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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. RandomForest4Life: a Random Forest for predicting ALS disease progression.

    PubMed

    Hothorn, Torsten; Jung, Hans H

    2014-09-01

    We describe a method for predicting disease progression in amyotrophic lateral sclerosis (ALS) patients. The method was developed as a submission to the DREAM Phil Bowen ALS Prediction Prize4Life Challenge of summer 2012. Based on repeated patient examinations over a three- month period, we used a random forest algorithm to predict future disease progression. The procedure was set up and internally evaluated using data from 1197 ALS patients. External validation by an expert jury was based on undisclosed information of an additional 625 patients; all patient data were obtained from the PRO-ACT database. In terms of prediction accuracy, the approach described here ranked third best. Our interpretation of the prediction model confirmed previous reports suggesting that past disease progression is a strong predictor of future disease progression measured on the ALS functional rating scale (ALSFRS). We also found that larger variability in initial ALSFRS scores is linked to faster future disease progression. The results reported here furthermore suggested that approaches taking the multidimensionality of the ALSFRS into account promise some potential for improved ALS disease prediction. PMID:25141076

  3. 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

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

    PubMed

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

    2014-06-01

    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 SOD1(G93A) and control: nontransgenic and SOD1(WT)) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1(G93A) 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

  5. EGFR Inhibitor Erlotinib Delays Disease Progression but Does Not Extend Survival in the SOD1 Mouse Model of ALS

    PubMed Central

    Le Pichon, Claire E.; Dominguez, Sara L.; Solanoy, Hilda; Ngu, Hai; Lewin-Koh, Nicholas; Chen, Mark; Eastham-Anderson, Jeffrey; Watts, Ryan; Scearce-Levie, Kimberly

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR) signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course. PMID:23638043

  6. Therapeutic AAV9-mediated Suppression of Mutant SOD1 Slows Disease Progression and Extends Survival in Models of Inherited ALS

    PubMed Central

    Foust, Kevin D; Salazar, Desirée L; Likhite, Shibi; Ferraiuolo, Laura; Ditsworth, Dara; Ilieva, Hristelina; Meyer, Kathrin; Schmelzer, Leah; Braun, Lyndsey; Cleveland, Don W; Kaspar, Brian K

    2013-01-01

    Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting in progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been linked to sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic patients and toxicity of astrocytes derived from sporadic ALS patients to motor neurons has been reported to be reduced by lowering the synthesis of SOD1. We now report slowed disease onset and progression in two mouse models following therapeutic delivery using a single peripheral injection of an adeno-associated virus serotype 9 (AAV9) encoding an shRNA to reduce the synthesis of ALS-causing human SOD1 mutants. Delivery to young mice that develop aggressive, fatal paralysis extended survival by delaying both disease onset and slowing progression. In a later-onset model, AAV9 delivery after onset markedly slowed disease progression and significantly extended survival. Moreover, AAV9 delivered intrathecally to nonhuman primates is demonstrated to yield robust SOD1 suppression in motor neurons and glia throughout the spinal cord and therefore, setting the stage for AAV9-mediated therapy in human clinical trials. PMID:24008656

  7. Synergistic Effects of GDNF and VEGF on Lifespan and Disease Progression in a Familial ALS Rat Model

    PubMed Central

    Krakora, Dan; Mulcrone, Patrick; Meyer, Michael; Lewis, Christina; Bernau, Ksenija; Gowing, Genevieve; Zimprich, Chad; Aebischer, Patrick; Svendsen, Clive N; Suzuki, Masatoshi

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord. We have recently shown that human mesenchymal stem cells (hMSCs) modified to release glial cell line-derived neurotrophic factor (GDNF) decrease disease progression in a rat model of ALS when delivered to skeletal muscle. In the current study, we determined whether or not this effect could be enhanced by delivering GDNF in concert with other trophic factors. hMSC engineered to secrete GDNF (hMSC-GDNF), vascular endothelial growth factor (hMSC-VEGF), insulin-like growth factor-I (hMSC-IGF-I), or brain-derived neurotrophic factor (hMSC-BDNF), were prepared and transplanted bilaterally into three muscle groups. hMSC-GDNF and hMSC-VEGF prolonged survival and slowed the loss of motor function, but hMSC-IGF-I and hMSC-BDNF did not have any effect. We then tested the efficacy of a combined ex vivo delivery of GDNF and VEGF in extending survival and protecting neuromuscular junctions (NMJs) and motor neurons. Interestingly, the combined delivery of these neurotrophic factors showed a strong synergistic effect. These studies further support ex vivo gene therapy approaches for ALS that target skeletal muscle. PMID:23712039

  8. 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; DAgostino, Dominic P.

    2014-01-01

    Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrigs 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

  9. Quantifying Disease Progression in Amyotrophic Lateral Sclerosis

    PubMed Central

    Simon, Neil G; Turner, Martin R; Vucic, Steve; Al-Chalabi, Ammar; Shefner, Jeremy; Lomen-Hoerth, Catherine; Kiernan, Matthew C

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic. PMID:25223628

  10. A novel acylaminoimidazole derivative, WN1316, alleviates disease progression via suppression of glial inflammation in ALS mouse model.

    PubMed

    Tanaka, Kazunori; Kanno, Takuya; 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 g/kg/day) WN1316 in ALS(SOD1(H46R)) and ALS(SOD1(G93A)) 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

  11. 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-1β 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

  12. Progression of glomerular diseases.

    PubMed

    Peten, E P; Striker, L J

    1994-09-01

    The nature and slope of progression of glomerular diseases is the subject of considerable discussion. The use of renal biopsies has been accompanied by considerable improvement in the classification of glomerular disease. However, the clinical and histological tools available to assess prognosis in individual patients lack accuracy, especially in slowly progressive glomerular diseases such as diabetes mellitus. The development of molecular biology tools provides a new approach to the analysis of glomerulosclerosis. The accumulation of extracellular matrix in the glomerulus results from an exaggerated synthesis of collagens and other molecules forming the basement membranes, and is accompanied by an increase in the corresponding mRNAs. The measure of local glomerular gene activation can therefore provide a dynamic view of glomerular scarring. Utilizing a method combining microdissection of the glomeruli, reverse transcription in situ and a competitive polymerase-chain-reaction assay we were able to measure minute amounts of mRNAs in single mouse and human glomeruli. Both in mouse models and in human glomerulosclerosis we found upregulation of basement membrane collagen genes in the glomeruli. The increase appeared to be parallel to the slope of progression of glomerulosclerosis in experimental animals. This new approach may therefore provide a quantitative and sensitive method to define the propensity to sclerosis in human disease. PMID:8077878

  13. Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression

    PubMed Central

    Gao, Hui-Ming; Hong, Jau-Shyong

    2016-01-01

    Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in discrete areas of the central nervous system (CNS). The mechanism(s) underlying their progressive nature remains unknown but a timely and well-controlled inflammatory reaction is essential for the integrity and proper function of the CNS. Substantial evidence has documented a common inflammatory mechanism in various neurodegenerative diseases. We hypothesize that in the diseased CNS, interactions between damaged neurons and dysregulated, overactivated microglia create a vicious self-propagating cycle causing uncontrolled, prolonged inflammation that drives the chronic progression of neurodegenerative diseases. We further propose that dynamic modulation of this inflammatory reaction by interrupting the vicious cycle might become a disease-modifying therapeutic strategy for neurodegenerative diseases. PMID:18599350

  14. Lou Gehrig's Disease (ALS)

    MedlinePlus

    ... but it is reassuring to know that the mind is not affected. People with the disease can think as clearly as ever, are able to maintain relationships with friends and family, and should be treated ...

  15. 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

  16. Rab11 in Disease Progression

    PubMed Central

    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

  17. Progression in prediagnostic Huntington disease

    PubMed Central

    Rupp, Jason; Blekher, Tanya; Jackson, Jacqueline; Beristain, Xabier; Marshall, Jeanine; Hui, Siu; Wojcieszek, Joanne; Foroud, Tatiana

    2010-01-01

    Objective To examine rates of decline in individuals at risk for Huntington disease (HD). Methods 106 individuals at risk for HD completed a battery of neurocognitive, psychomotor and oculomotor tasks at two visits, approximately 2.5 years apart. Participants were classified as: (1) without the CAG expansion (normal controls, NC; n=68) or (2) with the CAG expansion (CAG+; n=38). The CAG+ group was further subdivided into those near to (near; n=19) or far from (far; n=19) their estimated age of onset. Longitudinal performance in the CAG+ group was evaluated with a repeated measures model with two main effects (time to onset, visit) and their interaction. Analysis of covariance was employed to detect differences in longitudinal performance in the three groups (NC, near and far). Results In the CAG+, the interaction term was significant (p≤0.02) for four measures (movement time, alternate button tapping, variability of latency for a memory guided task and percentage of errors for a more complex memory guided task), suggesting the rate of decline was more rapid as subjects approached onset. Longitudinal progression in the three groups differed for several variables (p<0.05). In most, the near group had significantly faster progression than NC; however, comparisons of the NC and far groups were less consistent. Conclusions Different patterns of progression were observed during the prediagnostic period. For some measures, CAG+ subjects closer to estimated onset showed a more rapid decline while for other measures the CAG+ group had a constant rate of decline throughout the prediagnostic period that was more rapid than in NC. PMID:19726414

  18. Amyotrophic Lateral Sclerosis: A Focus on Disease Progression

    PubMed Central

    Calvo, Ana C.; Manzano, Raquel; Mendona, Deise M. F.; Muoz, Mara J.; Zaragoza, Pilar

    2014-01-01

    Since amyotrophic lateral sclerosis (ALS) was discovered and described in 1869 as a neurodegenerative disease in which motor neuron death is induced, a wide range of biomarkers have been selected to identify therapeutic targets. ALS shares altered molecular pathways with other neurodegenerative diseases, such as Alzheimer's, Huntington's, and Parkinson's diseases. However, the molecular targets that directly influence its aggressive nature remain unknown. What is the first link in the neurodegenerative chain of ALS that makes this disease so peculiar? In this review, we will discuss the progression of the disease from the viewpoint of the potential biomarkers described to date in human and animal model samples. Finally, we will consider potential therapeutic strategies for ALS treatment and future, innovative perspectives. PMID:25157374

  19. Slowly progressive apraxia in Alzheimer's disease.

    PubMed Central

    Green, R C; Goldstein, F C; Mirra, S S; Alazraki, N P; Baxt, J L; Bakay, R A

    1995-01-01

    Slowly progressive apraxia due to Alzheimer's disease was encountered in a 66 year old, right handed man whose initial impairments included coordinated movements of the left hand and some features of the alien hand syndrome. Over four years, the patient developed progressively worsening deficits of memory and language. A biopsy of his right temporal lobe showed numerous plaques and neurofibrillary tangles. Pronounced right parietal lobe hypoperfusion on serial SPECT suggests involvement of this region in contralateral praxis. Images PMID:7673964

  20. MAPK Usage in Periodontal Disease Progression

    PubMed Central

    Li, Qiyan; Valerio, Michael S.; Kirkwood, Keith L.

    2012-01-01

    In periodontal disease, host recognition of bacterial constituents, including lipopolysaccharide (LPS), induces p38 MAPK activation and subsequent inflammatory cytokine expression, favoring osteoclastogenesis and increased net bone resorption in the local periodontal environment. In this paper, we discuss evidence that the p38/MAPK-activated protein kinase-2 (MK2) signaling axis is needed for periodontal disease progression: an orally administered p38α inhibitor reduced the progression of experimental periodontal bone loss by reducing inflammation and cytokine expression. Subsequently, the significance of p38 signaling was confirmed with RNA interference to attenuate MK2-reduced cytokine expression and LPS-induced alveolar bone loss. MAPK phosphatase-1 (MKP-1), a negative regulator of MAPK activation, was also critical for periodontal disease progression. In MPK-1-deficient mice, p38-sustained activation increased osteoclast formation and bone loss, whereas MKP-1 overexpression dampened p38 signaling and subsequent cytokine expression. Finally, overexpression of the p38/MK2 target RNA-binding tristetraprolin (TTP) decreased mRNA stability of key inflammatory cytokines at the posttranscriptional level, thereby protecting against periodontal inflammation. Collectively, these studies highlight the importance of p38 MAPK signaling in immune cytokine production and periodontal disease progression. PMID:22315682

  1. 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

  2. Progression of Glomerular and Tubular Disease

    PubMed Central

    Woroniecki, Robert P.; Schnaper, H. William

    2015-01-01

    Chronic kidney disease may be stimulated by many different etiologies, but its progression involves a common, yet complex, series of events that lead to the replacement of normal tissue with scar. These events include altered physiology within the kidney leading to abnormal hemodynamics, chronic hypoxia, inflammation, cellular dysfunction and activation of fibrogenic biochemical pathways. The end result is the replacement of normal structures with extracellular matrix. Treatments are presently focused on delaying or preventing such progression, and are largely nonspecific. In pediatrics, such therapy is further complicated by both pathophysiological issues that render children a unique population. PMID:19615562

  3. Genetic determinants of disease progression in Alzheimer’s disease

    PubMed Central

    Wang, Xingbin; Lopez, Oscar L.; Sweet, Robert A.; Becker, James .T; DeKosky, Steven T.; Barmada, Mahmud M.; Demirci, F. Yesim; Kamboh, M. Ilyas.

    2014-01-01

    There is a strong genetic basis for late-onset of Alzheimer’s disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer’s Disease Research Center. Patients were classified as “rapid progressors” if the MMSE changed ≥3 points in 12 months and “slow progressors” if the MMSE changed ≤2 points. We also performed a genome-wide association study in this cohort in an effort to identify new loci for AD progression. Association analysis between SNPs and the progression status of the AD cases was performed using logistic regression model controlled for age, gender, dementia medication use, psychosis, and hypertension. While no significant association was observed with either APOE*4 (p=0.94) or APOE*2 (p=0.33) with AD progression, we found multiple nominally significant associations (p<0.05) either within or adjacent to seven known LOAD genes (INPP5D, MEF2C, TREM2, EPHA1, PTK2B, FERMT2 and CASS4) that harbor both risk and protective SNPs. Genome-wide association analyses identified four suggestive loci (PAX3, CCRN4L, PIGQ and ADAM19) at p<1E-05. Our data suggest that short-term clinical disease progression in AD has genetic basis. Better understanding of these genetic factors could help to improve clinical trial design and potentially affect the development of disease modifying therapies. PMID:25114068

  4. Multiple Orderings of Events in Disease Progression.

    PubMed

    Young, Alexandra L; Oxtoby, Neil P; Huang, Jonathan; Marinescu, Razvan V; Daga, Pankaj; Cash, David M; Fox, Nick C; Ourselin, Sebastien; Schott, Jonathan M; Alexander, Daniel C

    2015-01-01

    The event-based model constructs a discrete picture of disease progression from cross-sectional data sets, with each event corresponding to a new biomarker becoming abnormal. However, it relies on the assumption that all subjects follow a single event sequence. This is a major simplification for sporadic disease data sets, which are highly heterogeneous, include distinct subgroups, and contain significant proportions of outliers. In this work we relax this assumption by considering two extensions to the event-based model: a generalised Mallows model, which allows subjects to deviate from the main event sequence, and a Dirichlet process mixture of generalised Mallows models, which models clusters of subjects that follow different event sequences, each of which has a corresponding variance. We develop a Gibbs sampling technique to infer the parameters of the two models from multi-modal biomarker data sets. We apply our technique to data from the Alzheimer's Disease Neuroimaging Initiative to determine the sequence in which brain regions become abnormal in sporadic Alzheimer's disease, as well as the heterogeneity of that sequence in the cohort. We find that the generalised Mallows model estimates a larger variation in the event sequence across subjects than the original event-based model. Fitting a Dirichlet process model detects three subgroups of the population with different event sequences. The Gibbs sampler additionally provides an estimate of the uncertainty in each of the model parameters, for example an individual's latent disease stage and cluster assignment. The distributions and mixtures of sequences that this new family of models introduces offer better characterisation of disease progression of heterogeneous populations, new insight into disease mechanisms, and have the potential for enhanced disease stratification and differential diagnosis. PMID:26223048

  5. Pregnancy and chronic progressive pulmonary disease.

    PubMed

    Wexler, Isaiah D; Johannesson, Marie; Edenborough, Frank P; Sufian, Beth S; Kerem, Eitan

    2007-02-15

    Progressive pulmonary disease may preclude the option of pregnancy for a number of women in their child-bearing years due to the severity of the disease. For a subset of women with chronic lung disease including cystic fibrosis, pregnancy is possible, but can have a devastating effect both on the prospective mother and fetus. The potential hazards of pregnancy in cystic fibrosis or other progressive pulmonary diseases may trigger a moral conflict between physician and patient. The female patient may argue that her autonomy cannot be circumscribed and that the physician is obliged to assist her reproductive efforts. The physician can counter that his/her participation in potentially harmful interventions is not consistent with professional norms requiring adherence to the principles of beneficence and nonmaleficence. Whenever possible, the ethical conflict between physician and patient should be resolved before initiation of pregnancy. We propose that this best be done through structured negotiations between physician and patient with the goal of constructing an ethical framework for reducing the moral tension between the two. Steps in the negotiating process include defining the therapeutic alliance, information exchange, dialog, and deliberation. As part of the information exchange, it is important to discuss alternatives to pregnancy such as adoption and surrogacy, especially when there are strong contraindications to pregnancy. If negotiations reach a satisfactory conclusion for both sides, there should be a well-delineated consensual agreement to commence the pregnancy with the full support of the medical team. PMID:17110647

  6. [Progression of coronary disease: minutes, weeks, decades...].

    PubMed

    Weber, S

    2008-02-01

    The slow progression over decades of coronary atheroma is often compensated for by arterial remodeling and collateral circulation. Coronary artery disease is therefore often asymptomatic. Sudden rupture of unstable atheromatous plaque always leads to endocoronary thrombus formation. The magnitude and the time frame of this endovascular thrombotic process determine the severity of its clinical consequences: no symptoms, exercise angina, unstable angina, acute transmural myocardial infarction, or sudden death. Two amply validated treatments have the potential to decrease both the probability and the severity of plaque rupture: statins and platelet inhibitors, which are both indicated in all cases of coronary disease. The other therapeutic tools - anti-ischemic drugs, ACE inhibitors, angioplasty, and coronary bypass - are widely used in the management of coronary disease, but their indications should be tailored to each individual clinical situation. PMID:18472027

  7. Metabolome in progression to Alzheimer's disease

    PubMed Central

    Orešič, M; Hyötyläinen, T; Herukka, S-K; Sysi-Aho, M; Mattila, I; Seppänan-Laakso, T; Julkunen, V; Gopalacharyulu, P V; Hallikainen, M; Koikkalainen, J; Kivipelto, M; Helisalmi, S; Lötjönen, J; Soininen, H

    2011-01-01

    Mild cognitive impairment (MCI) is considered as a transition phase between normal aging and Alzheimer's disease (AD). MCI confers an increased risk of developing AD, although the state is heterogeneous with several possible outcomes, including even improvement back to normal cognition. We sought to determine the serum metabolomic profiles associated with progression to and diagnosis of AD in a prospective study. At the baseline assessment, the subjects enrolled in the study were classified into three diagnostic groups: healthy controls (n=46), MCI (n=143) and AD (n=47). Among the MCI subjects, 52 progressed to AD in the follow-up. Comprehensive metabolomics approach was applied to analyze baseline serum samples and to associate the metabolite profiles with the diagnosis at baseline and in the follow-up. At baseline, AD patients were characterized by diminished ether phospholipids, phosphatidylcholines, sphingomyelins and sterols. A molecular signature comprising three metabolites was identified, which was predictive of progression to AD in the follow-up. The major contributor to the predictive model was 2,4-dihydroxybutanoic acid, which was upregulated in AD progressors (P=0.0048), indicating potential involvement of hypoxia in the early AD pathogenesis. This was supported by the pathway analysis of metabolomics data, which identified upregulation of pentose phosphate pathway in patients who later progressed to AD. Together, our findings primarily implicate hypoxia, oxidative stress, as well as membrane lipid remodeling in progression to AD. Establishment of pathogenic relevance of predictive biomarkers such as ours may not only facilitate early diagnosis, but may also help identify new therapeutic avenues. PMID:22832349

  8. [Progress in epigenetic research on Alzheimer disease].

    PubMed

    Yang, Nannan; Wei, Yang; Xu, Qian; Tang, Beisha

    2016-04-01

    Alzheimer's disease(AD) is the most common neurodegenerative disorder, which features mainly with memory impairment as the initial symptom of progressive loss of cognitive function. Its main pathological changes include senile plaques and neurofibrillary tangles. The pathogenesis of AD is still unclear, though it may be connected with aging, genetic factors and environmental factors. Among these, aging and environmental factors can be modified by epigenetics. In this paper, advances in the study of epigenetic mechanisms related to the pathogenesis of AD are reviewed. PMID:27060329

  9. Experimental Progress on the NIST ^27Al^+ Optical Clock

    NASA Astrophysics Data System (ADS)

    Chou, Chin-Wen; Hume, David B.; Koelemeij, Jeroen C. J.; Rosenband, Till; Bergquist, James C.; Wineland, Dave J.

    2009-05-01

    A recent measurement of the frequency ratio between single-ion optical clocks based on ^27Al^+ and ^199Hg^+ at NIST showed a combined statistical and systematic uncertainty of 5.2 x 10-17[1]. Here we report progress on improving both the accuracy and stability of the ^27Al^+ optical clock. We have developed a new trap and laser systems that enable the use of ^25Mg^+ for sympathetic cooling and clock-state detection of ^27Al^+. These developments should reduce time-dilation shifts caused by harmonic motion of the ions and thus lower the dominant systematic uncertainty below 10-17. In the new clock apparatus we have demonstrated spectroscopy of the ^27Al^+ ^1S0 to ^3P0 transition with a quality factor of Q = 3.5 x 10^14 and simultaneously a contrast approaching unity. In addition, we have developed techniques for the sympathetic laser cooling and quantum logic spectroscopy of multiple aluminum ions with the goal of further improving measurement stability [2]. *supported by ONR and NIST [1] T. Rosenband et al., Science 319, 1808 (2008) [2] D. B. Hume et al., Phys. Rev. Lett. 99, 120502 (2007)

  10. Crevicular Fluid Biomarkers and Periodontal Disease Progression

    PubMed Central

    Oh, Min; Braun, Thomas M.; Ramseier, Christoph A.; Sugai, Jim V.; Giannobile, William V.

    2014-01-01

    Aim Assess the ability of a panel of gingival crevicular fluid (GCF) biomarkers as predictors of periodontal disease progression (PDP). Materials and Methods 100 individuals participated in a 12-month longitudinal investigation and categorized into 4 groups according to their periodontal status. GCF, clinical parameters, and saliva were collected bi-monthly. Sub-gingival plaque and serum were collected bi-annually. For 6 months, no periodontal treatment was provided. At 6-months, patients received periodontal therapy and continued participation from 6-12 months. GCF samples were analyzed by ELISA for MMP-8, MMP-9, OPG, CRP and IL-1β. Differences in median levels of GCF biomarkers were compared between stable and progressing participants using Wilcoxon Rank Sum test (p=0.05). Clustering algorithm was used to evaluate the ability of oral biomarkers to classify patients as either stable or progressing. Results Eighty-three individuals completed the 6-month monitoring phase. With the exception of GCF C-reactive protein, all biomarkers were significantly higher in the PDP group compared to stable patients. Clustering analysis showed highest sensitivity levels when biofilm pathogens and GCF biomarkers were combined with clinical measures, 74% (95% CI = 61,86). Conclusions Signature of GCF fluid-derived biomarkers combined with pathogens and clinical measures provides a sensitive measure for discrimination of PDP (ClinicalTrials.gov NCT00277745). PMID:24303954

  11. Measuring disease progression in corticobasal syndrome.

    PubMed

    Huang, Nancy; Hornberger, Michael; Hodges, John R; Burrell, James R

    2014-08-01

    Corticobasal syndrome (CBS) is a complex neurodegenerative disorder with marked clinical, neuropsychological, and pathological heterogeneity. Measurement of disease progression in CBS is complex and little understood. This study aimed to establish clinical and neuropsychological indicators of prognosis in CBS. Patients with CBS were retrospectively recruited from a frontotemporal dementia specific research clinic. All patients underwent detailed clinical and neuropsychological testing including the frontotemporal dementia rating scale (FRS). Using the differences in FRS logit scores over a period of 12 months, CBS patients were divided into rapid and slow progressor groups. Demographic, clinical and neuropsychological features were compared between the two groups. Sixteen participants who met defined criteria were included (9 males, 7 females; mean age 65.8 ± 22 years; median symptom duration 51.8 ± 22 years; mean duration of follow-up 11.4 ± 2.8 months). There were no significant differences between the rapid and slow progressors in age, gender, symptom duration, motor/cognitive presentation, and ACE-R scores at baseline. Clinically, slow progressors were significantly more likely to have a motor speech disorder, with a trend for more frequent dysgraphia, whereas rapid progressors were more likely to exhibit surface dyslexia. Rapid and slow progressor groups did not differ on neuropsychological performance. The presence of motor speech disorder, dysgraphia, and surface dyslexia may be useful in differentiating patients with rapid progression of CBS from those with a more indolent disease course. PMID:24893591

  12. 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

  13. Putaminal Diffusivity Correlates With Disease Progression in Parkinson's Disease

    PubMed Central

    Chan, Ling-Ling; Ng, Kia-Min; Yeoh, Chooi-Sum; Rumpel, H.; Li, Hui-Hua; Tan, Eng-King

    2016-01-01

    Abstract Diffusion tensor imaging (DTI) is an increasingly used noninvasive imaging tool. However its long-term clinical utility is unclear. Parkinson's disease (PD) is a common neurodegenerative disease. We prospectively examined a cohort of 46 Parkinson's disease (PD) patients who underwent diffusion tensor imaging (DTI) of the brain at baseline and 6 years later on a 1.5 Tesla scanner using a standardized protocol. DTI parameters of mean diffusivity (MD) and fractional anisotrophy (FA) were extracted using regions-of-interest (ROIs) analysis from various brain regions. Compared to the baseline scan, MD increased in all brain regions (P < 0.0001). FA increased in the substantia nigra and posterior putamen, but decreased in the frontal white matter (P < 0.0001). Linear regression analysis demonstrated that the MD in the anterior putamen increased 11.6 units (95% CI = [4.71, 18.43]) (P = 0.0003) for every unit increase of United PD Rating Scale (UPDRS). Our 6-year prospective longitudinal study demonstrated increased diffusivity in all brain regions and that in the anterior putamen correlated with disease progression. Serial diffusion data may be useful as an additional objective in vivo biomarker for motor progression in PD. PMID:26871779

  14. 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 EIMs 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 techniques 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

  15. Progressive Nodular Histiocytosis Associated with Eale's Disease

    PubMed Central

    Williams, Abhilasha; Thomas, Abraham G; Kwatra, Kanwardeep Singh; Jain, Kunal

    2015-01-01

    Progressive nodular histiocytosis (PNH) is a rare normolipemic macrophage disorder and belongs to a subgroup of non-Langerhans cell histiocytosis (LCHs) which is characterized by a progressive course with no sign of spontaneous resolution but without systemic involvement. We report a 30-year-old gentleman who presented with skin lesions all over the body associated with gradual bilateral painless loss of vision. On examination, approximately 30 to 40, skin-colored, firm, non-tender papules and nodules were noted over the body especially on the face and trunk. A skin biopsy revealed a cellular tumor in the dermis composed of oval to spindle-shaped cells, positive for CD68 but negative for S-100, CD34, CD21, CD35 and HMB45, supporting a diagnosis of spindle cell histiocytic tumor. Ophthalmic examination revealed a generalized arteriolar attenuation in both eyes. He received Tab Imatinib 400 mg OD for 5 months followed by Tab Pazopanib 800 mg OD for 4 months and both the drugs were stopped due to lack of any response in the skin lesions. We report this case due to its rarity, characteristic clinical presentation, and its association with Eale's disease. Primary treatment remains surgical excision of bothersome lesions and optimal systemic treatment is still unknown. PMID:26288410

  16. PABPN1 suppresses TDP-43 toxicity in ALS disease models.

    PubMed

    Chou, Ching-Chieh; Alexeeva, Olga M; Yamada, Shizuka; Pribadi, Amy; Zhang, Yi; Mo, Bi; Williams, Kathryn R; Zarnescu, Daniela C; Rossoll, Wilfried

    2015-09-15

    TAR DNA-binding protein 43 (TDP-43) is a major disease protein in amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases. Both the cytoplasmic accumulation of toxic ubiquitinated and hyperphosphorylated TDP-43 fragments and the loss of normal TDP-43 from the nucleus may contribute to the disease progression by impairing normal RNA and protein homeostasis. Therefore, both the removal of pathological protein and the rescue of TDP-43 mislocalization may be critical for halting or reversing TDP-43 proteinopathies. Here, we report poly(A)-binding protein nuclear 1 (PABPN1) as a novel TDP-43 interaction partner that acts as a potent suppressor of TDP-43 toxicity. Overexpression of full-length PABPN1 but not a truncated version lacking the nuclear localization signal protects from pathogenic TDP-43-mediated toxicity, promotes the degradation of pathological TDP-43 and restores normal solubility and nuclear localization of endogenous TDP-43. Reduced levels of PABPN1 enhances the phenotypes in several cell culture and Drosophila models of ALS and results in the cytoplasmic mislocalization of TDP-43. Moreover, PABPN1 rescues the dysregulated stress granule (SG) dynamics and facilitates the removal of persistent SGs in TDP-43-mediated disease conditions. These findings demonstrate a role for PABPN1 in rescuing several cytopathological features of TDP-43 proteinopathy by increasing the turnover of pathologic proteins. PMID:26130692

  17. Early and progressive impairment of spinal blood flow–glucose metabolism coupling in motor neuron degeneration of ALS model mice

    PubMed Central

    Miyazaki, Kazunori; Masamoto, Kazuto; Morimoto, Nobutoshi; Kurata, Tomoko; Mimoto, Takahumi; Obata, Takayuki; Kanno, Iwao; Abe, Koji

    2012-01-01

    The exact mechanism of selective motor neuron death in amyotrophic lateral sclerosis (ALS) remains still unclear. In the present study, we performed in vivo capillary imaging, directly measured spinal blood flow (SBF) and glucose metabolism, and analyzed whether if a possible flow–metabolism coupling is disturbed in motor neuron degeneration of ALS model mice. In vivo capillary imaging showed progressive decrease of capillary diameter, capillary density, and red blood cell speed during the disease course. Spinal blood flow was progressively decreased in the anterior gray matter (GM) from presymptomatic stage to 0.80-fold of wild-type (WT) mice, 0.61 at early-symptomatic, and 0.49 at end stage of the disease. Local spinal glucose utilization (LSGU) was transiently increased to 1.19-fold in anterior GM at presymptomatic stage, which in turn progressively decreased to 0.84 and 0.60 at early-symptomatic and end stage of the disease. The LSGU/SBF ratio representing flow–metabolism uncoupling (FMU) preceded the sequential pathological changes in the spinal cord of ALS mice and was preferentially found in the affected region of ALS. The present study suggests that this early and progressive FMU could profoundly involve in the whole disease process as a vascular factor of ALS pathology, and could also be a potential target for therapeutic intervention of ALS. PMID:22068226

  18. 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

  19. Progress Report on Alzheimer Disease: Volume III.

    ERIC Educational Resources Information Center

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

    This report summarizes advances in the understanding of Alzheimer's disease, the major cause of mental disability among older Americans. The demography of the disease is discussed, noting that approximately 2.5 million American adults are afflicted with the disease and that the large increase in the number of Alzheimer's disease patients is due to…

  20. When progressive disease does not mean treatment failure: reconsidering the criteria for progression.

    PubMed

    Oxnard, Geoffrey R; Morris, Michael J; Hodi, F Stephen; Baker, Laurence H; Kris, Mark G; Venook, Alan P; Schwartz, Lawrence H

    2012-10-17

    Although progression-based endpoints, such as progression-free survival, are often key clinical trial endpoints for anticancer agents, the clinical meaning of "objective progression" is much less certain. As scrutiny of progression-based endpoints in clinical trials increases, it should be remembered that the Response Evaluation Criteria In Solid Tumors (RECIST) progression criteria were not developed as a surrogate for survival. Now that progression-free survival has come to be an increasingly important trial endpoint, the criteria that define progression deserve critical evaluation to determine whether alternate definitions of progression might facilitate the development of stronger surrogate endpoints and more meaningful trial results. In this commentary, we review the genesis of the criteria for progression, highlight recent data that question their value as a marker of treatment failure, and advocate for several research strategies that could lay the groundwork for a clinically validated definition of disease progression in solid tumor oncology. PMID:22927506

  1. Stop chronic kidney disease progression: Time is approaching

    PubMed Central

    Sharaf El Din, Usama Abdel Azim; Salem, Mona Mansour; Abdulazim, Dina Ossama

    2016-01-01

    Progression of chronic kidney disease (CKD) is inevitable. However, the last decade has witnessed tremendous achievements in this field. Today we are optimistic; the dream of withholding this progression is about to be realistic. The recent discoveries in the field of CKD management involved most of the individual diseases leading the patients to end-stage renal disease. Most of these advances involved patients suffering diabetic kidney disease, chronic glomerulonephritis, polycystic kidney disease, renal amyloidosis and chronic tubulointerstitial disease. The chronic systemic inflammatory status and increased oxidative stress were also investigated. This inflammatory status influences the anti-senescence Klotho gene expression. The role of Klotho in CKD progression together with its therapeutic value are explored. The role of gut as a major source of inflammation, the pathogenesis of intestinal mucosal barrier damage, the role of intestinal alkaline phosphatase and the dietary and therapeutic implications add a novel therapeutic tool to delay CKD progression. PMID:27152262

  2. Stop chronic kidney disease progression: Time is approaching.

    PubMed

    Sharaf El Din, Usama Abdel Azim; Salem, Mona Mansour; Abdulazim, Dina Ossama

    2016-05-01

    Progression of chronic kidney disease (CKD) is inevitable. However, the last decade has witnessed tremendous achievements in this field. Today we are optimistic; the dream of withholding this progression is about to be realistic. The recent discoveries in the field of CKD management involved most of the individual diseases leading the patients to end-stage renal disease. Most of these advances involved patients suffering diabetic kidney disease, chronic glomerulonephritis, polycystic kidney disease, renal amyloidosis and chronic tubulointerstitial disease. The chronic systemic inflammatory status and increased oxidative stress were also investigated. This inflammatory status influences the anti-senescence Klotho gene expression. The role of Klotho in CKD progression together with its therapeutic value are explored. The role of gut as a major source of inflammation, the pathogenesis of intestinal mucosal barrier damage, the role of intestinal alkaline phosphatase and the dietary and therapeutic implications add a novel therapeutic tool to delay CKD progression. PMID:27152262

  3. Metabolic acidosis and the progression of chronic kidney disease

    PubMed Central

    2014-01-01

    Metabolic acidosis is a common complication of chronic kidney disease. Accumulating evidence identifies acidosis not only as a consequence of, but as a contributor to, kidney disease progression. Several mechanistic pathways have been identified in this regard. The dietary acid load, even in the absence of overt acidosis, may have deleterious effects. Several small trials now suggest that the treatment of acidosis with oral alkali can slow the progression of kidney disease. PMID:24708763

  4. Frontal deficits differentiate progressive supranuclear palsy from Parkinson's disease.

    PubMed

    Lee, Young-Eun C; Williams, David R; Anderson, Jacqueline F I

    2016-03-01

    The clinical differentiation of progressive supranuclear palsy from Parkinson's disease can be challenging, due to overlapping clinical features and a lack of diagnostic markers. Abnormalities in cognitive function form part of the clinical spectrums of these diseases and distinctive cognitive profiles may be helpful in differentiating these diseases in the diagnostic period. A comprehensive neuropsychological test battery was administered to 12 patients with clinically diagnosed progressive supranuclear palsy and 12 patients with Parkinson's disease matched for age and disease duration. Effect size (Cohen's d) was calculated for cognitive tests that were significantly different between groups. Patients with progressive supranuclear palsy performed significantly worse than those with Parkinson's disease on measures of processing speed, verbal fluency, planning, verbal abstract reasoning, verbal memory, and made more perseverative responses on a set shifting task. Measures of executive function, manual dexterity and processing speed were most diagnostically useful (Cohen's d > 2.0) in differentiating between progressive supranuclear palsy and Parkinson's disease. These findings suggest that more severe and prominent 'frontal' cognitive deficits in patients with progressive parkinsonism would be helpful in predicting progressive supranuclear palsy rather than Parkinson's disease and these findings may contribute to the development of diagnostic criteria. PMID:25223526

  5. 2014-2015 Alzheimer's Disease Progress Report

    MedlinePlus

    ... much of the world. In January 2011, President Obama signed the National Alzheimer’s Project Act (NAPA), which called for an aggressive and coordinated U.S. plan to accelerate Alzheimer’s disease research, provide better clinical care, and improve services for people with the disease ...

  6. 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…

  7. Progress and Challenges in Infectious Disease Cartography.

    PubMed

    Kraemer, Moritz U G; Hay, Simon I; Pigott, David M; Smith, David L; Wint, G R William; Golding, Nick

    2016-01-01

    Quantitatively mapping the spatial distributions of infectious diseases is key to both investigating their epidemiology and identifying populations at risk of infection. Important advances in data quality and methodologies have allowed for better investigation of disease risk and its association with environmental factors. However, incorporating dynamic human behavioural processes in disease mapping remains challenging. For example, connectivity among human populations, a key driver of pathogen dispersal, has increased sharply over the past century, along with the availability of data derived from mobile phones and other dynamic data sources. Future work must be targeted towards the rapid updating and dissemination of appropriately designed disease maps to guide the public health community in reducing the global burden of infectious disease. PMID:26604163

  8. 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 Δ≥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

  9. Suppressed autophagy flux in skeletal muscle of an amyotrophic lateral sclerosis mouse model during disease progression

    PubMed Central

    Xiao, Yajuan; Ma, Changling; Yi, Jianxun; Wu, Shaoping; Luo, Guo; Xu, Xiulong; Lin, Pei‐Hui; Sun, Jun; Zhou, Jingsong

    2015-01-01

    Abstract Accumulation of abnormal protein inclusions is implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Autophagy, an intracellular process targeting misfolded proteins and damaged organelles for lysosomal degradation, plays crucial roles in survival and diseased conditions. Efforts were made to understand the role of autophagy in motor neuron degeneration and to target autophagy in motor neuron for ALS treatment. However, results were quite contradictory. Possible autophagy defects in other cell types may also complicate the results. Here, we examined autophagy activity in skeletal muscle of an ALS mouse model G93A. Through overexpression of a fluorescent protein LC3‐RFP, we found a basal increase in autophagosome formation in G93A muscle during disease progression when the mice were on a regular diet. As expected, an autophagy induction procedure (starvation plus colchicine) enhanced autophagy flux in skeletal muscle of normal mice. However, in response to the same autophagy induction procedure, G93A muscle showed significant reduction in the autophagy flux. Immunoblot analysis revealed that increased cleaved caspase‐3 associated with apoptosis was linked to the cleavage of several key proteins involved in autophagy, including Beclin‐1, which is an essential molecule connecting autophagy and apoptosis pathways. Taking together, we provide the evidence that the cytoprotective autophagy pathway is suppressed in G93A skeletal muscle and this suppression may link to the enhanced apoptosis during ALS progression. The abnormal autophagy activity in skeletal muscle likely contributes muscle degeneration and disease progression in ALS. PMID:25602021

  10. Progressive endolysosomal deficits impair autophagic clearance beginning at early asymptomatic stages in fALS mice.

    PubMed

    Xie, Yuxiang; Zhou, Bing; Lin, Mei-Yao; Sheng, Zu-Hang

    2015-10-01

    Autophagy is an important homeostatic process that functions by eliminating defective organelles and aggregated proteins over a neuron's lifetime. One pathological hallmark in amyotrophic lateral sclerosis (ALS)-linked motor neurons (MNs) is axonal accumulation of autophagic vacuoles (AVs), thus raising a fundamental question as to whether reduced autophagic clearance due to an impaired lysosomal system contributes to autophagic stress and axonal degeneration. We recently revealed progressive lysosomal deficits in spinal MNs beginning at early asymptomatic stages in fALS-linked mice expressing the human (Hs) SOD1(G93A) protein. Such deficits impair the degradation of AVs engulfing damaged mitochondria from distal axons. These early pathological changes are attributable to mutant HsSOD1, which interferes with dynein-driven endolysosomal trafficking. Elucidation of this pathological mechanism is broadly relevant, because autophagy-lysosomal deficits are associated with several major neurodegenerative diseases. Therefore, enhancing autophagic clearance by rescuing endolysosomal trafficking may be a potential therapeutic strategy for ALS and perhaps other neurodegenerative diseases. PMID:26290961

  11. Microglial Activation Correlates with Disease Progression and Upper Motor Neuron Clinical Symptoms in Amyotrophic Lateral Sclerosis

    PubMed Central

    Brettschneider, Johannes; Toledo, Jon B.; Van Deerlin, Vivianna M.; Elman, Lauren; McCluskey, Leo; Lee, Virginia M.-Y.; Trojanowski, John Q.

    2012-01-01

    Background/Aims We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with alterations in microglial inflammatory activity. Methods Microglial pathology was assessed by IHC with 2 different antibodies (CD68, Iba1), myelin loss by Kluver-Barrera staining and myelin basic protein (MBP) IHC, and axonal loss by neurofilament protein (TA51) IHC, performed on 59 autopsy cases of ALS including 9 cases with C9ORF72 repeat expansion. Results Microglial pathology as depicted by CD68 and Iba1 was significantly more extensive in the corticospinal tract (CST) of ALS cases with a rapid progression of disease. Cases with C9ORF72 repeat expansion showed more extensive microglial pathology in the medulla and motor cortex which persisted after adjusting for disease duration in a logistic regression model. Higher scores on the clinical UMN scale correlated with increasing microglial pathology in the cervical CST. TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease. Conclusions This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits. PMID:22720079

  12. Recent achievements in restorative neurology: Progressive neuromuscular diseases

    SciTech Connect

    Dimitrijevic, M.R.; Kakulas, B.A.; Vrbova, G.

    1986-01-01

    This book contains 27 chapters. Some of the chapter titles are: Computed Tomography of Muscles in Neuromuscular Disease; Mapping the Genes for Muscular Dystrophy; Trophic Factors and Motor Neuron Development; Size of Motor Units and Firing Rate in Muscular Dystrophy; Restorative Possibilities in Relation to the Pathology of Progressive Neuromuscular Disease; and An Approach to the Pathogenesis of some Congenital Myopathies.

  13. [Various pathways leading to the progression of chronic liver diseases].

    PubMed

    Egresi, Anna; Lengyel, Gabriella; Somogyi, Anik; Blzovics, Anna; Hagymsi, Krisztina

    2016-02-01

    As the result of various effects (viruses, metabolic diseases, nutritional factors, toxic agents, autoimmune processes) abnormal liver function, liver steatosis and connective tissue remodeling may develop. Progression of this process is complex including various pathways and a number of factors. The authors summarize the factors involved in the progression of chronic liver disease. They describe the role of cells and the produced inflammatory mediators and cytokines, as well as the relationship between the disease and the intestinal flora. They emphasize the role of oxidative stress, mitochondrial dysfunction and cell death in disease progression. Insulin resistance and micro-elements (iron, copper) in relation to liver damage are also discussed, and genetic and epigenetic aspects underlying disease progression are summarized. Discovery of novel treatment options, assessment of the effectiveness of treatment, as well as the success and proper timing of liver transplantation may depend on a better understanding of the process of disease progression. Orv. Hetil., 2016, 157(8), 290-297. PMID:26876265

  14. Disease origin and progression in amyotrophic lateral sclerosis: an immunology perspective.

    PubMed

    Malaspina, Andrea; Puentes, Fabiola; Amor, Sandra

    2015-03-01

    The immune system is inextricably linked with many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a devastating neuromuscular disorder affecting motor cell function with an average survival of 3 years from symptoms onset. In ALS, there is a dynamic interplay between the resident innate immune cells, that is, microglia and astrocytes, which may become progressively harmful to motor neurons. Although innate and adaptive immune responses are associated with progressive neurodegeneration, in the early stages of ALS immune activation pathways are primarily considered to be beneficial promoting neuronal repair of the damaged tissues, though a harmful effect of T cells at this stage of disease has also been observed. In addition, although auto-antibodies against neuronal antigens are present in ALS, it is unclear whether these arise as a primary or secondary event to neuronal damage, and whether the auto-antibodies are indeed pathogenic. Understanding how the immune system contributes to the fate of motor cells in ALS may shed light on the triggers of disease as well as on the mechanisms contributing to the propagation of the pathology. Immune markers may also act as biomarkers while pathways involved in immune action may be targets of new therapeutic strategies. Here, we review the modalities by which the immune system senses the core pathological process in motor neuron disorders, focusing on tissue-specific immune responses in the neuromuscular junction and in the neuroaxis observed in affected individuals and in animal models of ALS. We elaborate on existing data on the immunological fingerprint of ALS that could be used to identify clues on the disease origin and patterns of progression. PMID:25344935

  15. Urinary Stone Disease: Progress, Status, and Needs.

    PubMed

    Kirkali, Ziya; Rasooly, Rebekah; Star, Robert A; Rodgers, Griffin P

    2015-10-01

    Urinary stone disease (USD) is an important healthcare problem in the US affecting both adults and children, and costs $10 billion to the nation. Prevalence of USD has nearly doubled during the last 15 years in parallel to the obesity and type 2 diabetes epidemic. Despite the advances in the management of an acute episode, one of three stone formers experience recurrence. A better understanding of stone formation is necessary to develop secondary prevention strategies. There are many unanswered research questions that require a multidisciplinary approach. National Institute of Diabetes and Digestive and Kidney Diseases recently held a workshop on USD, and is committed to continue conducting and supporting research in this field. PMID:26190090

  16. 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

  17. Markers predicting progression of human immunodeficiency virus-related disease.

    PubMed Central

    Tsoukas, C M; Bernard, N F

    1994-01-01

    Human immunodeficiency virus (HIV) interacts with the immune system throughout the course of infection. For most of the disease process, HIV activates the immune system, and the degree of activation can be assessed by measuring serum levels of molecules such as beta 2-microglobulin and neopterin, as well as other serum and cell surface phenotype markers. The levels of some of these markers correlate with clinical progression of HIV disease, and these markers may be useful as surrogate markers for development of clinical AIDS. Because the likelihood and timing of development of clinical AIDS following seroconversion, for any particular individual, are not readily predictable, the use of nonclinical disease markers has become critically important to patient management. Surrogate markers of HIV infection are, by definition, measurable traits that correlate with disease progression. An ideal marker should identify patients at highest risk of disease progression, provide information on how long an individual has been infected, help in staging HIV disease, predict development of opportunistic infections associated with AIDS, monitor the therapeutic efficacy of immunomodulating or antiviral treatments, and the easily quantifiable, reliable, clinically available, and affordable. This review examines the current state of knowledge and the role of surrogate markers in the natural history and treatment of HIV infection. The clinical usefulness of each marker is assessed with respect to the criteria outlined for the ideal surrogate marker for HIV disease progression. PMID:8118788

  18. 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

  19. [Progression factors for chronic kidney disease. Secondary prevention].

    TOXLINE Toxicology Bibliographic Information

    García de Vinuesa S

    2008-01-01

    The natural history of most chronic kidney diseases (CKD) indicates that glomerular filtration gradually declines over time, progressing to more advanced stages of kidney failure. Since the publication of the first studies by the Modification of Diet in Renal Disease (MDRD) Study Group, numerous factors have been identified that can accelerate this progression. Some are dependent on the etiology, but other are common to all and may accelerate progression of kidney disease: Non-modifiable progression factors for CKD: - Etiology of kidney disease - Degree of initial kidney function - Gender - Age - Ethnicity/Other genetic factors - Birth weight Modifiable progression factors for CKD: - Proteinuria - High blood pressure - Poor glycemic control in diabetes - Smoking - Obesity - Metabolic syndrome/Insulin resistance - Dyslipidemia - Anemia - Metabolic factors (Ca/P, uric acid) - Use of nephrotoxic drugs. Therapeutic intervention on these factors has shown that it reduce the rate of progression of CKD (Strength of Recommendation A).There is no clear evidence that correction of these factors slows CKD (Strength of Recommendation C), although it has been shown to have a beneficial effect on cardiovascular risk at other levels.

  20. Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity?

    PubMed

    Antel, Jack; Antel, Samson; Caramanos, Zografos; Arnold, Douglas L; Kuhlmann, Tanja

    2012-05-01

    Multiple sclerosis (MS), the most frequent demyelinating disease, is characterized by a variable disease course. The majority of patients starts with relapsing remitting (RR) disease; approximately 50-60% of these patients progress to secondary progressive (SP) disease. Only about 15% of the patients develop a progressive disease course from onset, termed primary progressive multiple sclerosis (PPMS); the underlying pathogenic mechanisms responsible for onset of the disease with either PPMS or relapsing remitting multiple sclerosis (RRMS) are unknown. Patients with PPMS do not show a female predominance and usually have a later onset of disease compared to patients with RRMS. Monozygous twins can be concordant or discordant for disease courses indicating that the disease course is not only genetically determined. Primary progressive multiple sclerosis and secondary progressive multiple sclerosis (SPMS) share many similarities in imaging and pathological findings. Differences observed among the different disease courses are more of a quantitative than qualitative nature suggesting that the different phenotypes are part of a disease spectrum modulated by individual genetic predisposition and environmental influences. In this review, we summarize the knowledge regarding the clinical, epidemiological, imaging, and pathological characteristics of PPMS and compare those characteristics with RRMS and SPMS. PMID:22327362

  1. Contribution of neural networks to Alzheimer disease's progression.

    PubMed

    Savioz, Armand; Leuba, Geneviève; Vallet, Philippe G; Walzer, Claude

    2009-10-28

    The neuropathology of Alzheimer disease is characterized by senile plaques, neurofibrillary tangles and cell death. These hallmarks develop according to the differential vulnerability of brain networks, senile plaques accumulating preferentially in the associative cortical areas and neurofibrillary tangles in the entorhinal cortex and the hippocampus. We suggest that the main aetiological hypotheses such as the beta-amyloid cascade hypothesis or its variant, the synaptic beta-amyloid hypothesis, will have to consider neural networks not just as targets of degenerative processes but also as contributors of the disease's progression and of its phenotype. Three domains of research are highlighted in this review. First, the cerebral reserve and the redundancy of the network's elements are related to brain vulnerability. Indeed, an enriched environment appears to increase the cerebral reserve as well as the threshold of disease's onset. Second, disease's progression and memory performance cannot be explained by synaptic or neuronal loss only, but also by the presence of compensatory mechanisms, such as synaptic scaling, at the microcircuit level. Third, some phenotypes of Alzheimer disease, such as hallucinations, appear to be related to progressive dysfunction of neural networks as a result, for instance, of a decreased signal to noise ratio, involving a diminished activity of the cholinergic system. Overall, converging results from studies of biological as well as artificial neural networks lead to the conclusion that changes in neural networks contribute strongly to Alzheimer disease's progression. PMID:19539730

  2. 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

  3. 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

  4. Alcohol’s Role in HIV Transmission and Disease Progression

    PubMed Central

    Pandrea, Ivona; Happel, Kyle I.; Amedee, Angela M.; Bagby, Gregory J.; Nelson, Steve

    2010-01-01

    Alcohol use has negative effects on HIV disease progression through several mechanisms, including transmission, viral replication, host immunity, and treatment efficacy. Research with animal models has explored the effect of alcohol intake on several aspects of simian immunodeficiency virus (SIV) disease progression. Data suggest that the increased SIV levels observed in alcohol-consuming animals may represent an increase in virus production as opposed to a decrease in host defense. Results also suggest that changes in nutritional balance and metabolism, as a possible consequence of a proinflammatory state, together with increased virus production in animals consuming alcohol, accelerate SIV and possibly HIV disease progression. Further studies using the animal model are necessary. PMID:23584062

  5. 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.

  6. Augmentative and alternative communication for people with progressive neuromuscular disease.

    PubMed

    Ball, Laura J; Fager, Susan; Fried-Oken, Melanie

    2012-08-01

    Individuals with progressive neuromuscular disease often experience complex communication needs and consequently find that interaction using their natural speech may not sufficiently meet their daily needs. Increasingly, assistive technology advances provide accommodations for and/or access to communication. Assistive technology related to communication is referred to as augmentative and alternative communication (AAC). The nature of communication challenges in progressive neuromuscular diseases can be as varied as the AAC options currently available. AAC systems continue to be designed and implemented to provide targeted assistance based on an individual's changing needs. PMID:22938882

  7. Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study

    PubMed Central

    Lu, Ching-Hua; Petzold, Axel; Topping, Jo; Allen, Kezia; Macdonald-Wallis, Corrie; Clarke, Jan; Pearce, Neil; Kuhle, Jens; Giovannoni, Gavin; Fratta, Pietro; Sidle, Katie; Fish, Mark; Orrell, Richard; Howard, Robin; Greensmith, Linda; Malaspina, Andrea

    2015-01-01

    Objective To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS). Methods A cross-sectional study involving 136 clinically heterogeneous patients with ALS and 104 healthy and neurological controls was extended to include a prospective analysis of 74 of these ALS cases, with samplings at approximately 3-month intervals in a follow-up period of up to 3 years. We analysed the correlation between longitudinal NfH-phosphoform levels and disease progression. Temporal patterns of NfH changes were evaluated using multilevel linear regression. Results Baseline plasma NfH levels were higher than controls only in patients with ALS with short disease duration to baseline sampling. Compared with controls, fast-progressing patients with ALS, particularly those with a short diagnostic latency and disease duration, had higher plasma NfH levels at an early stage and lower levels closer to end-stage disease. Lower NfH levels between visits were associated with rapid functional deterioration. We also detected antibodies against NfH, NfH aggregates and NfH cleavage products. Conclusions Disease progression in ALS involves defined trajectories of plasma NfH levels, reflecting speed of neurological decline and survival. Intervisit plasma NfH changes are also indicative of disease progression. This study confirms that longitudinal measurements of NfH plasma levels are more informative than cross-sectional studies, where the time of sampling may represent a bias in the interpretation of the results. Autoantibodies against NfH aggregates and NfH cleavage products may explain the variable expression of plasma NfH with disease progression. Trail registration number NIHRID6160. PMID:25009280

  8. Lack of sigma-1 receptor exacerbates ALS progression in mice.

    PubMed

    Mavlyutov, T A; Epstein, M L; Verbny, Y I; Huerta, M S; Zaitoun, I; Ziskind-Conhaim, L; Ruoho, A E

    2013-06-14

    The function of the sigma-1 receptor (S1R) has been implicated in modulating the activity of various ion channels. In the CNS S1R is enriched in cholinergic postsynaptic densities in spinal cord motoneurons (MNs). Mutations in S1R have been found in familial cases of amyotrophic lateral sclerosis (ALS). In this study we show that a knockout of S1R in the SOD1*G93A mouse model of ALS significantly reduces longevity (end stage). Electrophysiological experiments demonstrate that MN of mice lacking S1R exhibit increased excitability. Taken together the data suggest the S1R acts as a brake on excitability, an effect that might enhance longevity in an ALS mouse model. PMID:23458708

  9. LACK OF SIGMA-1 RECEPTOR EXACERBATES ALS PROGRESSION IN MICE

    PubMed Central

    Mavlyutov, Timur A.; Epstein, Miles L.; Verbny, Yakov I.; Huerta, Maria S.; Zaitoun, Ismail; Ziskind-Conhaim, Lea; Ruoho, Arnold E.

    2013-01-01

    The function of the sigma-1 receptor (S1R) has been implicated in modulating the activity of various ion channels. In the Central Nervous System (CNS) S1R is enriched in cholinergic postsynaptic densities in spinal cord motoneurons (MN). Mutations in S1R have been found in familial cases of Amyotrophic Lateral Sclerosis (ALS). In this study we show that a knockout of S1R in the SOD1*G93A mouse model of ALS significantly reduces longevity (end stage). Electrophysiological experiments demonstrate that MN of mice lacking S1R exhibit increased excitability. Taken together the data suggest the S1R acts as a brake on excitability, an effect that might enhance longevity in an ALS mouse model. PMID:23458708

  10. Induced pluripotent stem cells from ALS patients for disease modeling.

    PubMed

    Richard, Jean-Philippe; Maragakis, Nicholas J

    2015-05-14

    The ability to reprogram adult somatic cells into pluripotent stem cells that can differentiate into all three germ layers of the developing human has fundamentally changed the landscape of biomedical research. For a neurodegenerative disease like Amyotrophic Lateral Sclerosis (ALS), which does not manifest itself until adulthood and is a heterogeneous disease with few animal models, this technology may be particularly important. Induced pluripotent stem cells (iPSC) have been created from patients with several familial forms of ALS as well as some sporadic forms of ALS. These cells have been differentiated into ALS-relevant cell subtypes including motor neurons and astrocytes, among others. ALS-relevant pathologies have also been identified in motor neurons from these cells and may provide a window into understanding disease mechanisms in vitro. Given that this is a relatively new field of research, numerous challenges remain before iPSC methodologies can fulfill their potential as tools for modeling ALS as well as providing a platform for the investigation of ALS therapeutics. This article is part of a Special Issue entitled ALS complex pathogenesis. PMID:25223906

  11. 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

  12. 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 ...

  13. Systemic and renal lipids in kidney disease development and progression.

    PubMed

    Wahl, Patricia; Ducasa, Gloria Michelle; Fornoni, Alessia

    2016-03-15

    Altered lipid metabolism characterizes proteinuria and chronic kidney diseases. While it is thought that dyslipidemia is a consequence of kidney disease, a large body of clinical and experimental studies support that altered lipid metabolism may contribute to the pathogenesis and progression of kidney disease. In fact, accumulation of renal lipids has been observed in several conditions of genetic and nongenetic origins, linking local fat to the pathogenesis of kidney disease. Statins, which target cholesterol synthesis, have not been proven beneficial to slow the progression of chronic kidney disease. Therefore, other therapeutic strategies to reduce cholesterol accumulation in peripheral organs, such as the kidney, warrant further investigation. Recent advances in the understanding of the biology of high-density lipoprotein (HDL) have revealed that functional HDL, rather than total HDL per se, may protect from both cardiovascular and kidney diseases, strongly supporting a role for altered cholesterol efflux in the pathogenesis of kidney disease. Although the underlying pathophysiological mechanisms responsible for lipid-induced renal damage have yet to be uncovered, several studies suggest novel mechanisms by which cholesterol, free fatty acids, and sphingolipids may affect glomerular and tubular cell function. This review will focus on the clinical and experimental evidence supporting a causative role of lipids in the pathogenesis of proteinuria and kidney disease, with a primary focus on podocytes. PMID:26697982

  14. 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

  15. 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

  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. Fabrication, phase transformation studies and characterization of SiC-AlN-Al{sub 2}OC ceramics. Progress report

    SciTech Connect

    Virkar, A.V.

    1992-01-12

    SiC and AlN are two of the important high temperature structural ceramics. AlN and the 2H polytype of SiC are isostructural. Prior work has shown that they form an extension solid solution at temperatures {ge} 2000{degrees}C. At lower temperatures, the solid solution can undergo phase separation. Additionally, Al{sub 2}OC is also isostructural and can form extensive solid solutions with SiC and AlN. The formation of solid solutions in such refractory materials as well as the tendency to undergo diffusional phase transformations suggests that a potential exists to improve properties through alloying. The principal objective of the proposed work is to examine phase relations, phase transformations, the resulting precipitate morphologies and their influence on mechanical properties of SiC-AlN-Al{sub 2}OC ceramics. Formation of modulated structures have been documented in SiC-AlN ceramics in our work. It has been shown that modulations occur along directions other than the [0001] direction and this results in the formation of a tweed type of a microstructure. In the AlN-Al{sub 2}OC system, the occurrence of cellular precipitates as well as coherent, disc-shaped precipitates has been observed. During the past year, work has progressed in the following areas: (1) Phase separation in SiC-AlN system: The effect of coherency strain energy on the precipitate morphology. (2) High temperature creep of SiC-AlN ceramics containing modulated structures and SiC-Al{sub 2}OC ceramics. (3) Fabrication and characterization of damage-resistant SiC-AlN ceramics. Three manuscripts have been submitted for publication.

  19. Predictors of Autosomal Dominant Polycystic Kidney Disease Progression

    PubMed Central

    Brosnahan, Godela; Cadnapaphornchai, Melissa A.; Chonchol, Michel; Friend, Keith; Gitomer, Berenice; Rossetti, Sandro

    2014-01-01

    Autosomal dominant polycystic kidney disease is a genetic disorder associated with substantial variability in its natural course within and between affected families. Understanding predictors for rapid progression of this disease has become increasingly important with the emergence of potential new treatments. This systematic review of the literature since 1988 evaluates factors that may predict and/or effect autosomal dominant polycystic kidney disease progression. Predicting factors associated with early adverse structural and/or functional outcomes are considered. These factors include PKD1 mutation (particularly truncating mutation), men, early onset of hypertension, early and frequent gross hematuria, and among women, three or more pregnancies. Increases in total kidney volume and decreases in GFR and renal blood flow greater than expected for a given age also signify rapid disease progression. Concerning laboratory markers include overt proteinuria, macroalbuminuria, and perhaps, elevated serum copeptin levels in affected adults. These factors and others may help to identify patients with autosomal dominant polycystic kidney disease who are most likely to benefit from early intervention with novel treatments. PMID:24925719

  20. Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Balestro, Elisabetta; Calabrese, Fiorella; Turato, Graziella; Lunardi, Francesca; Bazzan, Erica; Marulli, Giuseppe; Biondini, Davide; Rossi, Emanuela; Sanduzzi, Alessandro; Rea, Federico; Rigobello, Chiara; Gregori, Dario; Baraldo, Simonetta; Spagnolo, Paolo

    2016-01-01

    The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (< or ≥10% predicted) was used to define “slow” or “rapid” disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression. PMID:27159038

  1. Antagonistic molecular interactions of photosynthetic pigments with molecular disease targets: a new approach to treat AD and ALS.

    PubMed

    Krishnaraj, R Navanietha; Kumari, S S Sreeja; Mukhopadhyay, Sudit Sekhar

    2016-01-01

    Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) are progressive neurodegenerative diseases that affect the neurons in the brain and the spinal cord. Neuroinflamation and apoptosis are key players in the progressive damage of the neurons in AD and ALS. Currently, there is no drug to offer complete cure for both these diseases. Riluzole is the only available drug that can prolong the life time of the ALS patients for nearly 3 months. Molecules that offer good HIT to the molecular targets of ALS will help to treat AD and ALS patients. P53 kinase receptor (4AT3), EphA4 (3CKH) and histone deacetylase (3SFF) are the promising disease targets of AD and ALS. This paper discusses on a new approach to combat neurodegenerative diseases using photosynthetic pigments. The docking studies were performed with the Autodock Vina algorithm to predict the binding of the natural pigments such as β carotene, chlorophyll a, chlorophyll b, phycoerythrin and phycocyanin on these targets. The β carotene, phycoerythrin and phycocyanin had higher binding energies indicating the antagonistic activity to the disease targets. These pigments serve as a potential therapeutic molecule to treat neuroinflammation and apoptosis in the AD and ALS patients. PMID:26053508

  2. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis

    PubMed Central

    Ebos, John M. L.; Kerbel, Robert S.

    2015-01-01

    Antiangiogenic drugs targeting the VEGF pathway have slowed metastatic disease progression in some patients, leading to progression-free survival (PFS) and overall survival benefits compared with controls. However, the results are more modest than predicted by most preclinical testing and benefits in PFS are frequently not accompanied by overall survival improvements. Questions have emerged about the basis of drug resistance and the limitations of predictive preclinical models, and also about whether the nature of disease progression following antiangiogenic therapy is different to classic cytotoxic therapies—in particular whether therapy may lead to more invasive or metastatic behavior. In addition, because of recent clinical trial failures of antiangiogenic therapy in patients with early-stage disease, and the fact that there are hundreds of trials underway in perioperative neoadjuvant and adjuvant settings, there is now greater awareness about the lack of appropriate preclinical testing that preceded these studies. Improved preclinical assessment of all stages of metastatic disease should be a priority for future antiangiogenic drug discovery and development. PMID:21364524

  3. Nutrient enrichment enhances black band disease progression in corals

    NASA Astrophysics Data System (ADS)

    Voss, Joshua D.; Richardson, Laurie L.

    2006-11-01

    Infectious diseases are recognized as significant contributors to the dramatic loss of corals observed worldwide. However, the causes of increased coral disease prevalence and severity are not well understood. One potential factor is elevated nutrient concentration related to localized anthropogenic activities such as inadequate waste water treatment or terrestrial runoff. In this study the effect of nutrient enrichment on the progression of black band disease (BBD) was investigated using both in situ and laboratory experiments. Experimental increases in localized nutrient availability using commercial time release fertilizer in situ resulted in doubling of BBD progression and coral tissue loss in the common reef framework coral Siderastrea siderea. Laboratory experiments in which artificially infected S. siderea colonies were exposed to increased nitrate concentrations (up to 3 μM) demonstrated similar increases in BBD progression. These findings provide evidence that the impacts of this disease on coral populations are exacerbated by nutrient enrichment and that management to curtail excess nutrient loading may be important for reducing coral cover loss due to BBD.

  4. 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

  5. Tissue stiffness dictates development, homeostasis, and disease progression.

    PubMed

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

    2015-01-01

    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. 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

  7. State-space size considerations for disease-progression models.

    PubMed

    Regnier, Eva D; Shechter, Steven M

    2013-09-30

    Markov models of disease progression are widely used to model transitions in patients' health state over time. Usually, patients' health status may be classified according to a set of ordered health states. Modelers lump together similar health states into a finite and usually small, number of health states that form the basis of a Markov chain disease-progression model. This increases the number of observations used to estimate each parameter in the transition probability matrix. However, lumping together observably distinct health states also obscures distinctions among them and may reduce the predictive power of the model. Moreover, as we demonstrate, precision in estimating the model parameters does not necessarily improve as the number of states in the model declines. This paper explores the tradeoff between lumping error introduced by grouping distinct health states and sampling error that arises when there are insufficient patient data to precisely estimate the transition probability matrix. PMID:23609629

  8. Current Progress in Therapeutic Gene Editing for Monogenic Diseases.

    PubMed

    Prakash, Versha; Moore, Marc; Yáñez-Muñoz, Rafael J

    2016-03-01

    Programmable nucleases allow defined alterations in the genome with ease-of-use, efficiency, and specificity. Their availability has led to accurate and widespread genome engineering, with multiple applications in basic research, biotechnology, and therapy. With regard to human gene therapy, nuclease-based gene editing has facilitated development of a broad range of therapeutic strategies based on both nonhomologous end joining and homology-dependent repair. This review discusses current progress in nuclease-based therapeutic applications for a subset of inherited monogenic diseases including cystic fibrosis, Duchenne muscular dystrophy, diseases of the bone marrow, and hemophilia and highlights associated challenges and future prospects. PMID:26765770

  9. 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

  10. Reversal of progressive nyctalopia in a patient with Crohn's disease.

    TOXLINE Toxicology Bibliographic Information

    Gans M; Taylor C

    1990-04-01

    A 51-year-old man who had undergone several partial bowel resections for Crohn's disease presented with progressively decreased night vision. Electroretinography showed a flat scotopic response and a diminished, delayed photopic response. Measurement of stool fat showed marked fat malabsorption. Treatment with parenteral nutrition, including administration of vitamin A, resulted in marked improvement in the scotopic and photopic response and subjective improvement in his night vision. Patients with malabsorption states should be followed to avoid irreversible visual loss.

  11. Reversal of progressive nyctalopia in a patient with Crohn's disease.

    PubMed

    Gans, M; Taylor, C

    1990-04-01

    A 51-year-old man who had undergone several partial bowel resections for Crohn's disease presented with progressively decreased night vision. Electroretinography showed a flat scotopic response and a diminished, delayed photopic response. Measurement of stool fat showed marked fat malabsorption. Treatment with parenteral nutrition, including administration of vitamin A, resulted in marked improvement in the scotopic and photopic response and subjective improvement in his night vision. Patients with malabsorption states should be followed to avoid irreversible visual loss. PMID:2113831

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

    PubMed Central

    Vaughan, Annalicia; Dent, Annette G.; OHare, 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

  13. Atheroembolic renal disease with rapid progression and fatal outcome.

    PubMed

    Faria, Bernardo; Vidinha, Joana; Pêgo, Cátia; Garrido, Jesus; Lemos, Sérgio; Lima, Carla; Sorbo, Giovanni; Gomes, Edgar Lorga; Carvalho, Teresa; Loureiro, Paulo; Sousa, Tânia

    2011-02-01

    Atheroembolic renal disease is caused by foreign-body reaction to cholesterol crystals flushed from the atherosclerotic plaques into the small-vessel system of the kidneys. It is an underdiagnosed entity, mostly related to vascular procedures and/or anticoagulation, and prognosis is considered to be poor. Besides the benefit of aggressive medical prevention of further embolic events, use of steroid therapy has been associated with greater survival. Here we report a case of a patient with a multisystemic presentation of the disease days after performance of percutaneous coronary intervention and anticoagulation initiation due to an episode of myocardial infarction. Renal, cutaneous, ophthalmic, neurological, and possibly muscular and mesenteric involvement was diagnosed. Although medical treatment with corticosteroids and avoidance of further anticoagulation was applied, the patient rapidly progressed to end-stage renal disease requiring hemodialysis and died 6 months after diagnosis. This is a case of catastrophic progression of the disease resistant to therapeutic measures. Focus on diagnosis and more efficient preventive and therapeutic protocols are therefore needed. PMID:21069411

  14. High Water Intake and Progression of Chronic Kidney Diseases.

    PubMed

    Choi, Hoon Young; Park, Hyeong Cheon; Ha, Sung Kyu

    2015-12-01

    Impact of water intake on the courses of chronic kidney and urinary tract diseases, such as urolithiasis, urinary tract infections, chronic kidney diseases (CKD), autosomal dominant polycystic kidney diseases and bladder cancer, has recently been studied. It still remains controversial whether increased water intake slows the progression of CKD or not. However, high water intake suppresses plasma levels of arginine vasopressin (AVP), which is expected to be beneficial for the preservation of the kidney function. Previous studies suggest that water intake suppresses plasma levels of AVP, and high levels of AVP have been suggested to play deleterious roles in animal models of kidney disease. Moreover, recent epidemic of CKD of unknown origin, which was supposed to be related to the insufficient water intake and chronic volume depletion, has been reported in Central America, further suggesting that the suppression of AVP by sustained water intake might be beneficial in this CKD population. Indeed, the data from recent studies were consistent with the view that high water intake is associated with slower progression of CKD. However, contradictory findings also exist. The intriguing effects of increased urine volume in preserving the glomerular filtration rate in human patients with CKD require more large and well-designed randomized prospective clinical trials. PMID:26848303

  15. High Water Intake and Progression of Chronic Kidney Diseases

    PubMed Central

    Choi, Hoon Young; Park, Hyeong Cheon

    2015-01-01

    Impact of water intake on the courses of chronic kidney and urinary tract diseases, such as urolithiasis, urinary tract infections, chronic kidney diseases (CKD), autosomal dominant polycystic kidney diseases and bladder cancer, has recently been studied. It still remains controversial whether increased water intake slows the progression of CKD or not. However, high water intake suppresses plasma levels of arginine vasopressin (AVP), which is expected to be beneficial for the preservation of the kidney function. Previous studies suggest that water intake suppresses plasma levels of AVP, and high levels of AVP have been suggested to play deleterious roles in animal models of kidney disease. Moreover, recent epidemic of CKD of unknown origin, which was supposed to be related to the insufficient water intake and chronic volume depletion, has been reported in Central America, further suggesting that the suppression of AVP by sustained water intake might be beneficial in this CKD population. Indeed, the data from recent studies were consistent with the view that high water intake is associated with slower progression of CKD. However, contradictory findings also exist. The intriguing effects of increased urine volume in preserving the glomerular filtration rate in human patients with CKD require more large and well-designed randomized prospective clinical trials. PMID:26848303

  16. Automated MRI measures predict progression to Alzheimer's disease

    PubMed Central

    Desikan, Rahul S.; Cabral, Howard J.; Settecase, Fabio; Hess, Christopher P.; Dillon, William P.; Glastonbury, Christine M.; Weiner, Michael W.; Schmansky, Nicholas J.; Salat, David H.; Fischl, Bruce

    2010-01-01

    The prediction of individuals with mild cognitive impairment (MCI) destined to develop Alzheimer's disease (AD) is of increasing clinical importance. In this study, using baseline T1-weighted MRI scans of 324 MCI individuals from two cohorts and automated software tools, we employed factor analyses and Cox proportional hazards models to identify a set of neuroanatomic measures that best predicted the time to progress from MCI to AD. For comparison, cerebrospinal fluid (CSF) assessments of cellular pathology and positron emission tomography (PET) measures of metabolic activity were additionally examined. By three years follow-up, 60 MCI individuals from the first cohort and 58 MCI individuals from the second cohort had progressed to a diagnosis of AD. Cox models on the first cohort demonstrated significant effects for the medial temporal factor [Hazards Ratio (HR) =0.43{95% Confidence Interval (CI), 0.32-0.55}, p < 0.0001], the fronto-parietoccipital factor [HR=0.59{95% CI, 0.48-0.80}, p < 0.001], and the lateral temporal factor [HR=0.67 {95% CI, 0.52-0.87}, p < 0.01]. When applied to the second cohort, these Cox models showed significant effects for the medial temporal factor [HR=0.44 {0.32-0.61}, p < 0.001] and lateral temporal factor [HR=0.49 {0.38-0.62}, p < 0.001]. In a combined Cox model, consisting of individual CSF, PET, and MRI measures that best predicted disease progression, only the medial temporal factor [HR=0.53 {95% CI, 0.34-0.81}, p < 0.001] demonstrated a significant effect. These findings illustrate that automated MRI measures of the medial temporal cortex accurately and reliably predict time to disease progression, outperform cellular and metabolic measures as predictors of clinical decline, and can potentially serve as a predictive marker for AD. PMID:20570399

  17. Acute progression of neuromuscular findings in infantile Pompe disease.

    PubMed

    Burrow, T Andrew; Bailey, Laurie A; Kinnett, Douglas G; Hopkin, Robert J

    2010-06-01

    A 2-year-old girl with Pompe disease developed an acute worsening of muscle weakness during a hospitalization, and required intubation for an upper respiratory infection. Electromyography and nerve conduction studies produced results consistent with a severe chronic motor axonal peripheral polyneuropathy, with no evidence of reinnervation. Magnetic resonance imaging of the brain demonstrated generalized hypomyelination and parenchymal volume loss, whereas magnetic resonance spectroscopy suggested neuronal injury and hypomyelination. This case provides compelling evidence for a slowly progressive neurodegenerative process in patients with infantile Pompe disease, affecting the motor neurons. Routine electromyography, nerve conduction studies, and cranial magnetic resonance imaging should be considered to delineate the presence of a neurodegenerative process in infantile-onset Pompe disease. PMID:20472203

  18. Peripheral Biomarkers of Parkinson's Disease Progression and Pioglitazone Effects.

    PubMed

    Simon, David K; Simuni, Tanya; Elm, Jordan; Clark-Matott, Joanne; Graebner, Allison K; Baker, Liana; Dunlop, Susan R; Emborg, Marina; Kamp, Cornelia; Morgan, John C; Ross, G Webster; Sharma, Saloni; Ravina, Bernard

    2015-01-01

    Pioglitazone, an oral hypoglycemic agent, recently failed to show promise as a disease-modifying agent in a 44-week phase 2 placebo-controlled study in 210 Parkinson's disease (PD) subjects. We analyzed peripheral biomarkers, including leukocyte PGC-1α and target gene expression, plasma interleukin 6 (IL-6) as a marker of inflammation, and urine 8-hydroxydeoxyguanosine (8OHdG) as a marker of oxidative DNA damage. Baseline or changes from baseline in biomarker levels were not associated with the rate of progression of PD. Pioglitazone did not significantly alter biomarker levels. Other agents that more effectively target these mechanisms remain of potential interest as disease modifying therapies in PD. PMID:26444095

  19. Angiotensinogen Expression Is Enhanced in the Progression of Glomerular Disease

    PubMed Central

    Urushihara, Maki; Kobori, Hiroyuki

    2011-01-01

    Intrarenal renin-angiotensin system (RAS) activation plays a critical role in the development and progression of renal injury. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by multiple independent mechanisms. Angiotensinogen (AGT) is the only known substrate for renin that is a rate-limiting enzyme of the RAS. Recently, enhanced intrarenal AGT levels have been shown to reflect the intrarenal RAS status in hypertension, chronic glomerular disease and diabetic nephropathy. In this review, we focus on AGT expression of the diseased glomeruli in the progression of glomerular disease. An anti-glomerular basement membrane nephritis rat model developed progressive proteinuria and glomerular crescent formation, accompanied by increased macrophage infiltration and glomerular expression of AGT and Ang II. The addition of Ang II type 1 receptor blocker to CC-chemokine recaptor 2 antagonist markedly attenuated the induction of macrophage infiltration, AGT and Ang II, and reduced glomerular crescent formation. Next, the levels of glomerular AGT expression and marker of reactive oxygen species in Zucker diabetic fatty (ZDF) obese rats were higher than those in ZDF lean rats. Hydrogen peroxide (H2O2) induced an increase in the AGT expression in primary rat mesangial cells. Furthermore, the H2O2-induced upregulation of AGT was inhibited by a mitogen-activated protein kinase kinase and a c-Jun N-terminal kinase inhibitor. These data suggest the potential contribution of enhanced AGT expression in glomeruli to the intrarenal RAS activation for the development of glomerular disease. PMID:22247811

  20. PNPLA3 I148M polymorphism and progressive liver disease.

    PubMed

    Dongiovanni, Paola; Donati, Benedetta; Fares, Roberta; Lombardi, Rosa; Mancina, Rosellina Margherita; Romeo, Stefano; Valenti, Luca

    2013-11-01

    The 148 Isoleucine to Methionine protein variant (I148M) of patatin-like phospholipase domain-containing 3 (PNPLA3), a protein is expressed in the liver and is involved in lipid metabolism, has recently been identified as a major determinant of liver fat content. Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver: from simple steatosis to steatohepatitis and progressive fibrosis. Furthermore, the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis, and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis, and possibly chronic hepatitis B virus hepatitis, hereditary hemochromatosis and primary sclerosing cholangitis. All in all, studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases. Remarkably, the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation, suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes, directly promoting fibrogenesis. Therefore, PNPLA3 is a key player in liver disease progression. Assessment of the I148M polymorphism will possibly inform clinical practice in the future, whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis. PMID:24222941

  1. 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-α and tumour necrosis factor-α 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

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

    PubMed Central

    Komarova, Natalia L.; Thalhauser, Craig J.

    2011-01-01

    There have been several reports on the varying rates of progression among Alzheimer's Disease (AD) patients; however, there has been no quantitative study of the amount of heterogeneity in AD. Obtaining a reliable quantitative measure of AD progression rates and their variances among the patients for each stage of AD is essential for evaluating results of any clinical study. The Global Deterioration Scale (GDS) and Functional Assessment Staging procedure (FAST) characterize seven stages in the course of AD from normal aging to severe dementia. Each GDS/FAST stage has a published mean duration, but the variance is unknown. We use statistical analysis to reconstruct GDS/FAST stage durations in a cohort of 648 AD patients with an average follow-up time of 4.78 years. Calculations for GDS/FAST stages 4–6 reveal that the standard deviations for stage durations are comparable with their mean values, indicating the presence of large variations in the AD progression among patients. Such amount of heterogeneity in the course of progression of AD is consistent with the existence of several sub-groups of AD patients, which differ by their patterns of decline. PMID:22072952

  3. 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-α, 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

  4. Initial letter and semantic category fluency in Alzheimer's disease, Huntington's disease, and progressive supranuclear palsy.

    PubMed Central

    Rosser, A; Hodges, J R

    1994-01-01

    Ten patients with dementia of Alzheimer's type, 10 patients with progressive supranuclear palsy, and 10 patients with Huntington's disease were compared on two types of verbal fluency task--namely, initial letter fluency and category (semantic) fluency. The groups were carefully matched for overall level of dementia on the dementia rating scale, and were compared with 25 age matched normal controls. The controls found letter fluency more difficult than category fluency, and this relative pattern of performance was repeated in the progressive supranuclear palsy and Huntington's disease groups, although both groups were significantly impaired on both tasks. By contrast, patients with Alzheimer's disease performed just as poorly as the progressive supranuclear palsy and Huntington's disease groups on the category tasks, but were significantly less impaired at letter fluency, performing at near normal levels on this task. From these results, it is suggested that the performances of patients with progressive supranuclear palsy and Huntington's disease relate largely to initiation and retrieval problems secondary to disruption of frontostriatal circuits, whereas in Alzheimer's disease, the poorer performance on category fluency is due principally to the breakdown of semantic knowledge, which probably reflects temporal neocortical involvement. Images PMID:7964817

  5. Epigenetics of Progression of Chronic Kidney Disease: Fact or Fantasy?

    PubMed Central

    Wing, Maria R.; Ramezani, Ali; Gill, Harindarpal S.; Devaney, Joseph M.; Raj, Dominic S.

    2013-01-01

    Summary Epigenetic modifications are important in the normal functioning of the cell, from regulating dynamic expression of essential genes and associated proteins to repressing those that are unneeded. Epigenetic changes are essential for development and functioning of the kidney, and aberrant methylation, histone modifications, and expression of microRNA could lead to chronic kidney disease (CKD). Here, epigenetic modifications modulate transforming growth factor β signaling, inflammation, profibrotic genes, and the epithelial-to-mesenchymal transition, promoting renal fibrosis and progression of CKD. Identification of these epigenetic changes is important because they are potentially reversible and may serve as therapeutic targets in the future to prevent subsequent renal fibrosis and CKD. In this review we discuss the different types of epigenetic control, methods to study epigenetic modifications, and how epigenetics promotes progression of CKD. PMID:24011578

  6. Staging Alzheimer’s Disease Progression with Multimodality Neuroimaging

    PubMed Central

    Ewers, Michael; Frisoni, Giovanni B.; Teipel, Stefan J.; Grinberg, Lea T.; Amaro, Edson; Heinsen, Helmut; Thompson, Paul M.; Hampel, Harald

    2011-01-01

    Rapid developments in medical neuroimaging have made it possible to reconstruct the trajectory of Alzheimer’s disease (AD) as it spreads through the living brain. The current review focuses on the progressive signature of brain changes throughout the different stages of AD. We integrate recent findings on changes in cortical gray matter volume, white matter fiber tracts, neuropathological alterations, and brain metabolism assessed with molecular positron emission tomography (PET). Neurofibrillary tangles accumulate first in transentorhinal and cholinergic brain areas, and 4-D maps of cortical volume changes show early progressive temporo-parietal cortical thinning. Findings from diffusion tensor imaging (DTI) for assessment fiber tract integrity show cortical disconnection in corresponding brain networks. Importantly, the developmental trajectory of brain changes is not uniform and may be modulated by several factors such as onset of disease mechanisms, risk-associated and protective genes, converging comorbidity, and individual brain reserve. There is a general agreement between in vivo brain maps of cortical atrophy and amyloid pathology assessed through PET, reminiscent of post mortem histopathology studies that paved the way in the staging of AD. The association between in vivo and post mortem findings will clarify the temporal dynamics of pathophysiological alterations in the development of preclinical AD. This will be important in designing effective treatments that target specific underlying disease AD mechanisms. PMID:21718750

  7. Quantifying Parkinson's disease progression by simulating gait patterns

    NASA Astrophysics Data System (ADS)

    Cárdenas, Luisa; Martínez, Fabio; Atehortúa, Angélica; Romero, Eduardo

    2015-12-01

    Modern rehabilitation protocols of most neurodegenerative diseases, in particular the Parkinson Disease, rely on a clinical analysis of gait patterns. Currently, such analysis is highly dependent on both the examiner expertise and the type of evaluation. Development of evaluation methods with objective measures is then crucial. Physical models arise as a powerful alternative to quantify movement patterns and to emulate the progression and performance of specific treatments. This work introduces a novel quantification of the Parkinson disease progression using a physical model that accurately represents the main gait biomarker, the body Center of Gravity (CoG). The model tracks the whole gait cycle by a coupled double inverted pendulum that emulates the leg swinging for the single support phase and by a damper-spring System (SDP) that recreates both legs in contact with the ground for the double phase. The patterns generated by the proposed model are compared with actual ones learned from 24 subjects in stages 2,3, and 4. The evaluation performed demonstrates a better performance of the proposed model when compared with a baseline model(SP) composed of a coupled double pendulum and a mass-spring system. The Frechet distance measured differences between model estimations and real trajectories, showing for stages 2, 3 and 4 distances of 0.137, 0.155, 0.38 for the baseline and 0.07, 0.09, 0.29 for the proposed method.

  8. Progress Toward Eliminating Hepatitis A Disease in the United States.

    PubMed

    Murphy, Trudy V; Denniston, Maxine M; Hill, Holly A; McDonald, Marian; Klevens, Monina R; Elam-Evans, Laurie D; Nelson, Noele P; Iskander, John; Ward, John D

    2016-01-01

    Hepatitis A virus (HAV) disease disproportionately affects adolescents and young adults, American Indian/Alaska Native and Hispanic racial/ethnic groups, and disadvantaged populations. During 1996-2006, the Advisory Committee on Immunization Practices (ACIP) made incremental changes in hepatitis A (HepA) vaccination recommendations to increase coverage for children and persons at high risk for HAV infection. This report examines the temporal association of ACIP-recommended HepA vaccination and disparities (on the absolute scale) in cases of HAV disease and on seroprevalence of HAV-related protection (measured as antibody to HAV [anti-HAV]). ACIP-recommended childhood HepA vaccination in the United States has eliminated most absolute disparities in HAV disease by age, race/ethnicity, and geographic area with relatively modest ?1-dose and ?2-dose vaccine coverage. However, the increasing proportion of cases of HAV disease among adults with identified and unidentified sources of exposure underscores the importance of considering new strategies for preventing HAV infection among U.S. adults. For continued progress to be made toward elimination of HAV disease in the United States, additional strategies are needed to prevent HAV infection among an emerging population of susceptible adults. Notably, HAV infection remains endemic in much of the world, contributing to U.S. cases through international travel and the global food economy. PMID:26916458

  9. 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

  10. Foot-and-mouth disease vaccines: progress and problems.

    PubMed

    Cao, Yimei; Lu, Zengjun; Liu, Zaixin

    2016-06-01

    Foot-and-mouth disease (FMD) has been a major threat to livestock across the world. The predominant method of controlling this disease in endemic regions is through regular vaccination with inactivated vaccine. However, there are many limitations. For instance, cultivation of virulent FMD virus (FMDV) in the manufacturing units poses a risk of escape from production sites. Vaccines may sometimes contain traces of FMD viral non-structural proteins (NSPs), therefore, interfering with the NSP-based serological differentiation infected from vaccinated animals (DIVA). Moreover, vaccines are unable to eliminate virus from carrier animals. To address the shortcomings of inactivated vaccines, many efforts are currently devoted to develop novel vaccines including attenuated and/or marker inactivated vaccines, recombinant protein vaccines, synthetic peptide vaccines, and empty capsid vaccines. Here, we review the research progress of novel vaccines, problems that remain to be solved, and also raise some suggestions that would help in the development of FMD vaccines. PMID:26760264

  11. Progressive wheeze: atrial myxoma masquerading as chronic obstructive pulmonary disease.

    PubMed

    Sinha, Aish; Apps, Andrew; Liong, Wei Chuen; Firoozan, Soroosh

    2015-01-01

    Atrial myxoma, the commonest primary cardiac neoplasm, presents with symptoms of heart failure, embolic phenomena or constitutional upset. We present an atypical case, with wheeze and symptomatic exacerbations typical of chronic obstructive pulmonary disease. With no early clinical evidence of heart failure, the patient was managed with inhaled steroids and bronchodilators, with little relief. Only when the patient was in extremis requiring intubation, due to respiratory failure, did clinical evidence of left heart failure become apparent, with echocardiography demonstrating a massive left atrial myxoma obstructing the mitral valve annulus. Following successful surgical resection, the patient's symptoms fully abated. This case highlights the importance of considering cardiac wheeze in those initially managed as obstructive airway disease not responding in a typical fashion to initial bronchodilator therapy, and particularly in those with rapidly progressive symptoms. Such patients should be referred early for cardiac imaging. The excellent prognosis and quick recovery after timely surgical resection of a myxoma are also highlighted. PMID:26206781

  12. 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

  13. 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

  14. Directed Progression Brain Networks in Alzheimer's Disease: Properties and Classification

    PubMed Central

    Young, Karl; Asif, Danial; Jutla, Inderjit; Liang, Michael; Wilson, Scott; Landsberg, Adam S.; Schuff, Norbert

    2014-01-01

    Abstract This article introduces a new approach in brain connectomics aimed at characterizing the temporal spread in the brain of pathologies like Alzheimer's disease (AD). The main instrument is the development of “directed progression networks” (DPNets), wherein one constructs directed edges between nodes based on (weakly) inferred directions of the temporal spreading of the pathology. This stands in contrast to many previously studied brain networks where edges represent correlations, physical connections, or functional progressions. In addition, this is one of a few studies showing the value of using directed networks in the study of AD. This article focuses on the construction of DPNets for AD using longitudinal cortical thickness measurements from magnetic resonance imaging data. The network properties are then characterized, providing new insights into AD progression, as well as novel markers for differentiating normal cognition (NC) and AD at the group level. It also demonstrates the important role of nodal variations for network classification (i.e., the significance of standard deviations, not just mean values of nodal properties). Finally, the DPNets are utilized to classify subjects based on their global network measures using a variety of data-mining methodologies. In contrast to most brain networks, these DPNets do not show high clustering and small-world properties. PMID:24901258

  15. Directed progression brain networks in Alzheimer's disease: properties and classification.

    PubMed

    Friedman, Eric J; Young, Karl; Asif, Danial; Jutla, Inderjit; Liang, Michael; Wilson, Scott; Landsberg, Adam S; Schuff, Norbert

    2014-06-01

    This article introduces a new approach in brain connectomics aimed at characterizing the temporal spread in the brain of pathologies like Alzheimer's disease (AD). The main instrument is the development of "directed progression networks" (DPNets), wherein one constructs directed edges between nodes based on (weakly) inferred directions of the temporal spreading of the pathology. This stands in contrast to many previously studied brain networks where edges represent correlations, physical connections, or functional progressions. In addition, this is one of a few studies showing the value of using directed networks in the study of AD. This article focuses on the construction of DPNets for AD using longitudinal cortical thickness measurements from magnetic resonance imaging data. The network properties are then characterized, providing new insights into AD progression, as well as novel markers for differentiating normal cognition (NC) and AD at the group level. It also demonstrates the important role of nodal variations for network classification (i.e., the significance of standard deviations, not just mean values of nodal properties). Finally, the DPNets are utilized to classify subjects based on their global network measures using a variety of data-mining methodologies. In contrast to most brain networks, these DPNets do not show high clustering and small-world properties. PMID:24901258

  16. Monitoring coagulation proteins during progression of liver disease.

    PubMed

    Hessien, Mohamed; Ayad, Mohamed; Ibrahim, Wafaa M; ulArab, Batoul Izz

    2015-04-01

    This work was designated to monitor the coagulation abnormalities associated with the gradual progression of liver diseases. The study included fifty patients; forty were diagnosed with liver cirrhosis with different stages categorized according to the Childs-Pugh classification and another ten patients were diagnosed with hepatocellular carcinoma (HCC). Haemostatic variables including fibrinogen (FI), calcium (FIV), transglutaminase (FXIII), prothrombin time (PT) and platelet count were estimated in patients and compared with the baseline levels of healthy subjects (n = 10). The results demonstrated that the fibrinogen level was progressively decreased, whereas PT was progressively prolonged in Child A, Child B and Child C groups. The maximum deterioration was observed in HCC patients. Calcium significantly increased in mild (Child A) and moderate (Child B) but not in Child C cirrhosis and HCC patients. FXIII level did not show any significant changes in cirrhotic patients compared to healthy group. Some of the haemostatic variables we investigated were correlated with serum albumin and bilirubin but not with aminotransferases (ALT and AST). The results indicated that the haemostatic abnormalities in fibrinogen, calcium and PT (but not FXIII) were deteriorated in parallel with the gradual regression of the constitutional function of liver. PMID:25883431

  17. Natural Progression of Canine Glycogen Storage Disease Type IIIa.

    PubMed

    Brooks, Elizabeth D; Yi, Haiqing; Austin, Stephanie L; Thurberg, Beth L; Young, Sarah P; Fyfe, John C; Kishnani, Priya S; Sun, Baodong

    2016-01-01

    Glycogen storage disease type IIIa (GSD IIIa) is caused by a deficiency of glycogen debranching enzyme activity. Hepatomegaly, muscle degeneration, and hypoglycemia occur in human patients at an early age. Long-term complications include liver cirrhosis, hepatic adenomas, and generalized myopathy. A naturally occurring canine model of GSD IIIa that mimics the human disease has been described, with progressive liver disease and skeletal muscle damage likely due to excess glycogen deposition. In the current study, long-term follow-up of previously described GSD IIIa dogs until 32 mo of age (n = 4) and of family-owned GSD IIIa dogs until 11 to 12 y of age (n = 2) revealed that elevated concentrations of liver and muscle enzyme (AST, ALT, ALP, and creatine phosphokinase) decreased over time, consistent with hepatic cirrhosis and muscle fibrosis. Glycogen deposition in many skeletal muscles; the tongue, diaphragm, and heart; and the phrenic and sciatic nerves occurred also. Furthermore, the urinary biomarker Glc4, which has been described in many types of GSD, was first elevated and then decreased later in life. This urinary biomarker demonstrated a similar trend as AST and ALT in GSD IIIa dogs, indicating that Glc4 might be a less invasive biomarker of hepatocellular disease. Finally, the current study further demonstrates that the canine GSD IIIa model adheres to the clinical course in human patients with this disorder and is an appropriate model for developing novel therapies. PMID:26884409

  18. Progressive biparietal atrophy: an atypical presentation of Alzheimer's disease.

    PubMed Central

    Ross, S J; Graham, N; Stuart-Green, L; Prins, M; Xuereb, J; Patterson, K; Hodges, J R

    1996-01-01

    OBJECTIVES: To define the clinical, neuropsychological, and radiological features of bilateral parietal lobe atrophy. METHODS: Four patients underwent a comprehensive longitudinal neuropsychological assessment, as well as MRI and HMPAO-SPECT. RESULTS: The consistent findings in the patients were early visuospatial problems, agraphia of a predominantly peripheral (or apraxic) type, and difficulty with bimanual tasks, all of which outweighted deficits in memory and language until later in the course of the illness. As the disease progressed, impairments in the phonological aspects of language and in auditory-verbal short term memory were often striking, perhaps reflecting spread from the parietal lobe to perisylvian language areas. Three patients went on to develop a global dementia and fulfilled the criteria for a clinical diagnosis of probable Alzheimer's disease; the fourth patient has only recently been identified. Neuroimaging disclosed bilateral parietal lobe atrophy (MRI) and hypoperfusion (SPECT), which was out of proportion to that seen elsewhere in the brain. One patient has died and had pathologically confirmed Alzheimer's disease with particular concentration in both superior parietal lobes. CONCLUSIONS: Bilateral biparietal atrophy is a recognisable clinical syndrome which can be the presenting feature of Alzheimer's disease. Although the label "posterior cortical atrophy" has been applied to such cases, review of the medical literature suggests that this broad rubric actually consists of two main clinical syndromes with features reflecting involvement of the occipitotemporal (ventral) and biparietal (dorsal) cortical areas respectively. Images PMID:8890778

  19. Evaluating Alzheimer's Disease Progression by Modeling Crosstalk Network Disruption

    PubMed Central

    Liu, Haochen; Wei, Chunxiang; He, Hua; Liu, Xiaoquan

    2016-01-01

    Aβ, tau, and P-tau have been widely accepted as reliable markers for Alzheimer's disease (AD). The crosstalk between these markers forms a complex network. AD may induce the integral variation and disruption of the network. The aim of this study was to develop a novel mathematic model based on a simplified crosstalk network to evaluate the disease progression of AD. The integral variation of the network is measured by three integral disruption parameters. The robustness of network is evaluated by network disruption probability. Presented results show that network disruption probability has a good linear relationship with Mini Mental State Examination (MMSE). The proposed model combined with Support vector machine (SVM) achieves a relative high 10-fold cross-validated performance in classification of AD vs. normal and mild cognitive impairment (MCI) vs. normal (95% accuracy, 95% sensitivity, 95% specificity for AD vs. normal; 90% accuracy, 94% sensitivity, 83% specificity for MCI vs. normal). This research evaluates the progression of AD and facilitates AD early diagnosis. PMID:26834548

  20. Rosuvastatin-induced arrest in progression of renal disease.

    PubMed

    Vidt, Donald G; Cressman, Michael D; Harris, Susan; Pears, John S; Hutchinson, Howard G

    2004-01-01

    Preclinical and limited clinical data suggest that statins decrease the progressive decline in renal function that occurs in patients with renal disease. Pooled analysis of data obtained from a population of hyperlipidemic patients enrolled in the rosuvastatin (Crestor) clinical development program permitted assessment of its effects on renal function both early and later in the course of treatment. Study participants were initially included in controlled clinical trials that evaluated the lipid-lowering efficacy and safety of rosuvastatin when compared with placebo or other lipid-lowering agents (i.e., atorvastatin, simvastatin, pravastatin, cholestyramine, fenofibrate or extended-release niacin). The median duration of treatment with the various doses of statins in these trials was approximately 8 weeks. Following completion of a controlled clinical trial, patients were permitted to enter an open-label extension trial and received rosuvastatin treatment. These data permitted assessment of renal function in a diverse group of over 10,000 patients who received rosuvastatin in its recommended dose range (5-40 mg) for up to 3.8 years. Mean serum creatinine concentrations were lower when compared with baseline both early and later in the course of rosuvastatin treatment. In contrast, no change in mean serum creatinine was observed with placebo. Mean glomerular filtration rates (GFR) predicted from the Modification of Diet in Renal Disease (MDRD) equation were higher when compared with baseline both early and later in the course of rosuvastatin treatment. No change in GFR was observed in the placebo group. Among patients who received long-term rosuvastatin treatment (> or =96 weeks), GFR was unchanged or tended to increase, rather than decrease, when compared with baseline irrespective of age, gender, hypertensive or diabetic status, level of renal function (GFR > or =60 vs. <60 ml/min/1.73 m(2)) at entry or urine dipstick protein status prior to or during the period of treatment. These findings suggest that rosuvastatin may arrest the progression of renal disease. PMID:15073451

  1. Assessment of coronary heart diseases in diabetics in al-Madinah al-Munawarah

    PubMed Central

    al-Nozha, Omar; Mojadadi, Moaz; Mosaad, Mohamed; El-Bab, Mohamed F

    2012-01-01

    Background Coronary heart disease is highly prevalent and a major cause of morbidity and mortality in diabetic patients. The aim of this study was to assess the major risk factors and their predictor score for coronary heart diseases in diabetic patients. Methods The present study was conducted in al-Madinah, Kingdom of Saudi Arabia. Using a cross-sectional case control study, 262 outpatient diabetics and 264 matched control subjects were examined for the risk factors and risk predictor scores for ischemic heart disease. The mean age of the patient and control groups was 49.61 ± 12.93 years and 48.39 ± 11.60 years, respectively. Results Diabetic patients had significantly higher positive family history of diabetes, but no significant difference regarding their family history of hypertension. There was a significantly higher body mass index (33.67 kg/m2), glycosylated hemoglobin (7.26%), significantly higher cholesterol, low-density lipoprotein, and triglyceride in diabetics compared to control. Diabetic patients had higher risk for developing coronary heart disease with a mean risk score of 6.07 while the control subject risk score was −6.81. However, females showed significantly higher risk for coronary heart diseases than did males. Conclusion Our study replicates the known fact of higher risk in diabetes, but higher risk of coronary heart disease in female diabetics compared with male diabetics. PMID:22393300

  2. Magnetic resonance imaging in the monitoring of disease progression in multiple sclerosis.

    PubMed

    Stevenson, V L; Miller, D H

    1999-08-01

    Disease progression and irreversible disability in multiple sclerosis results from incomplete recovery from relapses, but most importantly from insidious disease progression. Although magnetic resonance imaging parameters, such as new lesion rate and gadolinium enhancement, reflect inflammation and disease activity they have no bearing on disease progression. Until now the T2 lesion load or disease burden has been relied upon for this, despite its poor relationship with disability measures. This paper looks at the mechanisms responsible for disease progression and discusses the MR techniques now available to reflect these pathological processes. PMID:10467387

  3. Disease steps in multiple sclerosis: a longitudinal study comparing disease steps and EDSS to evaluate disease progression.

    PubMed

    Hohol, M J; Orav, E J; Weiner, H L

    1999-10-01

    Clinical assessment of outcome in multiple sclerosis (MS) patients is problematic since the disease can affect different aspects of the central nervous system and follow a variable course. Recently, we developed Disease Steps, a simple approach for evaluating disease progression. Previously, we found that Disease Steps was easy to use, had uniformly distributed scores and low inter-rater variability. Our current objective was to test the long-term use of Disease Steps together with the most widely utilized clinical outcome measure in MS, the Expanded Disability Status Scale (EDSS) in assessing clinical progression. Over 4 years, 804 patients were classified using both EDSS and Disease Steps. Each patient was assessed at least twice. Follow-up results included annual status and time-to-event analysis examining median staying times within a level of Disease Steps or EDSS. We found that the two scales behaved similarly and correlated strongly with each other. For both Disease Steps and EDSS, patients with milder levels of disability and relapsing-remitting disease demonstrated a higher likelihood of changing scores over time and shorter median staying times compared to more disabled, chronic progressive patients. These findings have important implications for patient selection in clinical trials and for the design of future measurements of clinical outcome in MS. Furthermore, Disease Steps may serve as a simple, practical tool for the nonspecialty neurologist to follow patients over time and serve as a guide in therapeutic decision making. Our findings further document the general progressive nature of MS when a large cohort is followed in an MS specialty clinic over time. PMID:10516779

  4. Pathogenesis and disease-modifying therapy in Alzheimer's disease: the flat line of progress.

    PubMed

    Castellani, Rudy J; Perry, George

    2012-11-01

    The lack of progress in the development of disease-modifying therapy in Alzheimer's disease (AD) was highlighted recently by the cessation of a phase 3 clinical trial studying the effects of bapineuzumab on mild to moderate disease. No treatment benefit was apparent, whereas several serious side effects occurred more commonly in the treatment group compared to placebo. This is the latest failure in a now long list of trials targeting lesional proteins believed to be fundamental drivers of the disease process. As the focus of the trial is directly tied to ostensible disease pathogenesis, objectivity compels us yet again to re-examine the amyloid cascade hypothesis as even a marginally significant pathogenic mediator of disease and to perhaps revert back to traditional science where repeated negative data leads one to consider other ideas. In the case of AD, amyloid-β metabolism and tau phosphorylation have been exhaustively studied, both to no avail. Oxidative stress has similarly been examined in detail by multiple mechanisms and targeted for treatment with a similar result. An appeal to the scientific community may be made to consider lesions in a different light. Have we been seduced by so-called hallmark lesions into believing that they are responsible for disease when in fact the reverse is true, and will we genuinely consider a systems biology approach to AD or instead continue on the path of the lesion, which has so far followed a flat line of progress? PMID:23085451

  5. [Palliative care in non-cancer, chronic, progressive diseases].

    PubMed

    Radványi, Ildikó; Nagy, Lajos; Balogh, Sándor; Csikós, Ágnes

    2015-10-18

    Malignant and other chronic diseases cause the death of 2.5 million people in Europe annually. It is anticipated that this number will grow due to the aging of the European population. The death of a significant proportion of patients having progressive chronic disease is preceded by an extended end of life stadium. In this stage the patients have severe symptoms and pain that necessitate their symptomatic treatment and palliative care. The assessment of the life expectancy of patients, estimation of the prognosis of their illness and, therefore, selection of patients with a need of intensified palliative care often pose difficulties. This paper provides a summary on the basic elements of "good palliative care". It introduces the most frequent models for the procession of chronic diseases and those indicators that help practicing doctors to recognise easier patients with a need of intensified palliative care, and as a result provides more adequate medical attendance that is better suited to the specific needs of the patients. PMID:26551310

  6. Global gene expression profile progression in Gaucher disease mouse models

    PubMed Central

    2011-01-01

    Background Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal functions are obscure. Results To elucidate this pathogenic pathway, developmental global gene expression analyses were conducted in distinct Gba1 point-mutated mice (V394L/V394L and D409 V/null). About 0.9 to 3% of genes had altered expression patterns (≥ ± 1.8 fold change), representing several categories, but particularly macrophage activation and immune response genes. Time course analyses (12 to 28 wk) of INFγ-regulated pro-inflammatory (13) and IL-4-regulated anti-inflammatory (11) cytokine/mediator networks showed tissue differential profiles in the lung and liver of the Gba1 mutant mice, implying that the lipid-storage macrophages were not functionally inert. The time course alterations of the INFγ and IL-4 pathways were similar, but varied in degree in these tissues and with the Gba1 mutation. Conclusions Biochemical and pathological analyses demonstrated direct relationships between the degree of tissue glucosylceramides and the gene expression profile alterations. These analyses implicate IFNγ-regulated pro-inflammatory and IL-4-regulated anti-inflammatory networks in differential disease progression with implications for understanding the Gaucher disease course and pathophysiology. PMID:21223590

  7. Identification of potential biomarkers of disease progression in bovine tuberculosis.

    PubMed

    Blanco, Federico Carlos; Bigi, Fabiana; Soria, Marcelo Abel

    2014-08-15

    Bovine tuberculosis (bTB) remains an important animal and zoonotic disease in many countries. The diagnosis of bTB is based on tuberculin skin test and IFN-γ release assays (IGRA). Positive animals are separated from the herd and sacrificed. The cost of this procedure is difficult to afford for developing countries with high prevalence of bTB; therefore, the improvement of diagnostic methods and the identification of animals in different stages of the disease will be helpful to control the infection. To identify biomarkers that can discriminate between tuberculin positive cattle with and without tuberculosis lesions (ML+ and ML-, respectively), we assessed a group of immunological parameters with three different classification methods: lineal discriminant analysis (LDA), quadratic discriminant analysis (QDA) and K nearest neighbors (k-nn). For this purpose, we used data from 30 experimentally infected cattle. All the classifiers (LDA, QDA and k-nn) selected IL-2 and IL-17 as the most discriminatory variables. The best classification method was LDA using IL-17 and IL-2 as predictors. The addition of IL-10 to LDA improves the performance of the classifier to discriminate ML-individuals (93.3% vs. 86.7%). Thus, the expression of IL-17, IL-2 and, in some cases, IL-10 would serve as an additional tool to study disease progression in herds with a history of bTB. PMID:24856732

  8. Antisense oligonucleotide therapy for the treatment of C9ORF72 ALS/FTD diseases.

    PubMed

    Riboldi, Giulietta; Zanetta, Chiara; Ranieri, Michela; Nizzardo, Monica; Simone, Chiara; Magri, Francesca; Bresolin, Nereo; Comi, Giacomo P; Corti, Stefania

    2014-12-01

    Motor neuron disorders, and particularly amyotrophic lateral sclerosis (ALS), are fatal diseases that are due to the loss of motor neurons in the brain and spinal cord, with progressive paralysis and premature death. It has been recently shown that the most frequent genetic cause of ALS, frontotemporal dementia (FTD), and other neurological diseases is the expansion of a hexanucleotide repeat (GGGGCC) in the non-coding region of the C9ORF72 gene. The pathogenic mechanisms that produce cell death in the presence of this expansion are still unclear. One of the most likely hypotheses seems to be the gain-of-function that is achieved through the production of toxic RNA (able to sequester RNA-binding protein) and/or toxic proteins. In recent works, different authors have reported that antisense oligonucleotides complementary to the C9ORF72 RNA transcript sequence were able to significantly reduce RNA foci generated by the expanded RNA, in affected cells. Here, we summarize the recent findings that support the idea that the buildup of "toxic" RNA containing the GGGGCC repeat contributes to the death of motor neurons in ALS and also suggest that the use of antisense oligonucleotides targeting this transcript is a promising strategy for treating ALS/frontotemporal lobe dementia (FTLD) patients with the C9ORF72 repeat expansion. These data are particularly important, given the state of the art antisense technology, and they allow researchers to believe that a clinical application of these discoveries will be possible soon. PMID:24809691

  9. [The concurrence of light-chain deposition disease, AL-amyloidosis, and cast nephropathy in a patient with multiple myeloma].

    PubMed

    Rekhtina, I G; Zakharova, E V; Stoliarevich, E S; Sinitsina, M N; Denisova, E N

    2015-01-01

    Despite of the fact that their clinical manifestations are similar, AL-amyloidosis (AL-A) and light chain deposition disease (LCDD) are individual nosological entities in view of considerable differences in their pathogenesis and pathomorphology. The paper describes a rare case of the concurrence of LCDD and AL-A in a patient with multiple myeloma. Clinically, there was dialysis-dependent renal failure, flail leg syndrome, myocardiopathy, and rhabdomyolysis. At the disease onset, his nephrobiopsy specimen could diagnose LCDD and myeloma or cast nephropathy. The disease was characterized by an aggressive course. Despite the administration of innovative agents, the patient had a short-term remission and died from disease progression. Autopsy additionally revealed amyloid deposition in the heart and kidney. The development of AL-A in the presence of prior LCDD may reflect the progression of the tumor and the appearance of an additional subclone of plasma cells that produce amyloidogenic light chains. The uncommonness of this case is that renal amyloid was found in the tubular casts and absent in the glomeruli, which may be considered as a special form--tubular AL-amyloidosis. PMID:26281203

  10. A Bayesian nonlinear mixed-effects disease progression model

    PubMed Central

    Kim, Seongho; Jang, Hyejeong; Wu, Dongfeng; Abrams, Judith

    2016-01-01

    A nonlinear mixed-effects approach is developed for disease progression models that incorporate variation in age in a Bayesian framework. We further generalize the probability model for sensitivity to depend on age at diagnosis, time spent in the preclinical state and sojourn time. The developed models are then applied to the Johns Hopkins Lung Project data and the Health Insurance Plan for Greater New York data using Bayesian Markov chain Monte Carlo and are compared with the estimation method that does not consider random-effects from age. Using the developed models, we obtain not only age-specific individual-level distributions, but also population-level distributions of sensitivity, sojourn time and transition probability. PMID:26798562

  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. Remnant nephron physiology and the progression of chronic kidney disease

    PubMed Central

    Schnaper, H. William

    2013-01-01

    In chronic kidney disease, ongoing failure of individual nephrons leads to the progressive loss of renal function. This process results in part from a cellular and molecular response to injury that represents an attempt to maintain homeostasis but instead initiates a program that damages the nephron. As nephrons are lost, compensation by the remaining nephrons exacerbates glomerular pathophysiology. Delivery of excessive amounts of biologically active molecules to the distal nephron and tubulointerstitium generates inflammation and cellular dedifferentiation. Energy requirements of hyperfunctioning nephrons exceed the metabolic substrate available to the renal tubule, and inadequacy of the local vascular supply promotes hypoxia/ischemia and consequent acidosis and reactive oxygen species generation. In this way, mechanisms activated to maintain biological balance ultimately lead to demise of the nephron. PMID:23715783

  13. 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 β-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

  14. Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis.

    PubMed

    El Oussini, Hajer; Bayer, Hanna; Scekic-Zahirovic, Jelena; Vercruysse, Pauline; Sinniger, Jérôme; Dirrig-Grosch, Sylvie; Dieterlé, Stéphane; Echaniz-Laguna, Andoni; Larmet, Yves; Müller, Kathrin; Weishaupt, Jochen H; Thal, Dietmar R; van Rheenen, Wouter; van Eijk, Kristel; Lawson, Roland; Monassier, Laurent; Maroteaux, Luc; Roumier, Anne; Wong, Philip C; van den Berg, Leonard H; Ludolph, Albert C; Veldink, Jan H; Witting, Anke; Dupuis, Luc

    2016-03-01

    Microglia are the resident mononuclear phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in mononuclear phagocytes are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT2B), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT2B mRNA in spinal cord and displayed less pronounced degeneration of Iba1 positive cells than patients carrying two copies of the more common A allele. Thus, the 5-HT2B receptor limits degeneration of spinal cord mononuclear phagocytes, most likely microglia, and slows disease progression in ALS. Targeting this receptor might be therapeutically useful. PMID:26744351

  15. Microglial genes regulating neuroinflammation in the progression of Alzheimer's disease.

    PubMed

    Villegas-Llerena, Claudio; Phillips, Alexandra; Garcia-Reitboeck, Pablo; Hardy, John; Pocock, Jennifer M

    2016-02-01

    Neuroinflammation is a pathological hallmark of Alzheimer's disease (AD), and microglia, the brain's resident phagocyte, are pivotal for the immune response observed in AD. Microglia act as sentinel and protective cells, but may become inappropriately reactive in AD to drive neuropathology. Recent Genome Wide Association Studies (GWAS) have identified more than 20 gene variants associated with an increased risk of late-onset AD (LOAD), the most prevalent form of AD [1]. The findings strongly implicate genes related to the immune response (CR1, CD33, MS4A, CLU, ABCA7, EPHA1 and HLA-DRB5-HLA-DRB1), endocytosis (BIN1, PICALM, CD2AP, EPHA1 and SORL1) and lipid biology (CLU, ABCA7 and SORL1) [2-8], and many encode proteins which are highly expressed in microglia [1]. Furthermore, recent identification of a low frequency mutation in the gene encoding the triggering receptor expressed in myeloid cells 2 protein (TREM2) confers increased risk of AD in LOAD cohorts with an effect size similar to that for APOE, until recently the only identified genetic risk factor associated with LOAD [9,10(••)] (Figure 1). The present review summarises our current understanding of the probable roles of microglial genes in the regulation of neuroinflammatory processes in AD and their relation to other processes affecting the disease's progression. PMID:26517285

  16. The Myth of Schizophrenia as a Progressive Brain Disease

    PubMed Central

    Zipursky, Robert B.

    2013-01-01

    Schizophrenia has historically been considered to be a deteriorating disease, a view reinforced by recent MRI findings of progressive brain tissue loss over the early years of illness. On the other hand, the notion that recovery from schizophrenia is possible is increasingly embraced by consumer and family groups. This review critically examines the evidence from longitudinal studies of (1) clinical outcomes, (2) MRI brain volumes, and (3) cognitive functioning. First, the evidence shows that although approximately 25% of people with schizophrenia have a poor long-term outcome, few of these show the incremental loss of function that is characteristic of neurodegenerative illnesses. Second, MRI studies demonstrate subtle developmental abnormalities at first onset of psychosis and then further decreases in brain tissue volumes; however, these latter decreases are explicable by the effects of antipsychotic medication, substance abuse, and other secondary factors. Third, while patients do show cognitive deficits compared with controls, cognitive functioning does not appear to deteriorate over time. The majority of people with schizophrenia have the potential to achieve long-term remission and functional recovery. The fact that some experience deterioration in functioning over time may reflect poor access, or adherence, to treatment, the effects of concurrent conditions, and social and financial impoverishment. Mental health professionals need to join with patients and their families in understanding that schizophrenia is not a malignant disease that inevitably deteriorates over time but rather one from which most people can achieve a substantial degree of recovery. PMID:23172002

  17. Sodium intake, RAAS-blockade and progressive renal disease.

    PubMed

    de Borst, Martin H; Navis, Gerjan

    2016-05-01

    Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin converting enzyme inhibitors or angiotensin receptor blockers is the current standard treatment to prevent progressive renal function loss in patients with chronic kidney disease. Yet in many patients the renal protective effect of RAAS-blockade is incomplete. Short-term clinical studies have demonstrated that dietary sodium restriction potentiates the antiproteinuric effect of RAAS-blockade. More recently, it was shown that this effect is accompanied by a lower risk of end-stage renal disease and adverse cardiovascular outcomes. The modulation of RAAS-blockade efficacy by sodium intake is likely multifactorial, and is mediated by effects of sodium on local tissue RAAS in kidney, vasculature and brain, and by effects on the immune system. Despite the evidence showing the beneficial effects of even a moderate sodium restriction (∼2.5g/d), it remains difficult to realize in clinical practice. In an analysis based on 24-h urinary sodium excretion data from more than 10,000 CKD patients and renal transplant recipients, we found that sodium intake in these patients is on average 3.8g/d, closely resembling the global general population (3.95g/d). Behavioral approaches including the use of online dietary coaching (ehealth) and feedback using data from 24-h urine collections may be useful to successfully lower dietary sodium intake, aiming to improve cardio-renal outcomes in patients with CKD. PMID:27041482

  18. Haematuria as a risk factor for chronic kidney disease progression in glomerular diseases: A review.

    PubMed

    Moreno, Juan Antonio; Yuste, Claudia; Gutiérrez, Eduardo; Sevillano, Ángel M; Rubio-Navarro, Alfonso; Amaro-Villalobos, Juan Manuel; Praga, Manuel; Egido, Jesús

    2016-04-01

    Haematuria has long been considered to be a benign condition associated with glomerular diseases. However, new evidences suggest that haematuria has a pathogenic role in promoting kidney disease progression. An increased risk for end-stage renal disease has been reported in adolescents and young adults with persistent microscopic haematuria. A persistent impairment of renal function has been also reported following macroscopic haematuria-associated acute kidney injury in immunoglobulin A nephropathy. Haematuria-induced renal damage has been related to oxidant, cytotoxic and inflammatory effects induced by haemoglobin or haem released from red blood cells. The pathophysiological origin of haematuria may be due to a more fragile and easily ruptured glomerular filtration barrier, as reported in several glomerular diseases. In this review we describe a number of the key issues associated with the epidemiology and pathogenesis of haematuria-associated diseases, provide an update of recent knowledge on the role of haematuria on renal function outcome and discuss specific therapeutic approaches in this setting. 1. Glomerular haematuria is a common observation in a number of renal diseases that may lead to persistent renal injury. 2. Haematuria in children differs from that in adults in specific aspects, particularly in the frequency of glomerular diseases and renal disease outcome. 3. Regular follow-up of renal function in children with isolated microhaematuria may be recommended. PMID:25980470

  19. Rootstock effects on progression of Pierce's disease symptom development and possible mechanisms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rootstocks are utilized to reduce incidence and severity of root-associated diseases. However, the ability of rootstocks to limit progression of stem-afflicting diseases has not been studied extensively. Rootstocks potentially could slow progression of scion-afflicting diseases such as Pierce’s dise...

  20. 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...

  1. Blood Platelets in the Progression of Alzheimer’s Disease

    PubMed Central

    Gowert, Nina S.; Donner, Lili; Chatterjee, Madhumita; Eisele, Yvonne S.; Towhid, Seyda T.; Münzer, Patrick; Walker, Britta; Ogorek, Isabella; Borst, Oliver; Grandoch, Maria; Schaller, Martin; Fischer, Jens W.; Gawaz, Meinrad; Weggen, Sascha; Lang, Florian; Jucker, Mathias; Elvers, Margitta

    2014-01-01

    Alzheimer’s disease (AD) is characterized by neurotoxic amyloid-ß plaque formation in brain parenchyma and cerebral blood vessels known as cerebral amyloid angiopathy (CAA). Besides CAA, AD is strongly related to vascular diseases such as stroke and atherosclerosis. Cerebrovascular dysfunction occurs in AD patients leading to alterations in blood flow that might play an important role in AD pathology with neuronal loss and memory deficits. Platelets are the major players in hemostasis and thrombosis, but are also involved in neuroinflammatory diseases like AD. For many years, platelets were accepted as peripheral model to study the pathophysiology of AD because platelets display the enzymatic activities to generate amyloid-ß (Aß) peptides. In addition, platelets are considered to be a biomarker for early diagnosis of AD. Effects of Aß peptides on platelets and the impact of platelets in the progression of AD remained, however, ill-defined. The present study explored the cellular mechanisms triggered by Aß in platelets. Treatment of platelets with Aß led to platelet activation and enhanced generation of reactive oxygen species (ROS) and membrane scrambling, suggesting enhanced platelet apoptosis. More important, platelets modulate soluble Aß into fibrillar structures that were absorbed by apoptotic but not vital platelets. This together with enhanced platelet adhesion under flow ex vivo and in vivo and platelet accumulation at amyloid deposits of cerebral vessels of AD transgenic mice suggested that platelets are major contributors of CAA inducing platelet thrombus formation at vascular amyloid plaques leading to vessel occlusion critical for cerebrovascular events like stroke. PMID:24587388

  2. 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

  3. The role of carotid atherosclerosis in Alzheimer's disease progression.

    PubMed

    Silvestrini, Mauro; Viticchi, Giovanna; Falsetti, Lorenzo; Balucani, Clotilde; Vernieri, Fabrizio; Cerqua, Raffaella; Luzzi, Simona; Bartolini, Marco; Provinciali, Leandro

    2011-01-01

    The aim of this 12-month prospective study was to establish whether severe internal carotid artery stenosis is associated with faster progression of the cognitive impairment in patients with Alzheimer's disease (AD). Four hundred and eleven patients with AD underwent extracranial carotid Doppler ultrasound evaluation. Cerebrovascular reactivity to hypercapnia was measured by means of the breath-holding index (BHI) in those with severe carotid artery stenosis using transcranial Doppler ultrasonography. Cognitive status was quantified with the Mini Mental State Evaluation (MMSE). Ninety-eight patients had severe carotid artery stenosis, 41 right (group 1), and 57 left (group 2), while 313 had no significant stenosis (group 3). Group 1 and 2 patients showed an increased probability compared with group 3 patients to develop severe dementia (MMSE scores < 21) during the 12-month follow-up period: OR 2.36 (95% CI: 1.14-4.87) and OR 4.90 (95% CI: 2.65-9.04), respectively (p < 0.05, multiple logistic regression analysis). A BHI value ipsilateral to the stenosis < 0.69 predicted a worse MMSE score at 12 months irrespective of the side of the stenosis. These findings suggest that severe internal carotid artery stenosis can be considered as a marker of a faster rate of progression of the cognitive decline in AD. They also indicate that cerebral hemodynamic evaluation could be applied to identify patients at higher risk of rapid cognitive decline, who may benefit from aggressive treatment, and warrant investigation of the advantages of carotid revascularization procedures in these patients. PMID:21508532

  4. 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

  5. Progression of coronary disease in a Behcet’s patient in remission

    PubMed Central

    Abeyewickreme, Anil; Ramoutar, Anil; Kabir, Alamgir

    2012-01-01

    Behcet’s disease is characterised histologically by vasculitis. In the heart this can lead to aneurysm formation and thrombosis. There is also accelerated atherosclerosis, the mechanism of which is unclear. Patients with external disease from Behcet’s disease are treated with immunosuppression. The authors present a case of aneurysmal disease in a Behcet’s patient. This case demonstrates that coronary disease may progress in Behcet’s patients despite external disease remission. Therefore, internal disease may progress in the absence of external symptoms when immunosuppressive therapy is usually stopped. This case raises the issue of whether immunosuppression should be continued in Behcet’s patients with coronary disease to suppress disease progression or included in a treatment protocol for patients with Behcet’s related coronary disease. Clinical trials on the use of immunosuppressive therapy for coronary disease in Behcet’s patients are needed. PMID:22761229

  6. Progression of autosomal dominant kidney disease: measurement of the stage transitions of chronic kidney disease

    PubMed Central

    Blanchette, Christopher M; Liang, Caihua; Lubeck, Deborah P; Newsome, Britt; Rossetti, Sandro; Gu, Xiangmei; Gutierrez, Benjamin; Lin, Nancy D

    2015-01-01

    Background: Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic disorder characterized by the development of numerous kidney cysts that result in kidney failure. Little is known regarding the key patient characteristics and utilization of healthcare resources for ADPKD patients along the continuum of disease progression. This observational study was designed to describe the characteristics of ADPKD patients and compare them with those of patients with other chronic kidney diseases. Methods: This retrospective cohort study involved patients with a claim for ADPKD or PKD unspecified from 1/1/20002/28/2013 and ?6 months of previous continuous enrollment (baseline) within a large database of administrative claims in the USA. A random sample of chronic kidney disease (CKD) patients served as comparators. For a subset of ADPKD patients who had only a diagnosis code of unspecified PKD, abstraction of medical records was undertaken to estimate the proportion of patients who had medical chart-confirmed ADPKD. In patients with linked electronic laboratory data, the estimated glomerular filtration rate was calculated via serum creatinine values to determine CKD stage at baseline and during follow-up. Proportions of patients transitioning to another stage and the mean age at transition were calculated. Results: ADPKD patients were, in general, younger and had fewer physician visits, but had more specific comorbidities at observation start compared with CKD patients. ADPKD patients had a longer time in the milder stages and longer duration before recorded transition to a more severe stage compared with CKD patients. Patients with ADPKD at risk of rapid progression had a shorter time-to-end-stage renal disease than patients with CKD and ADPKD patients not at risk, but stage duration was similar between ADPKD patients at risk and those not at risk. Conclusions: These results suggest that distribution of patients by age at transition to next stage may be useful for identification of ADPKD patients at risk of rapid progression. The results also suggest that medical claims with diagnosis codes for unspecified PKD, in absence of a diagnosis code for autosomal recessive polycystic kidney disease, may be a good proxy for ADPKD. PMID:25922609

  7. Genetic Biomarkers for ALS Disease in Transgenic SOD1G93A Mice

    PubMed Central

    Calvo, Ana C.; Manzano, Raquel; Atencia-Cibreiro, Gabriela; Oliván, Sara; Muñoz, María J.; Zaragoza, Pilar; Cordero-Vázquez, Pilar; Esteban-Pérez, Jesús; García-Redondo, Alberto; Osta, Rosario

    2012-01-01

    The pathophysiological mechanisms of both familial and sporadic Amyotrophic Lateral Sclerosis (ALS) are unknown, although growing evidence suggests that skeletal muscle tissue is a primary target of ALS toxicity. Skeletal muscle biopsies were performed on transgenic SOD1G93A mice, a mouse model of ALS, to determine genetic biomarkers of disease longevity. Mice were anesthetized with isoflurane, and three biopsy samples were obtained per animal at the three main stages of the disease. Transcriptional expression levels of seventeen genes, Ankrd1, Calm1, Col19a1, Fbxo32, Gsr, Impa1, Mef2c, Mt2, Myf5, Myod1, Myog, Nnt, Nogo A, Pax7, Rrad, Sln and Snx10, were tested in each muscle biopsy sample. Total RNA was extracted using TRIzol Reagent according to the manufacturer's protocol, and variations in gene expression were assayed by real-time PCR for all of the samples. The Pearson correlation coefficient was used to determine the linear correlation between transcriptional expression levels throughout disease progression and longevity. Consistent with the results obtained from total skeletal muscle of transgenic SOD1G93A mice and 74-day-old denervated mice, five genes (Mef2c, Gsr, Col19a1, Calm1 and Snx10) could be considered potential genetic biomarkers of longevity in transgenic SOD1G93A mice. These results are important because they may lead to the exploration of previously unexamined tissues in the search for new disease biomarkers and even to the application of these findings in human studies. PMID:22412900

  8. The Nrf2 pathway in the progression of renal disease.

    PubMed

    Zoja, Carlamaria; Benigni, Ariela; Remuzzi, Giuseppe

    2014-02-01

    The Nrf2/Keap1 system regulates the transcription of antioxidant and cytoprotective genes through direct Nrf2 binding to responsive elements in the promoter region of target genes or via Keap1-induced NF-kB inhibition. The association between oxidative stress and inflammation with progression of chronic kidney diseases (CKDs) directed attention towards bardoxolone methyl and its analogues, potent Nrf2/Keap1 inducers, as a potential modality of renoprotective intervention. In a phase II clinical trial (BEAM), bardoxolone methyl was shown to increase the estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes. The study generated great interest but raised concerns as well, on the adverse event profile of the drug. Experiments in rats with type 2 diabetic nephropathy treated with bardoxolone methyl analogues reproduced some drawbacks of bardoxolone methyl therapy in humans. Despite these warnings, a long-term phase III trial (BEACON) was started that was prematurely terminated because of an excess serious adverse events and mortality. Lessons from the above studies suggest that before jumping into use in clinical practice, adequately designed experiments in animal models are needed to provide insights into pathogenetic mechanisms as well as unexpected side effects. PMID:23761459

  9. Polymorphism in RANTES chemokine promoter affects HIV-1 disease progression

    PubMed Central

    Liu, Huanliang; Chao, David; Nakayama, Emi E.; Taguchi, Hitomi; Goto, Mieko; Xin, Xiaomi; Takamatsu, Jun-ki; Saito, Hidehiko; Ishikawa, Yoshihide; Akaza, Tatsuya; Juji, Takeo; Takebe, Yutaka; Ohishi, Takeshi; Fukutake, Katsuyuki; Maruyama, Yoshikazu; Yashiki, Shinji; Sonoda, Shunro; Nakamura, Tetsuya; Nagai, Yoshiyuki; Iwamoto, Aikichi; Shioda, Tatsuo

    1999-01-01

    RANTES (regulated on activation normal T cell expressed and secreted) is one of the natural ligands for the chemokine receptor CCR5 and potently suppresses in vitro replication of the R5 strains of HIV-1, which use CCR5 as a coreceptor. Previous studies showed that peripheral blood mononuclear cells or CD4+ lymphocytes obtained from different individuals had wide variations in their ability to secrete RANTES. These findings prompted us to analyze the upstream noncoding region of the RANTES gene, which contains cis-acting elements involved in RANTES promoter activity, in 272 HIV-1-infected and 193 non-HIV-1-infected individuals in Japan. Our results showed that there were two polymorphic positions, one of which was associated with reduced CD4+ lymphocyte depletion rates during untreated periods in HIV-1-infected individuals. This mutation, RANTES−28G, occurred at an allele frequency of ≈17% in the non-HIV-1-infected Japanese population and exerted no influence on the incidence of HIV-1 infection. Functional analyses of RANTES promoter activity indicated that the RANTES−28G mutation increases transcription of the RANTES gene. Taken together, these data suggest that the RANTES−28G mutation increases RANTES expression in HIV-1-infected individuals and thus delays the progression of the HIV-1 disease. PMID:10200305

  10. Verbal repetition in primary progressive aphasia and Alzheimer's disease.

    PubMed

    Leyton, Cristian E; Savage, Sharon; Irish, Muireann; Schubert, Samantha; Piguet, Olivier; Ballard, Kirrie J; Hodges, John R

    2014-01-01

    We aimed to explore the nature of verbal repetition deficits and infer the cognitive systems involved in primary progressive aphasia (PPA) and Alzheimer's disease (AD). A total of 63 patients (13 semantic variant (sv-PPA), 17 nonfluent/agrammatic variant (nfv-PPA), 10 logopenic variant (lv-PPA), 23 AD) and 13 matched healthy controls completed a battery of tests that included naming, word comprehension, digit span, repetition of multisyllabic single words, monosyllabic word span presented under similar and dissimilar phonological conditions, and sentence repetition. All patient groups displayed some level of impairment, however, specific patterns emerged in each variant. Participants with sv-PPA were the least impaired, showing marginal difficulties exclusively for sentence repetition, whereas those with lv-PPA had the worst overall performance. Cases with nfv-PPA showed compromised repetition of multisyllabic and phonologically similar words. The deficit in cases with AD was confined to span tasks. These distinctive patterns of language impairments can assist in the differential diagnosis of PPA variants and point toward the vulnerability of specific cognitive systems in each syndrome. PMID:24662100

  11. Tubular atrophy in the pathogenesis of chronic kidney disease progression.

    PubMed

    Schelling, Jeffrey R

    2016-05-01

    The longstanding focus in chronic kidney disease (CKD) research has been on the glomerulus, which is sensible because this is where glomerular filtration occurs, and a large proportion of progressive CKD is associated with significant glomerular pathology. However, it has been known for decades that tubular atrophy is also a hallmark of CKD and that it is superior to glomerular pathology as a predictor of glomerular filtration rate decline in CKD. Nevertheless, there are vastly fewer studies that investigate the causes of tubular atrophy, and fewer still that identify potential therapeutic targets. The purpose of this review is to discuss plausible mechanisms of tubular atrophy, including tubular epithelial cell apoptosis, cell senescence, peritubular capillary rarefaction and downstream tubule ischemia, oxidative stress, atubular glomeruli, epithelial-to-mesenchymal transition, interstitial inflammation, lipotoxicity and Na(+)/H(+) exchanger-1 inactivation. Once a a better understanding of tubular atrophy (and interstitial fibrosis) pathophysiology has been obtained, it might then be possible to consider tandem glomerular and tubular therapeutic strategies, in a manner similar to cancer chemotherapy regimens, which employ multiple drugs to simultaneously target different mechanistic pathways. PMID:26208584

  12. 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

  13. 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 β-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 (Aβ). 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 Aβ 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

  14. The Progress of Induced Pluripotent Stem Cells as Models of Parkinson's Disease.

    PubMed

    Kang, Ji-Feng; Tang, Bei-Sha; Guo, Ji-Feng

    2016-01-01

    In recent years, induced pluripotent stem cells (iPSCs) were widely used for investigating the mechanisms of Parkinson's disease (PD). Somatic cells from patients with SNCA (α-synuclein), LRRK2 (leucine-rich repeat kinase 2), PINK1 (PTEN induced putative kinase 1), Parkin mutations, and at-risk individuals carrying GBA (β-glucocerebrosidase) mutations have been successfully induced to iPSCs and subsequently differentiated into dopaminergic (DA) neurons. Importantly, some PD-related cell phenotypes, including α-synuclein aggregation, mitophagy, damaged mitochondrial DNA, and mitochondrial dysfunction, have been described in these iPSCs models, which further investigated the pathogenesis of PD. In 2007, Takahashi et al. and Vodyanik et al. generated iPSCs from human somatic cells for the first time. Since then, patients derived iPSCs were applied for disease modeling, drug discovery and screening, autologous cell replacement therapy, and other biological applications. iPSC research has now become a hot topic in a wide range of fields. This review summarizes the recent progress of PD patients derived iPSC models in pathogenic mechanism investigation and potential clinical applications, especially their promising strategy in pharmacological study and DA neurons transplantation therapy. However, the challenges of iPSC transplantation still exist, and it has a long way to go before it can be used in clinical application. PMID:26880962

  15. The Progress of Induced Pluripotent Stem Cells as Models of Parkinson's Disease

    PubMed Central

    Kang, Ji-feng; Tang, Bei-sha; Guo, Ji-feng

    2016-01-01

    In recent years, induced pluripotent stem cells (iPSCs) were widely used for investigating the mechanisms of Parkinson's disease (PD). Somatic cells from patients with SNCA (α-synuclein), LRRK2 (leucine-rich repeat kinase 2), PINK1 (PTEN induced putative kinase 1), Parkin mutations, and at-risk individuals carrying GBA (β-glucocerebrosidase) mutations have been successfully induced to iPSCs and subsequently differentiated into dopaminergic (DA) neurons. Importantly, some PD-related cell phenotypes, including α-synuclein aggregation, mitophagy, damaged mitochondrial DNA, and mitochondrial dysfunction, have been described in these iPSCs models, which further investigated the pathogenesis of PD. In 2007, Takahashi et al. and Vodyanik et al. generated iPSCs from human somatic cells for the first time. Since then, patients derived iPSCs were applied for disease modeling, drug discovery and screening, autologous cell replacement therapy, and other biological applications. iPSC research has now become a hot topic in a wide range of fields. This review summarizes the recent progress of PD patients derived iPSC models in pathogenic mechanism investigation and potential clinical applications, especially their promising strategy in pharmacological study and DA neurons transplantation therapy. However, the challenges of iPSC transplantation still exist, and it has a long way to go before it can be used in clinical application. PMID:26880962

  16. Progressive neuronal degeneration of childhood with liver disease (Alpers' disease) presenting in young adults.

    PubMed Central

    Harding, B N; Alsanjari, N; Smith, S J; Wiles, C M; Thrush, D; Miller, D H; Scaravilli, F; Harding, A E

    1995-01-01

    Two unrelated and previously healthy girls, aged 17 and 18, presented with a subacute encephalopathy, visual and sensory symptoms and signs, and prominent seizures that were difficult to control. Brain MRI showed lesions (high signal on T2 weighted images) in the occipital lobes and thalamus; EEG showed slow wave activity with superimposed polyspikes. Inexorable downhill progression led to death in hepatic failure within eight months of onset. Histopathological findings in both patients ((a) chronic hepatitis with prominent bile duct proliferation, fatty change, and fibrosis; (b) in the brain a patchy destruction of the cerebral cortex, predominantly involving striate cortex) were characteristic of progressive neuronal degeneration of childhood with liver disease--Alpers-Huttenlocher syndrome--a rare autosomal recessive disorder usually seen in infants and young children. Images PMID:7897414

  17. White Matter Abnormalities Track Disease Progression in PSEN1 Autosomal Dominant Alzheimer's Disease.

    PubMed

    Sánchez-Valle, Raquel; Monté, Gemma C; Sala-Llonch, Roser; Bosch, Beatriz; Fortea, Juan; Lladó, Albert; Antonell, Anna; Balasa, Mircea; Bargalló, Nuria; Molinuevo, José Luis

    2016-02-20

    PSEN1 mutations are the most frequent cause of autosomal dominant Alzheimer's disease (ADAD), and show nearly full penetrance. There is presently increasing interest in the study of biomarkers that track disease progression in order to test therapeutic interventions in ADAD. We used white mater (WM) volumetric characteristics and diffusion tensor imaging (DTI) metrics to investigate correlations with the normalized time to expected symptoms onset (relative age ratio) and group differences in a cohort of 36 subjects from PSEN1 ADAD families: 22 mutation carriers, 10 symptomatic (SMC) and 12 asymptomatic (AMC), and 14 non-carriers (NC). Subjects underwent a 3T MRI. WM morphometric data and DTI metrics were analyzed. We found that PSEN1 MC showed significant negative correlation between fractional anisotropy (FA) and the relative age ratio in the genus and body of corpus callosum and corona radiate (p <  0.05 Family-wise error correction (FWE) at cluster level) and positive correlation with mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD) in the splenium of corpus callosum. SMC presented WM volume loss, reduced FA and increased MD, AxD, and RD in the anterior and posterior corona radiate, corpus callosum (p <  0.05 FWE) compared with NC. No significant differences were observed between AMC and NC in WM volume or DTI measures. These findings suggest that the integrity of the WM deteriorates linearly in PSEN1 ADAD from the early phases of the disease; thus DTI metrics might be useful to monitor the disease progression. However, the lack of significant alterations at the preclinical stages suggests that these indexes might not be good candidates for early markers of the disease. PMID:26923015

  18. Abnormal Olfaction in Parkinson's Disease Is Related to Faster Disease Progression

    PubMed Central

    Cavaco, Sara; Gonçalves, Alexandra; Mendes, Alexandre; Vila-Chã, Nuno; Moreira, Inês; Fernandes, Joana; Damásio, Joana; Teixeira-Pinto, Armando; Bastos Lima, António

    2015-01-01

    Introduction. A possible association between olfactory dysfunction and Parkinson's disease (PD) severity has been a topic of contention for the past 40 years. Conflicting reports may be partially explained by procedural differences in olfactory assessment and motor symptom evaluation. Methods. One hundred and sixty-six nondemented PD patients performed the Brief-Smell Identification Test and test scores below the estimated 20th percentile as a function of sex, age, and education (i.e., 80% specificity) were considered demographically abnormal. Patients underwent motor examination after 12 h without antiparkinsonian medication. Results. Eighty-two percent of PD patients had abnormal olfaction. Abnormal performance on the Brief-Smell Identification Test was associated with higher disease severity (i.e., Hoehn and Yahr, Unified Parkinson's Disease Rating Scale-III, Freezing of Gait questionnaire, and levodopa equivalent dose), even when disease duration was taken into account. Conclusions. Abnormal olfaction in PD is associated with increased severity and faster disease progression. PMID:26136625

  19. 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 (β=-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

  20. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

    PubMed

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H; Barsottini, Orlando G P; Kawarai, Toshitaka; Orlacchio, Antonio

    2016-01-01

    Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease. PMID:26556829

  1. Learning Biomarker Models for Progression Estimation of Alzheimer’s Disease

    PubMed Central

    Ledig, Christian; Guerrero, Ricardo; Molina-Abril, Helena; Frangi, Alejandro; Rueckert, Daniel

    2016-01-01

    Being able to estimate a patient’s progress in the course of Alzheimer’s disease and predicting future progression based on a number of observed biomarker values is of great interest for patients, clinicians and researchers alike. In this work, an approach for disease progress estimation is presented. Based on a set of subjects that convert to a more severe disease stage during the study, models that describe typical trajectories of biomarker values in the course of disease are learned using quantile regression. A novel probabilistic method is then derived to estimate the current disease progress as well as the rate of progression of an individual by fitting acquired biomarkers to the models. A particular strength of the method is its ability to naturally handle missing data. This means, it is applicable even if individual biomarker measurements are missing for a subject without requiring a retraining of the model. The functionality of the presented method is demonstrated using synthetic and—employing cognitive scores and image-based biomarkers—real data from the ADNI study. Further, three possible applications for progress estimation are demonstrated to underline the versatility of the approach: classification, construction of a spatio-temporal disease progression atlas and prediction of future disease progression. PMID:27096739

  2. Cerebrovascular pathology during the progression of experimental Alzheimer's disease.

    PubMed

    Giannoni, Patrizia; Arango-Lievano, Margarita; Neves, Ines Das; Rousset, Marie-Claude; Baranger, Kévin; Rivera, Santiago; Jeanneteau, Freddy; Claeysen, Sylvie; Marchi, Nicola

    2016-04-01

    Clinical and experimental evidence point to a possible role of cerebrovascular dysfunction in Alzheimer's disease (AD). The 5xFAD mouse model of AD expresses human amyloid precursor protein and presenilin genes with mutations found in AD patients. It remains unknown whether amyloid deposition driven by these mutations is associated with cerebrovascular changes. 5xFAD and wild type mice (2 to 12months old; M2 to M12) were used. Thinned skull in vivo 2-photon microscopy was used to determine Aβ accumulation on leptomeningeal or superficial cortical vessels over time. Parenchymal microvascular damage was assessed using FITC-microangiography. Collagen-IV and CD31 were used to stain basal lamina and endothelial cells. Methoxy-XO4, Thioflavin-S or 6E10 were used to visualize Aβ accumulation in living mice or in fixed brain tissues. Positioning of reactive IBA1 microglia and GFAP astrocytes at the vasculature was rendered using confocal microscopy. Platelet-derived growth factor receptor beta (PDGFRβ) staining was used to visualize perivascular pericytes. In vivo 2-photon microscopy revealed Methoxy-XO4(+) amyloid perivascular deposits on leptomeningeal and penetrating cortical vessels in 5xFAD mice, typical of cerebral amyloid angiopathy (CAA). Amyloid deposits were visible in vivo at M3 and aggravated over time. Progressive microvascular damage was concomitant to parenchymal Aβ plaque accumulation in 5xFAD mice. Microvascular inflammation in 5xFAD mice presented with sporadic FITC-albumin leakages at M4 becoming more prevalent at M9 and M12. 3D colocalization showed inflammatory IBA1(+) microglia proximal to microvascular FITC-albumin leaks. The number of perivascular PDGFRβ(+) pericytes was significantly decreased at M4 in the fronto-parietal cortices, with a trend decrease observed in the other structures. At M9-M12, PDGFRβ(+) pericytes displayed hypertrophic perivascular ramifications contiguous to reactive microglia. Cerebral amyloid angiopathy and microvascular inflammation occur in 5xFAD mice concomitantly to parenchymal plaque deposition. The prospect of cerebrovascular pharmacology in AD is discussed. PMID:26774030

  3. 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

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

    MedlinePlus

    ... 2004 2003 2002 2001 2000 1999 Spotlight on Research 2011 September 2011 (historical) Research Finds Link Between Statin Use and Progressive Muscle ... as the drugs are taken. New NIAMS-supported research has found that for a subset of patients, ...

  5. 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

  6. 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...

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

    PubMed

    Ikeda, Ken; Iwasaki, Yasuo

    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

  8. 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.

  9. CDC Periodontal Disease Surveillance Project: background, objectives, and progress report.

    PubMed

    Eke, Paul I; Genco, Robert J

    2007-07-01

    This supplement contains papers presented at the 2006 International Association of Dental Research (IADR) symposium entitled "Development of Self-Reported Measures for Population-Based Surveillance of Periodontitis." These papers highlight activities of an independent periodontal disease surveillance workgroup convened by the Division of Oral Health (DOH), Centers for Disease Control and Prevention (CDC), in collaboration with the American Academy of Periodontology, to examine the feasibility of using self-reported measures for population-based surveillance of periodontal disease in the United States. This workgroup was convened in 2003 as part of a CDC periodontal disease surveillance project. PMID:17610396

  10. 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

  11. CSF biomarkers associated with disease heterogeneity in early Parkinson's disease: the Parkinson's Progression Markers Initiative study.

    PubMed

    Kang, Ju-Hee; Mollenhauer, Brit; Coffey, Christopher S; Toledo, Jon B; Weintraub, Daniel; Galasko, Douglas R; Irwin, David J; Van Deerlin, Vivianna; Chen-Plotkin, Alice S; Caspell-Garcia, Chelsea; Waligórska, Teresa; Taylor, Peggy; Shah, Nirali; Pan, Sarah; Zero, Pawel; Frasier, Mark; Marek, Kenneth; Kieburtz, Karl; Jennings, Danna; Tanner, Caroline M; Simuni, Tanya; Singleton, Andrew; Toga, Arthur W; Chowdhury, Sohini; Trojanowski, John Q; Shaw, Leslie M

    2016-06-01

    The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aβ1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aβ1-42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aβ1-42, or highest t-tau/Aβ1-42 and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aβ1-42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance. PMID:27021906

  12. A Computational Neurodegenerative Disease Progression Score: Method and Results with the Alzheimer’s Disease Neuroimaging Initiative Cohort

    PubMed Central

    Jedynak, Bruno M.; Lang, Andrew; Liu, Bo; Katz, Elyse; Zhang, Yanwei; Wyman, Bradley T.; Raunig, David; Jedynak, C. Pierre; Caffo, Brian; Prince, Jerry L.

    2012-01-01

    While neurodegenerative diseases are characterized by steady degeneration over relatively long timelines, it is widely believed that the early stages are the most promising for therapeutic intervention, before irreversible neuronal loss occurs. Developing a therapeutic response requires a precise measure of disease progression. However, since the early stages are for the most part asymptomatic, obtaining accurate measures of disease progression is difficult. Longitudinal databases of hundreds of subjects observed during several years with tens of validated biomarkers are becoming available, allowing the use of computational methods. We propose a widely applicable statistical methodology for creating a disease progression score (DPS), using multiple biomarkers, for subjects with a neurodegenerative disease. The proposed methodology was evaluated for Alzheimer’s disease (AD) using the publicly available AD Neuroimaging Initiative (ADNI) database, yielding an Alzheimer’s DPS or ADPS score for each subject and each time-point in the database. In addition, a common description of biomarker changes was produced allowing for an ordering of the biomarkers. The Rey Auditory Verbal Learning Test delayed recall was found to be the earliest biomarker to become abnormal. The group of biomarkers comprising the volume of the hippocampus and the protein concentration amyloid beta and Tau were next in the timeline, and these were followed by three cognitive biomarkers. The proposed methodology thus has potential to stage individuals according to their state of disease progression relative to a population and to deduce common behaviors of biomarkers in the disease itself. PMID:22885136

  13. 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

  14. Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group.

    PubMed

    Lai, E C; Felice, K J; Festoff, B W; Gawel, M J; Gelinas, D F; Kratz, R; Murphy, M F; Natter, H M; Norris, F H; Rudnicki, S A

    1997-12-01

    The objective of this study was to investigate the safety and efficacy of recombinant human insulinlike growth factor-I (rhIGF-I) in the treatment of sporadic ALS. A double-blind, placebo-controlled, randomized study of 266 patients was conducted at eight centers in North America. Placebo or rhIGF-I (0.05 mg/kg/day or 0.10 mg/kg/day) was administered for 9 months. The primary outcome measure was disease symptom progression, assessed by the rate of change (per patient slope) in the Appel ALS rating scale total score. The Sickness Impact Profile (SIP), a patient-perceived, health-related quality of life assessment, was a secondary outcome variable. Progression of functional impairment in patients receiving high-dose (0.10 mg/kg/day) rhIGF-I was 26% slower than in patients receiving placebo (p = 0.01). The high-dose treatment group was less likely to terminate the study due to protocol-defined markers of disease symptom progression, and members in this group exhibited a slower decline in quality of life, as assessed by the SIP. Patients receiving 0.05 mg/kg/day of rhIGF-I exhibited trends similar to those associated with high-dose treatment, suggesting a dose-dependent response. The incidence of clinically significant adverse experiences was comparable among the three treatment groups. Recombinant human insulin-like growth factor-I slowed the progression of functional impairment and the decline in health-related quality of life in patients with ALS with no medically important adverse effects. PMID:9409357

  15. 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

  16. Disease progresses more quickly in introverts. Shy, inhibited personalities may fare worse.

    PubMed

    2004-03-01

    Los Angeles researchers recently have discovered clinical evidence that HIV-positive people with shy and introverted personalities tend to have a faster disease progression and less optimal outcomes under antiretroviral treatment than do people with extroverted personalities. PMID:15206349

  17. Key pathways in renal disease progression of experimental diabetes.

    PubMed

    Zoja, Carlamaria; Zanchi, Cristina; Benigni, Ariela

    2015-08-01

    Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and the leading cause of end-stage kidney disease. Both diabetes and chronic kidney disease are risk factors for cardiovascular disease, and diabetic patients with renal involvement are three times more likely to eventually die of cardiovascular disease than diabetic patients without signs of renal failure. In type 2 diabetes, microalbuminuria is a marker of renal dysfunction and a crucial predictor of cardiovascular disease. Inhibitors of angiotensin II synthesis/activity, while preventing micro- or macroalbuminuria, also reduced cardiovascular events in diabetic patients. However, the effectiveness of renin angiotensin system blocking agents depends on the time when treatment is started, and imperfect renoprotection may occur if therapy begins at an advanced disease phase. This raises the need to identify novel multidrug approaches that simultaneously inhibit additional pathways other than angiotensin II for those diabetic patients who remain at high risk of both poor renal and cardiovascular outcomes. Studies in animal models of diabetes have contributed to defining relevant cellular mechanisms underlying the pathogenesis of DN that could represent possible targets for therapies. The pathogenesis of DN is multifactorial, involving a complex series of molecular processes. In this review, we report evidence obtained in experimental models of DN on some specific processes and pathways implicated in DN that may be crucial for managing this disease. PMID:26209738

  18. 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.

  19. 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)

  20. Long-term progression of Menière's disease.

    PubMed

    Stahle, J; Friberg, U; Svedberg, A

    1989-05-01

    A retrospective study of 161 patients with Menière's disease followed up for 9 years or more is presented. The development, with respect to hearing, caloric response, vertigo, and ability to work, was analyzed. The main functional loss was found to take place early in the course of the disease. There was an increase in bilaterality with time. A spontaneous relief in vertigo over the years has been noticed. PMID:2750865

  1. [The progress of corneal crosslink in corneal disease].

    PubMed

    Yu, Ji-feng; Huang, Yi-fei

    2010-05-01

    Corneal crosslink through UVA-riboflavin photochemistry has been shown to be an effective treatment for keratoconus, related keratectasias and infectious melting keratitis that did not respond to systemic therapy. It is a new approach to increase the mechanical and biochemical stability of the stromal tissue. The purpose of this paper is to review the basic principle, procedure, laboratory and clinical researches about corneal crosslink. In the current situation, it can state only that UVA-riboflavin induced corneal crosslink leads in the majority of the cases to a halt of the progression, and the complications of the corneal endothelial cells, crystalline lens and retina seem to be rare. PMID:20654221

  2. Rapidly Versus Slowly Progressing Patients With Alzheimer's Disease: Differences in Baseline Cognition.

    PubMed

    Seidl, Jennifer N Travis; Massman, Paul J

    2016-06-01

    Rate of progression of cognitive deficits is variable among patients with Alzheimer's disease (AD). The purpose of the current study was to compare demographic characteristics and performance on neuropsychological measures at baseline evaluation between rapidly and slowly progressing patients. Participants were divided into 2 groups based on change in Alzheimer's Disease Assessment Scale-Cognitive subscale score from baseline to 2-year follow-up, and baseline performance was compared between the groups. Participants were 55 rapidly progressing and 55 slowly progressing patients with probable AD who had a follow-up evaluation 21 to 27 months after the baseline evaluation. The groups differed in age and initial Clinical Dementia Rating. Performance differed significantly between the groups on Verbal Series Attention Test time, Logical Memory I, Visual Reproduction I, Block Design, and Controlled Oral Word Association Test. Differences were found between rapidly and slowly progressing patients on baseline neuropsychological testing. PMID:26646117

  3. Generative FDG-PET and MRI model of aging and disease progression in Alzheimer's disease.

    PubMed

    Dukart, Juergen; Kherif, Ferath; Mueller, Karsten; Adaszewski, Stanislaw; Schroeter, Matthias L; Frackowiak, Richard S J; Draganski, Bogdan

    2013-04-01

    The failure of current strategies to provide an explanation for controversial findings on the pattern of pathophysiological changes in Alzheimer's Disease (AD) motivates the necessity to develop new integrative approaches based on multi-modal neuroimaging data that captures various aspects of disease pathology. Previous studies using [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and structural magnetic resonance imaging (sMRI) report controversial results about time-line, spatial extent and magnitude of glucose hypometabolism and atrophy in AD that depend on clinical and demographic characteristics of the studied populations. Here, we provide and validate at a group level a generative anatomical model of glucose hypo-metabolism and atrophy progression in AD based on FDG-PET and sMRI data of 80 patients and 79 healthy controls to describe expected age and symptom severity related changes in AD relative to a baseline provided by healthy aging. We demonstrate a high level of anatomical accuracy for both modalities yielding strongly age- and symptom-severity- dependant glucose hypometabolism in temporal, parietal and precuneal regions and a more extensive network of atrophy in hippocampal, temporal, parietal, occipital and posterior caudate regions. The model suggests greater and more consistent changes in FDG-PET compared to sMRI at earlier and the inversion of this pattern at more advanced AD stages. Our model describes, integrates and predicts characteristic patterns of AD related pathology, uncontaminated by normal age effects, derived from multi-modal data. It further provides an integrative explanation for findings suggesting a dissociation between early- and late-onset AD. The generative model offers a basis for further development of individualized biomarkers allowing accurate early diagnosis and treatment evaluation. PMID:23592957

  4. Generative FDG-PET and MRI Model of Aging and Disease Progression in Alzheimer's Disease

    PubMed Central

    Dukart, Juergen; Kherif, Ferath; Mueller, Karsten; Adaszewski, Stanislaw; Schroeter, Matthias L.; Frackowiak, Richard S. J.; Draganski, Bogdan

    2013-01-01

    The failure of current strategies to provide an explanation for controversial findings on the pattern of pathophysiological changes in Alzheimer's Disease (AD) motivates the necessity to develop new integrative approaches based on multi-modal neuroimaging data that captures various aspects of disease pathology. Previous studies using [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and structural magnetic resonance imaging (sMRI) report controversial results about time-line, spatial extent and magnitude of glucose hypometabolism and atrophy in AD that depend on clinical and demographic characteristics of the studied populations. Here, we provide and validate at a group level a generative anatomical model of glucose hypo-metabolism and atrophy progression in AD based on FDG-PET and sMRI data of 80 patients and 79 healthy controls to describe expected age and symptom severity related changes in AD relative to a baseline provided by healthy aging. We demonstrate a high level of anatomical accuracy for both modalities yielding strongly age- and symptom-severity- dependant glucose hypometabolism in temporal, parietal and precuneal regions and a more extensive network of atrophy in hippocampal, temporal, parietal, occipital and posterior caudate regions. The model suggests greater and more consistent changes in FDG-PET compared to sMRI at earlier and the inversion of this pattern at more advanced AD stages. Our model describes, integrates and predicts characteristic patterns of AD related pathology, uncontaminated by normal age effects, derived from multi-modal data. It further provides an integrative explanation for findings suggesting a dissociation between early- and late-onset AD. The generative model offers a basis for further development of individualized biomarkers allowing accurate early diagnosis and treatment evaluation. PMID:23592957

  5. The pattern of depressive symptoms varies with progression of Parkinson's disease.

    PubMed Central

    Huber, S J; Freidenberg, D L; Paulson, G W; Shuttleworth, E C; Christy, J A

    1990-01-01

    Whether or not depressive symptoms increase in severity with progression of Parkinson's disease (PD) remains uncertain. Unlike previous studies, we examined whether the severity of specific features of depression (mood, self reproach, vegetative, and somatic symptoms) differ with respect to the progression of PD. Results indicated that symptoms related to both mood and self-reproach were present in the early stages of PD but did not increase in severity with advancing disease. Somatic features of depression were evident early and increased with disease progression, and vegetative symptoms were seen only in the later stages of PD. The different patterns of these depressive features with progression of PD may account in part for the variations seen in previous studies. PMID:2341838

  6. 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

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

    PubMed

    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

  8. Disease progression in patients with single, large-scale mitochondrial DNA deletions.

    PubMed

    Grady, John P; Campbell, Georgia; Ratnaike, Thiloka; Blakely, Emma L; Falkous, Gavin; Nesbitt, Victoria; Schaefer, Andrew M; McNally, Richard J; Gorman, Grainne S; Taylor, Robert W; Turnbull, Doug M; McFarland, Robert

    2014-02-01

    Single, large-scale deletions of mitochondrial DNA are a common cause of mitochondrial disease and cause a broad phenotypic spectrum ranging from mild myopathy to devastating multi-system syndromes such as Kearns-Sayre syndrome. Studies to date have been inconsistent on the value of putative predictors of clinical phenotype and disease progression such as mutation load and the size or location of the deletion. Using a cohort of 87 patients with single, large-scale mitochondrial DNA deletions we demonstrate that a variety of outcome measures such as COX-deficient fibre density, age-at-onset of symptoms and progression of disease burden, as measured by the Newcastle Mitochondrial Disease Adult Scale, are significantly (P < 0.05) correlated with the size of the deletion, the deletion heteroplasmy level in skeletal muscle, and the location of the deletion within the genome. We validate these findings with re-analysis of 256 cases from published data and clarify the previously conflicting information of the value of these predictors, identifying that multiple regression analysis is necessary to understand the effect of these interrelated predictors. Furthermore, we have used mixed modelling techniques to model the progression of disease according to these predictors, allowing a better understanding of the progression over time of this strikingly variable disease. In this way we have developed a new paradigm in clinical mitochondrial disease assessment and management that sidesteps the perennial difficulty of ascribing a discrete clinical phenotype to a broad multi-dimensional and progressive spectrum of disease, establishing a framework to allow better understanding of disease progression. PMID:24277717

  9. 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.

  10. Human Herpesviruses as Copathogens of HIV Infection, Their Role in HIV Transmission, and Disease Progression

    PubMed Central

    Munawwar, Arshi; Singh, Sarman

    2016-01-01

    Of eight human herpesviruses (HHVs), often, only herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) find mention in medical literature as both of these viruses are commonly associated with genital lesions and oral ulcers, commonly known as cold sores. However, role of human herpesviruses as copathogens and in aggravation and in the transmission of other human diseases, especially the Acquired immunodeficiency syndrome (HIV/AIDS) has only very recently been recognized. Therefore, screening and treating subclinical HHV infections may offer slowing of HIV infection, disease progression, and its transmission. Beside HSV-1 and HSV-2, HHV-3 a causative agent of herpes zoster remained one of the first manifestations of HIV disease before the era of highly active antiretroviral therapy (HAART). HHV-5 also known as human Cytomegalovirus infection remains a significant risk factor for HIV-associated mortality and morbidity even in HAART era. It is proposed that Cytomegalovirus viremia could be a better predictor of HIV disease progression than CD4+ T-lymphocyte count. The role of HHV-4 or Epstein–Burr virus and HHV-6, HHV-7, and HHV-8 is still being investigated in HIV disease progression. This review provides insight into the current understanding about these 8 HHVs, their co-pathogenesis, and role in HIV/AIDS disease progression. The review also covers recent literature in favor and against administering anti-HHV treatment along with HAART for slower AIDS progression and interrupted sexual transmission. PMID:27013807

  11. Human Herpesviruses as Copathogens of HIV Infection, Their Role in HIV Transmission, and Disease Progression.

    PubMed

    Munawwar, Arshi; Singh, Sarman

    2016-01-01

    Of eight human herpesviruses (HHVs), often, only herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) find mention in medical literature as both of these viruses are commonly associated with genital lesions and oral ulcers, commonly known as cold sores. However, role of human herpesviruses as copathogens and in aggravation and in the transmission of other human diseases, especially the Acquired immunodeficiency syndrome (HIV/AIDS) has only very recently been recognized. Therefore, screening and treating subclinical HHV infections may offer slowing of HIV infection, disease progression, and its transmission. Beside HSV-1 and HSV-2, HHV-3 a causative agent of herpes zoster remained one of the first manifestations of HIV disease before the era of highly active antiretroviral therapy (HAART). HHV-5 also known as human Cytomegalovirus infection remains a significant risk factor for HIV-associated mortality and morbidity even in HAART era. It is proposed that Cytomegalovirus viremia could be a better predictor of HIV disease progression than CD4+ T-lymphocyte count. The role of HHV-4 or Epstein-Burr virus and HHV-6, HHV-7, and HHV-8 is still being investigated in HIV disease progression. This review provides insight into the current understanding about these 8 HHVs, their co-pathogenesis, and role in HIV/AIDS disease progression. The review also covers recent literature in favor and against administering anti-HHV treatment along with HAART for slower AIDS progression and interrupted sexual transmission. PMID:27013807

  12. Synthesis of survival and disease progression outcomes for health technology assessment of cancer therapies.

    PubMed

    Welton, N J; Willis, S R; Ades, A E

    2010-07-01

    Studies of clinical efficacy commonly report more than one clinical endpoint. For example, randomized controlled trials of treatments for cancer will normally report time to disease progression as well as overall survival. It is likely that disease progression will be associated with higher mortality rates. Disease progression rates will also have consequences for the societal economic burden of the disease. Economic evaluation of the cost-effectiveness of different treatment regimes therefore requires the joint estimation of both disease progression and mortality. We describe a model to combine evidence from studies reporting time to event summaries for disease progression and/or mortality, motivated by a systematic review of 1st-line treatment for advanced breast cancer to provide inputs for an economic evaluation as part of the National Institute for Health and Clinical Excellence (NICE) clinical guideline on treatment of advanced breast cancer in England and Wales. The review identified a network of treatment comparisons, which provides the basis for indirect comparison. A variety of outcomes were reported: overall survival, time to progression (overall and responders only), and the proportion of responder, stable, progressive disease, and non-assessable patients. There were only five trials, and not all trials reported all outcomes. The scarcity of the available evidence required us to make strong assumptions in order to identify model parameters. However, this evidence structure often occurs in health technology assessment (HTA) of treatments for cancer. We discuss the validity of the assumptions made, and the potential to assess their validity in other applications of HTA of cancer therapies. Copyright © 2011 John Wiley & Sons, Ltd. PMID:26061469

  13. Disease Progression in Chronic Hepatitis B Patients under Long-Term Antiviral Therapy

    PubMed Central

    Moon, Jin Chang; Kim, Seong Hun; Kim, In Hee; Lee, Chang Hun; Kim, Sang Wook; Lee, Seung Ok; Lee, Soo Teik; Kim, Dae-Ghon

    2015-01-01

    Background/Aims We investigated factors associated with the disease progression and development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients during long-term oral nucleos(t)ide analog (NA) therapy. Methods This retrospective study included 524 naive CHB patients who received oral NA therapy for more than 48 weeks between January 2003 and December 2007. The primary outcome was 5-year cumulative probability of disease progression and HCC development. Disease progression was defined as cirrhosis development, cirrhotic complications, HCC or liver-related mortality. Results For the 524 patients, the cumulative probabilities of disease progression and HCC development at 1, 2, 3, 4 and 5 years were 1.1%, 6.3%, 9.0%, 11.6%, and 16.2% and 0.2%, 1.8%, 3.6%, 5.8%, and 9.3%, respectively. In multivariate analysis, age >50 years (hazard ratio [HR], 1.05) and cirrhosis (HR, 2.95) were significant factors for disease progression. Similarly, age >50 years (HR, 1.05), family history of HCC (HR, 5.48), and cirrhosis (HR, 17.16) were significant factors for HCC development. Importantly, longer duration (>12 months) of maintained virological response (<20 IU/mL) reduced the risks of disease progression (HR, 0.19) and HCC development (HR, 0.09). Conclusions Longer duration of maintained virological response significantly reduces the risk of disease progression or HCC development in CHB patients undergoing long-term oral NA therapy. PMID:25473072

  14. Autoimmune disease leading to pulmonary AL amyloidosis and pulmonary hypertension

    PubMed Central

    Ellender, Claire M; McLean, Catriona; Williams, Trevor J; Snell, Gregory I; Whitford, Helen M

    2015-01-01

    A 33-year-old woman with past history of Sjgren's syndrome and systemic lupus erythematosus presented with dyspnea and syncope secondary to pulmonary hypertension. After progressive symptoms over 4 years, she received bilateral lung transplantation. Histopathology of the explanted lungs showed isolated pulmonary amyloid light-chain amyloidosis and pulmonary cysts. No evidence of systemic amyloidosis was found at the time of transplantation. Seven years post lung transplantation, she remains well with no evidence of systemic amyloidosis recurrence. PMID:26090118

  15. A case of Gaucher's disease progressing to liver cirrhosis.

    PubMed

    Debnath, C R; Debnath, M R; Nabi, N; Khan, N A; Chakraborty, S

    2013-04-01

    We are going to present a 17 year old female with Gaucher's disease. The patient presented with fever, cough, respiratory distress & abdominal heaviness. There was mild pallor, redness of palm of hands & raised temperature. Liver was hugely enlarged along with splenomegaly. X-ray chest showed non specific bronchiectatic change in both lungs. Ultrasonography of abdomen revealed marked hepatosplenomegaly with no ascites. Bone marrow examination showed cellular marrow with plenty of megakaryocytes. Most of the cells were smear cells & there was histiocytes proliferation & infiltration of bone marrow by small atypical cells. Histologically, lipid was found in hepatocytes in moderate amount. The portal areas showed high lipid contents in macrophages. Different clinical findings & incidental diagnosis of lipid storage disease submerged us in diagnostic dilemma. We give conservative treatment with antibiotic cefuroxime, syrup lactulose & vitamins and this patient was improved. PMID:23715368

  16. [Recent progress in clinical trials for rheumatic diseases].

    PubMed

    Tanaka, Yoshiya

    2009-03-01

    Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that causes significant morbidity and mortality. RA patients should be started with DMARD represented by methotrexate (MTX) as early as possible. However, even use of MTX often fails to control disease activity and to prevent structural damage and, thereby, more effective treatment strategies are needed. Since TNF-alpha and IL-6 play a pivotal role in the pathological processes of RA, biologics targeting these cytokines with MTX, have revolutionized the treatment of RA, producing significant improvement in clinical, radiographic and functional outcomes not seen previously. However, even with these drugs the frequency and degree of responses are restricted. Therefore, new agents targeting cell surface molecules which are involved in cellular interaction and/or signaling on immune cells have been emerging, in order to increase response rates and to achieve high frequencies of remission or even cure. Two biologics abatacept, a CTLA4-Ig fusion protein, and rituximab, an anti-CD20 antibody, were launched in US and EU for the treatment of RA and many biologics are under the clinical trials from the similar concept. Thus, certain biologics have brought about paradigm shift in the treatment of rheumatic diseases, but an economical issue remains unsolved. In order to overcome the concern, low molecular weight chemical products have been rethought. Not a few agents targeting intracellular activation signaling in immune cells such as Jak and Syk are under clinical examinations and some of them appear to show wonderful results, which are comparable to biologics in the context of the treatment of rheumatic diseases. The prospects are here. PMID:19280942

  17. Progress toward vaccines against viruses that cause heart disease.

    PubMed

    Höfling, K; Kim, K S; Leser, J S; Chapman, N M; Willian, S; Gauntt, C J; Tracy, S

    2000-05-01

    Of the numerous viruses that have been implicated as causes of viral inflammatory cardiomyopathy, only the 6 serotypes of the group B coxsackieviruses (CVB 1-6) and adenovirus type 2 (Ad 2) have been regularly linked to heart disease on the basis of both clinical investigations as well as animal models (in the case of the coxsackieviruses). Of these, only the coxsackieviruses offer a truly well-characterized system for not only investigations using a small animal disease model (myocarditis in mice) but for studies of the virus at the molecular level and in cell culture systems. The pending worldwide eradication of the related enteroviruses, the polioviruses, will further emphasize the importance of the coxsackieviruses in years to come. Studies using poliovirus have shown that enteroviruses can be attenuated for disease to create highly successful and safe human vaccines. Furthermore, using recombinant DNA approaches, strains of polioviruses have been created that demonstrate a human enterovirus can express small proteins as well as foreign antigenic epitopes, thus creating multivalent chimeric vaccine strains of virus. Our laboratory has been exploring coxsackievirus 3-based vectors as models for both multivalent chimeric vaccines as well as expression vectors. The coxsackievirus can be successfully attenuated using both point mutations as well as chimeric genome technology. The coxsackievirus can also express intact small proteins in biologically active form as well as antigenic epitopes. Although it is doubtful that the marketplace will support the development of antiviral vaccines to combat human heart disease at present, the technology exists to make such vaccines a reality. PMID:10904854

  18. Long-term progression of Meniére's disease.

    PubMed

    Stahle, J; Friberg, U; Svedberg, A

    1991-01-01

    A retrospective study of 161 Meniére patients followed up for 9 years or more is presented. The development with respect to hearing, caloric response, vertigo and ability to work was analysed. The main functional loss was found to take place early in the course of the disease. There was an increase in bilaterality with time. Spontaneous relief in vertigo over the years has been noticed. PMID:1843175

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

    PubMed

    Woźniak-Kosek, Agnieszka; Kosek, Jarosław; 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

  20. Heart transplantation in rapidly progressive end-stage heart failure associated with celiac disease.

    PubMed

    Barrio, Juan P; Cura, Geraldine; Ramallo, German; Diez, Mirta; Vigliano, Carlos A; Katus, Hugo A; Mereles, Derliz

    2011-01-01

    Celiac disease is characterised by chronic immune-mediated malabsorption in genetically susceptible individuals induced by gluten proteins present in wheat, barley and rye. It occurs in adults and children at rates approaching 1% of the population. Cardiomyopathy associated with celiac disease is infrequent. The authors present here a first case of a severe progressive dilated cardiomyopathy that required heart transplantation in young woman with celiac disease. PMID:22696747

  1. Heart transplantation in rapidly progressive end-stage heart failure associated with celiac disease

    PubMed Central

    Barrio, Juan P; Cura, Geraldine; Ramallo, German; Diez, Mirta; Vigliano, Carlos A; Katus, Hugo A; Mereles, Derliz

    2011-01-01

    Celiac disease is characterised by chronic immune-mediated malabsorption in genetically susceptible individuals induced by gluten proteins present in wheat, barley and rye. It occurs in adults and children at rates approaching 1% of the population. Cardiomyopathy associated with celiac disease is infrequent. The authors present here a first case of a severe progressive dilated cardiomyopathy that required heart transplantation in young woman with celiac disease. PMID:22696747

  2. Serial surveillance of carcinoid heart disease: factors associated with echocardiographic progression and mortality

    PubMed Central

    Dobson, R; Burgess, M I; Valle, J W; Pritchard, D M; Vora, J; Wong, C; Chadwick, C; Keevi, B; Adaway, J; Hofmann, U; Poston, G J; Cuthbertson, D J

    2014-01-01

    Background: Carcinoid heart disease is a complication of metastatic neuroendocrine tumours (NETs). We sought to identify factors associated with echocardiographic progression of carcinoid heart disease and death in patients with metastatic NETs. Methods: Patients with advanced non-pancreatic NETs and documented liver metastases and/or carcinoid syndrome underwent prospective serial clinical, biochemical, echocardiographic and radiological assessment. Patients were categorised as carcinoid heart disease progressors, non-progressors or deceased. Multinomial regression was used to assess the univariate association between variables and carcinoid heart disease progression. Results: One hundred and thirty-seven patients were included. Thirteen patients (9%) were progressors, 95 (69%) non-progressors and 29 (21%) patients deceased. Baseline median levels of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in the progressors. Every 100 nmol l−1 increase in 5-HIAA yielded a 5% greater odds of disease progression (OR 1.05, 95% CI: 1.01, 1.09; P=0.012) and a 7% greater odds of death (OR 1.07, 95% CI: 1.03, 1.10; P=0.001). A 100 ng l−1 increase in NT-proBNP did not increase the risk of progression, but did increase the risk of death by 11%. Conclusions: The biochemical burden of disease, in particular baseline plasma 5-HIAA concentration, is independently associated with carcinoid heart disease progression and death. Clinical and radiological factors are less useful prognostic indicators of carcinoid heart disease progression and/or death. PMID:25211656

  3. 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

  4. Making choices-how stochastic decisions determine disease progression.

    PubMed

    Park, Ki-Sun; Pfeifer, Karl

    2016-03-01

    In this issue of Genes & Development, Ginart and colleagues (pp. 567-578) study a mouse model for Russell-Silver syndrome (RSS) and show that similar cells within one individual can display distinct gene expression patterns because of epigenetic marks that are established stochastically during early development. Their results provide an excellent explanation for phenotypes seen in RSS and other imprinting disorders and especially help us understand how patients with similar or even identical genetic mutations can display distinct disease profiles. PMID:26944674

  5. Multiple sclerosis: assessment of disease progression and effects of treatment.

    PubMed

    Paty, D W

    1987-08-01

    MS could well be a two stage disease. The first stage involves the sequential development of multiple small lesions, mostly inflammatory, that accumulate at a given rate. The second stage could be that of consolidation and confluence of lesions that involves not only demyelination but gliosis. MRI now gives us an opportunity to watch the evolution of these processes and also to monitor treatment effects. It is only after the evolution of this process is understood that we can design rational therapies directed toward the prevention of spasticity in MS. PMID:3315154

  6. Five-year follow-up of angiographic disease progression after medicine, angioplasty, or surgery

    PubMed Central

    2010-01-01

    Background Progression of atherosclerosis in coronary artery disease is observed through consecutive angiograms. Prognosis of this progression in patients randomized to different treatments has not been established. This study compared progression of coronary artery disease in native coronary arteries in patients undergoing surgery, angioplasty, or medical treatment. Methods Patients (611) with stable multivessel coronary artery disease and preserved ventricular function were randomly assigned to CABG, PCI, or medical treatment alone (MT). After 5-year follow-up, 392 patients (64%) underwent new angiography. Progression was considered a new stenosis of ≥ 50% in an arterial segment previously considered normal or an increased grade of previous stenosis > 20% in nontreated vessels. Results Of the 392 patients, 136 underwent CABG, 146 PCI, and 110 MT. Baseline characteristics were similar among treatment groups, except for more smokers and statin users in the MT group, more hypertensives and lower LDL-cholesterol levels in the CABG group, and more angina in the PCI group at study entry. Analysis showed greater progression in at least one native vessel in PCI patients (84%) compared with CABG (57%) and MT (74%) patients (p < 0.001). LAD coronary territory had higher progression compared with LCX and RCA (P < 0.001). PCI treatment, hypertension, male sex, and previous MI were independent risk factors for progression. No statistical difference existed between coronary events and the development of progression. Conclusion The angioplasty treatment conferred greater progression in native coronary arteries, especially in the left anterior descending territories and treated vessels. The progression was independently associated with hypertension, male sex, and previous myocardial infarction. PMID:20977758

  7. Prion Protein Polymorphisms Affect Chronic Wasting Disease Progression

    PubMed Central

    Johnson, Chad J.; Herbst, Allen; Duque-Velasquez, Camilo; Vanderloo, Joshua P.; Bochsler, Phil; Chappell, Rick; McKenzie, Debbie

    2011-01-01

    Analysis of the PRNP gene in cervids naturally infected with chronic wasting disease (CWD) suggested that PRNP polymorphisms affect the susceptibility of deer to infection. To test this effect, we orally inoculated 12 white-tailed deer with CWD agent. Three different PRNP alleles, wild-type (wt; glutamine at amino acid 95 and glycine at 96), Q95H (glutamine to histidine at amino acid position 95) and G96S (glycine to serine at position 96) were represented in the study cohort with 5 wt/wt, 3 wt/G96S, and 1 each wt/Q95H and Q95H/G96S. Two animals were lost to follow-up due to intercurrent disease. The inoculum was prepared from Wisconsin hunter-harvested homozygous wt/wt animals. All infected deer presented with clinical signs of CWD; the orally infected wt/wt had an average survival period of 693 days post inoculation (dpi) and G96S/wt deer had an average survival period of 956 dpi. The Q95H/wt and Q95H/G96S deer succumbed to CWD at 1,508 and 1,596 dpi respectively. These data show that polymorphisms in the PRNP gene affect CWD incubation period. Deer heterozygous for the PRNP alleles had extended incubation periods with the Q95H allele having the greatest effect. PMID:21445256

  8. [Progress in the treatment of and research on Hirschsprung's disease].

    PubMed

    Fukuzawa, Masahiro

    2014-11-01

    Hirschsprung's disease (HD) is a relatively common cause of intestinal obstruction in the newborn. The disease is named after Harald Hirschsprung, who first described two infants with the condition in 1888. It is characterized by the absence of ganglionic cells in the distal bowel beginning at the internal sphincter and extending proximally for varying distances. The aganglionosis is confined to the rectosigmoid in 80% of patients. HD occurs in about one in 5,000 Japanese children. The most accepted theory of the cause of HD is a defect in the craniocaudal migration of neuroblasts originating from the neural crest which occurs during the first 10 weeks of gestation, as proposed by Okamoto in 1967. The RET protooncogene accounts for the highest proportion of both familial and sporadic cases. Diagnostic techniques involve anorectal manometry, barium enema, and rectal biopsy. The treatment of HD consists of surgical removal (resection) of the abnormal section of the colon, followed by reanastomosis. Definitive surgery for HD has been performed for many years using one of the techniques developed by Swenson, Duhamel, or Soave. Recently, minimally invasive laparoscopic procedures have been introduced for the treatment of HD. PMID:25702510

  9. A Network Diffusion Model of Disease Progression in Dementia

    PubMed Central

    Raj, Ashish; Kuceyeski, Amy; Weiner, Michael

    2013-01-01

    SUMMARY Patterns of dementia are known to fall into dissociated but dispersed brain networks, suggesting that the disease is transmitted along neuronal pathways rather than by proximity. This view is supported by neuropathological evidence for “prion-like” transsynaptic transmission of disease agents like misfolded tau and beta amyloid. We mathematically model this transmission by a diffusive mechanism mediated by the brain’s connectivity network obtained from tractography of 14 healthy-brain MRIs. Subsequent graph theoretic analysis provides a fully quantitative, testable, predictive model of dementia. Specifically, we predict spatially distinct “persistent modes,” which, we found, recapitulate known patterns of dementia and match recent reports of selectively vulnerable dissociated brain networks. Model predictions also closely match T1-weighted MRI volumetrics of 18 Alzheimer’s and 18 frontotemporal dementia subjects. Prevalence rates predicted by the model strongly agree with published data. This work has many important implications, including dimensionality reduction, differential diagnosis, and especially prediction of future atrophy using baseline MRI morphometrics. PMID:22445347

  10. A network diffusion model of disease progression in dementia.

    PubMed

    Raj, Ashish; Kuceyeski, Amy; Weiner, Michael

    2012-03-22

    Patterns of dementia are known to fall into dissociated but dispersed brain networks, suggesting that the disease is transmitted along neuronal pathways rather than by proximity. This view is supported by neuropathological evidence for "prion-like" transsynaptic transmission of disease agents like misfolded tau and beta amyloid. We mathematically model this transmission by a diffusive mechanism mediated by the brain's connectivity network obtained from tractography of 14 healthy-brain MRIs. Subsequent graph theoretic analysis provides a fully quantitative, testable, predictive model of dementia. Specifically, we predict spatially distinct "persistent modes," which, we found, recapitulate known patterns of dementia and match recent reports of selectively vulnerable dissociated brain networks. Model predictions also closely match T1-weighted MRI volumetrics of 18 Alzheimer's and 18 frontotemporal dementia subjects. Prevalence rates predicted by the model strongly agree with published data. This work has many important implications, including dimensionality reduction, differential diagnosis, and especially prediction of future atrophy using baseline MRI morphometrics. PMID:22445347

  11. Low-level laser therapy ameliorates disease progression in a mouse model of multiple sclerosis.

    PubMed

    Gonçalves, Elaine D; Souza, Priscila S; Lieberknecht, Vicente; Fidelis, Giulia S P; Barbosa, Rafael I; Silveira, Paulo C L; de Pinho, Ricardo A; Dutra, Rafael C

    2016-03-01

    Multiple sclerosis (MS) is an autoimmune demyelinating inflammatory disease characterized by recurrent episodes of T cell-mediated immune attack on central nervous system (CNS) myelin, leading to axon damage and progressive disability. The existing therapies for MS are only partially effective and are associated with undesirable side effects. Low-level laser therapy (LLLT) has been clinically used to treat inflammation, and to induce tissue healing and repair processes. However, there are no reports about the effects and mechanisms of LLLT in experimental autoimmune encephalomyelitis (EAE), an established model of MS. Here, we report the effects and underlying mechanisms of action of LLLT (AlGaInP, 660 nm and GaAs, 904 nm) irradiated on the spinal cord during EAE development. EAE was induced in female C57BL/6 mice by immunization with MOG35-55 peptide emulsified in complete Freund's adjuvant. Our results showed that LLLT consistently reduced the clinical score of EAE and delayed the disease onset, and also prevented weight loss induced by immunization. Furthermore, these beneficial effects of LLLT seem to be associated with the down-regulation of NO levels in the CNS, although the treatment with LLLT failed to inhibit lipid peroxidation and restore antioxidant defense during EAE. Finally, histological analysis showed that LLLT blocked neuroinflammation through a reduction of inflammatory cells in the CNS, especially lymphocytes, as well as preventing demyelination in the spinal cord after EAE induction. Together, our results suggest the use of LLLT as a therapeutic application during autoimmune neuroinflammatory responses, such as MS. PMID:26703077

  12. 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

  13. Aberrant autophagy and parkinsonism: does correction rescue from disease progression?

    PubMed

    Mishra, Abhishek Kumar; ur Rasheed, Mohd Sami; Shukla, Saurabh; Tripathi, Manish Kumar; Dixit, Anubhuti; Singh, Mahendra Pratap

    2015-01-01

    Information generated from animal models, genome sequencing, and high-throughput technologies provide valuable sequence of events to understand the Parkinson's disease (PD) pathogenesis. A dynamic equilibrium between biosynthesis and biodegradation of sub-cellular components by ubiquitin proteasome system and autophagy is found to be responsible for sustaining the homeostasis of tyrosine hydroxylase-positive neurons. Autophagy degrades and eliminates ?-synuclein, Parkin, ubiquitin, etc., proteins along with damaged cellular components to maintain the homeostasis of the nigrostriatal dopaminergic neurons. Aberrant type II apoptosis is widely implicated in dopaminergic neurodegeneration leading to PD. The current article reviews the elementary role of autophagy in the degradation and elimination of superfluous and aggregated proteins and impaired mitochondria. The article also recapitulates the information, which implicated the role of aberrant autophagy in toxin-induced Parkinsonism. Moreover, the review sheds light on whether or not targeting the defective autophagy could reinstate the normal functioning of dopaminergic neurons, which could ultimately rescue from PD pathogenesis. PMID:24833602

  14. Atypical progression of multiple myeloma with extensive extramedullary disease.

    PubMed Central

    Jowitt, S N; Jacobs, A; Batman, P A; Sapherson, D A

    1994-01-01

    Multiple myeloma is a neoplastic disorder caused by the proliferation of a transformed B lymphoid progenitor cell that gives rise to a clone of immunoglobulin-secreting cells. Other plasma cell tumours include solitary plasmacytoma of bone (SPB) and extramedullary plasmacytomas (EMP). Despite an apparent common origin there exist pathological and clinical differences between these neoplasms and the association between them is not completely understood. A case of IgG multiple myeloma that presented with typical clinical and laboratory features, including a bone marrow infiltrated by well differentiated plasma cells, is reported. The tumour had an unusual evolution, with the development of extensive extramedullary disease while maintaining mature histological features. Images PMID:8163701

  15. 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

  16. Disease Severity and Progression in Progressive Supranuclear Palsy and Multiple System Atrophy: Validation of the NNIPPS – PARKINSON PLUS SCALE

    PubMed Central

    Payan, Christine A. M.; Viallet, François; Landwehrmeyer, Bernhard G.; Bonnet, Anne-Marie; Borg, Michel; Durif, Franck; Lacomblez, Lucette; Bloch, Frédéric; Verny, Marc; Fermanian, Jacques; Agid, Yves; Ludolph, Albert C.

    2011-01-01

    Background The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study. Methods and Findings Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α≥0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80–0.93), and moderate (Intra-class coefficient = 0.54–0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho≥0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar. Conclusions The NNIPPS-PPS has suitable validity, is reliable and sensitive, and therefore is appropriate for use in clinical studies with PSP or MSA. Trial Registration ClinicalTrials.gov NCT00211224 PMID:21829612

  17. Effect of organic solvent exposure on chronic kidney disease progression: the GN-PROGRESS cohort study

    PubMed Central

    Jacob, Sophie; Héry, Michel; Protois, Jean-Claude; Rossert, Jérôme; Stengel, Bénédicte

    2007-01-01

    It has been suggested that solvent exposure may have a role in the progression of glomerulonephritis (GN) to end-stage renal failure (ESRD), but this has never been tested with an appropriate cohort study design. We included 338 nonESRD patients with a first biopsy for primary GN between 1994 and 2001: 194 IgA nephropathies (IgAN), 75 membranous nephropathies (MN) and 69 focal and segmental glomerulosclerosis (FSGS). ESRD, defined as an estimated glomerular filtration rate < 15 mL/min/1.73m2 or dialysis, was registered over a mean follow-up period of 5 years. Patients’ lifelong solvent exposures before and after diagnosis were recorded by interview and assessed by industrial hygienist experts. We used Cox models to estimate adjusted hazard ratios (HR) of ESRD related to exposures. Overall, 15% of the patients had been exposed at a low level before diagnosis and 14% at a high level. Forty-two with IgA N reached ESRD, 12 with MN, and 22 with FSGS. A graded relationship was observed for MN: age- and gender-adjusted HR [95% confidence interval] for low exposure vs none 3.1 [0.5–18.2], and for high exposure vs none 8.2 [1.9–34.7], as well as for IgA N: 1.6 [0.7–3.9] and 2.2 [1.0–4.8], respectively, but not for FSGS. Solvent risk was only partly mediated by baseline proteinuria: adjusted HR for high exposure vs none = 5.5 [1.3 – 23.9] for MN and 1.8 [0.8 – 3.9] for IgA N. In patients with IgA N, there was a trend in increasing HR with exposure duration before and its persistence after diagnosis. These findings support the hypothesized association of solvent exposure with the progression of GN to ESRD. They should prompt clinicians to give greater attention to patients’ occupational exposures and possibly to consider professional reclassification. PMID:17135394

  18. 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.

  19. 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

  20. [Research Progress in Black Queen Cell Virus Causing Disease].

    PubMed

    Yang, Qian; Zhang, Jian; Song, Zhanyun; Zheng, Yan; Wang, Xianghui; Sui, Jiachen; Wang, Zhenguo; Mou, Jun

    2015-05-01

    In nature, honeybees are the most important pollinators. They play a vital role in both protecting the diversity of natural ecosystems, and maintaining the yield-improving effects of agroecosystems. But in recent years, epidemic disease in bees has caused huge losses. Black Queen Cell Virus (BQCV) is a bee pathogen that was first reported in 1955. It mainly infects bee larvae and pupae, making their bodies turn dark and black, and causing a massive decrease in the bee population. More specifically, the virus makes the exterior of the cell walls in the larvae and pupae turn black. BQCV is a seasonal epidemic, spread by means horizontal and vertical transmission, and is often unapparent. BQCV not only infects a variety of bee species, but also spiders, centipedes and other arthropods. It can also be coinfected with other honeybee viruses. In recent years, research has shown that the Nosema intestinal parasite plays an important role in BQCV transmission and bees carrying Nosema that become infected with BQCV have increased mortality. Here we summarize current research on the incidence, prevalence, geographical distribution and transmission of BQCV. PMID:26470541

  1. Byssinosis and small airways disease: Terminal progress report

    SciTech Connect

    Bradford, J.M.

    1989-01-01

    In a study of byssinosis and small-airway disease, pulmonary-function measurements including helium and oxygen flow volume curves were made on 470 cotton mill employees exposed to various dust levels. The employees in these cotton mills had been screened previously for pulmonary abnormalities, and some employees had moved to work areas with lower dust levels. Results showed that there was no significant increase in bronchitis or byssinosis in the dust areas nor were there any significant decreases in the percentages of normal forced vital capacity (PFVC) or forced expiratory volume in 1 second (PFEV1) in the dusty areas. These results differ from those reported from mills in which no previous pulmonary testing had been conducted. A strong smoking/tenure/dust exposure interaction on PFVC and PFEV1 was found, with the long-tenured, high-dust-exposure, smokers having the lowest PFVC and PFEV1. There was no significant increase in small airways abnormalities with increased dust and smoking, but the mean change in the density dependence ratio is too small to have clinical significance.

  2. Progression of motor and cognitive impairment in Parkinson's disease.

    PubMed

    Palazzini, E; Soliveri, P; Filippini, G; Fetoni, V; Zappacosta, B; Scigliano, G; Monza, D; Caraceni, T; Girotti, F

    1995-08-01

    We performed a longitudinal study (mean follow-up 86.7 months) to evaluate motor and mental deterioration in patients with Parkinson's disease. Of the original 91 patients, only 61 could be re-examined 7 years later and 11 of these had become demented (PD-Dems). PD-Dems were older with worse motor and, obviously, cognitive performance than non-demented parkinsonian patients (PDs). A global cognitive decay index (DI) was calculated for each patient. Based on this, non-demented PDs were further split into 38 stable parkinsonian patients (S-PDs) with DI-30% to +30%, and 10 deteriorated but non-demented parkinsonian patients (D-PDs) with a DI worse than -30% (as had PD-Dems). D-PDs were older and had greater motor impairment than S-PDs but did not differ from PD-Dems on these measures. D-PDs and PD-Dems deteriorated especially in attention, visuospatial and executive ability tests. Ageing seems to be the main predictive factor for mental deterioration. PMID:8530983

  3. Identifying informative risk factors and predicting bone disease progression via deep belief networks.

    PubMed

    Li, Hui; Li, Xiaoyi; Ramanathan, Murali; Zhang, Aidong

    2014-10-01

    Osteoporosis is a common disease which frequently causes death, permanent disability, and loss of quality of life in the geriatric population. Identifying risk factors for the disease progression and capturing the disease characteristics have received increasing attentions in the health informatics research. In data mining area, risk factors are features of the data and diagnostic results can be regarded as the labels to train a model for a regression or classification task. We develop a general framework based on the heterogeneous electronic health records (EHRs) for the risk factor (RF) analysis that can be used for informative RF selection and the prediction of osteoporosis. The RF selection is a task designed for ranking and explaining the semantics of informative RFs for preventing the disease and improving the understanding of the disease. Predicting the risk of osteoporosis in a prospective and population-based study is a task for monitoring the bone disease progression. We apply a variety of well-trained deep belief network (DBN) models which inherit the following good properties: (1) pinpointing the underlying causes of the disease in order to assess the risk of a patient in developing a target disease, and (2) discriminating between patients suffering from the disease and without the disease for the purpose of selecting RFs of the disease. A variety of DBN models can capture characteristics for different patient groups via a training procedure with the use of different samples. The case study shows that the proposed method can be efficiently used to select the informative RFs. Most of the selected RFs are validated by the medical literature and some new RFs will attract interests across the medical research. Moreover, the experimental analysis on a real bone disease data set shows that the proposed framework can successfully predict the progression of osteoporosis. The stable and promising performance on the evaluation metrics confirms the effectiveness of our model. PMID:24979059

  4. 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

  5. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells

    PubMed Central

    Zhong, Zhihui; Ilieva, Hristelina; Hallagan, Lee; Bell, Robert; Singh, Itender; Paquette, Nicole; Thiyagarajan, Meenakshisundaram; Deane, Rashid; Fernandez, Jose A.; Lane, Steven; Zlokovic, Anna B.; Liu, Todd; Griffin, John H.; Chow, Nienwen; Castellino, Francis J.; Stojanovic, Konstantin; Cleveland, Don W.; Zlokovic, Berislav V.

    2009-01-01

    Activated protein C (APC) is a signaling protease with anticoagulant activity. Here, we have used mice expressing a mutation in superoxide dismutase-1 (SOD1) that is linked to amyotrophic lateral sclerosis (ALS) to show that administration of APC or APC analogs with reduced anticoagulant activity after disease onset slows disease progression and extends survival. A proteolytically inactive form of APC with reduced anticoagulant activity provided no benefit. APC crossed the blood–spinal cord barrier in mice via endothelial protein C receptor. When administered after disease onset, APC eliminated leakage of hemoglobin-derived products across the blood–spinal cord barrier and delayed microglial activation. In microvessels, motor neurons, and microglial cells from SOD1-mutant mice and in cultured neuronal cells, APC transcriptionally downregulated SOD1. Inhibition of SOD1 synthesis in neuronal cells by APC required protease-activated receptor–1 (PAR1) and PAR3, which inhibited nuclear transport of the Sp1 transcription factor. Diminished mutant SOD1 synthesis by selective gene excision within endothelial cells did not alter disease progression, which suggests that diminished mutant SOD1 synthesis in other cells, including motor neurons and microglia, caused the APC-mediated slowing of disease. The delayed disease progression in mice after APC administration suggests that this approach may be of benefit to patients with familial, and possibly sporadic, ALS. PMID:19841542

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

    NASA Astrophysics Data System (ADS)

    Co?kun, A. mit; 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.

  7. A Clinical Index to Predict Progression from Mild Cognitive Impairment to Dementia Due to Alzheimer's Disease

    PubMed Central

    Lee, Sei J.; Ritchie, Christine S.; Yaffe, Kristine; Stijacic Cenzer, Irena; Barnes, Deborah E.

    2014-01-01

    Background Mild cognitive impairment is often a precursor to dementia due to Alzheimer's disease, but many patients with mild cognitive impairment never develop dementia. New diagnostic criteria may lead to more patients receiving a diagnosis of mild cognitive impairment. Objective To develop a prediction index for the 3-year risk of progression from mild cognitive impairment to dementia relying only on information that can be readily obtained in most clinical settings. Design and Participants 382 participants diagnosed with amnestic mild cognitive impairment enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI), a multi-site, longitudinal, observational study. Main Predictors Measures Demographics, comorbid conditions, caregiver report of participant symptoms and function, and participant performance on individual items from basic neuropsychological scales. Main Outcome Measure Progression to probable Alzheimer's disease. Key Results Subjects had a mean (SD) age of 75 (7) years and 43% progressed to probable Alzheimer's disease within 3 years. Important independent predictors of progression included being female, resisting help, becoming upset when separated from caregiver, difficulty shopping alone, forgetting appointments, number of words recalled from a 10-word list, orientation and difficulty drawing a clock. The final point score could range from 0 to 16 (mean [SD]: 4.2 [2.9]). The optimism-corrected Harrell's c-statistic was 0.71(95% CI: 0.68–0.75). Fourteen percent of subjects with low risk scores (0–2 points, n = 124) converted to probable Alzheimer's disease over 3 years, compared to 51% of those with moderate risk scores (3–8 points, n = 223) and 91% of those with high risk scores (9–16 points, n = 35). Conclusions An index using factors that can be obtained in most clinical settings can predict progression from amnestic mild cognitive impairment to probable Alzheimer's disease and may help clinicians differentiate between mild cognitive impairment patients at low vs. high risk of progression. PMID:25486250

  8. Hepatitis C virus infection: establishment of chronicity and liver disease progression

    PubMed Central

    Kwon, Young-Chan; Ray, Ratna B.; Ray, Ranjit

    2014-01-01

    Hepatitis C virus (HCV) often causes persistent infection, and is an important factor in the etiology of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). There are no preventive or therapeutic vaccines available against HCV. Treatment strategies of HCV infection are likely to improve with recently discovered direct antiviral agents (DAAs). However, a proportion of patients still progress to liver failure and/or HCC despite having been cured of the infection. Thus, there is a need for early diagnosis and therapeutic modalities for HCV related end stage liver disease prevention. HCV genome does not integrate into its host genome, and has a predominantly cytoplasmic life cycle. Therefore, HCV mediated liver disease progression appears to involve indirect mechanisms from persistent infection of hepatocytes. Studying the underlying mechanisms of HCV mediated evasion of immune responses and liver disease progression is challenging due to the lack of a naturally susceptible small animal model. We and other investigators have used a number of experimental systems to investigate the mechanisms for establishment of chronic HCV infection and liver disease progression. HCV infection modulates immune systems. Further, HCV infection of primary human hepatocytes promotes growth, induces phenotypic changes, modulates epithelial mesenchymal transition (EMT) related genes, and generates tumor initiating stem-like cells (TISCs). HCV infection also modulates microRNAs (miRNAs), and influences growth by overriding normal death progression of primary human hepatocytes for disease pathogenesis. Understanding these ob-servations at the molecular level should aid in developing strategies for additional effective therapies against HCV mediated liver disease progression. PMID:26417315

  9. 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

  10. 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

  11. Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways.

    PubMed

    Ingram, Melissa; Wozniak, Emily A L; Duvick, Lisa; Yang, Rendong; Bergmann, Paul; Carson, Robert; O'Callaghan, Brennon; Zoghbi, Huda Y; Henzler, Christine; Orr, Harry T

    2016-03-16

    SCA1, a fatal neurodegenerative disorder, is caused by a CAG expansion encoding a polyglutamine stretch in the protein ATXN1. We used RNA sequencing to profile cerebellar gene expression in Pcp2-ATXN1[82Q] mice with ataxia and progressive pathology and Pcp2-ATXN1[30Q]D776 animals having ataxia in absence of Purkinje cell progressive pathology. Weighted Gene Coexpression Network Analysis of the cerebellar expression data revealed two gene networks that significantly correlated with disease and have an expression profile correlating with disease progression in ATXN1[82Q] Purkinje cells. The Magenta Module provides a signature of suppressed transcriptional programs reflecting disease progression in Purkinje cells, while the Lt Yellow Module reflects transcriptional programs activated in response to disease in Purkinje cells as well as other cerebellar cell types. Furthermore, we found that upregulation of cholecystokinin (Cck) and subsequent interaction with the Cck1 receptor likely underlies the lack of progressive Purkinje cell pathology in Pcp2-ATXN1[30Q]D776 mice. PMID:26948890

  12. Activation of NK cells is associated with HIV-1 disease progression.

    PubMed

    Kuri-Cervantes, Leticia; de Oca, Gonzalo Salgado-Montes; Avila-Ros, Santiago; Hernndez-Juan, Ramn; Reyes-Tern, Gustavo

    2014-07-01

    The main predictor of HIV-1 disease progression is CD8(+) T cell activation, characterized by elevated expression of CD38 and HLA-DR. NK cells are also activated in viremic HIV-1-infected individuals. However, the relationship between NK cell activation and HIV-1 disease progression remains undefined. We characterized NK cell activation and its association with disease progression in treatment of naive HIV-1-infected individuals, who naturally maintained low/undetectable viremia (elite and viremic controllers), compared with progressors and AIDS subjects, and treated individuals. Our results show that CD38 expression on NK cells, predominantly in the cytotoxic CD56(dim)CD16(+) subset, is associated with HIV-1 disease progression (CD4(+) T cell count and pVL), T cell activation (percentage of CD38(+)HLA-DR(+) T cells), sCD14, inflammation, and innate immune activation. Moreover, NK cell activation is increased in HIV-1-infected subjects progressing to AIDS but not in elite and viremic controllers. ART partially reduces the proportion of activated NK cells. Furthermore, our results show that individuals, who naturally control viremia, maintain low levels of innate immune activation similar to those of uninfected controls. PMID:24399837

  13. Renal Gene and Protein Expression Signatures for Prediction of Kidney Disease Progression

    PubMed Central

    Ju, Wenjun; Eichinger, Felix; Bitzer, Markus; Oh, Jun; McWeeney, Shannon; Berthier, Celine C.; Shedden, Kerby; Cohen, Clemens D.; Henger, Anna; Krick, Stefanie; Kopp, Jeffrey B.; Stoeckert, Christian J.; Dikman, Steven; Schröppel, Bernd; Thomas, David B.; Schlondorff, Detlef; Kretzler, Matthias; Böttinger, Erwin P.

    2009-01-01

    Although chronic kidney disease (CKD) is common, only a fraction of CKD patients progress to end-stage renal disease. Molecular predictors to stratify CKD populations according to their risk of progression remain undiscovered. Here we applied transcriptional profiling of kidneys from transforming growth factor-β1 transgenic (Tg) mice, characterized by heterogeneity of kidney disease progression, to identify 43 genes that discriminate kidneys by severity of glomerular apoptosis before the onset of tubulointerstitial fibrosis in 2-week-old animals. Among the genes examined, 19 showed significant correlation between mRNA expression in uninephrectomized left kidneys at 2 weeks of age and renal disease severity in right kidneys of Tg mice at 4 weeks of age. Gene expression profiles of human orthologs of the 43 genes in kidney biopsies were highly significantly related (R2 = 0.53; P < 0.001) to the estimated glomerular filtration rates in patients with CKD stages I to V, and discriminated groups of CKD stages I/II and III/IV/V with positive and negative predictive values of 0.8 and 0.83, respectively. Protein expression patterns for selected genes were successfully validated by immunohistochemistry in kidneys of Tg mice and kidney biopsies of patients with IgA nephropathy and CKD stages I to V, respectively. In conclusion, we developed novel mRNA and protein expression signatures that predict progressive renal fibrosis in mice and may be useful molecular predictors of CKD progression in humans. PMID:19465643

  14. 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

  15. Depressive symptoms increase risk of HIV disease progression and mortality among women in Tanzania.

    PubMed

    Antelman, Gretchen; Kaaya, Sylvia; Wei, Ruilan; Mbwambo, Jessie; Msamanga, Gernard I; Fawzi, Wafaie W; Fawzi, Mary C Smith

    2007-04-01

    The effect of depression on HIV disease progression was examined among 996 HIV-positive Tanzanian women participating in a trial on micronutrients and pregnancy outcomes, vertical transmission, and disease progression. Depression and social support were measured 2 months after HIV screening and every 6 to 12 months thereafter. Depression measures from pregnancy and more than 12 months postpartum were included in this analysis. Participants' clinical condition and access to supportive individual or group counseling was assessed throughout the 6 to 8 years of follow-up. Cox proportional hazard models were used to estimate the time-varying effect of depression on progression to HIV clinical stage III/IV (World Health Organization) and all-cause mortality. Participation in group or individual counseling and baseline social support were also examined. More than half (57%) of the study sample had symptoms comparable with depression at least once during the follow-up period. Controlling for sociodemographic variables, psychosocial support, and clinical condition at enrollment, depression was associated with an increased risk of disease progression (HIV clinical stage III/IV [hazard ratio (HR) = 1.61, 95% confidence interval (CI): 1.28 to 2.03] and mortality [HR = 2.65, 95% CI: 1.89 to 3.71]). Depression is common among HIV-infected Tanzanian women and increases the risk of disease progression. Screening for depression and providing psychosocial interventions should be considered part of comprehensive HIV care. PMID:17179766

  16. Coronary leukocyte activation in relation to progression of coronary artery disease.

    PubMed

    de Vries, Marijke A; Alipour, Arash; Birnie, Erwin; Westzaan, Andrew; van Santen, Selvetta; van der Zwan, Ellen; Liem, Anho H; van der Meulen, Noëlle; Cabezas, Manuel Castro

    2016-03-01

    Leukocyte activation has been linked to atherogenesis, but there is little in vivo evidence for its role in the progression of atherosclerosis. We evaluated the predictive value for progression of coronary artery disease (CAD) of leukocyte activation markers in the coronary circulation. Monocyte and neutrophil CD11b, neutrophil CD66b expression and intracellular neutrophil myeloperoxidase (MPO) in the coronary arteries were determined by flow cytometry in patients undergoing coronary angiography. The primary outcome included fatal and nonfatal myocardial infarction or arterial vascular intervention due to unstable angina pectoris. In total 99 subjects who were included, 70 had CAD at inclusion (26 patients had single-vessel disease, 18 patients had twovessel disease and 26 patients had three-vessel disease). The median follow-up duration was 2242 days (interquartile range: 2142-2358). During follow-up, 13 patients (13%) developed progression of CAD. Monocyte CD11b, neutrophil CD11b and CD66b expression and intracellular MPO measured in blood obtained from the coronary arteries were not associated with the progression of CAD. These data indicate that coronary monocyte CD11b, neutrophil CD11b and CD66b expression and intracellular MPO do not predict the risk of progression of CAD. PMID:26831871

  17. Pharmacogenetics: progress, pitfalls and clinical potential for coronary heart disease.

    PubMed

    Humphries, Steve E; Hingorani, Aroon

    2006-02-01

    Much has been written about the potential of pharmacogenetic testing to inform therapy based on an individual's genetic makeup, and to decide the most effective choice of available drugs, or to avoid dangerous side effects. Currently, there is little hard data for either in the field of cardiovascular disease. The usual approach has been opportunistic use of drug trials in unrelated patients, and to look for differences in response or outcome by "candidate gene" genotype, for example genes coding for drug metabolising enzymes (activators and metabolisers), and enzymes and receptors involved in lipid metabolism, adrenergic response, etc. As with all association studies, initially promising results have often failed the test of replication in larger studies, and the relationship between the CETP Taq-I variant and response to statins has now been disproved. The strongest data to date is the report [Chasman, D.I., Posada, D., Subrahmanyan, L., Cook, N.R., Stanton Jr., V.P., Ridker, P.M., 2004. Pharmacogenetic study of statin therapy and cholesterol reduction. J. Am. Med. Assoc. 291, 2821-2827] of a poorer cholesterol-lowering response to Pravastatin in the 7% of patients carrying a certain haplotype of the HMG CoA reductase gene (14% fall versus 19%), but if this is overcome simply by a higher dose, it is of little clinical relevance. Currently, the best example of avoiding side effects is determining genotype at the CYP2C9 locus with respect of warfarin treatment, since carriers for functional variants (>20% of the population) require lower doses for optimal anticoagulation, and homozygotes, although rare, may well experience serious bleeding if given a usual dose. The full potential of this field will only be realised with much further work. PMID:16359930

  18. [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

  19. Magnetic resonance markers for early diagnosis and progression of Alzheimer's disease.

    PubMed

    Kantarci, Kejal

    2005-09-01

    With increasing life expectancy, the early diagnosis and treatment of Alzheimer's disease has become critical in sustaining a healthy society. Noninvasive markers of disease progression starting from the earliest stages of pathologic involvement are required for determining the effectiveness of putative disease-modifying therapies that are under development. Cross-sectional and longitudinal studies indicate that magnetic resonance-based volume measurements of atrophy are potential markers of the progression of Alzheimer's disease, starting from the preclinical stages. Other magnetic resonance techniques that are sensitive to the different aspects of Alzheimer's disease pathology, such as biochemical ((proton) magnetic resonance spectroscopy), microstructural (diffusion magnetic resonance imaging), functional (functional magnetic resonance imaging) and blood flow (perfusion magnetic resonance imaging) changes, have not been as extensively studied longitudinally. Recent efforts of imaging amyloid plaques with magnetic resonance imaging generate the prospect for in vivo imaging of the pathologic substrate of Alzheimer's disease in the future. In order for magnetic resonance modalities to qualify as surrogate markers for early diagnosis and progression of Alzheimer's disease, multicenter longitudinal studies are needed. PMID:16162090

  20. [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

  1. Quantitative Micro-Computed Tomography Imaging of Vascular Dysfunction in Progressive Kidney Diseases.

    PubMed

    Ehling, Josef; Bábíčková, Janka; Gremse, Felix; Klinkhammer, Barbara M; Baetke, Sarah; Knuechel, Ruth; Kiessling, Fabian; Floege, Jürgen; Lammers, Twan; Boor, Peter

    2016-02-01

    Progressive kidney diseases and renal fibrosis are associated with endothelial injury and capillary rarefaction. However, our understanding of these processes has been hampered by the lack of tools enabling the quantitative and noninvasive monitoring of vessel functionality. Here, we used micro-computed tomography (µCT) for anatomical and functional imaging of vascular alterations in three murine models with distinct mechanisms of progressive kidney injury: ischemia-reperfusion (I/R, days 1-56), unilateral ureteral obstruction (UUO, days 1-10), and Alport mice (6-8 weeks old). Contrast-enhanced in vivo µCT enabled robust, noninvasive, and longitudinal monitoring of vessel functionality and revealed a progressive decline of the renal relative blood volume in all models. This reduction ranged from -20% in early disease stages to -61% in late disease stages and preceded fibrosis. Upon Microfil perfusion, high-resolution ex vivo µCT allowed quantitative analyses of three-dimensional vascular networks in all three models. These analyses revealed significant and previously unrecognized alterations of preglomerular arteries: a reduction in vessel diameter, a prominent reduction in vessel branching, and increased vessel tortuosity. In summary, using µCT methodology, we revealed insights into macro-to-microvascular alterations in progressive renal disease and provide a platform that may serve as the basis to evaluate vascular therapeutics in renal disease. PMID:26195818

  2. Quantitative Micro-Computed Tomography Imaging of Vascular Dysfunction in Progressive Kidney Diseases

    PubMed Central

    Ehling, Josef; Bábíčková, Janka; Gremse, Felix; Klinkhammer, Barbara M.; Baetke, Sarah; Knuechel, Ruth; Kiessling, Fabian; Floege, Jürgen; Lammers, Twan; Boor, Peter

    2015-01-01

    Progressive kidney diseases and renal fibrosis are associated with endothelial injury and capillary rarefaction. However, our understanding of these processes has been hampered by the lack of tools enabling the quantitative and noninvasive monitoring of vessel functionality. Here, we used micro-computed tomography (μCT) for anatomical and functional imaging of vascular alterations in three murine models with distinct mechanisms of progressive kidney injury: ischemia-reperfusion (I/R, days 1–56), unilateral ureteral obstruction (UUO, days 1–10), and Alport mice (6–8 weeks old). Contrast-enhanced in vivo μCT enabled robust, noninvasive, and longitudinal monitoring of vessel functionality and revealed a progressive decline of the renal relative blood volume in all models. This reduction ranged from −20% in early disease stages to −61% in late disease stages and preceded fibrosis. Upon Microfil perfusion, high-resolution ex vivo μCT allowed quantitative analyses of three-dimensional vascular networks in all three models. These analyses revealed significant and previously unrecognized alterations of preglomerular arteries: a reduction in vessel diameter, a prominent reduction in vessel branching, and increased vessel tortuosity. In summary, using μCT methodology, we revealed insights into macro-to-microvascular alterations in progressive renal disease and provide a platform that may serve as the basis to evaluate vascular therapeutics in renal disease. PMID:26195818

  3. Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients.

    PubMed

    Liu, Meng-Lu; Zang, Tong; Zhang, Chun-Li

    2016-01-01

    Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Here, we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs) exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs) with skeletal muscles. Importantly, hiMNs converted from ALS patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification. PMID:26725112

  4. Direct lineage reprogramming reveals disease-specific phonotypes of motor neurons from human ALS patients

    PubMed Central

    Liu, Meng-Lu; Zang, Tong; Zhang, Chun-Li

    2015-01-01

    SUMMARY Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Here we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs) exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs) with skeletal muscles. Importantly, hiMNs converted from ALS-patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS-hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification. PMID:26725112

  5. 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

  6. 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

  7. 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

  8. 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.

  9. HCV genome-wide genetic analyses in context of disease progression and hepatocellular carcinoma.

    PubMed

    Donlin, Maureen J; Lomonosova, Elena; Kiss, Alexi; Cheng, Xiaohong; Cao, Feng; Curto, Teresa M; Di Bisceglie, Adrian; Tavis, John E

    2014-01-01

    Hepatitis C virus (HCV) is a major cause of hepatitis and hepatocellular carcinoma (HCC) world-wide. Most HCV patients have relatively stable disease, but approximately 25% have progressive disease that often terminates in liver failure or HCC. HCV is highly variable genetically, with seven genotypes and multiple subtypes per genotype. This variation affects HCV's sensitivity to antiviral therapy and has been implicated to contribute to differences in disease. We sequenced the complete viral coding capacity for 107 HCV genotype 1 isolates to determine whether genetic variation between independent HCV isolates is associated with the rate of disease progression or development of HCC. Consensus sequences were determined by sequencing RT-PCR products from serum or plasma. Positions of amino acid conservation, amino acid diversity patterns, selection pressures, and genome-wide patterns of amino acid covariance were assessed in context of the clinical phenotypes. A few positions were found where the amino acid distributions or degree of positive selection differed between in the HCC and cirrhotic sequences. All other assessments of viral genetic variation and HCC failed to yield significant associations. Sequences from patients with slow disease progression were under a greater degree of positive selection than sequences from rapid progressors, but all other analyses comparing HCV from rapid and slow disease progressors were statistically insignificant. The failure to observe distinct sequence differences associated with disease progression or HCC employing methods that previously revealed strong associations with the outcome of interferon α-based therapy implies that variable ability of HCV to modulate interferon responses is not a dominant cause for differential pathology among HCV patients. This lack of significant associations also implies that host and/or environmental factors are the major causes of differential disease presentation in HCV patients. PMID:25079603

  10. HCV Genome-Wide Genetic Analyses in Context of Disease Progression and Hepatocellular Carcinoma

    PubMed Central

    Donlin, Maureen J.; Lomonosova, Elena; Kiss, Alexi; Cheng, Xiaohong; Cao, Feng; Curto, Teresa M.; Di Bisceglie, Adrian; Tavis, John E.

    2014-01-01

    Hepatitis C virus (HCV) is a major cause of hepatitis and hepatocellular carcinoma (HCC) world-wide. Most HCV patients have relatively stable disease, but approximately 25% have progressive disease that often terminates in liver failure or HCC. HCV is highly variable genetically, with seven genotypes and multiple subtypes per genotype. This variation affects HCV’s sensitivity to antiviral therapy and has been implicated to contribute to differences in disease. We sequenced the complete viral coding capacity for 107 HCV genotype 1 isolates to determine whether genetic variation between independent HCV isolates is associated with the rate of disease progression or development of HCC. Consensus sequences were determined by sequencing RT-PCR products from serum or plasma. Positions of amino acid conservation, amino acid diversity patterns, selection pressures, and genome-wide patterns of amino acid covariance were assessed in context of the clinical phenotypes. A few positions were found where the amino acid distributions or degree of positive selection differed between in the HCC and cirrhotic sequences. All other assessments of viral genetic variation and HCC failed to yield significant associations. Sequences from patients with slow disease progression were under a greater degree of positive selection than sequences from rapid progressors, but all other analyses comparing HCV from rapid and slow disease progressors were statistically insignificant. The failure to observe distinct sequence differences associated with disease progression or HCC employing methods that previously revealed strong associations with the outcome of interferon α-based therapy implies that variable ability of HCV to modulate interferon responses is not a dominant cause for differential pathology among HCV patients. This lack of significant associations also implies that host and/or environmental factors are the major causes of differential disease presentation in HCV patients. PMID:25079603

  11. Association of apolipoprotein E with the progression of hepatitis B virus-related liver disease

    PubMed Central

    Shen, Yueshuang; li, Meng; Ye, Xiongwei; Bi, Qihua

    2015-01-01

    Hepatitis B virus (HBV) infection increases the risk of liver decompensation, cirrhosis and hepatocellular carcinoma (HCC). Apolipoprotein E (ApoE), one of the major cholesterol carriers, plays important role in the metabolism of lipoprotein and the regulation of immune response. The present study was aimed to explore whether the genetic variation in ApoE gene affected disease progression in HBV infected individuals. We collected sera samples from healthy volunteers (n=40), inactive HBV carriers (n=30), and patients with acute hepatitis (n=60), severe hepatitis (n=12), HBV-related liver cirrhosis (n=58) or primary HCC (n=39). We found that ApoE and interlukin-6 (IL-6) was progressively increased, while IL-2 was gradually decreased with the increasing grade of disease severity. Furthermore, high ApoE levels in HBV infected individuals were correlated with increased IL-6 and decreased IL-2 levels, indicating immune abnormalities in these patients. The frequency of E3/3 genotype was progressively increased from carriers group, hepatitis group to progressive group (cirrhosis and HCC). The serum levels of low-density lipoprotein cholesterol (LDL-C) differed among ApoE phenotypes, with E3/4, E4/4> E3/3>E2/3. Our study suggested that ApoE may have a role in the pathogenesis and progression of HBV-related liver disease and indicated the possible underlying mechanisms. PMID:26823800

  12. Iron homeostasis and progression to pulmonary tuberculosis disease among household contacts.

    PubMed

    Minchella, Peter A; Donkor, Simon; McDermid, Joann M; Sutherland, Jayne S

    2015-05-01

    Early identification of individuals at risk for progressing to active tuberculosis (TB) disease may limit new transmission and improve clinical outcomes. Evidence indicates altered iron homeostasis may identify those at greater risk of disease progression in HIV co-infection. We aimed to investigate iron homeostasis biomarkers as risk factors for progression to TB. Archived plasma samples were analyzed from household contacts of pulmonary TB index cases in The Gambia. Contacts were classified as asymptomatic non-progressors (n = 17) or TB-progressors (n = 10), which included two HIV-infected participants. Iron homeostasis (hemoglobin, ferritin, hepcidin, soluble transferrin receptor, transferrin) was assessed in all contacts at study recruitment. Plasma was collected a median of 910 days prior to TB diagnosis. Low transferrin around the time of known exposure to infectious TB was a disease progression risk factor among all TB-progressors (Poisson incidence rate ratio: 0.55; 95% CI: 0.35-0.89). Iron homeostasis also differed between early and delayed TB-progressors, with higher ferritin and hepcidin concentrations observed among early TB-progressors (mean ferritin 50.2 vs. 26.2 ng/ml; P = 0.027; mean hepcidin 37.7 vs. 5.6 ng/ml; P = 0.036). Iron homeostasis is associated with progression to TB among household contacts. Further studies are needed to elucidate mechanisms and determine the clinical utility of monitoring iron homeostasis biomarkers. PMID:25764944

  13. Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

    PubMed Central

    Limpert, Allison S; Mattmann, Margrith E

    2013-01-01

    Summary Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with few therapeutic options. While several gene mutations have been implicated in ALS, the exact cause of neuronal dysfunction is unknown and motor neurons of affected individuals display numerous cellular abnormalities. Ongoing efforts to develop novel ALS treatments involve the identification of small molecules targeting specific mechanisms of neuronal pathology, including glutamate excitotoxicity, mutant protein aggregation, endoplasmic reticulum (ER) stress, loss of trophic factors, oxidative stress, or neuroinflammation. Herein, we review recent advances in the discovery and preclinical characterization of lead compounds that may ultimately provide novel drugs to treat patients suffering from ALS. PMID:23766784

  14. Regulatory T cells delay disease progression in Alzheimer-like pathology.

    PubMed

    Dansokho, Cira; Ait Ahmed, Dylla; Aid, Saba; Toly-Ndour, Cécile; Chaigneau, Thomas; Calle, Vanessa; Cagnard, Nicolas; Holzenberger, Martin; Piaggio, Eliane; Aucouturier, Pierre; Dorothée, Guillaume

    2016-04-01

    Recent studies highlight the implication of innate and adaptive immunity in the pathophysiology of Alzheimer's disease, and foster immunotherapy as a promising strategy for its treatment. Vaccines targeting amyloid-β peptide provided encouraging results in mouse models, but severe side effects attributed to T cell responses in the first clinical trial AN1792 underlined the need for better understanding adaptive immunity in Alzheimer's disease. We previously showed that regulatory T cells critically control amyloid-β-specific CD4(+)T cell responses in both physiological and pathological settings. Here, we analysed the impact of regulatory T cells on spontaneous disease progression in a murine model of Alzheimer's disease. Early transient depletion of regulatory T cells accelerated the onset of cognitive deficits in APPPS1 mice, without altering amyloid-β deposition. Earlier cognitive impairment correlated with reduced recruitment of microglia towards amyloid deposits and altered disease-related gene expression profile. Conversely, amplification of regulatory T cells through peripheral low-dose IL-2 treatment increased numbers of plaque-associated microglia, and restored cognitive functions in APPPS1 mice. These data suggest that regulatory T cells play a beneficial role in the pathophysiology of Alzheimer's disease, by slowing disease progression and modulating microglial response to amyloid-β deposition. Our study highlights the therapeutic potential of repurposed IL-2 for innovative immunotherapy based on modulation of regulatory T cells in Alzheimer's disease. PMID:26912648

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

    PubMed Central

    Trias, Emiliano; Daz-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

  16. 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

  17. Tnni3k Modifies Disease Progression in Murine Models of Cardiomyopathy

    PubMed Central

    Wheeler, Ferrin C.; Tang, Hao; Marks, Odessa A.; Hadnott, Tracy N.; Chu, Pei-Lun; Mao, Lan; Rockman, Howard A.; Marchuk, Douglas A.

    2009-01-01

    The Calsequestrin (Csq) transgenic mouse model of cardiomyopathy exhibits wide variation in phenotypic progression dependent on genetic background. Seven heart failure modifier (Hrtfm) loci modify disease progression and outcome. Here we report Tnni3k (cardiac Troponin I-interacting kinase) as the gene underlying Hrtfm2. Strains with the more susceptible phenotype exhibit high transcript levels while less susceptible strains show dramatically reduced transcript levels. This decrease is caused by an intronic SNP in low-transcript strains that activates a cryptic splice site leading to a frameshifted transcript, followed by nonsense-mediated decay of message and an absence of detectable protein. A transgenic animal overexpressing human TNNI3K alone exhibits no cardiac phenotype. However, TNNI3K/Csq double transgenics display severely impaired systolic function and reduced survival, indicating that TNNI3K expression modifies disease progression. TNNI3K expression also accelerates disease progression in a pressure-overload model of heart failure. These combined data demonstrate that Tnni3k plays a critical role in the modulation of different forms of heart disease, and this protein may provide a novel target for therapeutic intervention. PMID:19763165

  18. 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)…

  19. 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…

  20. Heroin Use and HIV Disease Progression: Results from a Pilot Study of a Russian Cohort.

    PubMed

    Edelman, E Jennifer; Cheng, Debbie M; Krupitsky, Evgeny M; Bridden, Carly; Quinn, Emily; Walley, Alexander Y; Lioznov, Dmitry A; Blokhina, Elena; Zvartau, Edwin; Samet, Jeffrey H

    2015-06-01

    Opioids have immunosuppressive properties, yet their impact on HIV disease progression remains unclear. Using longitudinal data from HIV-infected antiretroviral therapy-naïve Russian individuals (n = 77), we conducted a pilot study to estimate the effect of heroin use on HIV disease progression. Heroin use was categorized based on past 30 days self-reported use at baseline, 6 and 12 months as none, intermittent or persistent. We estimated the effect of heroin use on HIV disease progression, measured as change in CD4 count from baseline to 12 months, using multivariable linear regression. Those with intermittent (n = 21) and no heroin use (n = 39) experienced mean decreases in CD4 count from baseline to 12 months (-103 and -10 cells/mm(3), respectively; adjusted mean difference (AMD) -93; 95 % CI -245, 58). Those with persistent use (n = 17) showed a mean increase of 53 cells/mm(3) (AMD 63; 95 % CI -95, 220). Future studies exploring the effects of heroin withdrawal on HIV disease progression are warranted. PMID:25413642

  1. Tnni3k modifies disease progression in murine models of cardiomyopathy.

    PubMed

    Wheeler, Ferrin C; Tang, Hao; Marks, Odessa A; Hadnott, Tracy N; Chu, Pei-Lun; Mao, Lan; Rockman, Howard A; Marchuk, Douglas A

    2009-09-01

    The Calsequestrin (Csq) transgenic mouse model of cardiomyopathy exhibits wide variation in phenotypic progression dependent on genetic background. Seven heart failure modifier (Hrtfm) loci modify disease progression and outcome. Here we report Tnni3k (cardiac Troponin I-interacting kinase) as the gene underlying Hrtfm2. Strains with the more susceptible phenotype exhibit high transcript levels while less susceptible strains show dramatically reduced transcript levels. This decrease is caused by an intronic SNP in low-transcript strains that activates a cryptic splice site leading to a frameshifted transcript, followed by nonsense-mediated decay of message and an absence of detectable protein. A transgenic animal overexpressing human TNNI3K alone exhibits no cardiac phenotype. However, TNNI3K/Csq double transgenics display severely impaired systolic function and reduced survival, indicating that TNNI3K expression modifies disease progression. TNNI3K expression also accelerates disease progression in a pressure-overload model of heart failure. These combined data demonstrate that Tnni3k plays a critical role in the modulation of different forms of heart disease, and this protein may provide a novel target for therapeutic intervention. PMID:19763165

  2. The Functional Transitions Model: Maximizing Ability in the Context of Progressive Disability Associated with Alzheimer's Disease

    ERIC Educational Resources Information Center

    Slaughter, Susan; Bankes, Jane

    2007-01-01

    The Functional Transitions Model (FTM) integrates the theoretical notions of progressive functional decline associated with Alzheimer's disease (AD), excess disability, and transitions occurring intermittently along the trajectory of functional decline. Application of the Functional Transitions Model to clinical practice encompasses the paradox of…

  3. 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.

  4. Unveiling Clusters of RNA Transcript Pairs Associated with Markers of Alzheimer’s Disease Progression

    PubMed Central

    Arefin, Ahmed Shamsul; Mathieson, Luke; Johnstone, Daniel; Berretta, Regina; Moscato, Pablo

    2012-01-01

    Background One primary goal of transcriptomic studies is identifying gene expression patterns correlating with disease progression. This is usually achieved by considering transcripts that independently pass an arbitrary threshold (e.g. p<0.05). In diseases involving severe perturbations of multiple molecular systems, such as Alzheimer’s disease (AD), this univariate approach often results in a large list of seemingly unrelated transcripts. We utilised a powerful multivariate clustering approach to identify clusters of RNA biomarkers strongly associated with markers of AD progression. We discuss the value of considering pairs of transcripts which, in contrast to individual transcripts, helps avoid natural human transcriptome variation that can overshadow disease-related changes. Methodology/Principal Findings We re-analysed a dataset of hippocampal transcript levels in nine controls and 22 patients with varying degrees of AD. A large-scale clustering approach determined groups of transcript probe sets that correlate strongly with measures of AD progression, including both clinical and neuropathological measures and quantifiers of the characteristic transcriptome shift from control to severe AD. This enabled identification of restricted groups of highly correlated probe sets from an initial list of 1,372 previously published by our group. We repeated this analysis on an expanded dataset that included all pair-wise combinations of the 1,372 probe sets. As clustering of this massive dataset is unfeasible using standard computational tools, we adapted and re-implemented a clustering algorithm that uses external memory algorithmic approach. This identified various pairs that strongly correlated with markers of AD progression and highlighted important biological pathways potentially involved in AD pathogenesis. Conclusions/Significance Our analyses demonstrate that, although there exists a relatively large molecular signature of AD progression, only a small number of transcripts recurrently cluster with different markers of AD progression. Furthermore, considering the relationship between two transcripts can highlight important biological relationships that are missed when considering either transcript in isolation. PMID:23029078

  5. Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease.

    PubMed

    Prudencio, Mercedes; Hart, P John; Borchelt, David R; Andersen, Peter M

    2009-09-01

    To date, 146 different mutations in superoxide dismutase 1 (SOD1) have been identified in patients with familial amyotrophic lateral sclerosis (ALS). The mean age of disease onset in patients inheriting mutations in SOD1 is 45-47 years of age. However, although the length of disease duration is highly variable, there are examples of consistent disease durations associated with specific mutations (e. g. A4V, less than 2 years). In the present study, we have used a large set of data from SOD1-associated ALS pedigrees to identify correlations between disease features and biochemical/biophysical properties of more than 30 different variants of mutant SOD1. Using a reliable cell culture assay, we show that all ALS-associated mutations in SOD1 increase the inherent aggregation propensity of the protein. However, the relative propensity to do so varied considerably among mutants. We were not able to explain the variation in aggregation rates by differences in known protein properties such as enzyme activity, protein thermostability, mutation position or degree of change in protein charge. Similarly, we were not able to explain variability in the duration of disease in SOD1-associated ALS pedigrees by these properties. However, we find that the majority of pedigrees in which patients exhibit reproducibly short disease durations are associated with mutations that show a high inherent propensity to induce aggregation of SOD1. PMID:19483195

  6. [Progress in pediatric cardiology, congenital heart disease in adults, and heart surgery for congenital heart disease].

    PubMed

    García-Guereta, Luis; Benito, Fernando; Portela, Francisco; Caffarena, José

    2010-01-01

    The field of pediatric cardiology is continually developing and now covers not only congenital and acquired heart disease in children but also congenital heart disease in adults and the prenatal diagnosis and prevention of heart disease. This review highlights new findings in the field of genetics, selected articles on the use of magnetic resonance imaging and multislice CT in diagnosis, and recent publications on electrophysiology and the surgical treatment of children and adults with congenital heart disease. In addition, the increasingly advanced use of mechanical assist devices as a bridge to heart transplantation in children is also discussed. PMID:20223177

  7. Disease Mechanisms in ALS: Misfolded SOD1 Transferred Through Exosome-Dependent and Exosome-Independent Pathways.

    PubMed

    Silverman, Judith M; Fernando, Sarah M; Grad, Leslie I; Hill, Andrew F; Turner, Bradley J; Yerbury, Justin J; Cashman, Neil R

    2016-04-01

    Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neuromuscular degenerative disorder with a poorly defined etiology. ALS patients experience motor weakness, which starts focally and spreads throughout the nervous system, culminating in paralysis and death within a few years of diagnosis. While the vast majority of clinical ALS is sporadic with no known cause, mutations in human copper-zinc superoxide dismutase 1 (SOD1) cause about 20 % of inherited cases of ALS. ALS with SOD1 mutations is caused by a toxic gain of function associated with the propensity of mutant SOD1 to misfold, presenting a non-native structure. The mechanisms responsible for the progressive spreading of ALS pathology have been the focus of intense study. We have shown that misfolded SOD1 protein can seed misfolding and aggregation of endogenous wild-type SOD1 similar to amyloid-β and prion protein seeding. Our recent observations demonstrate a transfer of the misfolded SOD1 species from cell to cell, modeling the intercellular transmission of disease through the neuroaxis. We have shown that both mutant and misfolded wild-type SOD1 can traverse cell-to-cell, either as protein aggregates that are released from dying cells and taken up by neighboring cells via macropinocytosis, or in association with vesicles which are released into the extracellular environment. Furthermore, once misfolding of wild-type SOD1 has been initiated in a human cell culture, it can induce misfolding in naïve cell cultures over multiple passages of media transfer long after the initial misfolding template is degraded. Herein we review the data on mechanisms of intercellular transmission of misfolded SOD1. PMID:26908139

  8. Assembly and Interrogation of Alzheimer’s Disease Genetic Networks Reveal Novel Regulators of Progression

    PubMed Central

    Crary, John F.; Lefort, Roger; Qureshi, Yasir H.; Lefebvre, Celine; Califano, Andrea; Shelanski, Michael L.

    2015-01-01

    Alzheimer’s disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe), yielded an interactome consisting of 488,353 transcription-factor/target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa), identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsy-derived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3) are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression. PMID:25781952

  9. 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.

  10. Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression.

    PubMed

    Aubry, Soline; Shin, William; Crary, John F; Lefort, Roger; Qureshi, Yasir H; Lefebvre, Celine; Califano, Andrea; Shelanski, Michael L

    2015-01-01

    Alzheimer's disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe), yielded an interactome consisting of 488,353 transcription-factor/target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa), identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsy-derived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3) are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression. PMID:25781952

  11. An Unrecognized Rash Progressing to Lyme Carditis: Important Features and Recommendations Regarding Lyme Disease.

    PubMed

    Lee, Shawn; Singla, Montish

    2016-01-01

    We present a case report of 46-year-old man with no medical history, who complained of extreme fatigue, near-syncope, and palpitations. He initially presented in complete heart block. A transvenous pacemaker was placed in the emergency department, and he was started empirically on Ceftriaxone for Lyme disease. He was admitted and over the course of the next few days, his rhythm regressed to Mobitz type I first-degree atrioventricular block and then to normal sinus rhythm. This case report highlights some important features regarding Lyme carditis, a rare presentation of early disseminated Lyme disease (seen in a few weeks to months after the initial tick bite). In 25%-30% of patients, the characteristic targetoid rash may not be seen, a likely culprit of the disease not being detected early and progressing to disseminated disease. The most common cardiac complaint of Lyme disease is palpitations, occurring in 6.6% of patients, which may not accurately reflect progression into disseminated Lyme disease because it is a nonspecific finding. Conduction abnormality, occurring in 1.8% of patients, is a more specific finding of Borrelia invading cardiac tissue. Finally, this case report highlights a recommendation that patients with confirmed Lyme disease or those presenting with cardiac abnormalities or symptoms who have an atypical profile for a cardiac event should be screened with a 12-lead electrocardiogram, Lyme serology, and be considered for antibiotic therapy with the possibility of temporary pacing. PMID:25730155

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

    PubMed Central

    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

    2015-01-01

    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

  13. Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease.

    PubMed

    El Machhour, Fala; Keuylian, Zela; Kavvadas, Panagiotis; Dussaule, Jean-Claude; Chatziantoniou, Christos

    2015-07-01

    Notch3 expression is found in the glomerular podocytes of patients with lupus nephritis or focal segmental GN but not in normal kidneys. Here, we show that activation of the Notch3 receptor in the glomeruli is a turning point inducing phenotypic changes in podocytes promoting renal inflammation and fibrosis and leading to disease progression. In a model of rapidly progressive GN, Notch3 expression was induced by several-fold in podocytes concurrently with disease progression. By contrast, mice lacking Notch3 expression were protected because they exhibited less proteinuria, uremia, and inflammatory infiltration. Podocyte outgrowth from glomeruli isolated from wild-type mice during the early phase of the disease was higher than outgrowth from glomeruli of mice lacking Notch3. In vitro studies confirmed that podocytes expressing active Notch3 reorganize their cytoskeleton toward a proliferative/migratory and inflammatory phenotype. We then administered antisense oligodeoxynucleotides targeting Notch3 or scramble control oligodeoxynucleotides in wild-type mice concomitant to disease induction. Both groups developed chronic renal disease, but mice injected with Notch3 antisense had lower values of plasma urea and proteinuria and inflammatory infiltration. The improvement of renal function was accompanied by fewer deposits of fibrin within the glomeruli and by decreased peritubular inflammation. Finally, abnormal Notch3 staining was observed in biopsy samples of patients with crescentic GN. These results demonstrate that abnormal activation of Notch3 may be involved in the progression of renal disease by promoting migratory and proinflammatory pathways. Inhibiting Notch3 activation could be a novel, promising approach to treat GN. PMID:25421557

  14. Modeling disease progression of Camellia twig blight using a recurrent event model.

    PubMed

    Thomson, J L; Copes, W E

    2009-04-01

    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 disease symptoms. Survival times (time from inoculation until symptom appearance) for the three disease stages (mild, moderate, and severe) were regressed against stem diameter, monthly mean hours/day within a specified temperature range (15 to 30 degrees C), and season (spring, summer, fall, and winter). For all three CTB disease stages, stem diameter had a protective effect on survival times, while monthly mean hours/day in the specified temperature range and warmer seasons were risk factors. Based upon median ratios, the mild disease stage developed 2 to 3 times faster in spring, summer, and fall than in winter. Similarly, moderate and severe disease stages developed 2 to 2.5 times faster. For all three disease stages, seasonal differences in stage development were smaller among fall, spring, and summer, varying from 1 to 1.6 times faster. Recurrent event modeling of CTB progression provides knowledge concerning developmental expression of this disease, information necessary for creating a comprehensive, integrated disease management program. PMID:19271979

  15. 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

  16. High resolution radiographic and fine immunologic definition of TB disease progression in the rhesus macaque.

    PubMed

    Lewinsohn, David M; Tydeman, Ian S; Frieder, Marisa; Grotzke, Jeff E; Lines, Rebecca A; Ahmed, Sheela; Prongay, Kamm D; Primack, Steven L; Colgin, Lois M A; Lewis, Anne D; Lewinsohn, Deborah A

    2006-09-01

    Mycobacterium tuberculosis infection in non-human primates parallels human tuberculosis, and provides a valuable vaccine evaluation model. However, this model is limited by the availability of real-time, non-invasive information regarding disease progression. Consequently, we have combined computed tomography scanning with enumeration of antigen-specific T cell responses. Four rhesus monkeys were infected with M. tuberculosis strain H37Rv (1000 cfu) in the right lower lobe via a bronchoscope. All uniformly developed progressive tuberculosis, and required euthanasia at 12 weeks. Computed tomography scanning provided detailed real-time imaging of disease progression. At necropsy, computed tomography and pathohistologic findings were tightly correlated, and characteristic of human disease. Immunologic monitoring demonstrated progressive evolution of high frequency M. tuberculosis-specific CD4(+) and CD8(+) T cell responses. Peripheral blood effector cell frequencies were similar to those observed in tissues. In summary, computed tomography scanning in conjunction with immunologic monitoring provides a non-invasive, accurate, and rapid assessment of tuberculosis in the non-human primate. PMID:16952476

  17. 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

  18. 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.

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

    PubMed

    Flyel, 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; Strling, 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

  20. Erdheim-Chester Disease: An Unusual Cause of Intracranial Vasculitis and Progressive Leukoencephalopathy.

    PubMed

    Sagnier, Sharmila; Debruxelles, Sabrina; Lepreux, Sébastien; Sibon, Igor

    2016-05-01

    Erdheim-Chester disease (ECD) is a non-Langerhans histiocytosis affecting multiple organs. Stroke as symptom onset of ECD with intracranial vasculitis is unusual. We report the case of a 64-year-old man who presented with an acute ischemic stroke associated with a moderate leukoencephalopathy and intracranial arteries stenosis. Four years later, he developed movement disorders with dysarthria and cognitive impairment. Neuroradiological findings demonstrated a rapidly progressive and diffuse leukoencephalopathy associated with brain atrophy and infiltration of the intracranial vertebral artery wall. Brain postmortem evaluation confirmed the diagnosis of ECD. This diagnosis should be evoked in patients with cryptogenic stroke, progressive leukoencephalopathy, and infiltration of the arterial wall. PMID:26996751

  1. Baseline Kidney Function as Predictor of Mortality and Kidney Disease Progression in HIV-Positive Patients

    PubMed Central

    Ibrahim, Fowzia; Hamzah, Lisa; Jones, Rachael; Nitsch, Dorothea; Sabin, Caroline; Post, Frank A.

    2012-01-01

    Background Chronic kidney disease (CKD) is associated with increased all-cause mortality and kidney disease progression. Decreased kidney function at baseline may identify human immunodeficiency virus (HIV)-positive patients at increased risk of death and kidney disease progression. Study Design Observational cohort study. Setting & Participants 7 large HIV cohorts in the United Kingdom with kidney function data available for 20,132 patients. Predictor Baseline estimated glomerular filtration rate (eGFR). Outcomes Death and progression to stages 4-5 CKD (eGFR <30 mL/min/1.73 m2 for >3 months) in Cox proportional hazards and competing-risk regression models. Results Median age at baseline was 34 (25th-75th percentile, 30-40) years, median CD4 cell count was 350 (25th-75th percentile, 208-520) cells/μL, and median eGFR was 100 (25th-75th percentile, 87-112) mL/min/1.73 m2. Patients were followed up for a median of 5.3 (25th-75th percentile, 2.0-8.9) years, during which 1,820 died and 56 progressed to stages 4-5 CKD. A U-shaped relationship between baseline eGFR and mortality was observed. After adjustment for potential confounders, eGFRs <45 and >105 mL/min/1.73 m2 remained associated significantly with increased risk of death. Baseline eGFR <90 mL/min/1.73 m2 was associated with increased risk of kidney disease progression, with the highest incidence rates of stages 4-5 CKD (>3 events/100 person-years) observed in black patients with eGFR of 30-59 mL/min/1.73 m2 and those of white/other ethnicity with eGFR of 30-44 mL/min/1.73 m2. Limitations The relatively small numbers of patients with decreased eGFR at baseline and low rates of progression to stages 4-5 CKD and lack of data for diabetes, hypertension, and proteinuria. Conclusions Although stages 4-5 CKD were uncommon in this cohort, baseline eGFR allowed the identification of patients at increased risk of death and at greatest risk of kidney disease progression. PMID:22521282

  2. Hypothesis: Chronic Progressive Nephropathy in Rodents as a Disease Caused by an Expanding Somatic Mutant Clone.

    PubMed

    Manskikh, V N

    2015-05-01

    Chronic progressive nephropathy is a common noninfectious disease in aging (mice, rats) and non-aging (naked mole rat) rodents, sometimes resulting in death. The etiology and pathogenesis of the disease remain mysterious. For instance, it remains unclear what is the immediate cause of the disease and where exactly in the kidneys, glomerular or tubulointerstitial compartment, do primary and secondary changes occur. Here, I propose a potential scenario for development of progressive nephropathy that is based on an assumption that the disease is caused by occurrence and spread of mutant cellular clones from tubular epithelium secreting proinflammatory and prosclerotic cytokines. The hypothesis considers some features of the disease that have never been discussed earlier. According to the proposed concept, a clone of mutant cells secretes cytokines inducing chronic inflammation, proliferation of fibroblasts, and active collagen production that eventually results in sclerosis and thickening of tubular basement membranes. Sclerosis of interstitium and thickening of tubular basement membranes cause narrowing of some parts of the nephron, especially collecting ducts, which hinders passage of the urine, elevates tubular hydrostatic pressure, and impairs filtration and reabsorption in the kidneys. High hydrostatic pressure and reabsorption-induced elevated concentration of macromolecular substances in the primary urine result in development of large cysts and glomerular hyalinosis followed by renal failure. Based on this, it might be concluded that chronic progressive nephropathy in rodents represents a special type of tubulointerstitial dysplasia (or "non-tumorous neoplasia") in kidneys with secondary glomerular disorder at late stage of the disease. The concept for development of the disease proposed here may be of special importance from the viewpoint of toxicological pathology and gerontology, particularly for analysis of pathological features resulting in death of non-aging animals (naked mole rats). PMID:26071776

  3. Synonymous Substitution Rates Predict HIV Disease Progression as a Result of Underlying Replication Dynamics

    PubMed Central

    Lemey, Philippe; Kosakovsky Pond, Sergei L; Drummond, Alexei J; Pybus, Oliver G; Shapiro, Beth; Barroso, Helena; Taveira, Nuno; Rambaut, Andrew

    2007-01-01

    Upon HIV transmission, some patients develop AIDS in only a few months, while others remain disease free for 20 or more years. This variation in the rate of disease progression is poorly understood and has been attributed to host genetics, host immune responses, co-infection, viral genetics, and adaptation. Here, we develop a new “relaxed-clock” phylogenetic method to estimate absolute rates of synonymous and nonsynonymous substitution through time. We identify an unexpected association between the synonymous substitution rate of HIV and disease progression parameters. Since immune activation is the major determinant of HIV disease progression, we propose that this process can also determine viral generation times, by creating favourable conditions for HIV replication. These conclusions may apply more generally to HIV evolution, since we also observed an overall low synonymous substitution rate for HIV-2, which is known to be less pathogenic than HIV-1 and capable of tempering the detrimental effects of immune activation. Humoral immune responses, on the other hand, are the major determinant of nonsynonymous rate changes through time in the envelope gene, and our relaxed-clock estimates support a decrease in selective pressure as a consequence of immune system collapse. PMID:17305421

  4. MAPPING THE PROGRESSION OF ATROPHY IN EARLY AND LATE ONSET ALZHEIMERS 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 Alzheimers 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

  5. Identifying progression related disease risk modules based on the human subcellular signaling networks.

    PubMed

    Xie, Ruiqiang; Huang, Hao; Li, Wan; Chen, Binbin; Jiang, Jing; He, Yuehan; Lv, Junjie; ma, Bo; Zhou, Yanyan; Feng, Chenchen; Chen, Lina; He, Weiming

    2014-12-01

    Many studies have shown that the structure and dynamics of the human signaling network are disturbed in complex diseases such as coronary artery disease, and gene expression profiles can distinguish variations in diseases since they can accurately reflect the status of cells. Integration of subcellular localization and the human signaling network holds promise for providing insight into human diseases. In this study, we performed a novel algorithm to identify progression-related-disease-risk modules (PRDRMs) among patients of different disease states within eleven subcellular sub-networks from a human signaling network. The functional annotation and literature retrieval showed that the PRDRMs were strongly associated with disease pathogenesis. The results indicated that the PRDRM expression values as classification features had a good classification performance to distinguish patients of different disease states. Our approach compared with the method PageRank had a better classification performance. The identification of the PRDRMs in response to the dynamic gene expression change could facilitate our understanding of the pathological basis of complex diseases. Our strategy could provide new insights into the potential use of prognostic biomarkers and the effective guidance of clinical therapy from the human subcellular signaling network perspective. PMID:25315201

  6. 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

  7. Progression of calcifications in breast arteries in women at high risk for coronary heart disease events

    PubMed Central

    Maas, A.H.E.M.; van der Schouw, Y.T.; Mali, W.P.Th.M.; van der Graaf, Y.

    2006-01-01

    Objective To study changes in breast artery calcifications (BAC) over time and its relation with coronary heart disease (CHD) risk factors. Methods Breast arterial calcifications were studied at baseline and after five years follow-up in 453 women participating in the Raloxifene Use for The Heart (RUTH) study. All mammograms were scored by two observers. With logistic regression analysis the independent effect of risk factors on the progression of BAC was evaluated. Results BAC was present in 94 of 453 (21%) women at baseline and in 116 of 453 (26%) women after 5.01.04 years. Progression of BAC was seen in 44 of 453 (10%) women. In 22 participants (5%) BAC was not present at baseline, while in 22 participants (5%) the severity of BAC merely changed from grade 1 to grade 2 calcification. Age was significantly associated with progression of BAC (OR 1.09, 95% CI 1.03 to 1.14). Multivariate regression analysis with adjustment for age and the duration of follow-up showed no association between CHD risk factors and the progression of BAC. Lipid-lowering drugs protected for progression (adjusted OR 0.5, 95% CI 0.22 to 0.98). The strongest determinant in the progression of BAC was BAC at baseline (adjusted OR 4.2, 95% CI 2.10 to 8.27). Conclusion Progression of BAC is not associated with CHD risk factors, but with increasing age and BAC at baseline. Lipid-lowering drugs protect against progression of BAC. PMID:25696661

  8. Amyloid β-Peptide (1–42)-Induced Oxidative Stress in Alzheimer Disease: Importance in Disease Pathogenesis and Progression

    PubMed Central

    Swomley, Aaron M.; Sultana, Rukhsana

    2013-01-01

    Abstract Significance: Alzheimer disease (AD) is an age-related neurodegenerative disease. AD is characterized by progressive cognitive impairment. One of the main histopathological hallmarks of AD brain is the presence of senile plaques (SPs) and another is elevated oxidative stress. The main component of SPs is amyloid beta-peptide (Aβ) that is derived from the proteolytic cleavage of amyloid precursor protein. Recent Advances: Recent studies are consistent with the notion that methionine present at 35 position of Aβ is critical to Aβ-induced oxidative stress and neurotoxicity. Further, we also discuss the signatures of oxidatively modified brain proteins, identified using redox proteomics approaches, during the progression of AD. Critical Issues: The exact relationships of the specifically oxidatively modified proteins in AD pathogenesis require additional investigation. Future Directions: Further studies are needed to address whether the therapies directed toward brain oxidative stress and oxidatively modified key brain proteins might help delay or prevent the progression of AD. Antioxid. Redox Signal. 19, 823–835. PMID:23249141

  9. Successful human epidermal growth receptor 2-targeted therapy beyond disease progression for extramammary Paget's disease.

    PubMed

    Watanabe, Satomi; Takeda, Masayuki; Takahama, Takayuki; Iwasa, Tsutomu; Tsurutani, Junji; Tanizaki, Junko; Shimizu, Toshio; Sakai, Kazuko; Wada, Yoshitaka; Isogai, Noritaka; Nishio, Kazuto; Nakagawa, Kazuhiko

    2016-06-01

    Extramammary Paget's disease is a malignant intraepithelial carcinoma, which constitutes less than 1 % of all vulvar malignancies. Surgical resection is the first treatment of choice and standard chemotherapy has not been established for advanced or recurrent disease. Experimental and clinical studies have identified human epidermal growth receptor 2 as a potential therapeutic target. A 63-year-old male was referred for recurrent extramammary Paget's disease after surgery. Human epidermal growth receptor 2 was shown to be overexpressed and amplified by immunohistochemical analysis and fluorescence in situ hybridization analysis, respectively. After two cycles of trastuzumab monotherapy, all lymph node metastases decreased in size. However, he experienced recurrence in the lymph nodes during the seven courses of trastuzumab. As a subsequent treatment, trastuzumab was administered in combination with docetaxel and pertuzumab; clinical response was sustained for 12 months without significant adverse events. PMID:26856856

  10. Sialoadhesin promotes neuroinflammation-related disease progression in two mouse models of CLN disease.

    PubMed

    Groh, Janos; Ribechini, Eliana; Stadler, David; Schilling, Tim; Lutz, Manfred B; Martini, Rudolf

    2016-05-01

    CLN diseases are mostly fatal lysosomal storage diseases that lead to neurodegeneration in the CNS. We have previously shown that CD8+ T-lymphocytes contribute to axonal perturbation and neuron loss in the CNS of Ppt1(-/-) mice, a model of CLN1 disease. We now investigated the role of the inflammation-related cell adhesion molecule sialoadhesin (Sn) in Ppt1(-/-) and Cln3(-/-) mice, a model of the most frequent form, CLN3 disease. Microglia/macrophages in the CNS of both models showed an upregulation of Sn and markers for proinflammatory M1 polarization and antigen presentation. Sn+ microglia/macrophages associated with SMI32+ axonal spheroids and CD8+ T-lymphocytes. To analyze their pathogenic impact, we crossbred both models with Sn-deficient mice and scored axonal degeneration and neuronal integrity using immunohistochemistry, electron microscopy and optical coherence tomography. Degenerative alterations in the retinotectal pathway of Ppt1(-/-) Sn(-/-) and Cln3(-/-) Sn(-/-) mice were significantly reduced. Ppt1(-/-) Sn(-/-) mice also showed a substantially improved clinical phenotype and extended lifespan, attenuated numbers of M1-polarized microglia/macrophages and reduced expression levels of proinflammatory cytokines. This was accompanied by an increased frequency of CD8+CD122+ T-lymphocytes in the CNS of Ppt1(-/-) Sn(-/-) mice, the regulatory phenotype of which was demonstrated by impaired survival of CD8+CD122- effector T-lymphocytes in co-culture experiments. We show for the first time that increased Sn expression on microglia/macrophages contributes to neural perturbation in two distinct models of CLN disease. Our data also indicate that a rarely described CD8+CD122+ T-cell population can regulate the corresponding diseases. These studies provide insights into CLN pathogenesis and may guide in designing immuno-regulatory treatment strategies. GLIA 2016;64:792-809. PMID:26775238

  11. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis.

    PubMed

    Weiner, Howard L

    2008-03-01

    Multiple sclerosis is postulated to be a T cell-mediated autoimmune disease characterised by a relapsing-remitting stage followed by a secondary progressive phase. The relapsing remitting phase may involve waves of proinflammatory Th1 and Th17 cells that infiltrate the nervous system, provoking a clinical attack. The activity of these cells is modulated by other populations of regulatory T cells and the balance between the pro-inflammatory and regulatory T cells is critical for determining disease activity. Promoting the activity of regulatory cells is a potentially beneficial therapeutic strategy, and probably contributes to the action of glatiramer acetate. The progressive phase of multiple sclerosis is believed to be secondary to neurodegenerative changes triggered by inflammation. The status of the innate immune system and its relationship to the stages of multiple sclerosis has been poorly defined until recently. However, recent data suggest that these results demonstrate abnormalities of dendritic cell activation or maturation may underlie the transition to the progressive phase of the disease. Preventing this transition, perhaps by acting at the level of the innate immune system, is an important treatment goal. The identification of biomarkers to predict disease course and treatment response is a major challenge in multiple sclerosis research. Studies using antigen arrays have identified antibody patterns related to CNS antigens and heat-shock proteins that are associated with different disease stages and with response to therapy. In the future, such antibody repertoires could be used as biomarkers for the diagnosis and evaluation of patients with multiple sclerosis, for matching treatments to individual patients and, potentially, to identify healthy individuals at risk for this autoimmune disease. PMID:18317671

  12. Association Between Lung Microbiome and Disease Progression in IPF: A Prospective Cohort Study

    PubMed Central

    Han, MeiLan K.; Zhou, Yueren; Murray, Susan; Tayob, Nabihah; Noth, Imre; Lama, Vibha N.; Moore, Bethany B.; White, Eric S.; Flaherty, Kevin R.; Huffnagle, Gary B.; Martinez, Fernando J.

    2014-01-01

    Background The lung microbiomes contribution to IPF pathogenesisis unknown. Using COMET-IPF (Correlating Outcomes with biochemical Markers to Estimate Time-progression in Idiopathic Pulmonary Fibrosis), the goal of this study was to determine whether unique microbial signatures would associate with disease progression. Methods IPF subjects within four years of diagnosis aged 3580 were eligible for inclusion. Subjects were followed for up to a maximum of 80 weeks. This completed observational study is registered with ClinicalTrials.gov, number NCT01071707. Progression-free survival was defined as death, acute exacerbation, lung transplant, or decline in FVC of 10% or DLCO of 15%.DNA was isolated from 55 bronchoscopic alveolar lavage (BAL) samples. 454 pyrosequencing was used to assign operational taxonomic units (OTUs) based on a 3% sequence divergence. Adjusted Cox models identified OTUs significantly associated with progression-free survival at a p<010 level. These OTUs were then used in principal components (PC) analysis. The association between PCs and microbes with high factor loadings from the PC analysis and progression-free survival were examined via Cox regression analyses. Findings Mean FVC was 701% and mean DLCO 423 %predicted. Significant associations with disease progression were noted with increased % relative abundance of two OTUs identified by PC analysis, a Streptococcus OTU. (p<00009) and a Staphylococcus OTU(p=001). Strength of associations using PCs versus two OTUs alone was similar. Threshold analysis helped define a cut point for % relative abundance for each OTU associated with progression-free survival, >39% for the Streptococcus OTU, HR 1019 (95% CI 294, 3535; p=00002) and >18% for the Staphylococcus OTU, HR 506 (171, 1493; p=0003). Interpretation These preliminary data suggest IPF disease progression is associated with presence of specific members within the Staphylococcus and Streptococcus genera. PMID:24767767

  13. Disease progression model for Clinical Dementia Rating–Sum of Boxes in mild cognitive impairment and Alzheimer’s subjects from the Alzheimer’s Disease Neuroimaging Initiative

    PubMed Central

    Samtani, Mahesh N; Raghavan, Nandini; Novak, Gerald; Nandy, Partha; Narayan, Vaibhav A

    2014-01-01

    Background The objective of this analysis was to develop a nonlinear disease progression model, using an expanded set of covariates that captures the longitudinal Clinical Dementia Rating Scale–Sum of Boxes (CDR–SB) scores. These were derived from the Alzheimer’s Disease Neuroimaging Initiative ADNI-1 study, of 301 Alzheimer’s disease and mild cognitive impairment patients who were followed for 2–3 years. Methods The model describes progression rate and baseline disease score as a function of covariates. The covariates that were tested fell into five groups: a) hippocampal volume; b) serum and cerebrospinal fluid (CSF) biomarkers; c) demographics and apolipoprotein Epsilon 4 (ApoE4) allele status; d) baseline cognitive tests; and e) disease state and comedications. Results Covariates associated with baseline disease severity were disease state, hippocampal volume, and comedication use. Disease progression rate was influenced by baseline CSF biomarkers, Trail-Making Test part A score, delayed logical memory test score, and current level of impairment as measured by CDR–SB. The rate of disease progression was dependent on disease severity, with intermediate scores around the inflection point score of 10 exhibiting high disease progression rate. The CDR–SB disease progression rate in a typical patient, with late mild cognitive impairment and mild Alzheimer’s disease, was estimated to be approximately 0.5 and 1.4 points/year, respectively. Conclusions In conclusion, this model describes disease progression in terms of CDR–SB changes in patients and its dependency on novel covariates. The CSF biomarkers included in the model discriminate mild cognitive impairment subjects as progressors and nonprogressors. Therefore, the model may be utilized for optimizing study designs, through patient population enrichment and clinical trial simulations. PMID:24926196

  14. Synergistic actions of microglia and astrocytes in the progression of Alzheimer's disease.

    PubMed

    Bouvier, David S; Murai, Keith K

    2015-01-01

    Microglia and astrocytes are essential components of brain homeostasis. Interestingly, when the brain is exposed to adverse conditions, both astrocytes and microglia acquire specialized 'reactive' or 'activated' phenotypes that relate to the characteristics of the insult. In most cases they become important perpetrators of inflammation and potentially neuronal dysfunction. In neurodegenerative diseases such as Alzheimer's disease, the reciprocal interactions between microglia and astrocytes may be particularly important for the development of neuronal pathology and disease states. An important challenge is to understand how microglia and astrocytes inter-communicate at different stages of disease and the importance of this crosstalk on the physiology of surrounding neurons. In this review we focus on the potential roles that microglia and astrocytes fulfill in early to late stages of AD and how their synergistic actions may shape the progression of AD pathology to affect brain health. PMID:25663025

  15. Effect of statin therapy on disease progression in pediatric ADPKD: Design and baseline characteristics of participants

    PubMed Central

    Cadnapaphornchai, Melissa A.; George, Diana M.; Masoumi, Amirali; McFann, Kim; Strain, John D.; Schrier, Robert W.

    2011-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney condition and is associated with important renal and cardiovascular manifestations in childhood. Renal cystic disease can be documented in some cases as early as in utero. Early intervention is critical if the long-term complications of this condition, including end-stage renal disease, are to be ameliorated. Here we describe our ongoing randomized double-blind placebo-controlled phase III clinical trial to assess the effect of pravastatin treatment on renal and cardiovascular disease progression in 107 children and young adults age 822 years with ADPKD who are receiving the angiotensin converting enzyme inhibitor lisinopril. Baseline demographic and laboratory data are provided. Results of this study could markedly impact the standard of care for evaluation and treatment of ADPKD in this population. PMID:21266204

  16. 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

  17. 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

  18. Planning for the progressive control of foot-and-mouth disease worldwide.

    PubMed

    Rweyemamu, M; Roeder, P; MacKay, D; Sumption, K; Brownlie, J; Leforban, Y

    2008-01-01

    In the wake of on-going successful programmes for global eradication of rinderpest and the current effort to contain the spread of avian influenza, the progressive world-wide control of FMD must be regarded as a major contribution to the international public good. FMD is the single most animal disease constraint to international trade in animal products. Its control is relevant, on the one hand, to protecting the livestock industries of industrialised countries and, on the other, to the livelihoods and income generation of developing countries, where, as a general rule, FMD continues to be endemic. The strategy that is advocated in this paper is one that is based on progressive risk reduction of FMD in the context of progressive market access of livestock commodities from developing countries. It is suggested that FMD control should be linked to improvement in livelihoods of livestock dependent communities in the FMD endemic settings. It is expected that this in turn will lead to increasing demand for effective national veterinary services and disease surveillance. This strategy has also taken lessons from the global rinderpest eradication programme and regional FMD control programmes in Europe and South America. The strategy that is advocated for the progressive control of FMD in the endemic settings is based on a seven stage process within a horizon of about 30 years, namely: (1) Assessing and defining national FMD status; (2) instituting vaccination and movement control; (3) suppressing virus transmission to achieve absence of clinical disease; (4) achieving freedom from FMD with vaccination in accordance with the OIE standards; (5) achieving freedom from FMD without vaccination in accordance with the OIE standards; (6) extending FMD free zones; and (7) maintaining FMD Freedom. Concomitant with progressive FMD control, there needs be the encouragement of such risk reduction measures as in-country commodity processing in order to encourage regulated trade in livestock commodities without unduly increasing the risk of disease spread. Finally, the progressive control of FMD should also be seen as part of reducing the overall, world-wide threat of infectious diseases to human health and economic development. PMID:18397510

  19. 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

  20. 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

  1. Progression and Natural History of Nonalcoholic Fatty Liver Disease in Adults.

    PubMed

    Marengo, Andrea; Jouness, Ramy Ibrahim Kamal; Bugianesi, Elisabetta

    2016-05-01

    Liver-related mortality is the third cause of death in patients with nonalcoholic fatty liver disease, but the long-term prognosis basically depends on the presence and severity of liver damage. Thus, life expectancy in patients with simple steatosis is not different from the general population, but liver-related mortality is significantly higher in patients with nonalcoholic steatohepatitis (NASH), particularly in those with advanced fibrosis. Progression of liver disease is observed in up to one-third of patients with NASH. The long-term hepatic prognosis mostly depends on the histologic stage at initial liver biopsy, but multiple risk factors may concur. PMID:27063271

  2. Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.

    PubMed

    Cohen, Mark L; Kim, Chae; Haldiman, Tracy; ElHag, Mohamed; Mehndiratta, Prachi; Pichet, Termsarasab; Lissemore, Frances; Shea, Michelle; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Appleby, Brian S; Surewicz, Krystyna; Surewicz, Witold K; Sajatovic, Martha; Tatsuoka, Curtis; Zhang, Shulin; Mayo, Ping; Butkiewicz, Mariusz; Haines, Jonathan L; Lerner, Alan J; Safar, Jiri G

    2015-04-01

    Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimer's disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid-β and rates of clinical decline in Alzheimer's disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-β in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimer's disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-β42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-β40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimer's disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid-β42, with higher levels of distinctly structured amyloid-β42 particles composed of 30-100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-β42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimer's disease phenotypes. These findings indicate that Alzheimer's disease exhibits a wide spectrum of amyloid-β42 structural states and imply the existence of prion-like conformational strains. PMID:25688081

  3. Different Scales of Cortical Organization are Selectively Targeted in the Progression to Alzheimer's Disease.

    PubMed

    Romero-Garcia, Rafael; Atienza, Mercedes; Cantero, Jose L

    2016-03-01

    Previous studies have shown that the topological organization of the cerebral cortex is altered in Alzheimer's disease (AD). However, it remains unknown whether different levels of the cortical hierarchy are homogeneously affected during disease progression, and which of these levels are mostly involved in the breakdown of metabolic (functional) connectivity. To fulfill these goals, we acquired structural magnetic resonance images (MRI) and positron emission tomography (PET) with the radiotracer 18F-fludeoxyglucose (FDG) in 29 healthy old (HO) adults, 29 amnestic mild cognitive impairment (aMCI) and 29 mild AD patients. Structural and metabolic connections were obtained from inter-regional correlations of cortical thickness and glucose consumption, respectively. Results showed that AD and HO groups differed at all levels of cortical organization (i.e. whole cortex, hemisphere, lobe and node), whereas differences among the three groups were only evident at the lobe and node levels. The correlation between structural and metabolic connectivity (F-S coupling) was also disturbed during AD progression, affecting to different connectivity scales: it decreased at the local level, revealing a progressive increase of metabolic connections in those local communities with fewer structural connections; whereas it increased at the global level, likely due to a parallel reduction of cortical thickness and glucose consumption between long-distance cortical regions. Collectively, these results reveal that different levels of cortical organization are selectively affected during the transition from normal aging to dementia, which could be helpful to track cortical dysfunctions in the progression to AD. PMID:26790483

  4. 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

  5. Have we made progress in the management of chronic graft-vs-host disease?

    PubMed Central

    Lee, Stephanie J.

    2010-01-01

    Chronic graft-vs-host disease (GVHD) is a common long-term complication of allogeneic hematopoietic cell transplant that is associated with very high morbidity and mortality. In order to understand whether we have made progress in the management of chronic GVHD, it is helpful to first propose a definition of meaningful “progress.” The following can be considered to be indicators of improved management of chronic GVHD: a decrease in the incidence or severity of chronic GVHD, better efficacy or decreased toxicity of therapies, better quality of life despite chronic GVHD, and improved overall and disease-free survival rates. However, to date, real progress has not been made in these areas, though there are promising new preventive strategies and treatments. Furthermore, a consensus has been reached in the research community about many different issues surrounding chronic GVHD definitions, management, and the conduct of clinical trials. These consensus documents will help to standardize efforts and data collection so that true comparisons can be made in the future and real clinical progress achieved. PMID:21130418

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

    PubMed

    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

    2015-09-01

    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

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

    PubMed Central

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

    2016-01-01

    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

  8. Differences in host susceptibility to disease progression in the human challenge model of Haemophilus ducreyi infection.

    PubMed

    Spinola, Stanley M; Bong, Cliffton T H; Faber, Andrew L; Fortney, Kate R; Bennett, Stacy L; Townsend, Carisa A; Zwickl, Beth E; Billings, Steven D; Humphreys, Tricia L; Bauer, Margaret E; Katz, Barry P

    2003-11-01

    With human volunteers inoculated at two sites with Haemophilus ducreyi, outcomes for a subject were not independent. In a reinfection trial, 2 of 11 previous pustule formers and 6 of 10 previous resolvers resolved all sites of infection. There was no correlation between serum bactericidal or phagocytic activity and outcome in the trial. These data indicate that different hosts are differentially susceptible to disease progression versus resolution in the model. PMID:14573692

  9. What can be learnt about disease progression in breast cancer dormancy from relapse data?

    PubMed

    Willis, Lisa; Graham, Trevor A; Alarcón, Tomás; Alison, Malcolm R; Tomlinson, Ian P M; Page, Karen M

    2013-01-01

    Breast cancer patients have an anomalously high rate of relapse many years--up to 25 years--after apparently curative surgery removed the primary tumour. Disease progression during the intervening years between resection and relapse is poorly understood. There is evidence that the disease persists as dangerous, tiny metastases that remain at a growth restricted, clinically undetectable size until a transforming event restarts growth. This is the starting point for our study, where patients who have metastases that are all tiny and growth-restricted are said to have cancer dormancy. Can long-term follow-up relapse data from breast cancer patients be used to extract knowledge about the progression of the undetected disease? Here, we evaluate whether this is the case by introducing and analysing four simple mathematical models of cancer dormancy. These models extend the common assumption that a random transforming event, such as a mutation, can restart growth of a tiny, growth-restricted metastasis; thereafter, cancer dormancy progresses to detectable metastasis. We find that physiopathological details, such as the number of random transforming events that metastases must undergo to escape from growth restriction, cannot be extracted from relapse data. This result is unsurprising. However, the same analysis suggested a natural question that does have a surprising answer: why are interesting trends in long-term relapse data not more commonly observed? Further, our models indicate that (a) therapies which induce growth restriction among metastases but do not prevent increases in metastases' tumourigenicity may introduce a time post-surgery when more patients are prone to relapse; and (b), if a number of facts about disease progression are first established, how relapse data might be used to estimate clinically relevant variables, such as the likely numbers of undetected growth-restricted metastases. This work is a necessary, early step in building a quantitative mechanistic understanding of cancer dormancy. PMID:23671591

  10. Phase progression of γ-Al2O3 nanoparticles synthesized in a solvent-deficient environment.

    PubMed

    Smith, Stacey J; Amin, Samrat; Woodfield, Brian F; Boerio-Goates, Juliana; Campbell, Branton J

    2013-04-15

    Our simple and uniquely cost-effective solvent-deficient synthetic method produces 3-5 nm Al2O3 nanoparticles which show promise as improved industrial catalyst-supports. While catalytic applications are sensitive to the details of the atomic structure, a diffraction analysis of alumina nanoparticles is challenging because of extreme size/microstrain-related peak broadening and the similarity of the diffraction patterns of various transitional Al2O3 phases. Here, we employ a combination of X-ray pair-distribution function (PDF) and Rietveld methods, together with solid-state NMR and thermogravimetry/differential thermal analysis-mass spectrometry (TG/DTA-MS), to characterize the alumina phase-progression in our nanoparticles as a function of calcination temperature between 300 and 1200 °C. In the solvent-deficient synthetic environment, a boehmite precursor phase forms which transitions to γ-Al2O3 at an extraordinarily low temperature (below 300 °C), but this γ-Al2O3 is initially riddled with boehmite-like stacking-fault defects that steadily disappear during calcination in the range from 300 to 950 °C. The healing of these defects accounts for many of the most interesting and widely reported properties of the γ-phase. PMID:23557087

  11. Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia.

    PubMed

    An, Ping; Penugonda, Sudhir; Thorball, Christian W; Bartha, Istvan; Goedert, James J; Donfield, Sharyne; Buchbinder, Susan; Binns-Roemer, Elizabeth; Kirk, Gregory D; Zhang, Wenyan; Fellay, Jacques; Yu, Xiao-Fang; Winkler, Cheryl A

    2016-03-01

    Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotype of A3F tagged by a codon-changing variant (p. I231V, with allele (V) frequency of 48% in European Americans) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (Relative Hazards (RH) = 0.71, 95% CI: 0.56, 0.91) and delayed development of pneumocystis pneumonia (PCP) (RH = 0.53, 95% CI: 0.37-0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. An in vitro assay revealed that the A3F I231V variant may influence Vif mediated A3F degradation. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression. PMID:26942578

  12. 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

  13. UCHL1 is a biomarker of aggressive multiple myeloma required for disease progression

    PubMed Central

    Hussain, Sajjad; Bedekovics, Tibor; Chesi, Marta; Bergsagel, P. Leif; Galardy, Paul J.

    2015-01-01

    The success of proteasome inhibition in multiple myeloma highlights the critical role for the ubiquitin-proteasome system (UPS) in this disease. However, there has been little progress in finding more specific targets within the UPS involved in myeloma pathogenesis. We previously found the ubiquitin hydrolase UCH-L1 to be frequently over-expressed in B-cell malignancies, including myeloma, and showed it to be a potent oncogene in mice. Here we show that UCH-L1 is a poor prognostic factor that is essential for the progression of myeloma. We found high levels of UCHL1 to predict early progression in newly diagnosed patients; a finding reversed by the inclusion of bortezomib. We also found high UCHL1 levels to be a critical factor in the superiority of bortezomib over high-dose dexamethasone in relapsed patients. High UCHL1 partially overlaps with, but is distinct from, known genetic risks including 4p16 rearrangement and 1q21 amplification. Using an orthotopic mouse model, we found UCH-L1 depletion delays myeloma dissemination and causes regression of established disease. We conclude that UCH-L1 is a biomarker of aggressive myeloma that may be an important marker of bortezomib response, and may itself be an effective target in disseminated disease. PMID:26513019

  14. Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia

    PubMed Central

    An, Ping; Penugonda, Sudhir; Thorball, Christian W.; Bartha, Istvan; Goedert, James J.; Donfield, Sharyne; Buchbinder, Susan; Binns-Roemer, Elizabeth; Kirk, Gregory D.; Zhang, Wenyan; Fellay, Jacques; Yu, Xiao-Fang; Winkler, Cheryl A.

    2016-01-01

    Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotype of A3F tagged by a codon-changing variant (p. I231V, with allele (V) frequency of 48% in European Americans) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (Relative Hazards (RH) = 0.71, 95% CI: 0.56, 0.91) and delayed development of pneumocystis pneumonia (PCP) (RH = 0.53, 95% CI: 0.37–0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. An in vitro assay revealed that the A3F I231V variant may influence Vif mediated A3F degradation. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression. PMID:26942578

  15. 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.

  16. A longitudinal EEG study of Alzheimer's disease progression based on a complex network approach.

    PubMed

    Morabito, Francesco Carlo; Campolo, Maurizio; Labate, Domenico; Morabito, Giuseppe; Bonanno, Lilla; Bramanti, Alessia; de Salvo, Simona; Marra, Angela; Bramanti, Placido

    2015-03-01

    A complex network approach is combined with time dynamics in order to conduct a space-time analysis applicable to longitudinal studies aimed to characterize the progression of Alzheimer's disease (AD) in individual patients. The network analysis reveals how patient-specific patterns are associated with disease progression, also capturing the widespread effect of local disruptions. This longitudinal study is carried out on resting electroence phalography (EEGs) of seven AD patients. The test is repeated after a three months' period. The proposed methodology allows to extract some averaged information and regularities on the patients' cohort and to quantify concisely the disease evolution. From the functional viewpoint, the progression of AD is shown to be characterized by a loss of connected areas here measured in terms of network parameters (characteristic path length, clustering coefficient, global efficiency, degree of connectivity and connectivity density). The differences found between baseline and at follow-up are statistically significant. Finally, an original topographic multiscale approach is proposed that yields additional results. PMID:25655033

  17. 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.

  18. Alzheimer's disease and infection: do infectious agents contribute to progression of Alzheimer's disease?

    PubMed

    Honjo, Kie; van Reekum, Robert; Verhoeff, Nicolaas P L G

    2009-07-01

    Infection with several important pathogens could constitute risk factors for cognitive impairment, dementia, and Alzheimer's disease (AD) in particular. This review summarizes the data related to infectious agents that appear to have a relationship with AD. Infections with herpes simplex virus type 1, picornavirus, Borna disease virus, Chlamydia pneumoniae, Helicobacter pylori, and spirochete were reported to contribute to the pathophysiology of AD or to cognitive changes. Based on these reports, it may be hypothesized that central nervous system or systemic infections may contribute to the pathogenesis or pathophysiology of AD, and chronic infection with several pathogens should be considered a risk factor for sporadic AD. If this hypothesis holds true, early intervention against infection may delay or even prevent the future development of AD. PMID:19560105

  19. Potential Clinical Value of Multiparametric PET in the Prediction of Alzheimer’s Disease Progression

    PubMed Central

    Chen, Xueqi; Zhou, Yun; Wang, Rongfu; Cao, Haoyin; Reid, Savina; Gao, Rui; Han, Dong

    2016-01-01

    Objective To evaluate the potential clinical value of quantitative functional FDG PET and pathological amyloid-β PET with cerebrospinal fluid (CSF) biomarkers and clinical assessments in the prediction of Alzheimer’s disease (AD) progression. Methods We studied 82 subjects for up to 96 months (median = 84 months) in a longitudinal Alzheimer’s Disease Neuroimaging Initiative (ADNI) project. All preprocessed PET images were spatially normalized to standard Montreal Neurologic Institute space. Regions of interest (ROI) were defined on MRI template, and standard uptake values ratios (SUVRs) to the cerebellum for FDG and amyloid-β PET were calculated. Predictive values of single and multiparametric PET biomarkers with and without clinical assessments and CSF biomarkers for AD progression were evaluated using receiver operating characteristic (ROC) analysis and logistic regression model. Results The posterior precuneus and cingulate SUVRs were identified for both FDG and amyloid-β PET in predicating progression in normal controls (NCs) and subjects with mild cognitive impairment (MCI). FDG parietal and lateral temporal SUVRs were suggested for monitoring NCs and MCI group progression, respectively. 18F-AV45 global cortex attained (78.6%, 74.5%, 75.4%) (sensitivity, specificity, accuracy) in predicting NC progression, which is comparable to the 11C-PiB global cortex SUVR’s in predicting MCI to AD. A logistic regression model to combine FDG parietal and posterior precuneus SUVR and Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) Total Mod was identified in predicating NC progression with (80.0%, 94.9%, 93.9%) (sensitivity, specificity, accuracy). The selected model including FDG posterior cingulate SUVR, ADAS-Cog Total Mod, and Mini-Mental State Exam (MMSE) scores for predicating MCI to AD attained (96.4%, 81.2%, 83.6%) (sensitivity, specificity, accuracy). 11C-PiB medial temporal SUVR with MMSE significantly increased 11C-PiB PET AUC to 0.915 (p<0.05) in predicating MCI to AD with (77.8%, 90.4%, 88.5%) (sensitivity, specificity, accuracy). Conclusion Quantitative FDG and 11C-PiB PET with clinical cognitive assessments significantly improved accuracy in the predication of AD progression. PMID:27183116

  20. Mortality model based on delays in progression of chronic diseases: alternative to cause elimination model.

    PubMed Central

    Manton, K G; Patrick, C H; Stallard, E

    1980-01-01

    For the analysis of the impact of major chronic diseases on a population, a life table model is proposed in which the age at death due to specific cause (chronic disease) is postponed. Even though many of the major causes of death related to intrinsic aging processes are impossible to eliminate, these causes might be significantly delayed or retarded. To illustrate the use of this model, the effects of a delay of 5, 10, and 15 years in deaths due to three chronic degenerative diseases (cancer, ischemic heart disease, and stroke) are calculated for specific race-sex components of the U.S. population in 1969. These calculations show that even moderate delays in the progression of major chronic diseases will yield a sizable portion of the total gain in longevity that would be available if the diseases were totally eliminated. Thus, they demonstrate that a life table model based on cause delay provides a more biomedically plausible representation of the health impact of a chronic disease on a population than does the cause elimination life table model. Additionally, the cause-delay model provides a mechanism for incorporating the likely effects of medical innovation on survival. PMID:7433613

  1. 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

  2. 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

  3. 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.

  4. Theoretical and Practical Progress of New Heliostat by Chen et al.

    NASA Astrophysics Data System (ADS)

    Kribus, A.

    2006-01-01

    Recently, Chen and his team were active in the theoretical and practical study of a new heliostat for the use of solar energy. This work represents the first innovation in the area of heliostats after many years of little progress. The mathematical development of the tracking and concentration optics principles, and the practical implementation and demonstration of the technology, are both very interesting advances in this field. Many applications are possible for this technology such as generation of solar electricity and solar industrial process heat.

  5. Effect of Intrastriatal Mesenchymal Stromal Cell Injection on Progression of a Murine Model of Krabbe Disease

    PubMed Central

    Wicks, Shawna E.; Londot, Heaven E.; Zhang, Bo; Dowden, Jennifer; Klopf-Eiermann, Jessica; Fisher-Perkins, Jeanne M.; Trygg, Cynthia B.; Scruggs, Brittni A.; Zhang, Xiujuan; Gimble, Jeffrey M.; Bunnell, Bruce A.; Pistell, Paul J.

    2011-01-01

    One of a family of devastating lysosomal storage disorders, Krabbe disease is characterized by demyelination, psychosine accumulation, and inflammation. Affected infants rarely survive longer than two years. Using the twitcher mouse model of the disease, this study evaluated the potential of intrastriatal injection of adipose or bone marrow-derived mesenchymal stromal cells (MSCs) as a treatment option. Neonatal pups were injected with MSCs at 3–4 days of age and subjected to a battery of behavioral tests beginning at 15 days. While MSC injection failed to increase lifespan of twitchers, improvements in rotarod performance and twitching severity were observed at 27–38 days of age using MSCs derived from bone marrow. This study tested several different tasks developed in adult mice for evaluation of disease progression in immature twitchers. Rotarod was both reliable and extremely sensitive. Automated gait analysis using the Treadscan program was also useful for early evaluation of differences prior to overt gait dysfunction. Finally, this study represents the first use of the Stone T-maze in immature mice. Validation of rotarod and automated gait analysis for detection of subtle differences in disease progression is important for early stage efforts to develop treatments for juvenile disorders. PMID:21840342

  6. Predicting Renal Failure Progression in Chronic Kidney Disease Using Integrated Intelligent Fuzzy Expert System

    PubMed Central

    Norouzi, Jamshid; Mirbagheri, Seyed Ahmad; Mazdeh, Mitra Mahdavi; Hosseini, Seyed Ahmad

    2016-01-01

    Background. Chronic kidney disease (CKD) is a covert disease. Accurate prediction of CKD progression over time is necessary for reducing its costs and mortality rates. The present study proposes an adaptive neurofuzzy inference system (ANFIS) for predicting the renal failure timeframe of CKD based on real clinical data. Methods. This study used 10-year clinical records of newly diagnosed CKD patients. The threshold value of 15 cc/kg/min/1.73 m2 of glomerular filtration rate (GFR) was used as the marker of renal failure. A Takagi-Sugeno type ANFIS model was used to predict GFR values. Variables of age, sex, weight, underlying diseases, diastolic blood pressure, creatinine, calcium, phosphorus, uric acid, and GFR were initially selected for the predicting model. Results. Weight, diastolic blood pressure, diabetes mellitus as underlying disease, and current GFR(t) showed significant correlation with GFRs and were selected as the inputs of model. The comparisons of the predicted values with the real data showed that the ANFIS model could accurately estimate GFR variations in all sequential periods (Normalized Mean Absolute Error lower than 5%). Conclusions. Despite the high uncertainties of human body and dynamic nature of CKD progression, our model can accurately predict the GFR variations at long future periods. PMID:27022406

  7. Predicting Renal Failure Progression in Chronic Kidney Disease Using Integrated Intelligent Fuzzy Expert System.

    PubMed

    Norouzi, Jamshid; Yadollahpour, Ali; Mirbagheri, Seyed Ahmad; Mazdeh, Mitra Mahdavi; Hosseini, Seyed Ahmad

    2016-01-01

    Background. Chronic kidney disease (CKD) is a covert disease. Accurate prediction of CKD progression over time is necessary for reducing its costs and mortality rates. The present study proposes an adaptive neurofuzzy inference system (ANFIS) for predicting the renal failure timeframe of CKD based on real clinical data. Methods. This study used 10-year clinical records of newly diagnosed CKD patients. The threshold value of 15 cc/kg/min/1.73 m(2) of glomerular filtration rate (GFR) was used as the marker of renal failure. A Takagi-Sugeno type ANFIS model was used to predict GFR values. Variables of age, sex, weight, underlying diseases, diastolic blood pressure, creatinine, calcium, phosphorus, uric acid, and GFR were initially selected for the predicting model. Results. Weight, diastolic blood pressure, diabetes mellitus as underlying disease, and current GFR(t) showed significant correlation with GFRs and were selected as the inputs of model. The comparisons of the predicted values with the real data showed that the ANFIS model could accurately estimate GFR variations in all sequential periods (Normalized Mean Absolute Error lower than 5%). Conclusions. Despite the high uncertainties of human body and dynamic nature of CKD progression, our model can accurately predict the GFR variations at long future periods. PMID:27022406

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

    PubMed Central

    2009-01-01

    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 to visualise disease progression on multiple variables simultaneously. Methods A variety of vector plots and a path plot have been developed for this purpose, and data from a longitudinal Huntington's disease study are used to illustrate the utility of these graphical methods for exploratory data analysis. Results Initial and final values for three outcome variables can be easily visualised per patient, along with the change in these variables over time. In addition to the disease trajectory, the path individual patients take from initial to final observation can be traced. Categorical variables can be coded with different types of vectors or paths (e.g. different colours, line types, line thickness) and separate panels can be used to include further categorical or continuous variables, allowing clear visualisation of further information for each individual. In addition, summary statistics such as mean vectors, bivariate interquartile ranges and convex polygons can be included to assist in interpreting trajectories, comparing groups, and detecting multivariate outliers. Conclusion Vector and path plots are useful graphical methods for exploratory data analysis when individual-level information on multiple variables over time is desired, and they have several advantages over plotting each variable separately. PMID:19473528

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

    PubMed

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

    2015-07-01

    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 β-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

  10. 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-β1 (TGF-β1). 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-β, 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 α-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 α-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-β1 and decreased expression of VDR and Klotho protein observed in VDD+IRI animals. Conclusion Through inflammatory pathways and involvement of TGF-β1 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

  11. 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 β-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

  12. Progressive resistance training in Parkinson's disease: a systematic review and meta-analysis

    PubMed Central

    Saltychev, Mikhail; Bärlund, Esa; Paltamaa, Jaana; Katajapuu, Niina; Laimi, Katri

    2016-01-01

    Objectives To investigate if there is evidence on effectiveness of progressive resistance training in rehabilitation of Parkinson disease. Design Systematic review and meta-analysis. Data sources: Central, Medline, Embase, Cinahl, Web of Science, Pedro until May 2014. Randomised controlled or controlled clinical trials. The methodological quality of studies was assessed according to the Cochrane Collaboration's domain-based evaluation framework. Data synthesis: random effects meta-analysis with test for heterogeneity using the I² and pooled estimate as the raw mean difference. Participants Adults with primary/idiopathic Parkinson's disease of any severity, excluding other concurrent neurological condition. Interventions Progressive resistance training defined as training consisting of a small number of repetitions until fatigue, allowing sufficient rest between exercises for recovery, and increasing the resistance as the ability to generate force improves. Comparison Progressive resistance training versus no treatment, placebo or other treatment in randomised controlled or controlled clinical trials. Primary and secondary outcome measures Any outcome. Results Of 516 records, 12 were considered relevant. Nine of them had low risk of bias. All studies were randomised controlled trials conducted on small samples with none or 1 month follow-up after the end of intervention. Of them, six were included in quantitative analysis. Pooled effect sizes of meta-analyses on fast and comfortable walking speed, the 6 min walking test, Timed Up and Go test and maximal oxygen consumption were below the level of minimal clinical significance. Conclusions There is so far no evidence on the superiority of progressive resistance training compared with other physical training to support the use of this technique in rehabilitation of Parkinson's disease. Systematic review registration number PROSPERO 2014:CRD42014009844. PMID:26743698

  13. Plasma concentrations of transforming growth factor beta 1 in non-progressive HIV-1 infection correlates with markers of disease progression.

    PubMed

    Maina, Edward K; Abana, C Z; Bukusi, E A; Sedegah, M; Lartey, M; Ampofo, W K

    2016-05-01

    The human immunodeficiency virus (HIV) infection shows variable rate of disease progression. The underlying biological and molecular mechanisms involved in determining progression of HIV infection are not fully understood. The aims of this study were to determine plasma concentrations of active TGF β 1, Th1 and Th2 cytokines in patients with non-progressive and those with progressive HIV-1 infection, as well as to determine if there is an association of these cytokines to disease progression. In a cross-sectional study of 61 HIV-1 infected individuals categorized according to disease progression as having non-progressive HIV-1 infection (n=14) and progressive infection (n=47), plasma levels of active TGF β 1, INF-γ, TNF-α, IL-10, IL-1β, IL-12p70 and IL-13 were compared with HIV uninfected healthy controls (n=12). Plasma concentration of these cytokines was measured using a highly sensitive luminex200 XMAP assay. Pearson correlation test was used to assess the correlation of cytokines with CD4+ and CD8+ T cells, CD4:CD8 ratio and plasma HIV-1 RNA in the different study groups. Plasma concentrations of TGF β 1 and IL-10 were significantly decreased while IL-1β, IL-12p70 and TNF-α were increased in patients with non-progressive HIV-1 infection compared to patients with progressive infection. Plasma levels of TGF β 1 and IL-10 showed an inverse correlation with CD8+ T cell counts and CD4:CD8 ratios in patients with non-progressive HIV-1 infection, while plasma HIV-1 RNA positively correlated with CD4+ T cell counts. Plasma levels of TNF-α, IL-1β, IL-12p70 and IL-13 positively correlated with CD4+ T cell counts and inversely correlated with plasma HIV-1 RNA, CD8+ T cell count and CD4:CD8 ratio in patients with non-progressive infection. The correlation of cytokines to the state of T-lymphocyte and plasma HIV-1 RNA found in this study may provide insight into the role of cytokines in both progressive and non-progressive HIV-1 infection. Additionally, these findings may have implications for systemic cytokine-based therapies in HIV-1 infection. PMID:26986868

  14. Presumptive service connection for disease associated with exposure to certain herbicide agents: AL amyloidosis. Final rule.

    PubMed

    2009-05-01

    This document amends the Department of Veterans Affairs (VA) adjudication regulations concerning presumptive service connection for a certain disease based on the most recent National Academy of Sciences (NAS) Institute of Medicine committee report, "Veterans and Agent Orange: Update 2006" (Update 2006). This amendment is necessary to implement a decision of the Secretary of Veterans Affairs that there is a positive association between exposure to herbicides used in the Republic of Vietnam during the Vietnam era and the subsequent development of AL amyloidosis. The intended effect of this amendment is to establish presumptive service connection for AL amyloidosis based on herbicide exposure. PMID:19507326

  15. A computational method for computing an Alzheimer’s Disease Progression Score; experiments and validation with the ADNI dataset

    PubMed Central

    Jedynak, Bruno M.; Liu, Bo; Lang, Andrew; Gel, Yulia; Prince, Jerry L.

    2014-01-01

    Understanding the time-dependent changes of biomarkers related to Alzheimer’s disease (AD) is a key to assessing disease progression and to measuring the outcomes of disease-modifying therapies. In this paper, we validate an Alzheimer’s disease progression score model which uses multiple biomarkers to quantify the AD progression of subjects following three assumptions: (1) there is a unique disease progression for all subjects, (2) each subject has a different age of onset and rate of progression, and (3) each biomarker is sigmoidal as a function of disease progression. Fitting the parameters of this model is a challenging problem which we approach using an alternating least squares optimization algorithm. In order to validate this optimization scheme under realistic conditions, we use the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. With the help of Monte Carlo simulations, we show that most of the global parameters of the model are tightly estimated, thus enabling an ordering of the biomarkers that fit the model well, ordered as: the Rey auditory verbal learning test with 30 minutes delay, the sum of the two lateral hippocampal volumes divided by the intra-cranial volume, followed by (the clinical dementia rating sum of boxes score and the mini mental state examination score) in no particular order and lastly the Alzheimer’s disease assessment scale-cognitive subscale. PMID:25444605

  16. The mild form of menkes disease: a 34 year progress report on the original case.

    PubMed

    Tchan, M C; Wilcken, B; Christodoulou, J

    2013-01-01

    Classical Menkes disease is a neurodegenerative disorder caused by mutations in the copper-transporting ATPase ATP7A gene which, when untreated, is usually fatal in early childhood. A mild form of Menkes disease was originally reported in 1981 and clinical progress of the patient at 10 years described subsequently. The causative mutation is c.4085C>T in exon 21, causing an alanine to valine substitution in the highly conserved TM7 domain at the C-terminal end of the Menkes protein. Here we report his status at 34 years of age. Intellectual impairment is mild. Ataxia has nearly resolved but motor retardation, dysarthria and an extreme slow speech rate remain. In contrast to patients with the occipital horn syndrome, there have been no connective tissue complications of his mild Menkes disease. He has been under long-term copper therapy for more than 30 years and he continues to enjoy a good quality of life. PMID:23430551

  17. Effect of oral alkali supplementation on progression of chronic kidney disease.

    PubMed

    Gaggl, Martina; Sliber, Christopher; Sunder-Plassmann, Gere

    2014-01-01

    Metabolic acidosis is a frequent but asymptomatic complication in chronic kidney disease (CKD). In early stages of CKD acidosis is limited to the renal tissue and progresses to reduced serum bicarbonate levels. Reduced renal tissue pH and increased ammoniagenesis are the key mechanisms of the kidney to enhance acid excretion to the urine. The expressed protein patterns in the proximal tubular epithelial cells change remarkably, the proximal convoluted tubule develops hypertrophy, and an intra-renal enhanced renin-angiotensin-system leads to interstitial fibrosis. Since nephrons are numerically reduced in CKD each remaining functional unit has to progressively increase these mechanisms to keep up the equilibrium. The adverse effects of chronic metabolic acidosis include aside from acceleration of progression of kidney disease, the development or exacerbation of bone disease, increased degradation of muscle with muscle wasting, enhanced protein degradation and inflammation. Genome wide association studies demonstrated that tubular acid-base transporters are involved in the development of arterial hypertension. Several retrospective analyses have indicated that low serum bicarbonate predicts death in cohorts with CKD and cardiovascular disease. All studies confirmed a U-shaped association of mortality and serum bicarbonate, indicating that both, acidosis and alkalosis are associated with increased mortality. Randomized controlled trials showed that base substitution, either by modification of the diet or by simply adding alkalizing agents, might halt the decline of kidney function in subjects with CKD. In 2012 a meta-analysis concluded that alkali therapy might provide a long-term favorable effect on renal function in patients with CKD. PMID:25549843

  18. 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

  19. 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

  20. Reflexive and Volitional Saccades: Biomarkers of Huntington Disease Severity and Progression

    PubMed Central

    Patel, Saumil S.; Jankovic, Joseph; Hood, Ashley J.; Jeter, Cameron B.; Sereno, Anne B.

    2011-01-01

    Background Huntington disease (HD) is a genetic, neurodegenerative disorder characterized by chorea, behavioral co-morbidities, cognitive deficits, and eye movement abnormalities. We sought to evaluate whether reflexive and voluntary orienting prove useful as biomarkers of disease severity in HD. Methods Eleven HD subjects were evaluated with the motor subscale of the Unified Huntington Disease Rating Scale (UHDRS) and the Montreal Cognitive Assessment. Using an infrared eye tracker, we also measured latency and error rates of horizontal and vertical saccades using prosaccade and antisaccade eye movement tasks. We calculated simple and age-controlled correlations between eye movement and clinical parameters. Results Prosaccade latency correlated with total chorea score. HD patients with greater clinical severity were significantly slower in the prosaccade task. Antisaccade error rate also correlated with UHDRS motor score and total chorea score. HD patients with greater clinical severity as measured by either measure made significantly more errors in the antisaccade task. All these correlations remained significant even when age was taken into account. Conclusions The results of the present age-controlled study show for the first time that both reflexive and voluntary eye motor control in HD patients decrease with increase in disease severity suggesting declines in both motor and cognitive function. Thus, relatively simple eye movement parameters (latency and error rate) obtained from simple tasks (prosaccade and antisaccade) may serve as quantitative biomarkers of sub-cortical and cortical disease severity in HD and could aid in predicting onset, distinguishing subtypes, or evaluating disease progression and novel therapies. PMID:22018763

  1. 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

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

    PubMed Central

    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

    2014-01-01

    Accumulating evidence implicates small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on T2-weighted MRI, 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 current 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, cortical thickness). Three hundred three non-demented older adults (mean age = 79.24±5.29) received high-resolution MRI at baseline and then again 4.6 years (SD=1.01) later. Over the follow-up interval 26 participants progressed to AD. Using structural equation modeling (SEM), we calculated latent difference scores of parietal/non-parietal WMH, hippocampus volumes, and cortical thickness values in AD-related regions. Within the SEM 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, in addition to degenerative changes in the medial temporal lobe, predict AD onset in addition to hallmark neurodegenerative changes typically associated with AD. PMID:25155654

  3. 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

  4. Weight Loss Predicts Progression of Mild Cognitive Impairment to Alzheimer’s Disease

    PubMed Central

    Cova, Ilaria; Rossi, Annalia; Cucumo, Valentina; Ghiretti, Roberta; Maggiore, Laura; Pomati, Simone; Galimberti, Daniela; Scarpini, Elio; Mariani, Claudio; Caracciolo, Barbara

    2016-01-01

    Background Weight loss is common in people with Alzheimer’s disease (AD) and it could be a marker of impending AD in Mild Cognitive Impairment (MCI) and improve prognostic accuracy, if accelerated progression to AD would be shown. Aims To assess weight loss as a predictor of dementia and AD in MCI. Methods One hundred twenty-five subjects with MCI (age 73.8 ± 7.1 years) were followed for an average of 4 years. Two weight measurements were carried out at a minimum time interval of one year. Dementia was defined according to DSM-IV criteria and AD according to NINCDS-ADRDA criteria. Weight loss was defined as a ≥4% decrease in baseline weight. Results Fifty-three (42.4%) MCI progressed to dementia, which was of the AD-type in half of the cases. Weight loss was associated with a 3.4-fold increased risk of dementia (95% CI = 1.5–6.9) and a 3.2-fold increased risk of AD (95% CI = 1.4–8.3). In terms of years lived without disease, weight loss was associated to a 2.3 and 2.5 years earlier onset of dementia and AD. Conclusions Accelerated progression towards dementia and AD is expected when weight loss is observed in MCI patients. Weight should be closely monitored in elderly with mild cognitive impairment. PMID:26990757

  5. "It's Back! My Remission Is Over": Online Communication of Disease Progression Among Adolescents With Cancer.

    PubMed

    Keim-Malpass, Jessica; Stegenga, Kristin; Loudin, Beth; Kennedy, Christine; Kools, Susan

    2016-05-01

    Cancer in adolescence presents unique challenges to patients and families due to the dramatic physical and psychological vulnerabilities that occur during a time of identity development. Additionally, adolescents who experience progression of their cancer, or failure of first-line therapies, represent an understudied group within pediatric oncology. Illness blogs offer a unique opportunity to understand the experience of a chronic or serious illness through a naturalistic and longitudinal perspective that is inherently patient centered. The purpose of this exploratory qualitative study was to describe the experiences of adolescents with cancer who experienced disease progression through analysis of their online illness blogs. Seven illness blogs written by adolescents with cancer diagnosed between the ages of 13 and 18 years were analyzed using thematic analysis. Several key themes were described among the adolescents, including normalizing the news, facing treatment failure, and reconciling chronos-the finite concept of time. These findings provide vital descriptive evidence for the experience of disease progression as described by adolescents, as well as identifying key points of further study and intervention development for nurse researchers and nurses who care for this vulnerable patient population. PMID:26483425

  6. Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression.

    PubMed

    Lindau, Alexandra; Hrdtner, Carmen; Hergeth, Sonja P; Blanz, Kelly Daryll; Dufner, Bianca; Hoppe, Natalie; Anto-Michel, Nathaly; Kornemann, Jan; Zou, Jiadai; Gerhardt, Louisa M S; Heidt, Timo; Willecke, Florian; Geis, Serjosha; Stachon, Peter; Wolf, Dennis; Libby, Peter; Swirski, Filip K; Robbins, Clinton S; McPheat, William; Hawley, Shaun; Braddock, Martin; Gilsbach, Ralf; Hein, Lutz; von Zur Mhlen, Constantin; Bode, Christoph; Zirlik, Andreas; Hilgendorf, Ingo

    2016-03-01

    Macrophages in the arterial intima sustain chronic inflammation during atherogenesis. Under hypercholesterolemic conditions murine Ly6C(high) monocytes surge in the blood and spleen, infiltrate nascent atherosclerotic plaques, and differentiate into macrophages that proliferate locally as disease progresses. Spleen tyrosine kinase (SYK) may participate in downstream signaling of various receptors that mediate these processes. We tested the effect of the SYK inhibitor fostamatinib on hypercholesterolemia-associated myelopoiesis and plaque formation in Apoe(-/-) mice during early and established atherosclerosis. Mice consuming a high cholesterol diet supplemented with fostamatinib for 8weeks developed less atherosclerosis. Histologic and flow cytometric analysis of aortic tissue showed that fostamatinib reduced the content of Ly6C(high) monocytes and macrophages. SYK inhibition limited Ly6C(high) monocytosis through interference with GM-CSF/IL-3 stimulated myelopoiesis, attenuated cell adhesion to the intimal surface, and blocked M-CSF stimulated monocyte to macrophage differentiation. In Apoe(-/-) mice with established atherosclerosis, however, fostamatinib treatment did not limit macrophage accumulation or lesion progression despite a significant reduction in blood monocyte counts, as lesional macrophages continued to proliferate. Thus, inhibition of hypercholesterolemia-associated monocytosis, monocyte infiltration, and differentiation by SYK antagonism attenuates early atherogenesis but not established disease when local macrophage proliferation dominates lesion progression. PMID:26891724

  7. 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, β-sitosterol β-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 α-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

  8. Atg4b-Dependent Autophagic Flux Alleviates Huntington’s Disease Progression

    PubMed Central

    Proenca, Catia C.; Stoehr, Natacha; Bernhard, Mario; Seger, Shanon; Genoud, Christel; Roscic, Ana; Paganetti, Paolo; Liu, Shanming; Murphy, Leon O.; Kuhn, Rainer; Bouwmeester, Tewis; Galimberti, Ivan

    2013-01-01

    The accumulation of aggregated mutant huntingtin (mHtt) inclusion bodies is involved in Huntigton’s disease (HD) progression. Medium sized-spiny neurons (MSNs) in the corpus striatum are highly vulnerable to mHtt aggregate accumulation and degeneration, but the mechanisms and pathways involved remain elusive. Here we have developed a new model to study MSNs degeneration in the context of HD. We produced organotypic cortico-striatal slice cultures (CStS) from HD transgenic mice mimicking specific features of HD progression. We then show that induction of autophagy using catalytic inhibitors of mTOR prevents MSNs degeneration in HD CStS. Furthermore, disrupting autophagic flux by overexpressing Atg4b in neurons and slice cultures, accelerated mHtt aggregation and neuronal death, suggesting that Atg4b-dependent autophagic flux influences HD progression. Under these circumstances induction of autophagy using catalytic inhibitors of mTOR was inefficient and did not affect mHtt aggregate accumulation and toxicity, indicating that mTOR inhibition alleviates HD progression by inducing Atg4b-dependent autophagic flux. These results establish modulators of Atg4b-dependent autophagic flux as new potential targets in the treatment of HD. PMID:23861892

  9. 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.

  10. 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 1-3μm 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.

  11. Potential of APDM mobility lab for the monitoring of the progression of Parkinson's disease.

    PubMed

    Mancini, Martina; Horak, Fay B

    2016-05-01

    APDM's Mobility Lab system provides portable, validated, reliable, objective measures of balance and gait that are sensitive to Parkinson's disease (PD). In this review, we describe the potential of objective measures collected with the Mobility Lab system for tracking longitudinal progression of PD. Balance and gait are among the most important motor impairments influencing quality of life for people with PD. Mobility Lab uses body-worn, Opal sensors on the legs, trunk and arms during prescribed tasks, such as the instrumented Get Up and Go test or quiet stance, to quickly quantify the quality of balance and gait in the clinical environment. The same Opal sensors can be sent home with patients to continuously monitor the quality of their daily activities. Objective measures have the potential to monitor progression of mobility impairments in PD throughout its course to improve patient care and accelerate clinical trials. PMID:26872510

  12. Proton magnetic resonance spectroscopy in Parkinson's disease and progressive supranuclear palsy.

    PubMed Central

    Federico, F; Simone, I L; Lucivero, V; De Mari, M; Giannini, P; Iliceto, G; Mezzapesa, D M; Lamberti, P

    1997-01-01

    OBJECTIVES: Proton magnetic resonance spectroscopy (1H-MRS) localised to the lentiform nucleus, was carried out in eight patients with idiopathic Parkinson's disease and five patients with progressive supranuclear palsy. The aim of the study was to assess the concentration of N-acetyl-aspartate (NAA), creatine and phosphocreatine (Cr), and choline containing compounds (Cho) in the putamen and globus pallidus of these patients. METHODS: Peak ratios obtained from patients were compared with those from nine healthy age matched controls. RESULTS: NAA/Cho and NAA/Cr ratios were reduced significantly in patients with progressive supranuclear palsy. CONCLUSION: These results suggest an NAA deficit, due to neuronal loss, in the lentiform nucleus of these patients. 1H-MRS is a non-invasive technique that can provide useful information concerning striatal neuronal loss in the basal ganglia of patients with parkinsonian syndromes. Images PMID:9069478

  13. 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

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

    PubMed

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

    2014-04-26

    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

  15. Cell cycle proteins in brain in mild cognitive impairment: insights into progression to Alzheimer disease.

    PubMed

    Keeney, Jeriel T R; Swomley, Aaron M; Harris, Jessica L; Fiorini, Ada; Mitov, Mihail I; Perluigi, Marzia; Sultana, Rukhsana; Butterfield, D Allan

    2012-10-01

    Recent studies have demonstrated the re-emergence of cell cycle proteins in brain as patients progress from the early stages of mild cognitive impairment (MCI) into Alzheimer's disease (AD). Oxidative stress markers present in AD have also been shown to be present in MCI brain suggesting that these events occur in early stages of the disease. The levels of key cell cycle proteins, such as CDK2, CDK5, cyclin G1, and BRAC1 have all been found to be elevated in MCI brain compared to age-matched control. Further, peptidyl prolyl cis-trans isomerase (Pin1), a protein that plays an important role in regulating the activity of key proteins, such as CDK5, GSK3-β, and PP2A that are involved in both the phosphorylation state of Tau and in the cell cycle, has been found to be oxidatively modified and downregulated in both AD and MCI brain. Hyperphosphorylation of Tau then results in synapse loss and the characteristic Tau aggregation as neurofibrillary tangles, an AD hallmark. In this review, we summarized the role of cell cycle dysregulation in the progression of disease from MCI to AD. Based on the current literature, it is tempting to speculate that a combination of oxidative stress and cell cycle dysfunction conceivably leads to neurodegeneration. PMID:22083458

  16. Efficient Learning of Continuous-Time Hidden Markov Models for Disease Progression

    PubMed Central

    Liu, Yu-Ying; Li, Shuang; Li, Fuxin; Song, Le; Rehg, James M.

    2016-01-01

    The Continuous-Time Hidden Markov Model (CT-HMM) is an attractive approach to modeling disease progression due to its ability to describe noisy observations arriving irregularly in time. However, the lack of an efficient parameter learning algorithm for CT-HMM restricts its use to very small models or requires unrealistic constraints on the state transitions. In this paper, we present the first complete characterization of efficient EM-based learning methods for CT-HMM models. We demonstrate that the learning problem consists of two challenges: the estimation of posterior state probabilities and the computation of end-state conditioned statistics. We solve the first challenge by reformulating the estimation problem in terms of an equivalent discrete time-inhomogeneous hidden Markov model. The second challenge is addressed by adapting three approaches from the continuous time Markov chain literature to the CT-HMM domain. We demonstrate the use of CT-HMMs with more than 100 states to visualize and predict disease progression using a glaucoma dataset and an Alzheimer’s disease dataset. PMID:27019571

  17. Is COPD a Progressive Disease? A Long Term Bode Cohort Observation

    PubMed Central

    de-Torres, Juan P.; Marín, Jose M.; Pinto-Plata, Víctor; Divo, Miguel; Sanchez-Salcedo, Pablo; Zagaceta, Jorge; Zulueta, Javier J.; Berto, Juan; Cabrera, Carlos; Celli, Bartolome R.; Casanova, Ciro

    2016-01-01

    Background The Global Initiative for Obstructive Lung Diseases (GOLD) defines COPD as a disease that is usually progressive. GOLD also provides a spirometric classification of airflow limitation. However, little is known about the long-term changes of patients in different GOLD grades. Objective Explore the proportion and characteristics of COPD patients that change their spirometric GOLD grade over long-term follow-up. Methods Patients alive for at least 8 years since recruitment and those who died with at least 4 years of repeated spirometric measurements were selected from the BODE cohort database. We purposely included the group of non survivors to avoid a “survival selection” bias. The proportion of patients that had a change (improvement or worsening) in their spirometric GOLD grading was calculated and their characteristics compared with those that remained in the same grade. Results A total of 318 patients were included in the survivor and 217 in the non-survivor groups. Nine percent of survivors and 11% of non survivors had an improvement of at least one GOLD grade. Seventy one percent of survivors and non-survivors remained in the same GOLD grade. Those that improved had a greater degree of airway obstruction at baseline. Conclusions In this selected population of COPD patients, a high proportion of patients remained in the same spirometric GOLD grade or improved in a long-term follow-up. These findings suggest that once diagnosed, COPD is usually a non-progressive disease. PMID:27100872

  18. Human Respiratory Syncytial Virus: Role of Innate Immunity in Clearance and Disease Progression.

    PubMed

    Farrag, Mohamed A; Almajhdi, Fahad N

    2016-01-01

    Human respiratory syncytial virus (HRSV) infections have worldwide records. The virus is responsible for bronchiolitis, pneumonia, and asthma in humans of different age groups. Premature infants, young children, and immunocompromised individuals are prone to severe HRSV infection that may lead to death. Based on worldwide estimations, millions of cases were reported in both developed and developing countries. In fact, HRSV symptoms develop mainly as a result of host immune response. Due to inability to establish long lasting adaptive immunity, HRSV infection is recurrent and hence impairs vaccine development. Once HRSV attached to the airway epithelia, interaction with the host innate immune components starts. HRSV interaction with pulmonary innate defenses is crucial in determining the disease outcome. Infection of alveolar epithelial cells triggers a cascade of events that lead to recruitment and activation of leukocyte populations. HRSV clearance is mediated by a number of innate leukocytes, including macrophages, natural killer cells, eosinophils, dendritic cells, and neutrophils. Regulation of these cells is mediated by cytokines, chemokines, and other immune mediators. Although the innate immune system helps to clear HRSV infection, it participates in disease progression such as bronchiolitis and asthma. Resolving the mechanisms by which HRSV induces pathogenesis, different possible interactions between the virus and immune components, and immune cells interplay are essential for developing new effective vaccines. Therefore, the current review focuses on how the pulmonary innate defenses mediate HRSV clearance and to what extent they participate in disease progression. In addition, immune responses associated with HRSV vaccines will be discussed. PMID:26679242

  19. 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

  20. The Trail Making Test in Prodromal Huntington Disease: Contributions of Disease Progression to Test Performance

    PubMed Central

    O’Rourke, Justin J.F.; Beglinger, Leigh J.; Smith, Megan M.; Mills, James; Moser, David J.; Rowe, Kelly C.; Langbehn, Douglas R.; Duff, Kevin; Stout, Julie C.; Harrington, Deborah L.; Carlozzi, Noelle; Paulsen, Jane S.

    2011-01-01

    We examined the Trail Making Test (TMT) in a sample of 767 participants with prodromal Huntington disease (prodromal HD) and 217 healthy comparisons to determine the contributions of motor, psychiatric, and cognitive changes to TMT scores. Eight traditional and derived TMT scores were also evaluated for their ability to differentiate prodromal participants closer to estimated age of diagnosis from those farther away and prodromal individuals from healthy comparisons. Results indicate that motor signs only mildly affected part A, and psychiatric symptoms did not affect either part. Tests of perceptual processing, visual scanning, and attention were primarily associated with part A, and executive functioning (response inhibition, set-shifting), processing speed, and working memory were associated with part B. Additionally, TMT scores differentiated between healthy comparisons and prodromal HD individuals as far as 9–15 years before estimated diagnosis. In participants manifesting prodromal motor signs and psychiatric symptoms, the TMT primarily measures cognition and is able to discriminate between groups based on health status and estimated time to diagnosis. PMID:21302170

  1. 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, Franois-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

  2. Molecular sampling of prostate cancer: a dilemma for predicting disease progression

    PubMed Central

    2010-01-01

    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 progression. Hence, we sought to develop a molecular panel for prostate cancer progression by reasoning that molecular profiles might further improve current clinical models. Methods We analyzed a Swedish Watchful Waiting cohort with up to 30 years of clinical follow up using a novel method for gene expression profiling. This cDNA-mediated annealing, selection, ligation, and extension (DASL) method enabled the use of formalin-fixed paraffin-embedded transurethral resection of prostate (TURP) samples taken at the time of the initial diagnosis. We determined the expression profiles of 6100 genes for 281 men divided in two extreme groups: men who died of prostate cancer and men who survived more than 10 years without metastases (lethals and indolents, respectively). Several statistical and machine learning models using clinical and molecular features were evaluated for their ability to distinguish lethal from indolent cases. Results Surprisingly, none of the predictive models using molecular profiles significantly improved over models using clinical variables only. Additional computational analysis confirmed that molecular heterogeneity within both the lethal and indolent classes is widespread in prostate cancer as compared to other types of tumors. Conclusions The determination of the molecularly dominant tumor nodule may be limited by sampling at time of initial diagnosis, may not be present at time of initial diagnosis, or may occur as the disease progresses making the development of molecular biomarkers for prostate cancer progression challenging. PMID:20233430

  3. Serum protein electrophoresis under effective control of HIV-1 disease progression

    PubMed Central

    Adedeji, Adebayo Lawrence; Adenikinju, Rufus Omotayo; Ajele, Joshua Olufemi; Olawoye, Theophilus Ladapo

    2014-01-01

    In this report, we compared the serum protein electrophoresis (SPE) patterns in a subset of HIV-1-infected subjects who did not progress to AIDS without antiretroviral treatment with those in whose control of disease progression was achieved by highly active antiretroviral therapy (HAART). SPE and immunofixation electrophoresis were performed on Helena Electrophoresis System according to manufacturer’s instructions. The percentage of SPE abnormalities, resembling chronic inflammation, was significantly higher in HIV-1-infected subject without HAART compared with those under HAART (p = 0.001). The majority of individuals under HAART showed evidence of oligoclonal bands on the γ-band against a polyclonal background compared with those without HAART but ß-γ-band bridging was more evident. Immunofixation pattern was consistent with oligoclonal hypergammaglobulinaemia of IgG kappa type, which was found to be more intense in group without HAART. HIV clinical status did not show appreciable effect on the SPE pattern in subjects without HAART. However, under effective HAART, subjects with better CD4 T-cell count were associated with higher γ-globulin band. In group without HAART, acute infection was found to be associated the higher γ-globulin fraction compared with chronic infection. The opposite was the case under effective HAART. HIV infected subjects that did not progress to AIDS were associated with markedly abnormal SPE pattern. Overall results reflect the host ability compensate defective cellular immunity in HIV-1 infection with humoral immune responses. These findings underscore the usefulness of SPE monitoring HIV disease management and identifying individuals that may not progress to full-blown AIDS in the absence of treatment. PMID:26417299

  4. TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets.

    PubMed

    Scotter, Emma L; Chen, Han-Jou; Shaw, Christopher E

    2015-04-01

    Therapeutic options for patients with amyotrophic lateral sclerosis (ALS) are currently limited. However, recent studies show that almost all cases of ALS, as well as tau-negative frontotemporal dementia (FTD), share a common neuropathology characterized by the deposition of TAR-DNA binding protein (TDP)-43-positive protein inclusions, offering an attractive target for the design and testing of novel therapeutics. Here we demonstrate how diverse environmental stressors linked to stress granule formation, as well as mutations in genes encoding RNA processing proteins and protein degradation adaptors, initiate ALS pathogenesis via TDP-43. We review the progressive development of TDP-43 proteinopathy from cytoplasmic mislocalization and misfolding through to macroaggregation and the addition of phosphate and ubiquitin moieties. Drawing from cellular and animal studies, we explore the feasibility of therapeutics that act at each point in pathogenesis, from mitigating genetic risk using antisense oligonucleotides to modulating TDP-43 proteinopathy itself using small molecule activators of autophagy, the ubiquitin-proteasome system, or the chaperone network. We present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS and frontotemporal dementia. PMID:25652699

  5. Risk Models to Predict Chronic Kidney Disease and Its Progression: A Systematic Review

    PubMed Central

    Echouffo-Tcheugui, Justin B.; Kengne, Andre P.

    2012-01-01

    Background Chronic kidney disease (CKD) is common, and associated with increased risk of cardiovascular disease and end-stage renal disease, which are potentially preventable through early identification and treatment of individuals at risk. Although risk factors for occurrence and progression of CKD have been identified, their utility for CKD risk stratification through prediction models remains unclear. We critically assessed risk models to predict CKD and its progression, and evaluated their suitability for clinical use. Methods and Findings We systematically searched MEDLINE and Embase (1 January 1980 to 20 June 2012). Dual review was conducted to identify studies that reported on the development, validation, or impact assessment of a model constructed to predict the occurrence/presence of CKD or progression to advanced stages. Data were extracted on study characteristics, risk predictors, discrimination, calibration, and reclassification performance of models, as well as validation and impact analyses. We included 26 publications reporting on 30 CKD occurrence prediction risk scores and 17 CKD progression prediction risk scores. The vast majority of CKD risk models had acceptable-to-good discriminatory performance (area under the receiver operating characteristic curve>0.70) in the derivation sample. Calibration was less commonly assessed, but overall was found to be acceptable. Only eight CKD occurrence and five CKD progression risk models have been externally validated, displaying modest-to-acceptable discrimination. Whether novel biomarkers of CKD (circulatory or genetic) can improve prediction largely remains unclear, and impact studies of CKD prediction models have not yet been conducted. Limitations of risk models include the lack of ethnic diversity in derivation samples, and the scarcity of validation studies. The review is limited by the lack of an agreed-on system for rating prediction models, and the difficulty of assessing publication bias. Conclusions The development and clinical application of renal risk scores is in its infancy; however, the discriminatory performance of existing tools is acceptable. The effect of using these models in practice is still to be explored. Please see later in the article for the Editors' Summary PMID:23185136

  6. An abnormal resting-state functional brain network indicates progression towards Alzheimer's disease.

    PubMed

    Xiang, Jie; Guo, Hao; Cao, Rui; Liang, Hong; Chen, Junjie

    2013-10-25

    Brain structure and cognitive function change in the temporal lobe, hippocampus, and prefrontal cortex of patients with mild cognitive impairment and Alzheimer's disease, and brain network-connection strength, network efficiency, and nodal attributes are abnormal. However, existing research has only analyzed the differences between these patients and normal controls. In this study, we constructed brain networks using resting-state functional MRI data that was extracted from four populations (normal controls, patients with early mild cognitive impairment, patients with late mild cognitive impairment, and patients with Alzheimer's disease) using the Alzheimer's Disease Neuroimaging Initiative data set. The aim was to analyze the characteristics of resting-state functional neural networks, and to observe mild cognitive impairment at different stages before the transformation to Alzheimer's disease. Results showed that as cognitive deficits increased across the four groups, the shortest path in the resting-state functional network gradually increased, while clustering coefficients gradually decreased. This evidence indicates that dementia is associated with a decline of brain network efficiency. In addition, the changes in functional networks revealed the progressive deterioration of network function across brain regions from healthy elderly adults to those with mild cognitive impairment and Alzheimer's disease. The alterations of node attributes in brain regions may reflect the cognitive functions in brain regions, and we speculate that early impairments in memory, hearing, and language function can eventually lead to diffuse brain injury and other cognitive impairments. PMID:25206600

  7. Estimating prevalence in single-gene kidney diseases progressing to renal failure.

    PubMed

    Levy, M; Feingold, J

    2000-09-01

    Incidence and prevalence, the measures of "frequency, " are often confused. While in a nonhereditary situation, the useful parameter is the incidence rate, evaluating the impact of an etiologic factor, it is prevalence that is considered useful in a hereditary disease. Prevalence may concern either the whole population or a fraction of this population, that is, males or females or individuals at a given age, for example, at birth. Pathologic phenotype and morbid genotype prevalences have to be clearly differentiated. In this article, we review the epidemiologic surveys allowing an estimation of the distribution of major single-gene kidney diseases progressing to renal failure in different populations. In order to compare their results, the geographic/ethnic composition of the population, the determination of its size, the choice and mode of calculation of the epidemiologic measure, the definition of the disease and modes of diagnosis, the inclusion of cases, the sources of ascertainment and the possible causes of underascertainment, and the period of time during which events were counted should be analyzed accurately. Although their impact in terms of morbidity, hospitalizations, mortality, and cost to society is high, this review shows that information on the prevalence of single-gene kidney diseases is far from complete. To date, the data essentially apply to large populations of European origin. A part of the variation among prevalence data may be due to methodological differences. Not representative are the small populations in which some rare diseases, especially recessive, are found with a high prevalence. PMID:10972657

  8. Hypovitaminosis D, neighborhood poverty, and progression of chronic kidney disease in disadvantaged populations

    PubMed Central

    Mehrotra, R; Norris, K

    2011-01-01

    In the United States, there are significant racial disparities in the incidence and prevalence of end-stage renal disease. The disparities are greatest for the Blacks and the magnitude of disparity is significantly greater than is evident from the incidence and prevalence data of end-stage renal disease – early stage chronic kidney disease is less common in Blacks and during that stage, mortality rate is significantly higher for that racial group. Recent studies have identified a genetic predisposition for non-diabetic renal disease among Blacks. However, genetic factors explain only part of the higher risk and the racial disparities are a result of a complex interplay of biology and sociology. Herein we focus on two factors and their role in explaining the higher risk for progression of chronic kidney disease among Blacks – one biologic (vitamin D deficiency) and one sociologic (neighborhood poverty). A greater Understanding of these factors is important in order to reduce the racial disparities in the United States. PMID:20979972

  9. Alzheimer's disease progression model based on integrated biomarkers and clinical measures

    PubMed Central

    Qiu, Yue; Li, Liang; Zhou, Tian-yan; Lu, Wei

    2014-01-01

    Aim: Biomarkers and image markers of Alzheimer's disease (AD), such as cerebrospinal fluid Aβ42 and p-tau, are effective predictors of cognitive decline or dementia. The aim of this study was to integrate these markers with a disease progression model and to identify their abnormal ranges. Methods: The data of 395 participants, including 86 normal subjects, 108 early mild cognitive impairment (EMCI) subjects, 120 late mild cognitive impairment (LMCI) subjects, and 81 AD subjects were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. For the participants, baseline and long-term data on cerebrospinal fluid Aβ42 and p-tau, hippocampal volume, and ADAS-cog were available. Various linear and nonlinear models were tested to determine the associations among the ratio of Aβ42 to p-tau (the Ratio), hippocampal volume and ADAS-cog. Results: The most likely models for the Ratio, hippocampal volume, and ADAS-cog (logistic, Emax, and linear models, respectively) were used to construct the final model. Baseline disease state had an impact on all the 3 endpoints (the Ratio, hippocampal volume, and ADAS-cog), while APOEε4 genotype and age only influence the Ratio and hippocampal volume. Conclusion: The Ratio can be used to identify the disease stage for an individual, and clinical measures integrated with the Ratio improve the accuracy of mild cognitive impairment (MCI) to AD conversion forecasting. PMID:25088003

  10. Association between Free Light Chain Levels, and Disease Progression and Mortality in Chronic Kidney Disease

    PubMed Central

    Desjardins, Lucie; Liabeuf, Sophie; Lenglet, Aurélie; Lemke, Horst-Dieter; Vanholder, Raymond; Choukroun, Gabriel; Massy, Ziad A.

    2013-01-01

    Immunoglobulin free light chains (FLCs) form part of the middle molecule group of uremic toxins. Accumulation of FLCs has been observed in patients with chronic kidney disease (CKD). The aim of the present study was to measure FLC levels in patients at different CKD stages and to assess putative associations between FLC levels on one hand and biochemical/clinical parameters and mortality on the other. One hundred and forty patients at CKD stages 2-5D were included in the present study. Routine clinical biochemistry assays and assays for FLC kappa (κ) and lambda (λ) and other uremic toxins were performed. Vascular calcification was evaluated using radiological techniques. The enrolled patients were prospectively monitored for mortality. Free light chain κ and λ levels were found to be elevated in CKD patients (especially in those on hemodialysis). Furthermore, FLC κ and λ levels were positively correlated with inflammation, aortic calcification and the levels of various uremic toxins levels. A multivariate linear regression analysis indicated that FLC κ and λ levels were independently associated with CKD stages and β2 microglobulin levels. Elevated FLC κ and λ levels appeared to be associated with mortality. However, this association disappeared after adjustment for a propensity score including age, CKD stage and aortic calcification. In conclusion, our results indicate that FLC κ and λ levels are elevated in CKD patients and are associated with inflammation, vascular calcification and levels of other uremic toxins. The observed link between elevated FLC levels and mortality appears to depend on other well-known factors. PMID:24217396

  11. Methylation in benign prostate and risk of disease progression in men subsequently diagnosed with prostate cancer.

    PubMed

    Rybicki, Benjamin A; Rundle, Andrew; Kryvenko, Oleksandr N; Mitrache, Nicoleta; Do, Kieu C; Jankowski, Michelle; Chitale, Dhananjay A; Trudeau, Sheri; Belinsky, Steven A; Tang, Deliang

    2016-06-15

    In DNA from prostate tumors, methylation patterns in gene promoter regions can be a biomarker for disease progression. It remains unclear whether methylation patterns in benign prostate tissue-prior to malignant transformation-may provide similar prognostic information. To determine whether early methylation events predict prostate cancer outcomes, we evaluated histologically benign prostate specimens from 353 men who eventually developed prostate cancer and received "definitive" treatment [radical prostatectomy (58%) or radiation therapy (42%)]. Cases were drawn from a large hospital-based cohort of men with benign prostate biopsy specimens collected between 1990 and 2002. Risk of disease progression associated with methylation was estimated using time-to-event analyses. Average follow-up was over 5 years; biochemical recurrence (BCR) occurred in 91 cases (26%). In White men, methylation of the APC gene was associated with increased risk of BCR, even after adjusting for standard clinical risk factors for prostate cancer progression (adjusted hazard ratio (aHR) = 2.26; 95%CI 1.23-4.16). APC methylation was most strongly associated with a significant increased risk of BCR in White men with low prostate specific antigen at cohort entry (HR = 3.66; 95%CI 1.51-8.85). In additional stratified analyses, we found that methylation of the RARB gene significantly increased risk of BCR in African American cases who demonstrated methylation of at least one of the other four genes under study (HR = 3.80; 95%CI 1.07-13.53). These findings may have implications in the early identification of aggressive prostate cancer as well as reducing unnecessary medical procedures and emotional distress for men who present with markers of indolent disease. PMID:26860439

  12. P2Y2 receptor deficiency aggravates chronic kidney disease progression

    PubMed Central

    Potthoff, Sebastian A.; Stegbauer, Johannes; Becker, Jan; Wagenhaeuser, P. Johannes; Duvnjak, Blanka; Rump, Lars C.; Vonend, Oliver

    2013-01-01

    Purinergic signaling is involved in a variety of physiological states. P2 receptors are mainly activated by adenosine triphosphate (ATP). Activation of specific P2Y receptor subtypes might influence progression of kidney disease. To investigate the in vivo effect of a particular P2 receptor subtype on chronic kidney disease progression, subtotal nephrectomy was performed on wild type (WT) and P2Y2 receptor knockout (KO) mice. During the observational period of 56 ± 2 days, survival of KO mice was inferior compared to WT mice after SNX. Subtotal nephrectomy reduced creatinine clearance in both groups of mice, but the decrease was significantly more pronounced in KO compared to WT mice (53.9 ± 7.7 vs. 84.3 ± 8.7μl/min at day 56). The KO mice also sustained a greater increase in systolic blood pressure after SNX compared to WT mice (177 ± 2 vs. 156 ± 7 mmHg) and a 2.5-fold increase in albuminuria compared to WT. In addition, WT kidneys showed a significant increase in remnant kidney mass 56 days after SNX, but significant attenuation of hypertrophy in KO mice was observed. In line with the observed hypertrophy in WT SNX mice, a significant dose-dependent increase in DNA synthesis, a marker of proliferation, was present in cultured WT glomerular epithelial cells upon ATP stimulation. Markers for tissue damage (TGF-β 1, PAI-1) and proinflammatory target genes (MCP1) were significantly upregulated in KO mice after SNX compared to WT SNX mice. In summary, deletion of the P2Y2 receptor leads to greater renal injury after SNX compared to WT mice. Higher systolic blood pressure and inability of compensatory hypertrophy in KO mice are likely causes for the accelerated progression of chronic kidney disease. PMID:24065922

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

    PubMed Central

    Verhagen, Lilly M.; Borgdorff, Martien W.; van Soolingen, Dick

    2015-01-01

    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

  14. Neutrophil gelatinase-associated lipocalin as a biomarker of disease progression in patients with chronic kidney disease

    PubMed Central

    Patel, M. L.; Sachan, R.; Verma, A.; Kamal, R.; Gupta, K. K.

    2016-01-01

    Chronic kidney disease (CKD) is associated with early mortality, decreased quality of life and increased health care expenditures. The aim of this study was to determine whether or not urinary NGAL (uNGAL) level is associated with renal damage and kidney disease progression in patients with CKD and to evaluate the predictive value of uNGAL in progression of CKD. Totally, 91 cases of CKD stage II, III, IV, and 50 age-matched healthy controls were enrolled. The follow-up end-point was 18 months; end-point of the study was progression to an estimated glomerular filtration rate (eGFR) of <15 ml/min and/or CKD stage V. Forty-five cases (49.4%) were progressors and 46 were nonprogressors. uNGAL levels were significantly higher in CKD subjects as compared to healthy controls (log 1.09 ± 0.22 μg/ml in controls versus log 1.22 ± 2.08 μg/ml in stage II, log 3.34 ± 2.74 μg/ml in stage III and log 3.70 ± 0.18 μg/ml in stage IV). Univariate Cox proportional hazards model showed that only eGFR (hazard ratio [HR]: 0.95; 95% confidence interval [CI]: 0.93–0.96; P < 0.001) and uNGAL (HR: 1.11; 95% CI: 1.01–1.20; P < 0.001) were significantly associated with end-point of CKD stage V, but multiple Cox proportional regression model showed significant association of uNGAL (HR: 1.11; 95% CI: 1.01–1.20; P < 0.001) and eGFR (HR: 0.962, 95% CI: 0.95–0.98; P < 0.001) with end-point of CKD stage V. This suggests that uNGAL would not be a simple surrogate index of baseline eGFR, but a marker of CKD progression beyond the information provided by eGFR estimation.

  15. FGF23, Albuminuria, and Disease Progression in Patients with Chronic IgA Nephropathy

    PubMed Central

    Qureshi, Abdul Rashid; Olivecrona, Sara; Gunnarsson, Iva; Jacobson, Stefan H.; Larsson, Tobias E.

    2012-01-01

    Summary Background and objectives Fibroblast growth factor-23 (FGF23) regulates mineral metabolism. Circulatory FGF23 levels are increased and predict outcomes in CKD. However, the relation of FGF23 to albuminuria and disease progression in patients with CKD and one underlying diagnosis is unknown. Design, setting, participants, & measurements Prospective, observational study in 180 patients with IgA nephropathy (IgAN), CKD stage 1–4, and median 55-month follow-up (range, 12–177 months). Primary outcomes were (1) time-averaged albuminuria, (2A) progression to CKD stage 5 or ≥50% loss of estimated GFR, (2B) progression to CKD stage 5 or ≥25% loss of estimated GFR within 10 years, and (3) annual loss of estimated GFR. Results FGF23 was independently associated with baseline and time-averaged albuminuria (change in 1 g/24 hour albuminuria per increase in log FGF23: β = 0.26; P=0.02). Log FGF23 predicted CKD progression in crude models and after adjustment for mineral metabolites (endpoints 2A and 2B). It remained significant after adjustments for age, sex, serum albumin, calcium, phosphate, parathyroid hormone, 25-hydroxyvitamin D, baseline albuminuria, baseline estimated GFR, mean arterial BP, body mass index, and angiotensin-converting enzyme inhibitors/angiotensin-receptor blocker use in endpoint 2B (hazard ratio, 2.53; P=0.02) but not endpoint 2A (hazard ratio, 2.01; P=0.43). Log FGF23 predicted annual loss of estimated GFR in the same model (change in ml/min per 1.73 m2 per increase in log FGF23, 1.50; P=0.008). Conclusions In patients with CKD and IgAN, FGF23 was associated with albuminuria and CKD progression, a finding that suggests its role as a potential biomarker in IgAN. PMID:22383747

  16. Using palliative care in progressive neuromuscular disease to maximize quality of life.

    PubMed

    Carter, Gregory T; Joyce, Nanette C; Abresch, Allison L; Smith, Amanda E; VandeKeift, Gregg K

    2012-11-01

    This article discusses the role of palliative care in the treatment pathway of patients with progressive neuromuscular disease (NDM), including amyotrophic lateral sclerosis and Duchenne muscular dystrophy (DMD). People with severe NMDs like DMD are now living much longer, well in to adulthood. This makes them suitable for the medical model of palliative care. Yet palliative medicine is a new area, especially for "adults" with DMD. Strategies for identifying the most effective modalities to alleviate suffering in patients with an NMD receiving palliative services and creating best practice standards in pain and symptom management for this patient population are discussed. PMID:23137745

  17. Involvement of ‘stress-response’ kinase pathways in Alzheimer’s disease progression

    PubMed Central

    Mairet-Coello, Georges

    2014-01-01

    Alzheimer’s disease (AD) is the most prevalent cause of dementia, affecting more than 25 million people worldwide. Current models of the pathophysiological mechanisms of AD suggest that the accumulation of soluble oligomeric forms of amyloid-β (Aβ) peptides causes early loss of excitatory synapses and impairs synaptic plasticity. The signaling pathways mediating Aβ oligomer-induced impairment of synaptic plasticity and loss of excitatory synapses are only beginning to be unraveled. Here, we review recent evidence supporting the critical contribution of conserved ‘stress-response’ kinase pathways in AD progression. PMID:24709372

  18. Progress on PEEM3 - An Aberration Corrected X-Ray PhotoemissionElectron Microscope at the ALS

    SciTech Connect

    MacDowell, Alastair A.; Feng, J.; DeMello, A.; Doran, A.; Duarte,R.; Forest, E.; Kelez, N.; Marcus, M.A.; Miller, T.; Padmore, H.A.; Raoux, S.; Robin, D.; Scholl, A.; Schlueter, R.; Schmid, P.; Stohr, J.; Wan, W.; Wei, D.H.; Wu, Y.

    2006-05-20

    A new ultrahigh-resolution photoemission electron microscope called PEEM3 is being developed and built at the Advanced Light Source (ALS). An electron mirror combined with a much-simplified magnetic dipole separator is to be used to provide simultaneous correction of spherical and chromatic aberrations. It is installed on an elliptically polarized undulator (EPU) beamline, and will be operated with very high spatial resolution and high flux to study the composition, structure, electric and magnetic properties of complex materials. The instrument has been designed and is described. The instrumental hardware is being deployed in 2 phases. The first phase is the deployment of a standard PEEM type microscope consisting of the standard linear array of electrostatic electron lenses. The second phase will be the installation of the aberration corrected upgrade to improve resolution and throughput. This paper describes progress as the instrument enters the commissioning part of the first phase.

  19. A computational method for computing an Alzheimer's disease progression score; experiments and validation with the ADNI data set.

    PubMed

    Jedynak, Bruno M; Liu, Bo; Lang, Andrew; Gel, Yulia; Prince, Jerry L

    2015-01-01

    Understanding the time-dependent changes of biomarkers related to Alzheimer's disease (AD) is a key to assessing disease progression and measuring the outcomes of disease-modifying therapies. In this article, we validate an AD progression score model which uses multiple biomarkers to quantify the AD progression of subjects following 3 assumptions: (1) there is a unique disease progression for all subjects; (2) each subject has a different age of onset and rate of progression; and (3) each biomarker is sigmoidal as a function of disease progression. Fitting the parameters of this model is a challenging problem which we approach using an alternating least squares optimization algorithm. To validate this optimization scheme under realistic conditions, we use the Alzheimer's Disease Neuroimaging Initiative cohort. With the help of Monte Carlo simulations, we show that most of the global parameters of the model are tightly estimated, thus enabling an ordering of the biomarkers that fit the model well, ordered as: the Rey auditory verbal learning test with 30 minutes delay, the sum of the 2 lateral hippocampal volumes divided by the intracranial volume, followed (by the clinical dementia rating sum of boxes score and the mini-mental state examination score) in no particular order and at last the AD assessment scale-cognitive subscale. PMID:25444605

  20. Hierarchical kernel mixture models for the prediction of AIDS disease progression using HIV structural gp120 profiles

    PubMed Central

    2010-01-01

    Changes to the glycosylation profile on HIV gp120 can influence viral pathogenesis and alter AIDS disease progression. The characterization of glycosylation differences at the sequence level is inadequate as the placement of carbohydrates is structurally complex. However, no structural framework is available to date for the study of HIV disease progression. In this study, we propose a novel machine-learning based framework for the prediction of AIDS disease progression in three stages (RP, SP, and LTNP) using the HIV structural gp120 profile. This new intelligent framework proves to be accurate and provides an important benchmark for predicting AIDS disease progression computationally. The model is trained using a novel HIV gp120 glycosylation structural profile to detect possible stages of AIDS disease progression for the target sequences of HIV+ individuals. The performance of the proposed model was compared to seven existing different machine-learning models on newly proposed gp120-Benchmark_1 dataset in terms of error-rate (MSE), accuracy (CCI), stability (STD), and complexity (TBM). The novel framework showed better predictive performance with 67.82% CCI, 30.21 MSE, 0.8 STD, and 2.62 TBM on the three stages of AIDS disease progression of 50 HIV+ individuals. This framework is an invaluable bioinformatics tool that will be useful to the clinical assessment of viral pathogenesis. PMID:21143806

  1. Calcium signalling toolkits in astrocytes and spatio-temporal progression of Alzheimer's disease.

    PubMed

    Lim, Dmitry; Rodríguez-Arellano, J J; Parpura, Vladimir; Zorec, Robert; Zeidán-Chuliá, Fares; Genazzani, Armando A; Verkhratsky, Alexei

    2016-01-01

    Pathological remodelling of astroglia represents an important component of the pathogenesis of Alzheimer's disease (AD). In AD astrocytes undergo both atrophy and reactivity; which may be specific for different stages of the disease evolution. Astroglial reactivity represents the generic defensive mechanism, and inhibition of astrogliotic response exacerbates b-amyloid pathology associated with AD. In animal models of AD astroglial reactivity is different in different brain regions, and the deficits of reactive response observed in entorhinal and prefrontal cortices may be linked to their vulnerability to AD progression. Reactive astrogliosis is linked to astroglial Ca(2+) signalling, this latter being widely regarded as a mechanism of astroglial excitability. The AD pathology evolving in animal models as well as acute or chronic exposure to β-amyloid induce pathological remodelling of Ca(2+) signalling toolkit in astrocytes. This remodelling modifies astroglial Ca(2+) signalling and may be linked to cellular mechanisms of AD pathogenesis. PMID:26567740

  2. Rapidly progressive glomerulonephritis due to coexistent anti-glomerular basement membrane disease and fibrillary glomerulonephritis

    PubMed Central

    Cheungpasitporn, Wisit; Zacharek, Claudia C.; Fervenza, Fernando C.; Cornell, Lynn D.; Sethi, Sanjeev; Herrera Hernandez, Loren P.; Nasr, Samih H.; Alexander, Mariam P.

    2016-01-01

    Anti-glomerular basement membrane (anti-GBM) disease is a major cause of rapidly progressive glomerulonephritis (RPGN). On the other hand, fibrillary glomerulonephritis (GN) typically presents as proteinuria, hematuria and renal insufficiency, but rarely as RPGN. Without electron microscopy, the diagnosis of fibrillary GN can be missed. We report a 68-year-old white woman who presented with RPGN with kidney biopsy demonstrating diffuse crescentic GN on light microscopy. By immunofluorescence, there was bright linear staining of the GBMs and smudgy mesangial staining for immunoglobulin G, C3, and kappa and lambda light chain. Electron microscopy revealed fibrillary deposits in the GBM and mesangium. A serum test for anti-GBM antibody was positive. To our knowledge, this is the first report of coexistence of fibrillary GN in a patient with anti-GBM disease. Electron microscopy is critical to identify the coexistence of other GN in patients presenting with crescentic GN. PMID:26798468

  3. 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.

  4. The Progress of Mitophagy and Related Pathogenic Mechanisms of the Neurodegenerative Diseases and Tumor

    PubMed Central

    Song, Ying; Ding, Wei; Xiao, Yan; Lu, Kong-jun

    2015-01-01

    Mitochondrion, an organelle with two layers of membrane, is extremely vital to eukaryotic cell. Its major functions are energy center and apoptosis censor inside cell. The intactness of mitochondrial membrane is important to maintain its structure and function. Mitophagy is one kind of autophagy. In recent years, studies of mitochondria have shown that mitophagy is regulated by various factors and is an important regulation mechanism for organisms to maintain their normal state. In addition, abnormal mitophagy is closely related to several neurodegenerative diseases and tumor. However, the related signal pathway and its regulation mechanism still remain unclear. As a result, summarizing the progress of mitophagy and its related pathogenic mechanism not only helps to reveal the complicated molecular mechanism, but also helps to find a new target to treat the related diseases. PMID:26779531

  5. 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.

  6. Progression of unilateral moyamoya disease resulted in spontaneous occlusion of ipsilateral cavernous dural arteriovenous fistula: Case report.

    PubMed

    Liu, Peng; Xu, Ya; Lv, Xianli; Ge, Huijian; Lv, Ming; Li, Youxiang

    2016-06-01

    The pathogenic association between cavernous dural arteriovenous fistula (CDAVF) and moyamoya disease remains unclear. This unusual case is the first report of a progression of unilateral moyamoya disease resulting in the spontaneous occlusion of ipsilateral CDAVF. A 52-year-old woman presented with two-week spontaneous exophthalmos, chemosis and tinnitus, and cerebral angiography showed a right CDAVF coexisting with ipsilateral moyamoya disease. Transvenous approaches through the inferior petrosal sinus and facial vein were attempted but failed. However, a progression of the moyamoya disease and disappearance of the CDAVF were observed on one month follow-up angiogram in accordance with the resolution of clinical symptoms. This extremely rare coincidental presentation may have deeper pathogenic implications. This case report may give a clue to the underlying mechanism of the progression of moyamoya disease and occlusion of the CDAVF. PMID:26916656

  7. Absence of CD14 Delays Progression of Prion Diseases Accompanied by Increased Microglial Activation

    PubMed Central

    Sakai, Keiko; Hasebe, Rie; Takahashi, Yusuke; Song, Chang-Hyun; Suzuki, Akio; Yamasaki, Takeshi

    2013-01-01

    Prion diseases are fatal neurodegenerative disorders characterized by accumulation of PrPSc, vacuolation of neurons and neuropil, astrocytosis, and microglial activation. Upregulation of gene expressions of innate immunity-related factors, including complement factors and CD14, is observed in the brains of mice infected with prions even in the early stage of infections. When CD14 knockout (CD14−/−) mice were infected intracerebrally with the Chandler and Obihiro prion strains, the mice survived longer than wild-type (WT) mice, suggesting that CD14 influences the progression of the prion disease. Immunofluorescence staining that can distinguish normal prion protein from the disease-specific form of prion protein (PrPSc) revealed that deposition of PrPSc was delayed in CD14−/− mice compared with WT mice by the middle stage of the infection. Immunohistochemical staining with Iba1, a marker for activated microglia, showed an increased microglial activation in prion-infected CD14−/− mice compared to WT mice. Interestingly, accompanied by the increased microglial activation, anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor β (TGF-β) appeared to be expressed earlier in prion-infected CD14−/− mice. In contrast, IL-1β expression appeared to be reduced in the CD14−/− mice in the early stage of infection. Double immunofluorescence staining demonstrated that CD11b- and Iba1-positive microglia mainly produced the anti-inflammatory cytokines, suggesting anti-inflammatory status of microglia in the CD14−/− mice in the early stage of infection. These results imply that CD14 plays a role in the disease progression by suppressing anti-inflammatory responses in the brain in the early stage of infection. PMID:24089559

  8. 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

  9. Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.

    PubMed

    Milanese, Marco; Giribaldi, Francesco; Melone, Marcello; Bonifacino, Tiziana; Musante, Ilaria; Carminati, Enrico; Rossi, Pia I A; Vergani, Laura; Voci, Adriana; Conti, Fiorenzo; Puliti, Aldamaria; Bonanno, Giambattista

    2014-04-01

    Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease reflecting degeneration of upper and lower motoneurons (MNs). The cause of ALS and the mechanisms of neuronal death are still largely obscure, thus impairing the establishment of efficacious therapies. Glutamate (Glu)-mediated excitotoxicity plays a major role in MN degeneration in ALS. We recently demonstrated that the activation of Group I metabotropic Glu autoreceptors, belonging to both type 1 and type 5 receptors (mGluR1 and mGluR5), at glutamatergic spinal cord nerve terminals, produces excessive Glu release in mice over-expressing human superoxide-dismutase carrying the G93A point mutation (SOD1(G93A)), a widely used animal model of human ALS. To establish whether these receptors are implicated in ALS, we generated mice expressing half dosage of mGluR1 in the SOD1(G93A) background (SOD1(G93A)Grm1(crv4/+)), by crossing the SOD1(G93A) mutant mouse with the Grm1(crv4/+) mouse, lacking mGluR1 because of a spontaneous recessive mutation. SOD1(G93A)Grm1(crv4/+) mice showed prolonged survival probability, delayed pathology onset, slower disease progression and improved motor performances compared to SOD1(G93A) mice. These effects were associated to reduction of mGluR5 expression, enhanced number of MNs, decreased astrocyte and microglia activation, normalization of metallothionein and catalase mRNA expression, reduced mitochondrial damage, and decrease of abnormal Glu release in spinal cord of SOD1(G93A)Grm1(crv4/+)compared to SOD1(G93A) mice. These results demonstrate that a lower constitutive level of mGluR1 has a significant positive impact on mice with experimental ALS, thus providing the rationale for future pharmacological approaches to ALS by selectively blocking Group I metabotropic Glu receptors. PMID:24361555

  10. Predictors of progression to severe Alzheimer’s disease in an incidence sample

    PubMed Central

    Rabins, Peter V.; Schwartz, Sarah; Black, Betty S.; Corcoran, Christopher; Fauth, Elizabeth; Mielke, Michele; Christensen, Jessica; Lyketsos, Constantine; Tschanz, JoAnn

    2013-01-01

    Background Little is known about factors influencing time to severe Alzheimer’s disease (AD). Methods Incident cases of AD in the Cache County Memory Study were identified. Severe AD was defined as Mini-Mental State Examination score of ≤10 or Clinical Dementia Rating Scale score of 3; cases with either Mini-Mental State Examination score of ≥16 or Clinical Dementia Rating <2 were not categorized as severe AD. Kaplan–Meier, log-rank tests, and Cox analyses were used to identify demographic, clinical, and genetic correlates of time to progression to severe AD. Results Sixty-eight of 335 cases of incident AD developed severe dementia. In bivariate analyses, female gender, less than high school education, at least one clinically significant Neuropsychiatric Inventory domain at baseline, and the youngest and oldest ages exhibited shorter time to severe AD. In competing risk analysis, subjects with mild or at least one clinically significant Neuropsychiatric Inventory domain score, and subjects with worse health were more likely to progress to severe dementia or death. Conclusions Demographic and clinical variables predict progression to severe AD. Further study should examine whether these relationships are causal or correlational. PMID:23123228

  11. Patterns of disease progression in type 2 and 3 SMA: Implications for clinical trials

    PubMed Central

    Mercuri, Eugenio; Finkel, Richard; Montes, Jacqueline; Mazzone, Elena S.; Sormani, Maria Pia; Main, Marion; Ramsey, Danielle; Mayhew, Anna; Glanzman, Allan M.; Dunaway, Sally; Salazar, Rachel; Pasternak, Amy; Quigley, Janet; Pane, Marika; Pera, Maria Carmela; Scoto, Mariacristina; Messina, Sonia; Sframeli, Maria; Vita, Gian Luca; D'Amico, Adele; van den Hauwe, Marleen; Sivo, Serena; Goemans, Nathalie; Kaufmann, Petra; Darras, Basil T.; Bertini, Enrico; Muntoni, Francesco; De Vivo, Darryl C.

    2016-01-01

    The aim of the study was to establish 12-month changes in the Hammersmith Functional motor scale in a large cohort of SMA patients, to identify patterns of disease progression and the effect of different variables. 268 patients were included in this multicentric study. Their age ranged between 2.5 and 55.5 years at baseline, 68 were ambulant and 200 non-ambulant. The baseline scores ranged between 0 and 66 (mean 23.91, SD 20.09). The 12-month change was between −14 and +9 (mean −0.56, SD 2.72). Of the 268 patients, 206 (76.86%) had changes between −2 and +2 points. Ambulant and non-ambulant subjects had a different relationship between baseline values and age (p for age X ambulation interaction = 0.007). There was no association with age in ambulant subjects, while there was a significant heterogeneity at different age for non-ambulant patients (p < 0.001). The 12-month change (adjusted for baseline) was not associated with age in ambulant patients (p = 0.34), but it was significantly different among various age groups in non-ambulant patients. Our results suggest that there are different profiles of progression in ambulant and non-ambulant patients, and that age may play an important role in the progression of non-ambulant patients. PMID:26776503

  12. Distinctive Pattern of Serum Elements During the Progression of Alzheimer’s Disease

    PubMed Central

    Paglia, Giuseppe; Miedico, Oto; Cristofano, Adriana; Vitale, Michela; Angiolillo, Antonella; Chiaravalle, Antonio Eugenio; Corso, Gaetano; Di Costanzo, Alfonso

    2016-01-01

    Element profiling is an interesting approach for understanding neurodegenerative processes, considering that compelling evidences show that element toxicity might play a crucial role in the onset and progression of Alzheimer’s disease (AD). Aim of this study was to profile 22 serum elements in subjects with or at risk of AD. Thirtyfour patients with probable AD, 20 with mild cognitive impairment (MCI), 24 with subjective memory complaint (SMC) and 40 healthy subjects (HS) were included in the study. Manganese, iron, copper, zinc, selenium, thallium, antimony, mercury, vanadium and molybdenum changed significantly among the 4 groups. Several essential elements, such as manganese, selenium, zinc and iron tended to increase in SMC and then progressively to decrease in MCI and AD. Toxic elements show a variable behavior, since some elements tended to increase, while others tended to decrease in AD. A multivariate model, built using a panel of six essential elements (manganese, iron, copper, zinc, selenium and calcium) and their ratios, discriminated AD patients from HS with over 90% accuracy. These findings suggest that essential and toxic elements contribute to generate a distinctive signature during the progression of AD, and their monitoring in elderly might help to detect preclinical stages of AD. PMID:26957294

  13. An alternative medical approach for the neuroprotective therapy to slow the progression of Parkinson's disease.

    PubMed

    Muroyama, Akiko

    2013-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the core symptoms such as bradykinesia, resting tremor, rigidity and postural instability. Currently, pharmacotherapy and surgical approaches for the treatments of PD can only improve the neurological symptoms. Therefore, to search neuroprotective therapies using pharmacological and nonpharmacological approaches could be important to delay the progression of pathogenesis in PD. Coenzyme Q10 (CoQ10) is a component of the electron transport chain as well as an important antioxidant in mitochondrial and lipid membranes. The central role of CoQ10 in two areas implicated in the pathogenesis of PD, mitochondrial dysfunction and oxidative damages, suggest that it may be useful for treatment to slow the progression of PD. The neuroprotective effect of CoQ10 has been reported in several in vivo and in vitro models of neurodegenerative disorders. Although CoQ10 attenuated the toxin-induced reduction of dopamine content and tyrosine hydroxylase-immunoreactive neurons in the striatum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, it is still unknown how this nutrition affects the mitochondrial function. We demonstrated that oral administration of CoQ10 significantly attenuated the loss of dopaminergic nerve terminals induced by MPTP treatment. Furthermore, our experimental data indicate that an inhibition of mitochondrial cytochrome c release is one of the primary targets for CoQ10 and may lead to a potent neuroprotection. PMID:23903224

  14. Distinctive Pattern of Serum Elements During the Progression of Alzheimer's Disease.

    PubMed

    Paglia, Giuseppe; Miedico, Oto; Cristofano, Adriana; Vitale, Michela; Angiolillo, Antonella; Chiaravalle, Antonio Eugenio; Corso, Gaetano; Di Costanzo, Alfonso

    2016-01-01

    Element profiling is an interesting approach for understanding neurodegenerative processes, considering that compelling evidences show that element toxicity might play a crucial role in the onset and progression of Alzheimer's disease (AD). Aim of this study was to profile 22 serum elements in subjects with or at risk of AD. Thirtyfour patients with probable AD, 20 with mild cognitive impairment (MCI), 24 with subjective memory complaint (SMC) and 40 healthy subjects (HS) were included in the study. Manganese, iron, copper, zinc, selenium, thallium, antimony, mercury, vanadium and molybdenum changed significantly among the 4 groups. Several essential elements, such as manganese, selenium, zinc and iron tended to increase in SMC and then progressively to decrease in MCI and AD. Toxic elements show a variable behavior, since some elements tended to increase, while others tended to decrease in AD. A multivariate model, built using a panel of six essential elements (manganese, iron, copper, zinc, selenium and calcium) and their ratios, discriminated AD patients from HS with over 90% accuracy. These findings suggest that essential and toxic elements contribute to generate a distinctive signature during the progression of AD, and their monitoring in elderly might help to detect preclinical stages of AD. PMID:26957294

  15. Host-directed therapies for infectious diseases: current status, recent progress, and future prospects.

    PubMed

    Zumla, Alimuddin; Rao, Martin; Wallis, Robert S; Kaufmann, Stefan H E; Rustomjee, Roxana; Mwaba, Peter; Vilaplana, Cris; Yeboah-Manu, Dorothy; Chakaya, Jeremiah; Ippolito, Giuseppe; Azhar, Esam; Hoelscher, Michael; Maeurer, Markus

    2016-04-01

    Despite extensive global efforts in the fight against killer infectious diseases, they still cause one in four deaths worldwide and are important causes of long-term functional disability arising from tissue damage. The continuing epidemics of tuberculosis, HIV, malaria, and influenza, and the emergence of novel zoonotic pathogens represent major clinical management challenges worldwide. Newer approaches to improving treatment outcomes are needed to reduce the high morbidity and mortality caused by infectious diseases. Recent insights into pathogen-host interactions, pathogenesis, inflammatory pathways, and the host's innate and acquired immune responses are leading to identification and development of a wide range of host-directed therapies with different mechanisms of action. Host-directed therapeutic strategies are now becoming viable adjuncts to standard antimicrobial treatment. Host-directed therapies include commonly used drugs for non-communicable diseases with good safety profiles, immunomodulatory agents, biologics (eg monoclonal antibodies), nutritional products, and cellular therapy using the patient's own immune or bone marrow mesenchymal stromal cells. We discuss clinically relevant examples of progress in identifying host-directed therapies as adjunct treatment options for bacterial, viral, and parasitic infectious diseases. PMID:27036359

  16. IgM exacerbates glomerular disease progression in complement induced glomerulopathy

    PubMed Central

    Panzer, Sarah E.; Laskowski, Jennifer; Renner, Brandon; Kulik, Liudmila; Ljubanovic, Danica; Huber, Kendra M.; Zhong, Weixiong; Pickering, Matthew C.; Holers, V. Michael; Thurman, Joshua M.

    2015-01-01

    While glomerular IgM deposition occurs in a variety of glomerular diseases the mechanism of deposition and its clinical significance remain controversial. Some have theorized IgM becomes passively trapped in areas of glomerulosclerosis. However, recent studies found that IgM specifically binds damaged glomeruli. Therefore, we tested whether natural IgM binds to neo-epitopes exposed after insults to the glomerulus and exacerbate disease in mice deficient in the complement regulatory protein factor H; a model of non-sclerotic and nonimmune-complex glomerular disease. Immunofluorescence microscopy demonstrated mesangial and capillary loop deposition of IgM while ultrastructural analysis found IgM deposition on endothelial cells and subendothelial areas. Factor H deficient mice lacking B cells were protected from renal damage, as evidenced by milder histologic lesions on light and electron microscopy. IgM, but not IgG, from wild-type mice bound to cultured murine mesangial cells. Furthermore, injection of purified IgM into mice lacking B cells bound within the glomeruli and induced proteinuria. A monoclonal natural IgM recognizing phospholipids also bound to glomeruli in vivo and induced albuminuria. Thus, our results indicate specific IgM antibodies bind to glomerular epitopes and that IgM contributes to the progression of glomerular damage in this mouse model of non-sclerotic glomerular disease. PMID:25945405

  17. Current and future disease progression of the chronic HCV population in the United States.

    PubMed

    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

  18. 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 α-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 α-synuclein, transmission and toxicity, that could help to understand the pathological characteristics of PD. One important feature of α-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 α-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 α-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

  19. [Musical long-term memory throughout the progression of Alzheimer disease].

    PubMed

    Groussard, Mathilde; Mauger, Caroline; Platel, Hervé

    2013-03-01

    In Alzheimer patients with a solid musical background, isolated case-reports have reported the maintenance of remarkable musical abilities despite clear difficulties in their verbal memory and linguistic functions. These reports have encouraged a number of scientists to undertake more systematic studies which would allow a rigorous approach to the analysis of musical memory in Alzheimer patients with no formal musical background. Although restricted in number, the latest data are controversial regarding preserved musical capacities in Alzheimer patients. Our current review of the literature addresses this topic and advances the hypothesis that the processes of musical memory are function of illness progression. In the earlier stages, the majority of evaluations concerned musical episodic memory and suggested a dysfunction of this memory whereas in the moderate and severe stages, musical semantic memory and implicit learning are the majority of investigations and seemed more resistant to Alzheimer disease. In summary, our current review bring to understand the memory circuits involved and highlight the necessity to adapted the investigational tools employed to conform with the severity of the signs and symptoms of progressive Alzheimer disease in order to demonstrate the preserved musical capacities. PMID:23508326

  20. Assessing the progression of mild cognitive impairment to Alzheimer's disease: current trends and future directions.

    PubMed

    Brooks, Larry G; Loewenstein, David A

    2010-01-01

    With the advent of advances in biomarker detection and neuropsychological measurement, prospects have improved for identifying and tracking the progression of Alzheimer's disease (AD) from its earliest stages through dementia. While new diagnostic techniques have exciting implications for initiating treatment earlier in the disease process, much work remains to be done to optimize the contributions of the expanding range of tools at the disposal of researchers and clinicians. The present paper examines recent work in cerebrospinal fluid biomarkers, magnetic resonance imaging, positron emission tomography, neuropsychological measures, and functional assessment. The strengths and weaknesses of current methodologies are explored and discussed. It is concluded that AD from its mild cognitive impairment state through dementia represents a continuous process, and that progression over time can best be accomplished by interval-level variables. Biomarkers that are most sensitive to early AD may not be the most optimal for monitoring longitudinal change, and it is likely that multivariate models incorporating cognitive measures, functional variables and biomarker data will be the most fruitful avenues for future research. PMID:20920147

  1. Progression of Voice and Speech Impairment in the Course of Parkinson's Disease: A Longitudinal Study

    PubMed Central

    Skodda, S.; Grönheit, W.; Mancinelli, N.; Schlegel, U.

    2013-01-01

    Impairment of voice and speech occurs in the majority of patients in the course of Parkinson's disease (PD). The aim of the current study was to survey the changes of voice and speech performance in the individual patients over time. 80 patients with PD and 60 healthy speakers were tested and retested after at least 12 months (average time interval: 32.5 months). Participants had to read a given text which was digitally recorded as a source for the perceptual and acoustic analysis. Stage of the disease and global motor impairment were rated according to the accepted scales. As a result, abnormalities of voice and speech were already present in mildly affected patients and there were significant deteriorations of quality of voice and articulatory velocity and precision between baseline and followup examination which showed no correlation with the time interval between the visits. Summarized, voice, and speech performance were found to further deteriorate in the individual patient in the course of time although global motor impairment was widely stable which might be a hint for nondopaminergic mechanisms of progression of dysarthrophonia. Further investigations are warranted to get a better insight into the dynamics of the progression of voice and speech impairment in PD as a precondition for the development of therapeutic approaches. PMID:24386590

  2. [Urological procedures for progressive renal dysfunction due to polycystic kidney disease].

    PubMed

    Nakatani, T; Kishimoto, T; Tsujino, T; Sugimura, T; Oyama, A; Kato, T; Higashihara, E

    2000-09-01

    Urological procedures for progressive renal dysfunction due to polycystic kidney disease (PKD) such as percutaneous puncture of renal cysts are merely symptomatic treatments and have little effect on renal function. At present, the two most effective methods of preventing renal dysfunction are blood pressure management and dietetic therapy, which are more effective with early initiation. Moreover, as PKD is an autosomal dominant disease, there is a high risk that family members of the patient may have asymptomatic PKD. It is essential to identify and treat such potential patients at an early stage in order to prevent progressive renal dysfunction. In place of the traditional nephrectomy, we attempted transcutaneous renal arterial embolization (TRAE) for hemorrhage into renal cysts, hematuria and obstruction of intestine due to proliferation of cysts after the introduction of hemodialysis. When TRAE was carried out on one kidney, the cysts in the other kidney proliferated and even though the renal arteries were completely embolized, it required 5 to 6 weeks for the kidney to contract. Our conclusions are TRAE is effective with no adverse reactions for PKD. These results suggest that in the future TRAE may become the preferred treatment for PKD in place of nephrectomy. PMID:11107537

  3. 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

  4. Cytokine Response Signatures in Disease Progression and Development of Severe Clinical Outcomes for Leptospirosis

    PubMed Central

    Reis, Eliana A. G.; Hagan, Jos E.; Ribeiro, Guilherme S.; Teixeira-Carvalho, Andrea; Martins-Filho, Olindo A.; Montgomery, Ruth R.; Shaw, Albert C.; Ko, Albert I.; Reis, Mitermayer G.

    2013-01-01

    Background The role of the immune response in influencing leptospirosis clinical outcomes is not yet well understood. We hypothesized that acute-phase serum cytokine responses may play a role in disease progression, risk for death, and severe pulmonary hemorrhage syndrome (SPHS). Methodology/Principal Findings We performed a case-control study design to compare cytokine profiles in patients with mild and severe forms of leptospirosis. Among patients hospitalized with severe disease, we compared those with fatal and nonfatal outcomes. During active outpatient and hospital-based surveillance we prospectively enrolled 172 patients, 23 with mild disease (outpatient) and 149 with severe leptospirosis (hospitalized). Circulating concentrations of pro- and anti-inflammatory cytokines at the time of patient presentation were measured using a multiplex bead array assay. Concentrations of IL-1?, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17A, and TNF-? were significantly higher (P<0.05) in severe disease compared to mild disease. Among severe patients, levels of IL-6 (P<0.001), IL-8 (P?=?0.0049) and IL-10 (P<0.001), were higher in fatal compared to non-fatal cases. High levels of IL-6 and IL-10 were independently associated (P<0.05) with case fatality after adjustment for age and days of symptoms. IL-6 levels were higher (P?=?0.0519) among fatal cases who developed SPHS than among who did not. Conclusion/Significance This study shows that severe cases of leptospirosis are differentiated from mild disease by a cytokine storm process, and that IL-6 and IL-10 may play an immunopathogenic role in the development of life-threatening outcomes in human leptospirosis. PMID:24069500

  5. Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models

    PubMed Central

    Armakola, Maria; Higgins, Matthew J.; Figley, Matthew D.; Barmada, Sami J.; Scarborough, Emily A.; Diaz, Zamia; Fang, Xiaodong; Shorter, James; Krogan, Nevan J.; Finkbeiner, Steven; Farese, Robert V.; Gitler, Aaron D.

    2012-01-01

    ALS is a devastating neurodegenerative disease primarily affecting motor neurons. Mutations in TDP-43 cause some forms of the disease, and cytoplasmic TDP-43 aggregates accumulate in degenerating neurons of most ALS patients. Thus, strategies aimed at targeting the toxicity of cytoplasmic TDP-43 aggregates may be effective. Here we report results from two genome-wide loss-of-function TDP-43 toxicity suppressor screens in yeast. The strongest suppressor of TDP-43 toxicity was deletion of Dbr1, which encodes RNA lariat debranching enzyme. We show that in the absence of Dbr1 enzymatic activity intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP-43 away from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of Dbr1 in a human neuronal cell line or in primary rodent neurons is also sufficient to rescue TDP-43 toxicity. Our findings provide insight into TDP-43 cytotoxicity and suggest decreasing Dbr1 activity could be a potential therapeutic approach for ALS. PMID:23104007

  6. Embryonic Stem Cells-loaded Gelatin Microcryogels Slow Progression of Chronic Kidney Disease

    PubMed Central

    Geng, Xiao-Dong; Zheng, Wei; Wu, Cong-Mei; Wang, Shu-Qiang; Hong, Quan; Cai, Guang-Yan; Chen, Xiang-Mei; Wu, Di

    2016-01-01

    Background: Chronic kidney disease (CKD) has become a public health problem. New interventions to slow or prevent disease progression are urgently needed. In this setting, cell therapies associated with regenerative effects are attracting increasing interest. We evaluated the effect of embryonic stem cells (ESCs) on the progression of CKD. Methods: Adult male Sprague–Dawley rats were subjected to 5/6 nephrectomy. We used pedicled greater omentum flaps packing ESC-loaded gelatin microcryogels (GMs) on the 5/6 nephrectomized kidney. The viability of ESCs within the GMs was detected using in vitro two-photon fluorescence confocal imaging. Rats were sacrificed after 12 weeks. Renal injury was evaluated using serum creatinine, urea nitrogen, 24 h protein, renal pathology, and tubular injury score results. Structural damage was evaluated by periodic acid-Schiff and Masson trichrome staining. Results: In vitro, ESCs could be automatically loaded into the GMs. Uniform cell distribution, good cell attachment, and viability were achieved from day 1 to 7 in vitro. After 12 weeks, in the pedicled greater omentum flaps packing ESC-loaded GMs on 5/6 nephrectomized rats group, the plasma urea nitrogen levels were 26% lower than in the right nephrectomy group, glomerulosclerosis index was 62% lower and tubular injury index was 40% lower than in the 5/6 nephrectomized rats group without GMs. Conclusions: In a rat model of established CKD, we demonstrated that the pedicled greater omentum flaps packing ESC-loaded GMs on the 5/6 nephrectomized kidney have a long-lasting therapeutic rescue function, as shown by the decreased progression of CKD and reduced glomerular injury. PMID:26879011

  7. Physiological changes in the pallidum in a progressive model of Parkinson's disease: Are oscillations enough?

    PubMed

    Muralidharan, A; Jensen, A L; Connolly, A; Hendrix, C M; Johnson, M D; Baker, K B; Vitek, J L

    2016-05-01

    Neurophysiological changes in the basal ganglia thalamo-cortical circuit associated with the development of parkinsonian motor signs remain poorly understood. Theoretical models have ranged from those emphasizing changes in mean discharge rate to increased oscillatory activity within the beta range. The present study characterized neuronal activity within and across the internal and external segments of the globus pallidus as a function of motor severity using a staged, progressively severe 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinsonism in three rhesus monkeys. An increase in coherence between neuronal pairs across the external and internal globus pallidus was present in multiple frequency bands in the parkinsonian state; both the peak frequency of oscillatory coherence and the variability were reduced in the parkinsonian state. The incidence of 8-20Hz oscillatory activity in the internal globus pallidus increased with the progression of the disease when pooling the data across the three animals; however it did not correlate with motor severity when assessed individually and increased progressively in only one of three animals. No systematic relationship between mean discharge rates or the incidence or structure of bursting activity and motor severity was observed. These data suggest that exaggerated coupling across pallidal segments contribute to the development of the parkinsonian state by inducing an exaggerated level of synchrony and loss of focusing within the basal ganglia. These data further point to the lack of a defined relationship between rate changes, the mere presence of oscillatory activity in the beta range and bursting activity in the basal ganglia to the motor signs of Parkinson's disease. PMID:26946223

  8. 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-β1–42 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 Aβ 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

  9. Molecular evolution of human immunodeficiency virus env in humans and monkeys: similar patterns occur during natural disease progression or rapid virus passage.

    PubMed

    Hofmann-Lehmann, Regina; Vlasak, Josef; Chenine, Agnès-Laurence; Li, Pei-Lin; Baba, Timothy W; Montefiori, David C; McClure, Harold M; Anderson, Daniel C; Ruprecht, Ruth M

    2002-05-01

    Neonatal rhesus macaque 95-3 was inoculated with nonpassaged simian-human immunodeficiency virus strain SHIV-vpu(+), which encodes env of the laboratory-adapted human immunodeficiency virus (HIV) strain IIIB and is considered nonpathogenic. CD4(+) T-cell counts dropped to <200 cells/microl within 4.6 years, and monkey 95-3 died with opportunistic infections 5.9 years postinoculation. Transfer of blood from 95-3 to two naive adult macaques resulted in high peak viral loads and rapid, persistent T-cell depletion. Progeny virus evolved in 95-3 despite high SHIV-vpu(+) neutralizing antibody titers and still used CXCR4 but, in contrast to parental SHIV-vpu(+), productively infected macrophages and resisted neutralization. Sequence analysis revealed three new potential glycosylation sites in gp120; another two were lost. Strikingly similar mutations were detected in a laboratory worker who progressed to AIDS after accidental HIV-IIIB infection (T. Beaumont et al., J. Virol. 75:2246-2252, 2001), thus supporting the SHIV-vpu(+)/rhesus macaque system as a relevant model. Similar mutations were also described after rapid passage of chimeric viruses encoding IIIB env in rhesus and pig-tailed macaques (M. Cayabyab et al., J. Virol. 73:976-984, 1999; Z. Q. Liu et al., Virology 260:295-307, 1999; S. V. Narayan et al., Virology 256:54-63, 1999; R. Raghavan et al., Brain Pathol. 7:851-861, 1997; E. B. Stephens et al., Virology 231:313-321, 1997). Thus, HIV-IIIB env evolved similarly in three different species; this selection occurred in chronically infected individuals during disease progression as well as after rapid virus passage. We postulate that evolutionary pressure led to the outgrowth of more aggressive viral variants in all three species. PMID:11967343

  10. Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.

    PubMed

    Nordström, Ulrika; Beauvais, Geneviève; Ghosh, Anamitra; Pulikkaparambil Sasidharan, Baby Chakrapani; Lundblad, Martin; Fuchs, Julia; Joshi, Rajiv L; Lipton, Jack W; Roholt, Andrew; Medicetty, Satish; Feinstein, Timothy N; Steiner, Jennifer A; Escobar Galvis, Martha L; Prochiantz, Alain; Brundin, Patrik

    2015-01-01

    Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1(+/-) mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1(+/-) mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1(+/-) mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1(+/-) mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1(+/-) nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1(+/-) mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies. PMID:25281317

  11. Different decision deficits impair response inhibition in progressive supranuclear palsy and Parkinson's disease.

    PubMed

    Zhang, Jiaxiang; Rittman, Timothy; Nombela, Cristina; Fois, Alessandro; Coyle-Gilchrist, Ian; Barker, Roger A; Hughes, Laura E; Rowe, James B

    2016-01-01

    Progressive supranuclear palsy and Parkinson's disease have distinct underlying neuropathology, but both diseases affect cognitive function in addition to causing a movement disorder. They impair response inhibition and may lead to impulsivity, which can occur even in the presence of profound akinesia and rigidity. The current study examined the mechanisms of cognitive impairments underlying disinhibition, using horizontal saccadic latencies that obviate the impact of limb slowness on executing response decisions. Nineteen patients with clinically diagnosed progressive supranuclear palsy (Richardson's syndrome), 24 patients with clinically diagnosed Parkinson's disease and 26 healthy control subjects completed a saccadic Go/No-Go task with a head-mounted infrared saccadometer. Participants were cued on each trial to make a pro-saccade to a horizontal target or withhold their responses. Both patient groups had impaired behavioural performance, with more commission errors than controls. Mean saccadic latencies were similar between all three groups. We analysed behavioural responses as a binary decision between Go and No-Go choices. By using Bayesian parameter estimation, we fitted a hierarchical drift-diffusion model to individual participants' single trial data. The model decomposes saccadic latencies into parameters for the decision process: decision boundary, drift rate of accumulation, decision bias, and non-decision time. In a leave-one-out three-way classification analysis, the model parameters provided better discrimination between patients and controls than raw behavioural measures. Furthermore, the model revealed disease-specific deficits in the Go/No-Go decision process. Both patient groups had slower drift rate of accumulation, and shorter non-decision time than controls. But patients with progressive supranuclear palsy were strongly biased towards a pro-saccade decision boundary compared to Parkinson's patients and controls. This indicates a prepotency of responding in combination with a reduction in further accumulation of evidence, which provides a parsimonious explanation for the apparently paradoxical combination of disinhibition and severe akinesia. The combination of the well-tolerated oculomotor paradigm and the sensitivity of the model-based analysis provides a valuable approach for interrogating decision-making processes in neurodegenerative disorders. The mechanistic differences underlying participants' poor performance were not observable from classical analysis of behavioural data, but were clearly revealed by modelling. These differences provide a rational basis on which to develop and assess new therapeutic strategies for cognition and behaviour in these disorders. PMID:26582559

  12. M2 Macrophages Play Critical Roles in Progression of Inflammatory Liver Disease in Hepatitis C Virus Transgenic Mice

    PubMed Central

    Ohtsuki, Takahiro; Kimura, Kiminori; Tokunaga, Yuko; Tsukiyama-Kohara, Kyoko; Tateno, Chise; Hayashi, Yukiko; Hishima, Tsunekazu

    2015-01-01

    ABSTRACT Macrophages in liver tissue are widely defined as important inflammatory cells in chronic viral hepatitis due to their proinflammatory activity. We reported previously that interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-?) play significant roles in causing chronic hepatitis in hepatitis C virus (HCV) transgenic mice (S. Sekiguchi et al., PLoS One 7:e51656, 2012, http://dx.doi.org/10.1371/journal.pone.0051656). In addition, we showed that recombinant vaccinia viruses expressing an HCV nonstructural protein (rVV-N25) could protect against the progression of chronic hepatitis by suppression of macrophage activation. Here, we focus on the role of macrophages in liver disease progression in HCV transgenic mice and examine characteristic features of macrophages following rVV-N25 treatment. The number of CD11b+ F4/80+ CD11c? CD206+ (M2) macrophages in the liver of HCV transgenic mice was notably increased compared to that of age-matched control mice. These M2 macrophages in the liver produced elevated levels of IL-6 and TNF-?. rVV-N25 infection suppressed the number and activation of M2 macrophages in liver tissue. These results suggested that inflammatory cytokines produced by M2-like macrophages contribute to the induction of chronic liver inflammation in HCV transgenic mice. Moreover, the therapeutic effect of rVV-N25 might be induced by the suppression of the number and activation of hepatic macrophages. IMPORTANCE HCV causes persistent infections that can lead to chronic liver diseases, liver fibrosis, and hepatocellular carcinoma; the search for an HCV curative is the focus of ongoing research. Recently, effective anti-HCV drugs have been developed; however, vaccine development still is required for the prevention and therapy of infection by this virus. We demonstrate here that M2 macrophages are important for the pathogenesis of HCV-caused liver diseases and additionally show that M2 macrophages contribute to the therapeutic mechanism observed following rVV-N25 treatment. PMID:26468521

  13. The effect of history of injection drug use and alcoholism on HIV disease progression.

    PubMed

    Lima, Viviane Dias; Kerr, Thomas; Wood, Evan; Kozai, Tsubasa; Salters, Kate A; Hogg, Robert S; Montaner, Julio S G

    2014-01-01

    The effectiveness of highly active antiretroviral therapy (HAART) in preventing disease progression can be negatively influenced by the high prevalence of substance use among patients. Here, we quantify the effect of history of injection drug use and alcoholism on virologic and immunologic response to HAART. Clinical and survey data, collected at the start of HAART and at the interview date, were based on the study Longitudinal Investigations into Supportive and Ancillary Health Services (LISA) in British Columbia, Canada. Substance use was a three-level categorical variable, combining information on history of alcohol dependence and of injection drug use, defined as: no history of alcohol and injection drug use; history of alcohol or injection drug use; and history of both alcohol and injection drug use. Virologic response (pVL) was defined by ≥ 2 log10 copy/mL drop in a viral load. Immunologic response was defined as an increase in CD4 cell count percent of ≥ 100%. We used cumulative logit modeling for ordinal responses to address our objective. Of the 537 HIV-infected patients, 112 (21%) were characterized as having a history of both alcohol and injection drug use, 173 (32%) were nonadherent (<95%), 196 (36%) had a CD4⁺/pVL⁺ (Best) response, 180 (34%) a CD4⁺/pVL⁻ or a CD4⁻ /pVL⁺ (Incomplete) response, and 161 (30%) a CD4⁻ /pVL⁻ (Worst) response. For individuals with history of both alcohol and injection drug use, the estimated probability of non-adherence was 0.61, and (0.15, 0.25, 0.60) of Best, Incomplete and Worse responses, respectively. Screening and detection of substance dependence will identify individuals at high-risk for nonadherence and ideally prevent their HIV disease from progressing to advanced stages where HIV disease can become difficult to manage. PMID:23767757

  14. 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

  15. Sustained seizure remission on perampanel in progressive myoclonic epilepsy (Lafora disease)☆

    PubMed Central

    Schorlemmer, Kathrin; Bauer, Sebastian; Belke, Marcus; Hermsen, Anke; Klein, Karl Martin; Reif, Philipp S.; Oertel, Wolfgang H.; Kunz, Wolfram S.; Knake, Susanne; Rosenow, Felix; Strzelczyk, Adam

    2013-01-01

    Aim The aim of this report is to provide initial evidence that add-on treatment with perampanel might be highly effective in progressive myoclonic epilepsy such as Lafora disease. Case report We report on a 21-year-old woman suffering from persistent myoclonus and generalized tonic–clonic seizures for more than seven years. Additionally, ataxia, a disturbance in speech and gait, as well as a cognitive decline were rapidly progressing. Subsequently, the diagnosis of Lafora disease was confirmed by the identification of a novel homozygous missense mutation in exon 3 of the EPM2A gene (c.538C>G; p.L180V). Adjunctive therapy with perampanel was started in this patient with advanced Lafora disease and was titrated up to 8 mg/day. A sustained and reproducible remission of myoclonus and GTCS could be achieved for a follow-up of three months. After dosage reduction to 6 mg/day, seizures recurred; however, on increasing the daily dose to 10 mg, seizures stopped for another three months. The patient also regained her ability to walk with help and the aid of a walker. Conclusions Perampanel is a selective, noncompetitive antagonist of AMPA-type glutamate receptors and recently licensed as adjunctive therapy for the treatment of refractory focal onset seizures. There is evidence for its effectiveness in generalized epilepsies, and phase III studies for this indication are on the way. Our case illustrates the possibility that perampanel might be a valuable option for treatment in PME. Considering its impressive efficacy in this case, we suggest a prospective, multicenter study evaluating perampanel in PME. PMID:25667843

  16. Skin Autofluorescence Is Associated with the Progression of Chronic Kidney Disease: A Prospective Observational Study

    PubMed Central

    Tanaka, Kenichi; Nakayama, Masaaki; Kanno, Makoto; Kimura, Hiroshi; Watanabe, Kimio; Tani, Yoshihiro; Kusano, Yuki; Suzuki, Hodaka; Hayashi, Yoshimitsu; Asahi, Koichi; Sato, Keiji; Miyata, Toshio; Watanabe, Tsuyoshi

    2013-01-01

    Background Advanced glycation end product (AGE) accumulation is thought to be a measure of cumulative metabolic stress that has been reported to independently predict cardiovascular disease in diabetes and renal failure. The aim of this study was to evaluate the association between AGE accumulation, measured as skin autofluorescence, and the progression of renal disease in pre-dialysis patients with chronic kidney disease (CKD). Methods Skin autofluorescence was measured noninvasively with an autofluorescence reader at baseline in 449 pre-dialysis patients with CKD. The primary end point was defined as a doubling of serum creatinine and/or need for dialysis. Results Thirty-three patients were lost to follow-up. Forty six patients reached the primary end point during the follow-up period (Median 39 months). Kaplan-Meier analysis showed a significantly higher risk of development of the primary end points in patients with skin autofluorescence levels above the optimal cut-off level of 2.31 arbitrary units, derived by receiver operator curve analysis. Cox regression analysis revealed that skin autofluorescence was an independent predictor of the primary end point, even after adjustment for age, gender, smoking history, diabetes, estimated glomerular filtration rate and proteinuria (adjusted hazard ratio 2.58, P = 0.004). Conclusions Tissue accumulation of AGEs, measured as skin autofluorescence, is a strong and independent predictor of progression of CKD. Skin autofluorescence may be useful for risk stratification in this group of patients; further studies should clarify whether AGE accumulation could be one of the therapeutic targets to improve the prognosis of CKD. PMID:24349550

  17. Local ASIC3 modulates pain and disease progression in a rat model of osteoarthritis

    PubMed Central

    2012-01-01

    Background Recent data have suggested a relationship between acute arthritic pain and acid sensing ion channel 3 (ASIC3) on primary afferent fibers innervating joints. The purpose of this study was to clarify the role of ASIC3 in a rat model of osteoarthritis (OA) which is considered a degenerative rather than an inflammatory disease. Methods We induced OA via intra-articular mono-iodoacetate (MIA) injection, and evaluated pain-related behaviors including weight bearing measured with an incapacitance tester and paw withdrawal threshold in a von Frey hair test, histology of affected knee joint, and immunohistochemistry of knee joint afferents. We also assessed the effect of ASIC3 selective peptide blocker (APETx2) on pain behavior, disease progression, and ASIC3 expression in knee joint afferents. Results OA rats showed not only weight-bearing pain but also mechanical hyperalgesia outside the knee joint (secondary hyperalgesia). ASIC3 expression in knee joint afferents was significantly upregulated approximately twofold at Day 14. Continuous intra-articular injections of APETx2 inhibited weight distribution asymmetry and secondary hyperalgesia by attenuating ASIC3 upregulation in knee joint afferents. Histology of ipsilateral knee joint showed APETx2 worked chondroprotectively if administered in the early, but not late phase. Conclusions Local ASIC3 immunoreactive nerve is strongly associated with weight-bearing pain and secondary hyperalgesia in MIA-induced OA model. APETx2 inhibited ASIC3 upregulation in knee joint afferents regardless of the time-point of administration. Furthermore, early administration of APETx2 prevented cartilage damage. APETx2 is a novel, promising drug for OA by relieving pain and inhibiting disease progression. PMID:22909215

  18. Alterations in urine, serum and brain metabolomic profiles exhibit sexual dimorphism during malaria disease progression

    PubMed Central

    2010-01-01

    Background Metabolic changes in the host in response to Plasmodium infection play a crucial role in the pathogenesis of malaria. Alterations in metabolism of male and female mice infected with Plasmodium berghei ANKA are reported here. Methods 1H NMR spectra of urine, sera and brain extracts of these mice were analysed over disease progression using Principle Component Analysis and Orthogonal Partial Least Square Discriminant Analysis. Results Analyses of overall changes in urinary profiles during disease progression demonstrate that females show a significant early post-infection shift in metabolism as compared to males. In contrast, serum profiles of female mice remain unaltered in the early infection stages; whereas that of the male mice changed. Brain metabolite profiles do not show global changes in the early stages of infection in either sex. By the late stages urine, serum and brain profiles of both sexes are severely affected. Analyses of individual metabolites show significant increase in lactate, alanine and lysine, kynurenic acid and quinolinic acid in sera of both males and females at this stage. Early changes in female urine are marked by an increase of ureidopropionate, lowering of carnitine and transient enhancement of asparagine and dimethylglycine. Several metabolites when analysed individually in sera and brain reveal significant changes in their levels in the early phase of infection mainly in female mice. Asparagine and dimethylglycine levels decrease and quinolinic acid increases early in sera of infected females. In brain extracts of females, an early rise in levels is also observed for lactate, alanine and glycerol, kynurenic acid, ureidopropionate and 2-hydroxy-2-methylbutyrate. Conclusions These results suggest that P. berghei infection leads to impairment of glycolysis, lipid metabolism, metabolism of tryptophan and degradation of uracil. Characterization of early changes along these pathways may be crucial for prognosis and better disease management. Additionally, the distinct sexual dimorphism exhibited in these responses has a bearing on the understanding of the pathophysiology of malaria. PMID:20412601

  19. The prevalence of sickle cell disease in Abu-AL-Khasib district of southern Iraq.

    PubMed

    Alkasab, F M; Al-Alusi, F A; Adnani, M S; Alkafajei, A M; Al-Shakerchi, N H; Noori, S F

    1981-04-01

    At attempt was made to estimate the prevalence of sickle cell disease among the primary school children in Abul-al-Khasib district of southern Iraq which is known for a relatively high prevalence. Examination of 706 children in the age group of 10 to 12 years from 10 out of 20 schools randomly chosen in four villages of Abu-al-Khasib showed an overall prevalence rate of 16% as compared to 2.5% seen in a control population of 525 children belonging to five urban schools in Basrah. Sickle cell trait was evident in 13.3% of the cases. Sickledex was used for initial testing and those showing positive sickling phenomenon were confirmed by cellulose acetate haemoglobin electrophoresis. The need for introducing early screening measures as well as marriage/genetic counselling as part of the overall health and welfare services in stressed. PMID:7218407

  20. Hyperperfusion in progressive multifocal leukoencephalopathy is associated with disease progression and absence of immune reconstitution inflammatory syndrome

    PubMed Central

    Khoury, Michael N.; Gheuens, Sarah; Ngo, Long; Wang, Xiaoen; Alsop, David C.

    2013-01-01

    We sought to characterize perfusion patterns of progressive multifocal leukoencephalopathy lesions by arterial spin labelling perfusion magnetic resonance imaging and to analyse their association with immune reconstitution inflammatory syndrome, and survival. A total of 22 patients with progressive multifocal leukoencephalopathy underwent a clinical evaluation and magnetic resonance imaging of the brain within 190 days of symptom onset. The presence of immune reconstitution inflammatory syndrome was determined based on clinical and laboratory criteria. Perfusion within progressive multifocal leukoencephalopathy lesions was determined by arterial spin labelling magnetic resonance imaging. We observed intense hyperperfusion within and at the edge of progressive multifocal leukoencephalopathy lesions in a subset of subjects. This hyperperfusion was quantified by measuring the fraction of lesion volume showing perfusion in excess of twice normal appearing grey matter. Hyperperfused lesion fraction was significantly greater in progressive multifocal leukoencephalopathy progressors than in survivors (12.8% versus 3.4% P = 0.02) corresponding to a relative risk of progression for individuals with a hyperperfused lesion fraction ≥ 4.0% of 9.1 (95% confidence interval of 1.4–59.5). The presence of hyperperfusion was inversely related to the occurrence of immune reconstitution inflammatory syndrome at the time of scan (P = 0.03). Indeed, within 3 months after symptom onset, hyperperfusion had a positive predictive value of 88% for absence of immune reconstitution inflammatory syndrome. Arterial spin labelling magnetic resonance imaging recognized regions of elevated perfusion within lesions of progressive multifocal leukoencephalopathy. These regions might represent virologically active areas operating in the absence of an effective adaptive immune response and correspond with a worse prognosis. PMID:24088807

  1. Progressive Supranuclear Palsy Syndrome and Semantic Dementia in Neuropathologically Proven Lewy Body Disease: A Report of Two Cases.

    PubMed

    Lagarde, Julien; Hamelin, Lorraine; Hahn, Valé; Habert, Marie-Odile; Seilhean, Danielle; Duyckaerts, Charles; Sarazin, Marie

    2015-01-01

    The impact of neuropathological lesions on the clinical symptoms and progression of Lewy body disease (LBD) remains unclear. To address this issue, we describe two illustrative cases of autopsy-proven LBD that presented atypical phenotypes of progressive supranuclear palsy syndrome and semantic dementia. Postmortem examination revealed diffuse LBD with massive brainstem involvement in case 1, whereas Lewy bodies predominated in the amygdala and neocortex in case 2. Alzheimer's disease pathology was present in both cases, and TDP-43 inclusions were noted in case 2. These cases illustrate two contrasted clinical presentations and highlight the heterogeneity within the underlying proteinopathies of neurodegenerative diseases. PMID:26402758

  2. Crosstalk between the Unfolded Protein Response and NF-κB-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-κB. Recent studies have demonstrated that sustained activation of the unfolded protein response (UPR) can initiate this NF-κB 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-κB 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

  3. Mapping progressive brain structural changes in early Alzheimer's disease and mild cognitive impairment.

    PubMed

    Apostolova, Liana G; Thompson, Paul M

    2008-01-01

    Alzheimer's disease (AD), the most common neurodegenerative disorder of the elderly, ranks third in health care cost after heart disease and cancer. Given the disproportionate aging of the population in all developed countries, the socio-economic impact of AD will continue to rise. Mild cognitive impairment (MCI), a transitional state between normal aging and dementia, carries a four- to sixfold increased risk of future diagnosis of dementia. As complete drug-induced reversal of AD symptoms seems unlikely, researchers are now focusing on the earliest stages of AD where a therapeutic intervention is likely to realize the greatest impact. Recently neuroimaging has received significant scientific consideration as a promising in vivo disease-tracking modality that can also provide potential surrogate biomarkers for therapeutic trials. While several volumetric techniques laid the foundation of the neuroimaging research in AD and MCI, more precise computational anatomy techniques have recently become available. This new technology detects and visualizes discrete changes in cortical and hippocampal integrity and tracks the spread of AD pathology throughout the living brain. Related methods can visualize regionally specific correlations between brain atrophy and important proxy measures of disease such as neuropsychological tests, age of onset or factors that may influence disease progression. We describe extensively validated cortical and hippocampal mapping techniques that are sensitive to clinically relevant changes even in the single individual, and can identify group differences in epidemiological studies or clinical treatment trials. We give an overview of some recent neuroimaging advances in AD and MCI and discuss strengths and weaknesses of the various analytic approaches. PMID:18395760

  4. Natural history of atherosclerotic disease progression as assessed by (18)F-FDG PET/CT.

    PubMed

    Hetterich, Holger; Rominger, Axel; Walter, Lisa; Habs, Maximilian; Volpers, Sarah; Hacker, Marcus; Reiser, Maximilian F; Bartenstein, Peter; Saam, Tobias

    2016-01-01

    The aim of this study was to assess the impact of cardiovascular risk factors and plaque inflammation on the progression of atherosclerosis as assessed by positron emission tomography/computed tomography (PET/CT) imaging with (18)F-radiolabled fluorodeoxyglucose ((18)F-FDG). This study was designed as a retrospective cohort study. Patients who received a (18)F-FDG PET/CT scan and follow-up scan 9-24 months later without systemic inflammation or steroid medication were eligible for the study. (18)F-FDG PET/CT included a full diagnostic contrast enhanced CT scan. Cardiovascular risk factors and medication were documented. Calcified plaque volume, lumen area and (18)F-FDG uptake, quantified by the target-to-background ratio (TBR), were measured in the carotid arteries, aorta and iliac arteries. Influence of cardiovascular risk factors and vessel wall inflammation on atherosclerotic disease progression was analyzed. Ninety-four patients underwent baseline and follow-up whole body (18)F-FDG PET/CT (mean follow-up time 14.5 ± 3.5 months). Annualized calcified plaque volume increased by 15.4 % (p < 0.0001), carotid and aortic lumen area decreased by 10.5 % (p < 0.0001) and 1.7 % (p = 0.045). There was no significant difference in (18)F-FDG uptake at baseline and follow-up (mean TBR 1.44 ± 0.18 vs. 1.42 ± 0.19, p = 0.18). Multiple linear regression analysis identified hypertension as an independent predictor for total, aortic and iliac calcified plaque volume progression (all p < 0.04). Carotid lumen reduction was predicted by hypercholesterolemia (p = 0.008) while aortic lumen reduction was associated with BMI and mean (18)F-FDG uptake (p ≤ 0.005). Furthermore we observed a dose response relationship between the number of cardiovascular risk factors and calcified plaque volume progression in the aorta (p = 0.03). Findings from this study provide data on the natural history of atherosclerotic disease burden in multiple vascular beds and emphasize the value of morphological and physiologic information provided by (18)F-FDG PET/CT imaging. PMID:25898891

  5. 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

  6. 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

  7. Evaluation of bakanae disease progression caused by Fusarium fujikuroi in Oryza sativa L.

    PubMed

    Hwang, In Sun; Kang, Woo-Ri; Hwang, Duk-Ju; Bae, Shin-Chul; Yun, Sung-Hwan; Ahn, Il-Pyung

    2013-12-01

    Bakanae disease caused by Fusarium fujikuroi is an important fungal disease in rice. Among the seven strains isolated from symptomatic rice grains in this study, one strain, FfB14, triggered severe root growth inhibition and decay in the crown and root of rice seedlings. The remaining six strains caused typical Bakanae symptoms such as etiolation and abnormal succulent rice growth. To reveal the relationship between mycelial growth in the infected tissues and Bakanae disease progression, we have established a reliable quantification method using real time PCR that employs a primer pair and dual-labeled probe specific to a unigene encoding F. fujikuroi PNG1 (FfPNG1), which is located upstream of the fumonisin biosynthesis gene cluster. Plotting the crossing point (CP) values from the infected tissue DNAs on a standard curve revealed the active fungal growth of FfB14 in the root and crown of rice seedlings, while the growth rate of FfB20 in rice was more than 4 times lower than FfB14. Massive infective mycelial growth of FfB14 was evident in rice stems and crown; however, FfB20 did not exhibit vigorous growth. Our quantitative evaluation system is applicable for the identification of fungal virulence factors other than gibberellin. PMID:24385365

  8. 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

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

    PubMed

    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

  10. Speech disorders reflect differing pathophysiology in Parkinson's disease, progressive supranuclear palsy and multiple system atrophy.

    PubMed

    Rusz, Jan; Bonnet, Cecilia; Klempíř, Jiří; Tykalová, Tereza; Baborová, Eva; Novotný, Michal; Rulseh, Aaron; Růžička, Evžen

    2015-01-01

    Although speech disorder is frequently an early and prominent clinical feature of Parkinson's disease (PD) as well as atypical parkinsonian syndromes (APS) such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), there is a lack of objective and quantitative evidence to verify whether any specific speech characteristics allow differentiation between PD, PSP and MSA. Speech samples were acquired from 77 subjects including 15 PD, 12 PSP, 13 MSA and 37 healthy controls. The accurate differential diagnosis of dysarthria subtypes was based on the quantitative acoustic analysis of 16 speech dimensions. Dysarthria was uniformly present in all parkinsonian patients but was more severe in PSP and MSA than in PD. Whilst PD speakers manifested pure hypokinetic dysarthria, ataxic components were more affected in MSA whilst PSP subjects demonstrated severe deficits in hypokinetic and spastic elements of dysarthria. Dysarthria in PSP was dominated by increased dysfluency, decreased slow rate, inappropriate silences, deficits in vowel articulation and harsh voice quality whereas MSA by pitch fluctuations, excess intensity variations, prolonged phonemes, vocal tremor and strained-strangled voice quality. Objective speech measurements were able to discriminate between APS and PD with 95% accuracy and between PSP and MSA with 75% accuracy. Dysarthria severity in APS was related to overall disease severity (r = 0.54, p = 0.006). Dysarthria with various combinations of hypokinetic, spastic and ataxic components reflects differing pathophysiology in PD, PSP and MSA. Thus, motor speech examination may provide useful information in the evaluation of these diseases with similar manifestations. PMID:25683763

  11. Clonal evolution in chronic lymphocytic leukemia: impact of subclonality on disease progression.

    PubMed

    Sutton, Lesley-Ann; Rosenquist, Richard

    2015-02-01

    In recent years, next-generation sequencing has unraveled the molecular landscape in chronic lymphocytic leukemia with the discovery of a number of recurrently mutated genes. Mutations in several of these genes, such as NOTCH1, SF3B1 and BIRC3, are linked to a more aggressive disease with early disease progression, short time-to-first-treatment and even chemorefractoriness. Although in its infancy, we have also begun to understand the complex dynamics of subclonal diversity and its impact on disease outcome. From pioneering studies, we know that certain genetic events are found in the majority of chronic lymphocytic leukemia cells and are considered as 'clonal driver mutations' (e.g., +12, 13q-), whereas others, present only in a fraction of the tumor, are deemed to be 'subclonal driver mutations' for example, TP53 and SF3B1. Over the coming years, we need to gain a deeper insight into the dynamics of this subclonal architecture to understand how, at an individual level, chronic lymphocytic leukemia patients should be followed, which will be particularly relevant as novel targeted therapies begin to emerge. PMID:25345442

  12. Compassionate Love as a Predictor of Reduced HIV Disease Progression and Transmission Risk

    PubMed Central

    Ironson, Gail; Stuetzle, Rick; Fletcher, Mary A.

    2013-01-01

    Objectives. This study examined if compassionate love (CL) predicts HIV disease progression and transmission risk. Scientific study of CL emerged with Underwood's working model of other-centered CL, defining five criteria: free choice, cognitive understanding, valuing/empowering, openness/receptivity for spirituality, and response of the heart. Method. This 10-year cohort study collected 6-monthly interviews/essays on coping with HIV and trauma of 177 people with HIV in South Florida. Secondary qualitative content analysis on other-centered CL inductively added the component of CL towards self. Deductively, we coded the presence of the five criteria of CL and rated the benefit of CL for the recipient on a 6-point Likert scale. Growth-curve modeling (reduced to 4 years due to cohort effects) investigated if CL predicts CD4 slope (HIV disease progression) and cumulative viral load detection (transmission risk). Results. Valuing/empowering and cognitive understanding were the essential criteria for CL to confer long-term benefits. CL had a higher benefit for recipients if given out of free choice. High scores of CL towards self were reciprocal with receiving (93%) and giving (77%) other-centered CL. Conversely, those rated low on CL towards self were least likely to score high on receiving (38%) and giving (49%) other-centered CL. Growth-curve modeling showed that CL towards self predicted 4-year cumulative undetectable viral load (independent from sociocultural differences, substance use disorder, baseline CD4 and viral load). Those high versus low on CL self were 2.25 times more likely to have undetectable viral load at baseline and 1.49 times more likely to maintain undetectable viral load over time. CL towards self predicted CD4 preservation after controlling for differences in CL giving. Conclusions. CL towards self is potentially the seed of being expressive and receptive of CL. Health care professionals prepared to walk the extra mile for those who neglect and isolate themselves may break a vicious circle since those lacking CL self were least likely to receive CL from others. Future studies should examine whether any enhancement of CL towards self may translate into slower disease progression and reduction of transmission risk. PMID:24348722

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

    PubMed

    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

    2015-06-01

    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

  14. 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

  15. [Progress of ultrasound microbubble contrast technology in the diagnosis and treatment of clinical diseases].

    PubMed

    Qiu, Li; Leng, Qian-ying; Luo, Yan

    2014-11-01

    Contrast enhanced ultrasound (CEUS) technology has made important developments over the past decade. It has been applied in the clinical diagnosis for various diseases of multiple organs including liver, kidney, thyroid, breast and so on, which greatly improves the accuracy of ultrasound diagnosis. The emergence of targeted ultrasound microbubble makes ultrasound molecular imaging possible. More than the improvement of ultrasound imaging, microbubble contrast agent also could be an effective drug or gene carrier. Microbubble will rupture under the irradiation effect of local ultrasound, and then the carried drugs or genes will be released to achieve the purpose of targeted therapy. We should pay more attention on the progress of ultrasound microbubble contrast technology in clinical and basic research. It will promote better understanding and clinical applications of this novel medical ultrasound technology. PMID:25571727

  16. Disruption of brain zinc homeostasis promotes the pathophysiological progress of Alzheimer's disease.

    PubMed

    Li, Lin-Bo; Wang, Zhan-You

    2016-06-01

    Zinc is abundant in the brain, where it plays an important role in synaptic plasticity and in learning; however, excessive zinc is toxic to neuronal cells, and dyshomeostasis of zinc in the brain is a contributing factor for Alzheimer's disease (AD). Deposition of zinc has been detected in senile plaques in the form of zinc-Aβ (β-amyloid) complexes. Recent studies have demonstrated that zinc exposure to the brain enhances β-amyloid precursor protein (APP) expression, amyloidogenic APP cleavage and plaque burden. Furthermore, alterations in zinc transporters, which are responsible for zinc homeostasis, occur in AD human brain and transgenic mouse models. These suggest that abnormal brain zinc homeostasis is involved in the pathophysiological progress of AD. PMID:26883958

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

    PubMed Central

    Brosens, I.; Gordts, S.; Benagiano, G.

    2013-01-01

    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

  18. 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

  19. Phenotype Variation in Human Immunodeficiency virus Type 1 Transmission and Disease Progression

    PubMed Central

    Cavarelli, Mariangela; Scarlatti, Gabriella

    2009-01-01

    Human immunodeficiency virus type I (HIV-1) infects target cells through interaction with the CD4 molecule and chemokine receptors, mainly CCR5 and CXCR4. Viral isolates can be phenotypically classified based on the co-receptor they utilize to infect target cells. Thus, R5 and X4 virus use respectively CCR5 and CXCR4, whereas R5X4 virus can use either CCR5 or CXCR4. This review describes the central role played by co-receptor expression and usage for HIV-1 cell tropism, transmission and pathogenesis. We discuss various hypotheses proposed to explain the preferential transmission of R5 viruses and the mechanisms driving the change of HIV-1 co-receptor usage in the course of infection. Recent insights in the intrinsic variability of R5 viruses and their role in influencing disease progression in both adults and children are also discussed. PMID:19893208

  20. Substitutes for Bear Bile for the Treatment of Liver Diseases: Research Progress and Future Perspective

    PubMed Central

    Li, Sha; Tan, Hor Yue; Wang, Ning; Hong, Ming; Li, Lei; Cheung, Fan; Feng, Yibin

    2016-01-01

    Bear bile has been a well-known Chinese medicine for thousands of years. Because of the endangered species protection, the concept on substitutes for bear bile was proposed decades ago. Based on their chemical composition and pharmacologic actions, artificial bear bile, bile from other animals, synthetic compounds, and medicinal plants may be the promising candidates to replace bear bile for the similar therapeutic purpose. Accumulating research evidence has indicated that these potential substitutes for bear bile have displayed the same therapeutic effects as bear bile. However, stopping the use of bear bile is a challenging task. In this review, we extensively searched PubMed and CNKI for literatures, focusing on comparative studies between bear bile and its substitutes for the treatment of liver diseases. Recent research progress in potential substitutes for bear bile in the last decade is summarized, and a strategy for the use of substitutes for bear bile is discussed carefully. PMID:27087822

  1. Biomarkers of rapid chronic kidney disease progression in type 2 diabetes.

    PubMed

    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

    2015-10-01

    Here we evaluated the performance of a large set of serum biomarkers for the prediction of rapid progression of chronic kidney disease (CKD) in patients with type 2 diabetes. We used a case-control design nested within a prospective cohort of patients with baseline eGFR 30-60 ml/min per 1.73 m(2). Within a 3.5-year period of Go-DARTS study patients, 154 had over a 40% eGFR decline and 153 controls maintained over 95% of baseline eGFR. A total of 207 serum biomarkers were measured and logistic regression was used with forward selection to choose a subset that were maximized on top of clinical variables including age, gender, hemoglobin A1c, eGFR, and albuminuria. Nested cross-validation determined the best number of biomarkers to retain and evaluate for predictive performance. Ultimately, 30 biomarkers showed significant associations with rapid progression and adjusted for clinical characteristics. A panel of 14 biomarkers increased the area under the ROC curve from 0.706 (clinical data alone) to 0.868. Biomarkers selected included fibroblast growth factor-21, the symmetric to asymmetric dimethylarginine ratio, β2-microglobulin, C16-acylcarnitine, and kidney injury molecule-1. Use of more extensive clinical data including prebaseline eGFR slope improved prediction but to a lesser extent than biomarkers (area under the ROC curve of 0.793). Thus we identified several novel associations of biomarkers with CKD progression and the utility of a small panel of biomarkers to improve prediction. PMID:26200946

  2. 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

  3. Disease Progression in Plasmodium knowlesi Malaria Is Linked to Variation in Invasion Gene Family Members

    PubMed Central

    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

    2014-01-01

    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

  4. 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 < 0.01), Anaerococcus tetradius (P < 0.05) and Peptostreptococcus anaerobius (P < 0.05) and lower levels of Lactobacillus jensenii (P < 0.01) compared to LSIL. Our results suggest advancing CIN disease severity is associated with increasing vaginal microbiota diversity and may be involved in regulating viral persistence and disease progression. PMID:26574055

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

    PubMed

    Rojas-Rivera, Jorge; Fernndez-Jurez, Gema; Praga, Manuel

    2015-10-01

    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

  6. Contingent Negative Variation Is Associated with Cognitive Dysfunction and Secondary Progressive Disease Course in Multiple Sclerosis

    PubMed Central

    Idiman, Fethi; Idiman, Egemen; Ozakbas, Serkan; Karakas, Sirel; Bruce, Jared

    2014-01-01

    Background and Purpose The relationship between contingent negative variation (CNV), which is an event-related potential, and cognition in multiple sclerosis (MS) has not been examined previously. The primary objective of the present study was thus to determine the association between CNV and cognition in a sample of MS patients. Methods The subjects of this study comprised 66 MS patients [50 with relapsing-remitting MS (RRMS) and 16 with secondary progressive MS (SPMS)] and 40 matched healthy volunteers. A neuropsychological battery was administered to all of the subjects; CNV recordings were made from the Cz, Fz, and Pz electrodes, and the amplitude and area under the curve (AUC) were measured at each electrode. Results RRMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls at Pz. SPMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls, and CNVs with a smaller amplitude than the RRMS patients at both Cz and Pz. After correcting for multiple comparisons, a lower CNV amplitude at Pz was significantly associated with worse performance on measures of speed of information processing, verbal fluency, verbal learning, and verbal recall. Conclusions CNV may serve as a marker for disease progression and cognitive dysfunction in MS. Further studies with larger samples and wider electrode coverage are required to fully assess the value of CNV in these areas. PMID:25324878

  7. [Progress or regress or both? ESC guidelines on pericardial diseases 2015].

    PubMed

    Maisch, B

    2015-12-01

    Eleven years after the publication of the first guidelines worldwide on pericardial diseases by the European Society of Cardiology (ESC), the international expert group of the ESC has updated the original document of 28 pages with 275 references. The final version of the new guidelines is more voluminous with 44 pages of recommendations but only 233 references. A continuing medical education (CME) certified update of the 2004 guidelines was published in the journal Herz volume 7/2014. In comparison to 2004 the 2015 guidelines have remained virtually unchanged in the sections detailing diagnostics, differential diagnosis, pathology and pathophysiology. Substantial progress has been made in magnetic resonance imaging (MRI) of pericarditis and epicarditis and in the practically universal recommendation of colchicine for all forms of pericarditis and pericardial effusion, whether acute, chronic or recurrent. This can truly be called progress; however, little has changed since 2004 even in tertiary referral centers or universities with respect to the etiological classification of acute or recurrent forms of pericarditis or pericardial effusion. By classifying pericardial syndromes much too often as idiopathic when a malignant or bacterial cause has been excluded, the underlying cause is often overlooked. Standstill in diagnosis is in the end regress because we too often lag behind our actual diagnostic and interventional possibilities. PMID:26644393

  8. Demyelination in Mild Cognitive Impairment Suggests Progression Path to Alzheimer’s Disease

    PubMed Central

    Carmeli, Cristian; Donati, Alessia; Antille, Valérie; Viceic, Dragana; Ghika, Joseph; von Gunten, Armin; Clarke, Stephanie; Meuli, Reto; Frackowiak, Richard S.; Knyazeva, Maria G.

    2013-01-01

    The preclinical Alzheimer's disease (AD) - amnestic mild cognitive impairment (MCI) - is manifested by phenotypes classified into exclusively memory (single-domain) MCI (sMCI) and multiple-domain MCI (mMCI). We suggest that typical MCI-to-AD progression occurs through the sMCI-to-mMCI sequence as a result of the extension of initial pathological processes. To support this hypothesis, we assess myelin content with a Magnetization Transfer Ratio (MTR) in 21 sMCI and 21 mMCI patients and in 42 age-, sex-, and education-matched controls. A conjunction analysis revealed MTR reduction shared by sMCI and mMCI groups in the medial temporal lobe and posterior structures including white matter (WM: splenium, posterior corona radiata) and gray matter (GM: hippocampus; parahippocampal and lingual gyri). A disjunction analysis showed the spread of demyelination to prefrontal WM and insula GM in executive mMCI. Our findings suggest that demyelination starts in the structures affected by neurofibrillary pathology; its presence correlates with the clinical picture and indicates the method of MCI-to-AD progression. In vivo staging of preclinical AD can be developed in terms of WM/GM demyelination. PMID:24023644

  9. 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-1β, IL-1α, IL-12, TNF-α, 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

  10. Measuring Alzheimer Disease Progression with Transition Probabilities: Estimates from NACC-UDS

    PubMed Central

    Spackman, D.E.; Kadiyala, S.; Neumann, P.J.; Veenstra, D.L.; Sullivan, S.D.

    2013-01-01

    Objectives Estimate the probabilities, for Alzheimer's disease (AD) patients, of transitioning between stages of disease severity (mild, moderate, severe, dead) and care settings (community, institutional). Methods Data were compiled by the National Alzheimer Coordinating Center. The main analyses were limited to 3,852 patients who were >50 years old, diagnosed with possible/probable AD and had at least two center visits. A multinomial logistic model accounting for patient and center level correlation was used to calculate transition probabilities between stages of the Clinical Dementia Rating (CDR). Separately we calculated the probabilities of being institutionalized based on CDR stage. Both analyses controlled for baseline age, time between visits, sex, marital status, whether white, whether Hispanic and number of years of education. Results The annual probabilities of dying for patients in mild, moderate and severe health states were 5.5%, 21.5% and 48.0%, respectively, while the annual probabilities for institutionalization were 1.2%, 3.4% and 6.6%, respectively. The majority of mild and moderate patients remain in the same health state after one year, 77.4% and 50.1% respectively. Progressing patients are most likely to transition one stage, but 1.3% of mild patients become severe in one year. Some patients revert to lower severity stages, 7% from moderate to mild. Conclusions Transition probabilities to higher CDR stages and to institutionalization are lower than those published previously, but the probability of death is higher. These results are useful for understanding AD progression and can be used in simulation models to evaluate costs and compare new treatments or policies. PMID:22175655

  11. Can oncologists predict survival for patients with progressive disease after standard chemotherapies?

    PubMed Central

    Taniyama, T.K.; Hashimoto, K.; Katsumata, N.; Hirakawa, A.; Yonemori, K.; Yunokawa, M.; Shimizu, C.; Tamura, K.; Ando, M.; Fujiwara, Y.

    2014-01-01

    Background Prediction of prognosis is important for patients so that they can make the most of the rest of their lives. Oncologists could predict survival, but the accuracy of such predictions is unclear. Methods In this observational prospective cohort study, 14 oncologists treating 9 major adult solid malignancies were asked to complete questionnaires predicting survival based on performance status, oral intake, and other clinical factors when patients experienced progressive disease after standard chemotherapies. Clinically predicted survival (cps) was calculated by the oncologists from the date of progressive disease to the predicted date of death. Actual survival (as) was compared with cps using Kaplan–Meier survival curves, and factors affecting inaccurate prediction were determined by logistic regression analysis. The prediction of survival time was considered accurate when the cps/as ratio was between 0.67 and 1.33. Results The study cohort consisted of 75 patients. Median cps was 120 days (interquartile range: 60–180 days), and median as was 121 days (interquartile range: 40–234 days). The participating oncologists accurately predicted as within a 33% range 36% of the time; the survival time was overestimated 36% of time and underestimated 28% of the time. The factors affecting the accuracy of the survival estimate were the experience of the oncologist, patient age, and information given about the palliative care unit. Conclusions Prediction of cps was accurate for just slightly more than one third of all patients in this study. Additional investigation of putative prognostic factors with a larger sample size is warranted. PMID:24764697