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1.  Outcomes After Implantable Left Ventricular Assist Device Replacement Procedures 
As the duration of support increases for patients with continuous flow left ventricular assist devices (LVADs), device replacement may still be necessary for a variety of indications. Outcomes after replacement LVAD surgeries have not been extensively described, and whether these patients experience outcomes similar to primary LVAD implant patients remains unclear. From 2003 to 2012, 342 consecutive implantable LVAD procedures took place at a single institution, of which 201 were considered destination therapy. Within this larger group, 30 patients underwent 35 replacement procedures. The three major indications for replacement LVAD procedures were mechanical/electrical failure (57%), hemolysis/thrombosis (29%), and infection (14%). Propensity matching using preoperative characteristics was used to generate a primary implant control group to determine the impact of the replacement status on outcomes. Thirty-day and 1-year survival after LVAD replacement was 90% and 48%, respectively. Survival outcomes were worse for patients undergoing device replacement compared with the matched primary cohort (p = 0.03). The need for transfusion and the incidence of postoperative right ventricular and renal dysfunction were similar between the two groups, as was length of hospitalization. There was no difference between the rates of postoperative infection or stroke. Emergent replacement procedures had a higher mortality than those done nonemergently. Given these findings, earlier timing for replacement, temporary stabilization with an extracorporeal device, and use of a nonsternotomy surgical approach should be investigated as strategies to improve outcomes.
PMCID: PMC4330192  PMID: 24270234
circulatory assist devices; reoperation; circulatory assist device; outcomes; statistics; survival analysis
2.  Association of Weight Change With Subsequent Outcomes in Patients Hospitalized with Acute Decompensated Heart Failure 
Association of weight loss achieved through various decongestive strategies with clinical outcomes in acute decompensated heart failure (HF) patients is not well described. Our goal was to determine the relationship between weight change during hospitalization and subsequent clinical events in decompensated HF patients. We evaluated data on 433 patients hospitalized with advanced HF enrolled in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. The influence of change in weight during hospitalization to clinical outcomes (days alive out of hospital in the first 6 months; death; death or rehospitalization; and death, rehospitalization or cardiac transplantation) was evaluated. On average patients lost approximately 3.6 Kg during hospitalization. When categorized into 3 weight loss tertiles, those in highest tertile were more likely to be older, females, smokers, with higher body weight, prior percutaneous coronary intervention(s), baseline heart rate, and BNP and blood urea nitrogen values, but lower ejection fraction and peak oxygen consumptions. No significant differences were observed between weight change and any in-hospital or follow-up events (days well HR 0.995 [95% CI 0.975–1.016]; 180 days death HR 1.012 [95% CI 0.969–1.057]; death/rehospitalization-180 days HR 1.014 [95% CI 0.990–1.038]). In conclusions, weight loss in patients with acute decompensated HF during hospitalization was not related to clinical end-points. This data challenges the merit of using weight as a surrogate endpoint for more important clinical events i.e. death and/or rehospitalization in patients with heart failure in the design of treatment strategies for novel therapeutic agents in randomized controlled clinical trials.
PMCID: PMC4286241  PMID: 19101234
heart failure; weight; outcomes
3.  VAD therapy 20/20: moving beyond the myopic view of a nascent therapy 
Annals of Cardiothoracic Surgery  2014;3(6):603-605.
The past five years have seen remarkable growth in the use of durable, continuous flow left ventricular assist devices (LVAD) with associated improvements in mortality, quality of life, functionality and end-organ function. To sustain the growth of this important therapy, the LVAD community must now address key issues focused around the costs of LVAD care, refined patient selection, and reducing complications associated with this therapy. In this perspective piece, we discuss many of these issues.
PMCID: PMC4250546  PMID: 25512902
Mechanical support; ventricular assist devices (VAD); advanced heart failure
4.  Dysphagia in the Setting of Left Ventricular Assist Device Hemolysis 
A 69-year-old man with advanced heart failure treated with a continuous-flow left ventricular assist device presented for evaluation of dark urine and severe dysphagia. Because of evidence of ongoing intravascular hemolysis with device dysfunction, there was a clinical suspicion for pump thrombosis. He had progressive end-organ dysfunction and was therefore treated with tissue plasminogen activator with prompt resolution in hemolysis and dysphagia. Although symptoms of smooth muscle dystonia could represent worsening heart failure in the setting of device failure, the observation may also be related to intravascular hemolysis as described in the prototypic hemolytic disease, paroxysmal nocturnal hemoglobinuria.
PMCID: PMC4158398  PMID: 23644623
left ventricular assist device; thrombosis; hemolysis; dysphagia
5.  PathoScope 2.0: a complete computational framework for strain identification in environmental or clinical sequencing samples 
Microbiome  2014;2:33.
Recent innovations in sequencing technologies have provided researchers with the ability to rapidly characterize the microbial content of an environmental or clinical sample with unprecedented resolution. These approaches are producing a wealth of information that is providing novel insights into the microbial ecology of the environment and human health. However, these sequencing-based approaches produce large and complex datasets that require efficient and sensitive computational analysis workflows. Many recent tools for analyzing metagenomic-sequencing data have emerged, however, these approaches often suffer from issues of specificity, efficiency, and typically do not include a complete metagenomic analysis framework.
We present PathoScope 2.0, a complete bioinformatics framework for rapidly and accurately quantifying the proportions of reads from individual microbial strains present in metagenomic sequencing data from environmental or clinical samples. The pipeline performs all necessary computational analysis steps; including reference genome library extraction and indexing, read quality control and alignment, strain identification, and summarization and annotation of results. We rigorously evaluated PathoScope 2.0 using simulated data and data from the 2011 outbreak of Shiga-toxigenic Escherichia coli O104:H4.
The results show that PathoScope 2.0 is a complete, highly sensitive, and efficient approach for metagenomic analysis that outperforms alternative approaches in scope, speed, and accuracy. The PathoScope 2.0 pipeline software is freely available for download at:
PMCID: PMC4164323  PMID: 25225611
6.  Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer’s disease 
Neuron  2013;79(5):873-886.
Phagocytosis controls CNS homeostasis by facilitating the removal of unwanted cellular debris. Accordingly, impairments in different receptors or proteins involved in phagocytosis result in enhanced inflammation and neurodegeneration. While various studies have identified extrinsic factors that modulate phagocytosis in health and disease, key intracellular regulators are less understood. Here we show that the autophagy protein beclin 1 is required for efficient phagocytosis in vitro and in mouse brains. Furthermore, we show that beclin 1-mediated impairments in phagocytosis are associated with dysfunctional recruitment of retromer to phagosomal membranes, reduced retromer levels, and impaired recycling of phagocytic receptors CD36 and Trem2. Interestingly, microglia isolated from human Alzheimer’s disease (AD) brains show significantly reduced beclin 1 and retromer protein levels. These findings position beclin 1 as a link between autophagy, retromer trafficking, and receptor-mediated phagocytosis and provide insight into mechanisms by which phagocytosis is regulated and how it may become impaired in AD.
PMCID: PMC3779465  PMID: 24012002
7.  Clinical PathoScope: rapid alignment and filtration for accurate pathogen identification in clinical samples using unassembled sequencing data 
BMC Bioinformatics  2014;15(1):262.
The use of sequencing technologies to investigate the microbiome of a sample can positively impact patient healthcare by providing therapeutic targets for personalized disease treatment. However, these samples contain genomic sequences from various sources that complicate the identification of pathogens.
Here we present Clinical PathoScope, a pipeline to rapidly and accurately remove host contamination, isolate microbial reads, and identify potential disease-causing pathogens. We have accomplished three essential tasks in the development of Clinical PathoScope. First, we developed an optimized framework for pathogen identification using a computational subtraction methodology in concordance with read trimming and ambiguous read reassignment. Second, we have demonstrated the ability of our approach to identify multiple pathogens in a single clinical sample, accurately identify pathogens at the subspecies level, and determine the nearest phylogenetic neighbor of novel or highly mutated pathogens using real clinical sequencing data. Finally, we have shown that Clinical PathoScope outperforms previously published pathogen identification methods with regard to computational speed, sensitivity, and specificity.
Clinical PathoScope is the only pathogen identification method currently available that can identify multiple pathogens from mixed samples and distinguish between very closely related species and strains in samples with very few reads per pathogen. Furthermore, Clinical PathoScope does not rely on genome assembly and thus can more rapidly complete the analysis of a clinical sample when compared with current assembly-based methods. Clinical PathoScope is freely available at:
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2105-15-262) contains supplementary material, which is available to authorized users.
PMCID: PMC4131054  PMID: 25091138
8.  Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer’s disease 
Neurobiology of aging  2012;34(6):1653-1661.
Synapses are essential for transmitting, processing, and storing information, all of which decline in aging and Alzheimer’s disease (AD). Because synapse loss only partially accounts for the cognitive declines seen in aging and AD, we hypothesized that existing synapses might undergo molecular changes that reduce their functional capacity. Microarrays were used to evaluate expression profiles of 340 synaptic genes in aging (20–99 years) and AD across 4 brain regions from 81 cases. The analysis revealed an unexpectedly large number of significant expression changes in synapse-related genes in aging, with many undergoing progressive downregulation across aging and AD. Functional classification of the genes showing altered expression revealed that multiple aspects of synaptic function are affected, notably synaptic vesicle trafficking and release, neurotransmitter receptors and receptor trafficking, postsynaptic density scaffolding, cell adhesion regulating synaptic stability, and neuromodulatory systems. The widespread declines in synaptic gene expression in normal aging suggests that function of existing synapses might be impaired, and that a common set of synaptic genes are vulnerable to change in aging and AD.
PMCID: PMC4022280  PMID: 23273601
Microarray; Synaptic vesicle trafficking; Neurotransmitter receptors; Scaffolding molecules; Cortex; Limbic; Molecular reprogramming
9.  Coupled Folding and Binding of the Disordered Protein PUMA Does Not Require Particular Residual Structure 
Many cellular proteins are ‘disordered’ in isolation. A subset of these intrinsically disordered proteins (IDPs) can, upon binding another molecule, fold to a well-defined three-dimensional structure. In the structurally heterogeneous, unbound ensemble of these IDPs, conformations are likely to exist that, in part, resemble the final bound form. It has been suggested that these conformations, displaying ‘residual structure’, could be important for the mechanism of such coupled folding and binding reactions. PUMA, of the BCL-2 family, is an IDP in isolation but will form a single, contiguous α-helix upon binding the folded protein MCL-1. Using the helix-breaking residue proline, we systematically target each potential turn of helix of unbound PUMA and assess the binding to MCL-1 using time-resolved stopped-flow techniques. All proline-containing mutants bound, and although binding was weaker than the wild-type protein, association rate constants were largely unaffected. We conclude that population of particular residual structure, containing a specific helical turn, is neither required for the binding nor for fast association of PUMA and MCL-1.
PMCID: PMC4017604  PMID: 24654952
10.  Prevalence and Clinical Characteristics of Mental Stress–Induced Myocardial Ischemia in Patients With Coronary Heart Disease 
The goal of this study was to evaluate the prevalence and clinical characteristics of mental stress–induced myocardial ischemia.
Mental stress–induced myocardial ischemia is prevalent and a risk factor for poor prognosis in patients with coronary heart disease, but past studies mainly studied patients with exercise-induced myocardial ischemia.
Eligible patients with clinically stable coronary heart disease, regardless of exercise stress testing status, underwent a battery of 3 mental stress tests followed by a treadmill test. Stress-induced ischemia, assessed by echocardiography and electrocardiography, was defined as: 1) development or worsening of regional wall motion abnormality; 2) left ventricular ejection fraction reduction ≥8%; and/or 3) horizontal or downsloping ST-segment depression ≥1 mm in 2 or more leads lasting for ≥3 consecutive beats during at least 1 mental test or during the exercise test.
Mental stress–induced ischemia occurred in 43.45%, whereas exercise-induced ischemia occurred in 33.79% (p = 0.002) of the study population (N = 310). Women (odds ratio [OR]: 1.88), patients who were not married (OR: 1.99), and patients who lived alone (OR: 2.24) were more likely to have mental stress–induced ischemia (all p < 0.05). Multivariate analysis showed that compared with married men or men living with someone, unmarried men (OR: 2.57) and married women (OR: 3.18), or living alone (male OR: 2.25 and female OR: 2.72, respectively) had higher risk for mental stress-induced ischemia (all p < 0.05).
Mental stress-induced ischemia is more common than exercise-induced ischemia in patients with clinically stable coronary heart disease. Women, unmarried men, and individuals living alone are at higher risk for mental stress-induced ischemia. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847)
PMCID: PMC3913125  PMID: 23410543
mental and exercise stress; myocardial ischemia
11.  p53 isoform profiling in glioblastoma and injured brain 
Oncogene  2012;32(26):3165-3174.
The tumor suppressor p53 has been found to be the most commonly mutated gene in human cancers; however, the frequency of p53 mutations varies from 10–70% across different cancer types. This variability can partly be explained by inactivating mechanisms aside from direct genomic polymorphisms. The p53 gene encodes 12 isoforms, which have been shown to modulate full-length p53 activity in cancer. In this study, we characterized p53 isoform expression patterns in glioblastoma, gliosis, non-tumor brain, and neural progenitor cells by SDS-PAGE, immunoblot, mass spectrometry, and RT-PCR.
At the protein level, we found that the most consistently expressed isoform in glioblastoma, Δ40p53, was uniquely expressed in regenerative processes, such as those involving neural progenitor cells and gliosis compared to tumor samples. Isoform profiling of glioblastoma tissues revealed the presence of both Δ40p53 and full-length p53, neither of which were detected in non-tumor cerebral cortex. Upon xenograft propagation of tumors, p53 levels increased. The variability of overall p53 expression and relative levels of isoforms suggest fluctuations in subpopulations of cells with greater or lesser capacity for proliferation, which can change as the tumor evolves under different growth conditions.
PMCID: PMC3904233  PMID: 22824800
gliosis; regeneration; astrocytoma
12.  Inflammation and Alzheimer’s disease 
Neurobiology of aging  2000;21(3):383-421.
Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer’s disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid β peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.
PMCID: PMC3887148  PMID: 10858586
Alzheimer’s disease; Inflammation; Nervous system; Neuroinflammation; Complement; Cytokine; Chemokine; Acute phase protein; Microglia; Astrocyte; Neuron
13.  Triage After Hospitalization with Advanced Heart Failure: The ESCAPE Risk Model and Discharge Score 
Journal of the American College of Cardiology  2010;55(9):10.1016/j.jacc.2009.08.083.
Identifying high-risk heart failure (HF) patients at hospital discharge may allow more effective triage to management strategies.
HF severity at presentation predicts outcomes, but the prognostic importance of clinical status changes due to interventions is less well described.
Predictive models using variables obtained during hospitalization were created using data from ESCAPE and internally validated by bootstrapping method. Model coefficients were converted to an additive risk score. Additionally, data from the FIRST (Flolan International Randomized Survival Trial) was used to externally validate this model.
Patients discharged with complete data (n=423) had 6-month mortality and death or rehospitalization rates of 18.7% and 64%. Discharge risk factors for mortality included BNP, per doubling (Hazard Ration [HR]: 1.42, 95% confidence interval [CI]: 1.15–1.75), cardiopulmonary resuscitation or mechanical ventilation during hospitalization (HR: 2.54, 95% CI: 1.12–5.78), blood urea nitrogen, per 20-U increase) (HR: 1.22, 95% CI: 0.96–1.55), serum sodium, per unit increase (HR: 0.93, 95% CI: 0.87–0.99), age >70 (HR: 1.05, 95% CI: 0.51–2.17), daily loop diuretic, furosemide equivalents >240 mg (HR: 1.49, 95% CI: 0.68–3.26), lack of beta-blocker (HR: 1.28, 95% CI: 0.68–2.41), and 6-minute walk, per 100 feet increase (HR: 0.955, 95% CI: 0.99–1.00; c index 0.76. A simplified discharge score discriminated mortality risk from 5% (score=0) to 94% (score =8). Bootstrap validation demonstrated good internal validation of the model (c index 0.78, 95% CI: 0.68–0.83).
The ESCAPE discharge risk model and score refine risk assessment after inhospital therapy for advanced decompensated systolic HF, allowing clinicians to focus surveillance and triage for early life-saving interventions in this high-risk population.
PMCID: PMC3835158  PMID: 20185037
heart failure; risk stratification; discharge risk model
14.  Folding and Binding of an Intrinsically Disordered Protein: Fast, but Not ‘Diffusion-Limited’ 
Coupled folding and binding of intrinsically disordered proteins (IDPs) is prevalent in biology. As the first step toward understanding the mechanism of binding, it is important to know if a reaction is ‘diffusion-limited’ as, if this speed limit is reached, the association must proceed through an induced fit mechanism. Here, we use a model system where the ‘BH3 region’ of PUMA, an IDP, forms a single, contiguous α-helix upon binding the folded protein Mcl-1. Using stopped-flow techniques, we systematically compare the rate constant for association (k+) under a number of solvent conditions and temperatures. We show that our system is not ‘diffusion-limited’, despite having a k+ in the often-quoted ‘diffusion-limited’ regime (105–106 M–1 s–1 at high ionic strength) and displaying an inverse dependence on solvent viscosity. These standard tests, developed for folded protein–protein interactions, are not appropriate for reactions where one protein is disordered.
PMCID: PMC3776562  PMID: 23301700
15.  Developing an evidence-based clinical pathway for the assessment, diagnosis and management of acute Charcot Neuro-Arthropathy: a systematic review 
Charcot Neuro-Arthropathy (CN) is one of the more devastating complications of diabetes. To the best of the authors’ knowledge, it appears that no clinical tools based on a systematic review of existing literature have been developed to manage acute CN. Thus, the aim of this paper was to systematically review existing literature and develop an evidence-based clinical pathway for the assessment, diagnosis and management of acute CN in patients with diabetes.
Electronic databases (Medline, PubMed, CINAHL, Embase and Cochrane Library), reference lists, and relevant key websites were systematically searched for literature discussing the assessment, diagnosis and/or management of acute CN published between 2002-2012. At least two independent investigators then quality rated and graded the evidence of each included paper. Consistent recommendations emanating from the included papers were then fashioned in a clinical pathway.
The systematic search identified 267 manuscripts, of which 117 (44%) met the inclusion criteria for this study. Most manuscripts discussing the assessment, diagnosis and/or management of acute CN constituted level IV (case series) or EO (expert opinion) evidence. The included literature was used to develop an evidence-based clinical pathway for the assessment, investigations, diagnosis and management of acute CN.
This research has assisted in developing a comprehensive, evidence-based clinical pathway to promote consistent and optimal practice in the assessment, diagnosis and management of acute CN. The pathway aims to support health professionals in making early diagnosis and providing appropriate immediate management of acute CN, ultimately reducing its associated complications such as amputations and hospitalisations.
PMCID: PMC3737070  PMID: 23898912
Charcot Neuro-Arthropathy; Management; Clinical pathway; Diabetes
18.  Stress and coping in caregivers of patients awaiting solid organ transplantation 
Clinical transplantation  2011;26(1):97-104.
Caregivers for patients undergoing solid organ transplantation play an essential role in the process of transplantation. However, little is known about stress and coping among these caregivers. Six hundred and twenty-one primary caregivers of potential candidates for lung (n = 317), liver (n = 147), heart (n = 115), and/or kidney (n = 42) transplantation completed a psychometric test battery at the time of the candidate’s initial pre-transplant psychosocial evaluation. Caregivers were generally well adjusted, with only 17% exhibiting clinical symptoms of depression (Beck Depression Inventory-II score > 13) and 13% reporting clinical levels of anxiety (State Trait Anxiety Inventory score >48). Greater caregiver burden and negative coping styles were associated with higher levels of depression. Greater objective burden and avoidant coping were associated with higher levels of anxiety. Caregivers evidenced a high degree of socially desirable (i.e., defensive) responding, which may reflect a deliberate effort to minimize fears or worries so as to not jeopardize patients’ listing status.
PMCID: PMC3635131  PMID: 21395692
anxiety; caregiver burden; caregivers; coping; depression; solid organ transplantation; stress
19.  Reduced RAN Expression and Disrupted Transport between Cytoplasm and Nucleus; A Key Event in Alzheimer’s Disease Pathophysiology 
PLoS ONE  2013;8(1):e53349.
Transcription of DNA is essential for cell maintenance and survival; inappropriate localization of proteins that are involved in transcription would be catastrophic. In Alzheimer’s disease brains, and in vitro studies, we have found qualitative and quantitative deficits in transport into the nucleus of DNA methyltransferase 1 (DNMT1) and RNA polymerase II (RNA pol II), accompanied by their abnormal sequestration in the cytoplasm. RAN (RAs-related Nuclear protein) knockdown, by siRNA and oligomeric Aβ42 treatment in neurons, replicate human data which indicate that transport disruption in AD may be mechanistically linked to reduced expression of RAN, a pivotal molecule in nucleocytoplasmic transport. In vitro studies also indicate a significant role for oligomeric Aβ42 in the observed phenomena. We propose a model in which reduced transcription regulators in the nucleus and their increased presence in the cytoplasm may lead to many of the cellular manifestations of Alzheimer’s disease.
PMCID: PMC3540085  PMID: 23308199
20.  Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment: Background, Design, and Method for the REMIT Trial 
American Heart Journal  2011;163(1):20-26.
Mental stress induced myocardial ischemia (MSIMI) is common in patients with clinically stable coronary heart disease (CHD) and is associated with poor outcomes. Depression is a risk factor of MSIMI. The Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment (REMIT) trial investigates whether selective serotonin reuptake inhibitor (SSRI) treatment can improve MSIMI. The rationale and outline of the study are described.
In this single center randomized clinical trial, adult patients with clinically stable CHD are recruited for baseline mental and exercise stress testing assessed by echocardiography. Additionally, psychometric questionnaires are administered and blood samples are collected for platelet activity analysis. Patients who demonstrate MSIMI, defined by new abnormal wall motion, ejection fraction reduction ≥8%, and/or development of ischemic ST change in electrocardiogram during mental stress testing, are randomized at a 1:1 ratio to escitalopram or placebo for 6 weeks. Approximately 120 patients with MSIMI are enrolled in the trial. The stress testing, platelet activity assessment and psychometric questionnaires are repeated at the end of the 6-week intervention. The hypothesis of the study is that SSRI treatment improves MSIMI via mood regulation and modification of platelet activity.
The REMIT study examines the effect of SSRI on MSIMI in vulnerable CHD patients and probes some potential underlying mechanisms.
PMCID: PMC3254211  PMID: 22172432
21.  Positron Emission Tomography and Neuropathologic Estimates of Fibrillar Amyloid-β in a Patient With Down Syndrome and Alzheimer Disease 
Archives of Neurology  2011;68(11):1461-1466.
Down syndrome appears to be associated with a virtually certain risk of fibrillar amyloid-β (Aβ) pathology by the age of 40 and a very high risk of dementia at older ages. The positron emission tomography (PET) ligand florbetapir F18 has been shown to characterize fibrillar Aβ in the living human brain and to provide a close correlation with subsequent Aβ neuropathology in individuals proximate to and after the end of life. The extent to which the most frequently used PET ligands can be used to detect fibrillar Aβ in patients with Down syndrome remains to be determined.
To characterize PET estimates of fibrillar Aβ burden in a Down syndrome patient very close to the end of life and to compare them with neuropathologic assessment made after his death.
With the family’s informed consent, florbetapir PET was used to study a 55-year-old Down syndrome patient with Alzheimer disease near the end of life; his brain was donated for neuropathologic assessment when he died 14 days later. Visual ratings of cerebral florbetapir uptake were performed by trained readers who were masked to the patient’s diagnosis as part of a larger study, and an automated algorithm was used to characterize regional-to-cerebellar standard uptake value ratios in 6 cerebral regions of interest. Neuropathologic assessments were performed masked to the patient’s diagnosis or PET measurements.
Visual ratings and automated analyses of the PET image revealed a heavy fibrillar Aβ burden in cortical, striatal, and thalamic regions, similar to that reported for patients with late-onset Alzheimer disease. This matched neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, except for neuropathologically demonstrated frequent cerebellar diffuse plaques and amyloid angiopathy that were not detected by the PET scan.
Florbetapir PET can be used to detect increased cerebral-to-cerebellar fibrillar Aβ burden in a Down syndrome patient with Alzheimer disease, even in the presence of frequent amyloid angiopathy and diffuse plaques in the cerebellum. Additional studies are needed to determine the extent to which PET could be used to detect and to track fibrillar Aβ and to evaluate investigational Aβ-modifying treatments in the presymptomatic and symptomatic stages of Alzheimer disease.
PMCID: PMC3346179  PMID: 22084131
22.  Protein Folding: Adding a Nucleus to Guide Helix Docking Reduces Landscape Roughness 
Journal of Molecular Biology  2012;423(3):273-283.
The elongated three-helix‐bundle spectrin domains R16 and R17 fold and unfold unusually slowly over a rough energy landscape, in contrast to the homologue R15, which folds fast over a much smoother, more typical landscape. R15 folds via a nucleation–condensation mechanism that guides the docking of the A and C-helices. However, in R16 and R17, the secondary structure forms first and the two helices must then dock in the correct register. Here, we use variants of R16 and R17 to demonstrate that substitution of just five key residues is sufficient to alter the folding mechanism and reduce the landscape roughness. We suggest that, by providing access to an alternative, faster, folding route over their landscape, R16 and R17 can circumvent their slow, frustrated wild-type folding mechanism.
Graphical Abstract
Research Highlights
► Homologous spectrin domains have very different folding behavior. ► Spectrin domain R16 folds slowly over an atypically rough energy landscape. ► We have substituted just five residues from R15 to R16. ► The mutated protein folds via a different folding mechanism (more like R15). ► This results in a faster folding across a smoother (more R15 like) landscape.
PMCID: PMC3469821  PMID: 22917971
protein folding; Φ-value analysis; energy landscape; helix bundle; minimal frustration
23.  Diabetes foot disease: the Cinderella of Australian diabetes management? 
Diabetes is one of the greatest public health challenges to face Australia. It is already Australia’s leading cause of kidney failure, blindness (in those under 60 years) and lower limb amputation, and causes significant cardiovascular disease. Australia’s diabetes amputation rate is one of the worst in the developed world, and appears to have significantly increased in the last decade, whereas some other diabetes complication rates appear to have decreased. This paper aims to compare the national burden of disease for the four major diabetes-related complications and the availability of government funding to combat these complications, in order to determine where diabetes foot disease ranks in Australia. Our review of relevant national literature indicates foot disease ranks second overall in burden of disease and last in evidenced-based government funding to combat these diabetes complications. This suggests public funding to address foot disease in Australia is disproportionately low when compared to funding dedicated to other diabetes complications. There is ample evidence that appropriate government funding of evidence-based care improves all diabetes complication outcomes and reduces overall costs. Numerous diverse Australian peak bodies have now recommended similar diabetes foot evidence-based strategies that have reduced diabetes amputation rates and associated costs in other developed nations. It would seem intuitive that “it’s time” to fund these evidence-based strategies for diabetes foot disease in Australia as well.
PMCID: PMC3488529  PMID: 23021818
Diabetes; Foot; Complication; Disease; Australia
24.  Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study 
This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer’s disease (AD).
In a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus.
Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II.
Unexpectedly, the extent of innate immune gene upregulation in AD was modest relative to the robust response apparent in the aged brain, consistent with the emerging idea of a critical involvement of inflammation in the earliest stages, perhaps even in the preclinical stage, of AD. Ultimately, our data suggest that an important strategy to maintain cognitive health and resilience involves reducing chronic innate immune activation that should be initiated in late midlife.
PMCID: PMC3419089  PMID: 22824372
Complement; Toll-like receptor; Inflammasome; Cryopyrin; Caspase-1; Myeloid-related protein; Calgranulin; Calprotectin; Alarmin; Endogenous danger signaling; Fractalkine
25.  Epigenetics Mechanisms in Alzheimer’s disease 
Neurobiology of aging  2011;32(7):1161-1180.
Epigenetic modifications help orchestrate sweeping developmental, aging, and disease-causing changes in phenotype by altering transcriptional activity in multiple genes spanning multiple biologic pathways. Although previous epigenetic research has focused primarily on dividing cells, particularly in cancer, recent studies have shown rapid, dynamic, and persistent epigenetic modifications in neurons that have significant neuroendocrine, neurophysiologic, and neurodegenerative consequences. Here, we provide a review of the major mechanisms for epigenetic modification and how they are reportedly altered in aging and Alzheimer’s disease (AD). Because of their reach across the genome, epigenetic mechanisms may provide a unique integrative framework for the pathologic diversity and complexity of AD.
PMCID: PMC3115415  PMID: 21482442
Epigenetics; DNA methylation; histone acetylation; rDNA; miRNA; genetics; gene expression; amyloid β peptide; inflammation; oxidative stress; cell cycle

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