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1

Kinematics of Disease Progression in Bulbar ALS  

PubMed Central

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 performance such as speaking rate and speech intelligibility. Movements of the lip and jaw were quantified with respect to their size (i.e., path distance measure), speed, and duration. The data revealed several changes in lip and jaw movement that coincided with ALS progression. In two out of three speakers, the changes in measures of path distance and speed anticipated the drop in speech intelligibility by approximately 3 months. With disease progression, increases in movement duration coincided with declines in speech intelligibility. Overall, the movement measures appeared to be sensitive to disease progression in ALS. Learning outcomes By the end of the manuscript, the reader should be able to: (1) describe the changes that occur in articulatory movements of the jaw and lower lip in ALS; (2) understand the relationship between physiologic measures of movement and speech intelligibility and speaking rate; (3) identify critical points in the disease progression and understand which quantitative measures reveal the state of the bulbar system at these time points.

Yunusova, Yana; Green, Jordan; Lindstrom, Mary; Ball, Laura; Pattee, Gary; Zinman, Lorne

2009-01-01

2

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

3

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.

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

4

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

PubMed

Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5-11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1(G93A) and control: nontransgenic and SOD1(WT)) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1(G93A) mice reached end stage ?8 days (?6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models. PMID:24598527

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

2014-06-01

5

Relationship between neuropathology and disease progression in the SOD1(G93A) ALS mouse.  

PubMed

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons. However, recent reports suggest an active role of non-neuronal cells in the pathogenesis of the disease. Here, we examined quantitatively the temporal development of neuropathologic features in the brain and spinal cord of a mouse model of ALS (SOD1(G93A)). Four phases of the disease were studied in both male and female SOD1(G93A) mice: presymptomatic (PRE-SYM), symptomatic (SYM), endstage (ES) and moribund (MB). Compared to their control littermates, SOD1(G93A) mice showed an increase in astrogliosis in the motor cortex, spinal cord and motor trigeminal nucleus in the SYM phase that worsened progressively in ES and MB animals. Associated with this increase in astrogliosis was a concomitant increase in motor neuron cell death in the spinal cord and motor trigeminal nucleus in both ES and MB mice, as well as in the ventrolateral thalamus in MB animals. In contrast, microglial activation was significantly increased in all the same regions but only when the mice were in the MB phase. These results suggest that astrogliosis preceded or occurred concurrently with neuronal degeneration whereas prominent microgliosis was evident later (MB stage), after significant motor neuron degeneration had occurred. Hence, our findings support a role for astrocytes in modulating the progression of non-cell autonomous degeneration of motor neurons, with microglia playing a role in clearing degenerating neurons. PMID:21145892

Yang, Wendy W; Sidman, Richard L; Taksir, Tatyana V; Treleaven, Christopher M; Fidler, Jonathan A; Cheng, Seng H; Dodge, James C; Shihabuddin, Lamya S

2011-02-01

6

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.

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

7

Electrophysiologic Biomarkers for Assessing Disease Progression and the Effect of Riluzole in SOD1 G93A ALS Mice  

PubMed Central

Objective To compare electrical impedance myography (EIM) 50 kHz phase to weight, motor score, paw grip endurance (PGE), CMAP amplitude, and MUNE for the identification of disease progression and the effect of riluzole in the SOD1 G93A mouse. Methods Twenty-three animals received 8 mg/kg/day riluzole in the drinking water starting at 6 weeks of age; 22 animals served as controls. Weight, motor score, PGE, CMAP, MUNE, and EIM were performed weekly to evaluate disease progression. Results No difference in clinical disease onset or survival was found between treated and untreated groups. In addition, all methods failed to identify any beneficial effect of riluzole. Thus, data from all animals were combined for additional analyses. Of the 4 parameters, EIM phase showed the earliest change from baseline and the most linear decline throughout the entire measurement period. In addition, EIM phase correlated with PGE, CMAP amplitude, and MUNE (Spearman r?=?0.92, 0.90, and 0.72, respectively, p<0.01 for all). The rate of EIM phase decline also correlated with individual animal survival (Spearman r?=??0.31, p<0.05). Conclusions At this dose, riluzole is ineffective in slowing progression of ALS. However, EIM phase shows early linear declines, supporting its potential as a useful new biomarker for preclinical drug testing.

Li, Jia; Sung, Minhee; Rutkove, Seward B.

2013-01-01

8

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.

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

2014-01-01

9

Plasma Neurofilament Heavy Chain Levels Correlate to Markers of Late Stage Disease Progression and Treatment Response in SOD1G93A Mice that Model ALS  

PubMed Central

Background Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder characterised by progressive degeneration of motor neurons leading to death, typically within 3–5 years of symptom onset. The diagnosis of ALS is largely reliant on clinical assessment and electrophysiological findings. Neither specific investigative tools nor reliable biomarkers are currently available to enable an early diagnosis or monitoring of disease progression, hindering the design of treatment trials. Methodology/Principal Findings In this study, using the well-established SOD1G93A mouse model of ALS and a new in-house ELISA method, we have validated that plasma neurofilament heavy chain protein (NfH) levels correlate with both functional markers of late stage disease progression and treatment response. We detected a significant increase in plasma levels of phosphorylated NfH during disease progression in SOD1G93A mice from 105 days onwards. Moreover, increased plasma NfH levels correlated with the decline in muscle force, motor unit survival and, more significantly, with the loss of spinal motor neurons in SOD1 mice during this critical period of decline. Importantly, mice treated with the disease modifying compound arimoclomol had lower plasma NfH levels, suggesting plasma NfH levels could be validated as an outcome measure for treatment trials. Conclusions/Significance These results show that plasma NfH levels closely reflect later stages of disease progression and therapeutic response in the SOD1G93A mouse model of ALS and may potentially be a valuable biomarker of later disease progression in ALS.

Lu, Ching-Hua; Petzold, Axel; Kalmar, Bernadett; Dick, James; Malaspina, Andrea; Greensmith, Linda

2012-01-01

10

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.

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

2014-01-01

11

Macrophages and progressive tubulointerstitial disease  

Microsoft Academic Search

Macrophages and progressive tubulointerstitial disease. In chronic renal disease, tubulointerstitial inflammation and injury is associated with infiltrating macrophages. As a consequence of primary injury, proteinuria, chronic hypoxia, and glomerular-derived cytokines may all differentially modulate the expression of factors that promote macrophage recruitment. In addition to adhesion molecules and chemokines, products of complement system and renin-angotensin system activation may direct this

KEVIN SEAN EARDLEY; PAUL COCKWELL

2005-01-01

12

Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia  

Microsoft Academic Search

Dominant mutations in superoxide dismutase cause amyotrophic lateral sclerosis (ALS), a progressive paralytic disease characterized by loss of motor neurons. With the use of mice carrying a deletable mutant gene, expression within motor neurons was shown to be a primary determinant of disease onset and of an early phase of disease progression. Diminishing the mutant levels in microglia had little

Séverine Boillée; Koji Yamanaka; Christian S. Lobsiger; Neal G. Copeland; Nancy A. Jenkins; George Kassiotis; George Kollias; Don W. Cleveland

2006-01-01

13

Shading reduces coral-disease progression  

NASA Astrophysics Data System (ADS)

The growing incidence of tropical-marine diseases is attributed to increases in pathogen prevalence and virulence associated with global warming. Additionally, the compromised-host hypothesis suggests that rising ocean temperatures may increase disease activity by making the corals more susceptible to ubiquitous pathogens. We tested the effects of reducing irradiance stress on coral-disease progression rates by shading corals showing signs consistent with white-plague disease. Our results showed that white-plague disease on shaded corals progressed significantly more slowly than on controls. Although the mechanisms are unknown, this study suggests that light intensity influences the rate of coral-disease progression.

Muller, E. M.; van Woesik, R.

2009-09-01

14

2012-2013 Alzheimer's Disease Progress Report  

MedlinePLUS

Alzheimer's Go4Life Español NIHSeniorHealth Publications Text Resize - A + A Search form Search ADEAR Center Home Home > Alzheimer's > 2012-2013 Alzheimer's Disease Progress Report 2012-2013 Alzheimer's Disease ...

15

Somatic symptom progression in idiopathic Parkinson's disease  

Microsoft Academic Search

The substantia nigra (SN) pars compacta is arranged somatotopically. Symptoms of idiopathic Parkinson's disease (IPD) are caused by a lesion in this nucleus, which spreads in a stereotyped spatio-temporal pattern during the course of the disease. We investigated the order of somatic symptom progression in a group of 30 patients with IPD to determine if progression of symptoms was consistent

Jon M. Dickson; Richard A. Grünewald

2004-01-01

16

Eales' disease with progressive spastic paraparesis.  

PubMed

Eales disease is a disease of unknown aetiology characterised by ophthalmic changes and often neurological involvement as in multiple sclerosis. We are reporting a case of Eales' disease in a 27 yr old male with chronic progressive non compressive motor myelopathy. PMID:8226608

Garg, R K; Kar, A M; Varma, M

1993-03-01

17

Modeling Disease Progression with Longitudinal Markers  

PubMed Central

In this paper we propose a Bayesian natural history model for disease progression based on the joint modeling of longitudinal biomarker levels, age at clinical detection of disease and disease status at diagnosis. We establish a link between the longitudinal responses and the natural history of the disease by using an underlying latent disease process which describes the onset of the disease and models the transition to an advanced stage of the disease as dependent on the biomarker levels. We apply our model to the data from the Baltimore Longitudinal Study of Aging on prostate specific antigen (PSA) to investigate the natural history of prostate cancer.

Inoue, Lurdes Y. T.; Etzioni, Ruth; Morrell, Christopher; Muller, Peter

2013-01-01

18

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

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

1995-01-01

19

MAPK Usage in Periodontal Disease Progression  

PubMed Central

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

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

2012-01-01

20

Exotic emerging viral diseases: progress and challenges  

Microsoft Academic Search

The agents causing viral hemorrhagic fever (VHF) are a taxonomically diverse group of viruses that may share commonalities in the process whereby they produce systemic and frequently fatal disease. Significant progress has been made in understanding the biology of the Ebola virus, one of the best known examples. This knowledge has guided our thinking about other VHF agents, including Marburg,

Thomas W Geisbert; Peter B Jahrling

2004-01-01

21

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.

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

2009-01-01

22

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

23

Recent Progress in Vaccines against Fungal Diseases  

PubMed Central

Diseases caused by fungi are increasingly impacting the health of the human population and now account for a large fraction of infectious disease complications in individuals with impaired immunity or breached tissue defenses. Antifungal therapy is often of limited effectiveness in these patients, resulting into treatment failures, chronic infections and unacceptable rates of mortality, morbidity and their associated costs. Consequently there is a real medical need for new treatments and preventive measures to combat fungal diseases and, toward this goal, safe and efficacious vaccines would constitute major progress. After decades of complacency and neglect of this critically important field of research, remarkable progress has been made in recent years. A number of highly immunogenic and protective vaccine formulations in preclinical setting have been developed, and at least two have undergone Phase 1 clinical trials as preventive and/or therapeutic tools against candidiasis.

Cassone, Antonio; Casadevall, Arturo

2012-01-01

24

Interstitial lung disease: progress and problems  

PubMed Central

Interstitial lung disease involves all areas of medicine as it often occurs in patients with comorbidities or as a consequence of systemic diseases and their treatment. Typically the physician is faced with a breathless patient, a diffusely abnormal chest radiograph, and a wide differential diagnosis. Progress has been made in using high resolution computed tomography as the key investigation in characterising the pattern and extent of the disease. Bronchoalveolar lavage is particularly important in excluding infection as a cause of diffuse lung infiltrates. Surgical lung biopsies have led to a new classification system for the range of histopathological patterns of disease that were previously known by the collective term cryptogenic fibrosing alveolitis. Problems persist in deciding when a surgical lung biopsy is clinically justified, in understanding the pathogenesis of these diseases, and in finding more effective treatments.

Bourke, S J

2006-01-01

25

Dose-Response Thresholds for Progressive Diseases  

PubMed Central

Many diseases, including cancers, heart diseases, and lung diseases, can usefully be viewed as arising from disruption of feedback control systems that normally maintain homeostasis of tissues and cell populations. Excessive exposure can destabilize feedback control loops, leading to sustained elevation of variables to saturated levels and clinical consequences such as chronic unresolved inflammation, destruction of tissue (as in emphysema), proliferation of cell populations (as in lung cancer), and increases in reactive oxygen species and protease levels (as in coronary heart diseases and chronic obstructive lung disease). We propose a framework for understanding how exposure can destabilize normally homeostatic feedback control systems and create sustained imbalances and elevated levels of disease-related variables, by creating a new, locally stable, alternative equilibrium for the dynamic system, in addition to its normal (homeostatic) equilibrium. The resulting model, which we call alternative-equilibria (AE) theory, implies the existence of an exposure threshold below which transition to the alternative equilibrium (potential disease) state will not occur. Once this threshold is exceeded, progression to the alternative equilibrium continues spontaneously, even without further exposure. These predictions may help to explain patterns observed in experimental and epidemiological data for diseases such as COPD, silicosis, and inflammation-mediated lung cancer.

Cox, Louis Anthony (Tony)

2012-01-01

26

Investigational drugs in Alzheimer's disease: current progress.  

PubMed

Introduction: Alzheimer's disease is a progressive neurodegenerative disorder affecting millions of people worldwide. Yet, this disease is presently incurable and treatable only in terms of modest delay of symptomatic progression. The need for more effective pharmacological intervention is becoming more pronounced as the patient population increases. Areas covered: This paper outlines and evaluates the current landscape of interventions in early phases of clinical study. Data and analysis for this review were procured from PubMed, clinicaltrials.gov, review of posters, abstracts and presentations from American Neurological Association, American Academy of Neurology meetings, Alzheimer's Association International Conference and Clinical Trials on Alzheimer's disease. Keywords and criteria searched included: Phase 0, I, and II trials related to Alzheimer's disease, amyloid-?, anti-tau, monoclonal antibodies and metabolism. Expert opinion: The development of novel pharmacological interventions would be more fruitful if multitarget therapies were introduced, and unexplored mechanisms of action were expanded upon. Additionally, there is a rationale for intervening earlier in the disease, perhaps preceding or at the advent of symptoms. PMID:24702504

Berk, Camryn; Paul, Gaurav; Sabbagh, Marwan

2014-06-01

27

Smoking and Disease Progression in Multiple Sclerosis  

PubMed Central

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

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

2009-01-01

28

Serum Immune Responses Predict Rapid Disease Progression among Children with Crohn's Disease: Immune Responses Predict Disease Progression  

Microsoft Academic Search

BACKGROUND AND AIM:Crohn's disease (CD) is a heterogeneous disorder characterized by diverse clinical phenotypes. Childhood-onset CD has been described as a more aggressive phenotype. Genetic and immune factors may influence disease phenotype and clinical course. We examined the association of immune responses to microbial antigens with disease behavior and prospectively determined the influence of immune reactivity on disease progression in

Marla C. Dubinsky; Ying-Chao Lin; Debra Dutridge; Yoana Picornell; Carol J. Landers; Sharmayne Farrior; Iwona Wrobel; Antonio Quiros; Eric A. Vasiliauskas; Bruce Grill; David Israel; Ron Bahar; Dennis Christie; Ghassan Wahbeh; Gary Silber; Saied Dallazadeh; Praful Shah; Danny Thomas; Drew Kelts; Robert M. Hershberg; Charles O. Elson; Stephan R. Targan; Kent D. Taylor; Jerome I. Rotter; Huiying Yang

2006-01-01

29

Problems and progresses in speciation of Al in human serum: an overview.  

PubMed

Aluminium (Al) is associated with many clinical disorders in renal patients. Al accumulation in brain has also been related to the neurodegenerative processes in Alzheimer's disease. In order to better understand Al transport in the human body, it is necessary to identify and quantify chemical species in which Al is present in body fluids and tissues. Among a variety of biological samples, Al speciation was the most frequently investigated in human serum. Improvements were made in the development of analytical techniques for the determination of the amount and composition of high molecular mass Al (HMM-Al) and low molecular mass Al (LMM-Al) species in human serum. However, due to the complex chemistry of Al in serum, its low total concentration and the high risk of contamination, speciation of Al in biological samples is still a difficult task for analytical chemists. In this work, problems related to speciation of Al in human serum are critically discussed. An overview of the progress that was made by the use of different analytical procedures, in order to propose analytical protocols for reliable speciation of Al in serum at low ng mL(-1) concentration range, is presented. PMID:19740542

Milacic, Radmila; Murko, Simona; Scancar, Janez

2009-11-01

30

EXPLORATORY ANALYSIS OF SEVEN ALZHEIMER'S DISEASE GENES: DISEASE PROGRESSION  

PubMed Central

The relationships between GWAS-identified and replicated genetic variants associated to Alzheimer’s disease (AD) risk and disease progression or therapeutic responses in AD patients are almost unexplored. 701 AD patients with at least three different cognitive evaluations and genotypic information for APOE and six GWAS-significant SNPs were selected for this study. Mean differences in GDS and MMSE were evaluated using non-parametric tests, GLM and mixed models for repeated measurements. Each chart was also reviewed for evidence of treatment with any cholinesterase inhibitor (AChEI), memantine or both. Relationships between therapeutic protocols, genetic markers and progression were explored using stratified analysis looking for specific effects on progression in each therapeutic category separately. Neither calculation rendered a Bonferroni-corrected statistically significant difference in any genetic marker. Mixed model results suggested differences in the average point in MMSE test for patients carrying PICALM GA or AA genotype compared to GG carriers at the end of the follow up (MMSE mean difference= ?0.57 C.I.95%[?1.145?0.009], p=0.047). This observations remained unaltered after covariate adjustments although did not achieve predefined multiple testing significance threshold. PICALM SNP also displayed a significant effect protecting against rapid progression during pharmacogenetics assays although it observed effect displayed heterogeneity among AD therapeutic protocols (p=0.039). None of studied genetic markers was convincingly linked to AD progression or drug response. However, by using different statistical approaches, PICALM rs3851179 marker displayed consistent but weak effects on disease progression phenotypes.

Ruiz, Agustin; Hernandez, Isabel; Ronsende-Roca, Maitee; Gonzalez-Perez, Antonio; Rodriguez-Noriega, Emma; Ramirez-Lorca, Reposo; Mauleon, Ana; Moreno-Rey, Concha; Boswell, Lucie; Tune, Larry; Valero, Sergi; Alegret, Montserrat; Gayan, Javier; Becker, James T.; Real, Luis Miguel; Tarraga, Lluis; Ballard, Clive; Terrin, Michael; Sherman, Stephanie; Payami, Haydeh; Lopez, Oscar L.; Mintzer, Jacobo E.; Boada, Merce

2014-01-01

31

Clinical phenotypes and natural progression for motor neuron disease: analysis from an Australian database.  

PubMed

From 1997 to 2003 we prospectively followed a cohort of ALS/MND patients. Patients were allocated to predetermined clinical phenotypes using the principles established in the modified El Escorial criteria. The date and region of symptom onset were carefully determined and their progression was scored using the Appel ALS rating scale. The four distinct clinical phenotypes: Global, Flail Arm, Flail Leg and Primary Lateral Sclerosis (PLS) demonstrated significantly different rates of progression and survival times. The Global ALS/MND phenotype can present with initial symptoms in any region and rapidly progresses to involve all segments, with symptoms due to a mixture of combined corticospinal tract and anterior horn cell dysfunction. The Global phenotype has the shortest survival and most rapid rate of disease progression. There was a significant difference in survival between Global bulbar onset and cervical onset disease but no significant difference in the rate of disease progression between the three Global subgroups as determined by the Appel/ALS rating scale. Flail patients had much slower rates of progression and significantly longer survival compared to the Global phenotype. Patients with Primary Lateral Sclerosis as expected progressed the slowest and survived the longest compared to the other clinical phenotypes. The utility of developing a method of assigning clinical phenotypes with similar survival and disease progression rates is discussed in relation to therapeutic trial design, practice benchmarking and clinico-pathological correlations. PMID:18608095

Talman, Paul; Forbes, Andrew; Mathers, Susan

2009-04-01

32

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

PubMed Central

Background Circulating 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 expand under pathological conditions and inhibit possible recruitment of helper T cells needed for fighting off the disease. Methods and Findings We tested this working hypothesis in amyotrophic lateral sclerosis (ALS) and its mouse model, which are characterized by a rapid progression once clinical symptoms are evident. Adaptive transfer of alternatively activated myeloid (M2) cells, which homed to the spleen and exhibited immune suppressive activity in G93A mutant superoxide dismutase-1 (mSOD1) mice at a stage before emergence of disease symptoms, resulted in earlier appearance of disease symptoms and shorter life expectancy. The same protocol mitigated the inflammation-induced disease model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), which requires circulating T cells for disease induction. Analysis of whole peripheral blood samples obtained from 28 patients suffering from sporadic ALS (sALS), revealed a two-fold increase in the percentage of circulating MDSCs (LIN?/LowHLA-DR?CD33+) compared to controls. Conclusions Taken together, these results emphasize the distinct requirements for fighting the inflammatory neurodegenerative disease, multiple sclerosis, and the neurodegenerative disease, ALS, though both share a local inflammatory component. Moreover, the increased levels of circulating MDSCs in ALS patients indicates the operation of systemic mechanisms that might lead to an impairment of T cell reactivity needed to overcome the disease conditions within the CNS. This high level of suppressive immune cells might represent a risk factor and a novel target for therapeutic intervention in ALS at least at the early stage.

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

2011-01-01

33

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

PubMed

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

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

2013-01-01

34

Illness experience in a chronic disease--ALS.  

PubMed

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 regarding causation, the use and evaluation of various therapies, use of illness role models, spiritual changes and symptom experience were also explored. Kleinman's concept of explanatory models guides the analysis of the data, although we argue for a greater emphasis on evaluation of therapies within this model. PMID:3775446

Cobb, A K; Hamera, E

1986-01-01

35

Do lamins influence disease progression in cancer?  

PubMed

For nearly 60 years, diagnosis of cancer has been based on pathological tests that look for enlargement and distortion of nuclear shape. Because of their involvement in supporting nuclear architecture, it has been postulated that the basis for nuclear shape changes during cancer progression is altered expression of nuclear lamins and in particular lamins A and C. However, studies on lamin expression patterns in a range of different cancers have generated equivocal and apparently contradictory results. This might have been anticipated since cancers are diverse and complex diseases. Moreover, whilst altered epigenetic control over gene expression is a feature of many cancers, this level of control cannot be considered in isolation. Here I have reviewed those studies relating to altered expression of lamins in cancers and argue that consideration of changes in the expression of individual lamins cannot be considered in isolation but only in the context of an understanding of their functions in transformed cells. PMID:24563367

Hutchison, Christopher J

2014-01-01

36

Exotic emerging viral diseases: progress and challenges.  

PubMed

The agents causing viral hemorrhagic fever (VHF) are a taxonomically diverse group of viruses that may share commonalities in the process whereby they produce systemic and frequently fatal disease. Significant progress has been made in understanding the biology of the Ebola virus, one of the best known examples. This knowledge has guided our thinking about other VHF agents, including Marburg, Lassa, the South American arenaviruses, yellow fever, Crimean-Congo and Rift Valley fever viruses. Comparisons among VHFs show that a common pathogenic feature is their ability to disable the host immune response by attacking and manipulating the cells that initiate the antiviral response. Of equal importance, these comparisons highlight critical gaps in our knowledge of these pathogens. PMID:15577929

Geisbert, Thomas W; Jahrling, Peter B

2004-12-01

37

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.

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

38

Characterizing aggressiveness and predicting future progression of CF lung disease.  

PubMed

Cystic fibrosis (CF) is a life-shortening genetic disease characterized by variability in age of death that is largely due to variability in rate of progression of lung disease, the primary cause of mortality. Recognizing which individuals have more aggressive disease phenotypes and predicting their risk of immediate lung disease progression is a critical step in managing CF lung disease and extending the life expectancy of CF patients. Studies using observational CF patient registries have yielded useful methods for predicting future rate of disease progression and can be used to determine the impact that chronic pulmonary therapies have on slowing rate of lung function decline. PMID:19460682

Konstan, Michael W; Wagener, Jeffrey S; VanDevanter, Donald R

2009-06-01

39

Progress Report on Alzheimer's Disease, 1996.  

National Technical Information Service (NTIS)

Contents: Alzheimer's Disease; National Institute on Aging; Structure and Function of the Brain; Changes in the Brain in Alzheimer's Disease; Advances in Identifying Risk Factors for Alzheimer's Disease; Advances in Diagnosing Alzheimer's Disease; Advance...

1996-01-01

40

Celiac disease: diagnostic criteria in progress.  

PubMed

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 presentations. The identification of CD is challenging because it can begin not only with diarrhea and weight loss but also with atypical gastrointestinal (constipation and recurrent abdominal pain) and extra-intestinal symptoms (anemia, raised transaminases, osteoporosis, recurrent miscarriages, aphthous stomatitis and associated autoimmune disorders), or it could be completely symptomless. Over the last 20 years, the diagnostic accuracy of serology for CD has progressively increased with the development of highly reliable tests, such as the detection of IgA tissue transglutaminase and antiendomysial and IgG antideamidated gliadin peptide antibodies. The routine use of antibody markers has allowed researchers to discover a very high number of 'borderline' cases, characterized by positive serology and mild intestinal lesions or normal small intestine architecture, which can be classified as potential CD. Therefore, it is evident that the 'old celiac disease' with flat mucosa is only a part of the spectrum of CD. It is possible that serology could identify CD in its early stages, before the appearance of severe intestinal damage. In cases with a positive serology but with mild or absent intestinal lesions, the detection of HLA-DQ2 and HLA-DQ8 can help reinforce or exclude the diagnosis of gluten sensitivity. PMID:21278763

Volta, U; Villanacci, V

2011-03-01

41

Progress and promise in the management of chronic kidney disease  

Microsoft Academic Search

1 for the management of chronic kidney disease provide clear guidance for the co- operative care of patients with chronic kidney disease by all health care providers throughout the spectrum of disease. There are specific stages and recommendations for interven- tions to slow disease progression, prevent complications, and reduce morbidity and mortality. This is a major para- digm shift on

Garabed Eknoyan

2008-01-01

42

Therapeutic strategies to slow chronic kidney disease progression  

Microsoft Academic Search

Childhood chronic kidney disease commonly progresses toward end-stage renal failure, largely independent of the underlying\\u000a disorder, once a critical impairment of renal function has occurred. Hypertension and proteinuria are the most important independent\\u000a risk factors for renal disease progression. Therefore, current therapeutic strategies to prevent progression aim at controlling\\u000a blood pressure and reducing urinary protein excretion. Renin-angiotensin-system (RAS) antagonists preserve

Elke Wühl; Franz Schaefer

2008-01-01

43

Progress Report on Alzheimer's Disease, 1997.  

National Technical Information Service (NTIS)

Contents: National Institute on Aging; Structure and Function of the Brain; Changes in the Brain in Alzheimer's Disease; Genetic Factors in Alzheimer's Disease; Advances in Identifying Risk Factors for Alzheimer's Disease; Advances in Diagnosing Alzheimer...

1997-01-01

44

Hypokinesia without decrement distinguishes progressive supranuclear palsy from Parkinson's disease.  

PubMed

Repetitive finger tapping is commonly used to assess bradykinesia in Parkinson's disease. The Queen Square Brain Bank diagnostic criterion of Parkinson's disease defines bradykinesia as 'slowness of initiation with progressive reduction in speed and amplitude of repetitive action'. Although progressive supranuclear palsy is considered an atypical parkinsonian syndrome, it is not known whether patients with progressive supranuclear palsy have criteria-defined bradykinesia. This study objectively assessed repetitive finger tap performance and handwriting in patients with Parkinson's disease (n?=?15), progressive supranuclear palsy (n?=?9) and healthy age- and gender-matched controls (n?=?16). The motion of the hand and digits was recorded in 3D during 15-s repetitive index finger-to-thumb tapping trials. The main finding was hypokinesia without decrement in patients with progressive supranuclear palsy, which differed from the finger tap pattern in Parkinson's disease. Average finger separation amplitude in progressive supranuclear palsy was less than half of that in controls and Parkinson's disease (P?progressive supranuclear palsy was nearly zero (0.01°/cycle) indicating a lack of decrement, which differed from the negative slope in patients with Parkinson's disease OFF levodopa (-0.20°/cycle, P?=?0.002). 'Hypokinesia', defined as <50% of control group's mean amplitude, combined with 'absence of decrement', defined as mean positive amplitude slope, were identified in 87% of finger tap trials in the progressive supranuclear palsy group and only 12% in the Parkinson's disease OFF levodopa group. In progressive supranuclear palsy, the mean amplitude was not correlated with disease duration or other clinimetric scores. In Parkinson's disease, finger tap pattern was compatible with criteria-defined bradykinesia, characterized by slowness with progressive reduction in amplitude and speed and increased variability in speed throughout the tap trial. In Parkinson's disease, smaller amplitude, slower speed and greater speed variability were all associated with a more severe Unified Parkinson's Disease Rating Scale motor score. Analyses of handwriting showed that micrographia, defined as smaller than 50% of the control group's mean script size, was present in 75% of patients with progressive supranuclear palsy and 15% of patients with Parkinson's disease (P?=?0.022). Most scripts performed by patients with progressive supranuclear palsy did not exhibit decrements in script size. In conclusion, patients with progressive supranuclear palsy have a specific finger tap pattern of 'hypokinesia without decrement' and they do not have criteria-defined limb bradykinesia. Similarly, 'micrographia' and 'lack of decrement in script size' are also more common in progressive supranuclear palsy than in Parkinson's disease. PMID:22396397

Ling, Helen; Massey, Luke A; Lees, Andrew J; Brown, Peter; Day, Brian L

2012-04-01

45

Disease progression and outcomes in chronic kidney disease and renal transplantation  

Microsoft Academic Search

Disease progression and outcomes in chronic kidney disease and renal transplantation.BackgroundIt is unknown whether renal transplant recipients (RTR) have better outcomes and disease progression rates compared to patients with chronic kidney disease (CKD) when matched for the level of kidney function.MethodsWe analyzed data on 1762 patients with CKD (N = 872) and RTR (N = 890) over 16 years, applying

Arjang Djamali; Christina Kendziorski; Peter C. Brazy; Bryan N. Becker

2003-01-01

46

Progressive bulbur paralysis(Fazio-Londe disease)  

Microsoft Academic Search

Progressive bulbar paralysis of childhood is characterised by progressive paralysis of muscles innervated by cranial nerves.\\u000a The authors report a case of progressive bulbar paralysis of childhood in a 12-year-old child. Child was admitted with the\\u000a complaints of drooping of eyelids, difficulty in swallowing and hoarse voice. She had involvement of III, VII, IX, X, XI and\\u000a XII cranial nerves

Taruna Gulati; Vivek Dewan; Praveen Kumar; Bina Ahuja I; V. K. Anand

2004-01-01

47

Cortical Processing of Swallowing in ALS Patients with Progressive Dysphagia - A Magnetoencephalographic Study  

PubMed Central

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

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

2011-01-01

48

Asymmetric Dimethylarginine and Progression of Chronic Kidney Disease: The Mild to Moderate Kidney Disease Study  

Microsoft Academic Search

Reduced bioavailability of nitric oxide (NO) is thought to play an important role in progression of renal damage. The hypothesis that the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is involved in progression of kidney disease was tested. Plasma ADMA concentrations and other putative progression factors were assessed in 227 relatively young patients (45.7 12.6 yr) with nondiabetic kidney diseases

Danilo Fliser; Florian Kronenberg; Jan T. Kielstein; Christian Morath; Stefanie M. Bode-Boger; Hermann Haller; Eberhard Ritz

2005-01-01

49

Alzheimer's Disease Progress Report, 2001-2002.  

National Technical Information Service (NTIS)

Contents: Introduction (The Impact of Alzheimer's Disease, Alzheimer's Disease: An Urgent National Health and Research Priority); 2001-2002 Research Advances: Opening Doors to New Discoveries (What Causes the Transformation from Healthy Aging to Alzheimer...

2003-01-01

50

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.

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

2010-01-01

51

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

52

Deciphering early development of complex diseases by progressive module network.  

PubMed

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

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

2014-06-01

53

Dopamine Transporter Imaging Assessment of Parkinson's Disease Progression.  

National Technical Information Service (NTIS)

The primary goal of this study is to investigate whether sequential dopamine transporter imaging using 123Ibeta-CIT and SPECT, a marker of dopamine terminal integrity, will provide a quantitative biomarker of Parkinson's disease progression in subjects wi...

K. L. Marek J. Seibyl

2001-01-01

54

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

Microsoft Academic Search

Antiangiogenic drugs targeting the VEGF pathway have slowed metastatic disease progression in some patients, leading to progression-free survival (PFS) and overall survival benefits compared with controls. However, the results are more modest than predicted by most preclinical testing and benefits in PFS are frequently not accompanied by overall survival improvements. Questions have emerged about the basis of drug resistance and

Robert S. Kerbel; John M. L. Ebos

2011-01-01

55

Biomarkers of inflammation and progression of chronic kidney disease  

Microsoft Academic Search

Biomarkers of inflammation and progression of chronic kidney disease.BackgroundChronic kidney disease is associated with higher levels of inflammatory biomarkers. Statins have anti-inflammatory properties and may attenuate loss of kidney function. Although inflammation may mediate progressive renal injury, the relation between statin use, markers of inflammation, and the rate of kidney function loss has not been elucidated. We examined the association

MARCELLO TONELLI; FRANK SACKS; MARC PFEFFER; GIAN S JHANGRI; GARY CURHAN

2005-01-01

56

GLOBAL DYNAMICS OF A STAGED PROGRESSION MODEL FOR INFECTIOUS DISEASES  

Microsoft Academic Search

We analyze a mathematical model for infectious diseases that progress through distinct stages within infected hosts. An example of such a disease is AIDS, which results from HIV infection. For a general n-stage stage-progression (SP) model with bilinear incidences, we prove that the global dynamics are completely determined by the basic reproduction number R0: If R0 • 1; then the

Hongbin Guo; Michael Y. Li

2006-01-01

57

Alcohol and HIV Disease Progression: Weighing the Evidence  

Microsoft Academic Search

Heavy alcohol use is commonplace among HIV-infected individuals; however, the extent that alcohol use adversely impacts HIV\\u000a disease progression has not been fully elucidated. Fairly strong evidence suggests that heavy alcohol consumption results\\u000a in behavioral and biological processes that likely increase HIV disease progression, and experimental evidence of the biological\\u000a effect of heavy alcohol on simian immunodeficiency virus in macaques

Judith A. Hahn; Jeffrey H. Samet

2010-01-01

58

Modeling Disease Progression in Acute Stroke Using Clinical Assessment Scales  

Microsoft Academic Search

This article demonstrates techniques for describing and predicting disease progression in acute stroke by modeling scores\\u000a measured using clinical assessment scales, accommodating dropout as an additional source of information. Scores assessed using\\u000a the National Institutes of Health Stroke Scale and the Barthel Index in acute stroke patients were used to model the time\\u000a course of disease progression. Simultaneous continuous and

Kristin E. Karlsson; Justin J. Wilkins; Fredrik Jonsson; Per-Henrik Zingmark; Mats O. Karlsson; E. Niclas Jonsson

2010-01-01

59

Progress Report on Alzheimer's Disease: Volume II.  

ERIC Educational Resources Information Center

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

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

60

Parkinson's Disease: Challenges, Progress, and Promise.  

National Technical Information Service (NTIS)

Ever since PD was first described in 1817, scientists have pursued the causes and treatment of the disease. In the early 1960s, scientists identified the primary problem underlying the disease: the loss of brain cells that produce a chemical called dopami...

2004-01-01

61

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.

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

2012-01-01

62

Dopaminergic function and progression of Parkinson's disease: PET findings.  

PubMed

Recent PET studies in Parkinson's disease (PD) have shown that the progression of neurodegeneration follows an exponential decay pattern. Most of the damage to the nigrostriatal dopamine system occurs during the presymptomatic phase of the disease and the first few years following symptom onset. The progressive loss of dopaminergic neurons is accompanied by several functional adaptive changes in surviving nerve terminals, which lead to increased dopamine turnover and raise the risk of treatment-related motor complications. Younger PD patients seem to have more efficient compensatory mechanisms and a slower rate of progression of neurodegeneration. PMID:20123555

Biju, G; de la Fuente-Fernández, R

2009-12-01

63

Long-term progression of Menière's disease.  

PubMed

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

Stahle, J; Friberg, U; Svedberg, A

1989-05-01

64

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

65

Emotion, behavior pattern and disease progression  

Microsoft Academic Search

Emotion represents a complex reaction that may influence human behavior. According to the bio-psycho-social model, the behavior may be a risk factor for many diseases. This paper shows results of own work and a brief literature review on the role of emotional processing in the pathogenesis of several pathological conditions and their outcome. Data obtained from investigations carried out in

Dan L. Dumitrascu

2006-01-01

66

Progress in spondylarthritis. Immunopathogenesis of spondyloarthritis: which cells drive disease?  

Microsoft Academic Search

Spondyloarthritides, or SpA, form a cluster of chronic inflammatory diseases with the axial skeleton as the most typical disease localisation, although extra-articular manifestations such as intestinal inflammation may frequently occur during the course of the disease. This review summarises recent progress in our understanding of the immunopathogenesis of SpA with special emphasis on the cellular constituents considered to be responsible

Lode Melis; Dirk Elewaut

2009-01-01

67

Iron storage disease: facts, fiction and progress.  

PubMed

There are many forms of iron storage disease, some hereditary and some acquired. The most common of the hereditary forms is HFE-associated hemochromatosis, and it is this disorder that is the main focus of this presentation. The body iron content is regulated by controlling absorption, and studies in the past decade have clarified, in part, how this regulation functions. A 25-amino-acid peptide hepcidin is up-regulated by iron and by inflammation, and it inhibits iron absorption and traps iron in macrophages by binding to and causing degradation of the iron transport protein ferroportin. Most forms of hemochromatosis results from dysregulation of hepcidin or defects of hepcidin or ferroportin themselves. Hereditary hemochromatosis was once considered to be very rare, but in the 1970s and 1980s, with the introduction of better diagnostic tests, it was considered the most common disease among Europeans. Controlled epidemiologic studies carried out in the last decade have shown, however, the disease itself actually is rare, and only its genotype and associated biochemical changes that are common. We do not understand why only a few homozygotes develop severe disease. It now seems unlikely that there are important modifying genes, and although alcohol is known to have some effect, excess drinking probably plays only a modest role in determining the hemochromatosis phenotype. Hereditary hemochromatosis is readily treated by phlebotomy. Secondary forms of the disease require chelation therapy, and the recent introduction of effective oral chelating agents is an important step forward in treating patients with disorders in which iron overload often proves to be fatal, such as thalassemia, myelodysplastic anemias, and dyserythropoietic anemias. While much has been learned about the regulation of iron homeostasis in the past decade, many mysteries remain and represent challenges that will keep us occupied for years to come. PMID:17540589

Beutler, Ernest

2007-01-01

68

Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study  

Microsoft Academic Search

Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. The Modification of Diet in Renal Disease (MDRD) Study examined the effects of dietary protein restriction and strict blood pressure control on the decline in glomerular filtration rate (GFR) in 840 patients with diverse renal diseases. We describe a systematic analysis to determine baseline

Lawrence G Hunsicker; Sharon Adler; Arlene Caggiula; Brian K England; Tom Greene; John W Kusek; Nancy L Rogers; Paul E Teschan; Gerald Beck

1997-01-01

69

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

70

Long-term progression of Meniére's disease.  

PubMed

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

Stahle, J; Friberg, U; Svedberg, A

1991-01-01

71

Role of Mesangial Cell Damage in Progressive Renal Disease  

Microsoft Academic Search

Mesangial cell proliferation and matrix accumulation are considered to contribute to the development of glomerulosclerosis. To investigate the pathological role played by mesangial cell damage in progressive renal disease appropriate progressive models initiated by a mesangial cell injury should be developed. Monoclonal antibody (mAb) 1–22–3 (IgG3) recognizes a critical epitope of the Thy–1.1 molecule on the mesangial cell surface, binding

F. Shimizu; H. Kawachi; M. Orikasa

1999-01-01

72

Pathogenesis of prion diseases: a progress report.  

PubMed

Almost 20 years have passed since Stanley Prusiner proposed that the agent causing transmissible spongiform encephalopathies consists exclusively of a protein and termed it prion. A mixed balance can be drawn from the enormous research efforts that have gone into prion research during this time. On the negative side, the protein-only hypothesis has not been conclusively proven yet. On the positive side, our understanding of spongiform encephalopathies has experienced tremendous advances, mostly through human genetics, mouse transgenetics, and biophysical methods. Perhaps the most astonishing development is the realization that many human neurodegenerative diseases for which transmissibility has been more or less stringently excluded, may follow pathogenetic principles similar to those of prion diseases. Also, the hypothesis that prion-like phenomena may underlie certain non-genetic traits observed in yeast has resulted in the surprising recognition that the instructional self-propagating changes in protein conformation may be much more prevalent in nature than previously thought. The latter developments have been astonishingly successful, and one could now argue that the prion principle is much more solidly established in yeast than in mammals. PMID:11279534

Aguzzi, A; Heppner, F L

2000-10-01

73

Patterns of subregional mesiotemporal disease progression in temporal lobe epilepsy  

PubMed Central

Objective: Evidence for disease progression in the mesiotemporal lobe is mainly derived from global volumetry of the hippocampus. In this study, we tracked progressive structural changes in the hippocampus, amygdala, and entorhinal cortex in drug-resistant temporal lobe epilepsy at a subregional level. Furthermore, we evaluated the relation between disease progression and surgical outcome. Methods: We combined cross-sectional modeling of disease duration in a large cohort of patients (n = 134) and longitudinal analysis in a subset that delayed surgery (n = 31). To track subregional pathology, we applied surface-shape analysis techniques on manual mesiotemporal labels. Results: Longitudinal and cross-sectional designs showed consistent patterns of progressive atrophy in hippocampal CA1, anterolateral entorhinal, and the amygdalar laterobasal group bilaterally. These regions also exhibited more marked age-related volume loss in patients compared with controls. We found a faster progression of hippocampal atrophy in patients with a seizure frequency ?6 per month. High rates of contralateral entorhinal cortex atrophy predicted postsurgical seizure relapse. Conclusion: We observed progressive atrophy in hippocampal, amygdalar, and entorhinal subregions that frequently display neuronal loss on histology. The bilateral character of cumulative atrophy highlights the importance of early surgery. In patients who nevertheless delay this procedure, serial scanning may provide markers of surgical outcome.

Bernhardt, Boris C.; Kim, Hosung

2013-01-01

74

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

75

Hormonal contraceptive use and risk of HIV-1 disease progression  

PubMed Central

Background For HIV-1 infected women, hormonal contraception prevents unintended pregnancy, excess maternal morbidity, and vertical HIV-1 transmission. Hormonal contraceptives are widely used but their effects on HIV-1 disease progression are unclear. Methods In a prospective study among 2269 chronically HIV-1 infected women from 7 countries in East and southern Africa and with enrollment CD4 counts ?250 cells/mm3, we compared rates of HIV-1 disease progression among those using and not using hormonal contraception (i.e. oral or injectable methods). The primary outcome was a composite endpoint of CD4 decline to <200 cells/mm3, initiation of antiretroviral therapy, or death. Results 372 women experienced HIV-1 disease progression during 3242 years of follow up (incidence rate=11.5 events per 100 person-years). Rates of HIV-1 disease progression among women who were currently using and not using hormonal contraception were 8.54 and 12.31 per 100 person-years, respectively (adjusted hazard ratio [HR] 0.74, 95% CI 0.56–0.98, p=0.04). Rates were 8.58 and 8.39 per 100 person-years for the subsets using injectable and oral contraception (adjusted HR=0.72, p=0.04 for injectable users and adjusted HR=0.83, p=0.5 for oral users compared to women not using hormonal contraception). Sensitivity analyses assessing enrollment or cumulative contraceptive use during the study demonstrated risk estimates closer to 1.0 with no evidence for accelerated disease progression. Conclusions Among African women with chronic HIV-1 infection, use of hormonal contraception was not associated with deleterious consequences for HIV-1 disease progression.

Heffron, Renee; Mugo, Nelly; Ngure, Kenneth; Celum, Connie; Donnell, Deborah; Were, Edwin; Rees, Helen; Kiarie, James; Baeten, Jared M.

2013-01-01

76

[Progress in PDE4 targeted therapy for inflammatory diseases].  

PubMed

cAMP-specific phosphodiesterase type 4 (PDE4) is one of the hot targets for treatment of inflammatory diseases. PDE4 inhibitors can suppress inflammation by increasing the concentration of cAMP in inflammatory cells. The efficacy and safety evaluations of several PDE4 inhibitors are currently carried on in clinical trials, for example GSK256066 in asthma, roflumilast and GSK256066 in chronic obstructive pulmonary disease, tetomilast in inflammatory bowel disease, and apremilast in dermatitis and arthritis etc. This article reviews the recent progress on PDE4-targeted therapy for inflammatory diseases. PMID:24998661

Song, Shun-de; Tang, Hui-Fang

2014-05-25

77

State of progress in treating cystic fibrosis respiratory disease.  

PubMed

Since the discovery of the gene associated with cystic fibrosis (CF), there has been tremendous progress in the care of patients with this disease. New therapies have entered the market and are part of the standard treatment of patients with CF, and have been associated with marked improvement in survival. Now there are even more promising therapies directed at different components of the pathophysiology of this disease. In this review, our current knowledge of the pathophysiology of lung disease in patients with CF is described, along with the current treatment of CF lung disease, and the therapies in development that offer great promise to our patients. PMID:22883684

Flume, Patrick A; Van Devanter, Donald R

2012-01-01

78

Metabolic network as a progression biomarker of premanifest Huntington's disease  

PubMed Central

Background. The evaluation of effective disease-modifying therapies for neurodegenerative disorders relies on objective and accurate measures of progression in at-risk individuals. Here we used a computational approach to identify a functional brain network associated with the progression of preclinical Huntington’s disease (HD). Methods. Twelve premanifest HD mutation carriers were scanned with [18F]-fluorodeoxyglucose PET to measure cerebral metabolic activity at baseline and again at 1.5, 4, and 7 years. At each time point, the subjects were also scanned with [11C]-raclopride PET and structural MRI to measure concurrent declines in caudate/putamen D2 neuroreceptor binding and tissue volume. The rate of metabolic network progression in this cohort was compared with the corresponding estimate obtained in a separate group of 21 premanifest HD carriers who were scanned twice over a 2-year period. Results. In the original premanifest cohort, network analysis disclosed a significant spatial covariance pattern characterized by progressive changes in striato-thalamic and cortical metabolic activity. In these subjects, network activity increased linearly over 7 years and was not influenced by intercurrent phenoconversion. The rate of network progression was nearly identical when measured in the validation sample. Network activity progressed at approximately twice the rate of single region measurements from the same subjects. Conclusion. Metabolic network measurements provide a sensitive means of quantitatively evaluating disease progression in premanifest individuals. This approach may be incorporated into clinical trials to assess disease-modifying agents. Trial registration. Registration is not required for observational studies. Funding. NIH (National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering) and CHDI Foundation Inc.

Tang, Chris C.; Feigin, Andrew; Ma, Yilong; Habeck, Christian; Paulsen, Jane S.; Leenders, Klaus L.; Teune, Laura K.; van Oostrom, Joost C.H.; Guttman, Mark; Dhawan, Vijay; Eidelberg, David

2013-01-01

79

Impact of Mast Cell Chymase on Renal Disease Progression  

PubMed Central

Chymase, a serine protease found in mast cell granules, is released into the interstitium following injury or inflammation. Chymase is the primary ACE-independent pathway of angiotensin II formation, and also functions to activate TGF-beta and other promoters of extracellular matrix degradation, thereby playing a role in tissue remodeling. In the diseased kidney, chymase-containing mast cells markedly increase and their density correlates with tubulointerstitial fibrosis severity. Studies in humans support the pathologic role of chymase in diabetic nephropathy, while animal studies form the basis for the importance of increased chymase-dependent angiotensin II formation in progressive hypertensive, diabetic and inflammatory nephropathies. Moreover, humans with kidney disease express chymase in diseased blood vessels in concordance with significantly elevated plasma chymase levels. Conversely, specific chymase inhibitors attenuate angiotensin II production and renal fibrosis in animal models, suggesting their potential therapeutic benefit in human nephropathy, where chymase-containing mast cells accumulate and contribute to progressive disease.

Wasse, Haimanot; Naqvi, Nawazish; Husain, Ahsan

2012-01-01

80

Prostate Cancer Susceptibility Variants Confer Increased Risk of Disease Progression  

PubMed Central

Background Genome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with the risk of prostate cancer. Our objective was to determine whether these SNPs impact progression of prostate cancer. Methods We genotyped 26 SNPs previously associated with prostate cancer risk among 788 aggressive prostate cancer patients who were treated by radical prostatectomy (RP) or radiation therapy (RT). Prostate cancer progression was defined as biochemical recurrence based on post-treatment prostate specific antigen levels >0.3 ng/ml for RP patients or 2 ng/ml increase above the nadir for RT patients, initiation of hormone treatment, or metastases. We assessed the association between independent and combined SNPs and disease progression by Cox proportional hazard regression. Results Five SNPs demonstrated independent associations with prostate cancer progression (rs12621278, rs629242, rs9364554, rs4430796, rs5945572) based on stepwise regression analysis. The strongest SNP was rs12621278 in the ITGA6 locus, which was associated with a 2.4-fold increased risk of progression (P = 0.0003). When considering the sum of risk alleles across these five SNPs, each additional allele was associated with a 29% increase in risk of progression (95% CI = 1.12-1-47). Conclusions We found that five of the recently highlighted prostate cancer susceptibility loci also influence prostate cancer progression beyond known clinicopathological predictors. If confirmed, these genetic variants may help clarify which tumors are likely to progress and require more aggressive treatment in contrast to those that may not have substantial impact on morbidity or mortality. Impact Genetic susceptibility variants for prostate cancer development may also inform disease progression.

Cheng, Iona; Plummer, Sarah J.; Neslund-Dudas, Christine; Klein, Eric A.; Casey, Graham; Rybicki, Benjamin A.; Witte, John S.

2010-01-01

81

Progressive Renal Disease: Fibroblasts, Extracellular Matrix, and Integrins  

Microsoft Academic Search

Progressive renal disease is characterized by expansion of the tubulo-interstitium and accumulation of extracellular matrix within this tissue compartment. Interstitial fibroblasts are the primary producers of the interstitial matrix, and in the evolution of tubulo-interstitial fibrosis these cells undergo changes, namely increased proliferation, differentiation to myofibroblasts, and altered extracellular matrix metabolism, all of which, in other cell types, have been

Jill T. Norman; Leon G. Fine

1999-01-01

82

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.

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

2011-01-01

83

Avoiding permanent atrial fibrillation: treatment approaches to prevent disease progression  

PubMed Central

Atrial fibrillation (AF) is the most common sustained arrhythmia and a major global public health problem due to its associated morbidity, including stroke and heart failure, diminished quality of life, and increased mortality. AF often presents initially in a paroxysmal form and may progress to a more sustained form over time. Evidence from randomized controlled trials suggests that there may be no mortality benefit to using a rhythm control approach in comparison with rate control of AF. Nevertheless, sustained forms of AF may be associated with increased symptoms and cardiovascular morbidity, and consequently they remain an additional target for therapy. The present review evaluates the clinical correlates of arrhythmia progression and risk stratification techniques available to assess probability of AF progression. Further, currently available management options for arrhythmia control in AF are evaluated and their therapeutic effect and efficacy on disease progression are explored.

Shukla, Ashish; Curtis, Anne B

2014-01-01

84

LACK OF SIGMA-1 RECEPTOR EXACERBATES ALS PROGRESSION IN MICE  

PubMed Central

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

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

2013-01-01

85

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

PubMed Central

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 SOD1G93A 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: r2=0.746; females: r2=0.707) and shorter survival times (males: r2=0.680; females: r2=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.—Fidler, J. A., Treleaven, C. M., Frakes, A., Tamsett, T. J., McCrate, M., Cheng, S. H., Shihabuddin, L. S., Kaspar, B. K., Dodge, J. C. Disease progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone.

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.

2011-01-01

86

Exosomes-associated neurodegeneration and progression of Parkinson's disease  

PubMed Central

Growing evidence indicates the role of exosomes in a variety of physiological pathways as conveyors of biological materials from cell-to-cell. However the molecular mechanism(s) of secretion and their interaction with receiving cells are yet unclear. Recently, it is emerging that exosomes are involved in pathological processes as potential carriers in the progression of neurodegenerative pathologies associated with misfolded proteins. In the current review we will discuss some recent findings on the key role of exosomes in the spreading of the aggregated products of ?-synuclein from neuron-to-neuron and of inflammatory response propagation from immune cell-to-cell; we will highlight the implication of exosomes in the neurodegeneration and progression of the disease and the their potential interplay with genes related to Parkinson’s disease. Increasing our knowledge on the cell-to-cell transmissions might provide new insights into mechanism of disease onset and progression and identify novel strategies for diagnosis and therapeutic intervention in Parkinson and other neurodegenerative diseases.

Russo, Isabella; Bubacco, Luigi; Greggio, Elisa

2012-01-01

87

Imaging and CFD in the analysis of vascular disease progression  

NASA Astrophysics Data System (ADS)

Conventional evaluation of the significance of vascular disease has focused on estimates of geometric factors. There is now substantial interest in investigating whether the onset and progression of vascular pathology can be related to hemodynamic factors. Current imaging modalities have excellent capabilities in delineating the geometric boundaries of the vascular lumen. Advanced non-invasive imaging modalities such as Multi Detector CT and MRI are also able to define the extent of disease within the vessel wall and to provide information on the composition of thrombotic and atherosclerotic components. Finally, it is also possible to use imaging techniques to measure flow velocities across the lumen of vessels of interest, and to determine the pulsatile variation of these velocities through the cardiac cycle. Despite these advanced capabilities, imaging alone is unable to determine important features of the vascular hemodynamics such as wall shear stress or pressure distributions. However, the information on lumenal geometry and the inlet and outlet flow conditions can be used as input into numerical simulation models that are able to predict those quantities. These Computational Fluid Dynamics models can be used to predict hemodynamic parameters on a patient-specific basis. It is therefore possible to use non-invasive imaging methods to follow the progression of vascular disease over time, and to relate changes in lumenal and wall structure to calculated hemodynamic descriptors. This approach can be used not only to understand the natural progression of vascular disease, but as a tool to predict the likely outcome of a surgical intervention.

Saloner, David; Acevedo-Bolton, Gabriel; Rayz, Vitaliy; Wintermark, Max; Martin, Alastair; Dispensa, Brad; Young, William; Lawton, Michael; Rapp, Joseph; Jou, Liang-Der

2006-03-01

88

Progress and prospects: stem cells and neurological diseases.  

PubMed

The central nervous system has limited capacity of regenerating lost tissue in slowly progressive, degenerative neurological conditions such as Parkinson's disease (PD), Alzheimer's disease or Huntington's disease (HD), or in acute injuries resulting in rapid cell loss for example, in cerebrovascular damage (for example, stroke) or spinal cord injury. Although the adult brain contains small numbers of stem cells in restricted areas, they do not contribute significantly to functional recovery. Transplantation of stem cells or stem cell-derived progenitors has long been seen as a therapeutic solution to repair the damaged brain. With the advent of the induced pluripotent stem cells technique a new and potentially better source for transplantable cells may be available in future. This review aims to highlight current strategies to replace lost cellular populations in neurodegenerative diseases with the focus on HD and PD and traumatic brain injuries such as stroke, discussing many of the technical and biological issues associated with central nervous system cell transplantation. PMID:20882052

Gögel, S; Gubernator, M; Minger, S L

2011-01-01

89

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

90

Resource use in decompensated heart failure by disease progression categories.  

PubMed

The purpose of this study was to quantify the total hospital resource use for decompensated heart failure according to disease progression categories. Clinical and cost information was obtained from an electronic data repository and chart review. During the 1-year period from June 2002 to June 2003, qualified patients were categorized based on disease progression as (1) new onset, (2) known heart failure, or (3) readmission. The primary outcome variables were total hospital resource use and resource use by services. Analysis of variance, Scheffé analysis for pairwise comparisons, and chi-square analysis were performed to determine differences among groups. Total hospitalization costs are similar whether it is a new diagnosis of heart failure, known diagnosis, or readmission. Among the 3 categories, 5 services contained statistically significant differences in costs (P<.05): echocardiography, electrophysiology, neurodiagnostic, nuclear cardiology, and pharmacy. Careful analysis of hospital resource use by services for heart failure patients provides opportunities for institutional cost containment. PMID:17268207

Kane-Gill, Sandra L; Seybert, Amy L; Lazar, Jessica; Shatzer, Melanie B; Saul, Melissa I; Kirisci, Levent; Murali, Srinivas

2007-01-01

91

The cholinergic hypothesis of Alzheimer's disease: a review of progress  

PubMed Central

Alzheimer's disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer's disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer's disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no "cure" for Alzheimer's disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer's disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.??

Francis, P.; Palmer, A.; Snape, M.; Wilcock, G.

1999-01-01

92

Glutathione dysregulation and the etiology and progression of human diseases  

PubMed Central

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

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

2009-01-01

93

[Can we influence the progression of chronic kidney disease?].  

PubMed

Chronic renal failure does not only involve the risk for the patient of becoming dependent on hemodialysis, but also increases the risk of premature death due to cardiovascular events. In most renal diseases, progressive chronic loss of renal function develops once a critical extent of renal damage has occurred, independent of the course of the underlying renal disease. The key factors driving the progressive loss of renal function are, apart from the underlying nephrological disease, arterial hypertension and diabetes mellitus. The loss of renal function is also promoted by other factors, such as increased intake of dietary proteins, chronic inflammation, smoking, and anemia. With the help of a multimodal therapeutic concept, the progression of chronic renal failure can be delayed effectively. This approach comprises strict blood pressure control with a target blood pressure of 130/80 mmHg in patients with micro-albuminuria and of 120/75 mmHg in patients with proteinuria of >1 g/d. The preferred drugs for the treatment of hypertension are ACE inhibitors and angiotensin receptor blockers. In diabetics with renal insufficiency, target HbA1c levels below 7% are to be aimed for. Dietary protein intake should be restricted to 0.8-1 g/kg body weight/d. Additional therapeutic targets include nicotine abstinence, early treatment of renal anemia, weight reduction, and, if indicated, lipid-lowering therapy. PMID:19590915

Kuhlmann, U; Hoyer, J

2009-07-01

94

Reevaluating measures of disease progression in facioscapulohumeral muscular dystrophy.  

PubMed

Recent advances in the understanding of the molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) have identified potential therapeutic targets. Consequently, an accurate understanding of disease progression in FSHD is crucial for the design of future clinical trials. Data from 228 subjects in 3 clinical trials and 1 natural history study were compared to examine disease progression in FSHD. All studies utilized the same techniques for manual muscle testing and maximum voluntary isometric contraction testing. Both techniques yield a total strength score that can be followed over time as an indicator of disease progression. Whereas natural history data showed a decrease in strength over 1 year, there was an apparent increase in strength at 6 months in 2 of the 3 clinical trials in both the placebo and treatment groups, that persisted for up to 1 year for maximum voluntary isometric contraction testing. Variability estimates from the clinical trial data were consistent with those seen in the natural history data. Patients in clinical trials in FSHD may have better outcomes than those in natural history studies, regardless of treatment assignment, emphasizing the importance of placebo groups and the need for caution when interpreting the strength results of controlled and uncontrolled trials. PMID:23406877

Statland, Jeffrey M; McDermott, Michael P; Heatwole, Chad; Martens, William B; Pandya, Shree; van der Kooi, E L; Kissel, John T; Wagner, Kathryn R; Tawil, Rabi

2013-04-01

95

Risk Factors for Progression of Chronic Kidney Disease  

PubMed Central

Purpose of Review Provides an overview of the identified risk factors for chronic kidney disease (CKD) progression emphasizing the pediatric population. Recent findings Over the past ten years, there have been significant changes to our understanding and study of pre-terminal kidney failure. Recent refinements in the measurement of glomerular filtration rate (GFR) and GFR estimating equations are important tools for identification and association of risk factors for CKD progression in children. In pediatric CKD, lower level of kidney function at presentation, higher levels of proteinuria, and hypertension are known markers for a more rapid decline in GFR. Anemia and other reported risk factors from the pre-genomic era have need for further study and validation. Genome-wide association studies have identified genetic loci which have provided novel genetic risk factors for CKD progression. Summary With cohort studies of children with CKD becoming mature, they have started to yield important refinements to the assessment of CKD progression. While many of the traditional risk factors for renal progression will certainly be assessed, such cohorts will be important for evaluating novel risk factors identified by genome-wide studies.

Staples, Amy; Wong, Craig

2010-01-01

96

Atheroembolic renal disease with rapid progression and fatal outcome.  

PubMed

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

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

2011-02-01

97

Radiation therapy in Hodgkin's disease - decades of steady progress.  

PubMed

The treatment of lymphoproliferative diseases has changed dramatically during the last decades. The improved therapeutic results for this disease group are included among the most important achievements of modern oncohaematology. They are due to better disease staging, use of new markers for risk assessment, patient stratification in separate risk groups, implementation of highly effective chemotherapy (CHT), progress of targeted therapies using monoclonal antibodies, proteasome inhibitors, modern radiation therapy (RT) and supportive care. The achieved progress, especially in the treatment of Hodgkin's disease (HD), is an example of the fundamental dependence of clinical practice on the scientific achievements, mainly in the field of diagnostics and in the two pure anticancer therapeutic modalities: chemo- and radiotherapy. The aim of this article was to discuss the basic variants of RT in the multimodal treatment of HD and the clinical experience accumulated during the last decades. The experience gained in the area of involved field RT (IFRT) and extended field RT (EFRT), both alone or as a part of the combined-therapy protocols, is considered in detail. The role of RT is also discussed as a part of the dose-escalated CHT combined programmes for patients recurring, progressing or partially responding to treatment, carried out mainly as IFRT, total lymphoid irradiation (TLI) or total body irradiation (TBI). Regardless of the already attained achievements of the combined treatment at the present stage of development of oncological knowledge, there is still no consensus with respect to the optimal therapy of HD in children and in adult patients. New trials addressing issues of the best modality, best RT technique, optimal dose of RT, optimal number of cycles and timing of CHT are still needed. The contemporary challenge is to optimize treatment so that it can be accomplished with the least toxicity, lowest cost, and greatest efficiency possible. PMID:20658714

Gocheva, L

2010-01-01

98

[SBMA: a rare disease but a classic ALS mimic syndrome].  

PubMed

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder of lower motor neurons characterized by proximal limb muscular atrophy, bulbar involvement, marked fasciculation, hand tremor and gynaecomastia. SBMA is caused by a CAG-repeat expansion in the androgen receptor gene on the X-chromosome. Due to its mode of transmission, only male are symptomatic and clinical features appear progressively in adulthood. Motor signs and symptoms are restricted to lower motor neuron involvement, in contrast with amyotrophic lateral sclerosis (ALS) characterized by the association with upper motor neuron involvement. The diminution of sensory potential at electroneuromyogram is a major criteria discriminating between SBMA and ALS. Diagnostic confirmation is based on genetic testing. PMID:24785145

Pradat, Pierre-François

2014-05-01

99

PNPLA3 I148M polymorphism and progressive liver disease  

PubMed Central

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

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

2013-01-01

100

PNPLA3 I148M polymorphism and progressive liver disease.  

PubMed

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

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

2013-11-01

101

A transcriptional network underlies susceptibility to kidney disease progression  

PubMed Central

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

Laouari, Denise; Burtin, Martine; Phelep, Aurelie; Bienaime, Frank; Noel, Laure-Helene; Lee, David C; Legendre, Christophe; Friedlander, Gerard; Pontoglio, Marco; Terzi, Fabiola

2012-01-01

102

A transcriptional network underlies susceptibility to kidney disease progression.  

PubMed

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

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

2012-08-01

103

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

104

Effect of maraviroc on HIV disease progression-related biomarkers.  

PubMed

The potential effect of blocking the CCR5 receptor on HIV disease progression biomarkers is not well understood. We showed that an 8-day maraviroc (MVC) monotherapy clinical test (MCT) can be used in selecting patients to receive MVC-containing combined antiretroviral therapy (cART). Using this MCT model, we assessed the effect of MVC on several HIV disease progression biomarkers during the MCT (MVC-specific effect) and following short-term (12-week) cART. We compared 45 patients on MVC monotherapy with a control group of 25 patients on MVC-sparing cART. We found that MVC did not modify any biomarkers in patients that had no virological response after the MCT. MVC-specific effects in patients with virological responses included increased CD8(+) T-cell activation and senescence levels, preservation of an increase in soluble CD14 (sCD14), and a decrease in D dimer levels. After 12 weeks, MVC-containing cART increased CD8(+) T-cell counts and preserved CD4(+) T-cell senescence levels compared with MVC-sparing cART. Moreover, there was a decrease in sCD14 levels in patients that received MVC-containing cART. In conclusion, effects compatible with CD8(+) T-cell redistribution in peripheral blood were observed after MVC therapy. However, MVC was associated with a favorable profile in HIV disease progression biomarkers only in patients with a virological response. These results support a potential clinical benefit of a therapy which includes MVC in HIV-infected patients. PMID:22948867

Romero-Sánchez, M Concepción; Machmach, Kawthar; Gonzalez-Serna, Alejandro; Genebat, Miguel; Pulido, Ildefonso; García-García, María; Alvarez-Ríos, Ana Isabel; Ferrando-Martinez, Sara; Ruiz-Mateos, Ezequiel; Leal, Manuel

2012-11-01

105

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

106

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

PubMed

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

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

2013-12-01

107

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

PubMed Central

Huntington's disease (HD) is caused by a dominant mutation in HTT, the HD gene. This discovery opens possibilities for treatment based on silencing of the disease-causing allele or with compounds that reduce the production of disease-causing mRNA and/or protein. Although additional developments are needed related to the delivery of gene silencing and discovery and development of drugs that reduce disease-causing gene products, these treatments are predicted to be effective since they act by reducing the source of toxicity. The identification of therapies that act by blocking toxicity is conceptually more complicated, as this requires an accurate understanding of the cellular location and the specific molecular dysfunctions that cause the phenotypes of HD, which is not yet available. Though challenges remain, significant progress has been made. Effective disease-modifying treatments will soon be tested and may lead to disease-altering therapies.

Johnson, Carl D.; Davidson, Beverly L.

2010-01-01

108

Cellular Transplantation Alters the Disease Progression in Becker's Muscular Dystrophy  

PubMed Central

Becker's Muscular Dystrophy (BMD) is a dystrophinopathy manifested as progressive muscle degeneration. Autologous Bone Marrow Mononuclear Cells (BMMNCs) have shown some myogenic potential. The paracrine effects of the BMMNCs reduce the inflammation and are thought to reduce muscle degeneration. We treated a 39 year old dental surgeon suffering from BMD. Muscle strength was reduced when measured using modified Medical Research Council's Manual Muscle Testing (mMRC-MMT). Static sitting balance was poor. He was wheelchair dependent for ambulation and moderately independent in Activities of Daily Living (ADL). Functional Independence Measure (FIM) score was 93. Musculoskeletal Magnetic Resonance Imaging (MRI-MSK) showed moderate fatty infiltration in the muscles. Three cellular transplantations were carried out. Clinical assessment and the investigations were repeated. Progressive increase in the muscle strength was noted. Ambulation was independent using push-knee splints and minimal assistance when weary. Static and dynamic balance in sitting and standing improved. FIM score increased from 93 to 105. There was no increase in the degree of fatty infiltration, as seen on the MRI-MSK. The case study provides evidence for the putative benefits of cellular therapy in altering the disease progression in BMD. It also suggests augmented clinical benefits of combination of cellular therapy and rehabilitation.

Sharma, Alok; Sane, Hemangi; Bhagawanani, Khushboo; Gokulchandran, Nandini; Badhe, Prerna

2013-01-01

109

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

110

Modeling Alzheimer's Disease Progression Using Disease Onset Time and Disease Trajectory Concepts Applied to CDR-SOB Scores From ADNI  

PubMed Central

Disease-onset time (DOT) and disease trajectory concepts were applied to derive an Alzheimer's disease (AD) progression population model using the clinical dementia rating scale—sum of boxes (CDR-SOB) from the AD neuroimaging initiative (ADNI) database. The model enabled the estimation of a DOT and a disease trajectory for each patient. The model also allowed distinguishing fast and slow-progressing subpopulations according to the functional assessment questionnaire, normalized hippocampal volume, and CDR-SOB score at study entry. On the basis of these prognostic factors, 81% of the mild cognitive impairment (MCI) subjects could correctly be assigned to slow or fast progressers, and 77% of MCI to AD conversions could be predicted whereas the model described correctly 84% of the conversions. Finally, synchronization of the biomarker-time profiles on estimated individual DOT virtually expanded the population observation period from 3 to 8 years. DOT-disease trajectory model is a powerful approach that could be applied to many progressive diseases.

Delor, I; Charoin, J-E; Gieschke, R; Retout, S; Jacqmin, P

2013-01-01

111

Evaluating Alzheimer's Disease Progression Using Rate of Regional Hippocampal Atrophy  

PubMed Central

Alzheimer’s disease (AD) is characterized by neurofibrillary tangle and neuropil thread deposition, which ultimately results in neuronal loss. A large number of magnetic resonance imaging studies have reported a smaller hippocampus in AD patients as compared to healthy elderlies. Even though this difference is often interpreted as atrophy, it is only an indirect measurement. A more direct way of measuring the atrophy is to use repeated MRIs within the same individual. Even though several groups have used this appropriate approach, the pattern of hippocampal atrophy still remains unclear and difficult to relate to underlying pathophysiology. Here, in this longitudinal study, we aimed to map hippocampal atrophy rates in patients with AD, mild cognitive impairment (MCI) and elderly controls. Data consisted of two MRI scans for each subject. The symmetric deformation field between the first and the second MRI was computed and mapped onto the three-dimensional hippocampal surface. The pattern of atrophy rate was similar in all three groups, but the rate was significantly higher in patients with AD than in control subjects. We also found higher atrophy rates in progressive MCI patients as compared to stable MCI, particularly in the antero-lateral portion of the right hippocampus. Importantly, the regions showing the highest atrophy rate correspond to those that were described to have the highest burden of tau deposition. Our results show that local hippocampal atrophy rate is a reliable biomarker of disease stage and progression and could also be considered as a method to objectively evaluate treatment effects.

Franko, Edit; Joly, Olivier

2013-01-01

112

Evaluating Alzheimer's disease progression using rate of regional hippocampal atrophy.  

PubMed

Alzheimer's disease (AD) is characterized by neurofibrillary tangle and neuropil thread deposition, which ultimately results in neuronal loss. A large number of magnetic resonance imaging studies have reported a smaller hippocampus in AD patients as compared to healthy elderlies. Even though this difference is often interpreted as atrophy, it is only an indirect measurement. A more direct way of measuring the atrophy is to use repeated MRIs within the same individual. Even though several groups have used this appropriate approach, the pattern of hippocampal atrophy still remains unclear and difficult to relate to underlying pathophysiology. Here, in this longitudinal study, we aimed to map hippocampal atrophy rates in patients with AD, mild cognitive impairment (MCI) and elderly controls. Data consisted of two MRI scans for each subject. The symmetric deformation field between the first and the second MRI was computed and mapped onto the three-dimensional hippocampal surface. The pattern of atrophy rate was similar in all three groups, but the rate was significantly higher in patients with AD than in control subjects. We also found higher atrophy rates in progressive MCI patients as compared to stable MCI, particularly in the antero-lateral portion of the right hippocampus. Importantly, the regions showing the highest atrophy rate correspond to those that were described to have the highest burden of tau deposition. Our results show that local hippocampal atrophy rate is a reliable biomarker of disease stage and progression and could also be considered as a method to objectively evaluate treatment effects. PMID:23951142

Frankó, Edit; Joly, Olivier

2013-01-01

113

Predicting disease progression in Alzheimer's disease: the role of neuropsychiatric syndromes on functional and cognitive decline.  

PubMed

Patients with Alzheimer's disease (AD) have heterogeneous rates of disease progression. The aim of the current study is to investigate whether neuropsychiatric disturbances predict cognitive and functional disease progression in AD, according to failure theory. We longitudinally examined 177 memory-clinic AD outpatients (mean age = 73.1, SD = 8.1; 70.6% women). Neuropsychiatric disturbances at baseline were categorized into five syndromes. Patients were followed for up to two years to detect rapid disease progression defined as a loss of ? 1 abilities in Activities of Daily living (ADL) or a drop of ? 5 points on Mini-Mental State Examination (MMSE). Hazard ratios (HR) were calculated with Gompertz regression, adjusting for sociodemographics, baseline cognitive and functional status, and somatic comorbidities. Most patients (74.6%) exhibited one or more neuropsychiatric syndromes at baseline. The most common neuropsychiatric syndrome was Apathy (63.8%), followed by Affective (37.3%), Psychomotor (8.5%), Manic (7.9%), and Psychotic (5.6%) syndromes. The variance between the observed (Kaplen Meier) and predicted (Gompertz) decline for disease progression in cognition (0.30, CI = 0.26-0.35), was higher than the variance seen for functional decline (0.22, CI = 0.18-0.26). After multiple adjustment, patients with the Affective syndrome had an increased risk of functional decline (HR = 2.0; CI = 1.1-3.6), whereas the risk of cognitive decline was associated with the Manic (HR = 3.2, CI = 1.3-7.5) syndrome. In conclusion, specific neuropsychiatric syndromes are associated with functional and cognitive decline during the progression of AD, which may help with the long-term planning of care and treatment. These results highlight the importance of incorporating a thorough psychiatric examination in the evaluation of AD patients. PMID:21157019

Palmer, Katie; Lupo, Federica; Perri, Roberta; Salamone, Giovanna; Fadda, Lucia; Caltagirone, Carlo; Musicco, Massimo; Cravello, Luca

2011-01-01

114

Slowing chronic kidney disease progression: results of prospective clinical trials in adults  

Microsoft Academic Search

Chronic kidney disease is generally thought to be a progressive disorder regardless of etiology. Over the past 15 years, investigations\\u000a into the mechanisms of disease progression and treatment designed to slow or halt disease progression have been conducted,\\u000a largely in the adult kidney disease population. Intervention trials have demonstrated that lowering blood pressure in hypertensive\\u000a patients and administration of drugs that

Robert D. Toto

2008-01-01

115

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.

2011-01-01

116

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

117

Blood Platelets in the Progression of Alzheimer's Disease  

PubMed Central

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.

Gowert, Nina S.; Donner, Lili; Chatterjee, Madhumita; Eisele, Yvonne S.; Towhid, Seyda T.; Munzer, 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

118

Identification of potential biomarkers of disease progression in bovine tuberculosis.  

PubMed

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

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

2014-08-15

119

Disease Progression in HIV-1-Infected Viremic Controllers  

PubMed Central

Background The mechanism of CD4+ T-cell decline in HIV-1 infection is unclear, but the association with plasma viral RNA load suggests viral replication is involved. Indeed, viremic controller patients with low viral RNA loads typically maintain high CD4+ T-cell counts. Within a local cohort of 86 viremic controllers, we identify a subgroup (18 “discord controllers”) with low CD4+ T-cell counts that present clinical uncertainty. The underlying mechanism accounting for CD4+ T-cell decline in the face of low or undetectable plasma (RNA) viral load remains unresolved. The objective of this study was to investigate the viral and host immune system dynamics in discord controllers by measuring cellular HIV-1 DNA load, T-cell populations, and T-cell activation markers. Methods We compared discord controllers (viral RNA load <2000 copies/mL, <450 CD4+ T-cells/mm3) with typical controllers (viral RNA load <2000 copies/mL, >450 CD4+ T-cells/mm3) and progressors (viral RNA load >10,000 copies/mL, <450 CD4+ T-cells/mm3). We quantified CD4+/CD8+ naive/central memory/effector memory subsets (CD45RA/RO ± CD62L), activation levels (CD38+HLA-DR+), and HIV-1 DNA load. Results Discord controllers resembled progressors showing high viral DNA load, depletion of naive CD4+ T-cells, and higher activation in all CD4+ T-cell subsets, compared with typical controllers. They were similar to typical controllers with lower CD8+ T-cell activation compared with progressors. Conclusions Our data are consistent with a relationship between CD4+ T-cell activation and disease progression. HIV-1 DNA load may be a better marker of viral replication and disease progression than viral RNA load. Lower level CD8+ T-cell activation correlates with low viral RNA load but not with disease progression or viral DNA load.

Groves, Katherine C.; Bibby, David F.; Clark, Duncan A.; Isaksen, Are; Deayton, Jane R.; Anderson, Jane; Orkin, Chloe; Stagg, Andrew J.; McKnight, Aine

2013-01-01

120

Role of Genetic Changes in the Progression of Cardiovascular Diseases  

PubMed Central

This review aims to investigate the role of genetic changes in the development of cardiovascular diseases [CVD]. Oxidation of Low density Lipoprotein (LDL) and mutations in LDL receptors gene are a trigger for numerous of atherogenic events. Also, endothelial nitric oxide synthase (eNOS) plays an important role in vasodilatation of blood vessels through synthesis of nitric oxide. Three single base pair changes, 786T/C, 922A/G, and 1468T/A, have been identified in the promoter region of the eNOS gene and are associated with coronary spasm. Moreover, two distinct variable nucleotide tandem repeats (VNTRs) in introns 4 and 13 have been detected. The presence of a minimum of 38 CA repeats in intron 13 has been associated with an independent 2.2-fold increase in the risk of coronary artery disease [CAD]. Plasma glutathione peroxidase (GPx-3) maintains the vascular bioavailability of nitric oxide (NO), through depletion of reactive oxygen species. Mutation(s) or polymorphism(s) in the plasma GPx-3 gene promoter may predispose to a thrombotic disorder, and constitute a genetic risk factor for thrombotic cerebrovascular disease. Hyperhomocysteinemia is another independent risk factor for atherosclerosis and arterial thrombosis. Severe hyperhomocysteinemia could be caused by cystathionine-?-synthase enzyme deficiency but it could be due to homozygosity of a common 677C/T point mutation in the coding region of the methylenetetrahydrofolate reductase (MTHFR) gene as a 3-fold increase in risk of CAD is associated with the MTHFR 677TT genotype. A second common variant in MTHFR 1298A/C is associated with decreased enzyme activity in vitro and in vivo, especially when occurring simultaneously with the 677 C/T polymorphism. Elevated fibrinogen, an essential component of the coagulation system, has been most consistently associated with arterial thrombotic disorders. Several polymorphisms (148C/T, 455G/A, and -854G/A) have been identified in the genes encoding the 3 pairs of fibrinogen polypeptide chains. The -455G/A, and -854G/A substitutions are the most physiologically relevant mutations. In addition the -455A allele has been associated with the progression of atheroma, and also with a 2.5-fold increase in risk of multiple lacunar infarcts in a cohort of elderly patients with stroke. It is concluded that genetic changes in the previously mentioned genes could play a significant role in the initiation and progression of CVD. This review provides useful information for both physicians and medical students whom are interested in human genetics which is related to cardiovascular diseases.

Sheweita, S. A.; Baghdadi, H.; Allam, A. R.

2011-01-01

121

Distinct patterns of sirtuin expression during progression of Alzheimer's disease.  

PubMed

Aging is one of the major risk factors for Alzheimer's disease (AD). Sirtuins are associated with prolonged life span. To examine whether the expression levels of sirtuins associate with the progression of AD or not, we performed a comparative immunoblotting and immunohistochemical study of SIRT1, 3, and 5 in the entorhinal cortex and hippocampal subregions and white matter in 45 cases grouped according to Braak and Braak stages of neurofibrillary degeneration. In addition, we compared the expression levels with the local load of tau and amyloid-beta deposits, evaluated using morphometry. Our study revealed that (1) the neuronal subcellular redistribution of SIRT1 parallels the decrease in its expression, suggesting stepwise loss of neuroprotection dependent on the neuronal population; (2) in contrast to SIRT1 and 3, expression of SIRT5 increases during the progression of AD; (3) which might be related to its appearance in activated microglial cells. The complex patterns of the expression of sirtuins in relation to tissue damage should be taken into account when searching for therapies interacting with sirtuins. PMID:24464653

Lutz, Mirjam I; Milenkovic, Ivan; Regelsberger, Günther; Kovacs, Gabor G

2014-06-01

122

Subthalamic Nucleus Neuronal Firing Rate Increases with Parkinson's Disease Progression  

PubMed Central

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic cells in the central nervous system, in particular the substantia nigra, resulting in an unrelenting loss of motor and non-motor function. Animal models of PD reveal hyperactive neurons in the subthalamic nucleus (STN) that have increased firing rates and bursting activity compared to controls. Although STN activity has been characterized in advanced stage PD patients, it has not been described in early stage PD patients. Here we present the results of STN neuronal recordings from early stage PD patients (Hoehn and Yahr stage II) enrolled in an ongoing clinical trial compared to recordings from age and sex matched advanced PD patients. STN neurons had a significantly lower firing rate in early versus advanced PD (28.7Hz vs. 36.3Hz; p<0.01). The overall activity of the STN was also significantly lower in early versus late PD, as measured by background neuronal noise (12.4mV vs. 14.0mV; p <0.05). No significant difference was identified between groups in the bursting or variability of neuronal firing in the STN, as measured by a burst index or the interspike interval coefficient of variability. The results suggest that neuronal firing in STN increases with PD progression.

Remple, Michael S.; Bradenham, Courtney H.; Kao, C. Chris; Charles, P. David; Neimat, Joseph S.; Konrad, Peter E.

2011-01-01

123

Pluripotent stem cells for Parkinson's disease: progress and challenges  

PubMed Central

Parkinson's disease (PD) is a common debilitating neurodegenerative disease. The motor symptoms of PD are caused mainly by a progressive loss of dopaminergic neurons from the substania nigra, resulting in a loss of dopamine production. Current therapies are palliative and, in the long term, ineffective. In addition, some can result in significant clinical side effects. The relatively localized pathology of PD makes it an ideal candidate for cell replacement therapy. Initial efforts focused on fetal cell transplantation, and significant clinical benefit lasting more than 10 years has been reported in some cases. However, the approach is controversial and results have been inconsistent. Inherent limitations of this approach for widespread use are the limited availability and variability of transplant material. In contrast, the self-renewal and differentiation potential of human pluripotent stem cells (hPSCs) make them a promising alternative cell source for cell replacement therapy for PD. Efforts in the past decade have demonstrated that hPSCs can be induced to differentiate in culture to functional dopaminergic neurons. Studies in delivering these cells into PD animal models have demonstrated survival, engraftment, and behavioral deficit improvements. Several groups are developing these cells with clinical trials in mind. Here, we review the state of the technology and consider the suitability of current manufacturing processes, cell purity, and tumorgenicity for clinical testing.

2013-01-01

124

The Myth of Schizophrenia as a Progressive Brain Disease  

PubMed Central

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

Zipursky, Robert B.

2013-01-01

125

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.

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

126

The effect of angiotensin-converting-enzyme inhibitors on progression of advanced polycystic kidney disease  

Microsoft Academic Search

The effect of angiotensin-converting-enzyme inhibitors on progression of advanced polycystic kidney disease.BackgroundIt is not known whether angiotensin-converting-enzyme (ACE) inhibitors slow the progression of polycystic kidney disease (PKD). We performed a patient-level meta-analysis to compare the effect of antihypertensive regimens, including ACE inhibitors, to those without ACE inhibitors (controls) on kidney disease progression in patients with PKD.MethodsWe analyzed a database of

Tazeen H. Jafar; Paul C. Stark; Christopher H. Schmid; SVEND STRANDGAARD; ANNE-LISE KAMPER; GIUSEPPE MASCHIO; GAVIN BECKER; Ronald D. Perrone; Andrew S. Levey

2005-01-01

127

Analysis of genetic copy number changes in cervical disease progression  

PubMed Central

Background Cervical dysplasia and tumorigenesis have been linked with numerous chromosomal aberrations. The goal of this study was to evaluate 35 genomic regions associated with cervical disease and to select those which were found to have the highest frequency of aberration for use as probes in fluorescent in-situ hybridization. Methods The frequency of gains and losses using fluorescence in-situ hybridization were assessed in these 35 regions on 30 paraffin-embedded cervical biopsy specimens. Based on this assessment, 6 candidate fluorescently labeled probes (8q24, Xp22, 20q13, 3p14, 3q26, CEP15) were selected for additional testing on a set of 106 cervical biopsy specimens diagnosed as Normal, CIN1, CIN2, CIN3, and SCC. The data were analyzed on the basis of signal mean, % change of signal mean between histological categories, and % positivity. Results The study revealed that the chromosomal regions with the highest frequency of copy number gains and highest combined sensitivity and specificity in high-grade cervical disease were 8q24 and 3q26. The cytological application of these two probes was then evaluated on 118 ThinPrep™ samples diagnosed as Normal, ASCUS, LSIL, HSIL and Cancer to determine utility as a tool for less invasive screening. Using gains of either 8q24 or 3q26 as a positivity criterion yielded specificity (Normal +LSIL+ASCUS) of 81.0% and sensitivity (HSIL+Cancer) of 92.3% based on a threshold of 4 positive cells. Conclusions The application of a FISH assay comprised of chromosomal probes 8q24 and 3q26 to cervical cytology specimens confirms the positive correlation between increasing dysplasia and copy gains and shows promise as a marker in cervical disease progression.

2010-01-01

128

Cardiac autoantibodies in dilated cardiomyopathy become undetectable with disease progression.  

PubMed Central

OBJECTIVE: To determine the relation of cardiac autoantibody and disease status in a consecutive series of patients with dilated cardiomyopathy by prospective antibody testing at diagnosis and at follow up. METHODS: Antibody status was assessed by indirect immunofluorescence in 110 patients with dilated cardiomyopathy (85 male, mean (SD) age 44 (13) years) at diagnosis and at follow up (mean (SD) 14 (12) months); in 57 of them cardiac specific anti-alpha myosin antibody titres were also measured by an enzyme-linked immunosorbent assay (ELISA). Patients underwent complete evaluation at diagnosis and clinical and non-invasive assessment at follow up, including exercise testing with maximal oxygen consumption measurements. RESULTS: The frequency of cardiac specific antibodies by immunofluorescence was lower at follow up than at diagnosis (28 (25%) v 11 (10%), P = 0.002). Mean (SEM) anti-alpha myosin antibody titres at follow up were also lower than at diagnosis (0.24 (0.02) v 0.30 (0.02), P = 0.038); 24% of patients at diagnosis and 14% at follow up had an abnormal ELISA result. None of the patients who were negative by immunofluorescence or ELISA at diagnosis became positive at follow up. Presence of antibody at diagnosis was associated with milder symptoms and greater exercise capacity at follow up and persistence of antibody at follow up was associated with stable disease and milder symptoms at diagnosis. CONCLUSIONS: Cardiac specific autoantibodies in dilated cardiomyopathy become undetectable with disease progression; this is a recognised feature of other autoimmune conditions, such as type 1 diabetes. Detection of these antibodies at diagnosis and at follow up may provide a non-invasive marker of early dilated cardiomyopathy.

Caforio, A. L.; Goldman, J. H.; Baig, M. K.; Haven, A. J.; Dalla Libera, L.; Keeling, P. J.; McKenna, W. J.

1997-01-01

129

Role of inflammation in HIV-1 disease progression and prognosis.  

PubMed

Inflammation and immune activation have been thrust to center stage in the understanding of HIV-1 disease pathogenesis and progression. Early work demonstrated that heightened levels of immune activation correlated with the extent of CD4?+?T cell death in lymphoid tissue; however, this concept was not incorporated into the general view of disease pathogenesis. Since these early studies, the extension of life for patients on combination antiretroviral therapies (cART) has heralded a new era of non-AIDS-related diseases and incomplete restoration of immune function. The common link appears to be ongoing inflammation and immune activation. Thus, despite good control of viral loads, persons living with HIV (PLWH) remain at increased risk of inflammatory-associated complications such as cardiovascular disease and certain cancers. HIV-specific mechanisms as well as non-specific generalized responses to infection contribute to ongoing activation of the immune system. An early loss of gastrointestinal (GI) tract mucosal integrity, the pro-inflammatory cytokine milieu, co-infections and marked destruction of lymph node architecture are all factors contributing to the ongoing activation of the immune system as well as impaired immune recovery. It is becoming increasingly evident that the CD4 count and viral load do not provide a complete picture of the underlying state of the immune system. Heightened levels of inflammatory markers have been shown to predict increased mortality and other adverse events. Therefore, it will be important to incorporate these markers into management algorithms as soon as possible. This is particularly relevant in resource-poor countries where difficulties in cART roll-out and access are still encountered and, therefore, a mechanism for prioritizing individuals for therapy would be of value. This review will focus on the closely inter-related concepts of immune activation and inflammation. Both are broad concepts involving the interaction of various key players in the immune system. Importantly, immune activation promotes inflammation and thrombosis and similarly, inflammation and thrombosis induce immune activation. These concepts are thus intricately linked. Studies highlighting the potentially harmful effects of ongoing inflammation/immune activation are reviewed and the contributions of the GI tract "damage" and other co-infections such as CMV are explored. The complications resulting from persistent immune activation include enhanced CD4?+?T cell death, lymphoid tissue destruction, and various pathologies related to chronic inflammation. Ultimately, we envision that the long-term management of the disease will incorporate both the identification and the amelioration of the potentially harmful effects of ongoing immune activation and inflammation. PMID:24479745

Ipp, Hayley; Zemlin, Annalise E; Erasmus, Rajiv T; Glashoff, Richard H

2014-04-01

130

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.

Raja, Karthick Raja Muthu; Hajek, Roman

2013-01-01

131

Urinary Matrix Metalloproteinase Activity in Diabetic Kidney Disease: A Potential Marker of Disease Progression  

PubMed Central

Background Progressive kidney fibrosis, associated with chronic kidney disease (CKD), results from an imbalance in extracellular matrix (ECM) homeostasis. Reduced matrix metalloproteinases (MMP) activity causing lower clearance of ECM proteins has been implicated mainly through an overproduction of tissue inhibitors of metalloproteinases (TIMP), but also by reduced MMP synthesis. We tested the hypothesis that MMP activity can be measured in human urine and can be used as a potential biomarker of the progression of diabetic kidney disease (DKD). Methods An observational prospective study was performed on 102 DKD patients using 21 diabetic patients without kidney disease and 21 healthy volunteers as controls. The Molecular Probes EnzChek Gelatinase/Collagenase Assay Kit were used to determine urinary MMP activity using DQ™ Gelatin (total MMPs), DQ™ Collagen I (interstitial collagenases) and DQ™ Collagen IV (gelatinises) substrates. A broad-spectrum synthetic inhibitor of all MMP, 1,10-phenanthroline, was used to confirm that the proteolytic activity is due to MMP activity. All MMP values were expressed per unit of urine creatinine. Results Overall urinary MMP activity (DQ Gelatin substrate) was significantly elevated in DKD patients (14.76 ± 3.65 ? fl/h/mmol creatinine) compared to diabetes mellitus controls (7.09 ± 2.12 ? fl/h/mmol creatinine) and healthy volunteers (1.87 ± 0.74 ? fl/h/mmol creatinine) (ANOVA p = 0.01). Within the DKD cohort, there was an approximate threefold higher urinary MMP activity in nonprogressive DKD patients compared to those with progressive disease (p = 0.002). The urinary MMP activity:creatinine ratio was significantly higher in normoalbuminuric and microalbuminuric DKD compared to macroalbuminuric DKD. Positive correlations were observed between the rate of total MMP activity and interstitial collagenases (r = 0.75, p < 0.0001) and gelatinases (r = 0.59, p = 0.0001). The accuracy of MMP activity to predict the rate of annual eGFR decline (ROC analysis) was 77% compared to 64% for albuminuria. Conclusions Total MMP activity can be easily measured in human urine. Surprisingly and in contrast to MMP activity in the kidney, urine MMP activity is elevated in DKD. However, there is a significantly lower MMP activity in patients with progressive DKD. ROC analysis demonstrates that single urine MMP activity estimation is superior to albuminuria in predicting DKD patients with progressive disease.

Altemtam, Nagi; Nahas, Meguid El; Johnson, Tim

2012-01-01

132

A review investigating the effect of allopurinol on the progression of kidney disease in hyperuricemic patients with chronic kidney disease.  

PubMed

This communication provides a brief report on the studies evaluating the use of allopurinol for delay of kidney disease progression and a discussion of the current limitations and future research needed. To date, only 5 studies have reported a delay in the progression of kidney disease with allopurinol use; a sixth study is currently underway. Allopurinol does seem to delay the progression of kidney disease as measured by using serum creatinine and glomerular filtration rates in hyperuricemic patients with chronic kidney disease. However, randomized, double-blind, placebo-controlled trials enrolling more patients and controlling for confounding variables are needed to confirm these findings. PMID:23140758

Kabul, Samaneh; Shepler, Brian

2012-12-01

133

In silico regulatory analysis for exploring human disease progression  

PubMed Central

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

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

2008-01-01

134

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.

2014-01-01

135

Identification of Unstable Network Modules Reveals Disease Modules Associated with the Progression of Alzheimer's Disease  

PubMed Central

Alzheimer’s disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid ? and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system.

Kikuchi, Masataka; Ogishima, Soichi; Miyamoto, Tadashi; Miyashita, Akinori; Kuwano, Ryozo; Nakaya, Jun; Tanaka, Hiroshi

2013-01-01

136

The Nrf2 pathway in the progression of renal disease.  

PubMed

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

Zoja, Carlamaria; Benigni, Ariela; Remuzzi, Giuseppe

2014-02-01

137

Bicarbonate therapy for prevention of chronic kidney disease progression.  

PubMed

Kidney injury in chronic kidney disease (CKD) is likely multifactorial, but recent data support that a component is mediated by mechanisms used by the kidney to increase acidification in response to an acid challenge to systemic acid-base status. If so, systemic alkalization might attenuate this acid-induced component of kidney injury. An acid challenge to systemic acid-base status increases nephron acidification through increased production of endothelin, aldosterone, and angiotensin II, each of which can contribute to kidney inflammation and fibrosis that characterizes CKD. Systemic alkalization that ameliorates an acid challenge might attenuate the contributions of angiotensin II, endothelin, and aldosterone to kidney injury. Some small clinical studies support the efficacy of alkalization in attenuating kidney injury and slowing glomerular filtration rate decline in CKD. This review focuses on the potential that orally administered NaHCO? prevents CKD progression and additionally addresses its mechanism of action, side effects, possible complications, dosage, interaction, galenic form description, and contraindications. Current National Kidney Foundation guidelines recommend oral alkali, including NaHCO?(-), in CKD patients with serum HCO?(-) <22 mmol/l. Although oral alkali can be provided by other medications and by base-inducing dietary constituents, oral NaHCO? will be the focus of this review because of its relative safety and apparent efficacy, and its comparatively low cost. PMID:24107852

?oniewski, Igor; Wesson, Donald E

2014-03-01

138

Virus phenotype switching and disease progression in HIV-1 infection.  

PubMed Central

One of the phenotypic distinctions between different strains of human immunodeficiency virus type 1 (HIV-1) has to do with the ability to cause target cells to form large multinucleate bodies known as syncytia. There are two phenotypes according to this characterization: syncytium-inducing (SI) and non-syncytium-inducing (NSI). NSI strains are usually present throughout infection, while SI strains are typically seen at the beginning of the infection and near the onset of AIDS. The late emergence of SI strains is referred to as phenotype switching. In this paper we analyse the factors that lead to phenotype switching and contribute to the dynamics of disease progression. We show that a strong immune system selects for NSI strains while a weak immune system favours SI strains. The model explicitly accounts for the fact that CD4+ cells are both targets of HIV infection and crucial for activating immune responses against HIV In such a model, SI strains can emerge after a long and variable period of NSI dominated infection. Furthermore, versions of the model which do not explicitly account for HIV-specific, activated CD4+ cells do not exhibit phenotype switching, emphasizing the critical importance of this pool of cells.

Callaway, D S; Ribeiro, R M; Nowak, M A

1999-01-01

139

Effects of HMG-CoA reductase inhibitors (statins) on progression of kidney disease  

Microsoft Academic Search

Chronic kidney disease, especially in the setting of proteinuria, is characterized by hyperlipidemia. In animal models, hyperlipidemia causes glomerular foam cells and glomerulosclerosis. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) ameliorates kidney disease in these models. The data of the role of hyperlipidemia in progression of human kidney disease are less clear. Data from small studies in glomerular disease

Linda F Fried

2008-01-01

140

MEMORY PRESERVATION DIET™ © 2005 TO REDUCE RISK AND SLOW PROGRESSION OF ALZHEIMER'S DISEASE (AD)  

Microsoft Academic Search

The Memory Preservation Diet™ (MPD), developed by a multidisciplinary, multi-university team is expected to reduce risk, or delay onset, of Alzheimer's disease (AD) in adults, reduce conversion of persons with progressive Mild Cognitive Impairment (MCI) to AD, and help slow progression of disease in persons who already have symptomatic AD. The MPD is an evidence- based comprehensive diet whose 6

N. B. EMERSON LOMBARDO; L. VOLICER; A. MARTIN; B. WU; X. W. ZHANG

141

Global dynamics of a staged-progression model with amelioration for infectious diseases  

Microsoft Academic Search

We analyze the global dynamics of a mathematical model for infectious diseases that progress through distinct stages within infected hosts with possibility of amelioration. An example of such diseases is HIV\\/AIDS that progresses through several stages with varying degrees of infectivity; amelioration can result from a host's immune action or more commonly from antiretroviral therapies, such as highly active antiretroviral

Hongbin Guo; Michael Y. Li

2008-01-01

142

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

143

Renal endothelin gene expression is increased in remnant kidney and correlates with disease progression  

Microsoft Academic Search

Renal endothelin gene expression is increased in remnant kidney and correlates with disease progression. We previously demonstrated that urinary endothelin excretion is increased in rats with extensive renal mass reduction, a model of progressive renal disease. Here we explored whether the increased urinary endothelin in this model were due to induction of renal pre-pro-endothelin-1 gene and whether changes in endothelin

Silvia Orisio; Ariela Benigni; Isabella Bruzzi; Daniela Corna; Norberto Perico; Carla Zoja; Luca Benatti; Giuseppe Remuzzi

1993-01-01

144

Conscientiousness Predicts Disease Progression (CD4 Number and Viral Load) in People Living With HIV  

Microsoft Academic Search

Objective: Psychosocial factors (e.g., depression, avoidant coping, life stress) have been related to disease progression in HIV. This study examined the relationship between the Big Five Conscientiousness factor and HIV disease progression (CD4 cell and viral load) over 1 year in 119 seropositive participants. The study also examined whether Conscientiousness effects were mediated by adherence, perceived stress, depression, or coping

Conall OCleirigh; Gail Ironson; Alexander Weiss

2007-01-01

145

Therapeutic induction of autophagy to modulate neurodegenerative disease progression  

PubMed Central

There is accumulating evidence that aggregating, misfolded proteins may have an impact on autophagic function, suggesting that this could be a secondary pathological mechanism in many diseases. In this review, we focus on the role of autophagy in four major neurodegenerative diseases: Alzheimer disease (AD), Huntington's disease (HD), Parkinson's disease (PD) and amyotropic lateral sclerosis.

Hochfeld, Warren E; Lee, Shirley; Rubinsztein, David C

2013-01-01

146

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

147

Mechanisms of copper ion mediated Huntington's disease progression.  

PubMed

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 Cu(2+)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

148

Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival.  

PubMed

Delaying clinical disease onset would greatly reduce neurodegenerative disease burden, but the mechanisms influencing early preclinical progression are poorly understood. Here, we show that in mouse models of familial motoneuron (MN) disease, SOD1 mutants specifically render vulnerable MNs dependent on endogenous neuroprotection signaling involving excitability and mammalian target of rapamycin (mTOR). The most vulnerable low-excitability FF MNs already exhibited evidence of pathology and endogenous neuroprotection recruitment early postnatally. Enhancing MN excitability promoted MN neuroprotection and reversed misfolded SOD1 (misfSOD1) accumulation and MN pathology, whereas reducing MN excitability augmented misfSOD1 accumulation and accelerated disease. Inhibiting metabotropic cholinergic signaling onto MNs reduced ER stress, but enhanced misfSOD1 accumulation and prevented mTOR activation in alpha-MNs. Modulating excitability and/or alpha-MN mTOR activity had comparable effects on the progression rates of motor dysfunction, denervation, and death. Therefore, excitability and mTOR are key endogenous neuroprotection mechanisms in motoneurons to counteract clinically important disease progression in ALS. PMID:24094105

Saxena, Smita; Roselli, Francesco; Singh, Katyayani; Leptien, Kerstin; Julien, Jean-Pierre; Gros-Louis, Francois; Caroni, Pico

2013-10-01

149

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

PubMed

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

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

2013-04-15

150

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

151

Glomerular hypertrophy in minimal change disease predicts subsequent progression to focal glomerular sclerosis  

Microsoft Academic Search

Glomerular hypertrophy in minimal change disease predicts subsequent progression to focal glomerular sclerosis. The study sought a diagnostic clue to identify the group of pediatric patients with apparent minimal change disease who subsequently develop focal glomerular sclerosis (FGS). Review of all renal biopsy material at our institutions identified 42 pediatric patients who met the standard criteria for minimal change disease

Agnes Fogo; Edith P Hawkins; Phillip L Berry; Alan D Glick; Myra L Chiang; Robert C MacDonell; Iekuni Ichikawa; Fogo

1990-01-01

152

USAFSAM Cardiovascular Disease Followup Study: 1972 Progress Report.  

National Technical Information Service (NTIS)

Because atherosclerotic heart disease (AHD) causes significant losses of USAF manpower and dollar resources, the USAFSAM Cardiovascular Disease Study was designed to delineate the relationship of serum lipid and lipoprotein levels to the development of AH...

D. A. Clark F. H. Wilson M. F. Allen

1972-01-01

153

Research Finds Link Between Statin Use and Progressive Muscle Disease  

MedlinePLUS

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

154

Weight preserving image registration for monitoring disease progression in lung CT.  

PubMed

We present a new image registration based method for monitoring regional disease progression in longitudinal image studies of lung disease. A free-form image registration technique is used to match a baseline 3D CT lung scan onto a following scan. Areas with lower intensity in the following scan compared with intensities in the deformed baseline image indicate local loss of lung tissue that is associated with progression of emphysema. To account for differences in lung intensity owing to differences in the inspiration level in the two scans rather than disease progression, we propose to adjust the density of lung tissue with respect to local expansion or compression such that the total weight of the lungs is preserved during deformation. Our method provides a good estimation of regional destruction of lung tissue for subjects with a significant difference in inspiration level between CT scans and may result in a more sensitive measure of disease progression than standard quantitative CT measures. PMID:18982686

Gorbunova, Vladlena; Lol, Pechin; Ashraf, Haseem; Dirksen, Asger; Nielsen, Mads; de Bruijne, Marleen

2008-01-01

155

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

PubMed Central

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

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

2014-01-01

156

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

NASA Astrophysics Data System (ADS)

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

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

2014-03-01

157

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

158

Neuropsychiatric Symptoms Are Associated with Progression from Mild Cognitive Impairment to Alzheimer’s Disease  

Microsoft Academic Search

Background: Neuropsychiatric disturbances are common in mild cognitive impairment (MCI). Depression and apathy may identify a subset of MCI subjects at higher risk of progression to Alzheimer’s disease (AD). However, it remains uncertain whether a broader spectrum of psychopathology is associated with progression to AD. Methods: Fifty-one MCI subjects were assessed for neuropsychiatric symptoms using the Neuropsychiatric Inventory. Subjects were

Edmond Teng; Po H. Lu; Jeffrey L. Cummings

2007-01-01

159

Dietary fatty acids and progression of coronary artery disease in men14  

Microsoft Academic Search

We examined associations between dietary fatty acids and progression of coronary artery disease (CAD) in 50 men receiving a lipid-lowering diet or usual care in the St Thomas' Atherosclerosis Regression Study. Nutrient intake was assessed by dietary history and computerized food tables. Progression of CAD over 39 mo, measured by a decrease in minimum absolute width of coronary segments (MinAWS)

Gerald F Watts; Penelope Jackson; Valerie Burke; Barry Lewis

160

Congenital cytomegalovirus: new progress in an old disease  

Microsoft Academic Search

Congenital cytomegalovirus (CMV) is the commonest congenital infection in the developed world with an estimated prevalence of 0.18–6.2% of all births. Despite recognition for many decades of CMV as an important contributor to neurodevelopmental and hearing impairment in infants, little progress has been made with regards to prevention and treatment of this often overlooked infection. In the past ten years,

Suzanne Luck; Mike Sharland

2009-01-01

161

Serum lipoprotein(a) concentrations are related to coronary disease progression without new myocardial infarction.  

PubMed Central

OBJECTIVE--To examine the association between serum lipoprotein(a) and angiographically assessed coronary artery disease progression without new myocardial infarction. PATIENTS AND DESIGN--85 patients with coronary artery disease who underwent serial angiography with an interval of at least two years were studied. Progression of coronary artery disease was defined as an increase in diameter stenosis of 15% or more. Vessels on which angioplasty had been performed were excluded from the analysis. The patients were classified into two groups: a progression group without new myocardial infarction (n = 48) and non-progression group (n = 37). Risk factors including lipoprotein(a) were evaluated to see how they were related to progression without myocardial infarction. RESULTS--There were no differences between the two groups in the following factors: age, gender, the time interval between the angiographic studies, the distribution of the analysed coronary arteries, and history of well established coronary risk factors. Univariate analysis showed that serum lipoprotein(a) (P = 0.0002), cigarette smoking between the studies (P = 0.002), serum high density lipoprotein (P = 0.003), and serum low density lipoprotein (P = 0.01) were related to progression without myocardial infarction. Multivariate analysis selected two independent factors for progression without myocardial infarction: serum lipoprotein(a) (P = 0.003) and serum high density lipoprotein (P = 0.03). CONCLUSIONS--Serum lipoprotein(a) concentrations are closely related to the progression of coronary artery disease without new myocardial infarction. Lipoprotein(a) lowering treatment may be needed to prevent disease progression in patients with coronary artery disease and high serum lipoprotein(a).

Tamura, A.; Watanabe, T.; Mikuriya, Y.; Nasu, M.

1995-01-01

162

Surveillance and control of infectious diseases: progress toward the 1990 objectives.  

PubMed Central

Great progress has been made in the United States in reducing infectious disease mortality. However, infectious diseases remain the greatest cause of morbidity in this country. Newer infectious diseases or agents have been recognized, but newer tools for surveillance and control have also been made available. Specific objectives for the reduction of infectious diseases by 1990 have been set by the Public Health Service. The opportunities appear to be good for achieving by 1990 objectives for nosocomial infections, Legionnaires' disease, tuberculosis, and surveillance and control of infectious diseases. Achievement of the 1990 objectives for hepatitis B, pneumococcal pneumonia, and bacterial meningitis, however, will require both scientific advances and additional resources.

Dowdle, W R

1983-01-01

163

NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: protection against impairments in axonal transport.  

PubMed

NAP (davunetide) is a novel neuroprotective compound with mechanism of action that appears to involve microtubule (MT) stabilization and repair. To evaluate, for the first time, the impact of NAP on axonal transport in vivo and to translate it to neuroprotection in a severe neurodegeneration, the SOD1-G93A mouse model for amyotrophic lateral sclerosis (ALS) was used. Manganese-enhanced magnetic resonance imaging (MRI), estimating axonal transport rates, revealed a significant reduction of the anterograde axonal transport in the ALS mice compared to healthy control mice. Acute NAP treatment normalized axonal transport rates in these ALS mice. Tau hyperphosphorylation, associated with MT dysfunction and defective axonal transport, was discovered in the brains of the ALS mice and was significantly reduced by chronic NAP treatment. Furthermore, in healthy wild type (WT) mice, NAP reversed axonal transport disruption by colchicine, suggesting drug-dependent protection against axonal transport impairment through stabilization of the neuronal MT network. Histochemical analysis showed that chronic NAP treatment significantly protected spinal cord motor neurons against ALS-like pathology. Sequential MRI measurements, correlating brain structure with ALS disease progression, revealed a significant damage to the ventral tegmental area (VTA), indicative of impairments to the dopaminergic pathways relative to healthy controls. Chronic daily NAP treatment of the SOD1-G93A mice, initiated close to disease onset, delayed degeneration of the trigeminal, facial and hypoglossal motor nuclei as was significantly apparent at days 90-100 and further protected the VTA throughout life. Importantly, protection of the VTA was significantly correlated with longevity and overall, NAP treatment significantly prolonged life span in the ALS mice. PMID:23631872

Jouroukhin, Yan; Ostritsky, Regina; Assaf, Yaniv; Pelled, Galit; Giladi, Eliezer; Gozes, Illana

2013-08-01

164

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

165

Effects of Hematopoietic Stem Cell Age on CML Disease Progression.  

National Technical Information Service (NTIS)

CML results from a chromosomal translocation in hematopoietic stem cells (HSC), yet the disease primarily presents as a myeloid hyperplasia with relatively infrequent lymphoid involvement. We proposed that age-associated defects in the potential of HSC to...

K. Dorshkind

2006-01-01

166

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

167

Deletion of galectin-3 exacerbates microglial activation and accelerates disease progression and demise in a SOD1G93A mouse model of amyotrophic lateral sclerosis  

PubMed Central

Galectins are pleiotropic carbohydrate-binding lectins involved in inflammation, growth/differentiation, and tissue remodeling. The functional role of galectins in amyotrophic lateral sclerosis (ALS) is unknown. Expression studies revealed increases in galectin-1 mRNA and protein in spinal cords from SOD1G93A mice, and in galectin-3 and -9 mRNAs and proteins in spinal cords of both SOD1G93A mice and sporadic ALS patients. As the increase in galectin-3 appeared in early presymptomatic stages and increased progressively through to end stage of disease in the mouse, it was selected for additional study, where it was found to be mainly expressed by microglia. Galectin-3 antagonists are not selective and do not readily cross the blood–brain barrier; therefore, we generated SOD1G93A/Gal-3?/? transgenic mice to evaluate galectin-3 deletion in a widely used mouse model of ALS. Disease progression, neurological symptoms, survival, and inflammation were assessed to determine the effect of galectin-3 deletion on the SOD1G93A disease phenotype. Galectin-3 deletion did not change disease onset, but resulted in more rapid progression through functionally defined disease stages, more severely impaired neurological symptoms at all stages of disease, and expiration, on average, 25 days earlier than SOD1G93A/Gal-3+/+ cohorts. In addition, microglial staining, as well as TNF-?, and oxidative injury were increased in SOD1G93A/Gal-3?/? mice compared with SOD1G93A/Gal-3+/+ cohorts. These data support an important functional role for microglial galectin-3 in neuroinflammation during chronic neurodegenerative disease. We suggest that elevations in galectin-3 by microglia as disease progresses may represent a protective, anti-inflammatory innate immune response to chronic motor neuron degeneration.

Lerman, Bruce J; Hoffman, Eric P; Sutherland, Margaret L; Bouri, Khaled; Hsu, Daniel K; Liu, Fu-Tong; Rothstein, Jeffrey D; Knoblach, Susan M

2012-01-01

168

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.

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

2013-01-01

169

Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis.  

PubMed

Mutations in copper/zinc superoxide dismutase (SOD1) cause a form of familial amyotrophic lateral sclerosis (ALS). The pathogenesis of familial ALS may be associated with aberrant copper chemistry through a cysteine residue in mutant SOD1. Ammonium tetrathiomolybdate (TTM) is a copper-chelating drug that is capable of removing a copper ion from copper-thiolate clusters, such as SOD1. We found that TTM exerted therapeutic benefits in a mouse model of familial ALS (SOD1(G93A)). TTM treatment significantly delayed disease onset, slowed disease progression and prolonged survival by approximately 20%, 42% and 25%, respectively. TTM also effectively depressed the spinal copper ion level and inhibited lipid peroxidation, with a significant suppression of SOD1 enzymatic activity in SOD1(G93A). These results support the hypothesis that aberrant copper chemistry through a cysteine residue plays a critical role in mutant SOD1 toxicity and that TTM may be a promising therapy for familial ALS with SOD1 mutants. PMID:18617166

Tokuda, Eiichi; Ono, Shin-ichi; Ishige, Kumiko; Watanabe, Shunsuke; Okawa, Eriko; Ito, Yoshihisa; Suzuki, Takashi

2008-09-01

170

Gender Differences in HIV Progression to AIDS and Death in Industrialized Countries: Slower Disease Progression Following HIV Seroconversion in Women  

Microsoft Academic Search

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

Inmaculada Jarrin; Ronald Geskus; Krishnan Bhaskaran; Maria Prins; Roberto Muga; Ildefonso Hernandez-Aguado; Laurence Meyer

171

Whole brain atrophy rate predicts progression from MCI to Alzheimer's disease.  

PubMed

For both clinical and research reasons, it is essential to identify which mild cognitive impairment (MCI) subjects subsequently progress to Alzheimer's disease (AD). The prediction may be facilitated by accelerated whole brain atrophy exhibited by AD subjects. Iterative principal component analysis (IPCA) was used to characterize whole brain atrophy rates using sequential MRI scans for 102 MCI subjects from the Kuopio University Hospital. We modelled the likelihood of progression to probable AD, and found that each additional percent of annualized whole brain atrophy rate was associated with a higher odds ratio (OR) of progression (OR=1.30, p=0.01, 95% CI=1.05-1.60). Our study demonstrates an association between whole brain atrophy rate and subsequent rate of clinical progression from MCI to AD. These findings suggest that IPCA could be an effective brain-imaging marker of progression to AD and useful tool for the evaluation of disease-modifying treatments. PMID:18829136

Spulber, Gabriela; Niskanen, Eini; MacDonald, Stuart; Smilovici, Oded; Chen, Kewei; Reiman, Eric M; Jauhiainen, Anne M; Hallikainen, Merja; Tervo, Susanna; Wahlund, Lars-Olof; Vanninen, Ritva; Kivipelto, Miia; Soininen, Hilkka

2010-09-01

172

A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease  

Microsoft Academic Search

Background: Chronic kidney diseases, particularly if presenting with significant proteinuria, are commonly associated with substantial alteration of serum lipid levels. Experimental evidence suggests that lipid abnormalities may contribute to the progression of kidney disease. However, studies in humans on the subject are scarce. Methods: In a prospective, controlled open-label study, the authors have evaluated the effects of one-year treatment with

Stefano Bianchi; Roberto Bigazzi; Alberto Caiazza; Vito M. Campese

2003-01-01

173

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

174

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

175

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

176

From secondary to primary prevention of progressive renal disease: The case for screening for albuminuria  

Microsoft Academic Search

From secondary to primary prevention of progressive renal disease: The case for screening for albuminuria. Many subjects nowadays present with end-stage renal failure and its attendant cardiovascular complications without known prior renal damage. In this report we review the evidence available to strongly suggest that the present practice of secondary prevention in those with known prior renal disease should be

Paul E. de Jong; Barry M. Brenner

2004-01-01

177

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

178

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

179

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.

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

2013-01-01

180

Agency for Toxic Substances and Disease Registry Releases First Set of Data from National ALS Registry  

MedlinePLUS

... Substances and Disease Registry releases first set of data from National ALS Registry About 4 in 100, ... in the United States, according to the first data summary released today by the Agency for Toxic ...

181

Searching for reliable premortem protein biomarkers for prion diseases: progress and challenges to date.  

PubMed

Prion diseases are a unique family of fatal neurodegenerative diseases caused by abnormal folding of normal cellular prion proteins in the brain. Due to the high risk of prion disease transmission and the lack of effective treatment to cure or delay the disease progression, prion diseases pose a serious threat to public health. To control and prevent prion diseases, an early diagnosis is urgently needed. Proteomic analysis has emerged as a powerful technology to decipher biological and pathophysiological processes and identify protein biomarkers indicative of disease. In this article, the authors review the use of the latest proteomic technologies for the identification of promising prion disease biomarkers, the challenges that exist in biomarker development pipelines and the new directions for utilizing proteomics for future biomarker discovery in the context of prion disease diagnostics. PMID:22809206

Ma, Di; Li, Lingjun

2012-06-01

182

Progress Report on Alzheimer's Disease, 2003: Research Advances at NIH.  

National Technical Information Service (NTIS)

The National Institute on Aging (NIA), part of the Federal Government's National Institutes of Health (NIH), has primary responsibility for basic research in Alzheimer's disease (AD) as well as research aimed at finding ways to prevent and treat AD. The I...

2004-01-01

183

SCIENTIFIC KNOWLEDGE AND PROGRESS IN CONTROL OF PARASITIC DISEASES  

Microsoft Academic Search

Human and animal parasites are known since the most remote antiquity. Chinese and Egyptian documents from thousands of years ago refers to ticks, mosquitoes, louses, round and flat worms etc.. However, it is curious to observe that the relation between parasites and disease is relatively recent, dating from the turning of the 19th to the 20th century. This came with

Luiz Hildebrando; Pereira da Silva

184

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

PubMed

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

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

2011-01-01

185

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

PubMed Central

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

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

2011-01-01

186

Rapidly Progressive Cardiac Manifestation of Beh?et's Disease Involving Conduction System and Aortic Valve  

PubMed Central

Cardiac conduction system impairment is a rare clinical manifestation of Behçet's disease. We report a patient who showed 1st degree atrioventricular block at first presentation, and showed aggravated finding of 3rd degree atrioventricular block on five months later. His cardiac manifestation finally developed to acute severe aortic regurgitation on six months later from his first cardiac manifestation. We observed this rapid progression during 6 months and successfully improved symptom and disease severity of the patient with treatment targeting Behçet's disease.

Yu, Jin Sok; Ji, Eun Hye; Kwon, Hee Sun; Kim, Jin Seok; Choi, Kyu Young; Kwon, Beom June; Kim, Dong Bin; Jang, Seong Won; Kim, Jae Hyung

2011-01-01

187

Cycad neurotoxins, consumption of flying foxes, and ALS-PDC disease in Guam.  

PubMed

The Chamorro people of Guam have been afflicted with a complex of neurodegenerative diseases (now known as ALS-PDC) with similarities to ALS, AD, and PD at a far higher rate than other populations throughout the world. Chamorro consumption of flying foxes may have generated sufficiently high cumulative doses of plant neurotoxins to result in ALS-PDC neuropathologies, since the flying foxes forage on neurotoxic cycad seeds. PMID:11914415

Cox, Paul Alan; Sacks, Oliver W

2002-03-26

188

Resting-state functional connectivity as a marker of disease progression in Parkinson's disease: A longitudinal MEG study?  

PubMed Central

The assessment of resting-state functional connectivity has become an important tool in studying brain disease mechanisms. Here we use magnetoencephalography to longitudinally evaluate functional connectivity changes in relation to clinical measures of disease progression in Parkinson's disease (PD). Using a source-space based approach with detailed anatomical mapping, functional connectivity was assessed for temporal, prefrontal and high order sensory association areas known to show neuropathological changes in early clinical disease stages. At baseline, early stage, untreated PD patients (n = 12) had lower parahippocampal and temporal delta band connectivity and higher temporal alpha1 band connectivity compared to controls. Longitudinal analyses over a 4-year period in a larger patient group (n = 43) revealed decreases in alpha1 and alpha2 band connectivity for multiple seed regions that were associated with motor or cognitive deterioration. In the earliest clinical stages of PD, delta and alpha1 band resting-state functional connectivity is altered in temporal cortical regions. With disease progression, a reversal of the initial changes in alpha1 and additional decreases in alpha2 band connectivity evolving in a more widespread cortical pattern. These changes in functional connectivity appear to reflect clinically relevant phenomena and therefore hold promise as a marker of disease progression, with potential predictive value for clinical outcome.

Olde Dubbelink, Kim T.E.; Stoffers, Diederick; Deijen, Jan Berend; Twisk, Jos W.R.; Stam, Cornelis J.; Hillebrand, Arjan; Berendse, Henk W.

2013-01-01

189

Molecular Signatures of Amyotrophic Lateral Sclerosis Disease Progression in Hind and Forelimb Muscles of an SOD1G93A Mouse Model  

PubMed Central

Abstract Aims: This study utilized proteomics, biochemical and enzymatic assays, and bioinformatics tools that characterize protein alterations in hindlimb (gastrocnemius) and forelimb (triceps) muscles in an amyotrophic lateral sclerosis (ALS) (SOD1G93A) mouse model. The aim of this study was to identify the key molecular signatures involved in disease progression. Results: Both muscle types have in common an early down-regulation of complex I. In the hindlimb, early increases in oxidative metabolism are associated with uncoupling of the respiratory chain, an imbalance of NADH/NAD+, and an increase in reactive oxygen species (ROS) production. The NADH overflow due to complex I inactivation induces TCA flux perturbations, leading to citrate production, triggering fatty acid synthase (FAS), and lipid peroxidation. These early metabolic changes in the hindlimb followed by sustained and comparatively higher metabolic and cytoskeletal derangements over time precede and may catalyze the progressive muscle wasting in this muscle at the late stage. By contrast, in the forelimb, there is an early down-regulation of complexes I and II that is associated with the reduction of oxidative metabolism, which promotes metabolic homeostasis that is accompanied by a greater cytoskeletal stabilization response. However, these early compensatory systems diminish by a later time point. Innovation: The identification of potential early- and late-stage disease molecular signatures in an ALS model: muscle albumin, complex I, complex II, citrate synthase, FAS, and phosphoinositide 3-kinase functions as diagnostic markers and peroxisome proliferator-activated receptor ? co-activator 1? (PGC1?), Sema-3A, and Rho-associated protein kinase 1 (ROCK1) play the role of disease progression markers. Conclusion: The differing pattern of cellular metabolism and cytoskeletal derangements in the hind and forelimb identifies the potential dysmetabolism/hypermetabolism molecular signatures associated with disease progression, which may serve as diagnostic/disease progression markers in ALS patients. Antioxid. Redox Signal. 17, 1333–1350.

Capitanio, Daniele; Vasso, Michele; Ratti, Antonia; Grignaschi, Giuliano; Volta, Manuela; Moriggi, Manuela; Daleno, Cristina; Bendotti, Caterina; Silani, Vincenzo

2012-01-01

190

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.

2013-01-01

191

Mechanisms of Copper Ion Mediated Huntington's Disease Progression  

Microsoft Academic Search

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

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

2007-01-01

192

Progress of Minimal Residual Disease Studies in Childhood Acute Leukemia  

Microsoft Academic Search

Submorphologic (ie, minimal) residual disease (MRD) can be monitored in virtually all children and adolescents with acute\\u000a myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) using methods such as flow cytometric detection of leukemic immunophenotypes\\u000a or polymerase chain reaction amplification of fusion transcripts, gene mutations, and clonal rearrangements of antigen-receptor\\u000a genes. Numerous studies have demonstrated the clinical importance of measuring

Dario Campana

2010-01-01

193

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

194

Local neuroinflammation and the progression of Alzheimer’s disease  

Microsoft Academic Search

Postmortem immunohistochemical studies have revealed a state of chronic inflammation limited to lesioned areas of brain in\\u000a Alzheimer’s disease. Some key actors in this inflammation are activated microglia (brain macrophages), proteins of the classical\\u000a complement cascade, the pentraxins, cytokines, and chemokines. The inflammation does not involve the adaptive immune system\\u000a or peripheral organs, but is rather due to the phylogenetically

Patrick L. McGeer; Edith G. McGeer

2002-01-01

195

Slowly progressing lower motor neuron disease caused by a novel duplication mutation in exon 1 of the SOD1 gene.  

PubMed

Familial amyotrophic lateral sclerosis accounts for about 5% of all cases of the neurodegenerative disorder amyotrophic lateral sclerosis. Genetic mutations in Cu/Zn superoxide dismutase (SOD1) have been associated with one kind of familial amyotrophic lateral sclerosis (ALS1). We identified a novel duplication mutation in exon 1 of the SOD1 gene in a Japanese family whose members had lower motor neuron diseases. The patients showed slow disease progression, with the onset of lower limb muscle weakness and exertional dyspnea. Some patients had mild motor and sensory neuropathy and/or bladder dysfunction, which is further evidence that SOD1 mutation results in a predominantly lower motor neuron phenotype. PMID:24838187

Nakamura, Akinori; Kuru, Satoshi; Hineno, Akiyo; Kobayashi, Chinatsu; Kinoshita, Tomomi; Miyazaki, Daigo; Ikeda, Shu-Ichi

2014-10-01

196

Progress in gene therapy of dystrophic heart disease  

PubMed Central

The heart is frequently afflicted in muscular dystrophy. In severe cases, cardiac lesion may directly result in death. Over the years, pharmacological and/or surgical interventions have been the mainstay to alleviate cardiac symptoms in muscular dystrophy patients. Although these traditional modalities remain useful, the emerging field of gene therapy has now provided an unprecedented opportunity to transform our thinking/approach in the treatment of dystrophic heart disease. In fact, the premise is already in place for genetic correction. Gene mutations have been identified and animal models are available for several types of muscular dystrophy. Most importantly, innovative strategies have been developed to effectively deliver therapeutic genes to the heart. Dystrophin-deficient Duchenne cardiomyopathy is associated with Duchenne muscular dystrophy (DMD), the most common lethal muscular dystrophy. Considering its high incidence, there has been a considerable interest and significant input in the development of Duchenne cardiomyopathy gene therapy. Using Duchenne cardiomyopathy as an example, here we illustrate the struggles and successes experienced in the burgeoning field of dystrophic heart disease gene therapy. In light of abundant and highly promising data with the adeno-associated virus (AAV) vector, we have specially emphasized on AAV-mediated gene therapy. Besides DMD, we have also discussed gene therapy for treating cardiac diseases in other muscular dystrophies such as limb-girdle muscular dystrophy.

Lai, Y; Duan, D

2013-01-01

197

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

Microsoft Academic Search

BACKGROUND AND AIMSTwin 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.METHODSWe have investigated

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

2001-01-01

198

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

199

Progressive disease following autologous transplantation in patients with chemosensitive relapsed or primary refractory Hodgkin's disease or aggressive non-Hodgkin's lymphoma  

Microsoft Academic Search

To determine the outcome of patients with chemosensitive relapsed or primary refractory Hodgkin's disease (HD) or aggressive non-Hodgkin's lymphoma (NHL) whose disease progresses after autologous stem cell transplantation (ASCT), we reviewed the records of 82 patients with HD and 139 patients with NHL transplanted between 1993 and 2000. Disease progression occurred in 25 patients with HD and 66 patients with

T Kewalramani; S D Nimer; A D Zelenetz; S Malhotra; J Qin; J Yahalom; C H Moskowitz

2003-01-01

200

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

201

Prion protein polymorphisms affect chronic wasting disease progression.  

PubMed

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

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

2011-01-01

202

SPARC Accelerates Disease Progression in Experimental Crescentic Glomerulonephritis  

PubMed Central

Podocytopenia characterizes many forms of glomerular disease, preceding the development of glomerulosclerosis. While detachment of viable podocytes from the underlying glomerular basement membrane is an important mechanism of podocyte loss, the underlying factors involved remain unclear. Secreted protein acidic and rich in cysteine (SPARC), a matricellular protein with counteradhesive properties, is normally expressed at low levels by the podocyte but is markedly increased following podocyte injury. Accordingly, we elucidate the role of SPARC in mediating experimental crescentic glomerulonephritis by inducing passive nephrotoxic nephritis in SPARC+/+ and SPARC?/? mice. By days 4, 7, and 21 following disease induction, podocyte number is better preserved, glomerulosclerosis is ameliorated, and proteinuria is reduced in SPARC?/? mice as compared with SPARC+/+ littermates. Moreover, the preserved podocyte number in SPARC?/? mice correlates with reduced urinary levels of both nephrin and podocin. To establish a causal role for SPARC in mediating detachment, cultured SPARC+/+ and SPARC?/? podocytes were subjected to mechanical strain as well as trypsin digestion, and detachment assays were performed. While podocytes lacking SPARC were more resistant to stretch-induced detachment, stable re-expression of SPARC restored detachment rates to levels comparable with SPARC+/+ podocytes. Taken together, this study proves that SPARC plays a causal role in mediating podocyte detachment and accelerating glomerulosclerosis in experimental crescentic glomerulonephritis.

Sussman, Amy N.; Sun, Tong; Krofft, Ronald M.; Durvasula, Raghu V.

2009-01-01

203

Acute kidney injury: a springboard for progression in chronic kidney disease.  

PubMed

Recently published epidemiological and outcome analysis studies have brought to our attention the important role played by acute kidney injury (AKI) in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). AKI accelerates progression in patients with CKD; conversely, CKD predisposes patients to AKI. This research gives credence to older, well-thought-out wisdom that recovery from AKI is often not complete and is marked by residual structural damage. It also mirrors older experimental observations showing that unilateral nephrectomy, a surrogate for loss of nephrons by disease, compromises structural recovery and worsens tubulointerstitial fibrosis after ischemic AKI. Moreover, review of a substantial body of work on the relationships among reduced renal mass, hypertension, and pathology associated with these conditions suggests that impaired myogenic autoregulation of blood flow in the setting of hypertension, the arteriolosclerosis that results, and associated recurrent ischemic AKI in microscopic foci play important roles in the development of progressively increasing tubulointerstitial fibrosis. How nutrition, an additional factor that profoundly affects renal disease progression, influences these events needs reevaluation in light of information on the effects of calories vs. protein and animal vs. vegetable protein on injury and progression. Considerations based on published and emerging data suggest that a pathology that develops in regenerating tubules after AKI characterized by failure of differentiation and persistently high signaling activity is the proximate cause that drives downstream events in the interstitium: inflammation, capillary rarefaction, and fibroblast proliferation. In light of this information, we advance a comprehensive hypothesis regarding the pathophysiology of AKI as it relates to the progression of kidney disease. We discuss the implications of this pathophysiology for developing efficient therapeutic strategies to delay progression and avert ESRD. PMID:20200097

Venkatachalam, Manjeri A; Griffin, Karen A; Lan, Rongpei; Geng, Hui; Saikumar, Pothana; Bidani, Anil K

2010-05-01

204

Acute kidney injury: a springboard for progression in chronic kidney disease  

PubMed Central

Recently published epidemiological and outcome analysis studies have brought to our attention the important role played by acute kidney injury (AKI) in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). AKI accelerates progression in patients with CKD; conversely, CKD predisposes patients to AKI. This research gives credence to older, well-thought-out wisdom that recovery from AKI is often not complete and is marked by residual structural damage. It also mirrors older experimental observations showing that unilateral nephrectomy, a surrogate for loss of nephrons by disease, compromises structural recovery and worsens tubulointerstitial fibrosis after ischemic AKI. Moreover, review of a substantial body of work on the relationships among reduced renal mass, hypertension, and pathology associated with these conditions suggests that impaired myogenic autoregulation of blood flow in the setting of hypertension, the arteriolosclerosis that results, and associated recurrent ischemic AKI in microscopic foci play important roles in the development of progressively increasing tubulointerstitial fibrosis. How nutrition, an additional factor that profoundly affects renal disease progression, influences these events needs reevaluation in light of information on the effects of calories vs. protein and animal vs. vegetable protein on injury and progression. Considerations based on published and emerging data suggest that a pathology that develops in regenerating tubules after AKI characterized by failure of differentiation and persistently high signaling activity is the proximate cause that drives downstream events in the interstitium: inflammation, capillary rarefaction, and fibroblast proliferation. In light of this information, we advance a comprehensive hypothesis regarding the pathophysiology of AKI as it relates to the progression of kidney disease. We discuss the implications of this pathophysiology for developing efficient therapeutic strategies to delay progression and avert ESRD.

Griffin, Karen A.; Lan, Rongpei; Geng, Hui; Saikumar, Pothana; Bidani, Anil K.

2010-01-01

205

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

PubMed

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

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

2014-05-01

206

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.

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

2014-01-01

207

Serum C-reactive protein and leptin as predictors of kidney disease progression in the Modification of Diet in Renal Disease Study  

Microsoft Academic Search

Serum C-reactive protein and leptin as predictors of kidney disease progression in the Modification of Diet in Renal Disease Study.BackgroundIn vitro and in vivo data suggest that markers of inflammation and nutritional status may be risk factors for the progression of chronic kidney disease.MethodsWe investigated whether higher levels of C-reactive protein (CRP) and leptin were risk factors for progression of

Mark J Sarnak; Anthony Poindexter; Shin-Ru Wang; Gerald J Beck; John W Kusek; Santica M Marcovina; Tom Greene; Andrew S Levey

2002-01-01

208

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

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

2011-01-01

209

Renal gene and protein expression signatures for prediction of kidney disease progression.  

PubMed

Although chronic kidney disease (CKD) is common, only a fraction of CKD patients progress to end-stage renal disease. Molecular predictors to stratify CKD populations according to their risk of progression remain undiscovered. Here we applied transcriptional profiling of kidneys from transforming growth factor-beta1 transgenic (Tg) mice, characterized by heterogeneity of kidney disease progression, to identify 43 genes that discriminate kidneys by severity of glomerular apoptosis before the onset of tubulointerstitial fibrosis in 2-week-old animals. Among the genes examined, 19 showed significant correlation between mRNA expression in uninephrectomized left kidneys at 2 weeks of age and renal disease severity in right kidneys of Tg mice at 4 weeks of age. Gene expression profiles of human orthologs of the 43 genes in kidney biopsies were highly significantly related (R(2) = 0.53; P < 0.001) to the estimated glomerular filtration rates in patients with CKD stages I to V, and discriminated groups of CKD stages I/II and III/IV/V with positive and negative predictive values of 0.8 and 0.83, respectively. Protein expression patterns for selected genes were successfully validated by immunohistochemistry in kidneys of Tg mice and kidney biopsies of patients with IgA nephropathy and CKD stages I to V, respectively. In conclusion, we developed novel mRNA and protein expression signatures that predict progressive renal fibrosis in mice and may be useful molecular predictors of CKD progression in humans. PMID:19465643

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

2009-06-01

210

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

PubMed Central

Although chronic kidney disease (CKD) is common, only a fraction of CKD patients progress to end-stage renal disease. Molecular predictors to stratify CKD populations according to their risk of progression remain undiscovered. Here we applied transcriptional profiling of kidneys from transforming growth factor-?1 transgenic (Tg) mice, characterized by heterogeneity of kidney disease progression, to identify 43 genes that discriminate kidneys by severity of glomerular apoptosis before the onset of tubulointerstitial fibrosis in 2-week-old animals. Among the genes examined, 19 showed significant correlation between mRNA expression in uninephrectomized left kidneys at 2 weeks of age and renal disease severity in right kidneys of Tg mice at 4 weeks of age. Gene expression profiles of human orthologs of the 43 genes in kidney biopsies were highly significantly related (R2 = 0.53; P < 0.001) to the estimated glomerular filtration rates in patients with CKD stages I to V, and discriminated groups of CKD stages I/II and III/IV/V with positive and negative predictive values of 0.8 and 0.83, respectively. Protein expression patterns for selected genes were successfully validated by immunohistochemistry in kidneys of Tg mice and kidney biopsies of patients with IgA nephropathy and CKD stages I to V, respectively. In conclusion, we developed novel mRNA and protein expression signatures that predict progressive renal fibrosis in mice and may be useful molecular predictors of CKD progression in humans.

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

2009-01-01

211

Minimally invasive treatment of Peyronie's disease: evidence-based progress.  

PubMed

Peyronie's disease (PD) is often physically and psychologically devastating for patients, and the goal of treatment is to improve symptoms and sexual function without adding treatment-related morbidity. The potential for treatment-related morbidity after more invasive interventions, e.g. surgery, creates a need for effective minimally invasive treatments. We critically examined the available literature using levels of evidence to determine the reported support for each treatment. Most available minimally invasive treatments lack critical support for effectiveness due to the absence of randomised, placebo-controlled trials (RCTs) or non-significant results after RCTs. Iontophoresis, oral therapies (vitamin E, potassium para-aminobenzoate, tamoxifen, carnitine, and colchicine), extracorporeal shockwave therapy, and intralesional injection with verapamil or nicardipine have shown mixed or negative results. Treatments that have decreased penile curvature deformity in Level 1 or Level 2 evidence-based, placebo-controlled studies include intralesional injection with interferon ?-2b or collagenase clostridium histolyticum. PMID:24447536

Jordan, Gerald H; Carson, Culley C; Lipshultz, Larry I

2014-07-01

212

New progress in endoscopic treatment of esophageal diseases  

PubMed Central

The technique of endoscopic submucosal dissection (ESD), which was developed for en bloc resection of large lesions in the stomach, has been widely accepted for the treatment of the entire gastrointestinal tract. Many minimally invasive endoscopic therapies based on ESD have been developed recently. Endoscopic submucosal excavation, submucosal tunneling endoscopic resection and laparoscopic-endoscopic cooperative surgery have been used to remove submucosal tumors, especially tumors which originate from the muscularis propria of the digestive tract. Peroral endoscopic myotomy has recently been described as a scarless and less invasive surgical myotomy option for the treatment of achalasia. Patients benefit from minimally invasive endoscopic therapy. This article, in the highlight topic series, provides detailed information on the indications and treatments for esophageal diseases.

Zhou, Ping-Hong; Shi, Qiang; Zhong, Yun-Shi; Yao, Li-Qing

2013-01-01

213

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

214

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.

Czaja, Albert J

2014-01-01

215

Postradiation imaging changes in the CNS: how can we differentiate between treatment effect and disease progression?  

PubMed

A familiar challenge for neuroradiologists and neuro-oncologists is differentiating between radiation treatment effect and disease progression in the CNS. Both entities are characterized by an increase in contrast enhancement on MRI and present with similar clinical signs and symptoms that may occur either in close temporal proximity to the treatment or later in the disease course. When radiation-related imaging changes or clinical deterioration are mistaken for disease progression, patients may be subject to unnecessary surgery and/or a change from otherwise effective therapy. Similarly, when disease progression is mistaken for treatment effect, a potentially ineffective therapy may be continued in the face of progressive disease. Here we describe the three types of radiation injury to the brain based on the time to development of signs and symptoms - acute, subacute and late - and then review specific imaging changes after intensity-modulated radiation therapy, stereotactic radiosurgery and brachytherapy. We provide an overview of these phenomena in the treatment of a wide range of malignant and benign CNS illnesses. Finally, we review the published data regarding imaging techniques under investigation to address this well-known problem. PMID:24947265

Walker, Amanda J; Ruzevick, Jake; Malayeri, Ashkan A; Rigamonti, Daniele; Lim, Michael; Redmond, Kristin J; Kleinberg, Lawrence

2014-05-01

216

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

PubMed

Preterm birth is associated with decreased nephron mass and obesity that may impact on kidney disease progression in later life. Our objectives were to examine the relative risks of obesity and preterm birth on the progression of kidney disease in children. In a retrospective cohort study, 80 (44 obese and 36 non-obese) patients with proteinuric kidney disease were studied for disease progression and glomerular histomorphometry. Of the obese, 22 had been born at term (Obese-T) and 22 had been preterm (Obese-PT). Seventeen non-obese children with focal glomerular sclerosis, born at term (NO-FSGS), and 19 non-obese preterm (NO-PT) children, served as controls. Insulin resistance as measured by the homeostatic model assessment (HOMA-IR) was elevated in all obese children. Obese-PT patients had increased risk of renal demise during childhood when compared with Obese-T children [hazard ratio 2.4; 95% Confidence interval (95% CI) 1.1 to 7.1; P = 0.04]. In obese children, although proteinuria often exceeded nephrotic range, average levels of serum albumin remained normal. Preterm patients were more likely to have reduced renal mass (odds ratio 4.7; P = 0.006), but obesity was not a factor. Renal histomorphometry showed glomerulomegaly in obese patients, regardless of birth weight. Obesity and preterm birth appear to impose additive risks for progression of kidney disease in childhood. PMID:19214591

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

2009-07-01

217

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

218

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

PubMed

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

Helmstaedter, C; Elger, C E

2009-10-01

219

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

220

Gene therapy for Parkinson's disease: progress and challenges.  

PubMed

Therapy for Parkinson's disease (PD), a common neurological disorder characterized by pathological degeneration of the nigrostriatal dopaminergic system, remains unsatisfactory. Gene therapy is considered one of the most promising approaches to developing a novel effective treatment for PD. Among the numerous candidate genes that have been tested as therapeutic agents, those encoding tyrosine hydroxylase, guanosine triphosphate cyclohydrolase I and aromatic L-amino acid decarboxylase all boost dopamine production, while glial cell line-derived neurotrophic factor promotes the survival of dopaminergic neurons and is generally believed to possess the greatest potential for successful restoration of the dopaminergic system. The genes encoding vesicular monoamine transporter-2 and glutamic acid decarboxylase have also produced therapeutic effects in animal models of PD. Both viral and non-viral vectors, each with its particular advantages and disadvantages, have been used to deliver these genes into the brain. Whether or not regulatable expression systems are essential to successful gene therapy for PD remains a critical issue in the clinical application of this emerging treatment. Here we review the current status of gene therapy for PD, including the application of control systems for transgene expression in the brain. PMID:15638712

Chen, Qin; He, Yi; Yang, Keyi

2005-02-01

221

Progress in defining the premotor phase of Parkinson's disease.  

PubMed

Several studies have suggested that a variety of non-motor symptoms (NMS) frequently antedate the development of the classical motor symptoms in Parkinson's disease (PD). Some of these premotor symptoms are well known, like REM sleep behaviour disorder, smell loss and constipation and can precede the motor symptoms by years or even decades. The appearance of these symptoms seems to correlate with the neuropathological changes occurring during Braaks stages I to III. Also studies of the nigrostriatal dopaminergic pathways with neuroimaging show that substantia nigra degeneration occurs before motor symptoms onset. Studies on the premotor phase of PD are important for our understanding of when and where does PD start and how it evolves in these initial stages. Several ongoing studies combine clinical, genetic and neuroimaging investigations to study the premotor phase in subjects at high risk for developing such as hyposmic individuals (PARS study) or nonmanifesting carriers of LRRK2 mutations (ASAP Study). The diagnosis of premotor PD remains still elusive but the information becoming available on premotor PD should guide the search for predictive biomarkers and the identification of risk or protective factors for PD. PMID:21679972

Tolosa, Eduardo; Pont-Sunyer, Claustre

2011-11-15

222

Superficial venous thrombosis: disease progression and evolving treatment approaches  

PubMed Central

Treatment of superficial venous thrombosis (SVT) has recently shifted as increasing evidence suggests a higher than initially recognized rate of recurrence as well as concomitant deep venous thrombosis. Traditional therapies aimed at symptom control and disruption of the saphenofemoral junction are being called into question. The incidence of deep venous thrombosis has been reported to be 6%–40%, with symptomatic pulmonary embolism occurring in 2%–13% of patients. Asymptomatic pulmonary embolism is said to occur in up to one third of patients with SVT based on lung scans. The role of anticoagulation, including newer agents, is being elucidated, and surgical disruption of the saphenofemoral junction, while still an option for specific cases, is less frequently used as first-line treatment. The individual risk factors, including history of prior episodes of SVT, the presence of varicosities, and provoking factors including malignancy and hypercoagulable disorders, must all be considered to individualize the treatment plan. Given the potential morbidity of untreated SVT, prompt recognition and understanding of the pathophysiology and sequelae are paramount for clinicians treating patients with this disease. A personalized treatment plan must be devised for individual patients because the natural history varies by risk factor, presence or absence of DVT, and extent of involvement.

Litzendorf, Maria E; Satiani, Bhagwan

2011-01-01

223

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

PubMed

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

Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

2004-07-01

224

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

PubMed Central

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

Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

2004-01-01

225

Hormonal contraceptive use and HIV disease progression among women in Uganda and Zimbabwe  

PubMed Central

Background HIV-infected women need highly effective contraception to reduce unintended pregnancies and mother-to-child HIV transmission. Previous studies report conflicting results regarding the effect of hormonal contraception (HC) on HIV disease progression. Methods HIV-infected women in Uganda and Zimbabwe were recruited immediately after seroconversion; CD4 testing and clinical exams were conducted quarterly. The study endpoint was time to AIDS (two successive CD4 ?200 cells/mm3 or WHO advanced stage 3 or stage 4 disease). We used marginal structural Cox survival models to estimate the effect of cumulative exposure to depot-medroxyprogesterone acetate (DMPA) and oral contraceptives (OC) on time to AIDS. Results 303 HIV-infected women contributed 1,408 person-years (py). 111 women (37%) developed AIDS. Cumulative probability of AIDS was 50% at 7 years and did not vary by country. AIDS incidence was 6.6, 9.3 and 8.8 per 100py for DMPA, OC and non-hormonal users. Neither DMPA (adjusted hazard ratio (AHR) = 0.90; 95% CI 0.76-1.08) nor OCs (AHR =1.07; 95% CI 0.89-1.29) were associated with HIV disease progression. Alternative exposure definitions of HC use during the year prior to AIDS or at time of HIV infection produced similar results. STI symptoms were associated with faster progression while young age at HIV infection (18-24 years) was associated with slower progression. Adding baseline CD4 level and setpoint viral load to models did not change the HC results but subtype D infection became associated with disease progression. Conclusion Hormonal contraceptive use was not associated with more rapid HIV disease progression but older age, STI symptoms and subtype D infection were.

Morrison, Charles S.; Chen, Pai-Lien; Nankya, Immaculate; Rinaldi, Anne; Van Der Pol, Barbara; Ma, Yun-Rong; Chipato, Tsungai; Mugerwa, Roy; Dunbar, Megan; Arts, Eric; Salata, Robert A.

2011-01-01

226

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

227

A protective effect of breastfeeding on the progression of non-alcoholic fatty liver disease  

Microsoft Academic Search

Objective:Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease characterised by accumulation of large-droplet fat in hepatocytes with possible progression to inflammation and fibrosis. Breastfeeding has benefits for child health, both during infancy and later in life, reducing the risk of manifestations of the metabolic syndrome. Here we investigated the association between early type of feeding (breastfed versus

V Nobili; G Bedogni; A Alisi; A Pietrobattista; A Alterio; C Tiribelli; C Agostoni

2009-01-01

228

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 patients with

William D Denney; W. Evans Kemp; Lowell B Anthony; John A Oates; Benjamin F Byrd

1998-01-01

229

Clinical Significance of Occult Hepatitis B Infection in Progression of Liver Disease and Carcinogenesis  

PubMed Central

Occult hepatitis B infection (OBI) is defined as long-lasting persistence of hepatitis B virus (HBV) DNA in the liver of patients with hepatitis B surface antigen (HBsAg)-negative status, with or without serological markers of previous exposure (antibodies to HBsAg and/or to hepatitis B core antigen). Over the past two decades, significant progress has been made in understanding OBI and its clinical implications. OBI as a cause of chronic liver disease in patients with HBsAg-negative status is becoming an important disease entity. In conditions of immunocompetence, OBI is inoffensive in itself and detection of HBV DNA in the liver does not always indicate active hepatitis. However, when other factors that cause liver damage, such as hepatitis C virus infection, obesity and alcohol abuse are present, the minimal lesions produced by the immunological response to OBI might worsen the clinical course of the underlying liver disease. Several lines of evidence suggest that OBI is associated with progression of liver fibrosis and the development of hepatocellular carcinoma in patients with chronic liver disease. The major interest in OBI is primarily associated with the growing, widely discussed evidence of its clinical impact. The aim of this review is to highlight recent data for OBI, with a major focus on disease progression or carcinogenesis in patients with chronic liver disease.

Nishikawa, Hiroki; Osaki, Yukio

2013-01-01

230

Prediction, progression, and outcomes of chronic kidney disease in older adults.  

PubMed

Chronic kidney disease is a large and growing problem among aging populations. Although progression of chronic kidney disease to end-stage renal disease (ESRD) is a costly and important clinical event with substantial morbidity, it appears less frequently in aging people compared with cardiovascular mortality. The measurement of kidney function and management of kidney disease in older individuals remain challenging, partly because the pathophysiologic mechanisms underlying age-related decline in kidney function, the interactions between age and other risk factors in renal progression, and the associations of chronic kidney disease with other comorbidities in older people are understudied and poorly understood. The Association of Specialty Professors, the American Society of Nephrology, the American Geriatrics Society, the National Institute on Aging, and the National Institute of Diabetes and Digestive and Kidney Diseases held a workshop, summarized in this article, to review what is known about chronic kidney disease, identify research gaps and resources available to address them, and identify priority areas for future research. Answers to emerging research questions will support the integration of geriatrics and nephrology and thus improve care for older patients at risk for chronic kidney disease. PMID:19470680

Anderson, Sharon; Halter, Jeffrey B; Hazzard, William R; Himmelfarb, Jonathan; Horne, Frances McFarland; Kaysen, George A; Kusek, John W; Nayfield, Susan G; Schmader, Kenneth; Tian, Ying; Ashworth, John R; Clayton, Charles P; Parker, Ryan P; Tarver, Erika D; Woolard, Nancy F; High, Kevin P

2009-06-01

231

Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics  

Microsoft Academic Search

In chronic kidney disease, functional impairment correlates with tubulointerstitial fibrosis characterised by inflammation, accumulation of extracellular matrix, tubular atrophy and rarefaction of peritubular capillaries. Loss of the microvasculature implies a hypoxic milieu and suggested an important role for hypoxia when the “chronic hypoxia hypothesis” was proposed a decade ago as an explanation for the progressive nature of fibrosis. Recent data

Leon G Fine; Jill T Norman

2008-01-01

232

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

233

Long-term course and mechanisms of progression of renal disease in hemolytic uremic syndrome  

Microsoft Academic Search

Long-term course and mechanisms of progression of renal disease in hemolytic uremic syndrome. In the classic form of hemolytic uremic syndrome associated with toxins of gram-negative enterobacteria, mortality in the acute stage has been lower than 5% since 1978 (data from the Nephrology Committee, Argentine Society of Pediatrics). Children usually die because of severe involvement of the central nervous system,

Horatio A. Repetto

2005-01-01

234

Whole brain atrophy rate predicts progression from MCI to Alzheimer’s disease  

Microsoft Academic Search

For both clinical and research reasons, it is essential to identify which mild cognitive impairment (MCI) subjects subsequently progress to Alzheimer’s disease (AD). The prediction may be facilitated by accelerated whole brain atrophy exhibited by AD subjects. Iterative principal component analysis (IPCA) was used to characterize whole brain atrophy rates using sequential MRI scans for 102 MCI subjects from the

Gabriela Spulber; Eini Niskanen; Stuart MacDonald; Oded Smilovici; Kewei Chen; Eric M. Reiman; Anne M. Jauhiainen; Merja Hallikainen; Susanna Tervo; Lars-Olof Wahlund; Ritva Vanninen; Miia Kivipelto; Hilkka Soininen

2010-01-01

235

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

ERIC Educational Resources Information Center

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

Slaughter, Susan; Bankes, Jane

2007-01-01

236

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

ERIC Educational Resources Information Center

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

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

2010-01-01

237

Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation  

Microsoft Academic Search

Huntington's disease (HD) is a neurodegenerative disorder with complex symptoms dominated by progressive motor dysfunction. Skeletal muscle atrophy is common in HD patients. Because the HD mutation is expressed in skeletal muscle as well as brain, we wondered whether the muscle changes arise from primary pathology. We used R6 ? 2 transgenic mice for our studies. Unlike denervation atrophy, skeletal

Richard R. Ribchester; Derek Thomson; Nigel I. Wood; Tim Hinks; Thomas H. Gillingwater; Thomas M. Wishart; Felipe A. Court; A. Jennifer Morton

2004-01-01

238

Use of predictive markers of HIV disease progression in vaccine trials  

Microsoft Academic Search

Generating broadly neutralizing antibodies with candidate vaccines has remained an elusive goal. Consequently, vaccine candidates developed have aimed at eliciting cell-mediated immune effector activities (CMI) that could delay disease progression, and maybe also limit secondary transmission, by controlling virus replication. There is considerable discussion about what types of endpoints would constitute definable standardized clinical benefit to the individual that would

S. Gurunathan; R. El Habib; L. Baglyos; C. Meric; S. Plotkin; B. Dodet; L. Corey; J. Tartaglia

2009-01-01

239

Search for genes expressed during progression and recovery in the diseased kidney  

Microsoft Academic Search

Kidneys can recovery from some type of injury. After an acute glomerulonephritis or a short-term ischemia, damaged glomerulus or tubules recover their normal structures with proliferation of the survived cells and infiltration of extrarenal cells. On the other hand, a prolonged or continuous injury leads to a progressive renal disease. We have investigated molecular events in reversible and irreversible renal

TOSHIAKI MONKAWA; MATSUHIKO HAYASHI

2005-01-01

240

Telomerase activity and cytogenetic changes in chronic myeloid leukemia with disease progression  

Microsoft Academic Search

Progressive telomere shortening is thought to be important in the regulation of cellular senescence and that the upregulation or reactivation of telomerase activity may be a critical if not rate limiting step in the development of neoplastic cells. To obtain information about telomeres and telomerase activity in hematopoietic neoplasia at various disease stages, we evaluated 54 samples obtained from 41

K Ohyashiki; JH Ohyashiki; H Iwama; S Hayashi; JW Shay; K Toyama

1997-01-01

241

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

242

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, resources, and strong management as well as clear compound progression criteria

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

2009-01-01

243

AAV2\\/1-TNFR:Fc gene delivery prevents periodontal disease progression  

Microsoft Academic Search

Periodontal disease is a chronic inflammatory condition induced by tooth-associated microbial biofilms that induce a host immune response. Therapeutic control of progressive tissue destruction in high-risk patients is a significant challenge in therapy. Soluble protein delivery of antagonists to tumor necrosis factor-? (TNF-?) inhibits alveolar bone resorption due to periodontitis. However, protein therapy raises several concerns, such as recurrence of

J A Cirelli; C H Park; K MacKool; M Taba; K H Lustig; H Burstein; W V Giannobile

2009-01-01

244

Burden of Pancreatic Cancer and Disease Progression: Economic Analysis in the US  

Microsoft Academic Search

Objectives: The few studies that have estimated the costs of pancreatic cancer were limited by small sample sizes, geography or patient age range. Using a large nationwide claims database, this study examines the cost of pancreatic cancer beginning with initial diagnosis and the additional costs when disease progresses. Methods: A retrospective cohort study was conducted using a claims database of

Stella Chang; Stacey R. Long; Lucie Kutikova; Lee Bowman; William H. Crown; Gary H. Lyman

2006-01-01

245

The role of fatty acids in the development and progression of nonalcoholic fatty liver disease  

Microsoft Academic Search

Nonalcoholic fatty liver disease (NAFLD) has emerged as a serious obesity-related disorder. NAFLD encompasses a wide spectrum of hepatic derangements ranging from a surfeit of fat in the liver (steatosis) to lipid surplus accompanied by fibrosis and cellular death (nonalcoholic steatohepatitis or NASH). The most widely accepted model to explain the progression from simple NAFLD to NASH is the “two-hit

Christopher L. Gentile; Michael J. Pagliassotti

2008-01-01

246

Dyslipidemia and progression of kidney disease: role of lipid-lowering drugs.  

PubMed

HMG-CoA reductase inhibitors (statins) have been shown to reduce cardiovascular morbidity in patients with normal and abnormal kidney function but not in patients with end-stage kidney disease. Evidence supports a role for statins in delaying the progression of kidney disease in a variety of experimental models in animals. However, the evidence that statins may retard CKD progression in humans is scant. In this review, we critically consider the available data supporting a role for statins in CKD progression in humans and the possibility that there might be differences among statins in regards to effects on the kidneys. Finally, we review the evidence that statins may increase the risk of acute kidney injury. PMID:24535025

Campese, Vito M

2014-04-01

247

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

SciTech Connect

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

Mohammed, Nasiruddin [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI (United States); Kestin, Larry Llyn, E-mail: lkestin@beaumont.ed [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI (United States); Grills, Inga Siiner; Battu, Madhu; Fitch, Dwight Lamar [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI (United States); Wong, Ching-yee Oliver [Department of Nuclear Medicine, William Beaumont Hospital, Royal Oak, MI (United States); Margolis, Jeffrey Harold [Department of Medical Oncology, William Beaumont Hospital, Royal Oak, MI (United States); Chmielewski, Gary William; Welsh, Robert James [Department of Thoracic Surgery, William Beaumont Hospital, Royal Oak, MI (United States)

2011-02-01

248

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

249

Altered neuronal nitric oxide synthase expression contributes to disease progression in Huntington’s disease transgenic mice  

Microsoft Academic Search

Reduced neuronal NOS (nNOS) expression and biochemical activity was found in the striatum (P<0.05) and cerebellum P<0.05) of late-stage R6\\/1 Huntington’s disease (HD) mice. The changes in NOS biochemical activity correlated with body weight (P<0.001), abnormal clasping (P<0.05) and motor functioning (P<0.05) scores. HD transgenic mice missing both copies of the nNOS gene showed accelerated disease progression relative to HD

A. Wallace Deckel; Vinsee Tang; Diane Nuttal; Keith Gary; Robert Elder

2002-01-01

250

Beta-2 microglobulin is important for disease progression in a murine model for amyotrophic lateral sclerosis  

PubMed Central

Beta-2 microglobulin (?2m) is an essential component of the major histocompatibility complex (MHC) class I proteins and in the nervous system ?2m is predominantly expressed in motor neurons. As ?2m can promote nerve regeneration, we investigated its potential role in amyotrophic lateral sclerosis (ALS) by investigating its expression level as well as the effect of genetically removing ?2m on the disease process in mutant superoxide dismutase 1 (SOD1G93A) mice, a model of ALS. We observed a strong upregulation of ?2m in motor neurons during the disease process and ubiquitous removal of ?2m dramatically shortens the disease duration indicating that ?2m plays an essential and positive role during the disease process. We hypothesize that ?2m contributes to plasticity that is essential for muscle reinnervation. Absence of this plasticity will lead to faster muscle denervation and counteracting this process could be a relevant therapeutic target.

Staats, Kim A.; Schonefeldt, Susann; Van Rillaer, Marike; Van Hoecke, Annelies; Van Damme, Philip; Robberecht, Wim; Liston, Adrian; Van Den Bosch, Ludo

2013-01-01

251

CRP Polymorphisms and Progression of Chronic Kidney Disease in African Americans  

PubMed Central

Background and objectives: Chronic inflammation may play a role in chronic kidney disease (CKD) progression. CRP gene polymorphisms are associated with serum C-reactive protein (CRP) concentrations. It is unknown if CRP polymorphisms are associated with CKD progression or modify the effectiveness of anti-hypertensive therapy in delaying CKD progression. Design, setting, participants, & measurements: We genotyped 642 participants with CKD from the African American Study of Kidney Disease and Hypertension (AASK), selecting five tag polymorphisms: rs2808630, rs1205, rs3093066, rs1417938, and rs3093058. We compared the minor allele frequencies (MAF) of single nucleotide polymorphisms (SNPs) in AASK to MAFs of African Americans from NHANES III. Among AASK participants, we evaluated the association of SNPs with CRP levels and prospectively with a composite: halving the GFR, ESRD, or death. Results: The MAF was higher for the rs2808630_G allele (P = 0.03) and lower for the rs1205_A allele (P = 0.03) in the AASK compared with NHANES III. Among AASK participants, the rs3093058_T allele predicted higher CRP concentrations (P < 0.0001) but not CKD progression. The rs2808630_GG genotype was associated with higher risk of the composite endpoint compared with the AA genotype (P = 0.002). Participants with the rs2808630_GG genotype on angiotensin converting enzyme inhibitors (ACEIs) versus ? blockers had increased risk of progression (P = 0.03). Conclusion: CRP SNPs that were associated with higher levels of CRP did not predict CKD progression. The rs2808630_GG genotype was associated with higher risk of CKD progression, and in patients with this genotype, ACEIs did not slow progression.

Crawford, Dana C.; Griffin, Marie R.; Brown-Gentry, Kristin; Lipkowitz, Michael S.; Siew, Edward D.; Cavanaugh, Kerri; Lewis, Julia B.; Ikizler, T. Alp

2010-01-01

252

[The progress and strategy of molecular diagnosis for human genetic diseases].  

PubMed

Recently, the human genome project has progressed and the responsible genes for many diseases have been discovered. Molecular diagnosis based on gene analysis techniques has developed. In this paper, the methods in molecular diagnosis were explained, taking as examples of several pediatric neurological diseases such as GM1- gangliosidosis, fragile X syndrome and congenital myotonic dystrophy. Next, we stressed the importance of the study on the gene function in related to the gene mutation. Finally the strategy to establish the molecular diagnosis of polygenic diseases, such as mental retardation and autism, was considered. PMID:9545776

Nanba, E

1998-03-01

253

Disease progression and adverse events in patients listed for elective percutaneous coronary intervention  

PubMed Central

Objective: To record disease progression and the timing of adverse events in patients on a waiting list for elective percutaneous coronary intervention (PCI). Design: Observational prospective study. Settings: A UK tertiary cardiothoracic centre, at a time when waiting lists for PCI were up to 18 months. Patients: 145 patients (116 men, median age 59.5 years) placed on an elective waiting list for PCI between October 1998 and September 1999. Main outcome measures: Adverse events recorded were death, myocardial infarction, need for urgent hospital admission because of unstable angina, and need for emergency revascularisation while waiting for PCI. Results: During a median follow up of 10 months (range 1–18 months), nine (6.2%) patients experienced an adverse event. Eight (5.52%) patients were admitted with unstable angina as emergencies. One was admitted with a myocardial infarction. Twenty nine (20.0%) patients had significant disease progression at the time of the repeat angiogram before PCI. In 10 (7%), disease had progressed so that PCI was no longer feasible and patients were referred for coronary artery bypass graft. Sixteen (11%) were removed from the PCI waiting list because of almost complete resolution of their anginal symptoms. Conclusion: Adverse coronary events and clinically significant disease progression occur commonly in patients waiting for PCI. Despite the presence of severe coronary lesions, myocardial infarction was rare and no patients died while on the waiting list. Resolution of anginal symptoms was also comparatively common. The pathophysiology of disease progression frequently necessitates a change in the treatment of patients waiting for PCI.

Talwar, S; Karpha, M; Thomas, R; Vurwerk, C; Cox, I; Burrell, C; Motwani, J; Gilbert, T; Haywood, G

2005-01-01

254

Quantitative evaluation of disease progression in a longitudinal mild cognitive impairment cohort.  

PubMed

Several neuropsychological tests and biomarkers of Alzheimer's disease (AD) have been validated and their evolution over time has been explored. In this study, multiple heterogeneous predictors of AD were combined using a supervised learning method called Disease State Index (DSI). The behavior of DSI values over time was examined to study disease progression quantitatively in a mild cognitive impairment (MCI) cohort. The DSI method was applied to longitudinal data from 140 MCI cases that progressed to AD and 149 MCI cases that did not progress to AD during the follow-up. The data included neuropsychological tests, brain volumes from magnetic resonance imaging, cerebrospinal fluid samples, and apolipoprotein E from the Alzheimer's Disease Neuroimaging Initiative database. Linear regression of the longitudinal DSI values (including the DSI value at the point of MCI to AD conversion) was performed for each subject having at least three DSI values available (147 non-converters, 126 converters). Converters had five times higher slopes and almost three times higher intercepts than non-converters. Two subgroups were found in the group of non-converters: one group with stable DSI values over time and another group with clearly increasing DSI values suggesting possible progression to AD in the future. The regression parameters differentiated between the converters and the non-converters with classification accuracy of 76.9% for the slopes and 74.6% for the intercepts. In conclusion, this study demonstrated that quantifying longitudinal patient data using the DSI method provides valid information for follow-up of disease progression and support for decision making. PMID:24121959

Runtti, Hilkka; Mattila, Jussi; van Gils, Mark; Koikkalainen, Juha; Soininen, Hilkka; Lötjönen, Jyrki

2014-01-01

255

Allelotype of Breast Cancer: Cumulative Alíele Losses Promote Tumor Progression in Primary Breast Cancer1  

Microsoft Academic Search

Alíele loss on a specific chromosome has implied the existence of a tumor suppressor gene such as the p53 gene and the Rlprogression in primary breast cancer, we analyzed the loss of heterozygosity for each autosomal chromosome arm by using 39 restriction fragment length

Takaaki Sato; Akira Tanigami; Kazuhiro Yamakawa; Futoshi Akiyama; Coi Sakamoto; Yusuke Nakamura

1990-01-01

256

Progression of wear in the mild wear regime of an Al18.5% Si (A390) alloy  

Microsoft Academic Search

The mild wear regime of a cast Al-18.5% Si (A390), a lightweight alloy used in automotive components requiring wear resistance, was investigated in order to characterize the progression of the sliding wear processes. Block-on-ring (SAE 52100 steel) type sliding wear tests were conducted under a controlled dry air environment with 5% relative humidity. It was observed that the mild wear

M. Elmadagli; A. T. Alpas

2006-01-01

257

Relationships between age and late progression of Parkinson's disease: a clinico-pathological study.  

PubMed

To investigate the relationships between age, the advanced clinical stages of Parkinson's disease and neuropathology, we surveyed 129 case records from donors with pathologically proven Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders. Cases were separated into five groups according to age at death, thus comparing patients who reached the advanced stage of the disease at different ages. Four milestones of advanced disease (frequent falls, visual hallucinations, dementia and need for residential care) occurred at a similar time from death in each group. There were no significant differences in disease duration across these age groupings, nor were there differences in the severity and distribution of Lewy body and other pathologies. The milestones of dementia (P < 0.0005) and visual hallucinations (P = 0.02) as well as the accumulation of multiple milestones (P < 0.0005) were associated with high cortical Lewy body scores. Demented cases also had significantly more Alzheimer neurofibrillary and amyloid-beta plaque pathology. Correlation analysis showed that the time intervals between disease onset and recording of milestones were strongly influenced by age at onset (P < 0.0001) and by total disease duration (P < 0.0001). The advanced disease phase plays out in a similar fashion at whatever age it occurs, with a common pathological endpoint. The clinico-pathological comparisons for the final stage of Parkinson's disease do support a staging system based on the rostral extent and severity of Lewy body pathology, although other pathologies may play a synergistic role in causing cognitive disability. The chief effects of age on the rate of progression are seen over the early-middle part of the disease. An exponential curve for clinical progression provides the best explanation for these observations about age and the disease course. PMID:20371510

Kempster, Peter A; O'Sullivan, Sean S; Holton, Janice L; Revesz, Tamas; Lees, Andrew J

2010-06-01

258

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

PubMed Central

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

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

2008-01-01

259

Premature Aging of T cells Is Associated With Faster HIV-1 Disease Progression  

PubMed Central

Objective To determine if untreated HIV-1 infection and progression is associated with premature aging of memory CD8+ and CD4+ T cells and naive CD4+ T cells. Methods Twenty HIV-1–infected fast progressors and 40 slow progressors were included in our study, using risk set sampling. The expression of cell surface markers reflecting the differentiation stages of lymphocytes was measured using flow cytometry analyses performed on cryopreserved peripheral blood mononuclear cells. Results We found that HIV-1 disease progression is associated with a decreased CD28 median florescence intensity on CD4+ and CD8+ T cells; an increased proportion of intermediate- and late-differentiated CD8+ T cells and a decreased CD31 median florescence intensity on naive CD4+ T cells of recent thymic origin. A selective depletion of peripherally expanded naive CD4+ T cells was found to be associated with HIV-1 infection but not with HIV-1 disease progression. Conclusions The overall change during HIV-1 infection and progression is associated with a shift in the T-cell population toward an aged conformation, which may be further compromised by impaired renewal of the less-differentiated CD4+ T-cell population. Our results suggest that HIV-1 infection induces an accelerated aging of T lymphocytes, which is associated with the clinical progression to AIDS and death.

Cao, Weiwei; Jamieson, Beth D.; Hultin, Lance E.; Hultin, Patricia M.; Effros, Rita B.; Detels, Roger

2009-01-01

260

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

PubMed

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

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

2006-09-01

261

Progress on stem cell research towards the treatment of Parkinson's disease  

PubMed Central

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of Lewy body inclusions along with selective destruction of dopaminergic (DA) neurons in the nigrostriatal tract of the brain. Genetic studies have revealed much about the pathophysiology of PD, enabling the identification of both biomarkers for diagnosis and genetic targets for therapeutic treatment, which are evolved in tandem with the development of stem cell technologies. The discovery of induced pluripotent stem (iPS) cells facilitates the derivation of stem cells from adult somatic cells for personalized treatment and thus overcomes not only the limited availability of human embryonic stem cells but also ethical concerns surrounding their use. Non-viral, non-integration, or non-DNA-mediated reprogramming technologies are being developed. Protocols for generating midbrain DA neurons are undergoing constant refinement. The iPS cell-derived DA neurons provide cellular models for investigating disease progression in vitro and for screening molecules of novel therapeutic potential and have beneficial effects on improving the behavior of parkinsonian animals. Further progress in the development of safer non-viral/non-biased reprogramming strategies and the subsequent generation of homogenous midbrain DA neurons shall pave the way for clinical trials. A combined approach of drugs, cell replacement, and gene therapy to stop disease progression and to improve treatment may soon be within our reach.

2012-01-01

262

The CJD Neurological Status Scale: A New Tool for Evaluation of Disease Severity and Progression in Creutzfeldt - Jakob disease  

PubMed Central

Objectives To develop a scale sensitive for the neurological manifestations of Creutzfeldt-Jakob disease (CJD). Methods A 26-item CJD neurological status scale (CJD-NS) was created based on characteristic disease manifestations. Each sign was assigned to one of eight neurological systems to calculate a total scale score (TSS) and a system involvement score (SIS). The scale was administered to 37 CJD patients, 101 healthy first-degree relatives of the patients and 14 elderly patients with Parkinson's disease (PD). Results The mean TSS (±SD) was significantly higher in patients with CJD (13.19±5.63) compared to normal controls (0.41±0.78) and PD patients (9.71±3.05). The mean SIS was also significantly different between the CJD (5.19±1.22) and PD (2.78±1.18 p<0.01) groups reflecting the disseminated nature of neurological involvement in CJD. Using a cutoff of TSS>4 yielded a sensitivity of 97% for CJD, and specificity of 100% against healthy controls. All individual items showed excellent specificity against healthy subjects, but sensitivity was highly variable. Repeat assessments of CJD patients over 3-9 months revealed a time-dependent increase of both the TSS and the SIS reflecting the scale's ability to track disease progression. Conclusions The CJD-NS scale is sensitive to neurological signs and their progression in CJD patients.

Cohen, Oren S.; Prohovnik, Isak; Korczyn, Amos D.; Ephraty, Lilach; Nitsan, Zeev; Tsabari, Rakefet; Appel, Shmuel; Rosenmann, Hanna; Kahana, Ester; Chapman, Joab

2011-01-01

263

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

PubMed Central

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

Limpert, Allison S; Mattmann, Margrith E

2013-01-01

264

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

PubMed Central

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.

Fl?yel, 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.; St?rling, Joachim; Pociot, Flemming

2014-01-01

265

Vitamin-D pathway genes and HIV-1 disease progression in injection drug users.  

PubMed

Vitamin-D has pleiotropic effects on calcium and bone metabolism, cellular growth control, cell differentiation and modulation of both innate and acquired immune response. Previous studies revealed the association of vitamin-D receptor gene (VDR) polymorphism with infection diseases including HIV-1 infection. To assess for association between polymorphisms of vitamin-D pathway genes CYP27B1, vitamin-D binding protein (VDBP) and VDR with HIV-1 infection, disease progression to acquired immunodeficiency syndrome (AIDS) was analysed according to CDC93 criteria in a cohort of 185 HIV-1 seroprevalent patients belonging to the injection drug users. Genotype data was obtained from rs10877012, rs3782130 and rs4646536 markers at CYP27B1 locus; rs7041 and rs4588 at VDBP locus; and rs11568820, rs4516035, rs2228570, rs1544410 and rs17878969 at VDR locus. Distribution of genotypes between patients grouped by outcome was compared by contingency table analysis. Marker-marker interaction was assessed by a MDR analysis. Assuming an additive model for VDR markers, a Kaplan-Meier survival analysis was employed to evaluate association with disease progression. Among vitamin-D pathway genes, VDR locus reveals specific 5'UTR and 3'UTR diplotype combinations associated with both, slower and faster progression to AIDS. Marker-marker interaction analysis indicates a strong interaction between VDR markers and a redundant effect for CYP27B1 markers. According to our results, VDR locus association follows an additive model in which increased genetic risk score for the VDR is directly correlated with AIDS progression rates. Our data supports a role of vitamin-D pathway gene variability on HIV-1 disease progression. PMID:24768180

Laplana, Marina; Sánchez-de-la-Torre, Manuel; Puig, Teresa; Caruz, Antonio; Fibla, Joan

2014-07-15

266

Benefit from autologous stem cell transplantation in primary refractory myeloma? Different outcomes in progressive versus stable disease  

PubMed Central

Background Several studies of autologous stem cell transplantation in primary refractory myeloma have produced encouraging results. However, the outcome of primary refractory patients with stable disease has not been analyzed separately from the outcome of patients with progressive disease. Design and Methods In the Spanish Myeloma Group 2000 trial, 80 patients with primary refractory myeloma (49 with stable disease and 31 with progressive disease), i.e. who were refractory to initial chemotherapy, were scheduled for tandem transplants (double autologous transplant or a single autologous transplant followed by an allogeneic transplant). Patients with primary refractory disease included those who never achieved a minimal response (?25% M-protein decrease) or better. Responses were assessed using the European Bone Marrow Transplant criteria. Results There were no significant differences in the rates of partial response or better between patients with stable or progressive disease. However, 38% of the patients with stable disease at the time of transplantation remained in a stable condition or achieved a minimal response after transplantation versus 7% in the group with progressive disease (P=0.0017) and the rate of early progression after transplantation was significantly higher among the group with progressive disease at the time of transplantation (22% versus 2%; P=0.0043). After a median follow-up of 6.6 years, the median survival after first transplant of the whole series was 2.3 years. Progression-free and overall survival from the first transplant were shorter in patients with progressive disease (0.6 versus 2.3 years, P=0.00004 and 1.1 versus 6 years, P=0.00002, respectively). Conclusions Our results show that patients with progressive refractory myeloma do not benefit from autologous transplantation, while patients with stable disease have an outcome comparable to those with chemosensitive disease. (ClinicalTrials.gov:NCT00560053)

Rosinol, Laura; Garcia-Sanz, Ramon; Lahuerta, Juan Jose; Hernandez-Garcia, Miguel; Granell, Miquel; de la Rubia, Javier; Oriol, Albert; Hernandez-Ruiz, Belen; Rayon, Consuelo; Navarro, Isabel; Garcia-Ruiz, Juan Carlos; Besalduch, Joan; Gardella, Santiago; Jimenez, Javier Lopez; Diaz-Mediavilla, Joaquin; Alegre, Adrian; Miguel, Jesus San; Blade, Joan

2012-01-01

267

View of God as benevolent and forgiving or punishing and judgmental predicts HIV disease progression.  

PubMed

This study assessed the predictive relationship between View of God beliefs and change in CD4-cell and Viral Load (VL) in HIV positive people over an extended period. A diverse sample of HIVseropositive participants (N = 101) undergoing comprehensive psychological assessment and blood draws over the course of 4 years completed the View of God Inventory with subscales measuring Positive View (benevolent/forgiving) and Negative View of God (harsh/judgmental/punishing). Adjusting for initial disease status, age, gender, ethnicity, education, and antiretroviral medication (at every 6-month visit), a Positive View of God predicted significantly slower disease-progression (better preservation of CD4-cells, better control of VL), whereas a Negative View of God predicted faster disease-progression over 4 years. Effect sizes were greater than those previously demonstrated for psychosocial variables known to predict HIV-disease-progression, such as depression and coping. Results remained significant even after adjusting for church attendance and psychosocial variables (health behaviors, mood, and coping). These results provide good initial evidence that spiritual beliefs may predict health outcomes. PMID:21340531

Ironson, Gail; Stuetzle, Rick; Ironson, Dale; Balbin, Elizabeth; Kremer, Heidemarie; George, Annie; Schneiderman, Neil; Fletcher, Mary Ann

2011-12-01

268

Synonymous substitution rates predict HIV disease progression as a result of underlying replication dynamics.  

PubMed

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

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

2007-02-16

269

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.

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

2013-01-01

270

Informed Consent and Prevention of Disease Progression in Veterans with Chronic Kidney Disease. Healthcare Inspection.  

National Technical Information Service (NTIS)

The VA Office of Inspector General Office of Healthcare Inspections assessed the extent to which informed consent was documented for veterans with chronic kidney disease who underwent procedures that involved intravascular injection of contrast media, and...

2011-01-01

271

Identification of serological biomarkers of infection, disease progression and treatment efficacy for leprosy.  

PubMed

Although leprosy is curable with drug treatment, the identification of biomarkers of infection, disease progression and treatment efficacy would greatly help to reduce the overall prevalence of the disease. Reliable biomarkers would also reduce the incidence of grade-2 disability by ensuring that those who are most at risk are diagnosed and treated early or offered repeated treatments in the case of relapse. In this study, we examined the reactivity of sera from lepromatous and tuberculoid leprosy patients (LPs) against a panel of 12 recombinant Mycobacterium leprae proteins and found that six proteins were strongly recognised by multibacillary (MB) patients, while only three were consistently recognised by paucibacillary patients. To better understand the dynamics of patient antibody responses during and after drug therapy, we measured antibody titres to four recombinant proteins, phenolic glycolipid-I and lipoarabinomannan at baseline and up to two years after diagnosis to investigate the temporal changes in the antibody titres. Reactivity patterns to individual antigens and decreases in antibody titres were patient-specific. Antibody titres to proteins declined more rapidly vs. those to carbohydrate and glycolipid antigens. Compared to baseline values, increases in antibody titres were observed during reactional episodes in one individual. Additionally, antibody responses against a subset of antigens that provided a good prognostic indicator of disease progression were analysed in 51 household contacts of MB index cases for up to two years. Although the majority of these contacts showed no change or exhibited decreases in antibody titres, seven individuals developed higher titres towards one or more of these antigens and one individual with progressively higher titres was diagnosed with borderline lepromatous leprosy 19 months after enrolment. The results of this study indicate that antibody titres to specific M. leprae antigens can be used to monitor treatment efficacy in LPs and assess disease progression in those most at risk for developing this disease. PMID:23283458

Spencer, John S; Duthie, Malcolm S; Geluk, Annemieke; Balagon, Marivic F; Kim, Hee Jin; Wheat, William H; Chatterjee, Delphi; Jackson, Mary; Li, Wei; Kurihara, Jade N; Maghanoy, Armi; Mallari, Irene; Saunderson, Paul; Brennan, Patrick J; Dockrell, Hazel M

2012-12-01

272

Inflammation in chronic kidney disease: role in the progression of renal and cardiovascular disease  

Microsoft Academic Search

Inflammation is the response of the vasculature or tissues to various stimuli. An acute and chronic pro-inflammatory state\\u000a exists in patients with chronic kidney disease (CKD), contributing substantially to morbidity and mortality. There are many\\u000a mediators of inflammation in adults with CKD and end-stage kidney disease (ESKD), including hypoalbuminemia\\/malnutrition,\\u000a atherosclerosis, advanced oxidation protein products, the peroxisome proliferators-activated receptor, leptin, the

Douglas M. Silverstein

2009-01-01

273

Disease progression model for Clinical Dementia Rating-Sum of Boxes in mild cognitive impairment and Alzheimer's subjects from the Alzheimer's Disease Neuroimaging Initiative  

PubMed Central

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

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

2014-01-01

274

Basic studies of submicron layers of Nb-Al. Progress report and summary of proposed research  

SciTech Connect

Recent work with powder metallurgy processed Nb-Al has shown that thin layers of extruded Nb and Al reacted at low temperatures can form superconducting Nb-Al with high transition temperatures well above that expected from the equilibrium phase diagram for Nb-Al and high critical current densities. The basic mechanisms for the low temperature reaction and the importance of surface effects, impurities, and the dependence of layer thickness in Nb-Al are not understood. Purpose of the research program is a basic study of model layered structures of Nb and Al in order to develop an understanding of the basic properties of low temperature reacted Nb-Al. The research employs bilayers and multilayers of Nb and Al to study the effects of layer structures, oxygen, third element additives, proximity, and mechanisms for high critical currents in thin layers. In a controlled manner, the model systems can be studied and analyzed, and made to approach the actual systems produced by powder processing techniques.

Not Available

1986-01-01

275

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

PubMed Central

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 genotypes, (iii) ventricular enlargement in subjects who progressed from MCI to AD, and (iv) sample sizes for multi-centre MCI and AD studies based on measures of ventricular enlargement. Three dimensional T1-weighted MRI and cognitive measures were acquired from 504 subjects (NEC n = 152, MCI n = 247 and AD n = 105) participating in the multi-centre Alzheimer's Disease Neuroimaging Initiative. Cerebral ventricular volume was quantified at baseline and after six months using semi-automated software. For the primary analysis of ventricle and neurocognitive measures, between group differences were evaluated using an analysis of covariance, and repeated measures t-tests were used for within group comparisons. For secondary analyses, all groups were dichotomized for Apolipoprotein E genotype based on the presence of an ?4 polymorphism. In addition, the MCI group was dichotomized into those individuals who progressed to a clinical diagnosis of AD, and those subjects that remained stable with MCI after six months. Group differences on neurocognitive and ventricle measures were evaluated by independent t-tests. General sample size calculations were computed for all groups derived from ventricle measurements and neurocognitive scores. The AD group had greater ventricular enlargement compared to both subjects with MCI (P = 0.0004) and NEC (P < 0.0001), and subjects with MCI had a greater rate of ventricular enlargement compared to NEC (P = 0.0001). MCI subjects that progressed to clinical AD after six months had greater ventricular enlargement than stable MCI subjects (P = 0.0270). Ventricular enlargement was different between Apolipoprotein E genotypes within the AD group (P = 0.010). The number of subjects required to demonstrate a 20% change in ventricular enlargement was substantially lower than that required to demonstrate a 20% change in cognitive scores. Ventricular enlargement represents a feasible short-term marker of disease progression in subjects with MCI and subjects with AD for multi-centre studies.

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

2008-01-01

276

Blood pressure, proteinuria, and phosphate as risk factors for progressive kidney disease: a hypothesis.  

PubMed

Chronic kidney disease (CKD) affects approximately 500 million people worldwide and is increasingly common in both industrialized and emerging countries. Although the mechanisms underlying the inexorable progression of CKD are incompletely defined, recent discoveries may pave the way to a more comprehensive understanding of the pathophysiology of CKD progression and the development of new therapeutic strategies. In particular, there is accumulating evidence indicating a key role for the complex and yet incompletely understood system of divalent cation regulation, which includes phosphate metabolism and the recently discovered fibroblast growth factor 23 (FGF-23)/klotho system, which seems inextricably associated with vitamin D deficiency. The aim of this review is to discuss the links between high blood pressure, proteinuria, phosphate levels, and CKD progression and explore new therapeutic strategies to win the fight against CKD. PMID:23664548

Cozzolino, Mario; Gentile, Giorgio; Mazzaferro, Sandro; Brancaccio, Diego; Ruggenenti, Piero; Remuzzi, Giuseppe

2013-11-01

277

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

PubMed

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

Weiner, Howard L

2008-03-01

278

Progressive sleep and electroencephalogram changes in mice carrying the Huntington's disease mutation.  

PubMed

Sleep disturbances in Huntington's disease may be deleterious to the cognitive performance, affective behaviour, and general well-being of patients, but a comprehensive description of the progression of changes in sleep and electroencephalogram in Huntington's disease has never been conducted. Here we studied sleep and electroencephalogram disturbances in a transgenic mouse model of Huntington's disease (R6/2 mice). We implanted 10 R6/2 mice and five wild-type littermates with electromyography electrodes, frontofrontal and frontoparietal electroencephalogram electrodes and then recorded sleep/wake behaviour at presymptomatic, symptomatic and late stages of the disease. In addition to sleep-wake scoring, we performed a spectral analysis of the sleep electroencephalogram. We found that sleep and electroencephalogram were already significantly disrupted in R6/2 mice at 9 weeks of age (presymptomatic stage). By the time they were symptomatic, R6/2 mice were unable to maintain long periods of wakefulness and had an increased propensity for rapid eye movement sleep. In addition, the peak frequency of theta rhythm was shifted progressively from 7 Hz to 6 Hz during rapid eye movement sleep, whereas slow wave activity decreased gradually during non-rapid eye movement sleep. Finally, as the disease progressed, an abnormal electroencephalogram gamma activity (30-40 Hz) emerged in R6/2 mice irrespective of sleep states. This is reminiscent of the increased gamma power described in schizophrenic patients during sleep and events of psychosis. Gaining a better understanding of sleep and electroencephalogram changes in patients with Huntington's disease should be a priority, since it will enable clinicians to initiate appropriate investigations and to instigate treatments that could dramatically improve patients' quality of life. PMID:23801737

Kantor, Sandor; Szabo, Lajos; Varga, Janos; Cuesta, Marc; Morton, A Jennifer

2013-07-01

279

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

PubMed Central

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney condition and is associated with important renal and cardiovascular manifestations in childhood. Renal cystic disease can be documented in some cases as early as in utero. Early intervention is critical if the long-term complications of this condition, including end-stage renal disease, are to be ameliorated. Here we describe our ongoing randomized double-blind placebo-controlled phase III clinical trial to assess the effect of pravastatin treatment on renal and cardiovascular disease progression in 107 children and young adults age 8–22 years with ADPKD who are receiving the angiotensin converting enzyme inhibitor lisinopril. Baseline demographic and laboratory data are provided. Results of this study could markedly impact the standard of care for evaluation and treatment of ADPKD in this population.

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

2011-01-01

280

High citrate diet delays progression of renal insufficiency in the ClC5 knockout mouse model of Dent's disease  

Microsoft Academic Search

High citrate diet delays progression of renal insufficiency in the ClC-5 knockout mouse model of Dent's disease.BackgroundDent's disease, an X-linked renal tubular disorder, is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. Dent's disease results from mutations of the voltage-gated chloride channel CLC-5.MethodsWe studied the effect of zero and high citrate diet on renal function of ClC-5

VALERIU CEBOTARU; SADHANA KAUL; OLIVIER DEVUYST; HUI CAI; LORRAINE RACUSEN; WILLIAM B GUGGINO; SANDRA E GUGGINO

2005-01-01

281

Recent progress in AlGaN\\/GaN-based optoelectronic devices  

Microsoft Academic Search

Unique optical and electronic properties of the InGaN\\/GaN\\/AlGaN material system open up numerous opportunities for visible-blind optoelectronic devices. GaN based optoelectronic devices include InGaN-AlGaN light emitting diodes (LEDs), GaN photoconductive, Schottky barrier, and p-n junction ultraviolet detectors, and optoelectronic AlGaN-GaN heterostructure field effect transistors. These devices have a high sensitivity and a large gain-bandwidth product and can be integrated with

M. Asif Khan; Michael S. Shur

1997-01-01

282

Role of levetiracetam in refractory seizures due to a rare progressive myoclonic epilepsy: Lafora body disease  

PubMed Central

Lafora disease is one of the rare, most fatal progressive myoclonic epilepsies reported. We present a case of a teenager with intractable seizures and progressive mental decline, diagnosed as Lafora body disease on axillary skin biopsy. He was admitted with status epilepticus with refractory myoclonic and generalised tonic clonic seizures. Despite on maximum doses of multiple antiepileptic drugs and infusions of propofol and midazolam, his seizures were refractory to all forms of medical therapy tried. Levetiracetam (LEV), a pyrrolidine derivative, was introduced; he showed a prompt response and was weaned off successfully from infusions of anticonvulsants and mechanical ventilation within 48 h of introduction of LEV, followed by an almost seizure-free status.

Hashmi, Mubashira; Saleem, Feroza; Mustafa, Muhammad Shahid; Sheerani, Mughis; Ehtesham, Zeeshan; Siddiqui, Khurram

2010-01-01

283

Different patterns of Mini Mental Status Examination responses in primary progressive aphasia and Alzheimer's disease.  

PubMed

Primary progressive aphasia (PPA) syndrome is frequently misdiagnosed--particularly in favour of Alzheimer's disease (AD). Misdiagnosis is related to the heterogeneity of language disorders at onset, variability in the rate of clinical progression and the low prevalence of PPA syndrome, compared with AD. The aim of this study was to determine whether a patient's first Mini Mental Status Examination (MMSE) might provide insight into differentiating between PPA and AD. We compared item scores for the first, complete MMSE in consecutive patients with PPA versus matched patients with AD. Word recall and constructional praxis were significantly better in patients subsequently diagnosed as suffering from PPA. Patients with AD performed significantly better in terms of word registration, object naming, repetition and verbal direction. Our findings indicate that the various MMSE item scores may be helpful in differentiating PPA and AD in the first few years of the disease. PMID:16987166

Le Rhun, E; Richard, F; Pasquier, F

2006-10-01

284

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.

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

2014-01-01

285

Progression of Alzheimer disease in Europe: data from the European ICTUS study.  

PubMed

The clinical progression of Alzheimer disease (AD) was studied in European subjects under treatment with AChE inhibitors (AChE-I) in relation to geographical location over a 2-years period. One thousand three hundred and six subjects from 11 European countries were clustered into 3 regions (North, South, West) and investigated with biannual follow-up over 2 years. Primary outcomes were cognitive, functional and behavioral measures. Caregiver burden, hospital admission and admission to nursing home were also recorded. Participant cognitive function declined non-linearly over time (MMSE: -1.5 pts/first year, -2.5 pts/second year; ADAScog: + 3.5 pts/first year, + 4.8 pts/second year), while the progression of behavioral disturbances (NPI scale) was linear. Neither scale showed regional differences, and progression of the disease was similar across Europe despite different health care systems. Functional decline (ADL, IADL) tended to progress more rapidly in Southern Europe (p=0.09), while progression of caregiver burden (Zarit Burden Interview) was most rapid in Northern Europe (5.6 pts/y, p=0.04). Incidences of hospital admission (10.44, 95%CI: 8.13-12.75, p < 0.001) and admission to nursing home (2.97, 95%CI: 1.83-4.11, p < 0.001) were lowest in Southern Europe. In general cognitive and functional decline was slower than in former cohorts. European geographical location reflecting differences in culture and in health care system does not impact on the progression of AD but does influence the management of AD subjects and caregiver burden. PMID:22742853

Vellas, B; Hausner, L; Frölich, L; Cantet, C; Gardette, V; Reynish, E; Gillette, S; Agüera-Morales, E; Auriacombe, S; Boada, M; Bullock, R; Byrne, J; Camus, V; Cherubini, A; Eriksdotter-Jönhagen, M; Frisoni, G B; Hasselbalch, S; Jones, R W; Martinez-Lage, P; Rikkert, M O; Tsolaki, M; Ousset, P-J; Pasquier, F; Ribera-Casado, J M; Rigaud, A S; Robert, P; Rodriguez, G; Salmon, E; Salva, A; Scheltens, P; Schneider, A; Sinclair, A; Spiru, L; Touchon, J; Zekry, D; Winblad, B; Andrieu, S

2012-10-01

286

Coated-platelet levels and progression from mild cognitive impairment to Alzheimer disease  

PubMed Central

Objectives: Coated-platelets are a subset of platelets produced by dual-agonist activation with collagen and thrombin. These platelets retain full-length amyloid precursor protein on their surface, are elevated in patients with amnestic as compared to nonamnestic mild cognitive impairment (MCI), and correlate with disease progression in Alzheimer disease (AD). Prompted by these findings, we investigated the association between coated-platelet production in amnestic MCI and rate of progression to AD. Methods: Coated-platelet levels were assayed in 74 patients with amnestic MCI who were subsequently followed longitudinally for up to 36 months in an outpatient dementia clinic. Levels are reported as percent of cells converted into coated-platelets. Subjects were categorized into tertiles of coated-platelet levels. The distributions of time to progression to AD were estimated for each tertile using cumulative incidence curves and compared statistically using a log-rank test. Cox proportional hazards regression was used to adjust for potential confounders. Results: The 24-month cumulative incidence of progression to AD was different among tertiles: 4% for the first tertile (lowest coated-platelet levels), 13% for the second tertile, and 37% for the third tertile (overall log-rank test, p = 0.02). The hazard rate of progression to AD for patients in the highest coated-platelet tertile was 5.1 times that for patients in the lowest tertile (p = 0.04), whereas the hazard rate for the middle tertile was similar to that for the lowest tertile (hazard rate ratio = 1.5, p = 0.7). Conclusions: Elevated coated-platelet levels in patients with amnestic MCI are associated with increased risk for progression to AD.

Ross, E.D.; Stoner, J.A.; Cowan, L.D.; Vincent, A.S.; Dale, G.L.

2011-01-01

287

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

PubMed Central

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

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

2010-01-01

288

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

PubMed

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

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

2010-11-01

289

The Chronic Kidney Disease Model: A General Purpose Model of Disease Progression and Treatment  

Microsoft Academic Search

Background  Chronic kidney disease (CKD) is the focus of recent national policy efforts; however, decision makers must account for multiple\\u000a therapeutic options, comorbidities and complications. The objective of the Chronic Kidney Disease model is to provide guidance\\u000a to decision makers. We describe this model and give an example of how it can inform clinical and policy decisions.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Monte Carlo simulation of

Lori A Orlando; Eric J Belasco; Uptal D Patel; David B Matchar

2011-01-01

290

Progressive Supranuclear Palsy Misdiagnosed as Parkinson's Disease: A Case Report and Review of Literature  

PubMed Central

Because of its increasingly recognized clinical diversity, progressive supranuclear palsy (PSP) may be difficult to diagnose, particularly in resource-poor settings where the means of getting supportive tests is a huge challenge. This often results in underdiagnosis or misdiagnosis of PSP, most commonly as Parkinson's disease. The author reported a case of how brain magnetic resonance imaging (MRI) was used to arrive at the diagnosis of PSP in a man previously misdiagnosed as Parkinson's disease. Relevant literatures regarding the diagnostic utility of MRI in PSP were also reviewed.

Owolabi, LF

2013-01-01

291

Pirfenidone: an anti-fibrotic and cytoprotective agent as therapy for progressive kidney disease  

PubMed Central

Importance of the field Many chronic diseases of various etiologies universally lead to fibrosis and organ dysfunction. Despite many advances in medicine in recent years, options to slow the progression of fibrotic diseases have remained limited. The recent availability of pirfenidone, an anti-fibrotic and anti-inflammatory investigational agent, thus offers a new hope for treating progressive fibrotic diseases. Areas covered in this review This review provides concise review of the available data regarding mechanism and pharmacokinetics of pirfenidone and preclinical and clinical data regarding efficacy and safety in fibrotic diseases of the kidney. It also reviews results of clinical trials involving pirfenidone in other fibrotic diseases. What the reader will gain The review will provide in-depth review of pirfenidone with a renal focus. Take home message Because many of the available clinical trials have been small and/or uncontrolled, conclusive evidence regarding efficacy and safety of pirfenidone is lacking, particularly in patients with renal or hepatic dysfunction. Larger studies are needed both to better understand long-term efficacy and safety of this medication in various patient populations.

Cho, Monique E; Kopp, Jeffrey B

2010-01-01

292

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.

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

2014-01-01

293

Positive Thought Induction for Arresting Disease Progression: A Hypnotherapeutic Application in HIV\\/AIDS  

Microsoft Academic Search

The present research aimed to investigate the effect of positive thought induction through hypnotherapeutic strategies, e.g.,\\u000a package of relaxation, guided imagery, positive suggestions, etc., on the coping strategies, clinical and immune parameters\\u000a of disease progression in people living with HIV\\/AIDS(PLWHA). Data were collected from 20 adults HIV+ patients having CD4\\u000a count above 250 and plasma viral load less than 5000,

Urmi Nanda Biswas

2011-01-01

294

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

PubMed Central

Background The natural history of HSV-2 infection and role of HSV-2 reactivations in HIV disease progression are unclear. Methods Clinical 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 longitudinally across three study visits and cross-sectionally at the last study visit. Results A dose dependent association between markers of HIV disease progression and degree of HSV-2 clinical activity was observed. In multivariate analyses after adjusting for baseline CD4+ T cell levels, active HSV-2 infection with frequent symptomatic reactivations was associated with 21% to 32% increase in the probability of detectable plasma HIV RNA (trend p?=?0.004), an average of 0.27 to 0.29 log10 copies/ml higher plasma HIV RNA on a continuous scale (trend p<0.001) and 51 to 101 reduced CD4+ T cells/mm3 over time compared to asymptomatic HSV-2 infection (trend p<0.001). Conclusions HIV induced CD4+ T cell loss was associated with frequent symptomatic HSV-2 reactivations. However, effect of HSV-2 reactivations on HIV disease progression markers in this population was modest and appears to be dependent on the frequency and severity of reactivations. Further studies will be necessary to determine whether HSV-2 reactivations contribute to acceleration of HIV disease progression.

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

2010-01-01

295

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

296

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

297

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

298

Disease progression and recurrence in women treated for vulvovaginal intraepithelial neoplasia  

PubMed Central

Objective The malignant potential of intraepithelial neoplasia of the vulva and vagina after treatment is not well defined. Our objective was to examine risk factors for recurrence and invasive disease. Methods Four hundred sixty-four women with biopsy proven high-grade intraepithelial neoplasia of the vulva and vagina were identified in the electronic databases of four colposcopy clinics. Inclusion criteria were a follow-up of more than one year, no history of invasive cancer and no invasive cancer within the first year after initial treatment. We investigated the potential factors associated with recurrence and progression using a logistic regression analysis to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results Of the 411 eligible patients, 123 patients (29.9%) recurred later than one year after initial treatment and 24 patients (5.8%) progressed to invasive disease. According to multivariate analyses, the risk factors associated with recurrence were multifocality (OR, 3.33; 95% CI, 2.02 to 5.51), immunosuppression (OR, 2.51; 95% CI, 1.09 to 5.81), excision as initial treatment (vs. laser evaporation; OR, 1.79; 95% CI, 1.11 to 2.91) and smoking (OR, 1.61; 95% CI, 1.02 to 2.55). Risk factors for progression to invasive disease were immunosuppression (OR, 4.00; 95% CI, 1.30 to 12.25), multifocality (OR, 3.05; 95% CI, 1.25 to 7.43) and smoking (OR, 2.97; 95% CI, 1.16 to 7.60), but not treatment modality. Conclusion Laser evaporation combined with extensive biopsy is at least as efficacious as initial treatment of intraepithelial neoplasia with excision. Smoking is a risk factor for both recurrence and progression to invasive disease. Hence, smoking cessation should be advised and maintaining a long follow-up period due to late relapses is necessary.

Baumann, Marc; Mueller, Michael; Fink, Daniel; Heinzl, Siegfried; Imesch, Patrick; Dedes, Konstantin

2013-01-01

299

The effect of LDL apheresis on progression of coronary artery disease in patients with familial hypercholesterolemia  

Microsoft Academic Search

This study investigated the effect of extracorporal lipid-lowering therapy by low-density lipoprotein (LDL) apheresis on coronary artery disease in a population characterized by early development and rapid progression of atherosclerosis. We treated 32 patients aged between 15 and 63 years with drug-refractory familial hypercholesterolemia, treated once a week by immuno-specific LDL apheresis for 3 years in a controlled prospective and

T. Waidner; D. Franzen; W. Voelker; M. Ritter; H. Borberg; V. Hombach; H. W. Höpp

1994-01-01

300

A Case of Cerebral Erdheim-Chester Disease With Progressive Cerebellar Syndrome  

Microsoft Academic Search

Erdheim-Chester disease (ECD) is a rare non-Langerhans form of histiocytosis. Cerebellar involvement is rare in this syndrome. We report a 37-year-old woman with slowly progressive cerebellar ataxia, dysmetria of limbs, nystagmus, and dysarthria, bilateral painful axillary masses, and generalized arthralgia. Brain MRI revealed cerebellar atrophy with focal lesions in the pons, middle cerebellar peduncle, and the cerebellum. She underwent incisional

Sang-Jun Na; Kee Ook Lee; Jung Eun Kim; Yong-Duk Kim

2008-01-01

301

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.

302

Magnetic Resonance Disease Severity Scale predicts clinical progression in multiple sclerosis  

PubMed Central

Objective Combine MRI measures of disease severity into a multiple sclerosis (MS) composite score. Design Retrospectively analysis of prospectively collected data Setting Community-based and referral subspecialty clinic in an academic hospital Patients 103 patients with MS [age (mean ± SD) 42.7 ± 9.1 years, disease duration 14.1 ± 9.2 years, EDSS score 3.3 ± 2.2, 60% (n=62) relapsing-remitting (RR), 32% (n=33) secondary progressive (SP), and 8% (n=8) primary progressive]. Main outcome measures Brain MRI measures included baseline T2 hyperintense (T2LV) and T1 hypointense (T1LV) lesion volume, and brain parenchymal fraction (BPF), a marker of global atrophy. The ratio of T1LV to T2LV assessed lesion severity. A Magnetic Resonance Disease Severity Scale (MRDSS) score, on a continuous scale from 0 to 10, was derived for each patient using T2LV, BPF, and T1/T2 ratio. Results MRDSS score averaged 5.1 ± 2.6. Baseline MRI and EDSS correlations were moderate for BPF, T1/T2, and MRDSS and weak for T2LV. MRDSS showed a larger effect size than any of the individual MRI components in distinguishing RR from SP patients. Models containing either T2LV or MRDSS were significantly associated with EDSS disability progression during the 3.2 ± 0.3 year observation period, when adjusting for baseline EDSS score. Conclusions Combining brain MRI lesion and atrophy measures can predict clinical progression in patients with MS and provides the basis to develop an MRI-based continuous scale as a marker of MS disease severity.

Bakshi, Rohit; Neema, Mohit; Healy, Brian C; Liptak, Zsuzsanna; Betensky, Rebecca A; Buckle, Guy J; Gauthier, Susan A; Stankiewicz, James; Meier, Dominik; Egorova, Svetlana; Arora, Ashish; Guss, Zachary D; Glanz, Bonnie; Khoury, Samia J; Guttmann, Charles RG; Weiner, Howard L

2009-01-01

303

Decreased Hepatotoxic Bile Acid Composition and Altered Synthesis in Progressive Human Nonalcoholic Fatty Liver Disease  

PubMed Central

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

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

2013-01-01

304

Aggregated  -synuclein activates microglia: a process leading to disease progression in Parkinson's disease  

Microsoft Academic Search

A growing body of evidence indicates that an inflammatory process in the substantia nigra, characterized by activation of resident microglia, likely either initiates or aggravates nigral neurodegeneration in Parkinson's disease (PD). To study the mechanisms by which nigral microglia are activated in PD, the potential role of -synuclein (a major component of Lewy bodies that can cause neurodegeneration when aggregated)

Wei Zhang; Tongguang Wang; Zhong Pei; David S. Miller; Xuefei Wu; Michelle L. Block; Belinda Wilson; Wanqin Zhang; Yong Zhou; Jau-Shyong Hong; Jing Zhang

2005-01-01

305

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

306

FUS-SMN protein interactions link the motor neuron diseases ALS and SMA  

PubMed Central

Summary Mutations in the RNA binding protein FUS cause ALS, a fatal adult motor neuron disease. Decreased expression of SMN causes the fatal childhood motor neuron disorder SMA. The SMN complex localizes in both the cytoplasm and nuclear Gems, and loss of Gems is a cellular hallmark of SMA patient fibroblasts. Here, we report that FUS associates with the SMN complex, an interaction mediated by U1 snRNP and by direct interactions between FUS and SMN. Functionally, we show that FUS is required for Gem formation in HeLa cells, and expression of FUS containing a severe ALS-causing mutation (R495X) also results in Gem loss. Strikingly, a reduction in Gems is observed in ALS patient fibroblasts expressing either mutant FUS or TDP-43, another ALS-causing protein that interacts with FUS. The physical and functional interactions between SMN, FUS, TDP-43, and Gems indicate that ALS and SMA share a biochemical pathway, adding strong new support to the view that these motor neuron diseases are related.

Yamazaki, Tomohiro; Chen, Shi; Yu, Yong; Yan, Biao; Haertlein, Tyler C.; Carrasco, Monica A.; Tapia, Juan C.; Zhai, Bo; Das, Rita; Lalancette-Hebert, Melanie; Sharma, Aarti; Chandran, Siddharthan; Sullivan, Gareth; Nishimura, Agnes Lumi; Shaw, Christopher E.; Gygi, Steve P.; Shneider, Neil A.; Maniatis, Tom

2012-01-01

307

Progression from Mild Cognitive Impairment to Alzheimer's disease: effects of gender, butyrylcholinesterase genotype and rivastigmine treatment  

PubMed Central

Objective Evaluate the influence of gender and butyrylcholinesterase (BuChE) genotype on incidence of progression to AD, rate of cognitive and functional decline, and response to rivastigmine treatment in mild cognitive impairment (MCI) subjects. Methods This retrospective exploratory analysis from a 3–4 year, randomized, placebo-controlled study of rivastigmine in MCI subjects included participants who consented to pharmacogenetic testing. Results Of 1018 total patients, 490 (253 [52%] female) were successfully genotyped for BuChE. In subjects receiving placebo, the BuChE wt/wt genotype was associated with a statistically significantly higher rate of progression to AD and functional decline in women, compared with men with the BuChE wt/wt genotype. In subjects with a BuChE-K allele receiving placebo, incidence of progression to AD and rate of functional decline were not significantly different by gender, however cognitive decline was significantly faster in men. Statistically significant benefits of rivastigmine treatment on progression to AD, functional decline, ventricular volume expansion, whole brain atrophy and white matter loss were evident in female BuChE wt/wt. Conclusion Gender appears to differentially influence the type of decline in MCI subjects according to BuChE genotype, with more rapid progression of cognitive decline in male BuChE-K, and more rapid progression to AD and functional decline in female BuChE wt/wt. Cognitive decline in male BuChE-K and functional decline and progression to AD in female BuChE wt/wt were significantly attenuated by rivastigmine. Rivastigmine treatment also significantly reduced ventricular expansion, whole brain atrophy rate and white matter loss in female BuChE wt/wt, suggesting a possible disease-modifying effect.

Ferris, Steven; Nordberg, Agneta; Soininen, Hilkka; Darreh-Shori, Taher; Lane, Roger

2014-01-01

308

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

309

The Progression of Cardiometabolic Disease: Validation of a New Cardiometabolic Disease Staging System Applicable to Obesity  

PubMed Central

Objective To validate a Cardiometabolic Disease Staging (CMDS) system for assigning risk level for diabetes, and all-cause and cardiovascular disease (CVD) mortality. Design, and Methods Two large national cohorts, CARDIA and NHANES III, were used to validate CMDS. CMDS: Stage 0: metabolically healthy; Stage 1: 1 or 2 Metabolic Syndrome risk factors (other than IFG); Stage 2: IFG or IGT or Metabolic Syndrome (without IFG); Stage 3: 2 of 3 (IFG, IGT, and/or Metabolic Syndrome); Stage 4: T2DM/CVD. Results In the CARDIA study, compared with Stage 0 metabolically healthy subjects, adjusted risk for diabetes exponentially increased from Stage 1 (HR 2.83, 95% CI 1.76–4.55), to Stage 2 (HR 8.06, 95% CI 4.91–13.2), to Stage 3 (HR 23.5, 95% CI 13.7–40.1) (p for trend <0.001). In NHANES III, both cumulative incidence and multivariable adjusted hazard ratios markedly increased for both all-cause and CVD mortality with advancement of the risk stage from Stage 0 to 4. Adjustment for BMI minimally affected the risks for diabetes and all-cause/CVD mortality using CMDS. Conclusion CMDS can discriminate a wide range of risk for diabetes, CVD mortality, and all-cause mortality independent of BMI, and should be studied as a risk assessment tool to guide interventions that prevent and treat cardiometabolic disease.

Guo, Fangjian; Moellering, Douglas R; Garvey, W. Timothy

2013-01-01

310

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.

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

311

Impact of lipid abnormalities in development and progression of transplant coronary disease: a serial intravascular ultrasound study  

Microsoft Academic Search

OBJECTIVESWe sought to determine the role of conventional atherosclerosis risk factors in the development and progression of transplant coronary artery disease (CAD) using serial intravascular ultrasound imaging.BACKGROUNDTransplant artery disease is a combination of allograft vasculopathy and donor atherosclerosis. The clinical determinants for each of these disease processes are not well characterized. Intravascular ultrasound imaging is the most sensitive tool to

Samir R Kapadia; Steven E Nissen; Khaled M Ziada; Gustavo Rincon; Timothy D Crowe; Navdeep Boparai; James B Young; E. Murat Tuzcu

2001-01-01

312

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

313

Circulating levels of soluble Fas ligand reflect disease progression in multiple myeloma.  

PubMed

Multiple myeloma (MM) plasma cells are apoptosis resistant. The system of Fas with its ligand (Fas-L) participates actively in the extrinsic apoptotic system. In oncology, its role is controversial, since it has been reported both to suppress and promote tumor growth. The aim of this study was to measure serum levels of soluble Fas-L (sFas-L) in patients with active MM and to correlate them with markers of disease activity. We studied 57 patients with active MM, along with 22 healthy controls. We measured serum levels of sFas-L and interleukin-6 (IL-6) by enzyme-linked immunosorbent assays, as well of beta-2 microglobulin (B2M), C-reactive protein (CRP) and lactate dehydrogenase (LDH). We also measured the degree of bone marrow infiltration. All parameters were increased in patients, compared with controls (p < 0.001 for all cases) and also in parallel with disease stage (p < 0.001 for all cases). Positive correlations were noted between serum levels of sFas-L with IL-6, infiltration (p < 0.001 for both cases) and LDH (p < 0.04), but not with CRP and B2M. We suggest that the system of Fas/Fas-L participates actively in MM progression in a complex manner and that serum levels of sFas-L may reflect disease progression. Further studies are needed to determine its usefulness as a marker of disease activity. PMID:24729186

Alexandrakis, Michael G; Pappa, Constantina A; Kolovou, Anna; Kyriakaki, Stavroula; Vyzoukaki, Rodanthi; Devetzoglou, Maria; Tsirakis, George

2014-05-01

314

Kidney transplants with progressing chronic diseases express high levels of acute kidney injury transcripts.  

PubMed

We previously reported that kidney transplants with early acute injury express transcripts indicating injury repair--the acute kidney injury signal. This study investigated the significance of this signal in transplants with other conditions, including rejection and recurrent disease. The injury signal was elevated in biopsies in many different conditions, including T cell-mediated rejection and potentially progressive diseases such as antibody-mediated rejection and glomerulonephritis. A high injury signal correlated with poor function and with inflammation in areas of fibrosis, but not with fibrosis without inflammation. In multivariate survival analysis, the injury signal in late kidney transplant biopsies strongly predicted future graft loss, similar to a published molecular risk score derived in late kidneys. Indeed, the injury signal shared many individual transcripts with the risk score, e.g. ITGB6, VCAN, NNMT. The injury signal was a better predictor of future graft loss than fibrosis, inflammation or expression of collagen genes. Thus the acute injury signal, first defined in early reversible injury, is present in many diseases as a reflection of parenchymal distress, where its significance is dictated by the inducing insult, i.e. treatable/self-limited versus untreatable and sustained. Progression in troubled transplants is primarily a function of ongoing parenchymal injury by disease, not fibrogenesis. PMID:23356967

Famulski, K S; Reeve, J; de Freitas, D G; Kreepala, C; Chang, J; Halloran, P F

2013-03-01

315

PIB Imaging Predicts Progression from Cognitively Normal to Symptomatic Alzheimer's Disease  

PubMed Central

Objective To determine whether preclinical Alzheimer’s disease (AD), as detected by the amyloid imaging agent Pittsburgh Compound B (PIB) in cognitively normal older adults, is associated with risk of symptomatic AD. Design A longitudinal cohort study of cognitively normal older adults assessed with positron emission tomography (PET) to determine the mean cortical binding potential for PIB and followed with annual clinical and cognitive assessments for progression to very mild dementia of the Alzheimer type (DAT). Setting Alzheimer’s Disease Research Center Participants One hundred and fifty-nine participants with mean age of 71.5 y in a longitudinal study of memory and aging had a PET PIB scan when cognitively normal with Clinical Dementia Rating (CDR) of 0. Outcome Measure Progression from CDR 0 status to CDR 0.5 (very mild dementia). Results Twenty-three participants progressed to CDR 0.5 at follow-up assessment (range: 1–5 assessments after PET PIB). Of these, 9 also were diagnosed with DAT. Higher MCBP values for PIB (hazard ratio 4.85, 95% CI, 1.22–19.01, p = .02) and age (hazard ratio 1.14, 95% CI 1.02–1.28, p = .03) predicted progression to CDR 0.5 DAT. The CDR 0.5 DAT group showed decline in three cognitive domains (episodic memory, semantic memory, and visuospatial performance) and had volume loss in the parahippocampal gyrus (includes entorhinal cortex) compared with individuals who remained CDR 0. Conclusions Preclinical AD, as detected by PET PIB, is not benign as it is associated with progression to symptomatic AD.

Morris, John C.; Roe, Catherine M.; Grant, Elizabeth A.; Head, Denise; Storandt, Martha; Goate, Alison M.; Fagan, Anne M.; Holtzman, David M.; Mintun, Mark A.

2009-01-01

316

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.)

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

317

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.

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

318

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

SciTech Connect

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

Becla, P.; Witt, A.F.

1995-12-31

319

CADASIL disease, an inherited slowly progressive vascular dementia: case report with radiologic and electron microscopic findings.  

PubMed

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease, a genetically determined arteriopathy, is a rare cause of vascular dementia. We present a case report of a 50-year-old man with migraines associated with left-sided weakness since age 34 years, a stroke at age 43 years, followed by progressive dementia. Magnetic resonance imaging revealed diffuse leukoencephalopathy with involvement of bilateral anterior temporal lobes. Skin biopsy was performed because of clinical suggestion of CADASIL and positive family history. Electron microscopy revealed granular osmophilic material deposits in dermal arterioles, diagnostic for CADASIL disease. A brief discussion of reasons for false-negative skin biopsy findings, differential diagnosis, and treatment of patients with CADASIL disease is presented. PMID:19900654

Shuja, Sania; Lindquist, Justin; Lee, Kevin P; Silliman, Scott; Makary, Raafat

2009-01-01

320

Comparison of cognitive and UHDRS measures in monitoring disease progression in Huntington's disease: a 12-month longitudinal study  

PubMed Central

Progressive cognitive decline is a feature of Huntington’s disease (HD), an inherited neurodegenerative movement disorder. Comprehensive neuropsychological testing is the ‘gold standard’ to establish cognitive status but is often impractical in time-constrained clinics. The study evaluated the utility of brief cognitive tests (MMSE and MoCA), UHDRS measures and a comprehensive neuropsychological tests battery in monitoring short-term disease progression in HD. Twenty-two manifest HD patients and 22 matched controls were assessed at baseline and 12-month. A linear mixed-effect model showed that although the HD group had minimal change in overall global cognition after 12 months, they did show a significant decline relative to the control group. The controls exhibited a practice effect in most of the cognitive domain scores over time. Cognitive decline at 12-month in HD was found in the executive function domain but the effect of this on global cognitive score was masked by the improvement in their language domain score. The varying practice effects by cognitive domain with repeated testing indicates the importance of comparing HD patients to control group in research trials and that cognitive progression over 12 months in HD should not be judged by changes in global cognitive score. The three brief cognitive tests effectively described cognition of HD patients on cross-sectional analysis. The UHDRS cognitive component, which focuses on testing executive function and had low variance over time, is a more reliable brief substitute for comprehensive neuropsychological testing than MMSE and MoCA in monitoring cognitive changes in HD patients after 12 months.

2014-01-01

321

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.

2014-01-01

322

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

PubMed Central

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

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

2005-01-01

323

Early Myeloid Dendritic Cell Dysregulation is Predictive of Disease Progression in Simian Immunodeficiency Virus Infection  

PubMed Central

Myeloid dendritic cells (mDC) are lost from blood in individuals with human immunodeficiency virus (HIV) infection but the mechanism for this loss and its relationship to disease progression are not known. We studied the mDC response in blood and lymph nodes of simian immunodeficiency virus (SIV)-infected rhesus macaques with different disease outcomes. Early changes in blood mDC number were inversely correlated with virus load and reflective of eventual disease outcome, as animals with stable infection that remained disease-free for more than one year had average increases in blood mDC of 200% over preinfection levels at virus set-point, whereas animals that progressed rapidly to AIDS had significant loss of mDC at this time. Short term antiretroviral therapy (ART) transiently reversed mDC loss in progressor animals, whereas discontinuation of ART resulted in a 3.5-fold increase in mDC over preinfection levels only in stable animals, approaching 10-fold in some cases. Progressive SIV infection was associated with increased CCR7 expression on blood mDC and an 8-fold increase in expression of CCL19 mRNA in lymph nodes, consistent with increased mDC recruitment. Paradoxically, lymph node mDC did not accumulate in progressive infection but rather died from caspase-8-dependent apoptosis that was reduced by ART, indicating that increased recruitment is offset by increased death. Lymph node mDC from both stable and progressor animals remained responsive to exogenous stimulation with a TLR7/8 agonist. These data suggest that mDC are mobilized in SIV infection but that an increase in the CCR7-CCL19 chemokine axis associated with high virus burden in progressive infection promotes exodus of activated mDC from blood into lymph nodes where they die from apoptosis. We suggest that inflamed lymph nodes serve as a sink for mDC through recruitment, activation and death that contributes to AIDS pathogenesis.

Wijewardana, Viskam; Soloff, Adam C.; Liu, Xiangdong; Brown, Kevin N.; Barratt-Boyes, Simon M.

2010-01-01

324

Early myeloid dendritic cell dysregulation is predictive of disease progression in simian immunodeficiency virus infection.  

PubMed

Myeloid dendritic cells (mDC) are lost from blood in individuals with human immunodeficiency virus (HIV) infection but the mechanism for this loss and its relationship to disease progression are not known. We studied the mDC response in blood and lymph nodes of simian immunodeficiency virus (SIV)-infected rhesus macaques with different disease outcomes. Early changes in blood mDC number were inversely correlated with virus load and reflective of eventual disease outcome, as animals with stable infection that remained disease-free for more than one year had average increases in blood mDC of 200% over preinfection levels at virus set-point, whereas animals that progressed rapidly to AIDS had significant loss of mDC at this time. Short term antiretroviral therapy (ART) transiently reversed mDC loss in progressor animals, whereas discontinuation of ART resulted in a 3.5-fold increase in mDC over preinfection levels only in stable animals, approaching 10-fold in some cases. Progressive SIV infection was associated with increased CCR7 expression on blood mDC and an 8-fold increase in expression of CCL19 mRNA in lymph nodes, consistent with increased mDC recruitment. Paradoxically, lymph node mDC did not accumulate in progressive infection but rather died from caspase-8-dependent apoptosis that was reduced by ART, indicating that increased recruitment is offset by increased death. Lymph node mDC from both stable and progressor animals remained responsive to exogenous stimulation with a TLR7/8 agonist. These data suggest that mDC are mobilized in SIV infection but that an increase in the CCR7-CCL19 chemokine axis associated with high virus burden in progressive infection promotes exodus of activated mDC from blood into lymph nodes where they die from apoptosis. We suggest that inflamed lymph nodes serve as a sink for mDC through recruitment, activation and death that contributes to AIDS pathogenesis. PMID:21203477

Wijewardana, Viskam; Soloff, Adam C; Liu, Xiangdong; Brown, Kevin N; Barratt-Boyes, Simon M

2010-01-01

325

Triple pelvic osteotomy: effect on limb function and progression of degenerative joint disease.  

PubMed

The objective of this study was to evaluate prospectively the outcome of 21 clinical patients treated with triple pelvic osteotomies during the year following surgery. Specific aims included documenting the time of and extent of improved limb function as measured by force plate analysis, evaluating the progression of degenerative joint disease (DJD) in the treated and untreated coxofemoral joints, and determining whether or not triple pelvic osteotomy resulted in degenerative joint changes in the ipsilateral stifle and hock. Twelve dogs were treated unilaterally and nine dogs were treated bilaterally with triple pelvic osteotomies. There were no differences in mean anteversion angles, angles of inclination, or preoperative DJD between treated hips and untreated hips. Degenerative joint disease progressed significantly in all hips regardless of treatment. Two cases developed hyperextension of their hocks after the triple pelvic osteotomies. However, no radiographic evidence of DJD was observed for any of the stifles or hocks at any observation time. A significant increase in vertical peak force (VPF) scores was noted for treated legs by two-to-three months after surgery, which continued over time. Untreated legs did not show a significant change in VPF scores over time. No differences were found in progression to higher scores when unilaterally treated legs, first-side treated legs, and second-side treated legs were compared. PMID:9590455

Johnson, A L; Smith, C W; Pijanowski, G J; Hungerford, L L

1998-01-01

326

Regular Exercise or Changing Diet Does Not Influence Aortic Valve Disease Progression in LDLR Deficient Mice  

PubMed Central

Background The development and progression of calcific aortic valve disease (CAVD) shares a number of similarities with atherosclerosis. Recently we could demonstrate that regular exercise training (ET) as primary prevention prevents aortic valve disease in LDL-receptor deficient (LDLR?/?) mice. We aimed to investigate the impact of exercise training on the progression of CAVD in LDLR?/? mice in the setting of secondary prevention Methods and Results Sixty-four LDLR?/? mice were fed with high cholesterol diet to induce aortic valve sclerosis. Thereafter the animals were divided into 3 groups: group 1 continuing on high cholesterol diet, group 2 continuing with cholesterol diet plus 1 h ET per day, group 3 continuing with normal mouse chow. After another 16 weeks the animal were sacrificed. Histological analysis of the aortic valve thickness demonstrated no significant difference between the three groups (control 98.3±4.5 µm, ET 88.2±6.6 µm, change in diet 87.5±4.0). Immunohistochemical staining for endothelial cells revealed a disrupted endothelial cell layer to the same extend in all groups. Furthermore no difference between the groups was evident with respect to the expression of inflammatory, fibroblastic and osteoblastic markers. Conclusion Based on the present study we have to conclude that once the development of a CAVD is initiated, exercise training or a change in diet does not have the potential to attenuate the progress of the CAVD.

Schlotter, Florian; Matsumoto, Yasuharu; Mangner, Norman; Schuler, Gerhard; Linke, Axel; Adams, Volker

2012-01-01

327

Messenger RNA Oxidation Occurs Early in Disease Pathogenesis and Promotes Motor Neuron Degeneration in ALS  

PubMed Central

Background Accumulating evidence indicates that RNA oxidation is involved in a wide variety of neurological diseases and may be associated with neuronal deterioration during the process of neurodegeneration. However, previous studies were done in postmortem tissues or cultured neurons. Here, we used transgenic mice to demonstrate the role of RNA oxidation in the process of neurodegeneration. Methodology/Principal Findings We demonstrated that messenger RNA (mRNA) oxidation is a common feature in amyotrophic lateral sclerosis (ALS) patients as well as in many different transgenic mice expressing familial ALS-linked mutant copper-zinc superoxide dismutase (SOD1). In mutant SOD1 mice, increased mRNA oxidation primarily occurs in the motor neurons and oligodendrocytes of the spinal cord at an early, pre-symptomatic stage. Identification of oxidized mRNA species revealed that some species are more vulnerable to oxidative damage, and importantly, many oxidized mRNA species have been implicated in the pathogenesis of ALS. Oxidative modification of mRNA causes reduced protein expression. Reduced mRNA oxidation by vitamin E restores protein expression and partially protects motor neurons. Conclusion/Significance These findings suggest that mRNA oxidation is an early event associated with motor neuron deterioration in ALS, and may be also a common early event preceding neuron degeneration in other neurological diseases.

Chang, Yueming; Kong, Qiongman; Shan, Xiu; Tian, Guilian; Ilieva, Hristelina; Cleveland, Don W.; Rothstein, Jeffrey D.; Borchelt, David R.; Wong, Philip C.; Lin, Chien-liang Glenn

2008-01-01

328

Potential Drugs and Methods for Preventing or Delaying the Progression of Huntington's Disease  

PubMed Central

Huntington’s disease (HD) is an autosomal dominant inherited and progressive neurodegenerative disorder with motor dysfunction and cognitive deficits. Although, there are no treatments to delay the appearance and the progression of HD, there are potential drugs currently in preclinical and clinical trials that are focused on HD therapy. The signaling pathways involved in HD are not yet clearly elucidated; however, expression of mutant huntingtin protein is considered a key factor in the induction and/or progression of HD. The demonstration that the onset and progression of HD in models of transgenic mice, in particular, are delayed or improved by the application of neurotrophic factors has emphasized their importance in neuroprotection in HD. In addition, other compounds targeting the HD gene or mutant huntingtin protein are currently in preclinical and clinical testing and may show promising neuroprotective effects. There are current patented drugs that are currently being considered as potential therapeutics for HD. These patented drugs may provide promising therapy for HD.

Sari, Youssef

2012-01-01

329

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

330

Synapse Stability in the Precuneus Early in the Progression of Alzheimer's Disease  

PubMed Central

Amnestic mild cognitive impairment (aMCI) is considered to be one of the early stages in the progression from no cognitive impairment (NCI) to Alzheimer’s disease (AD). Individuals with aMCI have increased levels of AD-type neuropathology in multiple regions of the neocortex and hippocampus and demonstrate a loss of synaptic connectivity. Recent neuroimaging studies have reported increased levels of 11C-PiB (Pittsburgh, compound B) in regions of the neocortex including the precuneus region of the medial parietal lobe. This cortical region has been implicated in episodic memory, which is disrupted early in the progression of AD. In this study, unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the precuneus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI did not reveal a statistically significant decline in total synapses compared to the NCI cohort while the AD group did show a modest but significant decline. Synaptic numbers failed to correlate with several different cognitive tasks including the Mini Mental State Examination scores and episodic memory scores. Although levels of [3H]PiB binding were elevated in both the aMCI and AD groups, it did not strongly correlate with synaptic counts. These results support the idea that despite increased amyloid load, the precuneus region does not show early changes in synaptic decline during the progression of AD.

Scheff, S. W.; Price, D.A.; Schmitt, F.A.; Roberts, K.N.; Ikonomovic, M.D.; Mufson, E.J.

2014-01-01

331

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

PubMed

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 PD. DESIGN, SETTING, AND PARTICIPANTS Inception cohort analysis of data from 413 patients with early, untreated PD who were enrolled in 2 multicenter, randomized, double-blind clinical trials. INTERVENTIONS Participants were randomly assigned to 1 of 5 treatments (67 received creatine, 66 received minocycline, 71 received coenzyme Q10, 71 received GPI-1485, and 138 received 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 OUTCOMES AND MEASURES 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 with regard to the Unified Parkinson's Disease Rating Scale (UPDRS) Part II score, the UPDRS Part III score, the modified Rankin Scale score, level of education, and treatment group, we assessed the rate of change for the following measurements: the UPDRS Part II score; the UPDRS Part III score; the Schwab and England Independence Scale score (which measures activities of daily living); the Total Functional Capacity scale; the 39-item Parkinson's Disease Questionnaire, summary index, and activities of daily living subscale; and version 2 of the 12-item Short Form Health Survey Physical Summary and Mental Summary. Variables reaching the 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 change (ie, worsening) in the UPDRS Part II score (hazard ratio, 1.15 [95% CI, 1.08-1.22] for 1 scale unit change per 6 months), the UPDRS Part III score (hazard ratio, 1.09 [95% CI, 1.06-1.13] for 1 scale unit change per 6 months), and the Schwab and England Independence Scale score (hazard ratio, 1.29 [95% CI, 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, the UPDRS Part II score and Part III score and the Schwab and England Independence Scale score can be used to measure disease progression, whereas the 39-item Parkinson's Disease Questionnaire and summary index, Total Functional Capacity scale, and the 12-item Short Form Health Survey Physical Summary and Mental Summary are not sensitive to change. TRIAL REGISTRATION clinicaltrials.gov Identifiers: NCT00063193 and NCT00076492. PMID:24711047

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

2014-06-01

332

A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease  

PubMed Central

The development of autoimmune disease is accompanied by the acquired recognition of new self-determinants, a process commonly referred to as determinant spreading. In this study, we addressed the question of whether determinant spreading is pathogenic for progression of chronic- relapsing experimental autoimmune encephalomyelitis (EAE), a disease with many similarities to multiple sclerosis (MS). Our approach involved a systematic epitope mapping of responses to myelin proteolipid protein (PLP) as well as assaying responses to known encephalitogenic determinants of myelin basic protein (MBP 87-89) and myelin oligodendrocyte glycoprotein (MOG 92-106) at various times after induction of EAE in (SWR X SJL)F1 mice immunized with PLP 139-151. We found that the order in which new determinants are recognized during the course of disease follows a predictable sequential pattern. At monthly intervals after immunization with p139-151, responses to PLP 249-273, MBP 87-99, and PLP 137-198 were sequentially accumulated in al mice examined. Three lines of evidence showed that determinant spreading is pathogenic for disease progression: (a) spreading determinants mediate passive transfer of acute EAE in naive (SWR X SJL)F1 recipients; (b) an invariant relationship exists between the development of relapse/progression and the spreading of recognition to new immunodominant encephalitogenic determinants; and (c) after EAE onset, the induction of peptide-specific tolerance to spreading but not to nonspreading encephalitogenic determinants prevents subsequent progression of EAE. Thus, the predictability of acquired self- determinant recognition provides a basis for sequential determinant- specific therapeutic intervention after onset of the autoimmune disease process.

1996-01-01

333

Progress in the Modeling of NiAl-Based Alloys Using the BFS Method  

NASA Technical Reports Server (NTRS)

The BFS method has been applied to the study of NiAl-based materials to assess the effect of alloying additions on structure. Ternary, quaternary and even pent-alloys based on Ni-rich NiAl with additions of Ti, Cr and Cu were studied. Two approaches were used, Monte Carlo simulations to determine ground state structures and analytical calculations of high symmetry configurations which give physical insight into preferred bonding. Site occupancy energetics for ternary and the more complicated case of quaternary additions were determined, and solubility limits and precipitate formation with corresponding information concerning structure and lattice parameter were also 'observed' computationally. The method was also applied to determine the composition of alloy surfaces and interfaces. Overall, the results demonstrate that the BFS method for alloys is a powerful tool for alloy design and with its simplicity and obvious advantages can be used to complement any experimental alloy design program.

Bozzolo, Guillermo; Noebe, Ronald D.; Ferrante, John; Garg, Anita

1997-01-01

334

Adipokines and Osteoarthritis: Novel Molecules Involved in the Pathogenesis and Progression of Disease  

PubMed Central

Obesity has been considered a risk factor for osteoarthritis and it is usually accepted that obesity contributes to the development and progression of osteoarthritis by increasing mechanical load of the joints. Nevertheless, recent advances in the physiology of white adipose tissue evidenced that fat cells produce a plethora of factors, called adipokines, which have a critical role in the development of ostearthritis, besides to mechanical effects. In this paper, we review the role of adipokines and highlight the cellular and molecular mechanisms at play in osteoarthritis elicited by adipokines. We also emphasize how defining the role of adipokines has broadned our understanding of the diversity of factors involved in the genesis and progression of osteoarthritis in the hope of modifying it to prevent and treat diseases.

Conde, Javier; Scotece, Morena; Gomez, Rodolfo; Lopez, Veronica; Gomez-Reino, Juan Jesus; Gualillo, Oreste

2011-01-01

335

Periodontal disease progression and glycaemic control among Gullah African Americans with type-2 diabetes  

PubMed Central

Aim To evaluate associations between glycaemic control and periodontitis progression among Gullah African Americans with type-2 diabetes mellitus (T2DM). Materials and Methods From an ongoing clinical trial among T2DM Gullah, we extracted a cohort previously in a cross-sectional study (N 5 88). Time from baseline (previous study) to follow-up (trial enrollment, before treatment interventions) ranged 1.93–4.08 years [mean 5 2.99, standard deviation (SD) = 0.36]. We evaluated tooth site-level periodontitis progression [clinical attachment loss (CAL) worsening of ? 2 mm, periodontal probing depth (PPD) increases of ? 2 mm and bleeding on probing (BOP) from none to present] by glycaemic control status (well-controlled = HbA1c < 7%, poorly-controlled = HbA1c ? 7%) using multivariable generalized estimating equations logistic regression, nesting tooth sites/person. Results Poorly-controlled T2DM (68.18%) was more prevalent than well-controlled T2DM (31.82%). Proportions of tooth sites/person with CAL progression between baseline and follow-up ranged 0.00–0.59 (mean = 0.12, SD = 0.12), while PPD and BOP progression ranged 0.00–0.44 (mean = 0.09, SD = 0.11) and 0.00–0.96 (mean = 0.24, SD = 0.18), respectively. Site-level PPD at baseline was a significant effect modifier of associations between poorly-controlled T2DM and site-level CAL and PPD progression [adjusted odds ratios (OR) according to poorly-controlled T2DM among PPD at baseline = 3, 5 and 7 mm, respectively: CAL progression = 1.93, 2.64, and 3.62, PPD progression = 1.98, 2.76, and 3.84; p < 0.05 for all]. Odds of site-level BOP progression were increased (OR = 1.24) for poorly-controlled T2DM, yet the results were not significant (p = 0.32). Conclusions These findings from a distinct, homogenous population further support the clinical relevance of identifying patients with poor glycaemic control and periodontitis, particularly among those with disparities for both diseases.

Bandyopadhyay, Dipankar; Marlow, Nicole M.; Fernandes, Jyotika K.; Leite, Renata S.

2010-01-01

336

Myocardial perfusion imaging following percutaneous coronary intervention: the importance of restenosis, disease progression, and directed reintervention.  

PubMed

Percutaneous coronary intervention (PCI) has become a mainstay in the treatment of patients with coronary artery disease. Currently, more than one million coronary angioplasty and stent implantation procedures are performed annually. Although increasingly complex lesions and higher risk patients are being successfully treated percutaneously, restenosis and disease progression continue to cause significant morbidity. Restenosis occurs in approximately one-third of patients, one-half of who remain asymptomatic, while disease progression occurs at rates approaching 7% per year. Despite technological advances, unadjusted mortality rates have actually increased since the mid-1980s, and the current annual risk of a major adverse cardiac event following PCI is 5% to 7%. Although randomized clinical trials are needed to more definitively show a benefit, when performed six or more months following PCI, myocardial perfusion imaging reliably identifies patients most at risk of a poor long-term outcome. Directed reintervention can have a salutary impact on the prognosis of these patients. In view of recent data showing a positive impact of imaging and reintervention in patients after PCI, current guidelines should be reassessed. PMID:15013110

Giedd, Kenneth N; Bergmann, Steven R

2004-02-01

337

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

PubMed

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

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

2014-04-26

338

Disease Progression Mediated by Egr-1 Associated Signaling in Response to Oxidative Stress  

PubMed Central

When cellular reducing enzymes fail to shield the cell from increased amounts of reactive oxygen species (ROS), oxidative stress arises. The redox state is misbalanced, DNA and proteins are damaged and cellular transcription networks are activated. This condition can lead to the initiation and/or to the progression of atherosclerosis, tumors or pulmonary hypertension; diseases that are decisively furthered by the presence of oxidizing agents. Redox sensitive genes, like the zinc finger transcription factor early growth response 1 (Egr-1), play a pivotal role in the pathophysiology of these diseases. Apart from inducing apoptosis, signaling partners like the MEK/ERK pathway or the protein kinase C (PKC) can activate salvage programs such as cell proliferation that do not ameliorate, but rather worsen their outcome. Here, we review the currently available data on Egr-1 related signal transduction cascades in response to oxidative stress in the progression of epidemiologically significant diseases. Knowing the molecular pathways behind the pathology will greatly enhance our ability to identify possible targets for the development of new therapeutic strategies.

Pagel, Judith-Irina; Deindl, Elisabeth

2012-01-01

339

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

PubMed Central

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.

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

2014-01-01

340

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

341

AAV2/1-TNFR:Fc Gene Delivery Prevents Periodontal Disease Progression  

PubMed Central

SUMMARY Periodontal disease is a chronic inflammatory condition induced by tooth-associated microbial biofilms that induce a host immune response. Therapeutic control of progressive tissue destruction in high-risk patients is a significant challenge in therapy. Soluble protein delivery of antagonists to tumor necrosis factor alpha (TNF-?) inhibits alveolar bone resorption due to periodontitis. However, protein therapy raises several concerns, such as recurrence of disease activity after treatment cessation and repeated dosing regimens. In this study, we used pseudotyped adeno-associated virus vector based on serotype 1 (AAV2/1) to deliver the TNF receptor-immunoglobulin Fc (TNFR:Fc) fusion gene to rats subjected to experimental Porphyromonas gingivalis (Pg)-lipopolysaccharide (LPS)-mediated bone loss. Animals received Pg-LPS delivered to the gingivae thrice weekly for 8 weeks, vehicle alone, Pg-LPS and intramuscular delivery of pseudotyped AAV2/1-TNFR:Fc vector (1×1011 DNase I-resistant particles) or AAV2/1-TNFR:Fc vector delivered to naïve animals. AAV2/1-TNFR:Fc therapy led to sustained therapeutic levels of serum TNFR protein and protected against Pg-LPS-mediated loss of bone volume and density. Furthermore, AAV2/1-TNFR:Fc administration reduced local levels of multiple pro-inflammatory cytokines and osteoclast-like cells at the periodontal lesions. These findings suggest that delivery of AAV2/1-TNFR:Fc may be a viable approach to modulate periodontal disease progression.

Cirelli, Joni A; Park, Chan Ho; MacKool, Kathryn; Taba, Mario; Lustig, Kurt H; Burstein, Haim; Giannobile, William V

2008-01-01

342

Progress of mesenchymal stem cell therapy for neural and retinal diseases  

PubMed Central

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

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

2014-01-01

343

C868T Single Nucleotide Polymorphism and HIV Type 1 Disease Progression Among Postpartum Women in Kenya  

PubMed Central

Abstract The C868T single nucleotide polymorphism in the CD4 receptor encodes an amino acid substitution of tryptophan for arginine in the third domain. Previous studies suggest that C868T increases the risk of HIV-1 acquisition; however, the influence of this single nucleotide polymorphism (SNP) on disease progression has not been established. The presence of the C868T polymorphism was not statistically significantly associated with HIV-1 disease progression outcomes in a cohort of postpartum Kenyan women.

Fowke, Keith R.; Juno, Jennifer; Lohman-Payne, Barbara; Oyugi, Julius O.; Brown, Elizabeth R.; Bosire, Rose; John-Stewart, Grace; Farquhar, Carey

2012-01-01

344

C868T single nucleotide polymorphism and HIV type 1 disease progression among postpartum women in Kenya.  

PubMed

The C868T single nucleotide polymorphism in the CD4 receptor encodes an amino acid substitution of tryptophan for arginine in the third domain. Previous studies suggest that C868T increases the risk of HIV-1 acquisition; however, the influence of this single nucleotide polymorphism (SNP) on disease progression has not been established. The presence of the C868T polymorphism was not statistically significantly associated with HIV-1 disease progression outcomes in a cohort of postpartum Kenyan women. PMID:21902583

Choi, Robert Y; Fowke, Keith R; Juno, Jennifer; Lohman-Payne, Barbara; Oyugi, Julius O; Brown, Elizabeth R; Bosire, Rose; John-Stewart, Grace; Farquhar, Carey

2012-06-01

345

Progress in research on tick-borne diseases: theileriosis and heartwater.  

PubMed

The rapid population growth in subsaharan Africa necessitates a great increase in animal production in the more humid zones. Vector-borne diseases occurring in these zones will assume more importance, but are difficult to control. They include theileriosis and heartwater. Recent developments in research on these diseases are presented. Indigenous animal populations in endemic areas, subjected to natural selection, are far less susceptible than exotic stock. Heartwater, caused by the rickettsia Cowdria ruminantium, transmitted by Amblyomma ticks, causes high mortality in exotic ruminants. It has received much attention in recent years, partly because the disease has been introduced from Africa into the Caribbean and threatens the American mainland. Since the recent success of in vitro culture, much progress in research has been made, but so far prevention still relies mainly on acaricidal tick control; an infection and treatment method is used on a limited scale. Antigenic diversity is a complication for immunization procedures. Theileria parva (East Coast fever, Corridor disease and January disease) and T.annulata (Mediterranean or tropical theileriosis) are the most pathogenic of the 6 species of this protozoan genus that infect cattle. Great progress has been made in recent years in knowledge on the immunology, the epidemiology, the taxonomy and the chemotherapy of theileriosis. Intensive acaricidal tick control can now be supplemented by an attenuated schizont vaccine against T.annulata, while immunization against East Coast fever is carried out on a limited scale using virulent sporozoite infection and treatment. Research on recombinant vaccines is promising. Antigenic diversity in T.parva is a serious complication. PMID:8372422

Uilenberg, G; Dobbelaere, D A; de Gee, A L; Koch, H T

1993-06-01

346

Involvement of CCR6/CCL20/IL-17 Axis in NSCLC Disease Progression  

PubMed Central

Objectives Autocrine and paracrine chemokine/chemokine receptor-based interactions promote non-small-cell-lung-cancer (NSCLC) carcinogenesis. CCL20/CCR6 interactions are involved in prostatic and colonic malignancy pathogenesis. The expression and function of CCL20/CCR6 and its related Th-17 type immune response in NSCLC is not yet defined. We sought to characterize the role of the CCL20/CCR6/IL-17 axis in NSCLC tumor growth. Methods A specialized histopathologist blindly assessed CCL20/CCR6 expression levels in 49 tissue samples of NSCLC patients operated in our department. Results were correlated to disease progression. Colony assays, ERK signaling and chemokine production were measured to assess cancer cell responsiveness to CCL20 and IL-17 stimulation. Results CCL20 was highly expressed in the majority (38/49, 77.5%) of tumor samples. Only a minority of samples (8/49, 16.5%) showed high CCR6 expression. High CCR6 expression was associated with a shorter disease-free survival (P?=?0.008) and conferred a disease stage-independent 4.87-fold increased risk for disease recurrence (P?=?0.0076, CI 95% 1.52–15.563). Cancerous cell colony-forming capacity was increased by CCL20 stimulation; this effect was dependent in part on ERK phosphorylation and signaling. IL-17 expression was detected in NSCLC; IL-17 potentiated the production of CCL20 by cancerous cells. Conclusion Our findings suggest that the CCL20/CCR6 axis promotes NSCLC disease progression. CCR6 is identified as a potential new prognostic marker and the CCL20/CCR6/IL-17 axis as a potential new therapeutic target. Larger scale studies are required to consolidate these observations.

Amir, Gail; Demma, Jonathan; Vernea, Fiona; Beider, Katia; Shlomai, Zippora; Wald, Hanna; Zamir, Gideon; Shapira, Oz M.; Peled, Amnon; Wald, Ori

2011-01-01

347

Effect of tobacco smoking on tissue protein citrullination and disease progression in patients with rheumatoid arthritis  

PubMed Central

The aim of the present work was to study the effect of tobacco smoking on disease progression in rheumatoid arthritis patients and its relation to anti-cyclical citrullinated peptide (anti-CCP) antibodies. The study included 54 patients; 20 non-smokers, 9 ex-smokers, 14 mild to moderate smokers and 11 heavy smokers. Fifteen normal volunteers were also studied as controls. Disease stage was clinically and radiologically determined, rheumatoid factor (RF) and anti-CCP antibodies were measured in serum. Higher percentage of severe disease (stage III) was seen in heavy smoker patients than mild to moderate smokers (54.6% versus 35.7%) and in moderate smokers than ex-smokers (35.7% versus 33.6%). Lowest percentage of severe disease was seen in non-smokers (15%). RF and anti-CCP were significantly higher in smoker than non-smoker and in heavy than mild to moderate smoker patients (p < 0.01, p < 0.05 and p < 0.01, p < 0.001, respectively). In smoker patients, both RF and anti-CCP antibodies correlated significantly and positively with smoking index (r = 0.581, p < 0.001; r = 0.661, p < 0.001). Also, smoking index and anti-CCP correlated significantly and positively with disease stage (r = 0.424, p < 0.05; r = 0.523, p < 0.01). It appears from our results that, tobacco smoking mostly play a role in progression of rheumatoid arthritis through tissue protein citrullination. So all rheumatoid arthritis patients must quit completely to achieve a good control.

Alsalahy, Mahmoud M.; Nasser, Hamdy S.; Hashem, Manal M.; Elsayed, Sahar M.

2010-01-01

348

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

NASA Astrophysics Data System (ADS)

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

Kribus, A.

2006-01-01

349

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.

2013-01-01

350

Characterization of LEDGF/p75 Genetic Variants and Association with HIV-1 Disease Progression  

PubMed Central

Background As Lens epithelium-derived growth factor (LEDGF/p75) is an important co-factor involved in HIV-1 integration, the LEDGF/p75-IN interaction is a promising target for the new class of allosteric HIV integrase inhibitors (LEDGINs). Few data are available on the genetic variability of LEDGF/p75 and the influence on HIV disease in vivo. This study evaluated the relation between LEDGF/p75 genetic variation, mRNA expression and HIV-1 disease progression in order to guide future clinical use of LEDGINs. Methods Samples were derived from a therapy-naïve cohort at Ghent University Hospital and a Spanish long-term-non-progressor cohort. High-resolution melting curve analysis and Sanger sequencing were used to identify all single nucleotide polymorphisms (SNPs) in the coding region, flanking intronic regions and full 3?UTR of LEDGF/p75. In addition, two intronic tagSNPs were screened based on previous indication of influencing HIV disease. LEDGF/p75 mRNA was quantified in patient peripheral blood mononuclear cells (PBMC) using RT-qPCR. Results 325 samples were investigated from patients of Caucasian (n?=?291) and African (n?=?34) origin, including Elite (n?=?49) and Viremic controllers (n?=?62). 21 SNPs were identified, comprising five in the coding region and 16 in the non-coding regions and 3?UTR. The variants in the coding region were infrequent and had no major impact on protein structure according to SIFT and PolyPhen score. One intronic SNP (rs2737828) was significantly under-represented in Caucasian patients (P<0.0001) compared to healthy controls (HapMap). Two SNPs showed a non-significant trend towards association with slower disease progression but not with LEDGF/p75 expression. The observed variation in LEDGF/p75 expression was not correlated with disease progression. Conclusions LEDGF/p75 is a highly conserved protein. Two non-coding polymorphisms were identified indicating a correlation with disease outcome, but further research is needed to clarify phenotypic impact. The conserved coding region and the observed variation in LEDGF/p75 expression are important characteristics for clinical use of LEDGINs.

Messiaen, Peter; De Spiegelaere, Ward; Alcami, Jose; Vervisch, Karen; Van Acker, Petra; Verhasselt, Bruno; Meuwissen, Pieter; Calonge, Esther; Gonzalez, Nuria; Gutierrez-Rodero, Felix; Rodriguez-Martin, Carmen; Sermijn, Erica; Poppe, Bruce; Vogelaers, Dirk; Verhofstede, Chris; Vandekerckhove, Linos

2012-01-01

351

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

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

2012-01-01

352

Alzheimer's disease Braak Stage progressions: reexamined and redefined as Borrelia infection transmission through neural circuits.  

PubMed

Brain structure in health is a dynamic energized equation incorporating chemistry, neuronal structure, and circuitry components. The chemistry "piece" is represented by multiple neurotransmitters such as Acetylcholine, Serotonin, and Dopamine. The neuronal structure "piece" incorporates synapses and their connections. And finally circuits of neurons establish "architectural blueprints" of anatomic wiring diagrams of the higher order of brain neuron organizations. In Alzheimer's disease, there are progressive losses in all of these components. Brain structure crumbles. The deterioration in Alzheimer's is ordered, reproducible, and stepwise. Drs. Braak and Braak have described stages in the Alzheimer disease continuum. "Progressions" through Braak Stages benchmark "Regressions" in Cognitive function. Under the microscope, the Stages of Braak commence in brain regions near to the hippocampus, and over time, like a tsunami wave of destruction, overturn healthy brain regions, with neurofibrillary tangle damaged neurons "marching" through the temporal lobe, neocortex and occipital cortex. In effect the destruction ascends from the limbic regions to progressively destroy the higher brain centers. Rabies infection also "begins low and finishes high" in its wave of destruction of brain tissue. Herpes Zoster infections offer the paradigm of clinical latency of infection inside of nerves before the "marching commences". Varicella Zoster virus enters neurons in the pediatric years. Dormant virus remains inside the neurons for 50-80 years, tissue damage late in life (shingles) demonstrates the "march of the infection" down neural pathways (dermatomes) as linear areas of painful blisters loaded with virus from a childhood infection. Amalgamation of Zoster with Rabies models produces a hybrid model to explain all of the Braak Stages of Alzheimer's disease under a new paradigm, namely "Alzheimer's neuroborreliosis" in which latent Borrelia infections ascend neural circuits through the hippocampus to the higher brain centers, creating a trail of neurofibrillary tangle injured neurons in neural circuits of cholinergic neurons by transsynaptic transmission of infection from nerve to nerve. PMID:17113237

MacDonald, Alan B

2007-01-01

353

Absolute CD4+ T-Lymphocyte Count as a Surrogate Marker of Pediatric HIV Disease Progression  

PubMed Central

Background Traditionally in pediatric HIV, the CD4+ T-lymphocyte percent is used in monitoring disease progression due to the variability in absolute CD4+ T-lymphocyte numbers. Because of the high cost of equipment, sophisticated and delicate technology, most laboratories in resource-limited settings use simple protocols that enumerate only the absolute CD4+ T-lymphocyte counts. We assessed the use of absolute CD4+ T-lymphocyte count as a surrogate marker of pediatric HIV disease progression. Methods We analyzed the CD4+ T-lymphocytes and HIV viral load over a 10-year period (1996 to 2006) of 97 HIV-infected children enrolled in the Yale Prospective Longitudinal Pediatric HIV Cohort using generalized linear mixed models. Both CD4+ T-lymphocytes and HIV viral load were assessed at baseline and every 2-3 months. The modeling approach utilized in this study allows the intercept and the rate at which outcome variables change over time to vary across participants. Results We determined that absolute CD4+ T-lymphocytes count was just as reliable at monitoring pediatric HIV as CD4+ T-lymphocyte percentage. Antiretroviral treatment, regardless of the regimen used, was associated with higher CD+ T-lymphocytes count (p < 0.01). Race was significantly associated with CD4+ T-lymphocytes counts (with lower values for blacks compared to non-blacks; p < 0.01). The presence of other infections was associated with lower CD4+ T-lymphocyte count (p=0.01) and higher viral load (p<0.01, respectively). Conclusions In situations where determination of CD4+ T-lymphocyte percentages is not readily available, the absolute count may provide an affordable and accessible laboratory surrogate marker of HIV disease progression in children.

Paintsil, Elijah; Ghebremichael, Musie; Romano, Sostena; Andiman, Warren A.

2010-01-01

354

Imaging the nigrostriatal system to monitor disease progression and treatment-induced complications.  

PubMed

Radiotracer imaging (RTI) techniques such as positron emission tomography (PET) allow the in vivo assessment of nigrostriatal DA function in Parkinson's disease and have provided valuable insights into the mechanisms of nigrostriatal degeneration and the consequent compensatory changes. Moreover, functional imaging serves as an excellent tool in the assessment of the progression of PD and the evolution of treatment-related complications. However, various studies have shown discordance between clinical progression of PD and nigrostriatal degeneration estimated by PET or SPECT, and no RTI technique can be reliably used as a biomarker for progression of PD. Presynaptic dopaminergic imaging has consistently demonstrated an anterior-posterior gradient of dopaminergic dysfunction predominantly affecting the putamen, with side-to-side asymmetry in tracer binding. Dopaminergic hypofunction in the striatum follows a negative exponential pattern with the fastest rate of decline in early disease. Evaluation of central pharmacokinetics of levodopa action by PET has demonstrated the role of increased synaptic dopamine turnover and downregulation of the dopamine transporter in the pathophysiology of levodopa-induced dyskinesias. In PD with behavioral complications such as impulse control disorders, increased levels of dopamine release have been observed in the ventral striatum during performance of a positive reward task, as well as loss of deactivation in orbitofrontal cortex in response to negative reward prediction errors. This suggests that there is a pathologically heightened "reward" response in the ventral striatum together with loss of the capacity to respond to negative outcomes. Overall, functional imaging with PET is an excellent tool for understanding the disease and its complications; however, caution must be applied in interpretation of the results. PMID:20887875

Kuriakose, Renju; Stoessl, A Jon

2010-01-01

355

P2Y2 receptor deficiency aggravates chronic kidney disease progression.  

PubMed

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

356

Enzyme replacement therapy attenuates disease progression in two Japanese siblings with mucopolysaccharidosis type VI.  

PubMed

Mucopolysaccharidosis type VI (MPS VI) is a progressive, multisystem autosomal recessive lysosomal disorder resulting from deficient N-acetylgalactosamine-4-sulphatase (ASB) and the consequent accumulation of glycosaminoglycan (GAG). Preclinical and clinical studies had demonstrated clinical benefits of early initiation of systemic therapies in patients with MPS. In this case report, two siblings with MPS VI started enzyme replacement therapy (ERT) with weekly infusions of recombinant human ASB (Galsulfase) at 1mg/kg. Sibling 1 started ERT 5.6 years of age and Sibling 2 was 6 weeks old. The disease status in these two siblings prior to and for no less than 36 months of ERT was followed up and compared. The treatment was well tolerated by both siblings. During 36 months of ERT, symptoms typical of MPS VI including short stature, progressive dysmorphic facial features, hepatosplenomegaly, hearing impairment, corneal clouding, and dysostosis multiplex were largely absent in the younger sibling. Her cardiac functions and joint mobility were well preserved. On the other hand, her affected brother had typical MPS VI phenotypic features described above before commencing ERT at the equivalent age, of 3 years. There was significant improvement in the shoulder range of motion and hearing loss after 36 months of treatment and cardiac function was largely preserved. His skeletal deformity and short stature remained unchanged. The results showed that early ERT initiated at newborn is safe and effective in preventing or slowing down disease progression of MPS VI including bone deformities. These observations indicate that early diagnosis and treatment of MPS VI before development of an irreversible disease is critical for optimal clinical outcome. PMID:21930407

Furujo, Mahoko; Kubo, Toshihide; Kosuga, Motomichi; Okuyama, Torayuki

2011-12-01

357

Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy  

PubMed Central

Aims Duchenne muscular dystrophy (DMD) is a muscle disease with serious cardiac complications. Changes in Ca2+ homeostasis and oxidative stress were recently associated with cardiac deterioration, but the cellular pathophysiological mechanisms remain elusive. We investigated whether the activity of ryanodine receptor (RyR) Ca2+ release channels is affected, whether changes in function are cause or consequence and which post-translational modifications drive disease progression. Methods and results Electrophysiological, imaging, and biochemical techniques were used to study RyRs in cardiomyocytes from mdx mice, an animal model of DMD. Young mdx mice show no changes in cardiac performance, but do so after ?8 months. Nevertheless, myocytes from mdx pups exhibited exaggerated Ca2+ responses to mechanical stress and ‘hypersensitive’ excitation–contraction coupling, hallmarks of increased RyR Ca2+ sensitivity. Both were normalized by antioxidants, inhibitors of NAD(P)H oxidase and CaMKII, but not by NO synthases and PKA antagonists. Sarcoplasmic reticulum Ca2+ load and leak were unchanged in young mdx mice. However, by the age of 4–5 months and in senescence, leak was increased and load was reduced, indicating disease progression. By this age, all pharmacological interventions listed above normalized Ca2+ signals and corrected changes in ECC, Ca2+ load, and leak. Conclusion Our findings suggest that increased RyR Ca2+ sensitivity precedes and presumably drives the progression of dystrophic cardiomyopathy, with oxidative stress initiating its development. RyR oxidation followed by phosphorylation, first by CaMKII and later by PKA, synergistically contributes to cardiac deterioration.

Kyrychenko, Sergii; Polakova, Eva; Kang, Chifei; Pocsai, Krisztina; Ullrich, Nina D.; Niggli, Ernst; Shirokova, Natalia

2013-01-01

358

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.

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

2013-01-01

359

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

PubMed Central

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

2010-01-01

360

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

361

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

PubMed

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 compared an immunophilin ligand (V-10,367) documented to bind the immunophilin FKBP12 with V-13,661, which does not bind FKBP12. Both molecules could prevent the loss of striatal DA innervation in a dose-dependent fashion during 10 days of oral administration. Second, to determine whether an immunophilin ligand can protect against progressive and slow DA degeneration typical of PD, an intrastriatal 6-hydroxydopamine-infusion rat model was utilized. Oral treatment with the FKBP12-binding immunophilin ligand began on the day of lesion and continued for 21 days. At this time point, post mortem analyses revealed that the treatment had prevented the progressive loss of DA innervation within the striatum and loss of DA neurons within the substantia nigra, related to functional outcome as measured by rotational behaviour. Notably, DA fibres extending into the area of striatal DA denervation were observed only in rats treated with the immunophilin ligand, indicating neuroprotection or sprouting of spared DA fibres. This is the first demonstration that immunophilin ligands can prevent a slow and progressive DA axonal degeneration and neuronal death in vivo. The effects of orally administered structurally related immunophilin ligands in acute and progressive models of DA degeneration are consistent with the idea that these compounds may have therapeutic value in PD. PMID:11285005

Costantini, L C; Cole, D; Chaturvedi, P; Isacson, O

2001-03-01

362

Adult clinically amyopathic dermatomyositis with rapid progressive interstitial lung disease: a retrospective cohort study.  

PubMed

The aim of the study was to investigate the characteristics of adult clinically amyopathic dermatomyositis (CADM) with rapid progressive interstitial lung disease (ILD). Hospitalized patients with dermatomyositis (DM) and polymyositis (PM) between 1998 and 2005 in the Shanghai Renji Hospital were retrospectively studied. One hundred and forty-five patients were classified into CADM, classic DM or PM according to the modified Sontheimer's definition or Bohan-Peter's classification criteria. They were further stratified based on the presence or absence of clinical ILD. The Kaplan-Meier survival analysis and COX regression were performed. The predictive factors for ILD and other clinical properties of CADM-ILD were explored. The presence of clinical ILD was a significant risk factor for the poor outcome of DM/PM (OR = 4.237, CI 95%: 1.239-14.49, p = 0.021). Other risk factors are the presence of rashes and elevated urea nitrogen. Patients with DM/PM complicated by ILD had different clinical courses. Patients with CADM-ILD showed a rapidly progressive pattern with 6-month survival rate of 40.8%. The DM-ILD manifested a progressive pattern with a 5-year survival rate of 54%, while PM-ILD was chronic with 5- and 10-year survival rate of 72.4% and 60.3%, respectively. Better preserved muscle strength, elevated erythrocyte sedimentation rate, and hypoalbuminemia may herald ILD in DM/PM. Patients with CADM-ILD who later died had lower PO(2), higher lactate dehydrogenase, and prominent arthritis/arthralgia compared with those who survived. The presence of antinuclear antibody seems to be protective. Rapid progressive CADM-ILD is refractory to conventional treatment. ILD is a common complication in over 40% of our hospitalized DM/PM cohort and is also a prominent prognostic indicator. CADM is a special phenotype of DM/PM. CADM-ILD, which is usually rapidly progressive and fatal, requires further investigation. PMID:17308858

Ye, Shuang; Chen, Xiao-xiang; Lu, Xiao-ye; Wu, Mei-fang; Deng, Yun; Huang, Wen-qun; Guo, Qiang; Yang, Cheng-de; Gu, Yue-ying; Bao, Chun-de; Chen, Shun-le

2007-10-01

363

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.

2012-01-01

364

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.

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

2012-01-01

365

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.

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

2013-01-01

366

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

PubMed Central

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.

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

2014-01-01

367

Rapid Progression of Cerebral Infarction after Intraventricular Hemorrhage in Adult Moyamoya Disease  

PubMed Central

The authors present a rare case of adult moyamoya disease in which a patient experienced rapid progression of cerebral infarction after intraventricular hemorrhage (IVH). A healthy 39-year-old woman was admitted to our hospital with sudden headache, a decreased level of consciousness and mild tetraparesis. Initial magnetic resonance imaging revealed small cerebral infarction and IVH. Although the patient underwent conservative therapy including hypervolemia, hemodilution, keeping moderate hypertension and administration of a free radical scavenger, she showed a fulminant clinical course of cerebral infarction. The authors discuss the possible pathophysiology and suggest the treatment for such cases.

Yoshida, Yasuhisa

2013-01-01

368

Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological characterization of SIRT1 and SIRT2 pathways.  

PubMed

Acetylation homeostasis is thought to play a role in amyotrophic lateral sclerosis, and treatment with inhibitors of histone deacetylases has been considered a potential and attractive therapeutic approach, despite the lack of a thorough study of this class of proteins. In this study, we have considerably extended previous knowledge on the expression of 13 histone deacetylases in tissues (spinal cord and muscle) from mice carrying two different ALS-linked SOD1 mutations (G93A-SOD1 and G86R-SOD1). We have then focused on class III histone deacetylases SIRT1 and SIRT2 that are considered relevant in neurodegenerative diseases. SIRT1 decreases in the spinal cord, but increases in muscle during the progression of the disease, and a similar expression pattern is observed in the corresponding cell models (neuroblastoma and myoblasts). SIRT2 mRNA expression increases in the spinal cord in both G93A-SOD1 and G86R-SOD1 mice but protein expression is substantially unchanged in all the models examined. At variance with other sirtuin modulators (sirtinol, AGK2 and SRT1720), the well-known SIRT1 inhibitor Ex527 has positive effects on survival of neuronal cells expressing mutant SOD1, but this effect is neither mediated by SIRT1 inhibition nor by SIRT2 inhibition. These data call for caution in proposing sirtuin modulation as a target for treatment. PMID:24946089

Valle, C; Salvatori, I; Gerbino, V; Rossi, S; Palamiuc, L; René, F; Carrì, M T

2014-01-01

369

Role of testosterone in the pathogenesis, progression, prognosis and comorbidity of men with chronic kidney disease.  

PubMed

Testosterone deficiency and hypogonadism are common conditions in men with chronic kidney disease (CKD). A disturbed hypothalamic-pituitary-gonadal axis due to CKD is thought to contribute to androgen deficiency. Data from experimental studies support the hypothesis that exogenous administration of testosterone may induce the activation of the renin-angiotensin system (RAS), the production of endothelin and the regulation of anti- or/and proinflammatory cytokines involved in the pathogenesis of hypertension and kidney damage. On the other hand, low testosterone levels in male patients with CKD are paradoxically associated with a higher risk of morbidity and mortality, possibly explained by anemia, osteoporosis and cardiovascular disease. In this article, we present an overview of clinical and experimental studies of the impact of testosterone on the progression and prognosis of male patients with CKD; even today, this remains a controversial issue. PMID:24119223

Dousdampanis, Periklis; Trigka, Konstantina; Fourtounas, Costas; Bargman, Joanne M

2014-06-01

370

[Research progress on minimal residual disease in acute leukemia detected by multiparametric flow cytometry].  

PubMed

In recent years, with the advent of new chemotherapeutic agents, the treatment of acute leukemia has made a great progress and its complete remission rate is up to 50%-80% in patients. However, some patients still relapse in 3 to 5 years after diagnosis. It is believed that the main cause is related to the minimal residual disease (MRD). At present, multiparametric flow cytometry (MFC) with high sensitivity and accurate quantity is one of the effective methods for detecting MRD. Leukemia cells and normal cells are differentiated by analyzing different immunophenotypes. The monotoring of MRD by MFC can help to assess efficacy of treatment, guide treatment selection and predict recurrence of the disease. This article reviewed advantages, challenges, clinical significance and prospect of MFC in detecting MRD. PMID:24989307

Jing, Hui; Feng, Ru

2014-05-01

371

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

PubMed Central

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

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

2012-01-01

372

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

PubMed

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease primarily affecting motor neurons. Mutations in the gene encoding TDP-43 cause some forms of the disease, and cytoplasmic TDP-43 aggregates accumulate in degenerating neurons of most individuals with ALS. Thus, strategies aimed at targeting the toxicity of cytoplasmic TDP-43 aggregates may be effective. Here, we report results from two genome-wide loss-of-function TDP-43 toxicity suppressor screens in yeast. The strongest suppressor of TDP-43 toxicity was deletion of DBR1, which encodes an RNA lariat debranching enzyme. We show that, in the absence of Dbr1 enzymatic activity, intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP-43, preventing it from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of Dbr1 in a human neuronal cell line or in primary rat neurons is also sufficient to rescue TDP-43 toxicity. Our findings provide insight into TDP-43-mediated cytotoxicity and suggest that decreasing Dbr1 activity could be a potential therapeutic approach for ALS. PMID:23104007

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

2012-12-01

373

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

PubMed Central

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

Latuskiewicz-Potemska, Joanna; Biernacka-Zielinska, Malgorzata; Stanczyk, Jerzy; Smolewska, Elzbieta

2013-01-01

374

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

PubMed Central

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

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

2013-01-01

375

Disease Progression Among Untreated HIV-Infected Patients in South Ethiopia: Implications for Patient Care  

PubMed Central

Context The natural course of HIV disease progression among resource-poor patient populations has not been clearly defined. Objective To describe predictors of HIV disease progression as seen at an outpatient clinic in a resource-limited setting in rural Ethiopia. Design This prospective cohort study included all adult HIV patients who visited an outpatient clinic at Arba Minch hospital in South Ethiopia between January 30, 2003 and April 1, 2004. Clinical and hematologic measurements were done at baseline and every 12 weeks thereafter until the patient was transferred, put on antiretroviral therapy, was lost to follow-up, or died. Community agents reported patient status every month. Setting A district hospital with basic facilities for HIV testing and patient monitoring. Main Outcome Measures Death, diagnosis of tuberculosis, and change in disease stage. Results We followed 207 patients for a median duration of 19 weeks (range, 0–60 weeks). A total of 132 (64%) of them were in WHO stage III. The overall mortality rate was 46 per 100 person-years of observation (PYO). Mortality increased with advancing disease stage. Diarrhea, oral thrush, and low total lymphocyte count were significant markers of mortality. The incidence of tuberculosis was 9.9 per 100 PYO. Baseline history of easy fatigability and fever were strongly associated with subsequent development of tuberculosis. Conclusions The mortality rate and the incidence of tuberculosis in our cohort are among the highest ever reported in sub-Saharan Africa. We identified oral thrush, diarrhea, and total lymphocyte count as predictors of mortality, and easy fatigability and fever as predictors of tuberculosis. The findings have practical implications for patient care in resource-limited settings.

Jerene, Degu; Lindtj?rn, Bernt

2005-01-01

376

Disease Progression Among Untreated HIV-Infected Patients in South Ethiopia: Implications for Patient Care  

PubMed Central

Context The natural course of HIV disease progression among resource-poor patient populations has not been clearly defined. Objective To describe predictors of HIV disease progression as seen at an outpatient clinic in a resource-limited setting in rural Ethiopia. Design This prospective cohort study included all adult HIV patients who visited an outpatient clinic at Arba Minch hospital in South Ethiopia between January 30, 2003 and April 1, 2004. Clinical and hematologic measurements were done at baseline and every 12 weeks thereafter until the patient was transferred, put on antiretroviral therapy, was lost to follow-up, or died. Community agents reported patient status every month. Setting A district hospital with basic facilities for HIV testing and patient monitoring. Main Outcome Measures Death, diagnosis of tuberculosis, and change in disease stage. Results We followed 207 patients for a median duration of 19 weeks (range, 0–60 weeks). A total of 132 (64%) of them were in WHO stage III. The overall mortality rate was 46 per 100 person-years of observation (PYO). Mortality increased with advancing disease stage. Diarrhea, oral thrush, and low total lymphocyte count were significant markers of mortality. The incidence of tuberculosis was 9.9 per 100 PYO. Baseline history of easy fatigability and fever were strongly associated with subsequent development of tuberculosis. Conclusion The mortality rate and the incidence of tuberculosis in our cohort are among the highest ever reported in sub-Saharan Africa. We identified oral thrush, diarrhea, and total lymphocyte count as predictors of mortality, and easy fatigability and fever as predictors of tuberculosis. The findings have practical implications for patient care in resource-limited settings.

2005-01-01

377

Rotigotine treatment partially protects from MPTP toxicity in a progressive macaque model of Parkinson's disease.  

PubMed

Clinical DA agonist monotherapy trials, which used in vivo imaging of the DA transporter (DAT) to assess the rate of progression of nigrostriatal degeneration, have failed to demonstrate consistent evidence for neuroprotection. The present study aims at reconciling these experimental and clinical data by testing the protective property of the continuously delivered D3/D2/D1 dopamine receptor agonist rotigotine. Using a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned (MPTP) macaque model that mimics the progression of Parkinson's disease in vivo ([99mTc]-TRODAT-1 single photon emission computed tomography (SPECT)) and ex vivo ([125I]-nortropane DAT labelling) endpoints were evaluated. After 38 days of treatment followed by two weeks of washout, rotigotine-treated animals were significantly less parkinsonian than the vehicle-treated ones. Such behavioural difference is the consequence of a partial protection of the DA terminals as could be confirmed by ex vivo DAT labelling. However, the protection of nerve terminals was not detected using SPECT. The data suggest that rotigotine exerts partial protection but that conventional imaging would not be able to identify such protection. PMID:17045989

Scheller, Dieter; Chan, Piu; Li, Qin; Wu, Tao; Zhang, Renling; Guan, Le; Ravenscroft, Paula; Guigoni, Celine; Crossman, Alan R; Hill, Michael; Bezard, Erwan

2007-02-01

378

Progressive micrographia shown in horizontal, but not vertical, writing in Parkinson's disease.  

PubMed

All published studies on micrographia, a diminution of letter size, examine handwriting in the horizontal direction. Writing horizontally typically requires increased wrist extension as handwriting progresses from left to right. Chinese characters, however, can be written not only horizontally from left to right, but also vertically from top to bottom. We examined the effect of handwriting direction on character size and stroke length. Fifteen participants with Parkinson's disease (PD) and 15 age-matched controls wrote the same Chinese characters both horizontally and vertically. Handwriting performance was recorded with a digitizing tablet, and a custom-written computer program was used to provide objective data about character size and stroke length. The PD group had a linear decrease in overall character size and horizontal strokes along the writing sequence in the horizontal direction, but not in the vertical direction. The controls had shorter horizontal strokes in the horizontal than the vertical direction, but there was no progressive shortening of stroke length along the writing sequence. The results suggest that traditionally reported progressive micrographia in horizontal writing may not be generalizable to vertical writing. The observed decrease of handwriting size in the horizontal direction suggests that micrographia in PD may be associated with wrist extension. For clinical implications, patients may mitigate their micrographia by changing handwriting direction. PMID:23242350

Ma, Hui-Ing; Hwang, Wen-Juh; Chang, Shao-Hsia; Wang, Tsui-Ying

2013-01-01

379

Progressive development of polycystic kidney disease in the mouse model expressing Pkd1 extracellular domain.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by slow progression of multiple cysts in both kidneys that lead to renal insufficiency in mid-life or later. ADPKD is associated with mutations mainly in the PKD1 gene (encoding polycystin-1 or PC1) and less frequently in the PKD2 gene (encoding polycystin-2 or PC2). To mimic naturally occurring human PKD1 mutations and gain insight into the PC1 extracellular domain function, four transgenic mouse lines were established with exclusively the extracellular domain of the Pkd1 gene (Pkd1(extra)) under endogenous transcriptional regulation. Expression of the Pkd1(extra) transgene was 2- to 80-fold above endogenous levels. Strikingly, the Pc1(extra) protein was more abundant, proportionally to the endogenous levels. All four transgenic mouse lines consistently displayed progressive renal cystic phenotype. Consequently, these transgenic mice reproducibly developed renal functional alterations similar to human ADPKD with proteinuria, renal insufficiency, anemia and died of renal failure late in life. In precystic kidneys, the Pkd1(extra) transgene modulated Pc2 expression and thereby, uncovered a potential Pc1-mutant/Pc2 pathogenic crosstalk mechanism. Moreover, the pathophysiologic mechanism also implicates c-myc, a major modulator of cystogenesis. Altogether, the novel Pkd1(extra) mouse model is the first Pc1 extracellular mutant that reproduces human ADPKD clinical progression and physiopathology. PMID:23439951

Kurbegovic, Almira; Trudel, Marie

2013-06-15

380

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

381

The morphology of myeloma cells changes with progression of the disease  

PubMed Central

Aim of the study Multiple myeloma is a heterogeneous entity with variable course. Plasma cells found in bone marrow smears are characterised by extremely high diversity of morphology. We have attempted to determine whether the morphological characteristics of myeloma cells vary with the natural course of the disease. We investigated the incidence of selected morphological features and planimetric parameters of myeloma cells present in bone marrow smears. Material and methods Material collected from 103 patients was evaluated at diagnosis and then during relapse. It was found that in the same patients, plasma cell morphology changes in the course of the disease: cell surface, nucleus surface, tumour cell anisocytosis and nuclear-cytoplasmic ratio increase significantly. Results The results suggest that some morphological features are more common in clinically advanced disease. These include the number of nucleoli, the number of myeloma cells with irregular nuclei, and larger nuclei. Using the classification systems according to Greipp and Goasguen, we have noted changes in morphological pattern of myeloma cells in some patients with progressive multiple myeloma. This was associated with the appearance of a cell clone characterised by a set of traits indicating a low degree of maturity. Conclusions We did not find that the type and intensity of cytostatic therapy significantly affect the morphology of plasma cells. Therefore, we suggest that some changes are due to natural, expansive course of the disease.

Sawicki, Waldemar

2013-01-01