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1

Kinematics of Disease Progression in Bulbar ALS  

ERIC Educational Resources Information Center

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…

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

2010-01-01

2

The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model  

PubMed Central

Mutant copper/zinc superoxide dismutase (SOD1)-overexpressing transgenic mice, a mouse model for familial amyotrophic lateral sclerosis (ALS), provides an excellent resource for developing novel therapies for ALS. Several observations suggest that mitochondria-dependent apoptotic signaling, including caspase-9 activation, may play an important role in mutant SOD1-related neurodegeneration. To elucidate the role of caspase-9 in ALS, we examined the effects of an inhibitor of X chromosome-linked inhibitor of apoptosis (XIAP), a mammalian inhibitor of caspase-3, -7 and -9, and p35, a baculoviral broad caspase inhibitor that does not inhibit caspase-9. When expressed in spinal motor neurons of mutant SOD1 mice using transgenic techniques, XIAP attenuated disease progression without delaying onset. In contrast, p35 delayed onset without slowing disease progression. Moreover, caspase-9 was activated in spinal motor neurons of human ALS subjects. These data strongly suggest that caspase-9 plays a crucial role in disease progression of ALS and constitutes a promising therapeutic target. PMID:14657037

Inoue, Haruhisa; Tsukita, Kayoko; Iwasato, Takuji; Suzuki, Yasuyuki; Tomioka, Masanori; Tateno, Minako; Nagao, Masahiro; Kawata, Akihiro; Saido, Takaomi C.; Miura, Masayuki; Misawa, Hidemi; Itohara, Shigeyoshi; Takahashi, Ryosuke

2003-01-01

3

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

PubMed Central

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

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

4

Progression of Liver Disease  

MedlinePLUS

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

5

Metabolic therapy with Deanna Protocol supplementation delays disease progression and extends survival in amyotrophic lateral sclerosis (ALS) mouse model.  

PubMed

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

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

2014-01-01

6

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

PubMed Central

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

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

2014-01-01

7

Quantifying disease progression in amyotrophic lateral sclerosis.  

PubMed

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. Ann Neurol 2014;76:643-657. PMID:25223628

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

2014-11-01

8

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

PubMed Central

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

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

2014-01-01

9

Lou Gehrig's Disease (ALS)  

MedlinePLUS

... Gehrig's disease is a disorder that's also called amyotrophic lateral sclerosis (say: ah-my-uh-TRO-fik ... spinal cord) "sclerosis" for hardening or scarring So, amyotrophic means that the muscles have lost their nourishment. ...

10

Longitudinal Relationships Between Alzheimer Disease Progression and  

E-print Network

Longitudinal Relationships Between Alzheimer Disease Progression and Psychosis, Depressed Mood characterized independent cross-sectional and longitudinal relationships between three BPSD (psychosisMental State Exam- ination, and Dependence Scale. Results: Both psychosis and depressed mood at study entry

11

Slowly progressive apraxia in Alzheimer's disease.  

PubMed Central

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

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

1995-01-01

12

Antisense peptide nucleic acid targeting GluR3 delays disease onset and progression in the SOD1 G93A mouse model of familial ALS.  

PubMed

Glutamate excitotoxicity is strongly implicated as a major contributing factor in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Excitotoxicity results from elevated intracellular calcium ion (Ca(2+)) levels, which in turn recruit cell death signaling pathways. Recent evidence suggests that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit (GluR) stoichiometry is a dominant factor leading to excess Ca(2+) loading in neurodegeneration. In particular, the Ca(2+) permeable glutamate receptor subunit 3 (GluR3) has been implicated in several neurologic conditions such as bipolar disorder and epilepsy. Recent proteomic analysis within our group on the copper zinc superoxide dismutase (SOD1)(G93A) transgenic mouse model of familial ALS (FALS) reveals a potentially deleterious upregulation of GluR3 in spinal cord compared to that in wild-type littermates. Based on this finding we designed a 12mer antisense peptide nucleic acid (PNA) directed against GluR3. This sequence significantly reduced levels of GluR3 protein and protected neuroblastoma x spinal cord (NSC-34) cells against death induced by the AMPA receptor-specific agonist (S)-5-fluorowillardiine. We subsequently treated SOD1(G93A) mice thrice weekly with intraperitoneal injections of the antisense PNA (2.5 mg/kg) commencing at postnatal day 50. Mice treated with the antisense sequence had significantly extended survival compared to mice injected with a nonsense sequence. Western blot analysis, however, did not reveal a significant reduction in GluR3 protein levels in whole extracts of the lumbar spinal cord. These results suggest that interference with the GluR3 component of the AMPA receptor assembly may be a novel strategy for controlling excitotoxic destruction of motor neurons and may lead to new therapeutic opportunities for the treatment of human ALS. PMID:15264227

Rembach, Alan; Turner, Bradley J; Bruce, Stephen; Cheah, Irwin K; Scott, Rachel L; Lopes, Elizabeth C; Zagami, Chrissandra J; Beart, Philip M; Cheung, Nam S; Langford, Steven J; Cheema, Surindar S

2004-08-15

13

Disease progression meta-analysis model in Alzheimer's disease  

Microsoft Academic Search

BackgroundVarious authors have evaluated disease progression in Alzheimer's disease (AD), using patient data from individual clinical studies or pooled data across various trials. We conducted a systematic review of public data sources from 1990 to 2008 for all available AChE inhibitor studies, as well as clinical studies that evaluated the rate of deterioration in AD patients. Unique to this analysis,

Kaori Ito; Sima Ahadieh; Brian Corrigan; Jonathan French; Terence Fullerton; Thomas Tensfeldt

2010-01-01

14

Progress in Alzheimer’s disease  

Microsoft Academic Search

After more than one century from Alois Alzheimer and Gaetano Perusini’s first report, progress has been made in understanding\\u000a the pathogenic steps of Alzheimer’s disease (AD), as well as in its early diagnosis. This review discusses recent findings\\u000a leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological\\u000a markers. In

Daniela Galimberti; Elio Scarpini

15

Al Qaeda's Scorecard: A Progress Report on Al Qaeda's Objectives  

Microsoft Academic Search

Terrorism scholars are divided over whether terrorism is an effective tactic. Disagreement derives from the fact that the objectives of terrorist groups are often highly contested. Nowhere is this clearer than in contemporary statements on Al Qaeda. This article explores the most common interpretations for why Al Qaeda attacked the United States on 11 September 2001, and then analyzes their

Max Abrahms

2006-01-01

16

Metabolome in progression to Alzheimer's disease  

Microsoft Academic Search

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

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

2011-01-01

17

The Axis of Progression of Disease  

PubMed Central

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

Tartakoff, Alan M; Wu, Di

2014-01-01

18

Targeting the Progression of Parkinson's Disease  

PubMed Central

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

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

2009-01-01

19

Al Eskan disease: Persian Gulf syndrome.  

PubMed

This article examines the potential relationship between Al Eskan disease and the Persian Gulf syndrome. Al Eskan disease, reported in Military Medicine in 1992, is a novel and previously unreported condition triggered by the exceptionally fine sand dust of the Central and Eastern Saudi Arabian peninsula. We repeat our study of the pathogenesis of Al Eskan disease to include the ultrastructural and microanalytical study of the sand, aerobiological studies of the Kingdom of Saudi Arabia, and the etiology, symptoms, and prevalence of the disease. We conclude that immunodepression resulting from the continued presence of sand particles less than 1 micron in diameter in the lungs and bodies of Persian Gulf veterans explains not only the symptoms of the hyperegic lung condition of phase I and the symptoms of phase II of Al Eskan disease, but also provides an important clue to a common factor in most cases of Persian Gulf illnesses. We include a discussion of most of the commonly suspected agents in the Persian Gulf syndrome. In this case, we conclude that each of these factors, such as oil well fires, old-world diseases, or depleted uranium, are probably adjuvant or contributing causes. The only common exposure that would lead to recognition of the Persian Gulf syndrome as a single medical condition, rather than a catch-all phrase for unrelated conditions, appears to be exposure to the ubiquitous, fine sand of the area, and a resulting immunosuppression that is aggravated by opportunistic infections and other nonmicrobial ailments. PMID:9002695

Korényi-Both, A L; Korényi-Both, A L; Juncer, D J

1997-01-01

20

Illness experience in a chronic disease--ALS  

Microsoft Academic Search

The representative case study method was used in a 1-year longitudinal study of two individuals with a chronic, degenerative, terminal neurological disease, ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig's Disease). Participants were interviewed in their homes every 2 months to examine the effects of the illness on relationships with family, friends and the health care system. Changing ideas

Ann Kuckelman Cobb; Edna Hamera

1986-01-01

21

Alcohol use accelerates HIV disease progression.  

PubMed

The effects of alcohol abuse on HIV disease progression have not been definitively established. A prospective, 30-month, longitudinal study of 231 HIV(+) adults included history of alcohol and illicit drug use, adherence to antiretroviral therapy (ART), CD4(+) cell count, and HIV viral load every 6 months. Frequent alcohol users (two or more drinks daily) were 2.91 times (95% CI: 1.23-6.85, p = 0.015) more likely to present a decline of CD4 to disease progression. The effect of alcohol on CD4(+) cell decline appears to be independent of ART, through a direct action on CD4 cells, although alcohol and substance abuse may lead to unmeasured behaviors that promote HIV disease progression. The effect of alcohol abuse on viral load, however, appears to be through reduced adherence to ART. PMID:20455765

Baum, Marianna K; Rafie, Carlin; Lai, Shenghan; Sales, Sabrina; Page, John Bryan; Campa, Adriana

2010-05-01

22

Alcohol Use Accelerates HIV Disease Progression  

PubMed Central

Abstract The effects of alcohol abuse on HIV disease progression have not been definitively established. A prospective, 30-month, longitudinal study of 231 HIV+ adults included history of alcohol and illicit drug use, adherence to antiretroviral therapy (ART), CD4+ cell count, and HIV viral load every 6 months. Frequent alcohol users (two or more drinks daily) were 2.91 times (95% CI: 1.23–6.85, p?=?0.015) more likely to present a decline of CD4 to ?200 cells/?l, independent of baseline CD4+ cell count and HIV viral load, antiretroviral use over time, time since HIV diagnosis, age, and gender. Frequent alcohol users who were not on ART also increased their risk for CD4 cell decline to ?200 cells/mm3 (HR?=?7.76: 95% CI: 1.2–49.2, p?=?0.03). Combined frequent alcohol use with crack-cocaine showed a significant risk of CD4+ cell decline (HR?=?3.57: 95% CI: 1.24–10.31, p?=?0.018). Frequent alcohol intake was associated with higher viral load over time (??=?0.259, p?=?0.038). This significance was maintained in those receiving ART (??=?0.384, p?=?0.0457), but not in those without ART. Frequent alcohol intake and the combination of frequent alcohol and crack-cocaine accelerate HIV disease progression. The effect of alcohol on CD4+ cell decline appears to be independent of ART, through a direct action on CD4 cells, although alcohol and substance abuse may lead to unmeasured behaviors that promote HIV disease progression. The effect of alcohol abuse on viral load, however, appears to be through reduced adherence to ART. PMID:20455765

Rafie, Carlin; Lai, Shenghan; Sales, Sabrina; Page, John Bryan; Campa, Adriana

2010-01-01

23

Metabolome in progression to Alzheimer's disease  

PubMed Central

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

Oresic, M; Hyotylainen, T; Herukka, S-K; Sysi-Aho, M; Mattila, I; Seppanan-Laakso, T; Julkunen, V; Gopalacharyulu, P V; Hallikainen, M; Koikkalainen, J; Kivipelto, M; Helisalmi, S; Lotjonen, J; Soininen, H

2011-01-01

24

Progressive intrahepatic cholestasis (Byler's disease): case report.  

PubMed Central

This paper reports the case of a child in which the clinical and laboratory data indicate a progressive intrahepatic cholestasis of the type described as Byler's disease. The histological and histochemical findings suggest an intrahepatic cholestasis. Electron microscopy reveals interruptions of the bile canalicular membrane, which have been described as characteristic of this disease. A striking feature in the present case is the remarkable increase of microfilamentous structures in the pericanalicular ectoplasm and in the hepatocytic cytoplasm. The findings suggest a primary disturbance in bile acid secretion as the casue of cholestasis, entailing a hypertrophy of pericanalicular microfilaments which supposedly play a role in the final step of biliary secretion. Images Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:1218817

De Vos, R; de Wolf-Peeters, C; Desmet, V; Eggermont, E; Van Acker, K

1975-01-01

25

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

PubMed

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

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

2013-01-01

26

Measuring disease progression in corticobasal syndrome.  

PubMed

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

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

2014-08-01

27

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

E-print Network

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

Perrimon, Norbert

28

Cognitive dysfunction in lower motor neuron disease: executive and memory deficits in progressive muscular atrophy  

Microsoft Academic Search

AimIn contrast with findings in amyotrophic lateral sclerosis (ALS), cognitive impairments have as yet not been shown in the lower motor neuron variant of motor neuron disease, progressive spinal muscular atrophy (PMA). The objective of this study was to investigate cognitive function in PMA and to compare the cognitive profile with that of ALS. In addition, visuospatial functions were assessed

Joost Raaphorst; Marianne de Visser; Marie-José van Tol; Wim H J P Linssen; Anneke J van der Kooi; Rob J de Haan; Leonard H van den Berg; Ben Schmand

2010-01-01

29

A Century of Progress: Milestones in Sickle Cell Disease  

E-print Network

Disease? Sickle cell disease, also known as sickle cell anemia, is inherited. People who have the disease as crises, as well as chronic damage to vital organs. Persons with sickle cell disease have life-long anemiaA Century of Progress: Milestones in Sickle Cell Disease Research and Care Introduction In 1910

Bandettini, Peter A.

30

Alzheimer disease: progress or profit? Claire Mount & Christian Downton  

E-print Network

Alzheimer disease: progress or profit? Claire Mount & Christian Downton Alzheimer disease people worldwide currently have dementia;Alzheimer disease affects about 18 million of them1. Increasing age is the greatest risk factor for Alzheimer disease. Its prevalence approxi- mately doubles every

Cai, Long

31

Electrical impedance myography as a biomarker to assess ALS progression  

PubMed Central

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

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

32

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

Microsoft Academic Search

Previous studies have shown tau pathology in the inferior colliculus (IC) and superior colliculus (SC) in Alzheimer's disease (AD); however, it has not been compared to other tauopathies, such as progressive supranuclear palsy (PSP), or characterized with respect to progression of tau pathology in AD. The main purpose of this study was to investigate frequency, neuroanatomical selectivity and disease specificity

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

2011-01-01

33

Metabolic acidosis and the progression of chronic kidney disease  

PubMed Central

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

2014-01-01

34

Posttraumatic Growth and HIV Disease Progression  

Microsoft Academic Search

The relationship between posttraumatic growth (PTG; perceiving positive changes since diagnosis) and disease status, determined by changes in viral load and CD4 count over time, was examined among 412 people living with HIV. In controlled multiple regression models, PTG was not associated with disease status over time for the entire sample. However, there were significant associations for certain subgroups. PTG

Joel Milam

2006-01-01

35

Non-suppressible secondary hyperparathyroidism in chronic progressive renal disease  

Microsoft Academic Search

Non-suppressible secondary hyperparathyroidism in chronic progressive renal disease. Secondary hyperparathyroidism is a frequent, and almost universal, concomitant of advancing chronic renal disease. When renal failure is of long standing, the degree of secondary hyperparathyroidism may be quite marked. Under such circumstances, short-term elevation of serum calcium concentration does not lead to a decrease in radioimmunoassayable parathyroid hormone to normal levels

Eduardo Slatopolsky; W Ernest Rutherford; Phillip E Hoffsten; Ivan O Elkan; Harvey R Butcher; Neal S Bricker

1972-01-01

36

Genetic susceptibility to coronary artery disease: from promise to progress  

Microsoft Academic Search

Family history is an important independent risk factor for coronary artery disease (CAD), and identification of susceptibility genes for this common, complex disease is a vital goal. Although there has been considerable success in identifying genetic variants that influence well-known risk factors, such as cholesterol levels, progress in unearthing novel CAD genes has been slow. However, advances are now being

Martin Farrall; Hugh Watkins

2006-01-01

37

Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Autosomal-dominant polycystic kidney disease results in renal failure at a varying age from childhood to old age. We postulated that factors other than the culprit gene alone contribute to the course of progression of the renal failure. We studied 580 subjects with autosomal-dominant polycystic kidney disease and 194

Patricia A Gabow; Ann M Johnson; William D Kaehny; William J Kimberling; Dennis C Lezotte; Irene T Duley; Richard H Jones

1992-01-01

38

Modeling Disease Progression via Fused Sparse Group Lasso  

PubMed Central

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

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

2013-01-01

39

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

PubMed Central

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

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

2012-01-01

40

Celiac disease: diagnostic criteria in progress  

Microsoft Academic Search

Until a few years ago, celiac disease (CD) was thought to be a rare food intolerance that was confined to childhood and characterized by severe malabsorption and flat intestinal mucosa. Currently, CD is regarded as an autoimmune disorder that is common in the general population (affecting 1 in 100 individuals), with possible onset at any age and with many possible

U Volta; V Villanacci

2011-01-01

41

Drug Development for Alzheimer's Disease: Recent Progress  

PubMed Central

Alzheimer's disease, the most common cause of dementia, is characterized by two major pathological hallmarks: amyloid plaques and neurofibrillary tangles. Based on these two indicators, an amyloid cascade hypothesis was proposed, and accordingly, most current therapeutic approaches are now focused on the removal of ?-amyloid peptides (A? from the brain. Additionally, strategies for blocking tau hyperphosphorylation and aggregation have been suggested, including the development of drugs that can block the formation of tangles. However, there are no true disease-modifying drugs in the current market, though many drugs based on theories other than A? and tau pathology are under development. The purpose of this review was to provide information on the current development of AD drugs and to discuss the issues related to drug development. PMID:22110351

Ji, Wonjin

2010-01-01

42

Alcohol's Role in HIV Transmission and Disease Progression  

PubMed Central

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

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

2010-01-01

43

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

PubMed

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

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

2014-06-01

44

Lipid-Altering Therapies and the Progression of Atherosclerotic Disease  

SciTech Connect

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.

Wierzbicki, Anthony S. [St. Thomas' Hospital, Department of Chemical Pathology (United Kingdom)], E-mail: Anthony.Wierzbicki@kcl.ac.uk

2007-04-15

45

[ALS disease modeling and drug screening using patient-specific iPS cells].  

PubMed

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which motor neuron (MN) loss in the spinal cord leads to progressive paralysis and death. Cytosolic aggregations in ALS MNs are composed of Tar DNA-binding protein-43 (TDP-43). Genetic analysis has identified more than twenty mutations of TDP-43 in ALS cases. Although accumulating evidence provides several hypotheses of disease mechanism, it is still needed to discover effective cure for ALS. We aimed to reveal cellular phenotypes in ALS MNs for identifying a drug-screening target for ALS using patient-specific induced pluripotent stem cells (iPSCs). To generate patient-specific iPSCs, dermal fibroblasts were obtained by biopsy from ALS patients carrying mutant TDP-43. The fibroblasts were reprogrammed by retrovirus or episomal vectors. Disease-specific iPSCs were differentiated into MNs expressing HB9 and SMI-32. Despite short culture period, ALS MNs recapitulated several disease phenotypes including detergent-insoluble TDP-43, shortened neurites and cellular vulnerability that observed in patient and animal models. Anacardic acid treatment reverted those phenotypes. Disease-specific iPSCs might provide a first step for drug-screening platform for ALS using patient-specific iPSCs. PMID:24291866

Egawa, Naohiro; Inoue, Haruhisa

2013-01-01

46

Imaging nigral pathology and clinical progression in Parkinson's disease  

PubMed Central

Background The pattern of dopamine cell loss in Parkinson's disease is known to be prominent in the ventrolateral and caudal substantia nigra, but less severe in the dorsal and rostral region. Both diffusion tensor imaging and R2* relaxometry of the substantia nigra have been reported as potential markers for Parkinson's disease, but their relative ability to mark disease progression and differences in pathophysiological bases remains unclear. Methods High resolution T2-weigthed, R2*, and diffusion tensor imaging were obtained from 28 controls and 40 Parkinson's disease subjects [15 early-stage (disease duration?1 year), 14 mid-stage (duration 2-5 years), and 11 late-stage (duration>5 years)]. Fractional anisotropy and R2* values in both rostral and caudal substantia nigra were obtained for all subjects, and clinical measures (disease duration; levodopa-equivalent daily dosage; “off”-drug Unified Parkinson's Disease Rating Scale motor score) were obtained for Parkinson's subjects. Results There was no correlation between fractional anisotropy and clinical measures, whereas R2* was strongly associated with disease progression. Compared to controls, fractional anisotropy in caudal substantia nigra was significantly decreased in Parkinson's disease patients of all stages, whereas in rostral substantia nigra it was decreased significantly only in the late-stage group. R2* in both substantia nigra regions was significantly increased in the mid-stage and late-stage, but not early-stage, of Parkinson's disease subjects. Conclusions These findings suggest that fractional anisotropy changes may mark early pathological changes in caudal substantia nigra, whereas the changes in R2* may more closely track Parkinson's disease's clinical progression after symptom onset. PMID:23008179

Du, Guangwei; Lewis, Mechelle M.; Sen, Suman; Wang, Jianli; Shaffer, Michele L.; Styner, Martin; Yang, Qing X.; Huang, Xuemei

2012-01-01

47

Beryllium Sensitization Progresses to Chronic Beryllium Disease A Longitudinal Study of Disease Risk  

Microsoft Academic Search

The blood beryllium lymphocyte proliferation test is used in medical surveillance to identify both beryllium sensitization and chronic beryllium disease. Approximately 50% of individuals with beryllium sensitization have chronic beryllium disease at the time of their initial clinical evaluation; however, the rate of progression from beryllium sensitization to chronic beryllium disease is unknown. We monitored a cohort of beryllium-sensitized patients

Lee S. Newman; Margaret M. Mroz; Ronald Balkissoon; Lisa A. Maier

2004-01-01

48

Rosuvastatin-Induced Arrest in Progression of Renal Disease  

Microsoft Academic Search

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

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

2004-01-01

49

Computational Approaches for Translational Clinical Research in Disease Progression  

PubMed Central

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

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

2011-01-01

50

Progression der Koronarsklerose als Monitoring des Therapieerfolgs bei Hperlipidämie  

Microsoft Academic Search

Hintergrund: Koronarkalk ist ein integraler Bestandteil der koronaren Atherosklerose, der bereits in frühen Stadien der Erkrankung durch aktiv regulierte Prozesse gebildet wird. Eine überschießende Progression von Koronarkalk (\\

Axel Schwermund; Raimund Erbel

2001-01-01

51

Predictors of autosomal dominant polycystic kidney disease progression.  

PubMed

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

Schrier, Robert W; Brosnahan, Godela; Cadnapaphornchai, Melissa A; Chonchol, Michel; Friend, Keith; Gitomer, Berenice; Rossetti, Sandro

2014-11-01

52

Striatal phosphoproteins in Parkinson disease and progressive supranuclear palsy.  

PubMed Central

This study was undertaken to evaluate the levels of cAMP-regulated phosphoproteins in the striatum of patients with neurodegenerative diseases of the dopaminergic system. Postmortem samples of caudate nucleus and putamen from 24 control subjects, 23 patients with Parkinson disease, and 13 patients with progressive supranuclear palsy were studied with immunoblotting techniques. The levels of tyrosine hydroxylase were reduced in patients with Parkinson disease (levels were 24% and 10% of controls in caudate nucleus and putamen, respectively) and with progressive supranuclear palsy (levels were 11% and 6% of controls in caudate nucleus and putamen, respectively). Five phosphoproteins, which are present in striatal neurons and are likely to play a role in the postsynaptic actions of dopamine, were measured. These included ARPP-16, ARPP-19, ARPP-21 (cAMP-regulated phosphoproteins of Mr 16,000, 19,000, and 21,000, respectively), DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32,000), and phosphatase inhibitor I. The levels of these phosphoproteins were inversely correlated with postmortem delay. In brains of patients with Parkinson disease or progressive supranuclear palsy with postmortem delays comparable to those of controls, the levels of these proteins as well as those of synaptic (synapsin I and synaptophysin) and glial (glial fibrillary acidic protein and myelin basic protein) markers were not significantly modified. We conclude that the levels of several phosphoproteins involved in signal transduction in striatal neurons are not altered in Parkinson disease and progressive supranuclear palsy. This observation supports the view that the striatal output neurons are intact in both diseases. Images PMID:2928345

Girault, J A; Raisman-Vozari, R; Agid, Y; Greengard, P

1989-01-01

53

Rapidly progressive dementias and the treatment of human prion diseases  

PubMed Central

Importance of the field Rapidly progressive dementia (RPD) has many possible etiologies and definitive treatment is reliant upon an accurate diagnosis from an appropriate diagnostic work-up. A large portion of the neurodegenerative causes of RPD are due to prion diseases (e.g., Creutzfeldt–Jakob disease). The study of prion diseases, for which there is no currently available treatment, has public health implications and is becoming increasingly more relevant to our understanding of other protein misfolding disorders including Alzheimer’s disease, frontotemporal degeneration, and Parkinson’s disease. Areas covered in this review This article begins with an overview of the etiologies and diagnostic work-up of RPD followed by a detailed review of the literature concerning the treatment of human prion diseases (1971 to present). What the reader will gain The reader will understand the differential diagnosis and work-up of RPD as it pertains to its treatment, as well as an in-depth understanding of treatments of human prion diseases. Take home message An accurate diagnosis of the cause of RPD is of paramount importance when determining appropriate treatment. Most studies of the treatment for human prion diseases are case reports or case series, and results from only one randomized, placebo-controlled study have been reported in the literature (flupirtine). Studies have been hindered by disease heterogeneity and lack of standardized outcome measures. Although no effective prion disease treatment has been revealed through these studies, they provide important considerations for future studies. PMID:21091283

Lyketsos, Constantine G

2012-01-01

54

Paediatric cholestatic liver disease: Diagnosis, assessment of disease progression and mechanisms of fibrogenesis  

PubMed Central

Cholestatic liver disease causes significant morbidity and mortality in children. The diagnosis and management of these diseases can be complicated by an inability to detect early stages of fibrosis and a lack of adequate interventional therapy. There is no single gold standard test that accurately reflects the presence of liver disease, or that can be used to monitor fibrosis progression, particularly in conditions such as cystic fibrosis. This has lead to controversy over how suspected liver disease in children is detected and diagnosed. This review discusses the challenges in using commonly available methods to diagnose hepatic fibrosis and monitor disease progression in children with cholestatic liver disease. In addition, the review examines the mechanisms hypothesised to be involved in the development of hepatic fibrogenesis in paediatric cholestatic liver injury which may ultimately aid in identifying new modalities to assist in both disease detection and therapeutic intervention. PMID:21607144

Pereira, Tamara N; Walsh, Meagan J; Lewindon, Peter J; Ramm, Grant A

2010-01-01

55

ALS: AN ETHICAL PERSPECTIVE  

Microsoft Academic Search

Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a relentlessly progressive, fatal and presently incurable motor neuron disorder caused by degeneration of both upper and lower neurons that control voluntary skeletal muscle. ALS variants include a progressive lower motor neuron disorder, Progressive Muscular Atrophy (PMA); a progressive upper motor neuron disorder, Primary Lateral Sclerosis (PLS); and a progressive disorder

Leo McCluskey

56

Naturalism about Health and Disease: Adding Nuance for Progress.  

PubMed

The literature on health and diseases is usually presented as an opposition between naturalism and normativism. This article argues that such a picture is too simplistic: there is not one opposition between naturalism and normativism, but many. I distinguish four different domains where naturalist and normativist claims can be contrasted: (1) ordinary usage, (2) conceptually clean versions of "health" and "disease," (3) the operationalization of dysfunction, and (4) the justification for that operationalization. In the process I present new arguments in response to Schwartz (2007) and Hausman (2012) and expose a link between the arguments made by Schwartz (2007) and Kingma (2010). Distinguishing naturalist claims at these four domains will allow us to make progress by (1) providing more nuanced, intermediate positions about a possible role for values in health and disease; and (2) assisting in the addressing of relativistic worries about the value-ladenness of health and disease. PMID:25376497

Kingma, Elselijn

2014-12-01

57

State-space size considerations for disease-progression models.  

PubMed

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

Regnier, Eva D; Shechter, Steven M

2013-09-30

58

Sulodexide and glycosaminoglycans in the progression of renal disease.  

PubMed

Experimental data in cell cultures and animal models suggest that sulodexide and glycosaminoglycans are potentially effective drugs to treat chronic kidney diseases and prevent progression to renal failure. However, no conclusive evidence support the use of them in human renal disease. In acute and chronic glomerulonephritis, only few studies have been performed. Sulodexide has been more intensely investigated in diabetic nephropathy (DN) where the body of data supports its effectiveness as an antialbuminuric agent in early stages. Unfortunately, there is no study in DN patients on the effect of sulodexide on clinical end points. PMID:24493873

Masola, Valentina; Zaza, Gianluigi; Gambaro, Giovanni

2014-02-01

59

A yeast functional screen predicts new candidate ALS disease genes  

PubMed Central

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery. PMID:22065782

Couthouis, Julien; Hart, Michael P.; Shorter, James; DeJesus-Hernandez, Mariely; Erion, Renske; Oristano, Rachel; Liu, Annie X.; Ramos, Daniel; Jethava, Niti; Hosangadi, Divya; Epstein, James; Chiang, Ashley; Diaz, Zamia; Nakaya, Tadashi; Ibrahim, Fadia; Kim, Hyung-Jun; Solski, Jennifer A.; Williams, Kelly L.; Mojsilovic-Petrovic, Jelena; Ingre, Caroline; Boylan, Kevin; Graff-Radford, Neill R.; Dickson, Dennis W.; Clay-Falcone, Dana; Elman, Lauren; McCluskey, Leo; Greene, Robert; Kalb, Robert G.; Lee, Virginia M.-Y.; Trojanowski, John Q.; Ludolph, Albert; Robberecht, Wim; Andersen, Peter M.; Nicholson, Garth A.; Blair, Ian P.; King, Oliver D.; Bonini, Nancy M.; Van Deerlin, Vivianna; Rademakers, Rosa; Mourelatos, Zissimos; Gitler, Aaron D.

2011-01-01

60

Evidence that soyasaponin Bb retards disease progression in a murine model of polycystic kidney disease  

Microsoft Academic Search

Evidence that soyasaponin Bb retards disease progression in a murine model of polycystic kidney disease.BackgroundWe reported a lessened cyst growth in the pcy mouse model of polycystic kidney disease (PKD) when mice were fed a soy protein isolate (SPI)–based diet and hypothesized that the soyasaponins may be associated with this therapeutic effect. The effects of feeding a saponin-enriched alcohol extract

Diana J Philbrick; Dominique P Bureau; F William Collins; Bruce J Holub

2003-01-01

61

Homeostasis of metals in the progression of Alzheimer's disease.  

PubMed

In order to study the involvement of metals in the progression of Alzheimer's disease, serum samples from patients with Alzheimer and mild cognitive impairment were investigated. For this purpose, metal content was analyzed after size-fractionation of species and then, inter-element and inter-fraction ratios were computed. In this way, the analysis allowed discovering changes that could be used as markers of disease, but also provided a new insight into the interactions in the homeostasis of elements in neurodegeneration and its progression. Aluminum and labile forms of iron and copper were increased in demented patients, while manganese, zinc and selenium were reduced. Interestingly, levels of different elements, principally iron, aluminum and manganese, were closely inter-related, which could evidence a complex interdependency between the homeostasis of the different metals in this disorder. On the other hand, imbalances in metabolism of copper, zinc and selenium could be associated to abnormal redox status. Therefore, this study may contribute to our understanding of the pathological mechanisms related to metals in Alzheimer's disease. PMID:24668390

González-Domínguez, Raúl; García-Barrera, Tamara; Gómez-Ariza, José Luis

2014-06-01

62

FoxO3a and disease progression  

PubMed Central

The Forkhead box O (FoxO) family has recently been highlighted as an important transcriptional regulator of crucial proteins associated with the many diverse functions of cells. So far, FoxO1, FoxO3a, FoxO4 and FoxO6 proteins have been identified in humans. Although each FoxO family member has its own role, unlike the other FoxO families, FoxO3a has been extensively studied because of its rather unique and pivotal regulation of cell proliferation, apoptosis, metabolism, stress management and longevity. FoxO3a alteration is closely linked to the progression of several types of cancers, fibrosis and other types of diseases. In this review, we will examine the function of FoxO3a in disease progression and also explore FoxO3a’s regulatory mechanisms. We will also discuss FoxO3a as a potential target for the treatment of several types of disease. PMID:25225602

Nho, Richard Seonghun; Hergert, Polla

2014-01-01

63

Tracking motor impairments in the progression of Huntington's disease.  

PubMed

The Unified Huntington's Disease Rating Scale is used to characterize motor impairments and establish motor diagnosis. Little is known about the timing of diagnostic confidence level categories and the trajectory of motor impairments during the prodromal phase. Goals of this study were to estimate the timing of categories, model the prodromal trajectory of motor impairments, estimate the rate of motor impairment change by category, and provide required sample size estimates for a test of efficacy in clinical trials. In total, 1010 gene-expanded participants from the Neurobiological Predictors of Huntington's Disease (PREDICT-HD) trial were analyzed. Accelerated failure time models were used to predict the timing of categories. Linear mixed effects regression was used to model the longitudinal motor trajectories. Age and length of gene expansion were incorporated into all models. The timing of categories varied significantly by gene expansion, with faster progression associated with greater expansion. For the median expansion, the third diagnostic confidence level category was estimated to have a first occurrence 1.5 years before diagnosis, and the second and first categories were estimated to occur 6.75 years and 19.75 years before diagnosis, respectively. Motor impairments displayed a nonlinear prodromal course. The motor impairment rate of change increased as the diagnostic confidence level increased, with added acceleration for higher progression scores. Motor items can detect changes in motor impairments before diagnosis. Given a sufficiently high progression score, there is evidence that the diagnostic confidence level can be used for prodromal staging. Implications for Huntington's disease research and the planning of clinical trials of efficacy are discussed. PMID:24150908

Long, Jeffery D; Paulsen, Jane S; Marder, Karen; Zhang, Ying; Kim, Ji-In; Mills, James A

2014-03-01

64

Modeling Stromal-Epithelial Interactions in Disease Progression  

PubMed Central

The role of tumor stroma in progression to malignancy has become the subject of intense experimental and clinical interest. The stromal compartment of organs is composed of all the non-epithelial cell types and maintains the proper architecture and nutrient levels required for epithelial and, ultimately, organ function. The composition of the reactive stroma surrounding tumors is vastly different from normal stromal tissue. Stromal phenotype can be correlated with, and predictive of, disease recurrence. In addition, the stroma is now seen as a legitimate target for therapeutic intervention. Although much has been learned about the role of the stromal compartment in development and disease in recent years, a number of key questions remain. Here we review how some of these questions are beginning to be addressed using new models of stromal-epithelial interaction. PMID:20587339

Strand, Douglas W.; Hayward, Simon W.

2014-01-01

65

Nicotine signaling and progression of chronic kidney disease in smokers  

PubMed Central

The deleterious health effects of cigarette smoking are far reaching, and it remains the most important modifiable risk factor for improving overall morbidity and mortality. In addition to being a risk factor for cancer, cardiovascular disease and lung disease, there is strong evidence, both from human and animal studies, demonstrating a role for cigarette smoking in the progression of chronic kidney disease (CKD). Clinical studies have shown a strong correlation between cigarette smoking and worsening CKD in patients with diabetes, hypertension, polycystic kidney disease, and post kidney transplant. Nicotine, in addition to its role in the addictive properties of cigarette smoking, has other biological effects via activation of non-neuronal nicotinic acetylcholine receptors (nAChRs). Several nAChR subunits are expressed in the normal kidney and blockade of the ?7-nAChR subunit ameliorates the effects of nicotine in animal models of CKD. Nicotine increases the severity of renal injury in animal models including acute kidney injury, diabetes, acute nephritis and subtotal nephrectomy. The renal effects of nicotine are also linked to increased generation of reactive oxygen species and activation of pro-fibrotic pathways. In humans, nicotine induces transitory increases in blood pressure accompanied by reductions in glomerular filtration rate and effective renal plasma flow. In summary, clinical and experimental evidence indicate that nicotine is at least in part responsible for the deleterious effects of cigarette smoking in the progression of CKD. The mechanisms involved are the subject of active investigation and may result in novel strategies to ameliorate the effects of cigarette smoking in CKD. PMID:23892062

Jain, Gaurav; Jaimes, Edgar A

2013-01-01

66

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

PubMed

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

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

2014-06-01

67

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

PubMed Central

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

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

2013-01-01

68

Global gene expression profile progression in Gaucher disease mouse models  

PubMed Central

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 INF?-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 INF? 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 IFN?-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

2011-01-01

69

Blood platelets in the progression of Alzheimer's disease.  

PubMed

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

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

70

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

PubMed

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

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

2011-03-17

71

Disease progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone.  

PubMed

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron cell loss, muscular atrophy, and a shortened life span. Survival is highly variable, as some patients die within months, while others live for many years. Exposure to stress or the development of a nonoptimal stress response to disease might account for some of this variability. We show in the SOD1(G93A) mouse model of ALS that recurrent exposure to restraint stress led to an earlier onset of astrogliosis and microglial activation within the spinal cord, accelerated muscular weakness, and a significant decrease in median survival (105 vs. 122 d) when compared to nonstressed animals. Moreover, during normal disease course, ALS mice display a cacostatic stress response by developing an aberrant serum corticosterone circadian rhythm. Interestingly, we also found that higher corticosterone levels were significantly correlated with both an earlier onset of paralysis (males: r(2)=0.746; females: r(2)=0.707) and shorter survival times (males: r(2)=0.680; females: r(2)=0.552) in ALS mice. These results suggest that stress is capable of accelerating disease progression and that strategies that modulate glucocorticoid metabolism might be a viable treatment approach for ALS. PMID:21876068

Fidler, Jonathan A; Treleaven, Christopher M; Frakes, Ashley; Tamsett, Thomas J; McCrate, Mary; Cheng, Seng H; Shihabuddin, Lamya S; Kaspar, Brian K; Dodge, James C

2011-12-01

72

HIV disease progression: immune activation, microbes, and a leaky gut.  

PubMed

Recent findings indicate that the majority of all CD4+ T lymphocytes are lost during acute HIV infection, with mucosal compartments being most severely affected. The frequency of infection is very high in gut CD4+ T cells, and depletion of these cells persists into the chronic phase of infection. Infection is associated with increased gut permeability, with microbial translocation being evidenced by increased circulating lipopolysaccharide (LPS) levels. Plasma LPS levels correlate with systemic immune activation, which drives chronic HIV infection. Antiretroviral therapy reduces plasma LPS, and greater CD4+ T cell reconstitution is associated with lower LPS levels. These findings have a number of implications for therapeutic strategies. This article summarizes a presentation on HIV disease progression made by Daniel Douek, MD, PhD, at an International AIDS Society-USA Continuing Medical Education course in San Francisco in May 2007. The original presentation is available as a Webcast at www.iasusa.org. PMID:17720995

Douek, Daniel

2007-01-01

73

Review: Mitochondria and disease progression in multiple sclerosis.  

PubMed

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Recent evidence suggests that dysfunction of surviving demyelinated axons and axonal degeneration contribute to the progression of MS. We review the evidence for and potential mechanisms of degeneration as well as dysfunction of chronically demyelinated axons in MS with particular reference to mitochondria, the main source of adenosine-5'-triphosphate in axons. Besides adenosine-5'-triphosphate production, mitochondria play an important role in calcium handling and produce reactive oxygen species. The mitochondrial changes in axons lacking healthy myelin sheaths as well as redistribution of sodium channels suggest that demyelinated axons would be more vulnerable to energy deficit than myelinated axons. A dysfunction of mitochondria in lesions as well as in the normal-appearing white and grey matter is increasingly recognized in MS and could be an important determinant of axonal dysfunction and degeneration. Mitochondria are a potential therapeutic target in MS. PMID:19076696

Mahad, D; Lassmann, H; Turnbull, D

2008-12-01

74

Quantitative MRI can detect subclinical disease progression in muscular dystrophy.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is a rare autosomal dominant muscular dystrophy with late onset and slow progression. The aim of this study was to compare different methods of quantitative MRI in the follow-up of OPMD to semiquantitative evaluation of MRI images and to functional parameters. We examined 8 patients with genetically confirmed OPMD and 5 healthy volunteers twice at an interval of 13 months. Motor function measurements (MFM) were assessed. Imaging at 1.5 T (Siemens Magnetom Avanto) comprised two axial slice groups at the largest diameter of thigh and calf and included T1w TSE, 2-point Dixon for muscular fat fraction (MFF) and a multi-contrast TSE sequence to calculate quantitative T2 values. T1 images were analyzed using Fischer's semiquantitative 5-point (0–4) scale. MFM and visual scores showed no significant difference over the study period. Overall T2 values increased in patients over the study period from 49.4 to 51.6 ms, MFF increased from 19.2 to 20.7%. Neither T2 values nor MFF increased in controls. Changes in T2 correlated with the time interval between examinations (r 2 = 0.42). In this small pilot trial, it was shown that quantitative muscle MRI can detect subclinical changes in patients with OPMD. Quantitative MRI might, therefore, be a useful tool for monitoring disease progression in future therapeutic trials. PMID:22297459

Fischmann, Arne; Hafner, Patricia; Fasler, Susanne; Gloor, Monika; Bieri, Oliver; Studler, Ueli; Fischer, Dirk

2012-08-01

75

Parameter adaptations during phenotype transitions in progressive diseases  

PubMed Central

Background The study of phenotype transitions is important to understand progressive diseases, e.g., diabetes mellitus, metabolic syndrome, and cardiovascular diseases. A challenge remains to explain phenotype transitions in terms of adaptations in molecular components and interactions in underlying biological systems. Results Here, mathematical modeling is used to describe the different phenotypes by integrating experimental data on metabolic pools and fluxes. Subsequently, trajectories of parameter adaptations are identified that are essential for the phenotypical changes. These changes in parameters reflect progressive adaptations at the transcriptome and proteome level, which occur at larger timescales. The approach was employed to study the metabolic processes underlying liver X receptor induced hepatic steatosis. Model analysis predicts which molecular processes adapt in time after pharmacological activation of the liver X receptor. Our results show that hepatic triglyceride fluxes are increased and triglycerides are especially stored in cytosolic fractions, rather than in endoplasmic reticulum fractions. Furthermore, the model reveals several possible scenarios for adaptations in cholesterol metabolism. According to the analysis, the additional quantification of one cholesterol flux is sufficient to exclude many of these hypotheses. Conclusions We propose a generic computational approach to analyze biological systems evolving through various phenotypes and to predict which molecular processes are responsible for the transition. For the case of liver X receptor induced hepatic steatosis the novel approach yields information about the redistribution of fluxes and pools of triglycerides and cholesterols that was not directly apparent from the experimental data. Model analysis provides guidance which specific molecular processes to study in more detail to obtain further understanding of the underlying biological system. PMID:22029623

2011-01-01

76

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

PubMed Central

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

Jicha, Gregory A.; Carr, Sarah A.

2010-01-01

77

The Alzheimer's Disease Neuroimaging Initiative: Progress report and future plans  

PubMed Central

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) beginning in October 2004, is a 6-year re-search project that studies changes of cognition, function, brain structure and function, and biomarkers in elderly controls, subjects with mild cognitive impairment, and subjects with Alzheimer’s disease (AD). A major goal is to determine and validate MRI, PET images, and cerebrospinal fluid (CSF)/blood biomarkers as predictors and outcomes for use in clinical trials of AD treatments. Structural MRI, FDG PET, C-11 Pittsburgh compound B (PIB) PET, CSF measurements of amyloid ? (A?) and species of tau, with clinical/cognitive measurements were performed on elderly controls, subjects with mild cognitive impairment, and subjects with AD. Structural MRI shows high rates of brain atrophy, and has high statistical power for determining treatment effects. FDG PET, C-11 Pittsburgh compound B PET, and CSF measurements of A? and tau were significant predictors of cognitive decline and brain atrophy. All data are available at UCLA/LONI/ADNI, without embargo. ADNI-like projects started in Australia, Europe, Japan, and Korea. ADNI provides significant new information concerning the progression of AD. PMID:20451868

Weiner, Michael W.; Aisen, Paul S.; Jack, Clifford R.; Jagust, William J.; Trojanowski, John Q.; Shaw, Leslie; Saykin, Andrew J.; Morris, John C.; Cairns, Nigel; Beckett, Laurel A.; Toga, Arthur; Green, Robert; Walter, Sarah; Soares, Holly; Snyder, Peter; Siemers, Eric; Potter, William; Cole, Patricia E.; Schmidt, Mark

2010-01-01

78

Hypoxemia in patients with COPD: cause, effects, and disease progression  

PubMed Central

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain. PMID:21660297

Kent, Brian D; Mitchell, Patrick D; McNicholas, Walter T

2011-01-01

79

Adipose tissue dysfunction tracks disease progression in two Huntington's disease mouse models  

PubMed Central

In addition to the hallmark neurological manifestations of Huntington's disease (HD), weight loss with metabolic dysfunction is often observed in the later stages of disease progression and is associated with poor prognosis. The mechanism for weight loss in HD is unknown. Using two mouse models of HD, the R6/2 transgenic and CAG140 knock-in mouse strains, we demonstrate that adipose tissue dysfunction is detectable at early ages and becomes more pronounced as the disease progresses. Adipocytes acquire a ‘de-differentiated’ phenotype characterized by impaired expression of fat storage genes. In addition, HD mice exhibit reduced levels of leptin and adiponectin, adipose tissue-derived hormones that regulate food intake and glucose metabolism. Importantly, some of these changes occur prior to weight loss and development of some of the characteristic neurological symptoms. We demonstrate that impaired gene expression and lipid accumulation in adipocytes can be recapitulated by expression of an inducible mutant huntingtin transgene in an adipocyte cell line and that mutant huntingtin inhibits transcriptional activity of the PGC-1? co-activator in adipocytes, which may contribute to aberrant gene expression. Thus, our findings indicate that mutant huntingtin has direct detrimental effects in cell types other than neurons. The results also indicate that circulating adipose-tissue-derived hormones may be accessible markers for HD prognosis and progression and suggest that adipose tissue may be a useful therapeutic target to improve standard of life for HD patients. PMID:19124532

Phan, Jack; Hickey, Miriam A.; Zhang, Peixiang; Chesselet, Marie-Francoise; Reue, Karen

2009-01-01

80

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

E-print Network

Medical Center St Radboud, Nijmegen, The Netherlands Keywords: disease severity, Parkinson's disease that patients with Parkinson's disease (PD) have deficits not only in motor performance, but also in patients with Parkinson's Disease (PD) (Adamovich et al., 2001; Ketcham et al., 2003). PD patients have

Gielen, C.C.A.M.

81

Antisense Oligonucleotide Therapy for the Treatment of C9ORF72 ALS/FTD Diseases.  

PubMed

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

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

2014-12-01

82

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

PubMed Central

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

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

2009-01-01

83

Saliva/Pathogen Biomarker Signatures and Periodontal Disease Progression  

PubMed Central

The purpose of this study was to determine the role of saliva-derived biomarkers and periodontal pathogens during periodontal disease progression (PDP). One hundred human participants were recruited into a 12-month investigation. They were seen bi-monthly for saliva and clinical measures and bi-annually for subtraction radiography, serum and plaque biofilm assessments. Saliva and serum were analyzed with protein arrays for 14 pro-inflammatory and bone turnover markers, while qPCR was used for detection of biofilm. A hierarchical clustering algorithm was used to group study participants based on clinical, microbiological, salivary/serum biomarkers, and PDP. Eighty-three individuals completed the six-month monitoring phase, with 44 exhibiting PDP, while 39 demonstrated stability. Participants assembled into three clusters based on periodontal pathogens, serum and salivary biomarkers. Cluster 1 members displayed high salivary biomarkers and biofilm; 82% of these individuals were undergoing PDP. Cluster 2 members displayed low biofilm and biomarker levels; 78% of these individuals were stable. Cluster 3 members were not discriminated by PDP status; however, cluster stratification followed groups 1 and 2 based on thresholds of salivary biomarkers and biofilm pathogens. The association of cluster membership to PDP was highly significant (p < 0.0002). The use of salivary and biofilm biomarkers offers potential for the identification of PDP or stability (ClinicalTrials.gov number, CT00277745). PMID:21406610

Kinney, J.S.; Morelli, T.; Braun, T.; Ramseier, C.A.; Herr, A.E.; Sugai, J.V.; Shelburne, C.E.; Rayburn, L.A.; Singh, A.K.; Giannobile, W.V.

2011-01-01

84

Polymorphism in RANTES chemokine promoter affects HIV-1 disease progression  

PubMed Central

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

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

85

Saliva/pathogen biomarker signatures and periodontal disease progression.  

PubMed

The purpose of this study was to determine the role of saliva-derived biomarkers and periodontal pathogens during periodontal disease progression (PDP). One hundred human participants were recruited into a 12-month investigation. They were seen bi-monthly for saliva and clinical measures and bi-annually for subtraction radiography, serum and plaque biofilm assessments. Saliva and serum were analyzed with protein arrays for 14 pro-inflammatory and bone turnover markers, while qPCR was used for detection of biofilm. A hierarchical clustering algorithm was used to group study participants based on clinical, microbiological, salivary/serum biomarkers, and PDP. Eighty-three individuals completed the six-month monitoring phase, with 39 [corrected] exhibiting PDP, while 44 [corrected] demonstrated stability. Participants assembled into three clusters based on periodontal pathogens, serum and salivary biomarkers. Cluster 1 members displayed high salivary biomarkers and biofilm; 71% [corrected] of these individuals were undergoing PDP. Cluster 2 members displayed low biofilm and biomarker levels; 76% [corrected] of these individuals were stable. Cluster 3 members were not discriminated by PDP status; however, cluster stratification followed groups 1 and 2 based on thresholds of salivary biomarkers and biofilm pathogens. The association of cluster membership to PDP was highly significant (p < 0.0007). [corrected] The use of salivary and biofilm biomarkers offers potential for the identification of PDP or stability (ClinicalTrials.gov number, CT00277745). PMID:21406610

Kinney, J S; Morelli, T; Braun, T; Ramseier, C A; Herr, A E; Sugai, J V; Shelburne, C E; Rayburn, L A; Singh, A K; Giannobile, W V

2011-06-01

86

Progress on thermobrachytherapy surface applicator for superficial tissue disease  

NASA Astrophysics Data System (ADS)

This work reports the ongoing development of a combination applicator for simultaneous heating of superficial tissue disease using a 915 MHz DCC (dual concentric conductor) array and High Dose Rate (HDR) brachytherapy delivered via an integrated conformal catheter array. The progress includes engineering design changes in the waterbolus, DCC configurations and fabrication techniques of the conformal multilayer applicator. The dosimetric impact of the thin copper DCC array is also assessed. Steady state fluid dynamics of the new waterbolus bag indicates nearly uniform flow with less than 1°C variation across a large (19×32cm) bolus. Thermometry data of the torso phantom acquired with computer controlled movement of fiberoptic temperature probes inside thermal mapping catheters indicate feasibility of real time feedback control for the DCC array. MR (magnetic resonance) scans of a torso phantom indicate that the waterbolus thickness across the treatment area is controlled by the pressure applied by the surrounding inflatable airbladder and applicator securing straps. The attenuation coefficient of the DCC array was measured as 3+/- 0.001% and 2.95+/-0.03 % using an ion chamber and OneDose dosimeters respectively. The performance of the combination applicator on patient phantoms provides valuable feedback to optimize the applicator prior use in the patient clinic.

Arunachalam, Kavitha; Craciunescu, Oana I.; Maccarini, Paolo F.; Schlorff, Jaime L.; Markowitz, Edward; Stauffer, Paul R.

2009-02-01

87

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

PubMed Central

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

2014-01-01

88

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

E-print Network

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

Sereno, Anne B.

89

Chronic progressive renal disease: Rate of change of serum creatinine concentration  

Microsoft Academic Search

Chronic progressive renal disease : Rate of change of serum concentration. The rate of change of the serum creatinine concentrations in 63 patients with chronic progressive renal disease of varied etiology was examined by linear regression analysis using the logarithm or the reciprocal of the serum creatinine concentration versus time. A single straight line was described by one or the

W Ernest Rutherford; Joan Blondin; J Philip Miller; Allen S Greenwalt; John D Vavra

1977-01-01

90

Helping, AdvAncing, MAking progress in pHysicAl THerApy into the Future  

E-print Network

Helping, AdvAncing, MAking progress in pHysicAl THerApy FAll 2010 PROFICIO Stepping into the Future Researchof #12;Helping, AdvAncing, MAking progress in pHysicAl THerApy FALL 2010 | issUe 19 PROFICIO Proficio is a publication of the University of Maryland School of Medicine's Department of Physical Therapy

Weber, David J.

91

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

Microsoft Academic Search

BackgroundThe 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 FindingsPatients were assessed

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

2011-01-01

92

Evidence for Angiogenesis in Parkinson's disease, Incidental Lewy Body disease, and Progressive Supranuclear Palsy  

PubMed Central

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

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

2012-01-01

93

Mechanisms of Copper Ion Mediated Huntington's Disease Progression  

PubMed Central

Huntington's disease (HD) is caused by a dominant polyglutamine expansion within the N-terminus of huntingtin protein and results in oxidative stress, energetic insufficiency and striatal degeneration. Copper and iron are increased in the striata of HD patients, but the role of these metals in HD pathogenesis is unknown. We found, using inductively-coupled-plasma mass spectroscopy, that elevations of copper and iron found in human HD brain are reiterated in the brains of affected HD transgenic mice. Increased brain copper correlated with decreased levels of the copper export protein, amyloid precursor protein. We hypothesized that increased amounts of copper bound to low affinity sites could contribute to pro-oxidant activities and neurodegeneration. We focused on two proteins: huntingtin, because of its centrality to HD, and lactate dehydrogenase (LDH), because of its documented sensitivity to copper, necessity for normoxic brain energy metabolism and evidence for altered lactate metabolism in HD brain. The first 171 amino acids of wild-type huntingtin, and its glutamine expanded mutant form, interacted with copper, but not iron. N171 reduced Cu2+ in vitro in a 1?1 copper?protein stoichiometry indicating that this fragment is very redox active. Further, copper promoted and metal chelation inhibited aggregation of cell-free huntingtin. We found decreased LDH activity, but not protein, and increased lactate levels in HD transgenic mouse brain. The LDH inhibitor oxamate resulted in neurodegeneration when delivered intra-striatially to healthy mice, indicating that LDH inhibition is relevant to neurodegeneration in HD. Our findings support a role of pro-oxidant copper-protein interactions in HD progression and offer a novel target for pharmacotherapeutics. PMID:17396163

Fox, Jonathan H.; Kama, Jibrin A.; Lieberman, Gregory; Chopra, Raman; Dorsey, Kate; Chopra, Vanita; Volitakis, Irene; Cherny, Robert A.; Bush, Ashley I.; Hersch, Steven

2007-01-01

94

Myeloperoxidase deficiency ameliorates progression of chronic kidney disease in mice.  

PubMed

Myeloperoxidase (MPO) is an enzyme expressed in neutrophils and monocytes/macrophages. Beside its well-defined role in innate immune defence, it may also be responsible for tissue damage. To identify the role of MPO in the progression of chronic kidney disease (CKD), we investigated CKD in a model of renal ablation in MPO knockout and wild-type mice. CKD was induced by 5/6 nephrectomy. Mice were followed for 10 wk to evaluate the impact of MPO deficiency on renal morbidity. Renal ablation induced CKD in wild-type mice with increased plasma levels of MPO compared with controls. No difference was found between MPO-deficient and wild-type mice regarding albuminuria 1 wk after renal ablation, indicating similar acute responses to renal ablation. Over the next 10 wk, however, MPO-deficient mice developed significantly less albuminuria and glomerular injury than wild-type mice. This was accompanied by a significantly lower renal mRNA expression of the fibrosis marker genes plasminogen activator inhibitor-I, collagen type III, and collagen type IV as well as matrix metalloproteinase-2 and matrix metalloproteinase-9. MPO-deficient mice also developed less renal inflammation after renal ablation, as indicated by a lower infiltration of CD3-positive T cells and F4/80-positive monocytes/macrophages compared with wild-type mice. In vitro chemotaxis of monocyte/macrophages isolated from MPO-deficient mice was impaired compared with wild-type mice. No significant differences were observed for mortality and blood pressure after renal ablation. In conclusion, these results demonstrate that MPO deficiency ameliorates renal injury in the renal ablation model of CKD in mice. PMID:24990898

Lehners, Alexander; Lange, Sascha; Niemann, Gianina; Rosendahl, Alva; Meyer-Schwesinger, Catherine; Oh, Jun; Stahl, Rolf; Ehmke, Heimo; Benndorf, Ralf; Klinke, Anna; Baldus, Stephan; Wenzel, Ulrich Otto

2014-08-15

95

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

E-print Network

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

Raffray, A. René

96

Obesity and preterm birth: additive risks in the progression of kidney disease in children  

Microsoft Academic Search

Preterm birth is associated with decreased nephron mass and obesity that may impact on kidney disease progression in later\\u000a life. Our objectives were to examine the relative risks of obesity and preterm birth on the progression of kidney disease\\u000a in children. In a retrospective cohort study, 80 (44 obese and 36 non-obese) patients with proteinuric kidney disease were\\u000a studied for

Carolyn L. Abitbol; Jayanthi Chandar; Maria M. Rodríguez; Mariana Berho; Wacharee Seeherunvong; Michael Freundlich; Gastón Zilleruelo

2009-01-01

97

Urine podocyte mRNAs, proteinuria, and progression in human glomerular diseases.  

PubMed

Model systems demonstrate that progression to ESRD is driven by progressive podocyte depletion (the podocyte depletion hypothesis) and can be noninvasively monitored through measurement of urine pellet podocyte mRNAs. To test these concepts in humans, we analyzed urine pellet mRNAs from 358 adult and pediatric kidney clinic patients and 291 controls (n=1143 samples). Compared with controls, urine podocyte mRNAs increased 79-fold (P<0.001) in patients with biopsy-proven glomerular disease and a 50% decrease in kidney function or progression to ESRD. An independent cohort of patients with Alport syndrome had a 23-fold increase in urinary podocyte mRNAs (P<0.001 compared with controls). Urinary podocyte mRNAs increased during active disease but returned to baseline on disease remission. Furthermore, urine podocyte mRNAs increased in all categories of glomerular disease evaluated, but levels ranged from high to normal, consistent with individual patient variability in the risk for progression. In contrast, urine podocyte mRNAs did not increase in polycystic kidney disease. The association between proteinuria and podocyturia varied markedly by glomerular disease type: a high correlation in minimal-change disease and a low correlation in membranous nephropathy. These data support the podocyte depletion hypothesis as the mechanism driving progression in all human glomerular diseases, suggest that urine pellet podocyte mRNAs could be useful for monitoring risk for progression and response to treatment, and provide novel insights into glomerular disease pathophysiology. PMID:24052633

Wickman, Larysa; Afshinnia, Farsad; Wang, Su Q; Yang, Yan; Wang, Fei; Chowdhury, Mahboob; Graham, Delia; Hawkins, Jennifer; Nishizono, Ryuzoh; Tanzer, Marie; Wiggins, Jocelyn; Escobar, Guillermo A; Rovin, Bradley; Song, Peter; Gipson, Debbie; Kershaw, David; Wiggins, Roger C

2013-12-01

98

A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C  

PubMed Central

Background: There is increasing interest in the influence of host genetic factors on hepatic fibrosis, and whether genetic markers can reliably identify subjects at risk of developing severe disease. We hypothesised that hepatitis C virus (HCV) infected subjects with progressive fibrosis, classified using strict criteria based on histology at biopsy in addition to disease duration would be more likely to inherit several genetic polymorphisms associated with disease progression compared with subjects with a low rate of disease progression. Methods: We examined polymorphisms in eight genes that have been reported to have an association with hepatic fibrosis. Results: Associations between polymorphisms in six genes and more rapidly progressing fibrosis were observed, with individual adjusted odds ratios ranging from 2.1 to 4.5. The relationship between rapidly progressing fibrosis and possession of ?3, ?4, or ?5 progression associated alleles was determined and the adjusted odds ratios increased with increasing number of progression associated alleles (9.1, 15.5, and 24.1, respectively). Using logistic regression analysis, a predictive equation was developed and tested using a second cohort of patients with rapidly progressing fibrosis. The predictive equation correctly classified 80% of patients in this second cohort. Conclusions: This approach may allow determination of a genetic profile predictive of rapid disease progression in HCV and identify patients warranting more aggressive therapeutic management. PMID:15994870

Richardson, M; Powell, E; Barrie, H; Clouston, A; Purdie, D; Jonsson, J

2005-01-01

99

Genetic Biomarkers for ALS Disease in Transgenic SOD1G93A Mice  

PubMed Central

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

Calvo, Ana C.; Manzano, Raquel; Atencia-Cibreiro, Gabriela; Olivan, Sara; Munoz, Maria J.; Zaragoza, Pilar; Cordero-Vazquez, Pilar; Esteban-Perez, Jesus; Garcia-Redondo, Alberto; Osta, Rosario

2012-01-01

100

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

E-print Network

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

Sereno, Anne B.

101

Predicting Progression of Alzheimer’s Disease With Magnetic Resonance  

Microsoft Academic Search

Advances in the field of molecular biology concerning Alzheimer’s disease (AD) generate the possibility of useful therapeutic\\u000a interventions in the near future. The major beneficiaries of disease-modifying treatments that are currently under development\\u000a will be those patients who have early pathological involvement. Improved methods for early diagnosis and noninvasive surrogates\\u000a of disease severity in AD are crucial for early therapeutic

Kejal Kantarci; Clifford R. Jack

102

Disease Severity in One Eye May Predict Progression in the Other  

MedlinePLUS

... page, please enable JavaScript. Disease Severity in One Eye May Predict Progression in the Other Study focuses ... severity of age-related macular degeneration in one eye is associated with the risk of developing the ...

103

Contribution of regulatory T cells to immunosuppression and disease progression in multiple myeloma patients  

PubMed Central

Multiple myeloma (MM) patients exhibit consistent degrees of immune dysfunction. Regulatory T cells contribute to the establishment of an immunosuppressive status in MM patients, hence favoring disease progression. PMID:24327932

Raja, Karthick Raja Muthu; Hajek, Roman

2013-01-01

104

Elevated 4-hydroxyhexenal in Alzheimer's disease (AD) progression  

Microsoft Academic Search

Multiple studies have demonstrated elevations of ?, ?-unsaturated aldehydes including 4-hydroxynonenal (HNE) and acrolein, in vulnerable regions of mild cognitive impairment (MCI), preclinical Alzheimer's disease (PCAD), and late stage Alzheimer's disease (LAD) brain. However, there has been limited study of a third member, 4-hydroxyhexenal (HHE), a diffusible lipid peroxidation product of the ?-3 polyunstataturated fatty acids (PUFAs). In the present

Melissa A. Bradley; Shuling Xiong-Fister; William R. Markesbery; Mark A. Lovell

105

Hepatitis C Increases the Risk of Progression of Chronic Kidney Disease in Patients with Glomerulonephritis  

Microsoft Academic Search

Background\\/Aims: We have shown that hepatitis C does not increase the risk of developing chronic kidney disease (CKD), but it is not known if hepatitis C worsens progression of existing CKD. Methods: We retrospectively identified patients with primary glomerulonephritis on biopsy over 4 years, evaluating the progression of CKD over time. Results: The cohort consisted of 111 patients: 21% were

Lama A. Noureddine; Sohail A. Usman; Zhangsheng Yu; Ranjani N. Moorthi; Sharon M. Moe

2010-01-01

106

Role for transforming growth factor-?1 in Alport renal disease progression  

Microsoft Academic Search

Role for transforming growth factor-?1 in Alport renal disease progression.BackgroundAlport syndrome results from mutations in either the ?3(IV), ?4(IV), or ?5(IV) collagen genes. The disease is characterized by a progressive glomerulonephritis usually associated with a high-frequency sensorineural hearing loss. A mouse model for an autosomal form of Alport syndrome [collagen ?3(IV) knockout] was produced and characterized. In this study, the

Robinlyn Sayers; Raghuram Kalluri; Kathyrn D. Rodgers; Charles F. Shield; Daniel T. Meehan; Dominic Cosgrove

1999-01-01

107

Progressive renal fibrosis in murine polycystic kidney disease: An immunohistochemical observation  

Microsoft Academic Search

Progressive renal fibrosis in murine polycystic kidney disease: An immunohistochemical observation.BackgroundThe appearance of interstitial fibrosis in polycystic kidneys is emblematic of progressive disease. Matrix forming this scar tissue is derived from local renal cells in response to cystogenesis. We investigated the phenotype of collagen-producing cells in the cystic kidneys of DBA\\/2-pcy mice to better characterize the spectrum of interstitial cells

Hirokazu Okada; Shinichi Ban; Shizuko Nagao; Hisahide Takahashi; Hiromichi Suzuki; Eric G Neilson

2000-01-01

108

Blood pressure and progression of chronic kidney disease: Importance of systolic, diastolic, or diurnal variation  

Microsoft Academic Search

Several studies show that systolic blood pressure is an important predictor of renal disease progression, just as it is linked\\u000a with cardiovascular consequences in hypertension. In contrast, particularly in older patients, diastolic blood pressure was\\u000a not independently associated with risk of kidney disease progression in the same studies. Pulse pressure has been shown to\\u000a be equivalent in predicting renal outcomes,

Evelyn Mentari; Mahboob Rahman

2004-01-01

109

Research Finds Link Between Statin Use and Progressive Muscle Disease  

MedlinePLUS

... corticosteroids and other drugs to suppress the immune system, with the goal of stopping progressive muscle damage, says Dr. Christopher-Stine. But even in these cases, she warns that stopping the statin — and ... to the cardiovascular system — may not be necessary. Treating with a statin ...

110

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

PubMed Central

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

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

2012-01-01

111

2006 Nature Publishing Group Alzheimer's disease is characterized by progressive  

E-print Network

on chromosomes 1, 14, 19 and 21, respectively. Products of these genes are involved in the trafficking for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston

Cai, Long

112

Progress in Early Diagnosis of Sickle Cell Disease  

ERIC Educational Resources Information Center

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)

Pearson, Howard A.

1971-01-01

113

Antigonadotropins: a novel strategy to halt Alzheimer's disease progression.  

PubMed

A significant amount of research has been focused on the relationship between hormones and Alzheimer's disease. However, the majority of this work has been on estrogen and more recently testosterone. A serendipitous patient encounter led one of us (RLB) to question whether other hormones of the hypothalamic-pituitary-gonadal axis could be playing a role in the pathogenesis of Alzheimer's disease. The age-related decline in reproductive function results in a dramatic decrease in serum estrogen and testosterone concentrations and an equally dramatic compensatory increase in serum luteinizing hormone concentrations. Indeed, there is growing evidence that the gonadotropin, luteinizing hormone, which regulates serum estrogen and testosterone concentrations, could be an important causative factor in the development of Alzheimer's disease. This review provides information supporting the "gonadotropin hypothesis," puts forth a novel mechanism of how changes in serum luteinizing hormone concentrations could contribute to the pathogenesis of Alzheimer's disease, and discusses potential therapeutic anti-gonadotropin compounds. PMID:16472158

Gregory, Christopher W; Atwood, Craig S; Smith, Mark A; Bowen, Richard L

2006-01-01

114

Stopping rules employing response rates, time to progression, and early progressive disease for phase II oncology trials  

PubMed Central

Background Response rate (RR), the most common early means of assessing oncology drugs, is not suitable as the sole endpoint for phase II trials of drugs which induce disease stability but not regression. Time to progression (TTP) may be more sensitive to such agents, but induces recruitment delays in multistage studies. Early progressive disease (EPD) is the earliest signal of time to progression, but is less intuitive to investigators, To study drugs with unknown anti-tumour effect, we designed the Combination Stopping Rule (CSR), which allows investigators to establish a hypothesis using RR and TTP, while the program also employs early progressive disease (EPD) to assess for drug inactivity during the first stage of study accrual. Methods A computer program was created to generate stopping rules based on specified error rates, trial size, and RR and median TTP of interest and disinterest for a two-stage phase II trial. Rules were generated for stage II such that the null hypothesis (Hnul) was rejected if either RR or TTP met desired thresholds, and accepted if both did not. Assuming an exponential distribution for progression, EPD thresholds were determined based on specified TTP values. Stopping rules were generated for stage I such that Hnul was accepted and the study stopped if both RR and EPD were unacceptable. Results Patient thresholds were generated for RR, median TTP, and EPD which achieved specified error rates and which allowed early stopping based on RR and EPD. For smaller proportional differences between interesting and disinteresting values of RR or TTP, larger trials are required to maintain alpha error, and early stopping is more common with a larger first stage. Conclusion Stopping rules are provided for phase II trials for drugs which have either a desirable RR or TTP. In addition, early stopping can be achieved using RR and EPD. PMID:22151297

2011-01-01

115

[Pulmonary lymphangioleiomyomatosis. A disease which may have a benign progression].  

PubMed

Pulmonary lymphangioleiomyomatosis (PLLM) is characterized by a benign proliferation of the smooth muscle around lymphatics, venulas and bronchiolus. It is usually fatal within 1 to 9 years. We present a case which remained with scarce symptoms despite receiving no treatment after at least 9 years of evolution of the disease. We highlight the clinical manifestations of the disease and the relevance of pulmonary biopsia with thoracotomy in order to establish the diagnosis. PMID:8518341

Barranco Simó, M J; Ciscar Vilanova, M A; Ibor Otamendi, J L; Ferrando Marco, J; Juan Samper, G

1993-05-01

116

The role of microglial activation in disease progression.  

PubMed

Microglia, a unique type of myeloid cell, play a key role in the inflammation-mediated neurodegeneration occurring during both acute and chronic stages of multiple sclerosis (MS). These highly specialized cells trigger neurotoxic pathways, producing pro-inflammatory cytokines, reactive oxygen and nitrogen species and proteolytic enzymes, causing progressive neurodegeneration. Microglia have also been associated with development of cortical lesions in progressive MS, as well as with alterations of synaptic transmission in experimental autoimmune encephalomyelitis (EAE). However, they also play an important role in the promotion of neuroprotection, downregulation of inflammation, and stimulation of tissue repair. Notably, microglia undergo changes in morphology and function with normal aging, resulting in a decline of their ability to repair central nervous system damage, making axons and neurons more vulnerable with age. Modulation of microglial activation for therapeutic purposes must consider suppressing deleterious effects of these cells, while simultaneously preserving their protective functions. PMID:24812046

Correale, Jorge

2014-09-01

117

Progress toward novel treatments for chronic kidney disease.  

PubMed

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

Shah, Sudhir V

2010-09-01

118

Role of IL-10 in the progression of kidney disease  

PubMed Central

Interleukin-10 (IL-10), a cytokine with anti-inflammatory and immunomodulatory functions, regulates the biology of B and T cells. The present review describes the role of IL-10 in normal renal physiology, during acute kidney injury and in the development of chronic renal failure. We further discuss IL-10-induced cellular and molecular pathways and their link to the progression of kidney injury. PMID:24392313

Sinuani, Inna; Beberashvili, Ilia; Averbukh, Zhan; Sandbank, Judith

2013-01-01

119

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

PubMed Central

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.

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

2014-01-01

120

Modeling progressive non-alcoholic fatty liver disease in the laboratory mouse.  

PubMed

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world and its prevalence is rising. In the absence of disease progression, fatty liver poses minimal risk of detrimental health outcomes. However, advancement to non-alcoholic steatohepatitis (NASH) confers a markedly increased likelihood of developing severe liver pathologies, including fibrosis, cirrhosis, organ failure, and cancer. Although a substantial percentage of NAFLD patients develop NASH, the genetic and molecular mechanisms driving this progression are poorly understood, making it difficult to predict which patients will ultimately develop advanced liver disease. Deficiencies in mechanistic understanding preclude the identification of beneficial prognostic indicators and the development of effective therapies. Mouse models of progressive NAFLD serve as a complementary approach to the direct analysis of human patients. By providing an easily manipulated experimental system that can be rigorously controlled, they facilitate an improved understanding of disease development and progression. In this review, we discuss genetically- and chemically-induced models of NAFLD that progress to NASH, fibrosis, and liver cancer in the context of the major signaling pathways whose disruption has been implicated as a driving force for their development. Additionally, an overview of nutritional models of progressive NAFLD is provided. PMID:24802098

Riordan, Jesse D; Nadeau, Joseph H

2014-10-01

121

Progressive multifocal leucoencephalopathy in the rheumatic diseases: assessing the risks of biological immunosuppressive therapies  

Microsoft Academic Search

Progressive multifocal leucoencephalopathy (PML) is a rare and often fatal opportunistic infection that has been well reported in patients with rheumatic diseases. The contributions of predisposing factors such as underlying disease and immunosuppressive drug selection are incompletely understood but it would appear that patients with systemic lupus erythematosus may be at highest risk. Natalizumab, a biological agent approved for multiple

L H Calabrese; E S Molloy

2008-01-01

122

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

Microsoft Academic Search

ABSTRACT: 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

Larry G Brooks; David A Loewenstein

2010-01-01

123

Predicting initiation and progression of chronic kidney disease: Developing renal risk scores  

Microsoft Academic Search

Epidemiological studies have raised awareness of the problem of undiagnosed chronic kidney disease (CKD) and suggest that early identification and treatment will reduce the global burden of patients requiring dialysis. This has highlighted the twin problems of how to identify subjects for screening and target intervention to those with CKD most likely to progress to end-stage renal disease. Prospective studies

M W Taal; B M Brenner

2006-01-01

124

Echocardiographic and Biochemical Evaluation of the Development and Progression of Carcinoid Heart Disease  

Microsoft Academic Search

Objectives. To study the applicability of a newly developed echocardiographic scoring system in the assessment of carcinoid valvular heart disease. Background. We investigated prospectively the development, progression and regression of carcinoid valvular heart disease in patients with carcinoid syndrome by serial echocardiography, correlating these features with urinary 5-HIAA levels and clinical data collected during therapy with somatostatin analog. Methods. Twenty-three

WILLIAM D. DENNEY; LOWELL B. ANTHONY; JOHN A. OATES; BENJAMIN F. BYRD III

125

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

Microsoft Academic Search

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

Micheline Levy; Josué Feingold

2000-01-01

126

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

PubMed Central

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

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

2013-01-01

127

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

PubMed

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

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

2013-04-01

128

Glomerular Hyperfiltration and Renal Disease Progression in Type 2 Diabetes  

PubMed Central

OBJECTIVE To describe the prevalence and determinants of hyperfiltration (glomerular filtration rate [GFR] ?120 mL/min/1.73 m2), GFR decline, and nephropathy onset or progression in type 2 diabetic patients with normo- or microalbuminuria. RESEARCH DESIGN AND METHODS We longitudinally studied 600 hypertensive type 2 diabetic patients with albuminuria <200 ?g/min and who were retrieved from two randomized trials testing the renal effect of trandolapril and delapril. Target blood pressure (BP) was <120/80 mmHg, and HbA1c was <7%. GFR, albuminuria, and glucose disposal rate (GDR) were centrally measured by iohexol plasma clearance, nephelometry in three consecutive overnight urine collections, and hyperinsulinemic euglycemic clamp, respectively. RESULTS Over a median (range) follow-up of 4.0 (1.7–8.1) years, GFR declined by 3.37 (5.71–1.31) mL/min/1.73 m2 per year. GFR change was bimodal over time: a larger reduction at 6 months significantly predicted slower subsequent decline (coefficient: ?0.0054; SE: 0.0009), particularly among hyperfiltering patients. A total of 90 subjects (15%) were hyperfiltering at inclusion, and 11 of 47 (23.4%) patients with persistent hyperfiltration progressed to micro- or macroalbuminuria versus 53 (10.6%) of the 502 who had their hyperfiltration ameliorated at 6 months or were nonhyperfiltering since inclusion (hazard ratio 2.16 [95% CI 1.13–4.14]). Amelioration of hyperfiltration was independent of baseline characteristics or ACE inhibition. It was significantly associated with improved BP and metabolic control, amelioration of GDR, and slower long-term GFR decline on follow-up. CONCLUSIONS Despite intensified treatment, patients with type 2 diabetes have a fast GFR decline. Hyperfiltration affects a subgroup of patients and may contribute to renal function loss and nephropathy onset or progression. Whether amelioration of hyperfiltration is renoprotective is worth investigating. PMID:22773704

Ruggenenti, Piero; Porrini, Esteban L.; Gaspari, Flavio; Motterlini, Nicola; Cannata, Antonio; Carrara, Fabiola; Cella, Claudia; Ferrari, Silvia; Stucchi, Nadia; Parvanova, Aneliya; Iliev, Ilian; Dodesini, Alessandro Roberto; Trevisan, Roberto; Bossi, Antonio; Zaletel, Jelka; Remuzzi, Giuseppe

2012-01-01

129

Herpes virus in Alzheimer's disease: relation to progression of the disease.  

PubMed

Studies regarding different viruses of the herpes family, such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), or human herpes virus 6 (HHV-6) in Alzheimer's disease (AD) are scarce. DNA from peripheral blood leukocytes (PBL) and brain samples were analyzed for the presence of CMV, EBV, or HHV-6. All samples were negative for CMV. EBV positivity was 6% in AD brains, whereas 45% of PBL samples from AD patients and 31% from controls were positive for EBV (p = 0.05). HHV-6 showed a 23% positivity in PBL samples from AD and 4% from controls (p = 0.002). 17% of AD brains were HHV-6 positive. Within a group of elderly individuals, followed up for 5 years, EBV-positive or HHV-6-positive PBL increased in those who developed clinical AD. Virus serological positivity was also investigated, and IgG levels for CMV and EBV antigens were also increased in those subjects who developed AD during the follow-up. Our findings suggest that EBV and HHV-6 may be environmental risk factors for cognitive deterioration and progression to AD in elderly persons. PMID:23916950

Carbone, Ilaria; Lazzarotto, Tiziana; Ianni, Manuela; Porcellini, Elisa; Forti, Paola; Masliah, Eliezer; Gabrielli, Liliana; Licastro, Federico

2014-01-01

130

Environmental Factors Affecting Inflammatory Bowel Disease: Have We Made Progress?  

Microsoft Academic Search

The pathogenesis of inflammatory bowel disease (IBD) is only partially understood; various environmental and host (e.g. genetic, epithelial, immune, and nonimmune) factors are involved. The critical role for environmental factors is strongly supported by recent worldwide trends in IBD epidemiology. One important environmental factor is smoking. A meta-analysis partially confirms previous findings that smoking was found to be protective against

Peter Laszlo Lakatos

2009-01-01

131

Self Antigen Prognostic for Human Immunodeficiency Virus Disease Progression  

Microsoft Academic Search

We have recently found that an extracellular protein, 1 proteinase inhibitor (1PI; 1 antitrypsin), is re- quired for in vitro human immunodeficiency virus (HIV) infectivity outcome. We show here in a study of HIV- seropositive patients that decreased viral load is significantly correlated with decreased circulating 1PI. In the asymptomatic category of HIV disease, 100% of patients manifest deficient levels

CYNTHIA L. BRISTOW; HIRENKUMAR PATEL; ROLAND R. ARNOLD

2001-01-01

132

From Pasteur to genomics: progress and challenges in infectious diseases  

Microsoft Academic Search

Over the past decade, microbiology and infectious disease research have undergone the most profound revolution since the times of Pasteur. Genomic sequencing has revealed the much-awaited blueprint of most pathogens. Screening blood for the nucleic acids of infectious agents has blunted the spread of pathogens by transfusion, the field of antiviral therapeutics has exploded and technologies for the development of

Rino Rappuoli

2004-01-01

133

Progression of Chronic Kidney Disease: Adrenergic Genetic Influence on Glomerular Filtration Rate Decline in Hypertensive Nephrosclerosis  

Microsoft Academic Search

Background: African-Americans are likely to develop hypertension and hypertensive nephrosclerosis. This grave prognosis, coupled with familial aggregation of end-stage renal disease (ESRD) in Blacks, prompts a search for genetic risk factors for ESRD. Recent evidence implicates a crucial role for the sympathetic nervous system in progressive renal disease. Methods: We used the African-American Study of Kidney Disease to probe whether

Yuqing Chen; Michael S. Lipkowitz; Rany M. Salem; Maple M. Fung; Vibha Bhatnagar; Manjula Mahata; Caroline M. Nievergelt; Fangwen Rao; Sushil K. Mahata; Nicholas J. Schork; Pamela J. Hicks; Donald W. Bowden; Barry I. Freedman; Victoria H. Brophy; Daniel T. O’Connor

2010-01-01

134

Optical Assessment of Vascular Disease Progression and Treatment  

NASA Astrophysics Data System (ADS)

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.

Samuels, Joshua A.

135

Ventricular enlargement as a possible measure of Alzheimer's disease progression validated using the Alzheimer's disease neuroimaging initiative database  

Microsoft Academic Search

Ventricular enlargement may be an objective and sensitive measure of neuropathological change associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD), suitable to assess disease progression for multi-centre studies.This study compared (i) ventricular enlargement after six months in subjects with MCI, AD and normal elderly controls (NEC) in a multi-centre study, (ii) volumetric and cognitive changes between Apolipoprotein E

Sean M. Nestor; Raul Rupsingh; Michael Borrie; Matthew Smith; Vittorio Accomazzi; Jennie L. Wells; Jennifer Fogarty; Robert Bartha

2008-01-01

136

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

PubMed Central

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

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

2013-01-01

137

Mutations in TJP2 cause progressive cholestatic liver disease  

PubMed Central

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

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

2014-01-01

138

HIV infection in Haiti: natural history and disease progression  

Microsoft Academic Search

Objective: A study was conducted to define the natural history and disease progres- sion of HIV infection in a developing country. Design: A prospective longitudinal cohort study. Methods: Forty-two patients with documented dates of HIV seroconversion were followed in Port-au-Prince, Haiti. Patients were seen at 3 month intervals or when ill. Patients were treated for bacterial, mycobacterial, parasitic, and fungal

Marie-Marcelle Deschamps; Daniel W. Fitzgerald; Jean William Pape; Warren D. Johnson Jr

2000-01-01

139

[Progress on dynamic neutralization system in treating lumbar degenerative diseases].  

PubMed

Dynamic stabilization technology has increasingly become the hot spot in basic and clinical research for treating lumbar degenerative diseases. As one kind of dynamic stabilization technology,dynamic neutralization system (Dynesys) keeps the spinal motion ability and improve clinical symptoms of patients, moreover, it shows a certain advantage in delaying the degeneration of adjacent segments. From the available documents,the preliminary biomechanical and clinical results of Dynesys were optimistically, it has become another choice in treating the lumbar degenerative diseases besides the lumbar fusion, and it primarily applies to the treatment of mild to moderate lumbar degenerative disease. However, it lacks a mechanism to maintain and restore the lumbar lordosis and patients need active stretching to achieve lordosis. What's more, how to extend the service life and prevent complications remain to be solved, the long-term effect and the mechanism of delaying the adjacent segment degeneration need further investigation. In this article, the design principle, biomechanical research, clinical outcome and clinical application of Dynesys was reviewed. PMID:24015664

Chen, Xi-Jun; Fan, Shun-Wu

2013-06-01

140

Herpes simplex virus type 2 and HIV disease progression: a systematic review of observational studies  

PubMed Central

Background Herpes simplex virus type 2 (HSV-2) is a common co-infection among HIV-infected adults that is hypothesized to accelerate HIV disease progression. Methods We searched Medline, EMBASE, relevant conference proceedings (2006–12) and bibliographies of identified studies without language restriction for cohort studies examining the impact of HSV-2 on highly active antiretroviral therapy-untreated HIV disease in adults. The exposure of interest was HSV-2 seropositivity or clinical/laboratory markers of HSV-2 activity. The primary outcome was HIV disease progression, defined as antiretroviral initiation, development of AIDS/opportunistic infection, or progression to CD4 count thresholds (?200 or ?350 cells/mm3). Secondary outcomes included HIV plasma viral load and CD4 count. Results Seven studies were included. No definitive relationship was observed between HSV-2 seropositivity and time to antiretroviral initiation (n=2 studies), CD4?350 (n=1), CD4?200 (n=1), death (n=1), viral load (n=6) or CD4 count (n=3). Although two studies each observed trends towards accelerated progression to clinical AIDS/opportunistic infection in HSV-2 seropositives, with pooled unadjusted hazard ratio=1.85 (95% CI=1.12,3.06; I2=2%), most OIs observed in the study for which data were available can occur at high CD4 counts and may not represent HIV progression. In contrast, a single study HSV-2 disease activity found that the presence of genital HSV-2 DNA was associated with a 0.4 log copies/mL increase in HIV viral load. Conclusions Despite an observation that HSV-2 activity is associated with increased HIV viral load, definitive evidence linking HSV-2 seropositivity to accelerated HIV disease progression is lacking. The attenuating effects of acyclovir on HIV disease progression observed in recent trials may result both from direct anti-HIV activity as well as from indirect benefits of HSV-2 suppression. PMID:24164861

2013-01-01

141

Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression.  

PubMed

We evaluated whether lysyl oxidase-like 2 (LOXL2), which promotes cross-linking of collagen in pathological stroma, was detectable in serum from idiopathic pulmonary fibrosis (IPF) patients, and assessed its relationship with IPF disease progression. Patients from the ARTEMIS-IPF (n=69) and the Genomic and Proteomic Analysis of Disease Progression in IPF (GAP) (n=104) studies were analysed. Baseline serum LOXL2 (sLOXL2) levels were compared with baseline clinical and physiological surrogates of disease severity, and the association with IPF disease progression was assessed using a classification and regression tree (CART) method. sLOXL2 correlated weakly with forced vital capacity and carbon monoxide diffusion capacity (r -0.24-0.05) in both cohorts. CART-determined thresholds were similar: ARTEMIS-IPF 800 pg·mL(-1) and GAP 700 pg·mL(-1). In ARTEMIS-IPF, higher sLOXL2 (>800 pg·mL(-1)) was associated with increased risk for disease progression (hazard ratio (HR) 5.41, 95% CI 1.65-17.73). Among GAP subjects with baseline spirometric data (n=70), higher sLOXL2 levels (>700 pg·mL(-1)) were associated with more disease progression events (HR 1.78, 95% CI 1.01-3.11). Among all GAP subjects, higher sLOXL2 levels were associated with increased risk for mortality (HR 2.28, 95% CI 1.18-4.38). These results suggest that higher sLOXL2 levels are associated with increased risk for IPF disease progression. However, due to multiple limitations, these results require validation. PMID:24177001

Chien, Jason W; Richards, Thomas J; Gibson, Kevin F; Zhang, Yingze; Lindell, Kathleen O; Shao, Lixin; Lyman, Susan K; Adamkewicz, Joanne I; Smith, Victoria; Kaminski, Naftali; O'Riordan, Thomas

2014-05-01

142

Research progress on natural products from traditional Chinese medicine in treatment of Alzheimer's disease.  

PubMed

Alzheimer's disease (AD) is a severe condition in aging societies. Although research on this disease is advancing rapidly, thus far few very effective drugs are available for AD patients. The currently widely used medicines such as donepezil and galantamine transiently improve the symptoms of patients with mild to moderate AD. They are hardly capable of preventing, halting or reversing the progression of this disease. In the long history of development of traditional Chinese medicine, many herbs have been discovered and employed to treat dementia diseases in clinics in China. In recent decades, a number of agents were isolated from these herbs and their efficacies against AD were tested. Some flavonoids, alkaloids, phenylpropanoids, triterpenoid saponins, and polysaccharides were demonstrated to have potential efficacies against AD via targeting multiple pathological changes of this disease. In this article, we reviewed research progress on the efficacies and underlying mechanisms of these agents. PMID:23715502

Gao, Jianjun; Inagaki, Yoshinori; Li, Xuan; Kokudo, Norihiro; Tang, Wei

2013-04-01

143

Bidirectional Translational Research: Progress in Understanding Addictive Diseases  

PubMed Central

The focus of this review is primarily on recent developments in bidirectional translational research on the addictions, within the Laboratory of the Biology of Addictive Diseases at The Rockefeller University. This review is subdivided into major interacting aspects, including: a) Investigation of neurobiological and molecular adaptations (e.g., in genes for the opioid receptors or endogenous neuropeptides) in response to cocaine or opiates, administered under laboratory conditions modeling chronic patterns of human self-exposure (e.g., chronic escalating “binge”). b) The impact of such drug exposure on the hypothalamic-pituitary-adrenal (HPA) axis and interacting neuropeptidergic systems (e.g., opioid, orexin and vasopressin). c) Molecular genetic association studies using candidate gene and whole genome approaches, to define particular systems involved in vulnerability to develop specific addictions, and response to pharmacotherapy. d) Neuroendocrine challenge studies in normal volunteers and current addictive disease patients along with former addicts in treatment, to investigate differential pharmacodynamics and responsiveness of molecular targets, in particular those also investigated in the experimental and molecular genetic approaches described above. PMID:18725235

Kreek, MJ; Schlussman, SD; Reed, B; Zhang, Y; Nielsen, DA; Levran, O; Zhou, Y; Butelman, ER

2009-01-01

144

Development assistance for neglected tropical diseases: progress since 2009.  

PubMed

Neglected tropical diseases (NTDs) is an umbrella term for a diverse group of debilitating infections that represent the most common afflictions for 2.7 billion people living on less than US$2 per day. Major efforts have recently re-focused attention on NTDs, including structured advocacy by the Bill and Melinda Gates Foundation, technical and political support by WHO and large-scale drug donation programs by pharmaceutical companies. An analysis of the Official Development Assistance (ODA) for NTDs in 2009 showed that Development Assistance Committee members and multilateral donors had largely ignored funding NTD control projects. This study reviews the changes since 2009 and finds an increased engagement by pharmaceutical manufacturers through drug donation programs substantially increased by the 'London Declaration' in 2012, a focused effort of 77 public and private partners on control or elimination of the 10 most common NTDs, but no increase in ODA for NTDs between 2008 and 2012. The allocation of ODA still does not reflect the respective importance of these diseases. PMID:25096331

Liese, Bernhard H; Houghton, Natalia; Teplitskaya, Lyubov

2014-09-01

145

Recent progress in gene therapy for Parkinson's disease.  

PubMed

Parkinson's disease (PD) is an age-related and the second most common neurodegenerative disorder beyond Alzheimer's disease. A neuropathological hallmark of PD is a prominent loss of dopaminergic neurons in the substantia nigra projecting into the caudate and putamen. Oral administration of L-dopa and/or dopamine agonists ameliorates cardinal motor symptoms of PD. However, an intermittent and long-term treatment with L-dopa frequently induces adverse side effects such as motor fluctuations and dyskinesia. As alternative therapeutic strategies, the following four approaches are currently under evaluation for clinical gene therapy trials in PD; 1) recombinant adeno-associated virus 2 system encoding aromatic L-amino acid decarboxylase (AADC), 2) glutamic acid decarboxylase (GAD) and 3) Neurturin, and 4) equine infectious anemia virus-based lentiviral system encoding AADC, tyrosine hydroxylase (TH) and GTP cyclohydrolase I (GCH) in a single transcriptional unit. GAD and Neurturin have been assessed in double blind placebocontrolled phase II studies; GAD showed a significant improvement in motor function, and Neurturin, although it failed to show significant effects at 12 months post-treatment, exhibited promising outcomes in additional examinations at 18 months. The other two approaches also represented significant effects in phase I or I/II studies. Adverse side effects due to surgery have not been observed. Here, we review preclinical and clinical trials encouraging further investigations of curative treatment for the patients suffering from PD. PMID:22834832

Nakata, Y; Yasuda, T; Mochizuki, H

2012-12-01

146

DiME: A Scalable Disease Module Identification Algorithm with Application to Glioma Progression  

PubMed Central

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

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

2014-01-01

147

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

PubMed

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

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

2014-01-01

148

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

PubMed Central

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

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

2014-01-01

149

Familial progressive tubulo-interstitial nephropathy and cholestatic liver disease – a newly recognized entity?  

Microsoft Academic Search

We describe two siblings (female and male) with progressive tubulo-interstitial nephropathy and cholestatic liver disease.\\u000a The main characteristics were progressive renal failure and elevated liver enzymes (AST, ALT and ?-GT). Dialysis was started\\u000a at the age of 1.9 and 6.5 years, respectively. Renal histology disclosed sclerosed glomeruli and atrophic tubules; the interstitium\\u000a was fibrotic and infiltrated by lymphocytes. Endoscopic retrograde

T. J. Neuhaus; T. Stallmach; E. Leumann; J. Altorfer; C. P. Braegger

1997-01-01

150

Body mass index, weight change, and clinical progression in mild cognitive impairment and Alzheimer disease.  

PubMed

The speed and severity of clinical progression after Alzheimer disease (AD) diagnosis varies and depends on multiple factors, most not well elucidated. We assessed whether body mass index (BMI) and 1-year weight change (WC) are associated with clinical progression in amnestic mild cognitive impairment (aMCI) and early-stage AD. Longitudinal data comprising 2268 aMCI and 1506 AD participants in the National Alzheimer's Coordinating Center's Uniform Data Set were used to examine nuances of clinical progression by BMI and WC, as well as potential variations in associations by age, sex, BMI (WC model), or apolipoprotein E genotype. In aMCI, high BMI (vs. moderate BMI) was associated with slower progression; weight loss (vs. no WC) was associated with faster progression. In AD, no significant differences were observed in clinical progression by BMI or WC. The association between BMI and clinical progression varied significantly by apolipoprotein E genotype in AD, and the association between WC and clinical progression varied significantly by sex and BMI in aMCI. Baseline BMI and 1-year WC in late life may serve as early prognostic indicators in aMCI and early-stage AD. If replicated, these results may help in counseling patients on anticipated clinical progression and suggest windows of opportunity for intervention. PMID:24126214

Besser, Lilah M; Gill, Dawn P; Monsell, Sarah E; Brenowitz, Willa; Meranus, Dana H; Kukull, Walter; Gustafson, Deborah R

2014-01-01

151

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

PubMed

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

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

152

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

PubMed Central

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 ??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

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

153

A new paradigm in the periodontal disease progression: Gingival connective tissue remodeling with simultaneous collagen degradation and fibers thickening  

Microsoft Academic Search

Bacterial dental plaque is considered to be the main cause of periodontal diseases, but progression of the disease is also related to the host inflammatory response. The earliest affected tissue is the gingiva, but the specific mechanisms involved in the onset of this condition remain unclear. Frequently, collagen degradation is pointed as the main marker of periodontal disease progression, but

M. Lorencini; J. A. F. Silva; C. A. Almeida; A. Bruni-Cardoso; H. F. Carvalho; D. R. Stach-Machado

2009-01-01

154

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

PubMed

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

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

2014-10-01

155

Hepatic inflammation and progressive liver fibrosis in chronic liver disease  

PubMed Central

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

Czaja, Albert J

2014-01-01

156

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

PubMed

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

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

2014-03-01

157

Integrative analysis reveals disease-associated genes and biomarkers for prostate cancer progression  

PubMed Central

Background Prostate cancer is one of the most common complex diseases with high leading cause of death in men. Identifications of prostate cancer associated genes and biomarkers are thus essential as they can gain insights into the mechanisms underlying disease progression and advancing for early diagnosis and developing effective therapies. Methods In this study, we presented an integrative analysis of gene expression profiling and protein interaction network at a systematic level to reveal candidate disease-associated genes and biomarkers for prostate cancer progression. At first, we reconstructed the human prostate cancer protein-protein interaction network (HPC-PPIN) and the network was then integrated with the prostate cancer gene expression data to identify modules related to different phases in prostate cancer. At last, the candidate module biomarkers were validated by its predictive ability of prostate cancer progression. Results Different phases-specific modules were identified for prostate cancer. Among these modules, transcription Androgen Receptor (AR) nuclear signaling and Epidermal Growth Factor Receptor (EGFR) signalling pathway were shown to be the pathway targets for prostate cancer progression. The identified candidate disease-associated genes showed better predictive ability of prostate cancer progression than those of published biomarkers. In context of functional enrichment analysis, interestingly candidate disease-associated genes were enriched in the nucleus and different functions were encoded for potential transcription factors, for examples key players as AR, Myc, ESR1 and hidden player as Sp1 which was considered as a potential novel biomarker for prostate cancer. Conclusions The successful results on prostate cancer samples demonstrated that the integrative analysis is powerful and useful approach to detect candidate disease-associate genes and modules which can be used as the potential biomarkers for prostate cancer progression. The data, tools and supplementary files for this integrative analysis are deposited at http://www.ibio-cn.org/HPC-PPIN/. PMID:25080090

2014-01-01

158

The Kidney Disease Center Progress Report 2007-2008 The Kidney Disease Center (KDC) was established July 1, 2005 under the direction of Richard  

E-print Network

The Kidney Disease Center Progress Report 2007-2008 The Kidney Disease Center (KDC) was established and breadth of its research programs. The research focus includes: the prevention of chronic kidney disease for the treatment of polycystic kidney disease, renal ischemia reperfusion injury and renal stone disease. #12

159

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

PubMed

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

Kuri-Cervantes, Leticia; de Oca, Gonzalo Salgado-Montes; Avila-Ríos, Santiago; Hernández-Juan, Ramón; Reyes-Terán, Gustavo

2014-07-01

160

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

SciTech Connect

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.

Ohnishi, T.; Hoshi, H.; Jinnouchi, S.; Nagamachi, S.; Watanabe, K.; Mituyama, Y. (Miyazaki Medical College (Japan))

1990-05-01

161

Urine Protein Analysis and Correlation of Urinary Biomarkers with Renal Disease Progression in Dogs with X-Linked Hereditary Nephropathy  

E-print Network

URINE PROTEIN ANALYSIS AND CORRELATION OF URINARY BIOMARKERS WITH RENAL DISEASE PROGRESSION IN DOGS WITH X-LINKED HEREDITARY NEPHROPATHY A Dissertation by MARY B. NABITY Submitted to the Office of Graduate Studies of Texas A... with Renal Disease Progression in Dogs with X-Linked Hereditary Nephropathy Copyright 2010 Mary B. Nabity URINE PROTEIN ANALYSIS AND CORRELATION OF URINARY BIOMARKERS WITH RENAL DISEASE PROGRESSION IN DOGS WITH X-LINKED HEREDITARY NEPHROPATHY A...

Nabity, Mary B.

2012-02-14

162

Tubular Deficiency of von Hippel-Lindau Attenuates Renal Disease Progression in Anti-GBM Glomerulonephritis  

PubMed Central

In many kidney diseases, the original insult primarily involves the glomerulus and may then pass onto the tubulointerstitium. Several hypotheses link glomerular disease to tubular injury; perhaps the foremost hypothesis involves chronic tubular hypoxia. The reported effects of hypoxia and consecutive stabilization of hypoxia-inducible factors (HIFs), however, are controversial. Hypoxia induces interstitial fibrosis but also has beneficial effects on renal disease progression when HIF is activated pharmacologically. To analyze the impact of HIF on tubulointerstitial disease development in primary glomerular disease, transgenic von Hippel Lindau (VHL)-knockout mice were generated and null expression was induced before the onset of autoimmune IgG-mediated anti–glomerular basement membrane glomerulonephritis (GN). Tubular VHL knockout and, thus, local HIF-? stabilization increased renal production of vascular endothelial growth factor, tumor growth factor–?1, and platelet-derived growth factor-B, resulting in augmented formation of capillaries and interstitial matrix, and conversion of fibroblasts to myofibroblasts. Within the glomerular disease, VHL knockout reduced the glomerular damage and attenuated tubulointerstitial injury. Likewise, proteinuria, plasma urea concentration, and tubulointerstitial matrix were decreased in VHL knockout with GN. These findings shown that tubular HIF-? stabilization in glomerular disease is beneficial for disease outcome. In comparison with VHL knockout alone, GN is a much stronger activator of fibrosis such that stimuli other than hypoxia may be considered important for renal disease progression. PMID:21925138

Theilig, Franziska; Enke, Anne Kathrin; Scolari, Brigitte; Polzin, Danny; Bachmann, Sebastian; Koesters, Robert

2011-01-01

163

Apolipoprotein A-IV predicts progression of chronic kidney disease: the mild to moderate kidney disease study.  

PubMed

It has not been established firmly whether dyslipidemia contributes independently to the progression of kidney disease. Lipid and lipoprotein parameters, including levels of total, HDL, and LDL cholesterol; triglycerides; lipoprotein(a); apolipoprotein A-IV; and the apolipoprotein E and A-IV polymorphisms, were assessed in 177 patients who had mostly mild to moderate renal insufficiency and were followed prospectively for up to 7 yr. Progression of kidney disease was defined as doubling of baseline serum creatinine and/or terminal renal failure necessitating renal replacement therapy. In univariate analysis, patients who reached a progression end point (n = 65) were significantly older and had higher serum creatinine and proteinuria as well as lower GFR and hemoglobin levels. In addition, baseline apolipoprotein A-IV and triglyceride concentrations were higher and HDL cholesterol levels were lower. Multivariate Cox regression analysis revealed that baseline GFR (hazard ratio 0.714; 95% confidence interval [CI] 0.627 to 0.814 for an increment of 10 ml/min per 1.73 m(2); P < 0.0001) and serum apolipoprotein A-IV concentrations (hazard ratio 1.062; 95% CI 1.018 to 1.108 for an increment of 1 mg/dl; P = 0.006) were significant predictors of disease progression. Patients with apolipoprotein A-IV levels above the median had a significantly faster progression (P < 0.0001), and their mean follow-up time to a progression end point was 53.7 mo (95% CI 47.6 to 59.8) as compared with 70.0 mo (95% CI 64.6 to 75.4) in patients with apolipoprotein A-IV levels below the median. For the apolipoprotein E polymorphism, only the genotype epsilon2/epsilon4 was associated with an increased risk for progression. In summary, this prospective study in patients with nondiabetic primary kidney disease demonstrated that apolipoprotein A-IV concentration is a novel independent predictor of progression. PMID:16382017

Boes, Eva; Fliser, Danilo; Ritz, Eberhard; König, Paul; Lhotta, Karl; Mann, Johannes F E; Müller, Gerhard A; Neyer, Ulrich; Riegel, Werner; Riegler, Peter; Kronenberg, Florian

2006-02-01

164

Longitudinal Association Between BMI at Diagnosis and HIV Disease Progression.  

PubMed

Increased body mass index (BMI) has been associated with adverse health outcomes but the effect of BMI on HIV immune markers over time post-HAART is not clearly established. Data were abstracted from 396 medical records at the Ryan White Clinic in South Carolina. All HIV-infected adults who were ?18 years of age, diagnosed between 1997 and 2010, had weight and height measured within 3 months of diagnosis and had at least one follow-up visit within 6 months of diagnosis, were eligible. The mean CD4 count was calculated for each BMI category and mixed regression analyses was used to determine the association between BMI and CD4 count over time. The overall mean BMI was 27.4 kg/m(2). Longitudinally, the mean CD4 count was 611.2 cells/mm(3) for obese individuals, 598.1 cells/mm(3) for overweight individuals and 550.5 cells/mm(3) for normal weight individuals. When compared to the normal weight category, the obese category had significantly larger increases in CD4 count (5.5 cells/mm(3), P < 0.001) versus the overweight category (-2.1 cells/mm(3), P < 0.001). HIV-infected individuals who were obese at diagnosis had larger increases in CD4 counts over time when compared to overweight individuals at diagnosis. This suggests that providers should pay closer attention to weight at diagnosis to predict the response to treatment and disease trajectory. PMID:24880700

Johnson, Kelly D; Cai, Bo; Duffus, Wayne; White, Kellee; Smieja, Marek; Divya, Ahuja; Merchant, Anwar T

2014-11-01

165

Disease progression model for cognitive deterioration from Alzheimer's Disease Neuroimaging Initiative database  

Microsoft Academic Search

BackgroundA mathematical model was developed to describe the longitudinal response in Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) obtained from the Alzheimer's Disease Neuroimaging Initiative.

Kaori Ito; Brian Corrigan; Qinying Zhao; Jonathan French; Raymond Miller; Holly Soares; Elyse Katz; Timothy Nicholas; Bill Billing; Richard Anziano; Terence Fullerton

2011-01-01

166

Cognitive and SPECT characteristics predict progression of Parkinson’s disease in newly diagnosed patients  

Microsoft Academic Search

Objective To identify features in cognitive functioning and regional cerebral blood flow (rCBF) in newly diagnosed Parkinson’s disease (PD) patients and to determine whether these factors are able to predict the progression of the disease in general and the development of cognitive decline in particular. Methods 50 previously treatment-naive PD patients participated in the study. Cognitive assessment and SPECT were

Kathy Dujardin; Luc Defebvre; Alain Duhamel; Pascal Lecouffe; Pascal Rogelet; Marc Steinling; Alain Destée

2004-01-01

167

Progression of Relapsing-Remitting Demyelinating Disease Does Not Require Increased TCR Affinity or Epitope Spread.  

PubMed

In this study, we investigate the basis of T cell recognition of myelin that governs the progression from acute symptoms into disease remission, relapse, and chronic progression in a secondary progressive model of demyelinating disease. Until now, the frequency and affinity of myelin-reactive CD4 T cells that elicit relapsing-remitting disease have not been quantified. The micropipette adhesion frequency assay was used to obtain a sensitive and physiologically relevant two-dimensional measurement of frequency and TCR affinity for myelin, as the inherent low affinity does not allow the use of specific peptide:MHC-II tetramers for this purpose. We found the highest affinity and frequency of polyclonal myelin oligodendrocyte glycoprotein-reactive cells infiltrate the CNS during acute disease, whereas affinities during remission, relapse, and chronic disease are not significantly different from each other. Frequency analysis revealed that the vast majority of CNS-infiltrating CD4 T cells are myelin oligodendrocyte glycoprotein reactive at all time points, demonstrating epitope spread is not a predominant factor for disease progression. Furthermore, time points at which mice were symptomatic were characterized by an infiltration of Th17 cells in the CNS, whereas symptom remission showed an enrichment of cells producing IFN-?. Also, the ratio of regulatory T cells to Foxp3(-) CD4 T cells was significantly higher in the CNS at remission than during acute disease. The results of this study indicate that a high frequency of T cells specific for a single myelin Ag, rather than increased TCR affinity or epitope spread, governs the transition from acute symptoms through remission, relapse, and chronic disease states. PMID:25267971

Kersh, Anna E; Edwards, Lindsay J; Evavold, Brian D

2014-11-01

168

Effect of Ethnicity on the Progression of Diabetic Kidney Disease Independent of Glycemic Control  

Microsoft Academic Search

Background\\/Aims: The prevalence of diabetic kidney disease (DKD) and risk of progression to end-stage renal disease is higher in African-Americans as compared to Caucasians. Whether the higher rate of estimated glomerular filtration rate (eGFR) decline in African-Americans is mediated by poor glycemic control is unclear. Methods: We conducted a prospective study of 183 (African-American, n = 95; Caucasian, n =

Moro O. Salifu; Syed Shah; Muhammad H. Iqbal; Mushtaq Nabi; Amir Hayat; Adam T. Whaley-Connell; James R. Sowers; Samy I. McFarlane

2009-01-01

169

Relaxin decreases renal interstitial fibrosis and slows progression of renal disease 1  

Microsoft Academic Search

Relaxin decreases renal interstitial fibrosis and slows progression of renal disease.BackgroundRelaxin, a hormone of the insulin-growth factor family, promotes collagen remodeling. In rodent models of pulmonary and dermal fibrosis, relaxin reduced interstitial fibrosis. To study relaxin's effect in renal disease, we used the experimental bromoethylamine (BEA) model that leads to severe renal interstitial fibrosis, a decrease in glomerular filtration rate,

Sandra L Garber; Yelena Mirochnik; Carolyn S Brecklin; Elaine N Unemori; Ashok K Singh; Leonid Slobodskoy; Beverly H Grove; Jose A L Arruda; George Dunea

2001-01-01

170

Amyotrophic Lateral Sclerosis (ALS)  

Microsoft Academic Search

ALS, commonly called Lou Gehrig's disease, is a devastating neurological dis- order characterized by selective upper and lower somatic, but not autonomic, motor neurone degeneration leading to paralysis and eventually death. The diagnosis of ALS requires the presence of both upper and lower motor neu- rone degeneration and progressive motor dysfunction. ALS occurs in 1 to 2.5 cases per 100,000

Chris G. Parsons; Wojciech Danysz

171

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

ERIC Educational Resources Information Center

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…

Marczinski, Cecile A.; Kertesz, Andrew

2006-01-01

172

A Randomized Trial of Multivitamin Supplements and HIV Disease Progression and Mortality  

Microsoft Academic Search

background Results from observational studies suggest that micronutrient status is a determinant of the progression of human immunodeficiency virus (HIV) disease. methods We enrolled 1078 pregnant women infected with HIV in a double-blind, placebo-con- trolled trial in Dar es Salaam, Tanzania, to examine the effects of daily supplements of vitamin A (preformed vitamin A and beta carotene), multivitamins (vitamins B,

Wafaie W. Fawzi; Gernard I. Msamanga; Donna Spiegelman; Ruilan Wei; Saidi Kapiga; Eduardo Villamor; Davis Mwakagile; Ferdinand Mugusi; Ellen Hertzmark; Max Essex; David J. Hunter

2004-01-01

173

Disease progression and evolution of the HIV-1 env gene in 24 infected infants  

E-print Network

Disease progression and evolution of the HIV-1 env gene in 24 infected infants§ Antonio Carvajal of Pediatrics, Columbia University College of Physicians and Surgeons and Harlem Hospital Center, NY, USA d and HIV-1 evolution in 24 infants classified as rapid or non-rapid progressors, during nearly the entire

Posada, David

174

Comparison of Selected Methods for Modeling of MultiState Disease Progression Processes: A Simulation Study  

Microsoft Academic Search

Prognostic studies are essential to understand the role of particular prognostic factors and, thus, improve prognosis. In most studies, disease progression trajectories of individual patients may end up with one of mutually exclusive endpoints or can involve a sequence of different events.One challenge in such studies concerns separating the effects of putative prognostic factors on these different endpoints and testing

Ella Huszti; Michal Abrahamowicz; Ahmadou Alioum; Catherine Quantin

2011-01-01

175

Advancing Drug Innovation for Neglected Diseases—Criteria for Lead Progression  

Microsoft Academic Search

The current drug R&D pipeline for most neglected diseases remains weak, and unlikely to support registration of novel drug classes that meet desired target product profiles in the short term. This calls for sustained investment as well as greater emphasis in the risky upstream drug discovery. Access to technologies, resourc- es, and strong management as well as clear compound progression

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

2009-01-01

176

Nonparametric Inference and Uniqueness for Periodically-Observed Progressive Disease Models  

PubMed Central

In many studies examining the progression of HIV and other chronic diseases, subjects are periodically monitored to assess their progression through disease states. This gives rise to a specific type of panel data which have been termed “chain-of-events data”; e.g. data that result from periodic observation of a progressive disease process whose states occur in a prescribed order and where state transitions are not observable. Using a discrete time semi-Markov model, we develop an algorithm for nonparametric estimation of the distribution functions of sojourn times in a J state progressive disease model. Issues of uniqueness for chain-of-events data are not well-understood. Thus, a main goal of this paper is to determine the uniqueness of the nonparametric estimators of the distribution functions of sojourn times within states. We develop sufficient conditions for uniqueness of the nonparametric maximum likelihood estimator, including situations where some but not all of its components are unique. We illustrate the methods with three examples. PMID:19629683

Griffin, Beth Ann; Lagakos, Stephen W.

2010-01-01

177

Methylprednisolone retards the progression of inherited polycystic kidney disease in rodents  

Microsoft Academic Search

Polycystic kidney disease in adult laboratory animals and humans is associated with enlarged kidneys and a progressive decline of renal function, resulting in death from uremia. Interstitial inflammation and fibrosis typically are observed in association with the development of renal insufficiency. To determine whether amelioration of interstitial inflammation and fibrosis may diminish cyst expansion\\/kidney enlargement and stabilize renal function, we

Vincent H. Gattone; Benjamin D. Cowley; Brian D. Barash; Shizuko Nagao; Hisahide Takahashi; Tamio Yamaguchi; Jared J. Grantham

1995-01-01

178

Electroacupuncture and Moxibustion Attenuate the Progression of Renal Disease in 5\\/6 Nephrectomized Rats  

Microsoft Academic Search

Background\\/Aim: Chronic kidney disease is a worldwide public health problem and the prevention of its progression is still a major challenge in nephrology. Specific therapies that inhibit or attenuate this process are neither available nor satisfactory. Traditional Chinese medicine has been increasingly recognized as an effective therapeutic approach in several fields of medicine. The aim of this study was to

Josne Carla Paterno; Anaflávia Oliveira Freire; Maria Fernanda Soares; Marcello Fabiano Franco; Nestor Schor; Vicente Paulo Castro Teixeira

2008-01-01

179

Progression of kidney disease in type 2 diabetes – beyond blood pressure control: an observational study  

Microsoft Academic Search

BACKGROUND: The risk factors for progression of chronic kidney disease (CKD) in type 2 diabetes mellitus (DM) have not been fully elucidated. Although uncontrolled blood pressure (BP) is known to be deleterious, other factors may become more important once BP is treated. METHODS: All patients seen in the outpatient clinics of our hospital between January 1993 and September 2002 with

David J Leehey; Holly J Kramer; Tarek M Daoud; Maninder P Chatha; Majd A Isreb

2005-01-01

180

Gender differences in HIV progression to AIDS and death in industrialized countries: slower disease progression following HIV seroconversion in women.  

PubMed

To evaluate sex differences in human immunodeficiency virus (HIV) disease progression before (pre-1997) and after (1997-2006) introduction of highly active antiretroviral therapy, the authors used data from a collaboration of 23 HIV seroconverter cohort studies from Europe, Australia, and Canada restricted to the 6,923 seroconverters infected through injecting drug use and sex between men and women. Within a competing risk framework, they used Cox proportional hazards models allowing for late entry to evaluate sex differences in time from HIV seroconversion to death, to acquired immunodeficiency syndrome (AIDS), and to each first AIDS-defining disease and death without AIDS. While no significant sex differences were found before 1997, from 1997 onward, women had a lower risk of AIDS (adjusted cumulative relative risk (aCRR) = 0.76, 95% confidence interval (CI): 0.63, 0.90) and death (adjusted hazard ratio = 0.68, 95% CI: 0.56, 0.82) than men did. Compared with men, women also had lower risks of AIDS dementia complex (aCRR = 0.23, 95% CI: 0.07, 0.74), tuberculosis (aCRR = 0.60, 95% CI: 0.39, 0.92), Kaposi's sarcoma (aCRR = 0.27, 95% CI: 0.07, 0.99), lymphomas (aCRR = 0.47, 95% CI: 0.23, 0.96), and death without AIDS (aCRR = 0.74, 95% CI: 0.56, 0.98). Sex differences in HIV disease progression have become larger and statistically significant in the era of highly active antiretroviral therapy, supporting a stronger impact of health interventions among women. PMID:18663213

Jarrin, Inmaculada; Geskus, Ronald; Bhaskaran, Krishnan; Prins, Maria; Perez-Hoyos, Santiago; Muga, Roberto; Hernández-Aguado, Ildefonso; Meyer, Laurence; Porter, Kholoud; del Amo, Julia

2008-09-01

181

Andriatahina et al. BMC Infectious Diseases 2010, 10:204 http://www.biomedcentral.com/1471-2334/10/204  

E-print Network

Andriatahina et al. BMC Infectious Diseases 2010, 10:204 http://www.biomedcentral.com/1471 of the article #12;Andriatahina et al. BMC Infectious Diseases 2010, 10:204 http://www.biomedcentral.com/1471

Paris-Sud XI, Université de

182

Vitamin D Related Host Genetic Variants Alter HIV Disease Progression in Children  

PubMed Central

Background Vitamin D deficiency is common in HIV infection and has been associated with advanced disease. This study investigated whether vitamin D related genetic variants were associated with disease progression in HIV-infected children. Methods The Fok-I (C/T), Bsm-I (G/A), GC (A/C), DHCR7 (G/T) and CYP2R1 (G/A) genetic variants were detected by RT-PCR in HIV-infected children who participated in the PACTG P152 and P300 protocols which pre-dated the availability of effective combination antiretroviral therapy. The primary endpoints included time to progression to the first HIV-related disease end-point (?2 OI's, weight-growth failure) or death, which constituted the progression-free-survival. Analyses were performed for age >2 years and ?2 years separately adjusting for race and treatment effect. Results Of the 998 children evaluated, 139 experienced HIV disease progression. For children >2 years, rapid disease progression was associated with the DHCR7 G allele compared to the T allele (G/G vs. T/T: HR=5.0, p=0.035, G/T vs. T/T: HR=4.5, p=0.042, G/G+G/T vs. T/T: HR=4.8, p=0.036), and the Bsm-I A allele compared to the G allele (A/G vs. G/G: HR=2.2, p=0.014 and A/G+A/A vs. G/G: HR=2.0, p=0.026). In children ?2 years, the Bsm-I A allele increased the risk of disease progression in Hispanics (A/A vs. G/A+G/G: HR=2.8, p=0.03; A/A vs. G/G: HR=2.8, p=0.046) and whites (A/A vs. G/G: HR=6.6, p=0.025; A/A vs. G/A+G/G: HR=3.6, p=0.038). Conclusions Vitamin D related host genetic variants that alter the availability and activity of vitamin D are associated with risk of HIV disease progression in children, and may vary by age and race. PMID:23736144

Moodley, Amaran; Qin, Min; Singh, Kumud K.; Spector, Stephen A.

2013-01-01

183

Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study.  

PubMed

It has not been firmly established whether disturbed calcium-phosphate metabolism affects progression of chronic kidney disease (CKD) in humans. In this cohort study of 227 nondiabetic patients with CKD, we assessed fibroblast growth factor 23 (FGF23) plasma concentrations in addition to other variables involved in calcium-phosphate metabolism, and we followed 177 of the patients prospectively for a median of 53 months to assess progression of renal disease. In the baseline cohort, we found a significant inverse correlation between glomerular filtration rate and both c-terminal and intact FGF23 levels (both P < 0.001). The 65 patients who experienced a doubling of serum creatinine and/or terminal renal failure were significantly older, had a significantly lower glomerular filtration rate at baseline, and significantly higher levels of intact parathormone, c-terminal and intact FGF23, and serum phosphate (all P < 0.001). Cox regression analysis revealed that both c-terminal and intact FGF23 independently predict progression of CKD after adjustment for age, gender, GFR, proteinuria, and serum levels of calcium, phosphate, and parathyroid hormone. The mean follow-up time to a progression end point was 46.9 (95% CI 40.2 to 53.6) months versus 72.5 (95% CI 67.7 to 77.3) months for patients with c-terminal FGF23 levels above or below the optimal cut-off level of 104 rU/mL (derived by receiver operator curve analysis), respectively. In conclusion, FGF23 is a novel independent predictor of progression of renal disease in patients with nondiabetic CKD. Its pathophysiological significance remains to be elucidated. PMID:17656479

Fliser, Danilo; Kollerits, Barbara; Neyer, Ulrich; Ankerst, Donna P; Lhotta, Karl; Lingenhel, Arno; Ritz, Eberhard; Kronenberg, Florian; Kuen, Erich; König, Paul; Kraatz, Günter; Mann, Johannes F E; Müller, Gerhard A; Köhler, Hans; Riegler, Peter

2007-09-01

184

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

PubMed Central

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

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

2014-01-01

185

Unveiling Clusters of RNA Transcript Pairs Associated with Markers of Alzheimer's Disease Progression  

PubMed Central

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

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

2012-01-01

186

HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility  

PubMed Central

BACKGROUND AND AIMS—Twin and family studies suggest that there is a genetic component to primary biliary cirrhosis (PBC) but the genetic associations which have been described are weak with marked variations between centres. PBC is heterogeneous and genetic associations with disease progression may be obscured when the PBC population is analysed only as a whole and not subdivided.?METHODS—We have investigated two candidate gene loci in 164 well characterised patients, 88 (54%) of whom had advanced disease.?RESULTS—There was an increased frequency of the HLA DRB1*0801-DQA1*0401-DQB1*0402 haplotype in patients who had progressed to late stage disease (23% v 2% of controls; p=0000044; odds ratio (OR) 15.5, 95% confidence interval (CI) 3.52-68.4) but not in those with early stage disease (4% v 2%). Patients had a higher frequency of the IL-1B*1,1 genotype and lower frequencies of the IL-1B*1,2 and *2,2 genotypes (p=0.00078; OR 2.37, 95% CI 1.38-4.06), and higher frequency of the IL-1RN*1,1 genotype and lower frequency of the IL-1RN*1,2 genotype (p=0.0011; OR 2.28, 95% CI 1.34-3.89). The difference in the IL-1B*1,1 genotype distribution was most marked in patients with early stage disease (77% v 43% of controls; p=0.000003; OR 4.8, 95% CI 2.31-10) but the IL-1RN genotype distribution was similar in patients with early and late stage disease.?CONCLUSIONS—These data indicate a complex relationship between immunoregulatory genes and PBC. While the IL-1 genes are markers of both disease susceptibility and progression, HLA genes appear to be principally associated with disease progression.???Keywords: human leucocyte antigens; primary biliary cirrhosis; interleukin 1 PMID:11171832

Donaldson, P; Agarwal, K; Craggs, A; Craig, W; James, O; Jones, D

2001-01-01

187

Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C.  

PubMed

Niemann-Pick disease, type C is a neurodegenerative, lysosomal storage disorder with a broad clinical spectrum and a variable age of onset. The absence of a universally accepted clinical outcome measure is an impediment to the design of a therapeutic trial for NPC. Thus, we developed a clinical severity scale to characterize and quantify disease progression. Clinical signs and symptoms in nine major (ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, and swallowing) and eight minor (auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, and respiratory problems) domains were scored. Data were collected from 18 current NPC patients and were extracted from records of 19 patients. Both patient cohorts showed a linear increase in severity scores over time. Cross-sectional evaluation of current patients showed a linear increase in the severity score. Longitudinal chart review of historical data demonstrated that although age of onset varied significantly, the rate of progression appeared linear, independent of age of onset, and similar in all patients. Combining the data from both cohorts, disease progression could be modeled by the following equation: ?(t0+x) = ?(t0) + 1.87x; where ?(t0) is the initial score and ?(t0+x) is the predicted future score after x years. Our observation that disease progression is similar across patients and independent of age of onset is consistent with a biphasic pathological model for NPC. This scale may prove useful in the characterization of potential biomarkers, and as an outcome measure to monitor disease progression in NPC patients. PMID:19415691

Yanjanin, Nicole M; Vélez, Jorge I; Gropman, Andrea; King, Kelly; Bianconi, Simona E; Conley, Sandra K; Brewer, Carmen C; Solomon, Beth; Pavan, William J; Arcos-Burgos, Mauricio; Patterson, Marc C; Porter, Forbes D

2010-01-01

188

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

NASA Astrophysics Data System (ADS)

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.

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

2000-04-01

189

Deworming helminth co-infected individuals for delaying HIV disease progression  

PubMed Central

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

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

2009-01-01

190

Funding agencies and disease organizations: resources and recommendations to facilitate ALS clinical research.  

PubMed

Ten groups presented their perspectives on facilitating clinical research in ALS including four federal agencies, four disease organizations, one foundation and one advocacy group. The federal agencies (National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Office of Rare Diseases Research, Department of Defense) encourage fostering a team approach between pre-clinical and clinical research investigators, coordinating with patient groups in the early phases of clinical studies, enhancing private and public partnerships, and investigating the interplay between genetic susceptibility and environmental exposure. The disease organizations (Muscular Dystrophy Association, ALS Association, ALS Society of Canada, and the Motor Neurone Disease Association UK) support fellowship training programs to develop ALS clinician scientists, and encourage work on the epidemiology of ALS, on genetic and epigenetic mechanisms that are relevant to ALS pathogenesis, on developing ALS registries and biobanks, and building bridges of collaboration among study groups. The Foundation supports innovative projects, including stem-cell research, and Patient Advocacy is committed to supporting excellence in ALS research and patient care, and believes strongly in enhancing communication between patients and members of the research community. PMID:23678881

Chad, David A; Bidichandani, Sanjay; Bruijn, Lucie; Capra, J Donald; Dickie, Brian; Ferguson, John; Figlewicz, Denise; Forsythe, Melissa; Kaufmann, Petra; Kirshner, Annette; Monti, William

2013-05-01

191

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

E-print Network

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

Chau, Phuong My

2010-08-31

192

Sirolimus attenuates disease progression in an orthologous mouse model of human autosomal dominant polycystic kidney disease  

Microsoft Academic Search

In autosomal dominant polycystic kidney disease (ADPKD), abnormal proliferation of tubular cells drives cyst development and growth. Sirolimus, an inhibitor of the protein kinase mammalian target of rapamycin (mTOR) and a potent anti-proliferative agent, decreases cyst growth in several genetically distinct rodent models of polycystic kidney disease (PKD). We determined here the effect of sirolimus on renal cyst growth in

Iram Zafar; Kameswaran Ravichandran; Franck A Belibi; R Brian; Charles L Edelstein

2010-01-01

193

Plasma 24S-hydroxycholesterol correlation with markers of Huntington disease progression  

PubMed Central

24S-hydroxycholesterol (24OHC) is involved in the conversion of excess cholesterol in the brain, and its level in plasma is related to the number of metabolically active neuronal cells. Previous research suggests that plasma 24OHC is substantially reduced in the presence of neurodegenerative disease. Huntington disease (HD) is an inherited autosomal dominant neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) triplet repeat expansion in the coding region of the huntingtin (HTT) gene. The current study focused on the relative importance of 24OHC as a marker of HD progression. Using mass spectrometry methods, plasma 24OHC levels were examined in three groups of gene-expanded individuals (Low, Medium, High) characterized by their progression at entry into the parent PREDICT-HD study, along with a group of non-gene-expanded controls (total N = 150). In addition, the correlation of 24OHC with a number of motor, cognitive, and imagining markers was examined, and effect sizes for group differences among the markers were computed for comparison with 24OHC. Results show a progression gradient as 24OHC levels decreased as the progression group increased (Low to High). The effect size of group differences for 24OHC was larger than all the other variables, except striatal volume. 24OHC was significantly correlated with many of the other key variables. The results are interpreted in terms of cholesterol synthesis and neuronal degeneration. This study provides evidence that 24OHC is a relatively important marker of HD progression. PMID:23557875

Leoni, Valerio; Long, Jeffrey D.; Mills, James A.; Di Donato, Stefano

2013-01-01

194

Plasma 24S-hydroxycholesterol correlation with markers of Huntington disease progression.  

PubMed

24S-hydroxycholesterol (24OHC) is involved in the conversion of excess cholesterol in the brain, and its level in plasma is related to the number of metabolically active neuronal cells. Previous research suggests that plasma 24OHC is substantially reduced in the presence of neurodegenerative disease. Huntington disease (HD) is an inherited autosomal dominant neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) triplet repeat expansion in the coding region of the huntingtin (HTT) gene. The current study focused on the relative importance of 24OHC as a marker of HD progression. Using mass spectrometry methods, we examined plasma 24OHC levels in three groups of gene-expanded individuals (Low, Medium, High) characterized by their progression at entry into the parent PREDICT-HD study, along with a group of non-gene-expanded controls (total N=150). In addition, the correlation of 24OHC with a number of motor, cognitive, and imagining markers was examined, and effect sizes for group differences among the markers were computed for comparison with 24OHC. Results show a progression gradient as 24OHC levels decreased as the progression group increased (Low to High). The effect size of group differences for 24OHC was larger than all the other variables, except striatal volume. 24OHC was significantly correlated with many of the other key variables. The results are interpreted in terms of cholesterol synthesis and neuronal degeneration. This study provides evidence that 24OHC is a relatively important marker of HD progression. PMID:23557875

Leoni, Valerio; Long, Jeffrey D; Mills, James A; Di Donato, Stefano; Paulsen, Jane S

2013-07-01

195

Inflammation in sputum relates to progression of disease in subjects with COPD: a prospective descriptive study  

PubMed Central

Background Inflammation is considered to be of primary pathogenic importance in COPD but the evidence on which current understanding is based does not distinguish between cause and effect, and no single mechanism can account for the complex pathology. We performed a prospective longitudinal study of subjects with COPD that related markers of sputum inflammation at baseline to subsequent disease progression. Methods A cohort of 56 patients with chronic bronchitis was characterized in the stable state at baseline and after an interval of four years, using physiological measures and CT densitometry. Sputum markers of airway inflammation were quantified at baseline from spontaneously produced sputum in a sub-group (n = 38), and inflammation severity was related to subsequent disease progression. Results Physiological and CT measures indicated disease progression in the whole group. In the sub-group, sputum myeloperoxidase correlated with decline in FEV1 (rs = -0.344, p = 0.019, n = 37). LTB4 and albumin leakage correlated with TLCO decline (rs = -0.310, p = 0.033, rs = -0.401, p = 0.008, respectively, n = 35) and IL-8 correlated with progression of lung densitometric indices (rs = -0.464, p = 0.005, n = 38). Conclusion The data support a principal causative role for neutrophilic inflammation in the pathogenesis of COPD and suggest that the measurement of sputum inflammatory markers may have a predictive role in clinical practice. PMID:17112387

Parr, David G; White, Andrew J; Bayley, Darren L; Guest, Peter J; Stockley, Robert A

2006-01-01

196

Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease  

PubMed Central

DJ-1 mutations cause autosomal recessive early-onset Parkinson disease (PD). We report a model of PD pathology: the DJ1-C57 mouse. A subset of DJ-1–nullizygous mice, when fully backcrossed to a C57BL/6J background, display dramatic early-onset unilateral loss of dopaminergic (DA) neurons in their substantia nigra pars compacta, progressing to bilateral degeneration of the nigrostriatal axis with aging. In addition, these mice exhibit age-dependent bilateral degeneration at the locus ceruleus nucleus and display mild motor behavior deficits at aged time points. These findings effectively recapitulate the early stages of PD. Therefore, the DJ1-C57 mouse provides a tool to study the preclinical aspects of neurodegeneration. Importantly, by exome sequencing, we identify candidate modifying genes that segregate with the phenotype, providing potentially critical clues into how certain genes may influence the penetrance of DJ-1–related degeneration in mice. PMID:23019375

Rousseaux, Maxime W. C.; Marcogliese, Paul C.; Qu, Dianbo; Hewitt, Sarah J.; Seang, Sarah; Kim, Raymond H.; Slack, Ruth S.; Schlossmacher, Michael G.; Lagace, Diane C.; Mak, Tak W.; Park, David S.

2012-01-01

197

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

PubMed

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

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

2014-07-15

198

Does study partner type impact the rate of Alzheimer’s disease progression?  

PubMed Central

Most patients with Alzheimer’s disease (AD) do not have a spouse. Despite this, the majority of AD research participants enroll with a spouse study partner. It remains unclear if differences between AD patients who do and do not have a spouse may bias study results. In this study, we examined whether AD patients with different study partner types (spouse vs adult child) demonstrate different rates of disease progression over two years on three outcome measures commonly used in AD research, including clinical trials. We used data from the National Alzheimer’s Coordinating Center Uniform Data Set to examine disease progression in participants age 55–90 with probable AD dementia. We examined disease progression as measured by the Clinical Dementia Rating Scale-Sum of the Boxes score, the Mini Mental Status Examination, and the Functional Assessment Questionnaire. Analyses were performed on data for all available eligible participants from the NACC UDS and after performing a propensity-matching model to better account for inherent differences between the populations of interest. Propensity matching was successful only when models did not include age and gender. For both propensity-matched analyses and those of all available data, we did not observe any differences between the study partner populations for any outcome measure. These results suggest that, if investigators can improve in recruiting AD patients with adult child caregivers to research, the implications to study results may be minimal. PMID:23985417

Grill, Joshua D.; Zhou, Yan; Karlawish, Jason; Elashoff, David

2013-01-01

199

Amyloid ?-Peptide (1-42)-Induced Oxidative Stress in Alzheimer Disease: Importance in Disease Pathogenesis and Progression  

PubMed Central

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 (A?) 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 A? is critical to A?-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

Swomley, Aaron M.; Sultana, Rukhsana

2013-01-01

200

Accelerated Disease Onset with Stabilized Familial Amyotrophic Lateral Sclerosis (ALS)-linked Mutant TDP-43 Proteins*  

PubMed Central

Abnormal protein accumulation is a pathological hallmark of neurodegenerative diseases, including accumulation of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS). Dominant mutations in the TDP-43 gene are causative for familial ALS; however, the relationship between mutant protein biochemical phenotypes and disease course and their significance to disease pathomechanism are not known. Here, we found that longer half-lives of mutant proteins correlated with accelerated disease onset. Based on our findings, we established a cell model in which chronic stabilization of wild-type TDP-43 protein provoked cytotoxicity and recapitulated pathogenic protein cleavage and insolubility to the detergent Sarkosyl, TDP-43 properties that have been observed in sporadic ALS lesions. Furthermore, these cells showed proteasomal impairment and dysregulation of their own mRNA levels. These results suggest that chronically increased stability of mutant or wild-type TDP-43 proteins results in a gain of toxicity through abnormal proteostasis. PMID:23235148

Watanabe, Shoji; Kaneko, Kumi; Yamanaka, Koji

2013-01-01

201

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

PubMed

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

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

2014-01-01

202

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

PubMed Central

In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials. DOI: http://dx.doi.org/10.7554/eLife.03821.001 PMID:25217531

Williams, James P; Hurst, Jacob; Stöhr, Wolfgang; Robinson, Nicola; Brown, Helen; Fisher, Martin; Kinloch, Sabine; Cooper, David; Schechter, Mauro; Tambussi, Giuseppe; Fidler, Sarah; Carrington, Mary; Babiker, Abdel; Weber, Jonathan

2014-01-01

203

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

PubMed

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

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

2013-01-01

204

Advancing Drug Innovation for Neglected Diseases—Criteria for Lead Progression  

PubMed Central

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

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

2009-01-01

205

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

PubMed Central

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

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

2014-01-01

206

Serum inflammatory markers and clinical\\/MRI markers of disease progression in multiple sclerosis  

Microsoft Academic Search

The aim of this study was to assess whether mean serum levels of inflammatory markers when measured serially correlate with\\u000a disease progression or putative MRI markers of axonal loss in a cohort of well-characterised multiple sclerosis (MS) patients.\\u000a Serial serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1),\\u000a nitric oxide metabolites nitrate and nitrite (NOx),

G. Giovannoni; D. H. Miller; N. A. Losseff; M. Sailer; N. Lewellyn-Smith; A. J. Thompson; E. J. Thompson

2001-01-01

207

Recent cigarette smoking and HIV disease progression: no evidence of an association  

Microsoft Academic Search

The association between smoking and HIV disease progression has been examined in several studies; however, findings have been inconsistent. We examined the effect of recent cigarette smoking on CD4 T cell count\\/µl (CD4 count) and HIV RNA concentration (HIV viral load (VL)) among two HIV-infected cohorts with alcohol problems in Massachusetts in the periods 1997–2001 and 2001–2006 using a prospective

Conrad Kabali; Debbie M. Cheng; Daniel Brooks; Carly Bridden; Robert Horsburgh Jr; Jeffrey H. Samet

2011-01-01

208

Immunologic characterization of children vertically infected with human immunodeficiency virus, with slow or rapid disease progression  

Microsoft Academic Search

Cytokine production of unstimulated and mitogen-stimulated peripheral blood mononuclear cells of 31 children vertically infected with human immunodeficiency virus type 1 (HIV) and with different patterns of disease progression was evaluated to establish possible correlations between the immunologic and the clinical findings. Production of interferon gamma and interleukin-2 (type 1 cytokines), and of interleukin-4 and interleukin-10 (type 2 cytokines), was

Alessandra Viganó; Nicola Principi; Maria Luisa Villa; Chiara Riva; Lina Crupi; Daria Trabattoni; Gene M. Shearer; Mario Clerici

1995-01-01

209

Clinical Reactivations of Herpes Simplex Virus Type 2 Infection and Human Immunodeficiency Virus Disease Progression Markers  

Microsoft Academic Search

BackgroundThe natural history of HSV-2 infection and role of HSV-2 reactivations in HIV disease progression are unclear.MethodsClinical symptoms of active HSV-2 infection were used to classify 1,938 HIV\\/HSV-2 co-infected participants of the Women's Interagency HIV Study (WIHS) into groups of varying degree of HSV-2 clinical activity. Differences in plasma HIV RNA and CD4+ T cell counts between groups were explored

Bulbulgul Aumakhan; Charlotte A. Gaydos; Thomas C. Quinn; Chris Beyrer; Lorie Benning; Howard Minkoff; Daniel J. Merenstein; Mardge Cohen; Ruth Greenblatt; Marek Nowicki; Kathryn Anastos; Stephen J. Gange

2010-01-01

210

Immunophilin ligands can prevent progressive dopaminergic degeneration in animal models of Parkinson's disease  

Microsoft Academic Search

Slowing or halting the progressive dopaminergic (DA) degeneration in Parkinson's disease (PD) would delay the onset and development of motor symptoms, prolong the efficacy of pharmacotherapies and decrease drug-induced side-effects. We tested the potential of two orally administered novel immunophilin ligands to protect against DA degeneration in two animal models of PD. First, in an MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model, we

Lauren C. Costantini; Douglas Cole; Ole Isacson

2001-01-01

211

BCL6 Oncoprotein in Breast Cancer: Loss of Expression in Disease Progression  

Microsoft Academic Search

Objective: To investigate the biological role of BCL-6 oncoprotein in breast cancer disease progression (recurrence and metastasis). Methods: The series consisted of 93 consecutive female patients with primary breast cancer and median follow-up of 10 years. BCL-6 expression was assessed in vivo by immunohistochemistry and real-time PCR. Breast cancer cell lines and some metastasis-related genes (CXCR4, Itg?-3 and FLT-1) were

António E. Pinto; Saudade André; Giovani Silva; Sara Vieira; Ana C. Santos; Sérgio Dias; Jorge Soares

2009-01-01

212

Progress in peripheral nerve disease research in the last two years.  

PubMed

Peripheral nerve disorders have been a Cinderella subspecialty for neurologists because of the limited treatment options and difficulties in obtaining a genetic diagnosis. In the last decade, there has been great progress in the management of patients with peripheral nerve disease. In this paper, we review a selection of diagnostic and therapeutic papers in this area published in the Journal of Neurology over the last 24 months. PMID:24154508

Evans, Matthew; Manji, Hadi

2013-12-01

213

Longitudinal association of alcohol use with HIV disease progression and psychological health of women with HIV  

Microsoft Academic Search

We evaluated the association of alcohol consumption and depression, and their effects on HIV disease progression among women with HIV. The study included 871 women with HIV who were recruited from 1993–1995 in four US cities. The participants had physical examination, medical record extraction, and venipuncture, CD4+T-cell counts determination, measurement of depression symptoms (using the self-report Center for Epidemiological Studies-Depression

Musie Ghebremichael; Elijah Paintsil; Jeannette R. Ickovics; David Vlahov; Paula Schuman; Robert Boland; Ellie Schoenbaum; Janet Moore; Heping Zhang

2009-01-01

214

The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease  

Microsoft Academic Search

The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease The renin-angiotensin-aldosterone system (RAAS) is a well known regulator of blood pressure (BP) and determinant of target-organ damage. It controls fluid and electrolyte balance through coordinated effects on the heart, blood vessels, and Kidneys. Angiotensin II (AII) is the main effector of the RAAS and exerts its vasoconstrictor

GIUSEPPE REMUZZI; NORBERTO PERICO; MANUEL MACIA; PIERO RUGGENENTI

2005-01-01

215

Neurofibrillary tangles in Alzheimer's disease and progressive supranuclear palsy: antigenic similarities and differences  

Microsoft Academic Search

The antigenic profile of neurofibrillary tangles (NFT) in Alzheimer's disease (AD), senile dementia of Alzheimer type (SDAT), progressive supranuclear palsy (PSP) and in non-demented aged humans was investigated by light and electron microscopic immunocytochemistry using antisera and monoclonal antibodies to tubulin, microtubule-associated proteins (MAP1, MAP2 and tau), neurofilament proteins and determinants unique to Alzheimer paired helical filaments (PHF). Antibodies to

C. Bancher; H. Lassmann; H. Budka; I. Grundke-Iqbal; K. Iqbal; G. Wiche; F. Seitelberger; H. M. Wisniewski

1987-01-01

216

Mass General study finds transition in cell type parallels treatment response, disease progression in breast cancer  

Cancer.gov

A process that normally occurs in developing embryos – the changing of one basic cell type into another – has also been suspected of playing a role in cancer metastasis. Now a study from researchers at the Massachusetts General Hospital Cancer Center, a component of the Dana-Farber Cancer Institute, has associated this process, called epithelial-mesenchymal transition or EMT, with disease progression and treatment response in breast cancer patients. The report also identifies underlying mechanisms that someday may become therapeutic targets.

217

Vgf is a novel biomarker associated with muscle weakness in amyotrophic lateral sclerosis (ALS), with a potential role in disease pathogenesis.  

PubMed

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Previous proteomic evidence revealed that the content of certain peptide fragments including Vgf-derived peptide aa 398-411 (Vgf(398-411)) of the precursor Vgf protein in the cerebral spinal fluid (CSF) correctly identified patients with ALS from normal and disease controls. Using quantitative ELISA immunoassay we found that the CSF levels of Vgf decreases with muscle weakness in patients with ALS. In SOD1 G93A transgenic mice, loss of full-length Vgf content in CSF, serum and in SMI-32 immunopositive spinal cord motor neurons is noted in asymptomatic animals (approximately 75 days old) and continues to show a progressive decline as animals weaken. In vitro studies show that viral-mediated exogenous Vgf expression in primary mixed spinal cord neuron cultures attenuates excitotoxic injury. Thus, while Vgf may be a reliable biomarker of progression of muscle weakness in patients with ALS, restoration of Vgf expression in spinal cord motor neurons may therapeutically rescue spinal cord motorneurons against excitotoxic injury. PMID:18432310

Zhao, Zhong; Lange, Dale J; Ho, Lap; Bonini, Sara; Shao, Belinda; Salton, Stephen R; Thomas, Sunil; Pasinetti, Giulio Maria

2008-01-01

218

Social and structural factors associated with HIV disease progression among illicit drug users: A systematic review  

PubMed Central

Objective To systematically review factors associated with HIV disease progression among illicit drug users, focusing on exposures exogenous to individuals that likely shape access and adherence to HIV treatment. Design A systematic review of peer-reviewed English-language studies among HIV-seropositive illicit drug users with at least one of these endpoint of interest: a diagnosis of AIDS; death; changes/differences in CD4 cell counts; or changes/differences in plasma HIV-1 RNA levels. Methods Articles were included if they reported factors associated with an outcome of interest among a group of illicit drug users. Studies were identified, screened and selected using systematic methods. Results Of 2,668 studies matching the search criteria, 58 (2%) met the inclusion criteria, all but one from North America or Western Europe. Overall, 41 (71%) studies contained significant individual-level clinical characteristics or behaviours (e.g., illicit drug use) associated with disease progression. Fifteen studies (26%) identified significant social, physical, economic or policy-level exposures, including incarceration, housing status or lack of legal income. Conclusion While past studies demonstrate important environmental exposures that appear to shape access to care and subsequent disease progression, the limited literature to examine these factors demonstrates the need for future research to consider risk environment characteristics and the role they may play in shaping health outcomes from HIV infection among drug users through determining access and adherence to evidence-based care. (198 words) PMID:22333747

Milloy, M-J; Marshall, Brandon; Kerr, Thomas; Buxton, Jane; Rhodes, Tim; Montaner, Julio; Wood, Evan

2014-01-01

219

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

SciTech Connect

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.

Crawford, F.; Bennett, C.; Osborne, A. [Univ. of South Florida, Tampa, FL (United States)] [and others

1994-09-01

220

Temporal Profile of the Renal Transcriptome of HIV-1 Transgenic Mice during Disease Progression  

PubMed Central

Profiling of temporal changes of gene expression in the same kidney over the course of renal disease progression is challenging because repeat renal biopsies are rarely indicated in clinical practice. Here, we profiled the temporal change in renal transcriptome of HIV-1 transgenic mice (Tg26), an animal model for human HIV-associated nephropathy (HIVAN), and their littermates at three different time points (4, 8, and 12 weeks of age) representing early, middle, and late stages of renal disease by serial kidney biopsy. We analyzed both static levels of gene expression at three stages of disease and dynamic changes in gene expression between different stages. Analysis of static and dynamic changes in gene expression revealed that up-regulated genes at the early and middle stages are mostly involved in immune response and inflammation, whereas down-regulated genes mostly related to fatty acid and retinoid metabolisms. We validated the expression of a selected panel of genes that are up-regulated at the early stage (CCL2, CCL5, CXCL11, Ubd, Anxa1, and Spon1) by real-time PCR. Among these up-regulated genes, Spon1, which is a previously identified candidate gene for hypertension, was found to be up-regulated in kidney of human with diabetic nephropathy. Immunostaining of human biopsy samples demonstrated that protein expression of Spon1 was also markedly increased in kidneys of patients with both early and late HIVAN and diabetic nephropathy. Our studies suggest that analysis of both static and dynamic changes of gene expression profiles in disease progression avails another layer of information that could be utilized to gain a more comprehensive understanding of disease progression and identify potential biomarkers and drug targets. PMID:24667548

Fan, Ying; Wei, Chengguo; Xiao, Wenzhen; Zhang, Weijia; Wang, Niansong; Chuang, Peter Y.; He, John Cijiang

2014-01-01

221

Novel White Matter Tract Integrity Metrics Sensitive to Alzheimer Disease Progression  

PubMed Central

BACKGROUND AND PURPOSE Along with cortical abnormalities, white matter microstructural changes such as axonal loss and myelin breakdown are implicated in the pathogenesis of Alzheimer disease. Recently, a white matter model was introduced that relates non-Gaussian diffusional kurtosis imaging metrics to characteristics of white matter tract integrity, including the axonal water fraction, the intra-axonal diffusivity, and the extra-axonal axial and radial diffusivities. MATERIALS AND METHODS This study reports these white matter tract integrity metrics in subjects with amnestic mild cognitive impairment (n = 12), Alzheimer disease (n = 14), and age-matched healthy controls (n = 15) in an effort to investigate their sensitivity, diagnostic accuracy, and associations with white matter changes through the course of Alzheimer disease. RESULTS With tract-based spatial statistics and region-of-interest analyses, increased diffusivity in the extra-axonal space (extra-axonal axial and radial diffusivities) in several white matter tracts sensitively and accurately discriminated healthy controls from those with amnestic mild cognitive impairment (area under the receiver operating characteristic curve = 0.82–0.95), while widespread decreased axonal water fraction discriminated amnestic mild cognitive impairment from Alzheimer disease (area under the receiver operating characteristic curve = 0.84). Additionally, these white matter tract integrity metrics in the body of the corpus callosum were strongly correlated with processing speed in amnestic mild cognitive impairment (r= |0.80–0.82|, P< .001). CONCLUSIONS These findings have implications for the course and spatial progression of white matter degeneration in Alzheimer disease, suggest the mechanisms by which these changes occur, and demonstrate the viability of these white matter tract integrity metrics as potential neuroimaging biomarkers of the earliest stages of Alzheimer disease and disease progression. PMID:23764722

Fieremans, E.; Benitez, A.; Jensen, J.H.; Falangola, M.F.; Tabesh, A.; Deardorff, R.L.; Spampinato, M.V.S.; Babb, J.S.; Novikov, D.S.; Ferris, S.H.; Helpern, J.A.

2014-01-01

222

Differential Virulence and Disease Progression following Mycobacterium tuberculosis Complex Infection of the Common Marmoset (Callithrix jacchus)  

PubMed Central

Existing small-animal models of tuberculosis (TB) rarely develop cavitary disease, limiting their value for assessing the biology and dynamics of this highly important feature of human disease. To develop a smaller primate model with pathology similar to that seen in humans, we experimentally infected the common marmoset (Callithrix jacchus) with diverse strains of Mycobacterium tuberculosis of various pathogenic potentials. These included recent isolates of the modern Beijing lineage, the Euro-American X lineage, and M. africanum. All three strains produced fulminant disease in this animal with a spectrum of progression rates and clinical sequelae that could be monitored in real time using 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT). Lesion pathology at sacrifice revealed the entire spectrum of lesions observed in human TB patients. The three strains produced different rates of progression to disease, various extents of extrapulmonary dissemination, and various degrees of cavitation. The majority of live births in this species are twins, and comparison of results from siblings with different infecting strains allowed us to establish that the infection was highly reproducible and that the differential virulence of strains was not simply host variation. Quantitative assessment of disease burden by FDG-PET/CT provided an accurate reflection of the pathology findings at necropsy. These results suggest that the marmoset offers an attractive small-animal model of human disease that recapitulates both the complex pathology and spectrum of disease observed in humans infected with various M. tuberculosis strain clades. PMID:23716617

Via, Laura E.; Weiner, Danielle M.; Schimel, Daniel; Lin, Philana Ling; Dayao, Emmanuel; Tankersley, Sarah L.; Cai, Ying; Coleman, M. Teresa; Tomko, Jaime; Paripati, Praveen; Orandle, Marlene; Kastenmayer, Robin J.; Tartakovsky, Michael; Rosenthal, Alexander; Portevin, Damien; Eum, Seok Yong; Lahouar, Saher; Gagneux, Sebastien; Young, Douglas B.; Flynn, JoAnne L.

2013-01-01

223

Sustained mobilization of endogenous neural progenitors delays disease progression in a transgenic model of Huntington's Disease  

PubMed Central

Huntington's disease (HD) is a neurodegenerative disease characterized in part by the loss of striatopallidal medium spiny projection neurons (MSNs). Expression of BDNF and noggin via intracerebroventricular (ICV) delivery in an adenoviral vector triggers the addition of new neurons to the neostriatum. In this study, we found that a single ICV injection of the adeno-associated viruses AAV4-BDNF and AAV4-noggin triggered the sustained recruitment of new MSNs in both wild-type and R6/2 mice, a model of HD. Mice treated with AAV4-BDNF/noggin, or with BDNF and noggin proteins, actively recruited subependymal progenitor cells to form new MSNs that matured and achieved circuit integration. Importantly, the AAV4-BDNF/noggin-treated R6/2 mice showed delayed deterioration of motor function and substantially increased survival. In addition, squirrel monkeys given ICV injections of AAV4-BDNF/noggin showed similar addition of striatal neurons. Induced neuronal addition may therefore represent a promising avenue for disease amelioration in HD. PMID:23746982

Benraiss, Abdellatif; Toner, Michael J.; Xu, Qiwu; Bruel-Jungerman, Elodie; Rogers, Eloise H.; Wang, Fushun; Economides, Aris N.; Davidson, Beverly L.; Kageyama, Ryoichiro; Nedergaard, Maiken; Goldman, Steven A.

2014-01-01

224

C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS.  

PubMed

ALS therapy development has been hindered by the lack of rodent animal models. The discovery of TDP-43, a transcription factor that accumulates in the cytoplasm of motor neurons (MNs) in most cases of ALS, prompted attempts to develop TDP-43-based models of the disease. The current study sought to examine, in extensive detail, the emerging disease phenotype of a transgenic mouse model that overexpresses a mutant human TDP-43 (hTDP-43) gene under mouse prion promoter control. Careful attention was given to ALS-like characteristics to determine the appropriateness of this model for testing therapies for ALS. In light of previous reports that gastrointestinal (GI) dysfunction is responsible for early death in these mice, gut immunohistochemistry (IHC) and longitudinal gut motility assays were used to identify the onset and the progression of these defects. IHC studies revealed that site-specific overexpression of the hTDP-43 transgene in colonic myenteric plexes resulted in progressive neurodegeneration in this region. This change was associated with progressively reduced GI motility, culminating in frank stasis that was primarily responsible for decreasing longevity in these mice. The disease phenotype was gender- and genetic background-dependent, with congenic C57BL/6J male mice exhibiting the most aggressive form of the disease. Spinal cord IHC revealed ubiquitin-positive inclusions, but not TDP-43 aggregates, in the cytoplasm of MNs. Neither gender exhibited compelling ALS-like neuromuscular deficits, irrespective of age. While this model may be useful for studying GI tract neurodegeneration, in its present state it does not display a phenotype suitable for testing ALS therapeutics. This article is part of a Special Issue entitled RNA Metabolism 2013. PMID:24141148

Hatzipetros, Theo; Bogdanik, Laurent P; Tassinari, Valerie R; Kidd, Joshua D; Moreno, Andy J; Davis, Crystal; Osborne, Melissa; Austin, Andrew; Vieira, Fernando G; Lutz, Cathleen; Perrin, Steve

2014-10-10

225

Characterization of metal profiles in serum during the progression of Alzheimer's disease.  

PubMed

Metal dyshomeostasis is closely related to Alzheimer's disease, so the characterization of the metal profiles in these patients is of special interest for studying associated neurodegenerative processes and to discover potential markers of disease. An analytical approach, based on non-denaturing precipitation of proteins, has been optimized for the fractionation of high molecular mass (HMM) and low molecular mass (LMM) metal-species from serum, which were subjected to multielemental analysis by inductively coupled plasma mass spectrometry (ICP-MS). This methodology was applied to healthy controls, Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients in order to study the progression of dementia. Thus, it was found that some metals, such as iron, copper, zinc and aluminium, suffer progressive changes along the advance of neurodegeneration, suggesting that these imbalances could be related to the decline of cognitive functions. On the other hand, elements such as manganese, lithium or vanadium allow discriminating between controls and diseased subjects, both AD and MCI, but no differences were found between these two clinical stages, so they could be considered as precursors in the early development of neurodegenerative failures. In addition, it should be noted the important role that low molecular mass fractions of iron, copper, aluminium and cobalt appear to play in pathogenesis of Alzheimer. Finally, correlation analysis indicated that these metal abnormalities can be interrelated, participating in common processes such as oxidative stress, altered homeostasis and uptake into brain, as well as impaired glucose metabolism. PMID:24343096

González-Domínguez, Raúl; García-Barrera, Tamara; Gómez-Ariza, José Luis

2014-02-01

226

Progress in restorative neurosurgery: human fetal striatal transplantation in Huntington's disease. Review.  

PubMed

The purpose of this paper was to offer a review of the rationale, methods, biological and clinical results of human fetal striatal transplantation (HFST) in the treatment of Huntington's disease (HD). HD is a heritable neurodegenerative disease in which degeneration of neurons in the striatum leads to motor, psychiatric and cognitive deficits. The disease is progressive and inexorably lethal. At present there are no curative treatments for HD. A restorative therapy based on the intrastriatal transplantation of striatal neuroblasts taken from human fetus is currently being explored as potential treatment in selected HD patients. Pilot clinical trials of HFST have been started in few neurosurgery restorative centres. Results demonstrated that HFST is feasible and safe without relevant adverse effects; grafted neuroblasts survive, grow without evidence of neoplasia or teratoma, build new tissue with striatal-like imaging features, and move into the host brain towards short and long-distance cortical and sub-cortical targets. HFST delays disease progression and provides a period of improvement and stability. Even though larger-scale studies are still necessary to establish the true value of such a treatment, at this time, HFST represents a promising experimental therapy for patients with HD and one of the most interesting clinical application of restorative neurosurgery. PMID:22198589

Gallina, P; Paganini, M; Lombardini, L; Giordano, G; Mascalchi, M; Romoli, A M; Ghelli, E; Porfirio, B; Vannelli, G B; Di Lorenzo, N

2011-12-01

227

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

PubMed Central

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

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

2014-01-01

228

Markers of and risk factors for the development and progression of diabetic kidney disease.  

PubMed

Diabetic kidney disease (DKD) occurs in 25%-40% of patients with diabetes. Given the dual problems of a significant risk of progression from DKD to end-stage renal disease (ESRD) and increased cardiovascular morbidity and mortality, it is important to identify patients at risk of DKD and ESRD and initiate protective renal and cardiovascular therapies. The importance of preventive therapy is emphasized further by worldwide increases in the incidence of diabetes. This review summarizes the evidence regarding the prognostic value and benefits of targeting established and novel risk markers for DKD development and progression. Family history of DKD, smoking history, and glycemic, blood pressure, and plasma lipid level control are established factors for identifying people at greatest risk of DKD development and progression. Absolute albumin excretion rate (AER) and glomerular filtration rate (GFR) measurements also are important, although AER categorization generally lacks the necessary specificity and sensitivity, and estimates of declining GFR are compromised by methodological limitations for GFRs in the normal-to-high range. Emerging risk markers for progressive loss of kidney function include markers of oxidation and inflammation, profibrotic cytokines, uric acid, advanced glycation end products, functional and structural markers of vascular dysfunction, kidney structural changes, and tubular biomarkers. Among these, the most promising are serum uric acid and soluble tumor necrosis factor receptor (type 1 and type 2) levels, especially in relation to GFR changes. At present, these can only be considered as risk markers because they only identify an individual at increased risk of progressive DKD and not necessarily related to the causal pathway promoting kidney damage. Further work is needed to establish whether modulating these factors improves the prognosis in DKD. Although change in urinary peptidome levels also is a promising marker, there currently is neither a clinical assay nor adequate studies defining its prognostic value. Until these or other novel markers become available for clinical use, predictive accuracy often may be increased with greater attention to established markers. PMID:24461729

Macisaac, Richard J; Ekinci, Elif I; Jerums, George

2014-02-01

229

Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism  

PubMed Central

Progressive HIV infection is characterized by dysregulation of the intestinal immune barrier, translocation of immunostimulatory microbial products, and chronic systemic inflammation that is thought to drive progression of disease to AIDS. Elements of this pathologic process persist despite viral suppression during highly active antiretroviral therapy (HAART) and drivers of these phenomena remain poorly understood. Disrupted intestinal immunity can precipitate dysbiosis that induces chronic inflammation in the mucosa and periphery of mice. However, putative microbial drivers of HIV-associated immunopathology versus recovery have not been identified in humans. Using high-resolution bacterial community profiling, we identified a dysbiotic mucosal-adherent community enriched in Proteobacteria and depleted of Bacteroidia members that was associated with markers of mucosal immune disruption, T cell activation, and chronic inflammation in HIV-infected subjects. Furthermore, this dysbiosis was evident among HIV-infected subjects undergoing HAART, and the extent of dysbiosis correlated with activity of the kynurenine pathway of tryptophan metabolism and plasma concentrations of the inflammatory cytokine interleukin-6 (IL-6), two established markers of disease progression. Gut-resident bacteria with capacity to metabolize tryptophan through the kynurenine pathway were found to be enriched in HIV-infected subjects, strongly correlated with kynurenine levels in HIV-infected subjects, and capable of kynurenine production in vitro. These observations demonstrate a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection, which is apparent even in the setting of viral suppression during HAART. This link suggests that gut-resident microbial populations may influence intestinal homeostasis during HIV disease. PMID:23843452

Vujkovic-Cvijin, Ivan; Dunham, Richard M.; Iwai, Shoko; Maher, M. Cyrus; Albright, Rebecca G.; Broadhurst, Mara J.; Hernandez, Ryan D.; Lederman, Michael M.; Huang, Yong; Somsouk, Ma; Deeks, Steven G.; Hunt, Peter W.; Lynch, Susan V.; McCune, Joseph M.

2014-01-01

230

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

PubMed Central

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

Gao, Jianjun; Inagaki, Yoshinori; Liu, Yang

2013-01-01

231

Cerebrospinal fluid detection of interleukin-1? in phase of remission predicts disease progression in multiple sclerosis  

PubMed Central

Background Absence of clinical and radiological activity in relapsing–remitting multiple sclerosis (RRMS) is perceived as disease remission. We explored the role of persisting inflammation during remission in disease evolution. Methods Cerebrospinal fluid (CSF) levels of interleukin 1? (IL-1?), a major proinflammatory cytokine, were measured in 170 RRMS patients at the time of clinical and radiological remission. These patients were then followed up for at least 4 years, and clinical, magnetic resonance imaging (MRI) and optical coherence tomography (OCT) measures of disease progression were recorded. Results Median follow-up of RRMS patients was 5 years. Detection of CSF IL-1? levels at the time of remission did not predict earlier relapse or new MRI lesion formation. Detection of IL-1? in the CSF was instead associated with higher progression index (PI) and Multiple Sclerosis Severity Scale (MSSS) scores at follow-up, and the number of patients with sustained Expanded Disability Status Scale (EDSS) or Multiple Sclerosis Functional Composite worsening at follow-up was higher in individuals with detectable levels of IL-1?. Patients with undetectable IL-1? in the CSF had significantly lower PI and MSSS scores and a higher probability of having a benign MS phenotype. Furthermore, patients with undetectable CSF levels of IL-1? had less retinal nerve fiber layer thickness and macular volume alterations visualized by OCT compared to patients with detectable IL-1?. Conclusions Our results suggest that persistence of a proinflammatory environment in RRMS patients during clinical and radiological remission influences midterm disease progression. Detection of IL-1? in the CSF at the time of remission appears to be a potential negative prognostic factor in RRMS patients. PMID:24548694

2014-01-01

232

Characterization of a spontaneous disease of white leghorn chickens resembling progressive systemic sclerosis (scleroderma)  

PubMed Central

University of California, Davis (UCD) line 200 White Leghorn Chickens spontaneously develop a syndrome that has many analogous features to human progressive systemic sclerosis. This syndrome is characterized by progressive involution of comb, dermal fibrosis, and distal polyarthritis. These three features occur within 6 wk after hatching, and are accompanied by a 40% mortality as a result of vaso-occlusive disease, with development of secondary infection of peripheral gangrenous lesions. Birds that survive greater than 2 mo after hatching progressively develop fibrosis of the esophagous and mononuclear infiltration of heart and kidney, with prominent occlusion of small and medium sized blood vessels. In addition, line 200 chickens develop rheumatoid factors, antinuclear antibodies, and antibodies to collagen, but do not have antibodies to thymocytes, DNA, or extractable nuclear antigens. Moreover, antinuclear antibodies when studied using HEp-2 cells as substrate demonstrate predominantly a speckled pattern. This syndrome of line 200 chickens is not detectable in F1 crosses to several UCD inbred lines. F1 X parental line BC1 backcrosses have an approximately 50% incidence of disease, suggesting that this syndrome is inherited as autosomal recessive. However, only 4% of F2 generation birds show abnormal symptoms, suggesting the presence of modifying genes. There is no appearance of IgG deposition, as determined by immunofluorescence, in either skin, blood vessels, esophagus, or heart. However, approximately 20% of chickens have a glomerulonephritis; this feature appears to be a terminal event and does not appear clinically significant. Although this syndrome of line 200 chickens has several features that are in sharp distinction to human scleroderma, the presence of common immunologic and pathologic denominators suggest that this spontaneous disease may be an appropriate model to develop a better understanding of autoimmune connective tissue diseases. PMID:7252423

1981-01-01

233

Accelerated Disease Progression after Discontinuation of Sorafenib in a Patient with Metastatic Papillary Thyroid Cancer  

PubMed Central

Distant metastases from papillary thyroid carcinoma (PTC) are rare and are associated with a poor prognosis. Here, we describe a patient with metastatic PTC who was treated with a tyrosine kinase inhibitor (TKI, sorafenib) for several months that was acutely exacerbated by discontinuation. A 43-year-old male was diagnosed with PTC in February 2004 and underwent total thyroidectomy followed by two courses of high-dose radioactive iodine (RAI) therapy. Despite two additional courses of high-dose RAI therapy, lung and muscle metastases were developed. Treatment with sorafenib was begun in September 2010. After 11 months treatment of sorafenib, newly developed metastatic lesions were found in mediastinal lymph nodes, liver, and bones. Considered as treatment failure, the administration of sorafenib was discontinued. Two weeks after sorafenib treatment was stopped, the disease progressed abruptly and caused death of the patient by respiratory failure. In our patient, PTC progressed rapidly after the cessation of sorafenib treatment. Patients with several other types of cancer have also experienced such rapid disease progression, termed "flare-ups." Physicians should be aware that flare-ups may occur in advanced PTC patients following the cessation of TKI therapy. PMID:25309799

Yun, Kyung-Jin; Kim, Woohyeon; Kim, Eun Hee; Lim, Dong-Jun; Kang, Moo-Il; Cha, Bong-Yun

2014-01-01

234

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

SciTech Connect

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.

Terstegge, K.; Hosten, N. (Universitaetsklinikum Rudolf Virchow, Berlin (Germany)); Kunath, B. (Klinik und Poliklinik fuer Neurologie, Dresden (Germany)); Felber, S.; Henkes, H. (Universitaetskliniken der Universitaet Homburg (Germany)); Speciali, J.G. (Universidade de Sao Paolo (Brazil))

1994-01-01

235

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

PubMed Central

Importance Optimizing assessments of rate of progression in Parkinson Disease (PD) is important in designing clinical trials, especially of potential disease-modifying agents. Objective To examine the value of measures of impairment, disability, and quality of life in assessing progression in early Parkinson disease. Design, Setting, and Participants Inception cohort analysis of data from 413 early, untreated PD patients, who were enrolled in two multicenter, randomized, double-blind clinical trials. Intervention Participants were randomized into five treatments: 67 received creatine, 66 minocycline, 71 Coenzyme Q10, 71 GPI-1485, and 138 placebo. We assessed the association between the rates of change in measures of impairment, disability, and quality of life and time to initiation of symptomatic treatment. Main Outcome Measure Time between baseline assessment and need for the initiation of symptomatic pharmaceutical treatment for PD was the primary indicator of disease progression. Results After adjusting for baseline confounding variables Unified Parkinson Disease Rating Scale (UPDRS) II, UPDRS III, modified Rankin score (mRS), level of education, and treatment group, the rate of change of the following measurements was assessed: UPDRS II, UPDRS III, Schwab and England ADL (S&E), Total Functional Capacity (TFC), Parkinson’s Disease Quality of Life Questionnaire – 39 (PDQ39) ADL and Summary Index (SI), Short Form -12v2 Health Survey (SF12) Physical Summary (PS), and SF12 Mental Summary (MS). Variables reaching statistical threshold in univariate analysis were entered into a multivariable Cox proportional hazards model using time to symptomatic treatment as the dependent variable. More rapid worsening of UPDRS II (HR 1.15, 95% C.I. 1.08 – 1.22 for 1 scale unit change per 6 months), UPDRS III (HR 1.09; 95% C.I. 1.06 – 1.13 for 1 scale unit change per 6 months), and S&E (HR 1.29 95% C.I. 1.12 – 1.48 for 5 percentage point change per 6 months), was associated with earlier need for symptomatic therapy. Conclusions and Relevance In early PD, UPDRS II and III, and S&E can be used to measure disease progression, while the PDQ39 ADL, PDQ39 SI, TFC, SF12 PH, and SF12 MH are not sensitive to change. Trial Registration clinicaltrials.gov identifiers NCT00063193 and NCT00076492 PMID:24711047

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

2014-01-01

236

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

PubMed

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

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

2014-06-01

237

Stromal cell-derived factor-1 genotype, coreceptor tropism, and HIV type 1 disease progression.  

PubMed

This study used a well characterized cohort of human immunodeficiency virus type 1 (HIV-1)-infected hemophiliacs to define the relationship between the SDF1-3'A allele, the plasma HIV-1 coreceptor tropism, and the natural history of HIV-1 disease. Subjects heterozygous or homozygous for the SDF1-3'A allele experienced higher rates of decline in CD4+ T cell counts over time than did those without the allele (P=.009). Moreover, they had an increased risk of progression to acquired immunodeficiency syndrome and death, a relationship that persisted even when baseline plasma HIV-1 RNA levels and CD4+ T cell counts or CCR5 Delta 32 and CCR2-64I genotype were controlled for. This relationship was even stronger in a subgroup of subjects for whom tropism data were available. Subjects with the SDF1-3'A allele were also more likely to have detectable X4-tropic viruses (P=.012), and, when tropism was included in the survival analyses, the effect of the SDF1-3'A allele on disease progression was no longer significant. Therefore, the increased frequency of X4-tropic viruses in subjects carrying the SDF1-3'A allele may explain the observed adverse effect that this allele has on the natural history of HIV-1 disease. PMID:16206074

Daar, Eric S; Lynn, Henry S; Donfield, Sharyne M; Lail, Alice; O'Brien, Stephen J; Huang, Wei; Winkler, Cheryl A

2005-11-01

238

PACAP signaling exerts opposing effects on neuroprotection and neuroinflammation during disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis?  

PubMed Central

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with autocrine neuroprotective and paracrine anti-inflammatory properties in various models of acute neuronal damage and neurodegenerative diseases. Therefore, we examined a possible beneficial role of endogenous PACAP in the superoxide dismutase 1, SOD1(G93A), mouse model of amyotrophic lateral sclerosis (ALS), a lethal neurodegenerative disease particularly affecting somatomotor neurons. In wild-type mice, somatomotor and visceromotor neurons in brain stem and spinal cord were found to express the PACAP specific receptor PAC1, but only visceromotor neurons expressed PACAP as a potential autocrine source of regulation of these receptors. In SOD1(G93A) mice, only a small subset of the surviving somatomotor neurons showed induction of PACAP mRNA, and somatomotor neuron degeneration was unchanged in PACAP-deficient SOD1(G93A) mice. Pre-ganglionic sympathetic visceromotor neurons were found to be resistant in SOD1(G93A) mice, while pre-ganglionic parasympathetic neurons degenerated during ALS disease progression in this mouse model. PACAP-deficient SOD1(G93A) mice showed even greater pre-ganglionic parasympathetic neuron loss compared to SOD1(G93A) mice, and additional degeneration of pre-ganglionic sympathetic neurons. Thus, constitutive expression of PACAP and PAC1 may confer neuroprotection to central visceromotor neurons in SOD1(G93A) mice via autocrine pathways. Regarding the progression of neuroinflammation, the switch from amoeboid to hypertrophic microglial phenotype observed in SOD1(G93A) mice was absent in PACAP-deficient SOD1(G93A) mice. Thus, endogenous PACAP may promote microglial cytodestructive functions thought to drive ALS disease progression. This hypothesis was consistent with prolongation of life expectancy and preserved tongue motor function in PACAP-deficient SOD1(G93A) mice, compared to SOD1(G93A) mice. Given the protective role of PACAP expression in visceromotor neurons and the opposing effect on microglial function in SOD1(G93A) mice, both PACAP agonism and antagonism may be promising therapeutic tools for ALS treatment, if stage of disease progression and targeting the specific auto- and paracrine signaling pathways are carefully considered. PMID:23466699

Ringer, Cornelia; Buning, Luisa-Sybille; Schafer, Martin K.H.; Eiden, Lee E.; Weihe, Eberhard; Schutz, Burkhard

2014-01-01

239

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

PubMed Central

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

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

2014-01-01

240

Variation in black and white band disease progression in corals of the Gulf of Mannar and Palk Bay, Southeastern India.  

PubMed

Information on the progression of coral diseases and transmission to live corals is scarce despite the fact that coral disease poses one of the most lethal threats to the survival of coral reefs. In this study, in situ progression rates of lesions similar to black band disease (BBD) and white band disease (WBD) were measured in different species of corals from the Gulf of Mannar (GoM) and Palk Bay, southeastern India, during the period between January and December of 2009. Maximum progression rates of 3 and 1.6 cm mo-1 for BBD and WBD, respectively, were observed during May, when the temperature exceeded 30°C. The annual progression rate was 10.9 and 4.9 cm yr-1 for BBD at GoM and Palk Bay, respectively. Significant variation in the progression rate (p < 0.001) was observed between months in all the examined species. Significant correlation between temperature and disease progression rates for BBD (R2 = 0.875, p ? 0.001) and WBD (R2 = 0.776, p ? 0.001) was recorded. Rates of disease progression were higher in Palk Bay than in GoM. This could be attributed to the higher temperature coupled with higher anthropogenic activities in Palk Bay. Severe mortality was observed due to both BBD and WBD. No sign of recovery was noticed in the disease-affected colonies at either study site. Anthropogenic activities should be checked, and further research on both the transmission and progression rate and role of the diseases in reef dynamics should be carried out to understand the causal factors in reef degradation and generate a plan to manage the reef properly. PMID:25114046

Thinesh, T; Mathews, G; Raj, K Diraviya; Patterson Edward, J K

2014-08-11

241

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

PubMed Central

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

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

242

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

PubMed Central

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

2013-01-01

243

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

PubMed

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

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

2013-10-25

244

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

PubMed Central

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

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

2012-01-01

245

Host Genetic Factors Associated with Symptomatic Primary HIV Infection and Disease Progression among Argentinean Seroconverters  

PubMed Central

Background Variants in HIV-coreceptor C-C chemokine receptor type 5 (CCR5) and Human leukocyte antigen (HLA) genes are the most important host genetic factors associated with HIV infection and disease progression. Our aim was to analyze the association of these genetic factors in the presence of clinical symptoms during Primary HIV Infection (PHI) and disease progression within the first year. Methods Seventy subjects diagnosed during PHI were studied (55 symptomatic and 15 asymptomatic). Viral load (VL) and CD4 T-cell count were evaluated. HIV progression was defined by presence of B or C events and/or CD4 T-cell counts <350 cell/mm3. CCR5 haplotypes were characterized by polymerase chain reaction and SDM-PCR-RFLP. HLA-I characterization was performed by Sequencing. Results Symptoms during PHI were significantly associated with lower frequency of CCR5-CF1 (1.8% vs. 26.7%, p?=?0.006). Rapid progression was significantly associated with higher frequency of CCR5-CF2 (16.7% vs. 0%, p?=?0.024) and HLA-A*11 (16.7% vs. 1.2%, p?=?0.003) and lower frequency of HLA-C*3 (2.8% vs. 17.5%, p?=?0.035). Higher baseline VL was significantly associated with presence of HLA-A*11, HLA-A*24, and absence of HLA-A*31 and HLA-B*57. Higher 6-month VL was significantly associated with presence of CCR5-HHE, HLA-A*24, HLA-B*53, and absence of HLA-A*31 and CCR5-CF1. Lower baseline CD4 T-cell count was significantly associated with presence of HLA-A*24/*33, HLA-B*53, CCR5-CF2 and absence of HLA-A*01/*23 and CCR5-HHA. Lower 6-month CD4 T-cell count was associated with presence of HLA-A*24 and HLA-B*53, and absence of HLA-A*01 and HLA-B*07/*39. Moreover, lower 12-month CD4 T-cell count was significantly associated with presence of HLA-A*33, HLA-B*14, HLA-C*08, CCR5-CF2, and absence of HLA-B*07 and HLA-C*07. Conclusion Several host factors were significantly associated with disease progression in PHI subjects. Most results agree with previous studies performed in other groups. However, some genetic factor associations are being described for the first time, highlighting the importance of genetic studies at a local level. PMID:25406087

Coloccini, Romina Soledad; Dilernia, Dario; Ghiglione, Yanina; Turk, Gabriela; Laufer, Natalia; Rubio, Andrea; Socías, María Eugenia; Figueroa, María Inés; Sued, Omar; Cahn, Pedro; Salomón, Horacio; Mangano, Andrea; Pando, María Ángeles

2014-01-01

246

P2Y2 receptor deficiency aggravates chronic kidney disease progression  

PubMed Central

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 ± 8.7?l/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-? 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

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

2013-01-01

247

Timing of progression from Chlamydia trachomatis infection to pelvic inflammatory disease: a mathematical modelling study  

PubMed Central

Background Pelvic inflammatory disease (PID) results from the ascending spread of microorganisms from the vagina and endocervix to the upper genital tract. PID can lead to infertility, ectopic pregnancy and chronic pelvic pain. The timing of development of PID after the sexually transmitted bacterial infection Chlamydia trachomatis (chlamydia) might affect the impact of screening interventions, but is currently unknown. This study investigates three hypothetical processes for the timing of progression: at the start, at the end, or throughout the duration of chlamydia infection. Methods We develop a compartmental model that describes the trial structure of a published randomised controlled trial (RCT) and allows each of the three processes to be examined using the same model structure. The RCT estimated the effect of a single chlamydia screening test on the cumulative incidence of PID up to one year later. The fraction of chlamydia infected women who progress to PID is obtained for each hypothetical process by the maximum likelihood method using the results of the RCT. Results The predicted cumulative incidence of PID cases from all causes after one year depends on the fraction of chlamydia infected women that progresses to PID and on the type of progression. Progression at a constant rate from a chlamydia infection to PID or at the end of the infection was compatible with the findings of the RCT. The corresponding estimated fraction of chlamydia infected women that develops PID is 10% (95% confidence interval 7-13%) in both processes. Conclusions The findings of this study suggest that clinical PID can occur throughout the course of a chlamydia infection, which will leave a window of opportunity for screening to prevent PID. PMID:22883325

2012-01-01

248

Outcome measures in relapsing-remitting multiple sclerosis: capturing disability and disease progression in clinical trials.  

PubMed

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

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

2014-01-01

249

Cocaine reduces thymic endocrine function: another mechanism for accelerated HIV disease progression.  

PubMed

Thymulin is a thymic peptide important for the maturation and differentiation of immature thymocytes, which have been found to be depressed in patients with low-level CD4(+) cell recovery despite viral control. Substance use is associated with faster progression of HIV disease, which has been ascribed to poor adherence to antiretroviral medication. Recent findings of an association between cocaine use and decline in CD4(+) cell counts independent of antiretroviral adherence indicate alternative mechanisms for disease progression. We evaluated the relationship between thymulin activity, CD4(+) and CD8(+) cell counts and the CD4(+)/CD8(+) ratio, and the covariate effects of substance use cross-sectionally in 80 HIV(+) active substance users and over 12 months in 40 participants. Thymulin activity was analyzed in plasma using a modification of the sheep rosette bioassay. Thymulin activity was negatively associated with cocaine use (? = -0.908,95% CI: -1.704, -0.112; p = 0.026). Compared to those who do not use cocaine, cocaine users were 37% less likely to have detectable thymulin activity (RR = 0.634, 95% CI: 0.406, 0.989 p = 0.045) and were 75 times more likely to show a decrease in thymulin activity (OR = 74.7, 95% CI: 1.59, 3519.74; p = 0.028) over time. CD4(+) cell count was positively associated with thymulin activity (? = 0.127, 95% CI: 0.048,0.205; p = 0.002), detectable thymulin activity was 2.32 times more likely in those with a CD4 cell count ?200 cells/?l (RR = 2.324, 95% CI: 1.196, 4.513, p = 0.013), and those with an increase in CD4 cell counts were more likely to show an increase in thymulin activity (OR = 1.02, 95% CI: 1.00, 1.034; p = 0.041) over time. Thymulin activity is predictive of HIV disease progression and is depressed in cocaine users independent of antiretroviral treatment (ART) and HIV viral load. Understanding the mechanisms for accelerated HIV disease progression provides opportunities to find alternative strategies to counteract immunosuppression. PMID:21142650

Rafie, Carlin; Campa, Adriana; Smith, Sylvia; Huffman, Fatma; Newman, Fred; Baum, Marianna K

2011-08-01

250

Cocaine Reduces Thymic Endocrine Function: Another Mechanism for Accelerated HIV Disease Progression  

PubMed Central

Abstract Thymulin is a thymic peptide important for the maturation and differentiation of immature thymocytes, which have been found to be depressed in patients with low-level CD4+ cell recovery despite viral control. Substance use is associated with faster progression of HIV disease, which has been ascribed to poor adherence to antiretroviral medication. Recent findings of an association between cocaine use and decline in CD4+ cell counts independent of antiretroviral adherence indicate alternative mechanisms for disease progression. We evaluated the relationship between thymulin activity, CD4+ and CD8+ cell counts and the CD4+/CD8+ ratio, and the covariate effects of substance use cross-sectionally in 80 HIV+ active substance users and over 12 months in 40 participants. Thymulin activity was analyzed in plasma using a modification of the sheep rosette bioassay. Thymulin activity was negatively associated with cocaine use (??=??0.908,95% CI: ?1.704, ?0.112; p?=?0.026). Compared to those who do not use cocaine, cocaine users were 37% less likely to have detectable thymulin activity (RR?=?0.634, 95% CI: 0.406, 0.989 p?=?0.045) and were 75 times more likely to show a decrease in thymulin activity (OR?=?74.7, 95% CI: 1.59, 3519.74; p?=?0.028) over time. CD4+ cell count was positively associated with thymulin activity (??=?0.127, 95% CI: 0.048,0.205; p?=?0.002), detectable thymulin activity was 2.32 times more likely in those with a CD4?cell count ?200?cells/?l (RR?=?2.324, 95% CI: 1.196, 4.513, p?=?0.013), and those with an increase in CD4?cell counts were more likely to show an increase in thymulin activity (OR?=?1.02, 95% CI: 1.00, 1.034; p?=?0.041) over time. Thymulin activity is predictive of HIV disease progression and is depressed in cocaine users independent of antiretroviral treatment (ART) and HIV viral load. Understanding the mechanisms for accelerated HIV disease progression provides opportunities to find alternative strategies to counteract immunosuppression. PMID:21142650

Campa, Adriana; Smith, Sylvia; Huffman, Fatma; Newman, Fred; Baum, Marianna K.

2011-01-01

251

Excess Circulating Alternatively Activated Myeloid (M2) Cells Accelerate ALS Progression While Inhibiting Experimental Autoimmune Encephalomyelitis  

Microsoft Academic Search

BackgroundCirculating immune cells including autoreactive T cells and monocytes have been documented as key players in maintaining, protecting and repairing the central nervous system (CNS) in health and disease. Here, we hypothesized that neurodegenerative diseases might be associated, similarly to tumors, with increased levels of circulating peripheral myeloid derived suppressor cells (MDSCs), representing a subset of suppressor cells that often

Ilan Vaknin; Gilad Kunis; Omer Miller; Oleg Butovsky; Shay Bukshpan; David R. Beers; Jenny S. Henkel; Eti Yoles; Stanley H. Appel; Michal Schwartz

2011-01-01

252

Lewy bodies in progressive supranuclear palsy represent an independent disease process.  

PubMed

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy characterized by Parkinsonism, vertical gaze palsy, and early falls. Lewy bodies (LBs) are detected in approximately 10% of PSP cases, but there is little information on the relationship of LBs to tau pathology. We determined the frequency of LBs in a large series of autopsy-confirmed cases of PSP and studied the density and distribution of LBs, including Parkinson disease stage, in cases with LBs (PSP/LBD). PSP/LBD was compared with pure LB disease (LBD), including assessment of neuronal loss in key brainstem nuclei. Immunohistochemistry for alpha-synuclein revealed LBs in 31 of 290 PSP cases (11%). One case had multiple system atrophy in addition to PSP and was excluded from further study along with 2 PSP/LBD cases with concurrent Alzheimer disease. The 29 cases of PSP/LBD were compared with 30 cases of PSP and 24 cases of LBD. The age, sex, brain weight, Braak neurofibrillary tangle (NFT) stage, as well as counts of NFTs and senile plaques were not different among PSP, LBD, and PSP/LBD, but disease duration was longer in LBD. The Parkinson disease stage was similar, but the density of LBs in most subcortical nuclei tended to be greater in LBD than in PSP/LBD. In contrast, substantia nigra neuronal loss was greater in PSP/LBD than both PSP and LBD. Double immunostaining demonstrated alpha-synuclein and tau in different neurons with few exceptions. The findings suggest that LBs in PSP are similar in distribution to those in LBD and independent of tau pathology. The greater density of LBs in LBD compared with PSP/LBD may be the result of longer disease duration in LBD, whereas greater neuronal loss in the substantia nigra in PSP/LBD may be the result of vulnerability of this brain region to both disease processes. PMID:16691119

Uchikado, Hirotake; DelleDonne, Anthony; Ahmed, Zeshan; Dickson, Dennis W

2006-04-01

253

Platelet count is associated with plasma HIV type 1 RNA and disease progression.  

PubMed

Thrombocytopenia is a common finding among HIV-1-infected individuals. In addition to their function in hemostasis, platelets have been found to play a role in host immune defenses and to directly interact with HIV-1. To explore the role of platelets in HIV-1 infection, we examined the relationship between platelet number and the natural history of HIV-1 disease in the well-characterized Hemophilia Growth and Development Study cohort. In a multivariate analysis platelets were found to be inversely related to plasma HIV-1 RNA with increasing platelets associated with lower plasma HIV-1 RNA levels (p < 0.001). Despite this, increasing platelet count was independently associated with enhanced risk of progression to AIDS and death (p < 0.001 for both). While there may be multiple explanations for these novel observations, they do generate hypotheses related to the potential influence platelets may have on the natural history of HIV-1 disease. PMID:17961113

Rieg, Gunter; Yeaman, Michael; Lail, Alice E; Donfield, Sharyne M; Gomperts, Edward D; Daar, Eric S

2007-10-01

254

The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer's disease  

PubMed Central

Background Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by intracellular tangles of hyperphosphorylated tau protein distributed throughout the neocortex, basal ganglia, and brainstem. A genome-wide association study identified EIF2AK3 as a risk factor for PSP. EIF2AK3 encodes PERK, part of the endoplasmic reticulum’s (ER) unfolded protein response (UPR). PERK is an ER membrane protein that senses unfolded protein accumulation within the ER lumen. Recently, several groups noted UPR activation in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, multiple system atrophy, and in the hippocampus and substantia nigra of PSP subjects. Here, we evaluate UPR PERK activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls. Results We found UPR activation primarily in disease-affected brain regions in both disorders. In PSP, the UPR was primarily activated in the pons and medulla and to a much lesser extent in the hippocampus. In AD, the UPR was extensively activated in the hippocampus. We also observed UPR activation in the hippocampus of some elderly normal controls, severity of which positively correlated with both age and tau pathology but not with A? plaque burden. Finally, we evaluated EIF2AK3 coding variants that influence PERK activation. We show that a haplotype associated with increased PERK activation is genetically associated with increased PSP risk. Conclusions The UPR is activated in disease affected regions in PSP and the genetic evidence shows that this activation increases risk for PSP and is not a protective response. PMID:24252572

2013-01-01

255

Progression of Chronic Kidney Disease: Adrenergic Genetic Influence on Glomerular Filtration Rate Decline in Hypertensive Nephrosclerosis  

PubMed Central

Background African-Americans are likely to develop hypertension and hypertensive nephrosclerosis. This grave prognosis, coupled with familial aggregation of end-stage renal disease (ESRD) in Blacks, prompts a search for genetic risk factors for ESRD. Recent evidence implicates a crucial role for the sympathetic nervous system in progressive renal disease. Methods We used the African-American Study of Kidney Disease to probe whether ?2-adrenergic receptor (ADRB2) predicts glomerular filtration rate (GFR) decline rate. A total of 580 participants were included. Baseline GFR was 51.2 ± 0.5 ml/min/1.73 m2. Subjects were randomized in a 2 × 3 block design: to intensively lowered (MAP ?92 mm Hg) versus ‘usual’ (MAP = 102–107 mm Hg) blood pressure goal groups, and also divided by three randomized antihypertensive drugs (ramipril, metoprolol, or amlodipine). We scored 4 SNPs at the ADRB2 locus. Results Haplotypes at ADRB2 predicted chronic GFR decline rate, GFR declined more slowely in individuals with haplotype-1 (?804G?173T?16Gly?27GIn), and faster in those who carried haplotype-3 (?804G?173T?16Arg?27Gln). ADRB2 genotype interacted with antihypertensive drug class to influence GFR slope (p = 0.001–0.037). We extended our findings to an independent case/control sample of Black hypertensive ESRD, in which we found that variant Gly16Arg that tagged the GFR slope-determining ADRB2 haplotype also conferred risk for the ESRD trait in Blacks. Conclusions The GFR decline/progression rate in hypertensive renal disease is controlled in part by genetic variation within the adrenergic pathway. PMID:20484896

Chen, Yuqing; Lipkowitz, Michael S.; Salem, Rany M.; Fung, Maple M.; Bhatnagar, Vibha; Mahata, Manjula; Nievergelt, Caroline M.; Rao, Fangwen; Mahata, Sushil K.; Schork, Nicholas J.; Hicks, Pamela J.; Bowden, Donald W.; Freedman, Barry I.; Brophy, Victoria H.; O'Connor, Daniel T.

2010-01-01

256

Is Fluid Overload More Important than Diabetes in Renal Progression in Late Chronic Kidney Disease?  

PubMed Central

Fluid overload is one of the major presentations in patients with late stage chronic kidney disease (CKD). Diabetes is the leading cause of renal failure, and progression of diabetic nephropathy has been associated with changes in extracellular fluid volume. The aim of the study was to assess the association of fluid overload and diabetes in commencing dialysis and rapid renal function decline (the slope of estimated glomerular filtration rate (eGFR) less than -3 ml/min per 1.73 m2/y) in 472 patients with stages 4-5 CKD. Fluid status was determined by bioimpedance spectroscopy method, Body Composition Monitor. The study population was further classified into four groups according to the median of relative hydration status (?HS =fluid overload/extracellular water) and the presence or absence of diabetes. The median level of relative hydration status was 7%. Among all patients, 207(43.9 %) were diabetic. 71 (15.0%) subjects had commencing dialysis, and 187 (39.6%) subjects presented rapid renal function decline during a median 17.3-month follow-up. Patients with fluid overload had a significantly increased risk for commencing dialysis and renal function decline independent of the presence or absence of diabetes. No significantly increased risk for renal progression was found between diabetes and non-diabetes in late CKD without fluid overload. In conclusion, fluid overload has a higher predictive value of an elevated risk for renal progression than diabetes in late CKD. PMID:24349311

Tsai, Yi-Chun; Tsai, Jer-Chia; Chiu, Yi-Wen; Kuo, Hung-Tien; Chen, Szu-Chia; Hwang, Shang-Jyh; Chen, Tzu-Hui; Kuo, Mei-Chuan; Chen, Hung-Chun

2013-01-01

257

Traditional and novel dietary interventions for preventing progression of chronic kidney disease.  

PubMed

Treatment of chronic kidney disease (CKD) and its complications remain largely unresolved. Currently used treatments include blood pressure control and the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which can slow down the progression of CKD but are unable to halt or reverse it. Dietary protein restriction represents an additional therapeutic measure used to slow the progression of CKD. The putative mechanisms of action responsible for its therapeutic effects include beneficial hemodynamic effects and the limitation of absorbable protein breakdown products that could lead to the accumulation of uremic waste and consequent various deleterious effects. The practical implementation of protein restriction through dietary intervention has been hindered on multiple levels, including patient nonadherence, lack of health care resources, and concerns related to adverse effects associated with the development of protein-energy wasting (PEW). As a result, alternative interventions have been designed to address some or all of these shortcomings and concerns. One such intervention is the administration of medications that prevent the absorption of protein catabolic products from the gut. This article reviews the various interventions using such a strategy to prevent or slow the progression of CKD, with special focus on recent advances in this field. PMID:23611554

Kovesdy, Csaba P

2013-05-01

258

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

PubMed

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

Muroyama, Akiko

2013-01-01

259

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

PubMed Central

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

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

260

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

PubMed Central

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

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

2013-01-01

261

Behavioral mediation of the relationship between psychosocial factors and HIV disease progression.  

PubMed

The psychological and physical demands of coping with medication side effects and comorbid illnesses can be overwhelming and may influence behaviors, such as medication adherence, substance use, sexual risk behavior, and exercise that, in turn, affect health outcomes. Cross-sectional and prospective studies among diverse populations of persons living with HIV suggest that these behavioral mechanisms may be associated with HIV disease progression. The motivation to change behavior is often highest in the immediate aftermath of a stressor. However, over time the motivation to continue a particular behavior change is often challenged by habits, environmental influences, and psychosocial factors. Furthermore, a number of studies suggest that behavioral mechanisms may mediate the relationship between psychosocial variables (e.g., stress, depression, coping, and social support) and disease progression in HIV. Thus, developing clinical interventions that address these psychosocial factors and enhance protective health behaviors and reduce behaviors that convey risk to health are likely to lessen overall morbidity and mortality among patients living with HIV/AIDS. PMID:18519885

Gore-Felton, Cheryl; Koopman, Cheryl

2008-06-01

262

Verbal and visuospatial span in logopenic progressive aphasia and Alzheimer's disease.  

PubMed

Logopenic progressive aphasia (LPA) is a form of primary progressive aphasia (PPA) characterized by hesitant speech with marked impairment in naming and repetition. LPA is associated with brain atrophy in the left temporal and inferior parietal cortices and is predominantly associated with Alzheimer’s disease (AD) pathology. In contrast to LPA, ‘‘typical’’ AD is commonly associated with episodic memory disturbance and bilateral medial temporal lobe atrophy. Recent evidence suggests verbal short-term memory is more impaired than visuospatial short-term memory in LPA. This study investigated verbal and visuospatial short-term memory in 12 LPA and 12 AD patients matched for disease severity, and in 12 age- and education-matched healthy controls. Overall, both patient groups showed significantly reduced verbal and visuospatial spans compared with controls. In addition, LPA patients performed significantly worse than AD patients on both forward and backward conditions of the Digit Span task. In contrast, no difference was present between patient groups on either version of the Spatial Span task. Importantly, LPA patients showed better visuospatial than verbal span whereas AD patients and controls did not differ across modality. This study demonstrates the specificity of the short-term memory disturbance in LPA, which arises from a breakdown of the phonological system. PMID:23298815

Foxe, David G; Irish, Muireann; Hodges, John R; Piguet, Olivier

2013-03-01

263

Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression.  

PubMed

Inflammation in HIV infection is predictive of non-AIDS morbidity and death, higher set point plasma virus load and virus acquisition; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may simultaneously confer both detrimental and beneficial effects. This dichotomy is particularly applicable to type I interferons (IFN-I) which, while contributing to innate control of infection, also provide target cells for the virus during acute infection, impair CD4 T-cell recovery, and are associated with disease progression. Here we manipulated IFN-I signalling in rhesus macaques (Macaca mulatta) during simian immunodeficiency virus (SIV) transmission and acute infection with two complementary in vivo interventions. We show that blockade of the IFN-I receptor caused reduced antiviral gene expression, increased SIV reservoir size and accelerated CD4 T-cell depletion with progression to AIDS despite decreased T-cell activation. In contrast, IFN-?2a administration initially upregulated expression of antiviral genes and prevented systemic infection. However, continued IFN-?2a treatment induced IFN-I desensitization and decreased antiviral gene expression, enabling infection with increased SIV reservoir size and accelerated CD4 T-cell loss. Thus, the timing of IFN-induced innate responses in acute SIV infection profoundly affects overall disease course and outweighs the detrimental consequences of increased immune activation. Yet, the clinical consequences of manipulation of IFN signalling are difficult to predict in vivo and therapeutic interventions in human studies should be approached with caution. PMID:25043006

Sandler, Netanya G; Bosinger, Steven E; Estes, Jacob D; Zhu, Richard T R; Tharp, Gregory K; Boritz, Eli; Levin, Doron; Wijeyesinghe, Sathi; Makamdop, Krystelle Nganou; del Prete, Gregory Q; Hill, Brenna J; Timmer, J Katherina; Reiss, Emma; Yarden, Ganit; Darko, Samuel; Contijoch, Eduardo; Todd, John Paul; Silvestri, Guido; Nason, Martha; Norgren, Robert B; Keele, Brandon F; Rao, Srinivas; Langer, Jerome A; Lifson, Jeffrey D; Schreiber, Gideon; Douek, Daniel C

2014-07-31

264

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

PubMed Central

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

Reis, Eliana A. G.; Hagan, Jose 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

265

Rituximab Retreatment after Disease Progression Is Comparable to Rituximab Maintenance Therapy in Patients with Low-Tumor Burden Follicular Lymphoma  

Cancer.gov

In a randomized clinical trial, patients with low–tumor burden follicular lymphoma whose cancer responded to initial treatment with rituximab (Rituxan®) experienced similar disease control regardless of whether they subsequently received maintenance therapy with rituximab or were retreated with rituximab only when there was evidence of disease progression.

266

Comparison of the pattern of atrophy of the corpus callosum in frontotemporal dementia, progressive supranuclear palsy, and Alzheimer's disease  

Microsoft Academic Search

OBJECTIVESThe loss of the neurons in layer 3, one of the groups of cortical neurons most vulnerable in various degenerative brain diseases, results in axonal degeneration leading to atrophy of the corpus callosum. Previous studies showed callosal atrophy in three degenerative dementias: frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD). However, it is unclear whether a characteristic

Hiroshi Yamauchi; Hidenao Fukuyama; Yasuhiro Nagahama; Yukinori Katsumi; Takuya Hayashi; Chisako Oyanagi; Junji Konishi; Hideo Shio

2000-01-01

267

MicroRNA-150 Is a Potential Biomarker of HIV/AIDS Disease Progression and Therapy  

PubMed Central

Background The surrogate markers of HIV/AIDS progression include CD4 T cell count and plasma viral load. But, their reliability has been questioned in patients on anti-retroviral therapy (ART). Five microRNAs (miRNAs) - miR-16, miR-146b-5p, miR-150, miR-191 and miR-223 in peripheral blood mononuclear cells (PBMCs) were earlier found to assign HIV/AIDS patients into groups with varying CD4 T cell counts and viral loads. In this pilot study, we profiled the expression of these five miRNAs in PBMCs, and two of these miRNAs (miR-146b-5p and miR-150) in the plasma of HIV/AIDS patients, including those on ART and those who developed ART resistance, to evaluate if these are biomarkers of disease progression and therapy. Results We quantified miRNA levels by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RNA isolated from PBMCs and plasma of healthy persons or HIV-infected patients who were (1) asymptomatic; (2) symptomatic and ART naïve; (3) on ART; and (4) failing ART. Our results show miR-150 (p<0.01) and to a lesser extent miR-146b-5p (p<0.05) levels in PBMCs to reliably distinguish between ART-naïve AIDS patients, those on ART, and those developing drug resistance and failing ART. The plasma levels of these two miRNAs also varied significantly between patients in these groups and between patients and healthy controls (p values <0.05). Conclusions We report for the first time that PBMC and plasma levels of miR-150 and miR-146b-5p are predictive of HIV/AIDS disease progression and therapy. PMID:24828336

Munshi, Saif Ullah; Panda, Harekrushna; Holla, Prasida; Rewari, Bharat Bhushan; Jameel, Shahid

2014-01-01

268

Immunity and neuronal repair in the progression of Alzheimer's disease: a brief overview.  

PubMed

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder characterized by memory loss and severe cognitive decline. The etiology of the disease has not been explored, although a significant body of evidence suggests that neuronal dysfunction is caused by hyperphosphorylation and intracellular accumulation of the Tau protein, extracellular accumulation of the amyloid beta-peptide (Abeta), and the associated chronic activation of glial cells. Clearance of toxic Abeta, apoptotic cells and debris from the brain together with induction of neuronal repair mechanisms may all take place partially throughout the progression of AD, but therapeutic approaches based on knowledge of these processes have been unsuccessfully developed. Here, we address the question of whether autoimmune mechanisms can be boosted to safely facilitate the above-mentioned clearance and neuronal repair in the AD brain. We have previously demonstrated that depending on genetic background, autoimmunity targeted to Abeta is already induced in elderly individuals and in patients with AD. We have shown in a mouse model of AD that given a preexisting proinflammatory milieu in the brain, immune cells can enter the brain tissue and participate in clearance of Abeta. Furthermore, the decline in cognitive functions and neurogenesis throughout the progression of AD may also be affected by autoimmune mechanisms operating in the periphery and in the brain. In light of the so-far unsuccessful anti-inflammatory approaches to treating AD, we suggest that boosting - rather than suppressing - the endogenous immune mechanisms induced in AD may enhance repair pathways in the brain, provided that this approach can be safely applied. PMID:17074458

Baron, Rona; Harpaz, Idan; Nemirovsky, Anna; Cohen, Hagit; Monsonego, Alon

2007-01-01

269

SQSTM1 mutations--bridging Paget disease of bone and ALS/FTLD.  

PubMed

Paget disease of bone (PDB) is a skeletal disorder common in Western Europe but extremely rare in the Indian subcontinent and Far East. The condition has a strong genetic element with mutations affecting the SQSTM1 gene, encoding the p62 protein, frequently identified. Recently SQSTM1 mutations have also been reported in a small number of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), neurodegenerative disorders in which significant coexistence with PDB has not been previously recognized. Although several SQSTM1 mutations are common to both ALS/FTLD and PDB, many are ALS/FTLD-specific. The p62 protein regulates various cellular processes including NF-?B signaling and autophagy pathways. Here we consider how knowledge of the impact of PDB-associated SQSTM1 mutations (several of which are now known to be relevant for ALS/FTLD) on these pathways, as well as the locations of the mutations within the p62 primary sequence, may provide new insights into ALS/FTLD disease mechanisms. PMID:24486447

Rea, Sarah L; Majcher, Veronika; Searle, Mark S; Layfield, Rob

2014-07-01

270

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

PubMed Central

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

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

2013-01-01

271

Metabolic Tumor Burden Predicts for Disease Progression and Death in Lung Cancer  

SciTech Connect

Purpose: In lung cancer, stage is an important prognostic factor for disease progression and survival. However, stage may be simply a surrogate for underlying tumor burden. Our purpose was to assess the prognostic value of tumor burden measured by {sup 18}F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging. Patients and Methods: We identified 19 patients with lung cancer who had staging PET-CT scans before any therapy, and adequate follow-up (complete to time of progression for 18, and death for 15 of 19). Metabolically active tumor regions were segmented on pretreatment PET scans semi-automatically using custom software. We determined the relationship between times to progression (TTP) and death (OS) and two PET parameters: total metabolic tumor volume (MTV), and standardized uptake value (SUV). Results: The estimated median TTP and OS for the cohort were 9.3 months and 14.8 months. On multivariate Cox proportional hazards regression analysis, an increase in MTV of 25 ml (difference between the 75th and 25th percentiles) was associated with increased hazard of progression and of death (5.4-fold and 7.6-fold), statistically significant (p = 0.0014 and p = 0.001) after controlling for stage, treatment intent (definitive or palliative), age, Karnofsky performance status, and weight loss. We did not find a significant relationship between SUV and TTP or OS. Conclusions: In this study, high tumor burden assessed by PET MTV is an independent poor prognostic feature in lung cancer, promising for stratifying patients in randomized trials and ultimately for selecting risk-adapted therapies. These results will need to be validated in larger cohorts with longer follow-up, and evaluated prospectively.

Lee, Percy; Weerasuriya, Dilani K. [Department of Radiation Oncology, Stanford University, Stanford, CA (United States); Lavori, Philip W. [Department of Health Research and Policy, Stanford University, Stanford, CA (United States); Quon, Andrew [Department of Radiology, Division of Nuclear Medicine, Stanford University, Stanford, CA (United States); Hara, Wendy; Maxim, Peter G.; Le, Quynh-Thu [Department of Radiation Oncology, Stanford University, Stanford, CA (United States); Wakelee, Heather A. [Department of Medicine, Division of Oncology, Stanford University, Stanford, CA (United States); Donington, Jessica S. [Department of Cardiothoracic Surgery, Stanford University, Stanford, CA (United States); Graves, Edward E. [Department of Radiation Oncology, Stanford University, Stanford, CA (United States); Loo, Billy W. [Department of Radiation Oncology, Stanford University, Stanford, CA (United States)], E-mail: BWLoo@Stanford.edu

2007-10-01

272

Significance of intracellular localization of survivin in cervical squamous cell lesions: Correlation with disease progression  

PubMed Central

Survivin is a member of the inhibitor of apoptosis protein family. Under normal circumstances, survivin is expressed in embryonic and fetal tissues, but is completely downregulated in normal adult tissues. Notably, this protein has been found to be prominently expressed in a variety of human malignant tumors. The present study was designed to evaluate the possible role of survivin in the tumorigenesis of cervical intraepithelial neoplasia and invasive squamous cell carcinoma (SCC) of the uterine cervix. In addition, it was investigated whether the nuclear or cytoplasmic expression of survivin is associated with tumor progression. In total, 71 samples of cervical squamous tissue were obtained, including 15 normal squamous epithelia, 25 high-grade squamous intraepithelial lesions (HSILs) and 31 SCCs, from cone biopsy and hysterectomy specimens and stained for survivin expression by immunohistochemistry. The intensity of survivin expression tended to increase with tumor progression (60.0% of normal mucosa, 76.0% of HSIL and 80.6% of SCC samples demonstrated high intensity survivin expression), but this correlation was not found to be statistically significant. However, a statistically significant difference was identified in the intracellular localization of survivin among the normal mucosa, HSIL and SCC samples (P<0.001). In total, 72% (18/25) of HSIL and 54.8% (17/31) of SCC cases expressed cytoplasmic staining in contrast to the nuclear staining of the normal mucosa. In addition, 64% (16/25) of HSIL and 42% (13/31) of SCC cases showed coexpression in the nucleus and cytoplasm. An inverse correlation was identified between the decrement of nuclear survivin expression and tumor progression, but was not statistically significant (P=0.08). These results indicated that analysis of the intracellular expression of survivin (particularly cytoplasmic expression) is a marker for predicting disease progression in the uterine cervix. PMID:24765182

KIM, SOO-AH; HONG, RAN

2014-01-01

273

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

PubMed

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

2009-05-01

274

Host factors determine differential disease progression after infection with nef-deleted simian immunodeficiency virus  

PubMed Central

Infection of macaques with live attenuated simian immunodeficiency virus (SIV) usually results in long-lasting efficient protection against infection with pathogenic immunodeficiency viruses. However, attenuation by deletion of regulatory genes such as nef is not complete, leading to a high viral load and fatal disease in some animals. To characterize immunological parameters and polymorphic host factors, we studied 17 rhesus macaques infected with attenuated SIVmac239?NU. Eight animals were able to control viral replication, whereas the remaining animals (non-controllers) displayed variable set-point viral loads. Peak viral load at 2 weeks post-infection (p.i.) correlated significantly with set-point viral load (P<0.0001). CD4+ T-cell frequencies differed significantly soon after infection between controllers and non-controllers. Abnormal B-cell activation previously ascribed to Nef function could already be observed in non-controllers 8 weeks after infection despite the absence of Nef. Two non-controllers developed an AIDS-like disease within 102 weeks p.i. Virus from these animals transmitted to naïve animals replicated at low levels and the recipients did not develop immunodeficiency. This suggested that host factors determined differential viral load and subsequent disease course. Known Mhc class I alleles associated with disease progression in SIV WT infection only marginally influenced the viral load in ?nef-infected animals. Protection from SIVmac251 was associated with homozygosity for MHC class II in conjunction with a TLR7 polymorphism and showed a trend with initial viral replication. We speculated that host factors whose effects were usually masked by Nef were responsible for the different disease courses in individual animals upon infection with nef-deleted viruses. PMID:24928910

Sopper, Sieghart; Matz-Rensing, Kerstin; Muhl, Thorsten; Heeney, Jonathan; Stahl-Hennig, Christiane

2014-01-01

275

Applying Proteomics to the Diagnosis and Treatment of ALS and Related Diseases  

PubMed Central

Protein-based biomarkers for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases (MNDs) have many potential clinical utilities, including diagnostic, prognostic, and drug development indications. During the past decade a number of potential protein biomarkers have been proposed for MNDs. Further verification studies, followed by large validation and qualification studies, are required to advance these initial discoveries toward clinical use. Study of additional patient populations, including disease mimics, is required during the validation phase of biomarker development. Important regulatory issues are discussed that will affect the timing and strategy for biomarker assay development in ALS and other MNDs. The continued development of protein biomarkers for MNDs requires extensive collaboration between academic clinicians and scientists in conjunction with the biotechnology and pharmaceutical industries. PMID:19670321

Lacomis, David

2010-01-01

276

Aetiology and causal agents of mango sudden decline disease in the Sultanate A. O. Al Adawi1  

E-print Network

Aetiology and causal agents of mango sudden decline disease in the Sultanate of Oman A. O. Al Adawi and Fisheries, P.O. Box 204 Sohar, 311, Sultanate of Oman; 2 Department of Crop Sciences, Sultan Qaboos University, P.O. Box 34 Al Khod, 123, Sultanate of Oman; 3 University of Nizwa, P.O. Box 33 Barkat Al Muz 616

277

8OHdG as a marker for Huntington disease progression.  

PubMed

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

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

2012-06-01

278

8OHdG as a marker for Huntington disease progression  

PubMed Central

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

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

2013-01-01

279

Uncovering Symptom Progression History from Disease Registry Data with Application to Young Cystic Fibrosis Patients  

PubMed Central

Summary The growing availability of various disease registry data has brought precious opportunities to epidemiologists to understand the natural history of the registered diseases. It also presents challenges to the traditional data analysis techniques due to complicated censoring/truncation schemes and temporal dynamics of covariate influences. In a case study of the Cystic Fibrosis Foundation Patient Registry data, we propose analyses of progressive symptoms using temporal process regressions, as an alternative to the commonly employed proportional hazards models. Two end points are considered, the prevalence of ever positive and currently positive for Pseudomonas aeruginosa (PA) infection in the lungs, which capture different aspect of the disease process. The analysis of ever PA positive via a time-varying coefficient model demonstrates the lack of fit, as well as the potential loss of information, in the standard proportional hazards analysis. The analysis of currently PA positive yields results which are clinically meaningful and have not previously been reported in the cystic fibrosis literature. Our analyses demonstrate that prenatal/neonatal screening results in lower prevalence of PA infection compared to traditional diagnosis via signs and symptoms, but this benefit attenuates with age. Calendar years of diagnosis also affect the risk of PA infection; patients diagnosed in more recent cohort show higher prevalence of ever PA positive but lower prevalence of currently PA positive. PMID:19522871

Yan, Jun; Cheng, Yu; Fine, Jason P.; Lai, HuiChuan J.

2013-01-01

280

Allele-specific RNAi Mitigates Phenotypic Progression in a Transgenic Model of Alzheimer's Disease  

PubMed Central

Despite recent advances suggesting new therapeutic targets, Alzheimer's disease (AD) remains incurable. Aberrant production and accumulation of the A? peptide resulting from altered processing of the amyloid precursor protein (APP) is central to the pathogenesis of disease, particularly in dominantly inherited forms of AD. Thus, modulating the production of APP is a potential route to effective AD therapy. Here, we describe the successful use of an allele-specific RNA interference (RNAi) approach targeting the Swedish variant of APP (APPsw) in a transgenic mouse model of AD. Using recombinant adeno-associated virus (rAAV), we delivered an anti-APPsw short-hairpin RNA (shRNA) to the hippocampus of AD transgenic mice (APP/PS1). In short- and long-term transduction experiments, reduced levels of APPsw transprotein were observed throughout targeted regions of the hippocampus while levels of wild-type murine APP remained unaltered. Moreover, intracellular production of transfer RNA (tRNA)-valine promoter–driven shRNAs did not lead to detectable neuronal toxicity. Finally, long-term bilateral hippocampal expression of anti-APPsw shRNA mitigated abnormal behaviors in this mouse model of AD. The difference in phenotype progression was associated with reduced levels of soluble A? but not with a reduced number of amyloid plaques. Our results support the development of allele-specific RNAi strategies to treat familial AD and other dominantly inherited neurodegenerative diseases. PMID:19532137

Rodriguez-Lebron, Edgardo; Gouvion, Cynthia M; Moore, Steven A; Davidson, Beverly L; Paulson, Henry L

2009-01-01

281

Hyperperfusion in progressive multifocal leukoencephalopathy is associated with disease progression and absence of immune reconstitution inflammatory syndrome  

PubMed Central

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

Khoury, Michael N.; Gheuens, Sarah; Ngo, Long; Wang, Xiaoen; Alsop, David C.

2013-01-01

282

Identity experience among progressive gay Muslims in North America: a qualitative study within Al-Fatiha.  

PubMed

This qualitative study aims to document the identity experience of progressive gay Muslim men in a North American context. Six in-depth interviews, supplemented with participant observation, were conducted of gay Muslim men who attended an international conference for lesbian, gay, bisexual, transgendered, and questioning (LGBTQ) Muslims. For progressive gay Muslims such as these, a Muslim identity appears three-dimensional (religious, ethno-cultural, and color) when integrated with a gay identity. As a religious identity, gay Muslim's relationship to Allah (God) and a reinterpretation of the Qur'an and traditional condemnation of homosexuality appears necessary. As a cultural identity, East-West ethno-cultural differences that impact on homo-sociality and gay identity construction, marriage and the impact of coming out on the Eastern family and siblings emerged as critical issues. As a color identity, internalized racism, dating relationships and social dynamics within gay subculture as Muslims of color in a white dominant context appear key challenges. PMID:16864192

Minwalla, Omar; Rosser, B R Simon; Feldman, Jamie; Varga, Christine

2005-03-01

283

Guidelines in motor neurone disease (MND)\\/amyotrophic lateral sclerosis (ALS) – from diagnosis to patient care  

Microsoft Academic Search

This paper reviews the scope of current guidelines in motor neurone disease (MND)\\/amyotrophic lateral sclerosis (ALS) and\\u000a examines issues which have arisen in the preparation of these documents. The review concludes with an evaluation of the impact\\u000a of the guidelines which have been produced to date and looks towards potential future developments in this area.

J. D. Mitchell

2000-01-01

284

Managing progressive disease in patients with GIST: factors to consider besides acquired secondary tyrosine kinase inhibitor resistance.  

PubMed

The use of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumors (GIST). Currently, imatinib mesylate is the standard first-line treatment for unresectable and/or metastatic GIST, extending recurrence-free and overall survival for many patients. Nonetheless, eventual progression during imatinib therapy is prevalent, and the development of treatment paradigms for managing GIST progression is of importance. Sunitinib malate has been approved as a second-line treatment for unresectable and/or metastatic GIST and is an option for patients who are intolerant to imatinib or experience disease progression due to acquired resistance, otherwise referred to as secondary resistance. In many cases, however, there may be other causes for GIST progression besides secondary resistance, and consideration of these factors is necessary before switching to second-line treatment. This review presents a treatment strategy for GIST patients who have progressed after initial imatinib responsiveness and addresses necessary considerations that include instances of false progression, insufficient TKI plasma levels, and patient non-adherence. In situations where true progression has occurred, patients may benefit from imatinib dose escalation. Surgery also provides a viable option for patients with stable disease or limited progression, and may prevent and/or delay the development of resistant clones by reducing tumor burden. Switching to second-line therapy with sunitinib should be considered for imatinib-intolerant or -resistant GIST patients. PMID:22035971

Patel, Shreyaskumar

2012-08-01

285

Diseases of the kidney in medieval Persia the--Hidayat of Al-Akawayni.  

PubMed

The centralization of socioeconomic resources following the rise of the Islamic empire in the 7th century nurtured an initial gathering and translation into Arabic of extant medical texts in Greek, Syriac, Hindu and Chinese. As Arabic became the lingua franca of scholarship, there followed a second period of assimilation, original observations, commentary and systematization of medical knowledge in Arabic texts, which became the basis of revival and learned medicine in the West in the 12th century. However, not all medical texts of the period were written in Arabic. As central power eroded, provincial principalities arose, and regional cultures flourished, medical texts began to be written in local dialects, particularly in Persia. Notable amongst those and probably the oldest is the Hidayat al-Muallimin fi-al-Tibb (Learner's; guide to medicine) written by Abubakr al-Akawayni al-Bokhari in the closing decades of the 10th century. Written in Farsi and dedicated to his son and other students of medicine, the Hidayat is a relatively short and simplified pandect of medicine at the time and provides a glimpse of the teaching of medicine of the period. The present article is a translation of the sections of the Hidayat related to the kidney and urinary tract and their diseases. These early writings provide insight into the care of patients with kidney disease during the Middle Ages in general, and in Persia in particular. PMID:17855422

Ardalan, Mohammad R; Shoja, Mohammadali M; Tubbs, R Shane; Eknoyan, Garabed

2007-12-01

286

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

PubMed Central

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

Brosens, I.; Gordts, S.; Benagiano, G.

2013-01-01

287

Progressive Resistance Exercise and Parkinson's Disease: A Review of Potential Mechanisms  

PubMed Central

This paper reviews the therapeutically beneficial effects of progressive resistance exercise (PRE) on Parkinson's disease (PD). First, this paper discusses the rationale for PRE in PD. Within the first section, the review discusses the central mechanisms that underlie bradykinesia and muscle weakness, highlights findings related to the central changes that accompany PRE in healthy individuals, and extends these findings to individuals with PD. It then illustrates the hypothesized positive effects of PRE on nigro-striatal-thalamo-cortical activation and connectivity. Second, it reviews recent findings of the use of PRE in individuals with PD. Finally, knowledge gaps of using PRE on individuals with PD are discussed along with suggestions for future research. PMID:22191068

David, Fabian J.; Rafferty, Miriam R.; Robichaud, Julie A.; Prodoehl, Janey; Kohrt, Wendy M.; Vaillancourt, David E.; Corcos, Daniel M.

2012-01-01

288

Disease Progression in Plasmodium knowlesi Malaria Is Linked to Variation in Invasion Gene Family Members  

PubMed Central

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

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

289

Involvement of renal sympathetic nerve overactivation in the progression of chronic kidney disease in rats.  

PubMed

Time-dependent changes in the renal sympathetic nerve activity (RSNA) in the progression of chronic kidney disease (CKD) have not been investigated, despite the fact that renal sympathetic nervous system is augmented in the condition of CKD. In the present study, we examined time-dependent changes in RSNA and renal venous norepinephrine concentrations for 12 weeks using 5 of 6 nephrectomized CKD rats. Both RSNA and norepinephrine concentrations were increased during the early phase in the progression of CKD. Urinary protein excretion and systolic blood pressure (SBP) were gradually increased during 12 weeks after 5 of 6 nephrectomy. Treatment with ?-aminobutyric acid or the combination of prazosin and propranolol in the early phase (0-4 weeks) after 5 of 6 nephrectomy significantly attenuated the increases in urinary protein excretion and SBP in 5 of 6 nephrectomized rats. On the other hand, the same treatment in the late phase (8-12 weeks) after 5 of 6 nephrectomy failed to suppress the proteinuria and increase in SBP. Treatment with hydralazine at hypotensive dose for 12 weeks also failed to affect the proteinuria in 5 of 6 nephrectomized CKD rats. In conclusion, the augmentation of renal sympathetic nervous system in early phase after 5 of 6 nephrectomy is closely related to the development of partial ablation-induced CKD in rats. PMID:24084211

Kobuchi, Shuhei; Tanaka, Ryosuke; Funai, Asami; Suzuki, Rie; Yazawa, Maki; Tsutsui, Hidenobu; Ohkita, Mamoru; Ayajiki, Kazuhide; Matsumura, Yasuo

2014-01-01

290

Contingent Negative Variation Is Associated with Cognitive Dysfunction and Secondary Progressive Disease Course in Multiple Sclerosis  

PubMed Central

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.

Idiman, Fethi; Idiman, Egemen; Ozakbas, Serkan; Karakas, Sirel; Bruce, Jared

2014-01-01

291

Glucocorticoid receptor gene polymorphisms associated with progression of lung disease in young patients with cystic fibrosis  

PubMed Central

Background The variability in the inflammatory burden of the lung in cystic fibrosis (CF) patients together with the variable effect of glucocorticoid treatment led us to hypothesize that glucocorticoid receptor (GR) gene polymorphisms may affect glucocorticoid sensitivity in CF and, consequently, may contribute to variations in the inflammatory response. Methods We evaluated the association between four GR gene polymorphisms, TthIII, ER22/23EK, N363S and BclI, and disease progression in a cohort of 255 young patients with CF. Genotypes were tested for association with changes in lung function tests, infection with Pseudomonas aeruginosa and nutritional status by multivariable analysis. Results A significant non-corrected for multiple tests association was found between BclI genotypes and decline in lung function measured as the forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC). Deterioration in FEV1 and FVC was more pronounced in patients with the BclI GG genotype compared to the group of patients with BclI CG and CC genotypes (p = 0.02 and p = 0.04 respectively for the entire cohort and p = 0.01 and p = 0.02 respectively for F508del homozygous patients). Conclusion The BclI polymorphism may modulate the inflammatory burden in the CF lung and in this way influence progression of lung function. PMID:18047640

Corvol, Harriet; Nathan, Nadia; Charlier, Celine; Chadelat, Katarina; Le Rouzic, Philippe; Tabary, Olivier; Fauroux, Brigitte; Henrion-Caude, Alexandra; Feingold, Josue; Boelle, Pierre-Yves; Clement, Annick

2007-01-01

292

Correlation of fibrinogen-like protein 2 with disease progression in patients with severe acute pancreatitis  

PubMed Central

It has recently been demonstrated that fibrinogen-like protein 2 (fgl2) is expressed on the surface of macrophages, T cells and endothelial cells and directly cleaves prothrombin to thrombin. The present study was designed to examine fgl2 expression in patients with severe acute pancreatitis (SAP) and its correlation with disease progression. Peripheral blood mononuclear cells (PBMCs) were isolated from 25 patients with SAP, 37 patients with mild acute pancreatitis (MAP) and 20 healthy volunteers as controls. Paraffin sections of pancreas were obtained from 18 postoperative patients with SAP between 2003 and 2012. Human fgl2 (hfgl2) gene expression was determined in the PBMCs by real-time PCR. A monoclonal antibody against hfgl2 was applied to detect hfgl2 protein expression in the pancreatic tissues as well as in the PBMCs by immunohistochemical staining. The levels of hfgl2 expression in the PBMCs from the 25 patients with SAP were markedly upregulated compared with the other groups, whereas no significant difference between the MAP group and healthy controls was observed. hfgl2 expression in the PBMCs and pancreatic tissues was detectable through using immunohistochemistry and was demonstrated to be specifically localized to the endothelium of microvessels and inflammatory infiltrative cells in the areas of acute focal, confluent necrosis. There were positive correlations between hfgl2 expression in the PBMCs and the severity of SAP, as indicated by scores of Ranson and Acute Physiology and Chronic Health Evaluation II. The results suggest that hfgl2 is involved in the pathogenesis of SAP and hfgl2 levels may serve as a biomarker during disease progression. PMID:24348769

YE, XIAOHUA; HUAI, JIAPING; CHEN, RENPIN; DING, JIN; CHEN, YANPING; CAI, ZHENZHAI

2014-01-01

293

Integrative EEG biomarkers predict progression to Alzheimer's disease at the MCI stage  

PubMed Central

Alzheimer's disease (AD) is a devastating disorder of increasing prevalence in modern society. Mild cognitive impairment (MCI) is considered a transitional stage between normal aging and AD; however, not all subjects with MCI progress to AD. Prediction of conversion to AD at an early stage would enable an earlier, and potentially more effective, treatment of AD. Electroencephalography (EEG) biomarkers would provide a non-invasive and relatively cheap screening tool to predict conversion to AD; however, traditional EEG biomarkers have not been considered accurate enough to be useful in clinical practice. Here, we aim to combine the information from multiple EEG biomarkers into a diagnostic classification index in order to improve the accuracy of predicting conversion from MCI to AD within a 2-year period. We followed 86 patients initially diagnosed with MCI for 2 years during which 25 patients converted to AD. We show that multiple EEG biomarkers mainly related to activity in the beta-frequency range (13–30 Hz) can predict conversion from MCI to AD. Importantly, by integrating six EEG biomarkers into a diagnostic index using logistic regression the prediction improved compared with the classification using the individual biomarkers, with a sensitivity of 88% and specificity of 82%, compared with a sensitivity of 64% and specificity of 62% of the best individual biomarker in this index. In order to identify this diagnostic index we developed a data mining approach implemented in the Neurophysiological Biomarker Toolbox (http://www.nbtwiki.net/). We suggest that this approach can be used to identify optimal combinations of biomarkers (integrative biomarkers) also in other modalities. Potentially, these integrative biomarkers could be more sensitive to disease progression and response to therapeutic intervention. PMID:24106478

Poil, Simon-Shlomo; de Haan, Willem; van der Flier, Wiesje M.; Mansvelder, Huibert D.; Scheltens, Philip; Linkenkaer-Hansen, Klaus

2013-01-01

294

1!Serum urate as a predictor of clinical and radiographic progression in Parkinson's disease  

PubMed Central

Context Prospective epidemiological studies consistently indicate that Parkinson’s disease (PD) risk declines with increasing serum urate. Objective To determine whether serum urate, a purine metabolite and potent antioxidant, predicts prognosis in PD. Design, Setting, and Participants Prospective study among 804 subjects with early PD enrolled in the PRECEPT study, a clinical trial of the neuroprotectant potential of CEP-1347, conducted between April 2002 and August 2005 (average follow-up time 21.4 months). Main Outcome Measures The primary study endpoint was progression to clinical disability sufficient to warrant dopaminergic therapy. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching endpoint according to quintiles of baseline serum urate, adjusting for gender, age and other potential covariates. Change in striatal uptake of [123I]?-CIT, a marker for the presynaptic dopamine transporter, was assessed with linear regression for a subset of 399 subjects. Results The adjusted HR of reaching endpoint declined with increasing baseline concentrations of urate; subjects in the top quintile reached the endpoint at only half the rate of subjects in the bottom quintile (HR=0.51; 95% CI: 0.37 to 0.72; p=0.0002). This association was markedly stronger in men (HR=0.39; 95% CI: 0.26 to 0.60; p<0.0001) than in women (HR=0.77; 95% CI: 0.39 to 1.50; p=0.4). The percent loss in striatal [123I]?-CIT uptake also improved with increasing serum urate concentrations (overall p for trend=0.002; men, p=0.0008; women, p= 0.4). Conclusion These findings identify serum urate as the first molecular factor directly linked to the progression of typical PD and suggest that targeting urate or its determinants could be an effective disease modifying therapy in PD. PMID:18413464

Schwarzschild, Michael A.; Schwid, Steven R.; Marek, Kenneth; Watts, Arthur; Lang, Anthony E.; Oakes, David; Shoulson, Ira; Ascherio, Alberto

2008-01-01

295

Progressive cerebellar ataxia, spasticity, psychomotor retardation, and hexosaminidase deficiency in a 10-year-old child: juvenile Sandhoff disease.  

PubMed

During the course of investigating a 10-year-old boy because of progressive deterioration of intellectual functioning, ataxia, and hemiplegia, an absence of serum hexosaminidase activity was noted. A skin biopsy examined by electron microscopy showed axonal accumulations of dense osmiophilic deposits. Because of the patient's age at onset and the slowly progressive nature of his ilness, we are reporting an atypical juvenile case of Sandhoff disease. PMID:559267

MacLeod, P M; Wood, S; Jan, J E; Applegarth, D A; Dolman, C L

1977-06-01

296

Distinctive cytokine, chemokine, and antibody responses in Echinococcus multilocularis-infected patients with cured, stable, or progressive disease.  

PubMed

Metacestode larvae of the tapeworm Echinococcus multilocularis can cause alveolar echinococcosis (AE), a severe parasitic disease in man, which, if it remains untreated, may cause organ failure and death. Spontaneous and parasite antigen-induced cellular responses were studied in patients with cured, stable, and progressive AE to differentiate the response profiles between the distinct states of infection. Antibody reactivity was evaluated in AE patients with cured, stable, and progressive disease. The spontaneous cellular release of pro-inflammatory IL-31 and IL-33 was clearly depressed in all AE patients, while regulatory IL-27, anti-inflammatory SDF-1/CXCL12, and eosinophil granulocyte attracting Eotaxin-1, Eotaxin-2, and Eotaxin-3 (CCL11, CCL24, CCL26) were enhanced with disease progression. Such distinctive response profiles could be applied for monitoring of AE disease progression or regression. E. multilocularis metacestode (Em) antigens (entire metacestode EmAg as well as EmVesicles) stimulated in vitro IL-31, IL-33, Eotaxin-1, Eotaxin-3, and CXCL12 cytokine and chemokine responses, which were similarly present in all AE patient groups, while regulatory IL-27 was suppressed and pro-inflammatory Eotaxin-2 was enhanced. E. multilocularis metacestode-specific IgG1, IgG3, and IgE responses progressively diminished with regression from active to stable and cured AE. IgG2 and IgG4 reactivity remained similarly high in stable and progressive cases, and lessened only with cured AE. Antibody reactivity against E. multilocularis vesicle antigen distinctively separated between cured, stable, or progressive AE, with the exception of IgG4. In sum, the combined and longitudinal study of several cytokines and chemokines, together with the evaluation of E. multilocularis vesicle-specific antibody responses, should provide a better understanding of the immune response during progression and regression of AE, and may help to improve the staging of AE patients. PMID:24509604

Huang, Xiangsheng; Grüner, Beate; Lechner, Christian J; Kern, Peter; Soboslay, Peter T

2014-06-01

297

Bolker et al.: p. 1 of 31 Disease as a selective force precluding widespread cannibalism: A case study of an  

E-print Network

Bolker et al.: p. 1 of 31 Disease as a selective force precluding widespread cannibalism: A case, phenotypic and genotypic frequency of cannibal morphs, but only by assuming very high disease levels. Disease of cannibalism to observed levels. Given the high forces of infection required to reduce genetic propensity

Storfer, Andrew

298

Variability in Zucker diabetic fatty rats: differences in disease progression in hyperglycemic and normoglycemic animals  

PubMed Central

Both obesity and chronic inflammation are often associated with insulin resistance and type 2 diabetes. The Zucker diabetic fatty (ZDF) rat (fa/fa) is an obese animal model frequently used in type 2 diabetes research. The current study determines whether chronic administration (from 5 weeks of age through 24 weeks of age) of salsalate, a salicylate with anti-inflammatory properties, would be effective in mitigating diabetes disease progression in ZDF rats. Although a trend existed for lower blood glucose in the salsalate-treated group, significant differences were obscured by high animal-level variability. However, even in the non-drug-treated group, not all ZDF rats became diabetic as expected. Therefore, animals were parsed into two groups, regardless of drug treatment: normoglycemic ZDF rats, which maintained blood glucose profiles identical to nondiabetic Zucker lean rats (ZLRs), and hyperglycemic ZDF rats, which exhibited progressive elevation in blood glucose. To ascertain the differences between ZDF rats that became hyperglycemic and those that did not, relevant physiological indices and expression levels of adiponectin, tumor necrosis factor-?, interleukin-6, and glucocorticoid-induced leucine zipper messenger RNAs in adipose tissue were measured at sacrifice. Plasma C-reactive protein concentrations and expression levels of cytokine and glucocorticoid-induced leucine zipper messenger RNAs suggested more prevalent chronic inflammation in hyperglycemic animals. Early elevation of the insulin-sensitizing adipokine, adiponectin, was present in both ZDF groups, with the rate of its age-related decline faster in hyperglycemic animals. The most marked difference between the two groups of ZDF animals was in insulin output. Although the two ZDF populations had very similar elevated plasma insulin concentrations for the first 10 weeks, after that time, plasma insulin decreased markedly in the animals that became hyperglycemic, whereas it remained high in the normoglycemic ZDF rats. Thus, hyperglycemic ZDF animals exhibit both insulin resistance and progressive beta cell failure, whereas normoglycemic ZDF rats exhibit a lesser degree of insulin resistance that does not progress to beta cell failure. In these respects, the normoglycemic ZDF rats appear to revert back to a phenotype that strongly resembles that of nondiabetic Zucker fatty rats from which they were derived. PMID:25419150

Wang, Xi; DuBois, Debra C; Sukumaran, Siddharth; Ayyar, Vivaswath; Jusko, William J; Almon, Richard R

2014-01-01

299

Uric acid as a risk factor for progression of non-diabetic chronic kidney disease? The Mild to Moderate Kidney Disease (MMKD) Study.  

PubMed

The kidney is one of the organs most prominently affected by aging. This can be seen by a loss of renal mass which is caused by a decrease in the number of nephrons resulting in hyperfiltration, hypertrophy and elevations in glomerular pressure. The factors influencing aging of the kidney are not fully elucidated. Epidemiological, experimental and interventional studies resulted in inconsistent results and have not firmly established whether uric acid levels affect progression of Chronic Kidney Disease (CKD). Therefore, we analyzed whether uric acid levels predict the progression of CKD in the Mild to Moderate Kidney Disease Study comprising at baseline 227 Caucasian patients aged 18-65 years with primary non-diabetic CKD of various degrees of renal impairment. Of them, 177 completed a prospective follow-up of 7 years. Primary endpoint was progression of CKD defined as doubling of baseline serum creatinine and/or terminal renal failure. Patients who reached a progression endpoint (n =6 5) were significantly older, had higher baseline serum creatinine and protein excretion rates as well as lower Glomerular Filtration Rate (GFR). Uric acid levels were only higher in patients with progression of disease when patients with uric acid-lowering drugs were excluded from the analysis. Cox regression analysis revealed that increasing uric acid levels predict disease progression only when the analysis was not adjusted for baseline kidney function parameters. As soon as we adjusted the analysis for GFR and proteinuria this association completely vanished. In summary, our prospective 7 year follow-up study in patients with non-diabetic primary CKD did not support uric acid as an independent predictor for CKD progression. PMID:18294794

Sturm, Gisela; Kollerits, Barbara; Neyer, Ulrich; Ritz, Eberhard; Kronenberg, Florian

2008-04-01

300

The effect of a high resistance exercise program in slowly progressive neuromuscular disease.  

PubMed

A 12-week high resistance home exercise program was completed by 10 subjects with slowly progressive neuromuscular diseases (NMD) and 6 normal control subjects (CTL). After evaluating baseline maximal isometric and isokinetic strength of the elbow flexors and knee extensors, subjects completed the home program using adjustable ankle and wrist cuff weights. One side of the body was randomly chosen for exercise. Subjects initially performed 1 set of 10 repetitions on 3 days a week and gradually increased to 5 sets of 10 repetitions on 4 days a week. The NMD group demonstrated significant (p < 0.05) gains in several knee extension isokinetic strength measures but loss of elbow flexion eccentric peak torque and work per degree. The CTL group demonstrated significant gains in all measures of knee extension strength, with improvement of elbow isokinetic eccentric work per degree as well. There was evidence of cross training to the nonexercised limbs for both groups. A high resistance training program, although well tolerated in NMD subjects with mild to moderate weakness, may cause some deleterious effects to diseased skeletal muscle. A high resistance training program appears to offer no advantage over a moderate resistance training program in this population. PMID:8185450

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

1994-05-01

301

Alteration of the microRNA network during the progression of Alzheimer's disease.  

PubMed

An overview of miRNAs altered in Alzheimer's disease (AD) was established by profiling the hippocampus of a cohort of 41 late-onset AD (LOAD) patients and 23 controls, showing deregulation of 35 miRNAs. Profiling of miRNAs in the prefrontal cortex of a second independent cohort of 49 patients grouped by Braak stages revealed 41 deregulated miRNAs. We focused on miR-132-3p which is strongly altered in both brain areas. Downregulation of this miRNA occurs already at Braak stages III and IV, before loss of neuron-specific miRNAs. Next-generation sequencing confirmed a strong decrease of miR-132-3p and of three family-related miRNAs encoded by the same miRNA cluster on chromosome 17. Deregulation of miR-132-3p in AD brain appears to occur mainly in neurons displaying Tau hyper-phosphorylation. We provide evidence that miR-132-3p may contribute to disease progression through aberrant regulation of mRNA targets in the Tau network. The transcription factor (TF) FOXO1a appears to be a key target of miR-132-3p in this pathway. PMID:24014289

Lau, Pierre; Bossers, Koen; Janky, Rekin's; Salta, Evgenia; Frigerio, Carlo Sala; Barbash, Shahar; Rothman, Roy; Sierksma, Annerieke S R; Thathiah, Amantha; Greenberg, David; Papadopoulou, Aikaterini S; Achsel, Tilmann; Ayoubi, Torik; Soreq, Hermona; Verhaagen, Joost; Swaab, Dick F; Aerts, Stein; De Strooper, Bart

2013-10-01

302

Alteration of the microRNA network during the progression of Alzheimer's disease  

PubMed Central

An overview of miRNAs altered in Alzheimer's disease (AD) was established by profiling the hippocampus of a cohort of 41 late-onset AD (LOAD) patients and 23 controls, showing deregulation of 35 miRNAs. Profiling of miRNAs in the prefrontal cortex of a second independent cohort of 49 patients grouped by Braak stages revealed 41 deregulated miRNAs. We focused on miR-132-3p which is strongly altered in both brain areas. Downregulation of this miRNA occurs already at Braak stages III and IV, before loss of neuron-specific miRNAs. Next-generation sequencing confirmed a strong decrease of miR-132-3p and of three family-related miRNAs encoded by the same miRNA cluster on chromosome 17. Deregulation of miR-132-3p in AD brain appears to occur mainly in neurons displaying Tau hyper-phosphorylation. We provide evidence that miR-132-3p may contribute to disease progression through aberrant regulation of mRNA targets in the Tau network. The transcription factor (TF) FOXO1a appears to be a key target of miR-132-3p in this pathway. PMID:24014289

Lau, Pierre; Bossers, Koen; Janky, Rekin's; Salta, Evgenia; Frigerio, Carlo Sala; Barbash, Shahar; Rothman, Roy; Sierksma, Annerieke S R; Thathiah, Amantha; Greenberg, David; Papadopoulou, Aikaterini S; Achsel, Tilmann; Ayoubi, Torik; Soreq, Hermona; Verhaagen, Joost; Swaab, Dick F; Aerts, Stein; De Strooper, Bart

2013-01-01

303

TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease  

PubMed Central

The clinical syndrome of primary progressive aphasia (PPA) can be associated with a variety of neuropathologic diagnoses at autopsy. Thirty percent of cases have Alzheimer disease (AD) pathology, most often in the usual distribution, which defies principles of brain–behavior organization, in that aphasia is not symptomatic of limbic disease. The present study investigated whether concomitant TDP-43 pathology could resolve the lack of clinicoanatomic concordance. In this paper, 16 cases of clinical PPA and 10 cases of primarily non-aphasic frontotemporal dementia (FTD), all with AD pathology, were investigated to determine whether their atypical clinical phenotypes reflected the presence of additional TDP-43 pathology. A comparison group consisted of 27 cases of pathologic AD with the typical amnestic clinical phenotype of probable AD. Concomitant TDP-43 pathology was discovered in only three of the FTD and PPA but in more than half of the typical amnestic clinical phenotypes. Hippocampal sclerosis (HS) was closely associated with TDP-43 pathology when all groups were combined for analysis. Therefore, the clinical phenotypes of PPA and FTD in cases with pathologic AD are only rarely associated with TDP-43 proteinopathy. Furthermore, medial temporal TDP-43 pathology is more tightly linked to HS than to clinical phenotype. These findings challenge the current notions about clinicopathologic correlation, especially about the role of multiple pathologies. PMID:20361198

Mishra, Manjari; Hatanpaa, Kimmo J.; White, Charles L.; Johnson, Nancy; Rademaker, Alfred; Weitner, Bing Bing; Deng, Han-Xiang; Dubner, Steven D.; Weintraub, Sandra; Mesulam, Marsel

2010-01-01

304

How do periodontal infections affect the onset and progression of Alzheimer's disease?  

PubMed

Chronic infection can cause slow progressive dementia, cortical atrophy and amyloid deposition in the atrophic form of general paresis. Due to the fact that specific bacterial ligands can increase the expression of proinflammatory molecules that can activate innate and adaptive immune systems, inflammation may play a significant role in the pathogenesis of Alzheimer's disease (AD). Furthermore, there is a significant association between AD and various types of spirochete. Periodontitis is a prevalent and persistent peripheral infection that is associated with gram-negative anaerobic bacteria and is capable of showing localized and systemic infections in the host. Periodontal disease related pathogens and their inflammatory products contribute to systemic inflammation and the pathogenesis of AD. In this minireview, we propose a hypothetical link between periodontitis, type 2 diabetes and AD. We also present the possible mechanistic links between periodontitis-related inflammation, type 2 diabetes and AD. Since this condition is treatable, periodontitis may be a readily-modifiable risk factor for AD. PMID:24059310

Shaik, Munvar M; Ahmad, Sultan; Gan, Siew H; Abuzenadah, Adel M; Ahmad, Ejaz; Tabrez, Shams; Ahmed, Farid; Kamal, Mohammad A

2014-04-01

305

Flare Response versus Disease Progression in Patients with Non-small Cell Lung Cancer  

PubMed Central

We present a case report of a patient with metastatic non-small cell lung cancer (NSCLC) who had a series of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scans for assessment of response to treatment. A restaging 18F-FDG PET/CT scan after six cycles showed increased FDG activity in the bone lesions with reduced activity in the lung and liver lesions. The increased bone activity was considered to be due to flare phenomenon rather than metastasis. A short interval follow up scan after 1 month was advised to confirm this interpretation but this repeat scan showed disease relapse. Although the flare phenomenon does exist, caution should be exercised in attributing increased tracer uptake in the lesions in patients with adenocarcinoma of lung and especially those who have received erlotinib during the course of their treatment. Distinguishing the 'flare phenomenon' and 'disease progression' is at times difficult but is important since misdiagnosis may result in an unnecessary delay in patient management. PMID:23372867

Al-Nabhani, Khalsa; Syed, Rizwan; Haroon, Athar; Almukhailed, Omar; Bomanji, Jamshed

2012-01-01

306

Exon skipping restores dystrophin expression, but fails to prevent disease progression in later stage dystrophic dko mice  

PubMed Central

Antisense therapy with both chemistries of phosphorodiamidate morpholino oligomers (PMOs) and 2?-O-methyl phosphorothioate has demonstrated the capability to induce dystrophin expression in Duchenne muscular dystrophy (DMD) patients in phase II–III clinical trials with benefit in muscle functions. However, potential of the therapy for DMD at different stages of the disease progression is not understood. In this study, we examined the effect of peptide-conjugated PMO (PPMO)-mediated exon skipping on disease progression of utrophin-dystrophin-deficient mice (dko) of four age groups (21–29, 30–39, 40–49 and 50+ days), representing diseases from early stage to advanced stage with severe kyphosis. Biweekly intravenous (i.v.) administration of the PPMO restored the dystrophin expression in nearly 100% skeletal muscle fibers in all age groups. This was associated with the restoration of dystrophin-associated proteins including functional glycosylated dystroglycan and neuronal nitric synthase. However, therapeutic outcomes clearly depended on severity of the disease at the time the treatment started. The PPMO treatment alleviated the disease pathology and significantly prolonged the life span of the mice receiving treatment at younger age with mild phenotype. However, restoration of high levels of dystrophin expression failed to prevent disease progression to the mice receiving treatment when disease was already at advanced stage. The results could be critical for design of clinical trials with antisense therapy to DMD. PMID:24942628

Wu, B; Cloer, C; Lu, P; Milazi, S; Shaban, M; Shah, SN; Marston-Poe, L; Moulton, HM; Lu, QL

2014-01-01

307

Postnatal progression of bone disease in the cervical spines of mucopolysaccharidosis I dogs  

PubMed Central

Introduction Mucopolysaccharidosis I (MPS I) is a lysosomal storage disorder characterized by deficient ?-L-iduronidase activity leading to accumulation of poorly degraded dermatan and heparan sulfate glycosaminoglycans (GAGs). MPS I is associated with significant cervical spine disease, including vertebral dysplasia, odontoid hypoplasia, and accelerated disc degeneration, leading to spinal cord compression and kypho-scoliosis. The objective of this study was to establish the nature and rate of progression of cervical vertebral bone disease in MPS I using a canine model. Methods C2 vertebrae were obtained post-mortem from normal and MPS I dogs at 3, 6 and 12 months-of-age. Morphometric parameters and mineral density for the vertebral trabecular bone and odontoid process were determined using micro-computed tomography. Vertebrae were then processed for paraffin histology, and cartilage area in both the vertebral epiphyses and odontoid process were quantified. Results Vertebral bodies of MPS I dogs had lower trabecular bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and bone mineral density (BMD) than normals at all ages. For MPS I dogs, BV/TV, Tb.Th and BMD plateaued after 6 months-of-age. The odontoid process appeared morphologically abnormal for MPS I dogs at 6 and 12 months-of-age, although BV/TV and TMD were not significantly different from normals. MPS I dogs had significantly more cartilage in the vertebral epiphyses at both 3 and 6 months-of-age. At 12 months-of-age, epiphyseal growth plates in normal dogs were absent, but in MPS I dogs they persisted. Conclusions In this study we report reduced trabecular bone content and mineralization, and delayed cartilage to bone conversion in MPS I dogs from 3 months-of-age, which may increase vertebral fracture risk and contribute to progressive deformity. The abnormalities of the odontoid process we describe likely contribute to increased incidence of atlanto-axial subluxation observed clinically. Therapeutic strategies that enhance bone formation may decrease incidence of spine disease in MPS I patients. PMID:23563357

Chiaro, Joseph A; Baron, Matthew D; del Alcazar, Chelsea; O'Donnell, Patricia; Shore, Eileen M; Elliott, Dawn M; Ponder, Katherine P; Haskins, Mark E; Smith, Lachlan J

2013-01-01

308

Diabetes, cardiovascular disease, selected cardiovascular disease risk factors, and the 5-year incidence of age-related cataract and progression of lens opacities: the beaver dam eye study  

Microsoft Academic Search

PURPOSE: To describe the relationships of diabetes mellitus, cardiovascular disease, and selected cardiovascular disease risk factors to cumulative incidence of age-related cataract and to progression of lens opacities over a 5-year interval.METHODS: A follow-up examination of the Beaver Dam Eye Study cohort was performed 5 years after the baseline evaluation. Ages at the census prior to baseline ranged from 43

Barbara E. K Klein; Ronald Klein; Kristine E Lee

1998-01-01

309

Bone marrow stroma CD40 expression correlates with inflammatory mast cell infiltration and disease progression in splenic marginal zone lymphoma.  

PubMed

Splenic marginal zone lymphoma (SMZL) is a mature B-cell neoplasm characterized by rather indolent clinical course. However, nearly one third of patients experience a rapidly progressive disease with a dismal outcome. Despite the characterization of clone genetics and the recognition of deregulated immunologic stimulation in the pathogenesis of SMZL, little is known about microenvironment dynamics and their potential biological influence on disease outcome. Here we investigate the effect of stroma-intrinsic features on SMZL disease progression by focusing on the microenvironment of the bone marrow (BM), which represents an elective disease localization endorsing diagnostic and prognostic relevance. We show that the quality of the BM stromal meshwork of SMZL infiltrates correlates with time to progression. In particular, we describe the unfavorable prognostic influence of dense CD40 expression by BM stromal cells, which involves the contribution of CD40 ligand (CD40L)-expressing bystander mast cells infiltrating SMZL BM aggregates. The CD40/CD40L-assisted crosstalk between mesenchymal stromal cells and mast cells populating the SMZL microenvironment finds correlation in p53(-/-) mice developing SMZL and contributes to the engendering of detrimental proinflammatory conditions. Our study highlights a dynamic interaction, playing between nonneoplastic elements within the SMZL niche, toward disease progression. PMID:24452203

Franco, Giovanni; Guarnotta, Carla; Frossi, Barbara; Piccaluga, Pier Paolo; Boveri, Emanuela; Gulino, Alessandro; Fuligni, Fabio; Rigoni, Alice; Porcasi, Rossana; Buffa, Salvatore; Betto, Elena; Florena, Ada Maria; Franco, Vito; Iannitto, Emilio; Arcaini, Luca; Pileri, Stefano Aldo; Pucillo, Carlo; Colombo, Mario Paolo; Sangaletti, Sabina; Tripodo, Claudio

2014-03-20

310

Expression profiling of cervical cancers in Indian women at different stages to identify gene signatures during progression of the disease  

PubMed Central

Cervical cancer is the second most common cancer among women worldwide, with developing countries accounting for >80% of the disease burden. Although in the West, active screening has been instrumental in reducing the incidence of cervical cancer, disease management is hampered due to lack of biomarkers for disease progression and defined therapeutic targets. Here we carried out gene expression profiling of 29 cervical cancer tissues from Indian women, spanning International Federation of Gynaecology and Obstetrics (FIGO) stages of the disease from early lesion (IA and IIA) to progressive stages (IIB and IIIA–B), and identified distinct gene expression signatures. Overall, metabolic pathways, pathways in cancer and signaling pathways were found to be significantly upregulated, while focal adhesion, cytokine–cytokine receptor interaction and WNT signaling were downregulated. Additionally, we identified candidate biomarkers of disease progression such as SPP1, proliferating cell nuclear antigen (PCNA), STK17A, and DUSP1 among others that were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in the samples used for microarray studies as well in an independent set of 34 additional samples. Integrative analysis of our results with other cervical cancer profiling studies could facilitate the development of multiplex diagnostic markers of cervical cancer progression. PMID:24403257

Thomas, Asha; Mahantshetty, Umesh; Kannan, Sadhana; Deodhar, Kedar; Shrivastava, Shyam K; Kumar-Sinha, Chandan; Mulherkar, Rita

2013-01-01

311

Heightened intrathecal release of axonal cytoskeletal proteins in multiple sclerosis is associated with progressive disease and clinical disability.  

PubMed

The pathologic basis of disease progression in multiple sclerosis (MS) is thought to involve axonal degeneration, which contributes to the accumulation of neurological disability. Recent reports suggest that intrathecal concentrations of the neurofilament protein in relapsing remitting MS correlate with disease activity and the degree of disability. We sought to investigate the intrathecal levels of other cytoskeletal components of axons, primarily actin, tubulin and the light subunit of neurofilament (NFL) in patients with progressive MS and relevant controls and correlate results with clinical parameters of disease severity. Cerebrospinal fluid (CSF) concentrations of actin, tubulin and NFL were significantly increased in MS patients when compared to corresponding levels in patients with other inflammatory or non-inflammatory neurological diseases. Moreover, the intrathecal release of actin and tubulin, and to a lesser extent NFL, was significantly more marked in patients with primary and secondary progressive MS when compared to patients with relapsing remitting disease and was correlated with clinical disability. Our findings suggest that progressive MS is associated with the heightened intrathecal release of axonal cytoskeletal proteins, and that CSF actin, tubulin and NFL are reliable markers of axonal damage. PMID:11777552

Semra, Y K; Seidi, O A; Sharief, M K

2002-01-01

312

Enhanced neuronal Met signalling levels in ALS mice delay disease onset  

PubMed Central

Signalling by receptor tyrosine kinases (RTKs) coordinates basic cellular processes during development and in adulthood. Whereas aberrant RTK signalling can lead to cancer, reactivation of RTKs is often found following stress or cell damage. This has led to the common belief that RTKs can counteract degenerative processes and so strategies to exploit them for therapy have been extensively explored. An understanding of how RTK stimuli act at cellular levels is needed, however, to evaluate their mechanism of therapeutic action. In this study, we genetically explored the biological and functional significance of enhanced signalling by the Met RTK in neurons, in the context of a neurodegenerative disease. Conditional met-transgenic mice, namely Rosa26LacZ?stop?Met, have been engineered to trigger increased Met signalling in a temporal and tissue-specific regulated manner. Enhancing Met levels in neurons does not affect either motor neuron (MN) development or maintenance. In contrast, increased neuronal Met in amyotrophic lateral sclerosis (ALS) mice prolongs life span, retards MN loss, and ameliorates motor performance, by selectively delaying disease onset. Thus, our studies highlight the properties of RTKs to counteract toxic signals in a disease characterized by dysfunction of multiple cell types by acting in MNs. Moreover, they emphasize the relevance of genetically assessing the effectiveness of agents targeting neurons during ALS evolution. PMID:21412276

Genestine, M; Caricati, E; Fico, A; Richelme, S; Hassani, H; Sunyach, C; Lamballe, F; Panzica, G C; Pettmann, B; Helmbacher, F; Raoul, C; Maina, F; Dono, R

2011-01-01

313

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

Microsoft Academic Search

Alzheimer's disease (AD) is the leading cause of dementia among the elderly population; however, knowledge about genetic risk factors involved in disease progression is limited. We conducted a genome-wide association study (GWAS) using clinical decline as measured by changes in the Clinical Dementia Rating-sum of boxes as a quantitative trait to test for single-nucleotide polymorphisms (SNPs) that were associated with

X Hu; E H Pickering; S K Hall; S Naik; Y C Liu; H Soares; E Katz; S A Paciga; W Liu; P S Aisen; K R Bales; T A Samad; S L John

2011-01-01

314

Systems biology approach to identify transcriptome reprogramming and candidate microRNA targets during the progression of polycystic kidney disease  

Microsoft Academic Search

Background  Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst formation throughout the kidney parenchyma.\\u000a It is caused by mutations in either of two genes, PKD1 and PKD2. Mice that lack functional Pkd1 (Pkd1\\u000a \\u000a -\\/-\\u000a ), develop rapidly progressive cystic disease during embryogenesis, and serve as a model to study human ADPKD. Genome wide\\u000a transcriptome reprogramming and the possible roles

Priyanka Pandey; Shan Qin; Jacqueline Ho; Jing Zhou; Jordan A Kreidberg

2011-01-01

315

Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD)  

Microsoft Academic Search

Background. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by dysregulated tubular epithelial cell growth, resulting in the forma- tion of multiple renal cysts and progressive renal failure. To date, there is no effective treatment for ADPKD. The mammalian target of rapamycin (mTOR) is an atypical protein kinase and a central controller of cell growth and proliferation. We examined the

Patricia R. Wahl; Andreas L. Serra; Michel Le Hir; Klaus D. Molle; Michael N. Hall; Rudolf P. Wuthrich

2006-01-01

316

Effective T-cell responses select human immunodeficiency virus mutants and slow disease progression.  

PubMed

The possession of some HLA class I molecules is associated with delayed progression to AIDS. The mechanism behind this beneficial effect is unclear. We tested the idea that cytotoxic T-cell responses restricted by advantageous HLA class I molecules impose stronger selection pressures than those restricted by other HLA class I alleles. As a measure of the selection pressure imposed by HLA class I alleles, we determined the extent of HLA class I-associated epitope variation in a cohort of European human immunodeficiency virus (HIV)-positive individuals (n=84). We validated our findings in a second, distinct cohort of African patients (n=516). We found that key HIV epitopes restricted by advantageous HLA molecules (B27, B57, and B51 in European patients and B5703, B5801, and B8101 in African patients) were more frequently mutated in individuals bearing the restricting HLA than in those who lacked the restricting HLA class I molecule. HLA alleles associated with clinical benefit restricted certain epitopes for which the consensus peptides were frequently recognized by the immune response despite the circulating virus's being highly polymorphic. We found a significant inverse correlation between the HLA-associated hazard of disease progression and the mean HLA-associated prevalence of mutations within epitopes (P=0.028; R2=0.34). We conclude that beneficial HLA class I alleles impose strong selection at key epitopes. This is revealed by the frequent association between effective T-cell responses and circulating viral escape mutants and the rarity of these variants in patients who lack these favorable HLA class I molecules, suggesting a significant pressure to revert. PMID:17409157

Frater, A J; Brown, H; Oxenius, A; Günthard, H F; Hirschel, B; Robinson, N; Leslie, A J; Payne, R; Crawford, H; Prendergast, A; Brander, C; Kiepiela, P; Walker, B D; Goulder, P J R; McLean, A; Phillips, R E

2007-06-01

317

Serum Level of Lactate Dehydrogenase is a Useful Clinical Marker to Monitor Progressive Multiple Myeloma Diseases: A Case Report  

PubMed Central

To follow the progression of multiple myeloma (MM) disease, serum lactate dehydrogenase (LDH) levels are as useful markers as beta-2 microglobulin and monoclonal immunoglobulin. With this study, we have presented a case of a patient with a multiple myeloma which was fulminant course, whose LDH levels were normal at the onset of diagnosis increasing as 27 times more than normal as the disease progressed and who showed the development of extramedullary plasmacytomas. The patient, an 80-year-old female, was diagnosed with stage IIIA IgA type multiple myeloma and melphalan-prednisolon (MP) treatment was started. Although the LDH levels were low during the diagnosis and chemotherapy, the LDH levels increased up to 7557 U/L following the progression and occurrence of extramedullary plasmacytomas and the patient died. During the observation of the patient with MM, if the LDH levels are abnormally high, the progression of the disease should be considered after eliminating the other causes. Bone marrow aspiration and biopsy should be examined and the progression or relapse should be shown. On the other hand, the patients with LDH levels are high should be considered to have added plasmacytomas, the whole body should be examined at an early stage before the development of clinical symptoms and early treatment should be started. PMID:24764735

Teke, Hava Uskudar; Basak, Mustafa; Teke, Deniz; Kanbay, Mehmet

2014-01-01

318

Progressive cholinergic decline in Alzheimer's Disease: consideration for treatment with donepezil 23 mg in patients with moderate to severe symptomatology.  

PubMed

Of the estimated 5.3 million people with Alzheimer's disease in the United States, more than half would be classified as having moderate or severe disease. Alzheimer's disease is a progressive disorder with the moderate to severe stages generally characterized by significant cognitive, functional, and behavioral dysfunction. Unsurprisingly, these advanced stages are often the most challenging for both patients and their caregivers/families. Symptomatic treatments for moderate to severe Alzheimer's disease are approved in the United States and include the acetylcholinesterase inhibitor donepezil and the glutamate receptor antagonist memantine. Progressive symptomatic decline is nevertheless inevitable even with the available therapies, and therefore additional treatment options are urgently needed for this segment of the Alzheimer's disease population. An immediate-release formulation of donepezil has been available at an approved dose of 5-10 mg/d for the past decade. Recently, the United States Food and Drug Administration approved a higher-dose (23 mg/d) donepezil formulation, which provides more gradual systemic absorption, a longer time to maximum concentration (8 hours) versus the immediate-release formulation (3 hours), and higher daily concentrations. Herein, we review (1) the scientific data on the importance of cholinergic deficits in Alzheimer's disease treatment strategies, (2) the rationale for the use of higher-dose acetylcholinesterase inhibitors in patients with advanced disease, and (3) recent clinical evidence supporting the use of higher-dose donepezil in patients with moderate to severe Alzheimer's disease. PMID:21299848

Sabbagh, Marwan; Cummings, Jeffrey

2011-01-01

319

Diabetes disease progression in Goto-Kakizaki rats: effects of salsalate treatment  

PubMed Central

This study investigates the antidiabetic effects of salsalate on disease progression of diabetes in non-obese diabetic Goto-Kakizaki (GK) rats, an experimental model of type 2 diabetes. Salsalate was formulated in rat chow (1,000 ppm) and used to feed rats from 5 to 21 weeks of age. At 5 weeks of age, GK and Wistar (WIS) control rats were subdivided into four groups, each composed of six rats: GK rats with standard diet (GK-C); GK rats with salsalate-containing diet (GK-S); WIS rats with standard diet (WIS-C); and WIS rats with salsalate-containing diet (WIS-S). The GK-C rats (167.2±11.6 mg/dL) showed higher blood glucose concentrations than WIS-C rats (133.7±4.9 mg/dL, P<0.001) at the beginning of the experiment, and had substantially elevated blood glucose from an age of 15 weeks until sacrifice at 21 weeks (341.0±133.6 mg/dL). The GK-S rats showed an almost flat profile of blood glucose from 4 weeks (165.1±11.0 mg/dL) until sacrifice at 21 weeks of age (203.7±22.2 mg/dL). While this difference in blood glucose between 4 and 21 weeks in GK-S animals was significant, blood glucose at 21 weeks was significantly lower in GK-S compared to GK-C animals. At sacrifice, salsalate decreased plasma insulin (GK-S =1.0±0.3; GK-C =2.0±0.3 ng/mL, P<0.001) and increased plasma adiponectin concentrations (GK-S =15.9±0.7; GK-C =9.7±2.0 ?g/mL, P<0.001). Salsalate also lowered total cholesterol in GK-S rats (96.1±8.5 mg/dL) compared with GK-C rats (128.0±11.4 mg/dL, P<0.001). Inflammation-related genes (Ifit1 and Iigp1) exhibited much higher mRNA expression in GK-C rats than WIS-C rats in liver, adipose, and muscle tissues, while salsalate decreased the Ifit1 and Iigp1 mRNA only in adipose tissue. These results suggest that salsalate acts to both increase adiponectin and decrease adipose tissue-based inflammation while preventing type 2 diabetes disease progression in GK rats. PMID:25120374

Wang, Xi; DuBois, Debra C; Cao, Yanguang; Jusko, William J; Almon, Richard R

2014-01-01

320

Convergent Evolution within the V3 Loop Domain of Human Immunodeficiency Virus Type 1 in Association with Disease Progression  

Microsoft Academic Search

Phylogenetic analysis was used to study in vivo genetic variation of the V3 region of human immunodefi- ciency virus type 1 in relation to disease progression in six infants with vertically acquired human immuno- deficiency virus type 1 infection. Nucleotide sequences from each infant formed a monophyletic group with similar average branch lengths separating the sets of sequences. In contrast

NATALY STRUNNIKOVA; STUART C. RAY; ROBERT A. LIVINGSTON; ELIZABETH RUBALCABA; ANDRAPHAEL P. VISCIDI

1995-01-01

321

Lack of genetic association among coat colors, progressive retinal atrophy and polycystic kidney disease in Persian cats  

Microsoft Academic Search

An inherited form of progressive retinal atrophy (PRA) is recognized in Persian cats; however, the prevalence of PRA in the breed has not been determined. Breeders suggest that cats from only brown (‘chocolate’) or Himalayan (‘pointed’) lines are at risk for PRA, suggesting the disease is not widespread. This study was designed to evaluate whether PRA in Persian cats is

HyungChul Rah; David J. Maggs; Leslie A. Lyons

2006-01-01

322

Cyclosporine A Slows the Progressive Renal Disease of Alport Syndrome (X-Linked Hereditary Nephritis): Results from a Canine Model  

Microsoft Academic Search

Alport syndrome refers to a hereditary disorder char- acterized by progressive renal disease and a multilaminar ap- pearance to the glomerular basement membrane (GBM). In a small group of patients with Alport syndrome, cyclosporine A was reported to decrease proteinuria and maintain stable renal function over 7 to 10 yr of follow-up. The present study examined the effect of cyclosporine

DILYS CHEN; BARBARA JEFFERSON; SCOTT J. HARVEY; KEQIN ZHENG; CATHY J. GARTLEY; ROBERT M. JACOBS; PAUL S. THORNER

2003-01-01

323

Does neurologic deterioration help to differentiate between pseudoprogression and true disease progression in newly diagnosed glioblastoma multiforme?  

PubMed

Enlarging or new lesions frequently appear on magnetic resonance imaging (mri) after concurrent administration of radiation therapy and temozolomide in glioblastoma multiforme (gbm) patients. However, in nearly half such cases, the observed radiologic changes are not due to true disease progression, but instead are a result of a post-radiation inflammatory state called "pseudoprogression." Retrospective studies have reported that neurologic deterioration at the time of the post-chemoradiotherapy mri is found more commonly in patients with true disease progression. We report a gbm patient with both radiologic progression on the post-chemoradiotherapy mri and concomitant neurologic deterioration, and we caution against incorporating clinical deterioration into the management schema of patients with possible pseudoprogression. PMID:22876160

Singh, A D; Easaw, J C

2012-08-01

324

Does neurologic deterioration help to differentiate between pseudoprogression and true disease progression in newly diagnosed glioblastoma multiforme?  

PubMed Central

Enlarging or new lesions frequently appear on magnetic resonance imaging (mri) after concurrent administration of radiation therapy and temozolomide in glioblastoma multiforme (gbm) patients. However, in nearly half such cases, the observed radiologic changes are not due to true disease progression, but instead are a result of a post-radiation inflammatory state called “pseudoprogression.” Retrospective studies have reported that neurologic deterioration at the time of the post-chemoradiotherapy mri is found more commonly in patients with true disease progression. We report a gbm patient with both radiologic progression on the post-chemoradiotherapy mri and concomitant neurologic deterioration, and we caution against incorporating clinical deterioration into the management schema of patients with possible pseudoprogression. PMID:22876160

Singh, A.D.; Easaw, J.C.

2012-01-01

325

The influence of renal manifestations to the progression of autosomal dominant polycystic kidney disease  

PubMed Central

Background: Renal stones, urinary tract infections (UTI) and gross hematuria (GH) are the most important renal manifestations of autosomal dominant polycystic kidney disease (ADPKD). They are not only common, but are also frequent cause of morbidity, influencing renal dysfunction. The aim of this study was to evaluate the frequency of these manifestations in our patients with ADPKD and their impact on renal function. Methods: One hundred eighty ADPKD patients were included in the study. Subjects were studied for the presence of UTI, gross hematuria frequency and responsible factors of nephrolithiasis. Survival times were calculated as the time to renal replacement therapy or time of serum creatinine value up to 10 mg/dl. Kaplan-Meier product-limit survival curves were constructed, and log rank test was used to compare the survival curves. Results: Kidney stones were present in 76/180 (42% of pts). The stones were composed of urate (47%) calcium oxalate (39%), and other compounds 14%. UTI was observed in 60% (108 patients). Patients treated with urinary disinfectants had a significant lower frequency of urinary infection (p<0.001) and hematuria (p<0.001) after one year than untreated patients. Gross hematuria was present in 113 patients (63%). In 43 patients hematuria was diagnosed before age 30 (38%), while in 70 patients it was diagnosed after age 30 (62%). Conclusions: UTI is frequent in our ADPKD patients. The correct treatment of UTI decreases its frequency and has beneficial role in the rate of progression to renal failure in ADPKD patients. Patients with recurrent episodes of gross hematuria may be at risk for more severe renal disease. PMID:19918304

Idrizi, A; Barbullushi, M; Petrela, E; Kodra, S; Koroshi, A; Thereska, N

2009-01-01

326

Effects of experimental warming on fungal disease progress in oilseed rape.  

PubMed

Global warming will influence the growth and development of both crops and pathogens. The aims of this study were to investigate potential effects of future warming on oilseed rape growth and the epidemiology of the three economically important pathogens Verticillium longisporum, Sclerotinia sclerotiorum, and Leptosphaeria maculans (anamorph: Phoma lingam). We utilized climate chambers and a soil warming facility, where treatments represented regional warming scenarios for Lower Saxony, Germany, by 2050 and 2100, and compared results of both approaches on a thermal time scale by calculating degree-days (dd) from day of sowing, December 1st and March 1st until sampling, the latter correlating best with disease progress. Regression analysis showed that plant growth and growth stages in spring responded almost linearly to increasing thermal time until 1000-1500 dd. Colonization of plant tissue by V. longisporum showed an exponential increase when exceeding 1300-1500 dd and reaching plant growth stage BBCH 74/75 (pod development). V. longisporum colonization of plants may be advanced, potentially leading to higher inoculum densities after harvest and increased economic importance of this pathogen under future warming. Sclerotia germination of S. sclerotiorum reached its maximum at 600-900 dd. Advance of these critical degree-days may lead to earlier apothecia production, potentially advancing the infection window, whereas the future importance of S. sclerotiorum may remain constant. Severity of phoma crown canker increased linearly with increasing thermal time, but showed also large variation in response to the warming scenarios, suggesting that factors such as canopy microclimate in fall or leaf shedding over winter may play a bigger role for L. maculans infection and disease severity than higher soil temperatures. Thermal time was a suitable tool to combine and integrate data on biological responses to soil and air temperature increases from climate chamber and field experiments. PMID:23505251

Siebold, Magdalena; von Tiedemann, Andreas

2013-06-01

327

Dysregulation of Anti-Inflammatory Annexin A1 Expression in Progressive Crohns Disease  

PubMed Central

Background Development of inflammatory bowel disease (IBD) involves the interplay of environmental and genetic factors with the host immune system. Mechanisms contributing to immune dysregulation in IBD are not fully defined. Development of novel therapeutic strategies is focused on controlling aberrant immune response in IBD. Current IBD therapy utilizes a combination of immunomodulators and biologics to suppress pro-inflammatory effectors of IBD. However, the role of immunomodulatory factors such as annexin A1 (ANXA1) is not well understood. The goal of this study was to examine the association between ANXA1 and IBD, and the effects of anti-TNF-?, Infliximab (IFX), therapy on ANXA1 expression. Methods ANXA1 and TNF-? transcript levels in PBMC were measured by RT PCR. Clinical follow up included the administration of serial ibdQs. ANXA1 expression in the gut mucosa was measured by IHC. Plasma ANXA1 levels were measured by ELISA. Results We found that the reduction in ANXA1 protein levels in plasma coincided with a decrease in the ANXA1 mRNA expression in peripheral blood of IBD patients. ANXA1 expression is upregulated during IFX therapy in patients with a successful intervention but not in clinical non-responders. The IFX therapy also modified the cellular immune activation in the peripheral blood of IBD patients. Decreased expression of ANXA1 was detected in the colonic mucosa of IBD patients with incomplete resolution of inflammation during continuous therapy, which correlated with increased levels of TNF-? transcripts. Gut mucosal epithelial barrier disruption was evident by increased plasma bacterial 16S levels. Conclusion Loss of ANXA1 expression may support inflammation during IBD and can serve as a biomarker of disease progression. Changes in ANXA1 levels may be predictive of therapeutic efficacy. PMID:24130820

Sena, Angela; Grishina, Irina; Thai, Anne; Goulart, Larissa; Macal, Monica; Fenton, Anne; Li, Jay; Prindiville, Thomas; Oliani, Sonia Maria; Dandekar, Satya; Goulart, Luiz; Sankaran-Walters, Sumathi

2013-01-01

328

Salivary DJ-1 could be an indicator of Parkinson's disease progression  

PubMed Central

Objective: The goal of the current investigation was to explore whether salivary DJ-1 could be a potential biomarker for monitoring disease progression in Parkinson's disease (PD) by evaluating the association between salivary DJ-1 concentrations and nigrostriatal dopaminergic function. Methods: First, in 74 patients with PD and 12 age-matched normal controls, single photon emission computed tomography (SPECT) imaging with labeled dopamine transporters (DAT) (99mTc-TRODAT-1), which has been used for measuring DAT density in PD was prformed. Then, the DJ-1 level in their saliva was analyzed by quantitative and sensitive Luminex assay and compared to caudate or putamen DAT density. Finally, based on the above, our cross-section study was carried out in 376 research volunteers (285 patients with PD and 91 healthy controls) to measure salivary DJ-1 level. Results: From our analysis, we found a correlation between salivary concentration of DJ-1 and putamen nucleus uptake of 99mTc-TRODAT-1 in the PD group. Although salivary DJ-1 levels were not affected by UPDRS scores, gender, age, and pharmacotherapy, DJ-1 levels in H&Y 4 stage of PD were higher than those in H&Y 1-3 stage as well as those in healthy controls. Salivary DJ-1 also decreased significantly in mixed type PD patients compared to the tremor-dominant type (TDT) and akinetic-rigid dominant type (ARDT) PD patients. Conclusions: According to the investigation in a large cohort, we reported for the first time the prognostic potential of the salivary DJ-1 as a biomarker for evaluating nigrostriatal dopaminergic function in PD. PMID:24936184

Kang, Wen-Yan; Yang, Qiong; Jiang, Xu-Feng; Chen, Wei; Zhang, Lin-Yuan; Wang, Xiao-Ying; Zhang, Li-Na; Quinn, Thomas J.; Liu, Jun; Chen, Sheng-Di

2014-01-01

329

T-plastin (PLS3) gene expression differentiates SS from MF and inflammatory skin diseases and can serve as a biomarker to monitor disease progression  

PubMed Central

Background Cutaneous T-cell lymphoma (CTCL) is a group of lymphoproliferative disorders that includes mycosis fungoides (MF) and Sezary syndrome (SS). T-Plastin (PLS3) is an actin-bundling protein that has been found to be highly expressed in Sezary cells but not in normal PBMCs. Here, we describe the value of using PLS3 as a sensitive molecular marker for differentiating stages of MF from SS, and for monitoring development of SS from MF. Objectives To determine the relationship between PLS3 expression level and SS, and disease progression and response to treatment in patients with MF/SS. Methods Total RNA from PBMCs from normal volunteers, MF/SS, and psoriasis patients were measured by quantitative PCR for PLS3 gene expression. Results In PBMCs from MF/SS and psoriasis patients, PLS3 expression was increased markedly in SS (greater than 400-fold) compared to that seen in early and late stage MF patients without SS cells or in patients with psoriasis. In a patient whose disease progressed to SS from MF, the PLS3 level in PBMCs showed an increased with disease progression. With treatment, the level of PLS3 decreased with chemotherapy and bone marrow transplantation. Conclusions PLS3 expression is a valuable and sensitive molecular biomarker to differentiate MF from SS. The measure of this gene may have value in conjunction with gene rearrangement studies to monitor disease severity or progression from MF to SS. Furthermore, PLS3 is not expressed in other inflammatory skin diseases, and may be valuable to distinguish SS from other cutaneous diseases associated with generalized erythroderma. PMID:19995369

Tang, Nikki; Gibson, Heather; Germeroth, Thomas; Porcu, Pierluigi; Lim, Henry W.; Wong, Henry K.

2013-01-01

330

Are coalminers, with low "risk factors" for ischaemic heart disease at greater risk of developing progressive massive fibrosis?  

PubMed

Coalminers with "A" shadows (the first stage of progressive massive fibrosis (PMF)) have a similar standardised mortality ratio (SMR) to those without PMF, and those with A shadows have a much higher specific mortality from pneumoconiosis. It is therefore argued that either A shadows confer immunity against some other disease(s) or that those developing A shadows are selected on the basis of increased life expectancy. These two hypotheses were investigated and as the selection hypothesis appeared promising further studies were made to discover which specific cause of death might be associated with this selection. This, surprisingly, appeared to be ischaemic heart disease. PMID:7093153

Cochrane, A L; Moore, F; Moncrieff, C B

1982-08-01

331

Spontaneous in vitro apoptosis of de novo chronic lymphocytic leukemia cells correlates with risk of the disease progression.  

PubMed

Despite significant progress in treatment, chronic lymphocytic leukemia (CLL) still remains an incurable disease. Major advances have been recently made to understand the molecular pathogenesis underlying CLL, but defects in apoptosis are considered to be the most important factors. Although neoplastic cells are resistant to apoptosis in vivo, they show decreased level of spontaneous in vitro apoptosis, with significant differences among CLL patients. This work compares the level of spontaneous CLL cell apoptosis with prognostic factors and clinical course of the disease. In vitro spontaneous apoptosis of peripheral blood lymphocytes was analyzed using Annexin-V assay (confirmed by TUNEL method) in 135 treatment naïve patients with CLL. Levels of apoptosis after 48 h culture in patients with stable disease were found to be significantly higher than in the group with progressive course of the disease (P?=?0.015). Moreover, the level of spontaneous apoptosis after 24 and 48 h of incubation correlated inversely with the progression free survival (P?=?0.026 and 0.009, respectively). These results suggest that in vitro spontaneous apoptosis of CLL cells may be a simple and cheap prognostic test which is relatively quick to use, and can predict the course of the disease and response to treatment. © 2014 International Clinical Cytometry Society. PMID:24515875

Witkowska, Magdalena; Nowak, Weronika; Cebula-Obrzut, Barbara; Majchrzak, Agata; Medra, Aleksandra; Robak, Tadeusz; Smolewski, Piotr

2014-11-01

332

Local Gene Transfer of OPG Prevents Joint Damage and Disease Progression in Collagen-Induced Arthritis  

PubMed Central

This study examined the influence of osteoprotegerin (OPG) gene transfer on a murine collagen-induced arthritis model. A single periarticular injection of AAV-OPG or AAV-LacZ on the arthritic paw successfully incorporated the exogenous gene to the local tissue and resulted in marked transgene expression in the joint homogenate for at least three weeks. Clinical disease scores were significantly improved in OPG treated mice starting at 28-day post-treatment (P < 0.05). Histological assessment demonstrated that OPG gene transfer dramatically protected mice from erosive joint changes compared with LacZ controls (P < 0.05), although treatment appeared less effective on the local inflammatory progress. MicroCT data suggested significant protection against subchondral bone mineral density changes in OPG treated CIA mice. Interestingly, mRNA expressions of IFN-g and MMP3 were noticeably diminished following OPG gene transfer. Overall, gene transfer of OPG effectively inhibited the arthritis-associated periarticular bone erosion and preserved the architecture of arthritic joints, and the study provides evidence that the cartilage protection of the OPG gene therapy may be associated with the down-regulation of MMP3 expression. PMID:24222748

Zhang, Qingguo; Gong, Weiming; Ning, Bin; Nie, Lin; Wooley, Paul H.

2013-01-01

333

Effect of Paget's disease of bone (osteitis deformans) on the progression of prostate cancer bone metastasis  

PubMed Central

Background: Patients with prostate cancer tend to die from bone metastases. Until now, no evidence has shown that Paget's disease of bone (PDB) affects the progression of bone metastasis or overall survival of patients with prostate cancer. Methods: We searched our patient database for men who had presented with prostate cancer and PDB between June 1993 and March 2009, and identified best-matched control patients according to stage, grade, age, date of diagnosis, treatment, and race. Results: Among 1346 consecutive patients with prostate cancer diagnosed before 2008, 15 were confirmed to have comorbid PDB. Twenty-six more were identified from the institutional billing search. Including the 41 best-matched controls, our total study population was 82 patients. In the Kaplan–Meier analysis, we estimated median times from diagnosis of prostate cancer to bone metastasis to be 21.5 years for those with PDB and 9.4 years for those without PDB (P=0.044). Median overall survival times were 11.8 and 9.2 years for the two groups, respectively (P=0.008). Conclusion: For the first time, we have obtained evidence that patients with prostate cancer and PDB have delayed time to bone metastases and improved overall survival than do patients with prostate cancer alone. PMID:22805323

Tu, S-M; Som, A; Tu, B; Logothetis, C J; Lee, M-H; Yeung, S-CJ

2012-01-01

334

Preventing the progression of chronic kidney disease: two case reports and review of the literature.  

PubMed

A variety of therapeutic modalities are available to alter the abnormalities seen in patients with chronic kidney disease (CKD). A comprehensive plan can now be developed to slow the progression of CKD. Two clinical cases of delay in the need for renal replacement therapy are described. This delay was achieved by using recognized recommendations for optimal diabetes therapy (HbA1c target 7 %), goals for blood pressure levels, reduction of proteinuria, and the proper use of ACEI/ARB therapies. Recent recommendations include BP <140/90 mmHg for patients <60 years old and <150/90 mmHg for older patients unless they have CKD or diabetes. Limits on dietary sodium and protein intake and body weight reduction will decrease proteinuria. Proper treatment for elevated serum phosphorous and parathyroid hormone levels is now appreciated as well as the benefits of therapy for dyslipidemias and anemia. Concerns regarding unfavorable outcomes with excess ESA therapy have led to hemoglobin goals in the 10-12 g/dL range. Finally, new therapeutic considerations for the treatment of acidosis and hyperuricemia are presented with data available to suggest that increasing serum bicarbonate to >22 mmol/L is beneficial, while serum uric acid therapeutic goals are still uncertain. Also, two as yet insufficiently understood approaches to altering the course of CKD (FGF-23 level reduction and balancing gut microbiota) are noted. PMID:24948202

Toor, Muhammad R; Singla, Anjali; Kim, Jin K; Sumin, Xenia; DeVita, Maria V; Michelis, Michael F

2014-11-01

335

Dynamic correlation between intrahost HIV-1 quasispecies evolution and disease progression.  

PubMed

Quantifying the dynamics of intrahost HIV-1 sequence evolution is one means of uncovering information about the interaction between HIV-1 and the host immune system. In the chronic phase of infection, common dynamics of sequence divergence and diversity have been reported. We developed an HIV-1 sequence evolution model that simulated the effects of mutation and fitness of sequence variants. The amount of evolution was described by the distance from the founder strain, and fitness was described by the number of offspring a parent sequence produces. Analysis of the model suggested that the previously observed saturation of divergence and decrease of diversity in later stages of infection can be explained by a decrease in the proportion of offspring that are mutants as the distance from the founder strain increases rather than due to an increase of viral fitness. The prediction of the model was examined by performing phylogenetic analysis to estimate the change in the rate of evolution during infection. In agreement with our modeling, in 13 out of 15 patients (followed for 3-12 years) we found that the rate of intrahost HIV-1 evolution was not constant but rather slowed down at a rate correlated with the rate of CD4+ T-cell decline. The correlation between the dynamics of the evolutionary rate and the rate of CD4+ T-cell decline, coupled with our HIV-1 sequence evolution model, explains previously conflicting observations of the relationships between the rate of HIV-1 quasispecies evolution and disease progression. PMID:19079613

Lee, Ha Youn; Perelson, Alan S; Park, Su-Chan; Leitner, Thomas

2008-12-01

336

Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates  

PubMed Central

HIV infection is associated with increased risk of cardiovascular complications, the underlying mechanism of which remains unclear. Plasma levels of the coagulation biomarker D-dimer (DD) correlate with increased mortality and cardiovascular events in HIV-infected patients. We compared the incidence of cardiovascular lesions and the levels of the coagulation markers DD and thrombin antithrombin in pathogenic SIV infections of rhesus and pigtailed macaques (PTMs) and in nonpathogenic SIV infection of African green monkeys (AGMs) and sooty mangabeys. Hypercoagulability and cardiovascular pathology were only observed in pathogenic SIV infections. In PTMs infected with SIV from AGMs (SIVagm), DD levels were highly indicative of AIDS progression and increased mortality and were associated with cardiovascular lesions, pointing to SIVagm-infected PTMs as an ideal animal model for the study of HIV-associated cardiovascular disease. In pathogenic SIV infection, DD increased early after infection, was strongly correlated with markers of immune activation/inflammation and microbial translocation (MT), and was only peripherally associated with viral loads. Endotoxin administration to SIVagm-infected AGMs (which lack chronic SIV-induced MT and immune activation) resulted in significant increases of DD. Our results demonstrate that hypercoagulation and cardiovascular pathology are at least in part a consequence of excessive immune activation and MT in SIV infection. PMID:22653975

Cornell, Elaine; Wilson, Cara; Ribeiro, Ruy M.; Ma, Dongzhu; Kristoff, Jan; Xu, Cuiling; Haret-Richter, George S.; Trichel, Anita; Apetrei, Cristian; Landay, Alan; Tracy, Russell

2012-01-01

337

Progress on ThermoBrachytherapy Surface Applicator for Superficial Tissue Diseases  

PubMed Central

This work reports the ongoing development of a combination applicator for simultaneous heating of superficial tissue disease using a 915 MHz DCC (dual concentric conductor) array and High Dose Rate (HDR) brachytherapy delivered via an integrated conformal catheter array. The progress includes engineering design changes in the waterbolus, DCC configurations and fabrication techniques of the conformal multilayer applicator. The dosimetric impact of the thin copper DCC array is also assessed. Steady state fluid dynamics of the new waterbolus bag indicates nearly uniform flow with less than 1°C variation across a large (19×32cm) bolus. Thermometry data of the torso phantom acquired with computer controlled movement of fiberoptic temperature probes inside thermal mapping catheters indicate feasibility of real time feedback control for the DCC array. MR (magnetic resonance) scans of a torso phantom indicate that the waterbolus thickness across the treatment area is controlled by the pressure applied by the surrounding inflatable airbladder and applicator securing straps. The attenuation coefficient of the DCC array was measured as 3± 0.001% and 2.95±0.03 % using an ion chamber and OneDose™ dosimeters respectively. The performance of the combination applicator on patient phantoms provides valuable feedback to optimize the applicator prior use in the patient clinic. PMID:24392196

Arunachalam, Kavitha; Craciunescu, Oana I.; Maccarini, Paolo F.; Schlorff, Jaime L.; Markowitz, Edward; Stauffer, Paul R.

2013-01-01

338

Hippocampus neuronal metabolic gene expression outperforms whole tissue data in accurately predicting Alzheimer's disease progression.  

PubMed

Numerous metabolic alterations are associated with the impairment of brain cells in Alzheimer's disease (AD). Here we use gene expression microarrays of both whole hippocampus tissue and hippocampal neurons of AD patients to investigate the ability of metabolic gene expression to predict AD progression and its cognitive decline. We find that the prediction accuracy of different AD stages is markedly higher when using neuronal expression data (0.9) than when using whole tissue expression (0.76). Furthermore, the metabolic genes' expression is shown to be as effective in predicting AD severity as the entire gene list. Remarkably, a regression model from hippocampal metabolic gene expression leads to a marked correlation of 0.57 with the Mini-Mental State Examination cognitive score. Notably, the expression of top predictive neuronal genes in AD is significantly higher than that of other metabolic genes in the brains of healthy subjects. All together, the analyses point to a subset of metabolic genes that is strongly associated with normal brain functioning and whose disruption plays a major role in AD. PMID:22560482

Stempler, Shiri; Waldman, Yedael Y; Wolf, Lior; Ruppin, Eytan

2012-09-01

339

Genetic determinants of pediatric HIV-1 infection: vertical transmission and disease progression among children.  

PubMed Central

It is very likely that perinatal human immunodeficiency virus type 1 (HIV-1) infection is influenced by a combination of virologic and host factors. A greater understanding of the role played by various risk factors for HIV-1 infection is crucial for the design of new preventive and therapeutic strategies. In recent years, a number of studies have suggested that host genetic factors are important determinants of both the susceptibility to perinatal HIV-1 infection and the subsequent pathogenesis of acquired immunodeficiency syndrome (AIDS). Control of HIV-1 infection involves the processing of specific viral peptides and their presentation to cells of the immune system by highly polymorphic human leukocyte antigen (HLA) alleles. The contribution of multiple HLA class I and II alleles in modulating pediatric HIV/AIDS outcomes has now been confirmed by several independent groups. Penetration of HIV-1 into cells is mediated by interaction between CD4 and chemokine receptors that serve as entry coreceptors. Genetic polymorphisms in chemokine ligand and chemokine receptor genes have recently been associated both with mother-to-child HIV-1 transmission and disease progression in children. These observations suggest a key role for genetic factors in pediatric HIV-1 infection. This article describes the current state of knowledge regarding host genetic influences on pediatric HIV-1 infection and discusses the role of these genes in HIV/AIDS pathogenesis. PMID:11778647

Matt, C.; Roger, M.

2001-01-01

340

Genetic determinants of pediatric HIV-1 infection: vertical transmission and disease progression among children.  

PubMed

It is very likely that perinatal human immunodeficiency virus type 1 (HIV-1) infection is influenced by a combination of virologic and host factors. A greater understanding of the role played by various risk factors for HIV-1 infection is crucial for the design of new preventive and therapeutic strategies. In recent years, a number of studies have suggested that host genetic factors are important determinants of both the susceptibility to perinatal HIV-1 infection and the subsequent pathogenesis of acquired immunodeficiency syndrome (AIDS). Control of HIV-1 infection involves the processing of specific viral peptides and their presentation to cells of the immune system by highly polymorphic human leukocyte antigen (HLA) alleles. The contribution of multiple HLA class I and II alleles in modulating pediatric HIV/AIDS outcomes has now been confirmed by several independent groups. Penetration of HIV-1 into cells is mediated by interaction between CD4 and chemokine receptors that serve as entry coreceptors. Genetic polymorphisms in chemokine ligand and chemokine receptor genes have recently been associated both with mother-to-child HIV-1 transmission and disease progression in children. These observations suggest a key role for genetic factors in pediatric HIV-1 infection. This article describes the current state of knowledge regarding host genetic influences on pediatric HIV-1 infection and discusses the role of these genes in HIV/AIDS pathogenesis. PMID:11778647

Matt, C; Roger, M

2001-09-01

341

Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates.  

PubMed

HIV infection is associated with increased risk of cardiovascular complications, the underlying mechanism of which remains unclear. Plasma levels of the coagulation biomarker D-dimer (DD) correlate with increased mortality and cardiovascular events in HIV-infected patients. We compared the incidence of cardiovascular lesions and the levels of the coagulation markers DD and thrombin antithrombin in pathogenic SIV infections of rhesus and pigtailed macaques (PTMs) and in nonpathogenic SIV infection of African green monkeys (AGMs) and sooty mangabeys. Hypercoagulability and cardiovascular pathology were only observed in pathogenic SIV infections. In PTMs infected with SIV from AGMs (SIVagm), DD levels were highly indicative of AIDS progression and increased mortality and were associated with cardiovascular lesions, pointing to SIVagm-infected PTMs as an ideal animal model for the study of HIV-associated cardiovascular disease. In pathogenic SIV infection, DD increased early after infection, was strongly correlated with markers of immune activation/inflammation and microbial translocation (MT), and was only peripherally associated with viral loads. Endotoxin administration to SIVagm-infected AGMs (which lack chronic SIV-induced MT and immune activation) resulted in significant increases of DD. Our results demonstrate that hypercoagulation and cardiovascular pathology are at least in part a consequence of excessive immune activation and MT in SIV infection. PMID:22653975

Pandrea, Ivona; Cornell, Elaine; Wilson, Cara; Ribeiro, Ruy M; Ma, Dongzhu; Kristoff, Jan; Xu, Cuiling; Haret-Richter, George S; Trichel, Anita; Apetrei, Cristian; Landay, Alan; Tracy, Russell

2012-08-16

342

White Matter Disease Correlates with Lexical Retrieval Deficits in Primary Progressive Aphasia  

PubMed Central

Objective: To relate fractional anisotropy (FA) changes associated with the semantic and logopenic variants of primary progressive aphasia (PPA) to measures of lexical retrieval. Methods: We collected neuropsychological testing, volumetric magnetic resonance imaging, and diffusion-weighted imaging on semantic variant PPA (svPPA) (n?=?11) and logopenic variant PPA (lvPPA) (n?=?13) patients diagnosed using published criteria. We also acquired neuroimaging data on a group of demographically comparable healthy seniors (n?=?34). FA was calculated and analyzed using a white matter (WM) tract-specific analysis approach. This approach utilizes anatomically guided data reduction to increase sensitivity and localizes results within canonically defined tracts. We used non-parametric, cluster-based statistical analysis to relate language performance to FA and determine regions of reduced FA in patients. Results: We found widespread FA reductions in WM for both variants of PPA. FA was related to both confrontation naming and category naming fluency performance in left uncinate fasciculus and corpus callosum in svPPA and left superior and inferior longitudinal fasciculi in lvPPA. Conclusion: SvPPA and lvPPA are associated with distinct disruptions of a large-scale network implicated in lexical retrieval, and the WM disease in each phenotype may contribute to language impairments including lexical retrieval. PMID:24409166

Powers, John P.; McMillan, Corey T.; Brun, Caroline C.; Yushkevich, Paul A.; Zhang, Hui; Gee, James C.; Grossman, Murray

2013-01-01

343

NAFLD in the absence of metabolic syndrome: different epidemiology, pathogenetic mechanisms, risk factors for disease progression?  

PubMed

Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that have been associated with an increased risk of developing nonalcoholic fatty liver disease (NAFLD). Insulin resistance and central obesity are the key components of MetS, ultimately leading to liver fat accumulation and the subsequent development of necroinflammatory liver injury. However, the origin and nature of the metabolic stressors responsible for stimulating the progression of simple steatosis to nonalcoholic steatohepatitis (NASH) remain to be clearly identified. In addition, epidemiologic research on the association between MetS and NAFLD has provided only limited information to guide the development of targeted interventions, in particular, nutrition and pharmacologic prevention programs. This review summarizes the evidence supporting the proposal that NAFLD is not invariably associated with the presence of MetS, and mechanisms other than insulin resistance may contribute to the chronic inflammatory processes that underpin the development of liver fat accumulation and the subsequent architectural distortion of the liver. A special focus is given to increased hemoglobin as a risk factor for the development of NAFLD in the absence of MetS. PMID:22418884

Yilmaz, Yusuf

2012-02-01

344

Early and progressive circadian abnormalities in Huntington's disease sheep are unmasked by social environment.  

PubMed

Insidious changes in behaviour herald the onset of progressive neurodegenerative disorders such as Huntington's disease (HD), sometimes years before overt symptoms are seen. Sleep and circadian disturbances are particularly disruptive symptoms in patients with neurological disorders, but they are difficult to measure in humans. Here we studied circadian behaviour in transgenic HD sheep expressing the full-length human huntingtin protein with an expanded CAG repeat mutation in the juvenile range. Young HD sheep with no other symptoms exhibited circadian behavioural abnormalities that worsened with age. The most obvious change was a disturbed evening behaviour reminiscent of 'sundowning' that is seen in some patients with dementia. There were no structural abnormalities seen with magnetic resonance imaging, even in 5-year-old HD sheep. Interestingly, detection of the circadian abnormalities depended upon their social grouping. Abnormalities emerged in sheep kept in an 'HD-only' flock, whereas the behaviour of HD sheep kept mixed with normal sheep was relatively normal. Sleep-wake abnormalities in HD patients are also likely to be hidden, and may precede overt symptoms by many years. Sleep disruption has deleterious effects, even in normal people. The knock-on effects of sleep-wake disturbance may exacerbate, or even cause symptoms such as irritability and depression that are common in early stage HD patients. HD sheep will be useful models for probing the mechanisms underlying circadian behavioural disorder in HD. PMID:24488771

Morton, A Jennifer; Rudiger, Skye R; Wood, Nigel I; Sawiak, Stephen J; Brown, Gregory C; Mclaughlan, Clive J; Kuchel, Timothy R; Snell, Russell G; Faull, Richard L M; Bawden, C Simon

2014-07-01

345

Rating disease progression of Friedreich's ataxia by the International Cooperative Ataxia Rating Scale: analysis of a 603-patient database  

PubMed Central

The aim of this cross-sectional study was to analyse disease progression in Friedreich’s ataxia as measured by the International Cooperative Ataxia Rating Scale. Single ratings from 603 patients with Friedreich’s ataxia were analysed as a function of disease duration, age of onset and GAA repeat lengths. The relative contribution of items and subscales to the total score was studied as a function of disease progression. In addition, the scaling properties were assessed using standard statistical measures. Average total scale progression per year depends on the age of disease onset, the time since diagnosis and the GAA repeat length. The age of onset inversely correlates with increased GAA repeat length. For patients with an age of onset ?14 years associated with a longer repeat length, the average yearly rate of decline was 2.5 ± 0.18 points in the total International Cooperative Ataxia Rating Scale for the first 20 years of disease duration, whereas patients with a later onset progress more slowly (1.8 ± 0.27 points/year). Ceiling effects in posture, gait and lower limb scale items lead to a reduced sensitivity of the scale in the severely affected population with a total score of >60 points. Psychometric scaling analysis shows generally favourable properties for the total scale, but the subscale grouping could be improved. This cross-sectional study provides a detailed characterization of the International Cooperative Ataxia Rating Scale. The analysis further provides rates of change separated for patients with early and late disease onset, which is driven by the GAA repeat length. Differences in the subscale dynamics merit consideration in the design of future clinical trials applying this scale as a neurological assessment instrument in Friedreich’s ataxia. PMID:23365101

Coppard, Nicholas; Cooper, Jonathon M.; Delatycki, Martin B.; Durr, Alexandra; Di Prospero, Nicholas A.; Giunti, Paola; Lynch, David R.; Schulz, J. B.; Rummey, Christian; Meier, Thomas

2013-01-01

346

Molecular Differentiation of Risk for Disease Progression: Delineating Stage-Specific Therapeutic Targets for Disease Management in Breast Cancer.  

National Technical Information Service (NTIS)

Cancer is a highly heterogeneous disease, both morphologically and genetically. A current shortcoming in cancer prognosis and treatment is a lack of methods that adequately address the complexity and diversity of the disease. Genome wide studies can provi...

M. J. Worsham, U. Raju, M. Lu

2006-01-01

347

Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury  

PubMed Central

The progression of kidney disease to renal failure correlates with infiltration of mononuclear immune cells into the tubulointerstitium. These infiltrates contain macrophages, DCs, and T cells, but the role of each cell type in disease progression is unclear. To investigate the underlying immune mechanisms, we generated transgenic mice that selectively expressed the model antigens ovalbumin and hen egg lysozyme in glomerular podocytes (NOH mice). Coinjection of ovalbumin-specific transgenic CD8+ CTLs and CD4+ Th cells into NOH mice resulted in periglomerular mononuclear infiltrates and inflammation of parietal epithelial cells, similar to lesions frequently observed in human chronic glomerulonephritis. Repetitive T cell injections aggravated infiltration and caused progression to structural and functional kidney damage after 4 weeks. Mechanistic analysis revealed that DCs in renal lymph nodes constitutively cross-presented ovalbumin and activated CTLs. These CTLs released further ovalbumin for CTL activation in the lymph nodes and for simultaneous presentation to Th cells by distinct DC subsets residing in the kidney tubulointerstitium. Crosstalk between tubulointerstitial DCs and Th cells resulted in intrarenal cytokine and chemokine production and in recruitment of more CTLs, monocyte-derived DCs, and macrophages. The importance of DCs was established by the fact that DC depletion rapidly resolved established kidney immunopathology. These findings demonstrate that glomerular antigen–specific CTLs and Th cells can jointly induce renal immunopathology and identify kidney DCs as a mechanistic link between glomerular injury and the progression of kidney disease. PMID:19381017

Heymann, Felix; Meyer-Schwesinger, Catherine; Hamilton-Williams, Emma E.; Hammerich, Linda; Panzer, Ulf; Kaden, Sylvia; Quaggin, Susan E.; Floege, Jurgen; Grone, Hermann-Josef; Kurts, Christian

2009-01-01

348

Accelerating effect of human leukocyte antigen-Bw6 homozygosity on disease progression in Chinese HIV-1-infected patients.  

PubMed

Most HIV-1-infected individuals progress to AIDS within 8 to 10 years after seroconversion. Less than 5% of them, however, remain asymptomatic, although their CD4 T-cell counts stay normal. In this study, our polymerase chain reaction sequence-specified primer (PCR-SSP) based human leukocyte antigen (HLA)-B genotyping of 28 typical progressors (TPs) and 15 long-term nonprogressors (LTNPs) revealed some evidence that an HLA-B locus polymorphism can influence the rate of disease progression in Chinese HIV-1-infected individuals: 12 of 28 TPs (43%) were HLA-Bw6 homozygotes. Only 1 of 15 LTNPs (6.7%) was homozygous for the polymorphism (P = 0.013), suggesting that HLA-Bw6 homozygosity is associated with accelerated disease progression. In contrast, 3 of 15 LTNPs (20%) were HLA-Bw4 homozygotes, whereas none of the 28 TPs were homozygotes (P = 0.037), supporting the conclusion that HLA-Bw4 homozygosity may have a protective role. Interestingly, the frequency of the HLA-B*15 allele was extremely high in the TP group (23.2%), which may be associated with faster disease progression in Chinese patients. PMID:16394843

Qing, Manli; Li, Taisheng; Han, Yang; Qiu, Zhifeng; Jiao, Yang

2006-02-01

349

Reciprocal functions of hepatocyte growth factor and transforming growth factor-?1 in the progression of renal diseases: A role for CD44?  

Microsoft Academic Search

Reciprocal functions of hepatocyte growth factor and transforming growth factor-?1 in the progression of renal diseases: A role for CD44? Progressive renal fibrosis occurs via common pathophysiologic mechanisms, regardless of the primary underlying disease. This cascade includes release of cytokines\\/chemokines and toxic molecules, interstitial inflammation, tubular cell damage, accumulation of myofibroblasts, and finally, fibrosis. Hepatocyte growth factor (HGF) and transforming

Sandrine Florquin; Kasper M. A. Rouschop

2003-01-01

350

Marijuana Smoking Does Not Accelerate Progression of Liver Disease in HIV-Hepatitis C Coinfection: A Longitudinal Cohort Analysis  

PubMed Central

Background.?Marijuana smoking is common and believed to relieve many symptoms, but daily use has been associated with liver fibrosis in cross-sectional studies. We aimed to estimate the effect of marijuana smoking on liver disease progression in a Canadian prospective multicenter cohort of human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected persons. Methods.?Data were analyzed for 690 HCV polymerase chain reaction positive (PCR-positive) individuals without significant fibrosis or end-stage liver disease (ESLD) at baseline. Time-updated Cox Proportional Hazards models were used to assess the association between the average number of joints smoked/week and progression to significant liver fibrosis (APRI ? 1.5), cirrhosis (APRI ? 2) or ESLD. Results?At baseline, 53% had smoked marijuana in the past 6 months, consuming a median of 7 joints/week (IQR, 1–21); 40% smoked daily. There was no evidence that marijuana smoking accelerates progression to significant liver fibrosis (APRI ? 1.5) or cirrhosis (APRI ? 2; hazard ratio [HR]: 1.02 [0.93–1.12] and 0.99 [0.88–1.12], respectively). Each 10 additional joints/week smoked slightly increased the risk of progression to a clinical diagnosis of cirrhosis and ESLD combined (HR, 1.13 [1.01–1.28]). However, when exposure was lagged to 6–12 months before the diagnosis, marijuana was no longer associated with clinical disease progression (HR, 1.10 [0.95–1.26]). Conclusions?In this prospective analysis we found no evidence for an association between marijuana smoking and significant liver fibrosis progression in HIV/HCV coinfection. A slight increase in the hazard of cirrhosis and ESLD with higher intensity of marijuana smoking was attenuated after lagging marijuana exposure, suggesting that reverse causation due to self-medication could explain previous results. PMID:23811492

Brunet, Laurence; Moodie, Erica E. M.; Rollet, Kathleen; Cooper, Curtis; Walmsley, Sharon; Potter, Martin; Klein, Marina B.

2013-01-01

351

Investigating the biochemical progression of liver disease through fibrosis, cirrhosis, dysplasia, and hepatocellular carcinoma using Fourier transform infrared spectroscopic imaging  

NASA Astrophysics Data System (ADS)

Hepatocellular carcinoma (HCC) is the most common form of primary hepatic carcinoma. HCC ranks the fourth most prevalent malignant tumor and the third leading cause of cancer related death in the world. Hepatocellular carcinoma develops in the context of chronic liver disease and its evolution is characterized by progression through intermediate stages to advanced disease and possibly even death. The primary sequence of hepatocarcinogenesis includes the development of cirrhosis, followed by dysplasia, and hepatocellular carcinoma.1 We addressed the utility of Fourier Transform Infrared (FT-IR) spectroscopic imaging, both as a diagnostic tool of the different stages of the disease and to gain insight into the biochemical process associated with disease progression. Tissue microarrays were obtained from the University of Illinois at Chicago tissue bank consisting of liver explants from 12 transplant patients. Tissue core biopsies were obtained from each explant targeting regions of normal, liver cell dysplasia including large cell change and small cell change, and hepatocellular carcinoma. We obtained FT-IR images of these tissues using a modified FT-IR system with high definition capabilities. Firstly, a supervised spectral classifier was built to discriminate between normal and cancerous hepatocytes. Secondly, an expanded classifier was built to discriminate small cell and large cell changes in liver disease. With the emerging advances in FT-IR instrumentation and computation there is a strong drive to develop this technology as a powerful adjunct to current histopathology approaches to improve disease diagnosis and prognosis.

Sreedhar, Hari; Pant, Mamta; Ronquillo, Nemencio R.; Davidson, Bennett; Nguyen, Peter; Chennuri, Rohini; Choi, Jacqueline; Herrera, Joaquin A.; Hinojosa, Ana C.; Jin, Ming; Kajdacsy-Balla, Andre; Guzman, Grace; Walsh, Michael J.

2014-03-01

352

Effects of chronic stress on the onset and progression of Huntington's disease in transgenic mice.  

PubMed

Huntington's disease (HD) is a neurodegenerative disease caused by a tandem repeat mutation encoding an expanded polyglutamine tract. Our previous work showed that memory deficits in HD transgenic mice could be accelerated by increased levels of stress hormone, while memory in WT mice remained unaffected. HD patients experience higher levels of stress compared to the general population and symptoms of HD also include motor, cognitive, psychiatric, sexual and olfactory abnormalities, and an associated decline in activities of daily living. Therefore we investigated the impact of a robust stressor (i.e. restraint) on the onset and progression of a range of behavioral phenotypes in R6/1 transgenic HD mice. Restraint was administered for 1h daily from 6weeks of age and continued until R6/1 mice were clearly motor symptomatic at 14weeks of age. Serum corticosterone levels in both R6/1 and WT littermates were elevated immediately after the last restraint session and weight gain was suppressed in restrained animals throughout the treatment period. Motor coordination and locomotor activity were enhanced by chronic restraint in males, regardless of genotype. However, there was no effect of restraint on motor performances in female animals. At 8weeks of age, olfactory sensitivity was impaired by restraint in R6/1 HD female mice, but not in WT mice. In male R6/1 mice, the olfactory deficit was exacerbated by restraint and olfaction was also impaired in male WT mice. The development of deficits in saccharin preference, Y-maze memory, nest-building and sexually-motivated vocalizations was unaffected by chronic restraint in R6/1 and had little impact on such behavioral performances in WT animals. We provide evidence that chronic stress can negatively modulate specific endophenotypes in HD mice, while the same functions were affected to a lesser extent in WT mice. This vulnerability in HD animals seems to be sex-specific depending on the stress paradigm used. It is hoped that our work will stimulate clinical investigations into the effects of stress on both pre-symptomatic and symptomatic gene-positive members of HD families, and inform the development of new therapeutic approaches. PMID:25088714

Mo, Christina; Renoir, Thibault; Hannan, Anthony J

2014-11-01

353

Progression of Epididymal Maldevelopment Into Hamartoma-like Neoplasia in VHL Disease1  

PubMed Central

Inactivation of the von Hippel-Lindau (VHL) gene and activation of the hypoxia-inducible factor (HIF) in susceptible cells precedes formation of tumorlets and frank tumor in the epididymis of male VHL patients. We performed detailed histologic and molecular pathologic analysis of tumor-free epididymal tissues from VHL patients to obtain further insight into early epididymal tumorigenesis. Four epididymides from two VHL patients were serially sectioned to allow for three-dimensional visualization of morphologic changes. Areas of interest were genetically analyzed by tissue microdissection, immunohistochemistry for HIF and markers for mesonephric differentiation, and in situ hybridization for HIF downstream target vascular endothelial growth factor. Structural analysis of the epididymides revealed marked deviations from the regular anatomic structure resulting from impaired organogenesis. Selected efferent ductules were represented by disorganized mesonephric cells, and the maldeveloped mesonephric material was VHL-deficient by allelic deletion analysis. Furthermore, we observed maldeveloped mesonephric material near cystic structures, which were also VHL-deficient and were apparent derivatives of maldeveloped material. Finally, a subset of VHL-deficient cells was structurally integrated in regular efferent ductules; proliferation of intraductular VHL-deficient cells manifests itself as papillary growth into the ductular lumen. Furthermore, we clarify that that there is a pathogenetic continuum between microscopic tumorlets and formation of tumor. In multiple locations, three-dimensional reconstruction revealed papillary growth to extend deeply into ductular lumina, indicative of progression into early hamartoma-like neoplasia. We conclude epididymal tumorigenesis in VHL disease to occur in two distinct sequential steps: maldevelopment of VHL-deficient mesonephric cells, followed by neoplastic papillary proliferation. PMID:18813354

Mehta, Gautam U; Shively, Sharon B; Duong, Heng; Tran, Maxine GB; Moncrief, Travis J; Smith, Jonathan H; Li, Jie; Edwards, Nancy A; Lonser, Russell R; Zhuang, Zhengping; Merrill, Marsha J; Raffeld, Mark; Maxwell, Patrick H; Oldfield, Edward H; Vortmeyer, Alexander O

2008-01-01

354

Candidate blood proteome markers of Alzheimer's disease onset and progression: a systematic review and replication study.  

PubMed

A blood-based protein biomarker, or set of protein biomarkers, that could predict onset and progression of Alzheimer's disease (AD) would have great utility; potentially clinically, but also for clinical trials and especially in the selection of subjects for preventative trials. We reviewed a comprehensive list of 21 published discovery or panel-based (> 100 proteins) blood proteomics studies of AD, which had identified a total of 163 candidate biomarkers. Few putative blood-based protein biomarkers replicate in independent studies but we found that some proteins do appear in multiple studies; for example, four candidate biomarkers are found to associate with AD-related phenotypes in five independent research cohorts in these 21 studies: ?-1-antitrypsin, ?-2-macroglobulin, apolipoprotein E, and complement C3. Using SomaLogic's SOMAscan proteomics technology, we were able to conduct a large-scale replication study for 94 of the 163 candidate biomarkers from these 21 published studies in plasma samples from 677 subjects from the AddNeuroMed (ANM) and the Alzheimer's Research UK/Maudsley BRC Dementia Case Registry at King's Health Partners (ARUK/DCR) research cohorts. Nine of the 94 previously reported candidates were found to associate with AD-related phenotypes (False Discovery Rate (FDR) q-value < 0.1). These proteins show sufficient replication to be considered for further investigation as a biomarker set. Overall, we show that there are some signs of a replicable signal in the range of proteins identified in previous studies and we are able to further replicate some of these. This suggests that AD pathology does affect the blood proteome with some consistency. PMID:24121966

Kiddle, Steven J; Sattlecker, Martina; Proitsi, Petroula; Simmons, Andrew; Westman, Eric; Bazenet, Chantal; Nelson, Sally K; Williams, Stephen; Hodges, Angela; Johnston, Caroline; Soininen, Hilkka; K?oszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Newhouse, Stephen; Lovestone, Simon; Dobson, Richard J B

2014-01-01

355

Choline Metabolism Provides Novel Insights into Non-alcoholic Fatty Liver Disease and its Progression  

PubMed Central

Purpose of review Choline is an essential nutrient and the liver is a central organ responsible for choline metabolism. Hepatosteatosis and liver cell death occur when humans are deprived of choline. In the last few years there have been significant advances in our understanding of the mechanisms that influence choline requirements in humans and in our understanding of choline’s effects on liver function. These advances are useful in elucidating why non-alcoholic fatty liver disease (NAFLD) occurs and progresses sometimes to hepatocarcinogenesis. Recent findings Humans eating low choline diets develop fatty liver and liver damage,. This dietary requirement for choline is modulated by estrogen and by single nucleotide polymorphisms (SNPs) in specific genes of choline and folate metabolism. The spectrum of choline’s effects on liver range from steatosis to development of hepatocarcinomas, and several mechanisms for these effects have been identified. They include abnormal phospholipid synthesis, defects in lipoprotein secretion, oxidative damage caused by mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Furthermore, the hepatic steatosis phenotype and can be characterized more fully via metabolomic signatures and is influenced by the gut microbiome. Importantly, the intricate connection between liver function, one carbon metabolism, and energy metabolism is just beginning to be elucidated. Summary Choline influences liver function, and the dietary requirement for this nutrient varies depending on an individual’s genotype and estrogen status. Understanding these individual differences is important for gastroenterologists seeking to understand why some individuals develop NAFLD and others do not, and why some patients tolerate total parenteral nutrition and others develop liver dysfunction. PMID:22134222

Corbin, Karen D.; Zeisel, Steven H.

2013-01-01

356

Oral Methylthioadenosine Administration Attenuates Fibrosis and Chronic Liver Disease Progression in Mdr2?/? Mice  

PubMed Central

Background Inflammation and fibrogenesis are directly related to chronic liver disease progression, including hepatocellular carcinoma (HCC) development. Currently there are few therapeutic options available to inhibit liver fibrosis. We have evaluated the hepatoprotective and anti-fibrotic potential of orally-administered 5?-methylthioadenosine (MTA) in Mdr2?/? mice, a clinically relevant model of sclerosing cholangitis and spontaneous biliary fibrosis, followed at later stages by HCC development. Methodology MTA was administered daily by gavage to wild type and Mdr2?/? mice for three weeks. MTA anti-inflammatory and anti-fibrotic effects and potential mechanisms of action were examined in the liver of Mdr2?/? mice with ongoing fibrogenesis and in cultured liver fibrogenic cells (myofibroblasts). Principal Findings MTA treatment reduced hepatomegaly and liver injury. ?-Smooth muscle actin immunoreactivity and collagen deposition were also significantly decreased. Inflammatory infiltrate, the expression of the cytokines IL6 and Mcp-1, pro-fibrogenic factors like TGF?2 and tenascin-C, as well as pro-fibrogenic intracellular signalling pathways were reduced by MTA in vivo. MTA inhibited the activation and proliferation of isolated myofibroblasts and down-regulated cyclin D1 gene expression at the transcriptional level. The expression of JunD, a key transcription factor in liver fibrogenesis, was also reduced by MTA in activated myofibroblasts. Conclusions/Significance Oral MTA administration was well tolerated and proved its efficacy in reducing liver inflammation and fibrosis. MTA may have multiple molecular and cellular targets. These include the inhibition of inflammatory and pro-fibrogenic cytokines, as well as the attenuation of myofibroblast activation and proliferation. Downregulation of JunD and cyclin D1 expression in myofibroblasts may be important regarding the mechanism of action of MTA. This compound could be a good candidate to be tested for the treatment of (biliary) liver fibrosis. PMID:21209952

Fernandez-Barrena, Maite G.; Rodriguez-Ortigosa, Carlos M.; Banales, Jesus M.; Urtasun, Raquel; Goni, Saioa; Mendez, Miriam; Arcelus, Sara; Juanarena, Nerea; Recio, Juan A.; Lotersztajn, Sophie; Prieto, Jesus; Berasain, Carmen; Corrales, Fernando J.; Lecanda, Jon; Avila, Matias A.

2010-01-01

357

The `subcortical dementia' of progressive supranuclear palsy  

Microsoft Academic Search

Progressive supranuclear palsy (Steele et al.) has a characteristic pattern of dementia: (1) forgetfulness, (2) slowing of thought processes, (3) emotional or personality changes (apathy or depression with occasional outbursts of irritability), and (4) impaired ability to manipulate acquired knowledge. In many neurological disease states associated with subcortical pathology a similar pattern of dementia exists. The neurobehavioural changes of progressive

Martin L. Albert; Robert G. Feldman; Anne L. Willis

1974-01-01

358

Biomarker Report from the Phase II Lamotrigine Trial in Secondary Progressive MS – Neurofilament as a Surrogate of Disease Progression  

PubMed Central

Objective Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment. Methods SPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12–24 and 0–24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored. Results Treatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12–24 months p?=?0.043, Nfh 0–24 months p?=?0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z-score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin. Conclusions The relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration. PMID:23936370

Gnanapavan, Sharmilee; Grant, Donna; Morant, Steve; Furby, Julian; Hayton, Tom; Teunissen, Charlotte E.; Leoni, Valerio; Marta, Monica; Brenner, Robert; Palace, Jacqueline; Miller, David H.; Kapoor, Raj; Giovannoni, Gavin

2013-01-01

359

Alzheimer's disease and blood-brain barrier function - Why have anti-?-amyloid therapies failed to prevent dementia progression?  

PubMed Central

Proteopathies of the brain are defined by abnormal, disease-inducing protein deposition that leads to functional abrogation and death of neurons. Immunization trials targeting the removal of amyloid-? plaques in Alzheimer's disease have so far failed to stop the progression of dementia, despite autopsy findings of reduced plaque load. Here, we summarize current knowledge of the relationship between AD pathology and blood-brain barrier function, and propose that the activation of the excretion function of the blood-brain barrier might help to achieve better results in trials targeting the dissolution of cerebral amyloid-? aggregates. We further discuss a possible role of oligomers in limiting the efficacy of immunotherapy. PMID:19481107

Pahnke, Jens; Walker, Lary C.; Scheffler, Katja; Krohn, Markus

2009-01-01

360

Body side and predominant motor features at the onset of Parkinson's disease are linked to motor and nonmotor progression.  

PubMed

Patients with Parkinson's disease most often have asymmetric motor features at onset, and specific motor signs (ie, tremor versus bradykinesia and rigidity) frequently characterize the first few years of disease evolution. Some previous clinical evidence has suggested that body side and a predominance of motor manifestations at disease onset are linked to long-term evolution and disease progression. We prospectively analyzed 206 patients with Parkinson's disease according to the most affected side and predominant motor signs at onset. Patients were divided into left-side rigid-akinetic (n?=?71), right-side rigid-akinetic (n?=?59), left-side tremor (n?=?41), and right-side tremor (n?=?35) subgroups. These subgroups were compared in terms of motor and cognitive functions, mean motor deterioration per year (calculated as the motor score divided by disease duration), total equivalent doses of dopaminergic drugs, and the presence of hallucinations and rapid eye movement sleep behavior disorder. Disease duration was similar in all groups. Motor fluctuations were more likely to occur in rigid-akinetic patients. In a multiple model analysis adjusted for potential confounders, faster disease progression was associated with right-side (P?=?0.045) and rigid-akinetic onset (P?=?0.001). With respect to nonmotor symptoms, the rigid-akinetic type was associated with increased risk of cognitive decline (P?=?0.004) compared with the tremor type. A trend was noticed toward an increased risk of developing visual hallucinations in rigid-akinetic patients and toward an increased frequency of rapid eye movement sleep behavior disorder in those who had left-sided onset of symptoms. Our findings corroborate that body side and type of motor signs at the time of diagnosis affect the evolution of motor severity and may also have an impact on some nonmotor manifestations. PMID:24105646

Baumann, Christian R; Held, Ulrike; Valko, Philipp O; Wienecke, Miriam; Waldvogel, Daniel

2014-02-01

361

Interaction of Fusarium graminearum and F. moniliforme in Maize Ears: Disease Progress, Fungal Biomass, and Mycotoxin Accumulation  

Microsoft Academic Search

Reid, L. M., Nicol, R. W., Ouellet, T., Savard, M., Miller, J. D., Y oung, J. C., Stewart, D. W., and Schaafsma, A. W. 1999. Interaction of Fusarium graminearum and F. moniliforme in maize ears: Disease progress, fungal biomass, and mycotoxin accumulation. Phytopathology 89:1028-1037. To investigate the interaction between two major ear-rotting pathogens, maize ears were inoculated with either Fusarium

L. M. Reid; R. W. Nicol; T. Ouellet; M. Savard; J. D. Miller; J. C. Young; D. W. Stewart; A. W. Schaafsma

1999-01-01

362

Human extraocular muscles in mitochondrial diseases: comparing chronic progressive external ophthalmoplegia with Leber’s hereditary optic neuropathy  

Microsoft Academic Search

Aims: To compare the ultrastructural aspects of human extraocular muscles in two types of mitochondrial disease: chronic progressive external ophthalmoplegia (CPEO) and Leber’s hereditary optic neuropathy (LHON).Methods: Muscle samples of the medial rectus obtained from surgery in a sporadic case of CPEO associated with deleted mitochondrial DNA, and post mortem in a case of 3460\\/ND1 LHON were processed for electron

A Carta; V Carelli; T D’Adda; F N Ross-Cisneros; A A Sadun

2005-01-01

363

Persistence of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T-Lymphocyte Clones in a Subject with Rapid Disease Progression  

PubMed Central

We longitudinally measured T-cell receptor transcript frequencies of human immunodeficiency virus type 1 (HIV-1) specific cytotoxic T lymphocytes (CTL) in an individual with rapidly progressive disease and high levels of viremia. CTL clones elicited during acute HIV-1 infection were present at the time of death, despite absent functional CTL responses, arguing against clonal deletion as a mechanism for the decline of CTL responses observed during HIV-1 infection. PMID:11312363

Islam, Sabina A.; Hay, Christine M.; Hartman, Kelly E.; He, Suqin; Shea, Amy K.; Trocha, Alicja K.; Dynan, Mark J.; Reshamwala, Neha; Buchbinder, Susan P.; Basgoz, Nesli O.; Kalams, Spyros A.

2001-01-01

364

Pattern and Progression of Cognitive Decline in Alzheimer’s Disease: Role of Premorbid Intelligence and ApoE Genotype  

Microsoft Academic Search

Background\\/Aims: Because of controversial results across studies, we evaluated the predictive value of premorbid intelligence and the apolipoprotein E (ApoE) genotype on baseline and progression of cognitive performance in Alzheimer’s disease (AD). Methods: Eighty-five mild AD cases, ApoE genotyped and included in a longitudinal cliniconeuropsychological-genetic study, underwent a premorbid intelligence test and up to 11 (average 5) neuropsychological assessments. We

Laura Bracco; Carolina Piccini; Michela Baccini; Valentina Bessi; Federica Biancucci; Benedetta Nacmias; Silvia Bagnoli; Sandro Sorbi

2007-01-01

365

The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients  

Microsoft Academic Search

Background\\/Aims: Questions remain regarding the etiology of steatosis in hepatitis C, and its impact on disease progression and treatment outcomes.Methods: We evaluated liver biopsies from 574 patients with chronic hepatitis C from a single center.Results: Severity of steatosis was associated with body mass index, HCV genotype 3 infection, age, and duration of infection (P?0.01). Serum HCV RNA levels were associated

Heather M Patton; Keyur Patel; Cynthia Behling; David Bylund; Lawrence M Blatt; Marc Vallée; Shanon Heaton; Andrew Conrad; Paul J Pockros; John G McHutchison

2004-01-01

366

Neuromelanin Activates Microglia and Induces Degeneration of Dopaminergic Neurons: Implications for Progression of Parkinson’s Disease  

Microsoft Academic Search

In Parkinson’s disease (PD), there is a progressive loss of neuromelanin (NM)-containing dopamine neurons in substantia nigra\\u000a (SN) which is associated with microgliosis and presence of extracellular NM. Herein, we have investigated the interplay between\\u000a microglia and human NM on the degeneration of SN dopaminergic neurons. Although NM particles are phagocytized and degraded\\u000a by microglia within minutes in vitro, extracellular

Wei Zhang; Kester Phillips; Albert R. Wielgus; Jie Liu; Alberto Albertini; Fabio A. Zucca; Rudolph Faust; Steven Y. Qian; David S. Miller; Colin F. Chignell; Belinda Wilson; Vernice Jackson-Lewis; Serge Przedborski; Danielle Joset; John Loike; Jau-Shyong Hong; David Sulzer; Luigi Zecca

2011-01-01

367

Clusters of Cognitive and Behavioral Disorders Clearly Distinguish Primary Progressive Aphasia from Frontal Lobe Dementia, and Alzheimer’s Disease  

Microsoft Academic Search

Background\\/Aims: Frontal lobe dementia (FLD) and primary nonfluent progressive aphasia (PnPA) are two forms of frontotemporal lobe degeneration. The relationship between these conditions remains unclear. Our study aimed to better define the behavioral and cognitive clusters characterizing PnPA patients. Methods: We cognitively and behaviorally evaluated three groups of newly diagnosed patients affected by Alzheimer’s disease (AD, n = 20), FLD

C. Marra; D. Quaranta; M. Zinno; S. Misciagna; A. Bizzarro; C. Masullo; A. Daniele; G. Gainotti

2007-01-01

368

"Masters and servants" in parkinsonian gait: a three-dimensional analysis of biomechanical changes sensitive to disease progression  

PubMed Central

Summary Gait disorder is a very frequent and disabling symptom in Parkinson’s disease (PD). The aim of this study was to identify the main kinetic and kinematic features of PD gait according to different disease stages: early (Early Group), intermediate without freezing (Non-Freezers) and intermediate with freezing (Freezers). Kinematic data showed a distal to proximal progression of impairment from the early to the intermediate with freezing stage. The Early Group showed more accentuated ankle dorsiflexion during stance than the other PD subgroups; the Freezers showed a more flexed hip position at initial contact and a reduced range of motion (ROM) during stance compared with the other patients. The individuals in the intermediate stage (with or without freezing) displayed limited knee ROM. Distal to proximal progression of lower limb impairment in PD might be an expression of a rostral to caudal degeneration of locomotor control centers. Evaluation of the relationship between gait features and disease progression may promote the development of tailored rehabilitation programs. PMID:25306119

Albani, Giovanni; Cimolin, Veronica; Fasano, Alfonso; Trotti, Claudio; Galli, Manuela; Mauro, Alessandro

2014-01-01

369

Usefulness of the computed tomography and magnetic resonance in evaluation of progress of treatment of the neoplasmatic diseases in children  

PubMed Central

Summary Background: Neoplastmatic diseases constitute about 1% diseases in children in Poland, what makes about 1200 new incidents during one year. Fast diagnosis in those illnesses is crucial in treatment results. The point of this work was to value usefulness of CT and MRI in diagnostics of neoplasmatic diseases in children. Material/Methods: The retrospective study involved 121 children examined in CT and MRI because of suspicion or during treatment of neoplasmatic disease. Together 184 CT and 119 MRI examination were performed. Eventually in 106 children neoplasmatic disease was diagnosed. In 16 cases neoplasm was excluded. Results: In the analyzed group of patients acute lymphoblastic and non lymphoblastic leukemia was diagnosed in 68 children (55.7%); among them mycosis was identified after radiological examinations in 7 cases (10.3%). 8 children (6.6%) with non Hodgkin lymphoma and 11 (9%) with Hodgkin lymphoma were examined. Nephroblastoma was found after MRI and CT in 6 cases (4.9%). Presence of tumors, that were classified histopatologically as PNET, was confirmed in 4 children. In 15 cases after MRI and CT neoplasmatic disease was excluded. Conclusions: Depending on the kind of sickness MRI and CT may fulfill basic or subsidiary role in diagnostic and estimating the progress of treatment in neoplasmatic diseases among children. PMID:23049581

Myga-Porosilo, Jolanta; Borowiak, Hanna; Sraga, Wojciech; Jackowska, Zuzanna; Serafin, Magdalena; Kluczewska, Ewa

2012-01-01

370

[The effects of hypoxia on initiation and progression of cardiovascular disease in patients with chronic obstructive pulmonary disease].  

PubMed

Hypoxia accompanied chronic obstructive pulmonary disease leads to hypercoagulation, vessels' inflammation, imbalance of oxidative and antioxidative systems. These pathological changes cause arterial hypertension, corpulmonale, metabolism disturbance of the whole organism. PMID:23534269

Lyzogub, V H; Savchenko, O V; Zaval's'ka, T V; Dykukha, I S; Tyravs'ka, Iu V

2012-01-01

371

Parkinson disease (PD) is a chronic, progressive neurodegenera-tive disorder that affects at least 1% of people by age 70 (13).  

E-print Network

History Parkinson disease (PD) is a chronic, progressive neurodegenera- tive disorder that affects to the development of motor complications including wearing-off (the Diagnosis and treatment of Parkinson disease, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Parkinson disease (PD

Hayar, Abdallah

372

Minocycline Slows Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis  

Microsoft Academic Search

There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (ALS). Because recent evidence suggests that secondary inflammation and caspase activation may contribute to neurodegeneration in ALS, we tested the effects of minocycline, a second-generation tetracycline with anti-inflammatory properties, in mice expressing a mutant superoxide dismutase (SOD1G37R) linked to human ALS. Administration of minocycline into the diet, beginning at

Jasna Kriz; Minh Dang Nguyen; Jean-Pierre Julien

2002-01-01

373

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain  

PubMed Central

Summary: Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies. PMID:22763635

Ferenczy, Michael W.; Marshall, Leslie J.; Nelson, Christian D. S.; Atwood, Walter J.; Nath, Avindra; Khalili, Kamel

2012-01-01

374

Serial MRI Features of Canine GM1 Gangliosidosis: A Possible Imaging Biomarker for Diagnosis and Progression of the Disease  

PubMed Central

GM1 gangliosidosis is a fatal neurodegenerative lysosomal storage disease caused by an autosomal recessively inherited deficiency of ?-galactosidase activity. Effective therapies need to be developed to treat the disease. In Shiba Inu dogs, one of the canine GM1 gangliosidosis models, neurological signs of the disease, including ataxia, start at approximately 5 months of age and progress until the terminal stage at 12 to 15 months of age. In the present study, serial MR images were taken of an affected dog from a model colony of GM1 gangliosidosis and 4 sporadic clinical cases demonstrating the same mutation in order to characterize the MRI features of this canine GM1 gangliosidosis. By 2 months of age at the latest and persisting until the terminal stage of the disease, the MR findings consistently displayed diffuse hyperintensity in the white matter of the entire cerebrum on T2-weighted images. In addition, brain atrophy manifested at 9 months of age and progressed thereafter. Although a definitive diagnosis depends on biochemical and genetic analyses, these MR characteristics could serve as a diagnostic marker in suspect animals with or without neurological signs. Furthermore, serial changes in MR images could be used as a biomarker to noninvasively monitor the efficacy of newly developed therapeutic strategies. PMID:22536126

Hasegawa, Daisuke; Yamato, Osamu; Nakamoto, Yuya; Ozawa, Tsuyoshi; Yabuki, Akira; Itamoto, Kazuhito; Kuwabara, Takayuki; Fujita, Michio; Takahashi, Kimimasa; Mizoguchi, Shunta; Orima, Hiromitsu

2012-01-01

375

Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain.  

PubMed

Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies. PMID:22763635

Ferenczy, Michael W; Marshall, Leslie J; Nelson, Christian D S; Atwood, Walter J; Nath, Avindra; Khalili, Kamel; Major, Eugene O

2012-07-01

376

Early transcriptional programming links progression to hepatitis C virus-induced severe liver disease in transplant patients  

PubMed Central

Liver failure due to chronic hepatitis C virus infection is a major cause for liver transplantation worldwide. Recurrent infection of the graft is universal in HCV patients following transplant and results in rapid progression to severe fibrosis and end-stage liver disease in one-third of all patients. No single clinical variable, or combination thereof, has so far proven accurate in identifying patients at risk of hepatic decompensation in the transplant setting. A combination of longitudinal, dimensionality reduction, and categorical analysis of the transcriptome from 111 liver biopsy specimens taken from 57 HCV-infected patients over time identified a molecular signature of gene expression of patients at risk of developing severe fibrosis. Significantly, alterations in gene expression occur prior to histologic evidence of liver disease progression, suggesting that events which occur during the acute phase of infection influence patient outcome. Additionally, a common precursor state for different severe clinical outcomes was identified. Hence, based on this patient cohort, incidence of severe liver disease is a process initiated early during HCV infection of the donor organ. The probable cellular network at the basis of the initial transition to severe liver disease was identified and characterized. PMID:22278598

Rasmussen, Angela L.; Tchitchek, Nicolas; Susnow, Nathan J.; Krasnoselsky, Alexei L.; Diamond, Deborah L.; Yeh, Matthew M.; Proll, Sean C.; Korth, Marcus J.; Walters, Kathie-Anne; Lederer, Sharon; Larson, Anne M.; Carithers, Robert L.; Benecke, Arndt; Katze, Michael G.

2012-01-01

377

Prevalence of Parkinson's disease and other types of Parkinsonism in Al Kharga district, Egypt  

PubMed Central

Parkinson’s disease (PD) is a common neurodegenerative disorder in older people. The prevalence of PD varies among ethnic and geographic groups around the world. In this study, we aimed to estimate the prevalence of PD and other types of Parkinsonism in persons aged ?40 years in the Al Kharga district of Egypt. The study was conducted on the total population of Al Kharga district (62,583 persons) between 2005 and 2009 and involved three neurology specialists and 15 female social workers undertaking a door-to-door survey. Suspected cases of Parkinsonism were subjected to meticulous clinical and neurological examination by three neurology staff members from Assiut University hospital who carried out their examinations separately. Of the total population surveyed, 15,482 persons were aged ?40 years and 49 of these were identified as having Parkinsonism (prevalence: 316.50 per 100,000 people [95% confidence interval {CI} 240.21–404.98]). Of the 49, 33 fulfilled the diagnostic criteria for PD, giving a prevalence rate of 213.15/100,000 (95% CI 150.51–285.80) while 14 fulfilled those for vascular Parkinsonism, with a prevalence rate of 90.43/100,000 (95% CI 49.60–137.78). Postencephalitic and unspecified Parkinsonism each had a prevalence rate of 6.46/100,000. The prevalence of Parkinsonism was found to increase steadily with age, and the prevalence of all types of Parkinsonism was statistically higher in rural compared with urban communities, with no significant difference between men and women. PMID:24379673

EL-Tallawy, Hamdy N; Farghaly, Wafaa M; Shehata, Ghaydaa A; Rageh, Tarek A; Hakeem, Nabil M Abdel; Hamed, Mohamed Abd Al; Badry, Reda

2013-01-01

378

Detecting the Progression of Eye Disease: CUSUM Charts for Assessing the Visual Field and Retinal Nerve Fiber Layer Thickness  

PubMed Central

Purpose The cumulative sum (CUSUM) is proposed and tested in a group of glaucoma patients and healthy subjects as a method for monitoring disease progression and for identifying clinically significant step changes in visual structure or function. Methods The CUSUM procedure is the recommended method for the timely detection of small step changes in manufacturing process control. The CUSUM procedure is discussed and compared with traditional approaches for the detection of change in the status of the visual system over time. The CUSUM approach is used to monitor over time visual field (VF) mean deviations and optical coherence tomography (OCT) measurements of retinal nerve fiber layer (RNFL) thickness in 53 healthy subjects and 103 patients with glaucoma. Results The CUSUM method detects VF progression for 35 of the 103 glaucoma patients (34.0%), and OCT RNFL reductions for 20 of the 103 glaucoma patients (19.4%). Conclusions The CUSUM method is effective in detecting small level changes. This method can be used to monitor the progression of disease and it benefits the clinician who must decide, on the basis of a time series of variable data, whether a change has occurred. Translational Relevance A cumulative sum chart helps the clinician decide whether a step change has taken place, and it does so as quickly as possible. This approach is particularly effective for detecting small step changes, which very likely are unnoticed with currently used change detection approaches. PMID:24083087

Ledolter, Johannes; Kardon, Randy

2013-01-01

379

Current progress in the management of rare diseases and orphan drugs in China  

PubMed Central

Summary Currently, the issues of how to treat rare diseases and to improve accessibility to orphan drugs are arousing more and more concerns in China. Here we describe the push and pull incentive policies for rare diseases and orphan drugs and analyze the coverage and reimbursement level of rare diseases in the current Chinese medical insurance system. Three key obstacle factors that hinder Chinese patients' accessibility to timely drug treatment are summarized. Based on a comprehensive analysis, the measures of orphan drugs legislation, incentive mechanism, supply mechanism, and reimbursement mechanism are urgently expected to be established with the purpose of improving healthcare for patients with rare diseases in China.

Gong, Shiwei; Jin, Si

2012-01-01

380

Emerging and reemerging infections. Progress and challenges in the subspecialty of infectious disease pathology.  

PubMed

Emerging and reemerging infections are attracting greater attention from the public health and medical communities. Pathologists and other physicians are increasingly aware of the importance of the subspecialty of infectious disease pathology as a tool for diagnosis, surveillance, and research of emerging infections. In this communication, we describe the role that infectious disease pathologists have played during the last 2 years in broadening our understanding of selected emerging infections, including such examples as new variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy, leptospirosis, microsporidiosis, Ebola hemorrhagic fever, and cyclosporiasis. The significance of providing pathology services, especially the autopsy, to patients with potentially hazardous communicable diseases is discussed with the supposition that it is unethical to exclude or withhold health care from a patient based on his or her underlying disease or on risk factors for acquiring a disease. The increasing occurrence of infectious diseases imported into the United States and other nations, including human immunodeficiency virus-1 group O, dengue fever, tuberculosis, malaria, diphtheria and cholera in immigrants and travelers, and Ebola virus in nonhuman primates, emphasizes the necessity for pathologists of having competence with infecti