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1.  Spatially Distributed Effects of Mental Exhaustion on Resting-State FMRI Networks 
PLoS ONE  2014;9(4):e94222.
Brain activity during rest is spatially coherent over functional connectivity networks called resting-state networks. In resting-state functional magnetic resonance imaging, independent component analysis yields spatially distributed network representations reflecting distinct mental processes, such as intrinsic (default) or extrinsic (executive) attention, and sensory inhibition or excitation. These aspects can be related to different treatments or subjective experiences. Among these, exhaustion is a common psychological state induced by prolonged mental performance. Using repeated functional magnetic resonance imaging sessions and spatial independent component analysis, we explored the effect of several hours of sustained cognitive performances on the resting human brain. Resting-state functional magnetic resonance imaging was performed on the same healthy volunteers in two days, with and without, and before, during and after, an intensive psychological treatment (skill training and sustained practice with a flight simulator). After each scan, subjects rated their level of exhaustion and performed an N-back task to evaluate eventual decrease in cognitive performance. Spatial maps of selected resting-state network components were statistically evaluated across time points to detect possible changes induced by the sustained mental performance. The intensive treatment had a significant effect on exhaustion and effort ratings, but no effects on N-back performances. Significant changes in the most exhausted state were observed in the early visual processing and the anterior default mode networks (enhancement) and in the fronto-parietal executive networks (suppression), suggesting that mental exhaustion is associated with a more idling brain state and that internal attention processes are facilitated to the detriment of more extrinsic processes. The described application may inspire future indicators of the level of fatigue in the neural attention system.
PMCID: PMC3976406  PMID: 24705397
2.  Effects of DCPD Cement Chemistry on Degradation Properties and Cytocompatibility: Comparison of MCPM/β-TCP and MCPM/HA Formulations 
Dicalcium phosphate dihydrate (DCPD) cements are attractive biomaterials for bone repair, and a number of different DCPD cement formulations have been proposed in the literature. In this study we have specifically compared monocalcium phosphate monohydrate (MCPM)/hydroxyapatite (HA) and MCPM/β-tricalcium phosphate (β-TCP) formulations to test the hypothesis that DCPD cement chemistry affects the degradation properties and cytocompatibility of the cement. Using simple in vitro models we found that MCPM/β-TCP formulations degraded primarily by DCPD dissolution, which was associated with a slight pH drop and relatively low mass loss. Cytocompatibility testing of cement conditioned culture media revealed no significant change in cell viability relative to the negative control for all of the MCPM/β-TCP formulations. In contrast, the MCPM/HA formulations were prone to undergo rapid conversion of DCPD to HA, resulting in a sharp pH drop and extensive mass loss. A stoichiometric excess of HA in the cement was found to accelerate the conversion process, and significant cytotoxicity was observed for the MCPM/HA formulations containing excess HA. Collectively, these results show that, although the product of the setting reaction is the same, DCPD cements produced with MCPM/HA and MCPM/β-TCP formulations differ significantly in their degradation properties and cytocompatibility. These differences may have important implications for the selection of a DCPD cement formulation for clinical application.
PMCID: PMC3649140  PMID: 23428798
calcium phosphate; cement; dicalcium phosphate dihydrate; brushite; degradation; cytocompatibility
3.  Multicenter Validation of Urinary CXCL9 as a Risk-Stratifying Biomarker for Kidney Transplant Injury 
Noninvasive biomarkers are needed to assess immune risk and ultimately guide therapeutic decision-making following kidney transplantation. A requisite step toward these goals is validation of markers that diagnose and/or predict relevant transplant endpoints. The Clinical Trials in Organ Transplantation-01 protocol is a multicenter observational study of biomarkers in 280 adult and pediatric first kidney transplant recipients. We compared and validated urinary mRNAs and proteins as biomarkers to diagnose biopsy-proven acute rejection (AR) and stratify patients into groups based on risk for developing AR or progressive renal dysfunction. Among markers tested for diagnosing AR, urinary CXCL9 mRNA (odds ratio [OR] 2.77, positive predictive value [PPV] 61.5%, negative predictive value [NPV] 83%) and CXCL9 protein (OR 3.40, PPV 67.6%, NPV 92%) were the most robust. Low urinary CXCL9 protein in 6-month posttransplant urines obtained from stable allograft recipients classified individuals least likely to develop future AR or a decrement in estimated glomerular filtration rate between 6 and 24 months (92.5–99.3% NPV). Our results support using urinary CXCL9 for clinical decision-making following kidney transplantation. In the context of acute dysfunction, low values can rule out infectious/immunological causes of injury. Absent urinary CXCL9 at 6 months posttransplant defines a subgroup at low risk for incipient immune injury.
PMCID: PMC3959786  PMID: 23968332
Acute rejection; biomarker; chemokines; kidney allograft; kidney graft function
4.  Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model 
Genes, brain, and behavior  2012;11(5):586-600.
Fragile X syndrome (FXS), the most common inherited form of intellectual disability and prevailing known genetic basis of autism, is caused by an expansion in the Fmr1 gene that prevents transcription and translation of fragile X mental retardation protein (FMRP). FMRP binds to and controls translation of mRNAs downstream of metabotropic glutamate receptor (mGluR) activation. Recent work identified striatal-enriched protein tyrosine phosphatase (STEP) as an FMRP target mRNA. STEP opposes synaptic strengthening and promotes synaptic weakening by dephosphorylating its substrates, including ERK1/2, p38, Fyn, Pyk2, and subunits of NMDA and AMPA receptors. Here we demonstrate that STEP translation is dysregulated in Fmr1KO mice, resulting in elevated basal levels of STEP with a concomitant loss of mGluR-dependent STEP translation. We hypothesized that the weakened synaptic strength and behavioral abnormalities reported in FXS may be linked to excess levels of STEP. To test this hypothesis, we reduced or eliminated STEP genetically in Fmr1KO mice. In addition to attenuating audiogenic seizures and seizure-induced c-Fos activation in the periaqueductal gray, genetically reducing STEP in Fmr1KO mice reversed characteristic social abnormalities, including approach, investigation, novelty-induced hyperactivity and anxiety. Loss of STEP also corrected select non-social anxiety-related behaviors in Fmr1KO mice, such as open arm exploration in the elevated plus maze. Our findings indicate that genetically reducing STEP significantly diminishes seizures and restores social and non-social anxiety-related behaviors in Fmr1KO mice, suggesting that strategies to inhibit STEP activity may be effective for treating patients with FXS.
PMCID: PMC3922131  PMID: 22405502
fragile X syndrome; behavior; audiogenic seizures; social; anxiety; c-Fos; tyrosine phosphatase; STEP
5.  Taking STEPs forward to understanding Fragile X Syndrome 
A priority of Fragile X Syndrome (FXS) research is to determine the molecular mechanisms underlying the functional, behavioral, and structural deficits in humans and in the FXS mouse model. Given that metabotropic glutamate receptor (mGluR) long-term depression (LTD) is exaggerated in FXS mice, considerable effort has focused on proteins that regulate this form of synaptic plasticity. STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific phosphatase implicated as an ‘LTD protein’ because it mediates AMPA receptor internalization during mGluR LTD. STEP also promotes NMDA receptor endocytosis and inactivates ERK1/2 and Fyn, thereby opposing synaptic strengthening. We hypothesized that dysregulation of STEP may contribute to the pathophysiology of FXS. We review how STEP’s expression and activity are regulated by dendritic protein synthesis, ubiquitination, proteolysis, and phosphorylation. We also discuss implications for STEP in FXS and other disorders, including Alzheimer’s disease. As highlighted here, pharmacological interventions targeting STEP may prove successful for FXS.
PMCID: PMC3922766  PMID: 22009355
6.  Histological Validation of DW-MRI Tractography in Human Postmortem Tissue 
Cerebral Cortex (New York, NY)  2012;23(2):442-450.
Despite several previous attempts, histological validation of diffusion-weighted magnetic resonance imaging (DW-MRI)-based tractography as true axonal fiber pathways remains difficult. In the present study, we establish a method to compare histological and tractography data precisely enough for statements on the level of single tractography pathways. To this end, we used carbocyanine dyes to trace connections in human postmortem tissue and aligned them to high-resolution DW-MRI of the same tissue processed within the diffusion tensor imaging (DTI) formalism. We provide robust definitions of sensitivity (true positives) and specificity (true negatives) for DTI tractography and characterize tractography paths in terms of receiver operating characteristics. With sensitivity and specificity rates of approximately 80%, we could show a clear correspondence between histological and inferred tracts. Furthermore, we investigated the effect of fractional anisotropy (FA) thresholds for the tractography and identified FA values between 0.02 and 0.08 as optimal in our study. Last, we validated the course of entire tractography curves to move beyond correctness determination based on pairs of single points on a tract. Thus, histological techniques, in conjunction with alignment and processing tools, may serve as an important validation method of DW-MRI on the level of inferred tractography projections between brain areas.
PMCID: PMC3584953  PMID: 22345356
diffusion tensor imaging; fluorescent dyes; human brain; receiver operating characteristics; single pathways
7.  Windowed Correlation: A Suitable Tool for Providing Dynamic fMRI-Based Functional Connectivity Neurofeedback on Task Difficulty 
PLoS ONE  2014;9(1):e85929.
The goal of neurofeedback training is to provide participants with relevant information on their ongoing brain processes in order to enable them to change these processes in a meaningful way. Under the assumption of an intrinsic brain-behavior link, neurofeedback can be a tool to guide a participant towards a desired behavioral state, such as a healthier state in the case of patients. Current research in clinical neuroscience regarding the most robust indicators of pathological brain processes in psychiatric and neurological disorders indicates that fMRI-based functional connectivity measures may be among the most important biomarkers of disease. The present study therefore investigated the general potential of providing fMRI neurofeedback based on functional correlations, computed from short-window time course data at the level of single task periods. The ability to detect subtle changes in task performance with block-wise functional connectivity measures was evaluated based on imaging data from healthy participants performing a simple motor task, which was systematically varied along two task dimensions representing two different aspects of task difficulty. The results demonstrate that fMRI-based functional connectivity measures may provide a better indicator for an increase in overall (motor) task difficulty than activation level-based measures. Windowed functional correlations thus seem to provide relevant and unique information regarding ongoing brain processes, which is not captured equally well by standard activation level-based neurofeedback measures. Functional connectivity markers, therefore, may indeed provide a valuable tool to enhance and monitor learning within an fMRI neurofeedback setup.
PMCID: PMC3896435  PMID: 24465794
8.  Processing of Natural Sounds: Characterization of Multipeak Spectral Tuning in Human Auditory Cortex 
The Journal of Neuroscience  2013;33(29):11888-11898.
We examine the mechanisms by which the human auditory cortex processes the frequency content of natural sounds. Through mathematical modeling of ultra-high field (7 T) functional magnetic resonance imaging responses to natural sounds, we derive frequency-tuning curves of cortical neuronal populations. With a data-driven analysis, we divide the auditory cortex into five spatially distributed clusters, each characterized by a spectral tuning profile. Beyond neuronal populations with simple single-peaked spectral tuning (grouped into two clusters), we observe that ∼60% of auditory populations are sensitive to multiple frequency bands. Specifically, we observe sensitivity to multiple frequency bands (1) at exactly one octave distance from each other, (2) at multiple harmonically related frequency intervals, and (3) with no apparent relationship to each other. We propose that beyond the well known cortical tonotopic organization, multipeaked spectral tuning amplifies selected combinations of frequency bands. Such selective amplification might serve to detect behaviorally relevant and complex sound features, aid in segregating auditory scenes, and explain prominent perceptual phenomena such as octave invariance.
PMCID: PMC3713728  PMID: 23864678
9.  Encoding of Natural Sounds at Multiple Spectral and Temporal Resolutions in the Human Auditory Cortex 
PLoS Computational Biology  2014;10(1):e1003412.
Functional neuroimaging research provides detailed observations of the response patterns that natural sounds (e.g. human voices and speech, animal cries, environmental sounds) evoke in the human brain. The computational and representational mechanisms underlying these observations, however, remain largely unknown. Here we combine high spatial resolution (3 and 7 Tesla) functional magnetic resonance imaging (fMRI) with computational modeling to reveal how natural sounds are represented in the human brain. We compare competing models of sound representations and select the model that most accurately predicts fMRI response patterns to natural sounds. Our results show that the cortical encoding of natural sounds entails the formation of multiple representations of sound spectrograms with different degrees of spectral and temporal resolution. The cortex derives these multi-resolution representations through frequency-specific neural processing channels and through the combined analysis of the spectral and temporal modulations in the spectrogram. Furthermore, our findings suggest that a spectral-temporal resolution trade-off may govern the modulation tuning of neuronal populations throughout the auditory cortex. Specifically, our fMRI results suggest that neuronal populations in posterior/dorsal auditory regions preferably encode coarse spectral information with high temporal precision. Vice-versa, neuronal populations in anterior/ventral auditory regions preferably encode fine-grained spectral information with low temporal precision. We propose that such a multi-resolution analysis may be crucially relevant for flexible and behaviorally-relevant sound processing and may constitute one of the computational underpinnings of functional specialization in auditory cortex.
Author Summary
How does the human brain analyze natural sounds? Previous functional neuroimaging research could only describe the response patterns that sounds evoke in the human brain at the level of preferential regional activations. A comprehensive account of the neural basis of human hearing, however, requires deriving computational models that are able to provide quantitative predictions of brain responses to natural sounds. Here, we make a significant step in this direction by combining functional magnetic resonance imaging (fMRI) with computational modeling. We compare competing computational models of sound representations and select the model that most accurately predicts the measured fMRI response patterns. The computational models describe the processing of three relevant properties of natural sounds: frequency, temporal modulations and spectral modulations. We find that a model that represents spectral and temporal modulations jointly and in a frequency-dependent fashion provides the best account of fMRI responses and that the functional specialization of auditory cortical fields can be partially accounted for by their modulation tuning. Our results provide insights on how natural sounds are encoded in human auditory cortex and our methodological approach constitutes an advance in the way this question can be addressed in future studies.
PMCID: PMC3879146  PMID: 24391486
10.  Intravenous injection of urocortin 1 induces a CRF2 mediated increase in circulating ghrelin and glucose levels through distinct mechanisms in rats 
Peptides  2012;39:164-170.
Urocortins (Ucns) injected peripherally decrease food intake and gastric emptying through peripheral CRF2 receptors in rodents. However, whether Ucns influence circulating levels of the orexigenic and prokinetic hormone, ghrelin has been little investigated. We examined plasma levels of ghrelin and blood glucose after intravenous (iv) injection of Ucn 1, the CRF receptor subtype involved and underlying mechanisms in ad libitum fed rats equipped with a chronic iv cannula. Ucn 1 (10 µg/kg, iv) induced a rapid onset and long lasting increase in ghrelin levels reaching 68% and 219% at 0.5 and 3 h post injection respectively and a 5-h hyperglycemic response. The selective CRF2 agonist, Ucn 2 (3 µg/kg, iv) increased fasting acyl (3 h: 49%) and des-acyl ghrelin levels (3 h: 30%) compared to vehicle while the preferential CRF1 agonist, CRF (3 µg/kg, iv) had no effect. Ucn 1’s stimulatory actions were blocked by the selective CRF2 antagonist, astressin2-B (100 µg/kg, iv). Hexamethonium (10 mg/kg, sc) prevented Ucn 1-induced rise in total ghrelin levels while not altering the hyperglycemic response. These data indicate that systemic injection of Ucns induces a CRF2-mediated increase in circulating ghrelin levels likely via indirect actions on gastric ghrelin cells that involves a nicotinic pathway independently from the hyperglycemic response.
PMCID: PMC3599411  PMID: 23183626
acyl ghrelin; astressin2-B; CRF; des-acyl ghrelin; radioimmunoassay; rat; urocortin
11.  Cost-Effectiveness of Latent Tuberculosis Screening Before Steroid Therapy for Idiopathic Nephrotic Syndrome in Children 
Guidelines differ on screening recommendations for latent tuberculosis infection (LTBI) prior to immunosuppressive therapy. We aimed to determine the most cost-effective LTBI screening strategy before long-term steroid therapy in a child with new onset idiopathic nephrotic syndrome.
Study Design
Markov state-transition model.
Setting and Population
Five year old male with new onset idiopathic nephrotic syndrome.
Model, Perspective, and Timeframe
The Markov model took a societal perspective over a lifetime horizon.
Three strategies were compared: universal tuberculin skin testing (TST), targeted screening using a risk-factor questionnaire, and no screening. A secondary model included the newer interferon-γ release assays (IGRA), requiring only one visit and having greater specificity than TST.
Marginal cost-effectiveness ratios (2010 United States $) with effectiveness measured as quality-adjusted life years (QALYs).
At a LTBI prevalence of 1.1% (the average United States childhood prevalence in our base-case), a no-screening strategy dominated ($2,201, 29.3356 QALYs) targeted screening ($2,218, 29.3356 QALYs) and universal TST ($2,481, 29.3347 QALYs). At a prevalence >10.3%, targeted screening with a risk-factor questionnaire was the most cost-effective option. Above a prevalence of 58.5%, universal TST was preferred. In the secondary model, targeted screening with a questionnaire followed by IGRA testing was cost-effective compared to no screening in the base case when the LTBI prevalence was >4.9%.
There is no established gold standard for the diagnosis of LTBI. Results of any modeling task are limited by the accuracy of available data.
Prior to starting steroids, only patients in areas with a high prevalence of LTBI will benefit from universal TST. As more evidence becomes available on the use of IGRA testing in children, the assay may become a component of cost-effective screening protocols in populations with a higher burden of LTBI.
PMCID: PMC3827973  PMID: 22784996
cost-effectiveness; nephrotic syndrome; tuberculosis; children
12.  Prospective Follow-Up of Patients with Acute Hepatitis C Virus Infection in Brazil 
The natural outcome of infection with hepatitis C virus (HCV) varies substantially among individuals. However, little is known about host and viral factors associated with a self-limiting or chronic evolution of HCV infection.
From 1 January 2001 through 31 December 2008, a consecutive series of 65 patients from Rio de Janeiro, Brazil, with a well-documented diagnosis of acute HCV infection, acquired via various routes, were enrolled in this study. Patients were prospectively followed up for a median of 40 months after the estimated date of HCV infection with serial measurements of serum alanine aminotransferase, HCV RNA, and anti-HCV antibodies. Spontaneous viral clearance (SVC) was defined as undetectable levels of HCV RNA in serum, in the absence of treatment, for 3 consecutive HCV polymerase chain reaction tests within the first 6 months of follow-up. Cox proportional hazards regression was used to identify host and viral predictors of SVC.
The cumulative rate of SVC was 44.6% (95% confidence interval, 32.3%–57.5%). Compared with chronic HCV evolution, patients with self-limiting disease had significantly lower peak levels of anti-HCV antibodies (median, 109.0 vs 86.7 optical density–to–cutoff ratio [od/co]; P < .02), experienced disease symptoms more frequently (69.4% vs 100%; P < .001), and had lower viral load at first clinical presentation (median, 4.3 vs 0.0 log copies; P =.01). In multivariate analyses, low peak anti-HCV level (<93.5 od/co) was the only independent predictor for SVC; the hazard ratio compared with high anti-HCV levels (≥93.5 od/co) was 2.62 (95% confidence interval, 1.11–6.19; P =.03).
Our data suggest that low levels of anti-HCV antibodies during the acute phase of HCV infection are independently related to spontaneous viral clearance.
PMCID: PMC3860186  PMID: 20235831
13.  UGT1A9, UGT2B7 and MRP2 genotypes can predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients 
Therapeutic drug monitoring  2012;34(6):671-679.
Mycophenolic acid (MPA) exposure in pediatric kidney transplant patients receiving body surface area (BSA)-based dosing exhibits large variability. Several genetic variants in glucuronosyl transferases (UGTs) and of multidrug resistance-associated protein 2 (MRP2) have independently been suggested to predict MPA exposure in adult patients with varying results. Here, the combined contribution of these genetic variants to MPA pharmacokinetic variability was investigated in pediatric renal transplant recipients who were on mycophenolic mofetil maintenance therapy.
MPA and MPA-Glucuronide (MPAG) concentrations from 32 patients were quantified by HPLC. MPA exposure (AUC) was estimated using a 4-point abbreviated sampling strategy (pre-dose/trough and 20min, 1h and 3h post-dose) using a validated pediatric Bayesian estimator. Genotyping was performed for all of the following single nucleotide polymorphisms (SNPs): UGT1A8 830G>A(*3), UGT1A9 98T>C(*3), UGT1A9-440C>T, UGT1A9-2152C>T, UGT1A9-275T>A, UGT2B7-900A>G and MRP2 -24T>C.
Recipients heterozygous for MRP2-24T>C who also had UGT1A9-440C>T and/or UGT2B7-900A>G (n=4), and MRP2-24T>C-negative recipients having both UGT1A9-440C>T and UGT2B7-900A>G (n=5) showed a 2.2 and 1.7-times higher dose- and BSA-normalized MPA-AUC compared to carriers of no or only one UGT-SNP (P < 0.001 and P=0.01, respectively) (n=7). Dose- and BSA-normalized pre-dose MPA concentrations were 3.0- and 2.4-times higher, respectively (P < 0.001). Inter-individual variability in peak concentrations could be explained by the presence of the UGT1A9-440C>T genotype (P<0.05).
Our preliminary study demonstrates that combined UGT1A9-440C>T, UGT2B7-900A>G and MRP2-24T>C polymorphisms can be important predictors of interindividual variability in MPA exposure in the pediatric population.
PMCID: PMC3498586  PMID: 23131697
Pediatric patient; Mycophenolic acid; Mycophenolate Mofetil; Pharmacogenetics; Pharmacokinetics; Kidney Transplantation; Uridine diphosphate glucuronosyltransferase; multidrug resistance-associated protein 2
14.  Differing Effects of Rapamycin or Calcineurin Inhibitor on T-Regulatory Cells in Pediatric Liver and Kidney Transplant Recipients 
In a cross-sectional study, we assessed effects of calcineurin inhibitor (CNI) or rapamycin on T-regulatory (Treg) cells from children with stable liver (n=53) or kidney (n=9) allografts several years post-transplant. We analyzed Treg number, phenotype, suppressive function, and methylation at the Treg-specific demethylation region (TSDR) using Tregs and peripheral blood mononuclear cells. 48 patients received CNI (39 as monotherapy) and 12 patients received rapamycin (9 as monotherapy). Treg numbers diminished over time on either regimen, but reached significance only with CNI (r=−0.424, p=0.017). CNI levels inversely correlated with Treg number (r=−0.371, p=0.026), and positively correlated with CD127+ expression by Tregs (r=0.437, p=0.023). Patients with CNI levels >3.6 ng/ml had weaker Treg function than those with levels <3.6 ng/ml, whereas rapamycin therapy positively correlated with Treg numbers (r=0.628, p=0.029) and their expression of CTLA4 (r=0.726, p=0.041). Overall, CTLA4 expression, TSDR demethylation and an absence of CD127 were important for Treg suppressive function. We conclude that rapamycin has beneficial effects on Treg biology, whereas long-term and high dose CNI use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft.
PMCID: PMC3513508  PMID: 22994804
Immunosuppression; immunoregulation; clinical transplantation
15.  Comparison of different metrics for analysis and visualization in spectroscopic optical coherence tomography 
Biomedical Optics Express  2013;4(12):2945-2961.
Spectroscopic Optical Coherence Tomography (S-OCT) extracts depth resolved spectra that are inherently available from OCT signals. The back scattered spectra contain useful functional information regarding the sample, since the light is altered by wavelength dependent absorption and scattering caused by chromophores and structures of the sample. Two aspects dominate the performance of S-OCT: (1) the spectral analysis processing method used to obtain the spatially-resolved spectroscopic information and (2) the metrics used to visualize and interpret relevant sample features. In this work, we focus on the second aspect, where we will compare established and novel metrics for S-OCT. These concepts include the adaptation of methods known from multispectral imaging and modern signal processing approaches such as pattern recognition. To compare the performance of the metrics in a quantitative manner, we use phantoms with microsphere scatterers of different sizes that are below the system’s resolution and therefore cannot be differentiated using intensity based OCT images. We show that the analysis of the spectral features can clearly separate areas with different scattering properties in multi-layer phantoms. Finally, we demonstrate the performance of our approach for contrast enhancement in bovine articular cartilage.
PMCID: PMC3862158  PMID: 24409393
(170.4500) Optical coherence tomography; (300.0300) Spectroscopy; (290.5850) Scattering, particles; (180.0180) Microscopy; (170.3880) Medical and biological imaging
16.  Medium-Level Laser in Chronic Tinnitus Treatment 
BioMed Research International  2013;2013:324234.
The purpose of this study was to evaluate the effect of medium-level laser therapy in chronic tinnitus treatment. In a prospective double-blind placebo-controlled trial, either active laser (450 mW, 830 nm combined Ga-Al-As diode laser) or placebo irradiation was applied through the external acoustic meatus of the affected ear towards the cochlea. Fourty-eight patients with chronic tinnitus were studied. The main outcome was measured using the Goebel tinnitus questionnaire, visual analogue scales measuring the perceived loudness of tinnitus, the annoyance associated with tinnitus, and the degree of attention paid to tinnitus as well as psycho-acoustical matches of tinnitus pitch and loudness. The results did show only very moderate temporary improvement of tinnitus. Moreover, no statistically relevant differences between laser and placebo group could be found. We conclude that medium-level laser therapy cannot be regarded as an effective treatment of chronic tinnitus in our therapy regime considering the limited number of patients included in our study.
PMCID: PMC3835591  PMID: 24294604
17.  Correction: Carbon Monoxide Abrogates Ischemic Insult to Neuronal Cells via the Soluble Guanylate Cyclase-cGMP Pathway 
PLoS ONE  2013;8(11):10.1371/annotation/f047d50f-761b-4c99-9e13-d2526fde71b7.
PMCID: PMC3817262  PMID: 24223685
18.  A Novel ABO Gene Variant Leads to Discrepant Results in Forward/Reverse and Molecular Blood Grouping 
Discrepant results in antigen and reverse ABO blood typing are often caused by a variant ABO gene. Molecular analysis can help to characterize such variants. Here, we describe the identification of a novel ABO gene variant in a patient with aberrant ABO phenotype and discrepant genotyping results.
A patient with discrepant results in automated forward and reverse ABO phenotyping was further investigated by serological (gel and tube technique) and molecular (commercial and inhouse PCR-SSP, DNA sequencing) methods. A PCR-SSP system was established to screen the novel mutation in 1,820 blood donors.
Standard serological tests confirmed blood group O, however, only anti-B isoagglutinins were present. A monoclonal anti-AB antibody detected very weak agglutination in gel technique. Standard ABO genotyping using PCR-SSP led to discrepant results (O1/O1 or O1/A) depending on the test system used. ABO exon re-sequencing identified a novel missense mutation in exon 6 at position 248A>G (Asp83Gly) in the binding region of PCR-SSP primers for the detection of 261G alleles. Blood donors with regular ABO blood groups were all negative for the 248G allele designated Aw34.
The novel ABO gene variant Aw34 is associated with very weak A antigen expression and absent anti-A isoagglutinins. The mutation is located in exon 6 close to the O1-specific 261G deletion in the binding region of PCR-SSP primers. Presumably, depending on the primer concentration used in commercial ABO genotyping kits, the mutation could lead to a false-negative reaction.
PMCID: PMC3901630  PMID: 24474897
ABO phenotyping and genotyping; ABO sequencing ABO gene variant; PCR-SSP
19.  How Skill Expertise Shapes the Brain Functional Architecture: An fMRI Study of Visuo-Spatial and Motor Processing in Professional Racing-Car and Naïve Drivers 
PLoS ONE  2013;8(10):e77764.
The present study was designed to investigate the brain functional architecture that subserves visuo-spatial and motor processing in highly skilled individuals. By using functional magnetic resonance imaging (fMRI), we measured brain activity while eleven Formula racing-car drivers and eleven ‘naïve’ volunteers performed a motor reaction and a visuo-spatial task. Tasks were set at a relatively low level of difficulty such to ensure a similar performance in the two groups and thus avoid any potential confounding effects on brain activity due to discrepancies in task execution. The brain functional organization was analyzed in terms of regional brain response, inter-regional interactions and blood oxygen level dependent (BOLD) signal variability. While performance levels were equal in the two groups, as compared to naïve drivers, professional drivers showed a smaller volume recruitment of task-related regions, stronger connections among task-related areas, and an increased information integration as reflected by a higher signal temporal variability. In conclusion, our results demonstrate that, as compared to naïve subjects, the brain functional architecture sustaining visuo-motor processing in professional racing-car drivers, trained to perform at the highest levels under extremely demanding conditions, undergoes both ‘quantitative’ and ‘qualitative’ modifications that are evident even when the brain is engaged in relatively simple, non-demanding tasks. These results provide novel evidence in favor of an increased ‘neural efficiency’ in the brain of highly skilled individuals.
PMCID: PMC3799613  PMID: 24204955
20.  Unexpected genetic differentiation between recently recolonized populations of a long-lived and highly vagile marine mammal 
Ecology and Evolution  2013;3(11):3701-3712.
Many species have been heavily exploited by man leading to local extirpations, yet few studies have attempted to unravel subsequent recolonization histories. This has led to a significant gap in our knowledge of the long-term effects of exploitation on the amount and structure of contemporary genetic variation, with important implications for conservation. The Antarctic fur seal provides an interesting case in point, having been virtually exterminated in the nineteenth century but subsequently staged a dramatic recovery to recolonize much of its original range. Consequently, we evaluated the hypothesis that South Georgia (SG), where a few million seals currently breed, was the main source of immigrants to other locations including Livingston Island (LI), by genotyping 366 individuals from these two populations at 17 microsatellite loci and sequencing a 263 bp fragment of the mitochondrial hypervariable region 1. Contrary to expectations, we found highly significant genetic differences at both types of marker, with 51% of LI individuals carrying haplotypes that were not observed in 246 animals from SG. Moreover, the youngest of three sequentially founded colonies at LI showed greater similarity to SG at mitochondrial DNA than microsatellites, implying temporal and sex-specific variation in recolonization. Our findings emphasize the importance of relict populations and provide insights into the mechanisms by which severely depleted populations can recover while maintaining surprisingly high levels of genetic diversity.
PMCID: PMC3810869  PMID: 24198934
Colonization; gene flow; genetic differentiation; genetic diversity; pinniped
21.  Inosine Monophosphate Dehydrogenase (IMPDH) Activity as a Pharmacodynamic Biomarker of Mycophenolic Acid Effects in Pediatric Kidney Transplant Recipients 
Journal of clinical pharmacology  2010;51(3):309-320.
Monitoring inosine monophosphate dehydrogenase (IMPDH) activity as a biomarker of mycophenolic acid (MPA)–induced immunosuppression may serve as a novel approach in pharmacokinetics (PK)/pharmacodynamics (PD)–guided therapy. The authors prospectively studied MPA pharmacokinetics and IMPDH inhibition in 28 pediatric de novo kidney transplant recipients. Pretransplant IMPDH activity and full PK/PD profiles were obtained at 3 different occasions: 1 to 3 days, 4 to 9 days, and approximately 6 months after transplant. Large intra- and interpatient variability was noted in MPA pharmacokinetics and exposure and IMPDH inhibition. MPA exposure (AUC0-12 h) was low early posttransplant and increased over time and stabilized at months 3 to 6. Mean pretransplant IMPDH activity (6.4 ± 4.6 nmol/h/mg protein) was lower than previously reported in adults. In most of the patients, IMPDH enzyme activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory Emax model (EC50 = 0.97 mg/L). This study suggests the importance of early PK/PD monitoring to improve drug exposure. Because IMPDH inhibition is well correlated to MPA concentration, pre-transplant IMPDH activity may serve as an early marker to guide the initial level of MPA exposure required in a pediatric population.
PMCID: PMC3769694  PMID: 20418509
pediatric patient; mycophenolic acid; pharmacodynamics; inosine monophosphate dehydrogenase (IMPDH); pharmacokinetics; kidney transplantation
22.  Does Integrated Practice Guideline Testing in Gastroenterology Fellowship Training Improve Fellows' Education? 
The Ochsner Journal  2013;13(3):385-388.
Multiple professional societies have issued practice guidelines that provide up-to-date evidence-based recommendations and expert opinions on patient care in the field of gastroenterology (GI). While most physicians are aware that formal guidelines exist, these GI guidelines have not been integrated into academic training curricula in most of the top-ranked GI fellowship programs.
Two fellows in the Ochsner GI fellowship program (the control group) reviewed 14 current American Society of Gastrointestinal Endoscopy guidelines deemed essential for GI fellowship training and wrote 200 questions based on these guidelines. Four additional fellows (the experimental group) had no knowledge of which articles would be tested. A 14-week curriculum focused on reviewing the guidelines. All 6 fellows took a pretest before the guideline review and then took a postreview test. All of the participating GI fellows completed a survey evaluating the perceived effectiveness of the formal guideline testing.
The experimental group had a 33% improvement in test scores between the pre- and posttest, while the control group had a 7% improvement. The survey showed that 100% of the fellows felt more secure in their knowledge of the guidelines and would recommend that this learning format be implemented into the annual academic curriculum. All also agreed that this format provided evidence-based knowledge to improve patient safety and provide optimal patient care.
We plan to continue formal practice guideline reviews in our fellowship and believe this format would benefit other medical training programs as well.
PMCID: PMC3776515  PMID: 24052769
Graduate medical education; patient safety; practice guidelines as topic
24.  The GPVI – Fc Fusion Protein Revacept Reduces Thrombus Formation and Improves Vascular Dysfunction in Atherosclerosis without Any Impact on Bleeding Times 
PLoS ONE  2013;8(8):e71193.
Glycoprotein VI (GPVI) is a key platelet receptor which mediates plaque-induced platelet activation and consecutive atherothrombosis, but GPVI is also involved in platelet-mediated atheroprogression. Therefore, interference in GPVI-mediated platelet activation has the potential to combine short-term and long-term beneficial effects, specificity and safety especially regarding bleeding complications.
Methods and Results
We investigated the effects of the soluble dimeric GPVI receptor fusion protein, Revacept, an antagonist of collagen-mediated platelet activation, in an animal model of atherosclerosis: twenty week old rabbits, which had been fed on a cholesterol-rich diet for 8 weeks, received Revacept (8 mg/kg) or control twice weekly for 4 weeks. Pharmacokinetics indicated a slight accumulation of the drug in the serum after repeated dosing of Revacept for 3 weeks. A significant improvement of endothelial dysfunction after 0.06 and 0.6 µg/min acetylcholine and a significant decrease of vessel wall thickening were found after Revacept treatment. Accordingly, aortic vessel weight was reduced, and plaque sizes, macrophage and T-cell invasion tended to be reduced in histological evaluations. Bleeding time was determined after tail clipping in mice. Revacept alone or in combination with widely used anti-platelet drugs revealed a high safety margin with no prolongation of bleeding times.
Repeated doses of Revacept led to a significant improvement of endothelial dysfunction and vascular morphology in atherosclerotic rabbits. Furthermore, no influence of Revacept on bleeding time alone or in combinations with various anti-platelet drugs was found in mice. Thus, the inhibition of collagen-mediated platelet interaction with the atherosclerotic endothelium by Revacept exerts beneficial effects on morphology and vascular function in vivo and seems to have a wide therapeutic window without influencing the bleeding time.
PMCID: PMC3741334  PMID: 23951109
Neurotoxicology  2009;30(2):305-311.
We developed Drosophila melanogaster as a model to study correlated behavioral, neuronal and genetic effects of the neurotoxin lead, known to affect cognitive and behavioral development in children. We showed that, as in vertebrates, lead affects both synaptic development and complex behaviors (courtship, fecundity, locomotor activity) in Drosophila. By assessing differential behavioral responses to developmental lead exposure among recombinant inbred Drosophila lines (RI), derived from parental lines Oregon R and Russian 2b, we have now identified a genotype by environment interaction (GEI) for a behavioral trait affected by lead. Drosophila Activity Monitors (TriKinetics, Waltham, MA), which measure activity by counting the number of times a single fly in a small glass tube walks through an infrared beam aimed at the middle of the tube, were used to measure activity of flies, reared from eggs to 4 days of adult age on either control or lead-contaminated medium, from each of 75 RI lines. We observed a significant statistical association between the effect of lead on average daytime activity across lines and one marker locus, 30AB, on chromosome 2; we define this as a Quantitative Trait Locus (QTL) associated with behavioral effects of developmental lead exposure. When 30AB was from Russian 2b, lead significantly increased locomotor activity, whereas, when 30AB was from Oregon R, lead decreased it. 30AB contains about 125 genes among which are likely “candidate genes” for the observed lead-dependent behavioral changes. Drosophila are thus a useful, underutilized model for studying behavioral, synaptic and genetic changes following chronic exposure to lead or other neurotoxins during development.
PMCID: PMC3734858  PMID: 19428504
developmental lead exposure; developmental plasticity; behavior; quantitative trait locus; locomotor activity; Drosophila; developmental neurotoxicology; neurotoxin; endocrine disruptor

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