases.

PubMed

Prescott, Susan L

2016-01-01

Early-life nutritional exposures are significant determinants of the development and future health of all organ systems. The dramatic rise in infant immune diseases, most notably allergy, indicates the specific vulnerability of the immune system to early environmental changes. Dietary changes are at the center of the emerging epigenetic paradigms that underpin the rise in many modern inflammatory and metabolic diseases. There is growing evidence that exposures in pregnancy and the early postnatal period can modify gene expression and disease susceptibility. Although modern dietary changes are complex and involve changing patterns of many nutrients, there is also interest in the developmental effects of specific nutrients. Oligosaccharides (soluble fiber), antioxidants, polyunsaturated fatty acids, folate and other vitamins have documented effects on immune function as well as metabolism. Some have also been implicated in modified risk of allergic diseases in observational studies. Intervention studies are largely limited to trials with polyunsaturated fatty acids and oligosaccharides, showing preliminary but yet unconfirmed benefits in allergy prevention. Understanding how environmental influences disrupt the finely balanced development of immune and metabolic programming is of critical importance. Diet-sensitive pathways are likely to be crucial in these processes. While an epigenetic mechanism provides a strong explanation of how nutritional exposures can affect fetal gene expression and subsequent disease risk, other diet-induced tissue compositional changes may also contribute directly to altered immune and metabolic function--including diet-induced changes in the microbiome. A better understanding of nutritional programming of immune health, nutritional epigenetics and the biological processes sensitive to nutritional exposures early in life may lead to dietary strategies that provide more tolerogenic conditions during early immune programming and reduce the

Impaired Early Attentional Processes in Parkinson’s Disease: A High-Resolution Event-Related Potentials Study

PubMed Central

Bocquillon, Perrine; Bourriez, Jean-Louis; Palmero-Soler, Ernesto; Defebvre, Luc; Derambure, Philippe; Dujardin, Kathy

2015-01-01

Introduction The selection of task-relevant information requires both the focalization of attention on the task and resistance to interference from irrelevant stimuli. A previous study using the P3 component of the event-related potentials suggested that a reduced ability to resist interference could be responsible for attention disorders at early stages of Parkinson’s disease (PD), with a possible role of the dorsolateral prefrontal cortex (DLPFC). Methods Our objective was to better determine the origin of this impairment, by studying an earlier ERP component, the N2, and its subcomponents, as they reflect early inhibition processes and as they are known to have sources in the anterior cingulate cortex (ACC), which is involved together with the DLPFC in inhibition processes. Fifteen early-stage PD patients and 15 healthy controls (HCs) performed a three-stimulus visual oddball paradigm, consisting in detecting target inputs amongst standard stimuli, while resisting interference from distracter ones. A 128-channel electroencephalogram was recorded during this task and the generators of the N2 subcomponents were identified using standardized weighted low-resolution electromagnetic tomography (swLORETA). Results PD patients displayed fewer N2 generators than HCs in both the DLPFC and the ACC, for all types of stimuli. In contrast to controls, PD patients did not show any differences between their generators for different N2 subcomponents. Conclusion Our data suggest that impaired inhibition in PD results from dysfunction of the DLPFC and the ACC during the early stages of attentional processes. PMID:26135906

Using a personality inventory to identify risk of distress and burnout among early stage medical students.

PubMed

Bughi, Stephanie A; Lie, Desiree A; Zia, Stephanie K; Rosenthal, Jane

2017-01-01

Distress and burnout are common among medical students and negatively impact students' physical, mental, and emotional health. Personality inventories such as the Myers-Briggs Type Indicator (MBTI), used in medical education, may have a role in identifying burnout risk early. The authors conducted a cross-sectional survey study among 185 1st year medical students with the MBTI, the general well-being schedule (GWB), and Maslach Burnout Inventory-Student Survey (MBI-SS). Descriptive statistics and one-way MANOVAs were used to identify the prevalence and differences in MBTI preferences and distress/burnout risk. Response rate was 185/185 (100%). Distress (GWB) was reported by 84/185 (45.4%). High scores on exhaustion were reported by 118/182 (64.8%), cynicism by 76/182 (41.8%), and decreased professional efficacy by 38/182 (20.9%) for the three dimensions of the MBI-SS. Only 21/182 (11.5%) of respondents had high scores on all three dimensions of burnout. Students with MBTI preferences for extraversion reported greater positive well-being (P < 0.05), self-control (P < 0.05), professional efficacy (P < 0.01), and lower levels of depression (P < 0.01) compared with those with introversion preference. Distress and burnout are prevalent early in medical training. The significant difference between extraversion and introversion in relation to distress and burnout deserves further study. Use of a personality inventory may help identify students at risk of burnout and allow appropriate early stress management.

Effects of early age at natural menopause on coronary heart disease and stroke in Chinese women.

PubMed

Shen, Lijun; Song, Lulu; Liu, Bingqing; Li, Hui; Zheng, Xiaoxuan; Zhang, Lina; Yuan, Jing; Liang, Yuan; Wang, Youjie

2017-08-15

Menopause is identified as a risk factor for cardiovascular disease because of the change of estrogen. The objective of the study was to explore the associations between early age at natural menopause (menopause at an age≤45years) and the presence of CHD and stroke. The study subjects were from the first follow-up survey of the Dongfeng-Tongji cohort study. A total of 16,515 postmenopausal women were included for the analysis. Logistic regression models were used to examine the associations between age at natural menopause (≤45, 45-52, >52years) and the presence of CHD and stroke adjusted for sociodemographic characteristics, lifestyle, reproductive history and metabolic factors. In the fully adjusted model, for each 1-year delay in menopausal age, the prevalence of CHD and stroke was reduced by 3% (OR, 0.97; 95% CI, 0.95-0.98) and 5% (OR, 0.95; 95% CI, 0.92-0.98), respectively. Women with early menopause (≤45years) had a higher prevalence of CHD (OR, 1.33; 95% CI, 1.13-1.57) compared with those with menopause at ages 45-52years. Similarly, women with early menopause (≤45years) was associated with higher prevalence of stroke (OR, 1.69; 95% CI, 1.25-2.30) compared with those with menopause at ages 45-52years. Early age at natural menopause is significantly associated with the presence of CHD and stroke among Chinese women. Copyright © 2017. Published by Elsevier B.V.

“Sentinel” Circulating Tumor Cells Allow Early Diagnosis of Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease

PubMed Central

Ilie, Marius; Hofman, Véronique; Long-Mira, Elodie; Selva, Eric; Vignaud, Jean-Michel; Padovani, Bernard; Mouroux, Jérôme; Marquette, Charles-Hugo; Hofman, Paul

2014-01-01

Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. Migration of circulating tumor cells (CTCs) into the blood stream is an early event that occurs during carcinogenesis. We aimed to examine the presence of CTCs in complement to CT-scan in COPD patients without clinically detectable lung cancer as a first step to identify a new marker for early lung cancer diagnosis. The presence of CTCs was examined by an ISET filtration-enrichment technique, for 245 subjects without cancer, including 168 (68.6%) COPD patients, and 77 subjects without COPD (31.4%), including 42 control smokers and 35 non-smoking healthy individuals. CTCs were identified by cytomorphological analysis and characterized by studying their expression of epithelial and mesenchymal markers. COPD patients were monitored annually by low-dose spiral CT. CTCs were detected in 3% of COPD patients (5 out of 168 patients). The annual surveillance of the CTC-positive COPD patients by CT-scan screening detected lung nodules 1 to 4 years after CTC detection, leading to prompt surgical resection and histopathological diagnosis of early-stage lung cancer. Follow-up of the 5 patients by CT-scan and ISET 12 month after surgery showed no tumor recurrence. CTCs detected in COPD patients had a heterogeneous expression of epithelial and mesenchymal markers, which was similar to the corresponding lung tumor phenotype. No CTCs were detected in control smoking and non-smoking healthy individuals. CTCs can be detected in patients with COPD without clinically detectable lung cancer. Monitoring “sentinel” CTC-positive COPD patients may allow early diagnosis of lung cancer. PMID:25360587

Whole Exome Analysis of Early Onset Alzheimer’s Disease

DTIC Science & Technology

2013-04-01

FTD), FTD with Parkinsonism , and early-onset Alzheimer Disease (EOAD)-like presentations. Using whole exome capture with subsequent sequencing, we...dementia. The MAPT R406W mutation is associated with EOAD-like symptoms and Parkinsonism without FTD, as well as distinct cognitive courses. KEY...OUTCOMES: Carney RM, Kohli MA, Kunkle BW, Naj AC, Gilbert JR, Züchner S, PERICAK-VANCE MA, Parkinsonism and distinct dementia patterns in a

Novel autoantibody markers for early and seronegative rheumatoid arthritis.

PubMed

Somers, Klaartje; Geusens, Piet; Elewaut, Dirk; De Keyser, Filip; Rummens, Jean-Luc; Coenen, Marieke; Blom, Marlies; Stinissen, Piet; Somers, Veerle

2011-02-01

Approximately one-third of rheumatoid arthritis (RA) patients are seronegative for the 2 serological RA markers, rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (ACCP). Moreover, the sensitivities of both markers are lower in the diagnostically important early disease phase. The aim of this study was to identify additional autoantibody markers for early RA and for RF-negative, ACCP-negative (seronegative) RA. We screened an RA synovium cDNA phage display library with autoantibodies in plasma from 10 early (symptoms of maximum 1 year) and 10 seronegative (RF-negative, ACCP-negative) RA patients with validation in 72 additional RA patients and 121 controls (38 healthy controls, 43 patients with other inflammatory rheumatic diseases, 20 osteoarthritis patients and 20 subjects with mechanical joint complaints). Fourteen novel autoantibodies were identified that showed a 54% sensitivity and 90% specificity for RA. For 11 of these autoantibodies, an exclusive presence was demonstrated in RA patients (100% specificity, 37% sensitivity) as compared to controls. All early RA patients were positive for at least one of the identified autoantibodies and antibody-positivity was associated with a shorter disease duration (P = 0.0087). 52% of RA patients who initially tested negative for RF and ACCP, tested positive for at least one of the 14 novel autoantibodies, resulting in a 19% increase in sensitivity compared to current serological testing. Moreover, 5 identified autoantibodies were detected more frequently in seronegative RA patients, indicating that these autoantibodies constitute novel candidate markers for this RA subtype. We demonstrated that the targets of 3 of these 5 autoantibodies had an increased expression in RA synovial tissue compared to control synovial tissue, pointing towards a biological rationale for these auto antibody targets in RA. In conclusion, we identified novel candidate autoantibody markers for RA that can be

Identifying patients with ischemic heart disease in an electronic medical record.

PubMed

Ivers, Noah; Pylypenko, Bogdan; Tu, Karen

2011-01-01

Increasing utilization of electronic medical records (EMRs) presents an opportunity to efficiently measure quality indicators in primary care. Achieving this goal requires the development of accurate patient-disease registries. This study aimed to develop and validate an algorithm for identifying patients with ischemic heart disease (IHD) within the EMR. An algorithm was developed to search the unstructured text within the medical history fields in the EMR for IHD-related terminology. This algorithm was applied to a 5% random sample of adult patient charts (n = 969) drawn from a convenience sample of 17 Ontario family physicians. The accuracy of the algorithm for identifying patients with IHD was compared to the results of 3 trained chart abstractors. The manual chart abstraction identified 87 patients with IHD in the random sample (prevalence = 8.98%). The accuracy of the algorithm for identifying patients with IHD was as follows: sensitivity = 72.4% (95% confidence interval [CI]: 61.8-81.5); specificity = 99.3% (95% CI: 98.5-99.8); positive predictive value = 91.3% (95% CI: 82.0-96.7); negative predictive value = 97.3 (95% CI: 96.1-98.3); and kappa = 0.79 (95% CI: 0.72-0.86). Patients with IHD can be accurately identified by applying a search algorithm for the medical history fields in the EMR of primary care providers who were not using standardized approaches to code diagnoses. The accuracy compares favorably to other methods for identifying patients with IHD. The results of this study may aid policy makers, researchers, and clinicians to develop registries and to examine quality indicators for IHD in primary care.

Semi-automated literature mining to identify putative biomarkers of disease from multiple biofluids

PubMed Central

2014-01-01

Background Computational methods for mining of biomedical literature can be useful in augmenting manual searches of the literature using keywords for disease-specific biomarker discovery from biofluids. In this work, we develop and apply a semi-automated literature mining method to mine abstracts obtained from PubMed to discover putative biomarkers of breast and lung cancers in specific biofluids. Methodology A positive set of abstracts was defined by the terms ‘breast cancer’ and ‘lung cancer’ in conjunction with 14 separate ‘biofluids’ (bile, blood, breastmilk, cerebrospinal fluid, mucus, plasma, saliva, semen, serum, synovial fluid, stool, sweat, tears, and urine), while a negative set of abstracts was defined by the terms ‘(biofluid) NOT breast cancer’ or ‘(biofluid) NOT lung cancer.’ More than 5.3 million total abstracts were obtained from PubMed and examined for biomarker-disease-biofluid associations (34,296 positive and 2,653,396 negative for breast cancer; 28,355 positive and 2,595,034 negative for lung cancer). Biological entities such as genes and proteins were tagged using ABNER, and processed using Python scripts to produce a list of putative biomarkers. Z-scores were calculated, ranked, and used to determine significance of putative biomarkers found. Manual verification of relevant abstracts was performed to assess our method’s performance. Results Biofluid-specific markers were identified from the literature, assigned relevance scores based on frequency of occurrence, and validated using known biomarker lists and/or databases for lung and breast cancer [NCBI’s On-line Mendelian Inheritance in Man (OMIM), Cancer Gene annotation server for cancer genomics (CAGE), NCBI’s Genes & Disease, NCI’s Early Detection Research Network (EDRN), and others]. The specificity of each marker for a given biofluid was calculated, and the performance of our semi-automated literature mining method assessed for breast and lung cancer

[Drug treatment of early-stage (de novo and "honeymoon") Parkinson disease].

PubMed

Cesaro, P; Defebvre, L

2014-04-01

In this article, we discuss the management of motor symptoms during the early phases of Parkinson's disease, excluding that of any other clinical manifestation. We relied primarily upon recently published data and do not describe older publications relating to anticholinergic drugs or amantadine. The initial pharmacological treatment of idiopathic Parkinson's disease (IPD) is symptomatic and remains based upon dopaminergic drugs. However, the development of new drugs has broadened the range of strategic options and improved overall patient management. Announcing the diagnosis is a critical moment, as pointed out by patients' associations. Patients should be advised to maintain personal, professional, social and physical activities as long as possible. The potential benefit of early pharmacological treatment should be explained, focusing on the possible disease-modifying effect of drugs such as rasagiline. According to current guidelines, L-Dopa is preferred in patients above 65years of age, while those below 65 should be treated with dopamine agonists. Like monoamine oxidase inhibitors B (MAOI-B), synthetic dopamine agonists exhibit several advantages: easy-to-use treatment with a once-daily administration, delayed L-Dopa initiation, significant efficacy on motor symptoms (although lower than that of L-Dopa). MOAI can be prescribed in association with L-Dopa or dopamine agonists. Rasagiline also delays L-Dopa initiation, and consequently motor complications. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Differential roles of osteopontin/Eta-1 in early and late lpr disease

PubMed Central

Weber, G F; Cantor, H

2001-01-01

The cytokine osteopontin (Eta-1) leads to macrophage-dependent polyclonal B-cell activation and is induced early in autoimmune prone mice with the lpr mutation, suggesting a significant pathogenic role for this molecule. Indeed, C57BL/6-Faslpr/lpr mice crossed with osteopontin−/– mice display delayed onset of polyclonal B-cell activation, as judged by serum immunoglobulin levels. In contrast, they are subject to normal onset, but late exacerbation of lymphoproliferation and evidence of kidney disease. These observations define two stages of Faslpr/lpr disease with respect to osteopontin-dependent pathogenesis that should be taken into account in the design of therapeutic approaches to the clinical disease. PMID:11737079

Depression is an early disease manifestation in lupus-prone MRL/lpr mice.

PubMed

Gao, Hua-Xin; Campbell, Sean R; Cui, Min-Hui; Zong, Pu; Hee-Hwang, Jong; Gulinello, Maria; Putterman, Chaim

2009-02-15

Many lupus patients develop neuropsychiatric manifestations, including cognitive dysfunction, depression, and anxiety. However, it is not clear if neuropsychiatric lupus is a primary disease manifestation, or is secondary to non-CNS disease. We found that MRL/lpr lupus-prone mice exhibited significant depression-like behavior already at 8 weeks of age, despite normal visual working memory, locomotor coordination and social preference. Moreover, depression was significantly correlated with titers of autoantibodies against DNA, NMDA receptors and cardiolipin. Our results indicate that lupus mice develop depression and CNS dysfunction very early in the course of disease, in the absence of substantial pathology involving other target organs.

Symptomatic Early Congenital Syphilis: A Common but Forgotten Disease.

PubMed

Rashid, Usman; Yaqoob, Usman; Bibi, Nazia; Bari, Attia

2015-10-01

Congenital syphilis is a severe, disabling infection often with grave consequences seen in infants. It occurs due to the transmission of the disease from an infected mother to the unborn infant through the placenta. Congenital syphilis can involve any organ system and present with various symptoms. However, early diagnosis of congenital syphilis is difficult because more than half of the affected infants are asymptomatic, and the signs in symptomatic infants may be subtle and nonspecific. The continuing prevalence of this disease reveals the failure of control measures established for its prevention. Here we report a case of a one-month infant who presented with skin rash. The report stresses upon the importance of implementing the World Health Organization's recommendation that all pregnant women should be screened for syphilis in the first antenatal visit in the first trimester and again in the late pregnancy.

Tau PET binding distinguishes patients with early-stage posterior cortical atrophy from amnestic Alzheimer disease dementia

PubMed Central

Day, Gregory S.; Gordon, Brian A.; Jackson, Kelley; Christensen, Jon J.; Ponisio, Maria Rosana; Su, Yi; Ances, Beau M; Benzinger, Tammie L.S.; Morris, John C.

2017-01-01

Background Flortaucipir (tau) PET binding distinguishes individuals with clinically well-established posterior cortical atrophy (PCA) due to Alzheimer disease (AD) from cognitively normal (CN) controls. However, it is not known whether tau PET binding patterns differentiate individuals with PCA from those with amnestic AD, particularly early in the symptomatic stages of disease. Methods Flortaucipir and florbetapir (β-amyloid) PET-imaging were performed in individuals with early-stage PCA (N=5), amnestic AD dementia (N=22), and CN controls (N=47). Average tau and β-amyloid deposition were quantified using standard uptake value ratios and compared at a voxel-wise level, controlling for age. Results PCA patients (median age-at-onset, 59 [51–61] years) were younger at symptom-onset than similarly-staged individuals with amnestic AD (75 [60–85] years) or CN controls (73 [61–90] years; p=0.002). Flortaucipir uptake was higher in individuals with early-stage symptomatic PCA versus those with early-stage amnestic AD or CN controls, and greatest in posterior regions. Regional elevations in florbetapir were observed in areas of greatest tau deposition in PCA patients. Conclusions and Relevance Flortaucipir uptake distinguished individuals with PCA and amnestic AD dementia early in the symptomatic course. The posterior brain regions appear to be uniquely vulnerable to tau deposition in PCA, aligning with clinical deficits that define this disease subtype. PMID:28394771

Tau-PET Binding Distinguishes Patients With Early-stage Posterior Cortical Atrophy From Amnestic Alzheimer Disease Dementia.

PubMed

Day, Gregory S; Gordon, Brian A; Jackson, Kelley; Christensen, Jon J; Rosana Ponisio, Maria; Su, Yi; Ances, Beau M; Benzinger, Tammie L S; Morris, John C

2017-01-01

Flortaucipir (tau) positron emission tomography (PET) binding distinguishes individuals with clinically well-established posterior cortical atrophy (PCA) due to Alzheimer disease (AD) from cognitively normal (CN) controls. However, it is not known whether tau-PET binding patterns differentiate individuals with PCA from those with amnestic AD, particularly early in the symptomatic stages of disease. Flortaucipir and florbetapir (β-amyloid) PET imaging were performed in individuals with early-stage PCA (N=5), amnestic AD dementia (N=22), and CN controls (N=47). Average tau and β-amyloid deposition were quantified using standard uptake value ratios and compared at a voxelwise level, controlling for age. PCA patients [median age-at-onset, 59 (51 to 61) years] were younger at symptom onset than similarly staged individuals with amnestic AD [75 (60 to 85) years] or CN controls [73 (61 to 90) years; P=0.002]. Flortaucipir uptake was higher in individuals with early-stage symptomatic PCA versus those with early-stage amnestic AD or CN controls, and greatest in posterior regions. Regional elevations in florbetapir were observed in areas of greatest tau deposition in PCA patients. Flortaucipir uptake distinguished individuals with PCA and amnestic AD dementia early in the symptomatic course. The posterior brain regions appear to be uniquely vulnerable to tau deposition in PCA, aligning with clinical deficits that define this disease subtype.

Early behavioral changes and quantitative analysis of neuropathological features in murine prion disease

PubMed Central

Borner, Roseane; Bento-Torres, João; Souza, Diego RV; Sadala, Danyelle B; Trevia, Nonata; Farias, José Augusto; Lins, Nara; Passos, Aline; Quintairos, Amanda; Diniz, José Antônio; Perry, Victor Hugh; Vasconcelos, Pedro Fernando; Cunningham, Colm

2011-01-01

Behavioral and neuropathological changes have been widely investigated in murine prion disease but stereological based unbiased estimates of key neuropathological features have not been carried out. After injections of ME7 infected (ME7) or normal brain homogenates (NBH) into dorsal CA1 of albino Swiss mice and C57BL6, we assessed behavioral changes on hippocampal-dependent tasks. We also estimated by optical fractionator at 15 and 18 weeks post-injections (w.p.i.) the total number of neurons, reactive astrocytes, activated microglia and perineuronal nets (PN) in the polymorphic layer of dentate gyrus (PolDG), CA1 and septum in albino Swiss mice. On average, early behavioral changes in albino Swiss mice start four weeks later than in C57BL6. Cluster and discriminant analysis of behavioral data in albino Swiss mice revealed that four of nine subjects start to change their behavior at 12 w.p.i. and reach terminal stage at 22 w.p.i and the remaining subjects start at 22 w.p.i. and reach terminal stage at 26 w.p.i. Biotinylated dextran-amine BDA-tracer experiments in mossy fiber pathway confirmed axonal degeneration and stereological data showed that early astrocytosis, microgliosis and reduction in the perineuronal nets are independent of a change in the number of neuronal cell bodies. Statistical analysis revealed that the septal region had greater levels of neuroinflammation and extracellular matrix damage than CA1. This stereological and multivariate analysis at early stages of disease in an outbred model of prion disease provided new insights connecting behavioral changes and neuroinflammation and seems to be important to understand the mechanisms of prion disease progression. PMID:21862877

Effect of intensive therapy on early macrovascular disease in young individuals with type 1 diabetes. A systematic review and meta-analysis.

PubMed

Lawson, M L; Gerstein, H C; Tsui, E; Zinman, B

1999-03-01

We conducted a systematic review of randomized controlled trials (RCTs) of intensive insulin therapy (IIT) in type 1 diabetes to determine the effect on macrovascular complications. MEDLINE (1966-1996), Citation Index, reference lists, and personal files were used to identify RCTs of > 2 years' duration comparing IIT to conventional therapy (CT) in type 1 diabetes. Two independent reviewers applied selection criteria and identified 11 studies; 5 were subsequently excluded because no data were available for macrovascular complications. Data were extracted on macrovascular disease and cardiovascular risk factors. Macrovascular disease was defined as angina, myocardial infarction, angioplasty, coronary artery bypass graft, stroke, claudication, or peripheral bypass. The first event of each type was counted. IIT decreased the number of macrovascular events (odds ratio [OR] 0.55, [95% CI 0.35-0.88], P = 0.015) but had no significant effect on the number of patients developing macrovascular disease (OR 0.72, [95% CI 0.44-1.17], P = 0.22) or on macrovascular mortality (OR 0.91, [95% CI 0.31-2.65], P = 0.93). IIT decreases the extent of early macrovascular disease in young individuals with type 1 diabetes but has no effect on the number of patients affected or on macrovascular mortality. These data suggest that IIT may stabilize macrovascular disease or prevent progression in those at risk.

POSTSURGICAL RECURRENT CUSHING DISEASE: CLINICAL BENEFIT OF EARLY INTERVENTION IN PATIENTS WITH NORMAL URINARY FREE CORTISOL.

PubMed

Carroll, Ty B; Javorsky, Bradley R; Findling, James W

2016-10-01

To assess the performance of biochemical markers in the detection of recurrent Cushing disease (CD), as well as the potential benefit of early intervention in recurrent CD patients with elevated late-night salivary cortisol (LNSC) and normal urinary free cortisol (UFC). The design was a single-center, retrospective chart review. Patients treated by the authors from 2008-2013 were included. Recurrence was defined by postsurgical remission of CD with subsequent abnormal LNSC, UFC, or dexamethasone suppression test (DST). We identified 15 patients with postsurgical recurrent CD after initial remission; all but one underwent testing with LNSC, DST, and UFC. Although 12 of 15 patients had normal UFC at time of recurrence, DST was abnormal in 11 of 15, and all 14 patients with LNSC results had ≥1 elevated measurement. Nine patients (7 with normal UFC) showed radiologic evidence of a pituitary tumor at time of recurrence. Among the 14 patients with available follow-up data, 12 have demonstrated significant improvement since receiving treatment. Five patients underwent repeat pituitary surgery and 4 achieved clinical and biochemical remission. Eight patients received mifepristone or cabergoline, and 6 showed clinical and/or biochemical improvement. Three patients (2 with prior mifepristone) underwent bilateral adrenalectomy and 2 demonstrated significant clinical improvements. LNSC is more sensitive than UFC or DST for detection of CD recurrence. Prompt intervention when LNSC is elevated, despite normal UFC, may yield significant clinical benefit for many patients with CD. Early treatment for patients with recurrent CD should be prospectively evaluated, utilizing LNSC elevation as an early biochemical marker. ACTH = adrenocorticotropic hormone CD = Cushing disease CS = Cushing syndrome CV = coefficient of variation DST = dexamethasone suppression test IPSS = inferior petrosal sinus sampling LNSC = late-night salivary cortisol QoL = quality of life TSS = transsphenoidal

Monitoring of early humoral immunity to identify lung recipients at risk for development of serious infections: A multicenter prospective study.

PubMed

Sarmiento, Elizabeth; Cifrian, Jose; Calahorra, Leticia; Bravo, Carles; Lopez, Sonia; Laporta, Rosalia; Ussetti, Piedad; Sole, Amparo; Morales, Carmen; de Pablos, Alicia; Jaramillo, Maria; Ezzahouri, Ikram; García, Sandra; Navarro, Joaquin; Lopez-Hoyos, Marcos; Carbone, Javier

2018-04-06

Infection is still a leading cause of death during the first year after lung transplantation. We performed a multicenter study among teaching hospitals to assess monitoring of early humoral immunity as a means of identifying lung recipients at risk of serious infections. We prospectively analyzed 82 adult lung recipients at 5 centers in Spain. Data were collected before transplantation and at 7 and 30 days after transplantation. Biomarkers included IgG, IgM, IgA, complement factors C3 and C4, titers of antibodies to pneumococcal polysaccharide antigens (IgG, IgA, IgM) and antibodies to cytomegalovirus (IgG), and serum B-cell activating factor (BAFF) levels. The clinical follow-up period lasted 6 months. Clinical outcomes were bacterial infections requiring intravenous anti-microbial agents, cytomegalovirus (CMV) disease, and fungal infections requiring therapy. We found that 33 patients (40.2%) developed at least 1 serious bacterial infection, 8 patients (9.8%) had CMV disease, and 10 patients (12.2%) had fungal infections. Lower IgM antibody levels against pneumococcal polysaccharide antigens at Day 7 (defined as <5 mg/dl) were a risk factor for serious bacterial infection (adjusted odds ratio [OR] 3.96; 95% confidence interval [CI] 1.39 to 11.26; p = 0.0099). At Day 7 after transplantation, IgG hypogammaglobulinemia (defined as IgG <600 mg/dl) was associated with a higher risk of CMV disease (after adjustment for CMV mismatch: OR 8.15; 95% CI 1.27 to 52.55; p = 0.028) and fungal infection (adjusted OR 8.03, 95% CI 1.51 to 42.72; p = 0.015). Higher BAFF levels before transplantation were associated with a higher rate of development of serious bacterial infection and acute cellular rejection. Early monitoring of specific humoral immunity parameters proved useful for the identification of lung recipients who are at risk of serious infections. Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights

Identifying Key Early Literacy and School Readiness Issues: Exploring a Strategy for Assessing Community Needs

ERIC Educational Resources Information Center

Weigel, Daniel J.; Martin, Sally S.

2006-01-01

Much effort has been expended in developing intervention programs to help improve the early literacy and school readiness skills of young children. This article presents the results of a needs assessment project aimed at identifying priorities for community intervention programs aimed at ensuring that young children enter school ready to learn. A…

Early childhood diarrhoeal diseases and cognition: are we missing the rest of the iceberg?

PubMed

MacIntyre, Jessica; McTaggart, Jennifer; Guerrant, Richard L; Goldfarb, David M

2014-11-01

Risk factors which interfere with cognitive function are especially important during the first 2 years of life - a period referred to as early child development and a time during which rapid growth and essential development occur. Malnutrition, a condition whose effect on cognitive function is well known, has been shown to be part of a vicious cycle with diarrhoeal diseases, and the two pathologies together continue to be the leading cause of illness and death in young children in developing countries. This paper reviews the burden of early childhood diarrhoeal diseases globally and the emerging evidence of their relationship with global disparities in neurocognitive development. The strength of evidence which indicates that the severe childhood diarrhoeal burden may be implicated in cognitive impairment of children from low- and middle-income counties is discussed. Findings suggest that greater investment in multi-site, longitudinal enteric infection studies that assess long-term repercussions are warranted. Furthermore, economic analyses using the concept of human capital should play a key role in advancing our understanding of the breadth and complexities of the health, social and economic ramifications of early childhood diarrhoeal diseases and enteric infections. This broadened awareness can serve to help advocate for more effective interventions, particularly in developing economies.

Anorectal Manometric Dysfunctions in Newly Diagnosed, Early-Stage Parkinson's Disease

PubMed Central

Sung, Hye Young; Kim, Yeong-In; Lee, Kwang-Soo

2012-01-01

Background and Purpose Anorectal dysmotility is common in advanced Parkinson's disease (PD), but there have been few evaluations in newly diagnosed PD patients. Methods We conducted anorectal manometric evaluations in 19 newly diagnosed, drug-naïve, early-stage PD patients. All of the PD patients were questioned regarding the presence of anorectal symptoms. Results Anorectal manometry was abnormal in 12 of the 19 patients. These abnormalities were more common in patients with more severe anorectal symptoms, as measured using a self-reported scale. However, more than 40% of patients with no or minimal symptoms also exhibited manometric abnormalities. Conclusions These results suggest that anorectal dysmotility manifests in many early-stage PD patients, which this represent evidence for the involvement of neuronal structures in such nonmotor manifestations in PD. PMID:23091527

Early tissue damage and microstructural reorganization predict disease severity in experimental epilepsy

PubMed Central

Janz, Philipp; Schwaderlapp, Niels; Heining, Katharina; Häussler, Ute; Korvink, Jan G; von Elverfeldt, Dominik; Hennig, Jürgen; Egert, Ulrich

2017-01-01

Mesial temporal lobe epilepsy (mTLE) is the most common focal epilepsy in adults and is often refractory to medication. So far, resection of the epileptogenic focus represents the only curative therapy. It is unknown whether pathological processes preceding epilepsy onset are indicators of later disease severity. Using longitudinal multi-modal MRI, we monitored hippocampal injury and tissue reorganization during epileptogenesis in a mouse mTLE model. The prognostic value of MRI biomarkers was assessed by retrospective correlations with pathological hallmarks Here, we show for the first time that the extent of early hippocampal neurodegeneration and progressive microstructural changes in the dentate gyrus translate to the severity of hippocampal sclerosis and seizure burden in chronic epilepsy. Moreover, we demonstrate that structural MRI biomarkers reflect the extent of sclerosis in human hippocampi. Our findings may allow an early prognosis of disease severity in mTLE before its first clinical manifestations, thus expanding the therapeutic window. DOI: http://dx.doi.org/10.7554/eLife.25742.001 PMID:28746029

An Early Warning Scoring System to Identify Septic Patients in the Prehospital Setting: The PRESEP Score.

PubMed

Bayer, Ole; Schwarzkopf, Daniel; Stumme, Christoph; Stacke, Angelika; Hartog, Christiane S; Hohenstein, Christian; Kabisch, Björn; Reichel, Jens; Reinhart, Konrad; Winning, Johannes

2015-07-01

The objective was to develop and evaluate an early sepsis detection score for the prehospital setting. A retrospective analysis of consecutive patients who were admitted by emergency medical services (EMS) to the emergency department of the Jena University Hospital was performed. Because potential predictors for sepsis should be based on consensus criteria, the following parameters were extracted from the EMS protocol for further analysis: temperature, heart rate (HR), respiratory rate (RR), oxygen saturation (SaO2 ), Glasgow Coma Scale score, blood glucose, and systolic blood pressure (sBP). Potential predictors were stratified based on inspection of Loess graphs. Backward model selection was performed to select risk factors for the final model. The Prehospital Early Sepsis Detection (PRESEP) score was calculated as the sum of simplified regression weights. Its predictive validity was compared to the Modified Early Warning Score (MEWS), the Robson screening tool, and the BAS 90-30-90. A total of 375 patients were included in the derivation sample; 93 (24.8%) of these had sepsis, including 60 patients with severe sepsis and 12 patients with septic shock. Backward model selection identified temperature, HR, RR, SaO2 , and sBP for inclusion in the PRESEP score. Simplified weights were as follows: temperature > 38°C = 4, temperature < 36°C = 1, HR > 90 beats/min = 2, RR > 22 breaths/min = 1, SaO2 < 92% = 2, and sBP < 90 mm Hg = 2. The cutoff value for a possible existing septic disease based on maximum Youden's index was ≥4 (sensitivity 0.85, specificity 0.86, positive predictive value [PPV] 0.66, and negative predictive value [NPV] 0.95). The area under the receiver operating characteristic curve (AUC) of the PRESEP score was 0.93 (95% confidence interval [CI] = 0.89 to 0.96) and was larger than the AUC of the MEWS (0.93 vs. 0.77, p < 0.001). The PRESEP score surpassed MEWS and BAS 90-60-90 for sensitivity (0.74 and 0.62, respectively), specificity (0.75 and 0

Multiple begomoviruses found associated with cotton leaf curl disease in Pakistan in early 1990 are back in cultivated cotton

USDA-ARS?s Scientific Manuscript database

The first epidemic of cotton leaf curl disease (CLCuD) in the early 1990’s on the Indian subcontinent was associated with several distinct begomoviruses along with a disease-specific betasatellite. Resistant cotton varieties were introduced in the late 1990’s, but resistance was broken in early 2000...

Phosphorus and proton magnetic resonance spectroscopy demonstrates mitochondrial dysfunction in early and advanced Parkinson's disease.

PubMed

Hattingen, Elke; Magerkurth, Jörg; Pilatus, Ulrich; Mozer, Anne; Seifried, Carola; Steinmetz, Helmuth; Zanella, Friedhelm; Hilker, Rüdiger

2009-12-01

Mitochondrial dysfunction hypothetically contributes to neuronal degeneration in patients with Parkinson's disease. While several in vitro data exist, the measurement of cerebral mitochondrial dysfunction in living patients with Parkinson's disease is challenging. Anatomical magnetic resonance imaging combined with phosphorus and proton magnetic resonance spectroscopic imaging provides information about the functional integrity of mitochondria in specific brain areas. We measured partial volume corrected concentrations of low-energy metabolites and high-energy phosphates with sufficient resolution to focus on pathology related target areas in Parkinson's disease. Combined phosphorus and proton magnetic resonance spectroscopic imaging in the mesostriatal region was performed in 16 early and 13 advanced patients with Parkinson's disease and compared to 19 age-matched controls at 3 Tesla. In the putamen and midbrain of both Parkinson's disease groups, we found a bilateral reduction of high-energy phosphates such as adenosine triphophosphate and phosphocreatine as final acceptors of energy from mitochondrial oxidative phosphorylation. In contrast, low-energy metabolites such as adenosine diphophosphate and inorganic phosphate were within normal ranges. These results provide strong in vivo evidence that mitochondrial dysfunction of mesostriatal neurons is a central and persistent phenomenon in the pathogenesis cascade of Parkinson's disease which occurs early in the course of the disease.

Contribution of early Alzheimer's Disease-related Pathophysiology to the Development of Acquired epilepsy.

PubMed

Gschwind, Tilo; Lafourcade, Carlos; Gfeller, Tim; Zaichuk, Mariana; Rambousek, Lukas; Knuesel, Irene; Fritschy, Jean-Marc

2018-06-04

Aberrant epileptic activity is detectable at early disease stages in Alzheimer's disease (AD) patients and in AD mouse models. Here, we investigated in young ArcticAβ mice whether AD-like pathology renders neuronal networks more susceptible to development of acquired epilepsy induced by unilateral intrahippocampal injection of kainic acid (IHK). In this temporal lobe epilepsy model, IHK induces a status epilepticus followed after two weeks by spontaneous recurrent seizures (SRS). ArcticAβ mice exhibited more severe status epilepticus and early onset of SRS. This hyperexcitable phenotype was characterized in CA1 neurons by decreased synaptic strength, increased kainic acid-induced LTP, and reduced frequency of spontaneous inhibitory currents. However, no difference in neurodegeneration, neuroinflammation, axonal reorganization or adult neurogenesis was observed in ArcticAβ mice compared to wildtype littermates following IHK-induced epileptogenesis. Neuropeptide Y (NPY) expression was reduced at baseline and its IHK-induced elevation in mossy fibers and granule cells was attenuated. However, although this alteration might underlie premature seizure onset, neutralization of soluble Aβ species by intracerebroventricular Aβ-specific antibody application mitigated the hyperexcitable phenotype of ArcticAβ mice and prevented early SRS onset. Therefore, development of seizures at early stages of AD is mediated primarily by Aβ species causing widespread changes in synaptic function. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Identifying new diseases and their causes: the dilemma of illnesses in Gulf War veterans.

PubMed

Gardner, John W; Gibbons, Robert V; Hooper, Tomoko I; Cunnion, Stephen O; Kroenke, Kurt; Gackstetter, Gary D

2003-03-01

Since the Gulf War, investigation continues of symptoms and illnesses among its veterans. Yet, identifying a specific "Gulf War Syndrome" remains elusive. With new disease entities, causal associations are relatively easily established when the condition is serious, verifiable, and has excess disease rates in specific groups. In common conditions, many excess cases are required to establish association with a specific exposure. Establishing causality in syndromes with variable symptoms is difficult because specific diagnostic algorithms must be established before causal factors can be properly investigated. Searching for an environmental cause is futile in the absence of an operational disease case definition. Common subjective symptoms (without objective physical or laboratory findings) account for over one-half of all medical outpatient visits, yet these symptoms lack an identified physical cause at least one-third of the time. Our medical care system has difficulty dealing with disorders where there is no identified anatomic abnormality or documented metabolic/physiological dysfunction.

Routine culture-based screening versus risk-based management for the prevention of early-onset group B streptococcus disease in the neonate: a systematic review.

PubMed

Kurz, Ella; Davis, Deborah

2015-04-17

Early-onset group B streptococcus disease, recognized as the most common cause of early onset neonatal sepsis in developed countries, is transmitted vertically from the group B streptococcus carrier mother to the neonate in the peripartum. Accordingly, early-onset group B streptococcus disease is prevented by halting the transmission of the microorganism from the mother to the infant. Two main methods, routine culture-based screening and risk-based management, may be used in the identification of mothers requiring intrapartum antibiotic prophylaxis in labor. While there are advantages and disadvantages to each, there is limited high level evidence available as to which method is superior. To identify the effectiveness of risk-based management versus routine culture-based screening in the prevention of early-onset group B streptococcus disease in the neonate. This review considered studies which treated pregnant women with intrapartum antibiotic prophylaxis following risk- and culture-based protocols for the prevention of early-onset group B streptococcus disease in the neonate. Types of intervention: This review considered studies that evaluated risk-based management against routine culture-based screening for the prevention of early-onset group B streptococcus disease in the neonate. Types of studies: This review looked for highest evidence available which in this case consisted of one quasi experimental study and eight comparative cohort studies with historical or concurrent control groups. Types of outcomes: Incidence of early-onset group B streptococcus disease in neonates as measured by positive group B streptococcus culture from an otherwise sterile site. Secondary outcomes include neonatal death due to group B streptococcus sepsis and percentage of women who received intrapartum antibiotic prophylaxis. A multi-step search strategy was used to find studies which were limited to the English language and published between January 2000 and June 2013. The quality

Incidence, disease phenotype at diagnosis, and early disease course in inflammatory bowel diseases in Western Hungary, 2002-2006.

PubMed

Lakatos, Laszlo; Kiss, Lajos S; David, Gyula; Pandur, Tunde; Erdelyi, Zsuzsanna; Mester, Gabor; Balogh, Mihaly; Szipocs, Istvan; Molnar, Csaba; Komaromi, Erzsebet; Lakatos, Peter Laszlo

2011-12-01

Recent trends indicate a change in the epidemiology of inflammatory bowel diseases (IBD), with previously low incidence areas now reporting a progressive rise in the incidence. Our aim was to analyze the incidence and disease phenotype at diagnosis in IBD in the population-based Veszprem Province database, which included incident patients diagnosed between January 1, 2002 and December 31, 2006. Data of 393 incident patients were analyzed (ulcerative colitis [UC]: 220, age-at-diagnosis: 40.5 years; Crohn's disease [CD]: 163, age-at-diagnosis: 32.5 years; and indeterminate colitis [IC]: 10). Both hospital and outpatient records were collected and comprehensively reviewed. Adjusted mean incidence rates were 8.9/10(5) person-years for CD and 11.9/10(5) person-years in UC. Peak onset age in both CD and UC patients was 21-30 years old. Location at diagnosis in UC was proctitis in 26.8%, left-sided colitis in 50.9%, and pancolitis in 22.3%. The probability of proximal extension and colectomy after 5 years was 12.7% and 2.8%. The disease location in CD was ileal in 20.2%, colonic in 35.6%, ileocolonic in 44.2%, and upper gastrointestinal in four patients. Behavior at diagnosis was stenosing/penetrating in 35.6% and perianal in 11.1%. Patients with colonic disease were older at diagnosis compared to patients with ileal or ileocolonic disease. In a Kaplan-Meier analysis, probability of surgical resection was 9.8%, 18.5%, and 21.3% after 1, 3, and 5 years of disease duration, respectively. The incidence of IBD in Veszprem Province in the last decade was high, equal to that in high-incidence areas in Western European countries. Early disease course is milder compared to data reported in the literature. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

Early Renal Involvement in a Girl with Classic Fabry Disease.

PubMed

Perretta, Fernando; Antongiovanni, Norberto; Jaurretche, Sebastián

2017-01-01

Fabry disease is an X-linked lysosomal storage disorder resulting from the deficiency or absence of the enzyme alpha galactosidase A; this defect leads to the systemic accumulation of globotriaosylceramide and its metabolites. Organic involvement in men is well known, but in women it is controversial, mainly due to the random X-chromosome inactivation in each of their cells (Lyon hypothesis). This would explain why women (heterozygotes) present a wide variability in the severity of their phenotype. The manifestations are multisystemic and begin in early childhood, reaching a severe compromise in adulthood. Typical acroparesthesia in hands and feet, gastrointestinal symptoms, angiokeratomas, dyshidrosis, hearing loss, arrhythmias, hypertrophic cardiomyopathy, cerebrovascular accidents, and renal failure can be observed. Nephropathy is one of the major complications of Fabry disease. Glomerular and vascular changes are present before progression to overt proteinuria and decreased glomerular filtration rate, even in pediatric patients. A case of incipient renal involvement in a girl with classic Fabry disease is reported.

Identifying economic hurdles to early adoption of preventative practices: The case of trunk diseases in California winegrape vineyards

USDA-ARS?s Scientific Manuscript database

Trunk diseases pose a serious threat to winegrape production. Despite the high likelihood of infection and the substantial yield losses from not managing trunk diseases, many practitioners routinely wait to adopt field-tested, preventative practices (delayed pruning, double pruning, application of p...

High-accuracy detection of early Parkinson's Disease using multiple characteristics of finger movement while typing

PubMed Central

2017-01-01

Parkinson’s Disease (PD) is a progressive neurodegenerative movement disease affecting over 6 million people worldwide. Loss of dopamine-producing neurons results in a range of both motor and non-motor symptoms, however there is currently no definitive test for PD by non-specialist clinicians, especially in the early disease stages where the symptoms may be subtle and poorly characterised. This results in a high misdiagnosis rate (up to 25% by non-specialists) and people can have the disease for many years before diagnosis. There is a need for a more accurate, objective means of early detection, ideally one which can be used by individuals in their home setting. In this investigation, keystroke timing information from 103 subjects (comprising 32 with mild PD severity and the remainder non-PD controls) was captured as they typed on a computer keyboard over an extended period and showed that PD affects various characteristics of hand and finger movement and that these can be detected. A novel methodology was used to classify the subjects’ disease status, by utilising a combination of many keystroke features which were analysed by an ensemble of machine learning classification models. When applied to two separate participant groups, this approach was able to successfully discriminate between early-PD subjects and controls with 96% sensitivity, 97% specificity and an AUC of 0.98. The technique does not require any specialised equipment or medical supervision, and does not rely on the experience and skill of the practitioner. Regarding more general application, it currently does not incorporate a second cardinal disease symptom, so may not differentiate PD from similar movement-related disorders. PMID:29190695

Long-term Assessment of Post-Treatment Symptoms in Patients With Culture-Confirmed Early Lyme Disease.

PubMed

Weitzner, Erica; McKenna, Donna; Nowakowski, John; Scavarda, Carol; Dornbush, Rhea; Bittker, Susan; Cooper, Denise; Nadelman, Robert B; Visintainer, Paul; Schwartz, Ira; Wormser, Gary P

2015-12-15

Lyme disease patients with erythema migrans are said to have post-treatment Lyme disease symptoms (PTLDS) if there is persistence of subjective symptoms for at least 6 months following antibiotic treatment and resolution of the skin lesion. The purpose of this study was to characterize PTLDS in patients with culture-confirmed early Lyme disease followed for >10 years. Adult patients with erythema migrans with a positive skin or blood culture for Borrelia burgdorferi were enrolled in a prospective study beginning in 1991 and followed up at 6 months and annually thereafter to determine the long-term outcome of this infection. The genotype of the infecting strain of B. burgdorferi was evaluated in subjects with PTLDS. One hundred twenty-eight subjects with culture-confirmed early Lyme disease, of whom 55% were male, were followed for a mean ± SD of 14.98 ± 2.71 years (median = 15 years; range = 11-20 years). Fourteen (10.9%) were regarded as having possible PTLDS, but only 6 (4.7%) had PTLDS documented at their last study visit. Nine (64.3%) had only a single symptom. None of the 6 with PTLDS at their last visit was considered to be functionally impaired by the symptom(s). PTLDS was not associated with a particular genotype of B. burgdorferi. PTLDS may persist for >10 years in some patients with culture-confirmed early Lyme disease. Such long-standing symptoms were not associated with functional impairment or a particular strain of B. burgdorferi. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Early pathology in sleep studies of patients with familial Creutzfeldt-Jakob disease.

PubMed

Givaty, Gili; Maggio, Nicola; Cohen, Oren S; Blatt, Ilan; Chapman, Joab

2016-10-01

In this study, we aimed to assess sleep function in patients with recent-onset familial Creutzfeldt-Jakob disease (fCJD). The largest cluster of fCJD patients is found in Jews of Libyan origin, linked to the prion protein gene (PRNP) E200K mutation. The high index of suspicion in these patients often leads to early diagnosis, with complaints of insomnia being a very common presenting symptom of the disease. The study included 10 fCJD patients diagnosed by clinical manifestations, magnetic resonance imaging (MRI) scan of the brain, elevated tau protein in the cerebrospinal fluid (CSF) and positive PRNP E200K mutation. Standard polysomnography was performed after a brief interview confirming the presence of sleep disturbances. All patients showed a pathological sleep pattern according to all scoring evaluation settings. The sleep stages were characterized by (i) disappearance of sleep spindles; (ii) outbursts of periodic sharp waves and shallowing of sleep consisting in increased Stage 2 and wake periods during the night, as well as decrease of slow-wave sleep and rapid eye movement (REM) sleep. Recordings of respiratory functions reported irregular breathing with central and obstructive apnea and hypopnea. The typical hypotonia occurring during the night and atonia during REM sleep were replaced by hyperactive sleep consisting of multiple jerks, movements and parasomnia (mainly talking) throughout the night. In conclusion, we report unique pathological sleep patterns in early fCJD associated with the E200K mutation. Specific respiratory disturbances and lack of atonia could possibly serve as new, early diagnostic tools in the disease. © 2016 European Sleep Research Society.

Severe and Rapid Progression in Very Early-Onset Chronic Granulomatous Disease-Associated Colitis.

PubMed

Kawai, Toshinao; Arai, Katsuhiro; Harayama, Shizuko; Nakazawa, Yumiko; Goto, Fumihiro; Maekawa, Takanobu; Tamura, Eiichiro; Uchiyama, Toru; Onodera, Masafumi

2015-08-01

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease that leads to recurrent infection and hyper-inflammation, occasionally represented by CGD-associated colitis (CGD colitis). Although clinical symptoms of CGD colitis mimic those of ulcerative colitis (UC), there is no reliable standard measurement of disease activity or standard therapeutic strategy for CGD colitis. Here, we examined the clinical manifestation of CGD colitis based on severity using a noninvasive measure of disease activity, the Pediatric Ulcerative Colitis Activity Index (PUCAI), which has been validated and widely used for pediatric UC. Sixteen of 35 CGD patients, who were diagnosed with CGD colitis based on colonoscopic and histological findings, were examined using the PUCAI. Both the PUCAI and the physician global assessment (PGA) tool were retrospectively scored by reviewing medical records. Disease activity defined by PUCAI was correlated with PGA, and increased at diagnosis of CGD colitis, especially in patients who were younger than 6 years of age (very early-onset CGD colitis: VEO-CGD colitis) when diagnosed with CGD colitis. All severe patients had a more progressive form of VEO-CGD colitis. Unlike mild and moderate patients, severe patients required multidrug therapy of corticosteroids and immunomodulator/immunosuppressants, and some were eventually treated with hematopoietic stem cell transplantation. Although the validation of PUCAI in CGD colitis should be considered for future use, our results indicate that noninvasive measures could be effective to measure disease activity and help to determine suitable treatment for CGD colitis. In patients with VEO-CGD colitis, multidrug therapy would need to be considered at an early stage on the basis of disease activity.

Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease.

PubMed

Lam, Alice D; Deck, Gina; Goldman, Alica; Eskandar, Emad N; Noebels, Jeffrey; Cole, Andrew J

2017-06-01

We directly assessed mesial temporal activity using intracranial foramen ovale electrodes in two patients with Alzheimer's disease (AD) without a history or EEG evidence of seizures. We detected clinically silent hippocampal seizures and epileptiform spikes during sleep, a period when these abnormalities were most likely to interfere with memory consolidation. The findings in these index cases support a model in which early development of occult hippocampal hyperexcitability may contribute to the pathogenesis of AD.

FDG-PET in early AD diagnosis.

PubMed

Chew, Jessica; Silverman, Daniel H S

2013-05-01

FDG-PET is a valuable tool that will continue to aid in identifying AD in its prodromal and early dementia stages, distinguishing it from other causes of dementia, and tracking progression of the disease. As brain FDG-PET scans and well-trained readers of these scans are becoming more widely available to clinicians who are becoming more informed about the role FDG-PET can play in early AD diagnosis, its use is expected to increase. Copyright © 2013 Elsevier Inc. All rights reserved.

Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer disease.

PubMed

Donovan, Nancy J; Amariglio, Rebecca E; Zoller, Amy S; Rudel, Rebecca K; Gomez-Isla, Teresa; Blacker, Deborah; Hyman, Bradley T; Locascio, Joseph J; Johnson, Keith A; Sperling, Reisa A; Marshall, Gad A; Rentz, Dorene M

2014-12-01

To examine neuropsychiatric and neuropsychological predictors of progression from normal to early clinical stages of Alzheimer disease (AD). From a total sample of 559 older adults from the Massachusetts Alzheimer's Disease Research Center longitudinal cohort, 454 were included in the primary analysis: 283 with clinically normal cognition (CN), 115 with mild cognitive impairment (MCI), and 56 with subjective cognitive concerns (SCC) but no objective impairment, a proposed transitional group between CN and MCI. Two latent cognitive factors (memory-semantic, attention-executive) and two neuropsychiatric factors (affective, psychotic) were derived from the Alzheimer's Disease Centers' Uniform Data Set neuropsychological battery and Neuropsychiatric Inventory brief questionnaire. Factors were analyzed as predictors of time to progression to a worse diagnosis using a Cox proportional hazards regression model with backward elimination. Covariates included baseline diagnosis, gender, age, education, prior depression, antidepressant medication, symptom duration, and interaction terms. Higher/better memory-semantic factor score predicted lower hazard of progression (hazard ratio [HR] = 0.4 for 1 standard deviation [SD] increase, p <0.0001), and higher/worse affective factor score predicted higher hazard (HR = 1.3 for one SD increase, p = 0.01). No other predictors were significant in adjusted analyses. Using diagnosis as a sole predictor of transition to MCI, the SCC diagnosis carried a fourfold risk of progression compared with CN (HR = 4.1, p <0.0001). These results identify affective and memory-semantic factors as significant predictors of more rapid progression from normal to early stages of cognitive decline and highlight the subgroup of cognitively normal elderly with SCC as those with elevated risk of progression to MCI. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Mild cognitive impairment: an opportunity to identify patients at high risk for progression to Alzheimer's disease.

PubMed

Levey, Allan; Lah, James; Goldstein, Felicia; Steenland, Kyle; Bliwise, Donald

2006-07-01

There is increasing evidence that subtle losses in cognitive function may be symptomatic of a transition to early Alzheimer's disease (AD). Ongoing research is focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to AD. Of the MCI subtypes, patients with amnestic MCI (a-MCI) are at greatest risk. The objectives of this article were to review the relationship between MCI, normal aging, and AD, and to summarize recent research on the diagnosis and potential treatment of MCI. Relevant articles were identified through searches of MEDLINE and EMBASE using the terms mild cognitive impairment; cognitive impairment, no dementia; and dementia prodrome, with no restrictions as to year. Additional papers of interest were identified from the reference lists of the identified articles. The search was current as of February 2006. Guidelines and recommendations are being developed to assist physicians in diagnosing MCI, identifying its subtype and etiology, understanding the risks for conversion to AD, and managing disease progression. Given the existence of a subset of individuals with a-MCI, who are at greatest risk for progression to AD but still have high levels of cognition and function, the ability to improve symptoms and delay progression to AD would be particularly beneficial. In a 3-year, randomized, double-blind, placebo-controlled study in 769 patients with a-MCI, treatment with the cholinesterase inhibitor donepezil was associated with a significantly lower rate of progression to AD compared with placebo during the first 12 months of treatment (hazard ratio=0.42; 95% CI, 0.24-0.76; P=0.004) but not at later time points. Of other types of agents that have been investigated (antioxidants, estrogen replacement therapy, cyclooxygenase-2-selective inhibitors), none have shown significant beneficial effects in delaying cognitive decline or progression to AD. New drugs such as secretase inhibitors, small

Genetic moderation of multiple pathways linking early cumulative socioeconomic adversity and young adults' cardiometabolic disease risk.

PubMed

Wickrama, Kandauda A S; Lee, Tae Kyoung; O'Neal, Catherine Walker

2018-02-01

Recent research suggests that psychosocial resources and life stressors are mediating pathways explaining socioeconomic variation in young adults' health risks. However, less research has examined both these pathways simultaneously and their genetic moderation. A nationally representative sample of 11,030 respondents with prospective data collected over 13 years from the National Study of Adolescent to Adult Health was examined. First, the association between early cumulative socioeconomic adversity and young adults' (ages 25-34) cardiometabolic disease risk, as measured by 10 biomarkers, through psychosocial resources (educational attainment) and life stressors (accelerated transition to adulthood) was examined. Second, moderation of these pathways by the serotonin transporter linked polymorphic region gene (5-HTTLPR) was examined. There was evidence for the association between early socioeconomic adversity and young adults' cardiometabolic disease risk directly and indirectly through educational attainment and accelerated transitions. These direct and mediating pathways were amplified by the 5-HTTLPR polymorphism. These findings elucidate how early adversity can have an enduring influence on young adults' cardiometabolic disease risk directly and indirectly through psychosocial resources and life stressors and their genetic moderation. This information suggests that effective intervention and prevention programs should focus on early adversity, youth educational attainment, and their transition to young adulthood.

Clues for early detection of autoimmune Addison's disease - myths and realities.

PubMed

Saevik, Å B; Åkerman, A-K; Grønning, K; Nermoen, I; Valland, S F; Finnes, T E; Isaksson, M; Dahlqvist, P; Bergthorsdottir, R; Ekwall, O; Skov, J; Nedrebø, B G; Hulting, A-L; Wahlberg, J; Svartberg, J; Höybye, C; Bleskestad, I H; Jørgensen, A P; Kämpe, O; Øksnes, M; Bensing, S; Husebye, E S

2018-02-01

Early detection of autoimmune Addison's disease (AAD) is important as delay in diagnosis may result in a life-threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well-described, but methodical investigations are scarce. Perform a retrospective audit of patient records with the aim of identifying biochemical markers for early diagnosis of AAD. A multicentre retrospective study including 272 patients diagnosed with AAD at hospitals in Norway and Sweden during 1978-2016. Scrutiny of medical records provided patient data and laboratory values. Low sodium occurred in 207 of 247 (84%), but only one-third had elevated potassium. Other common nonendocrine tests were largely normal. TSH was elevated in 79 of 153 patients, and hypoglycaemia was found in 10%. Thirty-three per cent were diagnosed subsequent to adrenal crisis, in whom electrolyte disturbances were significantly more pronounced (P < 0.001). Serum cortisol was consistently decreased (median 62 nmol L -1 [1-668]) and significantly lower in individuals with adrenal crisis (38 nmol L -1 [2-442]) than in those without (81 nmol L -1 [1-668], P < 0.001). The most consistent biochemical finding of untreated AAD was low sodium independent of the degree of glucocorticoid deficiency. Half of the patients had elevated TSH levels. Only a minority presented with marked hyperkalaemia or other nonhormonal abnormalities. Thus, unexplained low sodium and/or elevated TSH should prompt consideration of an undiagnosed AAD, and on clinical suspicion bring about assay of cortisol and ACTH. Presence of 21-hydroxylase autoantibodies confirms autoimmune aetiology. Anticipating additional abnormalities in routine blood tests may delay diagnosis. © 2017 The Association for the Publication of the Journal of Internal Medicine.

Signal and image processing for early detection of coronary artery diseases: A review

NASA Astrophysics Data System (ADS)

Mobssite, Youness; Samir, B. Belhaouari; Mohamad Hani, Ahmed Fadzil B.

2012-09-01

Today biomedical signals and image based detection are a basic step to diagnose heart diseases, in particular, coronary artery diseases. The goal of this work is to provide non-invasive early detection of Coronary Artery Diseases relying on analyzing images and ECG signals as a combined approach to extract features, further classify and quantify the severity of DCAD by using B-splines method. In an aim of creating a prototype of screening biomedical imaging for coronary arteries to help cardiologists to decide the kind of treatment needed to reduce or control the risk of heart attack.

Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex.

PubMed

Wilbe, Maria; Jokinen, Päivi; Truvé, Katarina; Seppala, Eija H; Karlsson, Elinor K; Biagi, Tara; Hughes, Angela; Bannasch, Danika; Andersson, Göran; Hansson-Hamlin, Helene; Lohi, Hannes; Lindblad-Toh, Kerstin

2010-03-01

The unique canine breed structure makes dogs an excellent model for studying genetic diseases. Within a dog breed, linkage disequilibrium is extensive, enabling genome-wide association (GWA) with only around 15,000 SNPs and fewer individuals than in human studies. Incidences of specific diseases are elevated in different breeds, indicating that a few genetic risk factors might have accumulated through drift or selective breeding. In this study, a GWA study with 81 affected dogs (cases) and 57 controls from the Nova Scotia duck tolling retriever breed identified five loci associated with a canine systemic lupus erythematosus (SLE)-related disease complex that includes both antinuclear antibody (ANA)-positive immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis-arteritis (SRMA). Fine mapping with twice as many dogs validated these loci. Our results indicate that the homogeneity of strong genetic risk factors within dog breeds allows multigenic disorders to be mapped with fewer than 100 cases and 100 controls, making dogs an excellent model in which to identify pathways involved in human complex diseases.

Disease Management of Early Childhood Caries: ECC Collaborative Project.

PubMed

Ng, Man Wai; Ramos-Gomez, Francisco; Lieberman, Martin; Lee, Jessica Y; Scoville, Richard; Hannon, Cindy; Maramaldi, Peter

2014-01-01

Until recently, the standard of care for early childhood caries (ECC) has been primarily surgical and restorative treatment with little emphasis on preventing and managing the disease itself. It is now recognized that surgical treatment alone does not address the underlying etiology of the disease. Despite costly surgeries and reparative treatment, the onset and progression of caries are likely to continue. A successful rebalance of risk and protective factors may prevent, slow down, or even arrest dental caries and its progression. An 18-month risk-based chronic disease management (DM) approach to address ECC in preschool children was implemented as a quality improvement (QI) collaborative by seven teams of oral health care providers across the United States. In the aggregate, fewer DM children experienced new cavitation, pain, and referrals to the operating room (OR) for restorative treatment compared to baseline historical controls. The teams found that QI methods facilitated adoption of the DM approach and resulted in improved care to patients and better outcomes overall. Despite these successes, the wide scale adoption and spread of the DM approach may be limited unless health policy and payment reforms are enacted to compensate providers for implementing DM protocols in their practice.

Air pollution in early life and adult mortality from chronic rheumatic heart disease.

PubMed

Phillips, David I W; Osmond, Clive; Williams, Martin L; Jones, Alexander

2017-08-01

Chronic rheumatic heart disease (RHD) remains a globally important cause of heart disease. The reasons for the continuing high prevalence of this disease are obscure, but it may have its origins in the poor social and economic conditions with which the disease has been consistently and strongly linked. Mortality studies from the UK have suggested the importance of adverse environmental factors in early life; these studies demonstrated specific geographical associations between high rates of chest infection during infancy and subsequent RHD. They raised the possibility that early air pollution, which is known to be strongly linked with chest infection during infancy, may predispose to RHD. We related estimates of air pollution and social conditions developed by Daly in 1951-52 for 78 urban areas in England and Wales to their subsequent RHD mortality rates at ages 35-74 in men and women during 1993-2012. There were strong relationships between domestic air pollution and RHD [relative risk per standard deviation (SD) increase in pollution 1.168, 95% confidence interval (CI): 1.128 to 1.210, P < 0.001). Inclusion of published data on social class, education, crowding and population density in multiple regression analyses showed that the air pollution association was independent of these; only overcrowding was separately linked with RHD. We present the first evidence of an association between air pollution in early life and RHD. Although there are several limitations to this study, the strength and consistency of the results, together with their biological plausibility, suggest a causal link. This deserves attention because it may have important consequences for the control of RHD in resource-poor countries where widespread use of biomass fuels and domestic pollution remain a problem. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association

Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease.

PubMed

Eriksson, D; Bianchi, M; Landegren, N; Nordin, J; Dalin, F; Mathioudaki, A; Eriksson, G N; Hultin-Rosenberg, L; Dahlqvist, J; Zetterqvist, H; Karlsson, Å; Hallgren, Å; Farias, F H G; Murén, E; Ahlgren, K M; Lobell, A; Andersson, G; Tandre, K; Dahlqvist, S R; Söderkvist, P; Rönnblom, L; Hulting, A-L; Wahlberg, J; Ekwall, O; Dahlqvist, P; Meadows, J R S; Bensing, S; Lindblad-Toh, K; Kämpe, O; Pielberg, G R

2016-12-01

Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10 -15 , MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex. Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment. © 2016 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

Identifying Multimodal Intermediate Phenotypes between Genetic Risk Factors and Disease Status in Alzheimer’s Disease