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1.  Emerging Issues in Pediatric Asthma: Gaps in EPR-3 Guidelines for Infants and Children 
There are many complexities to the treatment of infants and children with recurrent wheezing and asthma. NHLBI’s Expert Panel Report-3 (EPR3), published in 2007, provides guidance to clinicians who care for infants and children with asthma. Since that time, many important clinical trials have further informed the evidence base available to clinicians. In this manuscript, new approaches to long-term therapy, intermittent fixed-dose and dynamic dose therapies, and emerging therapies for asthma are reviewed. Further, additional gaps in guideline-base care and areas for future research are discussed.
doi:10.1007/s11882-014-0477-x
PMCID: PMC4330969  PMID: 25269401
Asthma; Wheezing; Children; Guideline; Infants; Inhaled Corticosteroids; Long Acting Beta Agonists; Anticholinergics; Biologics; Action Plan; Yellow Zone; Dynamic dose; Fixed dose
2.  Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma 
Nature Communications  2015;6:5965.
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case–parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10−6; OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12–21 asthma locus in the Latino and combined samples (P=7.81 × 10−8 and 4.09 × 10−8, respectively) and MTHFR in the African ancestry sample (P=1.72 × 10−6). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the ‘missing heritability’ of asthma.
Common variants account for only a small amount of the heritable risk for developing asthma. Using a meta-analysis approach, Igartua et al. identify one low-frequency missense mutation and two genes with functional variants that are associated with asthma, but only in specific ethnic groups.
doi:10.1038/ncomms6965
PMCID: PMC4309441  PMID: 25591454
3.  Asthma Across the Ages: Knowledge Gaps in Childhood Asthma Prepared for the 2014 theme issue in the Journal of Allergy and Clinical Immunology 
The Eunice Kennedy Shriver National Institute of Child Health and Human Development convened an Asthma Group in response to the Best Pharmaceuticals for Children Act (BPCA). The overall goal of the BPCA Program is to improve pediatric therapeutics through preclinical and clinical drug trials that lead to drug labeling changes.
While significant advances have been made in the understanding and management of asthma in adults with appropriately labeled medications, less information is available on the management of asthma in children. Indeed, many medications are inadequately labeled in children. In general, the younger the child, the less information there is available to guide clinicians. Since asthma often begins in early childhood, it is incumbent upon us to continue to address the primary questions raised in this review and carefully evaluate medications used to manage asthma in children.
Meanwhile, continued efforts should be made in defining effective strategies that reduce the risk of exacerbations. If the areas of defined need are addressed in the coming years, namely prevention of exacerbations and progression of disease, as well as primary intervention, we will see continuing reduction in asthma mortality and morbidity along with improved quality of life for children with asthma.
doi:10.1016/j.jaci.2013.10.018
PMCID: PMC3925634  PMID: 24290281
Asthma; asthma natural history; asthma progression; asthma biomarkers; childhood asthma; asthma pharmacotherapy
4.  The clinical characteristics of patients with glaucoma presenting to Botswana healthcare facilities: an observational study 
BMJ Open  2014;4(12):e005965.
Objective
This study aimed to establish the clinical characteristics of patients with glaucoma attending eye care facilities in Botswana, and management of glaucoma among patients who received care in these facilities. The study also aimed to calculate the number of new diagnoses of glaucoma within the glaucoma service.
Design
A prospective, hospital-based, observational study.
Setting
A multicentre study was undertaken in government-run eye departments in Botswana from June to August 2012.
Participants
All patients with a diagnosis of glaucoma attending clinics at seven study sites were invited to participate.
Outcome measures
Examination findings, diagnosis and management were extracted from individual patient-held medical charts. Sociodemographic characteristics, patient knowledge and understanding of glaucoma were assessed through face-to-face interviews. In addition, details of outpatient attendances for 2011 were collected from 21 government-run hospitals.
Results
The majority of the 366 patients interviewed had a diagnosis of primary glaucoma (86.6%). The diagnoses were mainly made by ophthalmologists (48.6%) and ophthalmic nurses (44.0%). Many patients (38.5%) had been symptomatic for over 6 months before visiting an eye clinic. The mean presenting intraocular pressure was 28.2 mm Hg (SD 11.9 mm Hg). Most follow-up patients (79.2%) had not received surgery, however, many (89.5%) would accept surgery. Only 11.5% of participants had heard of glaucoma prior to diagnosis. Many participants (35.9%) did not understand glaucoma after being diagnosed. The majority (94.9%) of living first-degree relatives had never been examined. The number of newly diagnosed glaucoma cases for 2011 in the south of the country was 14.1/100 000; 95% CI (12.0 to 16.5), in the north it was 16.2/100 000; 95% CI (13.8 to 19.0).
Conclusions
Glaucoma is a significant burden that presents challenges to ophthalmic services in Botswana. Many patients have limited understanding of the condition and poor access to services. There is a need to develop a treatment infrastructure to include safe surgery and a reliable supply of effective medication.
doi:10.1136/bmjopen-2014-005965
PMCID: PMC4256541  PMID: 25472657
EPIDEMIOLOGY
6.  Laparoscopic versus open colorectal resection for cancer and polyps: a cost-effectiveness study 
Background
Available evidence that compares outcomes from laparoscopic and open surgery for colorectal cancer shows no difference in disease free or survival time, or in health-related quality of life outcomes, but does not capture the short term benefits of laparoscopic methods in the early postoperative period.
Aim
To explore the cost-effectiveness of laparoscopic colorectal surgery, compared to open methods, using quality of life data gathered in the first 6 weeks after surgery.
Methods
Participants were recruited in 2006–2007 in a district general hospital in the south of England; those with a diagnosis of cancer or polyps were included in the analysis. Quality of life data were collected using EQ-5D, on alternate days after surgery for 4 weeks. Costs per patient, from a National Health Service perspective (in British pounds, 2006) comprised the sum of operative, hospital, and community costs. Missing data were filled using multiple imputation methods. The difference in mean quality adjusted life years and costs between surgery groups were estimated simultaneously using a multivariate regression model applied to 20 imputed datasets. The probability that laparoscopic surgery is cost-effective compared to open surgery for a given societal willingness-to-pay threshold is illustrated using a cost-effectiveness acceptability curve.
Results
The sample comprised 68 laparoscopic and 27 open surgery patients. At 28 days, the incremental cost per quality adjusted life year gained from laparoscopic surgery was £12,375. At a societal willingness-to-pay of £30,000, the probability that laparoscopic surgery is cost-effective, exceeds 65% (at £20,000 ≈60%). In sensitivity analyses, laparoscopic surgery remained cost-effective compared to open surgery, provided it results in a saving ≥£699 in hospital bed days and takes no more than 8 minutes longer to perform.
Conclusion
The study provides formal evidence of the cost-effectiveness of laparoscopic approaches and supports current guidelines that promote use of laparoscopy where suitably trained surgeons are available.
doi:10.2147/CEOR.S66247
PMCID: PMC4186576  PMID: 25298736
colorectal cancer; laparoscopy; cost-effectiveness; QALYs
7.  Whole-Genome Sequencing of Individuals from a Founder Population Identifies Candidate Genes for Asthma 
PLoS ONE  2014;9(8):e104396.
Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS.
doi:10.1371/journal.pone.0104396
PMCID: PMC4130548  PMID: 25116239
8.  Maternal microchimerism protects against the development of asthma 
Background
Maternal asthma and child’s sex are among the most significant and reproducible risk factors for the development of asthma. Although the mechanisms for these effects are unknown, they likely involve non-classical genetic mechanisms. One such mechanism could involve the transfer and persistence of maternal cells to her offspring, a common occurrence known as maternal microchimerism (MMc). MMc has been associated with many autoimmune diseases, but has not been investigated for a role in asthma or allergic disease.
Objective
We hypothesized that some of the observed risks for asthma may be due to different rates of transmission or persistence of maternal cells to children of mothers with asthma compared to children of mothers without asthma, or to sons compared to daughters. We further hypothesized that rates of MMc differ between children with and without asthma.
Methods
We tested these hypotheses in 317 subjects from three independent cohorts using a real-time quantitative PCR assay to detect a non-inherited HLA allele in the child.
Results
MMc was detected in 20.5% of subjects (range 16.8% – 27.1% in the three cohorts). We observed lower rates of asthma among MMc positive subjects compared to MMc negative subjects (odds ratio [OR] 0.38, 95% CI 0.19, 0.79; P=0.029). Neither maternal asthma nor sex of the child was a significant predictor of MMc in the child (P = 0.81 and 0.15, respectively).
Conclusions
Our results suggest for the first time that MMc may protect against the development of asthma.
doi:10.1016/j.jaci.2012.12.1575
PMCID: PMC3700564  PMID: 23434286
Microchimerism; maternal; asthma
9.  Do oral corticosteroids reduce the severity of acute lower respiratory tract illnesses in preschool children with recurrent wheezing? 
The Journal of allergy and clinical immunology  2013;131(6):10.1016/j.jaci.2013.01.034.
Background
Oral corticosteroids (OCSs) are recommended for severe wheezing episodes in children. However, limited evidence supports this intervention in preschool children with outpatient wheezing illnesses.
Objective
We sought to investigate whether OCSs reduce symptom scores during acute lower respiratory tract illnesses (LRTIs) in preschool children with recurrent wheeze
Methods
We performed post hoc and replication analyses in 2 outpatient cohorts of children aged 1 to 5 years with episodic wheezing participating in clinical trials. We compared symptom scores during LRTIs that were or were not treated with OCSs, adjusting for differences in disease and episode severity covariates.We stratified episodes by severity by using a propensity model. The primary outcome was the area under the curve (AUC) of total symptom scores among the more severe episodes.
Results
Two hundred fifteen participants from the Acute Intervention Management Strategies trial experienced 798 acute LRTIs, 112 of which were defined as severe based on propensity scores. The AUCs of total symptom scores did not differ between the episodes that were (n = 70) and were not (n = 42) treated with OCSs (P = .46) nor was there an OCS treatment effect on individual symptom scores. Similar analyses of the Maintenance Versus Intermittent Inhaled Corticosteroids in Wheezing Toddlers trial, involving 278 participants with 133 severe LRTIs, confirmed the above findings (P =.46 for AUC of total symptoms score comparison).
Conclusion
In 2 separate cohorts of preschool children with episodic wheezing, OCS treatment during clinically significant LRTIs did not reduce symptom severity during acute LRTIs, despite asthma controller medication use during most episodes. These findings need to be confirmed in a prospective randomized controlled trial.
doi:10.1016/j.jaci.2013.01.034
PMCID: PMC3810170  PMID: 23498594
Oral corticosteroids; episodic wheezing; preschool children
10.  Comparison of N-acetylmethionine reactivity between oxaliplatin and an oxaliplatin derivative with chiral (S,S) amine nitrogen atoms 
Inorganica chimica acta  2013;401:64-69.
We have synthesized an oxaliplatin derivative using N,N′-dimethyl-1,2-diaminocyclohexane (Me2dach) as the diamine ligand. The complex (S,R,R,S)-Pt(Me2dach)(oxalate), where S,R,R,S represents the chiralities at N,C,C,N, respectively, was prepared and characterized by 1H NMR spectroscopy, COSY, NOESY, and HMQC. Oxaliplatin reacts with N-acetylmethionine (N-AcMet) to form [Pt(dach)(N-AcMet-S)2] and [Pt(dach)(N-AcMet-S,N)], with the former favored at higher molar ratios of N-AcMet. In contrast, Pt(Me2dach)(oxalate) reacts to form [Pt(Me2dach)(N-AcMet-S,O)]+ even in the presence of excess N-AcMet. Molecular mechanics calculations are consistent with significant steric clashes in models of [Pt(Me2dach)(N-AcMet-S)2]. When N-AcMet was reacted with an excess of each platinum complex, the rate of N-AcMet decrease was very similar for both complexes. Thus, the methyl groups at the nitrogen atoms had little to no effect on the addition of the sulfur atom of a single N-acetylmethionine, but they prevented chelation of the amide nitrogen or coordination of a second N-acetylmethionine residue.
doi:10.1016/j.ica.2013.03.008
PMCID: PMC3635081  PMID: 23626375
Nuclear magnetic resonance; platinum; oxaliplatin; amino acids; methionine
11.  Infections and Their Role in Childhood Asthma Inception 
Summary
The association of early onset wheezing with common viral and bacterial infections has raised significant interest in the role of infections in childhood asthma inception. This article serves to review these relationships among infections, host factors, and asthma inception in childhood.
doi:10.1111/pai.12147
PMCID: PMC3977202  PMID: 24236893
inception; asthma; infection; wheezing; virus; childhood; genetics
12.  Gene Splicing of an Invertebrate Beta Subunit (LCavβ) in the N-Terminal and HOOK Domains and Its Regulation of LCav1 and LCav2 Calcium Channels 
PLoS ONE  2014;9(4):e92941.
The accessory beta subunit (Cavβ) of calcium channels first appear in the same genome as Cav1 L-type calcium channels in single-celled coanoflagellates. The complexity of this relationship expanded in vertebrates to include four different possible Cavβ subunits (β1, β2, β3, β4) which associate with four Cav1 channel isoforms (Cav1.1 to Cav1.4) and three Cav2 channel isoforms (Cav2.1 to Cav2.3). Here we assess the fundamentally-shared features of the Cavβ subunit in an invertebrate model (pond snail Lymnaea stagnalis) that bears only three homologous genes: (LCav1, LCav2, and LCavβ). Invertebrate Cavβ subunits (in flatworms, snails, squid and honeybees) slow the inactivation kinetics of Cav2 channels, and they do so with variable N-termini and lacking the canonical palmitoylation residues of the vertebrate β2a subunit. Alternative splicing of exon 7 of the HOOK domain is a primary determinant of a slow inactivation kinetics imparted by the invertebrate LCavβ subunit. LCavβ will also slow the inactivation kinetics of LCav3 T-type channels, but this is likely not physiologically relevant in vivo. Variable N-termini have little influence on the voltage-dependent inactivation kinetics of differing invertebrate Cavβ subunits, but the expression pattern of N-terminal splice isoforms appears to be highly tissue specific. Molluscan LCavβ subunits have an N-terminal “A” isoform (coded by exons: 1a and 1b) that structurally resembles the muscle specific variant of vertebrate β1a subunit, and has a broad mRNA expression profile in brain, heart, muscle and glands. A more variable “B” N-terminus (exon 2) in the exon position of mammalian β3 and has a more brain-centric mRNA expression pattern. Lastly, we suggest that the facilitation of closed-state inactivation (e.g. observed in Cav2.2 and Cavβ3 subunit combinations) is a specialization in vertebrates, because neither snail subunit (LCav2 nor LCavβ) appears to be compatible with this observed property.
doi:10.1371/journal.pone.0092941
PMCID: PMC3972191  PMID: 24690951
13.  Characterization of the pigmented shell-forming proteome of the common grove snail Cepaea nemoralis 
BMC Genomics  2014;15:249.
Background
With a diversity of pigmented shell morphotypes governed by Mendelian patterns of inheritance, the common grove snail, Cepaea nemoralis, has served as a model for evolutionary biologists and population geneticists for decades. Surprisingly, the molecular mechanisms by which C. nemoralis generates this pigmented shelled diversity, and the degree of evolutionary conservation present between molluscan shell-forming proteomes, remain unknown.
Results
Here, using next generation sequencing and high throughput proteomics, we identify and characterize the major proteinaceous components of the C. nemoralis shell, the first shell-proteome for a pulmonate mollusc. The recent availability of several marine molluscan shell-proteomes, and the dataset we report here, allow us to identify 59 evolutionarily conserved and novel shell-forming proteins. While the C. nemoralis dataset is dominated by proteins that share little to no similarity with proteins in public databases, almost half of it shares similarity with proteins present in other molluscan shells. In addition, we could not find any indication that a protein (or class of proteins) is directly associated with shell pigmentation in C. nemoralis. This is in contrast to the only other partially characterized molluscan-shell pigmentation mechanism employed by the tropical abalone Haliotis asinina.
Conclusions
The unique pulmonate shell-forming proteome that we report here reveals an abundance of both mollusc-specific and pulmonate-specific proteins, suggesting that novel coding sequences, and/or the extensive divergence of these sequences from ancestral sequences, supported the innovation of new shell types within the Conchifera. In addition, we report here the first evidence that molluscs use independently evolved mechanisms to pigment their shells. This proteome provides a solid foundation from which further studies aimed at the functional characterization of these shell-forming proteins can be conducted.
doi:10.1186/1471-2164-15-249
PMCID: PMC4023409  PMID: 24684722
Biomineralization; Calcification; Mollusc; Pulmonate; Pigment; Shell; Protein; Evolution; Cepaea nemoralis
14.  Evaluation of the Modified Asthma Predictive Index in High-Risk Preschool Children 
The journal of allergy and clinical immunology in practice  2012;1(2):10.1016/j.jaip.2012.10.008.
BACKGROUND
Prediction of subsequent school-age asthma during the preschool years has proven challenging.
OBJECTIVE
To confirm in a post hoc analysis the predictive ability of the modified Asthma Predictive Index (mAPI) in a high-risk cohort and a theoretical unselected population. We also tested a potential mAPI modification with a 2-wheezing episode requirement (m2API) in the same populations.
METHODS
Subjects (n = 289) with a family history of allergy and/or asthma were used to predict asthma at age 6, 8, and 11 years with the use of characteristics collected during the first 3 years of life. The mAPI and the m2API were tested for predictive value.
RESULTS
For the mAPI and m2API, school-age asthma prediction improved from 1 to 3 years of age. The mAPI had high predictive value after a positive test (positive likelihood ratio ranging from 4.9 to 55) for asthma development at years 6, 8, and 11. Lowering the number of wheezing episodes to 2 (m2API) lowered the predictive value after a positive test (positive likelihood ratio ranging from 1.91 to 13.1) without meaningfully improving the predictive value of a negative test. Posttest probabilities for a positive mAPI reached 72% and 90% in unselected and high-risk populations, respectively.
CONCLUSIONS
In a high-risk cohort, a positive mAPI greatly increased future asthma probability (eg, 30% pretest probability to 90% posttest probability) and is a preferred predictive test to the m2API. With its more favorable positive posttest probability, the mAPI can aid clinical decision making in assessing future asthma risk for preschool-age children.
doi:10.1016/j.jaip.2012.10.008
PMCID: PMC3811153  PMID: 24187656
Asthma; Wheezing; Children; Asthma predictive index; Modified asthma predictive index
15.  Specific Patterns of Allergic Sensitization in Early Childhood and Asthma & Rhinitis Risk 
BACKGROUND
Specific patterns of allergic sensitization as well as quantification of the in vitro IgE response in early life may provide relevant clinical insight into future rhinitis and asthma risk.
OBJECTIVE
To define relationships among established sensitization to particular aeroallergens, quantitative analyses of allergen-specific IgE levels, pet exposure and sensitization, and asthma and rhinitis risk.
METHODS
Children at high-risk for the development of asthma and allergic diseases were enrolled at birth into the Childhood Origins of ASThma (COAST) study. Allergen-specific IgE was assessed at ages 1, 3, 6, and 9 years by fluoroenzyme immunoassay (Unicap® 100, Pharmacia Diagnostics). Current asthma and rhinitis were diagnosed at age 6 and 8 years.
RESULTS
Sensitization to dog was strongly associated with increased asthma risk (p < 0.0001). Sensitization to perennial compared to seasonal allergens was more strongly associated with asthma risk, while sensitization to seasonal allergens was more closely associated with rhinitis risk. Increased levels of specific IgE to perennial allergens were associated with an increased asthma risk (p = 0.05), while any detectable level of IgE to seasonal allergens was associated with increased rhinitis risk (p = 0.0009). While dog and cat sensitization were both independently associated with increased asthma and rhinitis risk, dog exposure at birth was associated with a reduced risk of asthma, regardless of dog sensitization status during the first 6 years of life (p = 0.05).
CONCLUSIONS & CLINICAL RELEVANCE
Analyzing specific patterns of an individual’s allergic sensitization profile reveals additional relevant associations with asthma and rhinitis risk as opposed to the information gained from characterizing an individual as “atopic” by the presence of any demonstrable sensitization alone. Further, protective mechanisms of dog exposure with regards to asthma risk appear to be unrelated to the prevention of sensitization.
doi:10.1111/cea.12050
PMCID: PMC3557802  PMID: 23331564
asthma; rhinitis; children; IgE; allergic sensitization; pet exposure
16.  Pulmonary 3He Magnetic Resonance Imaging of Childhood Asthma 
Background
Magnetic resonance imaging (MRI) with 3He does not require ionizing radiation and has been shown to detect regional abnormalities in lung ventilation and structure in adult asthma, but the method has not been extended to childhood asthma. Measurements of regional lung ventilation and microstructure in childhood asthma could advance our understanding of disease mechanisms.
Objective
To determine whether 3He MRI in children can identify abnormalities related to diagnosis of asthma or prior history of respiratory illness.
Methods
Forty-four children aged 9-10 years were recruited from a birth cohort at increased risk of developing asthma and allergic diseases. For each subject a time-resolved three-dimensional (3D) image series and a 3D diffusion-weighted image were acquired in separate breathing maneuvers. The number and size of ventilation defects were scored, and regional maps and statistics of average 3He diffusion length were calculated.
Results
Children with mild to moderate asthma had lower average diffusion length, Xrms¯ (p=0.004), increased regional standard deviation of diffusion length (p=0.03), and higher defect scores (p=0.03) than those without asthma. Children with histories of wheezing illness with rhinovirus infection prior to the third birthday had lower Xrms¯ (p=0.01) and higher defect score (p=0.05).
Conclusion
MRI with 3He detected more and larger regions of ventilation defect and a greater degree of restricted gas diffusion in children with asthma compared to those without asthma. These measures are consistent with regional obstruction and smaller and more regionally variable dimensions of the peripheral airways and alveolar spaces.
doi:10.1016/j.jaci.2012.10.032
PMCID: PMC3563846  PMID: 23246019
asthma; pediatric; hyperpolarized MRI; apparent diffusion coefficient
17.  Safety of Intraventricular Hemorrhage (IVH) Thrombolysis Based on CT Localization of External Ventricular Drain (EVD) Fenestrations and Analysis of EVD Tract Hemorrhage 
Neurocritical care  2013;19(1):103-110.
Background
The purpose of the study is to review the CT findings associated with ventriculostomy placement in regards to the safety of an EVD plus recombinant tissue plasminogen activator (rt-PA) for IVH.
Methods
A retrospective review was conducted for patients receiving intraventricular rt-PA for IVH from January 2004 to September 2009. Safety was assessed by the presence of EVD tract hemorrhage by CT at baseline after EVD placement, worsening hemorrhage after rt-PA, and CSF infection. IVH volumetrics were assessed by the Le Roux score and outcomes by Glasgow Outcome Scale and modified Rankin Scale.
Results
Twenty-seven patients received rt-PA for IVH. Median dose was 2 mg (range 0.3–8) and a median of two doses (range 1–17) were given. Worsening EVD catheter tract hemorrhage after rt-PA was 46.7 %, with a significantly higher incidence of worsening tract hemorrhage seen with incorrectly placed EVDs (p = 0.04). IVH hematoma burden decreased by a median Le Roux score of 10 (range 3–16) prior to rt-PA to 4 (range 0–16) after rt-PA. There were no central nervous system bacterial infections.
Conclusion
Intraventricular rt-PA appears to be relatively safe especially when all EVD fenestrations are within the ventricle and reduces IVH burden similar to other studies. We describe a CT-based EVD tract hemorrhage grading scale to evaluate EVD tract hemorrhage before and after thrombolysis, and a bone-window technique to evaluate EVD fenestrations prior to IVH thrombolysis. Further research is needed evaluating these imaging techniques in regard to intraventricular thrombolytic safety and EVD tract hemorrhage.
doi:10.1007/s12028-012-9713-1
PMCID: PMC3785325  PMID: 22544476
Intracerebral hemorrhage; Intraventricular hemorrhage; Cerebrovascular disease; Stroke; Critical care
19.  Symbiophagy and biomineralization in the “living fossil” Astrosclera willeyana 
Autophagy  2013;10(3):408-415.
Representatives of all major metazoan lineages form biominerals. The molecular mechanisms that underlie this widespread and evolutionarily ancient ability are gradually being revealed for some lineages. However, until a wider range of metazoan biomineralization strategies are understood, the true diversity, and therefore the evolutionary origins of this process, will remain unknown. We have previously shown that the coralline demosponge, Astrosclera willeyana, in some way employs its endobiotic bacterial community to form its highly calcified skeleton. Here, using in situ hybridization and immunohistochemistry, we show that an ortholog of ATG8 (most likely a GABARAPL2/GATE-16 ortholog) is expressed in cells that construct the individual skeletal elements of the sponge. In TEM sections sponge cells can be observed to contain extensive populations of bacteria, and frequently possesses double-membrane structures which we interpret to be autophagosomes. In combination with our previous work, these findings support the hypothesis that the host sponge actively degrades a proportion of its bacterial community using an autophagy pathway, and uses the prokaryotic organic remains as a framework upon which calcification of the sponge skeleton is initiated.
doi:10.4161/auto.27319
PMCID: PMC4077880  PMID: 24343243
biomineralization; biocalcification; sponge; autophagy; symbiosis; symbiophagy; evolution; bacteria; GABARAPL2/GATE-16; ATG8
20.  Human Rhinovirus Species and Season of Infection Determine Illness Severity 
Rationale: Human rhinoviruses (HRVs) consist of approximately 160 types that cause a wide range of clinical outcomes, including asymptomatic infections, common colds, and severe lower respiratory illnesses.
Objectives: To identify factors that influence the severity of HRV illnesses.
Methods: HRV species and types were determined in 1,445 nasal lavages that were prospectively collected from 209 infants participating in a birth cohort who had at least one HRV infection. Questionnaires were used during each illness to identify moderate to severe illnesses (MSI).
Measurements and Main Results: Altogether, 670 HRV infections were identified, and 519 of them were solitary infections (only one HRV type). These 519 viruses belonged to 93 different types of three species: 49 A, 9 B, and 35 C types. HRV-A (odds ratio, 8.2) and HRV-C (odds ratio, 7.6) were more likely to cause MSI compared with HRV-B. In addition, HRV infections were 5- to 10-fold more likely to cause MSI in the winter months (P < 0.0001) compared with summer, in contrast to peak seasonal prevalence in spring and fall. When significant differences in host susceptibility to MSI (P = 0.004) were considered, strain-specific rates of HRV MSI ranged from less than 1% to more than 20%.
Conclusions: Factors related to HRV species and type, season, and host susceptibility determine the risk of more severe HRV illness in infancy. These findings suggest that anti-HRV strategies should focus on HRV-A and -C species and identify the need for additional studies to determine mechanisms for seasonal increases of HRV severity, independent of viral prevalence, in cold weather months.
doi:10.1164/rccm.201202-0330OC
PMCID: PMC3530215  PMID: 22923659
rhinovirus; severe illness; species; type; seasonality
21.  Rhinovirus Wheezing Illness and Genetic Risk of Childhood-Onset Asthma 
The New England journal of medicine  2013;368(15):1398-1407.
BACKGROUND
Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts.
METHODS
We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. Finally, we examined genotype-specific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs).
RESULTS
The 17q21 variants were associated with HRV wheezing illnesses in early life, but not with RSV wheezing illnesses. The associations of 17q21 variants with asthma were restricted to children who had had HRV wheezing illnesses, resulting in a significant interaction effect with respect to the risk of asthma. Moreover, the expression levels of ORMDL3 and of GSDMB were significantly increased in HRV-stimulated PBMCs, as compared with unstimulated PBMCs. The expression of these genes was associated with 17q21 variants in both conditions, although the increase with exposure to HRV was not genotype-specific.
CONCLUSIONS
Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses and with expression of two genes at this locus. The expression levels of both genes increased in response to HRV stimulation, although the relative increase was not associated with the 17q21 genotypes. (Funded by the National Institutes of Health.)
doi:10.1056/NEJMoa1211592
PMCID: PMC3755952  PMID: 23534543
22.  Innate Immune Responses to Rhinovirus are Reduced by the High-Affinity IgE Receptor in Allergic Asthmatic Children 
Background
Children with allergic asthma have more frequent and severe human rhinovirus (HRV)-induced wheezing and asthma exacerbations through unclear mechanisms.
Objective
To determine whether increased high-affinity IgE receptor (FcεRI) expression and cross-linking impairs innate immune responses to HRV, particularly in allergic asthmatic children.
Methods
Peripheral blood mononuclear cells (PBMC) were obtained from 44 children and surface expression of FcεRI on plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), monocytes, and basophils was assessed using flow cytometry. Cells were also incubated with rabbit anti-human IgE to cross-link FcεRI, followed by stimulation with HRV-16, and interferon (IFN)-α and -λ1 were measured by Luminex. The relationships among FcεRI expression and cross-linking, HRV-induced IFN-α and -λ1 production, and childhood allergy and asthma were subsequently analyzed.
Results
FcεRIα expression on pDCs was inversely associated with HRV-induced IFN- α and IFN-λ1 production. Cross-linking FcεRI prior to HRV stimulation further reduced PBMC IFN-α (47% relative reduction, 95% confidence interval [CI], 32–62%, p<0.0001) and IFN-λ1 (81% relative reduction, 95% CI, 69–93%, p<0.0001) secretion. Allergic asthmatic children had higher surface expression of FcεRIα on pDCs and mDCs when compared to non-allergic non-asthmatic children. Further, after FcεRI cross-linking, allergic asthmatic children had significantly lower HRV-induced IFN responses than allergic non-asthmatics (IFN-α, p=0.004; IFN-λ1, p=0.02) and non-allergic non-asthmatics (IFN-α, p=0.002; IFN-λ1, p=0.01).
Conclusions
Allergic asthmatic children have impaired innate immune responses to HRV that correlate with increased FcεRI expression on pDCs and are reduced by FcεRI cross-linking. These effects likely increase susceptibility to HRV-induced wheezing and asthma exacerbations.
doi:10.1016/j.jaci.2012.05.023
PMCID: PMC3437329  PMID: 22766097
asthma; allergic; rhinovirus; interferon; FcεRI; IgE receptor; plasmacytoid dendritic cells
23.  Protection from asthma in a high-risk birth cohort by attenuated P2X7 function 
Background
Viral illnesses are important factors in both asthma inception and exacerbations, and allergic sensitization in early life further enhances asthma risk through unclear mechanisms. Cellular damage due to infection or allergen inhalation increases ATP in the airways with subsequent purinergic receptor activation. The purinergic receptor P2X7 may enhance airway leukocyte recruitment to the airways and P2X7 knockout mice display a reduced asthma-like phenotype.
Objective
Based upon the P2X7 knockout mouse, we hypothesized that children with low functioning P2X7 would have decreased rates of asthma.
Methods
We utilized a functional assay to determine P2X7 pore-producing capacity in whole blood samples in a birth cohort study at high risk for asthma development. The P2X7 assay was validated with known loss-of-function alleles in humans. P2X7 pore status categorization was used to assess asthma and allergy status in the cohort.
Results
Attenuated P2X7 function was associated with lower asthma rates at ages 6 and 8 and the greatest effects were observed in boys. Children with asthma at age 11 who had low P2X7 capacity had less severe disease in the previous year. Attenuated P2X7 function was also associated with sensitization to fewer aeroallergens.
Conclusion
P2X7 functional capacity is associated with asthma risk or disease severity and these relationships appear to be age-related.
doi:10.1016/j.jaci.2012.05.040
PMCID: PMC3551624  PMID: 22743305
asthma; allergy; children; P2X7; ATP
24.  An ancient process in a modern mollusc: early development of the shell in Lymnaea stagnalis 
Background
The morphological variety displayed by the molluscan shell underlies much of the evolutionary success of this phylum. However, the broad diversity of shell forms, sizes, ornamentations and functions contrasts with a deep conservation of early cell movements associated with the initiation of shell construction. This process begins during early embryogenesis with a thickening of an ectodermal, ‘dorsal’ (opposite the blastopore) population of cells, which then invaginates into the blastocoel to form the shell gland. The shell gland evaginates to form the shell field, which then expands and further differentiates to eventually become the adult shell-secreting organ commonly known as the mantle. Despite the deep conservation of the early shell forming developmental program across molluscan classes, little is known about the fine-scale cellular or molecular processes that underlie molluscan shell development.
Results
Using modern imaging techniques we provide here a description of the morphogenesis of a gastropod shell gland and shell field using the pulmonate gastropod Lymnaea stagnalis as a model. We find supporting evidence for a hypothesis of molluscan shell gland specification proposed over 60 years ago, and present histochemical assays that can be used to identify a variety of larval shell stages and distinct cell populations in whole mounts.
Conclusions
By providing a detailed spatial and temporal map of cell movements and differentiation events during early shell development in L. stagnalis we have established a platform for future work aimed at elucidation of the molecular mechanisms and regulatory networks that underlie the evo-devo of the molluscan shell.
doi:10.1186/1471-213X-13-27
PMCID: PMC3728215  PMID: 23845038
Shell; Mollusc; Biomineralisation; Evolution; Development; Specification; Mantle; Alkaline phosphatase; Peroxidase

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