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1.  FUNCTIONAL NEUROANATOMY OF THE COGNITIVE PROCESS OF MAPPING DURING DISCOURSE COMPREHENSION 
Psychological science  2000;11(3):255-260.
We used functional magnetic resonance imaging (fMRI) to identify brain regions involved in the process of mapping coherent discourse onto a developing mental representation. We manipulated discourse coherence by presenting sentences with definite articles (which lead to more coherent discourse) or indefinite articles (which lead to less coherent discourse). Comprehending connected discourse, compared with reading unrelated sentences, produced more neural activity in the right than left hemisphere of the frontal lobe. Thus, the right hemisphere of the frontal lobe is involved in some of the processes underlying mapping. In contrast, left-hemisphere structures were associated with lower-level processes in reading (such as word recognition and syntactic processing). Our results demonstrate the utility of using fMRI to investigate the neural substrates of higher-level cognitive processes such as discourse comprehension.
PMCID: PMC4301434  PMID: 11273413
2.  Locus heterogeneity disease genes encode proteins with high interconnectivity in the human protein interaction network 
Frontiers in Genetics  2014;5:434.
Mutations in genes potentially lead to a number of genetic diseases with differing severity. These disease genes have been the focus of research in recent years showing that the disease gene population as a whole is not homogeneous, and can be categorized according to their interactions. Locus heterogeneity describes a single disorder caused by mutations in different genes each acting individually to cause the same disease. Using datasets of experimentally derived human disease genes and protein interactions, we created a protein interaction network to investigate the relationships between the products of genes associated with a disease displaying locus heterogeneity, and use network parameters to suggest properties that distinguish these disease genes from the overall disease gene population. Through the manual curation of known causative genes of 100 diseases displaying locus heterogeneity and 397 single-gene Mendelian disorders, we use network parameters to show that our locus heterogeneity network displays distinct properties from the global disease network and a Mendelian network. Using the global human proteome, through random simulation of the network we show that heterogeneous genes display significant interconnectivity. Further topological analysis of this network revealed clustering of locus heterogeneity genes that cause identical disorders, indicating that these disease genes are involved in similar biological processes. We then use this information to suggest additional genes that may contribute to diseases with locus heterogeneity.
doi:10.3389/fgene.2014.00434
PMCID: PMC4260505  PMID: 25538735
locus heterogeneity; protein interaction network; systems biology; Bardet–Biedl syndrome; Leigh syndrome; Kabuki syndrome
3.  Factors Associated with Siman Immunodeficiency Virus Transmission in a Natural African Nonhuman Primate Host in the Wild 
Journal of Virology  2014;88(10):5687-5705.
ABSTRACT
African green monkeys (AGMs) are naturally infected with simian immunodeficiency virus (SIV) at high prevalence levels and do not progress to AIDS. Sexual transmission is the main transmission route in AGM, while mother-to-infant transmission (MTIT) is negligible. We investigated SIV transmission in wild AGMs to assess whether or not high SIV prevalence is due to differences in mucosal permissivity to SIV (i.e., whether the genetic bottleneck of viral transmission reported in humans and macaques is also observed in AGMs in the wild). We tested 121 sabaeus AGMs (Chlorocebus sabaeus) from the Gambia and found that 53 were SIV infected (44%). By combining serology and viral load quantitation, we identified 4 acutely infected AGMs, in which we assessed the diversity of the quasispecies by single-genome amplification (SGA) and documented that a single virus variant established the infections. We thus show that natural SIV transmission in the wild is associated with a genetic bottleneck similar to that described for mucosal human immunodeficiency virus (HIV) transmission in humans. Flow cytometry assessment of the immune cell populations did not identify major differences between infected and uninfected AGM. The expression of the SIV coreceptor CCR5 on CD4+ T cells dramatically increased in adults, being higher in infected than in uninfected infant and juvenile AGMs. Thus, the limited SIV MTIT in natural hosts appears to be due to low target cell availability in newborns and infants, which supports HIV MTIT prevention strategies aimed at limiting the target cells at mucosal sites. Combined, (i) the extremely high prevalence in sexually active AGMs, (ii) the very efficient SIV transmission in the wild, and (iii) the existence of a fraction of multiparous females that remain uninfected in spite of massive exposure to SIV identify wild AGMs as an acceptable model of exposed, uninfected individuals.
IMPORTANCE We report an extensive analysis of the natural history of SIVagm infection in its sabaeus monkey host, the African green monkey species endemic to West Africa. Virtually no study has investigated the natural history of SIV infection in the wild. The novelty of our approach is that we report for the first time that SIV infection has no discernible impact on the major immune cell populations in natural hosts, thus confirming the nonpathogenic nature of SIV infection in the wild. We also focused on the correlates of SIV transmission, and we report, also for the first time, that SIV transmission in the wild is characterized by a major genetic bottleneck, similar to that described for HIV-1 transmission in humans. Finally, we report here that the restriction of target cell availability is a major correlate of the lack of SIV transmission to the offspring in natural hosts of SIVs.
doi:10.1128/JVI.03606-13
PMCID: PMC4019088  PMID: 24623416
4.  The pain interactome: Connecting pain-specific protein interactions 
Pain  2014;155(11):2243-2252.
Summary
Protein interactions from painful states form a coherent network that can be used to inform further study. We identify proteins key to painful subnetworks.
Understanding the molecular mechanisms associated with disease is a central goal of modern medical research. As such, many thousands of experiments have been published that detail individual molecular events that contribute to a disease. Here we use a semi-automated text mining approach to accurately and exhaustively curate the primary literature for chronic pain states. In so doing, we create a comprehensive network of 1,002 contextualized protein–protein interactions (PPIs) specifically associated with pain. The PPIs form a highly interconnected and coherent structure, and the resulting network provides an alternative to those derived from connecting genes associated with pain using interactions that have not been shown to occur in a painful state. We exploit the contextual data associated with our interactions to analyse subnetworks specific to inflammatory and neuropathic pain, and to various anatomical regions. Here, we identify potential targets for further study and several drug-repurposing opportunities. Finally, the network provides a framework for the interpretation of new data within the field of pain.
doi:10.1016/j.pain.2014.06.020
PMCID: PMC4247380  PMID: 24978826
Networks; Protein–protein interactions; Gene expression; Neuropathic pain; Inflammatory pain; Text mining
5.  Sensitive Deep-Sequencing-Based HIV-1 Genotyping Assay To Simultaneously Determine Susceptibility to Protease, Reverse Transcriptase, Integrase, and Maturation Inhibitors, as Well as HIV-1 Coreceptor Tropism 
With 29 individual antiretroviral drugs available from six classes that are approved for the treatment of HIV-1 infection, a combination of different phenotypic and genotypic tests is currently needed to monitor HIV-infected individuals. In this study, we developed a novel HIV-1 genotypic assay based on deep sequencing (DeepGen HIV) to simultaneously assess HIV-1 susceptibilities to all drugs targeting the three viral enzymes and to predict HIV-1 coreceptor tropism. Patient-derived gag-p2/NCp7/p1/p6/pol-PR/RT/IN- and env-C2V3 PCR products were sequenced using the Ion Torrent Personal Genome Machine. Reads spanning the 3′ end of the Gag, protease (PR), reverse transcriptase (RT), integrase (IN), and V3 regions were extracted, truncated, translated, and assembled for genotype and HIV-1 coreceptor tropism determination. DeepGen HIV consistently detected both minority drug-resistant viruses and non-R5 HIV-1 variants from clinical specimens with viral loads of ≥1,000 copies/ml and from B and non-B subtypes. Additional mutations associated with resistance to PR, RT, and IN inhibitors, previously undetected by standard (Sanger) population sequencing, were reliably identified at frequencies as low as 1%. DeepGen HIV results correlated with phenotypic (original Trofile, 92%; enhanced-sensitivity Trofile assay [ESTA], 80%; TROCAI, 81%; and VeriTrop, 80%) and genotypic (population sequencing/Geno2Pheno with a 10% false-positive rate [FPR], 84%) HIV-1 tropism test results. DeepGen HIV (83%) and Trofile (85%) showed similar concordances with the clinical response following an 8-day course of maraviroc monotherapy (MCT). In summary, this novel all-inclusive HIV-1 genotypic and coreceptor tropism assay, based on deep sequencing of the PR, RT, IN, and V3 regions, permits simultaneous multiplex detection of low-level drug-resistant and/or non-R5 viruses in up to 96 clinical samples. This comprehensive test, the first of its class, will be instrumental in the development of new antiretroviral drugs and, more importantly, will aid in the treatment and management of HIV-infected individuals.
doi:10.1128/AAC.02710-13
PMCID: PMC4023761  PMID: 24468782
6.  The Expression of Inflammatory Genes Is Upregulated in Peripheral Blood of Patients With Type 1 Diabetes 
Diabetes Care  2013;36(9):2794-2802.
OBJECTIVE
Our previous gene expression microarray studies identified a number of genes differentially expressed in patients with type 1 diabetes (T1D) and islet autoantibody-positive subjects. This study was designed to validate these gene expression changes in T1D patients and to identify gene expression changes in diabetes complications.
RESEARCH DESIGH AND METHODS
We performed high-throughput real-time RT-PCR to validate gene expression changes in peripheral blood mononuclear cells (PBMCs) from a large sample set of 928 T1D patients and 922 control subjects.
RESULTS
Of the 18 genes analyzed here, eight genes (S100A8, S100A9, MNDA, SELL, TGFB1, PSMB3, CD74, and IL12A) had higher expression and three genes (GNLY, PSMA4, and SMAD7) had lower expression in T1D patients compared with control subjects, indicating that genes involved in inflammation, immune regulation, and antigen processing and presentation are significantly altered in PBMCs from T1D patients. Furthermore, one adhesion molecule (SELL) and three inflammatory genes mainly expressed by myeloid cells (S100A8, S100A9, and MNDA) were significantly higher in T1D patients with complications (odds ratio [OR] 1.3–2.6, adjusted P value = 0.005–10−8), especially those patients with neuropathy (OR 4.8–7.9, adjusted P value <0.005).
CONCLUSIONS
These findings suggest that inflammatory mediators secreted mainly by myeloid cells are implicated in T1D and its complications.
doi:10.2337/dc12-1986
PMCID: PMC3747909  PMID: 23637351
7.  Extracting patterns of database and software usage from the bioinformatics literature 
Bioinformatics  2014;30(17):i601-i608.
Motivation: As a natural consequence of being a computer-based discipline, bioinformatics has a strong focus on database and software development, but the volume and variety of resources are growing at unprecedented rates. An audit of database and software usage patterns could help provide an overview of developments in bioinformatics and community common practice, and comparing the links between resources through time could demonstrate both the persistence of existing software and the emergence of new tools.
Results: We study the connections between bioinformatics resources and construct networks of database and software usage patterns, based on resource co-occurrence, that correspond to snapshots of common practice in the bioinformatics community. We apply our approach to pairings of phylogenetics software reported in the literature and argue that these could provide a stepping stone into the identification of scientific best practice.
Availability and implementation: The extracted resource data, the scripts used for network generation and the resulting networks are available at http://bionerds.sourceforge.net/networks/
Contact: robert.stevens@manchester.ac.uk
doi:10.1093/bioinformatics/btu471
PMCID: PMC4147923  PMID: 25161253
9.  Temporary elimination of orthostatic hypotension by norepinephrine infusion 
A cardinal manifestation of chronic autonomic failure is neurogenic orthostatic hypotension (OH), which often is associated with supine hypertension, posing a therapeutic dilemma. We report here success in a first step toward development of a “prosthetic baroreceptor system” to maintain blood pressure during orthostasis without worsening supine hypertension. In all of four patients with neurogenic OH, titrated i.v. NE infusion kept directly recorded intra-arterial pressure at or above baseline during progressive head-up tilt. We conclude that titrated i.v. NE infusion temporarily eliminates OH.
doi:10.1007/s10286-012-0176-4
PMCID: PMC4118053  PMID: 22983778
Norepinephrine; Orthostatic hypotension; Sympathetic nervous system; Baroreflex
10.  Sensitization of ovarian cancer cells to cisplatin by gold nanoparticles 
Oncotarget  2014;5(15):6453-6465.
Recently we reported that gold nanoparticles (AuNPs) inhibit ovarian tumor growth and metastasis in mice by reversing epithelial-mesenchymal transition (EMT). Since EMT is known to confer drug resistance to cancer cells, we wanted to investigate whether anti-EMT property of AuNP could be utilized to sensitize ovarian cancer cells to cisplatin. Herein, we report that AuNPs prevent cisplatin-induced acquired chemoresistance and stemness in ovarian cancer cells and sensitize them to cisplatin. AuNPs inhibit cisplatin induced EMT, decrease the side population cells and key stem cell markers such as ALDH1, CD44, CD133, Sox2, MDR1 and ABCG2 in ovarian cancer cells. Mechanistically, AuNPs prevent cisplatin-induced activation of Akt and NF-κB signaling axis in ovarian cancer cells that are critical for EMT, stem cell maintenance and drug resistance. In vivo, AuNPs sensitize orthotopically implanted ovarian tumor to a low dose of cisplatin and significantly inhibit tumor growth via facilitated delivery of both AuNP and cisplatin. These findings suggest that by depleting stem cell pools and inhibiting key molecular pathways gold nanoparticles sensitize ovarian cancer cells to cisplatin and may be used in combination to inhibit tumor growth and metastasis in ovarian cancer.
PMCID: PMC4171643  PMID: 25071019
gold nanoparticle; chemoresistance; cancer stem cell; EMT; NF-κB
11.  Combination ergotamine and caffeine improves seated blood pressure and presyncopal symptoms in autonomic failure 
Severely affected patients with autonomic failure require pressor agents to counteract the blood pressure fall and improve presyncopal symptoms upon standing. Previous studies suggest that combination ergotamine and caffeine may be effective in the treatment of autonomic failure, but the efficacy of this drug has not been evaluated in controlled trials. Therefore, we compared the effects of ergotamine/caffeine on seated blood pressure and orthostatic tolerance and symptoms in 12 primary autonomic failure patients without history of coronary artery disease. Patients were randomized to receive a single oral dose of placebo, midodrine (5–10 mg), or ergotamine and caffeine (1 and 100 mg, respectively) in a single-blind, crossover study. Blood pressure was measured while patients were seated and after standing for up to 10 min, at baseline and at 1 h post-drug. Ergotamine/caffeine increased seated systolic blood pressure (SBP), the primary outcome, compared with placebo (131 ± 19 and 95 ± 12 mmHg, respectively, at 1 h post-drug; p = 0.003 for time effect). Midodrine also significantly increased seated SBP (121 ± 19 mmHg at 1 h post-drug; p = 0.015 for time effect vs. placebo), but this effect was not different from ergotamine/caffeine (p = 0.621). There was no significant effect of either medication on orthostatic tolerance; however, ergotamine/caffeine improved presyncopal symptoms (p = 0.034). These findings suggest that combination ergotamine and caffeine elicits a seated pressor response that is similar in magnitude to midodrine, and improves symptoms in autonomic failure. Thus, ergotamine/caffeine could be used as an alternate treatment for autonomic failure, in carefully selected patients without comorbid coronary artery disease.
doi:10.3389/fphys.2014.00270
PMCID: PMC4109567  PMID: 25104940
autonomic failure; orthostatic hypotension; ergotamine; caffeine; pressor agent
12.  Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial 
Lancet neurology  2014;13(3):268-275.
Summary
Background
No available treatments slow or halt progression of multiple system atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of multiple system atrophy, rifampicin inhibited formation of α-synuclein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with multiple system atrophy.
Methods
In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30–80 years with possible or probable multiple system atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221.
Findings
Between April 22, 2011, and April 19, 2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0·62 points [SD 0·85] per month in the rifampicin group vs 0·47 points [0·48] per month in the placebo group; futility p=0·032; efficacy p=0·76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0·5 points (SD 0·7) per month for rifampicin and 0·5 points (0·5) per month for placebo (difference 0·0, 95% CI –0·24 to 0·24; p=0·82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment.
Interpretation
Our results show that rifampicin does not slow or halt progression of multiple system atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with multiple system atrophy.
Funding
National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds.
doi:10.1016/S1474-4422(13)70301-6
PMCID: PMC4030757  PMID: 24507091
13.  Postural Tachycardia Syndrome and Inappropriate Sinus Tachycardia: Role of Autonomic Modulation and Sinus Node Automaticity 
Background
Inappropriate sinus tachycardia (IST) and postural tachycardia syndrome (POTS) are 2 disorders characterized by sinus tachycardia. It is debated whether the pathophysiology of IST and POTS results from abnormal autonomic regulation or abnormal sinus node function. We hypothesized that intrinsic heart rate (IHR) after autonomic blockade would be increased in patients with IST but not POTS.
Methods and Results
We enrolled 48 POTS patients, 8 IST patients, and 17 healthy control (HC) subjects. Intravenous propranolol and atropine were given to block the sympathetic and parasympathetic limbs of the autonomic nervous system in order to determine the IHR. Patients with IST have a higher sympathetic contribution to heart rate when compared with POTS patients (31±13 bpm versus 12±7 bpm, P<0.001) and HC (8±4 bpm; P<0.001) and a trend to less parasympathetic contribution than POTS and HC (IST: 31±11 bpm versus POTS: 46±11 bpm versus HC: 48±11 bpm, ANOVA P=0.108). IHR was not significantly different between IST and either POTS or HC (IST: 111±11 bpm versus POTS: 108±11 bpm versus HC: 106±12 bpm, ANOVA P=0.237).
Conclusions
IST patients have more sympathetic tone when compared with either POTS or HC, but IST patients do not have abnormal sinus node automaticity. These data suggest that the treatment of IST and POTS should focus on sympatholysis, reserving sinus node modification for patients with continued debilitating symptoms after beta‐blockade and possibly ivabradine.
Clinical Trial Registration
URL: http://clinicaltrials.gov/. Unique identifier: NCT00262470.
doi:10.1161/JAHA.113.000700
PMCID: PMC4187519  PMID: 24721800
autonomic nervous system; inappropriate sinus tachycardia; postural tachycardia syndrome; sinus node; sympathetic nervous system
14.  CHBPR: ANGIOTENSIN II, INDEPENDENT OF PLASMA RENIN ACTIVITY, CONTRIBUTES TO THE HYPERTENSION OF AUTONOMIC FAILURE 
Hypertension  2012;61(3):701-706.
At least half of primary autonomic failure patients exhibit supine hypertension, despite profound impairments in sympathetic activity. While the mechanisms underlying this hypertension are unknown, plasma renin activity is often undetectable suggesting renin-angiotensin pathways are not involved. However, because aldosterone levels are preserved, we tested the hypothesis that angiotensin II is intact and contributes to the hypertension of autonomic failure. Indeed, circulating angiotensin II was paradoxically increased in hypertensive autonomic failure patients (52±5 pg/ml, n=11) compared to matched healthy controls (27±4 pg/ml, n=10; p=0.002), despite similarly low renin activity (0.19±0.06 versus 0.34±0.13 ng/ml/hr, respectively; p=0.449). To determine the contribution of angiotensin II to supine hypertension in these patients, we administered the AT1 receptor blocker losartan (50 mg) at bedtime in a randomized, double-blind, placebo-controlled study (n=11). Losartan maximally reduced systolic blood pressure by 32±11 mmHg at 6 hours after administration (p<0.05), decreased nocturnal urinary sodium excretion (p=0.0461), and did not worsen morning orthostatic tolerance. In contrast, there was no effect of the captopril on supine blood pressure in a subset of these patients. These findings suggest that angiotensin II formation in autonomic failure is independent of plasma renin activity, and perhaps angiotensin converting enzyme. Furthermore, these studies suggest that elevations in angiotensin II contribute to the hypertension of autonomic failure, and provide rationale for the use of AT1 receptor blockers for treatment of these patients.
doi:10.1161/HYPERTENSIONAHA.111.00377
PMCID: PMC3573256  PMID: 23266540
autonomic nervous system; hypertension; angiotensin; drugs; natriuresis
15.  Coexistent Autoimmune Autonomic Ganglionopathy and Myasthenia Gravis Associated with Non-Small Cell Lung Cancer 
Muscle & nerve  2010;41(3):416-419.
We report a case of a 55 year old man with non-small cell lung cancer who underwent radiation, chemotherapy with carbotaxol and paclitaxel, and left upper lobe removal two years prior to evaluation. He was referred for disabling orthostatic hypotension (113/69 supine, 66/47 mmHg standing after 10 minutes without a compensatory heart rate increase (57 to 59 bpm), fatigue, and constipation with episodes of ileus. Clinical examination showed mild ptosis bilaterally, fatiguable neck flexor weakness and hip flexor weakness. Blood pressure response to Valsalva maneuver was abnormal with absence of phase 4 overshoot and a Valsalva heart rate ratio of 1.04, The plasma norepinephrine level was low (79 pg/ml supine to 330 pg/ml standing). Single fiber EMG of the right extensor digitorum communis revealed normal mean MCD (jitter) but several pairs exceeded a jitter of 100 µs. Antibodies against muscle acetylcholine receptor [(AChR) 0.66 nmol/L, normal <0.02] and ganglionic AChR (0.34 nmol/L, normal <0.02) were present. Treatment with plasma exchange normalized responses to standing posture (105/68 supine to 118/82 mmHg standing, 66 to 79 bpm), to Valsalva (normal blood pressure overshoot, HR ratio 1.47), norepinephrine (194 pg/ml supine, 763 standing), and jitter measurements. We conclude that autoimmune autonomic ganglionopathy and myasthenia gravis can coexist and suggest that the latter should be excluded in patients with autoimmune autonomic ganglionopathy who complain of fatigue that is improved with non-supine rest.
doi:10.1002/mus.21528
PMCID: PMC3925506  PMID: 19882640
autoimmune autonomic ganglionopathy; myasthenia gravis; paraneoplastic syndrome
16.  Effect of Mild Hyperglycemia on Autonomic Function in Obstructive Sleep Apnea 
Obstructive sleep apnea (OSA) has been hypothesized to cause a hypersympathetic state, which may be the mechanism for the increased incidence of cardiovascular disease in OSA. However, there is a high prevalence of hyperglycemia in OSA patients which may also contribute to autonomic dysfunction.
Thirty-five patients with OSA and eleven controls with average body-mass index (BMI) of 32.0 ± 4.6 underwent polysomnography, glucose tolerance testing, autonomic function tests, lying and standing catecholamines, overnight urine collection, and baseline ECG and continuous blood pressure measurements for spectral analysis. A linear regression model adjusting for age and BMI was used to analyze spectral data, other outcome measures were analyzed with Kruskal-Wallis test.
Twenty-three OSA patients and two control patients had hyperglycemia (based on 2001 American Diabetes Association criteria). AHI correlated with total power and low frequency (LF) power (r=0.138, 0.177, p=0.031; and r= 0.013) but not with the LF/high frequency (HF) ratio (p=0.589). Glucose negatively correlated with LF systolic power (r=-0.171, p=0.038) but not AHI (p=0.586) and was marginally associated with pnn50, total power, LF, and HF power (p ranged from 0.07 to 0.08).
These data suggest that patients with OSA and mild hyperglycemia have a trend towards lower heart rate variability and sympathetic tone. Hyperglycemia is an important confounder and should be evaluated in studies of OSA and autonomic function.
doi:10.1007/s10286-011-0131-9
PMCID: PMC3925507  PMID: 21796355
17.  Nitric Oxide and Regulation of Heart Rate in Patients with Postural Tachycardia Syndrome and Healthy Subjects 
Hypertension  2013;61(2):376-381.
Objectives
To study the role of nitric oxide (NO) on cardiovascular regulation in healthy subjects and postural tachycardia syndrome (POTS) patients.
Background
Both reduced neuronal NO function, which could contribute to a hyperadrenergic state, and increased NO-induced vasodilation, which could contribute to orthostatic intolerance, have been reported in POTS.
Methods
In protocol 1, 13 healthy volunteers (33±3 years) underwent autonomic blockade with trimethaphan and were administered equipressor doses of L-NMMA (NO synthase inhibitor) and phenylephrine to determine the direct chronotropic effects of NO (independent of baroreflex modulation). In protocol 2, we compared the effects of L-NMMA in 9 POTS patients (31±3 years) and 14 healthy (32±2 years) volunteers during autonomic blockade.
Results
During autonomic blockade, L-NMMA and phenylephrine produced similar increases in systolic blood pressure (SBP; 27±2 vs. 27±3 mmHg). Phenylephrine produced only minimal heart rate (HR) changes, whereas L-NMMA produced a modest but significant bradycardia (−0.8±0.4 vs. −4.8±1.2 bpm, p=0.011). There were no differences between POTS and healthy volunteers in the SBP increase (22±2 and 28±5 mmHg) or HR decrease (−6±2 and −4±1 bpm for POTS and controls, respectively) produced by L-NMMA.
Conclusions
In the absence of baroreflex buffering, inhibition of endogenous NO synthesis results in a significant bradycardia, reflecting direct tonic modulation of heart rate by NO in healthy individuals. We found no evidence of a primary alteration in NO function in POTS. If NO dysfunction plays a role in POTS it is through its interaction with the autonomic nervous system.
doi:10.1161/HYPERTENSIONAHA.111.00203
PMCID: PMC3621717  PMID: 23283362
Nitric Oxide; Postural Tachycardia Syndrome; Autonomic Nervous System; Autonomic Blockade; Heart Rate; blood pressure
18.  Plugging the Attention Deficit: Perceptual Load Counters Increased Distraction in ADHD 
Neuropsychology  2013;28(1):91-97.
Objective: Increased vulnerability to extraneous distraction is a key symptom of Attention-Deficit Hyperactivity Disorder (ADHD), which may have particularly disruptive consequences. Here we apply Load Theory of attention to increase understanding of this symptom, and to explore a potential method for ameliorating it. Previous research in nonclinical populations has highlighted increased perceptual load as a means of improving the ability to focus attention and avoid distraction. The present study examines whether adults with ADHD can also benefit from conditions of high perceptual load to improve their focused attention abilities. Method: We tested adults with ADHD and age- and IQ-matched controls on a novel measure of irrelevant distraction under load, designed to parallel the form of distraction that is symptomatic of ADHD. During a letter search task, in which perceptual load was varied through search set size, participants were required to ignore salient yet entirely irrelevant distractors (colorful images of cartoon characters) presented infrequently (10% of trials). Results: The presence of these distractors produced a significantly greater interference effect on the search RTs for the adults with ADHD compared with controls, p = .005, ηp2 = .231. Perceptual load, however, significantly reduced distractor interference for the ADHD group and was as effective in reducing the elevated distractor interference in ADHD as it was for controls. Conclusions: These findings clarify the nature of the attention deficit underlying increased distraction in ADHD, and demonstrate a tangible method for overcoming it.
doi:10.1037/neu0000020
PMCID: PMC3906797  PMID: 24219607
attention-deficit hyperactivity disorder; ADHD; distraction; perceptual load; inattention
19.  GDNF-RET signaling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitors 
Cancer research  2013;73(12):3783-3795.
Most breast cancers at diagnosis are estrogen receptor (ER)-positive and depend on estrogen for growth and survival. Blocking estrogen biosynthesis by aromatase inhibitors (AI) has therefore become a first-line endocrine therapy for post-menopausal women with ER-positive breast cancers. Despite providing substantial improvements in patient outcome, AI resistance remains a major clinical challenge. The receptor tyrosine kinase RET and its co-receptor GFRα1 are upregulated in a subset of ER-positive breast cancers, and the RET ligand, glial-derived neurotrophic factor (GDNF) is upregulated by inflammatory cytokines. Here we report the findings of a multidisciplinary strategy to address the impact of GDNF-RET signaling in the response to AI treatment. In breast cancer cells in 2D and 3D culture, GDNF-mediated RET signaling is enhanced in a model of AI resistance. Further, GDNF-RET signaling promoted the survival of AI-resistant cells and elicited resistance in AI-sensitive cells. Both these effects were selectively reverted by the RET kinase inhibitor NVP-BBT594. Gene expression profiling in ER-positive cancers defined a proliferation-independent GDNF-response signature that prognosed poor patient outcome and, more importantly, predicted poor response to AI treatment with the development of resistance. We validated these findings by demonstrating increased RET protein expression levels in an independent cohort of AI-resistant patient specimens. Together, our results establish GDNF-RET signaling as a rational therapeutic target to combat or delay the onset of AI resistance in breast cancer.
doi:10.1158/0008-5472.CAN-12-4265
PMCID: PMC3686594  PMID: 23650283
aromatase inhibitor; breast cancer; GDNF; resistance; RET
20.  Beyond postural tachycardia syndrome 
Journal of neurology, neurosurgery, and psychiatry  2010;81(3):10.1136/jnnp.2009.180620.
doi:10.1136/jnnp.2009.180620
PMCID: PMC3848708  PMID: 20185461
21.  Experimental Arrest of Cerebral Blood Flow in Human Subjects 
Perspectives in biology and medicine  2011;54(2):10.1353/pbm.2011.0018.
Loss of consciousness in pilots during rapid ascent after bombing missions was a major problem in World War II, and experiments were undertaken to study the cause of this phenomenon. Postulating impaired cerebral blood flow as a likely mechanism, the investigators developed a neck device, the KRA Cuff, which when inflated could shut off blood supply to the brain. With cessation of blood flow for up to 100 seconds, the investigators observed a sequence of responses, including unconsciousness, followed by dilated pupils, tonic/clonic movements, loss of bladder and eventually bowel control, and appearance of pathological reflexes. This study, carried out in prisoners and patients with schizophrenia in 1941–42, largely disappeared from public discourse for a number of years. It has received occasional attention subsequently and been considered controversial. Recently discovered records, including extensive written and photographic data from the studies, shed new light on the methods and motives of the research team. We describe here this new information and its implications for the scientific and ethical assessment of the study.
doi:10.1353/pbm.2011.0018
PMCID: PMC3848716  PMID: 21532128
22.  A multi-centre cohort study of short term outcomes of hospital treatment for anorexia nervosa in the UK 
BMC Psychiatry  2013;13:287.
Background
Individual, family and service level characteristics and outcomes are described for adult and adolescent patients receiving specialist inpatient or day patient treatment for anorexia nervosa (AN). Potential predictors of treatment outcome are explored.
Method
Admission and discharge data were collected from patients admitted at 14 UK hospital treatment units for AN over a period of three years (adult units N = 12; adolescent N = 2) (patients N = 177).
Results
One hundred and seventy-seven patients with a severe and enduring illness with wide functional impairment took part in the study. Following inpatient care, physical improvement was moderate/good with a large increase in BMI, although most patients continued to have a clinical level of eating disorder symptoms at discharge. The potentially modifiable predictors of outcome included confidence to change, social functioning and carer expressed emotion and control.
Conclusions
Overall, the response to inpatient treatment was modest particularly in the group with a severe enduring form of illness. Adolescents had a better response. Although inpatient treatment produces an improvement in physical health there was less improvement in other eating disorder and mood symptoms. As predicted by the carer interpersonal maintenance model, carer behaviour may influence the response to inpatient care, as may improved social functioning and confidence to change.
doi:10.1186/1471-244X-13-287
PMCID: PMC3871017  PMID: 24200194
Eating disorders; Anorexia Nervosa; Inpatients; Treatment response; Predictors; Treatment
23.  Sensitive Cell-Based Assay for Determination of Human Immunodeficiency Virus Type 1 Coreceptor Tropism 
Journal of Clinical Microbiology  2013;51(5):1517-1527.
CCR5 antagonists are a powerful new class of antiretroviral drugs that require a companion assay to evaluate the presence of CXCR4-tropic (non-R5) viruses prior to use in human immunodeficiency virus (HIV)-infected individuals. In this study, we have developed, characterized, verified, and prevalidated a novel phenotypic test to determine HIV-1 coreceptor tropism (VERITROP) based on a sensitive cell-to-cell fusion assay. A proprietary vector was constructed containing a near-full-length HIV-1 genome with the yeast uracil biosynthesis (URA3) gene replacing the HIV-1 env coding sequence. Patient-derived HIV-1 PCR products were introduced by homologous recombination using an innovative yeast-based cloning strategy. The env-expressing vectors were then used in a cell-to-cell fusion assay to determine the presence of R5 and/or non-R5 HIV-1 variants within the viral population. Results were compared with (i) the original version of Trofile (Monogram Biosciences, San Francisco, CA), (ii) population sequencing, and (iii) 454 pyrosequencing, with the genotypic data analyzed using several bioinformatics tools, i.e., the 11/24/25 rule, Geno2Pheno (2% to 5.75%, 3.5%, or 10% false-positive rate [FPR]), and webPSSM. VERITROP consistently detected minority non-R5 variants from clinical specimens, with an analytical sensitivity of 0.3%, with viral loads of ≥1,000 copies/ml, and from B and non-B subtypes. In a pilot study, a 73.7% (56/76) concordance was observed with the original Trofile assay, with 19 of the 20 discordant results corresponding to non-R5 variants detected using VERITROP and not by the original Trofile assay. The degree of concordance of VERITROP and Trofile with population and deep sequencing results depended on the algorithm used to determine HIV-1 coreceptor tropism. Overall, VERITROP showed better concordance with deep sequencing/Geno2Pheno at a 0.3% detection threshold (67%), whereas Trofile matched better with population sequencing (79%). However, 454 sequencing using Geno2Pheno at a 10% FPR and 0.3% threshold and VERITROP more accurately predicted the success of a maraviroc-based regimen. In conclusion, VERITROP may promote the development of new HIV coreceptor antagonists and aid in the treatment and management of HIV-infected individuals prior to and/or during treatment with this class of drugs.
doi:10.1128/JCM.00092-13
PMCID: PMC3647936  PMID: 23486708
24.  Effects of Norepinephrine Reuptake Inhibition on Postural Tachycardia Syndrome 
Background
Postural tachycardia syndrome (POTS) is a disorder of chronic orthostatic intolerance accompanied by excessive orthostatic tachycardia. Patients with POTS commonly have comorbid conditions such as attention deficit hyperactivity disorder, depression, or fibromyalgia that are treated with medications that inhibit the norepinephrine reuptake transporter (NRI). NRI medications can increase sympathetic nervous system tone, which may increase heart rate (HR) and worsen symptoms in POTS patients. We sought to determine whether NRI with atomoxetine increases standing tachycardia or worsens the symptom burden in POTS patients.
Methods and Results
Patients with POTS (n=27) underwent an acute drug trial of atomoxetine 40 mg and placebo on separate mornings in a randomized, crossover design. Blood pressure (BP), HR, and symptoms were assessed while seated and after standing prior to and hourly for 4 hours following study drug administration. Atomoxetine significantly increased standing HR compared with placebo (121±17 beats per minute versus 105±15 beats per minute; P=0.001) in POTS patients, with a trend toward higher standing systolic BP (P=0.072). Symptom scores worsened with atomoxetine compared to placebo (+4.2 au versus −3.5 au; P=0.028) from baseline to 2 hours after study drug administration.
Conclusion
Norepinephrine reuptake inhibition with atomoxetine acutely increased standing HR and symptom burden in patients with POTS.
Clinical Trials Registration
URL: http://clinicaltrials.gov. Unique identifier: NCT00262470.
doi:10.1161/JAHA.113.000395
PMCID: PMC3835251  PMID: 24002370
atomoxetine; autonomic nervous system; drugs; orthostatic intolerance; sympathetic nervous system; tachycardia
25.  Desmopressin acutely decreases tachycardia and improves symptoms in the Postural Tachycardia Syndrome (POTS) 
Background
Postural Tachycardia Syndrome (POTS) induces disabling chronic orthostatic intolerance with an excessive increase in heart rate (HR) upon standing, and many POTS patients have low blood volume. Increasing blood volume is a promising approach to this problem.
Objective
We tested the hypothesis that desmopressin (DDAVP) will attenuate the tachycardia and improve symptom burden in patients with POTS.
Methods
In this protocol, patients with POTS (n=30) underwent acute drug trials with DDAVP 0.2 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressure, HR and symptoms were assessed while seated and after standing for up to 10 minutes prior to and hourly for 4 hours following study drug.
Results
Standing HR was significantly lower following DDAVP compared to placebo (101.9 ± 14.5 vs. 109.2 ± 17.4 bpm (P<0.001)). Standing blood pressure was not affected (P=0.28). The symptom burden improved with DDAVP (from a score of 18 ± 18 to 13 ± 15 arbitrary units [au] at 2 hours) compared with placebo (from 18 ± 17 to 19 ± 16 au; P=0.010).
Conclusion
Oral desmopressin significantly attenuated tachycardia and improved symptoms in POTS. The safety profile of this approach would need to be examined before it can be recommended for routine treatment of these patients.
doi:10.1016/j.hrthm.2012.05.002
PMCID: PMC3419341  PMID: 22561596
tachycardia; desmopressin; autonomic nervous system; blood volume; drugs; orthostatic intolerance

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