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Sample records for als disease progression

  1. Kinematics of Disease Progression in Bulbar ALS

    ERIC Educational Resources Information Center

    Yunusova, Yana; Green, Jordan R.; Lindstrom, Mary J.; Ball, Laura J.; Pattee, Gary L.; Zinman, Lorne

    2010-01-01

    The goal of this study was to investigate the deterioration of lip and jaw movements during speech longitudinally in three individuals diagnosed with bulbar amyotrophic lateral sclerosis (ALS). The study was motivated by the need to understand the relationship between physiologic changes in speech movements and clinical measures of speech…

  2. Effect of fluoxetine on disease progression in a mouse model of ALS

    PubMed Central

    Koschnitzky, J. E.; Quinlan, K. A.; Lukas, T. J.; Kajtaz, E.; Kocevar, E. J.; Mayers, W. F.; Siddique, T.

    2014-01-01

    Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5–11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1G93A and control: nontransgenic and SOD1WT) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1G93A mice reached end stage ?8 days (?6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models. PMID:24598527

  3. Transforming Growth Factor Beta (TGF-?) Is a Muscle Biomarker of Disease Progression in ALS and Correlates with Smad Expression

    PubMed Central

    Si, Ying; Kim, Soojin; Cui, Xiangqin; Zheng, Lei; Oh, Shin J.; Anderson, Tina; AlSharabati, Mohammad; Kazamel, Mohamed; Volpicelli-Daley, Laura; Bamman, Marcas M.; Yu, Shaohua; King, Peter H.

    2015-01-01

    We recently identified Smads1, 5 and 8 as muscle biomarkers in human ALS. In the ALS mouse, these markers are elevated and track disease progression. Smads are signal transducers and become activated upon receptor engagement of ligands from the TGF-? superfamily. Here, we sought to characterize ligands linked to activation of Smads in ALS muscle and their role as biomarkers of disease progression. RNA sequencing data of ALS muscle samples were mined for TGF-? superfamily ligands. Candidate targets were validated by qRT-PCR in a large cohort of human ALS muscle biopsy samples and in the G93A SOD1 mouse. Protein expression was evaluated by Western blot, ELISA and immunohistochemistry. C2C12 muscle cells were used to assess Smad activation and induction. TGF-?1, 2 and 3 mRNAs were increased in ALS muscle samples compared to controls and correlated with muscle strength and Smads1, 2, 5 and 8. In the G93A SOD1 mouse, the temporal pattern of TGF-? expression paralleled the Smads and increased with disease progression. TGF-?1 immunoreactivity was detected in mononuclear cells surrounding muscle fibers in ALS samples. In muscle cells, TGF-? ligands were capable of activating Smads. In conclusion, TGF-?1, 2 and 3 are novel biomarkers of ALS in skeletal muscle. Their correlation with weakness in human ALS and their progressive increase with advancing disease in the ALS mouse suggest that they, as with the Smads, can track disease progression. These ligands are capable of upregulating and activating Smads and thus may contribute to the Smad signaling pathway in ALS muscle. PMID:26375954

  4. Progression of Liver Disease

    MedlinePLUS

    ... Handouts Education Resources Support Services Helpful Links For Liver Health Information Call 1-800-GO-LIVER (1- ... The Progression of Liver Disease The Progression of Liver Disease There are many different types of liver ...

  5. Metabolic Therapy with Deanna Protocol Supplementation Delays Disease Progression and Extends Survival in Amyotrophic Lateral Sclerosis (ALS) Mouse Model

    PubMed Central

    Ari, Csilla; Poff, Angela M.; Held, Heather E.; Landon, Carol S.; Goldhagen, Craig R.; Mavromates, Nicholas; D’Agostino, Dominic P.

    2014-01-01

    Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP) is a metabolic therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG), the main ingredient of the DP, and the ketogenic diet (KD), would increase motor function and survival in a mouse model of ALS (SOD1-G93A). ALS mice were fed standard rodent diet (SD), KD, or either diets containing a metabolic therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5% (p?=?0.001) and 4.2% (p?=?0.006), respectively. Sixty-three percent of mice in the KD+DP and 72.7% of the SD+DP group lived past 125 days, while only 9% of the control animals survived past that point. Targeting energy metabolism with metabolic therapy produces a therapeutic effect in ALS mice which may prolong survival and quality of life in ALS patients. PMID:25061944

  6. A Pilot Trial of Pioglitazone HCl and Tretinoin in ALS: Cerebrospinal Fluid Biomarkers to Monitor Drug Efficacy and Predict Rate of Disease Progression

    PubMed Central

    Levine, Todd D.; Bowser, Robert; Hank, Nicole C.; Gately, Stephen; Stephan, Dietrich; Saperstein, David S.; Van Keuren-Jensen, Kendall

    2012-01-01

    Objectives. To determine if therapy with pioglitazone HCl and tretinoin could slow disease progression in patients with ALS. Levels of tau and pNFH in the cerebrospinal fluid were measured to see if they could serve as prognostic indicators. Methods. 27 subjects on stable doses of riluzole were enrolled. Subjects were randomized to receive pioglitazone 30?mg/d and tretinoin 10?mg/BID for six months or two matching placebos. ALSFRS-R scores were followed monthly. At baseline and at the final visit, lumbar punctures (LPs) were performed to measure cerebrospinal fluid (CSF) biomarker levels. Results. Subjects treated with tretinoin, pioglitazone, and riluzole had an average rate of decline on the ALSFRS-R scale of ?1.02 points per month; subjects treated with placebo and riluzole had a rate of decline of ?.86 (P = .18). Over six months of therapy, CSF tau levels decreased in subjects randomized to active treatment and increased in subjects on placebo. Further higher levels of pNF-H at baseline correlated with a faster rate of progression. Conclusion. ALS patients who were treated with tretinoin and pioglitazone demonstrated no slowing on their disease progression. Interestingly, the rate of disease progression was strongly correlated with levels of pNFH in the CSF at baseline. PMID:22830016

  7. A Novel Acylaminoimidazole Derivative, WN1316, Alleviates Disease Progression via Suppression of Glial Inflammation in ALS Mouse Model

    PubMed Central

    Yanagisawa, Yoshiko; Yasutake, Kaori; Inoue, Satoshi; Hirayama, Noriaki; Ikeda, Joh-E

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron degenerative disease. Given that oxidative stress and resulting chronic neuronal inflammation are thought to be central pathogenic, anti-oxidative agents and modulators of neuronal inflammation could be potential therapies for ALS. We report here that the novel small molecular compound, 2-[mesityl(methyl)amino]-N-[4-(pyridin-2-yl)-1H-imidazol-2-yl] acetamide trihydrochloride (WN1316) selectively suppresses oxidative stress-induced cell death and neuronal inflammation in the late-stage ALS mice. WN1316 has high blood-brain-barrier permeability and water solubility, and boosts both neuronal apoptosis inhibitory protein (NAIP) and NF-E2-related factor 2 (Nrf2) which governed glutathione (GSH)-related anti-oxidation pathway protecting motor neurons against oxidative injuries. Post-onset oral administration of low dose (1–100 µg/kg/day) WN1316 in ALS(SOD1H46R) and ALS(SOD1G93A) mice resulted in sustained improved motor function and post onset survival rate. Immunohistochemical analysis revealed less DNA oxidative damage and motor neuronal inflammation as well as repression of both microgliosis and astrocytosis, concomitant down regulation of interleukin-1? and inducible nitric oxide synthase, and preservation of the motoneurons in anterior horn of lumbar spinal cord and skeletal muscle (quadriceps femoris). Thus, WN1316 would be a novel therapeutic agent for ALS. PMID:24498180

  8. Diffusion Tensor Imaging of Parkinson's Disease, Multiple System Atrophy and Progressive Supranuclear

    E-print Network

    Sussex, University of

    Diffusion Tensor Imaging of Parkinson's Disease, Multiple System Atrophy and Progressive, Parkinson's disease (PD), Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) have, et al. (2014) Diffusion Tensor Imaging of Parkinson's Disease, Multiple System Atrophy

  9. Lou Gehrig's Disease (ALS)

    MedlinePLUS

    ... Gehrig's disease is a disorder that's also called amyotrophic lateral sclerosis (say: ah-my-uh-TRO-fik LA-tuh- ... for without "myo" for muscle "trophic" for nourishment "lateral" for ... or scarring So, amyotrophic means that the muscles have lost their nourishment. ...

  10. Modeling Disease Progression With Longitudinal Markers

    E-print Network

    Morrell, Christopher H.

    Modeling Disease Progression With Longitudinal Markers Lurdes Y. T. INOUE, Ruth ETZIONI, Christopher MORRELL, and Peter MÜLLER In this article we propose a Bayesian natural history model for disease progression based on the joint modeling of longitudinal biomarker levels, age at clinical detection of disease

  11. Rab11 in disease progression.

    PubMed

    Bhuin, Tanmay; Roy, Jagat Kumar

    2015-01-01

    Membrane/protein trafficking in the secretory/biosynthetic and endocytic pathways is mediated by vesicles. Vesicle trafficking in eukaryotes is regulated by a class of small monomeric GTPases: the Rab protein family. Rab proteins represent the largest branch of the Ras superfamily GTPases, and have been concerned in a variety of intracellular vesicle trafficking and different intracellular signalling pathways. Rab11 (a subfamily of the Ypt/Rab gene family), an evolutionarily conserved ubiquitously expressed subfamily of Rab GTPases, has been implicated in regulating vesicular trafficking through the recycling of endosomes. Rabs have been grouped into different subfamilies based on the distinct unambiguous sequence motifs. Three members: Rab11a, Rab11b and Rab25 make up the Rab11 GTPase subfamily. In this review article, we describe an overview over Rab11 subfamily with a brief structural aspect and its roles in implicating different disease progression. PMID:25815277

  12. 2013-2014 Alzheimer's Disease Progress Report

    MedlinePLUS

    Alzheimer's Go4Life Español NIHSeniorHealth Publications Text Resize - A + A Search form Search ADEAR Center Home Home > Alzheimer's > 2013-2014 Alzheimer's Disease Progress Report 2013-2014 Alzheimer's Disease ...

  13. Impact of cholesterol on disease progression.

    PubMed

    Lin, Chun-Jung; Lai, Cheng-Kuo; Kao, Min-Chuan; Wu, Lii-Tzu; Lo, U-Ging; Lin, Li-Chiung; Chen, Yu-An; Lin, Ho; Hsieh, Jer-Tsong; Lai, Chih-Ho; Lin, Chia-Der

    2015-06-01

    Cholesterol-rich microdomains (also called lipid rafts), where platforms for signaling are provided and thought to be associated with microbe-induced pathogenesis and lead to cancer progression. After treatment of cells with cholesterol disrupting or usurping agents, raft-associated proteins and lipids can be dissociated, and this renders the cell structure nonfunctional and therefore mitigates disease severity. This review focuses on the role of cholesterol in disease progression including cancer development and infectious diseases. Understanding the molecular mechanisms of cholesterol in these diseases may provide insight into the development of novel strategies for controlling these diseases in clinical scenarios. PMID:26048694

  14. Regionality of disease progression predicts prognosis in amyotrophic lateral sclerosis.

    PubMed

    van der Kleij, Lisa A; Jones, Ashley R; Steen, I Nick; Young, Carolyn A; Shaw, Pamela J; Shaw, Christopher E; Leigh, P Nigel; Turner, Martin R; Al-Chalabi, Ammar

    2015-12-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurological syndrome in which motor neurons degenerate relentlessly. Although the site of onset and the rate of spread have been studied extensively, little is known about whether focal as opposed to diffuse disease affects prognosis. We therefore tested the hypothesis that regionality of disease burden is a prognostic factor in ALS. We analysed clinical data from two large multicentre, longitudinal trials. Regionality was defined as the difference in progression rates in three domains as measured by the revised ALS Functional Rating Scale, omitting the respiratory domain from analysis. We used death by trial end as the outcome variable and tested this by logistic regression against predictor variables including regionality and overall rate of disease progression. There were 561 patients. Regionality of disease was independently associated with significantly higher chance of death by study end (odds ratio most diffuse against most focal category 0.354 (0.191, 0.657), p = 0.001), with a direct relationship between degree of regionality and odds of death. We have shown using clinical trial data that focal disease is associated with a worse prognosis in ALS. Measures of regionality warrant further independent consideration in the development of future prognostic models. PMID:26083873

  15. Hormonal contraception and HIV disease progression.

    PubMed

    Stringer, Elizabeth; Antonsen, Erik

    2008-10-01

    The majority of the 15.4 million human immunodeficiency virus (HIV)-infected women worldwide are of child-bearing age and need access to contraception. Hormonal methods of contraception are safe, acceptable, and effective in preventing unwanted pregnancies. Many published studies have examined the impact of hormonal contraception on HIV disease acquisition and transmissibility. Far fewer have investigated the relationship between hormonal contraception and HIV disease progression. This review examines available data on this relationship from clinical, animal, and immunological studies. Several clinical studies suggest an overall effect but are not definitive, and the mechanisms behind HIV disease progression are unclear. Animal and immunological data suggest that immunomodulation by hormonal contraceptive methods may affect the immune response to HIV infection. Additional work is needed in this area to elucidate the possible relationship between hormonal methods for birth control and progression to acquired immunodeficiency syndrome in HIV-infected women. PMID:18715161

  16. Regulatory Analysis for Exploring Human Disease Progression

    E-print Network

    Kon, Mark

    Regulatory Analysis for Exploring Human Disease Progression Dustin T. Holloway1 , Mark Kon2;Abstract A crucial goal in post-genomic research is unravelling the regulatory network of transcription provide a comprehensive platform for analysis of regulatory networks, and the results can be used to make

  17. The Axis of Progression of Disease

    PubMed Central

    Tartakoff, Alan M; Wu, Di

    2014-01-01

    Starting with genetic or environmental perturbations, disease progression can involve a linear sequence of changes within individual cells. More often, however, a labyrinth of branching consequences emanates from the initial events. How can one repair an entity so fine and so complex that its organization and functions are only partially known? How, given the many redundancies of metabolic pathways, can interventions be effective before the last redundant element has been irreversibly damaged? Since progression ultimately proceeds beyond a point of no return, therapeutic goals must target earlier events. A key goal is therefore to identify early changes of functional importance. Moreover, when several distinct genetic or environmental causes converge on a terminal phenotype, therapeutic strategies that focus on the shared features seem unlikely to be useful – precisely because the shared events lie relatively downstream along the axis of progression. We therefore describe experimental strategies that could lead to identification of early events, both for cancer and for other diseases. PMID:25374458

  18. Managing progressive renal disease before dialysis.

    PubMed Central

    Barrett, B. J.

    1999-01-01

    OBJECTIVE: To enhance awareness of issues affecting patients with chronic renal failure and to provide guidance for primary care practitioners managing such patients. QUALITY OF EVIDENCE: Randomized trials establish the efficacy of blood pressure control and angiotensin-converting enzyme (ACE) inhibition in slowing the progression of chronic renal disease. Some randomized trials and many prospective studies address management of anemia, hyperparathyroidism, and multidisciplinary predialysis care. The benefits of lipid lowering are suggested by randomized trials among patients without renal disease. MAIN MESSAGE: Progression of renal failure, particularly in patients with proteinuria, can be slowed by lowering blood pressure. Angiotensin-converting enzyme inhibitors are more beneficial than other antihypertensives in this situation. Partial correction of anemia with iron, erythropoietin, or androgens can improve quality of life and potentially prevent cardiac disease. Renal bone disease and secondary hyperparathyroidism can be prevented in part by early dietary phosphate restriction, use of calcium-containing phosphate binders, and activated vitamin D. Correction of acidosis could improve protein metabolism and bone and cardiovascular health. Treatment of hyperlipidemia might reduce cardiovascular disease. Early involvement of a nephrology-based multidisciplinary team has the potential to reduce morbidity and costs, enhance patients' knowledge of their condition, and prolong the period before dialysis is required. CONCLUSIONS: Care of patients with progressive renal failure is complex and requires attention to detail. Family doctors play a vital role in these efforts and should be involved in all aspects of care. PMID:10216796

  19. JAK INHIBITION AND PROGRESSIVE KIDNEY DISEASE

    PubMed Central

    Brosius, Frank C.; He, John Cijiang

    2015-01-01

    Purpose of review To review the role of JAK-STAT signaling in the progression of chronic kidney diseases. Recent findings The JAK-STAT pathway transmits signals from extracellular ligands, including many cytokines and chemokines. While these responses are best characterized in lymphoid cells, they also occur in kidney cells such as podocytes, mesangial cells, and tubular cells. JAK-STAT expression and signaling abnormalities occur in humans and animal models of different chronic kidney diseases. Enhanced expression and augmented activity of JAK1, JAK2 and STAT3 promote diabetic nephropathy and their inhibition appears to reduce disease. Activation of JAK-STAT signaling in autosomal dominant polycystic kidney disease may play an important role in cyst growth. Activation of JAK-STAT signaling promotes HIV-associated nephropathy and may also participate in the tubular responses to chronic obstructive uropathy. Based on data from experimental models, inhibition of JAK-STAT signaling, via increased expression of the suppressors of cytokine signaling proteins or pharmacologic inhibition of JAK and STAT proteins, could play a therapeutic role in multiple chronic kidney diseases. Summary Activation of the JAK-STAT pathway appears to play a role in the progression of some chronic kidney diseases. More work is needed to determine the specific role the pathway plays in individual diseases. PMID:25415616

  20. Smoking and Disease Progression in Multiple Sclerosis

    PubMed Central

    Healy, Brian C.; Ali, Eman; Guttmann, Charles R.G.; Chitnis, Tanuja; Glanz, Bonnie I.; Buckle, Guy; Houtchens, Maria; Stazzone, Lynn; Moodie, Jennifer; Berger, Annika M.; Duan, Yang; Bakshi, Rohit; Khoury, Samia; Weiner, Howard; Ascherio, Alberto

    2009-01-01

    Context Although cigarette smokers have an increased risk of developing multiple sclerosis (MS), the effect of smoking on MS progression remains uncertain. Objectives To establish the relationship between cigarette smoking and MS progression using clinical and MRI outcomes Design Cross-sectional survey and longitudinal follow-up for an average of 3.29 years, ending January 15, 2008. Setting Partners MS Center (Boston, MA), a referral center for MS patients Patients 1465 patients with clinically definite MS (25.1% men) with mean baseline age of 42.0 years (range: 16–75) and disease duration of 9.4 years (range: 0–50.4) -- 780 (53.2%) patients were never smokers, 428 (29.2%) ex-smokers, and 257 (17.5%) were current smokers. Main Outcome Measures Smoking groups were compared in terms of baseline clinical and MRI characteristics as well as progression and sustained progression on the expanded disability status scale (EDSS) at 2 years and 5 years and the time until conversion to secondary progressive MS. In addition, the rate of on-study change in the brain parenchymal fraction (BPF) and T2 hyperintense lesion volume was compared. Results Current smokers had significantly worse disease at baseline than never-smokers in terms of EDSS (adjusted p<0.0001), multiple sclerosis severity score (adjusted p<0.0001), and BPF (adjusted p=0.004). In addition, current smokers were significantly more likely to have primary progressive MS (adjusted odds ratio=2.41; 95% CI: 1.09, 5.34). In longitudinal analyses, smokers converted from relapsing remitting MS to secondary progressive MS faster than never-smokers (HR for current smokers versus never smokers, =2.50, 95% CI: 1.42, 4.41) and had a faster rate of increase in the T2 lesion volume (p=0.017) and a faster rate of decrease in BPF (p=0.021). Conclusion Our data suggest that cigarette smoke has an adverse influence on MS progression and accelerates the conversion from a relapsing-remitting to a progressive course. PMID:19597087

  1. The balance of the evidence on acid-base homeostasis and progression of chronic kidney disease.

    PubMed

    Scialla, Julia J

    2015-07-01

    Normalization of acid-base homeostasis in chronic kidney disease (CKD) holds promise for mitigating disease progression, but whether efforts should focus on patients with low serum bicarbonate or high dietary acid load is unknown. Vallet et al. report that low urinary ammonia excretion independently associates with increased progression in moderate CKD. Whether this finding implicates differences in endogenous acid production or the ability to excrete an acid load in the pathogenesis of progression requires further study. PMID:26126088

  2. Genetic architecture of human fibrotic diseases: disease risk and disease progression

    PubMed Central

    Gardet, Agnès; Zheng, Timothy S.; Viney, Joanne L.

    2013-01-01

    Genetic studies of human diseases have identified multiple genetic risk loci for various fibrotic diseases. This has provided insights into the myriad of biological pathways potentially involved in disease pathogenesis. These discoveries suggest that alterations in immune responses, barrier function, metabolism and telomerase activity may be implicated in the genetic risks for fibrotic diseases. In addition to genetic disease-risks, the identification of genetic disease-modifiers associated with disease complications, severity or prognosis provides crucial insights into the biological processes implicated in disease progression. Understanding the biological processes driving disease progression may be critical to delineate more effective strategies for therapeutic interventions. This review provides an overview of current knowledge and gaps regarding genetic disease-risks and genetic disease-modifiers in human fibrotic diseases. PMID:24391588

  3. Unsupervised Learning of Disease Progression Models IBM Research

    E-print Network

    Unsupervised Learning of Disease Progression Models Xiang Wang IBM Research Yorktown Heights, NY Yorktown Heights, NY fwang@us.ibm.com ABSTRACT Chronic diseases, such as Alzheimer's Disease, Diabetes, and Chronic Obstructive Pulmonary Disease, usually progress slowly over a long period of time, causing

  4. [Pharmacotherapy of Parkinson's disease: progress or regress?].

    PubMed

    Pytka, Karolina; Zygmunt, Ma?gorzata; Filipek, Barbara

    2013-01-01

    Parkinson's disease (PD) is a chronic, progressive disease of the central nervous system (CNS), characterized by a slow loss of dopaminergic neurons in the substantia nigra, leading to significant decrease in dopamine (DA) levels in the striatum. Currently used drugs, such as levodopa (L-DOPA), amantadine, dopamine agonists (D) or anticholinergic drugs, are not effective enough, and do not eliminate the causes of disease. Many research centers are conducting research on new forms of currently used drugs (e.g. Duodopa, XP21279, IPX066), new drugs of already known groups (e.g. safinamide), medicines that suppress side effects of L-DOPA (e.g. AFQ056, fipamezole), and, finally, compounds with a novel mechanism of action (e.g. PMY50028, A2A receptor antagonists). A lot of scientific reports indicate an important role of A2A receptors in the regulation of the central movement system, so a new group of compounds - selective antagonists of A2A receptors (e.g. istradefylline, preladenant, SYN115) - has been developed and their potential use in PD has been examined. Clinical studies of A2A receptor antagonists have shown that this group of compounds can shorten off periods and at the same time they do not worsen dyskinesias in patients with PD. Moreover, there is ongoing research on new forms of treatment, such as gene therapy. Attempts to apply the viral vector AAV-2, which will be able to infect neurons with a variety of genes, including the gene of glutamate decarboxylase (GAD), neurturin (NTN), or aromatic L-amino acid decarboxylase, are currently being carried out. The results of phase I and II clinical studies showed some efficacy of this form of treatment, but the method requires further studies. An analysis of potential future therapies of Parkinson's disease suggests that some progress in this field has been made. PMID:24018435

  5. INTRODUCTION Huntington's disease (HD) is an autosomal dominant, progressive

    E-print Network

    Perrimon, Norbert

    INTRODUCTION Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative protein, huntingtin (Htt) (The Huntington's Disease Collaborative Research Group, 1993). The polyQ tract in HD (The Huntington's Disease Collaborative Research Group, 1993). Numerous studies have demonstrated

  6. Amyotrophic lateral sclerosis progression: Iran-ALS clinical registry, a multicentre study.

    PubMed

    Shamshiri, Hosein; Fatehi, Farzad; Davoudi, Farnoush; Mir, Elham; Pourmirza, Behin; Abolfazli, Roya; Etemadifar, Masoud; Harirchian, Mohammad Hossein; Gharagozli, Koroush; Ayromlou, Hormoz; Basiri, Keivan; Zamani, Babak; Rohani, Mohammad; Sedighi, Behnaz; Roudbari, Ali; Delavar Kasmaei, Hossein; Nikkhah, Karim; Ranjbar Naeini, Alireza; Nafissi, Shahriar

    2015-12-01

    This study was designed to evaluate ALS progression among different subgroups of Iranian patients. Three hundred and fifty-eight patients from centres around the country were registered and their progression rate was evaluated using several scores including Manual Muscle Test scoring (MMT) and the revised ALS Functional Rating Scale (ALSFRS-R). Progression rate was analysed separately in subgroups regarding gender, onset site, stage of disease and riluzole consumption. A significant difference in MMT deterioration rate (p?=?0.01) was noted between those who used riluzole and those who did not. No significant difference was observed in progression rates between male/female and bulbar-onset/limb-onset groups using riluzole. In conclusion, riluzole has a significant effect on muscle force deterioration rate but not functional scale. Progression rate was not influenced by site of onset or gender. PMID:26437387

  7. Research Progress of Moyamoya Disease in Children

    PubMed Central

    Piao, Jianmin; Wu, Wei; Yang, Zhongxi; Yu, Jinlu

    2015-01-01

    During the onset of Moyamoya disease (MMD), progressive occlusion occurs at the end of the intracranial internal carotid artery, and compensatory net-like abnormal vessels develop in the skull base, generating the corresponding clinical symptoms. MMD can affect both children and adults, but MMD in pediatric patients exhibits distinct clinical features, and the treatment prognoses are different from adult patients. Children are the group at highest risk for MMD. In children, the disease mainly manifests as ischemia, while bleeding is the primary symptom in adults. The pathogenesis of MMD in children is still unknown, and some factors are distinct from those in adults. MMD in children could result in progressive, irreversible nerve functional impairment, and an earlier the onset corresponds to a worse prognosis. Therefore, active treatment at an early stage is highly recommended. The treatment methods for MMD in children mainly include indirect and direct surgeries. Indirect surgeries mainly include multiple burr-hole surgery (MBHS), encephalomyosynangiosis (EMS), and encephaloduroarteriosynangiosis (EDAS); direct surgeries mainly include intra- and extracranial vascular reconstructions that primarily consist of superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis. Indirect surgery, as a treatment for MMD in children, has shown a certain level of efficacy. However, a standard treatment approach should combine both indirect and direct procedures. Compared to MMD in adults, the treatment and prognosis of MMD in children has higher clinical significance. If the treatment is adequate, a satisfactory outcome is often achieved. PMID:26180513

  8. ALZHEIMER'S DISEASE: MRI IMAGING OF PROGRESSIVE BRAIN CHANGE

    E-print Network

    Thompson, Paul

    ALZHEIMER'S DISEASE: MRI IMAGING OF PROGRESSIVE BRAIN CHANGE Paul M. Thompson and Arthur W. Toga in the Journal of Neuroscience. #12;2 ALZHEIMER'S DISEASE: MRI IMAGING OF PROGRESSIVE BRAIN CHANGE Paul M, UCLA School of Medicine 1. Introduction Alzheimer's disease (AD) is the leading cause of senile

  9. A prediction model for progressive disease in systemic sclerosis

    PubMed Central

    Meijs, Jessica; Schouffoer, Anne A; Ajmone Marsan, Nina; Stijnen, Theo; Putter, Hein; Ninaber, Maarten K; Huizinga, Tom W J; de Vries-Bouwstra, Jeska K

    2015-01-01

    Objective To develop a model that assesses the risk for progressive disease in patients with systemic sclerosis (SSc) over the short term, in order to guide clinical management. Methods Baseline characteristics and 1?year follow-up results of 163 patients with SSc referred to a multidisciplinary healthcare programme were evaluated. Progressive disease was defined as: death, ?10% decrease in forced vital capacity, ?15% decrease in diffusing capacity for carbon monoxide, ?10% decrease in body weight, ?30% decrease in estimated-glomerular filtration rate, ?30% increase in modified Rodnan Skin Score (with ??5) or ?0.25 increase in Scleroderma Health Assessment Questionnaire. The number of patients with progressive disease was determined. Univariable and multivariable logistic regression analyses were used to assess the probability of progressive disease for each individual patient. Performance of the prediction model was evaluated using a calibration plot and area under the receiver operating characteristic curve. Results 63 patients had progressive disease, including 8 patients who died ?18?months after first evaluation. Multivariable analysis showed that friction rubs, proximal muscular weakness and decreased maximum oxygen uptake as % predicted, adjusted for age, gender and use of immunosuppressive therapy at baseline, were significantly associated with progressive disease. Using the prediction model, the predicted chance for progressive disease increased from a pretest chance of 37% to 67–89%. Conclusions Using the prediction model, the chance for progressive disease for individual patients could be doubled. Friction rubs, proximal muscular weakness and maximum oxygen uptake as % predicted were identified as relevant parameters. PMID:26688749

  10. Pulmonary arterial hypertension (PAH) is a fast progress-ing vascular disease characterized by proximal pulmo-

    E-print Network

    Chesler, Naomi C.

    1082 Pulmonary arterial hypertension (PAH) is a fast progress- ing vascular disease characterized and progression remains incom- pletely known. 17-Estradiol modifies age- and hypertension-related arte- rial Abstract--Pulmonary arterial hypertension (PAH), a rapidly fatal vascular disease, strikes women more often

  11. A Century of Progress: Milestones in Sickle Cell Disease

    E-print Network

    Shen, Jun

    A Century of Progress: Milestones in Sickle Cell Disease Research and Care Introduction In 1910 to be known as sickle cell disease. One hundred years later we know that the sickle-shaped cells are due take the characteristic "C"-shape that is the hallmark of sickle cell disease. What is Sickle Cell

  12. Deciphering early development of complex diseases by progressive module network.

    PubMed

    Zeng, Tao; Zhang, Chuan-chao; Zhang, Wanwei; Liu, Rui; Liu, Juan; Chen, Luonan

    2014-06-01

    There is no effective cure nowadays for many complex diseases, and thus it is crucial to detect and further treat diseases in earlier stages. Generally, the development and progression of complex diseases include three stages: normal stage, pre-disease stage, and disease stage. For diagnosis and treatment, it is necessary to reveal dynamical organizations of molecular modules during the early development of the disease from the pre-disease stage to the disease stage. Thus, we develop a new framework, i.e. we identify the modules presenting at the pre-disease stage (pre-disease module) based on dynamical network biomarkers (DNBs), detect the modules observed at the advanced stage (disease-responsive module) by cross-tissue gene expression analysis, and finally find the modules related to early development (progressive module) by progressive module network (PMN). As an application example, we used this new method to analyze the gene expression data for NOD mouse model of Type 1 diabetes mellitus (T1DM). After the comprehensive comparison with the previously reported milestone molecules, we found by PMN: (1) the critical transition point was identified and confirmed by the tissue-specific modules or DNBs relevant to the pre-disease stage, which is considered as an earlier event during disease development and progression; (2) several key tissues-common modules related to the disease stage were significantly enriched on known T1DM associated genes with the rewired association networks, which are marks of later events during T1DM development and progression; (3) the tissue-specific modules associated with early development revealed several common essential progressive genes, and a few of pathways representing the effect of environmental factors during the early T1DM development. Totally, we developed a new method to detect the critical stage and the key modules during the disease occurrence and progression, and show that the pre-disease modules can serve as warning signals for the pre-disease state (e.g. T1DM early diagnosis) whereas the progressive modules can be used as the therapy targets for the disease state (e.g. advanced T1DM), which were also validated by experimental data. PMID:24561825

  13. Electrical impedance myography as a biomarker to assess ALS progression

    PubMed Central

    Rutkove, Seward B.; Caress, James B.; Cartwright, Michael S.; Burns, Ted M.; Warder, Judy; David, William S.; Goyal, Namita; Maragakis, Nicholas J.; Clawson, Lora; Benatar, Michael; Usher, Sharon; Sharma, Khema R.; Gautam, Shiva; Narayanaswami, Pushpa; Raynor, Elizabeth M.; Watson, Mary Lou; Shefner, Jeremy M.

    2012-01-01

    Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM’s potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique’s correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials. PMID:22670883

  14. Quitting Smoking After MS Diagnosis May Delay Disease Progression

    MedlinePLUS

    ... news/fullstory_154524.html Quitting Smoking After MS Diagnosis May Delay Disease Progression Accelerates about 5 percent ... smoke compared to smokers who quit after their diagnosis, a new study finds. "This study demonstrates that ...

  15. Research Finds Link Between Statin Use and Progressive Muscle Disease

    MedlinePLUS

    ... Research Finds Link Between Statin Use and Progressive Muscle Disease Each year, millions of Americans take statins, ... people these benefits come at a cost: widespread muscle pain that persists as long as the drugs ...

  16. Progress Report on Alzheimer's Disease: Volume II.

    ERIC Educational Resources Information Center

    National Inst. on Aging (DHHS/PHS), Bethesda, MD.

    This document provides an overview of the state of scientific study of Alzheimer's disease, a disease of catastrophic proportions whose symptoms include serious forgetfulness; changes in personality; confused, restless, and irritable behavior; and problems with judgment, concentration, writing, reading, speech, and naming of objects. It discusses…

  17. Huntington's disease: progress toward effective disease-modifying treatments and a cure

    E-print Network

    Brutlag, Doug

    Huntington's disease: progress toward effective disease-modifying treatments and a cure Carl D. Johnson1, and Beverly L. Davidson2,3 1 Hereditary Disease Foundation, New York, NY 10032, USA and 2 Huntington's disease (HD) is caused by a dominant mutation in HTT, the HD gene. This discovery opens pos

  18. Modeling Disease Progression via Fused Sparse Group Lasso

    PubMed Central

    Zhou, Jiayu; Liu, Jun; Narayan, Vaibhav A.; Ye, Jieping

    2013-01-01

    Alzheimer’s Disease (AD) is the most common neurodegenerative disorder associated with aging. Understanding how the disease progresses and identifying related pathological biomarkers for the progression is of primary importance in the clinical diagnosis and prognosis of Alzheimer’s disease. In this paper, we develop novel multi-task learning techniques to predict the disease progression measured by cognitive scores and select biomarkers predictive of the progression. In multi-task learning, the prediction of cognitive scores at each time point is considered as a task, and multiple prediction tasks at different time points are performed simultaneously to capture the temporal smoothness of the prediction models across different time points. Specifically, we propose a novel convex fused sparse group Lasso (cFSGL) formulation that allows the simultaneous selection of a common set of biomarkers for multiple time points and specific sets of biomarkers for different time points using the sparse group Lasso penalty and in the meantime incorporates the temporal smoothness using the fused Lasso penalty. The proposed formulation is challenging to solve due to the use of several non-smooth penalties. One of the main technical contributions of this paper is to show that the proximal operator associated with the proposed formulation exhibits a certain decomposition property and can be computed efficiently; thus cFSGL can be solved efficiently using the accelerated gradient method. To further improve the model, we propose two non-convex formulations to reduce the shrinkage bias inherent in the convex formulation. We employ the difference of convex (DC) programming technique to solve the non-convex formulations. We have performed extensive experiments using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Results demonstrate the effectiveness of the proposed progression models in comparison with existing methods for disease progression. We also perform longitudinal stability selection to identify and analyze the temporal patterns of biomarkers in disease progression. PMID:25309808

  19. Modeling Disease Progression via Fused Sparse Group Lasso.

    PubMed

    Zhou, Jiayu; Liu, Jun; Narayan, Vaibhav A; Ye, Jieping

    2012-01-01

    Alzheimer's Disease (AD) is the most common neurodegenerative disorder associated with aging. Understanding how the disease progresses and identifying related pathological biomarkers for the progression is of primary importance in the clinical diagnosis and prognosis of Alzheimer's disease. In this paper, we develop novel multi-task learning techniques to predict the disease progression measured by cognitive scores and select biomarkers predictive of the progression. In multi-task learning, the prediction of cognitive scores at each time point is considered as a task, and multiple prediction tasks at different time points are performed simultaneously to capture the temporal smoothness of the prediction models across different time points. Specifically, we propose a novel convex fused sparse group Lasso (cFSGL) formulation that allows the simultaneous selection of a common set of biomarkers for multiple time points and specific sets of biomarkers for different time points using the sparse group Lasso penalty and in the meantime incorporates the temporal smoothness using the fused Lasso penalty. The proposed formulation is challenging to solve due to the use of several non-smooth penalties. One of the main technical contributions of this paper is to show that the proximal operator associated with the proposed formulation exhibits a certain decomposition property and can be computed efficiently; thus cFSGL can be solved efficiently using the accelerated gradient method. To further improve the model, we propose two non-convex formulations to reduce the shrinkage bias inherent in the convex formulation. We employ the difference of convex (DC) programming technique to solve the non-convex formulations. We have performed extensive experiments using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Results demonstrate the effectiveness of the proposed progression models in comparison with existing methods for disease progression. We also perform longitudinal stability selection to identify and analyze the temporal patterns of biomarkers in disease progression. PMID:25309808

  20. Repeat expansion disease: Progress and puzzles in disease pathogenesis

    PubMed Central

    La Spada, Albert R.; Taylor, J. Paul

    2015-01-01

    Repeat expansion mutations cause at least 22 inherited neurological diseases. The complexity of repeat disease genetics and pathobiology has revealed unexpected shared themes and mechanistic pathways among the diseases, for example, RNA toxicity. Also, investigation of the polyglutamine diseases has identified post-translational modification as a key step in the pathogenic cascade, and has shown that the autophagy pathway plays an important role in the degradation of misfolded proteins – two themes likely to be relevant to the entire neurodegeneration field. Insights from repeat disease research are catalyzing new lines of study that should not only elucidate molecular mechanisms of disease, but also highlight opportunities for therapeutic intervention for these currently untreatable disorders. PMID:20177426

  1. [Factors influencing development and progression of alcoholic liver disease].

    PubMed

    Abdelrahman, K; Marot, A; Deltenre, P

    2015-09-01

    Only a minority ot excessive drinkers develop cirrhosis. The main cofactors implicated in the pathophysiology of alcoholic liver disease are obesity, diabetes or the metabolic syndrome. Several genetic polymorphisms have been associated with a higher risk of alcoholic cirrhosis. Recent data indicate that gut microbiota could play a role in the pathogenesis of alcoholic liver disease. The aim of this review is to summarize the factors that influence development and progression of alcoholic liver disease. PMID:26502621

  2. 2014-2015 Alzheimer's Disease Progress Report

    MedlinePLUS

    ... Disease and Related Dementias A Growing Public Health Crisis The Economic Impact of Alzheimer’s Ramping Up Research Today, more ... common: they exact a terrible physical, emotional, and financial toll on those with ... Health Crisis In most people with Alzheimer’s, symptoms first appear ...

  3. Predicting the severity of motor neuron disease progression using electronic health record data with a cloud computing Big Data approach

    PubMed Central

    Ko, Kyung Dae; El-Ghazawi, Tarek; Kim, Dongkyu; Morizono, Hiroki

    2014-01-01

    Motor neuron diseases (MNDs) are a class of progressive neurological diseases that damage the motor neurons. An accurate diagnosis is important for the treatment of patients with MNDs because there is no standard cure for the MNDs. However, the rates of false positive and false negative diagnoses are still very high in this class of diseases. In the case of Amyotrophic Lateral Sclerosis (ALS), current estimates indicate 10% of diagnoses are false-positives, while 44% appear to be false negatives. In this study, we developed a new methodology to profile specific medical information from patient medical records for predicting the progression of motor neuron diseases. We implemented a system using Hbase and the Random forest classifier of Apache Mahout to profile medical records provided by the Pooled Resource Open-Access ALS Clinical Trials Database (PRO-ACT) site, and we achieved 66% accuracy in the prediction of ALS progress. PMID:25580472

  4. Recent progress on small vessel disease with cognitive impairment

    PubMed Central

    Gong, Li; Liu, Xue-Yuan; Fang, Min

    2015-01-01

    Vascular cognitive impairment (VCI) refers to different degrees of cognitive dysfunction syndrome caused by all kinds of cerebral vascular disease and vascular factors. Before in the development of vascular dementia (VaD), early diagnosis and intervention can prevent and delay the progress of VCI, even reverse cognitive impairment. In this review, we summarized the research progress of vascular cognitive impairment in pathophysiology, biomarkers and treatments, etc. PMID:26221320

  5. Recent progress on small vessel disease with cognitive impairment.

    PubMed

    Gong, Li; Liu, Xue-Yuan; Fang, Min

    2015-01-01

    Vascular cognitive impairment (VCI) refers to different degrees of cognitive dysfunction syndrome caused by all kinds of cerebral vascular disease and vascular factors. Before in the development of vascular dementia (VaD), early diagnosis and intervention can prevent and delay the progress of VCI, even reverse cognitive impairment. In this review, we summarized the research progress of vascular cognitive impairment in pathophysiology, biomarkers and treatments, etc. PMID:26221320

  6. Lipid-Altering Therapies and the Progression of Atherosclerotic Disease

    SciTech Connect

    Wierzbicki, Anthony S.

    2007-04-15

    Lipids play a key role in the progression of atherosclerosis, and lipid-lowering therapies have been studied for 30 years in coronary disease. Measurement of the progression of atherosclerosis through carotid intima-media thickness, coronary mean lumen diameter, and, mostly recently, intravascular ultrasound is generally accepted. This article reviews the role of lipid-lowering therapies in changing the rate of atherosclerosis progression in the coronary and carotid circulations. Statins are the primary therapy used to reduce atherosclerosis and cardiovascular events, including strokes and transient ischemic attacks, and have benefits in reducing events in patients undergoing carotid endarterectomy. In contrast, data for other agents, including fibrates and nicotinic acid, in reducing the progression of atherosclerosis are less extensive and not as well known. There is increasing interest in optimizing the whole lipid profile, as this might deliver extra benefits over and above statin therapy alone. Initial proof of this concept has recently come from studies that measured the progression of atherosclerosis and showed that adding nicotinic acid to statin therapy and, more directly, infusion of high-density lipoprotein-like particles reduced progression and indeed might induce regression of the disease. It is likely that the management of significant carotid stenosis will become ever more drug focused and will be customized to the lipid profile of each patient with intervention reserved only for late-stage symptomatic disease.

  7. Cortical Processing of Swallowing in ALS Patients with Progressive Dysphagia – A Magnetoencephalographic Study

    PubMed Central

    Teismann, Inga K.; Warnecke, Tobias; Suntrup, Sonja; Steinsträter, Olaf; Kronenberg, Linda; Ringelstein, E. Bernd; Dengler, Reinhard; Petri, Susanne; Pantev, Christo; Dziewas, Rainer

    2011-01-01

    Amyotrophic lateral sclerosis (ALS) is a rare disease causing degeneration of the upper and lower motor neuron. Involvement of the bulbar motor neurons often results in fast progressive dysphagia. While cortical compensation of dysphagia has been previously shown in stroke patients, this topic has not been addressed in patients suffering from ALS. In the present study, we investigated cortical activation during deglutition in two groups of ALS patients with either moderate or severe dysphagia. Whole-head MEG was employed on fourteen patients with sporadic ALS using a self-paced swallowing paradigm. Data were analyzed by means of time-frequency analysis and synthetic aperture magnetometry (SAM). Group analysis of individual SAM data was performed using a permutation test. We found a reduction of cortical swallowing related activation in ALS patients compared to healthy controls. Additionally a disease-related shift of hemispheric lateralization was observed. While healthy subjects showed bilateral cortical activation, the right sensorimotor cortex was predominantly involved in ALS patients. Both effects were even stronger in the group of patients with severe dysphagia. Our results suggest that bilateral degeneration of the upper motor neuron in the primary motor areas also impairs further adjusted motor areas, which leads to a strong reduction of ‘swallowing related’ cortical activation. While both hemispheres are affected by the degeneration a relatively stronger activation is seen in the right hemisphere. This right hemispheric lateralization of volitional swallowing observed in this study may be the only sign of cortical plasticity in dysphagic ALS patients. It may demonstrate compensational mechanisms in the right hemisphere which is known to predominantly coordinate the pharyngeal phase of deglutition. These results add new aspects to our understanding of the pathophysiology of dysphagia in ALS patients and beyond. The compensational mechanisms observed could be relevant for future research in swallowing therapies. PMID:21625445

  8. ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS): study methodology, recruitment, and baseline demographic and disease characteristics.

    PubMed

    Mitsumoto, Hiroshi; Factor-Litvak, Pam; Andrews, Howard; Goetz, Raymond R; Andrews, Leslie; Rabkin, Judith G; McElhiney, Martin; Nieves, Jeri; Santella, Regina M; Murphy, Jennifer; Hupf, Jonathan; Singleton, Jess; Merle, David; Kilty, Mary; Heitzman, Daragh; Bedlack, Richard S; Miller, Robert G; Katz, Jonathan S; Forshew, Dallas; Barohn, Richard J; Sorenson, Eric J; Oskarsson, Bjorn; Fernandes Filho, J Americo M; Kasarskis, Edward J; Lomen-Hoerth, Catherine; Mozaffar, Tahseen; Rollins, Yvonne D; Nations, Sharon P; Swenson, Andrea J; Shefner, Jeremy M; Andrews, Jinsy A; Koczon-Jaremko, Boguslawa A

    2014-06-01

    Abstract In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression. Methods utilize an extensive structured telephone interview ascertaining environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3-6 month intervals during the ensuing 30 months. Our biorepository includes DNA, plasma, urine, and skin. Three hundred and fifty-five patients were recruited. Subjects were enrolled over a 36-month period at 16 sites. To meet the target number of subjects, the recruitment period was prolonged and additional sites were included. Results showed that demographic and disease characteristics were similar between 477 eligible/non-enrolled and enrolled patients, the only difference being type of health insurance among enrolled patients. Sites were divided into three groups by the number of enrolled subjects. Comparing these three groups, the Columbia site had fewer 'definite ALS' diagnoses. This is the first prospective, interdisciplinary, in-depth, multicenter epidemiological investigation of OS related to ALS progression and has been accomplished by an aggressive recruitment process. The baseline demographic and disease features of the study sample are now fully characterized. PMID:24564738

  9. ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS): The study methodology, recruitment, and baseline demographic and disease characteristics

    PubMed Central

    Mitsumoto, Hiroshi; Factor-Litvak, Pam; Andrews, Howard; Goetz, Raymond R.; Andrews, Leslie; Rabkin, Judith G.; McElhiney, Martin; Nieves, Jeri; Santella, Regina M.; Murphy, Jennifer; Hupf, Jonathan; Singleton, Jess; Merle, David; Kilty, Mary; Heitzman, Daragh; Bedlack, Richard S.; Miller, Robert G; Katz, Jonathan S.; Forshew, Dallas; Barohn, Richard J.; Sorenson, Eric J.; Oskarsson, Bjorn; Filho, J Americo M. Fernandes; Kasarskis, Edward J.; Lomen-Hoerth, Catherine; Mozaffar, Tahseen; Rollins, Yvonne D.; Nations, Sharon P.; Swenson, Andrea J.; Shefner, Jeremy M.; Andrews, Jinsy A.; Koczon-Jaremko, Boguslawa A.

    2015-01-01

    Objective In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression. Methods An extensive structured telephone interview ascertained environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3 to 6 month intervals during the ensuing 30 months. Our biorepository includes DNA, plasma, urine, and skin. Results 355 patients were recruited. Subjects were enrolled over a 36 month-period at 16 sites. To meet the target number of subjects, the recruitment period was prolonged and additional sites were included. Demographic and disease characteristics were similar between 477 eligible/non-enrolled and enrolled patients, with the only difference being type of health insurance among enrolled patients. Sites were divided into 3 groups by the number of enrolled subjects. Comparing these 3 groups, the Columbia site had fewer “definite ALS” diagnoses. Conclusion This is the first prospective, interdisciplinary, in-depth, multicenter epidemiological investigation of OS related to ALS progression and was accomplished by an aggressive recruitment process. The baseline demographic and disease features of the study sample are now fully characterized. PMID:24564738

  10. Management of almond leaf scorch disease: long term data on yield, tree vitality, and disease progress

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Almond leaf scorch (ALS) disease has been a chronic problem for California almond growers. This disease is caused by the bacterial pathogen Xylella fastidiosa and is transmitted by xylem-feeding insects. Previous research suggested that retaining, rather than roguing, ALS-affected trees may be more ...

  11. Computational Approaches for Translational Clinical Research in Disease Progression

    PubMed Central

    McGuire, Mary F.; Iyengar, M. Sriram; Mercer, David W.

    2011-01-01

    Today, there is an ever-increasing amount of biological and clinical data available that could be used to enhance a systems-based understanding of disease progression through innovative computational analysis. In this paper we review a selection of published research regarding computational methodologies, primarily from systems biology, that support translational research from the molecular level to the bedside, with a focus on applications in trauma and critical care. Trauma is the leading cause of mortality in Americans under 45 years of age, and its rapid progression offers both opportunities and challenges for computational analysis of trends in molecular patterns associated with outcomes and therapeutic interventions. This review presents methods and domain-specific examples that may inspire the development of new algorithms and computational methods that utilize both molecular and clinical data for diagnosis, prognosis and therapy in disease progression. PMID:21712727

  12. Disruption of gut homeostasis by opioids accelerates HIV disease progression

    PubMed Central

    Meng, Jingjing; Sindberg, Gregory M.; Roy, Sabita

    2015-01-01

    Cumulative studies during the past 30 years have established the correlation between opioid abuse and human immunodeficiency virus (HIV) infection. Further studies also demonstrate that opioid addiction is associated with faster progression to AIDS in patients. Recently, it was revealed that disruption of gut homeostasis and subsequent microbial translocation play important roles in pathological activation of the immune system during HIV infection and contributes to accelerated disease progression. Similarly, opioids have been shown to modulate gut immunity and induce gut bacterial translocation. This review will explore the mechanisms by which opioids accelerate HIV disease progression by disrupting gut homeostasis. Better understanding of these mechanisms will facilitate the search for new therapeutic interventions to treat HIV infection especially in opioid abusing population. PMID:26167159

  13. Drug therapies to delay the progression of chronic kidney disease.

    PubMed

    Ward, Frank; Holian, John; Murray, Patrick T

    2015-12-01

    Chronic kidney disease (CKD) is associated with significant morbidity and mortality, impacted not alone by progression to end-stage kidney disease, but also by the high associated incidence of cardiovascular events and related mortality. Despite our current understanding of the pathogenesis of CKD and the treatments available, the reported incidence of CKD continues to rise worldwide, and is often referred to as the silent public healthcare epidemic. The significant cost to patient wellbeing and to the economy of managing the later stages of CKD have prompted efforts to develop interventions to delay the development and progression of this syndrome. In this article, we review established and novel agents that may aid in delaying the progression of CKD and improve patient outcomes. PMID:26621944

  14. Progress in Huntington’s disease: the search for markers of disease onset and progression

    E-print Network

    Mason, Sarah; Barker, Roger A.

    2015-03-21

    Unlike most neurodegenerative disorders, individuals at risk from Huntington’s disease can be identified prior to the onset of clinical signs of the disease by virtue of it being an autosomal dominant condition. This provides the hypothetical...

  15. Predictors of disease progression in HIV infection: a review.

    PubMed

    Langford, Simone E; Ananworanich, Jintanat; Cooper, David A

    2007-01-01

    During the extended clinically latent period associated with Human Immunodeficiency Virus (HIV) infection the virus itself is far from latent. This phase of infection generally comes to an end with the development of symptomatic illness. Understanding the factors affecting disease progression can aid treatment commencement and therapeutic monitoring decisions. An example of this is the clear utility of CD4+ T-cell count and HIV-RNA for disease stage and progression assessment. Elements of the immune response such as the diversity of HIV-specific cytotoxic lymphocyte responses and cell-surface CD38 expression correlate significantly with the control of viral replication. However, the relationship between soluble markers of immune activation and disease progression remains inconclusive. In patients on treatment, sustained virological rebound to >10,000 copies/mL is associated with poor clinical outcome. However, the same is not true of transient elevations of HIV RNA (blips). Another virological factor, drug resistance, is becoming a growing problem around the globe and monitoring must play a part in the surveillance and control of the epidemic worldwide. The links between chemokine receptor tropism and rate of disease progression remain uncertain and the clinical utility of monitoring viral strain is yet to be determined. The large number of confounding factors has made investigation of the roles of race and viral subtype difficult, and further research is needed to elucidate their significance. Host factors such as age, HLA and CYP polymorphisms and psychosocial factors remain important, though often unalterable, predictors of disease progression. Although gender and mode of transmission have a lesser role in disease progression, they may impact other markers such as viral load. Finally, readily measurable markers of disease such as total lymphocyte count, haemoglobin, body mass index and delayed type hypersensitivity may come into favour as ART becomes increasingly available in resource-limited parts of the world. The influence of these, and other factors, on the clinical progression of HIV infection are reviewed in detail, both preceding and following treatment initiation. PMID:17502001

  16. Recent Progress of Imaging Agents for Parkinson's Disease

    PubMed Central

    Wu, Xiaoai; Cai, Huawei; Ge, Ran; Li, Lin; Jia, Zhiyun

    2014-01-01

    Parkinson's disease (PD) is a common progressive, neurodegenerative brain disease that is promoted by mitochondrial dysfunction, oxidative stress, protein aggregation and proteasome dysfunction in the brain. Compared with computer tomography (CT) or magnetic resonance imaging (MRI), non-invasive nuclear radiopharmaceuticals have great significance for the early diagnosis of PD due to their high sensitivity and specificity in atypical and preclinical cases. Based on the development of coordination chemistry and chelator design, radionuclides may be delivered to lesions by attaching to PD-related transporters and receptors, such as dopamine, serotonin, and others. In this review, we comprehensively detailed the current achievements in radionuclide imaging in Parkinson’s disease. PMID:25977680

  17. Targeting the Progression of Parkinson’s Disease

    PubMed Central

    George, J.L; Mok, S; Moses, D; Wilkins, S; Bush, A.I; Cherny, R.A; Finkelstein, D.I

    2009-01-01

    By the time a patient first presents with symptoms of Parkinson’s disease at the clinic, a significant proportion (50-70%) of the cells in the substantia nigra (SN) has already been destroyed. This degeneration progresses until, within a few years, most of the cells have died. Except for rare cases of familial PD, the initial trigger for cell loss is unknown. However, we do have some clues as to why the damage, once initiated, progresses unabated. It would represent a major advance in therapy to arrest cell loss at the stage when the patient first presents at the clinic. Current therapies for Parkinson’s disease focus on relieving the motor symptoms of the disease, these unfortunately lose their effectiveness as the neurodegeneration and symptoms progress. Many experimental approaches are currently being investigated attempting to alter the progression of the disease. These range from replacement of the lost neurons to neuroprotective therapies; each of these will be briefly discussed in this review. The main thrust of this review is to explore the interactions between dopamine, alpha synuclein and redox-active metals. There is abundant evidence suggesting that destruction of SN cells occurs as a result of a self-propagating series of reactions involving dopamine, alpha synuclein and redox-active metals. A potent reducing agent, the neurotransmitter dopamine has a central role in this scheme, acting through redox metallo-chemistry to catalyze the formation of toxic oligomers of alpha-synuclein and neurotoxic metabolites including 6-hydroxydopamine. It has been hypothesized that these feed the cycle of neurodegeneration by generating further oxidative stress. The goal of dissecting and understanding the observed pathological changes is to identify therapeutic targets to mitigate the progression of this debilitating disease. PMID:19721815

  18. gems: An R Package for Simulating from Disease Progression Models

    PubMed Central

    Blaser, Nello; Vizcaya, Luisa Salazar; Estill, Janne; Zahnd, Cindy; Kalesan, Bindu; Egger, Matthias; Gsponer, Thomas; Keiser, Olivia

    2015-01-01

    Mathematical models of disease progression predict disease outcomes and are useful epidemiological tools for planners and evaluators of health interventions. The 𝖱 package gems is a tool that simulates disease progression in patients and predicts the effect of different interventions on patient outcome. Disease progression is represented by a series of events (e.g., diagnosis, treatment and death), displayed in a directed acyclic graph. The vertices correspond to disease states and the directed edges represent events. The package gems allows simulations based on a generalized multistate model that can be described by a directed acyclic graph with continuous transition-specific hazard functions. The user can specify an arbitrary hazard function and its parameters. The model includes parameter uncertainty, does not need to be a Markov model, and may take the history of previous events into account. Applications are not limited to the medical field and extend to other areas where multistate simulation is of interest. We provide a technical explanation of the multistate models used by gems, explain the functions of gems and their arguments, and show a sample application. PMID:26064082

  19. What is the new target inhibiting the progression of Alzheimer's disease

    PubMed Central

    Zhang, Lin; Yang, Jing; Cao, Yunpeng

    2013-01-01

    To stop the progression of Alzheimer's disease in the early stage, it is necessary to identify new therapeutic targets. We examined striatal-enriched phosphatase 61 expression in the brain tissues of 12-month-old APPswe/PSEN1dE9 transgenic mice. Immunohistochemistry showed that al-enriched phosphatase 61 protein expression was significantly increased but phosphorylated N-methyl-D-aspartate receptor 2B levels were significantly decreased in the cortex and hippocampus of APPswe/PSEN1dE9 transgenic mice. Western blotting of a cell model of Alzheimer's disease consisting of amyloid-beta peptide (1–42)-treated C57BL/6 mouse cortical neurons in vitro showed that valeric acid (AP5), an N-methyl-D-aspartate receptor antagonist, significantly inhibited amyloid-beta 1–42-induced increased activity of striatal-enriched phosphatase 61. In addition, the phosphorylation of N-methyl-D-aspartate receptor 2B at Tyr1472 was impaired in amyloid-beta 1–42-treated cortical neurons, but knockdown of striatal-enriched phosphatase 61 enhanced the phosphorylation of N-methyl-D-aspartate receptor 2B. Collectively, these findings indicate that striatal-enriched phosphatase 61 can disturb N-methyl-D-aspartate receptor transport and inhibit the progression of learning and study disturbances induced by Alzheimer's disease. Thus, al-enriched phosphatase 61 may represent a new target for inhibiting the progression of Alzheimer's disease. PMID:25206502

  20. [Progress of Autoantibody Examinations for Connective Tissue Diseases].

    PubMed

    Akashi, Kengo; Saegusa, Jun; Morinobu, Akio

    2015-05-01

    Connective tissue diseases are chronic inflammatory diseases that can affect multiple organs and, thus, have a broad spectrum of clinical presentations. Various autoantibodies are detected in patients with connective tissue diseases, represented by anti-nuclear antibody for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), Sjögren's syndrome, and mixed connective tissue disease. Assessment of the autoantibody profile is fundamental for the clinical management of patients with connective tissue diseases, providing important data for the diagnosis, clinical characterization, and disease activity evaluation. Anti-ribosomal P antibody and anti-NMDA receptor antibody are associated with neuropsychiatric SLE. Anti-synthetase syndrome comprises the association of myositis (PM/DM), interstitial lung disease, fever, Raynaud's phenomenon, mechanic's hands, and anti-aminoacyl tRNA synthetase antibodies. Anti-MDA5 antibody is detected in patients with clinically amyopathic DM, often complicated by rapidly progressive interstitial lung disease. Between 50 and 75% of malignancy-associated DM patients are positive for anti-TIF1-? antibody. Anti-RNA polymerase III antibody is associated with diffuse cutaneous SSc and renal crisis. This review focuses on the importance and usefulness of these autoantibodies for the diagnosis and management of patients with connective tissue diseases in clinical practice. PMID:26524895

  1. Disease Risk Factors and Disease Progress in Coast Live Oak and Tanoak Affected by

    E-print Network

    383 Disease Risk Factors and Disease Progress in Coast Live Oak and Tanoak Affected by Phytophthora ramorum Canker (Sudden Oak Death)1 Tedmund J. Swiecki2 and Elizabeth Bernhardt2 Abstract This paper on the development of Phytophthora ramorum stem canker (sudden oak death) in coast live oak (Quercus agrifolia

  2. Alzheimer's disease: a mathematical model for onset and progression

    E-print Network

    Bertsch, Michiel; Marcello, Norina; Tesi, Maria Carla; Tosin, Andrea

    2015-01-01

    In this paper we propose a mathematical model for the onset and progression of Alzheimer's disease based on transport and diffusion equations. We regard brain neurons as a continuous medium, and structure them by their degree of malfunctioning. Two different mechanisms are assumed to be relevant for the temporal evolution of the disease: i) diffusion and agglomeration of soluble polymers of amyloid, produced by damaged neurons; ii) neuron-to-neuron prion-like transmission. We model these two processes by a system of Smoluchowski equations for the amyloid concentration, coupled to a kinetic-type transport equation for the distribution function of the degree of malfunctioning of neurons. The second equation contains an integral term describing the random onset of the disease as a jump process localized in particularly sensitive areas of the brain. Even though we deliberately neglect many aspects of the complexity of the brain and the disease, numerical simulations are in good qualitative agreement with clinical...

  3. Glutathione dysregulation and the etiology and progression of human diseases

    PubMed Central

    Ballatori, Nazzareno; Krance, Suzanne M.; Notenboom, Sylvia; Shi, Shujie; Tieu, Kim; Hammond, Christine L.

    2009-01-01

    Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases. Because of GSH’s pleiotropic effects on cell functions, it has been quite difficult to define the role of GSH in the onset and/or the expression of human diseases, although significant progress is being made. GSH levels, turnover rates and/or oxidation state can be compromised by inherited or aquired defects in the enzymes, transporters, signaling molecules, or transcription factors that are involved in its homeostasis, or from exposure to reactive chemicals or metabolic intermediates. GSH deficiency or a decrease in the GSH/glutathione disulfide (GSSG) ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in diseases such as cancer, Parkinson’s disease, and Alzheimer’s disease. In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process. Just as low intracellular GSH levels decrease cellular antioxidant capacity, elevated GSH levels generally increase antioxidant capacity and resistance to oxidative stress, and this is observed in many cancer cells. The higher GSH levels in some tumor cells are also typically associated with higher levels of GSH-related enzymes and transporters. Although neither the mechanism nor the implications of these changes are well defined, the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment. The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases. PMID:19166318

  4. Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS

    PubMed Central

    Vieira, Fernando G.; Ping, Qinggong; Moreno, Andy J.; Kidd, Joshua D.; Thompson, Kenneth; Jiang, Bingbing; Lincecum, John M.; Wang, Monica Z.; De Zutter, Gerard S.; Tassinari, Valerie R.; Levine, Beth; Hatzipetros, Theo; Gill, Alan; Perrin, Steven

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons. The mechanisms leading to motor neuron degeneration in ALS are unclear. However, there is evidence for involvement of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in ALS, notably in mutant SOD1 mediated models of ALS. Stress induced phosphorylation of the eIF2 alpha subunit by eukaryotic translation initiation factor 2-alpha kinase 3 Perk activates the UPR. Guanabenz is a centrally acting alpha2 adrenergic receptor agonist shown to interact with a regulatory subunit of the protein phosphatase, Pp1/Gadd34, and selectively disrupt the dephosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eif2alpha). Here we demonstrate that guanabenz is protective in fibroblasts expressing G93A mutant SOD1 when they are exposed to tunicamycin mediated ER stress. However, in contrast to other reports, guanabenz treatment accelerated ALS-like disease progression in a strain of mutant SOD1 transgenic ALS mice. This study highlights challenges of pharmacological interventions of cellular stress responses in whole animal models of ALS. PMID:26288094

  5. Tissue Stiffness Dictates Development, Homeostasis, and Disease Progression

    PubMed Central

    Handorf, Andrew M; Zhou, Yaxian; Halanski, Matthew A; Li, Wan-Ju

    2015-01-01

    Abstract Tissue development is orchestrated by the coordinated activities of both chemical and physical regulators. While much attention has been given to the role that chemical regulators play in driving development, researchers have recently begun to elucidate the important role that the mechanical properties of the extracellular environment play. For instance, the stiffness of the extracellular environment has a role in orienting cell division, maintaining tissue boundaries, directing cell migration, and driving differentiation. In addition, extracellular matrix stiffness is important for maintaining normal tissue homeostasis, and when matrix mechanics become imbalanced, disease progression may ensue. In this article, we will review the important role that matrix stiffness plays in dictating cell behavior during development, tissue homeostasis, and disease progression. PMID:25915734

  6. DJ-1 Knockout Augments Disease Severity and Shortens Survival in a Mouse Model of ALS

    PubMed Central

    Lev, Nirit; Barhum, Yael; Lotan, Itay; Steiner, Israel; Offen, Daniel

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, neurodegenerative disorder, characterized by the degeneration of motor neurons. Oxidative stress plays a central role in the disease progression, in concert with an enhanced glutamate excitotoxicity and neuroinflammation. DJ-1 mutations, leading to the loss of functional protein, cause familial Parkinson’s disease and motor neuron disease in several patients. DJ-1 responds to oxidative stress and plays an important role in the cellular defense mechanisms. We aimed to investigate whether loss of functional DJ-1 alters the disease course and severity in an ALS mouse model. To this end we used mice that express the human SOD1G93A mutation, the commonly used model of ALS and knockout of DJ-1 mice to generate SOD1 DJ-1 KO mice. We found that knocking out DJ-1in the ALS model led to an accelerated disease course and shortened survival time. DJ-1 deficiency was found to increase neuronal loss in the spinal cord associated with increased gliosis in the spinal cord and reduced antioxidant response that was regulated by the Nrf2 mechanism.The importance of DJ-1 in ALS was also illustrated in a motor neuron cell line that was exposed to glutamate toxicity and oxidative stress. Addition of the DJ-1 derived peptide, ND-13, enhanced the resistance to glutamate and SIN-1 induced toxicity. Thus, our results maintain that DJ-1 plays a role in the disease process and promotes the necessity of further investigation of DJ-1 as a therapeutic target for ALS. PMID:25822630

  7. Biomarkers of progression of chronic obstructive pulmonary disease (COPD)

    PubMed Central

    Vaughan, Annalicia; Dent, Annette G.; O’Hare, Phoebe E.; Goh, Felicia; Bowman, Rayleen V.; Fong, Kwun M.; Yang, Ian A.

    2014-01-01

    Disease progression of chronic obstructive pulmonary disease (COPD) is variable, with some patients having a relatively stable course, while others suffer relentless progression leading to severe breathlessness, frequent acute exacerbations of COPD (AECOPD), respiratory failure and death. Radiological markers such as CT emphysema index, bronchiectasis and coronary artery calcification (CAC) have been linked with increased mortality in COPD patients. Molecular changes in lung tissue reflect alterations in lung pathology that occur with disease progression; however, lung tissue is not routinely accessible. Cell counts (including neutrophils) and mediators in induced sputum have been associated with lung function and risk of exacerbations. Examples of peripheral blood biological markers (biomarkers) include those associated with lung function (reduced CC-16), emphysema severity (increased adiponectin, reduced sRAGE), exacerbations and mortality [increased CRP, fibrinogen, leukocyte count, IL-6, IL-8, and tumor necrosis factor ? (TNF-?)] including increased YKL-40 with mortality. Emerging approaches to discovering markers of gene-environment interaction include exhaled breath analysis [volatile organic compounds (VOCs), exhaled breath condensate], cellular and systemic responses to exposure to air pollution, alterations in the lung microbiome, and biomarkers of lung ageing such as telomere length shortening and reduced levels of sirtuins. Overcoming methodological challenges in sampling and quality control will enable more robust yet easily accessible biomarkers to be developed and qualified, in order to optimise personalised medicine in patients with COPD. PMID:25478195

  8. Tumour necrosis factor-? inhibition can stabilize disease in progressive vitiligo.

    PubMed

    Webb, K C; Tung, R; Winterfield, L S; Gottlieb, A B; Eby, J M; Henning, S W; Le Poole, I C

    2015-09-01

    Tumour necrosis factor (TNF)-?, a proinflammatory cytokine central to many autoimmune diseases, has been implicated in the depigmentation process in vitiligo. We review its role in vitiligo by exploring its pro- and anti-inflammatory properties and examine the effects of blocking its actions with TNF-? antagonist therapeutics in reports available in the literature. We found that TNF-? inhibition halts disease progression in patients with progressive vitiligo but that, paradoxically, treatment can be associated with de novo vitiligo development in some patients when used for other autoimmune conditions, particularly when using adalimumab and infliximab. These studies reinforce the importance of stating appropriate outcomes measures, as most pilot trials propose to measure repigmentation, whereas halting depigmentation is commonly overlooked as a measure of success. We conclude that TNF-? inhibition has proven useful for patients with progressive vitiligo, where TNF-? inhibition is able to quash cytotoxic T-cell-mediated melanocyte destruction. However, a lingering concern for initiating de novo disease will likely prevent more widespread application of TNF inhibitors to treat vitiligo. PMID:26149498

  9. Neurobiology of Disease Loss of ALS2 Function Is Insufficient to Trigger Motor

    E-print Network

    , Baltimore, Maryland 21205 Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease stress Introduction Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, is caused

  10. Predicting Progression of Alzheimer’s Disease Using Ordinal Regression

    PubMed Central

    Doyle, Orla M.; Westman, Eric; Marquand, Andre F.; Mecocci, Patrizia; Vellas, Bruno; Tsolaki, Magda; K?oszewska, Iwona; Soininen, Hilkka; Lovestone, Simon; Williams, Steve C. R.; Simmons, Andrew

    2014-01-01

    We propose a novel approach to predicting disease progression in Alzheimer’s disease (AD) – multivariate ordinal regression – which inherently models the ordered nature of brain atrophy spanning normal aging (CTL) to mild cognitive impairment (MCI) to AD. Ordinal regression provides probabilistic class predictions as well as a continuous index of disease progression – the ORCHID (Ordinal Regression Characteristic Index of Dementia) score. We applied ordinal regression to 1023 baseline structural MRI scans from two studies: the US-based Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the European based AddNeuroMed program. Here, the acquired AddNeuroMed dataset was used as a completely independent test set for the ordinal regression model trained on the ADNI cohort providing an optimal assessment of model generalizability. Distinguishing CTL-like (CTL and stable MCI) from AD-like (MCI converters and AD) resulted in balanced accuracies of 82% (cross-validation) for ADNI and 79% (independent test set) for AddNeuroMed. For prediction of conversion from MCI to AD, balanced accuracies of 70% (AUC of 0.75) and 75% (AUC of 0.81) were achieved. The ORCHID score was computed for all subjects. We showed that this measure significantly correlated with MMSE at 12 months (??=?–0.64, ADNI and ??=?–0.59, AddNeuroMed). Additionally, the ORCHID score can help fractionate subjects with unstable diagnoses (e.g. reverters and healthy controls who later progressed to MCI), moderately late converters (12–24 months) and late converters (24–36 months). A comparison with results in the literature and direct comparison with a binary classifier suggests that the performance of this framework is highly competitive. PMID:25141298

  11. Biomarkers of Renal Disease and Progression in Patients with Diabetes.

    PubMed

    Hojs, Radovan; Ekart, Robert; Bevc, Sebastjan; Hojs, Nina

    2015-01-01

    Diabetes prevalence is increasing worldwide, mainly due to the increase in type 2 diabetes. Diabetic nephropathy occurs in up to 40% of people with type 1 or type 2 diabetes. It is important to identify patients at risk of diabetic nephropathy and those who will progress to end stage renal disease. In clinical practice, most commonly used markers of renal disease and progression are serum creatinine, estimated glomerular filtration rate and proteinuria or albuminuria. Unfortunately, they are all insensitive. This review summarizes the evidence regarding the prognostic value and benefits of targeting some novel risk markers for development of diabetic nephropathy and its progression. It is focused mainly on tubular biomarkers (neutrophil-gelatinase associated lipocalin, kidney injury molecule 1, liver-fatty acid-binding protein, N-acetyl-beta-d-glucosaminidase), markers of inflammation (pro-inflammatory cytokines, tumour necrosis factor-? and tumour necrosis factor-? receptors, adhesion molecules, chemokines) and markers of oxidative stress. Despite the promise of some of these new biomarkers, further large, multicenter prospective studies are still needed before they can be used in everyday clinical practice. PMID:26239462

  12. Biomarkers of Renal Disease and Progression in Patients with Diabetes

    PubMed Central

    Hojs, Radovan; Ekart, Robert; Bevc, Sebastjan; Hojs, Nina

    2015-01-01

    Diabetes prevalence is increasing worldwide, mainly due to the increase in type 2 diabetes. Diabetic nephropathy occurs in up to 40% of people with type 1 or type 2 diabetes. It is important to identify patients at risk of diabetic nephropathy and those who will progress to end stage renal disease. In clinical practice, most commonly used markers of renal disease and progression are serum creatinine, estimated glomerular filtration rate and proteinuria or albuminuria. Unfortunately, they are all insensitive. This review summarizes the evidence regarding the prognostic value and benefits of targeting some novel risk markers for development of diabetic nephropathy and its progression. It is focused mainly on tubular biomarkers (neutrophil-gelatinase associated lipocalin, kidney injury molecule 1, liver-fatty acid-binding protein, N-acetyl-beta-d-glucosaminidase), markers of inflammation (pro-inflammatory cytokines, tumour necrosis factor-? and tumour necrosis factor-? receptors, adhesion molecules, chemokines) and markers of oxidative stress. Despite the promise of some of these new biomarkers, further large, multicenter prospective studies are still needed before they can be used in everyday clinical practice. PMID:26239462

  13. Identification of B6SJL mSOD1(G93A) mouse subgroups with different disease progression rates.

    PubMed

    Haulcomb, Melissa M; Mesnard-Hoaglin, Nichole A; Batka, Richard J; Meadows, Rena M; Miller, Whitney M; Mcmillan, Kathryn P; Brown, Todd J; Sanders, Virginia M; Jones, Kathryn J

    2015-12-15

    Disease progression rates among patients with amyotrophic lateral sclerosis (ALS) vary greatly. Although the majority of affected individuals survive 3-5 years following diagnosis, some subgroups experience a more rapidly progressing form, surviving less than 1 year, and other subgroups experience slowly progressing forms, surviving nearly 50 years. Genetic heterogeneity and environmental factors pose significant barriers in investigating patient progression rates. Similar to the case for humans, variation in survival within the mSOD1 mouse has been well documented, but different progression rates have not been investigated. The present study identifies two subgroups of B6SJL mSOD1(G93A) mice with different disease progression rates, a fast progression group (FPG) and slow progression group, as evidenced by differences in the rate of motor function decline. In addition, increased disease-associated gene expression within the FPG facial motor nucleus confirmed the presence of a more severe phenotype. We hypothesize that a more severe disease phenotype could be the result of 1) an earlier onset of axonal disconnection with a consistent degeneration rate or 2) a more severe or accelerated degenerative process. We performed a facial nerve transection axotomy in both mSOD1 subgroups prior to disease onset as a method to standardize the axonal disconnection. Instead of leading to comparable gene expression in both subgroups, this standardization did not eliminate the severe phenotype in the FPG facial nucleus, suggesting that the FPG phenotype is the result of a more severe or accelerated degenerative process. We theorize that these mSOD1 subgroups are representative of the rapid and slow disease phenotypes often experienced in ALS. PMID:26010802

  14. A transcriptional network underlies susceptibility to kidney disease progression

    PubMed Central

    Laouari, Denise; Burtin, Martine; Phelep, Aurélie; Bienaime, Frank; Noel, Laure-Hélène; Lee, David C; Legendre, Christophe; Friedlander, Gérard; Pontoglio, Marco; Terzi, Fabiola

    2012-01-01

    The molecular networks that control the progression of chronic kidney diseases (CKD) are poorly defined. We have recently shown that the susceptibility to development of renal lesions after nephron reduction is controlled by a locus on mouse chromosome 6 and requires epidermal growth factor receptor (EGFR) activation. Here, we identified microphthalmia-associated transcription factor A (MITF-A), a bHLH-Zip transcription factor, as a modifier of CKD progression. Sequence analysis revealed a strain-specific mutation in the 5? UTR that decreases MITF-A protein synthesis in lesion-prone friend virus B NIH (FVB/N) mice. More importantly, we dissected the molecular pathway by which MITF-A modulates CKD progression. MITF-A interacts with histone deacetylases to repress the transcription of TGF-?, a ligand of EGFR, and antagonizes transactivation by its related partner, transcription factor E3 (TFE3). Consistent with the key role of this network in CKD, Tgfa gene inactivation protected FVB/N mice from renal deterioration after nephron reduction. These data are relevant to human CKD, as we found that the TFE3/MITF-A ratio was increased in patients with damaged kidneys. Our study uncovers a novel transcriptional network and unveils novel potential prognostic and therapeutic targets for preventing human CKD progression. PMID:22711280

  15. Connected speech as a marker of disease progression in autopsy-proven Alzheimer's disease.

    PubMed

    Ahmed, Samrah; Haigh, Anne-Marie F; de Jager, Celeste A; Garrard, Peter

    2013-12-01

    Although an insidious history of episodic memory difficulty is a typical presenting symptom of Alzheimer's disease, detailed neuropsychological profiling frequently demonstrates deficits in other cognitive domains, including language. Previous studies from our group have shown that language changes may be reflected in connected speech production in the earliest stages of typical Alzheimer's disease. The aim of the present study was to identify features of connected speech that could be used to examine longitudinal profiles of impairment in Alzheimer's disease. Samples of connected speech were obtained from 15 former participants in a longitudinal cohort study of ageing and dementia, in whom Alzheimer's disease was diagnosed during life and confirmed at post-mortem. All patients met clinical and neuropsychological criteria for mild cognitive impairment between 6 and 18 months before converting to a status of probable Alzheimer's disease. In a subset of these patients neuropsychological data were available, both at the point of conversion to Alzheimer's disease, and after disease severity had progressed from the mild to moderate stage. Connected speech samples from these patients were examined at later disease stages. Spoken language samples were obtained using the Cookie Theft picture description task. Samples were analysed using measures of syntactic complexity, lexical content, speech production, fluency and semantic content. Individual case analysis revealed that subtle changes in language were evident during the prodromal stages of Alzheimer's disease, with two-thirds of patients with mild cognitive impairment showing significant but heterogeneous changes in connected speech. However, impairments at the mild cognitive impairment stage did not necessarily entail deficits at mild or moderate stages of disease, suggesting non-language influences on some aspects of performance. Subsequent examination of these measures revealed significant linear trends over the three stages of disease in syntactic complexity, semantic and lexical content. The findings suggest, first, that there is a progressive disruption in language integrity, detectable from the prodromal stage in a subset of patients with Alzheimer's disease, and secondly that measures of semantic and lexical content and syntactic complexity best capture the global progression of linguistic impairment through the successive clinical stages of disease. The identification of disease-specific language impairment in prodromal Alzheimer's disease could enhance clinicians' ability to distinguish probable Alzheimer's disease from changes attributable to ageing, while longitudinal assessment could provide a simple approach to disease monitoring in therapeutic trials. PMID:24142144

  16. A Table of Areas Under Disease Progress Curves. 

    E-print Network

    Johnson, Dennis A.; Wilcoxson, Roy D.

    1980-01-01

    Bulletin] A TABLE OF AREAS UNDER DISEASE PROGRESS CURVES Technical Bullet in Texas Agricultural Experiment Station Texas A & M University System- [Blank Page in Original Bulletin] A TABLE OF AREAS UNDER D I S E A S E PROGRESS CURVES Introduction... 76384; and Professor Department of Plant Pathology University of Minnesota St. Paul, MN 55108 A T a b l e o f A r e a s Under D i s e a s e P r o g r e s s Curves 3 Denn i s A. J o h n s o n and Roy D . \\ W i l c o x s o n I n t r o d...

  17. Immune Evasion Mechanisms of Entamoeba histolytica: Progression to Disease

    PubMed Central

    Begum, Sharmin; Quach, Jeanie; Chadee, Kris

    2015-01-01

    Entamoeba histolytica (Eh) is a protozoan parasite that infects 10% of the world's population and results in 100,000 deaths/year from amebic dysentery and/or liver abscess. In most cases, this extracellular parasite colonizes the colon by high affinity binding to MUC2 mucin without disease symptoms, whereas in some cases, Eh triggers an aggressive inflammatory response upon invasion of the colonic mucosa. The specific host-parasite factors critical for disease pathogenesis are still not well characterized. From the parasite, the signature events that lead to disease progression are cysteine protease cleavage of the C-terminus of MUC2 that dissolves the mucus layer followed by Eh binding and cytotoxicity of the mucosal epithelium. The host mounts an ineffective excessive host pro-inflammatory response following contact with host cells that causes tissue damage and participates in disease pathogenesis as Eh escapes host immune clearance by mechanisms that are not completely understood. Ameba can modulate or destroy effector immune cells by inducing neutrophil apoptosis and suppressing respiratory burst or nitric oxide (NO) production from macrophages. Eh adherence to the host cells also induce multiple cytotoxic effects that can promote cell death through phagocytosis, apoptosis or by trogocytosis (ingestion of living cells) that might play critical roles in immune evasion. This review focuses on the immune evasion mechanisms that Eh uses to survive and induce disease manifestation in the host. PMID:26696997

  18. Neurologic markers of the progression of Alzheimer's disease.

    PubMed

    Franssen, E H; Reisberg, B

    1997-01-01

    This article describes the results of studies conducted to determine the usefulness of reflex changes as markers of disease severity in Alzheimer's disease (AD). Standardized and quantified muscle stretch reflexes, cutaneous reflexes, and developmental (primitive) reflexes were studied in normal older adults, in individuals with mild memory impairment, and in patients with AD, in all clinical severity stages as assessed with the Global Deterioration Scale (GDS), the Mini-Mental State Examination (MMSE), and the Functional Assessment Staging (FAST) procedure. Changes in frequency and intensity of these individual reflex variables, as well as of variables consisting of combinations of these individual reflexes, appeared to be sensitive indicators of the progression of AD. These neurological reflex variables showed high Pearson correlations with the GDS (.72), the MMSE (.74), and the FAST (.80). Standardized quantified neurological reflex measures are useful as noncognitive, education-independent, and culture-independent markers of the course of AD. PMID:9447450

  19. Evaluation of disease progression in INCL by MR spectroscopy

    PubMed Central

    Baker, Eva H; Levin, Sondra W; Zhang, Zhongjian; Mukherjee, Anil B

    2015-01-01

    Objective Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase-1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury. As part of a pilot study to evaluate treatment benefits of cysteamine bitartrate and N-acetylcysteine, we quantitatively measured brain metabolite levels using magnetic resonance spectroscopy (MRS). Methods A subset of two patients from a larger treatment and follow-up study underwent serial quantitative single-voxel MRS examinations of five anatomical sites. Three echo times were acquired in order to estimate metabolite T2. Measured metabolite levels included correction for partial volume of cerebrospinal fluid. Comparison of INCL patients was made to a reference group composed of asymptomatic and minimally symptomatic Niemann-Pick disease type C patients. Results In INCL patients, N-acetylaspartate (NAA) was abnormally low at all locations upon initial measurement, and further declined throughout the follow-up period. In the cerebrum (affected early in the disease course), choline and myo-inositol were initially elevated and fell during the follow-up period, whereas in the cerebellum and brainstem (affected later), choline and myo-inositol were initially normal and rose subsequently. Interpretation Choline and myo-inositol levels in our patients are consistent with patterns of neuroinflammation observed in two INCL mouse models. Low, persistently declining NAA was expected based on the progressive, irreversible nature of the disease. Progression of metabolite levels in INCL has not been previously quantified; therefore the results of this study serve as a reference for quantitative evaluation of future therapeutic interventions. PMID:26339674

  20. Beyond Guam: the cyanobacteria/BMAA hypothesis of the cause of ALS and other neurodegenerative diseases.

    PubMed

    Bradley, Walter G; Mash, Deborah C

    2009-01-01

    Excitement about neurogenetics in the last two decades has diverted attention from environmental causes of sporadic ALS. Fifty years ago endemic foci of ALS with a frequency one hundred times that in the rest of the world attracted attention since they offered the possibility of finding the cause for non-endemic ALS throughout the world. Research on Guam suggested that ALS, Parkinson's disease and dementia (the ALS/PDC complex) was due to a neurotoxic non-protein amino acid, beta-methylamino-L-alanine (BMAA), in the seeds of the cycad Cycas micronesica. Recent discoveries that found that BMAA is produced by symbiotic cyanobacteria within specialized roots of the cycads; that the concentration of protein-bound BMAA is up to a hundred-fold greater than free BMAA in the seeds and flour; that various animals forage on the seeds (flying foxes, pigs, deer), leading to biomagnification up the food chain in Guam; and that protein-bound BMAA occurs in the brains of Guamanians dying of ALS/PDC (average concentration 627 microg/g, 5 mM) but not in control brains have rekindled interest in BMAA as a possible trigger for Guamanian ALS/PDC. Perhaps most intriguing is the finding that BMAA is present in brain tissues of North American patients who had died of Alzheimer's disease (average concentration 95 microg/g, 0.8mM); this suggests a possible etiological role for BMAA in non-Guamanian neurodegenerative diseases. Cyanobacteria are ubiquitous throughout the world, so it is possible that all humans are exposed to low amounts of cyanobacterial BMAA, that protein-bound BMAA in human brains is a reservoir for chronic neurotoxicity, and that cyanobacterial BMAA is a major cause of progressive neurodegenerative diseases including ALS worldwide. Though Montine et al., using different HPLC method and assay techniques from those used by Cox and colleagues, were unable to reproduce the findings of Murch et al., Mash and colleagues using the original techniques of Murch et al. have recently confirmed the presence of protein-bound BMAA in the brains of North American patients dying with ALS and Alzheimer's disease (concentrations >100 microg/g) but not in the brains of non-neurological controls or Huntington's disease. We hypothesize that individuals who develop neurodegenerations may have a genetic susceptibility because of inability to prevent BMAA accumulation in brain proteins and that the particular pattern of neurodegeneration that develops depends on the polygenic background of the individual. PMID:19929726

  1. Differential progression of proprioceptive and visual information processing deficits in Parkinson's disease

    E-print Network

    Gielen, C.C.A.M.

    Differential progression of proprioceptive and visual information processing deficits in Parkinson Medical Center St Radboud, Nijmegen, The Netherlands Keywords: disease severity, Parkinson's disease that patients with Parkinson's disease (PD) have deficits not only in motor performance, but also

  2. The Omega-3 Fatty Acid Eicosapentaenoic Acid Accelerates Disease Progression in a Model of Amyotrophic Lateral Sclerosis

    PubMed Central

    Gladman, Stacy; Biggio, Maria Luigia; Marino, Marianna; Jayasinghe, Maduka; Ullah, Farhan; Dyall, Simon C.; Malaspina, Andrea; Bendotti, Caterina; Michael-Titus, Adina

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease characterised by loss of motor neurons that currently has no cure. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), have many health benefits including neuroprotective and myoprotective potential. We tested the hypothesis that a high level of dietary EPA could exert beneficial effects in ALS. The dietary exposure to EPA (300 mg/kg/day) in a well-established mouse model of ALS expressing the G93A superoxide dismutase 1 (SOD1) mutation was initiated at a pre-symptomatic or symptomatic stage, and the disease progression was monitored until the end stage. Daily dietary EPA exposure initiated at the disease onset did not significantly alter disease presentation and progression. In contrast, EPA treatment initiated at the pre-symptomatic stage induced a significantly shorter lifespan. In a separate group of animals sacrificed before the end stage, the tissue analysis showed that the vacuolisation detected in G93A-SOD1 mice was significantly increased by exposure to EPA. Although EPA did not alter motor neurone loss, EPA reversed the significant increase in activated microglia and the astrocytic activation seen in G93A-SOD1 mice. The microglia in the spinal cord of G93A-SOD1 mice treated with EPA showed a significant increase in 4-hydroxy-2-hexenal, a highly toxic aldehydic oxidation product of omega-3 fatty acids. These data show that dietary EPA supplementation in ALS has the potential to worsen the condition and accelerate the disease progression. This suggests that great caution should be exerted when considering dietary omega-3 fatty acid supplements in ALS patients. PMID:23620776

  3. Association Between Chronic Kidney Disease Progression and Cardiovascular Disease: Results from the CRIC Study

    PubMed Central

    Rahman, Mahboob; Xie, Dawei; Feldman, Harold I; Go, Alan S.; He, Jiang; Kusek, John W.; Lash, James; Miller, Edgar; Ojo, Akinlolo; Qiang, Pan; Seliger, Stephen; Steigerwalt, Susan; Townsend, Raymond R.

    2014-01-01

    Background and Aims There is limited information on the risk of progression of chronic kidney disease (CKD) among individuals with CVD (cardiovascular disease). We studied the association between prevalent CVD and risk of progression of CKD among persons enrolled in a long-term observational study. Methods A prospective cohort study of 3939 women and men with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study between June 2003 and June 2008. Prevalent cardiovascular disease (myocardial infarction/revascularization, heart failure, stroke and peripheral vascular disease) was determined by self-report at baseline. The primary outcome was a composite of either end-stage renal disease or a 50% decline in estimated glomerular filtration rate (eGFR) from baseline. Results One-third (1316 of 3939, 33.4%) of the study participants reported a history of any cardiovascular disease, and 9.6% (n=382) a history of heart failure at baseline. After a median follow up of 6.63 years, 1028 patients experienced the primary outcome. The composite of any CVD at baseline was not independently associated with the primary outcome (Hazard Ratio 1.04 95% CI (0.91, 1.19)). However, a history of heart failure was independently associated with a 29% higher risk of the primary outcome (Hazard Ratio 1.29 95% CI (1.06, 1.57)). The relationship between heart failure and risk of CKD progression was consistent in subgroups defined by age, race, gender, baseline eGFR and diabetes. Neither the composite measure of any CVD or heart failure was associated with rate of decline in eGFR. Conclusions Self-reported heart failure was an independent risk factor for the development of the endpoint of ESRD or 50% decline in GFR in a cohort of patients with chronic kidney disease. PMID:25401485

  4. What Is ALS?

    MedlinePLUS

    ... the gene mutation and may develop the disease. French neurologist Jean-Martin Charcot discovered the disease in ... reverses ALS, scientists have made significant progress in learning more about this disease . In addition, people with ...

  5. Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease.

    PubMed

    Bradbury, Allison M; Gray-Edwards, Heather L; Shirley, Jamie L; McCurdy, Victoria J; Colaco, Alexandria N; Randle, Ashley N; Christopherson, Pete W; Bird, Allison C; Johnson, Aime K; Wilson, Diane U; Hudson, Judith A; De Pompa, Nicholas L; Sorjonen, Donald C; Brunson, Brandon L; Jeyakumar, Mylvaganam; Platt, Frances M; Baker, Henry J; Cox, Nancy R; Sena-Esteves, Miguel; Martin, Douglas R

    2015-01-01

    The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme ?-N-acetylhexosaminidase (Hex). Due to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were largely normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated SD patients and those in future clinical trials. PMID:25284324

  6. Disease specificity and pathologic progression of tau pathology in brainstem nuclei of Alzheimer's disease and progressive supranuclear palsy.

    PubMed

    Dugger, Brittany N; Tu, Michael; Murray, Melissa E; Dickson, Dennis W

    2011-03-17

    Previous studies have shown tau pathology in the inferior colliculus (IC) and superior colliculus (SC) in Alzheimer's disease (AD); however, it has not been compared to other tauopathies, such as progressive supranuclear palsy (PSP), or characterized with respect to progression of tau pathology in AD. The main purpose of this study was to investigate frequency, neuroanatomical selectivity and disease specificity of tau pathology in visual and auditory nuclei (SC and lateral geniculate body (LGB); IC and medial geniculate body (MGB), respectively). We measured phospho-tau burden with immunohistochemistry and image analysis in 26 cases of AD, 37 PSP and 11 normal controls. Tau burden was also assessed in two unrelated brainstem nuclei (substantia nigra (SN) and pedunculopontine nucleus (PPN)) of the same cases. We found tau burden to be greater in the SC of PSP compared to AD and controls. Conversely, tau burden was greater in the IC of AD compared to PSP and controls. The MGB and LGB had sparse tau pathology in both AD and PSP. This disease selectivity parallels known deficits in visual reflexes in PSP and auditory reflexes in AD. Tau burden was greater in the SC, IC, and PPN in both PSP and AD compared to controls, and greater in the SN in PSP compared to AD and controls. Although present at early Braak neurofibrillary tangle stages, the SC, IC, PPN and SN did not accumulate tau consistently until later stages. These findings support a concept of tau pathology affecting the brainstem at mid-to-late stage AD. PMID:21236314

  7. Disease specificity and pathologic progression of tau pathology in brainstem nuclei of Alzheimer’s disease and progressive supranuclear palsy

    PubMed Central

    Dugger, Brittany N.; Tu, Michael; Murray, Melissa E.; Dickson, Dennis W.

    2011-01-01

    Previous studies have shown tau pathology in the inferior colliculus (IC) and superior colliculus (SC) in Alzheimer’s disease (AD); however, it has not been compared to other tauopathies, such as progressive supranuclear palsy (PSP), or characterized with respect to progression of tau pathology in AD. The main purpose of this study was to investigate frequency, neuroanatomical selectivity and disease specificity of tau pathology in visual and auditory nuclei (SC and lateral geniculate body (LGB); IC and medial geniculate body (MGB), respectively). We measured phospho-tau burden with immunohistochemistry and image analysis in 26 cases of AD, 37 PSP and 11 normal controls. Tau burden was also assessed in two unrelated brainstem nuclei (substantia nigra (SN) and pedunculopontine nucleus (PPN)) of the same cases. We found tau burden to be greater in the SC of PSP compared to AD and controls. Conversely, tau burden was greater in the IC of AD compared to PSP and controls. The MGB and LGB had sparse tau pathology in both AD and PSP. This disease selectivity parallels known deficits in visual reflexes in PSP and auditory reflexes in AD. Tau burden was greater in the SC, IC, and PPN in both PSP and AD compared to controls, and greater in the SN in PSP compared to AD and controls. Although present at early Braak neurofibrillary tangle stages, the SC, IC, PPN and SN did not accumulate tau consistently until later stages. These findings support a concept of tau pathology affecting the brainstem at mid-to-late stage AD. PMID:21236314

  8. The area under the disease progress stairs: calculation, advantage, and application

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Area Under the Disease Progress Curve (AUDPC) is frequently used to combine multiple observations of disease progress into a single value. However, our analysis shows that this approach severely underestimates the effect of the first and last observation. To get a better estimate of disease prog...

  9. ABCA4 disease progression and a proposed strategy for gene therapy

    E-print Network

    Palczewski, Krzysztof

    ABCA4 disease progression and a proposed strategy for gene therapy Artur V. Cideciyan1,Ã Autosomal recessive retinal diseases caused by mutations in the ABCA4 gene are being considered for gene- retinal gene therapy will aim to arrest disease progression in the extramacular retina. In 66 individuals

  10. Predictors of progression in hypertensive renal disease in children.

    PubMed

    Lurbe, Empar; Alvarez, Vicente; Redon, Josep

    2004-04-01

    In hypertensive renal disease in children, several risk factors influence the development and the rate of progression of renal damage, including blood pressure levels, proteinuria, lipid disorders, and genetic differences. The impact of blood pressure on renal structures, the most important of the factors, depends not only on blood pressure levels, but also on the persistence of the blood pressure levels over time, mainly during the hours when the patient is resting or sleeping. Abnormal circadian variability is frequently observed in patients with renal damage, and nocturnal blood pressure reduction should be a major therapeutic objective to protect against a decline in renal function. Proteinuria is a guide for establishing targets and for monitoring treatment. It should be reduced as much as possible to obtain maximal renoprotective effect. The role of the other factors, such as lipid disorders and genetics, remains elusive. PMID:15073472

  11. Smart garments in chronic disease management: progress and challenges

    NASA Astrophysics Data System (ADS)

    Khosla, Ajit

    2012-10-01

    This paper presents the progress made developments in the area of Smart Garments for chronic disease management over last 10 years. A large number of health monitoring smart garments and wearable sensors have been manufactured to monitor patient's physiological parameters such as electrocardiogram, blood pressure, body temperature, heart rate, oxygen saturation, while patient is not in hospital. In last few years with the advancement in smartphones and cloud computing it is now possible to send the measure physiological data to any desired location. However there are many challenges in the development of smart garment systems. The two major challenges are development of new lightweight power sources and there is a need for global standardization and a road map for development of smart garments. In this paper we will discuss current state-of-theart smart garments and wearable sensor systems. Also discussed will be the new emerging trends in smart garment research and development.

  12. Decreased RECQL5 correlated with disease progression of osteosarcoma.

    PubMed

    Wu, Junlong; Zhi, Liqiang; Dai, Xin; Cai, Qingchun; Ma, Wei

    2015-11-27

    Human RecQ helicase family, consisting of RECQL, RECQL4, RECQL5, BLM and WRN, has critical roles in genetic stability and tumorigenesis. Although RECQL5 has been reported to correlate with the susceptibility to malignances including osteosarcoma, the specific effect on tumor genesis and progression is not yet clarified. Here we focused on the relationship between RECQL5 expression and osteosarcoma disease progression, and further investigated the function of RECQL5 on MG-63 cell proliferation and apoptosis. By immunohistochemical analysis, qRT-PCR and western blot, we found that RECQL5 expression was downregulated in osteosarcoma tissues and cells. Patients with advanced tumor stage and low grade expressed lower RECQL5. To construct a stable RECQL5 overexpression osteosarcoma cell line (MG-63-RECQL5), RECQL5 gene was inserted into the human AAVS1 safe harbor by CRISPR/Cas9 system. The overexpression of RECQL5 was verified by qRT-PCR and western blot. Cell proliferation, cell cycle and apoptosis assay revealed that RECQL5 overexpression inhibited proliferation, induced G1-phase arrest and promoted apoptosis in MG-63 cells. Collectively, our results suggested RECQL5 as a tumor suppressor in osteosarcoma and may be a potential therapeutic target for osteosarcoma treatment. PMID:26499077

  13. Arterial Stiffness, Kidney Function, and Chronic Kidney Disease Progression

    PubMed Central

    Townsend, Raymond R.; Tomiyama, Hirofumi

    2013-01-01

    Arterial stiffness can nowadays be measured easily and noninvasively around the globe. Although well established as an independent predictor of cardiovascular events, less is known about the role of arterial stiffness in the progressive loss of kidney function once chronic kidney disease (CKD) is established. In addition to measures of arterial stiffness, a number of devices now noninvasively record the pulse profile from sites such as the radial artery and, using internal algorithms, are able to estimate central pressure profiles. Although these devices have generated much data on the prediction of cardiovascular events, e.g. measures of arterial stiffness, there is much less known about the predictive utility of these measures in CKD progression. In this review, we cover approaches to arterial stiffness as measured by pulse wave velocity and discuss measures of the systolic and diastolic contour of the pulse waveform vis-à-vis their relationship to declines in kidney function over time. We restrict our coverage to studies that have longitudinal data, but we also include a table of studies, which, to our knowledge, have only published cross-sectional data at this time.

  14. Diagnosis of dementia and treatment of Alzheimer's disease. Pharmacologic management of disease progression and cognitive impairment.

    PubMed Central

    van Reekum, R.; Simard, M.; Farcnik, K.

    1999-01-01

    OBJECTIVE: To highlight the importance of family physicians in the management of Alzheimer's disease (AD) and related dementias. To provide an update on the diagnostic workup of people with suspected dementia and on the pharmacologic management of cognitive impairment and disease progression in AD. QUALITY OF EVIDENCE: MEDLINE and Psychological Abstracts were searched using the terms "cognitive enhancers" or a specific drug name and "dementia (exp)." Evidence is generally limited but promising. Methodologic flaws in existing research likely to affect clinicians are briefly reviewed. MAIN MESSAGE: Increasing evidence suggests that early intervention can delay the progression of AD and improve the symptoms and function of those affected. Available treatments have modest but important effects on the outcome of patients with AD; some patients respond dramatically. Most currently available treatments are relatively safe in carefully selected cases. CONCLUSIONS: The diagnostic workup of most cases of dementia can at least be initiated in family physicians' offices. Beginning the workup is important because, for treating AD, the earlier you start, the better. Donepezil, vitamin E, and, in the near future, propentofylline are the main pharmacologic choices for improving cognition and slowing disease progression. PMID:10216793

  15. Optical coherence tomography findings in Huntington's disease: a potential biomarker of disease progression.

    PubMed

    Kersten, Hannah M; Danesh-Meyer, Helen V; Kilfoyle, Dean H; Roxburgh, Richard H

    2015-11-01

    Previous reports of ocular abnormalities in Huntington's disease (HD) have detailed eye movement disorders. The objective of this case-control study was to investigate optic nerve and macular morphology in HD using optical coherence tomography (OCT). A total of 26 HD patients and 29 controls underwent a thorough ophthalmic examination including spectral domain OCT scans of the macula and peripapillary retinal nerve fibre layer (RNFL). Genetic testing results, disease duration, HD disease burden scores and Unified HD Rating Scale motor scores were acquired for HD patients. Temporal RNFL thickness was significantly reduced in the HD group (62.3 vs. 69.8 ?m, p = 0.005), and there was a significant negative correlation between temporal RNFL thickness and disease duration (R (2) = -0.51, p = 0.04). Average peripapillary RNFL thickness was not significantly different between the HD and control groups. There was a significant negative correlation between macular volume and disease duration (R (2) = -0.71, p = 0.002), and motor scores (R (2) = -0.56, p = 0.01). Colour vision was significantly poorer in the HD group. Temporal RNFL is preferentially thinned in HD patients, possibly implicating mitochondrial dysfunction as the temporal RNFL is reduced in the patients with some mitochondrial disorders, including Leber's hereditary optic neuropathy. The correlation between the decrease in macular volume and temporal RNFL, and increasing disease severity suggests that OCT may be a useful biomarker for disease progression in HD. Larger, longitudinal studies are required. PMID:26233693

  16. In silico regulatory analysis for exploring human disease progression

    PubMed Central

    Holloway, Dustin T; Kon, Mark; DeLisi, Charles

    2008-01-01

    Background An important goal in bioinformatics is to unravel the network of transcription factors (TFs) and their targets. This is important in the human genome, where many TFs are involved in disease progression. Here, classification methods are applied to identify new targets for 152 transcriptional regulators using publicly-available targets as training examples. Three types of sequence information are used: composition, conservation, and overrepresentation. Results Starting with 8817 TF-target interactions we predict an additional 9333 targets for 152 TFs. Randomized classifiers make few predictions (~2/18660) indicating that our predictions for many TFs are significantly enriched for true targets. An enrichment score is calculated and used to filter new predictions. Two case-studies for the TFs OCT4 and WT1 illustrate the usefulness of our predictions: • Many predicted OCT4 targets fall into the Wnt-pathway. This is consistent with known biology as OCT4 is developmentally related and Wnt pathway plays a role in early development. • Beginning with 15 known targets, 354 predictions are made for WT1. WT1 has a role in formation of Wilms' tumor. Chromosomal regions previously implicated in Wilms' tumor by cytological evidence are statistically enriched in predicted WT1 targets. These findings may shed light on Wilms' tumor progression, suggesting that the tumor progresses either by loss of WT1 or by loss of regions harbouring its targets. • Targets of WT1 are statistically enriched for cancer related functions including metastasis and apoptosis. Among new targets are BAX and PDE4B, which may help mediate the established anti-apoptotic effects of WT1. • Of the thirteen TFs found which co-regulate genes with WT1 (p ? 0.02), 8 have been previously implicated in cancer. The regulatory-network for WT1 targets in genomic regions relevant to Wilms' tumor is provided. Conclusion We have assembled a set of features for the targets of human TFs and used them to develop classifiers for the determination of new regulatory targets. Many predicted targets are consistent with the known biology of their regulators, and new targets for the Wilms' tumor regulator, WT1, are proposed. We speculate that Wilms' tumor development is mediated by chromosomal rearrangements in the location of WT1 targets. Reviewers This article was reviewed by Trey Ideker, Vladimir A. Kuznetsov(nominated by Frank Eisenhaber), and Tzachi Pilpel. PMID:18564415

  17. Rhesus monkey model of liver disease reflecting clinical disease progression and hepatic gene expression analysis

    PubMed Central

    Wang, Hong; Tan, Tao; Wang, Junfeng; Niu, Yuyu; Yan, Yaping; Guo, Xiangyu; Kang, Yu; Duan, Yanchao; Chang, Shaohui; Liao, Jianpeng; Si, Chenyang; Ji, Weizhi; Si, Wei

    2015-01-01

    Alcoholic liver disease (ALD) is a significant public health issue with heavy medical and economic burdens. The aetiology of ALD is not yet completely understood. The development of drugs and therapies for ALD is hampered by a lack of suitable animal models that replicate both the histological and metabolic features of human ALD. Here, we characterize a rhesus monkey model of alcohol-induced liver steatosis and hepatic fibrosis that is compatible with the clinical progression of the biochemistry and pathology in humans with ALD. Microarray analysis of hepatic gene expression was conducted to identify potential molecular signatures of ALD progression. The up-regulation of expression of hepatic genes related to liver steatosis (CPT1A, FASN, LEPR, RXRA, IGFBP1, PPARGC1A and SLC2A4) was detected in our rhesus model, as was the down-regulation of such genes (CYP7A1, HMGCR, GCK and PNPLA3) and the up-regulation of expression of hepatic genes related to liver cancer (E2F1, OPCML, FZD7, IGFBP1 and LEF1). Our results demonstrate that this ALD model reflects the clinical disease progression and hepatic gene expression observed in humans. These findings will be useful for increasing the understanding of ALD pathogenesis and will benefit the development of new therapeutic procedures and pharmacological reagents for treating ALD. PMID:26442469

  18. Low-level laser therapy ameliorates disease progression in a mouse model of Alzheimer's disease.

    PubMed

    Farfara, Dorit; Tuby, Hana; Trudler, Dorit; Doron-Mandel, Ella; Maltz, Lidya; Vassar, Robert J; Frenkel, Dan; Oron, Uri

    2015-02-01

    Low-level laser therapy (LLLT) has been used to treat inflammation, tissue healing, and repair processes. We recently reported that LLLT to the bone marrow (BM) led to proliferation of mesenchymal stem cells (MSCs) and their homing in the ischemic heart suggesting its role in regenerative medicine. The aim of the present study was to investigate the ability of LLLT to stimulate MSCs of autologous BM in order to affect neurological behavior and ?-amyloid burden in progressive stages of Alzheimer's disease (AD) mouse model. MSCs from wild-type mice stimulated with LLLT showed to increase their ability to maturate towards a monocyte lineage and to increase phagocytosis activity towards soluble amyloid beta (A?). Furthermore, weekly LLLT to BM of AD mice for 2 months, starting at 4 months of age (progressive stage of AD), improved cognitive capacity and spatial learning, as compared to sham-treated AD mice. Histology revealed a significant reduction in A? brain burden. Our results suggest the use of LLLT as a therapeutic application in progressive stages of AD and imply its role in mediating MSC therapy in brain amyloidogenic diseases. PMID:24994540

  19. Rhesus monkey model of liver disease reflecting clinical disease progression and hepatic gene expression analysis.

    PubMed

    Wang, Hong; Tan, Tao; Wang, Junfeng; Niu, Yuyu; Yan, Yaping; Guo, Xiangyu; Kang, Yu; Duan, Yanchao; Chang, Shaohui; Liao, Jianpeng; Si, Chenyang; Ji, Weizhi; Si, Wei

    2015-01-01

    Alcoholic liver disease (ALD) is a significant public health issue with heavy medical and economic burdens. The aetiology of ALD is not yet completely understood. The development of drugs and therapies for ALD is hampered by a lack of suitable animal models that replicate both the histological and metabolic features of human ALD. Here, we characterize a rhesus monkey model of alcohol-induced liver steatosis and hepatic fibrosis that is compatible with the clinical progression of the biochemistry and pathology in humans with ALD. Microarray analysis of hepatic gene expression was conducted to identify potential molecular signatures of ALD progression. The up-regulation of expression of hepatic genes related to liver steatosis (CPT1A, FASN, LEPR, RXRA, IGFBP1, PPARGC1A and SLC2A4) was detected in our rhesus model, as was the down-regulation of such genes (CYP7A1, HMGCR, GCK and PNPLA3) and the up-regulation of expression of hepatic genes related to liver cancer (E2F1, OPCML, FZD7, IGFBP1 and LEF1). Our results demonstrate that this ALD model reflects the clinical disease progression and hepatic gene expression observed in humans. These findings will be useful for increasing the understanding of ALD pathogenesis and will benefit the development of new therapeutic procedures and pharmacological reagents for treating ALD. PMID:26442469

  20. FTD and ALS: a tale of two diseases

    PubMed Central

    Ferrari, Raffaele; Kapogiannis, Dimitrios; Huey, Edward D.; Momeni, Parastoo

    2012-01-01

    The first reports of disorders that in terms of cognitive and behavioral symptoms resemble frontotemporal dementia (FTD) and in terms of motor symptoms resemble amyotrophic lateral sclerosis (ALS) bring us back to the second half of the 1800s. Over the last 150 years, and especially in the last two decades, there has been growing evidence that FTD signs can be seen in patients primarily diagnosed with ALS, implying clinical overlap among these two disorders. In the last decade pathological investigations and genetic screening have contributed tremendously in elucidating the pathology and genetic variability associated with FTD and ALS. To the most important recentdiscoveries belong TAR DNA binding protein [TARDBP or TDP-43] and the fused in sarcoma gene [FUS] and their implication in these disorders. FTD and ALS are the focus of this review which aims to 1. summarize clinical features by describing the diagnostic criteria and specific symptomatology, 2. describe the morphological aspects and related pathology, 3. describe the genetic factors associated with the diseases and 4. summarize the current status of clinical trials and treatment options. A better understanding of the clinical, pathological and genetic features characterizing FTD and ALS will shed light into overlaps among these two disorders and the underpinning mechanisms that contribute to the onset and development. Nevertheless, advancements in the knowledge of the biology of these two disorders will help developing novel and, hopefully, more effective diagnostic and treatment options. PMID:21222600

  1. Development of a new scale for dysphagia in patients with progressive neuromuscular diseases: the Neuromuscular Disease Swallowing Status Scale (NdSSS).

    PubMed

    Wada, Ayako; Kawakami, Michiyuki; Liu, Meigen; Otaka, Eri; Nishimura, Atsuko; Liu, Fumio; Otsuka, Tomoyoshi

    2015-10-01

    Dysphagia is one of the most critical problems in patients with progressive neuromuscular diseases. However, clinically useful and practical scales to evaluate dysphagia are limited. Therefore, the aim of this study was to develop such a scale. An 8-stage Neuromuscular Disease Swallowing Status Scale (NdSSS) was developed and tested for its inter- and intrarater reliabilities, concurrent validity, and responsiveness. The NdSSS was used to evaluate 134 patients with Duchenne muscular dystrophy (DMD) and 84 patients with amyotrophic lateral sclerosis (ALS). Inter- and intrarater reliabilities were examined with weighted kappa statistics. Concurrent validity was assessed by correlating the NdSSS with the existing scales [Functional Oral Intake Scale (FOIS), Functional Intake LEVEL Scales (FILS), and ALS Functional Rating Scale-Revised Swallow (ALSFRS-R Sw)], using Spearman's correlation coefficients. Responsiveness was determined with the standardized response mean (SRM). For inter- and intrarater reliabilities, the weighted kappas were 0.95 and 1.00, respectively, for DMD; and 0.98 and 0.98, respectively, for ALS. The NdSSS showed strong correlations with the FOIS (rs = 0.87 for DMD, rs = 0.93 for ALS, p < 0.001), FILS (rs = 0.89 for DMD, rs = 0.92 for ALS, p < 0.001), and ALSFRS-R SW (rs = 0.93, p < 0.001). SRMs were 0.65 for DMD and 1.21 for ALS. The SRM was higher in DMD patients for the NdSSS than for the other scales, while it was similar in ALS patients and the other scales. Our originally developed NdSSS demonstrated sufficient reliability, validity, and responsiveness in patients with DMD and ALS. It is also useful in evaluating dysphagia in patients with progressive neuromuscular diseases. PMID:26142025

  2. Integration of network theory with gene expression data on disease progression significantly improves

    E-print Network

    Lee, H.C. Paul

    Integration of network theory with gene expression data on disease progression significantly-protein interaction, regulatory pathways, gene-disease relation, and disease-drug relation. Separately, microarray of biological condition types, including those of cancer. In a systems disease such as cancer, how genes

  3. Extensive dysregulations of oligodendrocytic and astrocytic connexins are associated with disease progression in an amyotrophic lateral sclerosis mouse model

    PubMed Central

    2014-01-01

    Background Non-cell-autonomous motor neuronal death is suggested in a mutant Cu/Zn superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis (ALS) model, in which glial cells play significant roles in disease progression. Connexins (Cxs) form homotypic or heterotypic gap junctions (GJs) and allow direct intercellular communications among nervous tissue cells. The role of Cxs in motor neuron disease has never been investigated; therefore, we aimed to evaluate alterations of Cxs in mSOD1-transgenic (mSOD1-Tg) mice in comparison with their non-transgenic (non-Tg) littermates at the same ages. Methods We pathologically evaluated temporal changes to astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 immunoreactivities at presymptomatic, disease-progressive, and end stages, relative to aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-2 (EAAT2), myelin-oligodendrocyte glycoprotein (MOG), and Nogo-A immunoreactivities, and observed neuronal loss by NeuN and neurofilament immunostaining, and microglial response by Iba-1 immunostaining. We also performed quantitative immunoblotting and real-time PCR analyses for Cxs. Results The mSOD1-Tg mice showed neuronal and axonal loss in the anterior horns of the lumbar spinal cord accompanied by increased activation of microglia compared with non-Tg mice at the disease-progressive and end stages. Expression patterns of Cxs were not different between mSOD1-Tg and non-Tg mice at the presymptomatic stage, but immunoreactivities for GFAP, Cx43, Cx30 and AQP4 were increased in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. By contrast, Cx47 and Cx32 immunoreactivities were markedly diminished in Nogo-A-positive oligodendrocytes in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages, especially in oligodendrocytes showing SOD1 accumulation. EAAT2 immunoreactivity was also diminished in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. Quantitative immunoblotting revealed a significant reduction in Cx47 and Cx32 protein levels in mSOD1-Tg mice at the disease-progressive and end stages. The levels of Cx47 and Cx32 mRNAs were also decreased at these stages. Conclusions Our findings indicate that oligodendrocytic and astrocytic GJ proteins in the anterior horns of spinal cord in mSOD1-Tg mice are profoundly affected at the disease-progressive and end stages, where disruption of GJs among glial cells may exacerbate motor neuronal death. PMID:24597481

  4. Cholinergic system during the progression of Alzheimer's disease: therapeutic implications

    PubMed Central

    Mufson, Elliott J; Counts, Scott E; Perez, Sylvia E; Ginsberg, Stephen D

    2009-01-01

    Alzheimer's disease (AD) is characterized by a progressive phenotypic downregulation of markers within cholinergic basal forebrain (CBF) neurons, frank CBF cell loss and reduced cortical choline acetyltransferase activity associated with cognitive decline. Delaying CBF neurodegeneration or minimizing its consequences is the mechanism of action for most currently available drug treatments for cognitive dysfunction in AD. Growing evidence suggests that imbalances in the expression of NGF, its precursor proNGF and the high (TrkA) and low (p75NTR) affinity NGF receptors are crucial factors underlying CBF dysfunction in AD. Drugs that maintain a homeostatic balance between TrkA and p75NTR may slow the onset of AD. A NGF gene therapy trial reduced cognitive decline and stimulated cholinergic fiber growth in humans with mild AD. Drugs treating the multiple pathologies and clinical symptoms in AD (e.g., M1 cholinoceptor and/or galaninergic drugs) should be considered for a more comprehensive treatment approach for cholinergic dysfunction. PMID:18986241

  5. Evidence for Angiogenesis in Parkinson’s disease, Incidental Lewy Body disease, and Progressive Supranuclear Palsy

    PubMed Central

    Bradaric, Brinda Desai; Patel, Aditiben; Schneider, Julie A.; Carvey, Paul M.; Hendey, Bill

    2012-01-01

    Angiogenesis has not been extensively studied in Parkinson’s disease (PD) despite being associated with other neurodegenerative disorders. Post-mortem human brain tissues were obtained from subjects with pathologically confirmed Parkinson’s disease (PD) and progressive supranuclear palsy (PSP), a rapidly progressing Parkinsonian-like disorder. Tissues were also obtained from subjects with incidental Lewy body disease (iLBD) who had Lewy bodies in the substantia nigra pars compacta (SNpc) but had not been diagnosed with PD and age-matched controls without Lewy body pathology. The SNpc, putamen, locus ceruleus (LC) and midfrontal cortex were examined for integrin ?v?3, a marker for angiogenesis, along with vessel number and activated microglia. All parkinsonian syndromes had greater ?v?3 in the LC and the SNpc, while only PD and PSP subjects had elevated ?v?3 in the putamen compared to controls. PD and PSP subjects also had increases in microglia number and activation in the SNpc suggesting a link between inflammation and clinical disease. Microglia activation in iLBD subjects was limited to the LC, an area involved at an early stage of PD. Likewise, iLBD subjects did not differ from controls in ?v?3 staining in the putamen, a late area of involvement in PD. The presence of ?v?3 reactive vessels in PD and its syndromes is indicative of newly created vessels that have not likely developed the restrictive properties of the blood brain barrier. Such angiogenic vessels could contribute to neuroinflammation by failing to protect the parenchyma from peripheral immune cells and inflammatory or toxic factors in the peripheral circulation. PMID:21748523

  6. Re-examining RAS-blocking treatment regimens for abrogating progression of chronic kidney disease.

    PubMed

    Epstein, Murray

    2009-01-01

    This commentary discusses the findings and profound clinical implications of a prespecified analysis of renal outcomes performed by Mann et al. in the large ONTARGET study. This study assessed the effects of the angiotensin-converting-enzyme (ACE) inhibitor ramipril and the angiotensin receptor blocker (ARB) telmisartan, separately and in combination, in patients aged at least 55 years who had established vascular disease or diabetes with organ damage. Mann et al. demonstrated that, in contrast to monotherapy with either drug, the combination of an ACE inhibitor and an ARB worsens all major renal outcomes with the exception of proteinuria. This commentary recommends that combination therapy with an ACE inhibitor and an ARB to retard progression of renal disease should be avoided in patients with proteinuria lower than 1 g per day. The utility of dual RAS blockade regimens comprising an ACE inhibitor and a direct renin inhibitor, or an ACE inhibitor or ARB plus an aldosterone blocker, remains to be determined and constitutes a high priority subject for future clinical investigation. PMID:18981997

  7. Haematuria Increases Progression of Advanced Proteinuric Kidney Disease

    PubMed Central

    Yuste, Claudia; Rubio-Navarro, Alfonso; Barraca, Daniel; Aragoncillo, Inés; Vega, Almudena; Abad, Soraya; Santos, Alba; Macias, Nicolás; Mahillo, Ignacio; Gutiérrez, Eduardo; Praga, Manuel; Egido, Jesús

    2015-01-01

    Background Haematuria has been traditionally considered as a benign hallmark of some glomerular diseases; however new studies show that haematuria may decrease renal function. Objective To determine the influence of haematuria on the rate of chronic kidney disease (CKD) progression in 71 proteinuric patients with advanced CKD (baseline eGFR <30 mL/min) during 12 months of follow-up. Results The mean rate of decline in eGFR was higher in patients with both haematuria and proteinuria (haemoproteinuria, HP, n=31) than in patients with proteinuria alone (P patients, n=40) (-3.8±8.9 vs 0.9±9.5 mL/min/1.73m2/year, p<0.05, respectively). The deleterious effect of haematuria on rate of decline in eGFR was observed in patients <65 years (-6.8±9.9 (HP) vs. 0.1±11.7 (P) mL/min/1.73m2/year, p<0.05), but not in patients >65 years (-1.2±6.8 (HP) vs. 1.5±7.7 (P) mL/min/1.73m2/year). Furthermore, the harmful effect of haematuria on eGFR slope was found patients with proteinuria >0.5 g/24 h (-5.8±6.4 (HP) vs. -1.37± 7.9 (P) mL/min/1.73m2/year, p<0.05), whereas no significant differences were found in patients with proteinuria < 0.5 g/24 h (-0.62±7.4 (HP) vs. 3.4±11.1 (P) mL/min/1.73m2/year). Multivariate analysis reported that presence of haematuria was significantly and independently associated with eGFR deterioration after adjusting for traditional risk factors, including age, serum phosphate, mean proteinuria and mean serum PTH (?=-4.316, p=0.025). Conclusions The presence of haematuria is closely associated with a faster decrease in renal function in advanced proteinuric CKD patients, especially in younger CKD patients with high proteinuria levels; therefore this high risk subgroup of patients would benefit of intensive medical surveillance and treatment. PMID:26016848

  8. Induced pluripotent stem cells (iPSCs) and neurological disease modeling: progress and promises

    PubMed Central

    Marchetto, Maria C.; Brennand, Kristen J.; Boyer, Leah F.; Gage, Fred H.

    2011-01-01

    The systematic generation of neurons from patients with neurological disorders can provide important insights into disease pathology, progression and mechanism. This review will discuss recent progress in modeling neurodegenerative and neurodevelopmental diseases using induced pluripotent stem cells (iPSCs) and highlight some of the current challenges in the field. Combined with other technologies previously used to study brain disease, iPSC modeling has the promise to influence modern medicine on several fronts: early diagnosis, drug development and effective treatment. PMID:21828073

  9. A Lipidomic Readout of Disease Progression in A Diet-Induced Mouse Model of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Sanyal, Arun J.; Pacana, Tommy

    2015-01-01

    Multiple changes in lipid metabolism occur in nonalcoholic fatty liver disease. However, it is not known which of these contribute to disease progression. The objective of this study was to define changes in hepatic lipid composition over time in a diet-induced model of nonalcoholic fatty liver disease to identify changes associated with disease progression. A lipidomic approach was used to quantify individual lipid species with lipid classes of interest including diacylglycerols (DAG), cholesterol, phospholipids, plasmalogens, sphingolipids, and eicosanoids. C57b/S129J mice fed a high-fat, high-cholesterol diet developed fatty liver, inflammation, and ballooning by 16 weeks and extensive fibrosis by week 52. There was a marked increase in monounsaturated fatty acid containing DAGs and cholesterol esters by week 16 which decreased by week 52. The changes in DAG were associated with a 500- to 600-fold increase in phosphatidic acid (< 0.001) and its downstream product phosphatidylglycerol (P <0.01) whereas phosphatidylethanolamine, phosphatidylcholine, and phsophatidylserine all decreased. Disease progression was associated with a significant further decrease in phosphatidylcholine and phosphatidylethanolamine while several lysolecithin species increased. Disease progression was associated with a significant increase in the plasmalogen PC-P 16:0/16:1. Saturated fatty acid (16:0 and 18:0) containing ceramides, sphingosine, sphingosine-1-phosphate, dihydrosphingosine, and dihydrophingosine-1-phosphate increased by week 16 after high-fat high-cholesterol diet. Globotrioseacylceramide (GB3) also increased significantly by week 16 and increased further with disease progression. 12-hydroxyeicosatetranoic acid decreased at week 16 but increased with disease progression. In conclusion, multiple lipids were associated with disease progression and provide clues regarding lipid drivers of nonalcoholic steatohepatitis. PMID:26330688

  10. Evaluating the Predictive Power of Multivariate Tensor-based Morphometry in Alzheimers Disease Progression via Convex

    E-print Network

    Wang, Yalin

    Evaluating the Predictive Power of Multivariate Tensor-based Morphometry in Alzheimers Disease ABSTRACT Prediction of Alzheimers disease (AD) progression based on baseline measures allows us. They showed that this can be used in predicting cognitive outcomes of Alzheimers Disease Neuroimaging

  11. Re exive and volitional saccades: Biomarkers of Huntington disease severity and progression

    E-print Network

    Sereno, Anne B.

    Re exive and volitional saccades: Biomarkers of Huntington disease severity and progression Saumil Background: Huntington disease (HD) is a genetic, neurodegenerative disorder characterized by chorea, behav: Eleven HD subjects were evaluated with the motor subscale of the Uni ed Huntington Disease Rating Scale

  12. National Plant Disease Recovery System PLANT HEALTH PROGRESS Vol. 16, No. 4, 2015 Page 173

    E-print Network

    Etxeberria, Edgardo

    National Plant Disease Recovery System PLANT HEALTH PROGRESS Vol. 16, No. 4, 2015 Page 173, Forest Health Section, Florida Forest Service, Gainesville, FL 32608; T. Pernas, National Park Service of several disease-specific documents produced as part of the National Plant Disease Recovery System (NPDRS

  13. Exploration of Anaemia as a Progression Factor in African Americans with Cardiovascular Disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Despite the higher incidence of end stage renal disease (ESRD) among African Americans, whites in the United States population have a higher prevalence of chronic kidney disease. This may be due, in part, to a faster rate of progression to ESRD among African Americans with kidney disease. Anemia i...

  14. High Degree of Heterogeneity in Alzheimer's Disease Progression Patterns

    E-print Network

    Komarova, Natalia L; Thalhauser, Craig J; Hunter, Lawrence E

    2011-01-01

    in the early stage of probable Alzheimer’ s disease. DementAlzheimer’s Disease (AD) shows a pattern of high variability, with patients transiting the stagesstages in AD, which is consistent with the reports November 2011 | Volume 7 | Issue 11 | e1002251 Heterogeneity of Alzheimer’s Disease

  15. PROGRESSION OF ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE: CLINICAL AND EXPERIMENTAL INSIGHTS AND QUERIES

    PubMed Central

    Zager, Richard A.

    2014-01-01

    There are an increasing number of clinical suggestions that acute kidney injury (AKI) can be complicated by the onset of progressive renal disease. Indeed, given the frequency of AKI in hospitalized patients, were AKI to initiate disease progression, it could potentially be a leading cause of, or contributor to, end stage renal disease. Insights into the natural history of AKI, and potential mechanisms for disease progression, can be gleaned for experimental studies. Although such studies underscore the principle that AKI can “heal with defects”, whether ongoing renal disease develops remains a subject of debate. Indeed, in the aftermath of AKI, a variety of secondary renal protective pathways are activated which may retard or prevent severe, chronic kidney disease (CKD). Furthermore, the onset of acute uremia, per se, may exert surprisingly potent renal protective effects. The purpose of this brief report is to review some of the clinical and experimental data that deal with these complex issues. PMID:25343820

  16. Does increased water intake prevent disease progression in autosomal dominant polycystic kidney disease?

    PubMed Central

    Higashihara, Eiji; Nutahara, Kikuo; Tanbo, Mitsuhiro; Hara, Hidehiko; Miyazaki, Isao; Kobayashi, Kuninori; Nitatori, Toshiaki

    2014-01-01

    Background The clinical effects of increased water intake on autosomal dominant polycystic kidney disease (ADPKD) progression are unknown. Methods ADPKD patients with creatinine clearance ?50 mL/min/1.73 m2 were divided into high (H-, n = 18) and free (F-, n = 16) water-intake groups, mainly according to their preference. Prior to the study, 30 patients underwent annual evaluation of total kidney volume (TKV) and 24-h urine for an average of 33 months. During the 1-year study period, TKV and 24-h urine were analyzed at the beginning and end of the study and every 4 months, respectively. Results During the pre-study period, urine volume (UV) in the H-group was higher (P = 0.034), but TKV and kidney function and their slopes were not significantly different between the two groups. After the study commenced, UV further increased (P < 0.001) in the H-group but not in the F-group. During the study period, TKV and kidney function slopes were not significantly different between the two groups (primary endpoint). Plasma copeptin was lower (P = 0.024) in the H-group than in the F-group. TKV and kidney function slopes became worse (P = 0.047 and 0.011, respectively) after high water intake (H-group) but not in the F-group. High UV was associated with increased urine sodium, and urine sodium positively correlated with the % TKV slope (P = 0.014). Conclusions Although the main endpoint was not significant, high water intake enhanced disease progression in the H-group when compared with the pre-study period. These findings necessitate a long-term randomized study before drawing a final conclusion. PMID:24739484

  17. Multi-stage Biomarker Models for Progression Estimation in Alzheimer's Disease.

    PubMed

    Schmidt-Richberg, Alexander; Guerrero, Ricardo; Ledig, Christian; Molina-Abril, Helena; Frangi, Alejandro F; Rueckert, Daniel

    2015-01-01

    The estimation of disease progression in Alzheimer's disease (AD) based on a vector of quantitative biomarkers is of high interest to clinicians, patients, and biomedical researchers alike. In this work, quantile regression is employed to learn statistical models describing the evolution of such biomarkers. Two separate models are constructed using (1) subjects that progress from a cognitively normal (CN) stage to mild cognitive impairment (MCI) and (2) subjects that progress from MCI to AD during the observation window of a longitudinal study. These models are then automatically combined to develop a multi-stage disease progression model for the whole disease course. A probabilistic approach is derived to estimate the current disease progress (DP) and the disease progression rate (DPR) of a given individual by fitting any acquired biomarkers to these models. A particular strength of this method is that it is applicable even if individual biomarker measurements are missing for the subject. Employing cognitive scores and image-based biomarkers, the presented method is used to estimate DP and DPR for subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Further, the potential use of these values as features for different classification tasks is demonstrated. For example, accuracy of 64% is reached for CN vs. MCI vs. AD classification. PMID:26221689

  18. Nov 13-14, 2001 A. R. Raffray, et al., Progress Report on Chamber Clearing Code Effort 1 Progress Report on Chamber Clearing Code

    E-print Network

    Raffray, A. René

    Nov 13-14, 2001 A. R. Raffray, et al., Progress Report on Chamber Clearing Code Effort 1 Progress Report on Chamber Clearing Code Development Effort A. R. Raffray, F. Najmabadi, Z. Dragojlovic, J Clearing Code Effort 2 Strategy Include Careful Planning and Analysis Effort for Most Efficient Code

  19. Association of foot and ankle characteristics with progression of venous disease.

    PubMed

    Kim, Tanner I; Forbang, Nketi I; Criqui, Michael H; Allison, Matthew A

    2015-04-01

    Although risk factors have been identified for the cross-sectional prevalence of venous disease, few studies have investigated risk factors for venous disease progression. Therefore, the aim of this study was to investigate the relationship between foot and ankle characteristics and the progression of venous disease. A total of 1025 participants from the San Diego Population Study were assessed at baseline and at follow-up 11 years later. Risk factors were assessed by questionnaire and physical measurements, while venous disease was determined by physical examination and Duplex ultrasound. Change in venous disease from baseline to 11-year follow-up was characterized as stable or progression. Those with venous disease progression were less likely to spend increased time lying per day, more likely to have a history of hypertension, lie supine for a surgical procedure greater than an hour, and report an occupation that was professional, technical, administrative, or management. Those with a normal arch reported the greatest degree of plantar flexion. In multivariable logistic regression, including adjustment for weight-bearing arch characteristics, greater dorsiflexion (per 5 degrees) was significantly associated with progression of venous disease (OR = 1.11, p = 0.01). A weight-bearing flat arch compared to a weight-bearing normal arch was of borderline significance as a protective factor against progression of venous disease with adjustment for dorsiflexion (OR = 0.56, p = 0.07). Our results indicate that the ability to have higher levels of dorsiflexion is a risk factor for the progression of venous disease, and suggest a role for connective tissue laxity in the pathogenesis of venous disease. PMID:25832598

  20. Visualising disease progression on multiple variables with vector plots and path plots

    E-print Network

    Lazic, Stanley E.; Mason, Sarah L.; Michell, Andrew W.; Barker, Roger A.

    2009-05-27

    Abstract Background It is often desirable to observe how a disease progresses over time in individual patients, rather than graphing group averages; and since multiple outcomes are typically recorded on each patient, it would be advantageous...

  1. Association of survival and disease progression with chromosomal instability: A genomic exploration of colorectal cancer

    E-print Network

    Sheffer, Michal

    During disease progression the cells that comprise solid malignancies undergo significant changes in gene copy number and chromosome structure. Colorectal cancer provides an excellent model to study this process. To indentify ...

  2. Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse

    PubMed Central

    2015-01-01

    Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 3–5 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 3–4 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group) or vehicle (n = 10), daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg) of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan. PMID:26469273

  3. Progress in Early Diagnosis of Sickle Cell Disease

    ERIC Educational Resources Information Center

    Pearson, Howard A.

    1971-01-01

    Discusses the basis of sickle cell Anemia, including: a description of the diseased blood, genetic implications, recognition of symptoms in infancy, the need for implementation of wide screening procedures, and the future prospects of a cure. (AJ)

  4. Evaluating the Predictive Power of Multivariate Tensor-based Morphometry in Alzheimers Disease Progression via Convex Fused Sparse Group Lasso

    PubMed Central

    Tsao, Sinchai; Gajawelli, Niharika; Zhou, Jiayu; Shi, Jie; Ye, Jieping; Wang, Yalin; Lepore, Natasha

    2014-01-01

    Prediction of Alzheimers disease (AD) progression based on baseline measures allows us to understand disease progression and has implications in decisions concerning treatment strategy. To this end we combine a predictive multi-task machine learning method1 with novel MR-based multivariate morphometric surface map of the hippocampus2 to predict future cognitive scores of patients. Previous work by Zhou et al.1 has shown that a multi-task learning framework that performs prediction of all future time points (or tasks) simultaneously can be used to encode both sparsity as well as temporal smoothness. They showed that this can be used in predicting cognitive outcomes of Alzheimers Disease Neuroimaging Initiative (ADNI) subjects based on FreeSurfer-based baseline MRI features, MMSE score demographic information and ApoE status. Whilst volumetric information may hold generalized information on brain status, we hypothesized that hippocampus specific information may be more useful in predictive modeling of AD. To this end, we applied Shi et al.2s recently developed multivariate tensor-based (mTBM) parametric surface analysis method to extract features from the hippocampal surface. We show that by combining the power of the multi-task framework with the sensitivity of mTBM features of the hippocampus surface, we are able to improve significantly improve predictive performance of ADAS cognitive scores 6, 12, 24, 36 and 48 months from baseline. PMID:25076826

  5. Evaluating the Predictive Power of Multivariate Tensor-based Morphometry in Alzheimers Disease Progression via Convex Fused Sparse Group Lasso.

    PubMed

    Tsao, Sinchai; Gajawelli, Niharika; Zhou, Jiayu; Shi, Jie; Ye, Jieping; Wang, Yalin; Lepore, Natasha

    2014-03-21

    Prediction of Alzheimers disease (AD) progression based on baseline measures allows us to understand disease progression and has implications in decisions concerning treatment strategy. To this end we combine a predictive multi-task machine learning method(1) with novel MR-based multivariate morphometric surface map of the hippocampus(2) to predict future cognitive scores of patients. Previous work by Zhou et al.(1) has shown that a multi-task learning framework that performs prediction of all future time points (or tasks) simultaneously can be used to encode both sparsity as well as temporal smoothness. They showed that this can be used in predicting cognitive outcomes of Alzheimers Disease Neuroimaging Initiative (ADNI) subjects based on FreeSurfer-based baseline MRI features, MMSE score demographic information and ApoE status. Whilst volumetric information may hold generalized information on brain status, we hypothesized that hippocampus specific information may be more useful in predictive modeling of AD. To this end, we applied Shi et al.(2)s recently developed multivariate tensor-based (mTBM) parametric surface analysis method to extract features from the hippocampal surface. We show that by combining the power of the multi-task framework with the sensitivity of mTBM features of the hippocampus surface, we are able to improve significantly improve predictive performance of ADAS cognitive scores 6, 12, 24, 36 and 48 months from baseline. PMID:25076826

  6. Evaluating the predictive power of multivariate tensor-based morphometry in Alzheimer's disease progression via convex fused sparse group Lasso

    NASA Astrophysics Data System (ADS)

    Tsao, Sinchai; Gajawelli, Niharika; Zhou, Jiayu; Shi, Jie; Ye, Jieping; Wang, Yalin; Lepore, Natasha

    2014-03-01

    Prediction of Alzheimers disease (AD) progression based on baseline measures allows us to understand disease progression and has implications in decisions concerning treatment strategy. To this end we combine a predictive multi-task machine learning method1 with novel MR-based multivariate morphometric surface map of the hippocampus2 to predict future cognitive scores of patients. Previous work by Zhou et al.1 has shown that a multi-task learning framework that performs prediction of all future time points (or tasks) simultaneously can be used to encode both sparsity as well as temporal smoothness. They showed that this can be used in predicting cognitive outcomes of Alzheimers Disease Neuroimaging Initiative (ADNI) subjects based on FreeSurfer-based baseline MRI features, MMSE score demographic information and ApoE status. Whilst volumetric information may hold generalized information on brain status, we hypothesized that hippocampus specific information may be more useful in predictive modeling of AD. To this end, we applied Shi et al.2s recently developed multivariate tensor-based (mTBM) parametric surface analysis method to extract features from the hippocampal surface. We show that by combining the power of the multi-task framework with the sensitivity of mTBM features of the hippocampus surface, we are able to improve significantly improve predictive performance of ADAS cognitive scores 6, 12, 24, 36 and 48 months from baseline.

  7. Retinitis pigmentosa (RP) is a degenerative eye disease characterized by progressive loss of photoreceptors in the

    E-print Network

    Smith, Andrew D.

    Retinitis pigmentosa (RP) is a degenerative eye disease characterized by progressive loss Molecular Vision 1612 A profile of transcriptomic changes in the rd10 mouse model of retinitis pigmentosa determinants of RP [1]. However, we hope our study comparing the retinal tran- scriptomes of diseased and wild

  8. Apelin beyond kidney failure and hyponatremia: a useful biomarker for cancer disease progression evaluation.

    PubMed

    Lacquaniti, Antonio; Altavilla, Giuseppe; Picone, Antonio; Donato, Valentina; Chirico, Valeria; Mondello, Patrizia; Aloisi, Carmela; Marabello, Grazia; Loddo, Saverio; Buemi, Antoine; Lorenzano, Giuseppina; Buemi, Michele

    2015-02-01

    Apelin regulates angiogenesis, stimulating endothelial cell proliferation and migration. It is upregulated during tumor angiogenesis, and its overexpression was reported to increase tumor growth. Furthermore, apelin controls vasopressin release and body fluid homeostasis. The aim of this study was to examine the correlations between apelin expression and clinical outcomes in oncologic patients, such as cancer disease progression and patient's survival. Apelin levels were evaluated in a cohort of 95 patients affected by different varieties of cancer. Partial remission and stable disease were assigned to the 'no progression' group, comparing it with the progressor group. Patients were followed up for 2 years. Receiver operating characteristics analysis was employed for identifying the progression of the oncologic disease and Kaplan-Meier curves assessed the survival. Adjusted risk estimates for progression endpoint were calculated using Cox proportional hazard regression analysis. Oncologic patients had higher apelin levels compared with healthy subjects, and apelin was closely related to the stages of the disease. In the hyponatremia group, apelin values were significantly higher than patients with eunatremia. After the follow-up of 24 months, 41 patients (43%) reached the endpoint. Progressor subjects presented significantly increased apelin values at baseline compared with non-progressor. Univariate followed by multivariate Cox proportional hazard regression analysis showed that apelin predicted cancer progression independently of other potential confounders. In patients with cancer, apelin closely reflects the stage of the disease and represents a strong and independent risk marker for cancer progression. PMID:24469934

  9. Progress toward novel treatments for chronic kidney disease.

    PubMed

    Shah, Sudhir V

    2010-09-01

    Chronic kidney failure remains a major health problem worldwide. Although current treatment is focused on the renin-angiotensin system, it is essential that new treatments targeted toward novel pathophysiological mechanisms are developed if we are to make significant progress in this area. In this review, we have outlined several promising new areas while emphasizing that large, randomized, well-controlled clinical trials are essential to reach a meaningful conclusion about the efficacy and safety of novel treatment. PMID:20797560

  10. Public health impact of disease-behavior dynamics. Comment on "Coupled disease-behavior dynamics on complex networks: A review" by Z. Wang et al.

    NASA Astrophysics Data System (ADS)

    Wells, Chad R.; Galvani, Alison P.

    2015-12-01

    In a loop of dynamic feedback, behavior such as the decision to vaccinate, hand washing, or avoidance influences the progression of the epidemic, yet behavior is driven by the individual's and population's perceived risk of infection during an outbreak. In what we believe will become a seminal paper that stimulates future research as well as an informative teaching aid, Wang et. al. comprehensively review methodological advances that have been used to incorporate human behavior into epidemiological models on the effects of coupling disease transmission and behavior on complex social networks [1]. As illustrated by the recent outbreaks of measles and Middle Eastern Respiratory Syndrome (MERS), here we highlight the importance of coupling behavior and disease transmission that Wang et al. address.

  11. Caprylic Triglyceride as a Novel Therapeutic Approach to Effectively Improve the Performance and Attenuate the Symptoms Due to the Motor Neuron Loss in ALS Disease

    PubMed Central

    Zhao, Wei; Varghese, Merina; Vempati, Prashant; Dzhun, Anastasiya; Cheng, Alice; Wang, Jun; Lange, Dale; Bilski, Amanda; Faravelli, Irene; Pasinetti, Giulio Maria

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and finally death. ALS patients suffer from asthenia and their progressive weakness negatively impacts quality of life, limiting their daily activities. They have impaired energy balance linked to lower activity of mitochondrial electron transport chain enzymes in ALS spinal cord, suggesting that improving mitochondrial function may present a therapeutic approach for ALS. When fed a ketogenic diet, the G93A ALS mouse shows a significant increase in serum ketones as well as a significantly slower progression of weakness and lower mortality rate. In this study, we treated SOD1-G93A mice with caprylic triglyceride, a medium chain triglyceride that is metabolized into ketone bodies and can serve as an alternate energy substrate for neuronal metabolism. Treatment with caprylic triglyceride attenuated progression of weakness and protected spinal cord motor neuron loss in SOD1-G93A transgenic animals, significantly improving their performance even though there was no significant benefit regarding the survival of the ALS transgenic animals. We found that caprylic triglyceride significantly promoted the mitochondrial oxygen consumption rate in vivo. Our results demonstrated that caprylic triglyceride alleviates ALS-type motor impairment through restoration of energy metabolism in SOD1-G93A ALS mice, especially during the overt stage of the disease. These data indicate the feasibility of using caprylic acid as an easily administered treatment with a high impact on the quality of life of ALS patients. PMID:23145119

  12. Comparison of gait in progressive supranuclear palsy, Parkinson’s disease and healthy older adults

    PubMed Central

    2012-01-01

    Background Progressive supranuclear palsy and Parkinson’s disease have characteristic clinical and neuropathologic profiles, but also share overlapping clinical features. This study aimed to analyze the gait of people with progressive supranuclear palsy (n=19) and compare it with people with Parkinson’s disease (n=20) and healthy older adults (n=20). Methods Gait was recorded at self-selected preferred, fast, very fast, slow and very slow speeds. Stride length was normalized to leg length. Linear regression analyses were carried out between cadence and stride length. Other gait variables were compared for each participant’s ‘walk’ which had stride length closest to 1.4. Results All groups showed a strong linear relationship between stride length and cadence with no difference between groups (p>0.05). The intercept between cadence and stride length was lowest in the progressive supranuclear palsy group and highest for older adults (p<0.001). The progressive supranuclear palsy group had higher cadence than older adults (p>0.05), and greater step width and greater double support phase compared with the other two groups (p<0.05). Conclusions The temporal-spatial gait characteristics of progressive supranuclear palsy and Parkinson’s disease are largely similar, with similar disruption to scaling of stride length. The additional findings of increased step width and double support percentage suggest increased severity of gait abnormality compared to Parkinson’s disease, despite similar disease duration. The findings are consistent with the clinical features of greater instability and more rapid disease progression in progressive supranuclear palsy compared to Parkinson’s disease and implicates the early pathological involvement of brain regions involved in gait control. PMID:23031506

  13. ALS as a distal axonopathy: molecular mechanisms affecting neuromuscular junction stability in the presymptomatic stages of the disease

    PubMed Central

    Moloney, Elizabeth B.; de Winter, Fred; Verhaagen, Joost

    2014-01-01

    Amyotrophic Lateral Sclerosis (ALS) is being redefined as a distal axonopathy, in that many molecular changes influencing motor neuron degeneration occur at the neuromuscular junction (NMJ) at very early stages of the disease prior to symptom onset. A huge variety of genetic and environmental causes have been associated with ALS, and interestingly, although the cause of the disease can differ, both sporadic and familial forms of ALS show a remarkable similarity in terms of disease progression and clinical manifestation. The NMJ is a highly specialized synapse, allowing for controlled signaling between muscle and nerve necessary for skeletal muscle function. In this review we will evaluate the clinical, animal experimental and cellular/molecular evidence that supports the idea of ALS as a distal axonopathy. We will discuss the early molecular mechanisms that occur at the NMJ, which alter the functional abilities of the NMJ. Specifically, we focus on the role of axon guidance molecules on the stability of the cytoskeleton and how these molecules may directly influence the cells of the NMJ in a way that may initiate or facilitate the dismantling of the neuromuscular synapse in the presymptomatic stages of ALS. PMID:25177267

  14. Prognostic models based on patient snapshots and time windows: Predicting disease progression to assisted ventilation in Amyotrophic Lateral Sclerosis.

    PubMed

    Carreiro, André V; Amaral, Pedro M T; Pinto, Susana; Tomás, Pedro; de Carvalho, Mamede; Madeira, Sara C

    2015-12-01

    Amyotrophic Lateral Sclerosis (ALS) is a devastating disease and the most common neurodegenerative disorder of young adults. ALS patients present a rapidly progressive motor weakness. This usually leads to death in a few years by respiratory failure. The correct prediction of respiratory insufficiency is thus key for patient management. In this context, we propose an innovative approach for prognostic prediction based on patient snapshots and time windows. We first cluster temporally-related tests to obtain snapshots of the patient's condition at a given time (patient snapshots). Then we use the snapshots to predict the probability of an ALS patient to require assisted ventilation after k days from the time of clinical evaluation (time window). This probability is based on the patient's current condition, evaluated using clinical features, including functional impairment assessments and a complete set of respiratory tests. The prognostic models include three temporal windows allowing to perform short, medium and long term prognosis regarding progression to assisted ventilation. Experimental results show an area under the receiver operating characteristics curve (AUC) in the test set of approximately 79% for time windows of 90, 180 and 365days. Creating patient snapshots using hierarchical clustering with constraints outperforms the state of the art, and the proposed prognostic model becomes the first non population-based approach for prognostic prediction in ALS. The results are promising and should enhance the current clinical practice, largely supported by non-standardized tests and clinicians' experience. PMID:26455265

  15. A Comparison of the Cingulum Tract in ALS-B Patients and Controls Using Kernel Matching

    E-print Network

    van Vliet, Lucas J.

    .w.a.caan@amc.uva.nl Abstract. Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with poor prognosis Introduction Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease fea- turing upper

  16. Serum Metabolomics of Slow vs. Rapid Motor Progression Parkinson’s Disease: a Pilot Study

    PubMed Central

    Roede, James R.; Uppal, Karan; Park, Youngja; Lee, Kichun; Tran, Vilinh; Walker, Douglas; Strobel, Frederick H.; Rhodes, Shannon L.; Ritz, Beate; Jones, Dean P.

    2013-01-01

    Progression of Parkinson’s disease (PD) is highly variable, indicating that differences between slow and rapid progression forms could provide valuable information for improved early detection and management. Unfortunately, this represents a complex problem due to the heterogeneous nature of humans in regards to demographic characteristics, genetics, diet, environmental exposures and health behaviors. In this pilot study, we employed high resolution mass spectrometry-based metabolic profiling to investigate the metabolic signatures of slow versus rapidly progressing PD present in human serum. Archival serum samples from PD patients obtained within 3 years of disease onset were analyzed via dual chromatography-high resolution mass spectrometry, with data extraction by xMSanalyzer and used to predict rapid or slow motor progression of these patients during follow-up. Statistical analyses, such as false discovery rate analysis and partial least squares discriminant analysis, yielded a list of statistically significant metabolic features and further investigation revealed potential biomarkers. In particular, N8-acetyl spermidine was found to be significantly elevated in the rapid progressors compared to both control subjects and slow progressors. Our exploratory data indicate that a fast motor progression disease phenotype can be distinguished early in disease using high resolution mass spectrometry-based metabolic profiling and that altered polyamine metabolism may be a predictive marker of rapidly progressing PD. PMID:24167579

  17. Optical Assessment of Vascular Disease Progression and Treatment

    NASA Astrophysics Data System (ADS)

    Samuels, Joshua A.

    Vascular disease manifests itself in many different forms, including chronic ulcers which do not heal, impaired blood flow to the limbs, or damage to the natural reperfusion process. The current forms of assessing vascular disease are often subjective and provide incomplete knowledge about the tissue of interest. This work focused on developing non-invasive techniques to quantitatively evaluate three specific elements of vascular disease: diabetic ulcers, venous ulcers, and peripheral arterial disease. Diffuse Near Infrared Spectroscopy (DNIRS) was used to predict healing (82% positive predictive value) in diabetic ulcers after 4 weeks of assessment (sensitivity of 0.9 and specificity of 0.86; p<0.002), proving to be an alternative and superior method to wound size reduction alone (the current gold standard). A novel therapeutic ultrasound treatment for venous ulcers, using a low-frequency (20kHz), low intensity (<100mW/cm2 ISPTP), fully-wearable applicator, was assessed using DNIRS and Diffuse Correlation Spectroscopy (DCS), wherein it was established that capillary flow changes over time in healing venous ulcers compared to wounds which do not heal (p<0.01). It was also determined that the ultrasound therapy was successful at improving wound outcomes, specifically the rate of wound closure per week (p<0.05 for wound size, p<0.01 for optical data). Finally, DNIRS and DCS were used in conjunction to assess the reactive hyperemic response in patients with suspected Peripheral Arterial Disease (PAD). It was found that the time between the release of cuff occlusion in the diseased limb and the first peak of reperfusion (flow mediated dilatation) correlated to PAD severity, with longer times (>30 seconds) belonging to patients with PAD (p<0.05). Additionally, it was discovered that the magnitude of the reperfusion did not relate to PAD, but rather to tobacco use. Patients who smoked had reduced hyperemic responses (p<0.02), whether or not they had PAD. Overall, this work represents an improvement over gold standard qualitative assessments of vascular health and the results obtained promise to develop new clinically relevant and quantitative techniques using non-invasive optical modalities.

  18. Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls

    PubMed Central

    Yeoh, Jiann Wei; Campbell, Erin J.; James, Morgan H.; Graham, Brett A.; Dayas, Christopher V.

    2014-01-01

    The tight regulation of sleep/wake states is critical for mental and physiological wellbeing. For example, dysregulation of sleep/wake systems predisposes individuals to metabolic disorders such as obesity and psychiatric problems, including depression. Contributing to this understanding, the last decade has seen significant advances in our appreciation of the complex interactions between brain systems that control the transition between sleep and wake states. Pivotal to our increased understanding of this pathway was the description of a group of neurons in the lateral hypothalamus (LH) that express the neuropeptides orexin A and B (hypocretin, Hcrt-1 and Hcrt-2). Orexin neurons were quickly placed at center stage with the demonstration that loss of normal orexin function is associated with the development of narcolepsy—a condition in which sufferers fail to maintain normal levels of daytime wakefulness. Since these initial seminal findings, much progress has been made in our understanding of the physiology and function of the orexin system. For example, the orexin system has been identified as a key modulator of autonomic and neuroendocrine function, arousal, reward and attention. Notably, studies in animals suggest that dysregulation of orexin function is associated with neuropsychiatric states such as addiction and mood disorders including depression and anxiety. This review discusses the progress associated with therapeutic attempts to restore orexin system function and treat neuropsychiatric conditions such as addiction, depression and anxiety. We also highlight potential pitfalls and challenges associated with targeting this system to treat these neuropsychiatric states. PMID:24616658

  19. Respiratory Syncytial Virus in Hematopoietic Cell Transplant Recipients: Factors Determining Progression to Lower Respiratory Tract Disease

    PubMed Central

    Kim, Yae-Jean; Guthrie, Katherine A.; Waghmare, Alpana; Walsh, Edward E.; Falsey, Ann R.; Kuypers, Jane; Cent, Anne; Englund, Janet A.; Boeckh, Michael

    2014-01-01

    Background.?Respiratory syncytial virus (RSV) lower respiratory tract disease (LRD) is a life-threatening complication in hematopoietic cell transplant (HCT) recipients. Lymphopenia has been associated with an increased risk of progression from upper respiratory tract infection (URI) to LRD. Methods.?This study retrospectively analyzed the significance of lymphocyte engraftment dynamics, lung function, smoking history, corticosteroids, antiviral treatment, viral subtypes, and RSV-specific neutralizing antibodies for the progression to LRD in 181 HCT recipients with RSV URI. Results.?In multivariable models, smoking history, conditioning with high-dose total body irradiation, and an absolute lymphocyte count (ALC) ?100/mm3 at the time of URI onset were significantly associated with disease progression. No progression occurred in patients with ALCs of >1000/mm3 at URI onset. Lymphocyte engraftment dynamics were similar in progressors and nonprogressors. Pre- and posttransplant donor and posttransplant recipient RSV subtype-specific neutralizing antibody levels, RSV viral subtypes, and corticosteroids also were not significantly associated with LRD progression. Conclusions.?Host and transplant related factors appear to determine the risk of progression to LRD more than viral factors. Dysfunctional cell-mediated immunity appears to be important in the pathogenesis of progressive RSV disease after HCT. A characterization of RSV-specific T-cell immunity is warranted. PMID:24368837

  20. Mutations in TJP2 cause progressive cholestatic liver disease

    PubMed Central

    Sambrotta, Melissa; Strautnieks, Sandra; Papouli, Efterpi; Rushton, Peter; Clark, Barnaby E.; Parry, David A.; Logan, Clare V.; Newbury, Lucy J.; Kamath, Binita M.; Ling, Simon; Grammatikopoulos, Tassos; Wagner, Bart E.; Magee, John C.; Sokol, Ronald J.; Mieli-Vergani, Giorgina; Smith, Joshua D.; Johnson, Colin A.; McClean, Patricia; Simpson, Michael A.; Knisely, A.S.; Bull, Laura N.; Thompson, Richard J.

    2014-01-01

    The elucidation of genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Protein-truncating mutations in the tight junction protein 2 gene (TJP2) are shown to cause failure of protein localisation, with disruption of tight-junction structure leading to severe cholestatic liver disease. This contrasts with the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species. PMID:24614073

  1. Progress in the Diagnosis and Control of Ebola Disease.

    PubMed

    Wo?niak-Kosek, Agnieszka; Kosek, Jaros?aw; Mierzejewski, Jerzy; Rapiejko, Piotr

    2015-01-01

    Ebola hemorrhagic fever is one of numerous viral hemorrhagic fevers. It is a severe, often fatal disease in humans and nonhuman primates (gorillas and chimpanzees). This article discusses the history of Ebola disease, already known routes of infection together with defining prevention methods and treatment trials. The importance of increasing awareness of the risk of disease among people who do not inhabit endemic regions is emphasized. This risk is associated especially with the increasing popularity of tourism to African countries, even to those where the virus is endemic. The research conducted over the years shows that three species of frugivorous bats are subjected to contamination by Ebola, but the infection is asymptomatic in them. It is believed that the saliva of these mammals and other body fluids may be a potential source of infection for primates and humans. In the laboratory, infection through small-particle aerosols has been demonstrated in primates, and airborne spread among humans is strongly suspected, although it has not yet been conclusively demonstrated. The importance of this route of transmission remains unclear. Poor hygienic conditions can aid the spread of the virus. These observations suggest approaches to the study of routes of transmission to and among humans. PMID:25724796

  2. DiME: a scalable disease module identification algorithm with application to glioma progression.

    PubMed

    Liu, Yunpeng; Tennant, Daniel A; Zhu, Zexuan; Heath, John K; Yao, Xin; He, Shan

    2014-01-01

    Disease module is a group of molecular components that interact intensively in the disease specific biological network. Since the connectivity and activity of disease modules may shed light on the molecular mechanisms of pathogenesis and disease progression, their identification becomes one of the most important challenges in network medicine, an emerging paradigm to study complex human disease. This paper proposes a novel algorithm, DiME (Disease Module Extraction), to identify putative disease modules from biological networks. We have developed novel heuristics to optimise Community Extraction, a module criterion originally proposed for social network analysis, to extract topological core modules from biological networks as putative disease modules. In addition, we have incorporated a statistical significance measure, B-score, to evaluate the quality of extracted modules. As an application to complex diseases, we have employed DiME to investigate the molecular mechanisms that underpin the progression of glioma, the most common type of brain tumour. We have built low (grade II)--and high (GBM)--grade glioma co-expression networks from three independent datasets and then applied DiME to extract potential disease modules from both networks for comparison. Examination of the interconnectivity of the identified modules have revealed changes in topology and module activity (expression) between low- and high- grade tumours, which are characteristic of the major shifts in the constitution and physiology of tumour cells during glioma progression. Our results suggest that transcription factors E2F4, AR and ETS1 are potential key regulators in tumour progression. Our DiME compiled software, R/C++ source code, sample data and a tutorial are available at http://www.cs.bham.ac.uk/~szh/DiME. PMID:24523864

  3. Modelling the natural history of Huntington’s disease progression

    E-print Network

    Kuan, W. L.; Kasis, A.; Yuan, Y.; Mason, S. L.; Lazar, A. S.; Barker, R. A.; Gonçalves, J.

    2014-12-16

    41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Confidential: For Review Only REFERENCE 1. O'Keeffe GC, Michell AW, Barker RA. Biomarkers in Huntington's and Parkinson's Disease. Ann N Y Acad Sci 2009; 1180: 97-110. 2. Sah DW... the information required for our analysis. The feature vector contained the following information: Patient's ID. Patient's age at the time the sample was taken. The length of their CAG repeats. The percentage of symptoms in the UHDRS motor scores...

  4. Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease)

    PubMed Central

    Katz, Martin L; Coates, Joan R; Sibigtroth, Christine M; Taylor, Jacob D; Carpentier, Melissa; Young, Whitney M; Wininger, Fred A; Kennedy, Derek; Vuillemenot, Brian R; O'Neill, Charles A

    2014-01-01

    Using a canine model of classical late-infantile neuronal ceroid lipofuscinosis (CLN2 disease), a study was conducted to evaluate the potential pharmacological activity of recombinant human tripeptidyl peptidase-1 (rhTPP1) enzyme replacement therapy administered directly to the cerebrospinal fluid (CSF). CLN2 disease is a hereditary neurodegenerative disorder resulting from mutations in CLN2, which encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Infants with mutations in both CLN2 alleles develop normally but in the late-infantile/early-childhood period undergo progressive neurological decline accompanied by pronounced brain atrophy. The disorder, a form of Batten disease, is uniformly fatal, with clinical signs starting between 2 and 4 years of age and death usually occurring by the early teenage years. Dachshunds homozygous for a null mutation in the canine ortholog of CLN2 (TPP1) exhibit a similar disorder that progresses to end stage at 10.5–11 months of age. Administration of rhTPP1 via infusion into the CSF every other week, starting at approximately 2.5 months of age, resulted in dose-dependent significant delays in disease progression, as measured by delayed onset of neurologic deficits, improved performance on a cognitive function test, reduced brain atrophy, and increased life span. Based on these findings, a clinical study evaluating the potential therapeutic value of rhTPP1 administration into the CSF of children with CLN2 disease has been initiated. PMID:24938720

  5. Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease).

    PubMed

    Katz, Martin L; Coates, Joan R; Sibigtroth, Christine M; Taylor, Jacob D; Carpentier, Melissa; Young, Whitney M; Wininger, Fred A; Kennedy, Derek; Vuillemenot, Brian R; O'Neill, Charles A

    2014-11-01

    Using a canine model of classical late-infantile neuronal ceroid lipofuscinosis (CLN2 disease), a study was conducted to evaluate the potential pharmacological activity of recombinant human tripeptidyl peptidase-1 (rhTPP1) enzyme replacement therapy administered directly to the cerebrospinal fluid (CSF). CLN2 disease is a hereditary neurodegenerative disorder resulting from mutations in CLN2, which encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Infants with mutations in both CLN2 alleles develop normally but in the late-infantile/early-childhood period undergo progressive neurological decline accompanied by pronounced brain atrophy. The disorder, a form of Batten disease, is uniformly fatal, with clinical signs starting between 2 and 4 years of age and death usually occurring by the early teenage years. Dachshunds homozygous for a null mutation in the canine ortholog of CLN2 (TPP1) exhibit a similar disorder that progresses to end stage at 10.5-11 months of age. Administration of rhTPP1 via infusion into the CSF every other week, starting at approximately 2.5 months of age, resulted in dose-dependent significant delays in disease progression, as measured by delayed onset of neurologic deficits, improved performance on a cognitive function test, reduced brain atrophy, and increased life span. Based on these findings, a clinical study evaluating the potential therapeutic value of rhTPP1 administration into the CSF of children with CLN2 disease has been initiated. PMID:24938720

  6. Wall Shear Stress Characteristics for the Progression of the Disease, Atherosclerosis

    NASA Astrophysics Data System (ADS)

    Goswami, P.; Mandal, D. K.; Manna, N. K.; Chakrabarti, S.

    2014-12-01

    Wall shear stress (WSS) characteristics of a stenosed artery which are the important physiological parameters for the progression of the arterial diseases atherosclerosis, are studied and compared for different Reynolds numbers and different Womersley numbers. Numerical simulations of physiological pulsatile flow through a model stenotic artery are performed by finite volume method. From this study, it is revealed that the chance of formation of atherosclerosis increases with increase in Reynolds number and decreases with increase in Womersley number. The phenomenon of mass transportation across arterial wall is more in case of increase in Womersley number rather than Reynolds number. The chance of formation of atheromatous plaque will be high with higher Reynolds number and Womersley number. In the low WSS region, high magnitude of Womersley number indicates high chance of progression of the disease atherosclerosis. High magnitude of Womersley number with low Reynolds number is more dangerous for the progression of the disease in the low WSS region.

  7. 4-hydroxynonenal in the pathogenesis and progression of human diseases

    PubMed Central

    Shoeb, Mohammad; Ansari, Naseem H; Srivastava, Satish K; Ramana, Kota V

    2014-01-01

    Metastable aldehydes produced by lipid peroxidation act as 'toxic second messengers' that extend the injurious potential of free radicals. 4-hydroxy 2-nonenal (HNE), a highly toxic and most abundant stable end product of lipid peroxidation, has been implicated in the tissue damage, dysfunction, injury associated with aging and other pathological states such as cancer, Alzheimer, diabetes, cardiovascular and inflammatory complications. Further, HNE has been considered as a oxidative stress marker and it act as a secondary signaling molecule to regulates a number of cell signaling pathways. Biological activity of HNE depends on its intracellular concentration, which can differentially modulate cell death, growth and differentiation. Therefore, the mechanisms responsible for maintaining the intracellular levels of HNE are most important, not only in the defense against oxidative stress but also in the pathophysiology of a number of disease processes. In this review, we discusse the significance of HNE in mediating various disease processes and how regulation of its metabolism could be therapeutically effective. PMID:23848536

  8. Pharmaceuticals targeting nonsense mutations in genetic diseases: progress in development.

    PubMed

    Rowe, Steven M; Clancy, John P

    2009-01-01

    Premature termination codons (PTCs) are a cause of numerous genetic disorders spanning diseases that affect children and adults, and are produced by base pair substitutions that create abnormal stop codons within the open reading frame. Several ribosome-binding drugs, including select aminoglycosides and synthetic novel small molecules, induce 'translational readthrough' of PTCs, restoring full-length functional protein in a number of preclinical and clinical settings. In this review, we examine the mechanistic underpinnings of PTC suppression, including the nature of the interactions between agents that suppress PTCs and the eukaryotic ribosome regulation of transcript levels in eukaryotic cells, and the importance of the mRNA context in suppression of PTCs. We also examine results from proof-of-concept studies in preclinical model systems and clinical trials (with a focus on PTC124). Several of the published studies in cystic fibrosis have reported improvements in cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers during short-term evaluation, including topical and systemic aminoglycoside treatment, and oral dosing with PTC124. These results, coupled with our improved understanding of how translation termination is regulated at PTCs, will help guide future directions of research involving this innovative treatment strategy for genetic diseases. PMID:19627168

  9. Role of salivary leukocyte protease inhibitor in periodontal disease progression

    PubMed Central

    Pateel, Deepak; Seema, H.; Kale, Akla

    2010-01-01

    Context: Proteases play a major role in the tissue destruction involved in periodontal disease. It is known that the balance between proteases and their inhibitors is a major determinant in maintaining tissue integrity. The association between the proteases and periodontitis is well established, but not many studies have been carried out to know the role played by a protease inhibitor like salivary leukocyte protease inhibitor (SLPI) in periodontitis. Aim: The aim of the present study was to correlate SLPI with periodontitis. Settings and Design: Case-control study. Materials and Methods: Seventy-five clinically confirmed cases of periodontitis and 20 controls were included in the study. A detailed case history and periodontal index (PI) were recorded. Two milliliters of unstimulated saliva samples was obtained and subjected to quantification of SLPI leaves using SLPI in enzyme-linked immunosorbent assay (ELISA) kit. Based on the periodontal index score of the individuals, the cases and controls were divided into groups A, B and C, and the obtained SLPI levels were compared among the groups. Statistical Analysis: Mann-Whitney U test and correlation coefficient test. Results: The results showed that in the initial stages of periodontitis there is a tendency of SLPI levels to be raised. The SLPI levels were found to be reduced in the terminal stages of periodontitis. Conclusion: It appears that SLPI accumulates in the local environment, at least in the initial stages of the periodontal disease, probably to inhibit the action of increased elastic activity. PMID:21691548

  10. Ketogenic diet prevents epileptogenesis and disease progression in adult mice and rats.

    PubMed

    Lusardi, Theresa A; Akula, Kiran K; Coffman, Shayla Q; Ruskin, David N; Masino, Susan A; Boison, Detlev

    2015-12-01

    Epilepsy is a highly prevalent seizure disorder which tends to progress in severity and become refractory to treatment. Yet no therapy is proven to halt disease progression or to prevent the development of epilepsy. Because a high fat low carbohydrate ketogenic diet (KD) augments adenosine signaling in the brain and because adenosine not only suppresses seizures but also affects epileptogenesis, we hypothesized that a ketogenic diet might prevent epileptogenesis through similar mechanisms. Here, we tested this hypothesis in two independent rodent models of epileptogenesis. Using a pentylenetetrazole kindling paradigm in mice, we first show that a KD, but not a conventional antiepileptic drug (valproic acid), suppressed kindling-epileptogenesis. Importantly, after treatment reversal, increased seizure thresholds were maintained in those animals kindled in the presence of a KD, but not in those kindled in the presence of valproic acid. Next, we tested whether a KD can halt disease progression in a clinically relevant model of progressive epilepsy. Epileptic rats that developed spontaneous recurrent seizures after a pilocarpine-induced status epilepticus were treated with a KD or control diet (CD). Whereas seizures progressed in severity and frequency in the CD-fed animals, KD-fed animals showed a prolonged reduction of seizures, which persisted after diet reversal. KD-treatment was associated with increased adenosine and decreased DNA methylation, the latter being maintained after diet discontinuation. Our findings demonstrate that a KD prevented disease progression in two mechanistically different models of epilepsy, and suggest an epigenetic mechanism underlying the therapeutic effects. PMID:26256422

  11. Electrostimulation to reduce synaptic scaling driven progression of Alzheimer's disease

    PubMed Central

    Rowan, Mark S.; Neymotin, Samuel A.; Lytton, William W.

    2014-01-01

    Cell death and synapse dysfunction are two likely causes of cognitive decline in AD. As cells die and synapses lose their drive, remaining cells suffer an initial decrease in activity. Neuronal homeostatic synaptic scaling then provides a feedback mechanism to restore activity. This homeostatic mechanism is believed to sense levels of activity-dependent cytosolic calcium within the cell and to adjust neuronal firing activity by increasing the density of AMPA synapses at remaining synapses to achieve balance. The scaling mechanism increases the firing rates of remaining cells in the network to compensate for decreases in network activity. However, this effect can itself become a pathology, as it produces increased imbalance between excitatory and inhibitory circuits, leading to greater susceptibility to further cell loss via calcium-mediated excitotoxicity. Here, we present a mechanistic explanation of how directed brain stimulation might be expected to slow AD progression based on computational simulations in a 470-neuron biomimetic model of a neocortical column. The simulations demonstrate that the addition of low-intensity electrostimulation (neuroprosthesis) to a network undergoing AD-like cell death can raise global activity and break this homeostatic-excitotoxic cascade. The increase in activity within the remaining cells in the column results in lower scaling-driven AMPAR upregulation, reduced imbalances in excitatory and inhibitory circuits, and lower susceptibility to ongoing damage. PMID:24765074

  12. GNE myopathy: a prospective natural history study of disease progression.

    PubMed

    Mori-Yoshimura, Madoka; Oya, Yasushi; Yajima, Hiroyuki; Yonemoto, Naohiro; Kobayashi, Yoko; Hayashi, Yukiko K; Noguchi, Satoru; Nishino, Ichizo; Murata, Miho

    2014-05-01

    Mutations in the glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase gene cause GNE myopathy, a mildly progressive autosomal recessive myopathy. We performed a prospective natural history study in 24 patients with GNE myopathy to select evaluation tools for use in upcoming clinical trials. Patient clinical conditions were evaluated at study entry and one-year follow-up. Of the 24 patients, eight (33.3%) completed a standard 6-min walk test without assistance. No cardiac events were observed. Summed manual muscle testing of 17 muscles, grip power, and percent force vital capacity (%FVC) were significantly reduced (p<0.05), and scores for 6-min walk test and gross motor function measure were decreased (p<0.1) after one year. The decrement in %FVC was significant among non-ambulant patients, whereas the decrement in grip power tended to be greater among ambulant patients. The 6-min walk test, gross motor function measure, manual muscle testing, grip power, and %FVC reflect annual changes and are thus considered good evaluation tools for clinical trials. PMID:24656604

  13. Multivariate clustering of progression profiles reveals different depression patterns in prodromal Huntington disease

    PubMed Central

    Kim, Ji-in; Long, Jeffrey D.; Mills, James A.; McCusker, Elizabeth; Paulsen, Jane S.

    2015-01-01

    Objective Although Huntington disease (HD) is caused by an autosomal dominant mutation, its phenotypic presentation differs widely. Variability in clinical phenotypes of HD may reflect the existence of disease subtypes. This hypothesis was tested in prodromal participants from the longitudinal Neurobiological Predictors of Huntington's Disease (PREDICT-HD) study. Method We performed clustering using longitudinal data assessing motor, cognitive, and depression symptoms. Using data from 521 participants with 2716 data points, we fit growth mixture models (GMM) that identify groups based on multivariate trajectories. Results In various GMM, different phases of disease progression were partitioned by progression trajectories of motor and cognitive signs, and by overall level of depression symptoms. More progressed motor signs were accompanied by more progressed cognitive signs, but not always by higher levels of depressive symptoms. In several models, there were at least two groups with similar trajectories for motor and cognitive signs that showed different levels for depression symptoms - one with a very low level of depression and the other with a higher level of depression. Conclusions Findings indicate that at least intermediate HD progression might be associated with different levels of depression. Depression is one of the few symptoms that is treatable in HD and has implications for clinical care. Identification of potential depression subtypes may also help to select appropriate patients for clinical trials. PMID:26011117

  14. Pathomechanisms: homeostatic chemokines in health, tissue regeneration, and progressive diseases.

    PubMed

    Anders, Hans-Joachim; Romagnani, Paola; Mantovani, Alberto

    2014-03-01

    Homeostatic chemokines control stem and progenitor cell migration and activation during vasculogenesis and organ development. They orchestrate hematopoietic stem cell (HSC) homing to their bone marrow niches and direct immature lymphocytes to a series of maturation sites within lymphoid organs. Along these lines, homeostatic chemokines regulate the niches of peripheral committed progenitor cell populations for tissue renewal. These biological functions support neovascularization and wound healing, including the recruitment of endothelial and other progenitor cells from the bone marrow. Here, we summarize the roles of homeostatic chemokines, their signaling receptors, and atypical decoy receptors during homeostasis and tissue regeneration in order to better understand their pathogenic roles in disease, for example, in diabetes complications, cancer, autoimmunity, epithelial hyperplasia, or hypertrophic scarring and fibrosis. PMID:24440002

  15. Hippocampal plasticity during the progression of Alzheimer's disease.

    PubMed

    Mufson, E J; Mahady, L; Waters, D; Counts, S E; Perez, S E; DeKosky, S T; Ginsberg, S D; Ikonomovic, M D; Scheff, S W; Binder, L I

    2015-11-19

    Neuroplasticity involves molecular and structural changes in central nervous system (CNS) throughout life. The concept of neural organization allows for remodeling as a compensatory mechanism to the early pathobiology of Alzheimer's disease (AD) in an attempt to maintain brain function and cognition during the onset of dementia. The hippocampus, a crucial component of the medial temporal lobe memory circuit, is affected early in AD and displays synaptic and intraneuronal molecular remodeling against a pathological background of extracellular amyloid-beta (A?) deposition and intracellular neurofibrillary tangle (NFT) formation in the early stages of AD. Here we discuss human clinical pathological findings supporting the concept that the hippocampus is capable of neural plasticity during mild cognitive impairment (MCI), a prodromal stage of AD and early stage AD. PMID:25772787

  16. Hepatic inflammation and progressive liver fibrosis in chronic liver disease

    PubMed Central

    Czaja, Albert J

    2014-01-01

    Chronic liver inflammation drives hepatic fibrosis, and current immunosuppressive, anti-inflammatory, and anti-viral therapies can weaken this driver. Hepatic fibrosis is reversed, stabilized, or prevented in 57%-79% of patients by conventional treatment regimens, mainly by their anti-inflammatory actions. Responses, however, are commonly incomplete and inconsistently achieved. The fibrotic mechanisms associated with liver inflammation have been clarified, and anti-fibrotic agents promise to improve outcomes as adjunctive therapies. Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes. Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species. Anti-oxidants (N-acetylcysteine, S-adenosyl-L-methionine, and vitamin E) and angiotensin inhibitors (losartin) have had anti-fibrotic actions in preliminary human studies, and they may emerge as supplemental therapies. Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease. PMID:24627588

  17. TWEAK and the progression of renal disease: clinical translation

    PubMed Central

    Sanz, Ana B.; Izquierdo, M. Concepcion; Sanchez-Niño, Maria Dolores; Ucero, Alvaro C.; Egido, Jesus; Ruiz-Ortega, Marta; Ramos, Adrián Mario; Putterman, Chaim; Ortiz, Alberto

    2014-01-01

    Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) activates the fibroblast growth factor-inducible-14 (Fn14) receptor. TWEAK has actions on intrinsic kidney cells and on inflammatory cells of potential pathophysiological relevance. The effects of TWEAK in tubular cells have been explored in most detail. In cultured murine tubular cells TWEAK induces the expression of inflammatory cytokines, downregulates the expression of Klotho, is mitogenic, and in the presence of sensitizing agents promotes apoptosis. Similar actions were observed on glomerular mesangial cells. In vivo TWEAK actions on healthy kidneys mimic cell culture observations. Increased expression of TWEAK and Fn14 was reported in human and experimental acute and chronic kidney injury. The role of TWEAK/Fn14 in kidney injury has been demonstrated in non-inflammatory compensatory renal growth, acute kidney injury and chronic kidney disease of immune and non-immune origin, including hyperlipidaemic nephropathy, lupus nephritis (LN) and anti-GBM nephritis. The nephroprotective effect of TWEAK or Fn14 targeting in immune-mediated kidney injury is the result of protection from TWEAK-induced injury of renal intrinsic cells, not from interference with the immune response. A phase I dose-ranging clinical trial demonstrated the safety of anti-TWEAK antibodies in humans. A phase II randomized placebo-controlled clinical trial exploring the efficacy, safety and tolerability of neutralizing anti-TWEAK antibodies as a tissue protection strategy in LN is ongoing. The eventual success of this trial may expand the range of kidney diseases in which TWEAK targeting should be explored. PMID:24493870

  18. Progress on conformal microwave array applicators for heating chestwall disease

    NASA Astrophysics Data System (ADS)

    Stauffer, P. R.; Maccarini, P. F.; Juang, T.; Jacobsen, S. K.; Gaeta, C. J.; Schlorff, J. L.; Milligan, A. J.

    2007-02-01

    Previous studies have reported the computer modeling, CAD design, and theoretical performance of single and multiple antenna arrays of Dual Concentric Conductor (DCC) square slot radiators driven at 915 and 433 MHz. Subsequently, practical CAD designs of microstrip antenna arrays constructed on thin and flexible printed circuit board (PCB) material were reported which evolved into large Conformal Microwave Array (CMA) sheets that could wrap around the surface of the human torso for delivering microwave energy to large areas of superficial tissue. Although uniform and adjustable radiation patterns have been demonstrated from multiple element applicators radiating into simple homogeneous phantom loads, the contoured and heterogeneous tissue loads typical of chestwall recurrent breast cancer have required additional design efforts to achieve good coupling and efficient heating from the increasingly larger conformal array applicators used to treat large area contoured patient anatomy. Thus recent work has extended the theoretical optimization of DCC antennas to improve radiation efficiency of each individual aperture and reduce mismatch reflections, radiation losses, noise, and cross coupling of the feedline distribution network of large array configurations. Design improvements have also been incorporated into the supporting bolus structure to maintain effective coupling of DCC antennas into contoured anatomy and to monitor and control surface temperatures under the entire array. New approaches for non-invasive monitoring of surface and sub-surface tissue temperatures under each independent heat source are described that make use of microwave radiometry and flexible sheet grid arrays of thermal sensors. Efforts to optimize the clinical patient interface and move from planar rectangular shapes to contoured vest applicators that accommodate entire disease in a larger number of patients are summarized. By applying heat more uniformly to large areas of contoured anatomy, the CMA applicator resulting from these enhancements should expand the number of patients that can benefit from effective heating of superficial disease in combination with radiation or chemotherapy.

  19. Computational fluid dynamics tools can be used to predict the progression of coronary artery disease

    NASA Astrophysics Data System (ADS)

    Co?kun, A. Ümit; Chen, Caixia; Stone, Peter H.; Feldman, Charles L.

    2006-03-01

    Atherosclerosis is focal and individual plaques evolve in an independent manner. The endothelium regulates arterial behavior by responding to its local shear stress. In vitro studies indicate that low endothelial shear stress (ESS) upregulates the genetic and molecular responses leading to the initiation and progression of atherosclerosis and promotes inflammation and formation of other features characteristic of vulnerable plaque. Physiologic ESS is vasculoprotective and fosters quiescence of the endothelium and vascular wall. High ESS promotes platelet aggregation. ESS and vascular wall morphology along the course of human coronary arteries can now be characterized in vivo, and may predict the focal areas in which atherosclerosis progression occurs. Rapidly evolving methodologies are able to characterize the arterial wall and the local hemodynamic factors likely responsible for progression of coronary disease in man. These new diagnostic modalities allow for identification of plaque progression. Accurate identification of arterial segments at high-risk for progression may permit pre-emptive intervention strategies to avoid adverse coronary events.

  20. [Progressive multifocal leukoencephalopathy following azathioprine and steroid treatment of pulmonary sarcoid disease].

    PubMed

    Franzen, Damian; Mathys, Christian; Vesper, Jan; Malzkorn, Bastian; Bohlen, Heribert; Seitz, Rüdiger J

    2015-08-01

    Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system following reactivation of the John-Cunningham-Virus (JVC) in an immunocompromised host. This rare condition is characterized by rapid progressing neurologic symptoms often leading to death. In the following, we report on a rapid evolving deterioration of mental status due to PML in an 53-year-old man during treatment of pulmonary sarcoid disease using azathioprine and steroids. In contrast to reported lethal outcomes, our patient experienced a slow recovery of his cognitive impairment and later on of his palsy following termination of immunosuppression. PMID:26306018

  1. Progress and problems in the biology, diagnostics, and therapeutics of prion diseases

    PubMed Central

    Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

    2004-01-01

    The term “prion” was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word “prion” has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the “mad cow” crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields. PMID:15254579

  2. Progress and problems in the biology, diagnostics, and therapeutics of prion diseases.

    PubMed

    Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

    2004-07-01

    The term "prion" was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word "prion" has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the "mad cow" crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields. PMID:15254579

  3. The utility of cerebral blood flow imaging in patients with the unique syndrome of progressive dementia with motor neuron disease

    SciTech Connect

    Ohnishi, T.; Hoshi, H.; Jinnouchi, S.; Nagamachi, S.; Watanabe, K.; Mituyama, Y. )

    1990-05-01

    Two patients presenting with progressive dementia coupled with motor neuron disease underwent brain SPECT using N-isopropyl-p iodine-123-iodoamphetamine (({sup 123}I)IMP). The characteristic clinical features of progressive dementia and motor neuron disease were noted. IMP SPECT also revealed reduced uptake in the bilateral frontal and temporal regions, with no reduction of uptake in the parietal, parietal-occipital regions. We conclude that IMP SPECT has potential for the evaluation of progressive dementia with motor neuron disease.

  4. Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease.

    PubMed

    Lake, April D; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald G; Reily, Michael D; Lehman-McKeeman, Lois D; Vaillancourt, Richard R; Cherrington, Nathan J

    2015-03-01

    Nonalcoholic fatty liver disease (NAFLD) is a globally widespread disease of increasing clinical significance. The pathological progression of the disease from simple steatosis to nonalcoholic steatohepatitis (NASH) has been well defined, however, the contribution of altered branched chain amino acid metabolomic profiles to the progression of NAFLD is not known. The three BCAAs: leucine, isoleucine and valine are known to mediate activation of several important hepatic metabolic signaling pathways ranging from insulin signaling to glucose regulation. The purpose of this study is to profile changes in hepatic BCAA metabolite levels with transcriptomic changes in the progression of human NAFLD to discover novel mechanisms of disease progression. Metabolomic and transcriptomic data sets representing the spectrum of human NAFLD (normal, steatosis, NASH fatty, and NASH not fatty livers) were utilized for this study. During the transition from steatosis to NASH, increases in the levels of leucine (127% of normal), isoleucine (139%), and valine (147%) were observed. Carnitine metabolites also exhibited significantly elevated profiles in NASH fatty and NASH not fatty samples and included propionyl, hexanoyl, lauryl, acetyl and butyryl carnitine. Amino acid and BCAA metabolism gene sets were significantly enriched among downregulated genes during NASH. These cumulative alterations in BCAA metabolite and amino acid metabolism gene profiles represent adaptive physiological responses to disease-induced hepatic stress in NASH patients. PMID:25534430

  5. Osteoarthritis in the XXIst Century: Risk Factors and Behaviours that Influence Disease Onset and Progression

    PubMed Central

    Musumeci, Giuseppe; Aiello, Flavia Concetta; Szychlinska, Marta Anna; Di Rosa, Michelino; Castrogiovanni, Paola; Mobasheri, Ali

    2015-01-01

    Osteoarthritis (OA) is a growing public health problem across the globe, affecting more than half of the over 65 population. In the past, OA was considered a wear and tear disease, leading to the loss of articular cartilage and joint disability. Nowadays, thanks to advancements in molecular biology, OA is believed to be a very complex multifactorial disease. OA is a degenerative disease characterized by “low-grade inflammation” in cartilage and synovium, resulting in the loss of joint structure and progressive deterioration of cartilage. Although the disease can be dependent on genetic and epigenetic factors, sex, ethnicity, and age (cellular senescence, apoptosis and lubricin), it is also associated with obesity and overweight, dietary factors, sedentary lifestyle and sport injuries. The aim of this review is to highlight how certain behaviors, habits and lifestyles may be involved in the onset and progression of OA and to summarize the principal risk factors involved in the development of this complicated joint disorder. PMID:25785564

  6. Failure to thrive, interstitial lung disease, and progressive digital necrosis with onset in infancy.

    PubMed

    Chia, Justin; Eroglu, Fehime Kara; Özen, Seza; Orhan, Dicle; Montealegre-Sanchez, Gina; de Jesus, Adriana A; Goldbach-Mansky, Raphaela; Cowen, Edward W

    2016-01-01

    Key teaching points • SAVI is a recently described interferonopathy resulting from constitutive action of STING and up-regulation of IFN-? signaling. • SAVI is characterized by facial erythema with telangiectasia, acral/cold-sensitive tissue ulceration and amputations, and interstitial lung disease. It has overlapping features with Aicardi-Goutières syndrome and familial chilblain lupus. • Traditional immunosuppressive medications and biologic therapies appear to be of limited benefit, but JAK inhibitors may impact disease progression. PMID:26584874

  7. Chronic temporal lobe epilepsy: a neurodevelopmental or progressively dementing disease?

    PubMed

    Helmstaedter, C; Elger, C E

    2009-10-01

    To what degree does the so-called 'initial hit' of the brain versus chronic epilepsy contribute towards the memory impairment observed in chronic temporal lobe epilepsy (TLE) patients? We examined cross-sectional comparisons of age-related regressions of verbal learning and memory in 1156 patients with chronic TLE (age range 6-68 years, mean epilepsy onset 14 +/- 11 years) versus 1000 healthy control subjects (age range 6-80 years) and tested the hypothesis that deviations of age regressions (i.e. slowed rise, accelerated decline) will reveal critical phases during which epilepsy interferes with cognitive development. Patients were recruited over a 20-year period at the Department of Epileptology, University of Bonn. Healthy subjects were drawn from an updated normative population of the Verbaler Lern- und Merkfähigkeitstest, the German pendant to the Rey Auditory Verbal learning Test. A significant divergence of age regressions indicates that patients fail to build up adequate learning and memory performance during childhood and particularly during adolescence. The learning peak (i.e. crossover into decline) is seen earlier in patients (at about the age of 16-17 years) than for controls (at about the age of 23-24 years). Decline in performance with ageing in patients and controls runs in parallel, but due to the initial distance between the groups, patients reach very poor performance levels much earlier than controls. Patients with left and right TLEs performed worse in verbal memory than controls. In addition, patients with left TLE performed worse than those with right TLE. However, laterality differences were evident only in adolescent and adult patients, and not (or less so) in children and older patients. Independent of age, hippocampal sclerosis was associated with poorer performance than other pathologies. The results indicate developmental hindrance plus a negative interaction of cognitive impairment with mental ageing, rather than a progressively dementing decline in chronic TLE patients. During childhood, and even more so during the decade following puberty, the critical phases for establishing episodic memory deficits appear. This increases the risk of premature 'dementia' later on, even in the absence of an accelerated decline. Material specific verbal memory impairment in left TLE is a characteristic of the mature brain and seems to disappear at an older age. The findings suggest that increased attention is to be paid to the time of epilepsy onset and thereafter. Early control of epilepsy is demanded to counteract developmental hindrance and damage at a younger age. PMID:19635728

  8. Conceptual evolution in Alzheimer’s disease: Implications for understanding the clinical phenotype of progressive neurodegenerative disease

    PubMed Central

    Jicha, Gregory A.; Carr, Sarah A.

    2010-01-01

    Over the past several decades our understanding of Alzheimer’s disease (AD) has seen an evolution from the dichotomous concept of normal versus AD in the dementia state to a more accurate and complete appreciation of AD as a progressive disorder with clinical, biological, and pathological features occurring along a continuum from normal to end-stage disease. Integrating our understanding of the relationships and interplay between the clinical, biological, and pathological features of AD may allow the identification of AD at even preclinical, completely asymptomatic stages of the disease. This review attempts to summarize the clinical stages of AD in terms of epidemiology, historical evolution of disease stage diagnoses, cognitive/neuropsychologic features, psychiatric/behavioral manifestations, and functional decline in the context of our developing understanding of the biological processes responsible for the pathogenesis of AD described in detail in the accompanying articles. PMID:20061643

  9. Amyotrophic Lateral Sclerosis (ALS/Lou Gehrig's Disease)

    E-print Network

    Brutlag, Doug

    of inheritance for genetic counseling purposes. #12; Clinical Trial of SB-509: SB-509 contains the gene and spinal chord pathology. Once the diagnosis of ALS has been made, molecular genetic testing of SOD1 gene

  10. Brain Substrates of Learning and Retention in Mild Cognitive Impairment Diagnosis and Progression to Alzheimer's Disease

    ERIC Educational Resources Information Center

    Chang, Yu-Ling; Bondi, Mark W.; Fennema-Notestine, Christine; McEvoy, Linda K.; Hagler, Donald J., Jr.; Jacobson, Mark W.; Dale, Anders M.

    2010-01-01

    Understanding the underlying qualitative features of memory deficits in mild cognitive impairment (MCI) can provide critical information for early detection of Alzheimer's disease (AD). This study sought to investigate the utility of both learning and retention measures in (a) the diagnosis of MCI, (b) predicting progression to AD, and (c)…

  11. Daily Sampling of an HIV-1 Patient with Slowly Progressing Disease Displays Persistence of Multiple env

    E-print Network

    Daily Sampling of an HIV-1 Patient with Slowly Progressing Disease Displays Persistence of Multiple of Medicine, Karolinska Institute, Stockholm, Sweden Abstract The molecular evolution of HIV-1 is characterized by frequent substitutions, indels and recombination events. In addition, a HIV-1 population may

  12. Non-monotonic reorganization of brain networks with Alzheimer's disease progression

    PubMed Central

    Kim, HyoungKyu; Yoo, Kwangsun; Na, Duk L.; Seo, Sang Won; Jeong, Jaeseung; Jeong, Yong

    2015-01-01

    Background: Identification of stage-specific changes in brain network of patients with Alzheimer's disease (AD) is critical for rationally designed therapeutics that delays the progression of the disease. However, pathological neural processes and their resulting changes in brain network topology with disease progression are not clearly known. Methods: The current study was designed to investigate the alterations in network topology of resting state fMRI among patients in three different clinical dementia rating (CDR) groups (i.e., CDR = 0.5, 1, 2) and amnestic mild cognitive impairment (aMCI) and age-matched healthy subject groups. We constructed density networks from these 5 groups and analyzed their network properties using graph theoretical measures. Results: The topological properties of AD brain networks differed in a non-monotonic, stage-specific manner. Interestingly, local and global efficiency and betweenness of the network were rather higher in the aMCI and AD (CDR 1) groups than those of prior stage groups. The number, location, and structure of rich-clubs changed dynamically as the disease progressed. Conclusions: The alterations in network topology of the brain are quite dynamic with AD progression, and these dynamic changes in network patterns should be considered meticulously for efficient therapeutic interventions of AD. PMID:26106325

  13. Category and Letter Fluency in Semantic Dementia, Primary Progressive Aphasia, and Alzheimer's Disease

    ERIC Educational Resources Information Center

    Marczinski, Cecile A.; Kertesz, Andrew

    2006-01-01

    This study examined the impact of various degenerative dementias on access to semantic knowledge and the status of semantic representations. Patients with semantic dementia, primary progressive aphasia, and Alzheimer's disease were compared with elderly controls on tasks of category and letter fluency, with number of words generated, mean lexical…

  14. A Case of Sarcoidosis with Interstitial Lung Disease Mimicking Clinically Amyopathic Dermatomyositis and Rapidly Progressive Interstitial Lung Disease

    PubMed Central

    Nogi, Shinichi; Sasaki, Noriko; Chinen, Naofumi; Honda, Kiri; Saito, Eiko; Wakabayashi, Takayuki; Yamada, Chiho; Suzuki, Yasuo

    2014-01-01

    Here, we report a patient with sarcoidosis who developed edematous erythema and interstitial lung disease. At the initial visit, clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD) was suspected because he had progressive dyspnea but no muscle weakness. The presence of anti-CADM-140/MDA5 autoantibodies was immediately assessed to facilitate a precise diagnosis, with negative results. Thereafter, skin and transbronchial lung biopsies revealed noncaseating granuloma with Langhans giant cells in both specimens, leading to a diagnosis of sarcoidosis. In this case, clinical features of skin and lung were unable to distinguish DM (including CADM) from sarcoidosis, but the lack of anti-CADM-140/MDA5 antibody was useful for differentiating CADM with RP-ILD mimicking sarcoidosis from bona fide sarcoidosis. PMID:25431723

  15. Rapid Disease Progression With Delay in Treatment of Non-Small-Cell Lung Cancer

    SciTech Connect

    Mohammed, Nasiruddin; Kestin, Larry Llyn; Grills, Inga Siiner; Battu, Madhu; Fitch, Dwight Lamar; Wong, Ching-yee Oliver; Margolis, Jeffrey Harold; Chmielewski, Gary William; Welsh, Robert James

    2011-02-01

    Purpose: To assess rate of disease progression from diagnosis to initiation of treatment for Stage I-IIIB non-small-cell lung cancer (NSCLC). Methods and Materials: Forty patients with NSCLC underwent at least two sets of computed tomography (CT) and 18-fluorodeoxyglucose positron emission tomography (PET) scans at various time intervals before treatment. Progression was defined as development of any new lymph node involvement, site of disease, or stage change. Results: Median time interval between first and second CT scans was 13.4 weeks, and between first and second PET scans was 9.0 weeks. Median initial primary maximum tumor dimension (MTD) was 3.5 cm (0.6-8.5 cm) with a median standardized uptake value (SUV) of 13.0 (1.7-38.5). The median MTD increased by a median of 1.0 cm (mean, 1.6 cm) between scans for a median relative MTD increase of 35% (mean, 59%). Nineteen patients (48%) progressed between scans. Rate of any progression was 13%, 31%, and 46% at 4, 8, and 16 weeks, respectively. Upstaging occurred in 3%, 13%, and 21% at these intervals. Distant metastasis became evident in 3%, 13%, and 13% after 4, 8, and 16 weeks, respectively. T and N stage were associated with progression, whereas histology, grade, sex, age, and maximum SUV were not. At 3 years, overall survival for Stage III patients with vs. without progression was 18% vs. 67%, p = 0.05. Conclusions: With NSCLC, treatment delay can lead to disease progression. Diagnosis, staging, and treatment initiation should be expedited. After 4-8 weeks of delay, complete restaging should be strongly considered.

  16. The effect of cigarette smoking, tea, and coffee consumption on the progression of Parkinson's disease.

    PubMed

    Kandinov, Boris; Giladi, Nir; Korczyn, Amos D

    2007-05-01

    Previous epidemiological studies found a negative association between cigarette smoking, tea or coffee drinking with the occurrence of Parkinson's disease (PD). However, it is unknown how these factors affect the rate of progression of the disease. A retrospective study was conducted among 278 consecutive PD patients. Data on smoking and coffee or tea consumption were obtained through direct or proxy interviews, and the time from onset of motor symptoms until reaching Hoehn & Yahr (H&Y) stage 3 was retrieved from the case records. Cox proportional hazards model and Kaplan-Meyer model were used to estimate whether the dependent variables (smoking, drinking coffee or tea) affect the rate of progression of the disease, which was measured by the time it took patients to reach H&Y stage 3. We found that disease progression was not affected by cigarette smoking, tea or coffee consumption. The present study suggests that these variables do not have a disease modifying effect in already diagnosed PD patients. PMID:17275394

  17. Utility of quantitative ultrasound for tracking the progression of polycystic kidney disease

    NASA Astrophysics Data System (ADS)

    Hall, Timothy J.; Khant, Htet A.; Insana, Michael F.; Wood, John G.; Zhu, Yanning; Preston, David; Cowley, Benjamin D.

    2000-04-01

    We are combining techniques of quantitative ultrasonic imaging to study polycystic kidney disease (PKD) as the disease progresses to renal failure. Our goal is to use ultrasound noninvasively to detect morphological changes early in the disease process when interventions are most likely to be successful and prior to a significant loss in renal function. We are examining the kidneys of normal rats and those with PKD at various ages with several techniques to obtain comprehensive knowledge of the disease progression. The Han:SPRD rat inherits PKD as an autosomal dominant trait (ADPKD) that closely mimics ADPKD in humans. Changes in renal function are assessed using tracer kinetics (DTPA) and IOH clearance). Ultrasonic techniques, based on measurements of acoustic backscatter coefficients and parameters derived from these measurements, are sensitive to microscopic changes in the tissue morphology. Elasticity imaging is used to study the changes in the tissue macrostructure. All acoustic measurements are made using a state-of-the-art clinical imaging system (Siemens Elegra). Our results show that ultrasonic techniques are very sensitive to early changes in renal microstructure and macrostructure. Ultrasound can be used to detect changes in the renal cortex long before there is a measurable loss of renal function. These techniques are also useful for monitoring the progression of the disease. Most importantly, these techniques are noninvasive and directly applicable to humans.

  18. Huntington's disease biomarker progression profile identified by transcriptome sequencing in peripheral blood.

    PubMed

    Mastrokolias, Anastasios; Ariyurek, Yavuz; Goeman, Jelle J; van Duijn, Erik; Roos, Raymund Ac; van der Mast, Roos C; van Ommen, GertJan B; den Dunnen, Johan T; 't Hoen, Peter Ac; van Roon-Mom, Willeke Mc

    2015-10-01

    With several therapeutic approaches in development for Huntington's disease, there is a need for easily accessible biomarkers to monitor disease progression and therapy response. We performed next-generation sequencing-based transcriptome analysis of total RNA from peripheral blood of 91 mutation carriers (27 presymptomatic and, 64 symptomatic) and 33 controls. Transcriptome analysis by DeepSAGE identified 167 genes significantly associated with clinical total motor score in Huntington's disease patients. Relative to previous studies, this yielded novel genes and confirmed previously identified genes, such as H2AFY, an overlap in results that has proven difficult in the past. Pathway analysis showed enrichment of genes of the immune system and target genes of miRNAs, which are downregulated in Huntington's disease models. Using a highly parallelized microfluidics array chip (Fluidigm), we validated 12 of the top 20 significant genes in our discovery cohort and 7 in a second independent cohort. The five genes (PROK2, ZNF238, AQP9, CYSTM1 and ANXA3) that were validated independently in both cohorts present a candidate biomarker panel for stage determination and therapeutic readout in Huntington's disease. Finally we suggest a first empiric formula predicting total motor score from the expression levels of our biomarker panel. Our data support the view that peripheral blood is a useful source to identify biomarkers for Huntington's disease and monitor disease progression in future clinical trials. PMID:25626709

  19. Transgenic over-expression of mammalian heparanase delays prion disease onset and progression.

    PubMed

    Kovalchuk Ben-Zaken, O; Nissan, I; Tzaban, S; Taraboulos, A; Zcharia, E; Matzger, S; Shafat, I; Vlodavsky, I; Tal, Y

    2015-08-28

    Cellular heparan sulfate (HS) has a dual role in scrapie pathogenesis; it is required for PrP(Sc) (scrapie prion protein) formation and facilitates infection of cells, mediating cellular uptake of prions. We examined the involvement of heparanase, a mammalian endoglycosidase degrading HS, in scrapie infection. In cultured cells, heparanase treatment or over-expression resulted in a profound decrease in PrP(Sc). Moreover, disease onset and progression were dramatically delayed in scrapie infected transgenic mice over-expressing heparanase. Together, our results provide direct in vivo evidence for the involvement of intact HS in the pathogenesis of prion disease and the protective role of heparanase both in terms of susceptibility to infection and disease progression. PMID:26168721

  20. Laterality of Motor Symptom Onset, Disease Progression, and Cognition in Parkinson's Disease

    E-print Network

    Chau, Phuong My

    2010-08-31

    The current study examined whether laterality of initial motor symptom onset (left-sided onset vs. right-sided onset) in Parkinson's disease (PD) would predict the pattern and/or severity of cognitive deficits measured at various stages of disease...

  1. Deworming helminth co-infected individuals for delaying HIV disease progression

    PubMed Central

    Walson, Judd L; Herrin, Bradley R; John-Stewart, Grace

    2009-01-01

    Background The HIV-1 pandemic has disproportionately affected individuals in resource-constrained settings where other infectious diseases, such as helminth infections, also are highly prevalent. There are biologically plausible reasons for possible effects of helminth infection in HIV-1-infected individuals, and findings from multiple studies suggest that helminth infection may adversely affect HIV-1 progression. Since initial publication of this review (Walson 2007), additional data from randomized controlled trials (RCTs) has become available. We sought to evaluate all currently available evidence to determine if treatment of helminth infection in HIV-1 co-infected individuals impacts HIV-1 progression. Objectives To determine if treating helminth infection in individuals with HIV-1 can reduce the progression of HIV-1 as determined by changes in CD4 count, viral load, or clinical disease progression. Search strategy In this 2008 update, we searched online for published and unpublished studies in The Cochrane Library, MEDLINE, EMBASE, CENTRAL, and AIDSEARCH. We also searched databases listing conference abstracts, scanned reference lists of articles, and contacted authors of included studies. Selection criteria We searched for RCTs and quasi-RCTs that compared HIV-1 progression as measured by changes in CD4 count, viral load, or clinical disease progression in HIV-1 infected individuals receiving anti-helminthic therapy. Data collection and analysis Data regarding changes in CD4 count, HIV-1 RNA levels, and/or clinical staging after treatment of helminth co-infection were extracted from identified studies. Main results Of 7,019 abstracts identified (6,384 from original searches plus 635 from updated searches), 17 abstracts were identified as meeting criteria for potential inclusion (15 from previous review plus an additional two RCTs). After restricting inclusion to RCTs, a total of three studies were eligible for inclusion in this updated review. All three trials showed individual beneficial effects of helminth eradication on markers of HIV-1 disease progression (HIV-1 RNA and/or CD4 counts). When data from these trials were pooled, the analysis demonstrated significant benefit of deworming on both plasma HIV-1 RNA and CD4 counts. Authors’ conclusions To date, three RCTs have evaluated the effects of deworming on markers of HIV-1 disease progression in helminth and HIV-1 co-infected individuals. All trials demonstrate benefit in attenuating or reducing plasma viral load and/or increasing CD4 counts. When taken together, there is evidence of benefit for deworming HIV-1 co-infected adults. Given that these studies evaluated different helminth species and different interventions, further trials are warranted to evaluate species-specific effects and to document long-term clinical outcomes following deworming. PMID:19588389

  2. Progress with anti-tumor necrosis factor therapeutics for the treatment of inflammatory bowel disease.

    PubMed

    Fernandes, Carlos; Allocca, Mariangela; Danese, Silvio; Fiorino, Gionata

    2015-01-01

    Anti-tumor necrosis factor (TNF) therapy is a valid, effective and increasingly used option in inflammatory bowel disease management. Nevertheless, further knowledge and therapeutic indications regarding these drugs are still evolving. Anti-TNF therapy may be essential to achieve recently proposed end points, namely mucosal healing, prevention of bowel damage and prevention of patient's disability. Anti-TNF drugs are also suggested to be more effective in early disease, particularly in early Crohn's disease. Moreover, its efficacy for prevention of postoperative recurrence in Crohn's disease is still debated. Costs and adverse effects, the relevance of drug monitoring and the possibility of anti-TNF therapy withdrawal in selected patients are still debated issues. This review aimed to describe and discuss the most relevant data about the progress with anti-TNF therapy for the management of inflammatory bowel disease. PMID:25713992

  3. The Relationship between Uric Acid Levels and Huntington’s Disease Progression

    PubMed Central

    Auinger, Peggy; Kieburtz, Karl; McDermott, Michael P.

    2009-01-01

    Uric acid (UA) may be associated with the progression of Parkinson’s disease and related neurodegenerative conditions; however, its association with Huntington’s disease (HD) progression has not been explored. A secondary analysis of 347 subjects from the CARE-HD clinical trial was performed to examine the relationship between baseline UA levels and the level of functional decline in HD. Outcomes included change in scores at 30 months for the Unified Huntington’s Disease Rating Scale components. There was less worsening of total functional capacity over time with increasing baseline UA levels (adjusted mean worsening in scores: 3.17, 2.99, 2.95, 2.28, 2.21, from lowest to highest UA quintile, p=0.03). These data suggest a possible association between higher UA levels and slower HD progression, particularly as measured by total functional capacity. If confirmed, UA could be an important predictor and potentially modifiable factor affecting the rate of HD progression. PMID:20063429

  4. Dependence of reversibility and progression of mouse neuronopathic Gaucher disease on acid ?-glucosidase residual activity levels

    PubMed Central

    Xu, You-Hai; Reboulet, Rachel; Quinn, Brian; Huelsken, Joerg; Witte, David; Grabowski, Gregory A.

    2008-01-01

    Genetic and chemically induced neuronopathic mouse models of Gaucher disease were developed to facilitate understanding of the reversibility and/or progression of CNS involvement. The lethality of the skin permeability barrier defect of the complete gene knock out [gba, (glucocerebrosidase) GCase] was avoided by conditional reactivation of a low activity allele (D409H) in keratinocytes (kn-9H). In kn-9H mice, progressive CNS disease and massive glucosylceramide storage in tissues led to death from CNS involvement by the age of 14 days. Conduritol B epoxide (CBE, a covalent inhibitor of GCase) treatment (for 8–12 days) of wild type, D409H, D409V or V394L homozygotes recapitulated the CNS phenotype of the kn-9H mice with seizures, tail arching, shaking, tremor, quadriparesis, extensive neuronal degeneration loss and apoptosis, and death by the age of 14 days. Minor CNS abnormalities occurred after daily CBE injections of 100 mg/kg/day for 6 doses, but neuronal degeneration was progressive and glucosylceramide storage persisted in D409V homozygotes in the 2 to 5 months after CBE cessation; wild type and D409H mice had persistent neurological damage without progression. The persistent CNS deterioration, histologic abnormalities, and glucosylceramide storage in the CBE-treated D409V mice revealed a threshold level of GCase activity necessary for the prevention of progression of CNS involvement. PMID:18346921

  5. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    SciTech Connect

    Lake, April D.; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D.; Lu, Zhenqiang; Lehman-McKeeman, Lois D.; Cherrington, Nathan J.

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ? Altered hepatic bile acid composition is observed in progressive NAFLD. ? Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ? Increased levels of taurine and conjugated bile acids are observed in NASH. ? Hepatic bile acid synthesis shifts toward the alternative pathway in NASH.

  6. CTSH regulates ?-cell function and disease progression in newly diagnosed type 1 diabetes patients.

    PubMed

    Fløyel, Tina; Brorsson, Caroline; Nielsen, Lotte B; Miani, Michela; Bang-Berthelsen, Claus Heiner; Friedrichsen, Martin; Overgaard, Anne Julie; Berchtold, Lukas A; Wiberg, Anna; Poulsen, Pernille; Hansen, Lars; Rosinger, Silke; Boehm, Bernhard O; Ram, Ramesh; Nguyen, Quang; Mehta, Munish; Morahan, Grant; Concannon, Patrick; Bergholdt, Regine; Nielsen, Jens H; Reinheckel, Thomas; von Herrath, Matthias; Vaag, Allan; Eizirik, Decio Laks; Mortensen, Henrik B; Størling, Joachim; Pociot, Flemming

    2014-07-15

    Over 40 susceptibility loci have been identified for type 1 diabetes (T1D). Little is known about how these variants modify disease risk and progression. Here, we combined in vitro and in vivo experiments with clinical studies to determine how genetic variation of the candidate gene cathepsin H (CTSH) affects disease mechanisms and progression in T1D. The T allele of rs3825932 was associated with lower CTSH expression in human lymphoblastoid cell lines and pancreatic tissue. Proinflammatory cytokines decreased the expression of CTSH in human islets and primary rat ?-cells, and overexpression of CTSH protected insulin-secreting cells against cytokine-induced apoptosis. Mechanistic studies indicated that CTSH exerts its antiapoptotic effects through decreased JNK and p38 signaling and reduced expression of the proapoptotic factors Bim, DP5, and c-Myc. CTSH overexpression also up-regulated Ins2 expression and increased insulin secretion. Additionally, islets from Ctsh(-/-) mice contained less insulin than islets from WT mice. Importantly, the TT genotype was associated with higher daily insulin dose and faster disease progression in newly diagnosed T1D patients, indicating agreement between the experimental and clinical data. In line with these observations, healthy human subjects carrying the T allele have lower ?-cell function, which was evaluated by glucose tolerance testing. The data provide strong evidence that CTSH is an important regulator of ?-cell function during progression of T1D and reinforce the concept that candidate genes for T1D may affect disease progression by modulating survival and function of pancreatic ?-cells, the target cells of the autoimmune assault. PMID:24982147

  7. CTSH regulates ?-cell function and disease progression in newly diagnosed type 1 diabetes patients

    PubMed Central

    Fløyel, Tina; Brorsson, Caroline; Nielsen, Lotte B.; Miani, Michela; Bang-Berthelsen, Claus Heiner; Friedrichsen, Martin; Overgaard, Anne Julie; Berchtold, Lukas A.; Wiberg, Anna; Poulsen, Pernille; Hansen, Lars; Rosinger, Silke; Boehm, Bernhard O.; Ram, Ramesh; Nguyen, Quang; Mehta, Munish; Morahan, Grant; Concannon, Patrick; Bergholdt, Regine; Nielsen, Jens H.; Reinheckel, Thomas; von Herrath, Matthias; Vaag, Allan; Eizirik, Decio Laks; Mortensen, Henrik B.; Størling, Joachim; Pociot, Flemming

    2014-01-01

    Over 40 susceptibility loci have been identified for type 1 diabetes (T1D). Little is known about how these variants modify disease risk and progression. Here, we combined in vitro and in vivo experiments with clinical studies to determine how genetic variation of the candidate gene cathepsin H (CTSH) affects disease mechanisms and progression in T1D. The T allele of rs3825932 was associated with lower CTSH expression in human lymphoblastoid cell lines and pancreatic tissue. Proinflammatory cytokines decreased the expression of CTSH in human islets and primary rat ?-cells, and overexpression of CTSH protected insulin-secreting cells against cytokine-induced apoptosis. Mechanistic studies indicated that CTSH exerts its antiapoptotic effects through decreased JNK and p38 signaling and reduced expression of the proapoptotic factors Bim, DP5, and c-Myc. CTSH overexpression also up-regulated Ins2 expression and increased insulin secretion. Additionally, islets from Ctsh?/? mice contained less insulin than islets from WT mice. Importantly, the TT genotype was associated with higher daily insulin dose and faster disease progression in newly diagnosed T1D patients, indicating agreement between the experimental and clinical data. In line with these observations, healthy human subjects carrying the T allele have lower ?-cell function, which was evaluated by glucose tolerance testing. The data provide strong evidence that CTSH is an important regulator of ?-cell function during progression of T1D and reinforce the concept that candidate genes for T1D may affect disease progression by modulating survival and function of pancreatic ?-cells, the target cells of the autoimmune assault. PMID:24982147

  8. High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer’s Disease in Human Cerebrospinal Fluid

    PubMed Central

    Lee, Anita Y. H.; Song, Qinghua; Liaw, Andy; Wiener, Matt; Paweletz, Cloud P.; Seeburger, Jeffrey L.; Li, Jenny; Meng, Fanyu; Deyanova, Ekaterina G.; Mazur, Matthew T.; Settlage, Robert E.; Zhao, Xuemei; Southwick, Katie; Du, Yi; Holder, Dan; Sachs, Jeffrey R.; Laterza, Omar F.; Dallob, Aimee; Chappell, Derek L.; Snyder, Karen; Modur, Vijay; King, Elizabeth; Joachim, Catharine; Bondarenko, Andrey Y.; Shearman, Mark; Soper, Keith A.; Smith, A. David; Potter, William Z.; Koblan, Ken S.; Sachs, Alan B.

    2015-01-01

    Disease modifying treatments for Alzheimer’s disease (AD) constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF) biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control) patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001) and SME-2 (p = 0.0004) for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR), in AD were 21% (p = 0.039) and 17% (p = 0.026) lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic. PMID:26270474

  9. Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer's type.

    PubMed

    Popp, Julius; Wolfsgruber, Steffen; Heuser, Isabella; Peters, Oliver; Hüll, Michael; Schröder, Johannes; Möller, Hans-Jürgen; Lewczuk, Piotr; Schneider, Anja; Jahn, Holger; Luckhaus, Christian; Perneczky, Robert; Frölich, Lutz; Wagner, Michael; Maier, Wolfgang; Wiltfang, Jens; Kornhuber, Johannes; Jessen, Frank

    2015-02-01

    Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1-42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline. PMID:25435336

  10. The Progressive BSSG Rat Model of Parkinson's: Recapitulating Multiple Key Features of the Human Disease

    PubMed Central

    Van Kampen, Jackalina M.; Baranowski, David C.; Robertson, Harold A.; Shaw, Christopher A.; Kay, Denis G.

    2015-01-01

    The development of effective neuroprotective therapies for Parkinson's disease (PD) has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. Here, we present a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients. Chronic exposure to dietary phytosterol glucosides has been found to be neurotoxic. When fed to rats, ?-sitosterol ?-d-glucoside (BSSG) triggers the progressive development of parkinsonism, with clinical signs and histopathology beginning to appear following cessation of exposure to the neurotoxic insult and continuing to develop over several months. Here, we characterize the progressive nature of this model, its non-motor features, the anatomical spread of synucleinopathy, and response to levodopa administration. In Sprague Dawley rats, chronic BSSG feeding for 4 months triggered the progressive development of a parkinsonian phenotype and pathological events that evolved slowly over time, with neuronal loss beginning only after toxin exposure was terminated. At approximately 3 months following initiation of BSSG exposure, animals displayed the early emergence of an olfactory deficit, in the absence of significant dopaminergic nigral cell loss or locomotor deficits. Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment. Late-stage cognitive impairment was observed in the form of spatial working memory deficits, as assessed by the radial arm maze. In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular ?-synuclein aggregates was also observed to develop progressively, appearing first in the olfactory bulb, then the striatum, the substantia nigra and, finally, hippocampal and cortical regions. The slowly progressive nature of this model, together with its construct, face and predictive validity, make it ideal for the screening of potential neuroprotective therapies for the treatment of PD. PMID:26439489

  11. MAPPING THE PROGRESSION OF ATROPHY IN EARLY AND LATE ONSET ALZHEIMER’S DISEASE

    PubMed Central

    Migliaccio, R; Agosta, F; Possin, KL; Canu, E; Filippi, M; Rabinovici, GD; Rosen, HJ; Miller, BL; Gorno-Tempini, ML

    2015-01-01

    The term early age-of-onset Alzheimer’s disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter (GM) atrophy in EOAD patients compared to late onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate. PMID:25737041

  12. Identification and Progression of Heart Disease Risk Factors in Diabetic Patients from Longitudinal Electronic Health Records

    PubMed Central

    Jonnagaddala, Jitendra; Liaw, Siaw-Teng; Ray, Pradeep; Kumar, Manish; Dai, Hong-Jie; Hsu, Chien-Yeh

    2015-01-01

    Heart disease is the leading cause of death worldwide. Therefore, assessing the risk of its occurrence is a crucial step in predicting serious cardiac events. Identifying heart disease risk factors and tracking their progression is a preliminary step in heart disease risk assessment. A large number of studies have reported the use of risk factor data collected prospectively. Electronic health record systems are a great resource of the required risk factor data. Unfortunately, most of the valuable information on risk factor data is buried in the form of unstructured clinical notes in electronic health records. In this study, we present an information extraction system to extract related information on heart disease risk factors from unstructured clinical notes using a hybrid approach. The hybrid approach employs both machine learning and rule-based clinical text mining techniques. The developed system achieved an overall microaveraged F-score of 0.8302. PMID:26380290

  13. Ion channel genes and human neurological disease: Recent progress, prospects, and challenges

    PubMed Central

    Cooper, Edward C.; Jan, Lily Yeh

    1999-01-01

    What do epilepsy, migraine headache, deafness, episodic ataxia, periodic paralysis, malignant hyperthermia, and generalized myotonia have in common? These human neurological disorders can be caused by mutations in genes for ion channels. Many of the channel diseases are “paroxysmal disorders” whose principal symptoms occur intermittently in individuals who otherwise may be healthy and active. Some of the ion channels that cause human neurological disease are old acquaintances previously cloned and extensively studied by channel specialists. In other cases, however, disease-gene hunts have led the way to the identification of new channel genes. Progress in the study of ion channels has made it possible to analyze the effects of human neurological disease-causing channel mutations at the level of the single channel, the subcellular domain, the neuronal network, and the behaving organism. PMID:10220366

  14. Genetic algorithm with logistic regression for prediction of progression to Alzheimer's disease

    PubMed Central

    2014-01-01

    Background Assessment of risk and early diagnosis of Alzheimer's disease (AD) is a key to its prevention or slowing the progression of the disease. Previous research on risk factors for AD typically utilizes statistical comparison tests or stepwise selection with regression models. Outcomes of these methods tend to emphasize single risk factors rather than a combination of risk factors. However, a combination of factors, rather than any one alone, is likely to affect disease development. Genetic algorithms (GA) can be useful and efficient for searching a combination of variables for the best achievement (eg. accuracy of diagnosis), especially when the search space is large, complex or poorly understood, as in the case in prediction of AD development. Results Multiple sets of neuropsychological tests were identified by GA to best predict conversions between clinical categories, with a cross validated AUC (area under the ROC curve) of 0.90 for prediction of HC conversion to MCI/AD and 0.86 for MCI conversion to AD within 36 months. Conclusions This study showed the potential of GA application in the neural science area. It demonstrated that the combination of a small set of variables is superior in performance than the use of all the single significant variables in the model for prediction of progression of disease. Variables more frequently selected by GA might be more important as part of the algorithm for prediction of disease development. PMID:25521394

  15. Progress in defining clinically meaningful changes for clinical trials in nonrenal manifestations of SLE disease activity.

    PubMed

    Choi, Chan-Bum; Liang, Matthew H; Bae, Sang-Cheol

    2016-01-01

    Since the 2002 Dusseldorf meeting, one new agent, Benlysta, has been approved by the US Food and Drug Administration for systemic lupus erythematosus. Experiences from the field in conducting trials of all the agents tested during this period have provided valuable practical insights. There has been incremental progress in defining the minimal clinically important difference (MCID) of key disease manifestations and the view is largely that of the health care providers and not that of the person suffering the disease. This basic methodological work on the MCID should improve the efficiency and the clinical relevance of future trials and their design. PMID:26732314

  16. Gut Microbiota in HIV Infection: Implication for Disease Progression and Management

    PubMed Central

    Nwosu, Felix Chinweije; Avershina, Ekaterina; Wilson, Robert; Rudi, Knut

    2014-01-01

    Survival rates among HIV patients have significantly improved since the introduction of antiretroviral therapy (ART) in HIV management. However, persistent disease progression and clinical complications in virally suppressed individuals point to additional contributing factors other than HIV replication; microbial translocation is one such factor. The role of underlying commensal microbes and microbial products that traverse the intestinal lumen into systemic circulation in the absence of overt bacteraemia is under current investigation. This review focuses on current knowledge of the complex microbial communities and microbial markers involved in the disruption of mucosal immune T-cells in the promotion of inflammatory processes in HIV infections. Unanswered questions and aims for future studies are addressed. We provide perspective for discussing potential future therapeutic strategies focused on modulating the gut microbiota to abate HIV disease progression. PMID:25024700

  17. Advancing Drug Innovation for Neglected Diseases—Criteria for Lead Progression

    PubMed Central

    Nwaka, Solomon; Ramirez, Bernadette; Brun, Reto; Maes, Louis; Douglas, Frank; Ridley, Robert

    2009-01-01

    The current drug R&D pipeline for most neglected diseases remains weak, and unlikely to support registration of novel drug classes that meet desired target product profiles in the short term. This calls for sustained investment as well as greater emphasis in the risky upstream drug discovery. Access to technologies, resources, and strong management as well as clear compound progression criteria are factors in the successful implementation of any collaborative drug discovery effort. We discuss how some of these factors have impacted drug discovery for tropical diseases within the past four decades, and highlight new opportunities and challenges through the virtual North–South drug discovery network as well as the rationale for greater participation of institutions in developing countries in product innovation. A set of criteria designed to facilitate compound progression from screening hits to drug candidate selection is presented to guide ongoing efforts. PMID:19707561

  18. HIV-1 DNA predicts disease progression and post-treatment virological control.

    PubMed

    Williams, James P; Hurst, Jacob; Stöhr, Wolfgang; Robinson, Nicola; Brown, Helen; Fisher, Martin; Kinloch, Sabine; Cooper, David; Schechter, Mauro; Tambussi, Giuseppe; Fidler, Sarah; Carrington, Mary; Babiker, Abdel; Weber, Jonathan; Koelsch, Kersten K; Kelleher, Anthony D; Phillips, Rodney E; Frater, John

    2014-01-01

    In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials. PMID:25217531

  19. The APOE locus advances disease progression in late onset familial Alzheimer`s disease but is not causative

    SciTech Connect

    Crawford, F.; Bennett, C.; Osborne, A.

    1994-09-01

    An association has been observed in several independent data sets between late onset Alzheimer`s disease (AD) and the APOE locus on chromosomes 19. We have examined the genotype in family history positive (FHP) and family history negative (FHN) cases and find a distortion of the APOE allele frequencies in accord with previous studies. However, when we examined the allele distribution of the at-risk siblings of the FHP group we found an excess of the {epsilon}4 allele which also differs significantly from historic controls but not from the affected siblings. The age distribution of the affected and unaffected siblings was similar, suggesting that the allelic frequency distortion in the unaffected siblings was not due to their being below the mean age of onset. Lod score linkage analysis, with age dependent onset and nonstringent specification of the genetic parameters, did not suggest linkage to the APOE locus. Furthermore, an analysis of variance of the age of disease-free survival suggested that APOE genotype contributes a small fraction of the total variance, indicating that the APOE locus is a poor predictor of disease-free survival time within late onset families. We suggest that the APOE locus enhances the rate of progression of the disease in otherwise predisposed individuals and that variation at this locus is not able in and of itself to cause this disease.

  20. Current Progress in Nanotechnology Applications for Diagnosis and Treatment of Kidney Diseases.

    PubMed

    Lee, Sue Hyun; Lee, Jung Bok; Bae, Min Soo; Balikov, Daniel A; Hwang, Amy; Boire, Timothy C; Kwon, Il Keun; Sung, Hak-Joon; Yang, Jae Won

    2015-09-01

    Significant progress has been made in nanomedicine, primarily in the form of nanoparticles, for theranostic applications to various diseases. A variety of materials, both organic and inorganic, have been used to develop nanoparticles with promise to achieve improved efficacy in medical applications as well as reduced systemic side effects compared to current standard of care medical practices. In particular, this article highlights the recent development and application of nanoparticles for diagnosing and treating nephropathologies. PMID:26121684

  1. Lipocalin 2 is essential for chronic kidney disease progression in mice and humans

    PubMed Central

    Viau, Amandine; El Karoui, Khalil; Laouari, Denise; Burtin, Martine; Nguyen, Clément; Mori, Kiyoshi; Pillebout, Evangéline; Berger, Thorsten; Mak, Tak Wah; Knebelmann, Bertrand; Friedlander, Gérard; Barasch, Jonathan; Terzi, Fabiola

    2010-01-01

    Mechanisms of progression of chronic kidney disease (CKD), a major health care burden, are poorly understood. EGFR stimulates CKD progression, but the molecular networks that mediate its biological effects remain unknown. We recently showed that the severity of renal lesions after nephron reduction varied substantially among mouse strains and required activation of EGFR. Here, we utilized two mouse strains that react differently to nephron reduction — FVB/N mice, which develop severe renal lesions, and B6D2F1 mice, which are resistant to early deterioration — coupled with genome-wide expression to elucidate the molecular nature of CKD progression. Our results showed that lipocalin 2 (Lcn2, also known as neutrophil gelatinase–associated lipocalin [NGAL]), the most highly upregulated gene in the FVB/N strain, was not simply a marker of renal lesions, but an active player in disease progression. In fact, the severity of renal lesions was dramatically reduced in Lcn2–/– mice. We discovered that Lcn2 expression increased upon EGFR activation and that Lcn2 mediated its mitogenic effect during renal deterioration. EGFR inhibition prevented Lcn2 upregulation and lesion development in mice expressing a dominant negative EGFR isoform, and hypoxia-inducible factor 1? (Hif-1?) was crucially required for EGFR-induced Lcn2 overexpression. Consistent with this, cell proliferation was dramatically reduced in Lcn2–/– mice. These data are relevant to human CKD, as we found that LCN2 was increased particularly in patients who rapidly progressed to end-stage renal failure. Together our results uncover what we believe to be a novel function for Lcn2 and a critical pathway leading to progressive renal failure and cystogenesis. PMID:20921623

  2. TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression

    PubMed Central

    Souza, Ana C P; Tsuji, Takayuki; Baranova, Irina N; Bocharov, Alexander V; Wilkins, Kenneth J; Street, Jonathan M; Alvarez-Prats, Alejandro; Hu, Xuzhen; Eggerman, Thomas; Yuen, Peter S T; Star, Robert A

    2015-01-01

    Chronic kidney disease (CKD) is associated with persistent low-grade inflammation and immunosuppression. In this study we tested the role of Toll-like receptor 4, the main receptor for endotoxin (LPS), in a mouse model of renal fibrosis and in a model of progressive CKD that better resembles the human disease. C3HeJ (TLR4 mutant) mice have a missense point mutation in the TLR4 gene, rendering the receptor nonfunctional. In a model of renal fibrosis after folic acid injection, TLR4 mutant mice developed less interstititial fibrosis in comparison to wild-type (WT) mice. Furthermore, 4 weeks after 5/6 nephrectomy with continuous low-dose angiotensin II infusion, C3HeOuJ (TLR4 WT) mice developed progressive CKD with albuminuria, increased serum levels of BUN and creatinine, glomerulosclerosis, and interstitial fibrosis, whereas TLR4 mutant mice were significantly protected from CKD progression. TLR4 WT mice also developed low-grade systemic inflammation, splenocyte apoptosis and increased expression of the immune inhibitory receptor PD-1 in the spleen, which were not observed in TLR4 mutant mice. In vitro, endotoxin (LPS) directly upregulated NLRP3 inflammasome expression in renal epithelial cells via TLR4. In summary, TLR4 contributes to renal fibrosis and CKD progression, at least in part, via inflammasome activation in renal epithelial cells, and may also participate in the dysregulated immune response that is associated with CKD. PMID:26416975

  3. -374 T/A RAGE Polymorphism Is Associated with Chronic Kidney Disease Progression in Subjects Affected by Nephrocardiovascular Disease

    PubMed Central

    Baragetti, Ivano; Norata, Giuseppe Danilo; Sarcina, Cristina; Baragetti, Andrea; Rastelli, Francesco; Buzzi, Laura; Grigore, Liliana; Garlaschelli, Katia; Pozzi, Claudio; Catapano, Alberico Luigi

    2013-01-01

    Background Chronic kidney disease (CKD) patients present elevated advanced glycation end products (AGEs) blood levels. AGEs promote inflammation through binding to their receptor (RAGE), located on the membrane of mesangial cells, endothelial cells and macrophages. Several genetic polymorphisms influence RAGE transcription, expression and activity, including the substitution of a thymine with an adenine (T/A) in the position -374 of the gene promoter of RAGE. Our study investigates the role of -374 T/A RAGE polymorphism in CKD progression in subjects affected by nephrocardiovascular disease. Methods 174 patients (119 males (68.4%) mean age 67.2±0.88 years; 55 females (31.6%): mean age 65.4±1.50 years) affected by mild to moderate nephrocardiovascular CKD were studied. Each subject was prospectively followed for 84 months, every 6–9 months. The primary endpoint of the study was a rise of serum creatinine concentrations above 50% of basal values or end stage renal disease. Results Carriers of the A/A and T/A genotype presented higher plasma levels of interleukin 6 (A/A 29.5±15.83; T/A 30.0±7.89, vs T/T 12.3±5.04 p?=?0.01 for both) and Macrophages chemoattractant protein 1 (A/A 347.1±39.87; T/A 411.8±48.41, vs T/T 293.5±36.20, p?=?0.04 for both) than T/T subjects. Carriers of the A allele presented a faster CKD progression than wild type patients (Log-Rank test: Chi square?=?6.84, p?=?0,03). Cox regression showed that -374 T/A RAGE polymorphism (p?=?0.037), albuminuria (p?=?0.01) and LDL cholesterol (p?=?0.038) were directly associated with CKD progression. HDL cholesterol (p?=?0.022) and BMI (p?=?0.04) were inversely related to it. No relationship was found between circulating RAGE and renal function decline. Conclusions -374 T/A RAGE polymorphism could be associated with CKD progression and inflammation. Further studies should confirm this finding and address whether inhibiting RAGE downstream signalling would be beneficial for CKD progression. PMID:23593165

  4. The effects of electroshock on immune function and disease progression in juvenile spring chinook salmon

    USGS Publications Warehouse

    VanderKooi, S.P.; Maule, A.G.; Schreck, C.B.

    2001-01-01

    Although much is known about the effects of electroshock on fish physiology, consequences to the immune system and disease progression have not received attention. Our objectives were to determine the effects of electroshock on selected immune function in juvenile spring chinook salmon Oncorhynchus tshawytscha, the mechanism of any observed alteration, and the effects of electroshock on disease progression. We found that the ability of anterior kidney leukocytes to generate antibody-producing cells (APC) was suppressed 3 h after a pulsed-DC electroshock (300 V, 50 Hz, 8 ms pulse width) but recovered within 24 h. This response was similar in timing and magnitude to that of fish subjected to an acute handling stress. The mechanism of suppression is hypothesized to be via an elevation of plasma cortisol concentrations in response to stress. Other monitored immune functions, skin mucous lysozyme levels, and respiratory burst activity were not affected by exposure to electroshock. The progression of a Renibacterium salmoninarum (RS) infection may have been altered after exposure to an electroshock. The electroshock did not affect infection severity or the number of mortalities, but may have accelerated the time to death. The limited duration of APC suppression and lack of effects on lysozyme and respiratory burst, as well as infection severity and mortality levels in RS-infected fish, led us to conclude that electrofishing under the conditions we tested is a safe procedure in regards to immunity and disease.

  5. The genetics of human autoimmune disease: A perspective on progress in the field and future directions.

    PubMed

    Seldin, Michael F

    2015-11-01

    Progress in defining the genetics of autoimmune disease has been dramatically enhanced by large scale genetic studies. Genome-wide approaches, examining hundreds or for some diseases thousands of cases and controls, have been implemented using high throughput genotyping and appropriate algorithms to provide a wealth of data over the last decade. These studies have identified hundreds of non-HLA loci as well as further defining HLA variations that predispose to different autoimmune diseases. These studies to identify genetic risk loci are also complemented by progress in gene expression studies including definition of expression quantitative trait loci (eQTL), various alterations in chromatin structure including histone marks, DNase I sensitivity, repressed chromatin regions as well as transcript factor binding sites. Integration of this information can partially explain why particular variations can alter proclivity to autoimmune phenotypes. Despite our incomplete knowledge base with only partial definition of hereditary factors and possible functional connections, this progress has and will continue to facilitate a better understanding of critical pathways and critical changes in immunoregulation. Advances in defining and understanding functional variants potentially can lead to both novel therapeutics and personalized medicine in which therapeutic approaches are chosen based on particular molecular phenotypes and genomic alterations. PMID:26343334

  6. [Exploration of pathogenesis and therapy development for ALS employing sporadic disease model].

    PubMed

    Tanaka, Fumiaki; Waza, Masahiro; Yamamoto, Masahiko; Sobue, Gen

    2009-11-01

    The mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remain poorly understood even now 140 years after the first description of the disease in 1869 by Jean-Martin Charcot. Exploration of pathogenesis of ALS has long been dependent on transgenic animal models with mutations in the copper/ zinc superoxide dismutase 1 (SOD1) gene. However, the lack of therapeutic concordance between these animal models and human sporadic ALS patients is troubling. The reasons include that there might exist the differences of pathogenesis between sporadic and familial ALS and/or the disease models for sporadic ALS have not been established. We have been working on screening motor neuron-specific genes critical for pathogenesis of sporadic ALS using cDNA microarray and laser capture microdissection techniques. Many of the resultant genes are of intense interest and may provide a powerful tool for determining the molecular mechanisms of sporadic ALS. In particular, dynactin-1, a major component of dynein/dynactin complex and several cell cycle-related genes are the targets of our research. Development and analysis of new disease models for sporadic ALS based on these genes will open an avenue for novel therapeutics. PMID:20030217

  7. Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression.

    PubMed

    Davis, Albert A; Andruska, Kristin M; Benitez, Bruno A; Racette, Brad A; Perlmutter, Joel S; Cruchaga, Carlos

    2016-01-01

    Multiple genetic variants have been linked to risk of Parkinson disease (PD), but known mutations do not explain a large proportion of the total PD cases. Similarly, multiple loci have been associated with PD risk by genome-wide association studies (GWAS). The influence that genetic factors confer on phenotypic diversity remains unclear. Few studies have been performed to determine whether the GWAS loci are also associated with age at onset (AAO) or motor progression. We used 2 PD case-control data sets (Washington University and the Parkinson's Progression Markers Initiative) to determine whether polymorphisms located at the GWAS top hits (GBA, ACMSD/TMEM163, STK39, MCCC1/LAMP3, GAK/TMEM175, SNCA, and MAPT) show association with AAO or motor progression. We found associations between single nucleotide polymorphisms at the GBA and MAPT loci and PD AAO and progression. These findings reinforce the complex genetic basis of PD and suggest that distinct genes and variants explain the genetic architecture of PD risk, onset, and progression. PMID:26601739

  8. Phenotypic transition of microglia into astrocyte-like cells associated with disease onset in a model of inherited ALS

    PubMed Central

    Trias, Emiliano; Díaz-Amarilla, Pablo; Olivera-Bravo, Silvia; Isasi, Eugenia; Drechsel, Derek A.; Lopez, Nathan; Bradford, C. Samuel; Ireton, Kyle E.; Beckman, Joseph S.; Barbeito, Luis

    2013-01-01

    Microglia and reactive astrocytes accumulate in the spinal cord of rats expressing the Amyotrophic lateral sclerosis (ALS)-linked SOD1 G93A mutation. We previously reported that the rapid progression of paralysis in ALS rats is associated with the appearance of proliferative astrocyte-like cells that surround motor neurons. These cells, designated as Aberrant Astrocytes (AbA cells) because of their atypical astrocytic phenotype, exhibit high toxicity to motor neurons. However, the cellular origin of AbA cells remains unknown. Because AbA cells are labeled with the proliferation marker Ki67, we analyzed the phenotypic makers of proliferating glial cells that surround motor neurons by immunohistochemistry. The number of Ki67 +AbA cells sharply increased in symptomatic rats, displaying large cell bodies with processes embracing motor neurons. Most were co-labeled with astrocytic marker GFAP concurrently with the microglial markers Iba1 and CD163. Cultures of spinal cord prepared from symptomatic SOD1 G93A rats yielded large numbers of microglia expressing Iba1, CD11b, and CD68. Cells sorted for CD11b expression by flow cytometry transformed into AbA cells within two weeks. During these two weeks, the expression of microglial markers largely disappeared, while GFAP and S100? expression increased. The phenotypic transition to AbA cells was stimulated by forskolin. These findings provide evidence for a subpopulation of proliferating microglial cells in SOD1 G93A rats that undergo a phenotypic transition into AbA cells after onset of paralysis that may promote the fulminant disease progression. These cells could be a therapeutic target for slowing paralysis progression in ALS. PMID:24399933

  9. APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease

    PubMed Central

    Parsa, Afshin; Kao, W.H. Linda; Xie, Dawei; Astor, Brad C.; Li, Man; Hsu, Chi-yuan; Feldman, Harold I.; Parekh, Rulan S.; Kusek, John W.; Greene, Tom H.; Fink, Jeffrey C.; Anderson, Amanda H.; Choi, Michael J.; Wright, Jackson T.; Lash, James P.; Freedman, Barry I.; Ojo, Akinlolu; Winkler, Cheryl A.; Raj, Dominic S.; Kopp, Jeffrey B.; He, Jiang; Jensvold, Nancy G.; Tao, Kaixiang; Lipkowitz, Michael S.; Appel, Lawrence J.

    2014-01-01

    BACKGROUND Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients. METHODS In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. RESULTS In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons). CONCLUSIONS Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.) PMID:24206458

  10. The fundamental role of mechanical properties in the progression of cancer disease and inflammation

    NASA Astrophysics Data System (ADS)

    Mierke, Claudia Tanja

    2014-07-01

    The role of mechanical properties in cancer disease and inflammation is still underinvestigated and even ignored in many oncological and immunological reviews. In particular, eight classical hallmarks of cancer have been proposed, but they still ignore the mechanics behind the processes that facilitate cancer progression. To define the malignant transformation of neoplasms and finally reveal the functional pathway that enables cancer cells to promote cancer progression, these classical hallmarks of cancer require the inclusion of specific mechanical properties of cancer cells and their microenvironment such as the extracellular matrix as well as embedded cells such as fibroblasts, macrophages or endothelial cells. Thus, this review will present current cancer research from a biophysical point of view and will therefore focus on novel physical aspects and biophysical methods to investigate the aggressiveness of cancer cells and the process of inflammation. As cancer or immune cells are embedded in a certain microenvironment such as the extracellular matrix, the mechanical properties of this microenvironment cannot be neglected, and alterations of the microenvironment may have an impact on the mechanical properties of the cancer or immune cells. Here, it is highlighted how biophysical approaches, both experimental and theoretical, have an impact on the classical hallmarks of cancer and inflammation. It is even pointed out how these biophysical approaches contribute to the understanding of the regulation of cancer disease and inflammatory responses after tissue injury through physical microenvironmental property sensing mechanisms. The recognized physical signals are transduced into biochemical signaling events that guide cellular responses, such as malignant tumor progression, after the transition of cancer cells from an epithelial to a mesenchymal phenotype or an inflammatory response due to tissue injury. Moreover, cell adaptation to mechanical alterations, in particular the understanding of mechano-coupling and mechano-regulating functions in cell invasion, appears as an important step in cancer progression and inflammatory response to injuries. This may lead to novel insights into cancer disease and inflammatory diseases and will overcome classical views on cancer and inflammation. In addition, this review will discuss how the physics of cancer and inflammation can help to reveal whether cancer cells will invade connective tissue and metastasize or how leukocytes extravasate and migrate through the tissue. In this review, the physical concepts of cancer progression, including the tissue basement membrane a cancer cell is crossing, its invasion and transendothelial migration as well as the basic physical concepts of inflammatory processes and the cellular responses to the mechanical stress of the microenvironment such as external forces and matrix stiffness, are presented and discussed. In conclusion, this review will finally show how physical measurements can improve classical approaches that investigate cancer and inflammatory diseases, and how these physical insights can be integrated into classical tumor biological approaches.

  11. Research progress on flavonoids isolated from traditional Chinese medicine in treatment of Alzheimer's disease

    PubMed Central

    Gao, Jianjun; Inagaki, Yoshinori; Liu, Yang

    2013-01-01

    Summary Alzheimer's disease (AD) is a severe condition in aging countries. The currently used drugs including donepezil, rivastigmine, galantamine, and memantine are effective in managing the symptoms. However, they are hardly capable of preventing, halting, or reversing the disease. In the long history of development of traditional Chinese medicine, much experience has accumulated and is summarized in treatment of diseases that correspond to the concept of AD. In recent years, exploration of natural active ingredients from medicinal herbs for treatment of AD has attracted substantial attention. Some flavonoids have been revealed to have a variety of biological actions such as scavenging free radicals, inhibiting neuron apoptosis, and nurturing neuronal cells that constitute the basis for treatment of AD. In this article, we review recent research progress on flavonoids isolated from traditional Chinese medicine against AD and their underlying mechanisms. PMID:25343094

  12. Severe hyponatraemia with absence of hyperkalaemia in rapidly progressive Addison's disease.

    PubMed

    Thompson, Michael D; Kalmar, Eileen; Bowden, Sasigarn A

    2015-01-01

    We present a case of rapidly progressing Addison's disease in adrenal crisis with severe hyponatraemia and absence of hyperkalaemia in a 10-year-old girl. She presented with 2?weeks of vomiting, fatigue and weight loss. Her serum electrolytes obtained 1?week prior to presentation were normal, except for mild hyponatraemia at 131?mmol/L, which dropped to 112?mmol/L on admission. She had normal serum potassium, low-serum osmolality, with elevated urine sodium and osmolality, indistinguishable from syndrome of inappropriate antidiuretic hormone (SIADH). Subsequently, Addison's disease was diagnosed on the basis of gingival hyperpigmentation and undetectable cortisol on adrenocorticotropic hormone stimulation test. She rapidly responded to stress dose hydrocortisone, followed by hydrocortisone and fludrocortisone replacement therapy. The absence of hyperkalaemia in the presence of severe hyponatraemia cannot rule out Addison's disease in children. The mechanism of hypo-osmolar hyponatraemia in primary adrenal insufficiency and clinical clues to differentiate it from SIADH are discussed. PMID:26021383

  13. Vitamin D Deficiency Aggravates Chronic Kidney Disease Progression after Ischemic Acute Kidney Injury

    PubMed Central

    Gonçalves, Janaína Garcia; de Bragança, Ana Carolina; Canale, Daniele; Shimizu, Maria Heloisa Massola; Sanches, Talita Rojas; Moysés, Rosa Maria Affonso; Andrade, Lúcia; Seguro, Antonio Carlos; Volpini, Rildo Aparecido

    2014-01-01

    Background Despite a significant improvement in the management of chronic kidney disease (CKD), its incidence and prevalence has been increasing over the years. Progressive renal fibrosis is present in CKD and involves the participation of several cytokines, including Transforming growth factor-?1 (TGF-?1). Besides cardiovascular diseases and infections, several studies show that Vitamin D status has been considered as a non-traditional risk factor for the progression of CKD. Given the importance of vitamin D in the maintenance of essential physiological functions, we studied the events involved in the chronic kidney disease progression in rats submitted to ischemia/reperfusion injury under vitamin D deficiency (VDD). Methods Rats were randomized into four groups: Control; VDD; ischemia/reperfusion injury (IRI); and VDD+IRI. At the 62 day after sham or IRI surgery, we measured inulin clearance, biochemical variables and hemodynamic parameters. In kidney tissue, we performed immunoblotting to quantify expression of Klotho, TGF-?, and vitamin D receptor (VDR); gene expression to evaluate renin, angiotensinogen, and angiotensin-converting enzyme; and immunohistochemical staining for ED1 (macrophages), type IV collagen, fibronectin, vimentin, and ?-smooth mucle actin. Histomorphometric studies were performed to evaluate fractional interstitial area. Results IRI animals presented renal hypertrophy, increased levels of mean blood pressure and plasma PTH. Furthermore, expansion of the interstitial area, increased infiltration of ED1 cells, increased expression of collagen IV, fibronectin, vimentin and ?-actin, and reduced expression of Klotho protein were observed. VDD deficiency contributed to increased levels of plasma PTH as well as for important chronic tubulointerstitial changes (fibrosis, inflammatory infiltration, tubular dilation and atrophy), increased expression of TGF-?1 and decreased expression of VDR and Klotho protein observed in VDD+IRI animals. Conclusion Through inflammatory pathways and involvement of TGF-?1 growth factor, VDD could be considered as an aggravating factor for tubulointerstitial damage and fibrosis progression following acute kidney injury induced by ischemia/reperfusion. PMID:25222475

  14. An estrogen-induced endometrial hyperplasia mouse model recapitulating human disease progression and genetic aberrations

    PubMed Central

    Yang, Chieh-Hsiang; Almomen, Aliyah; Wee, Yin Shen; Jarboe, Elke A; Peterson, C Matthew; Janát-Amsbury, Margit M

    2015-01-01

    Endometrial hyperplasia (EH) is a condition originating from uterine endometrial glands undergoing disordered proliferation including the risk to progress to endometrial adenocarcinoma. In recent years, a steady increase in EH cases among younger women of reproductive age accentuates the demand of therapeutic alternatives, which emphasizes that an improved disease model for therapeutic agents evaluation is concurrently desired. Here, a new hormone-induced EH mouse model was developed using a subcutaneous estradiol (E2)-sustained releasing pellet, which elevates the serum E2 level in mice, closely mimicking the effect known as estrogen dominance with underlying, pathological E2 levels in patients. The onset and progression of EH generated within this model recapitulate a clinically relevant, pathological transformation, beginning with disordered proliferation developing to simple EH, advancing to atypical EH, and then progressing to precancerous stages, all following a chronologic manner. Although a general increase in nuclear progesterone receptor (PR) expression occurred after E2 expression, a total loss in PR was noted in some endometrial glands as disease advanced to simple EH. Furthermore, estrogen receptor (ER) expression in the nucleus of endometrial cells was reduced in disordered proliferation and increased when EH progressed to atypical EH and precancerous stages. This EH model also resembles other pathological patterns found in human disease such as leukocytic infiltration, genetic aberrations in ?-catenin, and joint phosphatase and tensin homolog/paired box gene 2 (PTEN/PAX2) silencing. In summary, this new and comprehensively characterized EH model is cost-effective, easily reproducible, and may serve as a tool for preclinical testing of therapeutic agents and facilitate further investigation of EH. PMID:25809780

  15. Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1 G93A mouse model of amyotrophic lateral sclerosis

    PubMed Central

    Baker, David J.; Blackburn, Daniel J.; Keatinge, Marcus; Sokhi, Dilraj; Viskaitis, Paulius; Heath, Paul R.; Ferraiuolo, Laura; Kirby, Janine; Shaw, Pamela J.

    2015-01-01

    Astrocytes are key players in the progression of amyotrophic lateral sclerosis (ALS). Previously, gene expression profiling of astrocytes from the pre-symptomatic stage of the SOD1G93A model of ALS has revealed reduced lactate metabolism and altered trophic support. Here, we have performed microarray analysis of symptomatic and late-stage disease astrocytes isolated by laser capture microdissection (LCM) from the lumbar spinal cord of the SOD1G93A mouse to complete the picture of astrocyte behavior throughout the disease course. Astrocytes at symptomatic and late-stage disease show a distinct up-regulation of transcripts defining a reactive phenotype, such as those involved in the lysosome and phagocytic pathways. Functional analysis of hexosaminidase B enzyme activity in the spinal cord and of astrocyte phagocytic ability has demonstrated a significant increase in lysosomal enzyme activity and phagocytic activity in SOD1G93A vs. littermate controls, validating the findings of the microarray study. In addition to the increased reactivity seen at both stages, astrocytes from late-stage disease showed decreased expression of many transcripts involved in cholesterol homeostasis. Staining for the master regulator of cholesterol synthesis, SREBP2, has revealed an increased localization to the cytoplasm of astrocytes and motor neurons in late-stage SOD1G93A spinal cord, indicating that down-regulation of transcripts may be due to an excess of cholesterol in the CNS during late-stage disease possibly due to phagocytosis of neuronal debris. Our data reveal that SOD1G93A astrocytes are characterized more by a loss of supportive function than a toxic phenotype during ALS disease progression and future studies should focus upon restorative therapies. PMID:26528138

  16. Pharmacological Treatment of Alzheimer’s Disease: Is it Progressing Adequately?

    PubMed Central

    Robles, Alfredo

    2009-01-01

    Introduction: Between 1993 and 2000 four acetylcholinesterase inhibitors were marketed as a symptomatic treatment for Alzheimer’s disease (AD), as well as memantine in 2003. Current research is focused on finding drugs that favorably modify the course of the disease. However, their entrance into the market does not seem to be imminent. Research Development: The aim of AD research is to find substances that inhibit certain elements of the AD pathogenic chain (beta- and gamma-secretase inhibitors, alpha-secretase stimulants, beta-amyloid aggregability reducers or disaggregation and elimination inductors, as well as tau-hyperphosphorylation, glutamate excitotoxicity, oxidative stress and mitochondrial damage reducers, among other action mechanisms). Demonstrating a disease’s retarding effect demands longer trials than those necessary to ascertain symptomatic improvement. Besides, a high number of patients (thousands of them) is necessary, all of which turns out to be difficult and costly. Furthermore, it would be necessary to count on diagnosis and progression markers in the disease’s pre-clinical stage, markers for specific phenotypes, as well as high-selectivity molecules acting only where necessary. In order to compensate these difficulties, drugs acting on several defects of the pathogenic chain or showing both symptomatic and neuroprotective action simultaneously are being researched. Conclusions: There are multiple molecules used in research to modify AD progression. Although it turns out to be difficult to obtain drugs with sufficient efficacy so that their marketing is approved, if they were achieved they would lead to a reduction of AD prevalence. PMID:19461897

  17. Identification of Major Signaling Pathways in Prion Disease Progression Using Network Analysis

    PubMed Central

    Newaz, Khalique; Sriram, K.; Bera, Debajyoti

    2015-01-01

    Prion diseases are transmissible neurodegenerative diseases that arise due to conformational change of normal, cellular prion protein (PrPC) to protease-resistant isofrom (rPrPSc). Deposition of misfolded PrpSc proteins leads to an alteration of many signaling pathways that includes immunological and apoptotic pathways. As a result, this culminates in the dysfunction and death of neuronal cells. Earlier works on transcriptomic studies have revealed some affected pathways, but it is not clear which is (are) the prime network pathway(s) that change during the disease progression and how these pathways are involved in crosstalks with each other from the time of incubation to clinical death. We perform network analysis on large-scale transcriptomic data of differentially expressed genes obtained from whole brain in six different mouse strain-prion strain combination models to determine the pathways involved in prion diseases, and to understand the role of crosstalks in disease propagation. We employ a notion of differential network centrality measures on protein interaction networks to identify the potential biological pathways involved. We also propose a crosstalk ranking method based on dynamic protein interaction networks to identify the core network elements involved in crosstalk with different pathways. We identify 148 DEGs (differentially expressed genes) potentially related to the prion disease progression. Functional association of the identified genes implicates a strong involvement of immunological pathways. We extract a bow-tie structure that is potentially dysregulated in prion disease. We also propose an ODE model for the bow-tie network. Predictions related to diseased condition suggests the downregulation of the core signaling elements (PI3Ks and AKTs) of the bow-tie network. In this work, we show using transcriptomic data that the neuronal dysfunction in prion disease is strongly related to the immunological pathways. We conclude that these immunological pathways occupy influential positions in the PFNs (protein functional networks) that are related to prion disease. Importantly, this functional network involvement is prevalent in all the five different mouse strain-prion strain combinations that we studied. We also conclude that the dysregulation of the core elements of the bow-tie structure, which belongs to PI3K-Akt signaling pathway, leads to dysregulation of the downstream components corresponding to other biological pathways. PMID:26646948

  18. Oral health information systems--towards measuring progress in oral health promotion and disease prevention.

    PubMed Central

    Petersen, Poul Erik; Bourgeois, Denis; Bratthall, Douglas; Ogawa, Hiroshi

    2005-01-01

    This article describes the essential components of oral health information systems for the analysis of trends in oral disease and the evaluation of oral health programmes at the country, regional and global levels. Standard methodology for the collection of epidemiological data on oral health has been designed by WHO and used by countries worldwide for the surveillance of oral disease and health. Global, regional and national oral health databanks have highlighted the changing patterns of oral disease which primarily reflect changing risk profiles and the implementation of oral health programmes oriented towards disease prevention and health promotion. The WHO Oral Health Country/Area Profile Programme (CAPP) provides data on oral health from countries, as well as programme experiences and ideas targeted to oral health professionals, policy-makers, health planners, researchers and the general public. WHO has developed global and regional oral health databanks for surveillance, and international projects have designed oral health indicators for use in oral health information systems for assessing the quality of oral health care and surveillance systems. Modern oral health information systems are being developed within the framework of the WHO STEPwise approach to surveillance of noncommunicable, chronic disease, and data stored in the WHO Global InfoBase may allow advanced health systems research. Sound knowledge about progress made in prevention of oral and chronic disease and in health promotion may assist countries to implement effective public health programmes to the benefit of the poor and disadvantaged population groups worldwide. PMID:16211160

  19. Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease.

    PubMed

    Toivola, Diana M; Ku, Nam-On; Resurreccion, Evelyn Z; Nelson, David R; Wright, Teresa L; Omary, M Bishr

    2004-08-01

    Keratin 8 and 18 (K8/18) phosphorylation plays a significant and site-specific role in regulating keratin filament organization, association with binding proteins, and modulation of cell cycle progression. Keratin hyperphosphorylation correlates with exposure to a variety of stresses in cultured cells and in mouse models of liver, pancreatic, and gallbladder injury, and it is found in association with mouse and human Mallory bodies. We asked whether K8/18 phosphorylation correlates with human liver disease progression by analyzing liver explants and biopsies of patients with chronic noncirrhotic hepatitis C virus (HCV) or cirrhosis. We also examined the effect of HCV therapy with interleukin-10 on keratin phosphorylation. Using site-specific antiphosphokeratin antibodies we found keratin hyperphosphorylation on most K8/18 sites in all cirrhotic liver explants tested and in most liver biopsies from patients with chronic HCV infection. Immunofluorescence staining of precirrhotic HCV livers showed focal keratin hyperphosphorylation and limited reorganization of keratin filament networks. In cirrhotic livers, keratin hyperphosphorylation occurred preferentially in hepatic nodule cells adjacent to bridging fibrosis and associated with increased stress kinase activation and apoptosis. Histological and serological improvement after interleukin-10 therapy was accompanied by normalization of keratin hyperphosphorylation on some sites in 7 of 10 patients. In conclusion, site-specific keratin phosphorylation in liver disease is a progression marker when increased and a likely regression marker when decreased. PMID:15368451

  20. Cerebrospinal Fluid ?-Synuclein Predicts Cognitive Decline in Parkinson Disease Progression in the DATATOP Cohort

    PubMed Central

    Stewart, Tessandra; Liu, Changqin; Ginghina, Carmen; Cain, Kevin C.; Auinger, Peggy; Cholerton, Brenna; Shi, Min; Zhang, Jing

    2015-01-01

    Most patients with Parkinson disease (PD) develop both cognitive and motor impairment, and biomarkers for progression are urgently needed. Although ?-synuclein is altered in cerebrospinal fluid of patients with PD, it is not known whether it predicts motor or cognitive deterioration. We examined clinical data and ?-synuclein in >300 unmedicated patients with PD who participated in the deprenyl and tocopherol antioxidative therapy of parkinsonism (DATATOP) study, with up to 8 years of follow-up. Longitudinal measures of motor and cognitive function were studied before (phase 1) and during (phase 2) levodopa therapy; cerebrospinal fluid was collected at the beginning of each phase. Correlations and linear mixed models were used to assess ?-synuclein association with disease severity and prediction of progression in the subsequent follow-up period. Despite decreasing ?-synuclein (phase 1 to phase 2 change of ?0.05 ± 0.21 log-transformed values, P < 0.001), no correlations were observed between ?-synuclein and motor symptoms. Longitudinally, lower ?-synuclein predicted better preservation of cognitive function by several measures [Selective Reminding Test total recall ?-synuclein × time interaction effect coefficient, ?0.12 (P = 0.037); delayed recall, ?0.05 (P = 0.002); New Dot Test, ?0.03 (P = 0.002)]. Thus, ?-synuclein, although not clinically useful for motor progression, might predict cognitive decline, and future longitudinal studies should include this outcome for further validation. PMID:24625392

  1. Modulation of TGF-beta signaling during progression of chronic liver diseases.

    PubMed

    Matsuzaki, Koichi

    2009-01-01

    A large body of work has established roles for epithelial cells as important mediators of progressive fibrosis and carcinogenesis. Transforming growth factor-beta (TGF-beta) and pro-inflammatory cytokines are important inducers of fibro-carcinogenesis. TGF-beta signaling involves phosphorylation of Smad3 at middle linker and/or C-terminal regions. Reversible shifting of Smad3-dependent signaling between tumor-suppression and oncogenesis in hyperactive Ras-expressing epithelial cells indicates that Smad3 phosphorylated at the C-terminal region (pSmad3C) transmits a tumor-suppressive TGF-beta signal, while oncogenic activities such as cell proliferation and invasion are promoted by Smad3 phosphorylated at the linker region (pSmad3L). Notably, pSmad3L-mediated signaling promotes extracellular matrix deposition by activated mesenchymal cells. During progression of chronic liver diseases, hepatic epithelial hepatocytes undergo transition from the tumor-suppressive pSmad3C pathway to the fibrogenic/oncogenic pSmad3L pathway, accelerating liver fibrosis and increasing risk of hepatocellular carcinoma. c-Jun N-terminal kinase activated by pro-inflammatory cytokines is mediating this perturbed hepatocytic TGF-beta signaling. Thus, TGF-beta signaling of hepatocytes affected by chronic inflammation offers a general framework for understanding the molecular mechanisms of human fibro-carcinogenesis during progression of chronic liver diseases. PMID:19273245

  2. The Role of Dendritic Cells in Fibrosis Progression in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Almeda-Valdes, Paloma; Aguilar Olivos, Nancy E.; Barranco-Fragoso, Beatriz; Uribe, Misael; Méndez-Sánchez, Nahum

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease. NAFLD encompasses a wide range of pathologies, from simple steatosis to steatosis with inflammation to fibrosis. The pathogenesis of NAFLD progression has not been completely elucidated, and different liver cells could be implicated. This review focuses on the current evidence of the role of liver dendritic cells (DCs) in the progression from NAFLD to fibrosis. Liver DCs are a heterogeneous population of hepatic antigen-presenting cells; their main function is to induce T-cell mediated immunity by antigen processing and presentation to T cells. During the steady state liver DCs are immature and tolerogenic. However, in an environment of chronic inflammation, DCs are transformed to potent inducers of immune responses. There is evidence about the role of DC in liver fibrosis, but it is not clearly understood. Interestingly, there might be a link between lipid metabolism and DC function, suggesting that immunogenic DCs are associated with liver lipid storage, representing a possible pathophysiological mechanism in NAFLD development. A better understanding of the interaction between inflammatory pathways and the different cell types and the effect on the progression of NAFLD is of great relevance. PMID:26339640

  3. Reconsidering harbingers of dementia: progression of parietal lobe white matter hyperintensities predicts Alzheimer's disease incidence.

    PubMed

    Brickman, Adam M; Zahodne, Laura B; Guzman, Vanessa A; Narkhede, Atul; Meier, Irene B; Griffith, Erica Y; Provenzano, Frank A; Schupf, Nicole; Manly, Jennifer J; Stern, Yaakov; Luchsinger, José A; Mayeux, Richard

    2015-01-01

    Accumulating evidence implicates small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging, in the pathogenesis and diagnosis of Alzheimer's disease (AD). Cross-sectional volumetric measures of WMH, particularly in the parietal lobes, are associated with increased risk of AD. In the present study, we sought to determine whether the longitudinal regional progression of WMH predicts incident AD above-and-beyond traditional radiological markers of neurodegeneration (i.e., hippocampal atrophy and cortical thickness). Three hundred three nondemented older adults (mean age = 79.24 ± 5.29) received high-resolution magnetic resonance imaging at baseline and then again 4.6 years (standard deviation = 1.01) later. Over the follow-up interval 26 participants progressed to AD. Using structural equation modeling, we calculated latent difference scores of parietal and nonparietal WMH, hippocampus volumes, and cortical thickness values in AD-related regions. Within the structural equation modeling framework, we determined whether baseline or change scores or both predicted AD conversion, while controlling for several time-invariant relevant variables. Smaller baseline hippocampus volume, change in hippocampus volume (i.e., atrophy), higher baseline parietal lobe WMH, and increasing parietal lobe WMH volume but not WMH in other regions or measures of cortical thickness, independently predicted progression to AD. The findings provide strong evidence that regionally accumulating WMH predict AD onset in addition to hallmark neurodegenerative changes typically associated with AD. PMID:25155654

  4. Indexing Disease Progression at Study Entry with Individuals At-Risk for Huntington Disease

    PubMed Central

    Zhang, Ying; Long, Jeffrey D.; Mills, James A.; Warner, John H.; Lu, Wenjing; Paulsen, Jane S.

    2011-01-01

    The identification of clinical and biological markers of disease in persons at risk for Huntington Disease (HD) has increased in efforts to better quantify and characterize the epoch of prodrome prior to clinical diagnosis. Such efforts are critical in the design and implementation of clinical trials for HD so that interventions can occur at a time most likely to increase neuronal survival and maximize daily functioning. A prime consideration in the examination of prodromal individuals is their proximity to diagnosis. It is necessary to quantify proximity so that individual differences in key marker variables can be properly interpreted. We take a data-driven approach to develop an index that can be viewed as a proxy for time to HD diagnosis known as the CAG-Age Product Scaled or CAPS. CAPS is an observed utility variable computed for all genetically at-risk individuals based on age at study entry and CAG repeat length. Results of a longitudinal receiver operating characteristic (ROC) analysis showed that CAPS had a relatively strong ability to predict individuals who became diagnosed, especially in the first 2 years. Bootstrap validation provided evidence that CAPS computed on a new sample from the same population could have similar discriminatory power. Cutoffs for the empirical CAPS distribution can be used to create a classification for mutation-positive individuals (Low-Med-High) that is useful for comparison with the naturally occurring mutation-negative Control group. The classification is an improvement over the one currently in use as it is based on observed data rather than model-based estimated values. PMID:21858921

  5. Indexing disease progression at study entry with individuals at-risk for Huntington disease.

    PubMed

    Zhang, Ying; Long, Jeffrey D; Mills, James A; Warner, John H; Lu, Wenjing; Paulsen, Jane S

    2011-12-01

    The identification of clinical and biological markers of disease in persons at risk for Huntington disease (HD) has increased in efforts to better quantify and characterize the epoch of prodrome prior to clinical diagnosis. Such efforts are critical in the design and implementation of clinical trials for HD so that interventions can occur at a time most likely to increase neuronal survival and maximize daily functioning. A prime consideration in the examination of prodromal individuals is their proximity to diagnosis. It is necessary to quantify proximity so that individual differences in key marker variables can be properly interpreted. We take a data-driven approach to develop an index that can be viewed as a proxy for time to HD diagnosis known as the CAG-Age Product Scaled or CAP(S) . CAP(S) is an observed utility variable computed for all genetically at-risk individuals based on age at study entry and CAG repeat length. Results of a longitudinal receiver operating characteristic (ROC) analysis showed that CAP(S) had a relatively strong ability to predict individuals who became diagnosed, especially in the first 2 years. Bootstrap validation provided evidence that CAP(S) computed on a new sample from the same population could have similar discriminatory power. Cutoffs for the empirical CAP(S) distribution can be used to create a classification for mutation-positive individuals (Low-Med-High), which is, useful for comparison with the naturally occurring mutation-negative Control group. The classification is an improvement over the one currently in use as it is based on observed data rather than model-based estimated values. © 2011 Wiley-Liss, Inc. PMID:21858921

  6. Predicting the Impact of CD8+ T Cell Polyfunctionality on HIV Disease Progression

    PubMed Central

    Regoes, Roland R.

    2014-01-01

    ABSTRACT During the chronic phase of HIV-1 infection, polyfunctional CD8+ T cell responses, which are characterized by a high frequency of cells able to secrete multiple cytokines simultaneously, are associated with lower virus loads and slower disease progression. This relationship may arise for different reasons. Polyfunctional responses may simply be stronger. Alternatively, it could be that the increased functional diversity in polyfunctional responses leads to lower virus loads and slower disease progression. Lastly, polyfunctional responses could contain more CD8+ T cells that mediate a specific key function that is primarily responsible for viral control. Disentangling the influences of overall strength, functional diversity, and specific function on viral control and disease progression is very relevant for the rational design of vaccines and immunotherapy using cellular immune responses. We developed a mathematical model to study how polyfunctional CD8+ T cell responses mediating lytic and nonlytic effector functions affect the CD4+ T cell count and plasma viral load. We based our model on in vitro data on the efficacy of gamma interferon (IFN-?) and macrophage inflammatory protein 1? (MIP-1?)/RANTES against HIV. We find that the strength of the response is a good predictor of disease progression, while functional diversity has only a minor influence. In addition, our model predicts for realistic levels of cytotoxicity that immune responses dominated by nonlytic effector functions most positively influence disease outcome. IMPORTANCE It is an open question in HIV research why polyfunctional CD8+ T cell responses are associated with better viral control, while individual functional correlates of protection have not been identified so far. Identifying the role of CD8+ T cells in HIV-1 infection has important implications for the potential development of effective T cell-based vaccines. Our analysis provides new ways to think about a causative role of CD8+ T cells by studying different hypotheses regarding why polyfunctional CD8+ T cells might be more advantageous. We identify measurements that have to be obtained in order to evaluate the role of CD8+ T cells in HIV-1 infection. In addition, our method shows how individual cell functionality data can be used in population-based virus dynamics models. PMID:24965450

  7. MR of brain involvement in progressive facial hemiatrophy (Romberg disease): Reconsideration of a syndrome

    SciTech Connect

    Terstegge, K.; Hosten, N. ); Kunath, B. ); Felber, S.; Henkes, H. ); Speciali, J.G. )

    1994-01-01

    To gain further insight into the pathogenesis of progressive facial hemiatrophy, a sporadic disease of unclear etiology characterized by shrinking and deformation of one side of the face. We investigated possible brain involvement. MR of the head and face was performed in three female patients with progressive facial hemiatrophy. The central-nervous-system findings were correlated to a clinical protocol and a review of the literature. One patient with epilepsy had abnormal brain findings confined to the cerebral hemisphere homolateral to the facial hemiatrophy. These consisted of monoventricular enlargement, meningocortical dysmorphia, and white-matter changes. These MR findings, and corresponding neuroradiologic data disclosed by the review, indicate that homolateral hemiatrophy occasionally occurs in a subgroup of patients with progressive facial hemiatrophy. The MR features do not seem consistent with an underlying simple or nutritive atrophic process. We propose chronic localized meningoencephalitis with vascular involvement as a possible underlying cause of the occasional brain involvement in progressive facial hemiatrophy. 29 refs., 2 figs.

  8. Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression.

    PubMed

    Zhang, Yujin; Berka, Vladimir; Song, Anren; Sun, Kaiqi; Wang, Wei; Zhang, Weiru; Ning, Chen; Li, Chonghua; Zhang, Qibo; Bogdanov, Mikhail; Alexander, Danny C; Milburn, Michael V; Ahmed, Mostafa H; Lin, Han; Idowu, Modupe; Zhang, Jun; Kato, Gregory J; Abdulmalik, Osheiza Y; Zhang, Wenzheng; Dowhan, William; Kellems, Rodney E; Zhang, Pumin; Jin, Jianping; Safo, Martin; Tsai, Ah-Lim; Juneja, Harinder S; Xia, Yang

    2014-06-01

    Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates multicellular functions through interactions with its receptors on cell surfaces. S1P is enriched and stored in erythrocytes; however, it is not clear whether alterations in S1P are involved in the prevalent and debilitating hemolytic disorder sickle cell disease (SCD). Here, using metabolomic screening, we found that S1P is highly elevated in the blood of mice and humans with SCD. In murine models of SCD, we demonstrated that elevated erythrocyte sphingosine kinase 1 (SPHK1) underlies sickling and disease progression by increasing S1P levels in the blood. Additionally, we observed elevated SPHK1 activity in erythrocytes and increased S1P in blood collected from patients with SCD and demonstrated a direct impact of elevated SPHK1-mediated production of S1P on sickling that was independent of S1P receptor activation in isolated erythrocytes. Together, our findings provide insights into erythrocyte pathophysiology, revealing that a SPHK1-mediated elevation of S1P contributes to sickling and promotes disease progression, and highlight potential therapeutic opportunities for SCD. PMID:24837436

  9. Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression

    PubMed Central

    Zhang, Yujin; Berka, Vladimir; Song, Anren; Sun, Kaiqi; Wang, Wei; Zhang, Weiru; Ning, Chen; Li, Chonghua; Zhang, Qibo; Bogdanov, Mikhail; Alexander, Danny C.; Milburn, Michael V.; Ahmed, Mostafa H.; Lin, Han; Idowu, Modupe; Zhang, Jun; Kato, Gregory J.; Abdulmalik, Osheiza Y.; Zhang, Wenzheng; Dowhan, William; Kellems, Rodney E.; Zhang, Pumin; Jin, Jianping; Safo, Martin; Tsai, Ah-Lim; Juneja, Harinder S.; Xia, Yang

    2014-01-01

    Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates multicellular functions through interactions with its receptors on cell surfaces. S1P is enriched and stored in erythrocytes; however, it is not clear whether alterations in S1P are involved in the prevalent and debilitating hemolytic disorder sickle cell disease (SCD). Here, using metabolomic screening, we found that S1P is highly elevated in the blood of mice and humans with SCD. In murine models of SCD, we demonstrated that elevated erythrocyte sphingosine kinase 1 (SPHK1) underlies sickling and disease progression by increasing S1P levels in the blood. Additionally, we observed elevated SPHK1 activity in erythrocytes and increased S1P in blood collected from patients with SCD and demonstrated a direct impact of elevated SPHK1-mediated production of S1P on sickling that was independent of S1P receptor activation in isolated erythrocytes. Together, our findings provide insights into erythrocyte pathophysiology, revealing that a SPHK1-mediated elevation of S1P contributes to sickling and promotes disease progression, and highlight potential therapeutic opportunities for SCD. PMID:24837436

  10. Progress of mesenchymal stem cell therapy for neural and retinal diseases

    PubMed Central

    Ng, Tsz Kin; Fortino, Veronica R; Pelaez, Daniel; Cheung, Herman S

    2014-01-01

    Complex circuitry and limited regenerative power make central nervous system (CNS) disorders the most challenging and difficult for functional repair. With elusive disease mechanisms, traditional surgical and medical interventions merely slow down the progression of the neurodegenerative diseases. However, the number of neurons still diminishes in many patients. Recently, stem cell therapy has been proposed as a viable option. Mesenchymal stem cells (MSCs), a widely-studied human adult stem cell population, have been discovered for more than 20 years. MSCs have been found all over the body and can be conveniently obtained from different accessible tissues: bone marrow, blood, and adipose and dental tissue. MSCs have high proliferative and differentiation abilities, providing an inexhaustible source of neurons and glia for cell replacement therapy. Moreover, MSCs also show neuroprotective effects without any genetic modification or reprogramming. In addition, the extraordinary immunomodulatory properties of MSCs enable autologous and heterologous transplantation. These qualities heighten the clinical applicability of MSCs when dealing with the pathologies of CNS disorders. Here, we summarize the latest progress of MSC experimental research as well as human clinical trials for neural and retinal diseases. This review article will focus on multiple sclerosis, spinal cord injury, autism, glaucoma, retinitis pigmentosa and age-related macular degeneration. PMID:24772238

  11. Identification of MMP-9 as a biomarker for detecting progression of chronic obstructive pulmonary disease.

    PubMed

    Abd El-Fatah, Marwa F; Ghazy, Mohamed A; Mostafa, Mohamed S; El-Attar, May M; Osman, Ahmed

    2015-12-01

    Chronic obstructive pulmonary disease (COPD) is a complex immunological disease with multiple pathological features that is primarily induced by smoking together with additional genetic risk factors. COPD is frequently underdiagnosed; forced expiratory volume in the first second (FEV1) is considered to be the main diagnostic measure for COPD, yet it is insufficiently sensitive to monitor disease progression. Biomarkers capable of monitoring COPD progression and severity are needed. In this report, we evaluated matrix metalloproteinase-9 (MMP-9) as an early marker for the detection and staging of COPD, by assessing the mRNA levels of MMP-9 in peripheral blood samples collected from 22 COPD patients, 6 asymptomatic smokers, and 5 healthy controls. Our results demonstrate that the mRNA levels of MMP-9 increased more than two-fold in severe COPD relative to non-COPD smokers or moderate COPD groups. Moreover, in the very severe COPD group, MMP-9 mRNA levels showed a 4-fold increase relative to the non-COPD smokers or the moderate COPD groups, while there was a mild increase (?40%) when compared to the severe COPD group. Taken together, our results suggest that MMP-9 serves as a biomarker for the grade and severity of COPD. PMID:26291981

  12. Chronic Kidney Disease Progression in Elderly Iranian Patients: A Cohort Study

    PubMed Central

    Shojamoradi, Mohammad Hossein; Saberi Isfeedvajani, Mohsen; Mahdavi-Mazdeh, Mitra; Ahmadi, Farrokhlagha; Gatmiri, Seyed Mansour; Abbasi Larki, Rozina

    2014-01-01

    Background: In the past few decades, Chronic Kidney Disease (CKD) - a disease with progressive decline in renal function - has become an important problem of global public health, not only in developed countries, but also in developing countries with less economic power. Objectives: In this study, CKD progression to death or End Stage Renal Disease (ESRD) in elderly Iranian patients was compared with younger counterparts. Patients and Methods: This retrospective cohort study was conducted on CKD patients with estimated Glomerular Filtration Rate (eGFR) < 60 mL/min, in a nephrology clinic in Tehran from December of 2006 until December of 2012. eGFR trend, death and need to renal replacement therapy (RRT) were evaluated as outcomes and compared between patients younger and older than 60 years. Data were analyzed using SPSS version 13. Results: Five-hundred and two patients were enrolled and followed up for an average of 37.6 months. Two thirds of the patients were older than 60 years. The incidence density of ESRD in patients younger and older than 60 years were 6.3 and 3.6 for 100 persons per year, respectively. Younger ones showed more rapid decline in their eGFR, while older patients had more stable renal function. Conclusions: It seems necessary to conduct more researches in order to redefine CKD and identify its prognostic markers in elderly population. PMID:25695035

  13. Chronic Alcohol Abuse and HIV Disease Progression: Studies with the Non-Human Primate Model

    PubMed Central

    Amedee, Angela M.; Nichols, Whitney A.; Robichaux, Spencer; Bagby, Gregory J.; Nelson, Steve

    2015-01-01

    The populations at risk for HIV infection, as well as those living with HIV, overlap with populations that engage in heavy alcohol consumption. Alcohol use has been associated with high-risk sexual behavior and an increased likelihood of acquiring HIV, as well as poor outcome measures of disease such as increased viral loads and declines in CD4+ T lymphocytes among those living with HIV-infections. It is difficult to discern the biological mechanisms by which alcohol use affects the virus:host interaction in human populations due to the numerous variables introduced by human behavior. The rhesus macaque infected with simian immunodeficiency virus has served as an invaluable model for understanding HIV disease and transmission, and thus, provides an ideal model to evaluate the effects of chronic alcohol use on viral infection and disease progression in a controlled environment. In this review, we describe the different macaque models of chronic alcohol consumption and summarize the studies conducted with SIV and alcohol. Collectively, they have shown that chronic alcohol consumption results in higher levels of plasma virus and alterations in immune cell populations that potentiate SIV replication. They also demonstrate a significant impact of chronic alcohol use on SIV-disease progression and survival. These studies highlight the utility of the rhesus macaque in deciphering the biological effects of alcohol on HIV disease. Future studies with this well-established model will address the biological influence of alcohol use on susceptibility to HIV, as well as the efficacy of anti-retroviral therapy. PMID:25053367

  14. Longitudinal deformation models, spatial regularizations and learning strategies to quantify Alzheimer's disease progression

    PubMed Central

    Fiot, Jean-Baptiste; Raguet, Hugo; Risser, Laurent; Cohen, Laurent D.; Fripp, Jurgen; Vialard, François-Xavier

    2014-01-01

    In the context of Alzheimer's disease, two challenging issues are (1) the characterization of local hippocampal shape changes specific to disease progression and (2) the identification of mild-cognitive impairment patients likely to convert. In the literature, (1) is usually solved first to detect areas potentially related to the disease. These areas are then considered as an input to solve (2). As an alternative to this sequential strategy, we investigate the use of a classification model using logistic regression to address both issues (1) and (2) simultaneously. The classification of the patients therefore does not require any a priori definition of the most representative hippocampal areas potentially related to the disease, as they are automatically detected. We first quantify deformations of patients' hippocampi between two time points using the large deformations by diffeomorphisms framework and transport these deformations to a common template. Since the deformations are expected to be spatially structured, we perform classification combining logistic loss and spatial regularization techniques, which have not been explored so far in this context, as far as we know. The main contribution of this paper is the comparison of regularization techniques enforcing the coefficient maps to be spatially smooth (Sobolev), piecewise constant (total variation) or sparse (fused LASSO) with standard regularization techniques which do not take into account the spatial structure (LASSO, ridge and ElasticNet). On a dataset of 103 patients out of ADNI, the techniques using spatial regularizations lead to the best classification rates. They also find coherent areas related to the disease progression. PMID:24936423

  15. Progression of mild Alzheimer’s disease: knowledge and prediction models required for future treatment strategies

    PubMed Central

    2013-01-01

    Introduction Knowledge of longitudinal progression in mild Alzheimer’s disease (AD) is required for the evaluation of disease-modifying therapies. Our aim was to observe the effects of long-term cholinesterase inhibitor (ChEI) therapy in mild AD patients in a routine clinical setting. Methods This was a prospective, open-label, non-randomized, multicenter study of ChEI treatment (donepezil, rivastigmine or galantamine) conducted during clinical practice. The 734 mild AD patients (Mini-Mental State Examination (MMSE) score 20 to 26) were assessed at baseline and then semi-annually over three years. Outcome measures included the MMSE, Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), Clinician’s Interview-Based Impression of Change (CIBIC) and Instrumental Activities of Daily Living (IADL) scale. Results After three years of ChEI therapy, 31% (MMSE) and 33% (ADAS-cog) of the patients showed improved/unchanged cognitive ability, 33% showed improved/unchanged global performance and 14% showed improved/unchanged IADL capacity. Higher mean dose of ChEI and lower educational level were both predictors of more positive longitudinal cognitive and functional outcomes. Older participants and those with a better IADL score at baseline exhibited a slower rate of cognitive decline, whereas younger participants and those with higher cognitive status showed more preserved IADL ability over time. Gender and apolipoprotein E (APOE) genotype showed inconsistent results. Prediction models using the abovementioned scales are presented. Conclusions In naturalistic mild AD patients, a marked deterioration in IADL compared with cognitive and global long-term outcomes was observed, indicating the importance of functional assessments during the early stages of the disease. The participants’ time on ChEI treatment before inclusion in studies of new therapies might affect their rate of decline and thus the comparisons of changes in scores between various studies. An increased understanding of expected disease progression in different domains and potential predictors of disease progression is essential for assessment of future therapies in AD. PMID:24099236

  16. Variable course of primary simian immunodeficiency virus infection in lymph nodes: relation to disease progression.

    PubMed Central

    Chakrabarti, L; Cumont, M C; Montagnier, L; Hurtrel, B

    1994-01-01

    To investigate the dynamics of spread of simian immunodeficiency virus (SIV) in the lymphoid organs, we sequentially analyzed the viral burden in lymph nodes (LN) of eight rhesus macaques inoculated intravenously with a high or low dose of the pathogenic SIVmac 251 isolate. For each animal, four axillary or inguinal LN were collected during the first weeks of infection and a fifth LN was taken 6 or 8 months later to estimate disease progression. Measurement of SIV RNA by in situ hybridization showed that all of the macaques studied had a phase of acute viral replication in LN between 7 and 14 days postinoculation which paralleled that observed in the blood. In a second phase, productive infection was controlled and viral particles were trapped in the germinal centers that developed in LN. While the peaks of productive infection were similar for the eight animals, marked differences in the numbers of productively infected cells that persisted in LN after primary infection were seen. Differences were less pronounced in the blood, where productive infection was efficiently controlled in all cases. The persistence of productively infected cells in LN after primary infection was found to be associated with more rapid disease progression, as measured by the decrease of the T4/T8 ratio and the occurrence of clinical signs. However, the persistence of a significant level of viral particles in germinal centers was observed even in animals that remained healthy over a 1- to 2-year observation period. This study indicates that the course of primary SIV infection in LN is variable, and it suggests that the initial capacity of the host to control productive infection in LN may determine the rate of disease progression. Images PMID:7916061

  17. Transmission and Progression to Disease of Mycobacterium tuberculosis Phylogenetic Lineages in The Netherlands.

    PubMed

    Nebenzahl-Guimaraes, Hanna; Verhagen, Lilly M; Borgdorff, Martien W; van Soolingen, Dick

    2015-10-01

    The aim of this study was to determine if mycobacterial lineages affect infection risk, clustering, and disease progression among Mycobacterium tuberculosis cases in The Netherlands. Multivariate negative binomial regression models adjusted for patient-related factors and stratified by patient ethnicity were used to determine the association between phylogenetic lineages and infectivity (mean number of positive contacts around each patient) and clustering (as defined by number of secondary cases within 2 years after diagnosis of an index case sharing the same fingerprint) indices. An estimate of progression to disease by each risk factor was calculated as a bootstrapped risk ratio of the clustering index by the infectivity index. Compared to the Euro-American reference, Mycobacterium africanum showed significantly lower infectivity and clustering indices in the foreign-born population, while Mycobacterium bovis showed significantly lower infectivity and clustering indices in the native population. Significantly lower infectivity was also observed for the East African Indian lineage in the foreign-born population. Smear positivity was a significant risk factor for increased infectivity and increased clustering. Estimates of progression to disease were significantly associated with age, sputum-smear status, and behavioral risk factors, such as alcohol and intravenous drug abuse, but not with phylogenetic lineages. In conclusion, we found evidence of a bacteriological factor influencing indicators of a strain's transmissibility, namely, a decreased ability to infect and a lower clustering index in ancient phylogenetic lineages compared to their modern counterparts. Confirmation of these findings via follow-up studies using tuberculin skin test conversion data should have important implications on M. tuberculosis control efforts. PMID:26224845

  18. Comparison of motor, cognitive, and behavioral features in progressive supranuclear palsy and Parkinson's disease.

    PubMed

    Cordato, Nicholas J; Halliday, Glenda M; Caine, Diana; Morris, John G L

    2006-05-01

    Major clinical features and global measures were systematically evaluated and compared in progressive supranuclear palsy (PSP) and Parkinson's disease (PD). In addition to gaze palsy and early postural instability in PSP, absence of levodopa-induced dyskinesia, frontalis muscle overactivity, primitive reflexes, visuospatial impairment, and substantial frontal behavioral disturbances differentiated almost all patients with this disorder from PD. For PSP, behavioral changes related to severity of general disability, thereby challenging previous models of relationships between behavior, motor, and cognitive disturbance for this disorder. PMID:16353177

  19. Outcome Measures in Relapsing-Remitting Multiple Sclerosis: Capturing Disability and Disease Progression in Clinical Trials

    PubMed Central

    Lavery, Amy M.; Verhey, Leonard H.; Waldman, Amy T.

    2014-01-01

    Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease that manifests as acute relapses and progressive disability. As a primary endpoint for clinical trials in MS, disability is difficult to both characterize and measure. Furthermore, the recovery from relapses and the rate of disability vary considerably among patients. Given these challenges, investigators have developed and studied the performance of various outcome measures and surrogate endpoints in MS clinical trials. This review defines the outcome measures and surrogate endpoints used to date in MS clinical trials and presents challenges in the design of both adult and pediatric trials. PMID:24883205

  20. Rapid Disease Progression in HIV-1 Subtype C–Infected South African Women

    PubMed Central

    Mlisana, Koleka; Werner, Lise; Garrett, Nigel J.; McKinnon, Lyle R.; van Loggerenberg, Francois; Passmore, Jo-Ann S.; Gray, Clive M.; Morris, Lynn; Williamson, Carolyn; Abdool Karim, Salim S.

    2014-01-01

    Background.?Whereas human immunodeficiency virus (HIV) subtype B–infected individuals generally progress to AIDS within 8–10 years, limited data exist for other clades, especially from Africa. We investigated rates of HIV disease progression of clade C–infected South African women. Methods.?Prospective seroincidence cohorts in KwaZulu-Natal were assessed for acute HIV infection monthly (n = 245) or every 3 months (n = 594) for up to 4 years. Rapid disease progression was defined as CD4 decline to <350 cells/µL by 2 years postinfection. Serial clinical and laboratory assessments were compared using survival analysis and logistic regression models. Results.?Sixty-two women were identified at a median of 42 days postinfection (interquartile range, 34–59), contributing 282 person-years of follow-up. Mean CD4 count dropped by 39.6% at 3 months and 46.7% at 6 months postinfection in women with preinfection measurements. CD4 decline to <350 cells/µL occurred in 31%, 44%, and 55% of women at 1, 2, and 3 years postinfection, respectively, and to <500 cells/µL in 69%, 79%, and 81% at equivalent timepoints. Predictors of rapid progression were CD4 count at 3 months postinfection (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.31–3.28; P = .002), setpoint viral load (HR, 3.82; 95% CI, 1.51–9.67; P = .005), and hepatitis B coinfection (HR, 4.54; 95% CI, 1.31–15.69; P = .017). Conversely, presence of any of HLAB*1302, B*27, B*57, B*5801, or B*8101 alleles predicted non–rapid progression (HR, 0.19; 95% CI, .05–.74; P = .016). Conclusions.?Nearly half of subtype C–infected women progressed to a CD4 count <350 cells/µL within 2 years of infection. Implementing 2013 World Health Organization treatment guidelines (CD4 count <500 cells/µL) would require most individuals to start antiretroviral therapy within 1 year of HIV infection. PMID:25038116

  1. Mechanisms of disease: epithelial-mesenchymal transition and back again: does cellular plasticity fuel neoplastic progression?

    SciTech Connect

    Bissell, Mina J; Turley, Eva A.; Veiseh, Mandana; Radisky, Derek C.; Bissell, Mina J.

    2008-02-13

    Epithelial-mesenchymal transition (EMT) is a conversion that facilitates organ morphogenesis and tissue remodeling in physiological processes such as embryonic development and wound healing. A similar phenotypic conversion is also detected in fibrotic diseases and neoplasia, which is associated with disease progression. EMT in cancer epithelial cells often seems to be an incomplete and bi-directional process. In this Review, we discuss the phenomenon of EMT as it pertains to tumor development, focusing on exceptions to the commonly held rule that EMT promotes invasion and metastasis. We also highlight the role of the RAS-controlled signaling mediators, ERK1, ERK2 and PI3-kinase, as microenvironmental responsive regulators of EMT.

  2. Delayed Disease Progression in Cynomolgus Macaques Infected with Ebola Virus Makona Strain

    PubMed Central

    Marzi, Andrea; Feldmann, Friederike; Hanley, Patrick W.; Scott, Dana P.; Günther, Stephan

    2015-01-01

    In late 2013, the largest documented outbreak of Ebola hemorrhagic fever started in Guinea and has since spread to neighboring countries, resulting in almost 27,000 cases and >11,000 deaths in humans. In March 2014, Ebola virus (EBOV) was identified as the causative agent. This study compares the pathogenesis of a new EBOV strain, Makona, which was isolated in Guinea in 2014 with the prototype strain from the 1976 EBOV outbreak in the former Zaire. Both strains cause lethal disease in cynomolgus macaques with similar pathologic changes and hallmark features of Ebola hemorrhagic fever. However, disease progression was delayed in EBOV-Makona–infected animals, suggesting decreased rather than increased virulence of this most recent EBOV strain. PMID:26402165

  3. Predicting disease progression from short biomarker series using expert advice algorithm

    NASA Astrophysics Data System (ADS)

    Morino, Kai; Hirata, Yoshito; Tomioka, Ryota; Kashima, Hisashi; Yamanishi, Kenji; Hayashi, Norihiro; Egawa, Shin; Aihara, Kazuyuki

    2015-05-01

    Well-trained clinicians may be able to provide diagnosis and prognosis from very short biomarker series using information and experience gained from previous patients. Although mathematical methods can potentially help clinicians to predict the progression of diseases, there is no method so far that estimates the patient state from very short time-series of a biomarker for making diagnosis and/or prognosis by employing the information of previous patients. Here, we propose a mathematical framework for integrating other patients' datasets to infer and predict the state of the disease in the current patient based on their short history. We extend a machine-learning framework of ``prediction with expert advice'' to deal with unstable dynamics. We construct this mathematical framework by combining expert advice with a mathematical model of prostate cancer. Our model predicted well the individual biomarker series of patients with prostate cancer that are used as clinical samples.

  4. Chronic ?9-Tetrahydrocannabinol Administration May Not Attenuate Simian Immunodeficiency Virus Disease Progression in Female Rhesus Macaques

    PubMed Central

    Amedee, Angela M.; Nichols, Whitney A.; LeCapitaine, Nicole J.; Stouwe, Curtis Vande; Birke, Leslie L.; Lacour, Nedra; Winsauer, Peter J.

    2014-01-01

    Abstract Persons living with HIV/AIDS (PLWHA) frequently use cannabinoids, either recreationally by smoking marijuana or therapeutically (delta-9-tetrahydrocannabinol; ?9-THC dronabinol). Previously, we demonstrated that chronic ?9-THC administration decreases early mortality in male simian immunodeficiency virus (SIV)-infected macaques. In this study, we sought to examine whether similar protective effects resulted from chronic cannabinoid administration in SIV-infected female rhesus macaques. Clinical and viral parameters were evaluated in eight female rhesus macaques that received either ?9-THC (0.18–0.32?mg/kg, intramuscularly, twice daily) or vehicle (VEH) starting 28 days prior to intravenous inoculation with SIVmac251. SIV disease progression was assessed by changes in body weight, mortality, viral levels in plasma and mucosal sites, and lymphocyte subsets. In contrast to our results in male animals, chronic ?9-THC did not protect SIV-infected female rhesus macaques from early mortality. Markers of SIV disease, including viral load and CD4+/CD8+ ratio, were not altered by ?9-THC compared to control females; however, females that received chronic ?9-THC did not gain as much weight as control animals. In addition, ?9-THC administration increased total CXCR4 expression in both peripheral and duodenal CD4+ and CD8+ T lymphocytes prior to SIV inoculation. Although protection from early mortality was not evident, chronic ?9-THC did not affect clinical markers of SIV disease progression. The contrasting effects of chronic ?9-THC in males versus females remain to be explained, but highlight the need for further studies to explore the sex-dependent effects of ?9-THC and other cannabinoids on the HIV disease course and their implications for virus transmission. PMID:25113915

  5. Marsh el al. Dugongs in health and disease Dugongs in Health and Disease

    E-print Network

    Marsh, Helene

    ProtectionandBiodiversity Cow ervationAct I 999 (Cwlth); . Vulnerableunderschedule3 of the NafiireConservation); . SpeciallyPrctectedrmdertke Wildlife ConservationAct 1950(V,/A). . ProtectedundertheNationalPqrksand WildlifeAct ACKNOWLEDGEMENTS REFERENCES 301 #12;Marsh et al. 1.0 STATUS l.l General Thedugongis listedin The World Conservation

  6. A repetitive peptide of Leishmania can activate T helper type 2 cells and enhance disease progression

    PubMed Central

    1990-01-01

    Leishmaniasis provides a biologically relevant model to analyze the heterogeneity of CD4+ T cells and may lead to answering the major question of the mechanism for the preferential induction of T helper type 1 (Th1) and Th2 cells. Using synthetic peptides corresponding to the tandemly repeating regions of Leishmania proteins, we have identified an epitope that can preferentially induce the disease- exacerbating Th2 cells in susceptible BALB/c mice. Lymph node cells from BALB/c mice immunized subcutaneously with the octamer (p183) of the repeating 10-mer peptide EAEEAARLQA proliferated strongly against the peptide as well as the soluble antigen extract (SolAg) of Leishmania major. The proliferative T cells are CD4+, major histocompatibility complex class II restricted, and secrete interleukin 4 (IL-4) but little or no IL-2 and interferon gamma when stimulated with the peptide in vitro. T cells from BALB/c mice with progressive disease, but not from BALB/c mice cured of the infection, recognized this epitope. BALB/c mice injected subcutaneously with p183 developed significantly exacerbated disease when subsequently challenged with L. major. Furthermore, subcutaneous injection with p183 prevented the subsequent induction of resistance against L. major by intravenous immunization with soluble antigen. The T cell response to p183 is H-2d restricted. Immunization of the genetically resistant B10.D2 mice with p183 also produced strong T cell responses and exacerbated disease when challenged with L. major. PMID:2146362

  7. Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity.

    PubMed

    Mitra, A; MacIntyre, D A; Lee, Y S; Smith, A; Marchesi, J R; Lehne, B; Bhatia, R; Lyons, D; Paraskevaidis, E; Li, J V; Holmes, E; Nicholson, J K; Bennett, P R; Kyrgiou, M

    2015-01-01

    Persistent infection with oncogenic Human Papillomavirus (HPV) is necessary for cervical carcinogenesis. Although evidence suggests that the vaginal microbiome plays a functional role in the persistence or regression of HPV infections, this has yet to be described in women with cervical intra-epithelial neoplasia (CIN). We hypothesised that increasing microbiome diversity is associated with increasing CIN severity. llumina MiSeq sequencing of 16S rRNA gene amplicons was used to characterise the vaginal microbiota of women with low-grade squamous intra-epithelial lesions (LSIL; n?=?52), high-grade (HSIL; n?=?92), invasive cervical cancer (ICC; n?=?5) and healthy controls (n?=?20). Hierarchical clustering analysis revealed an increased prevalence of microbiomes characterised by high-diversity and low levels of Lactobacillus spp. (community state type-CST IV) with increasing disease severity, irrespective of HPV status (Normal?=?2/20,10%; LSIL?=?11/52,21%; HSIL?=?25/92,27%; ICC?=?2/5,40%). Increasing disease severity was associated with decreasing relative abundance of Lactobacillus spp. The vaginal microbiome in HSIL was characterised by higher levels of Sneathia sanguinegens (P?disease severity is associated with increasing vaginal microbiota diversity and may be involved in regulating viral persistence and disease progression. PMID:26574055

  8. Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity

    PubMed Central

    Mitra, A.; MacIntyre, D. A.; Lee, Y. S.; Smith, A.; Marchesi, J. R.; Lehne, B.; Bhatia, R.; Lyons, D.; Paraskevaidis, E.; Li, J. V.; Holmes, E.; Nicholson, J. K.; Bennett, P. R.; Kyrgiou, M.

    2015-01-01

    Persistent infection with oncogenic Human Papillomavirus (HPV) is necessary for cervical carcinogenesis. Although evidence suggests that the vaginal microbiome plays a functional role in the persistence or regression of HPV infections, this has yet to be described in women with cervical intra-epithelial neoplasia (CIN). We hypothesised that increasing microbiome diversity is associated with increasing CIN severity. llumina MiSeq sequencing of 16S rRNA gene amplicons was used to characterise the vaginal microbiota of women with low-grade squamous intra-epithelial lesions (LSIL; n?=?52), high-grade (HSIL; n?=?92), invasive cervical cancer (ICC; n?=?5) and healthy controls (n?=?20). Hierarchical clustering analysis revealed an increased prevalence of microbiomes characterised by high-diversity and low levels of Lactobacillus spp. (community state type-CST IV) with increasing disease severity, irrespective of HPV status (Normal?=?2/20,10%; LSIL?=?11/52,21%; HSIL?=?25/92,27%; ICC?=?2/5,40%). Increasing disease severity was associated with decreasing relative abundance of Lactobacillus spp. The vaginal microbiome in HSIL was characterised by higher levels of Sneathia sanguinegens (P?disease severity is associated with increasing vaginal microbiota diversity and may be involved in regulating viral persistence and disease progression. PMID:26574055

  9. Incidence and Risk Factors for Progressive Multifocal Leukoencephalopathy among Patients with Selected Rheumatic Diseases

    PubMed Central

    Bharat, A; Xie, F; Baddley, JW; Beukelman, T; Chen, L; Calabrese, L; Delzell, E; Grijalva, CG; Patkar, N; Saag, K; Winthrop, K; Curtis, JR

    2011-01-01

    We conducted a large, population-based study to describe the incidence and risk factors for progressive multifocal leukoencephalopathy (PML) among patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (PsO), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), and ankylosing spondylitis (AS) using national inpatient and outpatient administrative data from the entire Center for Medicare and Medicaid Services (CMS) from 2000–2009. Suspected PML cases were identified using hospital discharge diagnosis codes. Risk factors for PML were evaluated using outpatient data >= 6 months prior to PML diagnosis. Among 2,030,578 patients with autoimmune diseases of interest, a total of 53 PML cases were identified (2.6/100,000 patients). Most PML cases had HIV and/or cancer. Nine PML cases had evidence for biologic use prior to PML hospitalization, of which 3 had neither HIV nor malignancy and were exposed to biologics within 12 (rituximab) or 6 months(all other biologics) prior to PML diagnosis. PML occurred at an estimated incidence of 0.2/100,000 patients with autoimmune diseases who did not have HIV or malignancy. PML occurs at a very low incidence among patients with rheumatic diseases but can occur even in the absence of HIV or malignancy. PMID:22162369

  10. The Quantitative Assessment of Imaging Features for the Study of Hirayama Disease Progression

    PubMed Central

    Shao, Minghao; Yin, Jun; Lu, Feizhou; Zheng, Chaojun; Wang, Hongli; Jiang, Jianyuan

    2015-01-01

    Objective. To evaluate the forward shifting of cervical spinal cords in different segments of patients with Hirayama disease to determine whether the disease is self-limiting. Methods. This study was performed on 11 healthy subjects and 64 patients. According to the duration, the patients were divided into 5 groups (?1 year, 1-2 years, 2-3 years, 3-4 years, and ?4 years). Cervical magnetic resonance imaging (MRI) of flexion and conventional position was performed. The distances between the posterior edge of the spinal cord and the cervical spinal canal (X), the anterior and posterior wall of the cervical spinal canal (Y), and the anterior-posterior (A) and the transverse diameter (B) of spinal cord cross sections were measured at different cervical spinal segments (C4 to T1). Results. In cervical flexion position, a significant increase in X/Y of C4-5 segments was found in groups 2–5, the C5-6 and C6-7 segments in groups 1–5, and the C7-T1 segments in group 5 (P < 0.05). The degree of the increased X/Y and cervical flexion X/Y of C5-6 segments were different among the 5 groups (P < 0.05), which was likely due to rapid increases in X/Y during the course of Hirayama's disease. Conclusion. The X/Y change progression indicates that Hirayama disease may not be self-limiting. PMID:26558283

  11. Mixed connective tissue disease presenting with progressive scleroderma symptoms in a 10-year-old girl

    PubMed Central

    Latu?kiewicz-Potemska, Joanna; Biernacka-Zieli?ska, Ma?gorzata; Sta?czyk, Jerzy; Smolewska, El?bieta

    2013-01-01

    Mixed connective tissue disease (MCTD) is a systemic inflammatory disease affecting connective tissue with the underlying autoimmunological mechanism. The core of MCTD is an appearance of symptoms of several other inflammatory diseases of connective tissue – systemic lupus erythematosus, systemic scleroderma, poly- or dermatomyositis, rheumatoid arthritis at the same time, accompanied by a high level of anti-ribonucleoprotein antibodies (anti-U1RNP). The disease was described more than 40 years ago by Sharp et al. During recent years, many efforts to better understand clinical and serological features of MCTD have been made. Diagnosis of MCTD can be difficult. Obligatory international diagnostic criteria are required to be fulfilled. Several versions of such criteria have been proposed, but the most widely used one was described by Kasukawa. There is no consensus about treatment – a choice of drugs depends on symptoms. We present a case of a 10-year-old girl with sclerodactyly and trophic damages of fingers accompanied by symptoms of Raynaud's phenomenon. After an almost 2-year course of the disease, a diagnosis of MCTD has been established. PMID:24353496

  12. Penalized regression for interval-censored times of disease progression: Selection of HLA markers in psoriatic arthritis.

    PubMed

    Wu, Ying; Cook, Richard J

    2015-09-01

    Times of disease progression are interval-censored when progression status is only known at a series of assessment times. This situation arises routinely in clinical trials and cohort studies when events of interest are only detectable upon imaging, based on blood tests, or upon careful clinical examination. We consider the problem of selecting important prognostic biomarkers from a large set of candidates when disease progression status is only known at irregularly spaced and individual-specific assessment times. Penalized regression techniques (e.g., LASSO, adaptive LASSO, and SCAD) are adapted to handle interval-censored time of disease progression. An expectation-maximization algorithm is described which is empirically shown to perform well. Application to the motivating study of the development of arthritis mutilans in patients with psoriatic arthritis is given and several important human leukocyte antigen (HLA) variables are identified for further investigation. PMID:25773729

  13. Hepcidin-25 in Diabetic Chronic Kidney Disease Is Predictive for Mortality and Progression to End Stage Renal Disease

    PubMed Central

    Wagner, Martin; Ashby, Damien R.; Kurtz, Caroline; Alam, Ahsan; Busbridge, Mark; Raff, Ulrike; Zimmermann, Josef; Heuschmann, Peter U.; Wanner, Christoph; Schramm, Lothar

    2015-01-01

    Background Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD). It may be explained by reduced erythropoietin (EPO) synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25—the key hormone of iron-metabolism—on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels. Methods 249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD), were enrolled (2003–2005), if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine) were analyzed by Cox proportional hazards models. Results Patients (age 67 yrs, 53% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml) were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7%) and forty (16.1%) patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05). Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05). Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05). Conclusions We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the potential to further define “high risk” populations in CKD. PMID:25894587

  14. Cyclooxygenase product inhibition with acetylsalicylic acid slows disease progression in the Han:SPRD-Cy rat model of polycystic kidney disease.

    PubMed

    Ibrahim, Naser H M; Gregoire, Melanie; Devassy, Jessay G; Wu, Yinhong; Yoshihara, Daisuke; Yamaguchi, Tamio; Nagao, Shizuko; Aukema, Harold M

    2015-01-01

    Renal cyclooxygenase (COX) derived eicosanoids are elevated and lipoxygenase (LOX) products are reduced in the Han:SPRD-Cy rat model of polycystic kidney disease (PKD). Selective COX2 inhibition reduces kidney disease progression, but COX1 levels also are elevated in this model. Since the effect of reducing the products of both COX isoforms and the role of LOX products is not known, weanling normal and diseased Han:SPRD-cy littermates were given either low dose acetylsalicylic acid (ASA), nordihydroguaiaretic (NDGA) or no treatment for eight weeks. Renal eicosanoids were altered in the diseased compared to normal cortex, with COX products being higher and LOX products being lower. ASA reduced COX products, cyst growth and kidney water content, while NDGA reduced LOX products without altering disease progression or kidney function. Hence, a human equivalent ASA dose equal to less than one regular strength aspirin per day slowed disease progression, while further reduction of LOX products did not worsen disease progression. PMID:25447343

  15. Economic impact of disease progression following front-line therapy in classical Hodgkin lymphoma.

    PubMed

    Yasenchak, Christopher A; Tseng, Wan-Yu; Yap, Mark; Rembert, Debra; Patt, Debra A

    2015-11-01

    The current study aimed to assess the economic burden of progressive disease among patients with Hodgkin lymphoma (HL) receiving second- or third-line therapy in a large US network of community-based practices. This retrospective, observational cohort analysis used electronic health records to examine adult patients with classical HL who received chemotherapy between 2007 and 2011. Of 291 observations, 112 had non-progressive disease (received only one line of therapy; LOT1), 114 received second-line therapy (LOT2), and 65 received third-line therapy (LOT3). In LOT2, 49 patients (43%) underwent transplant. In LOT3, 13 patients (20%) underwent transplant. The mean total cost per line of therapy was $21 956 in LOT1, $77 219 in LOT2, and $59 442 in LOT3. When transplant was required, the mean total cost per line of therapy increased 7- to 8-fold when compared with the cost of LOT1 (approximately $154 000 for LOT2 and $193 000 for LOT3). Future therapies that intervene as early as possible in the treatment algorithm to prevent or significantly delay relapse will likely result in significant cost savings. PMID:25860233

  16. Features of alpha-synuclein that could explain the progression and irreversibility of Parkinson's disease

    PubMed Central

    Gallegos, Scarlet; Pacheco, Carla; Peters, Christian; Opazo, Carlos M.; Aguayo, Luis G.

    2015-01-01

    Alpha-synuclein is a presynaptic protein expressed throughout the central nervous system, and it is the main component of Lewy bodies, one of the histopathological features of Parkinson's disease (PD) which is a progressive and irreversible neurodegenerative disorder. The conformational flexibility of ?-synuclein allows it to adopt different conformations, i.e., bound to membranes or form aggregates, the oligomers are believed to be the more toxic species. In this review, we will focus on two major features of ?-synuclein, transmission and toxicity, that could help to understand the pathological characteristics of PD. One important feature of ?-synuclein is its ability to be transmitted from neuron to neuron using mechanisms such as endocytosis, plasma membrane penetration or through exosomes, thus propagating the Lewy body pathology to different brain regions thereby contributing to the progressiveness of PD. The second feature of ?-synuclein is that it confers cytotoxicity to recipient cells, principally when it is in an oligomeric state. This form causes mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, proteasome impairment, disruption of plasma membrane and pore formation that lead to apoptosis pathway activation and consequent cell death. The complexity of ?-synuclein oligomerization and formation of toxic species could be a major factor for the irreversibility of PD and could also explain the lack of successful therapies to halt the disease. PMID:25805964

  17. New Insights about Treg and Th17 Cells in HIV Infection and Disease Progression

    PubMed Central

    Valverde-Villegas, Jacqueline María; Matte, Maria Cristina Cotta; de Medeiros, Rúbia Marília; Chies, José Artur Bogo

    2015-01-01

    Treg and Th17 cell subsets are characterized by the expression of specific transcriptional factors and chemokine receptor as well as by secretion of specific cytokine and chemokines. These subsets are important to the differentiation, expansion, homing capacity, and recruitment of several different immune cell populations to the site of infection. Whereas Treg cells maintain self-tolerance and control the activation and expansion of autoreactive CD4+ T effector cells through an anti-inflammatory response, Th17 cells, in an exacerbated unregulated proinflammatory response, can promote autoimmunity. Despite such apparently opposite functions, Th17 and Treg cells share common characteristics, and their differentiation pathways are interconnected. Recent studies have revealed quite intricate relations between Treg and Th17 cells in HIV infection and progression to AIDS. Considering Treg cells, different subsets were already investigated in the context of HIV infection, indicating a fluctuation in the total number and frequency throughout the disease course. This review focuses on the recent findings regarding the role of regulatory T and Th17 cells in the context of HIV infection, highlighting the importance of the balance between these two subsets on disease progression. PMID:26568963

  18. Loss of Peripheral Tolerance in Emphysema. Phenotypes, Exacerbations, and Disease Progression.

    PubMed

    Bhavani, Sivasubramanium; Yuan, Xiaoyi; You, Ran; Shan, Ming; Corry, David; Kheradmand, Farrah

    2015-11-01

    Heterogeneity in the development and progression of cigarette smoke-induced lung diseases strongly argues for a need to improve the clinical and phenotypic characterization of patients with chronic obstructive lung disease and emphysema. Smokers with emphysema are at a much higher risk for accelerated loss of lung function, increased cardiovascular morbidity, and development of lung cancer. Recent evidence in human translational studies and animal models suggests that emphysema is associated with activation of specialized antigen-presenting cells and that cigarette smoke can disrupt the induction of immune tolerance in the lungs. Quantitative assessment of cytokines expressed by autoreactive T lymphocytes in response to human lung elastin fragments has shown a strong positive correlation between T helper Type 1 (Th1) and Th17 cells' immune responses and emphysema. In search of factors that could reduce the threshold for induction of autoimmune inflammation, we have discovered that cleavage of complement protein 3 (C3) generates bioactive molecules (e.g., C3a) and activates lung antigen-presenting cells. The autocrine and paracrine function of C3a and its receptor are required in T cell-mediated inflammatory responses to cigarette smoke in both human and preclinical models of emphysema. Targeting upstream molecules that reduce the potential for generation of autoreactive T cells could lead to the development of novel therapeutics to prevent progression of emphysema in smokers. PMID:26595734

  19. High STAT5 levels mediate imatinib resistance and indicate disease progression in chronic myeloid leukemia.

    PubMed

    Warsch, Wolfgang; Kollmann, Karoline; Eckelhart, Eva; Fajmann, Sabine; Cerny-Reiterer, Sabine; Hölbl, Andrea; Gleixner, Karoline V; Dworzak, Michael; Mayerhofer, Matthias; Hoermann, Gregor; Herrmann, Harald; Sillaber, Christian; Egger, Gerda; Valent, Peter; Moriggl, Richard; Sexl, Veronika

    2011-03-24

    In BCR-ABL1(+) leukemia, drug resistance is often associated with up-regulation of BCR-ABL1 or multidrug transporters as well as BCR-ABL1 mutations. Here we show that the expression level of the transcription factor STAT5 is another parameter that determines the sensitivity of BCR-ABL1(+) cells against tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, or dasatinib. Abelson-transformed cells, expressing high levels of STAT5, were found to be significantly less sensitive to TKI-induced apoptosis in vitro and in vivo but not to other cytotoxic drugs, such as hydroxyurea, interferon-?, or Aca-dC. The STAT5-mediated protection requires tyrosine phosphorylation of STAT5 independent of JAK2 and transcriptional activity. In support of this concept, under imatinib treatment and with disease progression, STAT5 mRNA and protein levels increased in patients with Ph(+) chronic myeloid leukemia. Based on our data, we propose a model in which disease progression in BCR-ABL1(+) leukemia leads to up-regulated STAT5 expression. This may be in part the result of clonal selection of cells with high STAT5 levels. STAT5 then accounts for the resistance against TKIs, thereby explaining the dose escalation frequently required in patients reaching accelerated phase. It also suggests that STAT5 may serve as an attractive target to overcome imatinib resistance in BCR-ABL1(+) leukemia. PMID:21220747

  20. Impeded progression of Friend disease in mice by an inhibitor of retroviral proteases.

    PubMed

    Lai, M H; Tang, J; Wroblewski, V; Dee, A G; Margolin, N; Vlahos, C; Bowdon, B; Buckheit, R; Colacino, J; Hui, K Y

    1993-01-01

    The protease of the human immunodeficiency virus type 1 (HIV-1) is essential for the processing of GAG and POL polyproteins and maturation of the virus particles. Using recombinant protease and a truncated GAG polyprotein as substrate, we developed a Western blot assay for the evaluation of inhibitors of the enzyme. Two statine-based inhibitors of the enzyme, KH161 and KH164, were effective in blocking the replication of HIV-1 in acutely infected human T4 lymphoid cells, with potency approaching that of zidovudine (ZDV) when tested in parallel. In chronically infected cells, the production of infectious virus was inhibited by KH161 and KH164, while ZDV was ineffective. Both KH161 and KH164 were also active as antivirals against the replication of murine leukemia virus (MLV) in cultured mouse cells. In an animal model of a murine retroviral disease, KH164 was shown to inhibit in a dose-dependent manner the progression of the disease induced by Friend virus complex (a mixture of Friend MLV and spleen focus-forming virus). The results suggest that the progression of the acquired immune deficiency syndrome (AIDS) may be impeded by inhibitors of HIV-1 protease. PMID:8093263

  1. Recurrent and metastatic clivus chordoma: systemic palliative therapy retards disease progression.

    PubMed

    Schönegger, Katharina; Gelpi, Ellen; Prayer, Daniela; Dieckmann, Karin; Matula, Christian; Hassler, Marco; Hainfellner, Johannes A; Marosi, Christine

    2005-11-01

    We report on a male patient with progressive and metastatic clivus chordoma treated over a period of 9 years by a multidisciplinary approach. Within the first 4 years, the patient underwent surgery four times. Thereafter, he received radiotherapy and subsequent chemotherapy. Stabilization of disease was achieved repeatedly for variable periods under local radiotherapy, systemic chemotherapy, immunomodulatory and anti-angiogenic therapy with isotretinoin and interferon-alpha, followed by thalidomide. Due to the occurrence of brain and lung metastases 8 years after initial diagnosis, liposomal doxorubicin was added to thalidomide. At the last follow-up control the patient had stable disease, with no progression of the intracranial tumor and regression of pulmonary metastases. He is in a good physical, psychological and neurological condition with a Karnofsky score of 80. Our observations show that multimodal therapy including a systemic palliative approach is associated with long quiescent intervals in recurrent chordoma and with regression of its metastases. Use of substances with high efficacy on tumor tissue and low toxicity, allowing long-term administration, seems promising in similar situations. PMID:16222158

  2. Retinal pigment epithelial detachments and tears, and progressive retinal degeneration in light chain deposition disease

    PubMed Central

    Spielberg, Leigh H; Heckenlively, John R; Leys, Anita M

    2013-01-01

    Background/purpose Light-chain deposition disease (LCDD) is a rare condition characterised by deposition of monoclonal immunoglobulin light chains (LCs) in tissues, resulting in varying degrees of organ dysfunction. This study reports the characteristic clinical ocular findings seen in advanced LCDD upon development of ocular fundus changes. This is the first report to describe this entity in vivo in a series of patients. Methods A case series of ocular fundus changes in three patients with kidney biopsy-proven LCDD. All patients underwent best corrected visual acuity (BCVA) exam, perimetry, colour fundus photography and fluorescein angiography; two patients underwent indocyanine green angiography, optical coherence tomography, ultrasound and electroretinography; and one patient underwent fundus autofluorescence. Results Three patients, 53–60?years old at initial presentation, were studied. All three presented with night blindness, poor dark adaptation, metamorphopsia and visual loss. Examination revealed serous and serohaemorrhagic detachments, multiple retinal pigment epithelial (RPE) tears, diffuse RPE degeneration and progressive fibrotic changes. Neither choroidal neovascularisation nor other vascular abnormalities were present. Final best corrected visual acuity (BCVA) ranged from 20/40 to 20/300. Conclusions Progressive LC deposition in the fundus seems to damage RPE pump function with flow disturbance between choroid and retina. This pathogenesis can explain the evolution to RPE detachments and subsequent rips and progressive retinal malfunction. PMID:23385633

  3. Current and Future Disease Progression of the Chronic HCV Population in the United States

    PubMed Central

    Zalesak, Martin; Francis, Kevin; Gedeon, Alex; Gillis, John; Hvidsten, Kyle; Kidder, Phyllis; Li, Hong; Martyn, Derek; Orne, Leslie; Smith, Amanda; Kwong, Ann

    2013-01-01

    Chronic hepatitis C virus (HCV) infection can lead to advanced liver disease (AdvLD), including cirrhosis, decompensated cirrhosis, and liver cancer. The aim of this study was to determine recent historical rates of HCV patient progression to AdvLD and to project AdvLD prevalence through 2015. We first determined total 2008 US chronic HCV prevalence from the National Health and Nutrition Evaluation Surveys. Next, we examined disease progression and associated non-pharmacological costs of diagnosed chronic HCV-infected patients between 2007–2009 in the IMS LifeLink and CMS Medicare claims databases. A projection model was developed to estimate AdvLD population growth through 2015 in patients diagnosed and undiagnosed as of 2008, using the 2007–2009 progression rates to generate a “worst case” projection of the HCV-related AdvLD population (i.e., scenario where HCV treatment is the same in the forecasted period as it was before 2009). We found that the total diagnosed chronic HCV population grew from 983,000 to 1.19 million in 2007–2009, with patients born from 1945–1964 accounting for 75.0% of all patients, 83.7% of AdvLD patients, and 79.2% of costs in 2009, indicating that HCV is primarily a disease of the “baby boomer” population. Non-pharmacological costs grew from $7.22 billion to $8.63 billion, with the majority of growth derived from the 60,000 new patients that developed AdvLD in 2007–2009, 91.5% of whom were born between 1945 and 1964. The projection model estimated the total AdvLD population would grow from 195,000 in 2008 to 601,000 in 2015, with 73.5% of new AdvLD cases from patients undiagnosed as of 2008. AdvLD prevalence in patients diagnosed as of 2008 was projected to grow 6.5% annually to 303,000 patients in 2015. These findings suggest that strategies to diagnose and treat HCV-infected patients are urgently needed to increase the likelihood that progression is interrupted, particularly for patients born from 1945–1964. PMID:23704962

  4. Expression of Muscle-Specific MiRNA 206 in the Progression of Disease in a Murine SMA Model

    PubMed Central

    Valsecchi, Valeria; Boido, Marina; De Amicis, Elena; Piras, Antonio; Vercelli, Alessandro

    2015-01-01

    Spinal muscular atrophy (SMA) is a severe neuromuscular disease, the most common in infancy, and the third one among young people under 18 years. The major pathological landmark of SMA is a selective degeneration of lower motor neurons, resulting in progressive skeletal muscle denervation, atrophy, and paralysis. Recently, it has been shown that specific or general changes in the activity of ribonucleoprotein containing micro RNAs (miRNAs) play a role in the development of SMA. Additionally miRNA-206 has been shown to be required for efficient regeneration of neuromuscular synapses after acute nerve injury in an ALS mouse model. Therefore, we correlated the morphology and the architecture of the neuromuscular junctions (NMJs) of quadriceps, a muscle affected in the early stage of the disease, with the expression levels of miRNA-206 in a mouse model of intermediate SMA (SMAII), one of the most frequently used experimental model. Our results showed a decrease in the percentage of type II fibers, an increase in atrophic muscle fibers and a remarkable accumulation of neurofilament (NF) in the pre-synaptic terminal of the NMJs in the quadriceps of SMAII mice. Furthermore, molecular investigation showed a direct link between miRNA-206-HDAC4-FGFBP1, and in particular, a strong up-regulation of this pathway in the late phase of the disease. We propose that miRNA-206 is activated as survival endogenous mechanism, although not sufficient to rescue the integrity of motor neurons. We speculate that early modulation of miRNA-206 expression might delay SMA neurodegenerative pathway and that miRNA-206 could be an innovative, still relatively unexplored, therapeutic target for SMA. PMID:26030275

  5. Dispositional Optimism and the Mechanisms by Which It Predicts Slower Disease Progression in HIV: Proactive Behavior, Avoidant Coping, and Depression

    PubMed Central

    Ironson, Gail; Balbin, Elizabeth; Stuetzle, Rick; Fletcher, Mary Ann; O’Cleirigh, Conall; Laurenceau, J. P.; Schneiderman, Neil; Solomon, George

    2008-01-01

    The issue of whether optimism may prospectively protect against disease progression is one that has generated much interest, with mixed results in the literature. The purpose of this study was to determine whether dispositional optimism predicts slower disease progression in HIV. Two indicators of disease progression, CD4 counts and viral load, were assessed over 2 years in a diverse group (men, women, White, African American, Hispanic) of 177 people with HIV in the midrange of disease at entry to the study. Optimism predicted slower disease progression (less decrease in CD4 and less increase in viral load) controlling for baseline CD4 and viral load, antiretroviral treatment, gender, race, education, and drug use. Those low on optimism (25th percentile) lost CD4 cells at a rate 1.55 times faster than those high on optimism (75th percentile). Optimists had higher proactive behavior, less avoidant coping, and less depression: These variables mediated the linear optimism–disease progression relationship. Thus, optimists may reap health benefits partly through behavioral (proactive behavior), cognitive (avoidant coping), and affective (depression) pathways. Implications, limitations, and interpretations are discussed. PMID:15901217

  6. Heterogeneity of Regional Brain Atrophy Patterns Associated with Distinct Progression Rates in Alzheimer’s Disease

    PubMed Central

    Byun, Min Soo; Kim, Song E.; Park, Jinsick; Yi, Dahyun; Choe, Young Min; Sohn, Bo Kyung; Choi, Hyo Jung; Baek, Hyewon; Han, Ji Young; Woo, Jong Inn; Lee, Dong Young

    2015-01-01

    We aimed to identify and characterize subtypes of Alzheimer’s disease (AD) exhibiting different patterns of regional brain atrophy on MRI using age- and gender-specific norms of regional brain volumes. AD subjects included in the Alzheimer's Disease Neuroimaging Initiative study were classified into subtypes based on standardized values (Z-scores) of hippocampal and regional cortical volumes on MRI with reference to age- and gender-specific norms obtained from 222 cognitively normal (CN) subjects. Baseline and longitudinal changes of clinical characteristics over 2 years were compared across subtypes. Whole-brain-level gray matter (GM) atrophy pattern using voxel-based morphometry (VBM) and cerebrospinal fluid (CSF) biomarkers of the subtypes were also investigated. Of 163 AD subjects, 58.9% were classified as the “both impaired” subtype with the typical hippocampal and cortical atrophy pattern, whereas 41.1% were classified as the subtypes with atypical atrophy patterns: “hippocampal atrophy only” (19.0%), “cortical atrophy only” (11.7%), and “both spared” (10.4%). Voxel-based morphometric analysis demonstrated whole-brain-level differences in overall GM atrophy across the subtypes. These subtypes showed different progression rates over 2 years; and all subtypes had significantly lower CSF amyloid-?1–42 levels compared to CN. In conclusion, we identified four AD subtypes exhibiting heterogeneous atrophy patterns on MRI with different progression rates after controlling the effects of aging and gender on atrophy with normative information. CSF biomarker analysis suggests the presence of A? neuropathology irrespective of subtypes. Such heterogeneity of MRI-based neuronal injury biomarker and related heterogeneous progression patterns should be considered in clinical trials and practice with AD patients. PMID:26618360

  7. Crosstalk between the Unfolded Protein Response and NF-?B-Mediated Inflammation in the Progression of Chronic Kidney Disease

    PubMed Central

    Cruz, Gaile L.; Dickhout, Jeffrey G.

    2015-01-01

    The chronic inflammatory response is emerging as an important therapeutic target in progressive chronic kidney disease. A key transcription factor in the induction of chronic inflammation is NF-?B. Recent studies have demonstrated that sustained activation of the unfolded protein response (UPR) can initiate this NF-?B signaling phenomenon and thereby induce chronic kidney disease progression. A key factor influencing chronic kidney disease progression is proteinuria and this condition has now been demonstrated to induce sustained UPR activation. This review details the crosstalk between the UPR and NF-?B pathways as pertinent to chronic kidney disease. We present potential tools to study this phenomenon as well as potential therapeutics that are emerging to regulate the UPR. These therapeutics may prevent inflammation specifically induced in the kidney due to proteinuria-induced sustained UPR activation. PMID:25977931

  8. Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis

    PubMed Central

    Zhang, Yi; Cook, Anna; Kim, Jinho; Baranov, Sergei V.; Jiang, Jiying; Smith, Karen; Cormier, Kerry; Bennett, Erik; Browser, Robert P.; Day, Arthur L.; Carlisle, Diane; Ferrante, Robert J.; Wang, Xin; Friedlander, Robert M.

    2013-01-01

    Caspase-mediated cell death contributes to the pathogenesis of motor neuron degeneration in the mutant SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS), along with other factors such as inflammation and oxidative damage. By screening a drug library, we found that melatonin, a pineal hormone, inhibited cytochrome c release in purified mitochondria and prevented cell death in cultured neurons. In this study, we evaluated whether melatonin would slow disease progression in SOD1G93A mice. We demonstrate that melatonin significantly delayed disease onset, neurological deterioration and mortality in ALS mice. ALS-associated ventral horn atrophy and motor neuron death were also inhibited by melatonin treatment. Melatonin inhibited Rip2/caspase-1 pathway activation, blocked the release of mitochondrial cytochrome c, and reduced the overexpression and activation of caspase-3. Moreover, for the first time, we determined that disease progression was associated with the loss of both melatonin and the melatonin receptor 1A (MT1) in the spinal cord of ALS mice. These results demonstrate that melatonin is neuroprotective in transgenic ALS mice, and this protective effect is mediated through its effects on the caspase-mediated cell death pathway. Furthermore, our data suggest that melatonin and MT1 receptor loss may play a role in the pathological phenotype observed in ALS. The above observations indicate that melatonin and modulation of Rip2/caspase-1/cytochrome c or MT1 pathways may be promising therapeutic approaches for ALS. PMID:23537713

  9. ALS Patient Stem Cells for Unveiling Disease Signatures of Motoneuron Susceptibility: Perspectives on the Deadly Mitochondria, ER Stress and Calcium Triad

    PubMed Central

    Kaus, Anjoscha; Sareen, Dhruv

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a largely sporadic progressive neurodegenerative disease affecting upper and lower motoneurons (MNs) whose specific etiology is incompletely understood. Mutations in superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TARDBP/TDP-43) and C9orf72, have been identified in subsets of familial and sporadic patients. Key associated molecular and neuropathological features include ubiquitinated TDP-43 inclusions, stress granules, aggregated dipeptide proteins from mutant C9orf72 transcripts, altered mitochondrial ultrastructure, dysregulated calcium homeostasis, oxidative and endoplasmic reticulum (ER) stress, and an unfolded protein response (UPR). Such impairments have been documented in ALS animal models; however, whether these mechanisms are initiating factors or later consequential events leading to MN vulnerability in ALS patients is debatable. Human induced pluripotent stem cells (iPSCs) are a valuable tool that could resolve this “chicken or egg” causality dilemma. Relevant systems for probing pathophysiologically affected cells from large numbers of ALS patients and discovering phenotypic disease signatures of early MN susceptibility are described. Performing unbiased ‘OMICS and high-throughput screening in relevant neural cells from a cohort of ALS patient iPSCs, and rescuing mitochondrial and ER stress impairments, can identify targeted therapeutics for increasing MN longevity in ALS. PMID:26635528

  10. A longitudinal model for disease progression was developed and applied to multiple sclerosis

    PubMed Central

    Lawton, Michael; Tilling, Kate; Robertson, Neil; Tremlett, Helen; Zhu, Feng; Harding, Katharine; Oger, Joel; Ben-Shlomo, Yoav

    2015-01-01

    Objectives To develop a model of disease progression using multiple sclerosis (MS) as an exemplar. Study Design and Settings Two observational cohorts, the University of Wales MS (UoWMS), UK (1976), and British Columbia MS (BCMS) database, Canada (1980), with longitudinal disability data [the Expanded Disability Status Scale (EDSS)] were used; individuals potentially eligible for MS disease-modifying drugs treatments, but who were unexposed, were selected. Multilevel modeling was used to estimate the EDSS trajectory over time in one data set and validated in the other; challenges addressed included the choice and function of time axis, complex observation-level variation, adjustments for MS relapses, and autocorrelation. Results The best-fitting model for the UoWMS cohort (404 individuals, and 2,290 EDSS observations) included a nonlinear function of time since onset. Measurement error decreased over time and ad hoc methods reduced autocorrelation and the effect of relapse. Replication within the BCMS cohort (978 individuals and 7,335 EDSS observations) led to a model with similar time (years) coefficients, time [0.22 (95% confidence interval {CI}: 0.19, 0.26), 0.16 (95% CI: 0.10, 0.22)] and log time [?0.13 (95% CI: ?0.39, 0.14), ?0.15 (95% CI: ?0.70, 0.40)] for BCMS and UoWMS, respectively. Conclusion It is possible to develop robust models of disability progression for chronic disease. However, explicit validation is important given the complex methodological challenges faced. PMID:26071892

  11. Fatal Progression of Gorham Disease: A Case Report and Review of the Literature.

    PubMed

    Kim, Min-Keun; Hong, Jong-Rak; Kim, Seong-Gon; Lee, Seok-Keun

    2015-12-01

    Gorham disease is an idiopathic massive osteolysis, and maxillofacial involvement is rare. This report describes a case of a 12-year-old boy with severe progressive osteolysis in the mandible, hyoid bone, mastoid process, and cervical spine. Radiation therapy and interferon-? therapy were followed by bisphosphonate therapy. The patient died of respiratory failure. To describe the clinicopathologic features of Gorham disease of the jaws with an emphasis on the fatal types, 64 cases in the literature were reviewed (female-to-male ratio, 1:1.78; average age, 33.02 ± 19.38 yr). Most lesions were located only in the mandible or in other locations in combination with the mandible, except for 3 cases. During follow-up, there were 7 cases of disease-specific death, resulting in a mortality rate of 10.94%. The main causes of death were chylothorax, rib fractures secondary to osteolysis, or spinal fractures. Although most patients received surgical treatment (43.75%), the type of treatment was not related to prognosis. PMID:26169484

  12. 8OHdG as a marker for Huntington disease progression

    PubMed Central

    Long, Jeffrey D.; Matson, Wayne R.; Juhl, Andrew R.; Leavitt, Blair R.; Paulsen, Jane S.

    2013-01-01

    Leukocyte 8-hydroxydeoxyguanosine (8OHdG) is an indicator of oxidative stress, impaired metabolism, and mitochondrial dysfunction, features that have been implicated in Huntington disease (HD). Increased levels of 8OHdG have been reported in the caudate, parietal cortex, and peripherally in the serum and leukocytes, in patients diagnosed with HD. However, little is known about levels in prodromal patients and changes that might occur as the disease progresses. To address these issues, 8OHdG was tracked over time for a subset of participants enrolled in the PREDICT-HD study. Participants were stratified into four groups based on proximity to HD diagnosis at study entry: Controls (gene-negative individuals), Low (low probability of near future diagnosis), Medium, and High. Blood samples were analyzed using Liquid Chromatography Electrochemical Array, and for comparison purposes, a separate cross-sectional sample was analyzed using liquid chromatography coupled with multiple-reaction-monitoring mass spectrometry. Longitudinal data analysis showed that initial status (at study entry) and annual rate of change varied as a function of proximity group, adjusting for sex, education, age at study entry, and site effects. Overall levels were lowest for the Control group and highest for the High group, and the rate of increase varied in a similar manner. The finding that 8OHdG concentrations increased as a function of proximity to projected disease diagnosis and duration indicates support for the continued assessment of 8OHdG as a robust clinical HD biomarker. PMID:22414782

  13. Effect of Treatment for CHC on Liver Disease Progression and Hepatocellular Carcinoma Development in African Americans

    PubMed Central

    Reddy, Naveen; Naylor, Paul; Hakim, Zaher; Asbahi, Redwan; Ravindran, Karthik; May, Elizabeth; Ehrinpreis, Murray; Mutchnick, Milton

    2015-01-01

    Background and Aims: African Americans (AA) historically have a low response rate to hepatitis C therapies, and there is limited information available for this patient population regarding the development and treatment of chronic hepatitis C (CHC). The aim of this study was to evaluate liver disease progression and hepatocellular carcinoma (HCC) development in AA with CHC. Methods: Between 1995 and 2008, 246 AA patients with CHC were identified from a database of patients and followed until 2012-2013 (average 8 years) or the development of HCC after 2008. Results: Viral clearance (intent to treat; sustained virus response (SVR)) was achieved in 15% of patients with interferon based therapies with or without ribavirin. AA patients who achieved an SVR (n=22) did not develop HCC or new onset cirrhosis, whereas the HCC incidence in untreated AA patients was 23% (51/203). Patients who achieved an SVR also had improved fibrosis, as defined by the AST Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4) score, relative to nonresponders and untreated patients. Conclusions: The severity of liver disease at the first visit (except for cirrhosis) correlated with the development of HCC, but because of the overlap in values between patients, these measurements were not useful for predicting individual risk. Since cirrhosis at the first visit was not a predictive factor, treatment with newer antiviral therapies is the best option for reducing the incidence of advanced liver disease and its harmful outcomes in the AA population. PMID:26623262

  14. 8OHdG as a marker for Huntington disease progression.

    PubMed

    Long, Jeffrey D; Matson, Wayne R; Juhl, Andrew R; Leavitt, Blair R; Paulsen, Jane S

    2012-06-01

    Leukocyte 8-hydroxydeoxyguanosine (8OHdG) is an indicator of oxidative stress, impaired metabolism, and mitochondrial dysfunction, features that have been implicated in Huntington disease (HD). Increased levels of 8OHdG have been reported in the caudate, parietal cortex, and peripherally in the serum and leukocytes, in patients diagnosed with HD. However, little is known about levels in prodromal patients and changes that might occur as the disease progresses. To address these issues, 8OHdG was tracked over time for a subset of participants enrolled in the PREDICT-HD study. Participants were stratified into four groups based on proximity to HD diagnosis at study entry: Controls (gene-negative individuals), Low (low probability of near-future diagnosis), Medium, and High. Blood samples were analyzed using Liquid Chromatography Electrochemical Array, and for comparison purposes, a separate cross-sectional sample was analyzed using liquid chromatography coupled with multiple-reaction-monitoring mass spectrometry. Longitudinal data analysis showed that initial status (at study entry) and annual rate of change varied as a function of proximity group, adjusting for sex, education, age at study entry, and site effects. Overall levels were lowest for the Control group and highest for the High group, and the rate of increase varied in a similar manner. The finding that 8OHdG concentrations increased as a function of proximity to projected disease diagnosis and duration indicates support for the continued assessment of 8OHdG as a robust clinical HD biomarker. PMID:22414782

  15. High Serum GFAP Levels in SCA3/MJD May Not Correlate with Disease Progression.

    PubMed

    Shi, Yuting; Wang, Chunrong; Huang, Fengzhen; Chen, Zhao; Sun, Zhanfang; Wang, Junling; Tang, Beisha; Ashizawa, Tetsuo; Klockgether, Thomas; Jiang, Hong

    2015-12-01

    Spinocerebellar ataxia type 3(SCA3), also known as Machado-Joseph disease (MJD), is the most frequent subtype of autosomal dominant inherited spinocerebellar ataxias, which caused by the expansion of CAG repeats in the ATXN3 gene. The number of CAG repeats of the abnormal allele determines the rate of disease progression in patients with SCA3/MJD. Markers to assess the clinical severity, to predict the course of illness and to monitor the efficacy of therapeutic measures, can be clinical, biological, and radiological. Here, we aimed to explore whether the serum glial fibrillary acidic protein (GFAP) may act as a biomarker in SCA3/MJD patients and to evaluate the correlation between some markers with the number of CAG repeats in SCA3/MJD patients. We showed that the serum levels of GFAP were significantly higher in SCA3/MJD patients than in controls. There was a strong positive correlation between the age-adjusted GFAP levels with the number of CAG repeats. Age-adjusted International Cooperative Ataxia Rating Scale (ICARS) scores and Scale for the Assessment and Rating of Ataxia (SARA) scores correlated with the number of CAG repeats. Raw scores and disease duration-adjusted GFAP levels, ICARS scores, and SARA scores were not correlated with the number of CAG repeats. Our results reveal novel evidence for the role of the triplet expansion in SCA3/MJD-associated neuronal damage. PMID:25869927

  16. PNPLA3 genetic variation in alcoholic steatosis and liver disease progression

    PubMed Central

    Hampe, Jochen; Trépo, Eric; Datz, Christian; Romeo, Stefano

    2015-01-01

    Alcoholic liver disease (ALD) accounts for the majority of chronic liver diseases in Western countries, and alcoholic cirrhosis is among the premier causes of liver failure, hepatocellular carcinoma (HCC) and liver-related mortality causes. Studies in different genders and ethnic groups, as well as in twins provide strong evidence for a significant contribution of host genetic factors to liver disease development in drinkers. The intense quest for genetic modifiers of alcohol-induced fibrosis progression have identified and repeatedly confirmed a genetic polymorphism in the gene coding for patatin-like phospholipase domain-containing 3 (PNPLA3; adiponutrin; rs738409 C/G, M148I) as a risk factor for alcoholic cirrhosis and its related complication, HCC, in different populations. Although carriership of one or both mutated PNPLA3 alleles does not explain the entire liver phenotypic variability in drinkers, it clearly represents one of the strongest single genetic modulators in a complex trait such as ALD. As more genetic data supporting its important role aggregates, novel insight as to PNPLA3’s function and that of its genetic variation in liver injury is unveiled pointing to an important novel pathway in alcohol-mediated hepatic lipid turnover with strong implications on inflammation, extra cellular matrix remodelling, and hepatocarcinogenesis. Future study shall decipher whether the gathered knowledge can be translated into therapeutic benefits of patients. PMID:26151055

  17. Chronic follicular bronchiolitis requires antigen-specific regulatory T cell control to prevent fatal disease progression.

    PubMed

    Schmitt, Erica G; Haribhai, Dipica; Jeschke, Jonathan C; Co, Dominic O; Ziegelbauer, Jennifer; Yan, Ke; Iwakura, Yoichiro; Mishra, Manoj K; Simpson, Pippa; Salzman, Nita H; Williams, Calvin B

    2013-12-01

    To study regulatory T (Treg) cell control of chronic autoimmunity in a lymphoreplete host, we created and characterized a new model of autoimmune lung inflammation that targets the medium and small airways. We generated transgenic mice that express a chimeric membrane protein consisting of hen egg lysozyme and a hemoglobin epitope tag under the control of the Clara cell secretory protein promoter, which largely limited transgene expression to the respiratory bronchioles. When Clara cell secretory protein-membrane hen egg lysozyme/hemoglobin transgenic mice were crossed to N3.L2 TCR transgenic mice that recognize the hemoglobin epitope, the bigenic progeny developed dense, pseudo-follicular lymphocytic peribronchiolar infiltrates that resembled the histological pattern of follicular bronchiolitis. Aggregates of activated IFN-?- and IL-17A-secreting CD4(+) T cells as well as B cells surrounded the airways. Lung pathology was similar in Ifng(-/-) and Il17a(-/-) mice, indicating that either cytokine is sufficient to establish chronic disease. A large number of Ag-specific Treg cells accumulated in the lesions, and Treg cell depletion in the affected mice led to an interstitial spread of the disease that ultimately proved fatal. Thus, Treg cells act to restrain autoimmune responses, resulting in an organized and controlled chronic pathological process rather than a progressive disease. PMID:24163409

  18. RTN1 mediates progression of kidney disease by inducing ER stress

    PubMed Central

    Fan, Ying; Xiao, Wenzhen; Li, Zhengzhe; Li, Xuezhu; Chuang, Peter Y.; Jim, Belinda; Zhang, Weijia; Wei, Chengguo; Wang, Niansong; Jia, Weiping; Xiong, Huabao; Lee, Kyung; He, John C.

    2015-01-01

    Identification of new biomarkers and drug targets for chronic kidney disease (CKD) is required for the development of more effective therapy. Here we report an association between expression of reticulon 1 (RTN1) and severity of CKD. An isoform-specific increase in the expression of RTN1A is detected in the diseased kidneys from mice and humans, and correlates inversely with renal function in patients with diabetic nephropathy. RTN1 overexpression in renal cells induces ER stress and apoptosis, whereas RTN1 knockdown attenuates tunicamycin-induced and hyperglycaemia-induced ER stress and apoptosis. RTN1A interacts with PERK through its N-terminal and C-terminal domains, and mutation of these domains prevents this effect on ER stress. Knockdown of Rtn1a expression in vivo attenuates ER stress and renal fibrosis in mice with unilateral ureteral obstruction, and also attenuates ER stress, proteinuria, glomerular hypertrophy and mesangial expansion in diabetic mice. Together, these data indicate that RTN1A contributes to progression of kidney disease by inducing ER stress. PMID:26227493

  19. Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection

    PubMed Central

    Adland, Emily; Paioni, Paolo; Thobakgale, Christina; Laker, Leana; Mori, Luisa; Muenchhoff, Maximilian; Csala, Anna; Clapson, Margaret; Flynn, Jacquie; Novelli, Vas; Hurst, Jacob; Naidoo, Vanessa; Shapiro, Roger; Huang, Kuan-Hsiang Gary; Frater, John; Prendergast, Andrew; Prado, Julia G.; Ndung’u, Thumbi; Walker, Bruce D.; Carrington, Mary; Jooste, Pieter; Goulder, Philip J. R.

    2015-01-01

    HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression. PMID:26076345

  20. DNA methylation changes in ovarian cancer are cumulative with disease progression and identify tumor stage

    PubMed Central

    Watts, George S; Futscher, Bernard W; Holtan, Nicholas; DeGeest, Koen; Domann, Frederick E; Rose, Stephen L

    2008-01-01

    Background Hypermethylation of promoter CpG islands with associated loss of gene expression, and hypomethylation of CpG-rich repetitive elements that may destabilize the genome are common events in most, if not all, epithelial cancers. Methods The methylation of 6,502 CpG-rich sequences spanning the genome was analyzed in 137 ovarian samples (ten normal, 23 low malignant potential, 18 stage I, 16 stage II, 54 stage III, and 16 stage IV) ranging from normal tissue through to stage IV cancer using a sequence-validated human CpG island microarray. The microarray contained 5' promoter-associated CpG islands as well as CpG-rich satellite and Alu repetitive elements. Results Results showed a progressive de-evolution of normal CpG methylation patterns with disease progression; 659 CpG islands showed significant loss or gain of methylation. Satellite and Alu sequences were primarily associated with loss of methylation, while promoter CpG islands composed the majority of sequences with gains in methylation. Since the majority of ovarian tumors are late stage when diagnosed, we tested whether DNA methylation profiles could differentiate between normal and low malignant potential (LMP) compared to stage III ovarian samples. We developed a class predictor consisting of three CpG-rich sequences that was 100% sensitive and 89% specific when used to predict an independent set of normal and LMP samples versus stage III samples. Bisulfite sequencing confirmed the NKX-2-3 promoter CpG island was hypermethylated with disease progression. In addition, 5-aza-2'-deoxycytidine treatment of the ES2 and OVCAR ovarian cancer cell lines re-expressed NKX-2-3. Finally, we merged our CpG methylation results with previously published ovarian expression microarray data and identified correlated expression changes. Conclusion Our results show that changes in CpG methylation are cumulative with ovarian cancer progression in a sequence-type dependent manner, and that CpG island microarrays can rapidly discover novel genes affected by CpG methylation in clinical samples of ovarian cancer. PMID:18826610

  1. Disease progression in Plasmodium knowlesi malaria is linked to variation in invasion gene family members.

    PubMed

    Ahmed, Atique M; Pinheiro, Miguel M; Divis, Paul C; Siner, Angela; Zainudin, Ramlah; Wong, Ing Tien; Lu, Chan Woon; Singh-Khaira, Sarina K; Millar, Scott B; Lynch, Sean; Willmann, Matthias; Singh, Balbir; Krishna, Sanjeev; Cox-Singh, Janet

    2014-08-01

    Emerging pathogens undermine initiatives to control the global health impact of infectious diseases. Zoonotic malaria is no exception. Plasmodium knowlesi, a malaria parasite of Southeast Asian macaques, has entered the human population. P. knowlesi, like Plasmodium falciparum, can reach high parasitaemia in human infections, and the World Health Organization guidelines for severe malaria list hyperparasitaemia among the measures of severe malaria in both infections. Not all patients with P. knowlesi infections develop hyperparasitaemia, and it is important to determine why. Between isolate variability in erythrocyte invasion, efficiency seems key. Here we investigate the idea that particular alleles of two P. knowlesi erythrocyte invasion genes, P. knowlesi normocyte binding protein Pknbpxa and Pknbpxb, influence parasitaemia and human disease progression. Pknbpxa and Pknbpxb reference DNA sequences were generated from five geographically and temporally distinct P. knowlesi patient isolates. Polymorphic regions of each gene (approximately 800 bp) were identified by haplotyping 147 patient isolates at each locus. Parasitaemia in the study cohort was associated with markers of disease severity including liver and renal dysfunction, haemoglobin, platelets and lactate, (r = ? 0.34, p =? <0.0001 for all). Seventy-five and 51 Pknbpxa and Pknbpxb haplotypes were resolved in 138 (94%) and 134 (92%) patient isolates respectively. The haplotypes formed twelve Pknbpxa and two Pknbpxb allelic groups. Patients infected with parasites with particular Pknbpxa and Pknbpxb alleles within the groups had significantly higher parasitaemia and other markers of disease severity. Our study strongly suggests that P. knowlesi invasion gene variants contribute to parasite virulence. We focused on two invasion genes, and we anticipate that additional virulent loci will be identified in pathogen genome-wide studies. The multiple sustained entries of this diverse pathogen into the human population must give cause for concern to malaria elimination strategists in the Southeast Asian region. PMID:25121807

  2. On the central role of brain connectivity in neurodegenerative disease progression

    PubMed Central

    Iturria-Medina, Yasser; Evans, Alan C.

    2015-01-01

    Increased brain connectivity, in all its variants, is often considered an evolutionary advantage by mediating complex sensorimotor function and higher cognitive faculties. Interaction among components at all spatial scales, including genes, proteins, neurons, local neuronal circuits and macroscopic brain regions, are indispensable for such vital functions. However, a growing body of evidence suggests that, from the microscopic to the macroscopic levels, such connections might also be a conduit for in intra-brain disease spreading. For instance, cell-to-cell misfolded proteins (MP) transmission and neuronal toxicity are prominent connectivity-mediated factors in aging and neurodegeneration. This article offers an overview of connectivity dysfunctions associated with neurodegeneration, with a specific focus on how these may be central to both normal aging and the neuropathologic degenerative progression. PMID:26052284

  3. Endometriosis in adolescents is a hidden, progressive and severe disease that deserves attention, not just compassion.

    PubMed

    Brosens, I; Gordts, S; Benagiano, G

    2013-08-01

    Endometriosis in the adolescent has, in recent years, been discovered to be a challenging problem in gynaecology. Although the pain may start at a young age, even before the onset of menstruation, the diagnosis by laparoscopy is almost always postponed for several years, by which time destructive lesions have affected the tubo-ovarian structures and severely compromised fecundability. Several factors may play a role, but one important reason for this disease progression is likely to be the delay in diagnosis. Therefore, transvaginal ultrasounds and transvaginal access with a less invasive needle endoscopy are recommended for exploration of the pelvis, diagnosis of endometriosis and treatment at an early stage before severe lesions develop. PMID:23739215

  4. Camurati-Engelmann disease (progressive diaphyseal dysplasia) in a Moroccan family.

    PubMed

    Simsek, S; Janssens, K; Kwee, M L; Van Hul, W; Veenstra, J; Netelenbos, J C

    2005-09-01

    We report on a 46-year-old mother of Moroccan origin, suffering mainly from painful, swollen legs, and her 26-year-old son who had experienced intense pain in his legs, without fever, for approximately 3 years. They did not have dysmorphic features or abnormal gaits. Radiographic studies of the mother revealed diaphyseal sclerosis of the tibia and spondylosis of the thoracal and lumbar vertebrae. The son had sclerosis of the diaphyses of the metacarpalia of the left hand, the femur and the fibula. The other parts of the skeleton were normal. Several osteosclerotic/hyperostotic disorders, such as melorheostosis (present mostly in sporadic cases and affecting lower extremities) and van Buchem's disease (autosomal recessive and commonly affecting the mandible) were considered as a diagnosis in the proposita. However, similar symptoms in the son of the proposita suggested an autosomal dominant inheritance pattern. This brought us to the diagnosis of progressive diaphyseal dysplasia (PDD) or Camurati-Engelmann disease (CED), an autosomal dominant disorder characterized by limb pain, reduced muscle mass, weakness, a waddling gait, progressive periosteal and endosteal sclerosis of the diaphyses of the long bones and sclerosis of the skull base. Mutations in the transforming growth factor (TGF)-beta1 gene on chromosome 19q13.1 have been reported to cause this disorder. The diagnosis of PDD/CED in this family was confirmed at the molecular level by detection of a C-to-T transition at position 466, leading to an arginine-to-cysteine amino acid change (position 156) in exon 2 of the transforming growth factor-beta1 (TGFB1) gene. PMID:15959620

  5. Moderate resistance exercise program: its effect in slowly progressive neuromuscular disease.

    PubMed

    Aitkens, S G; McCrory, M A; Kilmer, D D; Bernauer, E M

    1993-07-01

    A 12-week moderate resistance exercise program was performed by 27 patients with slowly progressive neuromuscular diseases (NMD) and 14 control subjects (CTL) in order to determine safety and efficacy of a strengthening program. A 3-day per week submaximal regimen of home exercise using ankle and wrist weights and hand grip exerciser was prescribed. One side of the body was randomly chosen for exercise. Subjects were tested for maximal isokinetic and isometric strength at baseline and after weeks 4 and 12 of the training protocol, and the prescribed amount of work was gradually increased throughout the program. Both the NMD and CTL groups demonstrated significant (p < .05) increases in most strength measures. Both groups responded similarly to the exercise program, and strength gains did not significantly differ between the exercised and nonexercised limbs in either group. This study provides evidence that a 12-week submaximal strength training program is practical and safe in slowly progressive NMD and produces moderate improvement in measured strength. PMID:8328892

  6. Rapidly progressive IgA nephropathy: a form of vasculitis or a complement-mediated disease?

    PubMed Central

    Rojas-Rivera, Jorge; Fernández-Juárez, Gema; Praga, Manuel

    2015-01-01

    A rapidly progressive and crescentic IgA nephropathy (IgAN) is uncommon, but it has a high risk of progression to end-stage renal disease and variable response to immunosuppression. The importance of a positive anti-neutrophil cytoplasmic antibody (ANCA) serology in this group of patients is not fully understood but may have prognostic significance. On the other hand, there is growing evidence of the role of complement in the pathogenesis of IgAN, especially in cases of crescentic IgAN. Therapies directed against the complement system are a potential and rational therapeutic approach. In this issue, two clinical studies of crescentic IgAN are presented. The first work, is a retrospective case–control study describing clinical presentation, histological findings and response to treatment of crescentic IgAN/positive ANCA patients, comparing them with IgAN/negative ANCA patients and ANCA vasculitis patients. The second is a case report showing the effect of eculizumab, a humanized monoclonal antibody that is a terminal cascade complement inhibitor, as salvage therapy for crescentic IgAN resistant to conventional immunosuppression. Both studies broaden our approach to patients with aggressive forms of IgAN. PMID:26413269

  7. AST-120 for the management of progression of chronic kidney disease

    PubMed Central

    Schulman, Gerald; Vanholder, Raymond; Niwa, Toshimitsu

    2014-01-01

    Uremic toxins such as indoxyl sulfate contribute to the pathogenesis of chronic kidney disease (CKD) by promoting glomerulosclerosis and interstitial fibrosis with loss of nephrons and vascular damage. AST-120, an orally administered intestinal sorbent, adsorbs indole, a precursor of indoxyl sulfate, thereby reducing serum and urinary concentrations of indoxyl sulfate. AST-120 has been available in Japan since 1991, and subsequently Korea (2005), and the Philippines (2010) as an agent to prolong the time to initiation of hemodialysis and for improvement of uremic symptoms in patients with CKD. A Medline search was performed to identify data supporting clinical experience with AST-120 for managing CKD. Prospective open-label and double-blind trials as well as retrospective analyses were included. In prospective trials and retrospective analyses, AST-120 has been shown to prolong the time to initiation of hemodialysis, and slow decline in glomerular filtration rate and the increase serum creatinine. In an initial randomized, double-blind, placebo-controlled trial in the United States, AST-120 was associated with a significant dose-dependent reduction in serum indoxyl sulfate levels and a decrease in uremia-related malaise. The Evaluating Prevention of Progression in CKD (EPPIC) trials, two double-blind, placebo-controlled trials undertaken in North America/Latin America and Europe, are evaluating the efficacy of AST-120 for preventing the progression of CKD. The results of the EPPIC trials will further define the role of AST-120 in this debilitating condition. PMID:24501542

  8. AlSb photonic detectors for gamma-ray spectroscopy. Progress report, October 1994--August 1995

    SciTech Connect

    Becla, P.; Witt, A.F.

    1995-12-31

    Aluminum antimony (AlSb) is an indirect band gap semiconductor with Eg of about 1.62 eV at 300 K and about 1.75 eV at 77 K. This material, is extremely difficult to obtain in single crystal form because of the very high reactivity of aluminum with oxygen, and the high volatility of antimony. Moreover, molten AlSb reacts with nearly all crucible materials available. Since Welker`s first attempts in 1952, only very few different experimental approaches have been used to grow single crystals of AlSb, e.g. by Bridgman, Czochralski and MBE. All experimental results, however, indicate that many of the properties of AlSb, e.g. carrier concentration, electron-hole mobility and carrier life-time, differ significantly from the theoretically predicted values. The main objective of this research period has been to develop a method leading to improved crystallographic and electronic quality of AlSb crystals, making them more suitable for device applications. The research program was aimed along the following two directions: (1) study the growth of AlSb via Bridgman, Czochralski and THM techniques; (2) comprehensive characterization of grown material, related to the use of compounds for high energy gamma detectors. Variables in the growth study were growth temperature, equilibrium pressure, growth rate, doping, crucible material, seeding and encapsulation. The characterization study included crystallographic quality (grain size, etch pits, precipitates, inclusions), electronic quality (conductivity type, carrier concentration and mobility), optical properties (spectral absorption, photoconductivity, persistent absorption) and others (SIMS, EPR).

  9. Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice.

    PubMed

    Pan-Montojo, Francisco; Anichtchik, Oleg; Dening, Yanina; Knels, Lilla; Pursche, Stefan; Jung, Roland; Jackson, Sandra; Gille, Gabriele; Spillantini, Maria Grazia; Reichmann, Heinz; Funk, Richard H W

    2010-01-01

    In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20 nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how environmental factors could trigger PD and suggests a transsynaptic mechanism by which PD might spread throughout the central nervous system. PMID:20098733

  10. Sad and happy facial emotion recognition impairment in progressive supranuclear palsy in comparison with Parkinson's disease.

    PubMed

    Pontieri, Francesco E; Assogna, Francesca; Stefani, Alessandro; Pierantozzi, Mariangela; Meco, Giuseppe; Benincasa, Dario; Colosimo, Carlo; Caltagirone, Carlo; Spalletta, Gianfranco

    2012-08-01

    The severity of motor and non-motor symptoms of progressive supranuclear palsy (PSP) has a profound impact on social interactions of affected individuals and may, consequently, contribute to alter emotion recognition. Here we investigated facial emotion recognition impairment in PSP with respect to Parkinson's disease (PD), with the primary aim of outlining the differences between the two disorders. Moreover, we applied an intensity-dependent paradigm to examine the different threshold of encoding emotional faces in PSP and PD. The Penn emotion recognition test (PERT) was used to assess facial emotion recognition ability in PSP and PD patients. The 2 groups were matched for age, disease duration, global cognition, depression, anxiety, and daily L-Dopa intake. PSP patients displayed significantly lower recognition of sad and happy emotional faces with respect to PD ones. This applied to global recognition, as well as to low-intensity and high-intensity facial emotion recognition. These results indicate specific impairment of recognition of sad and happy facial emotions in PSP with respect to PD patients. The differences may depend upon diverse involvement of cortical-subcortical loops integrating emotional states and cognition between the two conditions, and might represent a neuropsychological correlate of the apathetic syndrome frequently encountered in PSP. PMID:22595619

  11. Lymphocyte Mitochondria: Towards Identification of Peripheral Biomarkers in Progression of Alzheimer Disease

    PubMed Central

    Sultana, Rukhsana; Baglioni, Mauro; Cecchetti, Roberta; Cai, Jian; Klein, Jon B; Bastiani, Patrizia; Ruggiero, Carmelinda; Mecocci, Patrizia; Butterfield, D. Allan

    2013-01-01

    Alzheimer disease is an age-related neurodegenerative condition. AD is histopathologically characterized by the presence of three main hallmarks: senile plaque (SP, rich in amyloid-beta peptide), neuronal fibrillary tangles (NFT, rich in phosphorylated tau protein), and synapse loss. However, definitive biomarkers for this devastating disease in living people are still lacking. In the present study, we showed that levels of oxidative stress markers are significantly increased in the mitochondria isolated from lymphocytes of subjects with mild cognitive impairment (MCI) compared to cognitively normal individuals. Further, increase in mitochondrial oxidative stress in MCI is associated with the MMSE scores, vitamin E components, and beta-carotene. Further, proteomics approach showed that the alterations in the levels of thioredoxin-dependent peroxide reductase, myosin light polypeptide 6, and ATP synthase subunit beta might be important in the progression and pathogenesis of AD. Increased understanding of oxidative stress and protein alterations in easily obtainable peripheral tissues will be helpful in developing biomarkers to combat this devastating disorder. PMID:23933528

  12. MRI signal and texture features for the prediction of MCI to Alzheimer's disease progression

    NASA Astrophysics Data System (ADS)

    Martínez-Torteya, Antonio; Rodríguez-Rojas, Juan; Celaya-Padilla, José M.; Galván-Tejada, Jorge I.; Treviño, Victor; Tamez-Peña, José G.

    2014-03-01

    An early diagnosis of Alzheimer's disease (AD) confers many benefits. Several biomarkers from different information modalities have been proposed for the prediction of MCI to AD progression, where features extracted from MRI have played an important role. However, studies have focused almost exclusively in the morphological characteristics of the images. This study aims to determine whether features relating to the signal and texture of the image could add predictive power. Baseline clinical, biological and PET information, and MP-RAGE images for 62 subjects from the Alzheimer's Disease Neuroimaging Initiative were used in this study. Images were divided into 83 regions and 50 features were extracted from each one of these. A multimodal database was constructed, and a feature selection algorithm was used to obtain an accurate and small logistic regression model, which achieved a cross-validation accuracy of 0.96. These model included six features, five of them obtained from the MP-RAGE image, and one obtained from genotyping. A risk analysis divided the subjects into low-risk and high-risk groups according to a prognostic index, showing that both groups are statistically different (p-value of 2.04e-11). The results demonstrate that MRI features related to both signal and texture, add MCI to AD predictive power, and support the idea that multimodal biomarkers outperform single-modality biomarkers.

  13. Injectable and oral contraception and the incidence and progression of cervical disease in HIV-infected women in South Africa

    PubMed Central

    Westreich, Daniel; Jamal, Naiomi; Smith, Jennifer S.; Schulze, Doreen; Williams, Sophie; Michelow, Pam; Levin, Simon; Firnhaber, Cynthia

    2014-01-01

    Background Few data exist regarding the effect of hormonal contraception (HC) on incidence and progression of cervical disease (e.g., cervical dysplasia, squamous intraepithelial lesions, cervical intraepithelial neoplasia) in HIV-infected African women. Study Design We conducted an observational study of HIV-seropositive women in Johannesburg, South Africa. The effect of individual HC types on the incidence and progression of cervical disease was determined using Poisson regression to obtain adjusted incidence rate ratios (IRR). Results We evaluated 594 HIV-infected women, with median follow-up time of 445 days; 75 of these women were receiving some form of hormonal contraception (largely DMPA, NET-EN, or COCs) at baseline. Risks of incidence and progression of cervical disease were similar comparing women not receiving HCs to women receiving DMPA, NET-EN, or COCs both individually by HC-type and considering all HC together. Conclusions There was no statistically significant effect of particular HC methods or of HC use in general on rates of incidence or progression of cervical disease in this study. These results should reassure us that use of HC is unlikely to substantially increase risks of cervical disease among HIV-positive women. PMID:24485095

  14. Genetic polymorphisms of Trim5a are associated with disease progression in acutely and chronically HIV-infected patients

    PubMed Central

    Sun, Xin; Li, Wei; Liu, Wenzhen; Wang, Rui; Li, Qunhui; Wu, Hao

    2015-01-01

    Background: The tripartite interaction motif 5a (Trim5a) plays critical roles in restricting various kinds of retroviruses in different species. It has been shown that Trim5a could inhibit HIV-1 inhibition in vitro. Methods: In this study, 16 SNPs of Trim5a gene were screened in 236 acutely HIV-infected patients (169 common type (CT) patients and 67 patients with rapid disease progression). In addition, they were screened in 162 chronically HIV-infected patients (147 common type patients and 15 long-term non-progressors (LTNP)). The potential effects of polymorphisms at Trim5a genes on HIV-infection disease progression were analyzed. Results: Among all tested SNP sites, 3 SNPs (rs3824949, rs2291841 and rs11038628) were identified to be associated with rapid disease progression in acutely HIV-infected patients. Carriage of rs3824949 allele G, rs2291841 allele C or rs11038628 allele T associated with rapid disease progression. In chronically HIV-infected patients, Patients carrying rs3802981 allele C or rs3802980 allele A had increased opportunity to be LTNP. We also found that greater age was associated with disease deterioration. Conclusions: Different genetic polymorphisms of Trim5a may have an impact on the clinical course of both acute and chronic stages of HIV-infection. PMID:26629134

  15. Myofibrotic malformation vessels: unique angiodysplasia toward the progression of hemorrhoidal disease

    PubMed Central

    Li, Sheng-Long; Jing, Fang-Yan; Ma, Li-Li; Guo, Li-Li; Na, Feng; An, Sheng-Li; Ye, Yan; Yang, Jun-Ming; Bao, Ming; Kang, Dong; Sun, Xiao-Lan; Deng, Yong-Jian

    2015-01-01

    Background The etiology and pathogenesis of hemorrhoids is unclear, although hemorrhoids are a worldwide disease in men and women, with peak prevalence at 45–65 years of age. Hemorrhoidal cushions as the anal venous plexi are normal anatomical structures from infancy. This study attempts to reveal the angiodysplasia and other pathological changes in association with different degrees of symptomatic hemorrhoids. Materials and methods A total of 281 patients with internal hemorrhoids from degree I to IV underwent hemorrhoidectomy. The vascular changes were analyzed by microscopic assessment and software analysis, with Masson’s trichrome, CD34, and smooth muscle actin. Results The hemorrhoidal tissues exhibited abnormal vessels in the mucosae and submucosae that we termed them as myofibrotic malformation vessels (MMVs). MMVs are not ascribed to arteries or veins because they exhibit enlarged and tortuous lumens with smooth muscle dysplasia and fibrotic deposition in the walls without overlying mucosal ulceration. The muscularis mucosae also showed smooth muscle dysplasia and fibrosis, even if it were interrupted by the intruding MMVs. The statistical data indicated that the severity of all the changes correlate positively with the progression of hemorrhoids (P<0.001). Hemorrhoidal patients are prone for reoccurrence even with prolapsing hemorrhoid when compared with the conventional hemorrhoidectomy. Multiple logistic regression analysis showed that MMVs in mucosal propria, mean thickness of mucosal muscularis layer, and fibrotic changes in MMV were independent risk factors for MMVs in hemorrhoidal disease. Conclusion MMVs and muscularis mucosae dysplasia reciprocally contribute to hemorrhoidal exacerbation. The novel findings of this study propose that the characteristic features of MMVs and muscularis mucosae dysplasia of the anorectal tube ultimately cause symptomatic hemorrhoids, which could affect the clinical management of hemorrhoidal disease through the use of surgery to target the malformed vessels. PMID:26316703

  16. Application of Systems Theory in Longitudinal Studies on the Origin and Progression of Alzheimer's Disease.

    PubMed

    Lista, Simone; Khachaturian, Zaven S; Rujescu, Dan; Garaci, Francesco; Dubois, Bruno; Hampel, Harald

    2016-01-01

    This chapter questions the prevailing "implicit" assumption that molecular mechanisms and the biological phenotype of dominantly inherited early-onset alzheimer's disease (EOAD) could serve as a linear model to study the pathogenesis of sporadic late-onset alzheimer's disease (LOAD). Now there is growing evidence to suggest that such reductionism may not be warranted; these suppositions are not adequate to explain the molecular complexities of LOAD. For example, the failure of some recent amyloid-centric clinical trials, which were largely based on the extrapolations from EOAD biological phenotypes to the molecular mechanisms in the pathogenesis of LOAD, might be due to such false assumptions. The distinct difference in the biology of LOAD and EOAD is underscored by the presence of EOAD cases without evidence of familial clustering or Mendelian transmission and, conversely, the discovery and frequent reports of such clustering and transmission patterns in LOAD cases. The primary thesis of this chapter is that a radically different way of thinking is required for comprehensive explanations regarding the distinct complexities in the molecular pathogenesis of inherited and sporadic forms of Alzheimer's disease (AD). We propose using longitudinal analytical methods and the paradigm of systems biology (using transcriptomics, proteomics, metabolomics, and lipidomics) to provide us a more comprehensive insight into the lifelong origin and progression of different molecular mechanisms and neurodegeneration. Such studies should aim to clarify the role of specific pathophysiological and signaling pathways such as neuroinflammation, altered lipid metabolism, apoptosis, oxidative stress, tau hyperphosphorylation, protein misfolding, tangle formation, and amyloidogenic cascade leading to overproduction and reduced clearance of aggregating amyloid-beta (A?) species. A more complete understanding of the distinct difference in molecular mechanisms, signaling pathways, as well as comparability of the various forms of AD is of paramount importance. The development of knowledge and technologies for early detection and characterization of the disease across all stages will improve the predictions regarding the course of the disease, prognosis, and response to treatment. No doubt such advances will have a significant impact on the clinical management of both EOAD and LOAD patients. The approach propped here, combining longitudinal studies with the systems biology paradigm, will create a more effective and comprehensive framework for development of prevention therapies in AD. PMID:26235059

  17. Association of relative telomere length with progression of chronic kidney disease in two cohorts: effect modification by smoking and diabetes

    PubMed Central

    Raschenberger, Julia; Kollerits, Barbara; Ritchie, James; Lane, Beverley; Kalra, Philip A.; Ritz, Eberhard; Kronenberg, Florian

    2015-01-01

    Chronic kidney disease (CKD) is a highly progressive disease. We studied the association between relative telomere length (RTL) and CKD progression and tested whether this association is modified by smoking and diabetes mellitus. RTL was measured by qPCR in two prospective cohort studies, the MMKD-Study (n?=?166) and the CRISIS-Study (n?=?889) with a median follow-up of 4.5 and 2.8 years, respectively. Progression was defined as doubling of baseline serum creatinine (MMKD-Study) and/or end stage renal disease (both studies). 59 and 105 of the patients from MMKD and CRISIS experienced a progression of CKD. Mean standardized pooled RTL was 0.74?±?0.29. In the meta-analysis shorter RTL at baseline showed a borderline association with CKD progression (HR?=?1.07 [95%CI 1.00–1.15]; p?=?0.06). We observed an effect modification of RTL and CKD progression by smoking and diabetes (p-values of interaction p?=?0.02 and p?=?0.09, respectively). Each 0.1 unit shorter RTL was significantly associated with an increased hazard for CKD progression in active-smokers by 44% (HR?=?1.44 [1.16–1.81]; p?=?0.001) and in patients with diabetes mellitus by 16% (HR?=?1.16 [1.01–1.34]; p?=?0.03). Estimates were adjusted for baseline age, sex, proteinuria and GFR. This study in two independent cohorts reinforces that RTL is a marker and potentially a pathogenetic factor for CKD progression. PMID:26149682

  18. Type I Vs. Type II Cytokine Levels as a Function of SOD1 G93A Mouse Amyotrophic Lateral Sclerosis Disease Progression

    PubMed Central

    Jeyachandran, Amilia; Mertens, Benjamin; McKissick, Eric A.; Mitchell, Cassie S.

    2015-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a fatal motoneuron disease that is characterized by the degradation of neurons throughout the central nervous system. Inflammation have been cited a key contributor to ALS neurodegeneration, but the timeline of cytokine upregulation remains unresolved. The goal of this study was to temporally examine the correlation between the varying levels of pro-inflammatory type I cytokines (IL-1?, IL-1?, IL-12, TNF-?, and GFAP) and anti-inflammatory type II cytokines (IL-4, IL-6, IL-10) throughout the progression of ALS in the SOD1 G93A mouse model. Cytokine level data from high copy SOD1 G93A transgenic mice was collected from 66 peer-reviewed studies. For each corresponding experimental time point, the ratio of transgenic to wild type (TG/WT) cytokine was calculated. One-way ANOVA and t-tests with Bonferonni correction were used to analyze the data. Meta-analysis was performed for four discrete stages: early, pre-onset, post-onset, and end stage. A significant increase in TG cytokine levels was found when compared to WT cytokine levels across the entire SOD1 G93A lifespan for majority of the cytokines. The rates of change of the individual cytokines, and type I and type II were not significantly different; however, the mean fold change of type I was expressed at significantly higher levels than type II levels across all stages with the difference between the means becoming more pronounced at the end stage. An overexpression of cytokines occurred both before and after the onset of ALS symptoms. The trend between pro-inflammatory type I and type II cytokine mean levels indicate a progressive instability of the dynamic balance between pro- and anti-inflammatory cytokines as anti-inflammatory cytokines fail to mediate the pronounced increase in pro-inflammatory cytokines. Very early immunoregulatory treatment is necessary to successfully interrupt ALS-induced neuroinflammation. PMID:26648846

  19. Familial and primary (AL) cardiac amyloidosis: echocardiographically similar diseases with distinctly different clinical outcomes.

    PubMed Central

    Dubrey, S. W.; Cha, K.; Skinner, M.; LaValley, M.; Falk, R. H.

    1997-01-01

    OBJECTIVE: To determine whether patients with myocardial amyloidosis due either to AL (primary) amyloid or familial amyloid have distinguishing echocardiographic or electrocardiographic features; and to compare the prevalence of heart failure and survival in the two types of amyloidosis in relation to echocardiographic findings. DESIGN: Blinded group comparison of randomly selected cases of cardiac amyloidosis. SETTING: International referral centre for amyloid research and treatment. PATIENTS: 36 patients with cardiac amyloid heart disease, of whom 12 had familial and 24 had primary AL amyloidosis. RESULTS: Familial and AL echocardiograms were morphologically indistinguishable, with similar left ventricular wall thickness, mean (SD) 15.4 (2.3) nu 15.8 (2.5) mm, respectively; right ventricular wall thickness was also similar between amyloid types: 9.6 (2.8) nu 9.7 (6.5) mm, respectively. Doppler indices of left and right ventricular function, left ventricular volume, and ejection fraction were also similar. Low voltage electrocardiograms (< 0.5 mV) were more common in the AL (16/24, 67%) than in the familial group (4/12, 25%), P < 0.05. The one year survival for familial and AL forms was 92% (11/12) nu 38% (6/24), respectively, with virtually all deaths due to cardiac causes. CONCLUSIONS: Although cardiac involvement is echocardiographically indistinguishable, cardiac mortality is very different between the two forms of amyloidosis. Preservation of electrocardiographic voltage in familial amyloidosis suggests that the particular biochemical characteristics of distinct types of amyloid fibril have different pathological effects on the myocardium. This distinction becomes critical in the evaluation, treatment, and management of patients who have a diagnosis within the spectrum of the protein deposition diseases. Images PMID:9290406

  20. Modeling diabetes disease progression and salsalate intervention in Goto-Kakizaki rats.

    PubMed

    Cao, Yanguang; Dubois, Debra C; Sun, Hao; Almon, Richard R; Jusko, William J

    2011-12-01

    Type 2 diabetes mellitus (T2DM) arises owing to insulin resistance and ?-cell dysfunction. Chronic inflammation is widely identified as a cause of T2DM. The Goto-Kakizaki (GK) rat is a spontaneous rodent model for T2DM with chronic inflammation. The purpose of this study was to characterize diabetes progression in GK rats and evaluate the potential role of the anti-inflammatory agent salsalate. The GK rats were divided into control groups (n = 6) and salsalate treatment groups (n = 6), which were fed a salsalate-containing diet from 5 to 21 weeks of age. Blood glucose and salicylate concentrations were measured once a week. Glucose concentrations showed a biphasic increase in which the first phase started at approximately 5 weeks, resulting in an increase by 15 to 25 mg/dl and a second phase at 14 to 15 weeks with an upsurge of more than 100 mg/dl. A mechanism-based model was proposed to describe the natural diabetes progression and salsalate pharmacodynamics by using a population method in S-ADAPT. Two transduction cascades were applied to mimic the two T2DM components: insulin resistance and ?-cell dysfunction. Salsalate suppressed both disease factors by a fraction of 0.622 on insulin resistance and 0.134 on ?-cell dysfunction. The substantial alleviation of diabetes by salsalate supports the hypothesis that chronic inflammation is a pathogenic factor of diabetes in GK rats. In addition, body weight and food intake were measured and further modeled by a mechanism-based growth model. Modeling results suggest that salsalate reduces weight gain by enhancing metabolic rate and energy expenditure in both GK and Wister-Kyoto rats. PMID:21903749

  1. Which Neuropsychological Tests Predict Progression to Alzheimer’s Disease in Hispanics?

    PubMed Central

    Weissberger, Gali H.; Salmon, David P.; Bondi, Mark W.; Gollan, Tamar H.

    2013-01-01

    Objective To investigate which neuropsychological tests predict eventual progression to Alzheimer’s disease (AD) in both Hispanic and non-Hispanic individuals. Although our approach was exploratory, we predicted that tests that underestimate cognitive ability in healthy aging Hispanics might not be sensitive to future cognitive decline in this cultural group. Method We compared first-year data of 22 older adults (11 Hispanic) who were diagnosed as cognitively normal but eventually developed AD (decliners), to 60 age- and education-matched controls (27 Hispanic) who remained cognitively normal. To identify tests that may be culturally biased in our sample, we compared Hispanic with non-Hispanic controls on all tests and asked which tests were sensitive to future decline in each cultural group. Results Compared to age-, education-, and gender-matched non-Hispanic controls, Hispanic controls obtained lower scores on tests of language, executive function, and some measures of global cognition. Consistent with our predictions, some tests identified non-Hispanic, but not Hispanic, decliners (vocabulary, semantic fluency). Contrary to our predictions, a number of tests on which Hispanics obtained lower scores than non-Hispanics nevertheless predicted eventual progression to AD in both cultural groups (e.g., Boston Naming Test [BNT], Trails A and B). Conclusions Cross-cultural variation in test sensitivity to decline may reflect greater resistance of medium difficulty items to decline and bilingual advantages that initially protect Hispanics against some aspects of cognitive decline commonly observed in non-Hispanics with preclinical AD. These findings highlight a need for further consideration of cross-cultural differences in neuropsychological test performance and development of culturally unbiased measures. PMID:23688216

  2. Oxidation of Al-bearing III-V materials: A review of key progress

    NASA Astrophysics Data System (ADS)

    Dallesasse, J. M.; Holonyak, N.

    2013-02-01

    Since the discovery of III-V oxidation by Dallesasse and Holonyak in 1989, significant progress has been made both technically and commercially in the use of oxides in compound semiconductor devices. Devices ranging from lasers to transistors have been fabricated that capitalize on the process-induced modification of refractive index and conductivity, allowing control of the two carriers of information in opto-electronic systems—the photon and the electron. Of particular note has been the use of oxidation for the fabrication of high-speed vertical-cavity surface-emitting lasers, which have extensive use in optical data links found in enterprise networks, data centers, and supercomputing applications. The discovery of III-V oxidation and key technical milestones in the fabrication of photonic and electronic devices that use oxidation are reviewed.

  3. Early ALS-type gait abnormalities in AMP-dependent protein kinase-deficient mice suggest a role for this metabolic sensor in early stages of the disease.

    PubMed

    Vergouts, Maxime; Marinangeli, Claudia; Ingelbrecht, Caroline; Genard, Geraldine; Schakman, Olivier; Sternotte, Anthony; Calas, André-Guilhem; Hermans, Emmanuel

    2015-12-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motoneurons. While the principal cause of the disease remains so far unknown, the onset and progression of the pathology are increasingly associated with alterations in the control of cell metabolism. On the basis of the well-known key roles of 5'-adenosine monophosphate-activated protein kinase (AMPK) in sensing and regulating the intracellular energy status, we hypothesized that mice with a genetic deletion of AMPK would develop locomotor abnormalities that bear similarity with those detected in the very early disease stage of mice carrying the ALS-associated mutated gene hSOD1(G93A). Using an automated gait analysis system (CatWalk), we here show that hSOD1(G93A) mice and age-matched mice lacking the neuronal and skeletal muscle predominant ?2 catalytic subunit of AMPK showed an altered gait, clearly different from wild type control mice. Double mutant mice lacking AMPK ?2 and carrying hSOD1(G93A) showed the same early gait abnormalities as hSOD1(G93A) mice over an age span of 8 to 16 weeks. Taken together, these data support the concept that altered AMPK function and associated bioenergetic abnormalities could constitute an important component in the early pathogenesis of ALS. Therapeutic interventions acting on metabolic pathways could prove beneficial on early locomotor deficits, which are sensitively detectable in rodent models using the CatWalk system. PMID:26152932

  4. Ventilatory Control in ALS

    PubMed Central

    Nichols, Nicole L.; Van Dyke, J.; Nashold, L.; Satriotomo, I.; Suzuki, M.; Mitchell, G.S.

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease. ALS selectively causes degeneration in upper and lower (spinal) motor neurons, leading to muscle weakness, paralysis and death by ventilatory failure. Although ventilatory failure is generally the cause of death in ALS, little is known concerning the impact of this disorder on respiratory motor neurons, the consequences of respiratory motor neuron cell death, or the ability of the respiratory control system to “fight back” via mechanisms of compensatory respiratory plasticity. Here we review known effects of ALS on breathing, including possible effects on rhythm generation, respiratory motor neurons, and their target organs: the respiratory muscles. We consider evidence for spontaneous compensatory plasticity, preserving breathing well into disease progression despite dramatic loss of spinal respiratory motor neurons. Finally, we review current and potential therapeutic approaches directed toward preserving the capacity to breathe in ALS patients. PMID:23692930

  5. Oscillation of Angiogenesis and Vascular Dropout in Progressive Human Vascular Disease. [Vascular Pattern as Useful Read-Out of Complex Molecular Signaling

    NASA Technical Reports Server (NTRS)

    Parsons-Wingerter, Patricia

    2010-01-01

    When analyzed by VESsel GENeration Analysis (VESGEN) software, vascular patterns provide useful integrative read-outs of complex, interacting molecular signaling pathways. Using VESGEN, we recently discovered and published our innovative, surprising findings that angiogenesis oscillated with vascular dropout throughout progression of diabetic retinopathy, a blinding vascular disease. Our findings provide a potential paradigm shift in the current prevailing view on progression and treatment of this disease, and a new early-stage window of regenerative therapeutic opportunities. The findings also suggest that angiogenesis may oscillate with vascular disease in a homeostatic-like manner during early stages of other inflammatory progressive diseases such as cancer and coronary vascular disease.

  6. Letter Report Documenting Progress of Second Generation ATF FeCrAl Alloy Fabrication

    SciTech Connect

    Yamamoto,, Y.; Yang, Y.; Field, K. G.; Terrani, K.; Pint, B. A.; Snead, L. L.

    2014-06-10

    Development of the 2nd generation ATF FeCrAl alloy has been initiated, and a candidate alloy was selected for trial tube fabrication through hot-extrusion and gun-drilling processes. Four alloys based on Fe-13Cr-4.5Al-0.15Y in weight percent were newly cast with minor alloying additions of Mo, Si, Nb, and C to promote solid-solution and second-phase precipitate strengthening. The alloy compositions were selected with guidance from computational thermodynamic tools. The lab-scale heats of ~ 600g were arc-melted and drop-cast, homogenized, hot-forged and -rolled, and then annealed producing plate shape samples. An alloy with Mo and Nb additions (C35MN) processed at 800°C exhibits very fine sub-grain structure with the sub-grain size of 1-3?m which exhibited more than 25% better yield and tensile strengths together with decent ductility compared to the other FeCrAl alloys at room temperature. It was found that the Nb addition was key to improving thermal stability of the fine sub-grain structure. Optimally, grains of less than 30 microns are desired, with grains up to and order of magnitude in desired produced through Nb addition. Scale-up effort of the C35MN alloy was made in collaboration with a commercial cast company who has a capability of vacuum induction melting. A 39lb columnar ingot with ~81mm diameter and ~305mm height (with hot-top) was commercially cast, homogenized, hot-extruded, and annealed providing 10mm-diameter bar-shape samples with the fine sub-grain structure. This commercial heat proved consistent with materials produced at ORNL at the lab-scale. Tubes and end caps were machined from the bar sample and provided to another work package for the ATF-1 irradiation campaign in the milestone M3FT-14OR0202251.

  7. PROGRESSION OF DISEASES CAUSED BY THE OYSTER PARASITES, PERKINSUS MARINUS AND HAPLOSPORIDIUM NELSONI, IN CRASSOSTREA VIRGINICA ON CONSTRUCTED INTERTIDAL REEFS

    EPA Science Inventory

    The progression of diseases caused by the oyster parasites, Perkinsus marinus and Haplosporidium nelsoni, were evaluated by periodic sampling (May 1994-Dec. 1995) of oysters, Crassostrea virginica, that set on an artificial reef located in the Piankatank River, Virginia, in Augus...

  8. Mamu-A*01 allele-mediated attenuation of disease progression in simian-human immunodeficiency virus infection.

    PubMed

    Zhang, Zhi-Qiang; Fu, Tong-Ming; Casimiro, Danilo R; Davies, Mary-Ellen; Liang, Xiaoping; Schleif, William A; Handt, Larry; Tussey, Lynda; Chen, Minchun; Tang, Aimin; Wilson, Keith A; Trigona, Wendy L; Freed, Daniel C; Tan, Charles Y; Horton, Melanie; Emini, Emilio A; Shiver, John W

    2002-12-01

    Expression of several major histocompatibility complex (MHC) class I alleles is associated with a protective effect against disease progression in both human immunodeficiency virus type 1 and simian immunodeficiency virus infection. To understand the mechanism underlying this effect, we investigated the expression of the MHC class I allele Mamu-A*01 in simian-human immunodeficiency virus (SHIV) infection, one of the major models for evaluation of AIDS vaccine candidates. We found that disease progression was significantly delayed in Mamu-A*01-positive rhesus monkeys infected with the highly pathogenic SHIV 89.6P. The delay corresponded not only to a noted Mamu-A*01-restricted dominant cytotoxic T-lymphocyte (CTL) response but also to a lower viral load in lymph nodes (LN) and, importantly, to minimal destruction of LN structure during early infection. In contrast, Mamu-A*01-negative monkeys exhibited massive destruction of LN structure with accompanying rapid disease progression. These data indicate that MHC class I allele-restricted CTL responses may play an important role in preservation of lymphoid tissue structure, thereby resulting in attenuation of disease progression in immunodeficiency virus infection. PMID:12438610

  9. Presence of specific MHC Class II expressed alleles associates with clinical disease in ovine progressive pneumonia virus (OPPV) infected sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A genetic tool hypothesized to predict which OPPV infected sheep will progress to debilitating clinical disease is MHC Class II Ovis aries (Ovar)-DRB1. Previously, fifteen Ovar-DRB1 beta 1 expressed alleles were identified in a ewe-lamb flock of 32 originating from an Idaho flock using RT-PCR, clon...

  10. Genome-wide association study identifies multiple novel loci associated with disease progression in subjects with mild cognitive impairment.

    PubMed

    Hu, X; Pickering, E H; Hall, S K; Naik, S; Liu, Y C; Soares, H; Katz, E; Paciga, S A; Liu, W; Aisen, P S; Bales, K R; Samad, T A; John, S L

    2011-01-01

    Alzheimer's disease (AD) is the leading cause of dementia among the elderly population; however, knowledge about genetic risk factors involved in disease progression is limited. We conducted a genome-wide association study (GWAS) using clinical decline as measured by changes in the Clinical Dementia Rating-sum of boxes as a quantitative trait to test for single-nucleotide polymorphisms (SNPs) that were associated with the rate of progression in 822 Caucasian subjects of amnestic mild cognitive impairment (MCI). There was no significant association with disease progress for any of the recently identified disease susceptibility variants in CLU, CR1, PICALM, BIN1, EPHA1, MS4A6A, MS4A4E or CD33 following multiple testing correction. We did, however, identify multiple novel loci that reached genome-wide significance at the 0.01 level. These top variants (rs7840202 at chr8 in UBR5: P=4.27 × 10(-14); rs11637611 with a cluster of SNPs at chr15q23 close to the Tay-Sachs disease locus: P=1.07 × 10(-15); and rs12752888 at chr1: P=3.08 × 10(-11)) were also associated with a significant decline in cognition as well as the conversion of subjects with MCI to a diagnosis of AD. Taken together, these variants define approximately 16.6% of the MCI sub-population with a faster rate of decline independent of the other known disease risk factors. In addition to providing new insights into protein pathways that may be involved with the progress to AD in MCI subjects, these variants if further validated may enable the identification of a more homogeneous population of subjects at an earlier stage of disease for testing novel hypotheses and/or therapies in the clinical setting. PMID:22833209

  11. Progressive Cognitive Deficit, Motor Impairment and Striatal Pathology in a Transgenic Huntington Disease Monkey Model from Infancy to Adulthood

    PubMed Central

    Chan, Anthony W. S.; Prucha, Melinda S.; Hu, Yijuan; Chi, Tim; Moran, Sean; Rahim, Tayeb; Li, Shihua; Li, Xiaojiang; Zola, Stuart M.; Testa, Claudia M.; Mao, Hui; Villalba, Rosa; Smith, Yoland; Zhang, Xiaodong; Bachevalier, Jocelyne

    2015-01-01

    One of the roadblocks to developing effective therapeutics for Huntington disease (HD) is the lack of animal models that develop progressive clinical traits comparable to those seen in patients. Here we report a longitudinal study that encompasses cognitive and motor assessment, and neuroimaging of a group of transgenic HD and control monkeys from infancy to adulthood. Along with progressive cognitive and motor impairment, neuroimaging revealed a progressive reduction in striatal volume. Magnetic resonance spectroscopy at 48 months of age revealed a decrease of N-acetylaspartate (NAA), further suggesting neuronal damage/loss in the striatum. Postmortem neuropathological analyses revealed significant neuronal loss in the striatum. Our results indicate that HD monkeys share similar disease patterns with HD patients, making them potentially suitable as a preclinical HD animal model. PMID:25966278

  12. Unification of the "burst" and "linear" theories of periodontal disease progression: a multilevel manifestation of the same phenomenon.

    PubMed

    Gilthorpe, M S; Zamzuri, A T; Griffiths, G S; Maddick, I H; Eaton, K A; Johnson, N W

    2003-03-01

    Previously, burst and linear theories for periodontal disease progression were proposed based on different but limited statistical methods of analysis. Multilevel modeling provides a new approach, yielding a more comprehensive model. Random coefficient models were used to analyze longitudinal periodontal data consisting of repeated measures (level 1), sites (level 2), teeth (level 3), and subjects (level 4). Large negative and highly significant correlations between random linear and quadratic time coefficients indicated that subjects and teeth with greater-than-average linear change experienced decelerated variation. Conversely, subjects and teeth with less-than-average linear change experienced accelerated variation. Change therefore exhibited a dynamic regression to the mean at the tooth and subject levels. Since no equilibrium was attained throughout the study, changes were cyclical. When considered as a multilevel system, the "linear" and "burst" theories of periodontal disease progression are a manifestation of the same phenomenon: Some sites improve while others progress, in a cyclical manner. PMID:12598549

  13. Interim-treatment quantitative PET parameters predict progression and death among patients with hodgkin's disease

    PubMed Central

    2012-01-01

    Purpose We hypothesized that quantitative PET parameters may have predictive value beyond that of traditional clinical factors such as the International Prognostic Score (IPS) among Hodgkin's disease (HD) patients. Methods Thirty HD patients treated at presentation or relapse had staging and interim-treatment PET-CT scans. The majority of patients (53%) had stage III-IV disease and 67% had IPS ? 2. Interim-treatment scans were performed at a median of 55 days from the staging PET-CT. Chemotherapy regimens used: Stanford V (67%), ABVD (17%), VAMP (10%), or BEACOPP (7%). Hypermetabolic tumor regions were segmented semiautomatically and the metabolic tumor volume (MTV), mean standardized uptake value (SUVmean), maximum SUV (SUVmax) and integrated SUV (iSUV) were recorded. We analyzed whether IPS, absolute value PET parameters or the calculated ratio of interim- to pre-treatment PET parameters were associated with progression free survival (PFS) or overall survival (OS). Results Median follow-up of the study group was 50 months. Six of the 30 patients progressed clinically. Absolute value PET parameters from pre-treatment scans were not significant. Absolute value SUVmax from interim-treatment scans was associated with OS as determined by univariate analysis (p < 0.01). All four calculated PET parameters (interim/pre-treatment values) were associated with OS: MTVint/pre (p < 0.01), SUVmeanint/pre (p < 0.05), SUVmaxint/pre (p = 0.01), and iSUVint/pre (p < 0.01). Absolute value SUVmax from interim-treatment scans was associated with PFS (p = 0.01). Three calculated PET parameters (int/pre-treatment values) were associated with PFS: MTVint/pre (p = 0.01), SUVmaxint/pre (p = 0.02) and iSUVint/pre (p = 0.01). IPS was associated with PFS (p < 0.05) and OS (p < 0.01). Conclusions Calculated PET metrics may provide predictive information beyond that of traditional clinical factors and may identify patients at high risk of treatment failure early for treatment intensification. PMID:22260710

  14. The role of interstitial changes in the progression of chronic kidney disease.

    PubMed

    Sulikowska, Beata; Rutkowski, Boles?aw; Marsza?ek, Andrzej; Manitius, Jacek

    2015-01-01

    Interstitium - the renal tubulointerstitial compartment - is located between the renal tubule basement membrane and microcirculation vessels. Interstitial fibroblasts produce the extracellular matrix and constitute the structure's cellular skeleton, regulating spatial relationships between its components (microenvironment). The tubular epithelium and endothelium cooperate within an integrated microenvironment. Structural or functional impairment of the extracellular matrix, microcirculation vessels or tubular epithelium results in disturbances of tubulointerstitial compartment components. In the course of glomerular kidney diseases, the intrarenal RAA system becomes activated and inflammatory mediators are released. Interstitial inflammation and microcirculatory disorders develop, inducing adverse consequences, manifested mainly through the process of hypoxia and inflammation. Inflammation-induced increase in interleukin-1 (TNF-?) expression leads to increased concentrations of VEGF, ICAM-1, angiotensin II, IL-6 and IL-8. Cytokines activate fibroblasts, myofibroblasts and endothelial cells. Fibrosis is also triggered by HIF-1alpha pathway activation, resulting in vascular growth and fibroblast proliferation. This reaction likewise occurs through activation of NF-??, EPO, GLUT-1, IGF-1 and INOS. Interstitial fibrosis is one of the factors determining the clinical course of kidney diseases. Apart from inducing fibrosis, microcirculatory disorders lead to the progression of hypoxia. Angiogenesis is a part of the repair process accompanying fibrosis. Its determinant is the normal function and structure of endothelial cells manifested by their ability to migrate and proliferate in response to, inter alia, angiopoietins, VEGF and nitric oxide synthase. Administering a three-drug RAAS-inhibiting therapy to patients with chronic glomerulopathies improves tubular function, measured by the decrease in excretion of NAG and propeptide of type III procollagen fibres, and contributes to the improvement in microcirculation functioning. PMID:26206996

  15. Progression of gait dysfunction in incident Parkinson's disease: impact of medication and phenotype.

    PubMed

    Galna, Brook; Lord, Sue; Burn, David J; Rochester, Lynn

    2015-03-01

    Gait impairment in Parkinson's disease (PD) persists despite the use of dopaminergic therapy. Motor phenotype associated with greater postural instability and gait difficulty is related to a greater risk of motor decline and may be influenced by non-dopaminergic pathology. This study documents the progression of gait impairment over 18 months in an incident cohort of PD with regard to phenotype and medication. Gait characteristics were measured in 121 PD and 184 controls, and 18 months later in 108 PD participants. Sixteen gait characteristics were examined with respect to five broad domains for PD and motor phenotype. Correlations between change in levodopa (l-dopa) equivalent daily dose and gait were used to identify dopa-responsive and nonresponsive characteristics. Pace and rhythm deteriorated over 18 months in people with PD, with other gait domains remaining stable. People with a postural instability and gait difficulty phenotype had more impaired gait at baseline compared with a tremor-dominant phenotype, which was most evident in temporal characteristics. In contrast, pace and variability deteriorated over the subsequent 18 months in the tremor-dominant phenotype only. Weak but statistically significant correlations were found between increased l-dopa medication and less deterioration in pace and asymmetry. Significant gait impairment is evident in very early disease despite optimal medication. Change over 18 months is subtle and discrete, and is more pronounced in the tremor-dominant phenotype. Some features of gait are refractory to dopaminergic therapy, implicating a non-dopaminergic contribution. This may explain more temporal gait disturbance in the postural instability and gait difficulty phenotype. PMID:25546558

  16. Obesity dependent metabolic signatures associated with nonalcoholic fatty liver disease progression

    PubMed Central

    Barr, J.; Caballería, J.; Martínez-Arranz, I.; Domínguez-Díez, A.; Alonso, C.; Muntané, J.; Pérez-Cormenzana, M.; García-Monzón, C.; Mayo, R.; Martín-Duce, A.; Romero-Gómez, M.; Iacono, O. Lo; Tordjman, J.; Andrade, R.J.; Pérez-Carreras, M.; Le Marchand-Brustel, Y.; Tran, A.; Fernández-Escalante, C.; Arévalo, E.; García–Unzueta, M.; Clement, K.; Crespo, J.; Gual, P.; Gómez-Fleitas, M.; Martínez-Chantar, M.L.; Castro, A.; Lu, S.C.; Vázquez-Chantada, M.; Mato, J.M.

    2012-01-01

    Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultra-performance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual’s level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values = 0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention. PMID:22364559

  17. HIV infection--induced posttranslational modification of T cell signaling molecules associated with disease progression.

    PubMed Central

    Stefanová, I; Saville, M W; Peters, C; Cleghorn, F R; Schwartz, D; Venzon, D J; Weinhold, K J; Jack, N; Bartholomew, C; Blattner, W A; Yarchoan, R; Bolen, J B; Horak, I D

    1996-01-01

    In attempt to elucidate the mechanism of the HIV infection induced T cell unresponsiveness, we studied signal-transducing molecules proximal to the T cell receptor (TCR) in T lymphocytes of HIV-infected individuals. Total amounts of protein tyrosine kinases (PTKs) Lck, Fyn, and ZAP-70 and the zeta chain of the TCR were found significantly decreased in T cells of symptomatic/AIDS patients as well as in T cells of individuals in acute and early asymptomatic stages of HIV infection. Unexpectedly, the detection of Lck, Fyn, and ZAP-70 was reversed after the treatment of cell lysates with dithiothreitol. This suggests that PTKs Lck, Fyn, and ZAP-70 were modified by a mechanism altering the status of sulfhydryl groups. Moreover, this mechanism seems to affect selectively T cells of HIV infected patients since B cell PTKs Syk and Lyn were detected structurally and functionally intact. Interestingly, similar alterations of signaling molecules were not detected in T cells of HIV-infected long-term asymptomatic individuals. Modification of T cell PTKs may thus underlie the HIV-induced impairment of lymphocyte function and may potentially predict disease progression. PMID:8823293

  18. Hepatitis C virus molecular evolution: Transmission, disease progression and antiviral therapy

    PubMed Central

    Preciado, Maria Victoria; Valva, Pamela; Escobar-Gutierrez, Alejandro; Rahal, Paula; Ruiz-Tovar, Karina; Yamasaki, Lilian; Vazquez-Chacon, Carlos; Martinez-Guarneros, Armando; Carpio-Pedroza, Juan Carlos; Fonseca-Coronado, Salvador; Cruz-Rivera, Mayra

    2014-01-01

    Hepatitis C virus (HCV) infection represents an important public health problem worldwide. Reduction of HCV morbidity and mortality is a current challenge owned to several viral and host factors. Virus molecular evolution plays an important role in HCV transmission, disease progression and therapy outcome. The high degree of genetic heterogeneity characteristic of HCV is a key element for the rapid adaptation of the intrahost viral population to different selection pressures (e.g., host immune responses and antiviral therapy). HCV molecular evolution is shaped by different mechanisms including a high mutation rate, genetic bottlenecks, genetic drift, recombination, temporal variations and compartmentalization. These evolutionary processes constantly rearrange the composition of the HCV intrahost population in a staging manner. Remarkable advances in the understanding of the molecular mechanism controlling HCV replication have facilitated the development of a plethora of direct-acting antiviral agents against HCV. As a result, superior sustained viral responses have been attained. The rapidly evolving field of anti-HCV therapy is expected to broad its landscape even further with newer, more potent antivirals, bringing us one step closer to the interferon-free era. PMID:25473152

  19. Framingham risk score can predict cognitive decline progression in Alzheimer's disease.

    PubMed

    Viticchi, Giovanna; Falsetti, Lorenzo; Buratti, Laura; Boria, Cristiano; Luzzi, Simona; Bartolini, Marco; Provinciali, Leandro; Silvestrini, Mauro

    2015-11-01

    The role of vascular factors in influencing cognitive decline has been extensively investigated, and some difficulties in defining their weight in dementia pathogenesis have emerged. The aim of the study was to investigate the relevance of the Framingham cardiovascular risk profile (FCRP) in influencing cognitive deterioration in a population of Alzheimer's disease (AD) patients. Two hundred eighty-four consecutive AD patients were enrolled. For each patient, FCRP score was calculated. We did a 1-year follow-up to quantify the cognitive decline by recording changes in the Clinical Dementia Rating score. The FCRP score predicted cognitive deterioration with an area under the curve of 0.63 (95% confidence interval: 0.57-0.69; p < 0.0001). In the subpopulation of patients with a genetic increased predisposition to develop cognitive deterioration and with an advanced vascular impairment, the FCRP predictive value significantly increased with an area under the curve of 0.77 (95% confidence interval: 0.52-0.93; p < 0.05). Our findings show that FCRP can predict the progression of deterioration in AD patients. This was particularly evident in patients with major genetic and atherosclerotic risk factors. PMID:26279114

  20. Gene therapeutic approaches to oxidative stress-induced cardiac disease: principles, progress, and prospects.

    PubMed

    Hingtgen, S D; Davisson, R L

    2001-06-01

    Heart and vascular diseases continue to rank among the most frequent and devastating disorders to affect adults in many parts of the world. Increasing evidence from a variety of experimental models indicates that reactive oxygen species can play a key role in the development of myocardial damage from ischemia/reperfusion, the development of cardiac hypertrophy, and the transition of hypertrophy to cardiac failure. The recent dramatic increase in availability of genomic data has included information on the genetic modulation of reactive oxygen species and the antioxidant systems that normally prevent damage from these radicals. Nearly simultaneously, progressively more sophisticated and powerful methods for altering the genetic complement of selected tissues and cells have permitted application of gene therapeutic methods to understand better the pathophysiology of reactive oxygen species-mediated myocardial damage and to attenuate or treat that damage. Although exciting and promising, gene therapy approaches to these common disorders are still in the experimental and developmental stages. Improved understanding of pathophysiology, better gene delivery systems, and specific gene therapeutic strategies will be needed before gene therapy of oxyradical-mediated myocardial damage becomes a clinical reality. PMID:11491655

  1. RhoA determines disease progression by controlling neutrophil motility and restricting hyperresponsiveness.

    PubMed

    Jennings, Richard T; Strengert, Monika; Hayes, Patti; El-Benna, Jamel; Brakebusch, Cord; Kubica, Malgorzata; Knaus, Ulla G

    2014-06-01

    Neutrophil responses are central to host protection and inflammation. Neutrophil activation follows a 2-step process in which priming amplifies responses to activating stimuli. Priming is essential for life span extension, chemotaxis, and respiratory burst activity. Here we show that the cytoskeletal organizer RhoA suppresses neutrophil priming via formins. Premature granule exocytosis in Rho-deficient neutrophils activated numerous signaling pathways and amplified superoxide generation. Deletion of Rho altered front-to-back coordination by simultaneously increasing uropod elongation, leading edge formation, and random migration. Concomitant negative and positive regulation of ?2 integrin-independent and ?2 integrin-dependent migration, respectively, reveal Rho as a key decision point in the neutrophil response to discrete chemotactic agents. Although even restricted influx of Rho-deficient hyperactive neutrophils exacerbated lipopolysaccharide-mediated lung injury, deleting Rho in innate immune cells was highly protective in influenza A virus infection. Hence, Rho is a key regulator of disease progression by maintaining neutrophil quiescence and suppressing hyperresponsiveness. PMID:24782506

  2. Investigation of the phenotypic and genotypic determinants of disease susceptibility and progression in Crohn’s Disease 

    E-print Network

    Phillips, Anne Mairead

    2011-07-05

    The inflammatory bowel diseases (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the gastrointestinal tract. Their aetiology is not fully understood but is thought ...

  3. ALS liquid hydrogen turbopump: Advanced Development Program. Monthly Progress Report, 20 May - 23 Jun. 1989

    SciTech Connect

    Shimp, N.R.; Claffy, G.J.

    1989-07-01

    The point of departure (POD) turbopump concept was reviewed and finalized. The basis for the POD was the configuration presented in the Aerojet proposal. After reviewing this proposal concept, several modifications were made. These modifications include the following: (1) the dual pump discharge arrangement was changed to a single discharge; (2) commonality of the turbine inlet manifold with the advanced launch system (ALS) liquid oxygen (LOX) TPA was dropped for this program; (3) the turbine housing flange arrangement was improved by relocating it away from the first stage nozzles; (4) a ten percent margin (five percent diameter increase) was built into the impeller design to ensure meeting the required discharge pressure without the need for increasing speed; (5) a ten percent turbine power margin was imposed which is to be obtained by increasing turbine inlet pressure if required; and (6) the backup concept, as an alternative to the use of cast impellers, now incorporates forged/machined shrouded impellers, rather than the unshrouded type originally planned.

  4. Progressive endothelin-1 gene activation initiates chronic/end stage renal disease following experimental ischemic-reperfusion injury

    PubMed Central

    Zager, Richard A.; Johnson, Ali CM; Andress, Dennis; Becker, Kirsten

    2013-01-01

    This study assessed whether endothelin-1 (ET1) helps mediate post-ischemic acute kidney injury (AKI) progression to chronic kidney disease (CKD). The impact(s) of potent ETA or ETB receptor-specific antagonists (Atrasentan and BQ-788, respectively) on disease progression were assessed 24 hours or 2 weeks following 30 minutes of unilateral ischemia in CD-1 mice. Unilateral ischemia caused progressive renal ET-1 protein/mRNA increases with concomitant ETA, but not ETB, mRNA elevations. Extensive histone remodeling consistent with gene activation and increased RNA polymerase II binding occurred at the ET-1 gene. Unilateral ischemia produced progressive renal injury as indicated by severe histologic injury and a 40% loss of renal mass. Pre- and post-ischemia or just post-ischemic treatment with Atrasentan conferred dramatic protective effects such as decreased tubule/microvascular injury, normalized tissue lactate, and total preservation of renal mass. Nuclear KI-67 staining was not increased by Atrasentan, implying that increased tubule proliferation was not involved. Conversely, ETB blockade had no protective effect. Thus, our findings provide the first evidence that ET-1 operating through ETA can play a critical role in ischemic AKI progression to CKD. Blockade of ETA provided dramatic protection, indicating the functional significance of these results. PMID:23698233

  5. Progressive endothelin-1 gene activation initiates chronic/end-stage renal disease following experimental ischemic/reperfusion injury.

    PubMed

    Zager, Richard A; Johnson, Ali C M; Andress, Dennis; Becker, Kirsten

    2013-10-01

    This study assessed whether endothelin-1 (ET-1) helps mediate postischemic acute kidney injury (AKI) progression to chronic kidney disease (CKD). The impact(s) of potent ETA or ETB receptor-specific antagonists (Atrasentan and BQ-788, respectively) on disease progression were assessed 24?h or 2 weeks following 30?min of unilateral ischemia in CD-1 mice. Unilateral ischemia caused progressive renal ET-1 protein/mRNA increases with concomitant ETA, but not ETB, mRNA elevations. Extensive histone remodeling consistent with gene activation and increased RNA polymerase II (Pol II) binding occurred at the ET-1 gene. Unilateral ischemia produced progressive renal injury as indicated by severe histologic injury and a 40% loss of renal mass. Pre- and post-ischemia or just postischemic treatment with Atrasentan conferred dramatic protective effects such as decreased tubule/microvascular injury, normalized tissue lactate, and total preservation of renal mass. Nuclear KI-67 staining was not increased by Atrasentan, implying that increased tubule proliferation was not involved. Conversely, ETB blockade had no protective effect. Thus, our findings provide the first evidence that ET-1 operating through ETA can have a critical role in ischemic AKI progression to CKD. Blockade of ETA provided dramatic protection, indicating the functional significance of these results. PMID:23698233

  6. Dependence of reversibility and progression of mouse neuronopathic Gaucher disease on acid beta-glucosidase residual activity levels.

    PubMed

    Xu, You-Hai; Reboulet, Rachel; Quinn, Brian; Huelsken, Joerg; Witte, David; Grabowski, Gregory A

    2008-06-01

    Genetic and chemically induced neuronopathic mouse models of Gaucher disease were developed to facilitate understanding of the reversibility and/or progression of CNS involvement. The lethality of the skin permeability barrier defect of the complete gene knock out [gba, (glucocerebrosidase) GCase] was avoided by conditional reactivation of a low activity allele (D409H) in keratinocytes (kn-9H). In kn-9H mice, progressive CNS disease and massive glucosylceramide storage in tissues led to death from CNS involvement by the age of 14 days. Conduritol B epoxide (CBE, a covalent inhibitor of GCase) treatment (for 8-12 days) of wild type, D409H, D409V or V394L homozygotes recapitulated the CNS phenotype of the kn-9H mice with seizures, tail arching, shaking, tremor, quadriparesis, extensive neuronal degeneration loss and apoptosis, and death by the age of 14 days. Minor CNS abnormalities occurred after daily CBE injections of 100 mg/kg/day for 6 doses, but neuronal degeneration was progressive and glucosylceramide storage persisted in D409V homozygotes in the 2 to 5 months after CBE cessation; wild type and D409H mice had persistent neurological damage without progression. The persistent CNS deterioration, histologic abnormalities, and glucosylceramide storage in the CBE-treated D409V mice revealed a threshold level of GCase activity necessary for the prevention of progression of CNS involvement. PMID:18346921

  7. Marijuana Smoking Does Not Accelerate Progression of Liver Disease in HIV–Hepatitis C Coinfection: A Longitudinal Cohort Analysis

    PubMed Central

    Brunet, Laurence; Moodie, Erica E. M.; Rollet, Kathleen; Cooper, Curtis; Walmsley, Sharon; Potter, Martin; Klein, Marina B.

    2013-01-01

    Background.?Marijuana smoking is common and believed to relieve many symptoms, but daily use has been associated with liver fibrosis in cross-sectional studies. We aimed to estimate the effect of marijuana smoking on liver disease progression in a Canadian prospective multicenter cohort of human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected persons. Methods.?Data were analyzed for 690 HCV polymerase chain reaction positive (PCR-positive) individuals without significant fibrosis or end-stage liver disease (ESLD) at baseline. Time-updated Cox Proportional Hazards models were used to assess the association between the average number of joints smoked/week and progression to significant liver fibrosis (APRI ? 1.5), cirrhosis (APRI ? 2) or ESLD. Results?At baseline, 53% had smoked marijuana in the past 6 months, consuming a median of 7 joints/week (IQR, 1–21); 40% smoked daily. There was no evidence that marijuana smoking accelerates progression to significant liver fibrosis (APRI ? 1.5) or cirrhosis (APRI ? 2; hazard ratio [HR]: 1.02 [0.93–1.12] and 0.99 [0.88–1.12], respectively). Each 10 additional joints/week smoked slightly increased the risk of progression to a clinical diagnosis of cirrhosis and ESLD combined (HR, 1.13 [1.01–1.28]). However, when exposure was lagged to 6–12 months before the diagnosis, marijuana was no longer associated with clinical disease progression (HR, 1.10 [0.95–1.26]). Conclusions?In this prospective analysis we found no evidence for an association between marijuana smoking and significant liver fibrosis progression in HIV/HCV coinfection. A slight increase in the hazard of cirrhosis and ESLD with higher intensity of marijuana smoking was attenuated after lagging marijuana exposure, suggesting that reverse causation due to self-medication could explain previous results. PMID:23811492

  8. HIV Type 1 Polymerase Gene Polymorphisms Are Associated With Phenotypic Differences in Replication Capacity and Disease Progression

    PubMed Central

    Ng, Oon Tek; Laeyendecker, Oliver; Redd, Andrew D.; Munshaw, Supriya; Grabowski, Mary K.; Paquet, Agnes C.; Evans, Mark C.; Haddad, Mojgan; Huang, Wei; Robb, Merlin L.; Reynolds, Steven J.; Gray, Ronald H.; Wawer, Maria J.; Serwadda, David; Eshleman, Susan H.; Quinn, Thomas C.

    2014-01-01

    Background.?Determinants of intersubtype differences in human immunodeficiency virus type 1 (HIV-1) clinical disease progression remain unknown. Methods.?HIV-1 subtype was independently determined for 5 separate genomic regions in 396 HIV-1 seroconverters from Rakai, Uganda, using a multiregion hybridization assay. Replication capacities (RC) in samples from a subset of 145 of these subjects were determined. HIV-1 genomic regions and pol RC were examined for association with disease progression. Amino acid polymorphisms were examined for association with pol RC. Results.?In multivariate analyses, the hazard for progression to the composite end point (defined as a CD4+ T-cell count <250 cells/mm3, antiretroviral therapy initiation, or death) among patients with subtype D pol infection was 2.4 times the hazard for those infected with subtype A pol infection (P = .001). Compared with subtype A pol (the reference group), the hazard for progression to the composite end point for subtype D pol infection with a pol RC >67% (ie, the median pol RC) was significantly greater (HR, 4.6; 95% confidence interval [CI], 1.9–11.0; P = .001), whereas the hazard for progression to the composite end point for subtype D pol infection with a pol RC ?67% was not significantly different (HR, 2.2; 95% CI, 1.0–4.9; P = .051). Amino acid substitutions at protease positions 62 and 64 and at reverse transcriptase position 272 were associated with significant differences in pol RC. Conclusions.?HIV-1 pol gene intersubtype and RC differences are associated with disease progression and may be influenced by amino acid polymorphisms. PMID:23922373

  9. Predictors of Rapid Progression of Glomerular and Non-Glomerular Kidney Disease in Children: The CKiD Cohort

    PubMed Central

    Warady, Bradley A.; Abraham, Alison G.; Schwartz, George J.; Wong, Craig S.; Muñoz, Alvaro; Betoko, Aisha; Mitsnefes, Mark; Kaskel, Frederick; Greenbaum, Larry A.; Mak, Robert H.; Flynn, Joseph; Moxey-Mims, Marva M.; Furth, Susan

    2015-01-01

    Background Few studies have prospectively evaluated the progression of chronic kidney disease (CKD) in children and factors associated with progression. Study Design Prospective assessment of risk factors for the composite event of renal replacement therapy (RRT) or 50% glomerular filtration rate (GFR) decline. Setting and Participants 496 children with CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study. Outcomes Parametric failure time models were used to characterize adjusted associations between baseline levels and changes of predictors and the time to composite event. Results The cohort consisted of 398 children with non-glomerular and 98 children with glomerular disease, of whom 29% and 41%, respectively progressed to the composite event after a median follow-up of 5.2 and 3.7 years. Demographic, clinical characteristics and outcomes differed substantially according to underlying diagnosis, hence risk factors for progression were assessed in stratified analyses and formal interactions by diagnosis were performed. Among non-glomerular patients and after adjusting for baseline GFR, times to the composite event were significantly reduced with Up/c > 2 mg/mg, hypoalbuminemia, elevated blood pressure, dyslipidemia, male gender and anemia by 79%, 69%, 38%, 40%, 38% and 45%, respectively. Among patients with glomerular disease, Up/c > 0.5 mg/mg, hypoalbuminemia and elevated blood pressure significantly reduced times to the composite event by 94%, 71% and 67%, respectively. Variables expressing change in patient clinical status over the initial year of the study contributed significantly to the model which was cross validated internally. Limitations small number of events in glomerular patients and use of internal cross validation. Conclusions Characterization and modeling of risk factors for CKD progression can be used to predict the extent to which these factors, either alone or in combination, would shorten the time to RRT/50% decline of GFR in children with CKD. PMID:25799137

  10. Aetiology and causal agents of mango sudden decline disease in the Sultanate A. O. Al Adawi1

    E-print Network

    Aetiology and causal agents of mango sudden decline disease in the Sultanate of Oman A. O. Al Adawi, Hypocryphalus mangiferae, Lasiodiplodia theobromae Abstract Mango sudden decline is a recently introduced, economically serious disease in Oman. Affected mango trees have wilting symptoms that usually begin on one side

  11. Investigating the biochemical progression of liver disease through fibrosis, cirrhosis, dysplasia, and hepatocellular carcinoma using Fourier transform infrared spectroscopic imaging

    NASA Astrophysics Data System (ADS)

    Sreedhar, Hari; Pant, Mamta; Ronquillo, Nemencio R.; Davidson, Bennett; Nguyen, Peter; Chennuri, Rohini; Choi, Jacqueline; Herrera, Joaquin A.; Hinojosa, Ana C.; Jin, Ming; Kajdacsy-Balla, Andre; Guzman, Grace; Walsh, Michael J.

    2014-03-01

    Hepatocellular carcinoma (HCC) is the most common form of primary hepatic carcinoma. HCC ranks the fourth most prevalent malignant tumor and the third leading cause of cancer related death in the world. Hepatocellular carcinoma develops in the context of chronic liver disease and its evolution is characterized by progression through intermediate stages to advanced disease and possibly even death. The primary sequence of hepatocarcinogenesis includes the development of cirrhosis, followed by dysplasia, and hepatocellular carcinoma.1 We addressed the utility of Fourier Transform Infrared (FT-IR) spectroscopic imaging, both as a diagnostic tool of the different stages of the disease and to gain insight into the biochemical process associated with disease progression. Tissue microarrays were obtained from the University of Illinois at Chicago tissue bank consisting of liver explants from 12 transplant patients. Tissue core biopsies were obtained from each explant targeting regions of normal, liver cell dysplasia including large cell change and small cell change, and hepatocellular carcinoma. We obtained FT-IR images of these tissues using a modified FT-IR system with high definition capabilities. Firstly, a supervised spectral classifier was built to discriminate between normal and cancerous hepatocytes. Secondly, an expanded classifier was built to discriminate small cell and large cell changes in liver disease. With the emerging advances in FT-IR instrumentation and computation there is a strong drive to develop this technology as a powerful adjunct to current histopathology approaches to improve disease diagnosis and prognosis.

  12. Rapid and Progressive Regional Brain Atrophy in CLN6 Batten Disease Affected Sheep Measured with Longitudinal Magnetic Resonance Imaging

    PubMed Central

    Sawiak, Stephen J.; Perumal, Sunthara Rajan; Rudiger, Skye R.; Matthews, Loren; Mitchell, Nadia L.; McLaughlan, Clive J.; Bawden, C. Simon; Palmer, David N.; Kuchel, Timothy; Morton, A. Jennifer

    2015-01-01

    Variant late-infantile Batten disease is a neuronal ceroid lipofuscinosis caused by mutations in CLN6. It is a recessive genetic lysosomal storage disease characterised by progressive neurodegeneration. It starts insidiously and leads to blindness, epilepsy and dementia in affected children. Sheep that are homozygous for a natural mutation in CLN6 have an ovine form of Batten disease Here, we used in vivo magnetic resonance imaging to track brain changes in 4 unaffected carriers and 6 affected Batten disease sheep. We scanned each sheep 4 times, between 17 and 22 months of age. Cortical atrophy in all sheep was pronounced at the baseline scan in all affected Batten disease sheep. Significant atrophy was also present in other brain regions (caudate, putamen and amygdala). Atrophy continued measurably in all of these regions during the study. Longitudinal MRI in sheep was sensitive enough to measure significant volume changes over the relatively short study period, even in the cortex, where nearly 40% of volume was already lost at the start of the study. Thus longitudinal MRI could be used to study the dynamics of progression of neurodegenerative changes in sheep models of Batten disease, as well as to assess therapeutic efficacy. PMID:26161747

  13. Human immunodeficiency virus type 1 cellular RNA load and splicing patterns predict disease progression in a longitudinally studied cohort.

    PubMed Central

    Michael, N L; Mo, T; Merzouki, A; O'Shaughnessy, M; Oster, C; Burke, D S; Redfield, R R; Birx, D L; Cassol, S A

    1995-01-01

    We report the results of a longitudinal study of RNA splicing patterns in 31 early-stage human immunodeficiency virus disease patients with an average follow-up time of 3 years. Eighteen patients showed no evidence for disease progression, whereas 13 patients either showed a > or = 50% reduction in baseline CD4 count or developed opportunistic infections. Levels of unspliced, tat, rev, and nef mRNAs in peripheral blood mononuclear cells were measured by a reverse transcriptase-quantitative, competitive PCR assay. Viral RNA was detected in all patients at all time points. All 13 rapid progressors had viral RNA loads that were > or = 1 log unit greater than those of the slow progressors. In addition, seven of the rapid progressors showed a reduction of more than threefold in the ratio of spliced to unspliced RNA over the 3 years of follow-up. Conversely, two slow progressors with intermediate levels of viral RNA showed no splicing shift. These results confirm earlier observations that viral RNA is uniformly expressed in early-stage patients. We further show that cellular RNA viral load is predictive of disease progression. Importantly, the shift from a predominately spliced or regulatory viral mRNA pattern to a predominately unspliced pattern both is associated with disease progression and adds predictive utility to measurement of either RNA class alone. PMID:7853528

  14. Clinically meaningful parameters of progression and long-term outcome of Parkinson disease: An international consensus statement.

    PubMed

    Puschmann, Andreas; Brighina, Laura; Markopoulou, Katerina; Aasly, Jan; Chung, Sun Ju; Frigerio, Roberta; Hadjigeorgiou, Georgios; Kõks, Sulev; Krüger, Rejko; Siuda, Joanna; Wider, Christian; Zesiewicz, Theresa A; Maraganore, Demetrius M

    2015-07-01

    Parkinson disease (PD) is associated with a clinical course of variable duration, severity, and a combination of motor and non-motor features. Recent PD research has focused primarily on etiology rather than clinical progression and long-term outcomes. For the PD patient, caregivers, and clinicians, information on expected clinical progression and long-term outcomes is of great importance. Today, it remains largely unknown what factors influence long-term clinical progression and outcomes in PD; recent data indicate that the factors that increase the risk to develop PD differ, at least partly, from those that accelerate clinical progression and lead to worse outcomes. Prospective studies will be required to identify factors that influence progression and outcome. We suggest that data for such studies is collected during routine office visits in order to guarantee high external validity of such research. We report here the results of a consensus meeting of international movement disorder experts from the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium, who convened to define which long-term outcomes are of interest to patients, caregivers and clinicians, and what is presently known about environmental or genetic factors influencing clinical progression or long-term outcomes in PD. We propose a panel of rating scales that collects a significant amount of phenotypic information, can be performed in the routine office visit and allows international standardization. Research into the progression and long-term outcomes of PD aims at providing individual prognostic information early, adapting treatment choices, and taking specific measures to provide care optimized to the individual patient's needs. PMID:25952959

  15. Significant correlation between expression level of HSP gp96 and progression of hepatitis B virus induced diseases

    PubMed Central

    Zhu, Xiao-Dong; Li, Cheng-Lin; Lang, Zhen-Wei; Gao, George F; Tien, Po

    2004-01-01

    AIM: Gp96, also known as Grp94, is a member of heat shock protein (HSP) family and binds repertoires of peptides thereof eliciting peptide-specific T cell immune responses. It predominantly locates inside the endoplasmic reticulum (ER) with some cell surface expression in certain cancerous cells. Previous studies have shown that gp96 expression level was up-regulated in tumor cells, including hepatocellular carcinoma (HCC). However, relationship between the extent of gp96 expression and disease progression especially HBV-induced chronic infection, cirrhosis and hepatocellular carcinoma, has not been addressed before. As primary HCC can be induced and progressed from chronic hepatitis B virus (HBV) infection and HBV-induced cirrhosis, we designed an immunohistochemical experiment to test the correlation between gp96 expression level and HBV-induced disease progression, from chronic HBV infection, cirrhosis to HCC. METHODS: We chose liver samples from different patients of hepatitis B virus induced diseases, including chronic hepatitis B (77 patients), cirrhosis (27 patients) and primary HCC (30 patients), to test the expression level of gp96 in different affected groups. Formalin-fixed, and paraffin-embedded liver tissues taken from these patients were immuno-stained by using an anti-gp96 monoclonal antibody for the expression level of gp96 protein in the sections. In addition, Western blotting of whole cell lysates derived from established human embryonic liver cell lines and several human HCC cell lines (Huh7, HepG2, SSMC-7721) was compared with the expression of gp96. RESULTS: We found that the extent of elevated gp96 expression was significantly correlated with the disease progression, and was the highest in HCC patients, lowest in chronic HBV infection and was that of the cirrhosis in the middle. CONCLUSION: Increased expression of gp96 might be used as a diagnostic or prognostic bio-marker for the HBV infection and HBV-induced diseases. PMID:15069714

  16. Ameliorating Role Exerted by Al-Hijamah in Autoimmune Diseases: Effect on Serum Autoantibodies and Inflammatory Mediators

    PubMed Central

    Baghdadi, Hussam; Abdel-Aziz, Nada; Ahmed, Nagwa Sayed; Mahmoud, Hany Salah; Barghash, Ayman; Nasrat, Abdullah; Nabo, Manal Mohamed Helmy; El Sayed, Salah Mohamed

    2015-01-01

    Autoimmune diseases have common properties characterized by abnormal blood chemistry with high serum autoimmune antibodies, and inflammatory mediators. Those causative pathological substances (CPS) cannot be excreted by physiological mechanisms. Current treatments for autoimmune diseases involve steroids, cytotoxic drugs, plasmapheresis and monoclonal antibodies. Wet cupping therapy (WCT) of prophetic medicine is called Al-hijamah that treats numerous diseases having different etiology and pathogenesis via a pressure-dependent and size-dependent non-specific filtration then excretion of CPS causing clearance of blood and interstitial fluids. Al-hijamah clears blood passing through the fenestrated skin capillaries. Medical bases of Al-hijamah were reported in the evidence-based Taibah mechanism (Taibah theory). Al-hijamah was reported to be an excellent treatment for rheumatoid arthritis that improved patients’ blood chemistry and induced significant clinical improvement and pharmacological potentiation. Al-hijamah improved the natural immunity and suppressed the pathological immunity through decreasing the serum level of autoantibodies, inflammatory mediators, and serum ferritin (a key player in autoimmunity). Al-hijamah reduced significantly pain severity, number of swollen joints and disease activity with no significant side effects. Main steps of Al-hijamah are skin suction (cupping), scarification (sharatmihjam in Arabic) and second suction (triple S technique) that is better therapeutically than the traditional WCT (double S technique). Whenever an excess noxious substance is to be removed from patients’ blood and interstitial fluids, Al-hijamah is indicated. Shartatmihjam is a curative treatment in prophetic teachings according to the prophetic hadeeth: “Cure is in three: in shartatmihjam, oral honey and cauterization. I do not recommend my nation to cauterize”. Al-hijamah may have better therapeutic benefits than plasmapheresis. Al-hijamah may be promising in treating autoimmune diseases as a sole treatment or adjuvant treatment. PMID:26309442

  17. Effect of Sodium-Glucose Cotransport Inhibition on Polycystic Kidney Disease Progression in PCK Rats

    PubMed Central

    Kapoor, Sarika; Rodriguez, Daniel; Riwanto, Meliana; Edenhofer, Ilka; Segerer, Stephan; Mitchell, Katharyn; Wüthrich, Rudolf P.

    2015-01-01

    The sodium-glucose-cotransporter-2 (SGLT2) inhibitor dapagliflozin (DAPA) induces glucosuria and osmotic diuresis via inhibition of renal glucose reabsorption. Since increased diuresis retards the progression of polycystic kidney disease (PKD), we investigated the effect of DAPA in the PCK rat model of PKD. DAPA (10 mg/kg/d) or vehicle was administered by gavage to 6 week old male PCK rats (n=9 per group). Renal function, albuminuria, kidney weight and cyst volume were assessed after 6 weeks of treatment. Treatment with DAPA markedly increased glucose excretion (23.6 ± 4.3 vs 0.3 ± 0.1 mmol/d) and urine output (57.3 ± 6.8 vs 19.3 ± 0.8 ml/d). DAPA-treated PCK rats had higher clearances for creatinine (3.1 ± 0.1 vs 2.6 ± 0.2 ml/min) and BUN (1.7 ± 0.1 vs 1.2 ± 0.1 ml/min) after 3 weeks, and developed a 4-fold increase in albuminuria. Ultrasound imaging and histological analysis revealed a higher cyst volume and a 23% higher total kidney weight after 6 weeks of DAPA treatment. At week 6 the renal cAMP content was similar between DAPA and vehicle, and staining for Ki67 did not reveal an increase in cell proliferation. In conclusion, the inhibition of glucose reabsorption with the SGLT2-specific inhibitor DAPA caused osmotic diuresis, hyperfiltration, albuminuria and an increase in cyst volume in PCK rats. The mechanisms which link glucosuria to hyperfiltration, albuminuria and enhanced cyst volume in PCK rats remain to be elucidated. PMID:25927597

  18. Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress.

    PubMed

    Zhang, Xiao-Liang; Pang, Wei; Hu, Xin-Tian; Li, Jia-Li; Yao, Yong-Gang; Zheng, Yong-Tang

    2014-11-18

    Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China's growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China's life sciences and pharmaceutical industry, and enhance China's position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China. PMID:25465081

  19. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43.

    PubMed

    Arnold, Eveline S; Ling, Shuo-Chien; Huelga, Stephanie C; Lagier-Tourenne, Clotilde; Polymenidou, Magdalini; Ditsworth, Dara; Kordasiewicz, Holly B; McAlonis-Downes, Melissa; Platoshyn, Oleksandr; Parone, Philippe A; Da Cruz, Sandrine; Clutario, Kevin M; Swing, Debbie; Tessarollo, Lino; Marsala, Martin; Shaw, Christopher E; Yeo, Gene W; Cleveland, Don W

    2013-02-19

    Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43(Q331K) and TDP-43(M337V)), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell type-selective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43-dependent alternative splicing events conferred by both human wild-type and mutant TDP-43(Q331K), but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43(Q331K) enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage. PMID:23382207

  20. Results of treatment intensification for progressive locoregional disease in head-and-neck cancer patients undergoing postoperative radiotherapy

    SciTech Connect

    Corry, June . E-mail: June.Corry@petermac.org; Rischin, Danny; Mukesh, Bickol N.; Porceddu, Sandro; Peters, Lester J.

    2005-04-01

    Purpose: Patients who develop progressive locoregional disease during radical surgery and postoperative radiotherapy for squamous cell carcinoma of the head and neck represent a management dilemma. We present our experience using treatment intensification for such patients. Methods and materials: A prospective record of eligible patients was kept between May 1998 and December 2001. The study included 15 patients, 11 men and 4 women (median age, 60 years); 67% had Stage III-IV disease. The sites of progression were primary in 3, nodes/scar in 10, and both primary and nodes in 2. Relative to the initial plan, treatment intensification was achieved by an increased radiation dose in 7 (using accelerated fractionation in 5), an increased radiation dose and the addition of concomitant chemotherapy in 7, and the addition of concomitant chemotherapy alone in 1 patient. Results: The median follow-up was 40 months. Eight patients had a complete response to intensified treatment. At the closeout date, 6 patients were alive with no evidence of disease. Eight patients had died with locoregional disease; two also had distant metastases. One patient was lost to follow-up after achieving a complete response. The median failure-free survival for all patients was 6 months, but for those with a complete response, it was 37 months. The median overall survival time was 28 months. The 2-year and 3-year overall survival rate was 50% and 42%, respectively. Acute mucosal and skin toxicity was increased relative to standard postoperative radiotherapy but was not dissimilar to that expected after radical definitive chemoradiotherapy. Conclusion: Intensification of treatment in patients who develop progressive locoregional disease is warranted, because it can lead to long-term disease control in a subset of patients with significant but acceptable toxicity.

  1. MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study

    PubMed Central

    Morrow, Jasper M; Sinclair, Christopher D J; Fischmann, Arne; Machado, Pedro M; Reilly, Mary M; Yousry, Tarek A; Thornton, John S; Hanna, Michael G

    2016-01-01

    Summary Background A substantial impediment to progress in trials of new therapies in neuromuscular disorders is the absence of responsive outcome measures that correlate with patient functional deficits and are sensitive to early disease processes. Irrespective of the primary molecular defect, neuromuscular disorder pathological processes include disturbance of intramuscular water distribution followed by intramuscular fat accumulation, both quantifiable by MRI. In pathologically distinct neuromuscular disorders, we aimed to determine the comparative responsiveness of MRI outcome measures over 1 year, the validity of MRI outcome measures by cross-sectional correlation against functionally relevant clinical measures, and the sensitivity of specific MRI indices to early muscle water changes before intramuscular fat accumulation beyond the healthy control range. Methods We did a prospective observational cohort study of patients with either Charcot-Marie-Tooth disease 1A or inclusion body myositis who were attending the inherited neuropathy or muscle clinics at the Medical Research Council (MRC) Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK. Genetic confirmation of the chromosome 17p11·2 duplication was required for Charcot-Marie-Tooth disease 1A, and classification as pathologically or clinically definite by MRC criteria was required for inclusion body myositis. Exclusion criteria were concomitant diseases and safety-related MRI contraindications. Healthy age-matched and sex-matched controls were also recruited. Assessments were done at baseline and 1 year. The MRI outcomes—fat fraction, transverse relaxation time (T2), and magnetisation transfer ratio (MTR)—were analysed during the 12-month follow-up, by measuring correlation with functionally relevant clinical measures, and for T2 and MTR, sensitivity in muscles with fat fraction less than the 95th percentile of the control group. Findings Between Jan 19, 2010, and July 7, 2011, we recruited 20 patients with Charcot-Marie-Tooth disease 1A, 20 patients with inclusion body myositis, and 29 healthy controls (allocated to one or both of the 20-participant matched-control subgroups). Whole muscle fat fraction increased significantly during the 12-month follow-up at calf level (mean absolute change 1·2%, 95% CI 0·5–1·9, p=0·002) but not thigh level (0·2%, ?0·2 to 0·6, p=0·38) in patients with Charcot-Marie-Tooth disease 1A, and at calf level (2·6%, 1·3–4·0, p=0·002) and thigh level (3·3%, 1·8–4·9, p=0·0007) in patients with inclusion body myositis. Fat fraction correlated with the lower limb components of the inclusion body myositis functional rating score (?=–0·64, p=0·002) and the Charcot-Marie-Tooth examination score (?=0·63, p=0·003). Longitudinal T2 and MTR changed consistently with fat fraction but more variably. In muscles with a fat fraction lower than the control group 95th percentile, T2 was increased in patients compared with controls (regression coefficients: inclusion body myositis thigh 4·0 ms [SE 0·5], calf 3·5 ms [0·6]; Charcot-Marie-Tooth 1A thigh 1·0 ms [0·3], calf 2·0 ms [0·3]) and MTR reduced compared with controls (inclusion body myositis thigh ?1·5 percentage units [pu; 0·2], calf ?1·1 pu [0·2]; Charcot-Marie-Tooth 1A thigh ?0·3 pu [0·1], calf ?0·7 pu [0·1]). Interpretation MRI outcome measures can monitor intramuscular fat accumulation with high responsiveness, show validity by correlation with conventional functional measures, and detect muscle water changes preceding marked intramuscular fat accumulation. Confirmation of our results in further cohorts with these and other muscle-wasting disorders would suggest that MRI biomarkers might prove valuable in experimental trials. Funding Medical Research Council UK. PMID:26549782

  2. An adaptive genetic algorithm for selection of blood-based biomarkers for prediction of Alzheimer's disease progression

    PubMed Central

    2015-01-01

    Background Alzheimer's disease is a multifactorial disorder that may be diagnosed earlier using a combination of tests rather than any single test. Search algorithms and optimization techniques in combination with model evaluation techniques have been used previously to perform the selection of suitable feature sets. Previously we successfully applied GA with LR to neuropsychological data contained within the The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, to select cognitive tests for prediction of progression of AD. This research addresses an Adaptive Genetic Algorithm (AGA) in combination with LR for identifying the best biomarker combination for prediction of the progression to AD. Results The model has been explored in terms of parameter optimization to predict conversion from healthy stage to AD with high accuracy. Several feature sets were selected - the resulting prediction moddels showed higher area under the ROC values (0.83-0.89). The results has shown consistency with some of the medical research reported in literature. Conclusion The AGA has proven useful in selecting the best combination of biomarkers for prediction of AD progression. The algorithm presented here is generic and can be extended to other data sets generated in projects that seek to identify combination of biomarkers or other features that are predictive of disease onset or progression. PMID:26680269

  3. Disease Progression/Clinical Outcome Model for Castration-Resistant Prostate Cancer in Patients Treated With Eribulin

    PubMed Central

    van Hasselt, JGC; Gupta, A; Hussein, Z; Beijnen, JH; Schellens, JHM; Huitema, ADR

    2015-01-01

    Frameworks that associate cancer dynamic disease progression models with parametric survival models for clinical outcome have recently been proposed to support decision making in early clinical development. Here we developed such a disease progression clinical outcome model for castration-resistant prostate cancer (CRPC) using historical phase II data of the anticancer agent eribulin. Disease progression was captured using the dynamics of prostate-specific antigen (PSA). For clinical outcome, overall survival (OS) was used. The model for PSA dynamics comprised parameters for baseline PSA (23.2 ng/ml, relative standard error (RSE) 16.5%), growth rate (0.00879 day?1, RSE 12.6%), drug effect (0.241 µg·h·l?1 day?1, RSE 32.6%), and resistance development (0.0113 day?1, RSE 44.3%). OS was modeled according to a Weibull distribution. Predictors for survival included model-predicted PSA time to nadir (TTN), PSA growth rate, Eastern Cooperative Oncology Group (ECOG) score, and baseline PSA. The developed framework can be considered to support informative design and analysis of drugs developed for CRPC. PMID:26312162

  4. Usefulness of the computed tomography and magnetic resonance in evaluation of progress of treatment of the neoplasmatic diseases in children

    PubMed Central

    Myga-Porosi?o, Jolanta; Borowiak, Hanna; Sraga, Wojciech; Jackowska, Zuzanna; Serafin, Magdalena; Kluczewska, Ewa

    2012-01-01

    Summary Background: Neoplastmatic diseases constitute about 1% diseases in children in Poland, what makes about 1200 new incidents during one year. Fast diagnosis in those illnesses is crucial in treatment results. The point of this work was to value usefulness of CT and MRI in diagnostics of neoplasmatic diseases in children. Material/Methods: The retrospective study involved 121 children examined in CT and MRI because of suspicion or during treatment of neoplasmatic disease. Together 184 CT and 119 MRI examination were performed. Eventually in 106 children neoplasmatic disease was diagnosed. In 16 cases neoplasm was excluded. Results: In the analyzed group of patients acute lymphoblastic and non lymphoblastic leukemia was diagnosed in 68 children (55.7%); among them mycosis was identified after radiological examinations in 7 cases (10.3%). 8 children (6.6%) with non Hodgkin lymphoma and 11 (9%) with Hodgkin lymphoma were examined. Nephroblastoma was found after MRI and CT in 6 cases (4.9%). Presence of tumors, that were classified histopatologically as PNET, was confirmed in 4 children. In 15 cases after MRI and CT neoplasmatic disease was excluded. Conclusions: Depending on the kind of sickness MRI and CT may fulfill basic or subsidiary role in diagnostic and estimating the progress of treatment in neoplasmatic diseases among children. PMID:23049581

  5. Differing patterns of striatal sup 18 F-dopa uptake in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy

    SciTech Connect

    Brooks, D.J.; Ibanez, V.; Sawle, G.V.; Quinn, N.; Lees, A.J.; Mathias, C.J.; Bannister, R.; Marsden, C.D.; Frackowiak, R.S. )

    1990-10-01

    Using positron emission tomography (PET), we studied regional striatal 18F-dopa uptake in 16 patients with L-dopa-responsive Parkinson's disease (PD), 18 patients with multiple system atrophy, and 10 patients with progressive supranuclear palsy. Results were compared with those of 30 age-matched normal volunteers. The patients with PD showed significantly reduced mean uptake of 18F-dopa in the caudate and putamen compared to controls, but while function in the posterior part of the putamen was severely impaired (45% of normal), function in the anterior part of the putamen and in the caudate was relatively spared (62% and 84% of normal). Mean 18F-dopa uptake in the posterior putamen was depressed to similar levels in all patients. Unlike patients with PD, the patients with progressive supranuclear palsy showed equally severe impairment of mean 18F-dopa uptake in the anterior and posterior putamen. Caudate 18F-dopa uptake was also significantly lower in patients with progressive supranuclear palsy than in patients with PD, being depressed to the same level as that in the putamen. Mean 18F-dopa uptake values in the anterior putamen and caudate in patients with multiple system atrophy lay between PD and progressive supranuclear palsy levels. Locomotor disability of individual patients with PD or multiple system atrophy correlated with decline in striatal 18F-dopa uptake, but this was not the case for the patients with progressive supranuclear palsy. We conclude that patients with PD have selective nigral pathological features with relative preservation of the dopaminergic function in the anterior putamen and caudate, whereas there is progressively more extensive nigral involvement in multiple system atrophy and progressive supranuclear palsy.

  6. Newcastle Disease: Progress and gaps in the development of vaccines and diagnostic tools

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Newcastle disease (ND) is a contagious disease of birds that can have severe economic consequences for any poultry producer, including a serious impact on the international trade of poultry and eggs. Newcastle disease virus (NDV) isolates are also called avian paramyxovirus serotype-1 isolates, but ...

  7. Stimulation of endothelin B receptors by IRL-1620 decreases the progression of Alzheimer's disease.

    PubMed

    Briyal, S; Nguyen, C; Leonard, M; Gulati, A

    2015-08-20

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment that ultimately leads to death. Endothelin (ET) and its receptors have been considered as therapeutic targets for AD. Recent studies in our lab have shown that stimulation of ETB receptors provide significant neuroprotection following A?1-40 administration. It is possible that IRL-1620 may be neuroprotective due to angiogenesis. However, the effect of IRL-1620 on neurovascular remodeling following A?1-40 administration has not been established. The purpose of this study was to determine the effect of stimulation of ETB receptors by IRL-1620 on vascular and neuronal growth factors after A?1-40 administration. Rats were treated with A?1-40 (day 1, 7 and 14) in the lateral cerebral ventricles using stereotaxically implanted cannula and received three intravenous injections of IRL-1620 (an ETB agonist), and/or BQ788 (an ETB antagonist) at 2-h interval on day 8; experiments were performed on day 15. Rats were sacrificed for estimation of brain ETB receptors, vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) expression using immunofluorescence and Western blot. In the Morris swim task, amyloid-? (A?)-treated rats showed a significant (p<0.0001) impairment in spatial memory. Rats treated with IRL-1620 significantly (p<0.001) reduced the cognitive impairment induced by A?. BQ788 treatment completely blocked IRL-1620-induced improvement in cognitive impairment. IRL-1620 treatment enhanced the number of blood vessels labeled with VEGF compared to vehicle treatment. Additionally, cells showed increased (p<0.001) positive staining for NGF in IRL-1620-treated animals. ETB, VEGF and NGF protein expression significantly (p<0.001) increased in the brain of IRL-1620-treated rats as compared to vehicle. Pretreatment with BQ788 blocked the effects of IRL-1620, thus confirming the role of ETB receptors in the neurovascular remodeling actions of IRL-1620. Results of the present study demonstrate that IRL-1620 improves both acquisition (learning) and retention (memory) on the water maze task and enhances angiogenic and neurogenic remodeling. These findings indicate that the ETB receptor may be a novel therapeutic target for AD and other neurovascular degenerative disorders. PMID:26022359

  8. Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

    PubMed Central

    Ferenczy, Michael W.; Marshall, Leslie J.; Nelson, Christian D. S.; Atwood, Walter J.; Nath, Avindra; Khalili, Kamel

    2012-01-01

    Summary: Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies. PMID:22763635

  9. Applications of Data Mining Methods in the Integrative Medical Studies of Coronary Heart Disease: Progress and Prospect

    PubMed Central

    Wang, Yixin; Guo, Fang

    2014-01-01

    A large amount of studies show that real-world study has strong external validity than the traditional randomized controlled trials and can evaluate the effect of interventions in a real clinical setting, which open up a new path for researches of integrative medicine in coronary heart disease. However, clinical data of integrative medicine in coronary heart disease are large in amount and complex in data types, making exploring the appropriate methodology a hot topic. Data mining techniques are to analyze and dig out useful information and knowledge from the mass data to guide people's practices. The present review provides insights for the main features of data mining and their applications of integrative medical studies in coronary heart disease, aiming to analyze the progress and prospect in this field. PMID:25544853

  10. Unilaterally and rapidly progressing white matter lesion and elevated cytokines in a patient with Tay-Sachs disease.

    PubMed

    Hayase, Tomomi; Shimizu, Jun; Goto, Tamako; Nozaki, Yasuyuki; Mori, Masato; Takahashi, Naoto; Namba, Eiji; Yamagata, Takanori; Momoi, Mariko Y

    2010-03-01

    We report the case of a girl with Tay-Sachs disease who had convulsions and deteriorated rapidly after an upper respiratory infection at the age of 11 months. At the age of 16 months, her seizures became intractable and magnetic resonance imaging of the brain showed high signal intensity on T2-weighted images and marked swelling in the white matter and basal nucelei of the right hemisphere. Her seizures and right hemisphere lesion improved with glycerol and dexamethasone treatment. When dexamethasone was discontinued, her symptoms worsened and lesions later appeared in the left hemisphere. Her cerebrospinal fluid showed elevated levels of the cytokines TNF-alpha and IL-5. It is considered that inflammation contributes to disease progression in Tay-Sachs disease. PMID:19278800

  11. Minimally Invasive Early Operative Treatment of Progressive Foot and Ankle Deformity Associated With Charcot-Marie-Tooth Disease.

    PubMed

    Boffeli, Troy J; Tabatt, Jessica A

    2015-01-01

    Charcot-Marie-Tooth disease is a neuromuscular disorder that commonly results in a predictable pattern of progressive bilateral lower extremity weakness, numbness, contracture, and deformity, including drop foot, loss of ankle eversion strength, dislocated hammertoes, and severe cavus foot deformity. Late stage reconstructive surgery will be often necessary if the deformity becomes unbraceable or when neuropathic ulcers have developed. Reconstructive surgery for Charcot-Marie-Tooth deformity is generally extensive and sometimes staged. Traditional reconstructive surgery involves a combination of procedures, including tendon lengthening or transfer, osteotomy, and arthrodesis. The described technique highlights our early surgical approach, which involves limited intervention before the deformity becomes rigid, severe, or disabling. We present 2 cases to contrast our early minimally invasive technique with traditional late stage reconstruction. Charcot-Marie-Tooth disease affects different muscles at various stages of disease progression. As 1 muscle becomes weak, the antagonist will overpower it and cause progressive deformity. The focus of the early minimally invasive approach is to decrease the forces that cause progressive deformity yet maintain function, where possible. Our goal has been to maintain a functional and braceable foot and ankle, with the hope of avoiding or limiting the extent of future major reconstructive surgery. The presented cases highlight the patient selection criteria, the ideal timing of early surgical intervention, the procedure selection criteria, and operative pearls. The early minimally invasive approach includes plantar fasciotomy, Achilles tendon lengthening, transfer of the peroneus longus to the fifth metatarsal, Hibbs and Jones tendon transfer, and hammertoe repair of digits 1 to 5. PMID:25131389

  12. Vitamin E Attenuates the Progression of Non-Alcoholic Fatty Liver Disease Caused by Partial Hepatectomy in Mice

    PubMed Central

    Karimian, Golnar; Kirschbaum, Marc; Veldhuis, Zwanida J.; Bomfati, Fernanda; Porte, Robert J.; Lisman, Ton

    2015-01-01

    Background and Aim The progression of non-alcoholic fatty liver disease (NAFLD) likely involves a ‘multiple hit’ mechanism. We hypothesized that partial hepatectomy, a procedure performed frequently in patients with NAFLD, would accelerate the progression of disease. Methods C57BL/6JolaHsd mice were fed a choline-deficient L-amino acid-defined diet (CD-AA) or a choline-sufficient L-amino acid-defined control diet (CS-AA). Part of the mice in the CD-AA group received a diet enriched in vitamin E (~20 mg /day). Two weeks after the start of the diet, mice underwent a partial hepatectomy or a sham operation. Results In the CD-AA group, NAFLD activity scores were significantly higher at 7 days after partial hepatectomy compared to the sham operated mice (3.7 ± 1.3 vs. 1.8 ± 0.7; P<0.05). In addition, TBARS, a measure for oxidative stress, in liver tissue of the CD-AA group were significantly higher at day 1, 3 and 7 after partial hepatectomy compared to the sham operated mice (P<0.05). Vitamin E therapy significantly reduced TBARS level at day 7 after partial hepatectomy compared to the CD-AA diet group (P< 0.05). Vitamin E suppletion reduced NAFLD activity score at day 7 after partial hepatectomy compared to the CD-AA group (2.3 ± 0.8 vs. 3.8 ± 1.0; P<0.05). Conclusion Partial hepatectomy accelerates the progression of NAFLD. Disease progression induced by partial hepatectomy is substantially attenuated by vitamin E. PMID:26600128

  13. Characterization of the Contribution of Genetic Background and Gender to Disease Progression in the SOD1 G93A Mouse Model of Amyotrophic Lateral Sclerosis: A Meta-Analysis

    PubMed Central

    Pfohl, Stephen R.; Halicek, Martin T.; Mitchell, Cassie S.

    2015-01-01

    Background The SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS) is the most frequently used model to examine ALS pathophysiology. There is a lack of homogeneity in usage of the SOD1 G93A mouse, including differences in genetic background and gender, which could confound the field’s results. Objective In an analysis of 97 studies, we characterized the ALS progression for the high transgene copy control SOD1 G93A mouse on the basis of disease onset, overall lifespan, and disease duration for male and female mice on the B6SJL and C57BL/6J genetic backgrounds and quantified magnitudes of differences between groups. Methods Mean age at onset, onset assessment measure, disease duration, and overall lifespan data from each study were extracted and statistically modeled as the response of linear regression with the sex and genetic background factored as predictors. Additional examination was performed on differing experimental onset and endpoint assessment measures. Results C57BL/6 background mice show delayed onset of symptoms, increased lifespan, and an extended disease duration compared to their sex-matched B6SJL counterparts. Female B6SJL generally experience extended lifespan and delayed onset compared to their male counterparts, while female mice on the C57BL/6 background show delayed onset but no difference in survival compared to their male counterparts. Finally, different experimental protocols (tremor, rotarod, etc.) for onset determination result in notably different onset means. Conclusions Overall, the observed effect of sex on disease endpoints was smaller than that which can be attributed to the genetic background. The often-reported increase in lifespan for female mice was observed only for mice on the B6SJL background, implicating a strain-dependent effect of sex on disease progression that manifests despite identical mutant SOD1 expression. PMID:26594635

  14. Risk factors for disease progression in HER2-positive breast cancer patients based on the location of metastases

    PubMed Central

    Nowara, El?bieta

    2015-01-01

    Introduction Trastuzumab therapy significantly improves progression-free and overall survival in HER2-positive [HER2(+)] breast cancer (BC) patients. However, in most patients with HER2(+) metastatic BC, the disease progress occurred. The aim of this study was to evaluate the clinicopathological risk factors for progression in HER2-positive breast cancer patients during trastuzumab therapy. Material and methods The analysis included medical records of HER2(+) metastatic BC patients treated with trastuzumab between 2006 and 2013. Results The most common site of progression during trastuzumab therapy were lungs 25 (39%), central nervous system (CNS) 8 (13%), skin 9 (14%), locoregional lymph nodes 19 (30%), liver 18 (28%) and bone 17 (27%). Patients with lung metastases significantly more often had a history of cancer in the family than women with other metastasis sites (24% vs. 2.6%), p = 0.048. Metastases to lungs occurred also more often during therapy containing trastuzumab with chemotherapy than trastuzumab alone 17/8 (58% vs. 41%), p = 0.043. Central nervous system metastases were observed insignificantly more frequently in postmenopausal women than premenopausal patients 8/0 (22% vs. 0%), p = 0.093. There was reported a tendency to liver metastases in ER-negative tumors 13/20 (72% vs. 44%, p = 0.053). Bone metastases were associated with the positive steroid receptor status (p = 0.019) and second neoplasm in history (p = 0.06). Conclusions Risk factors for disease progression were the menopausal status (CNS metastases), steroid receptor status (liver, lymph nodes and bone metastases), history of cancer in the family (lung metastases) and history of cigarette smoking (liver metastases). PMID:26528105

  15. Stable intrachain and interchain complexes of neurofilament peptides: a putative link between Al3+ and Alzheimer disease.

    PubMed Central

    Hollósi, M; Shen, Z M; Perczel, A; Fasman, G D

    1994-01-01

    The etiologic role of Al3+ in Alzheimer disease has been controversial. Circular dichroism (CD) spectroscopic studies on two synthetic fragments of human neurofilament protein mid-sized subunit (NF-M), NF-M13 (KSPVPKSPVEEKG) and NF-M17 (EEKGKSPVPKSPVEEKG), and their alanine-substituted and/or serine-phosphorylated derivatives were carried out in an attempt to find a molecular mechanism for the effect of Al3+ to induce aggregation of neuronal proteins or their catabolic fragments. Al3+ and Ca2+ ions were found to induce beta-pleated sheet formation in the phosphorylated fragments. The cation sensitivity depended on the length and charge distribution of the sequence and site of phosphorylation. Al3+-induced conformational changes were irreversible to citric acid chelation, whereas Ca(2+)-induced conformational changes were reversible with citric acid. Studies of the alanine derivatives demonstrated which residues affected Al3+ or Ca2+ binding. Peptides containing at least one free (nonphosphorylated) serine residue were shown to form an intramolecular Al3+ complex, rather than an intermolecular one. In the intramolecular (intrachain) complex, the ligand function of the deprotonated serine hydroxyl was delineated [(Al.pepH-1)-type complex]. Ca2+ ions did not show a tendency for intramolecular complexing. The potential role of Al3+ in Alzheimer disease tangle and plaque formation is strongly suggested. PMID:8197154

  16. High Frequencies of Polyfunctional CD8+ NK Cells in Chronic HIV-1 Infection Are Associated with Slower Disease Progression

    PubMed Central

    Ahmad, Fareed; Hong, Henoch S.; Jäckel, Marc; Jablonka, Alexandra; Lu, I-Na; Bhatnagar, Nupur; Eberhard, Johanna M.; Bollmann, Benjamin A.; Ballmaier, Matthias; Zielinska-Skowronek, Margot; Schmidt, Reinhold E.

    2014-01-01

    ABSTRACT Natural killer (NK) cells are effector and regulatory innate immune cells and play a critical role in the first line of defense against various viral infections. Although previous reports have indicated the vital contributions of NK cells to HIV-1 immune control, nongenetic NK cell parameters directly associated with slower disease progression have not been defined yet. In a longitudinal, retrospective study of 117 untreated HIV-infected subjects, we show that higher frequencies as well as the absolute numbers of CD8+ CD3? lymphocytes are linked to delayed HIV-1 disease progression. We show that the majority of these cells are well-described blood NK cells. In a subsequent cross-sectional study, we demonstrate a significant loss of CD8+ NK cells in untreated HIV-infected individuals, which correlated with HIV loads and inversely correlated with CD4+ T cell counts. CD8+ NK cells had modestly higher frequencies of CD57-expressing cells than CD8? cells, but CD8+ and CD8? NK cells showed no differences in the expression of a number of activating and inhibiting NK cell receptors. However, CD8+ NK cells exhibited a more functional profile, as detected by cytokine production and degranulation. IMPORTANCE We demonstrate that the frequency of highly functional CD8+ NK cells is inversely associated with HIV-related disease markers and linked with delayed disease progression. These results thus indicate that CD8+ NK cells represent a novel NK cell-derived, innate immune correlate with an improved clinical outcome in HIV infection. PMID:25122796

  17. Pathogenesis of Progressive Scarring Trachoma in Ethiopia and Tanzania and Its Implications for Disease Control: Two Cohort Studies

    PubMed Central

    Burton, Matthew J.; Rajak, Saul N.; Hu, Victor H.; Ramadhani, Athumani; Habtamu, Esmael; Massae, Patrick; Tadesse, Zerihun; Callahan, Kelly; Emerson, Paul M.; Khaw, Peng T.; Jeffries, David; Mabey, David C. W.; Bailey, Robin L.; Weiss, Helen A.; Holland, Martin J.

    2015-01-01

    Background Trachoma causes blindness through a conjunctival scarring process initiated by ocular Chlamydia trachomatis infection; however, the rates, drivers and pathophysiological determinants are poorly understood. We investigated progressive scarring and its relationship to conjunctival infection, inflammation and transcript levels of cytokines and fibrogenic factors. Methodology/Principal Findings We recruited two cohorts, one each in Ethiopia and Tanzania, of individuals with established trachomatous conjunctival scarring. They were followed six-monthly for two years, with clinical examinations and conjunctival swab sample collection. Progressive scarring cases were identified by comparing baseline and two-year photographs, and compared to individuals without progression. Samples were tested for C. trachomatis by PCR and transcript levels of S100A7, IL1B, IL13, IL17A, CXCL5, CTGF, SPARCL1, CEACAM5, MMP7, MMP9 and CD83 were estimated by quantitative RT-PCR. Progressive scarring was found in 135/585 (23.1%) of Ethiopian participants and 173/577 (30.0%) of Tanzanian participants. There was a strong relationship between progressive scarring and increasing inflammatory episodes (Ethiopia: OR 5.93, 95%CI 3.31–10.6, p<0.0001. Tanzania: OR 5.76, 95%CI 2.60–12.7, p<0.0001). No episodes of C. trachomatis infection were detected in the Ethiopian cohort and only 5 episodes in the Tanzanian cohort. Clinical inflammation, but not scarring progression, was associated with increased expression of S100A7, IL1B, IL17A, CXCL5, CTGF, CEACAM5, MMP7, CD83 and reduced SPARCL1. Conclusions/Significance Scarring progressed in the absence of detectable C. trachomatis, which raises uncertainty about the primary drivers of late-stage trachoma. Chronic conjunctival inflammation appears to be central and is associated with enriched expression of pro-inflammatory factors and altered expression of extracellular matrix regulators. Host determinants of scarring progression appear more complex and subtle than the features of inflammation. Overall this indicates a potential role for anti-inflammatory interventions to interrupt progression and the need for trichiasis disease surveillance and surgery long after chlamydial infection has been controlled at community level. PMID:25970613

  18. The Emerging Role of Disturbed CoQ Metabolism in Nonalcoholic Fatty Liver Disease Development and Progression

    PubMed Central

    Botham, Kathleen M.; Napolitano, Mariarosaria; Bravo, Elena

    2015-01-01

    Although non-alcoholic fatty liver disease (NAFLD), characterised by the accumulation of triacylglycerol in the liver, is the most common liver disorder, the causes of its development and progression to the more serious non-alcoholic steatohepatitis (NASH) remain incompletely understood. Oxidative stress has been implicated as a key factor in both these processes, and mitochondrial dysfunction and inflammation are also believed to play a part. Coenzyme Q (CoQ) is a powerful antioxidant found in all cell membranes which has an essential role in mitochondrial respiration and also has anti-inflammatory properties. NAFLD has been shown to be associated with disturbances in plasma and liver CoQ concentrations, but the relationship between these changes and disease development and progression is not yet clear. Dietary supplementation with CoQ has been found to be hepatoprotective and to reduce oxidative stress and inflammation as well as improving mitochondrial dysfunction, suggesting that it may be beneficial in NAFLD. However, studies using animal models or patients with NAFLD have given inconclusive results. Overall, evidence is now emerging to indicate that disturbances in CoQ metabolism are involved in NAFLD development and progression to NASH, and this highlights the need for further studies with human subjects to fully clarify its role. PMID:26633474

  19. Modelling the tumour microenvironment in long-term microencapsulated 3D co-cultures recapitulates phenotypic features of disease progression.

    PubMed

    Estrada, Marta F; Rebelo, Sofia P; Davies, Emma J; Pinto, Marta T; Pereira, Hugo; Santo, Vítor E; Smalley, Matthew J; Barry, Simon T; Gualda, Emilio J; Alves, Paula M; Anderson, Elizabeth; Brito, Catarina

    2016-02-01

    3D cell tumour models are generated mainly in non-scalable culture systems, using bioactive scaffolds. Many of these models fail to reflect the complex tumour microenvironment and do not allow long-term monitoring of tumour progression. To overcome these limitations, we have combined alginate microencapsulation with agitation-based culture systems, to recapitulate and monitor key aspects of the tumour microenvironment and disease progression. Aggregates of MCF-7 breast cancer cells were microencapsulated in alginate, either alone or in combination with human fibroblasts, then cultured for 15 days. In co-cultures, the fibroblasts arranged themselves around the tumour aggregates creating distinct epithelial and stromal compartments. The presence of fibroblasts resulted in secretion of pro-inflammatory cytokines and deposition of collagen in the stromal compartment. Tumour cells established cell-cell contacts and polarised around small lumina in the interior of the aggregates. Over the culture period, there was a reduction in oestrogen receptor and membranous E-cadherin alongside loss of cell polarity, increased collective cell migration and enhanced angiogenic potential in co-cultures. These phenotypic alterations, typical of advanced stages of cancer, were not observed in the mono-cultures of MCF-7 cells. The proposed model system constitutes a new tool to study tumour-stroma crosstalk, disease progression and drug resistance mechanisms. PMID:26650685

  20. Current progress in the management of rare diseases and orphan drugs in China

    PubMed Central

    Gong, Shiwei; Jin, Si

    2012-01-01

    Summary Currently, the issues of how to treat rare diseases and to improve accessibility to orphan drugs are arousing more and more concerns in China. Here we describe the push and pull incentive policies for rare diseases and orphan drugs and analyze the coverage and reimbursement level of rare diseases in the current Chinese medical insurance system. Three key obstacle factors that hinder Chinese patients' accessibility to timely drug treatment are summarized. Based on a comprehensive analysis, the measures of orphan drugs legislation, incentive mechanism, supply mechanism, and reimbursement mechanism are urgently expected to be established with the purpose of improving healthcare for patients with rare diseases in China. PMID:25343073

  1. Molecular Determinants and Genetic Modifiers of Aggregation and Toxicity for the ALS Disease Protein

    E-print Network

    Shorter, James

    inclusions in some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD: ALS, amyotrophic lateral sclerosis; EM, electron microscopy; FTLD, frontotemporal lobar degeneration

  2. ?-Galactosidase A knockout mice: progressive organ pathology resembles the type 2 later-onset phenotype of Fabry disease.

    PubMed

    Bangari, Dinesh S; Ashe, Karen M; Desnick, Robert J; Maloney, Colleen; Lydon, John; Piepenhagen, Peter; Budman, Eva; Leonard, John P; Cheng, Seng H; Marshall, John; Thurberg, Beth L

    2015-03-01

    Fabry disease is an X-linked lysosomal storage disease caused by deficient activity of ?-galactosidase A and the resultant systemic accumulation of globotrioasylceramide (GL-3) and related glycolipids. ?-Galactosidase A gene knockout (Gla KO) mice have no ?-galactosidase A activity and progressively accumulate GL-3 in tissues and fluids, similarly to FD patients. The nature and temporal effects of the progressive substrate accumulation on tissue histology in these mice have not previously been characterized. Here, we report the pathology of young to old (3 to 17 months old) Gla KO mice and compare these changes with those in strain-matched control animals. Gla KO mice accumulated GL-3 in various tissues and fluids with age. Lysosomal GL-3 inclusions increased with age in multiple cell types, including renal epithelial, intestinal, and vascular smooth muscle cells, and neurons in trigeminal and dorsal root ganglia, as detected by light and electron microscopy. However, unlike the case for male FD patients with the type 1 classic phenotype, GL-3 inclusions were not detected in vascular endothelial cells or cardiomyocytes. The histological changes in Gla KO mice better resemble the type 2 later-onset phenotype observed in patients with residual ?-galactosidase A activity. GL-3 accumulation in the small intestine and sensory ganglia of Gla KO mice provides a model for study of enteropathy and neuropathy in Fabry disease. PMID:25553976

  3. Effects of temperature on disease progression and swimming stamina in Ichthyophonus-infected rainbow trout, Oncorhynchus mykiss (Walbaum)

    USGS Publications Warehouse

    Kocan, R.; Hershberger, P.; Sanders, G.; Winton, J.

    2009-01-01

    Rainbow trout, Oncorhynchus mykiss, were infected with Ichthyophonus sp. and held at 10 ??C, 15 ??C and 20 ??C for 28 days to monitor mortality and disease progression. Infected fish demonstrated more rapid onset of disease, higher parasite load, more severe host tissue reaction and reduced mean-day-to-death at higher temperature. In a second experiment, Ichthyophonus-infected fish were reared at 15 ??C for 16 weeks then subjected to forced swimming at 10 ??C, 15 ??C and 20 ??C. Stamina improved significantly with increased temperature in uninfected fish; however, this was not observed for infected fish. The difference in performance between infected and uninfected fish became significant at 15 ??C (P = 0.02) and highly significant at 20 ??C (P = 0.005). These results have implications for changes in the ecology of fish diseases in the face of global warming and demonstrate the effects of higher temperature on the progression and severity of ichthyophoniasis as well as on swimming stamina, a critical fitness trait of salmonids. This study helps explain field observations showing the recent emergence of clinical ichthyophoniasis in Yukon River Chinook salmon later in their spawning migration when water temperatures were high, as well as the apparent failure of a substantial percentage of infected fish to successfully reach their natal spawning areas. ?? 2009 Blackwell Publishing Ltd.

  4. Molecular Mechanisms and the Role of Saturated Fatty Acids in the Progression of Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Leamy, Alexandra K.; Egnatchik, Robert A.; Young, Jamey D.

    2013-01-01

    The steady rise in Western obesity rates has been closely linked to significant increases in a multitude of accompanying health problems including Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD severity ranges from simple steatosis to acute steatohepatitis, but the molecular mechanisms controlling progression of this disease are poorly understood. Recent literature suggests that elevated free fatty acids (FFAs), especially saturated FFAs, may play an important role in lipotoxic mechanisms, both in experimental models and in NAFLD patients. This review highlights important cellular pathways involved in hepatic lipotoxicity and how the degree of intrahepatic lipid saturation controls cell fate in response to an elevated FFA load. Relevant cellular processes that have been causally linked to lipid-induced apoptosis, known as lipoapoptosis, include endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial dysfunction, and Jun N-terminal kinase (JNK) signaling. In contrast, increased triglyceride synthesis has been shown to have a protective effect against lipotoxicity, despite being one of the hallmark traits of NAFLD. Developing a more nuanced understanding of the molecular mechanisms underlying NAFLD progression will lead to more targeted and effective therapeutics for this increasingly prevalent disease, which to date has no proven pharmacologic treatment to prevent or reverse its course. PMID:23178552

  5. Alzheimer's Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: Genetics core aims, progress, and plans

    E-print Network

    Thompson, Paul

    Alzheimer's Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: Genetics core C. Greenj , Lars Bertramk , Clifford R. Jack, Jr.l , Michael W. Weinerm,n,o,p ; and the Alzheimer of Veterans Affairs Medical Center, San Francisco, CA, USA Abstract The role of the Alzheimer's Disease

  6. Modeling disease progression of camellia twig blight using a recurrent event model.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To improve control of camellia twig blight (CTB) using sanitation methods, a more complete epidemiologic understanding of this disease is necessary. Three CTB disease stages were modeled using recurrent event analysis. Wound inoculated stems were observed at regular intervals for appearance of dise...

  7. Progressive Apraxia of Speech as a Sign of Motor Neuron Disease

    ERIC Educational Resources Information Center

    Duffy, Joseph R.; Peach, Richard K.; Strand, Edythe A.

    2007-01-01

    Purpose: To document and describe in detail the occurrence of apraxia of speech (AOS) in a group of individuals with a diagnosis of motor neuron disease (MND). Method: Seven individuals with MND and AOS were identified from among 80 patients with a variety of neurodegenerative diseases and AOS (J. R. Duffy, 2006). The history, presenting…

  8. Correlation between cell free DNA levels and medical evaluation of disease progression in systemic lupus erythematosus patients.

    PubMed

    Tug, Suzan; Helmig, Susanne; Menke, Julia; Zahn, Daniela; Kubiak, Thomas; Schwarting, Andreas; Simon, Perikles

    2014-01-01

    High levels of cell free DNA (cfDNA) in human blood plasma have been described in patients with autoimmune diseases. The aim of this study was to determine the levels of cfDNA in systemic lupus erythematosus (SLE) patients and to assess fluctuations of cfDNA concentrations compared to the course of disease progression under standard treatment. Therefore, nuclear cfDNA concentrations in plasma were measured in 59 SLE patients and 59 healthy controls. Follow-up blood plasma was collected from 27 of the 59 SLE patients. Patients were characterised by clinical parameters (antinuclear antibodies (ANA), anti-dsDNA-antibodies, C3, C4, and CRP), SLE disease activity index (SLEDAI) and medical therapy. Our results showed that cfDNA concentrations were significantly higher in SLE patients compared to healthy individuals. Levels of cfDNA assessed in serial samples correlated significantly with the medical evaluation of disease activity in SLE patients. Our results could implicate cfDNA as a global marker for disease activity. PMID:25243646

  9. Complexity of chronic asthma and chronic obstructive pulmonary disease: implications for risk assessment, and disease progression and control

    PubMed Central

    Frey, Urs; Suki, Béla

    2009-01-01

    Although assessment of asthma control is important to guide treatment, it is difficult since the temporal pattern and risk of exacerbations are often unpredictable. In this Review, we summarise the classic methods to assess control with unidimensional and multidimensional approaches. Next, we show how ideas from the science of complexity can explain the seemingly unpredictable nature of bronchial asthma and emphysema, with implications for chronic obstructive pulmonary disease. We show that fluctuation analysis, a method used in statistical physics, can be used to gain insight into asthma as a dynamic disease of the respiratory system, viewed as a set of interacting subsystems (eg, inflammatory, immunological, and mechanical). The basis of the fluctuation analysis methods is the quantification of the long-term temporal history of lung function parameters. We summarise how this analysis can be used to assess the risk of future asthma episodes, with implications for asthma severity and control both in children and adults. PMID:18805337

  10. The effect of abnormal birth history on ambulatory blood pressure and disease progression in children with chronic kidney disease

    PubMed Central

    Flynn, Joseph T; Ng, Derek K; Chan, Grace J; Samuels, Joshua; Furth, Susan; Warady, Bradley; Greenbaum, Larry A.

    2014-01-01

    Objective To examine the associations between abnormal birth history (birth weight [BW] <2500 grams, gestational age <36 weeks, or small for gestational age), BP, and renal function among 332 participants (97 with abnormal and 235 with normal birth history) in the Chronic Kidney Disease in Children (CKiD) Study, a cohort of children with chronic kidney disease (CKD). Study design Casual and 24-hour ambulatory BP were obtained. Glomerular filtration rate (GFR) was determined by iohexol disappearance. Confounders (birth and maternal characteristics, socioeconomic status) were used to generate predicted probabilities of abnormal birth history for propensity score matching. Weighted linear and logistic regression models with adjustment for quintiles of propensity scores and CKD diagnosis were used to assess the impact of birth history on BP and GFR. Results Age at enrollment, percent with glomerular disease, and baseline GFR were similar between the groups. Those with abnormal birth history were more likely to be female, of Black race or Hispanic ethnicity, to have low household income, or part of a multiple birth. Unadjusted BP measurements, baseline GFR and change in GFR did not differ significantly between the groups; no differences were seen after adjusting for confounders by propensity score matching. Conclusions Abnormal birth history does not appear to have exerted a significant influence on BP or GFR in this cohort of children with CKD. The absence of an observed association is likely secondary to the dominant effects of underlying CKD and its treatment. PMID:24698454

  11. Lifestyle factors may modify the effect of disease activity on radiographic progression in patients with ankylosing spondylitis: a longitudinal analysis

    PubMed Central

    Ramiro, Sofia; Landewé, Robert; van Tubergen, Astrid; Boonen, Annelies; Stolwijk, Carmen; Dougados, Maxime; van den Bosch, Filip; van der Heijde, Désirée

    2015-01-01

    Objectives To investigate the complex relationship between inflammation, mechanical stress and radiographic progression in patients with ankylosing spondylitis (AS), using job type as a proxy for continuous mechanical stress. Methods Patients from the Outcome in Ankylosing Spondylitis International Study were followed up for 12?years, with 2-yearly assessments. Two readers independently scored the X-rays according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Disease activity was assessed by the AS Disease Activity Score C reactive protein (ASDAS-CRP). The relationship between ASDAS and spinal radiographic progression was investigated with longitudinal analysis, with job type at baseline (physically demanding (‘blue-collar’) versus sedentary (‘white-collar’) labour) as a potential factor influencing this relationship. The effects of smoking status and socioeconomic factors were also investigated. Results In total, 184 patients were included in the analyses (70% males, 83% human leucocyte antigen-B27 positive, 39% smokers, 48% blue-collar workers (65/136 patients in whom data on job type were available)). The relationship between disease activity and radiographic progression was significantly and independently modified by job type: In ‘blue-collar’ workers versus ‘white-collar’ workers, every additional unit of ASDAS resulted in an increase of 1.2 versus 0.2 mSASSS-units/2-years (p=0.014 for the difference between blue-collar and white-collar workers). In smokers versus non-smokers, every additional unit of ASDAS resulted in an increase of 1.9 versus 0.4 mSASSS-units/2-years. Conclusions Physically demanding jobs may amplify the potentiating effects of inflammation on bone formation in AS. Smoking and socioeconomic factors most likely confound this relationship and may have separate effects on bone formation. PMID:26535153

  12. Elevated serum levels of macrophage migration inhibitory factor are associated with progressive chronic cardiomyopathy in patients with Chagas disease.

    PubMed

    Cutrullis, Romina A; Petray, Patricia B; Schapachnik, Edgardo; Sánchez, Rubén; Postan, Miriam; González, Mariela N; Martín, Valentina; Corral, Ricardo S

    2013-01-01

    Clinical symptoms of chronic Chagas disease occur in around 30% of the individuals infected with Trypanosoma cruzi and are characterized by heart inflammation and dysfunction. The pathogenesis of chronic chagasic cardiomyopathy (CCC) is not completely understood yet, partially because disease evolution depends on complex host-parasite interactions. Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that promotes numerous pathophysiological processes. In the current study, we investigated the link between MIF and CCC progression.Immunohistochemical analysis demonstrated MIF overexpression in the hearts from chronically T. cruzi-infected mice, particularly those showing intense inflammatory infiltration. We also found that MIF exogenously added to parasite-infected murine macrophage cultures is capable of enhancing the production of TNF-? and reactive oxygen species, both with pathogenic roles in CCC. Thus, the integrated action of MIF and other cytokines and chemokines may account for leukocyte influx to the infected myocardium, accompanied by enhanced local production of multiple inflammatory mediators. We further examined by ELISA the level of MIF in the sera from chronic indeterminate and cardiomyopathic chagasic patients, and healthy subjects. CCC patients displayed significantly higher MIF concentrations than those recorded in asymptomatic T. cruzi-infected and uninfected individuals. Interestingly, increased MIF levels were associated with severe progressive Chagas heart disease, in correlation with elevated serum concentration of high sensitivity C-reactive protein and also with several echocardiographic indicators of left ventricular dysfunction, one of the hallmarks of CCC. Our present findings represent the first evidence that enhanced MIF production is associated with progressive cardiac impairment in chronic human infection with T. cruzi, strengthening the relationship between inflammatory response and parasite-driven pathology. These observations contribute to unravel the elements involved in the pathogenesis of CCC and may also be helpful for the design of novel therapies aimed to control long-term morbidity in chagasic patients. PMID:23451183

  13. Comparison of four methods of analysis of lipoprotein particle subfractions for their association with angiographic progression of coronary artery disease

    PubMed Central

    Williams, Paul T.; Zhao, Xue-Qiao; Marcovina, Santica M.; Otvos, James D; Brown, B Greg; Krauss, Ronald M

    2014-01-01

    Background Compare gradient gel electrophoresis (GGE), vertical auto profile (VAP-II), nuclear magnetic resonance spectroscopy (NMR), and ion mobility for their ability to relate low-(LDL), intermediate- (IDL), very-low-density (VLDL) and high-density lipoprotein (HDL) subfraction concentrations to atherosclerotic progression. Methods and Results Regression analyses of 136 patients who received baseline and follow-up coronary angiographies and subfraction measurements by all four methods in the HDL Atherosclerosis Treatment Study. Prior analyses have shown that the intervention primarily affected disease progression in proximal arteries with <30% stenoses at baseline. Three-year increases in percent stenoses were consistently associated with higher on-study plasma concentrations of small, dense LDL as measured by GGE (LDLIIIb, P=10?6; LDLIVa, P=0.006; LDLIVb, P=0.02), VAP-II (LDL4, P=0.002), NMR (small LDL, P=0.001), and ion mobility (LDL IIb, P=0.04; LDLIIIa, P=0.002; LDLIIIb, P=0.0007; LDLIVa, P=0.05). Adjustment for triglycerides, HDL-cholesterol, and LDL-cholesterol failed to eliminate the statistical significance for on-study GGE estimated LDLIIIb (P=10?5) and LDLIVa (P=0.04); NMR-estimated small LDL (P=0.03); or ion mobility estimated large LDLIIIa (P=0.04) or LDLIIIb (P=0.02). All methods show that the effects were significantly greater for the on-study than the baseline small, dense LDL concentrations, thus establishing that the values concurrent to the progression of disease were responsible. The rate of disease progression was also related to individual VLDL, IDL, and HDL subclasses to differing extents among the various analytic methods. Conclusion Four methodologies confirm the association of small, dense LDL with greater coronary atherosclerosis progression, and GGE, NMR, and ion mobility confirm that the associations were independent of standard lipid measurements. Clinical Trial Registration clinicaltrials.gov/ct2/show/NCT00000553 PMID:24603218

  14. Contributions of Ibn Al-Nafis (1210-1288 AD) to the progress of medicine and urology. A study and translations from his medical works.

    PubMed

    Abdel-Halim, Rabie E

    2008-01-01

    This primary-source study of 4 medical works of the 13th century Muslim scholar Ibn Al-Nafis confirmed that his Kitab Al-Mujaz Fi Al-Tibb was authored as an independent book meant to be a handbook for medical students and practitioners not as an epitome of Kitab Al-Qanun of Ibn Sina as thought by recent historians. His huge medical encyclopedia, Al-Shamil, represents a wave of intense scientific activity that spread among the scholars of Cairo and Damascus following the massive destruction of books by Hulako's Army during the devastation of Baghdad in 1258. Like his predecessors in the Islamic Era, Ibn Al-Nafis critically appraised the views of scholars before him in the light of his own experimentation and direct observations. Accordingly, in his books Sharh Tashreeh Al-Qanun, Risalat al-Aadaa and Al-Risalah Al-Kameleyyah, we find the first description of the coronary vessels and the true concept of the blood supply of the heart as well as the correct description of the pulmonary circulation and the beginnings of the proper understanding of the systemic circulation. Those discoveries of Ibn Al-Nafis, translated to Latin by Andreas Alpagus printed in Venice in 1547, appeared, 6 years later, in the Christianismi Restituto of Servetus and, in 1555, in the De Fabrica Humani Corporis of Vesalius 2nd edition then in the works of Valvarde 1554, Columbus 1559, Cesalpino 1571, and finally Harvey in 1628. Furthermore, this study documented several other contributions of Ibn Al-Nafis to the progress of human functional anatomy and to advances in medical and surgical practice. PMID:18176669

  15. Progress and promise in understanding the genetic basis of common diseases.

    PubMed

    Price, Alkes L; Spencer, Chris C A; Donnelly, Peter

    2015-12-22

    Susceptibility to common human diseases is influenced by both genetic and environmental factors. The explosive growth of genetic data, and the knowledge that it is generating, are transforming our biological understanding of these diseases. In this review, we describe the technological and analytical advances that have enabled genome-wide association studies to be successful in identifying a large number of genetic variants robustly associated with common disease. We examine the biological insights that these genetic associations are beginning to produce, from functional mechanisms involving individual genes to biological pathways linking associated genes, and the identification of functional annotations, some of which are cell-type-specific, enriched in disease associations. Although most efforts have focused on identifying and interpreting genetic variants that are irrefutably associated with disease, it is increasingly clear that-even at large sample sizes-these represent only the tip of the iceberg of genetic signal, motivating polygenic analyses that consider the effects of genetic variants throughout the genome, including modest effects that are not individually statistically significant. As data from an increasingly large number of diseases and traits are analysed, pleiotropic effects (defined as genetic loci affecting multiple phenotypes) can help integrate our biological understanding. Looking forward, the next generation of population-scale data resources, linking genomic information with health outcomes, will lead to another step-change in our ability to understand, and treat, common diseases. PMID:26702037

  16. Novel Therapeutic Targets and Drug Candidates for Modifying Disease Progression in Adrenoleukodystrophy.

    PubMed

    Pujol, Aurora

    2016-01-01

    X-linked adrenoleukodystrophy (X-ALD) is the most frequent inherited monogenic demyelinating disease. It is often lethal and currently lacks a satisfactory therapy. The disease is caused by loss of function of the ABCD1 gene, a peroxisomal ATP-binding cassette transporter, resulting in the accumulation of very-long-chain fatty acids (VLCFA) in organs and plasma. Recent findings on pathomechanisms of the peroxisomal neurometabolic disease X-ALD have provided important clues on therapeutic targets. Here we describe the impact of chronic redox imbalance caused by the excess VLCFA on mitochondrial biogenesis and respiration, and explore the consequences on the protein quality control systems essential for cell survival, such as the proteasome and autophagic flux. Defective proteostasis, together with mitochondrial malfunction, is a hallmark of the most prevalent neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, and of the aging process. Thus, we discuss molecular targets and emerging treatment options that may be common to both multifactorial neurodegenerative disorders and X-ALD. New-generation antioxidants, some of them mitochondrial targeted, mitochondrial biogenesis boosters such as pioglitazone and resveratrol, and the mTOR inhibitor temsirolimus hold promise as disease-modifying therapies. PMID:26684655

  17. [Progress in the study of near-infrared fluorescent probes for the detection of ?-amyloid deposition in Alzheimer's disease].

    PubMed

    Du, Lei; Feng, Hai-wei; Li, Yu-yan

    2015-05-01

    Alzheimer's disease (AD) is the most common cause of cognitive impairment in older people. With the aging of society is more and more serious, AD caused great burden to patients and society. A ? is a classical biomarker of AD, which has been widely used in clinical diagnosis of AD patients. Compared with positron emission tomography (PET) and single photon emission computed tomography (SPECT), near infrared fluorescence imaging has many advantages including highly sensitive, non-invasive, safety and inexpensive. Therefore, many research groups have focused on developing the molecular probes of near-infrared fluorescence (NIRF) imaging. In this article, we will review the progress of the probes of NIRF. PMID:26234131

  18. HCV Coinfection Associated with Slower Disease Progression in HIV-Infected Former Plasma Donors Naïve to ART

    PubMed Central

    Peng, Hong; Ma, Yan; Han, Lifeng; Ruan, Yuhua; Su, Bing; Wang, Ning; Shao, Yiming

    2008-01-01

    Background It remains controversial how HCV coinfection influences the disease progression during HIV-1 infection. This study aims to define the influence of HCV infection on the replication of HIV-1 and the disease progression in HIV-infected former plasma donors (FPDs) naïve to ART. Methodology/Principal Findings 168 HIV-1-infected FPDs were enrolled into a cohort study from Anhui province in central China, and thereafter monitored at month 3, 9, 15, 21 and 33. Fresh whole blood samples were used for CD4+ T-cell counting. Their plasma samples were collected and stored for quantification of HIV-1 viral loads and for determination of HCV and Toxoplasma. Out of 168 HIV-infected FBDs, 11.9% (20 cases), 80.4% (135 cases) and 7.7% (13 cases) were infected with HIV-1 alone, HIV-1/HCV and HIV/HCV/Toxoplasma, respectively. During the 33-month follow-up, only 35% (7 out of 20 cases) HIV-1 mono-infected subjects remained their CD4+ T-cell counts above 200 cells/µl and retained on the cohort study, which was significantly lower than 56% (75 out of 135 cases) for HIV/HCV group and 69% (9 out of 13 cases) for HIV/HCV/Toxoplasma group (p<0.05). CD4+ T cells in HIV mono infection group were consistently lower than that in HIV/HCV group (p?=?0.04, 0.18, 0.03 and 0.04 for baseline, month 9, month 21 and month 33 visit, respectively). In accordance with those observations, HIV viral loads in HIV mono-infection group were consistently higher than that in HIV/HCV group though statistical significances were only reached at baseline (p?=?0.04). Conclusions/Significance These data indicated HCV coinfection with HIV-1 is associated with the slower disease progression at the very late stage when comparing with HIV-1 mono-infection. The coinfection of Toxoplasma with HIV and HCV did not exert additional influence on the disease progression. It will be highly interesting to further explore the underlying mechanism for this observation in the future. PMID:19098990

  19. The intercellular cell adhesion molecule-1 (icam-1) in lung cancer: implications for disease progression and prognosis.

    PubMed

    Kotteas, Elias A; Boulas, Panagiotis; Gkiozos, Ioannis; Tsagkouli, Sofia; Tsoukalas, George; Syrigos, Konstantinos N

    2014-09-01

    The intercellular cell-adhesion molecule-1 (ICAM-1) is a transmembrane molecule and a distinguished member of the Immunoglobulin superfamily of proteins that participates in many important processes, including leukocyte endothelial transmigration, cell signaling, cell-cell interaction, cell polarity and tissue stability. ICAM-1and its soluble part are highly expressed in inflammatory conditions, chronic diseases and a number of malignancies. In the present article we present the implications of ICAM-1 in the progression and prognosis of one of the major global killers of our era: lung cancer. PMID:25202042

  20. Genome-Wide Association Studies: Progress in Identifying Genetic Biomarkers in Common, Complex Diseases

    PubMed Central

    Kingsmore, Stephen F.; Lindquist, Ingrid E.; Mudge, Joann; Beavis, William D.

    2007-01-01

    Novel, comprehensive approaches for biomarker discovery and validation are urgently needed. One particular area of methodologic need is for discovery of novel genetic biomarkers in complex diseases and traits. Here, we review recent successes in the use of genome wide association (GWA) approaches to identify genetic biomarkers in common human diseases and traits. Such studies are yielding initial insights into the allelic architecture of complex traits. In general, it appears that complex diseases are associated with many common polymorphisms, implying profound genetic heterogeneity between affected individuals. PMID:19662211

  1. High amylose resistant starch diet ameliorates oxidative stress, inflammation, and progression of chronic kidney disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Inflammation is a major mediator of CKD progression and is partly driven by altered gut microbiome and intestinal barrier disruption, events which are caused by: urea influx in the intestine resulting in dominance of urease-possessing bacteria; disruption of epithelial barrier by urea-derived ammoni...

  2. A resistant starch fiber diet ameliorates oxidative stress, inflammation, and progression of chronic kidney disease (CKD)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Inflammation is a constant feature and a major mediator of CKD progression. It is, in part, driven by altered gut microbiome and disruption of intestinal epithelial barrier, events which are primarily caused by: 1- urea influx in the intestine resulting in dominance of urease-possessing bacteria; 2-...

  3. Interstitial fluid flow in cancer: implications for disease progression and treatment

    PubMed Central

    Munson, Jennifer M; Shieh, Adrian C

    2014-01-01

    As cancer progresses, a dynamic microenvironment develops that creates and responds to cellular and biophysical cues. Increased intratumoral pressure and corresponding increases in interstitial flow from the tumor bulk to the healthy stroma is an observational hallmark of progressing cancers. Until recently, the role of interstitial flow was thought to be mostly passive in the transport and dissemination of cancer cells to metastatic sites. With research spanning the past decade, we have seen that interstitial flow has a promigratory effect on cancer cell invasion in multiple cancer types. This invasion is one mechanism by which cancers can resist therapeutics and recur, but the role of interstitial flow in cancer therapy is limited to the understanding of transport of therapeutics. Here we outline the current understanding of the role of interstitial flow in cancer and the tumor microenvironment through cancer progression and therapy. We also discuss the current role of fluid flow in the treatment of cancer, including drug transport and therapeutic strategies. By stating the current understanding of interstitial flow in cancer progression, we can begin exploring its role in therapeutic failure and treatment resistance. PMID:25170280

  4. Progression of Coronary Calcium and Incident Coronary Heart Disease Events: The Multi-Ethnic Study of Atherosclerosis

    PubMed Central

    Budoff, Matthew J.; Young, Rebekah; Lopez, Victor A.; Kronmal, Richard A.; Nasir, Khurram; Blumenthal, Roger S.; Detrano, Robert C.; Bild, Diane E.; Guerci, Alan D.; Liu, Kiang; Shea, Steven; Szklo, Moyses; Post, Wendy; Lima, Joao; Bertoni, Alain; Wong, Nathan D.

    2014-01-01

    Background Coronary artery calcium (CAC) predicts coronary heart disease (CHD) events and serial measurement of CAC has been proposed to evaluate atherosclerosis progression. We examined whether progression of CAC is a predictor of future CHD events. Methods and Results We studied 6,778 persons (52.8% female) aged 45–84 years from the Multi-Ethnic Study of Atherosclerosis. 5,682 persons had baseline and follow-up CAC scans approximately 2.5 ± 0.8 years apart; multiple imputation was used to account for the remainder (n=1,096) missing follow-up scans. Median follow-up duration from the baseline was 7.6 (max=9.0) years. CAC change was assessed by absolute change between baseline and follow-up CAC. Cox proportional hazards regression providing hazard ratios (HR) examined the relation of change in CAC with CHD events, adjusting for age, gender, ethnicity, baseline calcium score, and other risk factors. 343 total and 206 hard CHD events occurred. The annual change in CAC averaged 24.9 ± 65.3 units. Among persons without CAC at baseline (n=3,396), a 5 unit annual change in CAC was associated with an adjusted HR of 1.4 (1.0–1.9) for total and 1.5 (1.1–2.1) for hard CHD. Among those with CAC>0 at baseline HR’s (per 100 unit annual change) were 1.2 (1.1–1.4) and 1.3 (1.1–1.5), respectively. Among participants with baseline CAC, those with annual progression of ?300 units had adjusted HR’s of 3.8 (1.5–9.6) for total and 6.3 (1.9–21.5) for hard CHD compared to those without progression. Conclusions Progression of CAC is associated with an increased risk for future hard and total CHD events. PMID:23500326

  5. Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease

    PubMed Central

    Hill, Rebecca M.; Kuijper, Sanne; Lindsey, Janet C.; Petrie, Kevin; Schwalbe, Ed C.; Barker, Karen; Boult, Jessica K.R.; Williamson, Daniel; Ahmad, Zai; Hallsworth, Albert; Ryan, Sarra L.; Poon, Evon; Robinson, Simon P.; Ruddle, Ruth; Raynaud, Florence I.; Howell, Louise; Kwok, Colin; Joshi, Abhijit; Nicholson, Sarah Leigh; Crosier, Stephen; Ellison, David W.; Wharton, Stephen B.; Robson, Keith; Michalski, Antony; Hargrave, Darren; Jacques, Thomas S.; Pizer, Barry; Bailey, Simon; Swartling, Fredrik J.; Weiss, William A.; Chesler, Louis; Clifford, Steven C.

    2015-01-01

    Summary We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. PMID:25533335

  6. Epigenetic pathway targets for the treatment of disease: accelerating progress in the development of pharmacological tools: IUPHAR Review 11

    PubMed Central

    Tough, David F; Lewis, Huw D; Rioja, Inmaculada; Lindon, Matthew J; Prinjha, Rab K

    2014-01-01

    The properties of a cell are determined both genetically by the DNA sequence of its genes and epigenetically through processes that regulate the pattern, timing and magnitude of expression of its genes. While the genetic basis of disease has been a topic of intense study for decades, recent years have seen a dramatic increase in the understanding of epigenetic regulatory mechanisms and a growing appreciation that epigenetic misregulation makes a significant contribution to human disease. Several large protein families have been identified that act in different ways to control the expression of genes through epigenetic mechanisms. Many of these protein families are finally proving tractable for the development of small molecules that modulate their function and represent new target classes for drug discovery. Here, we provide an overview of some of the key epigenetic regulatory proteins and discuss progress towards the development of pharmacological tools for use in research and therapy. PMID:25060293

  7. Molecular sampling of prostate cancer: a dilemma for predicting disease progression

    E-print Network

    Sboner, Andrea

    Background: Current prostate cancer prognostic models are based on pre-treatment prostate specific antigen (PSA) levels, biopsy Gleason score, and clinical staging but in practice are inadequate to accurately predict disease ...

  8. [Progresses and existed problems on the diagnosis and treatment of Vogt-Koyanagi-Harada disease].

    PubMed

    Zheng, Yue-zhong

    2012-06-01

    Vogt-Koyanagi-Harada disease is a multi-systems inflammatory disease that affects the eye, skin, inner ear and meninges. The characteristics of this disease are with meningismus, auditory dysfunction and integumentary changes. Bilateral granulomatous panuveitis with serous retinal detachments are the typical ocular findings. Vogt-koyanagi-Harada disease is characterized by the acute onset, poor response to the treatment and high blindness rate. The diagnosis is mainly made on the history and ocular findings with various systemic manifestations. Fundus angiography is often used to assist in the diagnosis. High dosages of systemic corticosteroids are the first line therapeutical choice. The immunosuppressive agents and biologic agents combined with systemic corticosteroids shows good results in some recurrent cases. The good visual prognosis is guarded with earlier accurate diagnosis and aggressive treatment. PMID:22943816

  9. Fungal sinusitis: progression of disease in immunosuppression--a case report.

    PubMed

    Gungor, A; Adusumilli, V; Corey, J P

    1998-03-01

    Fungal sinusitis is a disease which can be grouped into invasive and noninvasive forms. The invasive entities include the acute/fulminant and chronic/indolent forms. The noninvasive entities include the fungus ball and allergic forms. The noninvasive forms, however, can develop into invasive disease under certain immunosuppressive states. The patient in this case report had the fungus ball form of fungal sinusitis which evolved into chronic, and then the acute/fulminant form approximately two weeks after undergoing cadaver-donor kidney transplantation. Due to the patient's immunosuppressed state, the fungus spread beyond the sinus region and eventually lead to fulminant disseminated disease. The severity of the fungal disease corresponded directly to the severity of the patient's immunosuppression. PMID:9557411

  10. IFN-? and TNF-? are involved during Alzheimer disease progression and correlate with nitric oxide production: a study in Algerian patients.

    PubMed

    Belkhelfa, Mourad; Rafa, Hayet; Medjeber, Oussama; Arroul-Lammali, Amina; Behairi, Nassima; Abada-Bendib, Myriam; Makrelouf, Mohamed; Belarbi, Soreya; Masmoudi, Ahmed Nacer; Tazir, Meriem; Touil-Boukoffa, Chafia

    2014-11-01

    Alzheimer's disease (AD) is a neurodegenerative disease leading to a progressive and irreversible loss of mental functions. It is characterized by 3 stages according to the evolution and the severity of the symptoms. This disease is associated with an immune disorder, which appears with significant rise in the inflammatory cytokines and increased production of free radicals such as nitric oxide (NO). Our study aims to investigate interferon (IFN)-? and tumor necrosis factor-? (TNF-?) involvement in NO production, in vivo and ex vivo, in peripheral blood mononuclear cells from Algerian patients (n=25), according to the different stages of the disease (mild Alzheimer's, moderate Alzheimer's, and severe Alzheimer's) in comparison to mild cognitive impairment (MCI) patients. Interestingly, we observed that in vivo IFN-? and TNF-? levels assessed in patients with AD in mild and severe stages, respectively, are higher than those observed in patients with moderate stage and MCI. Our in vivo and ex vivo results show that NO production is related to the increased levels of IFN-? and TNF-?, in mild and severe stages of AD. Remarkably, significant IFN-? level is only detected in mild stage of AD. Our study suggests that NO production is IFN-? dependent both in MCI and mild Alzheimer's patients. Further, high levels of NO are associated with an elevation of TNF-? levels in severe stage of AD. Collectively, our data indicate that the proinflammatory cytokine production seems, in part, to be involved in neurological deleterious effects observed during the development of AD through NO pathway. PMID:24831467

  11. Progress and prospects of engineered sequence-specific DNA modulating technologies for the management of liver diseases

    PubMed Central

    Nicholson, Samantha A; Moyo, Buhle; Arbuthnot, Patrick B

    2015-01-01

    Liver diseases are one of the leading causes of mortality in the world. The hepatic illnesses, which include inherited metabolic disorders, hemophilias and viral hepatitides, are complex and currently difficult to treat. The maturation of gene therapy has heralded new avenues for developing effective intervention for these diseases. DNA modification using gene therapy is now possible and available technology may be exploited to achieve long term therapeutic benefit. The ability to edit DNA sequences specifically is of paramount importance to advance gene therapy for application to liver diseases. Recent development of technologies that allow for this has resulted in rapid advancement of gene therapy to treat several chronic illnesses. Improvements in application of derivatives of zinc finger proteins (ZFPs), transcription activator-like effectors (TALEs), homing endonucleases (HEs) and clustered regularly interspaced palindromic repeats (CRISPR) and CRISPR associated (Cas) systems have been particularly important. These sequence-specific technologies may be used to modify genes permanently and also to alter gene transcription for therapeutic purposes. This review describes progress in development of ZFPs, TALEs, HEs and CRISPR/Cas for application to treating liver diseases. PMID:25937863

  12. Continuum of therapy in progressive renal diseases (from predialysis to transplantation): analysis of a new organizational model.

    PubMed

    Piccoli, Giuseppe; Piccoli, Giorgina Barbara; Mezza, Elisabetta; Burdese, Manuel; Rosetti, Maura; Guarena, Cesare; Messina, Maria; Pacitti, Alfonso; Thea, Alessandra; Malfi, Bernardo; Soragna, Giorgio; Gai, Massimo; Mangiarotti, Giovanni; Jeantet, Alberto; Segoloni, Giuseppe Paolo

    2004-09-01

    In the aging of Western populations, decreased mortality is counterbalanced by an increase in morbidity, particularly involving chronic diseases such as most renal diseases. The price of the successful care of chronic conditions, such as cardiovascular diseases or diabetes, is a continuous increase in new dialysis patients. However, the increased survival of patients on chronic renal replacement therapies poses new challenges to nephrologists and calls for new models of care. Since its split from internal medicine, nephrology has seen a progressive trend toward super specialization and the differentiation into at least 3 major branches (nephrology, dialysis, and transplantation), following a path common to several other fields of internal medicine. The success in the care of chronic patients is owed not only to a careful technical prescription, but also to the ability to teach self-care and attain compliance; this requires good medical practice and a sound patient-physician relationship. In this context, the usual models of care may fail to provide adequate coordination and, despite valuable single elements, could end up as an orchestra without a conductor. We propose an integrated model of care oriented to the type of patient (tested in our area especially for diabetic patients): the patient is followed-up by the same team from the first signs of renal disease to eventual dialysis or transplantation. This model offers an interesting alternative both for patients, who usually seek continuity of care, and for nephrologists who prefer a holistic and integrated patient-physician approach. PMID:15490421

  13. Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets.

    PubMed

    Giorgio, Valentina; Prono, Federica; Graziano, Francesca; Nobili, Valerio

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. NAFLD has emerged to be extremely prevalent, and predicted by obesity and male gender. It is defined by hepatic fat infiltration >5% hepatocytes, in the absence of other causes of liver pathology. It includes a spectrum of disease ranging from intrahepatic fat accumulation (steatosis) to various degrees of necrotic inflammation and fibrosis (non-alcoholic steatohepatatis [NASH]). NAFLD is associated, in children as in adults, with severe metabolic impairments, determining an increased risk of developing the metabolic syndrome. It can evolve to cirrhosis and hepatocellular carcinoma, with the consequent need for liver transplantation. Both genetic and environmental factors seem to be involved in the development and progression of the disease, but its physiopathology is not yet entirely clear. In view of this mounting epidemic phenomenon involving the youth, the study of NAFLD should be a priority for all health care systems. This review provides an overview of current and new clinical-histological concepts of pediatric NAFLD, going through possible implications into patho-physiolocical and therapeutic perspectives. PMID:23530957

  14. Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets

    PubMed Central

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. NAFLD has emerged to be extremely prevalent, and predicted by obesity and male gender. It is defined by hepatic fat infiltration >5% hepatocytes, in the absence of other causes of liver pathology. It includes a spectrum of disease ranging from intrahepatic fat accumulation (steatosis) to various degrees of necrotic inflammation and fibrosis (non-alcoholic steatohepatatis [NASH]). NAFLD is associated, in children as in adults, with severe metabolic impairments, determining an increased risk of developing the metabolic syndrome. It can evolve to cirrhosis and hepatocellular carcinoma, with the consequent need for liver transplantation. Both genetic and environmental factors seem to be involved in the development and progression of the disease, but its physiopathology is not yet entirely clear. In view of this mounting epidemic phenomenon involving the youth, the study of NAFLD should be a priority for all health care systems. This review provides an overview of current and new clinical-histological concepts of pediatric NAFLD, going through possible implications into patho-physiolocical and therapeutic perspectives. PMID:23530957

  15. Parkinson disease (PD) is a chronic, progressive neurodegenera-tive disorder that affects at least 1% of people by age 70 (13).

    E-print Network

    Hayar, Abdallah

    History Parkinson disease (PD) is a chronic, progressive neurodegenera- tive disorder that affects at least 1% of people by age 70 (1­3). James Parkinson provided the first detailed description to the development of motor complications including wearing-off (the Diagnosis and treatment of Parkinson disease

  16. Brown rust disease control in winter wheat: I. Exploring an approach for disease progression based on night weather conditions.

    PubMed

    El Jarroudi, Moussa; Kouadio, Louis; Delfosse, Philippe; Tychon, Bernard

    2014-04-01

    An empirical approach for simulating the infection and progress of leaf rust (caused by Puccinia triticina) during stem elongation on winter wheat was analysed for the 2000 to 2006 growing seasons. The approach was elaborated based on night weather conditions (i.e., air temperature, relative humidity and rainfall) and leaf rust occurrences. Data from three consecutive cropping seasons (2000-2002) at four representative sites of the Grand-Duchy of Luxembourg were used in the set-up phase. The capability to correctly simulate the occurrence expression of P. triticina infections on the upper leaf layers was then assessed over the 2003-2006 period. Our study revealed that the development of leaf rust required a period of at least 12 consecutive hours with air temperatures ranging between 8 and 16 °C, a relative humidity greater than 60 % (optimal values being 12-16 °C and up to 80 % for air temperatures and relative humidity, respectively) and rainfall less than 1 mm. Moreover, leaf rust occurrences and infections were satisfactorily simulated. The false alarm ratio was ranged from 0.06 to 0.20 in all the study sites. The probability of detection and critical success index for WLR infection were also close to 1 (perfect score). PMID:24374621

  17. The dual roles of immunity in ALS: injury overrides protection.

    PubMed

    Murdock, Benjamin J; Bender, Diane E; Segal, Benjamin M; Feldman, Eva L

    2015-05-01

    Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease affecting motor neurons. Disease progression is accompanied by a multi-phased immune response, and recent studies indicate that the immune system is not simply a bystander during disease, but plays an active role in shaping ALS pathology. The role of the immune system during ALS progression is highly complex, however, as it has been found to have a role in both enhancing neurodegeneration as well as protecting the central nervous system. Previous reports have established that the immune response can therefore be separated into two distinct phases: a protective Type 2 response followed by a neurotoxic Type 1 response. This review will address the two phases of the immune response in ALS and describe their roles during disease progression. More importantly, it will also examine the likely sources of immune polarization that are responsible for shifting immunity from the protective T2 phase to the neurotoxic T1 phase. PMID:25726748

  18. The Effect of Disease Modifying Therapies on Disease Progression in Patients with Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis

    PubMed Central

    Tsivgoulis, Georgios; Katsanos, Aristeidis H.; Grigoriadis, Nikolaos; Hadjigeorgiou, Georgios M.; Heliopoulos, Ioannis; Papathanasopoulos, Panagiotis; Kilidireas, Constantinos; Voumvourakis, Konstantinos; Dardiotis, Efthimios

    2015-01-01

    Importance A number of officially approved disease-modifying drugs (DMD) are currently available for the early intervention in patients with relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to systematically evaluate the effect of DMDs on disability progression in RRMS Methods We performed a systematic review on MEDLINE and SCOPUS databases to include all available placebo-controlled randomized clinical trials (RCTs) of RRMS patients that reported absolute numbers or percentages of disability progression during each study period. Observational studies, case series, case reports, RCTs without placebo subgroups and studies reporting the use of RRMS therapies that are not still officially approved were excluded. Risk ratios (RRs) were calculated in each study protocol to express the comparison of disability progression in RRMS patients treated with a DMD and those RRMS patients receiving placebo. The mixed-effects model was used to calculate both the pooled point estimate in each subgroup and the overall estimates. Results DMDs for RRMS were found to have a significantly lower risk of disability progression compared to placebo (RR = 0.72, 95%CI: 0.66–0.79; p<0.001), with no evidence of heterogeneity or publication bias. In subsequent subgroup analyses, neither dichotomization of DMDs as “first” and “second” line RRMS therapies [(RR = 0.72, 95% CI = 0.65–0.80) vs. (RR = 0.72, 95% = 0.57–0.91); p = 0.96] nor the route of administration (injectable or oral) [RR = 0.75 (95% CI = 0.64–0.87) vs. RR = 0.74 (95% CI = 0.66–0.83); p = 0.92] had a differential effect on the risk of disability progression. Either considerable (5–20%) or significant (>20%) rates of loss to follow-up were reported in many study protocols, while financial and/or other support from pharmaceutical industries with a clear conflict of interest on the study outcomes was documented in all included studies. Conclusions Available DMD are effective in reducing disability progression in patients with RRMS, independently of the route of administration and their classification as “first” or “second” line therapies. Attrition bias needs to be taken into account in the interpretation of these findings. PMID:26642051

  19. Chiral cyclohexane 1,3-diones as inhibitors of mutant SOD1-dependent protein aggregation for the treatment of ALS

    E-print Network

    Morimoto, Richard

    or no effect on life extension in the G93A SOD1 mouse model for amyotrophic lateral sclerosis (ALS). Additional Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disease characterized by progressive

  20. Hippocampal Glutamate NMDA Receptor Loss Tracks Progression in Alzheimer’s Disease: Quantitative Autoradiography in Postmortem Human Brain

    PubMed Central

    Kravitz, Efrat; Gaisler-Salomon, Inna; Biegon, Anat

    2013-01-01

    Early Alzheimer's disease (AD) is characterized by memory loss and hippocampal atrophy with relative sparing of basal ganglia. Activation of glutamate NMDA receptors in the hippocampus is an important step in memory formation. We measured the density of NMDA receptors in samples of hippocampus, entorhinal cortex and basal ganglia obtained from subjects who died with pathologically confirmed AD and age- and sex- matched non-demented controls. We found significant decreases in NMDA receptor density in the hippocampus and entorhinal cortex but not in the basal ganglia. Loss of NMDA receptors was significantly correlated with neuropathological progression as assessed by Braak staging postmortem. The same samples were probed for neuroinflammation by measuring the density and gene expression of translocator protein 18kDA (TSPO), an established marker of microglial activation. Unlike NMDA receptor loss, increased densities of TSPO were found in all of the brain regions sampled. However hippocampal, but not striatal TSPO density and gene expression were inversely correlated with NMDA receptor density and positively correlated with Braak stage, suggesting NMDA receptors exacerbate neuroniflammatory damage. The high correlation between hippocampal NMDA receptor loss and disease progression supports the use of non invasive imaging with NMDA receptor tracers and positron emission tomography as a superior method for diagnosis, staging and treatment monitoring of AD in vivo. PMID:24312282

  1. Influence of fibrinogen and C-RP on progression of peripheral arterial disease in type 2 diabetes: a preliminary report

    PubMed Central

    2013-01-01

    Background Limited studies have suggested that inflammatory biomarkers play a role in the initiation and progression of atherosclerosis in diabetic patients. This study assesses the effect of inflammatory biomarkers: fibrinogen and C-reactive protein (C-RP) on the progression of peripheral arterial disease (PAD) in type 2 diabetic (T2D) patients. Methods Sixty two patients with T2D and PAD (mean age 60.28?±?27 years and diabetes duration of 8.58?±?6.17 years) were enrolled in a cohort prospective study of 36 months. Ankle-brachial index (ABI) was measured in all patients at baseline and after 36 months. Multiple linear regression analysis was used to determine the predictivity of variables for fibrinogen, C-RP, plasma lipid fractions, fasting plasma glucose, Body Mass Index (BMI), duration of diabetes status and the age on changes in ABI value. Results Linear regression analysis defined F as a predictor for endpoint value of ABI (??=?0.469, p?=?0.007). Value of C-RP determinates change of minimal value of ABI (??=?0.449, p?=?0.037) and change of mean ABI per year (??=?0.442, p?=?0.025). Conclusion Our data indicate that plasma determination of fibrinogen and C-RP might have a clinical implication in defining the process of progression of PAD in T2D population. PMID:23375154

  2. Evidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer`s disease but is not causative

    SciTech Connect

    Bennett, C.; Crawford, F.; Osborne, A.; Diaz, P.

    1995-02-27

    An association has been observed in several independent data sets between late onset Alzheimer`s Disease (AD) and the APOE locus on chromosome 19. We have examined the genotype in family history positive (FHP) and family history negative (FHN) cases and find a distortion of the APOE allele frequencies in accord with previous studies. However, when we examined the allele distribution of the at-risk siblings of the FHP group we found an excess of the {epsilon}4 allele which also differs significantly from historic controls but not from the affected siblings. The age distribution of the affected and unaffected siblings was similar, suggesting that the allelic frequency distortion in the unaffected siblings was not due to their being below the mean age of onset. Lod score linkage analysis, with age dependent onset and non-stringent specification of the genetic parameters, did not suggest linkage to the APOE locus. Furthermore, an analysis of variance of the age of disease free survival suggested that APOE genotype contributes a small fraction of the total variance indicating that the APOE locus is a poor predictor of disease free survival age within late onset families. One explanation for the age dependent association reported by other groups, and our results, is that the APOE locus enhances the rate of progression of the disease process in otherwise predisposed individuals and that variation at this locus is not able in and of itself to cause the disease. We suggest this hypothesis is compatible with the current literature regarding APOE and AD. 19 refs., 1 fig., 2 tabs.

  3. Disease progression in iridocorneal angle tissues of BMP2-induced ocular hypertensive mice with optical coherence tomography

    PubMed Central

    Li, Guorong; Farsiu, Sina; Qiu, Jianming; Dixon, Angela; Song, Chunwei; McKinnon, Stuart J.; Yuan, Fan; Gonzalez, Pedro

    2014-01-01

    Purpose The goal of the present study was to test for the first time whether glaucomatous-like disease progression in a mouse can be assessed morphologically and functionally with spectral domain optical coherence tomography (SD-OCT). Methods We monitored progressive changes in conventional outflow tissues of living mice overexpressing human bone morphogenetic protein 2 (BMP2), a model for glaucoma. Intraocular pressure (IOP) and outflow tissue morphology/Young's modulus were followed in mice for 36 days with rebound tonometry and SD-OCT, respectively. Results were compared to standard histological methods. Outflow facility was calculated from flow measurements with direct cannulation of anterior chambers subjected to three sequential pressure steps. Results Overexpression of BMP2 significantly elevated IOP in a biphasic manner over time compared to mice that overexpressed green fluorescent protein in outflow cells and naïve controls. SD-OCT revealed changes in outflow tissues overexpressing BMP2 that corresponded with the timing of the IOP phases and decreased outflow facility. In the first phase, the angle was open, but the trabecular meshwork and the cornea were thickened. OCT detected increased trabecular meshwork stiffness after provocative IOP challenges of the BMP2 eyes, which corresponded to increased collagen deposition with transmission electron microscopy. In contrast, the angle was closed in the second phase. IOP elevation over 36 days due to BMP2 overexpression resulted in significant retinal ganglion cell and axon loss. Conclusions Although not a feasible open-angle glaucoma model, the BMP2 mice were useful for demonstrating the utility of SD-OCT in following disease progression and differentiating between two forms of ocular pathology over time that resulted in ocular hypertension. PMID:25558173

  4. Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients.

    PubMed

    Lucas, C M; Harris, R J; Holcroft, A K; Scott, L J; Carmell, N; McDonald, E; Polydoros, F; Clark, R E

    2015-07-01

    High cancerous inhibitor of PP2A (CIP2A) protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib-treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A; these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive feedback loop, which imatinib cannot overcome. PMID:25765543

  5. The SDREM Method for Reconstructing Signaling and Regulatory Response Networks: Applications for Studying Disease Progression.

    PubMed

    Gitter, Anthony; Bar-Joseph, Ziv

    2016-01-01

    The Signaling and Dynamic Regulatory Events Miner (SDREM) is a powerful computational approach for identifying which signaling pathways and transcription factors control the temporal cellular response to a stimulus. SDREM builds end-to-end response models by combining condition-independent protein-protein interactions and transcription factor binding data with two types of condition-specific data: source proteins that detect the stimulus and changes in gene expression over time. Here we describe how to apply SDREM to study human diseases, using epidermal growth factor (EGF) response impacting neurogenesis and Alzheimer's disease as an example. PMID:26235087

  6. Influence of gut bacteria on development and progression of non-alcoholic fatty liver disease

    PubMed Central

    Abdul-Hai, Ali; Abdallah, Ali; Malnick, Stephen DH

    2015-01-01

    The intestine of the human contains a dynamic population of microbes that have a symbiotic relationship with the host. In addition, there is an effect of the intestinal microbiota on metabolism and digestion. Non-alcoholic fatty liver disease (NAFLD) is a common cause worldwide of hepatic pathology and is thought to be the hepatic manifestation of the metabolic syndrome. In this review we examine the effect of the human microbiome on the components and pathogenesis of the metabolic syndrome. We are now on the threshold of therapeutic interventions on the human microbiome in order to effect human disease including NAFLD. PMID:26140087

  7. Biomarkers of rapid chronic kidney disease progression in type 2 diabetes

    E-print Network

    Looker, Helen C.; Colombo, Marco; Hess, Sibylle; Brosnan, Mary J.; Farran, Bassam; Dalton, R. Neil; Wong, Max C.; Turner, Charles; Palmer, Colin N. A.; Nogoceke, Everson; Groop, Leif; Salomaa, Veikko; Dunger, David B.; Agakov, Felix; McKeigue, Paul M.; Colhoun, Helen M.

    2015-07-22

    ;102:193-202. 9. Gore MO, Luneburg N, Schwedhelm E, et al. Symmetrical dimethylarginine predicts mortality in the general population: observations from the Dallas heart study. Arterioscler Thromb Vasc Biol. 2013;33:2682-8. 10. Richard S, Morel M, Cleroux P...

  8. Lung disease associated with progressive systemic sclerosis. Assessment of interlobar variation by bronchoalveolar lavage and comparison with noninvasive evaluation of disease activity

    SciTech Connect

    Miller, K.S.; Smith, E.A.; Kinsella, M.; Schabel, S.I.; Silver, R.M. )

    1990-02-01

    Progressive systemic sclerosis (PSS), or scleroderma, is a disease of unknown etiology that involves many organ systems, including the lungs. The interstitial lung disease of systemic sclerosis is becoming an increasing cause of morbidity and mortality. This process has been previously evaluated with single-site bronchoalveolar lavage (BAL), gallium scanning, pulmonary function testing, and, occasionally, by open lung biopsy. As BAL has been shown to correlate well with open lung biopsy in systemic sclerosis, we sought to determine if single-site BAL accurately reflects alveolitis in a second site in the lung, and if BAL results correlate with other noninvasive tests of lung inflammation: gallium uptake, chest radiography, or arterial blood gas analysis. We performed 17 studies in 13 patients with scleroderma and found no significant lobar differences in lavage results or gallium scanning. By our criteria for normal versus active alveolitis, only two of 17 patient lavages would have been classified as normal by one side and abnormal by the other side. Although percent gallium uptake was equal bilaterally and supported the concept of alveolitis uniformity, gallium uptake intensity did not correlate with activity as measured by BAL. Furthermore, chest radiograph and arterial blood gas analysis did not correlate with BAL results or gallium scanning. We believe these data support the suitability of single-site lavage in the investigation of systemic-sclerosis-associated alveolitis and diminish the importance of gallium scanning in the investigation of systemic sclerosis pulmonary disease.

  9. EMBO workshop al fin del mundo: a meeting on membrane trafficking and its implication for polarity and diseases.

    PubMed

    Marzolo, María-Paz; Faundez, Victor; Galli, Thierry

    2015-07-01

    The EMBO worskhop at the "end of the world'" (al fin del mundo), a meeting on membrane trafficking and its implication for polarity and diseases, took place in the Chilean Patagonia surrounded by the landscapes once witnessed by Charles Darwin. The meeting showcased some of the best membrane trafficking science with an emphasis in neuroscience and disease models. Speakers from Europe, USA, South America and the graduate students behind it; embarked on an enthusiastic and eclectic dialog where a wide range of cell types, model genetic systems, and diseases where discussed. This meeting demonstrated the power of trafficking concepts to integrate diverse biology and to formulate mechanisms of normal and disease cells. PMID:26133153

  10. Letter to the Editor Underestimation of Disease Progress Rates with the Logistic, Monomolecular, and Gompertz Models

    E-print Network

    Neher, Deborah A.

    thank I. Chet, R. Cohen, S. Freeman, C. M. Kenerley, D. 0. Koch, L. V. Madden, A. F. Nash, B. D. Nelson were calculated Madden (4, p. 204) is that there is a constant host area to be as r. = p (2m + 2)/K, and Gompertz Models When Maximum Disease Intensity is Less Than 100 Percent Deborah A. Neher and C. Lee

  11. Framing Progress In Global Tobacco Control To Inform Action On Noncommunicable Diseases.

    PubMed

    Wipfli, Heather L; Samet, Jonathan

    2015-09-01

    Much has been learned about the tobacco epidemic, including its consequences, effective measures to control it, and the actors involved. This article identifies lessons learned that are applicable to the other principal external causes of noncommunicable diseases: alcohol abuse, poor nutrition, and physical inactivity. Among these lessons are the development of evidence-based strategies such as proven cessation methods, tax increases, and smoke-free policies; the role of multinational corporations in maintaining markets and undermining control measures; and the need for strategies that reach across the life course and that begin with individuals and extend to higher levels of societal organization. Differences are also clear. Tobacco products are relatively homogeneous and have no direct benefit to consumers, whereas food and alcohol consumed in moderation are not inherently dangerous. Some tobacco-related diseases have the singular predominant cause of smoking, while many noncommunicable diseases have multiple interlocking causes such as poor diet, excess alcohol consumption, insufficient physical activity, and smoking, along with genetics. Thus, the tobacco control model of comprehensive multilevel strategies is applicable to the control of noncommunicable diseases, but the focus must be on multiple risk factors. PMID:26355049

  12. Progress in Brassicaceae seed meal formulation and application for replant disease control in organic apple orchards

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Brassicaceae seed meals when used independently do not provide uniform or sufficient control of the pathogen complex that incites apple replant disease. Trials were established at multiple sites (STM, SR and Tukey orchards) in Washington State to evaluate the efficacy of seed meal formulations for ...

  13. Recent progress in the study of occupational lung diseases in Romania.

    PubMed Central

    Barhad, B; Pilat, L; Teculescu, D

    1975-01-01

    This paper reviews studies of occupational lung diseases in Romania in the last two decades. Work concerned with the effects of exposure to textile fibres, irritant gases and fumes in the chemical industry, welding fumes, asbestos, cadmium oxide, and the relation between dust exposure, pneumoconiosis, and chronic bronchitis is briefly presented. PMID:1093564

  14. Inconsequential effect of nutritional treatments on Huanglongbing control, fruit quality, bacterial titer and disease progress

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of an enhanced nutritional programs (ENPs) to minimize the deleterious effects of the vector transmitted bacterial disease, citrus huanglongbing (HLB) caused by Candidatus Liberibacter asiaticus (Las), has been a topic of considerable discussion and debate since the discovery of HLB in Flori...

  15. Renal Expression of FGF23 in Progressive Renal Disease of Diabetes and the Effect of Ace Inhibitor

    PubMed Central

    Benigni, Ariela; Corna, Daniela; Tomasoni, Susanna; Rottoli, Daniela; Gaspari, Flavio; Remuzzi, Giuseppe; Zoja, Carlamaria

    2013-01-01

    Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone mainly produced by bone that acts in the kidney through FGF receptors and Klotho. Here we investigated whether the kidney was an additional source of FGF23 during renal disease using a model of type 2 diabetic nephropathy. Renal expression of FGF23 and Klotho was assessed in Zucker diabetic fatty (ZDF) and control lean rats at 2, 4, 6, 8 months of age. To evaluate whether the renoprotective effect of angiotensin converting enzyme (ACE) inhibitor in this model was associated with changes in FGF23 and Klotho, ZDF rats received ramipril from 4, when proteinuric, to 8 months of age. FGF23 mRNA was not detectable in the kidney of lean rats, nor of ZDF rats at 2 months of age. FGF23 became measurable in the kidney of diabetic rats at 4 months and significantly increased thereafter. FGF23 protein localized in proximal and distal tubules. Renal Klotho mRNA and protein decreased during time in ZDF rats. As renal disease progressed, serum phosphate levels increased in parallel with decline of fractional phosphorus excretion. Ramipril limited proteinuria and renal injury, attenuated renal FGF23 upregulation and ameliorated Klotho expression. Ramipril normalized serum phosphate levels and tended to increase fractional phosphorus excretion. These data indicate that during progressive renal disease the kidney is a site of FGF23 production which is limited by ACE inhibition. Interfering pharmacologically with the delicate balance of FGF23 and phosphorus in diabetes may have implications in clinics. PMID:23967103

  16. Sustained Response and Prevention of Damage Progression in Patients With Neonatal-Onset Multisystem Inflammatory Disease Treated With Anakinra

    PubMed Central

    Sibley, Cailin H.; Plass, Nikki; Snow, Joseph; Wiggs, Edythe A.; Brewer, Carmen C.; King, Kelly A.; Zalewski, Christopher; Kim, H. Jeffrey; Bishop, Rachel; Hill, Suvimol; Paul, Scott M.; Kicker, Patrick; Phillips, Zachary; Dolan, Joseph G.; Widemann, Brigitte; Jayaprakash, Nalini; Pucino, Frank; Stone, Deborah L.; Chapelle, Dawn; Snyder, Christopher; Butman, John A.; Wesley, Robert; Goldbach-Mansky, Raphaela

    2012-01-01

    Objective Blocking interleukin-1 with anakinra in patients with the autoinflammatory syndrome neonatal-onset multisystem inflammatory disease (NOMID) reduces systemic and organ-specific inflammation. However, the impact of long-term treatment has not been established. This study was undertaken to evaluate the long-term effect of anakinra on clinical and laboratory outcomes and safety in patients with NOMID. Methods We conducted a cohort study of 26 NOMID patients ages 0.80–42.17 years who were followed up at the NIH and treated with anakinra 1–5 mg/kg/day for at least 36 months. Disease activity was assessed using daily diaries, questionnaires, and C-reactive protein level. Central nervous system (CNS) inflammation, hearing, vision, and safety were evaluated. Results Sustained improvements in diary scores, parent’s/patient’s and physician’s global scores of disease activity, parent’s/patient’s pain scores, and inflammatory markers were observed (all P < 0.001 at 36 and 60 months). At 36 and 60 months, CNS inflammation was suppressed, with decreased cerebrospinal fluid white blood cell counts (P = 0.0026 and P = 0.0076, respectively), albumin levels, and opening pressures (P = 0.0012 and P < 0.001, respectively). Most patients showed stable or improved hearing. Cochlear enhancement on magnetic resonance imaging correlated with continued hearing loss. Visual acuity and peripheral vision were stable. Low optic nerve size correlated with poor visual field. Bony lesions progressed. Adverse events other than viral infections were rare, and all patients continued to receive the medication. Conclusion These findings indicate that anakinra provides sustained efficacy in the treatment of NOMID for up to 5 years, with the requirement of dose escalation. Damage progression in the CNS, ear, and eye, but not bone, is preventable. Anakinra is well tolerated overall. PMID:22294344

  17. Comparison of two progressive treadmill tests in patients with peripheral arterial disease.

    PubMed

    Riebe, D; Patterson, R B; Braun, C M

    2001-11-01

    In a vascular rehabilitation program, 28% of our frail elderly patients are unable to be tested with traditional progressive exercise protocols at program entry due to the high (2.0 miles/h or 3.2 km/h) initial treadmill speeds. The purpose of this investigation was to compare a new progressive treadmill protocol which has a reduced initial speed (1.0 mile/h or 1.6 km/h) to an established protocol performed at 2.0 miles/h (3.2 km/h) to determine the comparability and reproducibility of the new protocol. Eleven patients with arterial claudication performed three symptom-limited exercise tests in random order. Two tests used the new protocol while the remaining trial used the established protocol. Claudication pain was measured using a 5-point scale. Oxygen consumption, heart rate, minute ventilation, respiratory exchange ratio and blood pressure at peak exercise were similar among the three trials. There were strong intraclass correlations for peak oxygen consumption (r = 0.97), onset of claudication (r = 0.96) and maximum walking time (r = 0.98) between the two trials using the new protocol. There was also a significant correlation between the new protocol and the established protocol for peak oxygen consumption (r = 0.90) and maximum walking time (r = 0.89). The new progressive treadmill protocol represents a valid, reliable protocol for patients with arterial claudication. This protocol may be useful for testing patients with a low functional capacity so that clinically appropriate exercise prescriptions can be established and the efficacy of treatments can be determined. PMID:11958386

  18. Progress in pediatrics in 2011. Choices in endocrinology, gastroenterology, hemato-oncology, infectious diseases, otolaryngology, pharmacotherapy and respiratory tract illnesses

    PubMed Central

    2012-01-01

    Main progresses in endocrinology, gastroenterology, hemato-oncology, infectious diseases, otolaryngology, pharmacotherapy, and respiratory tract illnesses selected from articles published in The Italian Journal of Pediatrics in 2011 were reviewed. Risk factors for gastroenteritis and appendicitis in developing countries may be useful in improving our understanding of these diseases. Childhood hearing impairment is a world-wide problem which continues to have an high prevalence in newborns. Among the mechanisms of diseases, obese children often have asthma and high hepcidin levels that may reduce serum iron concentrations. In cystic fibrosis, 18q distal deletion has been described as a novel mutation. Hypothyroidism in children with central nervous system infections may increase mortality rates. Infrared tympanic thermometer (IRTT) in oral mode for the measurement of body temperature may be useful in fever screening in a busy setup. In newborns, the transmission of CMV infection through breast milk may be prevented through freezing or pasteurization. Recent advances in treatment of constipation, urinary tract infections, leukemia, pain in children with cancer, neonates with sepsis or difficult weaning from mechanical ventilation will likely contribute towards optimizing management of these common disorders. The work of the Family Pediatricians Medicines for Children Research Network aims to develop competence, infrastructure, networking and education for pediatric clinical trials. PMID:22682313

  19. Slow Progression of Cognitive Dysfunction of Alzheimer's Disease in Sexagenarian Women with Schizophrenia

    PubMed Central

    Sakai, Kazuo; Oda, Haruhiko; Terashima, Akira; Ishii, Kazunari; Maeda, Kiyoshi

    2015-01-01

    Although both schizophrenia (SCZ) and Alzheimer's disease (AD) are among the most common psychiatric diseases, the interaction of these two is not well-understood. We investigated three women with SCZ who developed AD in their 60s. The patients presented with cognitive dysfunction such as loss of recent memory, which was confirmed by both clinical observations and neuropsychological tests. Their magnetic resonance and functional imaging findings were consistent with AD. Their brain atrophy advanced significantly during a 6-year observation period. However, their global cognitive function did not deteriorate significantly during this period. Although the cognitive reserve model might account for this discrepancy, our results suggest some interactions between the neuropathology of SCZ and AD and warrant further research. PMID:26246928

  20. Progression of the load of waterborne and intestinal parasitic diseases in the State of Amazonas.

    PubMed

    Martins, Marilaine; Lacerda, Marcus Vinícius Guimarães; Monteiro, Wuelton Marcelo; Moura, Marco Antonio Saboia; Santos, Eyde Cristianne Saraiva; Saraceni, Valéria; Saraiva, Maria Graças Gomes

    2015-01-01

    In the State of Amazonas, Brazil, urban expansion together with precarious basic sanitation conditions and human settlement on river banks has contributed to the persistence of waterborne and intestinal parasitic diseases. Time series of the recorded cases of cholera, typhoid fever, hepatitis A and leptospirosis are described, using data from different levels of the surveillance systems. The sources for intestinal parasitosis prevalence data (non-compulsory reporting in Brazil) were Medical Literature Analysis and Retrieval System Online (MEDLINE), Literatura Latino-Americana (LILACS) and the annals of major scientific meetings. Relevant papers and abstracts in all languages were accessed by two independent reviewers. The references cited by each relevant paper were scrutinized to locate additional papers. Despite its initial dissemination across the entire State of Amazonas, cholera was controlled in 1998. The magnitude of typhoid fever has decreased; however, a pattern characterized by eventual outbreaks still remains. Leptospirosis is an increasing cause of concern in association with the annual floods. The overall prevalence of intestinal parasites is high regardless of the municipality and the characteristics of areas and populations. The incidence of hepatitis A has decreased over the past decade. A comparison of older and recent surveys shows that the prevalence of intestinal parasitic diseases has remained constant. The load of waterborne and intestinal parasitic diseases ranks high among the health problems present in the State of Amazonas. Interventions aiming at basic sanitation and vaccination for hepatitis A were formulated and implemented, but assessment of their effectiveness in the targeted populations is still needed. PMID:26061370

  1. A Novel Acute Retroviral Syndrome Severity Score Predicts the Key Surrogate Markers for HIV-1 Disease Progression

    PubMed Central

    Braun, Dominique L.; Kouyos, Roger; Oberle, Corinna; Grube, Christina; Joos, Beda; Fellay, Jacques; McLaren, Paul J.; Kuster, Herbert; Günthard, Huldrych F.

    2014-01-01

    Objective: Best long-term practice in primary HIV-1 infection (PHI) remains unknown for the individual. A risk-based scoring system associated with surrogate markers of HIV-1 disease progression could be helpful to stratify patients with PHI at highest risk for HIV-1 disease progression. Methods: We prospectively enrolled 290 individuals with well-documented PHI in the Zurich Primary HIV-1 Infection Study, an open-label, non-randomized, observational, single-center study. Patients could choose to undergo early antiretroviral treatment (eART) and stop it after one year of undetectable viremia, to go on with treatment indefinitely, or to defer treatment. For each patient we calculated an a priori defined “Acute Retroviral Syndrome Severity Score” (ARSSS), consisting of clinical and basic laboratory variables, ranging from zero to ten points. We used linear regression models to assess the association between ARSSS and log baseline viral load (VL), baseline CD4+ cell count, and log viral setpoint (sVL) (i.e. VL measured ?90 days after infection or treatment interruption). Results Mean ARSSS was 2.89. CD4+ cell count at baseline was negatively correlated with ARSSS (p?=?0.03, n?=?289), whereas HIV-RNA levels at baseline showed a strong positive correlation with ARSSS (p<0.001, n?=?290). In the regression models, a 1-point increase in the score corresponded to a 0.10 log increase in baseline VL and a CD4+cell count decline of 12/µl, respectively. In patients with PHI and not undergoing eART, higher ARSSS were significantly associated with higher sVL (p?=?0.029, n?=?64). In contrast, in patients undergoing eART with subsequent structured treatment interruption, no correlation was found between sVL and ARSSS (p?=?0.28, n?=?40). Conclusion The ARSSS is a simple clinical score that correlates with the best-validated surrogate markers of HIV-1 disease progression. In regions where ART is not universally available and eART is not standard this score may help identifying patients who will profit the most from early antiretroviral therapy. PMID:25490090

  2. Recent progress of 220-280 nm-band AlGaN based deep-UV LEDs

    NASA Astrophysics Data System (ADS)

    Hirayama, Hideki

    2010-02-01

    We demonstrated 222-282 nm AlGaN-based efficient deep-ultraviolet (DUV) light-emitting diodes (LEDs) fabricated on low threading dislocation density (TDD) AlN template. Low TDD AlN on sapphire were realized by using ammonia (NH3) pulse-flow multilayer (ML) growth technique. We obtained quite high IQE (~80%) from slightly-Inincorporated (0.3%) InAlGaN QWs and obtained over 10 mW CW output power for 280 nm-band InAlGaN based LED. The maximum output power obtained were over 10 mW for 264-282 nm LEDs, 1.2-5mW for 240-256 nm LEDs and sub-milliwatt for 222-237 nm LEDs. The maximum external quantum efficiency (EQE) of 280 nm-band LED was 1.2%.

  3. Association between Hemoglobin Concentration and the Progression or Development of Albuminuria in Diabetic Kidney Disease

    PubMed Central

    Okada, Hiroshi; Hasegawa, Goji; Tanaka, Muhei; Osaka, Takafumi; Shiotsu, Yayoi; Narumiya, Hiromichi; Inoue, Mamoru; Nakano, Koji; Nakamura, Naoto; Fukui, Michiaki

    2015-01-01

    Aims Anemia, which might contribute to pathogenesis of kidney dysfunction, is a common finding in patients with type 2 diabetes. The aim of this study was to investigate if hemoglobin concentration is associated with the degree of change in urinary albumin-creatinine ratio or the development of albuminuria in patients with type 2 diabetes. Methods We measured hemoglobin concentration in 470 (296 men and 174 women) consecutive type 2 diabetic patients without albuminuria. We performed a follow-up study to assess the progression or development of albuminuria, the interval of which was 3.0 years. Then we evaluated relationships between hemoglobin concentration and albuminuria, using multivariate linear regression analyses and logistic regression analyses. Results Eighty four patients developed albuminuria during follow-up duration. In multivariate analyses, hemoglobin concentration was negatively associated with a change in urinary albumin-creatinine ratio in men (ß = -0.259, P = 0.0002) and women (ß = -0.194, P = 0.030). Moreover, multivariate adjusted odds ratio associated with 1 g/L in hemoglobin for the development of albuminuria was 0.93 (95% confidence interval; 0.89-0.96) in men and 0.94 (95% confidence interval; 0.88-0.99) in women, respectively. And, multivariate analyses revealed that adjusted odds ratios for the development of albuminuria were 4.78 (95% confidence interval; 1.65-13.91) in men and 4.62 (95% confidence interval; 1.34-16.68) in women with anemia (hemoglobin < 130 g/L for men and < 120 g/L for women), which were higher than those without anemia. Conclusions Low hemoglobin concentration could be a predictor for the progression and development of albuminuria in patients with type 2 diabetes. PMID:26023923

  4. Retarding the progression of chronic kidney disease with renin angiotensin system blockade.

    PubMed

    Limesh, M; Annigeri, R A; Mani, M K; Kowdle, P C; Rao, B Subba; Balasubramanian, S; Seshadri, R

    2012-03-01

    We assessed the effect of renin angiotensin system blockade (RASB) in chronic kidney disease (CKD) of diverse etiology. Two hundred and sixty-five consecutive CKD patients attending our renal clinic, with estimated glomerular filtration rate (eGFR) of 20-70 ml/min/1.73m(2) at baseline and a minimal follow-up of 1 year, were studied retrospectively. We devised a scoring system to quantify RASB, wherein the maximum dose of an agent recommended for control of hypertension was scored as 1. The renal endpoints studied were the rate of change in eGFR (?eGFR) and decline of eGFR>50%. The mean age was 48 ± 11.2 years and 69% were male. The mean duration of follow-up was 4 ± 2.7 years. The rate of ?eGFR was -1.5 ± 5.0 ml/min/1.73 m(2) per year in patients who received RASB (N=168) and -6.0 ± 5.4 in those who did not (N=97) (P<0.001). The incidence of decline of eGFR >50% was 11.3% with RASB and 24.7% without (P=0.003). In a subgroup of patients who received RASB, the incidence of decline of eGFR >50% was 17.8% in the low-dose RASB group (N=84, RASB score 0.63 ± 0.38) and 4.8% in the high-dose group (N=84, RASB score 2.5 ± 0.7) (P=0.001). RASB was associated with significantly better renoprotection in CKD of diverse etiology, even in nonproteinuric diseases. This effect appeared to be dose-dependent, with higher supramaximal doses exhibiting better renoprotection than the lower conventional doses. Our results make a strong case for use of aggressive RASB in all CKD patients to postpone end-stage renal disease. PMID:22787312

  5. Grapevine rootstock effects on scion sap phenolic levels, resistance to Xylella fastidiosa infection, and progression of Pierce's disease.

    PubMed

    Wallis, Christopher M; Wallingford, Anna K; Chen, Jianchi

    2013-01-01

    The xylem-limited bacterium Xylella fastidiosa (Xf) causes Pierce's disease (PD), an important disease of grapevine, Vitis vinifera L. Grapevine rootstocks were developed to provide increased resistance to root disease, but rootstock effects on cane and vine diseases remain unclear. Grapevines that consisted of Cabernet Sauvignon or Chardonnay grafted to 13 different rootstocks were inoculated with Xf and evaluated for PD severity and Xf titer after 6 months. A subset of six rootstock/scion combinations had xylem sap phenolic levels assessed in non-infected and Xf-infected grapevines. Vigor also was analyzed by measuring root lengths and masses. Cabernet Sauvignon grafted to 101-14MG, 1103P, 420A, or Schwarzmann had reduced PD severity compared to Cabernet Sauvignon grafted to 110R, 5BB, or SO4. Chardonnay grafted to Salt Creek or Freedom had reduced PD severity compared to Chardonnay grafted to RS3 or Schwarzmann. Chardonnay grafted to RS3 had greater Xf titer than Chardonnay grafted to 101-14MG, Freedom, or Salt Creek. No other differences in Xf titer among rootstocks were observed. Of the six scion/rootstock combinations which had xylem sap phenolics analyzed, Chardonnay/RS3 had the highest levels of most phenolics whereas Cabernet Sauvignon/101-14MG had the lowest phenolic levels. However, Chardonnay/101-14MG, which had mild PD symptoms, had greater sap levels of caftaric acid than other scion/rootstock combinations. Sap levels of caftaric acid, methyl salicylate, a procyanidin trimer, and quinic acid were greater in Xf-infected vs. non-infected grapevines. Chardonnay on 101-14MG or Salt Creek had greater root mass than Chardonnay on RS3. Cabernet Sauvignon on 101-14MG had greater root mass than Cabernet Sauvignon on 110R. These results identified rootstocks with the capacity for reducing PD symptom progression. Rootstocks also were shown to affect Xf titer, xylem sap phenolic levels, and plant vigor. PMID:24376452

  6. T cell populations in the pancreatic lymph node naturally and consistently expand and contract in NOD mice as disease progresses

    PubMed Central

    Marrero, Idania; Vong, Allen; Dai, Yang; Davies, Joanna D.

    2013-01-01

    Nonobese diabetic (NOD) mice develop spontaneous autoimmune Type 1 diabetes (T1D) that results from the destruction of insulin secreting ? cells by diabetogenic T cells. The activation of autoreactive T cells occurs in the pancreatic lymph nodes (PLN) from where effector T cells migrate to the pancreas. This study was designed to explore whether T cell populations in the NOD PLN expand in a predictable and reproducible way during disease progression. Complementary determining region (CDR) 3 length spectratype analysis of 19 TCR V? families was used to identify the relative frequency of T populations in PLN of 4 and 10 week old NOD mice and mice at T1D onset. Significant and highly reproducible changes in specific T cell populations were detected in 14 of V? families tested at all stages of disease. However, of these, the CDR3 spectratype of only four V? families was significantly more perturbed at T1D onset than in 10 week old mice. Intriguingly, when diabetes was induced in 10 week old mice with cyclophosphamide (CYP) the same four V? families, V?5.1, V?9, V?10, and V?15, were again significantly more perturbed than in the untreated non-diabetic age matched mice. Taken together the data show that while T cell responses in PLN of NOD mice are heterogeneous, they are ordered and consistent throughout disease development. The finding that within this heterogeneous response four V? families are significantly more perturbed in diabetic mice, whether spontaneous or induced, strongly suggests their selection as part of the disease process. PMID:22580347

  7. Grapevine rootstock effects on scion sap phenolic levels, resistance to Xylella fastidiosa infection, and progression of Pierce's disease

    PubMed Central

    Wallis, Christopher M.; Wallingford, Anna K.; Chen, Jianchi

    2013-01-01

    The xylem-limited bacterium Xylella fastidiosa (Xf) causes Pierce's disease (PD), an important disease of grapevine, Vitis vinifera L. Grapevine rootstocks were developed to provide increased resistance to root disease, but rootstock effects on cane and vine diseases remain unclear. Grapevines that consisted of Cabernet Sauvignon or Chardonnay grafted to 13 different rootstocks were inoculated with Xf and evaluated for PD severity and Xf titer after 6 months. A subset of six rootstock/scion combinations had xylem sap phenolic levels assessed in non-infected and Xf-infected grapevines. Vigor also was analyzed by measuring root lengths and masses. Cabernet Sauvignon grafted to 101-14MG, 1103P, 420A, or Schwarzmann had reduced PD severity compared to Cabernet Sauvignon grafted to 110R, 5BB, or SO4. Chardonnay grafted to Salt Creek or Freedom had reduced PD severity compared to Chardonnay grafted to RS3 or Schwarzmann. Chardonnay grafted to RS3 had greater Xf titer than Chardonnay grafted to 101-14MG, Freedom, or Salt Creek. No other differences in Xf titer among rootstocks were observed. Of the six scion/rootstock combinations which had xylem sap phenolics analyzed, Chardonnay/RS3 had the highest levels of most phenolics whereas Cabernet Sauvignon/101-14MG had the lowest phenolic levels. However, Chardonnay/101-14MG, which had mild PD symptoms, had greater sap levels of caftaric acid than other scion/rootstock combinations. Sap levels of caftaric acid, methyl salicylate, a procyanidin trimer, and quinic acid were greater in Xf-infected vs. non-infected grapevines. Chardonnay on 101-14MG or Salt Creek had greater root mass than Chardonnay on RS3. Cabernet Sauvignon on 101-14MG had greater root mass than Cabernet Sauvignon on 110R. These results identified rootstocks with the capacity for reducing PD symptom progression. Rootstocks also were shown to affect Xf titer, xylem sap phenolic levels, and plant vigor. PMID:24376452

  8. Human leukocyte antigen genotype and risk of HIV disease progression before and after initiation of antiretroviral therapy.

    PubMed

    Kuniholm, Mark H; Gao, Xiaojiang; Xue, Xiaonan; Kovacs, Andrea; Anastos, Kathryn; Marti, Darlene; Greenblatt, Ruth M; Cohen, Mardge H; Minkoff, Howard; Gange, Stephen J; Fazzari, Melissa; Young, Mary A; Strickler, Howard D; Carrington, Mary

    2011-10-01

    While the human leukocyte antigen (HLA) genotype has been associated with the rate of HIV disease progression in untreated patients, little is known regarding these relationships in patients using highly active antiretroviral therapy (HAART). The limited data reported to date identified few HLA-HIV disease associations in patients using HAART and even occasional associations that were opposite of those found in untreated patients. We conducted high-resolution HLA class I and II genotyping in a random sample (n = 860) of HIV-seropositive women enrolled in a long-term cohort initiated in 1994. HLA-HIV disease associations before and after initiation of HAART were examined using multivariate analyses. In untreated HIV-seropositive patients, we observed many of the predicted associations, consistent with prior studies. For example, HLA-B*57 (? = -0.7; 95% confidence interval [CI] = -0.9 to -0.5; P = 5 × 10?¹¹) and Bw4 (? = -0.2; 95% CI = -0.4 to -0.1; P = 0.009) were inversely associated with baseline HIV viral load, and B*57 was associated with a low risk of rapid CD4+ decline (odds ratio [OR] = 0.2; 95% CI = 0.1 to 0.6; P = 0.002). Conversely, in treated patients, the odds of a virological response to HAART were lower for B*57:01 (OR = 0.2; 95% CI = 0.0 to 0.9; P = 0.03), and Bw4 (OR = 0.4; 95% CI = 0.1 to 1.0; P = 0.04) was associated with low odds of an immunological response. The associations of HLA genotype with HIV disease are different and sometimes even opposite in treated and untreated patients. PMID:21849458

  9. Presentation of Progressive Familial Intrahepatic Cholestasis Type 3 Mimicking Wilson Disease: Molecular Genetic Diagnosis and Response to Treatment

    PubMed Central

    Jain, Dhanpat; Schilsky, Michael L.

    2015-01-01

    Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal recessive disorder of cholestasis of hepatocellular origin, typically seen in infancy or childhood caused by a defect in the ABCB4 located on chromosome 7. Here we report on an older patient, aged 15, who presented with biochemical testing that led to an initial consideration of a diagnosis of Wilson disease (WD) resulting in a delayed diagnosis of PFIC3. Diagnosis of PFIC3 was later confirmed by molecular studies that identified novel mutations in the ABCB4 gene. Cholestasis due to PFIC3 can cause elevated hepatic copper and increased urine copper excretion that overlap with current diagnostic criteria for WD. Molecular diagnostics are very useful for establishing the diagnosis of PFIC3. Ursodeoxycholic acid ameliorates cholestasis in PFIC3, and may help mediate a reduction in hepatic copper content in response to treatment. PMID:26473142

  10. Cerebrospinal fluid leakage in Gorham-Stout disease due to dura mater involvement after progression of an osteolytic lesion in the thoracic spine.

    PubMed

    Suero Molina, Eric Jose; Niederstadt, Thomas; Ruland, Vincent; Kayser, Gian; Stummer, Walter; Ewelt, Christian; Rössler, Jochen

    2014-12-01

    Patients with Gorham-Stout disease (GSD), a rare disease of poorly understood etiopathophysiology, suffer from progressive osteolysis. Destruction of bone matrix is caused by lymphatic vessels, which can lead to CSF leakage if parts of bony structures adjacent to CSF spaces are involved. So far, fewer than 200 patients have been reported in the literature; only 4 of these patients presented with CSF leakage. The authors report the case of a 30-year-old man with GSD and CSF leakage due to dura mater involvement after progression of an osteolytic lesion in the thoracic spine. Neurosurgical intervention, including dura repair, was needed. Experimental medical therapy with rapamycin was started, leading to disease control for more than 12 months. Progression of GSD can lead to destruction of the meninges, causing CSF leakage. The authors review 4 other cases reported in the literature and discuss therapeutic options. PMID:25325172

  11. Mapping Alzheimer’s disease progression in 1309 MRI scans: Power estimates for different inter-scan intervals?

    PubMed Central

    Hua, Xue; Lee, Suh; Hibar, Derrek P.; Yanovsky, Igor; Leow, Alex D.; Toga, Arthur W.; Jack, Clifford R.; Bernstein, Matt A.; Reiman, Eric M.; Harvey, Danielle J.; Kornak, John; Schuff, Norbert; Alexander, Gene E.; Weiner, Michael W.; Thompson, Paul M.

    2010-01-01

    Neuroimaging centers and pharmaceutical companies are working together to evaluate treatments that might slow the progression of Alzheimer’s disease (AD), a common but devastating late-life neuropathology. Recently, automated brain mapping methods, such as tensor-based morphometry (TBM) of structural MRI, have outperformed cognitive measures in their precision and power to track disease progression, greatly reducing sample size estimates for drug trials. In the largest TBM study to date, we studied how sample size estimates for tracking structural brain changes depend on the time interval between the scans (6–24 months). We analyzed 1309 brain scans from 91 probable AD patients (age at baseline: 75.4±7.5 years) and 189 individuals with mild cognitive impairment (MCI; 74.6±7.1 years), scanned at baseline, 6, 12, 18, and 24 months. Statistical maps revealed 3D patterns of brain atrophy at each follow-up scan relative to the baseline; numerical summaries were used to quantify temporal lobe atrophy within a statistically-defined region-of-interest. Power analyses revealed superior sample size estimates over traditional clinical measures. Only 80, 46, and 39 AD patients were required for a hypothetical clinical trial, at 6, 12, and 24 months respectively, to detect a 25% reduction in average change using a two-sided test (?=0.05, power=80%). Correspondingly, 106, 79, and 67 subjects were needed for an equivalent MCI trial aiming for earlier intervention. A 24-month trial provides most power, except when patient attrition exceeds 15–16%/year, in which case a 12-month trial is optimal. These statistics may facilitate clinical trial design using voxel-based brain mapping methods such as TBM. PMID:20139010

  12. Meta-analysis: increased mortality associated with HCV in HIV-infected persons is not related to HIV disease progression

    PubMed Central

    Chen, Ting-Yi; Ding, Eric L.; Seage, George R.; Kim, Arthur Y.

    2009-01-01

    Background It is unclear whether coinfection with HCV increases mortality in HIV patients in the HAART era. Using a meta-analysis, we estimated the effect of HCV on HIV disease progression and overall mortality in the pre- and HAART era. Method PubMed and EMBASE were searched for studies published until April 30, 2008. Additional studies were identified from cited references. Studies reporting disease progression or mortality in HCV/HIV coinfected patients were selected. Cross sectional studies, studies without HCV negative controls and studies among children and/or post-liver transplant were excluded. Two authors reviewed articles and extracted data on demographics of study populations and risk estimates. Meta-regression was used to explore heterogeneity. Results 10 pre-HAART studies and 27 HAART era studies were selected. In the pre-HAART era, the risk ratio for overall mortality among HCV/HIV coinfected patients was 0.68 (95% CI: 0.53~0.87) compared to patients with HIV infection alone. In the HAART era, the risk ratio was 1.12 (95% CI: 0.82~1.51) for AIDS-defining events and 1.35 (95% CI: 1.11~1.63) for overall mortality in coinfected patients compared to HIV monoinfection. Conclusions HCV coinfection did not increase mortality in HIV patients before the introduction of HAART. In contrast, HCV coinfection increases the risk of mortality but not AIDS-defining events compared to HIV infection alone in the HAART era. Future studies should determine whether successfully treated HCV could reduce this excess risk of mortality in coinfected patients. PMID:19842982

  13. Evolution of human immunodeficiency virus type 1 in perinatally infected infants with rapid and slow progression to disease.

    PubMed Central

    Salvatori, F; Masiero, S; Giaquinto, C; Wade, C M; Brown, A J; Chieco-Bianchi, L; De Rossi, A

    1997-01-01

    We addressed the relationship between the origin and evolution of human immunodeficiency virus type 1 (HIV-1) variants and disease outcome in perinatally infected infants by studying the V3 regions of viral variants in samples obtained from five transmitting mothers at delivery and obtained sequentially over the first year of life from their infected infants, two of whom (rapid progressors) rapidly progressed to having AIDS. Phylogenetic analyses disclosed that the V3 sequences from each mother-infant pair clustered together and were clearly distinct from those of the other pairs. Within each pair, the child's sequences formed a monophyletic group, indicating that a single variant initiated the infection in both rapid and slow progressors. Plasma HIV-1 RNA levels increased in all five infants during their first months of life and then declined within the first semester of life only in the three slow progressors. V3 variability increased over time in all infants, but no differences in the pattern of V3 evolution in terms of potential viral phenotype were observed. The numbers of synonymous and nonsynonymous substitutions varied during the first semester of life regardless of viral load, CD4+-cell count, and disease progression. Conversely, during the second semester of life the rate of nonsynonymous substitutions was higher than that of synonymous substitutions in the slow progressors but not in the rapid progressors, thus suggesting a stronger host selective pressure in the former. In view of the proposal that V3 genetic evolution is driven mainly by host immune constraints, these findings suggest that while the immune response to V3 might contribute to regulating viral levels after the first semester of life, it is unlikely to play a determinant role in the initial viral decline soon after birth. PMID:9151863

  14. Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain.

    PubMed Central

    Major, E O; Amemiya, K; Tornatore, C S; Houff, S A; Berger, J R

    1992-01-01

    Studies of the pathogenesis and molecular biology of JC virus infection over the last two decades have significantly changed our understanding of progressive multifocal leukoencephalopathy, which can be described as a subacute viral infection of neuroglial cells that probably follows reactivation of latent infection rather than being the consequence of prolonged JC virus replication in the brain. There is now sufficient evidence to suggest that JC virus latency occurs in kidney and B cells. However, JC virus isolates from brain or kidney differ in the regulatory regions of their viral genomes which are controlled by host cell factors for viral gene expression and replication. DNA sequences of noncoding regions of the viral genome display a certain heterogeneity among isolates from brain and kidney. These data suggest that an archetypal strain of JC virus exists whose sequence is altered during replication in different cell types. The JC virus regulatory region likely plays a significant role in establishing viral latency and must be acted upon for reactivation of the virus. A developing hypothesis is that reactivation takes place from latently infected B lymphocytes that are activated as a result of immune suppression. JC virus enters the brain in the activated B cell. Evidence for this mechanism is the detection of JC virus DNA in peripheral blood lymphocytes and infected B cells in the brains of patients with progressive multifocal leukoencephalopathy. Once virus enters the brain, astrocytes as well as oligodendrocytes support JC virus multiplication. Therefore, JC virus infection of neuroglial cells may impair other neuroglial functions besides the production and maintenance of myelin. Consequently our increased understanding of the pathogenesis of progressive multifocal leukoencephalopathy suggests new ways to intervene in JC virus infection with immunomodulation therapies. Perhaps along with trials of nucleoside analogs or interferon administration, this fatal disease, for which no consensus of antiviral therapy exists, may yield to innovative treatment protocols. Images PMID:1310438

  15. Syntax, action verbs, action semantics, and object semantics in Parkinson's disease: Dissociability, progression, and executive influences.

    PubMed

    Bocanegra, Yamile; García, Adolfo M; Pineda, David; Buriticá, Omar; Villegas, Andrés; Lopera, Francisco; Gómez, Diana; Gómez-Arias, Catalina; Cardona, Juan F; Trujillo, Natalia; Ibáñez, Agustín

    2015-08-01

    Several studies have recently shown that basal ganglia (BG) deterioration leads to distinctive impairments in the domains of syntax, action verbs, and action semantics. In particular, such disruptions have been repeatedly observed in Parkinson's disease (PD) patients. However, it remains unclear whether these deficits are language-specific and whether they are equally dissociable from other reported disturbances -viz., processing of object semantics. To address these issues, we administered linguistic, semantic, and executive function (EFs) tasks to two groups of non-demented PD patients, with and without mild cognitive impairment (PD-MCI and PD-nMCI, respectively). We compared these two groups with each other and with matched samples of healthy controls. Our results showed that PD patients exhibited linguistic and semantic deficits even in the absence of MCI. However, not all domains were equally related to EFs and MCI across samples. Whereas EFs predicted disturbances of syntax and object semantics in both PD-nMCI and PD-MCI, they had no impact on action-verb and action-semantic impairments in either group. Critically, patients showed disruptions of action-verb production and action semantics in the absence of MCI and without any executive influence, suggesting a sui generis deficit present since early stages of the disease. These findings indicate that varied language domains are differentially related to the BG, contradicting popular approaches to neurolinguistics. PMID:26103601

  16. MRI Correlates of Parkinson's Disease Progression: A Voxel Based Morphometry Study

    PubMed Central

    Fioravanti, Valentina; Benuzzi, Francesca; Codeluppi, Luca; Contardi, Sara; Cavallieri, Francesco; Nichelli, Paolo; Valzania, Franco

    2015-01-01

    We investigated structural brain differences between a group of early-mild PD patients at different phases of the disease and healthy subjects using voxel-based morphometry (VBM). 20 mild PD patients compared to 15 healthy at baseline and after 2 years of follow-up. VBM is a fully automated technique, which allows the identification of regional differences in the gray matter enabling an objective analysis of the whole brain between groups of subjects. With respect to controls, PD patients exhibited decreased GM volumes in right putamen and right parietal cortex. After 2 years of disease, the same patients confirmed GM loss in the putamen and parietal cortex; a significant difference was also observed in the area of pedunculopontine nucleus (PPN) and in the mesencephalic locomotor region (MLR). PD is associated with brain morphological changes in cortical and subcortical structures. The first regions to be affected in PD seem to be the parietal cortex and the putamen. A third structure that undergoes atrophy is the part of the inferior-posterior midbrain, attributable to the PPN and MLR. Our findings provide new insight into the brain involvement in PD and could contribute to a better understanding of the sequence of events occurring in these patients. PMID:25628916

  17. Identifying disease mutations in genomic medicine settings: current challenges and how to accelerate progress

    PubMed Central

    2012-01-01

    The pace of exome and genome sequencing is accelerating, with the identification of many new disease-causing mutations in research settings, and it is likely that whole exome or genome sequencing could have a major impact in the clinical arena in the relatively near future. However, the human genomics community is currently facing several challenges, including phenotyping, sample collection, sequencing strategies, bioinformatics analysis, biological validation of variant function, clinical interpretation and validity of variant data, and delivery of genomic information to various constituents. Here we review these challenges and summarize the bottlenecks for the clinical application of exome and genome sequencing, and we discuss ways for moving the field forward. In particular, we urge the need for clinical-grade sample collection, high-quality sequencing data acquisition, digitalized phenotyping, rigorous generation of variant calls, and comprehensive functional annotation of variants. Additionally, we suggest that a 'networking of science' model that encourages much more collaboration and online sharing of medical history, genomic data and biological knowledge, including among research participants and consumers/patients, will help establish causation and penetrance for disease causal variants and genes. As we enter this new era of genomic medicine, we envision that consumer-driven and consumer-oriented efforts will take center stage, thus allowing insights from the human genome project to translate directly back into individualized medicine. PMID:22830651

  18. Multiple-time-scale framework for understanding the progression of Parkinson's disease

    NASA Astrophysics Data System (ADS)

    Andres, D. S.; Gomez, F.; Ferrari, F. A. S.; Cerquetti, D.; Merello, M.; Viana, R.; Stoop, R.

    2014-12-01

    Parkinson's disease is marked by neurodegenerative processes that affect the pattern of discharge of basal ganglia neurons. The main features observed in the parkinsonian globus pallidus pars interna (GPi), a subdomain of the basal ganglia that is involved in the regulation of voluntary movement, are pathologically increased and synchronized neuronal activity. How these changes affect the implemented neuronal code is not well understood. Our experimental temporal structure-function analysis shows that in parkinsonian animals the rate-coding window of GPi neurons needed for the proper performance of voluntary actions is reduced. The model of the GPi network that we develop and discuss here reveals indeed that the size of the rate-coding window shrinks as the network activity increases and is expanded if the coupling strength among the neurons is increased. This leads to the novel interpretation that the pathological neuronal synchronization in Parkinson's disease in the GPi is the result of a collective attempt to counterbalance the shrinking of the rate-coding window due to increased activity in GPi neurons.

  19. Oxidative Stress during the Progression of ?-Amyloid Pathology in the Neocortex of the Tg2576 Mouse Model of Alzheimer's Disease

    PubMed Central

    Porcellotti, Sara; Fanelli, Francesca; Fracassi, Anna; Sepe, Sara; Cecconi, Francesco; Bernardi, Cinzia; Cimini, AnnaMaria; Cerù, Maria Paola; Moreno, Sandra

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive neurodegeneration. Pathogenetic mechanisms, triggered by ?-amyloid (A?) accumulation, include oxidative stress, derived from energy homeostasis deregulation and involving mitochondria and peroxisomes. We here addressed the oxidative stress status and the elicited cellular response at the onset and during the progression of A? pathology, studying the neocortex of Tg2576 model of AD. Age-dependent changes of oxidative damage markers, antioxidant enzymes, and related transcription factors were analysed in relation to the distribution of A? peptide and oligomers, by a combined molecular/morphological approach. Nucleic acid oxidative damage, accompanied by defective antioxidant defences, and decreased PGC1? expression are already detected in 3-month-old Tg2576 neurons. Conversely, PPAR? is increased in these cells, with its cytoplasmic localization suggesting nongenomic, anti-inflammatory actions. At 6 months, when intracellular A? accumulates, PMP70 is downregulated, indicating impairment of fatty acids peroxisomal translocation and their consequent harmful accumulation. In 9-month-old Tg2576 neocortex, A? oligomers and acrolein deposition correlate with GFAP, GPX1, and PMP70 increases, supporting a compensatory response, involving astroglial peroxisomes. At severe pathological stages, when senile plaques disrupt cortical cytoarchitecture, antioxidant capacity is gradually lost. Overall, our data suggest early therapeutic intervention in AD, also targeting peroxisomes. PMID:25973140

  20. Oxidative Stress during the Progression of ?-Amyloid Pathology in the Neocortex of the Tg2576 Mouse Model of Alzheimer's Disease.

    PubMed

    Porcellotti, Sara; Fanelli, Francesca; Fracassi, Anna; Sepe, Sara; Cecconi, Francesco; Bernardi, Cinzia; Cimini, AnnaMaria; Cerù, Maria Paola; Moreno, Sandra

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive neurodegeneration. Pathogenetic mechanisms, triggered by ?-amyloid (A?) accumulation, include oxidative stress, derived from energy homeostasis deregulation and involving mitochondria and peroxisomes. We here addressed the oxidative stress status and the elicited cellular response at the onset and during the progression of A? pathology, studying the neocortex of Tg2576 model of AD. Age-dependent changes of oxidative damage markers, antioxidant enzymes, and related transcription factors were analysed in relation to the distribution of A? peptide and oligomers, by a combined molecular/morphological approach. Nucleic acid oxidative damage, accompanied by defective antioxidant defences, and decreased PGC1? expression are already detected in 3-month-old Tg2576 neurons. Conversely, PPAR? is increased in these cells, with its cytoplasmic localization suggesting nongenomic, anti-inflammatory actions. At 6 months, when intracellular A? accumulates, PMP70 is downregulated, indicating impairment of fatty acids peroxisomal translocation and their consequent harmful accumulation. In 9-month-old Tg2576 neocortex, A? oligomers and acrolein deposition correlate with GFAP, GPX1, and PMP70 increases, supporting a compensatory response, involving astroglial peroxisomes. At severe pathological stages, when senile plaques disrupt cortical cytoarchitecture, antioxidant capacity is gradually lost. Overall, our data suggest early therapeutic intervention in AD, also targeting peroxisomes. PMID:25973140

  1. Gait Abnormalities and Progressive Myelin Degeneration in a New Murine Model of Pelizaeus-Merzbacher Disease with Tandem Genomic Duplication

    PubMed Central

    Clark, Kristi; Sakowski, Lauren; Sperle, Karen; Banser, Linda; Landel, Carlisle P.; Bessert, Denise A.; Skoff, Robert P.

    2013-01-01

    Pelizaeus-Merzbacher disease (PMD) is a hypomyelinating leukodystrophy caused by mutations of the proteolipid protein 1 gene (PLP1), which is located on the X chromosome and encodes the most abundant protein of myelin in the central nervous sytem. Approximately 60% of PMD cases result from genomic duplications of a region of the X chromosome that includes the entire PLP1 gene. The duplications are typically in a head-to-tail arrangement, and they vary in size and gene content. Although rodent models with extra copies of Plp1 have been developed, none contains an actual genomic rearrangement that resembles those found in PMD patients. We used mutagenic insertion chromosome engineering resources to generate the Plp1dup mouse model by introducing an X chromosome duplication in the mouse genome that contains Plp1 and five neighboring genes that are also commonly duplicated in PMD patients. The Plp1dup mice display progressive gait abnormalities compared with wild-type littermates. The single duplication leads to increased transcript levels of Plp1 and four of the five other duplicated genes over wild-type levels in the brain beginning the second postnatal week. The Plp1dup mice also display altered transcript levels of other important myelin proteins leading to a progressive degeneration of myelin. Our results show that a single duplication of the Plp1 gene leads to a phenotype similar to the pattern seen in human PMD patients with duplications. PMID:23864668

  2. Gait abnormalities and progressive myelin degeneration in a new murine model of Pelizaeus-Merzbacher disease with tandem genomic duplication.

    PubMed

    Clark, Kristi; Sakowski, Lauren; Sperle, Karen; Banser, Linda; Landel, Carlisle P; Bessert, Denise A; Skoff, Robert P; Hobson, Grace M

    2013-07-17

    Pelizaeus-Merzbacher disease (PMD) is a hypomyelinating leukodystrophy caused by mutations of the proteolipid protein 1 gene (PLP1), which is located on the X chromosome and encodes the most abundant protein of myelin in the central nervous sytem. Approximately 60% of PMD cases result from genomic duplications of a region of the X chromosome that includes the entire PLP1 gene. The duplications are typically in a head-to-tail arrangement, and they vary in size and gene content. Although rodent models with extra copies of Plp1 have been developed, none contains an actual genomic rearrangement that resembles those found in PMD patients. We used mutagenic insertion chromosome engineering resources to generate the Plp1dup mouse model by introducing an X chromosome duplication in the mouse genome that contains Plp1 and five neighboring genes that are also commonly duplicated in PMD patients. The Plp1dup mice display progressive gait abnormalities compared with wild-type littermates. The single duplication leads to increased transcript levels of Plp1 and four of the five other duplicated genes over wild-type levels in the brain beginning the second postnatal week. The Plp1dup mice also display altered transcript levels of other important myelin proteins leading to a progressive degeneration of myelin. Our results show that a single duplication of the Plp1 gene leads to a phenotype similar to the pattern seen in human PMD patients with duplications. PMID:23864668

  3. De novo deletion 17p13.1 as a predictor for disease progression in chronic lymphocytic leukemia.

    PubMed

    El-Ghammaz, Amro M S; Abdelwahed, Essam; Mostafa, Nevine N; Mansour, Dina A

    2015-11-01

    To determine the prognostic impact of de novo deletion 17p13.1 (17p-) in previously untreated chronic lymphocytic leukemia (CLL) patients, we prospectively studied the outcome of 71 treatment-naïve CLL patients. About 18.3 % of them had 17p- detected by interphase fluorescent in situ hybridization (FISH) at diagnosis. There was statistically significant difference between 17p- negative and positive patients as regards 2-year overall survival [OS] (89.7 vs. 53.8 %, respectively; P = 0.001). On the other hand, 2-year progression-free survival [PFS] was also significantly higher in 17p- negative group than in 17p- positive one (82.8 vs. 23.1 %, respectively; P < 0.001). On univariate analysis for OS, 17p- positivity was significantly associated with shorter OS (P = 0.003). However, when we performed multivariate analysis, 17p- lost its significant impact. On the other hand, 17p- positivity was a significant risk factor for PFS in both univariate and multivariate analyses [independent risk factor] (P < 0.001 and P = 0.02, respectively). So, 17p- is a predictor for disease progression, but not for survival in CLL patients. PMID:25300358

  4. Is progressive multifocal leukoencephalopathy a chronic disease because of defective interfering particles or temperature-sensitive mutants of JC virus?

    PubMed Central

    Grinnell, B W; Martin, J D; Padgett, B L; Walker, D L

    1982-01-01

    JC virus was examined for temperature sensitivity and for evidence of defective interfering particles as a means of explaining the slow chronic nature of progressive multifocal leukoencephalopathy (PML). JC virus direct from the brain tissue of seven persons with PML was not temperature sensitive as indicated by in vitro assay at 37 and 39 degrees C. In fact, more cells contained viral antigen at 39 than at 37 degrees C. The amount of infectious virus also was increased at 39 degrees C. Virions isolated directly from diseased brain tissue had a higher buoyant density than did virus from the same PML patient passaged in culture and containing genomic deletions. In contrast to DNA from culture-passed virus, DNA extracted from virions direct from brain tissue was homogeneous in length. In 13 separate cases examined, the viral DNA direct from the brain was homogeneous although variations in length were noted among DNAs from different cases. Restriction enzyme cleavage patterns identified all as JC virus DNA. It was concluded that neither temperature sensitivity nor DI particles can be used to explain the slow, progressive nature of PML. Images PMID:6292458

  5. Primary CXCR4 co-receptor use in acute HIV infection leads to rapid disease progression in the AE subtype.

    PubMed

    Jiao, Yanmei; Song, Yingxue; Kou, Buxin; Wang, Rui; Liu, Zhiying; Huang, Xiaojie; Chen, Dexi; Zhang, Tong; Wu, Hao

    2012-08-01

    This is a comparative study of HIV co-receptor usage in the early stages of HIV infection between two distinct patient groups, one with a low CD4 count (group 1), and the other with a high CD4 count (group 2). Group 1 progressed to a CD4 count below 200 cells/?L within 2 y, while group 2 had a CD4 count above 500 cells/?L within 2 y. Viral RNA was extracted from the plasma of these patients, and the C2-V5 region of the HIV-1 env genes were cloned and sequenced. The co-receptor usage was predicated based on V3 loop amino acid sequences using Geno2pheno and PSSM programs. Our results indicate that in acute HIV infection of rapid progressors (low CD4 count; group 1), the primary co-receptor usage is CXCR4, while in the high CD4 count group (group 2), the co-receptor usage is predominantly CCR5. One-year follow-up data from these patients showed no obvious change in HIV co-receptor usage in either group. Sequence analysis of patients from both study groups showed prevalence of the AE subtype, and therefore we can speculate that the CXCR4 co-receptor may be the primary HIV-1 co-receptor used in the HIV-1 AE subtype, and may be responsible for rapid HIV-1 disease progression in the MSM cohort. PMID:22783935

  6. nature neuroscience volume 5 no 4 april 2002 301 Amyotrophic lateral sclerosis (ALS), a progressive, fatal neurode-

    E-print Network

    articles nature neuroscience · volume 5 no 4 · april 2002 301 Amyotrophic lateral sclerosis (ALS amyotrophic lateral sclerosis (FALS). We tested this hypothesis by ablating the gene encoding the copper

  7. Quantitative-profiling of neurotransmitter abnormalities in the disease progression of experimental diabetic encephalopathy rat.

    PubMed

    Zhou, Xueyan; Zhu, Qiuxiang; Han, Xiaowen; Chen, Renguo; Liu, Yaowu; Fan, Hongbin; Yin, Xiaoxing

    2015-11-01

    Diabetic encephalopathy (DE) is one of the most prevalent chronic complications of diabetes mellitus (DM), with neither effective prevention nor proven therapeutic regimen. This study aims to uncover the potential dysregulation pattern of the neurotransmitters in a rat model of streptozotocin (STZ)-induced experimental DE. For that purpose, male Sprague-Dawley (SD) rats were treated with a single intraperitoneal injection of STZ. Cognitive performance was detected with the Morris water maze (MWM) test. Serum, cerebrospinal fluid (CSF), and brain tissues were collected to measure the levels of neurotransmitters. Compared with the control rats, the acetylcholine (ACh) levels in serum, CSF, hippocampus, and cortex were all significantly down-regulated as early as 6 weeks in the STZ treatment group. In contrast, the glutamate (Glu) levels were decreased in CSF and the hippocampus, but unaffected in the serum and cortex of STZ-treated rats. As for ?-aminobutyric acid (GABA), it was down-regulated in serum, but up-regulated in CSF, hippocampus, and the cortex in the STZ-treated group. The mRNA expressions of neurotransmitter-related rate limiting enzymes (including AChE, GAD1, and GAD2) and pro-inflammatory cytokines (including IL-1? and TNF-?) were all increased in the DE rats. Our data suggest that DM induces isoform-dependent and tissue-specific neurotransmitter abnormalities, and that neuroinflammation may underlay the nervous system dysfunction observed in the progression of DE. PMID:26426748

  8. Progress in detecting genetic alterations and their association with human disease.

    PubMed

    Schwartz, Charles E; Chen, Chin-Fu

    2013-11-01

    The completion of the Human Genome Project provided a reference sequence to which researchers could compare sequences from individual patients in the hope of identifying disease-causing mutations. However, this still necessitated candidate gene testing or a very limited screen of multiple genes using Sanger sequencing. With the advent of high-throughput Sanger sequencing, it became possible to screen hundreds of patients for alterations in hundreds of genes. This process was time consuming and limited to a few locations/institutions that had the space to house tens of sequencing equipment. The development of next generation sequencing revolutionized the process. It is now feasible to sequence the entire exome of multiple individuals in about 10 days. However, this meant that a massive amount of data needed to be filtered to identify the relevant alteration. This is presently the rate-limiting step in providing a convincing association between a genetic alteration and a human disorder. PMID:23876707

  9. Mechanistic population modeling of diabetes disease progression in Goto-Kakizaki rat muscle

    PubMed Central

    Nie, Jing; DuBois, Debra C.; Jusko, William J.; Almon, Richard R.

    2010-01-01

    Pyruvate dehydrogenase kinase 4 (PDK4) is a lipid status responsive gene involved in muscle fuel selection. Evidence is mounting in support of the therapeutic potential of PDK4 inhibitors to treat diabetes. Factors that regulate PDK4 mRNA expression include plasma corticosterone, insulin and free fatty acids. Our objective was to determine the impact of those plasma factors on PDK4 mRNA and to develop and validate a population mathematical model to differentiate aging, diet and disease effects on muscle PDK4 expression. The Goto-Kakizaki (GK) rat, a polygenic non-obese model of type 2 diabetes, was used as the diabetic animal model. We examined muscle PDK4 mRNA expression by real-time QRTPCR. Groups of GK rats along with controls fed with either a normal or high fat diet were sacrificed at 4, 8, 12, 16, and 20 weeks of age. Plasma corticosterone, insulin and free fatty acid were measured. The proposed mechanism-based model successfully described the age, disease and diet effects and the relative contribution of these plasma regulators on PDK4 mRNA expression. Muscle growth reduced the PDK4 mRNA production rate by 14% per gram increase. High fat diet increased the initial production rate constant in GK rats by 2.19-fold. The model indicated that corticosterone had a moderate effect and PDK4 was more sensitive to free fatty acid than insulin fluxes, which was in good agreement with the literature data. PMID:21162119

  10. Mutations in PRKN and SNCA Genes Important for the Progress of Parkinson’s Disease

    PubMed Central

    Oczkowska, Anna; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

    2013-01-01

    Although Parkinson’s disease (PD) was first described almost 200 years ago, it remains an incurable disease with a cause that is not fully understood. Nowadays it is known that disturbances in the structure of pathological proteins in PD can be caused by more than environmental and genetic factors. Despite numerous debates and controversies in the literature about the role of mutations in the SNCA and PRKN genes in the pathogenesis of PD, it is evident that these genes play a key role in maintaining dopamine (DA) neuronal homeostasis and that the dysfunction of this homeostasis is relevant to both familial (FPD) and sporadic (SPD) PD with different onset. In recent years, the importance of alphasynuclein (ASN) in the process of neurodegeneration and neuroprotective function of the Parkin is becoming better understood. Moreover, there have been an increasing number of recent reports indicating the importance of the interaction between these proteins and their encoding genes. Among others interactions, it is suggested that even heterozygous substitution in the PRKN gene in the presence of the variants +2/+2 or +2/+3 of NACP-Rep1 in the SNCA promoter, may increase the risk of PD manifestation, which is probably due to ineffective elimination of over-expressed ASN by the mutated Parkin protein. Finally, it seems that genetic testing may be an important part of diagnostics in patients with PD and may improve the prognostic process in the course of PD. However, only full knowledge of the mechanism of the interaction between the genes associated with the pathogenesis of PD is likely to help explain the currently unknown pathways of selective damage to dopaminergic neurons in the course of PD. PMID:24532983

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

    PubMed

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

    2015-01-01

    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 ?-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. PMID:26658617

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

    PubMed Central

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

    2015-01-01

    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 ?-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. PMID:26658617

  13. Yeast Cells Expressing the Human Mitochondrial DNA Polymerase Reveal Correlations between Polymerase Fidelity and Human Disease Progression*

    PubMed Central

    Qian, Yufeng; Kachroo, Aashiq H.; Yellman, Christopher M.; Marcotte, Edward M.; Johnson, Kenneth A.

    2014-01-01

    Mutations in the human mitochondrial polymerase (polymerase-? (Pol-?)) are associated with various mitochondrial disorders, including mitochondrial DNA (mtDNA) depletion syndrome, Alpers syndrome, and progressive external opthamalplegia. To correlate biochemically quantifiable defects resulting from point mutations in Pol-? with their physiological consequences, we created “humanized” yeast, replacing the yeast mtDNA polymerase (MIP1) with human Pol-?. Despite differences in the replication and repair mechanism, we show that the human polymerase efficiently complements the yeast mip1 knockouts, suggesting common fundamental mechanisms of replication and conserved interactions between the human polymerase and other components of the replisome. We also examined the effects of four disease-related point mutations (S305R, H932Y, Y951N, and Y955C) and an exonuclease-deficient mutant (D198A/E200A). In haploid cells, each mutant results in rapid mtDNA depletion, increased mutation frequency, and mitochondrial dysfunction. Mutation frequencies measured in vivo equal those measured with purified enzyme in vitro. In heterozygous diploid cells, wild-type Pol-? suppresses mutation-associated growth defects, but continuous growth eventually leads to aerobic respiration defects, reduced mtDNA content, and depolarized mitochondrial membranes. The severity of the Pol-? mutant phenotype in heterozygous diploid humanized yeast correlates with the approximate age of disease onset and the severity of symptoms observed in humans. PMID:24398692

  14. A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression

    PubMed Central

    Cho, Hyoung-Soo; Shin, Hyun Mu; Haberstock-Debic, Helena; Xing, Yan; Owens, Timothy D.; Funk, Jens Oliver; Hill, Ronald J.; Bradshaw, J. Michael

    2015-01-01

    In T cells, the Tec kinases IL-2–inducible T cell kinase (ITK) and resting lymphocyte kinase (RLK) are activated by TCR stimulation and are required for optimal downstream signaling. Studies of CD4+ T cells from Itk?/? and Itk?/?Rlk?/? mice have indicated differential roles of ITK and RLK in Th1, Th2, and Th17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice. In this study, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro Th polarization experiments indicate that PRN694 is a potent inhibitor of Th1 and Th17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-? production by colitogenic CD4+ T cells. Consistent with these findings, Th1 and Th17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Taken together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in Th1-mediated inflammatory diseases. PMID:26466958

  15. Magnetic Analysis of Post-mortem Hippocampal Tissue from Alzheimer's Patients: Changes with Progression of the Disease.

    NASA Astrophysics Data System (ADS)

    Fuller, M.; Zinin, P.; Favia, J.; Tatsumi, L.; Kletetschka, G.; Adachi, T.

    2007-12-01

    Increases of iron in the human brain with age have been observed and may be accompanied by the development of neurodegenerative diseases, such as Alzheimer's. We have measured the magnetic characteristics of several sets of slides of hippocampal tissue from deceased Alzheimer patients. The slides were made available by the Harvard Brain Bank. The pathology of the tissue was classified in the Braak stages I to VI used to describe the progression of the disease. In general, the slides from patients with higher Braak stages and development of fibrillary tangles and plaques had greater magnetic moments than did those with Braak stage II. However, the peak values were at stage IV and V. To mitigate errors due to the inevitable differences in masses of the tissue on individual slides and their precise location in the hippocampus, ratios of magnetic properties were also observed. Ratios of Anhysteretic Remanent Magnetizaton (ARM) to Isothermal Remanent Magnetization (IRM) were obtained and showed a decrease from Stage II to the more advanced stages, with the minimum values at stages IV and V. The acquisition and demagnetization of IRM are consistent with the presence of magnetite, but also indicate a magnetically harder phase.

  16. A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression.

    PubMed

    Cho, Hyoung-Soo; Shin, Hyun Mu; Haberstock-Debic, Helena; Xing, Yan; Owens, Timothy D; Funk, Jens Oliver; Hill, Ronald J; Bradshaw, J Michael; Berg, Leslie J

    2015-11-15

    In T cells, the Tec kinases IL-2-inducible T cell kinase (ITK) and resting lymphocyte kinase (RLK) are activated by TCR stimulation and are required for optimal downstream signaling. Studies of CD4(+) T cells from Itk(-/-) and Itk(-/-)Rlk(-/-) mice have indicated differential roles of ITK and RLK in Th1, Th2, and Th17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice. In this study, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro Th polarization experiments indicate that PRN694 is a potent inhibitor of Th1 and Th17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-? production by colitogenic CD4(+) T cells. Consistent with these findings, Th1 and Th17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Taken together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in Th1-mediated inflammatory diseases. PMID:26466958

  17. Yeast cells expressing the human mitochondrial DNA polymerase reveal correlations between polymerase fidelity and human disease progression.

    PubMed

    Qian, Yufeng; Kachroo, Aashiq H; Yellman, Christopher M; Marcotte, Edward M; Johnson, Kenneth A

    2014-02-28

    Mutations in the human mitochondrial polymerase (polymerase-? (Pol-?)) are associated with various mitochondrial disorders, including mitochondrial DNA (mtDNA) depletion syndrome, Alpers syndrome, and progressive external opthamalplegia. To correlate biochemically quantifiable defects resulting from point mutations in Pol-? with their physiological consequences, we created "humanized" yeast, replacing the yeast mtDNA polymerase (MIP1) with human Pol-?. Despite differences in the replication and repair mechanism, we show that the human polymerase efficiently complements the yeast mip1 knockouts, suggesting common fundamental mechanisms of replication and conserved interactions between the human polymerase and other components of the replisome. We also examined the effects of four disease-related point mutations (S305R, H932Y, Y951N, and Y955C) and an exonuclease-deficient mutant (D198A/E200A). In haploid cells, each mutant results in rapid mtDNA depletion, increased mutation frequency, and mitochondrial dysfunction. Mutation frequencies measured in vivo equal those measured with purified enzyme in vitro. In heterozygous diploid cells, wild-type Pol-? suppresses mutation-associated growth defects, but continuous growth eventually leads to aerobic respiration defects, reduced mtDNA content, and depolarized mitochondrial membranes. The severity of the Pol-? mutant phenotype in heterozygous diploid humanized yeast correlates with the approximate age of disease onset and the severity of symptoms observed in humans. PMID:24398692

  18. Analysis of families at risk for insulin-dependent diabetes mellitus reveals that HLA antigens influence progression to clinical disease.

    PubMed Central

    Honeyman, M. C.; Harrison, L. C.; Drummond, B.; Colman, P. G.; Tait, B. D.

    1995-01-01

    BACKGROUND: Individuals at risk for insulin-dependent diabetes mellitus (IDDM), with an affected first-degree relative, can be identified by the presence of islet cell antibodies (ICA). ICA-positive relatives progress at variable rates to IDDM and identification of those at highest risk is a prerequisite for possible preventative treatment. Those who develop IDDM may exhibit less genetic heterogeneity than their ICA-positive or ICA-negative relatives. Specific human leucocyte antigen (HLA) genes predispose to IDDM but could also influence the rate of progression of preclinical disease. Therefore, by comparing HLA antigen frequencies between first-degree relatives, we sought to identify HLA genes that influence progression to IDDM. MATERIALS AND METHODS: HLA antigen frequencies were compared in 68 IDDM, 53 ICA-positive, and 96 ICA-negative first-degree relatives from 40 Caucasoid families. Predictions were tested in a panel of 270 unrelated IDDM subjects. HLA typing was performed serologically (HLA class I and II) and by sequence-specific oligotyping (11th International Histocompatibility Workshop protocol) (HLA class II). ICA tests were measured by an internationally standardized indirect immunofluorescence assay. RESULTS: In general, known susceptibility class II HLA antigens increased in frequency and known protective class II HLA antigens decreased in frequency, from ICA-negative to ICA-positive to IDDM relatives. Thus, DR4 and DQ8 increased whereas DR2 and DQ6 decreased; DR3 and DQ2 increased from ICA-negative to ICA-positive relatives, but not further in IDDM relatives. The high-risk DR3, 4 phenotype increased across the three groups; DR4,X was unchanged, and DR3,X and DRX,X both decreased. The HLA class I antigen, A24, occurred more frequently in ICA-positive relatives who developed IDDM and, in 270 unrelated IDDM subjects, was associated with an earlier age at diagnosis of IDDM in those with the lower risk class II phenotypes DR4,4 and DR3,X. CONCLUSIONS: HLA-DR3 and DQ2 predispose to islet autoimmunity, but not development of clinical IDDM in the absence and DR4 and DQ8. DR4 and DQ8 predispose to the development of clinical IDDM in ICA-positive relatives, in combination with DR3-DQ2 and other haplotypes but not when homozygous. HLA-A24 is significantly associated with rapid progression to IDDM in ICA-positive relatives and with an earlier age at clinical diagnosis. Analysis of IDDM families reveals that HLA genes not only predispose to islet autoimmunity but influence progression to clinical disease. The findings have implications for identifying high-risk relatives as candidates for possible preventative therapy. PMID:8529124

  19. The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons

    PubMed Central

    Wang, Wenzhang; Li, Li; Lin, Wen-Lang; Dickson, Dennis W.; Petrucelli, Leonard; Zhang, Teng; Wang, Xinglong

    2013-01-01

    Mutations in TDP-43 lead to familial ALS. Expanding evidence suggests that impaired mitochondrial dynamics likely contribute to the selective degeneration of motor neurons in SOD1-associated ALS. In this study, we investigated whether and how TDP-43 mutations might impact mitochondrial dynamics and function. We demonstrated that overexpression of wild-type TDP-43 resulted in reduced mitochondrial length and density in neurites of primary motor neurons, features further exacerbated by ALS-associated TDP-43 mutants Q331K and M337V. In contrast, suppression of TDP-43 resulted in significantly increased mitochondrial length and density in neurites, suggesting a specific role of TDP-43 in regulating mitochondrial dynamics. Surprisingly, both TDP-43 overexpression and suppression impaired mitochondrial movement. We further showed that abnormal localization of TDP-43 in cytoplasm induced substantial and widespread abnormal mitochondrial dynamics. TDP-43 co-localized with mitochondria in motor neurons and their colocalization was enhanced by ALS associated mutant. Importantly, co-expression of mitochondrial fusion protein mitofusin 2 (Mfn2) could abolish TDP-43 induced mitochondrial dynamics abnormalities and mitochondrial dysfunction. Taken together, these data suggest that mutant TDP-43 impairs mitochondrial dynamics through enhanced localization on mitochondria, which causes mitochondrial dysfunction. Therefore, abnormal mitochondrial dynamics is likely a common feature of ALS which could be potential new therapeutic targets to treat ALS. PMID:23827948

  20. Biochemical characterization of protein quality control mechanisms during disease progression in the C22 mouse model of CMT1A

    PubMed Central

    Chittoor, Vinita G.; Sooyeon, Lee; Rangaraju, Sunitha; Nicks, Jessica R.; Schmidt, Jordan T.; Madorsky, Irina; Narvaez, Diana C.; Notterpek, Lucia

    2013-01-01

    Charcot–Marie–Tooth disease type 1A (CMT1A) is a hereditary demyelinating neuropathy linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Transgenic C22 mice, a model of CMT1A, display many features of the human disease, including slowed nerve conduction velocity and demyelination of peripheral nerves. How overproduction of PMP22 leads to compromised myelin and axonal pathology is not fully understood, but likely involves subcellular alterations in protein homoeostatic mechanisms within affected Schwann cells. The subcellular response to abnormally localized PMP22 includes the recruitment of the ubiquitin–proteasome system (UPS), autophagosomes and heat-shock proteins (HSPs). Here we assessed biochemical markers of these protein homoeostatic pathways in nerves from PMP22-overexpressing neuropathic mice between the ages of 2 and 12 months to ascertain their potential contribution to disease progression. In nerves of 3-week-old mice, using endoglycosidases and Western blotting, we found altered processing of the exogenous human PMP22, an abnormality that becomes more prevalent with age. Along with the ongoing accrual of misfolded PMP22, the activity of the proteasome becomes compromised and proteins required for autophagy induction and lysosome biogenesis are up-regulated. Moreover, cytosolic chaperones are consistently elevated in nerves from neuropathic mice, with the most prominent change in HSP70. The gradual alterations in protein homoeostatic response are accompanied by Schwann cell de-differentiation and macrophage infiltration. Together, these results show that while subcellular protein quality control mechanisms respond appropriately to the presence of the overproduced PMP22, with aging they are unable to prevent the accrual of misfolded proteins. PMID:24175617

  1. Increased Nucleosomes and Neutrophil Activation Link to Disease Progression in Patients with Scrub Typhus but Not Murine Typhus in Laos

    PubMed Central

    Paris, Daniel H.; Stephan, Femke; Bulder, Ingrid; Wouters, Diana; van der Poll, Tom; Newton, Paul N.; Day, Nicholas P. J.; Zeerleder, Sacha

    2015-01-01

    Cell-mediated immunity is essential in protection against rickettsial illnesses, but the role of neutrophils in these intracellular vasculotropic infections remains unclear. This study analyzed the plasma levels of nucleosomes, FSAP-activation (nucleosome-releasing factor), and neutrophil activation, as evidenced by neutrophil-elastase (ELA) complexes, in sympatric Lao patients with scrub typhus and murine typhus. In acute scrub typhus elevated nucleosome levels correlated with lower GCS scores, raised respiratory rate, jaundice and impaired liver function, whereas neutrophil activation correlated with fibrinolysis and high IL-8 plasma levels, a recently identified predictor of severe disease and mortality. Nucleosome and ELA complex levels were associated with a 4.8-fold and 4-fold increased risk of developing severe scrub typhus, beyond cut off values of 1,040 U/ml for nucleosomes and 275 U/ml for ELA complexes respectively. In murine typhus, nucleosome levels associated with pro-inflammatory cytokines and the duration of illness, while ELA complexes correlated strongly with inflammation markers, jaundice and increased respiratory rates. This study found strong correlations between circulating nucleosomes and neutrophil activation in patients with scrub typhus, but not murine typhus, providing indirect evidence that nucleosomes could originate from neutrophil extracellular trap (NET) degradation. High circulating plasma nucleosomes and ELA complexes represent independent risk factors for developing severe complications in scrub typhus. As nucleosomes and histones exposed on NETs are highly cytotoxic to endothelial cells and are strongly pro-coagulant, neutrophil-derived nucleosomes could contribute to vascular damage, the pro-coagulant state and exacerbation of disease in scrub typhus, thus indicating a detrimental role of neutrophil activation. The data suggest that increased neutrophil activation relates to disease progression and severe complications, and increased plasma levels of nucleosomes and ELA complexes represent independent risk factors for developing severe scrub typhus. PMID:26317419

  2. Increased Nucleosomes and Neutrophil Activation Link to Disease Progression in Patients with Scrub Typhus but Not Murine Typhus in Laos.

    PubMed

    Paris, Daniel H; Stephan, Femke; Bulder, Ingrid; Wouters, Diana; van der Poll, Tom; Newton, Paul N; Day, Nicholas P J; Zeerleder, Sacha

    2015-08-01

    Cell-mediated immunity is essential in protection against rickettsial illnesses, but the role of neutrophils in these intracellular vasculotropic infections remains unclear. This study analyzed the plasma levels of nucleosomes, FSAP-activation (nucleosome-releasing factor), and neutrophil activation, as evidenced by neutrophil-elastase (ELA) complexes, in sympatric Lao patients with scrub typhus and murine typhus. In acute scrub typhus elevated nucleosome levels correlated with lower GCS scores, raised respiratory rate, jaundice and impaired liver function, whereas neutrophil activation correlated with fibrinolysis and high IL-8 plasma levels, a recently identified predictor of severe disease and mortality. Nucleosome and ELA complex levels were associated with a 4.8-fold and 4-fold increased risk of developing severe scrub typhus, beyond cut off values of 1,040 U/ml for nucleosomes and 275 U/ml for ELA complexes respectively. In murine typhus, nucleosome levels associated with pro-inflammatory cytokines and the duration of illness, while ELA complexes correlated strongly with inflammation markers, jaundice and increased respiratory rates. This study found strong correlations between circulating nucleosomes and neutrophil activation in patients with scrub typhus, but not murine typhus, providing indirect evidence that nucleosomes could originate from neutrophil extracellular trap (NET) degradation. High circulating plasma nucleosomes and ELA complexes represent independent risk factors for developing severe complications in scrub typhus. As nucleosomes and histones exposed on NETs are highly cytotoxic to endothelial cells and are strongly pro-coagulant, neutrophil-derived nucleosomes could contribute to vascular damage, the pro-coagulant state and exacerbation of disease in scrub typhus, thus indicating a detrimental role of neutrophil activation. The data suggest that increased neutrophil activation relates to disease progression and severe complications, and increased plasma levels of nucleosomes and ELA complexes represent independent risk factors for developing severe scrub typhus. PMID:26317419

  3. Toward the Treatment and Prevention of Alzheimer’s Disease: Rational Strategies and Recent Progress

    PubMed Central

    Gandy, Sam; DeKosky, Steven T.

    2013-01-01

    Alzheimer’s disease (AD) is the major cause of late-life brain failure. In the past 25 years, autosomal dominant forms of AD were found to be primariy attributable to mutations in one of two presenilins, polytopic proteins that contain the catalytic site of the ?-secretase protease that releases the amyloid beta (A?) peptide. Some familial AD is also due to mutations in the amyloid precursor protein (APP), but recently a mutation in APP was discovered that reduces A? generation and is protective against AD, further implicating amyloid metabolism. Prion-like seeding of amyloid fibrils and neurofibrillary tangles has been invoked to explain the stereotypical spread of AD within the brain. Treatment trials with anti-A? antibodies have shown target engagement, if not significant treatment effects. Attention is increasingly focused on presymptomatic intervention, because A? mismetabolism begins up to 25 years before symptoms begin. AD trials deriving from new biological information involve extraordinary international collaboration and may hold the best hope for success in the fight against AD. PMID:23327526

  4. DNA vaccines targeting human papillomavirus-associated diseases: progresses in animal and clinical studies

    PubMed Central

    Han, Kyusun Torque

    2013-01-01

    Human papillomavirus (HPV) infection is a major cause of cervical cancer and its precancerous diseases. Cervical cancer is the second deadliest cancer killer among women worldwide. Moreover, HPV is also known to be a causative agent of oral, pharyngeal, anal and genital cancer. Recent application of HPV structural protein (L1)-targeted prophylactic vaccines (Gardasil® and Cervarix®) is expected to reduce the incidence of HPV infection and cervical cancer, and possibly other HPV-associated cancers. However, the benefit of the prophylactic vaccines for treating HPV-infected patients is unlikely, underscoring the importance of developing therapeutic vaccines against HPV infection. In this regard, numerous types of therapeutic vaccine approaches targeting the HPV regulatory proteins, E6 and E7, have been tested for their efficacy in animals and clinically. In this communication, we review HPV vaccine types, in particular DNA vaccines, their designs and delivery by electroporation and their immunologic and antitumor efficacy in animals and humans, along with the basics of HPV and its pathogenesis. PMID:23858401

  5. Cortical Bone Mechanical Properties Are Altered in an Animal Model of Progressive Chronic Kidney Disease

    PubMed Central

    Newman, Christopher L.; Moe, Sharon M.; Chen, Neal X.; Hammond, Max A.; Wallace, Joseph M.; Nyman, Jeffry S.; Allen, Matthew R.

    2014-01-01

    Chronic kidney disease (CKD), which leads tocortical bone loss and increasedporosity,increases therisk of fracture. Animal models have confirmed that these changes compromise whole bone mechanical properties. Estimates from whole bone testing suggest that material properties are negatively affected, though tissue-level assessmentshavenot been conducted. Therefore, the goal of the present study was to examine changes in cortical bone at different length scales using a rat model with theprogressive development of CKD. At 30 weeks of age (?75% reduction in kidney function), skeletally mature male Cy/+ rats were compared to their normal littermates. Cortical bone material propertieswere assessed with reference point indentation (RPI), atomic force microscopy (AFM), Raman spectroscopy,and high performance liquid chromatography (HPLC). Bones from animals with CKD had higher (+18%) indentation distance increase and first cycle energy dissipation (+8%) as measured by RPI.AFM indentation revealed a broader distribution of elastic modulus values in CKD animals witha greater proportion of both higher and lower modulus values compared to normal controls. Yet, tissue composition, collagen morphology, and collagen cross-linking fail to account for these differences. Though the specific skeletal tissue alterations responsible for these mechanical differences remain unclear, these results indicate that cortical bone material properties are altered in these animals and may contribute to the increased fracture risk associated with CKD. PMID:24911162