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1.  Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype 
Molecular psychiatry  2008;15(2):146-153.
Despite compelling evidence for a major genetic contribution to risk of bipolar mood disorder, conclusive evidence implicating specific genes or pathophysiological systems has proved elusive. In part this is likely to be related to the unknown validity of current phenotype definitions and consequent aetiological heterogeneity of samples. In the recent Wellcome Trust Case Control Consortium (WTCCC) genome-wide association analysis of bipolar disorder (1868 cases, 2938 controls) one of the most strongly associated polymorphisms lay within the gene encoding the GABAA receptor β1 subunit, GABRB1. Aiming to increase biological homogeneity, we sought the diagnostic subset that showed the strongest signal at this polymorphism and used this to test for independent evidence of association with other members of the GABAA receptor gene family. The index signal was significantly enriched in the 279 cases meeting Research Diagnostic Criteria for schizoaffective disorder, bipolar type (p=3.8×10−6). Independently, these cases showed strong evidence that variation in GABAA receptor genes influences risk for this phenotype (independent system-wide p=6.6×10−5) with association signals also at GABRA4, GABRB3, GABRA5 and GABRR1. Our findings have the potential to inform understanding of presentation, pathogenesis and nosology of bipolar disorders. Our method of phenotype refinement may be useful in studies of other complex psychiatric and non-psychiatric disorders.
doi:10.1038/mp.2008.66
PMCID: PMC3967096  PMID: 19078961
2.  Genome Wide Association Analysis of Copy Number Variation in Recurrent Depressive Disorder 
Molecular psychiatry  2011;18(2):183-189.
Large, rare copy number variants (CNV) have been implicated in a variety of psychiatric disorders, but the role of CNVs in recurrent depression is unclear. We performed a genome-wide analysis of large, rare CNVs in 3,106 cases of recurrent depression, 459 controls screened for lifetime-absence of psychiatric disorder and 5,619 unscreened controls from phase 2 of the Wellcome Trust Case Control Consortium (WTCCC2). We compared the frequency of cases with CNVs against the frequency observed in each control group, analysing CNVs over the whole genome, genic, intergenic, intronic and exonic regions. We found that deletion CNVs were associated with recurrent depression while duplications were not. The effect was significant when comparing cases to WTCCC2 controls (p=7.7×10−6, OR =1.25 (95% CI 1.13 - 1.37)) and to screened controls (p=5.6×10−4, OR=1.52 (95% CI 1.20 - 1.93). Further analysis showed that CNVs deleting protein coding regions were largely responsible for the association. Within an analysis of regions previously implicated in schizophrenia, we found an overall enrichment of CNVs in our cases when compared to screened controls (p=0.019). We observe an ordered increase of samples with deletion CNVs, with the lowest proportion seen in screened controls, the next highest in unscreened controls and the highest in cases. This may suggest that the absence of deletion CNVs, especially in genes, is associated with resilience to recurrent depression.
doi:10.1038/mp.2011.144
PMCID: PMC3939438  PMID: 22042228
4.  Toward a definition of “fresh” whole blood: an in vitro characterization of coagulation properties in refrigerated whole blood for transfusion 
Transfusion  2011;51(1):10.1111/j.1537-2995.2010.02772.x.
Background
The hemostatic property of “fresh” whole blood (WB) has been observed in military application and cardiac surgery and is associated with reduced blood loss, transfusion requirements, and donor exposures. The time from donation to transfusion defining “fresh” has not been systematically studied. We undertook an in vitro study of coagulation properties of refrigerated WB stored for 31 days.
Study design and methods
Twenty-one WB units were obtained from healthy volunteer donors and stored under standard AABB refrigerated conditions. Samples were obtained on the day after donation and again on Days 2, 4, 7, 11, 14, 17, 21, 24, and 31. Tests included complete blood count, pH, pO2, pCO2, glucose, lactate, thromboelastography (TEG), and platelet function by light transmission aggregometry (LTA).
Results
There was progressive decline in pH, pO2, glucose, and sodium, but progressive increase in potassium, pCO2, and lactate. TEG variables in all units were normal through Day 11; abnormal values in some variables in some units began on Day 14. Final aggregation levels exhibited no change from Day 1 to Day 21 with adenosine diphosphate and epinephrine, but a decline with collagen (Day 7) and ristocetin (Day 17).
Conclusion
This in vitro study of coagulation properties demonstrates preservation of normal integrated coagulation function to a minimum of 11 days under standard conditions of refrigerated storage of WB for transfusion. These observations strongly suggest that the hemostatic quality of WB may extend beyond current transfusion practices. If confirmed clinically, this would increase availability and extend benefits of reduced donor exposure and transfusion requirements.
doi:10.1111/j.1537-2995.2010.02772.x
PMCID: PMC3821701  PMID: 20663116
5.  Amiodarone-Associated Optic Neuropathy: A Critical Review 
The American Journal of Medicine  2012;125(5):447-453.
Although amiodarone is the most commonly prescribed antiarrhythmic drug, its use is limited by serious toxicities, including optic neuropathy. Current reports of amiodarone associated optic neuropathy identified from the Food and Drug Administration's Adverse Event Reporting System (FDA-AERS) and published case reports were reviewed. A total of 296 reports were identified: 214 from AERS, 59 from published case reports, and 23 from adverse events reports for patients enrolled in clinical trials. Mean duration of amiodarone therapy before vision loss was 9 months (range 1-84 months). Insidious onset of amiodarone associated optic neuropathy (44%) was the most common presentation, and nearly one-third were asymptomatic. Optic disc edema was present in 85% of cases. Following drug cessation, 58% had improved visual acuity, 21% were unchanged, and 21% had further decreased visual acuity. Legal blindness (< 20/200) was noted in at least one eye in 20% of cases. Close ophthalmologic surveillance of patients during the tenure of amiodarone administration is warranted.
doi:10.1016/j.amjmed.2011.09.020
PMCID: PMC3322295  PMID: 22385784
amiodarone; vision loss; optic neuropathy
6.  Genome Wide Linkage Analysis of 972 Bipolar Pedigrees Using Single Nucleotide Polymorphisms 
Molecular Psychiatry  2011;17(8):818-826.
Because of the high costs associated with ascertainment of families most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. While microsatellite markers spaced every 10 centimorgans typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carry out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 SNPs. Of the ~1100 families, 972 were informative for further analyses and mean information content was 0.86 after pruning for LD. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with Bipolar II disorder (BPII) and 702 subjects with Recurrent Major Depression. Three affection status models were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus Recurrent Major Depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (Nonparametric Pairs Lod 3.4 for rs1046943 at 119 cM) and 9q21 (Nonparametric Pairs Lod 3.4 for rs722642 at 78 cM) using only BPI and SA, BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis we observed 59 parametric lods of 2 or greater, many of which are likely to be close to maximum possible scores. While some linkage findings may be false positives the results could help prioritize the search for rare variants using whole exome or genome sequencing.
doi:10.1038/mp.2011.89
PMCID: PMC3204161  PMID: 21769101
Bipolar disorder; Whole genome linkage; Single Nucleotide Polymorphisms; 6q21; 9q21; 2q12
7.  Genome Wide Linkage Analysis of 972 Bipolar Pedigrees Using Single Nucleotide Polymorphisms 
Molecular psychiatry  2011;17(8):818-826.
Because of the high costs associated with ascertainment of families most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. While microsatellite markers spaced every 10 centimorgans typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carry out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 SNPs. Of the ~1100 families, 972 were informative for further analyses and mean information content was 0.86 after pruning for LD. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with Bipolar II disorder (BPII) and 702 subjects with Recurrent Major Depression. Three affection status models were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus Recurrent Major Depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (Nonparametric Pairs Lod 3.4 for rs1046943 at 119 cM) and 9q21 (Nonparametric Pairs Lod 3.4 for rs722642 at 78 cM) using only BPI and SA, BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis we observed 59 parametric lods of 2 or greater, many of which are likely to be close to maximum possible scores. While some linkage findings may be false positives the results could help prioritize the search for rare variants using whole exome or genome sequencing.
doi:10.1038/mp.2011.89
PMCID: PMC3204161  PMID: 21769101
Bipolar disorder; Whole genome linkage; Single Nucleotide Polymorphisms; 6q21; 9q21; 2q12
8.  Fast Photochemical Oxidation of Proteins (FPOP) for Epitope Mapping 
Analytical chemistry  2011;83(20):7657-7661.
The growing use of monoclonal antibodies as therapeutics underscores the importance of epitope mapping as an essential step in characterizing antibody-antigen complexes. The use of protein footprinting coupled with mass spectrometry, which is emerging as a tool in structural biology, offers opportunities to map antibody-binding regions of antigens. We report here the use of footprinting via fast photochemical oxidation of proteins (FPOP) with OH radicals to characterize the epitope of the serine-protease thrombin. The data correlate well with previously published results that determined the epitope of thrombin. This study marks the first time oxidative labeling has been used for epitope mapping.
doi:10.1021/ac2007366
PMCID: PMC3193551  PMID: 21894996
Mass spectrometry; oxidation; epitope mapping; protein footprinting
9.  Functional neuroimaging of the baboon during concurrent image-guided transcranial magnetic stimulation 
NeuroImage  2011;57(4):1393-1401.
Transcranial magnetic stimulation (TMS) has well-established applications in basic neuroscience and promising applications in neurological and psychiatric disorders. However the underlying mechanisms of TMS-induced alterations in brain function are not well understood. As a result, treatment design parameters are determined ad hoc and not informed by any coherent theory or model. Once the mechanisms underlying TMS’s modulatory effects on brain systems are better understood and modeled, TMS’s potential as a therapeutic and/or investigative tool will be more readily explored and exploited. An animal model is better suited to study different TMS variables, therefore we developed a baboon model to facilitate testing of some of the current theoretical models of TMS interactions with brain regions. We have demonstrated the feasibility of this approach by successfully imaging cerebral blood flow (CBF) changes with H215O positron emission tomography imaging during high-frequency, suprathreshold repetitive TMS in the primary motor cortex of five healthy, adult baboons.
doi:10.1016/j.neuroimage.2011.05.065
PMCID: PMC3139451  PMID: 21664276
TMS; fMRI; PET; animal models; motor cortex
10.  Echocardiographic Findings and Their Impact on Outcomes of Critically Ill Patients with AIDS in the Era of HAART 
Pulmonary Medicine  2012;2012:575793.
Objective. To describe the echocardiographic findings in critically ill patients with AIDS and their impact on clinical outcome. Design. A retrospective chart review of consecutive AIDS patients over 18 years of age, who had a trans-thoracic echocardiogram performed during the course of intensive care unit stay over the course of 2 years at a tertiary care hospital. Main outcome measures. The prevalence of echocardiogram abnormalities in this population and its impact on ICU mortality, ICU length of stay, hospital mortality, hospital length of stay and 60 day survival. Results. Among 107 patients who met the inclusion criteria, an admission echocardiogram was performed in 62 (58%). The prevalence of cardiac abnormalities was 60%. The most common admission diagnosis was respiratory failure n = 27 (43%). The most common finding on echocardiogram was left ventricular (LV) dysfunction n = 31 (50%) followed by pulmonary hypertension n = 25 (40%). None of these findings had a significant impact on clinical outcomes. There was trend toward reduced 60 day survival among patients with depressed LV function. Conclusions. Although echocardiogram abnormalities were prevalent among this population none of these findings had a significant impact on ICU mortality or hospital mortality and ICU length of stay or hospital length of stay.
doi:10.1155/2012/575793
PMCID: PMC3337497  PMID: 22567277
11.  Stressful life events and the serotonin transporter gene (5-HTT) in recurrent clinical depression. 
Journal of affective disorders  2011;136(1-2):189-193.
Background
An interaction between recent stressful life events (SLEs) and a serotonin transporter promoter polymorphism (5-HTTLPR) in depression has been inconsistently reported. Some of this variability may be due to a previous focus on sub-clinical depression, inclusion of individuals at the lower or upper ends of the age-span, or assumptions concerning the degree of dominance of the low expressing allele. Therefore, a large sample of patients with recurrent clinically diagnosed depression and controls screened for absence of depression was utilised to examine the moderating effect of each 5-HTTLPR genetic model on the association between SLEs and severe depressive episodes.
Method
A sample of 1236 recurrent unipolar depression cases and 598 age-matched, never psychiatrically ill controls completed the List of Threatening Experiences Questionnaire to assess the number of SLEs experienced in the 6 months prior to the most severe depressive episode (cases) or interview (controls). DNA extracted from blood or cheek swabs was genotyped for the short (s) and long (l) alleles of 5-HTTLPR.
Results
A greater number of SLEs were reported by cases than controls and this held across all genotypic groups. There was no main effect of 5-HTTLPR on depression and no evidence of interaction between total SLEs and any of the 5-HTTLPR genetic models. The results were the same for men and women.
Limitations
Utilisation of retrospective self-reported SLEs may have reduced the accuracy of the findings and the cross-sectional design prevents causal inference.
Conclusions
This study failed to find evidence of gene-environment interplay in recurrent clinical depression.
doi:10.1016/j.jad.2011.09.016
PMCID: PMC3272366  PMID: 21982504
Stressful life events; unipolar depression; recurrent; serotonin transporter gene; gene-environment interaction; 5-HTTLPR
13.  Fast Photochemical Oxidation of Proteins (FPOP) for Comparing Structures of Protein/Ligand Complexes: The Calmodulin-peptide Model System 
Analytical chemistry  2010;83(1):311-318.
Fast Photochemical Oxidation of Proteins (FPOP) is a mass-spectrometry-based protein footprinting method that modifies proteins on the microsecond time scale. Highly reactive •OH, produced by laser photolysis of hydrogen peroxide, oxidatively modifies the side chains of approximately one half the common amino acids on this time scale. Owing to the short labeling exposure, only solvent-accessible residues are sampled. Quantification of the modification extent for the apo and holo states of a protein-ligand complex should provide structurally sensitive information at the amino-acid level to compare the structures of unknown protein complexes with known ones. We report here the use of FPOP to monitor the structural changes of calmodulin in its established binding to M13 of the skeletal muscle myosin light chain kinase. We use the outcome to establish the unknown structures resulting from binding with melittin and mastoparan. The structural comparison follows from a comprehensive examination of the extent of FPOP modifications as measured by proteolysis and LC-MS/MS for each protein-ligand equilibrium. The results not only show that the three calmodulin-peptide complexes have similar structures but also reveal those regions of the protein that became more or less solvent-accessible upon binding. This approach has the potential for relatively high throughput, information-dense characterization of a series of protein-ligand complexes in biochemistry and drug discovery when the structure of one reference complex is known, as is the case for calmodulin and M13 of the skeletal muscle myosin light chain kinase, and the structures of related complexes are not,.
doi:10.1021/ac102426d
PMCID: PMC3078576  PMID: 21142124
14.  A targeted proteomics–based pipeline for verification of biomarkers in plasma 
Nature biotechnology  2011;29(7):625-634.
High-throughput technologies can now identify hundreds of candidate protein biomarkers for any disease with relative ease. However, because there are no assays for the majority of proteins and de novo immunoassay development is prohibitively expensive, few candidate biomarkers are tested in clinical studies. We tested whether the analytical performance of a biomarker identification pipeline based on targeted mass spectrometry would be sufficient for data-dependent prioritization of candidate biomarkers, de novo development of assays and multiplexed biomarker verification. We used a data-dependent triage process to prioritize a subset of putative plasma biomarkers from >1,000 candidates previously identified using a mouse model of breast cancer. Eighty-eight novel quantitative assays based on selected reaction monitoring mass spectrometry were developed, multiplexed and evaluated in 80 plasma samples. Thirty-six proteins were verified as being elevated in the plasma of tumor-bearing animals. The analytical performance of this pipeline suggests that it should support the use of an analogous approach with human samples.
doi:10.1038/nbt.1900
PMCID: PMC3232032  PMID: 21685906
15.  Genomewide Association Scan of Suicidal Thoughts and Behaviour in Major Depression 
PLoS ONE  2011;6(7):e20690.
Background
Suicidal behaviour can be conceptualised as a continuum from suicidal ideation, to suicidal attempts to completed suicide. In this study we identify genes contributing to suicidal behaviour in the depression study RADIANT.
Methodology/Principal Findings
A quantitative suicidality score was composed of two items from the SCAN interview. In addition, the 251 depression cases with a history of serious suicide attempts were classified to form a discrete trait. The quantitative trait was correlated with younger onset of depression and number of episodes of depression, but not with gender. A genome-wide association study of 2,023 depression cases was performed to identify genes that may contribute to suicidal behaviour. Two Munich depression studies were used as replication cohorts to test the most strongly associated SNPs. No SNP was associated at genome-wide significance level. For the quantitative trait, evidence of association was detected at GFRA1, a receptor for the neurotrophin GDRA (p = 2e-06). For the discrete trait of suicide attempt, SNPs in KIAA1244 and RGS18 attained p-values of <5e-6. None of these SNPs showed evidence for replication in the additional cohorts tested. Candidate gene analysis provided some support for a polymorphism in NTRK2, which was previously associated with suicidality.
Conclusions/Significance
This study provides a genome-wide assessment of possible genetic contribution to suicidal behaviour in depression but indicates a genetic architecture of multiple genes with small effects. Large cohorts will be required to dissect this further.
doi:10.1371/journal.pone.0020690
PMCID: PMC3130038  PMID: 21750702
16.  Strength of Tobacco Control in Rural Communities 
Purpose
This study aimed to: (a) describe the Strength of Tobacco Control (SoTC) capacity, efforts and resources in rural communities, and (b) examine the relationships between SoTC scores and sociodemographic, political and health-ranking variables.
Methods
Data were collected during the baseline pre-intervention phase of a community-based randomized, controlled trial. Rural counties were selected using stratified random sampling (n = 39). Key informant interviews were employed. The SoTC, originally developed and tested with states, was adapted to a county-level measure assessing capacity, efforts, and resources. Univariate analysis and bivariate correlations assessed the SoTC total score and construct scores, as well as their relationships. Multiple regression examined the relationships of county-level sociodemographic, political and health-ranking variables with SoTC total and construct scores.
Findings
County population size was positively correlated with capacity (r = 0.44; P < .01), efforts (r = 0.54; P = .01) and SoTC total score (r = 0.51; P < .01). Communities with more resources for tobacco control had better overall county health rankings (r = .43; P < .01). With population size, percent Caucasian, tobacco production, and smoking prevalence as potential predictors of SoTC total score, only population size was significant.
Conclusions
SoTC scores may be useful in determining local tobacco control efforts and appropriate planning for additional public health interventions and resources. Larger rural communities were more likely to have strong tobacco control programs than smaller communities. Smaller rural communities may need to be targeted for training and technical assistance. Leadership development and allocation of resources are needed in all rural communities to address disparities in tobacco use and tobacco control policies.
doi:10.1111/j.1748-0361.2010.00273.x
PMCID: PMC2948793  PMID: 20446998
tobacco control; strength of tobacco control; environmental tobacco smoke pollution; rural communities
17.  Methylenetetrahydrofolate Reductase Gene Variant (MTHFR C677T) and Migraine: A Case Control Study and Meta-analysis 
BMC Neurology  2011;11:66.
Background
Migraine is a common disorder that often coexists with depression. While a functional polymorphism in methyleneterahydrofolate reductase gene (MTHFR C677T) has been implicated in depression; the evidence to support an association of MTHFR with migraine has been inconclusive. We aim to investigate the effect of this variant on propensity for migraine and to perform a systematic review and meta-analysis of studies of MTHFR and migraine to date.
Methods
Individuals with migraine (n = 447) were selected from the Depression Case Control (DeCC) study to investigate the association between migraine and MTHFR C677T single nucleotide polymorphism (SNP) rs1801133 using an additive model compared to non-migraineurs adjusting for depression status. A meta-analysis was performed and included 15 studies of MTHFR and migraine.
Results
MTHFR C677T polymorphism was associated with migraine with aura (MA) (OR 1.31, 95% CI 1.01-1.70, p = 0.039) that remained significant after adjusting for age, sex and depression status. A meta-analysis of 15 case-control studies showed that T allele homozygosity is significantly associated with MA (OR = 1.42; 95% CI, 1.10-1.82) and total migraine (OR = 1.37; 95% CI, 1.07-1.76), but not migraine without aura (OR = 1.16; 95% CI, 0.36-3.76). In studies of non-Caucasian population, the TT genotype was associated with total migraine (OR= 3.46; 95% CI, 1.22-9.82), whereas in studies of Caucasians this variant was associated with MA only (OR = 1.28; 95% CI, 1.002-1.63).
Conclusions
MTHFR C677T is associated with MA in individuals selected for depression study. A meta-analysis of 15 studies supports this association and demonstrated effects across ethnic groups.
doi:10.1186/1471-2377-11-66
PMCID: PMC3120667  PMID: 21635773
18.  An On-Line, High-Pressure Digestion System for Protein Characterization by Hydrogen/Deuterium Exchange and Mass Spectrometry 
Analytical chemistry  2010;82(4):1171-1174.
The rapid and complete digestion of proteins is important when protein characterization by hydrogen deuterium exchange (HDX) is coupled with mass spectrometry. We developed a single-pump, on-line, high pressure digestion system that relies on UPLC technology to aid in the digestion of proteins. Two model proteins, Aβ1–42 and NBSA, were used to demonstrate the efficacy of the high pressure system. Both model proteins readily aggregate and are difficult to digest under normal conditions. Our high pressure system successfully digests these proteins into small, overlapping peptides. The extra information afforded by overlapping peptides allows us to pinpoint HDX protection to protein segments smaller than the digested peptide. The calculated average segment length (ASL) for both model proteins decreased by 2-fold for high pressure digestion compared to digestion at ambient pressure.
doi:10.1021/ac902477u
PMCID: PMC2826105  PMID: 20095571
High pressure; pepsin; protein digestion; hydrogen deuterium exchange; mass spectrometry
19.  MRI of Perfusion-Diffusion Mismatch in Non-Human Primate (Baboon) Stroke: A Preliminary Report  
The goal of this study was to develop a clinically relevant non-human primate (baboon) stroke model and multi-parametric MRI protocols on a clinical scanner with long-term goals to better model human stroke and facilitate clinical translations of novel therapeutic strategies. Baboons were chosen because of their relatively large brain volume and that they are evolutionarily close to humans. Middle cerebral artery occlusion (MCAO) was induced using a minimally invasive endovascular approach to guide an inflatable balloon catheter into the MCA and followed by permanently or transiently inflate the balloon. Using multimodal MRI, including perfusion and diffusion imaging, the spatiotemporal dynamic evolution of the ischemic lesions in permanent and transient occlusion experiments in baboons were investigated. Perfusion-diffusion mismatch, which approximates the ischemic penumbra, was detected. In the permanent MCAO group (n = 2), the mean infarct volume was 29 ml (17% of total brain volume) whereas in the transient MCAO group (n = 2, 60 or 90 min of occlusion), the mean infarct volume was 15 ml (9% of total brain volume). Substantial perfusion-diffusion mismatch tissue (~50%) was salvaged by reperfusion compared to permanent MCAO. This baboon stroke model has the potential to become a translational platform to better design clinical studies, guide clinical diagnosis and improve treatment time windows in patients.
doi:10.2174/1874440001105010147
PMCID: PMC3257583  PMID: 22253656
Penumbra; cerebral ischemia; middle cerebral artery occlusion; nonhuman primate; perfusion; diffusion; magnetic resonance imaging.
20.  Utility of the pooling approach as applied to whole genome association scans with high-density Affymetrix microarrays 
BMC Research Notes  2010;3:274.
Background
We report an attempt to extend the previously successful approach of combining SNP (single nucleotide polymorphism) microarrays and DNA pooling (SNP-MaP) employing high-density microarrays. Whereas earlier studies employed a range of Affymetrix SNP microarrays comprising from 10 K to 500 K SNPs, this most recent investigation used the 6.0 chip which displays 906,600 SNP probes and 946,000 probes for the interrogation of CNVs (copy number variations). The genotyping assay using the Affymetrix SNP 6.0 array is highly demanding on sample quality due to the small feature size, low redundancy, and lack of mismatch probes.
Findings
In the first study published so far using this microarray on pooled DNA, we found that pooled cheek swab DNA could not accurately predict real allele frequencies of the samples that comprised the pools. In contrast, the allele frequency estimates using blood DNA pools were reasonable, although inferior compared to those obtained with previously employed Affymetrix microarrays. However, it might be possible to improve performance by developing improved analysis methods.
Conclusions
Despite the decreasing costs of genome-wide individual genotyping, the pooling approach may have applications in very large-scale case-control association studies. In such cases, our study suggests that high-quality DNA preparations and lower density platforms should be preferred.
doi:10.1186/1756-0500-3-274
PMCID: PMC2984392  PMID: 21040578
21.  BOLD fMRI of visual and somatosensory–motor stimulations in baboons 
NeuroImage  2010;52(4):1420-1427.
Baboon, with its large brain size and extensive cortical folding compared to other non-human primates, serves as a good model for neuroscience research. This study reports the implementation of a baboon model for blood oxygenation level-dependent (BOLD) fMRI studies (1.5 × 1.5 × 4 mm resolution) on a clinical 3 T-MRI scanner. BOLD fMRI responses to hypercapnic (5% CO2) challenge, 10 Hz flicker visual, and vibrotactile somatosensory–motor stimulations were investigated in baboons anesthetized sequentially with isoflurane and ketamine. Hypercapnia evoked robust BOLD increases. Paralysis was determined to be necessary to achieve reproducible functional activations within and between subjects under our experimental conditions. With optimized anesthetic doses (0.8–1.0% isoflurane or 6–8 mg/kg/h ketamine) and adequate paralysis (vecuronium, 0.2 mg/kg), robust activations were detected in the visual (V), primary (S1) and secondary (S2) somatosensory, primary motor (M cortices), supplementary motor area (SMA), lateral geniculate nucleus (LGN) and thalamus (Th). Data were tabulated for 11 trials under isoflurane and 10 trials under ketamine on 5 baboons. S1, S2, M, and V activations were detected in essentially all trials (90–100% of the time, except 82% for S2 under isoflurane and 70% for M under ketamine). LGN activations were detected 64–70% of the time under both anesthetics. SMA and Th activations were detected 36–45% of the time under isoflurane and 60% of the time under ketamine. BOLD percent changes among different structures were slightly higher under ketamine than isoflurane (0.75% versus 0.58% averaging all structures), but none was statistically different (P>0.05). This baboon model offers an opportunity to non-invasively image brain functions and dysfunctions in large non-human primates.
doi:10.1016/j.neuroimage.2010.05.014
PMCID: PMC2949958  PMID: 20471483
Blood oxygenation level-dependent (BOLD); fMRI; Non-human primates; Cerebral blood flow; Thalamus; Brain mapping; Anesthetic; Animal models
23.  Children's Ocular Components and Age, Gender, and Ethnicity 
Purpose
This cross-sectional report includes ocular component data as a function of age, gender, and ethnicity from the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) Study.
Methods
The ocular components of 4881 school-aged children were examined using cycloplegic autorefraction (refractive error), keratometry (corneal curvature), ultrasonography (axial dimensions), and videophakometry (lens curvature).
Results
The average age (± SD) was 8.8 ± 2.3 years, and 2458 were girls (50.4%). Sixteen percent were African American, 14.8% were Asian, 22.9% were Hispanic, 11.6% were Native American, and 34.9% were White. More myopic/less hyperopic refractive error was associated with greater age, especially in Asians, less in Whites and African Americans. Corneal power varied slightly with age, with girls showing a greater mean corneal power. Native-American children had greater corneal toricity with a markedly flatter horizontal corneal power. Anterior chambers were deeper with age, and boys had deeper anterior chambers. Native-American children had the shallowest anterior chambers and Whites the deepest. Girls had higher Gullstrand and calculated lens powers than boys. Boys had longer vitreous chambers and axial lengths, and both were deeper with age. Native Americans had the longest vitreous chambers and Whites the shortest.
Conclusions
Most ocular components showed little clinically meaningful variation by ethnicity. The shallower anterior chambers and deeper vitreous chambers of Native-American children appeared to be offset by flatter corneas. The relatively deeper anterior chamber and shallower vitreous chambers of White children appeared to be offset by steeper corneas. Asian children had more myopic spherical equivalent refractive errors, but for a given refractive error the ocular parameters of Asian children were moderate in value compared to those of other ethnic groups. Asian children may develop longer, myopic eyes more often than other ethnic groups, but the eyes of Asian emmetropes do not appear to be innately longer.
PMCID: PMC2901932  PMID: 19650241
hyperopia; myopia; refractive error; ocular components; children; astigmatism
24.  Accommodation, Acuity, and their Relationship to Emmetropization in Infants 
Purpose
To evaluate the relationship between accommodation, visual acuity, and emmetropization in human infancy.
Methods
Defocus at distance and near (57cm) was assessed using Mohindra and dynamic retinoscopy, respectively, in 262 normal birthweight infants at 3, 9, and 18 months of age. Preferential looking provided acuity data at the same ages. The spherical equivalent refractive error was measured by cycloplegic retinoscopy (cyclopentolate 1%).
Results
Univariate linear regression analyses showed no associations between the change in refractive error and defocus at distance or near. Change in refractive error was linearly related to the accommodative response at distance (R2 = 0.17, p<0.0001) and near (R2 = 0.13, p<0.0001). The ten subjects with the poorest emmetropization relative to the change predicted by the linear effects of their refractive error had higher average levels of hyperopic defocus at distance and near (p-values <0.043). Logistic regression showed a decrease in the odds of reaching +2.00D or less hyperopia by 18 months with increasing levels of hyperopia at 3 months, or if Mohindra retinoscopy was myopic combined with acuity better than the median level of 1.25 logMAR (area under the receiver operating characteristic curve = 0.78 (95% CI = 0.68, 0.88)).
Conclusions
The level of cycloplegic refractive error was the best single factor for predicting emmetropization by 18 months of age, with smaller contributions from visual acuity and Mohindra retinoscopy. The lack of correlation between defocus and change in refractive error does not support a simple model of emmetropization in response to the level of hyperopic defocus. Infants were capable of maintaining accurate average levels of accommodation across a range of moderate hyperopic refractive errors at 3 months of age. The association between the change in refractive error and accommodative response suggests that the amount of accommodation is a plausible visual signal for emmetropization.
doi:10.1097/OPX.0b013e3181a6174f
PMCID: PMC2706284  PMID: 19417711
emmetropization; refractive error; accommodation; infant vision; visual development
25.  Parental History of Myopia, Sports and Outdoor Activities, and Future Myopia 
PURPOSE
To identify whether parental history of myopia and/or parent-reported children’s visual activity levels can predict juvenile-onset myopia.
METHODS
Survey-based data from Orinda Longitudinal Study of Myopia subjects from 1989 to 2001 were used to predict future myopia. Univariate and multiple logistic regression analyses were performed, and receiver operator characteristic (ROC) curves were generated. Differences among the areas under the ROC curves were compared using the method of multiple comparison with the best.
RESULTS
Of the 514 children eligible for this analysis, 111 (21.6%) became myopic. Differences in the third grade between eventual myopes and nonmyopes were seen for the number of myopic parents (P < 0.001) and for the number of sports and outdoor activity hours per week (11.65 ± 6.97 hours for nonmyopes vs. 7.98 ± 6.54 hours for future myopes, P < 0.001). Analysis of the areas under the ROC curves showed three variables with a predictive value better than chance: the number of myopic parents, the number of sports and outdoor activity hours per week, and the number of reading hours per week. After controlling for sports and outdoor hours per week and parental myopia history, reading hours per week was no longer a statistically significant factor. The area under the curve for the parental myopia history and sports and outdoor activities model was 0.73. A significant interaction in the logistic model showed a differential effect of sport and outdoor activity hours per week based on a child’s number of myopic parents.
CONCLUSIONS
Parental history of myopia was an important predictor in univariate and multivariate models, with a differential effect of sports and outdoor activity hours per week based on the number of myopic parents. Lower amounts of sports and outdoor activity increased the odds of becoming myopic in those children with two myopic parents more than in those children with either zero or one myopic parent. The chance of becoming myopic for children with no myopic parents appears lowest in the children with the highest amount of sports and outdoor activity, compared with those with two myopic parents.
doi:10.1167/iovs.06-1118
PMCID: PMC2871403  PMID: 17652719

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