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Transition from pediatric to adult health care for adolescents with epilepsy is challenging for the patient, family, and health care workers. This paper is the first of three that summarize the main findings from the 2nd Symposium on Transition in Epilepsies, held in Paris from June 14–25, 2016. In this paper we describe five basic themes that have an important effect on transition. First, there are important brain changes in adolescence that leave an imbalance between risk taking and pleasure seeking behaviors and frontal executive function compared with adults. Second, puberty is a major change during the transition age. The three most important but separate neuroendocrine axes involved in puberty are gonadarche (activation of the gonads), adrenarche (activation of adrenal androgen production), and activation of the growth hormone-insulin like growth factor. Third, sexual debut occurs during the transition years, and at an earlier age in adolescents with epilepsy than controls. Adult sexual performance is often unsatisfactory. Although AED-induced alterations in sexual hormones and temporal lobe epilepsy may play a role in hyposexuality, depression, anxiety, and other social factors appear most important. Fourth, psychological development is very important with an evolution from an early stage (ages 10–13 years) with concrete thinking, to a middle stage (ages 14–17) with analytic and more abstract introspective thinking, and then to a late stage (ages 18–21) with at least the beginnings of adult reasoning. Epilepsy may derail this relatively orderly progression. Adolescents with autistic spectrum disorder may present with severe behavior problems that are sometimes related to undiagnosed epilepsy. Fifth, bone health in adolescence is critical to establish adequate mineralization for all of adult life. While AED interference with Vitamin D metabolism is important, there is evidence that the effects of AEDs on bone are more complex and involve changes in remodeling. Hence, some non-inducing AEDs may have a significant effect on bone health. All five of these themes lead to recommendations for how to approach adolescents and young adults during transition and some specific interventions to achieve maximum long-term adult independence and quality of life. [ABSTRACT FROM AUTHOR]

Over the past 25 years, about 3 dozen clinical reports have been published regarding the safety and possible efficacy of neurotrophic factors in patients with various neurodegenerative diseases. This effort involved a half dozen different neurotrophic factors, using at least 5 different general delivery approaches for ALS (amyolateral sclerosis), peripheral neuropathies, PD (Parkinson's disease) and AD (Alzheimer's disease). While none of these efforts have yet produced efficacy data sufficiently robust or reliable to establish neurotrophic factors as treatments for any human disease, the obstacles encountered and novel information reported, when viewed collectively, provide important insight to help future efforts. Three consistent themes emerge from these publications: (1) unexpected and undesirable side effects, at times serious, have plagued many efforts to deliver neurotrophic factors to humans; (2) the magnitude and consistency of clinical benefit has been disappointing; (3) by far that most consistently proposed reason for the side effects and poor efficacy has been inadequate dosing and delivery. This paper reviews and attempts to synthesize the available data derived from clinical tests of neurotrophic factors for neurodegenerative diseases. The obstacles encountered, the solutions attempted, and the lessons learned are discussed. The vast majority of solutions have involved changes in dosing paradigms and dose levels, which has primarily led to improved safety outcomes. However, lack of adequate efficacy remains a significant issue. While current efforts continue to focus exclusively on still-further changes in dosing parameters, a review of available data argues that it may now be the time to ask whether other, non-dose-related variables should be given more serious consideration as being responsible for the great divide that exists between the robust effects seen in animal models and the relatively weak effects seen in human neurodegenerative patients. Foremost among these appears to be the severe degeneration seen in the majority of patients enrolled in past and current trials testing neurotrophic factors in humans. A companion paper ( Bartus and Johnson, 2016 ), reviews the contemporary data and concludes that compelling empirical evidence already exists for enrolling earlier-stage subjects as likely essential to achieving more robust and reliable benefit. [ABSTRACT FROM AUTHOR]

Abstract: Multiple sclerosis (MS) is a chronic inflammatory disease characterized by demyelination, remyelination and loss of functions. Even though its etiology is unknown viral, genetic and environmental factors are considered triggers of the disease. MS shows a heterogeneous clinical course, but most patients exhibit exacerbations and remissions from the onset, eventually leading to secondary progressive multiple sclerosis. Systemic inflammatory events are known to signal into the central nervous system (CNS), and can induce a general response known as sickness behavior. Several research papers have demonstrated that a peripheral stimulus can induce the synthesis of cytokines in the brain. In different neurodegenerative diseases peripheral inflammation generates exacerbation to ongoing damage in the brain. In MS, relapsing and remitting episodes are unpredictable; however, peripheral inflammation may exacerbate these events. Clinical studies revealed an association between infections and relapses, which may lead to the worsening of neurological damage. A similar scenario was described in MS animal models demonstrating that peripheral inflammation recrudesced a central ongoing demyelinating lesion. In this paper, we reviewed the existing data on the inflammatory component of MS, with special attention on the effect of peripheral infections in the etiology and progression of MS and its effect on the relapsing and remitting episodes. We also analyzed data concerning the effect of peripheral inflammatory events in MS experimental animal models. This article is part of a Special Issue entitled ''Neuroinflammation in neurodegeneration and neurodysfunction''. [Copyright &y& Elsevier]

Endometriosis, a common gynecological disease, is associated with pelvic pain and infertility. Endometriosis affects approximately 10% of women, but that number increases to 30–50% in symptomatic premenopausal women. Despite the prevalence of endometriosis, the cause has yet to be fully elucidated. Recent study of the molecular pathways of endometrial cancer has brought the long non-coding RNA (lncRNA) H19 to our attention. In this paper, we explored the role of lncRNA-H19 in endometrial tissue proliferation. We found that ectopic endometrial cells taken from women with endometriosis showed elevated levels of lncRNA-H19, with expression levels correlating to disease progression. Knockdown of H19 in ectopic endometrial cells inhibited cell proliferation and invasion. Coinciding with this change was an increase in microRNA-124-3p (miR-124-3p) and a decrease in integrin beta-3 (ITGB3) levels. The addition of a miR-124-3p inhibitor mitigated this decrease in ITGB3. Up-regulation of miR-124-3p markedly suppressed ITGB3 expression by binding to the 3′ untranslated region (3' UTR), while inhibition of miR-124-3p had the opposite effect. ITGB3 overexpression potently counteracted the effects of miR-124-3p mimics on ectopic endometrial cells. From these results, we can infer that in endometriosis both miR-124-3p and ITGB3 operate as downstream effector proteins in the H19-signaling pathway. Down-regulation of lncRNA-H19 could inhibit ectopic endometrial cell proliferation and invasion by modulating miR-124-3p and ITGB3, offering a novel target for treatment. [ABSTRACT FROM AUTHOR]

Abstract An increase in the vasculature is one of most representative changes in the synovial tissue of joints in rheumatoid arthritis (RA) and is closely associated with disease progression. Although the vasculatures are believed to be a result of VE-cadherin-dependent angiogenesis and a possible therapeutic target of the disease, synovial fibroblastic cells express VE-cadherin and form tube-like structures, suggesting that vasculatures in RA synovium may not simply result from angiogenesis. This paper analyzes a mechanism of VE-cadherin expression by rheumatoid arthritic synovial fibroblast-like cells (RSFLs) and their involvement in the tube-like formation. A representative angiogenic factor, vascular endothelial growth factor (VEGF), and its binding to a predominant receptor (VEGFR2) activated VE-cadherin expression and the signaling pathways of ERK/MAPK and PI3K/AKT/mTOR. Treatment of RSFLs with signaling pathway inhibitors, VEGFR2 siRNA and a VEGF-antagonizing mimicking peptide inhibited VE-cadherin expression dose-dependently. VEGF-stimulated tube-like formation by RSFLs on Matrigel was hindered by the mimicking peptide and inhibitor treatment. This data demonstrates that RSFLs activated by VEGF binding of VEGFR2 express VE-cadherin and formed tube-like structure under the control of ERK/MAPK and PI3K/AKT/mTOR pathways suggesting that the inhibition suppresses vascular development in RA synovium. Highlights • VE-cadherin-mediated vasculatures are increased in RA synovium. • Synovial fibroblastic cells expressed VE-cadherin in response to VEGF. • VEGF-receptor binding was required for VE-cadherin expression and tube formation. • ERK/MAPK and PI3K/AKT/mTOR signaling were key pathways. • VEGF and the signaling may develop vasculatures in RA synovium. [ABSTRACT FROM AUTHOR]

Highlights • Accurate TB diagnosis, capacity for large scale immune sample collection and advances in systems technologies have enabled rapid advances in immune correlates studies. • We do not have an immune correlate of protection (CoP) for a TB vaccine as there have been no TB vaccine trials with both efficacy and sample availability for such an analysis to be performed. • New TB vaccine efficacy trials with disease and infection endpoints will provide future opportunities for immune CoP analysis. • Vaccine efficacy trials and observational studies in populations at high risk of TB disease have enabled the identification of Correlates or Risk (CoR) of progression to TB • Correlates of risk analysis using whole systems approaches provide deeper insight into mechanisms of immune protection and lead to the development of new and better interventions for TB disease. Abstract Tuberculosis (TB) is the leading cause of death due to a single infectious disease and an effective vaccine would substantially accelerate global efforts to control TB. An immune correlate of protection (CoP) from TB disease could aid vaccine optimization and licensure. This paper summarises opportunities for identifying CoP and highlights results from correlates of risk studies. Although we don't have CoP, there are ongoing efficacy trials with both disease and infection endpoints which provide opportunities for such an analysis. Transcriptomics has successfully identified robust CoR, with transcripts found in the Type I IFN pathway. Correlates of lower risk include BCG antigen specific IFN-γ and natural killer cells. Collating evidence from multiple studies using a range of systems approaches supports a role for IFN-γ in protection from TB disease. In addition, the cells that express the IFN-γ receptor are also important in protective immunity. Protection is a culmination not only of the amount of IFN-γ produced by T cells and NK cells but by the ability of IFN-γ receptor expressing monocytes to respond to IFN-γ. To better understand IFN-γ as a correlate we need to understand host-factors such as age, sex, co-infection, nutritional status and stress which may alter or impair the ability of cells to respond to IFN-γ. These studies highlight recent advances in our understanding of the immune mechanisms of TB disease risk and show the importance of whole systems approaches to correlates of risk analysis. CoP may be useful tools for specific vaccine products in specific populations, but a well-designed CoR analysis can identify novel immune mechanisms and provide insights critical for the development of new and better TB vaccines. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is a cancer of the hematopoietic system initiated by a single genetic mutation which results in the oncogenic fusion protein Bcr-Abl. Untreated, patients pass through different phases of the disease beginning with the rather asymptomatic chronic phase and ultimately culminating into blast crisis, an acute leukemia resembling phase with a very high mortality. Although many processes underlying the chronic phase are well understood, the exact mechanisms of disease progression to blast crisis are not yet revealed. In this paper we develop a mathematical model of CML based on causal Bayesian networks in order to study possible disease progression mechanisms. Our results indicate that an increase of Bcr-Abl levels alone is not sufficient to explain the phenotype of blast crisis and that secondary changes such as additional mutations are necessary to explain disease progression and the poor therapy response of patients in blast crisis. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a serious disease that presents a major health problem worldwide. There is a desperate need to explore novel biomarkers to further facilitate the early diagnosis and effective treatment in DKD patients, thus preventing them from developing end-stage renal disease (ESRD). However, most regulation mechanisms at the genetic level in DKD still remain unclear. In this paper, we describe our innovative methodologies that integrate biological, computational, and statistical approaches to investigate important roles performed by regulations among microRNAs (miRs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs) in DKD. We conducted fully transparent, rigorously designed experiments. Our robust and reproducible results identified hsa-miR-223-3p as a candidate novel biomarker performing important roles in DKD disease process. [ABSTRACT FROM AUTHOR]

• A multi-channel model based on recurrent variational autoencoders was proposed to capture spatial and temporal evolution of AD using multimodal data. • Proposed model was evaluated on synthetic and real datasets. • Model outperforms a set of baselines for missing data reconstruction across modalities. [Display omitted] The progression of neurodegenerative diseases, such as Alzheimer's Disease, is the result of complex mechanisms interacting across multiple spatial and temporal scales. Understanding and predicting the longitudinal course of the disease requires harnessing the variability across different data modalities and time, which is extremely challenging. In this paper, we propose a model based on recurrent variational autoencoders that is able to capture cross-channel interactions between different modalities and model temporal information. These are achieved thanks to its multi-channel architecture and its shared latent variational space, parametrized with a recurrent neural network. We evaluate our model on both synthetic and real longitudinal datasets, the latter including imaging and non-imaging data, with N = 897 subjects. Results show that our multi-channel recurrent variational autoencoder outperforms a set of baselines (KNN, random forest, and group factor analysis) for the task of reconstructing missing modalities, reducing the mean absolute error by 5 % (w.r.t. the best baseline) for both subcortical volumes and cortical thickness. Our model is robust to missing features within each modality and is able to generate realistic synthetic imaging biomarkers trajectories from cognitive scores. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is an overwhelming neurodegenerative disorder caused by deterioration of a neurotransmitter, known as dopamine. Lack of this chemical messenger impairs several brain regions and yields various motor and non-motor symptoms. Incidence of PD is predicted to double in the next two decades, which urges more research to focus on its early diagnosis and treatment. In this paper, we propose an approach to diagnose PD using magnetic resonance imaging (MRI) data. Specifically, we first introduce a joint feature-sample selection (JFSS) method for selecting an optimal subset of samples and features, to learn a reliable diagnosis model. The proposed JFSS model effectively discards poor samples and irrelevant features. As a result, the selected features play an important role in PD characterization, which will help identify the most relevant and critical imaging biomarkers for PD. Then, a robust classification framework is proposed to simultaneously de-noise the selected subset of features and samples, and learn a classification model. Our model can also de-noise testing samples based on the cleaned training data. Unlike many previous works that perform de-noising in an unsupervised manner, we perform supervised de-noising for both training and testing data, thus boosting the diagnostic accuracy. Experimental results on both synthetic and publicly available PD datasets show promising results. To evaluate the proposed method, we use the popular Parkinson's progression markers initiative (PPMI) database. Our results indicate that the proposed method can differentiate between PD and normal control (NC), and outperforms the competing methods by a relatively large margin. It is noteworthy to mention that our proposed framework can also be used for diagnosis of other brain disorders. To show this, we have also conducted experiments on the widely-used ADNI database. The obtained results indicate that our proposed method can identify the imaging biomarkers and diagnose the disease with favorable accuracies compared to the baseline methods. [ABSTRACT FROM AUTHOR]

It is estimated that 80% of new hepatitis C virus (HCV) infections occur among people who inject drugs (PWID). Eradicating HCV from this population is key for the complete eradication of the disease, and the advent of simple to use, high efficacy treatments could conceivably make this scenario possible. This paper presents a mathematical model where transmission of HCV is studied in a simulated population of PWID where fibrosis progression is explicitly tracked. The stability thresholds that determine whether HCV will remain endemic or become eradicated were established numerically, and analytically on a reduced version of the model. Conditions on testing and treatment rates for eradication to occur were determined, within the context of the new high efficacy therapies. The results show that HCV eradication in the PWID population of the Vancouver, BC test scenario is achievable, but testing and especially treatment rates will need to increase significantly from current rates. Parameter estimates were drawn from published data. [ABSTRACT FROM AUTHOR]

Although a considerable number of studies have been undertaken to date, it is still controversial as to whether or not coinfection with schistosomiasis increases the susceptibility to or progression from Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection. This review is a closer examination of the key studies conducted on human populations on clinical factors that were published in English between 1975 and January 2015. Our review is mainly based on tables containing the salient information, which are arranged first by study population, country of study and publication date. We provide further explanation, clarification and discussion in the text. As such, it includes both studies that have been conducted on general populations who are largely asymptomatic for clinical disease (Table 3), as well as those focussing on special populations, which are usually comprised of clinical patients. These special populations have been presented as follows: subjects with chronic liver disease or related conditions such as cirrhosis, Table 4; subjects with primary liver cancer, Table 5; subjects with schistosomiasis, Table 6; subjects with acute or chronic hepatitis resulting from HBV, Table 7 and, subjects with HCV, Table 8. We have presented studies that compared two mono-infected groups with one that is coinfected separately in Table 9, as these offer us the best basis from which to evaluate if any synergistic effects accompany coinfection. A number of factors contributed to the results reported in our tables. These included, but are not limited to: subject selection (i.e. asymptomatic cases typically drawn from the general population vs subjects presenting to a hospital or clinic with clinical disease); study design, which directly impacts our ability to infer causality (i.e. case series, cross-sectional, case-control, cohort study); use and choice of control population (i.e. apparently healthy subjects vs other hospital patients vs none); sample size, which directly impacts statistical power and can result in a Type II error; geographic area, which may reflect differences in population genetics, public health history, environmental differences or any number of other important factors (i.e. Egypt, Brazil, China); method of testing for schistosomal infections (i.e. stool vs antibody test); method of testing to determine if advanced schistosomal disease was present (i.e. ultrasound, liver biopsy vs none); method of serological testing for HBV (i.e. use of HBsAg alone or with other markers or DNA testing); method of serological testing for HCV (i.e. use of anti-HCV alone or with RNA testing) and, year of the study, which reflects among other things, technological improvements between tests as well as possible changes in the frequency of exposure in the populations under study (i.e. use of parenteral antischistosomal therapy vs the oral antischistosomal medication). Despite all these differences, throughout this review we have observed general patterns that seem largely consistent with one another. Studies conducted on general, largely asymptomatic populations tend to support the view that having one of the diseases in question (i.e. schistosomiasis) does not necessarily predispose one to becoming coinfected with another (i.e. HBV or HCV). Rather, the probability of becoming coinfected seems most closely associated with modes of transmission for either HBV or HCV in schistosome-endemic areas, such as the past use of parenteral antischistosomal therapy or frequent blood transfusion. Once coinfected, however, the clinical course of illness for those with Schistosoma-HBV or Schistosoma-HCV infections are typically much more severe than for mono-infected subjects. The strongest evidence for this was found in the half-dozen or so prospective cohort studies that systematically monitored disease progression in their subjects. With respect to HBV infection, coinfection with Schistosoma prolonged the carriage state and more often resulted in chronic hepatitis with greater cirrhosis as well as higher mortality. Much of the same was also observed with respect to HCV, where coinfection with Schistosoma was associated with a reduced ability to spontaneously resolve the viral infection and more often resulted in rapid fibrosis as well as higher mortality. Furthermore, two of these studies which were fully comparative in nature, support the supposition that there is a synergistic association between Schistosoma-HCV for both liver fibrosis and mortality. Immunological studies, all conducted on HCV, also generally seem to support this. The results of our research argue for greater primary prevention for both HBV and HCV in Schistosoma-endemic populations. Although no vaccine currently exists for HCV as it does for HBV, additional steps can still be taken to reduce transmission in high-risk populations. Greater use of the HBV vaccine is particularly advisable. Finally, additional observational, longitudinal studies conducted on human populations that are fully comparative in nature could help answer some of the remaining questions on both Schistosoma-HBV as well as Schistosoma-HCV coinfections. Some of these include the role of active versus past schistosomal infections, the role of genetic variants, as well as the effect of coinfection on treatment. Future studies should make a particular effort to use a sufficient sample size to ensure adequate statistical power, which was not often properly considered in many of the studies we reviewed for this paper. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy is a complex disorder induced by long standing diabetes. Many signaling pathways and transcription factors have been proposed to be involved in the development and progression of related processes. Years of research points to critical role of oxidative stress, neuroinflammation and apoptosis in the pathogenesis of neuropathy in diabetes. Heme oxygenase-1 (HO-1) is heat-shock protein induced under conditions of different kinds of stress and has been implicated in cellular defense against oxidative stress. HO-1 degrades heme to biliverdin, carbon monoxide (CO) and free iron. Biliverdin and CO are gaining particular interest because these two have been found to mediate most of anti-inflammatory, antioxidant and anti-apoptotic effects of HO-1. Although extensively studied in different kinds of cancers and cardiovascular conditions, role of HO-1 in diabetic neuropathy is still under investigation. In this paper, we review the unique therapeutic potential of HO-1 and its role in mitigating various pathological processes that lead to diabetic neuropathy. This review also highlights the therapeutic approaches such as pharmacological and natural inducers of HO-1, gene delivery of HO-1 or its reaction products that in future, could lead to progression of HO-1 activators through the preclinical stages of drug development to clinical trials. [ABSTRACT FROM AUTHOR]

Patients with HIV infection are at increased risk of developing non-Hodgkin lymphoma and Hodgkin lymphoma. While the pathogenesis of these lymphomas is incompletely understood, evidence indicates that immune deregulation, genetic alterations and cytokine production play an important role in HIV lymphomagenesis. The lymphoma microenvironment in this heterogeneous group of lymphomas plays an equally critical role in their development, growth and progression. Important components of the microenvironment in HIV-related lymphomas include EBV and/or HHV-8 coinfection, reactive inflammatory cells, tumor microvasculature, and soluble factors. This paper provides a brief overview of HIV-related lymphomas and focuses on their lymphomagenesis and microenvironment. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is classified as the third leading cancer globally and one of the major causes of morbidity and mortality around the world. The interaction of the immune system with the cancer cells plays a vital role in CRC progression. Regulatory T cells (Tregs) are a form of T cells, which regulate and suppress unwanted activation of the immune system and play a major role in preventing autoimmune diseases. Tregs exhibit a significant role in immune modulation during CRC progression through accumulation in the tumor microenvironment (TME) and suppression of immunity against tumor specific antigens promoting tumor progression. The role of Tregs in CRC progression and its interaction with other immune cells within CRC TME and current clinical trials were reviewed in this paper. [Display omitted] • Discusses the role of Tregs in immune modulation during CRC progression. • Explores the role of Tregs in CRC tumor microenvironment. • Highlights the mechanism of Tregs in CRC growth and metastasis. • Identifies and discusses current clinical trials targeting Tregs in CRC therapy. [ABSTRACT FROM AUTHOR]

Abstract: The presence of amyloid plaques in the brain is one of the pathological hallmarks of Alzheimer's disease, which might already be present in the early stage of the disease. Therefore it is important to track amyloid plaques as early as possible. In this paper, we report magnetization transfer contrast magnetic resonance imaging (MTC MRI) as a novel approach to detect amyloid plaques in vivo. Two mice models, APP/PS1 and BRI, developing amyloid pathology were investigated with MTC MRI, T2 relaxation measurements and immunohistochemistry (IHC). MT-ratios of several brain regions were compared to T2-values and correlated with quantitative IHC, revealing amyloid load and gliosis in different brain regions. APP/PS1 mice develop large compact plaques, resembling late stage Alzheimer's disease, while rather small and diffuse plaques are deposited in BRI mice, reflecting early stage of Alzheimer's disease. We found significantly higher MT-ratio's in the brain of APP/PS1 mice as compared to their controls and similar trends in BRI mice. A region based MT-ratio and IHC analysis and correlations between MT-ratios and quantitative IHC indicate amyloid plaques as the main substrate for altered MT-ratios in transgenic animals. We additionally demonstrated the improved sensitivity of MTC MRI to amyloid pathology as compared to traditional T2 relaxation measurements. Our results suggest that MTC MRI reveals extensive, and potentially even early amyloid pathology. Further unraveling the MT-effect of each pathological feature during each stage of AD might indicate MTC MRI as a useful diagnostic technique. [Copyright &y& Elsevier]

Abstract: Alzheimer's disease (AD), the most common type of dementia, is a severe neurodegenerative disorder. Identifying biomarkers that can track the progress of the disease has recently received increasing attentions in AD research. An accurate prediction of disease progression would facilitate optimal decision-making for clinicians and patients. A definitive diagnosis of AD requires autopsy confirmation, thus many clinical/cognitive measures including Mini Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog) have been designed to evaluate the cognitive status of the patients and used as important criteria for clinical diagnosis of probable AD. In this paper, we consider the problem of predicting disease progression measured by the cognitive scores and selecting biomarkers predictive of the progression. Specifically, we formulate the prediction problem as a multi-task regression problem by considering the prediction at each time point as a task and propose two novel multi-task learning formulations. We have performed extensive experiments using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Specifically, we use the baseline MRI features to predict MMSE/ADAS-Cog scores in the next 4years. Results demonstrate the effectiveness of the proposed multi-task learning formulations for disease progression in comparison with single-task learning algorithms including ridge regression and Lasso. We also perform longitudinal stability selection to identify and analyze the temporal patterns of biomarkers in disease progression. We observe that cortical thickness average of left middle temporal, cortical thickness average of left and right Entorhinal, and white matter volume of left Hippocampus play significant roles in predicting ADAS-Cog at all time points. We also observe that several MRI biomarkers provide significant information for predicting MMSE scores for the first 2years, however very few are shown to be significant in predicting MMSE score at later stages. The lack of predictable MRI biomarkers in later stages may contribute to the lower prediction performance of MMSE than that of ADAS-Cog in our study and other related studies. [Copyright &y& Elsevier]

Abstract: We introduce a novel image-processing framework for tracking longitudinal changes in white matter microstructure using diffusion tensor imaging (DTI). Charting the trajectory of such temporal changes offers new insight into disease progression but to do so accurately faces a number of challenges. Recent developments have highlighted the importance of processing each subject''s data at multiple time points in an unbiased way. In this paper, we aim to highlight a different challenge critical to the processing of longitudinal DTI data, namely the approach to image alignment. Standard approaches in the literature align DTI data by registering the corresponding scalar-valued fractional anisotropy (FA) maps. We propose instead a DTI registration algorithm that leverages full tensor information to drive improved alignment. This proposed pipeline is evaluated against the standard FA-based approach using a DTI dataset from an ongoing study of Alzheimer''s disease (AD). The dataset consists of subjects scanned at two time points and at each time point the DTI acquisition consists of two back-to-back repeats in the same scanning session. The repeated scans allow us to evaluate the specificity of each pipeline, using a test–retest design, and assess precision, using bootstrap-based method. The results show that the tensor-based pipeline achieves both higher specificity and precision than the standard FA-based approach. Tensor-based registration for longitudinal processing of DTI data in clinical studies may be of particular value in studies assessing disease progression. [Copyright &y& Elsevier]

Abstract: Life history data arising in clusters with pre-specified assessment time points for patients often feature incomplete data since patients may choose to visit the clinic based on their needs. Markov process models provide a useful tool describing disease progression for life history data. The literature mainly focuses on time homogeneous process. In this paper we develop methods to deal with non-homogeneous Markov process with incomplete clustered life history data. A correlated random effects model is developed to deal with the nonignorable missingness, and a time transformation is employed to address the non-homogeneity in the transition model. Maximum likelihood estimate based on the Monte-Carlo EM algorithm is advocated for parameter estimation. Simulation studies demonstrate that the proposed method works well in many situations. We also apply this method to an Alzheimer’s disease study. [Copyright &y& Elsevier]

Abstract: Clinical trials are typically conducted over a population within a defined time period in order to illuminate certain characteristics of a health issue or disease process. These cross-sectional studies give us a ‘snapshot’ of this disease process over a large number of people but do not allow us to model the temporal nature of disease, thereby allowing for modelling detailed prognostic predictions. The aim of this paper is to explore an extension of the temporal bootstrap to identify intermediate stages in a disease process and sub-categories of the disease exhibiting subtly different symptoms. Our approach is compared to a strawman method and investigated in its ability to explain the dynamics of progression on biomedical data from three diseases: Glaucoma, Breast Cancer and Parkinson’s disease. We focus on creating reliable time-series models from large amounts of historical cross-sectional data using the temporal bootstrap technique. Two issues are explored: how to build time-series models from cross-sectional data, and how to automatically identify different disease states along these trajectories, as well as the transitions between them. Our approach of relabeling trajectories allows us to explore the temporal nature of how diseases progress even when time-series data is not available (if the cross-sectional study is large enough). We intend to expand this research to deal with multiple studies where we can combine both cross-sectional and longitudinal datasets and to focus on the junctions of the trajectories as key stages in the progression of disease. [Copyright &y& Elsevier]

Abstract: Neutral mutations play an important role in many biological processes including cancer initiation and progression, the generation of drug resistance in bacterial and viral diseases as well as cancers, and the development of organs in multicellular organisms. In this paper we study how neutral mutants are accumulated in nonlinearly growing colonies of cells subject to growth constraints such as crowding or lack of resources. We investigate different types of growth control which range from “division-controlled” to “death-controlled” growth (and various mixtures of both). In division-controlled growth, the burden of handling overcrowding lies with the process of cell-divisions, the divisions slow down as the carrying capacity is approached. In death-controlled growth, it is death rate that increases to slow down expansion. We show that division-controlled growth minimizes the number of accumulated mutations, and death-controlled growth corresponds to the maximum number of mutants. We check that these results hold in both deterministic and stochastic settings. We further develop a general (deterministic) theory of neutral mutations and achieve an analytical understanding of the mutant accumulation in colonies of a given size in the absence of back-mutations. The long-term dynamics of mutants in the presence of back-mutations is also addressed. In particular, with equal forward- and back-mutation rates, if division-controlled and a death-controlled types are competing for space and nutrients, cells obeying division-controlled growth will dominate the population. [Copyright &y& Elsevier]

Abstract: In this paper, we propose and discuss a possible mechanism, which, via continuous mutations and evolution, eventually enables HIV to break from immune control. In order to investigate this mechanism, we employ a simple mathematical model, which describes the relationship between evolving HIV and the specific CTL response and explicitly takes into consideration the role of CD4+T cells (helper T cells) in the activation of the CTL response. Based on the assumption that HIV evolves towards higher replication rates, we quantitatively analyze the dynamical properties of this model. The model exhibits the existence of two thresholds, defined as the immune activation threshold and the immunodeficiency threshold, which are critical for the activation and persistence of the specific cell-mediated immune response: the specific CTL response can be established and is able to effectively control an infection when the virus replication rate is between these two thresholds. If the replication rate is below the immune activation threshold, then the specific immune response cannot be reliably established due to the shortage of antigen-presenting cells. Besides, the specific immune response cannot be established when the virus replication rate is above the immunodeficiency threshold due to low levels of CD4+T cells. The latter case implies the collapse of the immune system and beginning of AIDS. The interval between these two thresholds roughly corresponds to the asymptomatic stage of HIV infection. The model shows that the duration of the asymptomatic stage and progression of the disease are very sensitive to variations in the model parameters. In particularly, the rate of production of the naive lymphocytes appears to be crucial. [Copyright &y& Elsevier]

Abstract: Axonal degeneration is responsible for the progression of the irreversible destruction caused by multiple sclerosis (MS) resulting ultimately in permanent disability. The KIF1B protein, a member of the kinesin family, is necessary for axon growth and myelination in vertebrates. In the recent paper, Aulchenko et al. suggested that the rs10492972[C] variant of KIF1B increases susceptibility to MS, but three following replication study didn''t confirm this association. We studied the association of the polymorphic locus rs10492972 present in the KIF1B gene with genetic predisposition and its occurrence in clinical presentations of MS patients resident in western Siberia and the Sakha Republic (Yakutia), Russia. rs10492972 has been genotype in 833 samples of MS patient and 689 healthy controls. Distribution of rs10492972 genotypes corresponded with a Hardy–Weinberg distribution in both the MS patient and control groups, with the frequency of the C allele being the same in both groups (33%). Frequencies of occurrence of the genotypes were not shown to be associated with different disease courses or other characteristics of the disease, such as age at onset or duration. A complete meta-analysis of all analogous studies published to date showed that the protective effect of the rs10492972[C] allele is statistically significant (OR=0.95, C.I.95% [0.90–0.99], p =0.02). [Copyright &y& Elsevier]

Abstract: This paper presents a novel, publicly available repository of anatomically segmented brain images of healthy subjects as well as patients with mild cognitive impairment and Alzheimer''s disease. The underlying magnetic resonance images have been obtained from the Alzheimer''s Disease Neuroimaging Initiative (ADNI) database. T1-weighted screening and baseline images (1.5T and 3T) have been processed with the multi-atlas based MAPER procedure, resulting in labels for 83 regions covering the whole brain in 816 subjects. Selected segmentations were subjected to visual assessment. The segmentations are self-consistent, as evidenced by strong agreement between segmentations of paired images acquired at different field strengths (Jaccard coefficient: 0.802±0.0146). Morphometric comparisons between diagnostic groups (normal; stable mild cognitive impairment; mild cognitive impairment with progression to Alzheimer''s disease; Alzheimer''s disease) showed highly significant group differences for individual regions, the majority of which were located in the temporal lobe. Additionally, significant effects were seen in the parietal lobe. Increased left/right asymmetry was found in posterior cortical regions. An automatically derived white-matter hypointensities index was found to be a suitable means of quantifying white-matter disease. This repository of segmentations is a potentially valuable resource to researchers working with ADNI data. [Copyright &y& Elsevier]

Abstract: In contrast to the more common Diffusion Tensor Imaging (DTI), High Angular Resolution Diffusion Imaging (HARDI) allows superior delineation of angular microstructures of brain white matter, and makes possible multiple-fiber modeling of each voxel for better characterization of brain connectivity. However, the complex orientation information afforded by HARDI makes registration of HARDI images more complicated than scalar images. In particular, the question of how much orientation information is needed for satisfactory alignment has not been sufficiently addressed. Low order orientation representation is generally more robust than high order representation, although the latter provides more information for correct alignment of fiber pathways. However, high order representation, when naïvely utilized, might not necessarily be conducive to improving registration accuracy since similar structures with significant orientation differences prior to proper alignment might be mistakenly taken as non-matching structures. We present in this paper a HARDI registration algorithm, called SPherical Harmonic Elastic REgistration (SPHERE), which in a principled means hierarchically extracts orientation information from HARDI data for structural alignment. The image volumes are first registered using robust, relatively direction invariant features derived from the Orientation Distribution Function (ODF), and the alignment is then further refined using spherical harmonic (SH) representation with gradually increasing orders. This progression from non-directional, single-directional to multi-directional representation provides a systematic means of extracting directional information given by diffusion-weighted imaging. Coupled with a template–subject-consistent soft-correspondence-matching scheme, this approach allows robust and accurate alignment of HARDI data. Experimental results show marked increase in accuracy over a state-of-the-art DTI registration algorithm. [Copyright &y& Elsevier]

Abstract: Simian immunodeficiency virus (SIV) has been shown to evolve from a relatively slowly replicating and mildly cytopathic virus early in the infection (SIVMneCL8) to a faster replicating and more cytopathic virus at later stages of the infection (SIVMne170). It has recently been demonstrated that the early and mildly cytopathic variant SIVMneCL8 out-competed the late and highly cytopathic strain SIVMne170 in cell culture experiments, because the fitness disadvantage derived from the higher cytopathicity was not matched by a sufficient increase in the viral replication rate. However, in another set of experiments where the life span of cells in culture was artificially limited, the late and more cytopathic virus won the competition, because under this condition cytopahticity was not an important determinant of viral fitness. It was hypothesized that the limited life span experiment reflected the immune-mediated high turnover environment in vivo more accurately, and that the presence of immune responses accounts for the selection of the cytopathic strain SIVmne170 during later stages of the infection. This paper investigates the effect of immune responses, in particular cytotoxic T lymphocyte (CTL) responses, on the competition dynamics between these two SIV strains with the help of mathematical models. Model analysis and parameter estimates derived from previously published data on SIV growth kinetics suggest that the SIV-specific CTL response might not be the driving force that leads to the selection of the cytopathic strain SIVMne170 during later stages of the infection. This implies that more complex evolutionary mechanisms might have to be invoked in order to explain the emergence of these strains in vivo. One possibility is that the ability of multiple virus particles to infect the same cell (coinfection) might be a pre-requisite for the emergence of the cytopathic strain SIVMne170 as the disease progresses. [Copyright &y& Elsevier]

Restoring the lost physiological functions of the substantia nigra in Parkinson's disease (PD) is an important goal of PD therapy. The present article reviews a) novel drug targets that should be targeted to slow PD progression, and b) clinical and experimental research data reporting new treatments targeting immune-inflammatory and oxidative pathways. A systematic search was performed based on the major databases, i.e., ScienceDirect, Web of Science, PubMed, CABI Direct databases, and Scopus, on relevant studies performed from 1900 to 2020. This review considers the crucial roles of mitochondria and immune-inflammatory and oxidative pathways in the pathophysiology of PD. High levels of oxidative stress in the substantia nigra, as well as modifications in glutathione regulation, contribute to mitochondrial dysfunction, with a decline in complex I of the mitochondrial electron transport chain reported in PD patients. Many papers suggest that targeting antioxidative systems is a crucial aspect of preventive and protective therapies, even justifying the utilization of N-acetylcysteine (NAC) supplementation to fortify the protection afforded by intracellular glutathione. Dietary recommended panels including ketogenetic diet, muscular exercise, nutraceutical supplementation including NAC, glutathione, nicotine, caffeine, melatonin, niacin, and butyrate, besides to nonsteroidal anti-inflammatory drugs (NSAIDs), and memantine treatment are important aspects of PD therapy. The integration of neuro-immune, antioxidant, and nutritional approaches to treatment should afford better neuroprotection, including by attenuating neuroinflammation, nitro-oxidative stress, mitochondrial dysfunction, and neurodegenerative processes. Future research should clarify the efficacy, and interactions, of nicotine receptor agonists, gut microbiome-derived butyrate, melatonin, and NSAIDs in the treatment of PD. [ABSTRACT FROM AUTHOR]

Abstract Purpose This paper addressed the nature and level of EMP exposure found at an industrial grade talc mine (R.T. Vanderbilt Company [RTV]) in upstate NY operated from 1948 to 2008, updates the pneumoconiosis experience of these talc miners and millers and contrasts this experience to other EMP and non-EMP exposed populations. EMP was defined as any particle with a length/width ratio of 3 to 1 or greater and 5 μm or greater length. Methods The study population consisted of all male workers with at least one chest radiograph actively employed at the mine/mill for any period of time from 1978 to 2008 and subject to serial chest X-rays. The ILO pneumoconiosis classification system was used to classify parenchymal abnormalities by type, size, degree of profusion and progression. Pleural abnormalities were addressed as well. Studies of platy talc, amphibole asbestos workers and populations not exposed to occupational dusts were used as comparative groups. Results The radiographic occurrence of pneumoconiosis was similar to that found among platy talc workers not exposed to EMP and the general unexposed population (below 5%) despite long exposures and elevated EMP levels for RTV talc workers. When detected, pneumoconiosis showed little progression with only one case reaching a radiographic stage >1/1. No occurrence among a subset of formerly employed RTV talc workers after 8 years post exposure was found. The prevalence of pneumoconiosis among amphibole asbestos workers was significantly higher (30 to >75%) with severity including category 2 or greater cases and evidence of accelerated progression at a lower cumulative EMP exposure than that found among RTV talc workers. Importantly, the total EMP airborne exposure for the talc workers exceeded the asbestos permissible fiber exposure standard by a factor of 15 to 20 and the EMP components found in NY talc that consisted of elongate amphibole cleavage fragment and fibrous/asbestiform talc each separately exceeded this standard by a factor of 7 to 10 (averaged over a span of decades). Pleural plaque in some but not all talc workers (industrial and platy) with little to no functional impairment was also noted. Discussion The low toxicity of RTV EMPs with respect to pneumoconiosis is supported by worker mortality, animal and cell studies of this talc. Controversy involving diagnostic reliability and competing risk has occurred more recently with respect to human mesothelioma. The similar occurrence of pneumoconiosis and pleural plaques in RTV and platy talc-exposed workers with similar respirable dust exposure suggest the mineral talc is the particulate component most associated with the occurrence of pulmonary abnormalities. Conclusion Elevated exposure in this study to a non-asbestos asbestiform EMP (talc fiber) suggests that the mineral type with its attending physiochemical/elemental properties matters - in addition to particle dimension, bio-durability and growth habit. Ref. Journal of Epidemiology and Preventive Medicine: June 26, 2017 http://elynsgroup.com (open access). [ABSTRACT FROM AUTHOR]