Pre-disease State Research Articles

Identifying critical transitions of complex diseases based on a single sample

Unlike traditional diagnosis of an existing disease state, detecting the pre-disease state just before the serious deterioration of a disease is a challenging task, because the state of the system may show little apparent change or symptoms before this critical transition during disease progression. By exploring the rich interaction information provided by high-throughput data, the dynamical network biomarker (DNB) can identify the pre-disease state, but this requires multiple samples to reach a correct diagnosis for one individual, thereby restricting its clinical application. In this article, we have developed a novel computational approach based on the DNB theory and differential distributions between the expressions of DNB and non-DNB molecules, which can detect the pre-disease state reliably even from a single sample taken from one individual, by compensating insufficient samples with existing datasets from population studies. Our approach has been validated by the successful identification of pre-disease samples from subjects or individuals before the emergence of disease symptoms for acute lung injury, influenza and breast cancer.

Chondrogenic Differentiation of Human Adipose-Derived Stem Cells: A New Path in Articular Cartilage Defect Management?

According to data published by the Centers for Disease Control and Prevention, over 6 million people undergo a variety of medical procedures for the repair of articular cartilage defects in the U.S. each year. Trauma, tumor, and age-related degeneration can cause major defects in articular cartilage, which has a poor intrinsic capacity for healing. Therefore, there is substantial interest in the development of novel cartilage tissue engineering strategies to restore articular cartilage defects to a normal or prediseased state. Special attention has been paid to the expansion of chondrocytes, which produce and maintain the cartilaginous matrix in healthy cartilage. This review summarizes the current efforts to generate chondrocytes from adipose-derived stem cells (ASCs) and provides an outlook on promising future strategies.

Early Diagnosis of Complex Diseases by Molecular Biomarkers, Network Biomarkers, and Dynamical Network Biomarkers

Many studies have been carried out for early diagnosis of complex diseases by finding accurate and robust biomarkers specific to respective diseases. In particular, recent rapid advance of high-throughput technologies provides unprecedented rich information to characterize various disease genotypes and phenotypes in a global and also dynamical manner, which significantly accelerates the study of biomarkers from both theoretical and clinical perspectives. Traditionally, molecular biomarkers that distinguish disease samples from normal samples are widely adopted in clinical practices due to their ease of data measurement. However, many of them suffer from low coverage and high false-positive rates or high false-negative rates, which seriously limit their further clinical applications. To overcome those difficulties, network biomarkers (or module biomarkers) attract much attention and also achieve better performance because a network (or subnetwork) is considered to be a more robust form to characterize diseases than individual molecules. But, both molecular biomarkers and network biomarkers mainly distinguish disease samples from normal samples, and they generally cannot ensure to identify predisease samples due to their static nature, thereby lacking ability to early diagnosis. Based on nonlinear dynamical theory and complex network theory, a new concept of dynamical network biomarkers (DNBs, or a dynamical network of biomarkers) has been developed, which is different from traditional static approaches, and the DNB is able to distinguish a predisease state from normal and disease states by even a small number of samples, and therefore has great potential to achieve "real" early diagnosis of complex diseases. In this paper, we comprehensively review the recent advances and developments on molecular biomarkers, network biomarkers, and DNBs in particular, focusing on the biomarkers for early diagnosis of complex diseases considering a small number of samples and high-throughput data (or big data). Detailed comparisons of various types of biomarkers as well as their applications are also discussed.

Detecting early-warning signals of type 1 diabetes and its leading biomolecular networks by dynamical network biomarkers

BackgroundType 1 diabetes (T1D) is a complex disease and harmful to human health, and most of the existing biomarkers are mainly to measure the disease phenotype after the disease onset (or drastic deterioration). Until now, there is no effective biomarker which can predict the upcoming disease (or pre-disease state) before disease onset or disease deterioration. Further, the detail molecular mechanism for such deterioration of the disease, e.g., driver genes or causal network of the disease, is still unclear.MethodsIn this study, we detected early-warning signals of T1D and its leading biomolecular networks based on serial gene expression profiles of NOD (non-obese diabetic) mice by identifying a new type of biomarker, i.e., dynamical network biomarker (DNB) which forms a specific module for marking the time period just before the drastic deterioration of T1D.ResultsTwo dynamical network biomarkers were obtained to signal the emergence of two critical deteriorations for the disease, and could be used to predict the upcoming sudden changes during the disease progression. We found that the two critical transitions led to peri-insulitis and hyperglycemia in NOD mices, which are consistent with other independent experimental results from literature.ConclusionsThe identified dynamical network biomarkers can be used to detect the early-warning signals of T1D and predict upcoming disease onset before the drastic deterioration. In addition, we also demonstrated that the leading biomolecular networks are causally related to the initiation and progression of T1D, and provided the biological insight into the molecular mechanism of T1D. Experimental data from literature and functional analysis on DNBs validated the computational results.

Diagnosing and Managing Predisease States in Women's Health

Diagnosing and Managing Predisease States in Women's Health

Clinical relevance of differential lymphocyte recovery after alemtuzumab therapy for multiple sclerosis

Alemtuzumab is potentially a highly effective treatment for relapsing multiple sclerosis (MS) acting via complement-mediated lysis of circulating lymphocytes. Variability in posttreatment lymphocyte recovery time is observed, with some patients showing striking durability in the efficacy of treatment. This study aims to establish whether this observed variation affects clinical and imaging parameters of disease activity. A total of 56 patients were followed for a median of 39.5 months post alemtuzumab treatment with interval clinical assessments, lymphocyte immunophenotyping, and MRI. Timing and degree of CD4+, CD8+, and CD19+ recovery were correlated with the re-emergence of disease activity defined as clinical relapse, increasing disability, and new T2/enhancing lesions on MRI. New disease activity was recorded in 14% of patients. Mean time to CD19+, CD8+, and CD4+ reconstitution was 6, 10, and 36 months. No differences were observed in CD8+ and CD19+ reconstitution between patients with active disease and those in remission. Patients with active disease showed an accelerated recovery of CD4+ cells (p = 0.001) with a difference in absolute CD4+ counts at 24 months (p = 0.009). CD4+ counts <388.5 × 10(6) cells/mL predicted MRI stability. Differential lymphocyte recovery in MS following alemtuzumab may be a biomarker for relapse and also inform monitoring and treatment protocols. This study provides Class IV evidence that differential lymphocyte reconstitution after alemtuzumab treatment may be a biomarker for relapse.

Associations of Lifestyle Factors, Disease History and Awareness with Health-Related Quality of Life in a Thai Population

BackgroundThe impact of the presence and awareness of individual health states on quality of life (HRQoL) is often documented. However, the impacts of different health states have rarely been compared amongst each other, whilst quality of life data from Asia are relatively sparse. We examined and compared the effects of different health states on quality of life in a Thai population.MethodsIn 2008–2009, 5,915 corporate employees were invited to participate in a survey where HRQoL was measured by the Short Form 36 (SF-36) questionnaire. The adjusted mean SF-36 scores were calculated for each self-reported illness, number of chronic conditions, lifestyle factors and awareness of diabetes and hypertension. The effect sizes (ES) were compared using Cohen's d.ResultsThe response rate was 82% and 4,683 (79.1%) had complete data available for analysis. Physical and Mental Component Summary (PCS and MCS) scores decreased as the number of chronic conditions increased monotonically (p<0.0001). Diabetes and hypertension negatively influenced PCS (mean score differences −0.6 and −1.5, p<0.001 respectively) but not MCS, whereas awareness of diabetes and hypertension negatively influenced MCS (−2.9 and −1.6, p<0.005 respectively) but not PCS. Arthritis had the largest ES on PCS (−0.37), while awareness of diabetes had the largest ES on MCS (−0.36). CVD moderately affected PCS and MCS (ES −0.34 and −0.27 respectively). Obesity had a negative effect on PCS (ES −0.27). Exercise positively affected PCS and MCS (ES +0.08 and +0.21 (p<0.01) respectively).ConclusionHealth promotion to reduce the prevalence of chronic diseases is important to improve the quality of life in Asian populations. Physical activity is an important part of such programs. Awareness of diseases may have greater impacts on mental health than having the disease itself. This has implications for the evaluation of the cost-benefit of screening and labeling of individuals with pre-disease states.

Characterization of the multiple sclerosis traits: Nuclear receptors (NR) impaired apoptosis pathway and the role of 1-alpha 25-dihydroxyvitamin D3

Low expression of NR4A gene family members (NR4A1, NR4A3) and 1-alpha, 25-dihydroxyvitamin D3 receptor (VDR) genes was demonstrated in peripheral blood mononuclear cells (PBMC) of subjects evaluated during the pre-disease state of multiple sclerosis (MS-to-be, MS2b), in patients with clinically isolated syndrome (CIS) during the very early presentation of neurological symptomatology and in relapsing-remitting MS (RRMS) patients. Both NR4A1 and NR4A3 are known to be involved in T-cell receptor-induced apoptosis and are regulated by VDR. We further evaluated the precise implications of apoptosis signaling regulators in relation to MS pathogenesis at the cellular level by studying the effects of 1-alpha, 25-dihydroxyvitamin D3 (Vit D3) upon NR4A1 expression. We demonstrated that the low apoptotic level in MS patients was repaired by Vit D3 mainly through NR4A1 and to a lesser extent thorough BCL2-associated X protein (BAX). These findings prove a role for Vit D3 as a possible therapeutic intervention in MS patients aimed to activate the repressed apoptosis and enhance better control of the disease.

SAMP1/YitFc mouse strain: A spontaneous model of Crohnʼs disease-like ileitis

The SAMP1/YitFc mouse strain represents a model of Crohn's disease (CD)-like ileitis that is ideal for investigating the pathogenesis of chronic intestinal inflammation. Different from the vast majority of animal models of colitis, the ileal-specific phenotype characteristic of SAMP1/YitFc mice occurs spontaneously, without genetic, chemical, or immunological manipulation. In addition, SAMP1/YitFc mice possess remarkable similarities to the human condition with regard to disease location, histologic features, incidence of extraintestinal manifestations, and response to conventional therapies. SAMP1/YitFc mice also display a well-defined time course of a predisease state and phases of acute and chronic ileitis. As such, the SAMP1/YitFc model is particularly suitable for elucidating pathways that precede the clinical phenotype that may lead to preventive, and therefore more efficacious, intervention with the natural course of disease, or alternatively, for the development of therapeutic strategies directed against chronic, established ileitis. In this review we summarize important contributions made by our group and others that uncover potential mechanisms in the pathogenesis of CD using this unique murine model of chronic intestinal inflammation.

Assessment of insulin resistance in normoglycemic young adults

Detection of Insulin resistance (IR) in normoglycemic young subjects before the onset of Impaired Glucose Tolerance (IGT) is of importance as it affords implementation of preventive measures in such high risk subject. Very few studies have specifically evaluated for the presence of IR in younger age group with normal glucose tolerance. The gold standard for investigating and quantifying insulin resistance is the "hyperinsulinemic euglycemic clamp," the complicated nature of the "clamp" technique, alternatives have been sought to simplify the measurement of insulin resistance. The oral glucose tolerance test (OGTT) is one of the most commonly used methods to evaluate whole body glucose tolerance in vivo. IR & IS values of HOMA-IR, ISI 0-120, QUICKIE mathematical models derived from OGTT have been shown to produce equivalent results as in Euglycemic clamp technique we hypothesized that normoglycemic young adult who are siblings of type II diabetics (SD) probably have higher IR values than the siblings of non diabetics as they are genetically predisposed. In this study 79 normal young adult volunteers, 40 subjects with family history of diabetes (SD) and 39 subjects without family history of diabetes (SND), in the age range of 18 to 25 years were evaluated for Insulin resistance. Standard (75 g) OGTT was performed on all the study subjects after an overnight fast. Fasting (basal), 30, 120 min venous plasma glucose & Corresponding specific insulin concentration was determined by radioimmuno assay (RIA) using a human specific antibody RIA kit. In each subject, the degree of insulin resistance was estimated by various parameters of Insulin resistance & sensitivity that were calculated using physiological mathematical models like HOMA-IR, ISI0-120, IGI, QUICKIE and their formulas derived from OGTT. The mean age of the study population was 19.01 (18 to 25 years), Male: 33 (41.3%) and Female: 47 (58.8%). The normoglycemic subjects were categorized as Siblings of Diabetics (SD n = 40) and siblings of non-diabetics(SND n = 39). Both the groups were matched by physical, clinical and routine laboratory parameters and were not statistically significant different. Siblings of diabetics had a statistically significant higher values of insulin at baseline, 30 min & 120 minutes and glucose at 30 minutes. Siblings of diabetics had a significantly higher insulin resistance and lower insulin sensitivity indices as in HOMA-IR (2.01527, p < 0.017), ISIO-120 (56.27, p < 0.002) and I0/G0 ratio (0.122381, p < 0.012) and a trend towards significance for QUICKIE(0.29578, p < 0.056). Detection of insulin resistance in normoglycemic young adult subjects in pre-disease state is feasible using mathematical models like HOMA IR, ISIO-120 from OGTT. OGTT is simple and a generally acceptable test. Siblings of diabetics had higher Insulin resistance values and lower Insulin sensitivity values. Physiological models like HOMA IR, QUICKIE, I0/G0 ratio, IGI, ISIO-120 are simple & cost effective method for screening Insulin resistance. Diagnosis of Insulin resistance in pre-disease state allows initiation of preventive measures like life style modification, diet & exercise, thereby preventing the high risk subjects from progressing to disease state.

A Review of Metabolic Syndrome as Systemic Pre-disease State Developing Through Adipose Tissue Disease

A Review of Metabolic Syndrome as Systemic Pre-disease State Developing Through Adipose Tissue Disease

Microarray analysis identifies altered regulation of nuclear receptor family members in the pre-disease state of multiple sclerosis

Molecular mechanisms that influence susceptibility to multiple sclerosis are poorly understood. We analyzed peripheral blood gene expression profiles in nine healthy subjects up to nine years before the onset of multiple sclerosis in comparison with 11 age-, gender-, and origin-matched healthy subjects who remained multiple sclerosis-free, and 31 subjects during the first clinical episode of multiple sclerosis. Within the 1051 highly variable genes that differentiated between multiple sclerosis-to-be and multiple sclerosis-free subjects, we identified activation of TCR signaling that triggered the Cbl and MAPK cascade in concert with downstream synergic over-expression of NFAT and MEF2B, but failed to augment the expression of the nuclear receptor gene family members NR4A1, NR2F1, VDR and MEF2B, that further resulted in impaired apoptotic machinery. Comparison between multiple sclerosis-to-be and first clinical onset of multiple sclerosis operating module networks demonstrated the evolution of altered regulation of nuclear receptor-dependent apoptosis. Our findings demonstrating a silent multiple sclerosis trait that is associated with suppressed expression of the nuclear receptor network and inhibited apoptosis of activated T-cells support the role of these transcription signals in the evolution of the autoimmune processes that operate in the pre-disease stage of multiple sclerosis.

Noopept stimulates the expression of NGF and BDNF in rat hippocampus

We studied the effect of original dipeptide preparation Noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111) with nootropic and neuroprotective properties on the expression of mRNA for neurotropic factors NGF and BDNF in rat hippocampus. Expression of NGF and BDNF mRNA in the cerebral cortex and hippocampus was studied by Northern blot analysis. Taking into account the fact that pharmacological activity of Noopept is realized after both acute and chronic treatment, we studied the effect of single and long-term treatment (28 days) with this drug. Expression of the studied neurotropic factors in the cerebral cortex was below the control after single administration of Noopept, while chronic administration caused a slight increase in BDNF expression. In the hippocampus, expression of mRNA for both neurotrophins increased after acute administration of Noopept. Chronic treatment with Noopept was not followed by the development of tolerance, but even potentiated the neurotrophic effect. These changes probably play a role in neuronal restoration. We showed that the nootropic drug increases expression of neurotrophic factors in the hippocampus. Our results are consistent with the hypothesis that neurotrophin synthesis in the hippocampus determines cognitive function, particularly in consolidation and delayed memory retrieval. Published data show that neurotrophic factor deficiency in the hippocampus is observed not only in advanced Alzheimer's disease, but also at the stage of mild cognitive impairment (pre-disease state). In light of this our findings suggest that Noopept holds much promise to prevent the development of Alzheimer's disease in patients with mild cognitive impairment. Moreover, therapeutic effectiveness of Noopept should be evaluated at the initial stage of Alzheimer's disease.

Evidence-Based Management of Nutrigenomics Expectations and ELSIs

Nutrigenomics is a new application context for genomics technologies that focuses on the bidirectional study of genetic factors influencing host (individuals' or populations') response to diet and the effects of bioactive constituents in food on host genome and gene expression. Nutrigenomics is considered the next wave after pharmacogenomics for individualization of health interventions. However, relatively little attention has been given to the specific ethical-legal-social issues (ELSIs) and sociotechnical expectations raised by nutrigenomics research. Some of the ELSIs, such as ensuring privacy of genetic information and implications of genetic testing for health insurance and employment, may be shared across the continuum of genomic technology applications in human disease genetics, pharmacogenomics and nutrigenomics. However, there are certain aspects of nutrigenomics research that may result in unique or unprecedented ELSIs. For example, nutrigenomics has a strong focus on public health and the prevention/modification of 'predisease phenotypes' in apparently healthy individuals. Thus, in contrast to previous applications of genomics technologies, where the goal is to distinguish existing disease from absence of disease, the aim of nutrigenomics is the discernment of nuanced differences in predisease states. Moreover, there is evidence to suggest that ELSIs may be different in biomarker discovery, translational research and clinical testing stages of nutrigenomics. Ideally, ELSI research and nutrigenomics bioscience should progress in parallel and in a commensurate manner. We suggest that qualitative research methods, using a hypothesis-free approach, can be employed to gain deeper insights on complex bioethics issues that do not ordinarily lend themselves to formal hypothesis testing with the quantitative methods used in biomedical sciences.

Total Hip Arthroplasty and the Golfer: A Study of Participation and Performance Before and After Surgery for Osteoarthritis

Many patients who undergo total hip arthroplasty still have a high level of activity. A popular low-intensity exercise in this patient group is golf. This study sought to investigate the group of patients who have had a hip arthroplasty procedure and who list golf as one of their pastimes, assessing the impact of surgery on their ability to participate in and perform at the game. Seven hundred fifty consecutive patients who had undergone total hip arthroplasty were sent questionnaires relating to their golfing habits. There was no significant change from their predisease state to their 1-year postoperative golf performance and level of participation. Harris hip scores were significantly higher for the golfing population both preoperatively and at all stages of follow-up.

Pregnancy outcomes before and after a diagnosis of systemic lupus erythematosus

The purpose of this study was to evaluate pregnancy outcomes before and after diagnosis of lupus. Successive selection criterion applied to 148 lupus and 78,905 non-lupus pregnancies, generated 3 groups: lupus group, 84 pregnancies (not-yet-diagnosed group, 15 women; already-diagnosed group, 69 women), and control group, 51,000 pregnancies. Three-way analysis of variance and the chi-squared test were used for analyses. Stillbirth outcome was increased in the lupus group compared with the control group (odds ratio, 4.84 [95% CI, 1.72,11.08]); the not-yet-diagnosed group (odds ratio, 9.89 [95% CI, 1.09,42.63]), and the already-diagnosed group (odds ratio, 3.85 [95% CI, 1.02,10.31]). Considering >1 pregnancy per patient would have overestimated the stillbirth rate. Stillbirth risk was increased significantly in severe maternal disease that was marked by central nervous system involvement. The already-diagnosed group had more hypertensive complications (P = .001 and .0001). Both lupus groups showed a significantly greater proportion of preterm births (P = .03), growth restriction (P = .019), and infants in the very low birth weight category (P = .021) compared with the control group. Poor fetal outcomes are seen in pregnancies that are complicated by lupus, even before clinical appearance of disease, which supports a predisease state.

This month in Gastroenterology

This month in Gastroenterology

Acute exacerbation of systemic scleroderma in Borrelia burgdorferi infection

In recent years a possible aetiological connection between skin sclerosis and an infection with Borrelia burgdorferi has been discussed, but this association has not yet been reported for systemic scleroderma. Several treatment modalities are suggested for systemic scleroderma, but no treatment has yet been found to alter the overall course of the disease. This report describes a 61-year-old woman with Raynaud's phenomenon, nail-fold changes and circulating anticentromere antibodies, who showed an abrupt onset of erythemas and doughy swellings involving the face and upper trunk, followed by thickening and induration of the skin mimicking diffuse systemic scleroderma. Laboratory tests including enzyme-linked immunosorbent assay (ELISA), immunoblot and urine polymerase chain reaction (PCR) showed an infection with B. burgdorferi sensu lato that was successfully treated with intravenous ceftriaxone, an antibiotic recommended for Lyme borreliosis. Fourteen days after the end of treatment the skin was no longer stiff and indurated and had returned to its normal predisease state. This case suggests that Lyme disease should be considered in atypical cases of skin sclerosis in patients predisposed to the development of systemic scleroderma.

Tumors and Transplantation: The 2003 Third Annual ASTS State-of-the-Art Winter Symposium

Tumors and Transplantation: The 2003 Third Annual ASTS State-of-the-Art Winter Symposium

Expansion of marginal zone B cells is not sufficient for the development of renal disease in NZBxNZW F1 mice.

The mechanisms which govern the production of autoantibodies and of tissue damage during systemic lupus (SLE) are still unclear. In the NZBxNZW F1 (BW) model of SLE glomerulonephritis, the activation and commitment of B cells are thought to play a major role in disease progression. Previous analysis has suggested that these mice have a substantial increase of marginal zone (MZ) B cells before the occurrence of the disease. Owing to the probable role of this B cell subset in autoantibody production, it was important to define the possible link between this abnormality and the occurrence of kidney damage. Using cytofluorometry analysis, we followed the splenic MZ B cell phenotype in different series of mice with shared autoimmune genetic background and histologically defined renal status. By comparing BW females and BW males, NZB and NZW mice, we confirm that BW mice have an increase in MZ B cells but this MZ B cells expansion is not directly linked to tissue lesions. Genetically modified BW female mice with a restricted repertoire of B and T cell antigen receptors, and which do not develop nephritis, exhibit the same increase of MZ B cells, suggesting that this increase does not depend on a specific set of antigens. Moreover, our analysis brings to light a pre-disease state in BW males, with autoantibody production and mesangial deposits.