Prenatal vaccination of mothers and hepatitis B vaccination of their infants.

Tetanus, diphtheria, and acellular pertussis (Tdap) vaccination and influenza vaccination are recommended during pregnancy primarily to prevent influenza and pertussis in mothers and their infants. This study examines associations between prenatal Tdap vaccination and influenza vaccination of mothers and hepatitis B vaccination of their infants. A retrospective cohort study was conducted using data from electronic medical records from 15,468 deliveries to 14,925 mothers occurring April 2, 2014-December 3, 2016 at a university hospital in Texas. Hepatitis B vaccine receipt in the first 3 days of life was dichotomized. Margins post-estimation commands in Stata SE 15.1 were used to obtain predicted probabilities and risk differences after estimating odds ratios in logistic regression with robust variance estimates. Adjusted models included maternal age, race/ethnicity, Medicaid use, year of delivery, parity, and gravidity. Infants of mothers who received prenatal influenza vaccination in the 2014-2015 and 2015-2016 influenza seasons were more likely than those of mothers who did not to receive a hepatitis B vaccine in their first 3 days of life (adjusted risk difference (RD) 2.8%, 95% confidence interval (CI) 1.5-4.1% and RD 2.2%, 95% CI 0.9-3.5%, respectively). Hepatitis B vaccination was also higher among infants of Tdap-eligible mothers who received prenatal Tdap vaccination during pregnancy compared to those of mothers who did not (adjusted RD 9.1%, 95% CI 7.6-10.5%). Overall, prenatal vaccination was significantly associated with uptake of infant hepatitis B vaccine.

Cognitive enhancing treatment with a PPARγ agonist normalizes dentate granule cell presynaptic function in Tg2576 APP mice.

Hippocampal network hyperexcitability is considered an early indicator of Alzheimer's disease (AD) memory impairment. Some AD mouse models exhibit similar network phenotypes. In this study we focused on dentate gyrus (DG) granule cell spontaneous and evoked properties in 9-month-old Tg2576 mice that model AD amyloidosis and cognitive deficits. Using whole-cell patch-clamp recordings, we found that Tg2576 DG granule cells exhibited spontaneous EPSCs that were higher in frequency but not amplitude compared with wild-type mice, suggesting hyperactivity of DG granule cells via a presynaptic mechanism. Further support of a presynaptic mechanism was revealed by increased I-O relationships and probability of release in Tg2576 DG granule cells. Since we and others have shown that activation of the peroxisome proliferator-activated receptor gamma (PPARγ) axis improves hippocampal cognition in mouse models for AD as well as benefitting memory performance in some humans with early AD, we investigated how PPARγ agonism affected synaptic activity in Tg2576 DG. We found that PPARγ agonism normalized the I-O relationship of evoked EPSCs, frequency of spontaneous EPSCs, and probability of release that, in turn, correlated with selective expression of DG proteins essential for presynaptic SNARE function that are altered in patients with AD. These findings provide evidence that DG principal cells may contribute to early AD hippocampal network hyperexcitability via a presynaptic mechanism, and that hippocampal cognitive enhancement via PPARγ activation occurs through regulation of presynaptic vesicular proteins critical for proper glutamatergic neurotransmitter release, synaptic transmission, and short-term plasticity.

Cognitive enhancement with rosiglitazone links the hippocampal PPARγ and ERK MAPK signaling pathways.

We previously reported that the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (RSG) improved hippocampus-dependent cognition in the Alzheimer's disease (AD) mouse model, Tg2576. RSG had no effect on wild-type littermate cognitive performance. Since extracellular signal-regulated protein kinase mitogen-activated protein kinase (ERK MAPK) is required for many forms of learning and memory that are affected in AD, and since both PPARγ and ERK MAPK are key mediators of insulin signaling, the current study tested the hypothesis that RSG-mediated cognitive improvement induces a hippocampal PPARγ pattern of gene and protein expression that converges with the ERK MAPK signaling axis in Tg2576 AD mice. In the hippocampal PPARγ transcriptome, we found significant overlap between peroxisome proliferator response element-containing PPARγ target genes and ERK-regulated, cAMP response element-containing target genes. Within the Tg2576 dentate gyrus proteome, RSG induced proteins with structural, energy, biosynthesis and plasticity functions. Several of these proteins are known to be important for cognitive function and are also regulated by ERK MAPK. In addition, we found the RSG-mediated augmentation of PPARγ and ERK2 activity during Tg2576 cognitive enhancement was reversed when hippocampal PPARγ was pharmacologically antagonized, revealing a coordinate relationship between PPARγ transcriptional competency and phosphorylated ERK that is reciprocally affected in response to chronic activation, compared with acute inhibition, of PPARγ. We conclude that the hippocampal transcriptome and proteome induced by cognitive enhancement with RSG harnesses a dysregulated ERK MAPK signal transduction pathway to overcome AD-like cognitive deficits in Tg2576 mice. Thus, PPARγ represents a signaling system that is not crucial for normal cognition yet can intercede to restore neural networks compromised by AD.

Using power spectrum analysis to evaluate (18)O-water labeling data acquired from low resolution mass spectrometers.

We describe a method for ratio estimations in (18)O-water labeling experiments acquired from low resolution isotopically resolved data. The method is implemented in a software package specifically designed for use in experiments making use of zoom-scan mode data acquisition. Zoom-scan mode data allow commonly used ion trap mass spectrometers to attain isotopic resolution, which makes them amenable to use in labeling schemes such as (18)O-water labeling, but algorithms and software developed for high resolution instruments may not be appropriate for the lower resolution data acquired in zoom-scan mode. The use of power spectrum analysis is proposed as a general approach that may be uniquely suited to these data types. The software implementation uses a power spectrum to remove high-frequency noise and band-filter contributions from coeluting species of differing charge states. From the elemental composition of a peptide sequence, we generate theoretical isotope envelopes of heavy-light peptide pairs in five different ratios; these theoretical envelopes are correlated with the filtered experimental zoom scans. To automate peptide quantification in high-throughput experiments, we have implemented our approach in a computer program, MassXplorer. We demonstrate the application of MassXplorer to two model mixtures of known proteins and to a complex mixture of mouse kidney cortical extract. Comparison with another algorithm for ratio estimations demonstrates the increased precision and automation of MassXplorer.

Use of patient navigators to increase HPV vaccination rates in a pediatric clinical population.

A patient navigator (PN) program was implemented in pediatric clinics to increase uptake of the human papillomavirus (HPV) vaccine. The purpose of this study is to examine the impact of this program. All visits between April 1, 2013 and December 31, 2017 for 9-17 year old patients at 3 program and 5 non-program clinics were examined using electronic medical records. These dates included patient visits before and after program initiation (February 1, 2015). Visits including 1 dose of the HPV vaccine were assessed as a proportion of total visits for each month. Multivariable binary logistic regression was used to examine the odds of HPV vaccination across time, between program and non-program clinics, and age group. A total of 128,051 visits by 21,395 patients were examined. HPV vaccines were administered during 12,742 visits (10.0%). Odds of HPV vaccination during visits by 13-17 year olds was greater than during visits by 9-12 year olds in the pre-intervention period (odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.04-1.19). However, this association changed during the intervention period, with odds of HPV vaccination among visits by 13-17 year olds lower compared to visits by 9-12 year olds (OR: 0.78, 95% CI: 0.75-0.82). The odds of HPV vaccination were elevated among 9-12 year olds in program clinics as compared to 2014, the year before the program was implemented. Having on-site PNs can increase the frequency of HPV vaccination in pediatric clinics, particularly among patients 9-12 years of age.

Regional variations in human papillomavirus prevalence across time in NHANES (2003-2014).

INTRODUCTION: The consequences of low human papillomavirus (HPV) vaccination in Census regions with higher incidence of cervical cancer may contribute to continued disparities. Our purpose was to evaluate regional variations in HPV prevalence across time. METHODS: Repeated cross-sectional data from the National Health and Nutrition Examination Survey (NHANES), 2003-2014 were examined. Participants included females 14 to 34 years old who provided adequate vaginal samples for HPV DNA typing (N = 6387). Region of residence and HPV vaccination status associations with HPV prevalence were examined using chi-square and multivariable logistic regression. HPV types were grouped according to vaccine-type HPV (types 6, 11, 16, 18) and risk (high or low-risk). Time and vaccination status were included in subsequent models for post-licensure survey cycles (2007-2014) to assess their effects on observed associations. RESULTS: No decreases in vaccine-type HPV prevalence were found between the prevaccine cycles (2003-2006) and early post-licensure cycles (2007-2010, p > 0.05). Vaccine-type HPV prevalence decreased in late post-licensure years (2011-2014) compared to prevaccine years (2003-2006, p = 0.001). The highest prevalence of vaccine-type HPV occurred in the South (8.6%) and Midwest (8.6%), followed by the West (4.8%), and the Northeast (3.5%) in late post-licensure years. Lower odds of vaccine-type HPV across time in post-licensure survey cycles were found to be attributable to time, and more strongly to HPV vaccination. CONCLUSIONS: There were regional variations in vaccine-type HPV prevalence between prevaccine and post-licensure years. These decreases appeared to be at least partially attributable to HPV vaccination. Programs are needed to address geographical disparities in HPV vaccination.

Impact of human papillomavirus vaccination on racial/ethnic disparities in vaccine-type human papillomavirus prevalence among 14-26 year old females in the U.S.

BACKGROUND: Low human papillomavirus (HPV) vaccination rates early after introduction, particularly among low income and minority adolescents, may have resulted in disparities in vaccine-type HPV prevalence (types 6, 11, 16, 18). The purpose of this study was to examine racial/ethnic variations in HPV prevalence, and evaluate how HPV vaccination has affected vaccine-type HPV prevalence across time. METHODS: This study was a retrospective analysis of 6 cycles of the National Health and Nutrition Examination Survey (NHANES) data (2003-2014). Results on HPV status from vaginal samples of 14-26 year old females who responded about HPV vaccination were used to determine HPV prevalence. Prevaccine HPV prevalence was compared to post-licensure prevalence. Racial/ethnic comparisons were made across time, and models were developed to examine the role of HPV vaccination in observed variations for vaccine-type HPV prevalence. RESULTS: Among 4080 females, 29.7% were black, 25.6% were Mexican American, 8.9% were Hispanic, and 35.8% were white. Compared to prevaccine years (2003-2006), vaccine-type HPV did not decrease until late post-licensure years (2011-2014; 14.2% vs. 5.2%, p < 0.001). Most of the decrease occurred among white females between prevaccine and late post-licensure periods (15.2% vs. 4.1%, p < 0.001). Although a decrease in prevalence was observed among black females during the same periods (16.9% vs. 9.8%, p < 0.05), it was not as large as among white females. Prevalence decreased among Mexican Americans (8.2 vs. 4.0, p > 0.05) during the same periods, but the difference was not significant. Interactions between race and time were significant (p < 0.001), with uneven vaccination between black and white females contributing to the disparities observed. CONCLUSIONS: HPV vaccination was low in among black and Mexican American females, which contributed to disparities in HPV prevalence. Increasing vaccination among all adolescents, particularly 11-12 year olds, is important because most children this age will not have been exposed.

Diabetes-induced activation of canonical and noncanonical nuclear factor-kappaB pathways in renal cortex.

Evidence of diabetes-induced nuclear factor-kappaB (NF-kappaB) activation has been provided with DNA binding assays or nuclear localization with immunohistochemistry, but few studies have explored mechanisms involved. We examined effects of diabetes on proteins comprising NF-kappaB canonical and noncanonical activation pathways in the renal cortex of diabetic mice. Plasma concentrations of NF-kappaB-regulated cytokines were increased after 1 month of hyperglycemia, but most returned to control levels or lower by 3 months, when the same cytokines were increased significantly in renal cortex. Cytosolic content of NF-kappaB canonical pathway proteins did not differ between experimental groups after 3 months of diabetes, while NF-kappaB noncanonical pathway proteins were affected, including increased phosphorylation of inhibitor of kappaB kinase-alpha and several fold increases in NF-kappaB-inducing kinase and RelB, which were predominantly located in tubular epithelial cells. Nuclear content of all NF-kappaB pathway proteins was decreased by diabetes, with the largest change in RelB and p50 (approximately twofold decrease). Despite this decrease, measurable increases in protein binding to DNA in diabetic versus control nuclear extracts were observed with electrophoretic mobility shift assay. These results provide evidence for chronic NF-kappaB activation in the renal cortex of db/db mice and suggest a novel, diabetes-linked mechanism involving both canonical and noncanonical NF-kappaB pathway proteins.

Concordance of adolescent human papillomavirus vaccination parental report with provider report in the National Immunization Survey-Teen (2008-2013).

OBJECTIVES: To examine the accuracy of parental report of HPV vaccination through examination of concordance, with healthcare provider vaccination report as the comparison. METHODS: The 2008-2013 National Immunization Survey (NIS)-Teen was used to examine accuracy of parent reports of HPV vaccination for their female daughters aged 13-17years, as compared with provider report of initiation and number of doses. Multivariable logistic regression models were used to examine associations related to concordance of parent and provider report. RESULTS: Of 51,746 adolescents, 84% concordance for HPV vaccine initiation and 70% concordance for number of doses was observed. Accuracy varied by race/ethnicity, region, time, and income. The parent report of number of doses was more likely to be accurate among parents of 13 and 14year old females than 17year olds. Accuracy of initiation and number of doses were lower among Hispanic and black adolescents compared to white parents. The odds of over-report was higher among minorities compared to whites, but the odds of underreport was also markedly higher in these groups compared to parents of white teens. Accuracy of parental vaccine report decreased across time. CONCLUSIONS: These findings are important for healthcare providers who need to ascertain the vaccination status of young adults. Strengthening existing immunization registries to improve data sharing capabilities and record completeness could improve vaccination rates, while avoiding costs associated with over-vaccination.

Detection of structural and metabolic changes in traumatically injured hippocampus by quantitative differential proteomics.

Traumatic brain injury (TBI) is a complex and common problem resulting in the loss of cognitive function. In order to build a comprehensive knowledge base of the proteins that underlie these cognitive deficits, we employed unbiased quantitative mass spectrometry, proteomics, and bioinformatics to identify and quantify dysregulated proteins in the CA3 subregion of the hippocampus in the fluid percussion model of TBI in rats. Using stable isotope 18O-water differential labeling and multidimensional tandem liquid chromatography (LC)-MS/MS with high stringency statistical analyses and filtering, we identified and quantified 1002 common proteins, with 124 increased and 76 decreased. The ingenuity pathway analysis (IPA) bioinformatics tool identified that TBI had profound effects on downregulating global energy metabolism, including glycolysis, the Krebs cycle, and oxidative phosphorylation, as well as cellular structure and function. Widespread upregulation of actin-related cytoskeletal dynamics was also found. IPA indicated a common integrative signaling node, calcineurin B1 (CANB1, CaNBα, or PPP3R1), which was downregulated by TBI. Western blotting confirmed that the calcineurin regulatory subunit, CANB1, and its catalytic binding partner PP2BA, were decreased without changes in other calcineurin subunits. CANB1 plays a critical role in downregulated networks of calcium signaling and homeostasis through calmodulin and calmodulin-dependent kinase II to highly interconnected structural networks dominated by tubulins. This large-scale knowledge base lays the foundation for the identification of novel therapeutic targets for cognitive rescue in TBI.

Proteomics and systems biology for understanding diabetic nephropathy.

Like many diseases, diabetic nephropathy is defined in a histopathological context and studied using reductionist approaches that attempt to ameliorate structural changes. Novel technologies in mass spectrometry-based proteomics have the ability to provide a deeper understanding of the disease beyond classical histopathology, redefine the characteristics of the disease state, and identify novel approaches to reduce renal failure. The goal is to translate these new definitions into improved patient outcomes through diagnostic, prognostic, and therapeutic tools. Here, we review progress made in studying the proteomics of diabetic nephropathy and provide an introduction to the informatics tools used in the analysis of systems biology data, while pointing out statistical issues for consideration. Novel bioinformatics methods may increase biomarker identification, and other tools, including selective reaction monitoring, may hasten clinical validation.

The National NeuroAIDS Tissue Consortium brain gene array: two types of HIV-associated neurocognitive impairment.

BACKGROUND: The National NeuroAIDS Tissue Consortium (NNTC) performed a brain gene expression array to elucidate pathophysiologies of Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders. METHODS: Twenty-four human subjects in four groups were examined A) Uninfected controls; B) HIV-1 infected subjects with no substantial neurocognitive impairment (NCI); C) Infected with substantial NCI without HIV encephalitis (HIVE); D) Infected with substantial NCI and HIVE. RNA from neocortex, white matter, and neostriatum was processed with the Affymetrix® array platform. RESULTS: With HIVE the HIV-1 RNA load in brain tissue was three log(10) units higher than other groups and over 1,900 gene probes were regulated. Interferon response genes (IFRGs), antigen presentation, complement components and CD163 antigen were strongly upregulated. In frontal neocortex downregulated neuronal pathways strongly dominated in HIVE, including GABA receptors, glutamate signaling, synaptic potentiation, axon guidance, clathrin-mediated endocytosis and 14-3-3 protein. Expression was completely different in neuropsychologically impaired subjects without HIVE. They had low brain HIV-1 loads, weak brain immune responses, lacked neuronally expressed changes in neocortex and exhibited upregulation of endothelial cell type transcripts. HIV-1-infected subjects with normal neuropsychological test results had upregulation of neuronal transcripts involved in synaptic transmission of neostriatal circuits. INTERPRETATION: Two patterns of brain gene expression suggest that more than one pathophysiological process occurs in HIV-1-associated neurocognitive impairment. Expression in HIVE suggests that lowering brain HIV-1 replication might improve NCI, whereas NCI without HIVE may not respond in kind; array results suggest that modulation of transvascular signaling is a potentially promising approach. Striking brain regional differences highlighted the likely importance of circuit level disturbances in HIV/AIDS. In subjects without impairment regulation of genes that drive neostriatal synaptic plasticity reflects adaptation. The array provides an infusion of public resources including brain samples, clinicopathological data and correlative gene expression data for further exploration (http://www.nntc.org/gene-array-project).

Altered retinoic acid metabolism in diabetic mouse kidney identified by O isotopic labeling and 2D mass spectrometry.

BACKGROUND: Numerous metabolic pathways have been implicated in diabetes-induced renal injury, yet few studies have utilized unbiased systems biology approaches for mapping the interconnectivity of diabetes-dysregulated proteins that are involved. We utilized a global, quantitative, differential proteomic approach to identify a novel retinoic acid hub in renal cortical protein networks dysregulated by type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: Total proteins were extracted from renal cortex of control and db/db mice at 20 weeks of age (after 12 weeks of hyperglycemia in the diabetic mice). Following trypsinization, (18)O- and (16)O-labeled control and diabetic peptides, respectively, were pooled and separated by two dimensional liquid chromatography (strong cation exchange creating 60 fractions further separated by nano-HPLC), followed by peptide identification and quantification using mass spectrometry. Proteomic analysis identified 53 proteins with fold change >or=1.5 and p