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1.  Pre-B cell colony enhancing factor (PBEF/NAMPT/Visfatin) and vascular endothelial growth factor (VEGF) cooperate to increase the permeability of the human placental amnion 
Placenta  2012;34(1):42-49.
Fluid efflux across the region of the amnion overlying the placenta is an essential component of the intramembranous absorption pathway that maintains amniotic fluid volume homeostasis. Dysregulation of this pathway may result in adverse pregnancy outcomes, however the factors controlling amnion permeability are unknown. Here, we report a novel mechanism that increases placental amnion permeability. Pre-B Cell Colony Enhancing Factor (PBEF) is a stress-responsive cytokine expressed by the human amnion, and is known to induce Vascular Endothelial Growth Factor (VEGF) production by other cell types. Interestingly, VEGF is up-regulated in the ovine amnion when intramembranous absorption is augmented. In this study, we show that PBEF induced VEGF secretion by primary human amniotic epithelial cells (AEC) derived from the placental amnion, as well as from the reflected amnion that lines the remainder of the gestational sac. Further, PBEF treatment led to the increased expression of VEGFR2 in placental AEC, but not reflected AEC. To test the hypothesis that PBEF and VEGF increase placental amnion permeability, we monitored the transfer of 2′,7′-dichlorofluorescein (DCF) from the fetal to the maternal side of human amnion explants. A treatment regimen including both PBEF and VEGF increased the rate of DCF transfer across the placental amnion, but not the reflected amnion. In summary, our results suggest that by augmenting VEGFR2 expression in the placental amnion, PBEF primes the tissue for a VEGF-mediated increase in permeability. This mechanism may have important implications in amniotic fluid volume control throughout gestation.
doi:10.1016/j.placenta.2012.10.008
PMCID: PMC3541826  PMID: 23151382
Pre-B cell colony enhancing factor (PBEF); Visfatin; Nicotinamide phosphoribosyltransferase (NAMPT); Vascular endothelial growth factor (VEGF); Amnion; Permeability
2.  Observation of T2-like coherent optical phonons in epitaxial Ge2Sb2Te5/GaSb(001) films 
Scientific Reports  2013;3:2965.
The phonon spectrum of Ge2Sb2Te5 is a signature of its crystallographic structure and underlies the phase transition process used in memory applications. Epitaxial materials allow coherent optical phonons to be studied in femtosecond anisotropic reflectance measurements. A dominant phonon mode with frequency of 3.4 THz has been observed in epitaxial Ge2Sb2Te5 grown on GaSb(001). The dependence of signal strength upon pump and probe polarization is described by a theory of transient stimulated Raman scattering that accounts for the symmetry of the crystallographic structure through use of the Raman tensor. The 3.4 THz mode has the character of the 3 dimensional T2 mode expected for the Oh point group, confirming that the underlying crystallographic structure is cubic. New modes are observed in both Ge2Sb2Te5 and GaSb after application of large pump fluences, and are interpreted as 1 and 2 dimensional modes associated with segregation of Sb.
doi:10.1038/srep02965
PMCID: PMC3797426  PMID: 24129388
3.  Mirrored pyramidal wells for simultaneous multiple vantage point microscopy 
Journal of microscopy  2008;232(1):1-6.
Summary
We report a novel method for obtaining simultaneous images from multiple vantage points of a microscopic specimen using size-matched microscopic mirrors created from anisotropically etched silicon. The resulting pyramidal wells enable bright-field and fluorescent side-view images, and when combined with z-sectioning, provide additional information for 3D reconstructions of the specimen. We have demonstrated the 3D localization and tracking over time of the centrosome of a live Dictyostelium discoideum. The simultaneous acquisition of images from multiple perspectives also provides a five-fold increase in the theoretical collection efficiency of emitted photons, a property which may be useful for low-light imaging modalities such as bioluminescence, or low abundance surface-marker labelling.
doi:10.1111/j.1365-2818.2008.02110.x
PMCID: PMC3789065  PMID: 19017196
Confocal microscopy; fluorescence microscopy; PSF; tilted views; 3D microscopy; 3D reconstruction
4.  Influence of Patients’ Coronary Artery Calcium on Subsequent Medication Use Patterns 
Objectives
To determine whether information on the presence and extent of coronary artery calcium (CAC) is associated with the likelihood of physicians’ prescribing preventive therapies.
Method
In a longitudinal design, asymptomatic participants (N=510) were evaluated by computed tomography for CAC. Changes to medications were at the discretion of the patient’s primary care provider, who received the CT report.
Results
In multivariable analysis, the likelihood of patients reporting that their primary care physician prescribed preventive therapies was significantly associated with the presence and extent of CAC.
Conclusions
This study suggests that physicians’ prescribing practices are influenced by patients’ CAC scores obtained via CT.
doi:10.5993/AJHB.36.5.5
PMCID: PMC3753401  PMID: 22584090
coronary calcium; computed tomography; physician prescribing practices; preventive therapies
5.  Cajachalcone: An Antimalarial Compound from Cajanus cajan Leaf Extract 
Cajanus cajan L, a member of the family Fabaceae, was identified from the Nigerian antimalarial ethnobotany as possessing antimalarial properties. The bioassay-guided fractionation of the crude methanol extract of C. cajan leaves was done in vitro using the multiresistant strain of Plasmodium falciparum (K1) in the parasite lactate dehydrogenase assay. Isolation of compound was achieved by a combination of chromatographic techniques, while the structure of the compound was elucidated by spectroscopy. This led to the identification of a cajachalcone, 2′,6′-dihydroxy-4-methoxy chalcone, as the biologically active constituent from the ethyl acetate fraction. Cajachalcone had an IC50 value of 2.0 μg/mL (7.4 μM) and could be a lead for anti-malarial drug discovery.
doi:10.1155/2013/703781
PMCID: PMC3732606  PMID: 23970954
6.  DNA Sequencing Research Group (DSRG): Evaluation of RNA Amplification Kits at Subnanogram Input Amounts of Total RNA for RNA-Seq 
Multiple recent publications on RNA-Seq have demonstrated the power of next generation sequencing technologies in whole transcriptome analysis. The vendor specific protocols used for RNA library construction typically require at least 100ng of total RNA. However, under certain conditions such as single cells, stem cells, difficult to isolate cell types, or fractionated cancer cells, only a small amount of material is available. In these cases, effective transcriptome profiling requires amplification of subnanogram amounts of RNA. Several RNA amplification kits are available for amplification prior to library construction and next generation sequencing but these kits have not been comprehensively field evaluated for accuracy and performance of RNA-Seq for picogram amounts of RNA.
This study conducted by the DNA Sequencing Research Group (DSRG) focuses on the evaluation of amplification kits for RNA-Seq. Four commercial amplification kits were chosen: Ovation v2 (NuGEN Technologies), SMARTer (Clontech), Seqplex (Sigma Aldrich), and Super-AMP (Miltenyi Biotech). Starting material was 5ng, 500pg and 50pg of human total reference RNA (Clontech) spiked with Ambion ERCC control mix (Life Technologies) following the manufacturer's protocol. Each kit was tested at 3 different sites to assess reproducibility. Total RNA and ERCC RNA spike-in control mixes from the same lots were sent to 12 ABRF lab sites for amplification and cDNA generation. Ideally, this would have resulted in 36 different amplified samples, 3 from each input RNA. Libraries were constructed at one site from the amplified cDNAs using the TruSeq RNA library preparation kit on the Tecan Freedom EVO Liquid Handling Robot. As an unamplified control, ribosomal depletion and PolyA selection were performed separately using 5ng, 100ng and 1ug of total RNA prior to library construction. All libraries were pooled and sequenced using the Illumina HiSeq platform. An overview of the study and the results will be presented.
PMCID: PMC3635359
7.  Comparing the performance of six human papillomavirus tests in a screening population 
British Journal of Cancer  2013;108(4):908-913.
Background:
Several new assays have been developed for high-risk HPV testing of cervical samples; we compare six HPV tests in a screening population.
Methods:
Residual material from liquid-based PreservCyt samples was assayed. Four tests (Hybrid Capture 2, Cobas, Abbott and Becton-Dickinson (BD)) measured HPV DNA while two used RNA (APTIMA and NorChip).
Results:
Positivity rates ranged from 13.4 to 16.3% for the DNA-based tests with a significantly lower positivity rate for the Abbott assay. The Gen-Probe APTIMA assay was positive in 10.3% of women, which was significantly lower than all the DNA tests; the NorChip PreTect HPV-Proofer test was much lower at 5.2%. 40 CIN2+ cases were identified, of which 19 were CIN3+. All CIN3+ cases were HPV positive by all tests except for one, which was negative by the Abbott assay and five which were negative by the NorChip test.
Conclusion:
All HPV tests except NorChip showed high sensitivity for high-grade lesions positive by cytology, suggesting co-testing is unnecessary when using HPV tests. Positivity rates in cytology-negative specimens were similar for the DNA-based tests, but lower for the APTIMA test suggesting this maintains the high sensitivity of DNA tests, but with better specificity.
doi:10.1038/bjc.2013.22
PMCID: PMC3590662  PMID: 23370211
biomarkers; cervix; HPV
8.  Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice 
Annals of Oncology  2011;22(12):2616-2624.
Background: Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care.
Methods: We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping.
Results: Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and β-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy.
Conclusions: Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.
doi:10.1093/annonc/mdr489
PMCID: PMC3493130  PMID: 22071650
carcinoma; non-small cell; genotype; molecular targeted therapy
9.  Lower prevalence of silent brain infarcts in the physically active 
Neurology  2011;76(24):2112-2118.
Objective:
To examine the independent association between physical activity and subclinical cerebrovascular disease as measured by silent brain infarcts (SBI) and white matter hyperintensity volume (WMHV).
Methods:
The Northern Manhattan Study (NOMAS) is a population-based prospective cohort examining risk factors for incident vascular disease, and a subsample underwent brain MRI. Our primary outcomes were SBI and WMHV. Baseline measures of leisure-time physical activity were collected in person. Physical activity was categorized by quartiles of the metabolic equivalent (MET) score. We used logistic regression models to examine the associations between physical activity and SBI, and linear regression to examine the association with WMHV.
Results:
There were 1,238 clinically stroke-free participants (mean age 70 ± 9 years) of whom 60% were women, 65% were Hispanic, and 43% reported no physical activity. A total of 197 (16%) participants had SBI. In fully adjusted models, compared to those who did not engage in physical activity, those in the upper quartile of MET scores were almost half as likely to have SBI (adjusted odds ratio 0.6, 95% confidence interval 0.4–0.9). Physical activity was not associated with WMHV.
Conclusions:
Increased levels of physical activity were associated with a lower risk of SBI but not WMHV. Engaging in moderate to heavy physical activities may be an important component of prevention strategies aimed at reducing subclinical brain infarcts.
doi:10.1212/WNL.0b013e31821f4472
PMCID: PMC3111237  PMID: 21653889
11.  Intensity-modulated radiotherapy increases dose to the brachial plexus compared with conventional radiotherapy for head and neck cancer 
The British Journal of Radiology  2011;84(997):58-63.
Objective
The preferential use of intensity-modulated radiotherapy (IMRT) over conventional radiotherapy (CRT) in the treatment of head and neck cancer has raised concerns regarding dose to non-target tissue. The purpose of this study was to compare dose-volume characteristics with the brachial plexus between treatment plans generated by IMRT and CRT using several common treatment scenarios.
Method
The brachial plexus was delineated on radiation treatment planning CT scans from 10 patients undergoing IMRT for locally advanced head and neck cancer using a Radiation Therapy Oncology Group-endorsed atlas. No brachial plexus constraint was used. For each patient, a conventional three-g0ield shrinking-g0ield plan was generated and the dose-volume histogram (DVH) for the brachial plexus was compared with that of the IMRT plan.
Results
The mean irradiated volumes of the brachial plexus using the IMRT vs the CRT plan, respectively, were as follows: V50 (18±5 ml) vs (11±6 ml), p = 0.01; V60 (6±4 ml) vs (3±3 ml), p = 0.02; V66 (3±1 ml) vs (1±1 ml), p = 0.04, V70 (0±1 ml) vs (0±1 ml), p = 0.68. The maximum point dose to the brachial plexus was 68.9 Gy (range 62.3–78.7 Gy) and 66.1 Gy (range 60.2–75.6 Gy) for the IMRT and CRT plans, respectively (p = 0.01).
Conclusion
Dose to the brachial plexus is significantly increased among patients undergoing IMRT compared with CRT for head and neck cancer. Preliminary studies on brachial plexus-sparing IMRT are in progress.
doi:10.1259/bjr/62332495
PMCID: PMC3473798  PMID: 20858665
12.  A Methodology Study for Metagenomics Using Next Generation Sequencers 
Metagenomic studies have benefited immensely from next-generation sequencing. However, although much has been published, there are still many unanswered questions. In this DSRG study we aim to answer some of the larger questions by evaluating different DNA extraction methods and comparing two platforms, the Roche/454 and theIllumina next-generation systems. We are using differentanalysis methods to evaluate the sequence data off these platforms in order to determine how the method and/or platform performs comparatively, as well as to establish arecommended analysis pipeline for future users. The results should help establish preferred experimental and technical strategies for gene prediction and determination of biodiversity within microbial communities.
PMCID: PMC3630548
13.  DSRG Metagenomics Study: Next-Generation Techniques and Data Analysis 
Next-generation sequencing has vastly changed the processes associated with metagenomic research and there is a current rush of scientific studies in this field. However, although much has been published, there are still many unanswered questions. In this DSRG study we aim to answer some of the larger questions by evaluating different DNA extraction methods and comparing two platforms, the Roche/454 and the Illumina next-generation systems. Here, we present initial results from two community samples using one extraction method. We examined both 16S and whole genome DNA samples from each and sequenced all samples on the two next-generation platforms. We detail the different analysis methods used to evaluate the sequence data off these platforms and show how the platforms perform comparatively. Future goals of the study will also be highlighted with results helping to establish preferred experimental and technical strategies for metagenomic analysis studies.
PMCID: PMC3630662
14.  β-catenin Initiates Tooth Neogenesis in Adult Rodent Incisors 
Journal of Dental Research  2010;89(9):909-914.
β-catenin signaling is required for embryonic tooth morphogenesis and promotes continuous tooth development when activated in embryos. To determine whether activation of this pathway in the adult oral cavity could promote tooth development, we induced mutation of epithelial β-catenin to a stabilized form in adult mice. This caused increased proliferation of the incisor tooth cervical loop, outpouching of incisor epithelium, abnormal morphology of the epithelial-mesenchymal junction, and enhanced expression of genes associated with embryonic tooth development. Ectopic dental-like structures were formed from the incisor region following implantation into immunodeficient mice. Thus, forced activation of β-catenin signaling can initiate an embryonic-like program of tooth development in adult rodent incisor teeth.
doi:10.1177/0022034510370090
PMCID: PMC3148824  PMID: 20530729
tooth; development; β-catenin; Wnt; dental
15.  Periodontitis is associated with cognitive impairment among older adults: analysis of NHANES-III 
Background
Periodontitis is ubiquitous and associated with serological evidence of exposure to periodontal organisms, systemic inflammation and vascular disease. Dementia is a major public health problem likely related to a complex interaction between genetics and diseases associated with systemic inflammation, including diabetes, smoking and stroke.
Methods
To assess relationships between systemic exposure to periodontal pathogens and cognitive test outcomes, data were analysed from the Third National Health and Nutrition Examination Survey (NHANES-III), a nationally representative cross sectional observational study among older adults. We included 2355 participants ≥60 years who completed measures of cognition and Poryphyromonas gingivalis IgG. Using SUDAAN, logistic regression models examined the association of P gingivalis IgG with cognitive test performance.
Results
Poor immediate verbal memory (<5/9 points) was prevalent in 5.7% of patients, and 6.5% overall had impaired delayed recall (<4/9); 22.1% had difficulty with serial subtractions (<5/5 trials correct). Individuals with the highest P gingivalis IgG (>119 ELISA Units (EU)) were more likely to have poor delayed verbal recall (OR 2.89, 95% CI 1.14 to 7.29) and impaired subtraction (OR 1.95, 95% CI 1.22 to 3.11) than those with the lowest (≤57 EU), with dose–response relationships for both (p trend, delayed memory=0.045, subtraction=0.04). After adjusting for socioeconomic and vascular variables, these relationships remained robust for the highest P gingivalis IgG group (delayed verbal memory OR 3.01 (95% CI 1.06 to 8.53); subtraction OR 2.00 (95% CI 1.19 to 3.36)). In contrast, immediate verbal memory was not significantly associated with P gingivalis.
Conclusion
A serological marker of periodontitis is associated with impaired delayed memory and calculation. Further exploration of relationships between oral health and cognition is warranted.
doi:10.1136/jnnp.2009.174029
PMCID: PMC3073380  PMID: 19419981
16.  Label-free Quantitative Proteomics Reveals Differentially Regulated Proteins Influencing Urolithiasis* 
Molecular & Cellular Proteomics : MCP  2011;10(8):M110.005686.
Urinary proteins have been implicated as inhibitors of kidney stone formation (urolithiasis). As a proximal fluid, prefiltered by the kidneys, urine is an attractive biofluid for proteomic analysis in urologic conditions. However, it is necessary to correct for variations in urinary concentration. In our study, individual urine samples were normalized for this variation by using a total protein to creatinine ratio. Pooled urine samples were compared in two independent experiments. Differences between the urinary proteome of stone formers and nonstone-forming controls were characterized and quantified using label-free nano-ultraperformance liquid chromatography high/low collision energy switching analysis. There were 1063 proteins identified, of which 367 were unique to the stone former groups, 408 proteins were unique to the control pools, and 288 proteins were identified for comparative quantification. Proteins found to be unique in stone-formers were involved in carbohydrate metabolism pathways and associated with disease states. Thirty-four proteins demonstrated a consistent >twofold change between stone formers and controls. For ceruloplasmin, one of the proteins was shown to be more than twofold up-regulated in the stone-former pools, this observation was validated in individuals by enzyme-linked immunosorbent assay. Moreover, in vitro crystallization assays demonstrated ceruloplasmin had a dose-dependent increase on calcium oxalate crystal formation. Taken together, these results may suggest a functional role for ceruloplasmin in urolithiasis.
doi:10.1074/mcp.M110.005686
PMCID: PMC3149087  PMID: 21474797
17.  The use of light-emitting diode fluorescence to diagnose mycobacterial lymphadenitis in fine-needle aspirates from children 
SUMMARY
BACKGROUND
Fine-needle aspiration biopsy (FNAB) is a simple, safe and effective method for investigating suspected mycobacterial lymphadenitis in children. Fluorescence microscopy can provide rapid mycobacterial confirmation. Light-emitting diodes (LEDs) provide a cheap and robust excitation light source, making fluorescence microscopy feasible in resource-limited settings.
OBJECTIVE
To compare the diagnostic performance of LED fluorescence microscopy on Papanicolaou (PAP) stained smears with the conventional mercury vapour lamp (MVL).
METHODS
FNAB smears routinely collected from palpable lymph nodes in children with suspected mycobacterial disease were PAP-stained and evaluated by two independent microscopists using different excitatory light sources (MVL and LED). Mycobacterial culture results provided the reference standard. A manually rechargeable battery-powered LED power source was evaluated in a random subset.
RESULTS
We evaluated 182 FNAB smears from 121 children (median age 31 months, interquartile range 10–67). Mycobacterial cultures were positive in 84 of 121 (69%) children. The mean sensitivity with LED (mains-powered), LED (rechargeable battery-powered) and MVL was respectively 48.2%, 50.0% and 51.8% (specificity 78.4%, 86.7% and 78.4%). Inter-observer variation was similar for LED and MVL (κ = 0.5).
CONCLUSION
LED fluorescence microscopy provides a reliable alternative to conventional methods and has many favourable attributes that would facilitate improved, decentralised diagnostic services.
PMCID: PMC3070151  PMID: 21276297
LED fluorescence microscopy; fine-needle aspiration biopsy; children; mycobacteria; tuberculosis
18.  Construction and calibration of a 50 T/m z-gradient coil for quantitative diffusion microimaging 
Q-space imaging is capable of providing quantitative geometrical information of structures at cellular resolution. However, the size of restrictions that can be probed hinges on available gradient amplitude and places very high demands on gradient performance. In this work we describe the design and construction of a small, high-amplitude (50 T/m) z-gradient coil, interfaced with a commercial 9.4 T microimaging system. We also describe a method to calibrate the coil for quantitative measurements of molecular diffusion at very high gradient amplitudes. Calibration showed linear current response up to 50 T/m, with a gain = 1.255 T/m/A. The z-gradient coil was combined with the commercial x- and y-gradients for tri-axial imaging, and its performance was demonstrated by ADC maps of free water and by q-space experiments on water sequestered around polystyrene microspheres (4.5 μm diameter), which showed the expected diffraction peak. In addition, diffusion-weighted images of a fixed mouse spinal cord illustrated the capability of this coil for quantitative imaging of tissue microstructure.
doi:10.1016/j.jmr.2007.01.011
PMCID: PMC3069633  PMID: 17280847
gradient coil; diffusion; NMR microimaging; q-space; spinal cord
19.  Health behavior modification after electron beam computed tomography and physician consultation 
Journal of Behavioral Medicine  2010;34(2):148-155.
This study aimed to determine whether participants reported altering health behaviors (physical activity, diet, and alcohol consumption) after seeing results from an electron-beam computed tomography (EBCT) scan for coronary artery calcium and reviewing these results with a physician. Clinicians attempt to motivate patients to control cardiovascular risk factors by adopting healthy behaviors and reducing harmful actions. Asymptomatic patients (N = 510) were evaluated by EBCT for the extent of coronary artery calcium. Information pertaining to demographics, health history, and lifestyle/health behaviors was obtained from each participant at the time of the EBCT scan. Patients were given their numerical calcium score, shown images of their coronary arteries, and counseled by a physician for lifestyle and medical risk modification based on their coronary artery calcium score. Approximately 6 years after the scan, participants completed a follow-up questionnaire related to lifestyle modifications. In multivariable analysis, the presence and extent of coronary artery calcium was significantly associated with beneficial health behavior modifications. Specifically, the greater a patient’s coronary artery calcium score, the more likely they were to report increasing exercise (odds ratio = 1.34, P = 0.02), changing diet (odds ratio = 1.40, P < 0.01), and changing alcohol intake (odds ratio = 1.46, P = 0.05). This study suggests that seeing and being counseled on the presence and extent of coronary artery calcium is significantly associated with behavior change.
doi:10.1007/s10865-010-9294-4
PMCID: PMC3048462  PMID: 20857186
Health behavior; Physical activity; Nutrition; Coronary artery calcium; Imaging
20.  A new spontaneous mutation in the mouse protocadherin 15 gene 
Hearing research  2006;219(1-2):110-120.
We have characterized a new allele of the protocadherin 15 gene (designatedPcdh15av-6J) that arose as a spontaneous, recessive mutation in the C57BL/6J inbred strain at Jackson Laboratory. Analysis revealed an inframe deletion in Pcdh15, which is predicted to result in partial deletion of cadherin domain (domain 9) in Pcdh15. Morphologic study revealed normal to moderately defective cochlear hair cell stereocilia in Pcdh15av-6J mutants at postnatal day 2 (P2). Stereocilia abnormalities were consistently present at P5 and P10. Degenerative changes including loss of inner and outer hair cells were seen at P20, with severe sensory cell loss in all cochlear turns occurring by P40. The hair cell phenotype observed in the 6J allele between P0 and P20 is the least severe phenotype yet observed in Pcdh15 alleles. However, young Pcdh15av-6J mice are unresponsive to auditory stimulation and show circling behavior indicative of vestibular dysfunction. Since these animals show severe functional deficits but have relatively mild stereocilia defects at a young age they may provide an appropriate model to test for a direct role of Pcdh15 in mechanotransduction.
doi:10.1016/j.heares.2006.06.010
PMCID: PMC2855306  PMID: 16887306
Deafness; Cochlear hair cells; Pcdh15; Mouse
21.  Stringent Specificity in the Construction of a GABAergic Pre-Synaptic Inhibitory Circuit 
Cell  2009;139(1):161-174.
Summary
GABAergic interneurons are key elements in neural coding, but the mechanisms that assemble inhibitory circuits remain unclear. In the spinal cord, the transfer of sensory signals to motor neurons is filtered by GABAergic interneurons that act pre-synaptically to inhibit sensory transmitter release and post-synaptically to inhibit motor neuron excitability. We show here that the connectivity and synaptic differentiation of GABAergic interneurons that mediate pre-synaptic inhibition is directed by their sensory targets. In the absence of sensory terminals these GABAergic neurons shun other available targets, fail to undergo pre-synaptic differentiation, and withdraw axons from the ventral spinal cord. A sensory-specific source of brain derived neurotrophic factor induces synaptic expression of the GABA synthetic enzyme GAD65 – a defining biochemical feature of this set of interneurons. The organization of a GABAergic circuit that mediates pre-synaptic inhibition in the mammalian CNS is therefore controlled by a stringent program of sensory recognition and signaling.
doi:10.1016/j.cell.2009.08.027
PMCID: PMC2812434  PMID: 19804761
22.  Failure to thrive: the prevalence and concurrence of anthropometric criteria in a general infant population 
Archives of Disease in Childhood  2006;92(2):109-114.
Background
Failure to thrive (FTT) in early childhood is associated with subsequent developmental delay and is recognised to reflect relative undernutrition. Although the concept of FTT is widely used, no consensus exists regarding a specific definition, and it is unclear to what extent different anthropometric definitions concur.
Objective
To compare the prevalence and concurrence of different anthropometric criteria for FTT and test the sensitivity and positive predictive values of these in detecting children with “significant undernutrition”, defined as the combination of slow conditional weight gain and low body mass index (BMI).
Methods
Seven criteria of FTT, including low weight for age, low BMI, low conditional weight gain and Waterlow's criterion for wasting, were applied to a birth cohort of 6090 Danish infants. The criteria were compared in two age groups: 2–6 and 6–11 months of life.
Results
27% of infants met one or more criteria in at least one of the two age groups. The concurrence among the criteria was generally poor, with most children identified by only one criterion. Positive predictive values of different criteria ranged from 1% to 58%. Most single criteria identified either less than half the cases of significant undernutrition (found in 3%) or included far too many, thus having a low positive predictive value. Children with low weight for height tended to be relatively tall.
Conclusions
No single measurement on its own seems to be adequate for identifying nutritional growth delay. Further longitudinal population studies are needed to investigate the discriminating power of different criteria in detecting significant undernutrition and subsequent outcomes.
doi:10.1136/adc.2005.080333
PMCID: PMC2083342  PMID: 16531456
23.  Eosinophilic vasculitis in an isolated central nervous system distribution 
Background
Eosinophilic vasculitis has been described as part of the Churg–Strauss syndrome, but affects the central nervous system (CNS) in <10% of cases; presentation in an isolated CNS distribution is rare. We present a case of eosinophilic vasculitis isolated to the CNS.
Case report
A 39‐year‐old woman with a history of migraine without aura presented to an institution (located in the borough of Queens, New York, USA; no academic affiliation) in an acute confusional state with concurrent headache and left‐sided weakness and numbness. Laboratory evaluation showed increased cerebrospinal fluid (CSF) protein level, but an otherwise unremarkable serological investigation. Magnetic resonance imaging showed bifrontal polar gyral‐enhancing brain lesions. Her symptoms resolved over 2 weeks without residual deficit. After 18 months, later the patient presented with similar symptoms and neuroradiological findings involving territories different from those in her first episode. Again, the CSF protein level was high. She had a raised C reactive protein level and erythrocyte sedimentation rate. Brain biopsy showed transmural, predominantly eosinophilic, inflammatory infiltrates of medium‐sized leptomeningeal arteries without granulomas. She improved, without recurrence, when treated with a prolonged course of corticosteroids.
Conclusions
To our knowledge, this is the first case of non‐granulomatous eosinophilic vasculitis isolated to the CNS. No aetiology for this patient's primary CNS eosinophilic vasculitis has yet been identified. Spontaneous resolution and recurrence of her syndrome is an unusual feature of the typical CNS vasculitis and may suggest an environmental epitope with immune reaction as the cause.
doi:10.1136/jnnp.2005.085191
PMCID: PMC2117771  PMID: 16926236
24.  Heart disease risk factors in midlife predict subclinical coronary atherosclerosis more than 25 years later in survivors without clinical heart disease: The Rancho Bernardo Study 
Objective
To determine which of the classic modifiable coronary heart disease (CHD) risk factors, measured in midlife, are associated with subclinical coronary atherosclerosis in older age.
Design
Prospective study
Setting
Community based
Participants
Participants were 400 community-dwelling middle-aged adults who had no history of CHD at baseline (1972–4) when CHD risk factors were measured, and who were still free of known CHD in 2000–2002.
Measurements
Coronary artery plaque burden was assessed by coronary artery calcium (CAC) score using computed tomography in 2000–2002.
Results
Ordinal logistic regression analysis was used to compare baseline risk factors with severity of CAC. Mean age was 42 years at baseline and 69 years at the time of CAC assessment; 46.5% were male. In analyses adjusted for age, sex, and all other risk factors, one standard deviation increase in body mass index [OR 1.24 (CI 95% 1.02–1.51) P = 0.03], cholesterol [OR 1.28 (CI 95% 1.03–1.58) P = 0.02], pulse pressure [OR 1.24 (CI 95% 1.03–1.50) P = 0.03], and log triglycerides [OR1.22 (CI 95% 0.99–1.50 P = 0.06] each independently predicted the presence and severity of coronary artery atherosclerosis.
Conclusions
Plaque burden in elderly survivors without clinical heart disease is influenced by modifiable risk factors measured more than 25 years earlier.
PMCID: PMC2701669  PMID: 19507296
coronary artery calcium; midlife risk factors

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