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1.  Indoor Environmental Exposures and Exacerbation of Asthma: An Update to the 2000 Review by the Institute of Medicine 
Background: Previous research has found relationships between specific indoor environmental exposures and exacerbation of asthma.
Objectives: In this review we provide an updated summary of knowledge from the scientific literature on indoor exposures and exacerbation of asthma.
Methods: Peer-reviewed articles published from 2000 to 2013 on indoor exposures and exacerbation of asthma were identified through PubMed, from reference lists, and from authors’ files. Articles that focused on modifiable indoor exposures in relation to frequency or severity of exacerbation of asthma were selected for review. Research findings were reviewed and summarized with consideration of the strength of the evidence.
Results: Sixty-nine eligible articles were included. Major changed conclusions include a causal relationship with exacerbation for indoor dampness or dampness-related agents (in children); associations with exacerbation for dampness or dampness-related agents (in adults), endotoxin, and environmental tobacco smoke (in preschool children); and limited or suggestive evidence for association with exacerbation for indoor culturable Penicillium or total fungi, nitrogen dioxide, rodents (nonoccupational), feather/down pillows (protective relative to synthetic bedding), and (regardless of specific sensitization) dust mite, cockroach, dog, and dampness-related agents.
Discussion: This review, incorporating evidence reported since 2000, increases the strength of evidence linking many indoor factors to the exacerbation of asthma. Conclusions should be considered provisional until all available evidence is examined more thoroughly.
Conclusion: Multiple indoor exposures, especially dampness-related agents, merit increased attention to prevent exacerbation of asthma, possibly even in nonsensitized individuals. Additional research to establish causality and evaluate interventions is needed for these and other indoor exposures.
Citation: Kanchongkittiphon W, Mendell MJ, Gaffin JM, Wang G, Phipatanakul W. 2015. Indoor environmental exposures and exacerbation of asthma: an update to the 2000 review by the Institute of Medicine. Environ Health Perspect 123:6–20;
PMCID: PMC4286274  PMID: 25303775
2.  Single copies of mutant KRAS and mutant PIK3CA cooperate in immortalized human epithelial cells to induce tumor formation 
Cancer research  2013;73(11):3248-3261.
The selective pressures leading to cancers with mutations in both KRAS and PIK3CA are unclear. Here we demonstrate that somatic cell knock in of both KRAS G12V and oncogenic PIK3CA mutations in human breast epithelial cells results in cooperative activation of the PI3 Kinase and MAP Kinase pathways in vitro, and leads to tumor formation in immunocompromised mice. Xenografts from double knock in cells retain single copies of mutant KRAS and PIK3CA suggesting that tumor formation does not require increased copy number of either oncogene, and these results were also observed in human colorectal cancer specimens. Mechanistically, the cooperativity between mutant KRAS and PIK3CA is mediated in part by Ras/p110α binding, as inactivating point mutations within the Ras binding domain of PIK3CA significantly abates pathway signaling. In addition, Pdk1 activation of the downstream effector p90RSK is also increased by the combined presence of mutant KRAS and PIK3CA. These results provide new insights into mutant KRAS function and its role in carcinogenesis.
PMCID: PMC3674106  PMID: 23580570
Tumorigenicity; cancer; KRAS; PIK3CA
3.  A blinded study of bone marrow examinations in patients with primary immune thrombocytopenia 
European journal of haematology  2012;90(2):121-126.
The role of bone marrow examinations in patients with primary immune thrombocytopenia (ITP) is uncertain. The objectives of this study were to determine the inter-rater reliability of bone marrow examinations and to identify distinguishing morphological features of ITP bone marrows under controlled conditions.
Histological slides of bone marrow biopsy specimens and aspirates from 32 adult patients with severe primary ITP who had failed a median of two treatments, and 51 non-thrombocytopenic controls were retrieved from hospital archives. Slides were arranged in random order in a slide box and coded. Blinded to the diagnosis and platelet counts, three independent hematopathologists were asked to identify the ITP bone marrows and to evaluate megakaryocyte number, morphology, and distribution.
Overall chance-corrected agreement on ITP classification among the three raters was poor [kappa (κ) = 0.30; 95% confidence interval 0.22–0.38]. Raters were generally unable to correctly identify the ITP bone marrows from controls. Increased number of megakaryocytes, while an uncommon finding, was more frequent among ITP patients compared with controls (6/32, 18.8%; vs. 2/51, 3.9%; P = 0.05), and abnormal megakaryocyte morphology often led individual raters to reach a diagnosis of ITP. Overall sensitivity and specificity of bone marrow examinations were 24% and 90%, respectively.
This study confirms methodologically that bone marrow examinations are unreliable and frequently non-diagnostic in ITP. Thus, they are not useful for patients with typical disease. Rare subsets of patients with severe ITP demonstrated unique features such as increased number of megakaryocytes.
PMCID: PMC3938453  PMID: 23140198 CAMSID: cams4134
platelets; bone marrow; megakaryocyte; immune thrombocytopenia; reliability
4.  Strategies to Identify the Lynch Syndrome Among Patients With Colorectal Cancer 
Annals of internal medicine  2011;155(2):69-79.
Testing has been advocated for all persons with newly diagnosed colorectal cancer to identify families with the Lynch syndrome, an autosomal dominant cancer-predisposition syndrome that is a paradigm for personalized medicine.
To estimate the effectiveness and cost-effectiveness of strategies to identify the Lynch syndrome, with attention to sex, age at screening, and differential effects for probands and relatives.
Markov model that incorporated risk for colorectal, endometrial, and ovarian cancers.
Data Sources
Published literature.
Target Population
All persons with newly diagnosed colorectal cancer and their relatives.
Time Horizon
Third-party payer.
Strategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery.
Outcome Measures
Life-years, cancer cases and deaths, costs, and incremental cost-effectiveness ratios.
Results of Base-Case Analysis
The benefit of all strategies accrued primarily to relatives with a mutation associated with the Lynch syndrome, particularly women, whose life expectancy could increase by approximately 4 years with hysterectomy and salpingo-oophorectomy and adherence to colorectal cancer screening recommendations. At current rates of germline testing, screening, and prophylactic surgery, the strategies reduced deaths from colorectal cancer by 7% to 42% and deaths from endometrial and ovarian cancer by 1% to 6%. Among tumor-testing strategies, immunohistochemistry followed by BRAF mutation testing was preferred, with an incremental cost-effectiveness ratio of $36 200 per life-year gained.
Results of Sensitivity Analysis
The number of relatives tested per proband was a critical determinant of both effectiveness and cost-effectiveness, with testing of 3 to 4 relatives required for most strategies to meet a threshold of $50 000 per life-year gained. Immunohistochemistry followed by BRAF mutation testing was preferred in 59% of iterations in probabilistic sensitivity analysis at a threshold of $100 000 per life-year gained. Screening for the Lynch syndrome with immunohistochemistry followed by BRAF mutation testing only up to age 70 years cost $44 000 per incremental life-year gained compared with screening only up to age 60 years, and screening without an upper age limit cost $88 700 per incremental life-year gained compared with screening only up to age 70 years.
Other types of cancer, uncertain family pedigrees, and genetic variants of unknown significance were not considered.
Widespread colorectal tumor testing to identify families with the Lynch syndrome could yield substantial benefits at acceptable costs, particularly for women with a mutation associated with the Lynch syndrome who begin regular screening and have risk-reducing surgery. The cost-effectiveness of such testing depends on the participation rate among relatives at risk for the Lynch syndrome.
Primary Funding Source
National Institutes of Health.
PMCID: PMC3793257  PMID: 21768580
5.  Adding an endovascular aortic surgery program to a rural regional medical centre 
Canadian Journal of Surgery  2013;56(5):E105-E113.
Abdominal aortic aneurysms requiring surgical intervention are generally treated by endovascular means. Such procedures are not always offered in rural hospitals, possibly leaving patients underserved. We reviewed our experience initiating an endoaortic surgery program.
A surgeon in a rural centre was credentialed to perform endovascular aortic aneurysm repair through collaboration with a university centre and was proctored locally for the first 5 abdominal aneurysm repairs. Web-based image storage was used to review complex cases as part of an ongoing partnership. Referred patients were screened for multiple aneurysms and underwent long-term monitoring.
In all, 160 patients were evaluated for 176 aortic pathologies. Twenty-five patients (17 men) aged 55–89 years underwent 26 endovascular abdominal (n = 23) or thoracic (n = 3) aortic procedures. Emergent endovascular procedures were not performed. There were no operative deaths, requirements for dialysis or conversions to open repair. Two endoleaks required early reintervention. The median length of stay in hospital for endovascular procedures was 2.5 days. Chronic endoleaks were observed in 7 patients. An additional 8 patients underwent open abdominal aneurysm repair locally and 15 patients were referred to the university program.
Creation of an endovascular aortic surgery program in a rural hospital is feasible through collaboration with a high-volume centre. Patient safety is enhanced by obtaining second opinions using web-based image review. Most interventions are for abdominal aortic aneurysms, but planning for a comprehensive aortic clinic is preferable.
PMCID: PMC3788019  PMID: 24067525
6.  Biomarker Use in Colorectal Cancer Therapy 
Biomarkers reflective of the molecular and genetic heterogeneity in colorectal cancers now guide certain aspects of clinical management and offer great potential for enrichment, stratification, and identification of novel therapeutic targets in drug development. Using case-based examples, this article reviews biomarkers that have an established role in the clinical management of colorectal cancer: mismatch repair protein testing and KRAS and BRAF mutational analysis. A selection of biomarkers undergoing validation for future clinical application is presented, and the dynamic and challenging interface between biomarkers in research and clinical practice is discussed.
PMCID: PMC3696980  PMID: 22056657
Colon cancer; colorectal cancer; biomarker; KRAS; BRAF; microsatellite instability; mismatch repair
7.  Repeated exposure to moderate doses of ethanol augments hippocampal glutamate neurotransmission by increasing release 
Addiction biology  2010;16(2):229-237.
The present study used conventional and quantitative microdialysis to assess glutamatergic and GABAergic neurotransmission in the hippocampal CA3 area of the rat following a moderate-dose ethanol treatment regimen. Male Wistar rats received 3.4 g/kg of ethanol or water for 6 days via gastric gavage. Microdialysis experiments commenced 2 days later. Basal and depolarization-induced glutamate overflow were significantly elevated in ethanol-treated animals. Basal and depolarization-induced gamma-aminobutyric acid (GABA) overflow were unaltered. Quantitative no-net-flux microdialysis was used to determine if changes in dialysate glutamate levels following ethanol administration are due to an increase in release or a decrease in uptake.To confirm the validity of this method for quantifying basal glutamate dynamics, extracellular concentrations of glutamate and the extraction fraction, which reflects changes in analyte clearance, were quantified in response to retro-dialysis of the glutamate uptake blocker trans-pyrrolidine-2,4-dicarboxylic acid (tPDC). tPDC significantly decreased the extraction fraction for glutamate, resulting in augmented extracellular glutamate concentrations. Repeated ethanol administration did not alter the glutamate extraction fraction. However, extracellular glutamate concentrations were significantly elevated, indicating that glutamate release is increased as a consequence of repeated ethanol administration. These data demonstrate that repeated bouts of moderate ethanol consumption alter basal glutamate dynamics in the CA3 region of the dorsal hippocampus. Basal glutamate release is augmented, whereas glutamate uptake is unchanged. Furthermore, they suggest that dysregulation of glutamate transmission in this region may contribute to the previously documented deficits in cognitive function associated with moderate dose ethanol use.
PMCID: PMC3684957  PMID: 21182572
Ethanol; GABA; glutamate; hippocampus; microdialysis; rat
8.  Compromised Mitochondrial Fatty Acid Synthesis in Transgenic Mice Results in Defective Protein Lipoylation and Energy Disequilibrium 
PLoS ONE  2012;7(10):e47196.
A mouse model with compromised mitochondrial fatty acid synthesis has been engineered in order to assess the role of this pathway in mitochondrial function and overall health. Reduction in the expression of mitochondrial malonyl CoA-acyl carrier protein transacylase, a key enzyme in the pathway encoded by the nuclear Mcat gene, was achieved to varying extents in all examined tissues employing tamoxifen-inducible Cre-lox technology. Although affected mice consumed more food than control animals, they failed to gain weight, were less physically active, suffered from loss of white adipose tissue, reduced muscle strength, kyphosis, alopecia, hypothermia and shortened lifespan. The Mcat-deficient phenotype is attributed primarily to reduced synthesis, in several tissues, of the octanoyl precursors required for the posttranslational lipoylation of pyruvate and α-ketoglutarate dehydrogenase complexes, resulting in diminished capacity of the citric acid cycle and disruption of energy metabolism. The presence of an alternative lipoylation pathway that utilizes exogenous free lipoate appears restricted to liver and alone is insufficient for preservation of normal energy metabolism. Thus, de novo synthesis of precursors for the protein lipoylation pathway plays a vital role in maintenance of mitochondrial function and overall vigor.
PMCID: PMC3471957  PMID: 23077570
9.  Influence of Patient Preferences on the Cost-Effectiveness of Screening for Lynch Syndrome 
Journal of Oncology Practice  2012;8(3 Suppl):e24s-e30s.
This cost-utility analysis reports on the effect of quality of life on the value of screening all new patients with colorectal cancer for Lynch syndrome.
Patients and relatives have varying preferences for genetic testing and interventions related to hereditary cancer syndromes. We examined how the impact of these services on quality of life (QoL) affects the cost-effectiveness of screening for Lynch syndrome among probands newly diagnosed with colorectal cancer and their relatives.
We constructed a state-transition model comparing screening strategies (clinical criteria, prediction algorithms, tumor testing, and upfront germline testing) with no screening to identify Lynch syndrome. The model incorporated individuals' health state utilities after screening, germline testing, and risk-reducing surgeries, with utilities persisting for 12 months in the base case. Outcomes consisted of quality-adjusted life-years (QALYs), costs, and cost per QALY gained. Sensitivity analyses assessed how the duration and magnitude of changes in QoL influenced results.
Multiple screening strategies yielded gains in QALYs at acceptable costs compared with no screening. The preferred strategy—immunohistochemistry of tumors followed by BRAF mutation testing (IHC/BRAF)—cost $59,700 per QALY gained in the base case. The duration and magnitude of decreases in QoL after decisions related to germline testing and surgeries were key determinants of the cost-effectiveness of screening. IHC/BRAF cost > $100,000 per QALY gained when decrements to QoL persisted for 21 months.
Screening for Lynch syndrome in the population is likely to yield long-term gains in life expectancy that outweigh any short-term decreases in QoL, at acceptable costs. Counseling for individuals should aim to mitigate potential negative impact of genetic testing and risk-reducing interventions on QoL.
PMCID: PMC3348599  PMID: 22942831
10.  Tradeoffs of Using Administrative Claims and Medical Records to Identify the Use of Personalized Medicine for Patients with Breast Cancer 
Medical Care  2011;49(6):e1-e8.
Administrative claims and medical records are important data sources to examine healthcare utilization and outcomes. Little is known about identifying personalized medicine technologies in these sources.
To describe agreement, sensitivity, and specificity of administrative claims compared to medical records for two pairs of targeted tests and treatments for breast cancer.
Research Design
Retrospective analysis of medical records linked to administrative claims from a large health plan. We examined whether agreement varied by factors that facilitate tracking in claims (coding and cost) and that enhance medical record completeness (records from multiple providers).
Women (35 – 65 years) with incident breast cancer diagnosed in 2006–2007 (n=775).
Use of human epidermal growth factor receptor 2 (HER2) and gene expression profiling (GEP) testing, trastuzumab and adjuvant chemotherapy in claims and medical records.
Agreement between claims and records was substantial for GEP, trastuzumab, and chemotherapy, and lowest for HER2 tests. GEP, an expensive test with unique billing codes, had higher agreement (91.6% vs. 75.2%), sensitivity (94.9% vs. 76.7%), and specificity (90.1% vs. 29.2%) than HER2, a test without unique billing codes. Trastuzumab, a treatment with unique billing codes, had slightly higher agreement (95.1% vs. 90%) and sensitivity (98.1% vs. 87.9%) than adjuvant chemotherapy.
Higher agreement and specificity were associated with services that had unique billing codes and high cost. Administrative claims may be sufficient for examining services with unique billing codes. Medical records provide better data for identifying tests lacking specific codes and for research requiring detailed clinical information.
PMCID: PMC3383782  PMID: 21422962
medical record; claims data; breast neoplasm; personalized medicine
11.  Establishment of murine basal cell carcinoma allografts – a potential model for preclinical drug testing and for molecular analysis 
Dysregulated hedgehog (HH) signaling has been found in numerous cancers, suggesting that therapeutic targeting of this pathway may be useful vs. a wide range of cancers. Basal cell carcinoma (BCC) is an excellent model system for studying the influence of the HH pathway on carcinogenesis because aberrant activation of HH signaling not only is crucial for the development but also for the maintenance of BCC. Genetically engineered BCC mouse models provide one important tool for the study of the biology of human BCCs and for evaluating therapeutic interventions since these mice produce multiple genetically defined tumors within a relatively short period of time. However, these models remain expensive and cumbersome to use for large-scale pre-clinical drug testing. Here we report a method for growing allografts from murine BCC tumors in NOD/SCID mice. These allografts develop faster and reproduce the histology, immunophenotypes and response to at least one anti-BCC drug of the parental autochthonous tumors from which they arise. Therefore, the allograft model provides a practical model for (i) studying BCC carcinogenesis and (ii) initial pre-clinical screening for anti-HH pathway and other anti-BCC drugs.
PMCID: PMC3193585  PMID: 21833014
Basal cell carcinoma; allograft; mouse model
12.  The growth response to androgen receptor signaling in ERα-negative human breast cells is dependent on p21 and mediated by MAPK activation 
Although a high frequency of androgen receptor (AR) expression in human breast cancers has been described, exploiting this knowledge for therapy has been challenging. This is in part because androgens can either inhibit or stimulate cell proliferation in pre-clinical models of breast cancer. In addition, many breast cancers co-express other steroid hormone receptors that can affect AR signaling, further obfuscating the effects of androgens on breast cancer cells.
To create better-defined models of AR signaling in human breast epithelial cells, we took estrogen receptor (ER)-α-negative and progesterone receptor (PR)-negative human breast epithelial cell lines, both cancerous and non-cancerous, and engineered them to express AR, thus allowing the unambiguous study of AR signaling. We cloned a full-length cDNA of human AR, and expressed this transgene in MCF-10A non-tumorigenic human breast epithelial cells and MDA-MB-231 human breast-cancer cells. We characterized the responses to AR ligand binding using various assays, and used isogenic MCF-10A p21 knock-out cell lines expressing AR to demonstrate the requirement for p21 in mediating the proliferative responses to AR signaling in human breast epithelial cells.
We found that hyperactivation of the mitogen-activated protein kinase (MAPK) pathway from both AR and epidermal growth factor receptor (EGFR) signaling resulted in a growth-inhibitory response, whereas MAPK signaling from either AR or EGFR activation resulted in cellular proliferation. Additionally, p21 gene knock-out studies confirmed that AR signaling/activation of the MAPK pathway is dependent on p21.
These studies present a new model for the analysis of AR signaling in human breast epithelial cells lacking ERα/PR expression, providing an experimental system without the potential confounding effects of ERα/PR crosstalk. Using this system, we provide a mechanistic explanation for previous observations ascribing a dual role for AR signaling in human breast cancer cells. As previous reports have shown that approximately 40% of breast cancers can lack p21 expression, our data also identify potential new caveats for exploiting AR as a target for breast cancer therapy.
PMCID: PMC3496145  PMID: 22321971
13.  PIK3CA mutations and EGFR overexpression predict for lithium sensitivity in human breast epithelial cells 
Cancer Biology & Therapy  2011;11(3):358-367.
A high frequency of somatic mutations has been found in breast cancers within the gene encoding the catalytic p110α subunit of PI3K, PIK3CA. Using isogenic human breast epithelial cells, we have previously demonstrated that oncogenic PIK3CA “hotspot” mutations predict for response to the toxic effects of lithium. However, other somatic genetic alterations occur within this pathway in breast cancers, and it is possible that these changes may also predict for lithium sensitivity. We overexpressed the epidermal growth factor receptor (EGFR) into the non-tumorigenic human breast epithelial cell line MCF-10A, and compared these cells to isogenic cell lines previously created via somatic cell gene targeting to model Pten loss, PIK3CA mutations, and the invariant AKT1 mutation, E17K. EGFR overexpressing clones were capable of cellular proliferation in the absence of EGF and were sensitive to lithium similar to the results previously seen with cells harboring PIK3CA mutations. In contrast, AKT1 E17K cells and PTEN−/− cells displayed resistance or partial sensitivity to lithium, respectively. Western blot analysis demonstrated that lithium sensitivity correlated with significant decreases in both PI3K and MAPK signaling that were observed only in EGFR overexpressing and mutant PIK3CA cell lines. These studies demonstrate that EGFR overexpression and PIK3CA mutations are predictors of response to lithium, whereas Pten loss and AKT1 E17K mutations do not predict for lithium sensitivity. Our findings may have important implications for the use of these genetic lesions in breast cancer patients as predictive markers of response to emerging PI3K pathway inhibitors.
PMCID: PMC3047087  PMID: 21124076
breast cancer; AKT; PI3K; Pten; EGFR
14.  Basal Cell Carcinomas Arise From Hair Follicle Stem Cells in Ptch1+/− Mice 
Cancer cell  2011;19(1):114-124.
Basal cell carcinomas (BCCs) are hedgehog-driven tumors that resemble follicular and interfollicular epidermal basal keratinocytes and hence long have been thought to arise from these cells. However, the actual cell of origin is unknown. Using cell fate tracking of X-ray induced BCCs in Ptch1+/− mice, we found their essentially exclusive origin to be keratin 15-expressing stem cells of the follicular bulge. However, conditional loss of p53 not only enhanced BCC carcinogenesis from the bulge but also produced BCCs from the interfollicular epidermis, at least in part by enhancing Smo expression. This latter finding is consistent with the lack of visible tumors on ears and tail, sites lacking Smo expression, in Ptch1+/− mice.
PMCID: PMC3061401  PMID: 21215705
Basal cell carcinoma; stem cell; Ptch1; Hedgehog
16.  Capacity building for assessing new technologies: approaches to examining personalized medicine in practice 
Personalized medicine  2010;7(4):427-439.
This article focuses on the overarching question: how can we use existing data to develop the capacity to improve the evidence base on personalized medicine technologies and particularly regarding their utilization and clinical utility? We focus on data from health payers who are key stakeholders in capacity building, as they need data to guide decisions and they develop data as part of operations. Broadly defined, health payers include insurance carriers, third party payers, health-plan sponsors and organized delivery systems. Data from health payers have not yet been widely used to assess personalized medicine. Now, with an increasing number of personalized technologies covered and reimbursed by health payers, and an increasing number of emerging technologies that will require policy decisions, there is a great opportunity to develop the evidence base using payer data and by engaging with these stakeholders. Here, we describe data that are available from, and are being developed by, health payers and assess how these data can be further developed to increase the capacity for future research, using three examples. The examples suggest that payer data can be used to examine clinical utility and approaches can be developed that simultaneously address the characteristics of personalized medicine, real world data and organizations. These examples can now help us to elucidate how to best examine clinical utility in actual practice and build evaluation approaches that can be applied to future technologies.
PMCID: PMC3157083  PMID: 21857867
cancer; data development; evidence development; health payer; organized delivery system; personalized medicine; pharmacy benefits manager
17.  Risk of Losing Insurance During the Transition into Adulthood Among Insured Youth with Disabilities 
To compare insured youth (age 15–25 years) with and without disabilities on risk of insurance loss. We conducted a cross-sectional study using data from the Survey of Income and Program Participation 2001. Descriptive statistics characterized insured youth who maintained and lost insurance for at least 3 months over a 3-year time frame. We conducted logistic regression to calculate the association between disability and insurance loss. Adjustment variables were gender, race, ethnicity, age, work or school status, poverty status, type of insurance at study onset, state generosity, and an interaction between disability and insurance type. This study includes 2,123 insured youth without disabilities, 320 insured youth with non-severe disabilities, and 295 insured youth with severe disabilities. Thirty-six percent of insured youth without disabilities lost insurance compared to 43% of insured youth with non-severe disabilities and 41% of insured youth with severe disabilities (P = .07). Youth with non-severe disabilities on public insurance have an estimated 61% lower odds of losing insurance (OR: 0.39; 95% CI: 0.16, 0.93; P = .03) compared to youth without disabilities on public insurance. Further, youth with severe disabilities on public insurance have an estimated 81% lower odds of losing insurance (OR: 0.19; 95% CI: 0.09, 0.40; P < .001) compared to youth without disabilities. When examining youth with private insurance, we find that youth with severe disabilities have 1.63 times higher odds (OR: 1.63; 95% CI: 1.03, 2.57; P = .04) of losing health insurance compared to youth without disabilities. Insurance type interacts with disability severity to affect odds of insurance loss among insured youth.
PMCID: PMC3115452  PMID: 19517074
Disability; Youth with special health care needs; Insurance; Transition; Adolescent health
18.  Knock in of the AKT1 E17K mutation in human breast epithelial cells does not recapitulate oncogenic PIK3CA mutations 
Oncogene  2010;29(16):2337-2345.
An oncogenic mutation (G49A:E17K) in the AKT1 gene has been described recently in human breast, colon and ovarian cancers. The low frequency of this mutation and perhaps other selective pressures have prevented the isolation of human cancer cell lines that harbor this mutation thereby limiting functional analysis. Here we create a physiologic in vitro model to study the effects of this mutation by employing somatic cell gene targeting using the nontumorigenic human breast epithelial cell line, MCF10A. Surprisingly, knock in of E17K into the AKT1 gene had minimal phenotypic consequences and importantly, did not recapitulate the biochemical and growth characteristics seen with somatic cell knock in of PIK3CA hotspot mutations. These results suggest that mutations in critical genes within the PI3K pathway are not functionally equivalent, and that other cooperative genetic events may be necessary to achieve oncogenic PI3K pathway activation in cancers that contain the AKT1 E17K mutation.
PMCID: PMC3042798  PMID: 20101210
Akt1; oncogene; knock in; gene targeting; breast epithelial cells
19.  Health insurance regain after a spell of uninsurance: a longitudinal comparison of youth with and without disabilities transitioning into adulthood 
To examine insurance regain among youth with no, non-severe, and severe disabilities.
The data source for this study was the Survey of Income and Program Participation 2001–2004. We examined insurance regain among youth with no, non-severe, and severe disabilities between 15 and 25 using a longitudinal design. Kaplan-Meier survival functions provided estimates of uninsurance spell durations measured in waves, or 4-month intervals. We conducted a discrete time survival analysis adjusting for personal characteristics.
This study includes 1310 youth who entered the SIPP with insurance and became uninsured. 985 youth (75%) regained insurance. Based on SIPP waves, median duration of uninsurance was 2 waves (between 5 and 8 months) for youth with severe disabilities and 3 waves (between 9 and 12 months) for youth with non-severe disability. Youth with non-severe disabilities had decreased odds of regaining health insurance compared to youth without disabilities (OR: .73; 95% CI: .57, .92; p=.01).
Youth with severe disabilities and youth without disabilities had similar odds of and durations to insurance regain. In contrast, youth with non-severe disabilities had lower odds of regaining insurance and experienced longer durations of uninsurance compared to peers without disabilities. We recommend additional research into the implications of Medicaid eligibility pathways and employment barriers for youth with non-severe disabilities.
PMCID: PMC2808142  PMID: 19931827
20.  KRAS mutational analysis for colorectal cancer 
PLoS Currents  2010;2:RRN1175.
KRAS mutational analysis is a genetic test used in clinical practice for determining the status of the KRAS gene (wild type or mutant) in tumors from patients with metastatic colorectal cancer (CRC). Persons whose tumors are wild type may respond to therapies cetuximab (Erbitux) or panitumumab (Vectibix).
PMCID: PMC2940138  PMID: 20877448
21.  Dynamic Range Adaptation to Sound Level Statistics in the Auditory Nerve 
The auditory system operates over a vast range of sound pressure levels (100–120 dB) with nearly constant discrimination ability across most of the range, well exceeding the dynamic range of most auditory neurons (20–40 dB). Dean et al. (Nat. Neurosci. 8:1684, 2005) have reported that the dynamic range of midbrain auditory neurons adapts to the distribution of sound levels in a continuous, dynamic stimulus by shifting towards the most frequently occurring level. Here we show that dynamic range adaptation, distinct from classic firing rate adaptation, also occurs in primary auditory neurons in anesthetized cats for tone and noise stimuli. Specifically, the range of sound levels over which firing rates of auditory-nerve (AN) fibers grows rapidly with level shifts nearly linearly with the most probable levels in a dynamic sound stimulus. This dynamic range adaptation was observed for fibers with all characteristic frequencies and spontaneous discharge rates. As in the midbrain, dynamic range adaptation improved the precision of level coding by the AN fiber population for the prevailing sound levels in the stimulus. However, dynamic range adaptation in the AN was weaker than in the midbrain, and not sufficient (0.25 dB/dB on average for broadband noise) to prevent a significant degradation of the precision of level coding by the AN population above 60 dB SPL. These findings suggest that adaptive processing of sound levels first occurs in the auditory periphery and is enhanced along the auditory pathway.
PMCID: PMC2774902  PMID: 19889991
dynamic range problem; rate-level function; adaptation; sound level statistics; intensity coding; anesthetized cat
22.  Endovascular Repair of the Thoracic Aorta 
The emergence of endovascular repair of the thoracic aorta (TEVAR) quickly followed the development of technology for the exclusion of infrarenal abdominal aortic aneurysms. Stent grafts comprised of metal struts covered with fabric made of Dacron/polyester or polytetrafluoroethylene were developed for the purpose of achieving an adequate seal at the proximal and distal aspects of thoracic aneurysms, thus excluding sac flow. The recognition of the decreased morbidity of this approach compared with open repair was readily apparent, as it avoided left thoracotomy, aortic cross-clamping, and left heart bypass. Since then, TEVAR is increasingly being used for other aortic pathologies such as complicated type B dissection, traumatic aortic transection, and aneurysmal disease extending into the arch or visceral segment, requiring debranching procedures.
PMCID: PMC3036454  PMID: 21326527
Aneurysm; stent graft; thoracic
23.  Use of multiple methods for genotyping Fusarium during an outbreak of contact lens associated fungal keratitis in Singapore 
In Singapore, an outbreak of fungal keratitis caused by members of the Fusarium solani species complex (FSSC) was identified in March 2005 to May 2006 involving 66 patients. Epidemiological investigations have indicated that improper contact lens wear and the use of specific contact lens solutions were risk factors.
We assessed the genetic diversity of the isolates using AFLP, Rep-PCR, and ERIC-PCR and compared the usefulness of these typing schemes to characterize the isolates.
AFLP was the most discriminative typing scheme and appears to group FSSC from eye infections and from other infections differently.
There was a high genomic heterogeneity among the isolates confirming that this was not a point source outbreak.
PMCID: PMC2483985  PMID: 18627616
24.  Translating a Community-Based Motivational Support Program to Increase Physical Activity Among Older Adults With Diabetes at Community Clinics: A Pilot Study of Physical Activity for a Lifetime of Success (PALS) 
Preventing Chronic Disease  2007;5(1):A18.
Regular physical activity is an important goal for elders with chronic health conditions.
This report describes Physical Activity for a Lifetime of Success (PALS), an attempt to translate a motivational support program for physical activity, Active Choices, for use by a group of diverse, low-income, community-dwelling elders with diabetes.
PALS linked physical activity assessment and brief counseling by primary care providers with a structured referral to a community-based motivational telephone support program delivered by older adult volunteers. People with diabetes aged 65 years or older who were receiving care at two community clinics were randomized to receive either immediate or delayed intervention. The main intended outcome measure was physical activity level; the secondary outcome measure was mean hemoglobin A1c.
One-third of those offered referral to the PALS program in the clinic setting declined. Another 44% subsequently declined enrollment or were unreachable by the support center. Only 14 (21%) of those offered referral enrolled in the program. Among these 14, the percentage who were sufficiently active was higher at follow-up than at enrollment, though not significantly so. Using an intent-to-treat analysis, which included all randomized clinic patients, we found no significant change in mean hemoglobin A1c for the intervention group compared with controls.
A community-based referral and support program to increase physical activity among elderly, ethnically diverse, low-income people with diabetes, many of whom are not English-speaking, may be thwarted by unforeseen barriers. Those who enroll and participate in the PALS program appear to increase their level of physical activity.
PMCID: PMC2248781  PMID: 18082007
25.  Ultrasonic Contrast Agent Shell Rupture Detected by Inertial Cavitation and Rebound Signals 
Determining the rupture pressure threshold of ultrasound contrast agent microbubbles has significant applications for contrast imaging, development of therapeutic agents, and evaluation of potential bioeffects. Using a passive cavitation detector, this work evaluates rupture based on acoustic emissions from single, encapsulated, gas-filled microbubbles. Sinusoidal ultrasound pulses were transmitted into weak solutions of OptisonTM at different center frequencies (0.9, 2.8, and 4.6 MHz), pulse durations (three, five, and seven cycles of the center frequencies), and peak rarefactional pressures (0.07 to 5.39 MPa). Pulse repetition frequency was 10 Hz. Signals detected with a 13-MHz, center-frequency transducer revealed postexcitation acoustic emissions (between 1 and 5 μs after excitation) with broadband spectral content. The observed acoustic emissions were consistent with the acoustic signature that would be anticipated from inertial collapse followed by “rebounds” when a microbubble ruptures and thus generates daughter/free bubbles that grow and collapse. The peak rarefactional pressure threshold for detection of these emissions increased with frequency (e.g., 0.53, 0.87, and 0.99 MPa for 0.9, 2.8, and 4.6 MHz, respectively; five-cycle pulse duration) and decreased with pulse duration. The emissions identified in this work were separated from the excitation in time and spectral content, and provide a novel determination of microbubble shell rupture.
PMCID: PMC2013305  PMID: 16471439

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