There are few data on the persistence of individual human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) mutations in the absence of selective drug pressure. We studied 313 patients in whom TDR mutations were detected at their first resistance test and who had a subsequent test performed while ART-naive. The rate at which mutations became undetectable was estimated using exponential regression accounting for interval censoring. Most thymidine analogue mutations (TAMs) and T215 revertants (but not T215F/Y) were found to be highly stable, with NNRTI and PI mutations being relatively less persistent. Our estimates are important for informing HIV transmission models.
persistence; transmitted; HIV-1; resistance; mutations
To determine protease mutations that develop at viral failure for protease inhibitor (PI)-naive patients on a regimen containing the PI atazanavir.
Resistance tests on patients failing atazanavir, conducted as part of routine clinical care in a multicentre observational study, were randomly matched by subtype to resistance tests from PI-naive controls to account for natural polymorphisms. Mutations from the consensus B sequence across the protease region were analysed for association and defined using the IAS-USA 2011 classification list.
Four hundred and five of 2528 (16%) patients failed therapy containing atazanavir as a first PI over a median (IQR) follow-up of 1.76 (0.84–3.15) years and 322 resistance tests were available for analysis. Recognized major atazanavir mutations were found in six atazanavir-experienced patients (P < 0.001), including I50L and N88S. The minor mutations most strongly associated with atazanavir experience were M36I, M46I, F53L, A71V, V82T and I85V (P < 0.05). Multiple novel mutations, I15S, L19T, K43T, L63P/V, K70Q, V77I and L89I/T/V, were also associated with atazanavir experience.
Viral failure on atazanavir-containing regimens was not common and major resistance mutations were rare, suggesting that adherence may be a major contributor to viral failure. Novel mutations were described that have not been previously documented.
HIV; drug resistance mutations; naive patients; protease inhibitors; virological failure
Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations.
Association results for a dichotomized cigarettes smoked per day (CPD) phenotype in 27 datasets (European ancestry (N=14,786), Asian (N=6,889), and African American (N=10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations.
We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (p < 0.01) in each of these three populations (OR=1.33, 95%C.I.=1.25–1.42, p=1.1×10−17 in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans.
The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments.
smoking; genetics; meta-analysis; cross-population
Life abounds with genetic variations writ in sequences that are often only a few hundred nucleotides long. Rapid detection of these variations for identification of genetic diseases, pathogens and organisms has become the mainstay of molecular science and medicine. This report describes a new, highly informative closed-tube polymerase chain reaction (PCR) strategy for analysis of both known and unknown sequence variations. It combines efficient quantitative amplification of single-stranded DNA targets through LATE-PCR with sets of Lights-On/Lights-Off probes that hybridize to their target sequences over a broad temperature range. Contiguous pairs of Lights-On/Lights-Off probes of the same fluorescent color are used to scan hundreds of nucleotides for the presence of mutations. Sets of probes in different colors can be combined in the same tube to analyze even longer single-stranded targets. Each set of hybridized Lights-On/Lights-Off probes generates a composite fluorescent contour, which is mathematically converted to a sequence-specific fluorescent signature. The versatility and broad utility of this new technology is illustrated in this report by characterization of variant sequences in three different DNA targets: the rpoB gene of Mycobacterium tuberculosis, a sequence in the mitochondrial cytochrome C oxidase subunit 1 gene of nematodes and the V3 hypervariable region of the bacterial 16 s ribosomal RNA gene. We anticipate widespread use of these technologies for diagnostics, species identification and basic research.
Every year in the United States, thousands of young children are injured by passenger vehicles in driveways or parking areas. Little is known about risk factors, and incidence rates are difficult to estimate because ascertainment using police collision reports or media sources is incomplete. This study used surveillance at trauma centers to identify incidents and parent interviews to obtain detailed information on incidents, vehicles, and children.
Eight California trauma centers conducted surveillance of nontraffic pedestrian collision injury to children aged 14 years or younger from January 2005 to July 2007. Three of these centers conducted follow-up interviews with family members.
Ninety-four injured children were identified. Nine children (10%) suffered fatal injury. Seventy children (74%) were 4 years old or younger. Family members of 21 victims from this study (23%) completed an interview. Of these 21 interviewed victims, 17 (81%) were male and 13 (62%) were 1 or 2 years old. In 13 cases (62%), the child was backed over, and the driver was the mother or father in 11 cases (52%). Fifteen cases (71%) involved a sport utility vehicle, pickup truck, or van. Most collisions occurred in a residential driveway.
Trauma center surveillance can be used for case ascertainment and for collecting information on circumstances of nontraffic pedestrian injuries. Adoption of a specific external cause-of-injury code would allow passive surveillance of these injuries. Research is needed to understand the contributions of family, vehicular, and environmental characteristics and injury risk to inform prevention efforts.
Gli3 is a zinc-finger transcription factor whose activity is dependent on the level of hedgehog (Hh) ligand. Hh signaling has key roles during endochondral ossification; however, its role in intramembranous ossification is still unclear. In this study, we show that Gli3 performs a dual role in regulating both osteoprogenitor proliferation and osteoblast differentiation during intramembranous ossification. We discovered that Gli3Xt−J/Xt−J mice, which represent a Gli3-null allele, exhibit craniosynostosis of the lambdoid sutures and that this is accompanied by increased osteoprogenitor proliferation and differentiation. These cellular changes are preceded by ectopic expression of the Hh receptor Patched1 and reduced expression of the transcription factor Twist1 in the sutural mesenchyme. Twist1 is known to delay osteogenesis by binding to and inhibiting the transcription factor Runx2. We found that Runx2 expression in the lambdoid suture was altered in a pattern complimentary to that of Twist1. We therefore propose that loss of Gli3 results in a Twist1-, Runx2-dependent expansion of the sutural osteoprogenitor population as well as enhanced osteoblastic differentiation which results in a bony bridge forming between the parietal and interparietal bones. We show that FGF2 will induce Twist1, normalize osteoprogenitor proliferation and differentiation and rescue the lambdoid suture synostosis in Gli3Xt−J/Xt−J mice. Taken together, we define a novel role for Gli3 in osteoblast development; we describe the first mouse model of lambdoid suture craniosynostosis and show how craniosynostosis can be rescued in this model.
Genome-wide scans of nucleotide variation in human subjects are providing an increasing number of replicated associations with complex disease traits. Most of the variants detected have small effects and, collectively, they account for a small fraction of the total genetic variance. Very large sample sizes are required to identify and validate findings. In this situation, even small sources of systematic or random error can cause spurious results or obscure real effects. The need for careful attention to data quality has been appreciated for some time in this field, and a number of strategies for quality control and quality assurance (QC/QA) have been developed. Here we extend these methods and describe a system of QC/QA for genotypic data in genome-wide association studies. This system includes some new approaches that (1) combine analysis of allelic probe intensities and called genotypes to distinguish gender misidentification from sex chromosome aberrations, (2) detect autosomal chromosome aberrations that may affect genotype calling accuracy, (3) infer DNA sample quality from relatedness and allelic intensities, (4) use duplicate concordance to infer SNP quality, (5) detect genotyping artifacts from dependence of Hardy-Weinberg equilibrium (HWE) test p-values on allelic frequency, and (6) demonstrate sensitivity of principal components analysis (PCA) to SNP selection. The methods are illustrated with examples from the ‘Gene Environment Association Studies’ (GENEVA) program. The results suggest several recommendations for QC/QA in the design and execution of genome-wide association studies.
GWAS; DNA sample quality; genotyping artifact; Hardy-Weinberg equilibrium; chromosome aberration
All-trans retinoic acid (ATRA) induces granulocytic maturation of WEHI-3B D+ leukemia cells and LiCl enhances this maturation, while WEHI-3B D− cells are non-responsive to ATRA. Transfection of SCL, expressed in D− but absent in D+ cells, into D+ cells, caused resistance to ATRA, while transfection of GATA-1 into D+ cells produced resistance to the combination of ATRA and LiCl. SCL expression in D+ cells did not induce the expression of c-Kit, a putative target gene for SCL. LiCl, known to inhibit some kinases by displacing Mg2+, did not affect tyrosine kinase activity of the cytoplasmic domain of c-Kit.
WEHI-3B D+; WEHI-3B D−; SCL (TAL1); GATA-1; All-trans retinoic acid (ATRA); Lithium chloride (LiCl); c-Kit
Classical research has suggested that early palate formation develops via epithelial-mesenchymal interactions, and in this study we reveal which signals control this process. Using Fgf10–/–, FGF receptor 2b–/– (Fgfr2b–/–), and Sonic hedgehog (Shh) mutant mice, which all exhibit cleft palate, we show that Shh is a downstream target of Fgf10/Fgfr2b signaling. Our results demonstrate that mesenchymal Fgf10 regulates the epithelial expression of Shh, which in turn signals back to the mesenchyme. This was confirmed by demonstrating that cell proliferation is decreased not only in the palatal epithelium but also in the mesenchyme of Fgfr2b–/– mice. These results reveal a new role for Fgf signaling in mammalian palate development. We show that coordinated epithelial-mesenchymal interactions are essential during the initial stages of palate development and require an Fgf-Shh signaling network.
Poly-d-lysine of high molecular weight enhances interferon induction in mice by the double-stranded complex of polyinosinic and polycytidylic acids and is superior to diethylaminoethyl-dextran in this respect.
We have compiled the DNA sequence data for E. coli available from the GENBANK and EMBL data libraries and independently from the literature. Starting with this update of our Escherichia coli database (ECD release 20) we provide major changes compared to previous issues. This update not only represents another substantial increase in sequence information, it also allows now to find the exact physical location of each individual gene or regulatory region, even regarding discrepancies in nomenclature. In order to save space this printed version does not contain the database itself anymore, but we provide several examples. The complete database is publically available in electronic form together with a self explaining application program or as a flat file. The complete compilation including a full set of genetic map data and the E. coli protein index can be obtained in machine readable form from the EMBL data library as a part of the CD-ROM issue of the EMBL sequence database, released and updated every three months. After deletion of all detected overlaps a total of 2,878,364 individual bp is found to be determined till the end of June 1994. This corresponds to a total of 60.98% of the entire E. coli chromosome consisting of about 4,720 kbp. This number may actually be higher by 9161 bp derived from other strains of E. coli.
Here we review evidence that the reactive oxygen species,
peroxide (H2O2), meets the criteria for classification
as a neuromodulator through its effects on striatal dopamine (DA)
release. This evidence was obtained using fast-scan cyclic voltammetry
to detect evoked DA release in striatal slices, along with whole-cell
and fluorescence imaging to monitor cellular activity and H2O2 generation in striatal medium spiny neurons (MSNs).
The data show that (1) exogenous H2O2 suppresses
DA release in dorsal striatum and nucleus accumbens shell and the
same effect is seen with elevation of endogenous H2O2 levels; (2) H2O2 is generated downstream
from glutamatergic AMPA receptor activation in MSNs, but not DA axons;
(3) generation of modulatory H2O2 is activity
dependent; (4) H2O2 generated in MSNs diffuses
to DA axons to cause transient DA release suppression by activating
ATP-sensitive K+ (KATP) channels on DA axons;
and (5) the amplitude of H2O2-dependent inhibition
of DA release is attenuated by enzymatic degradation of H2O2, but the subsecond time course is determined by H2O2 diffusion rate and/or KATP-channel
kinetics. In the dorsal striatum, neuromodulatory H2O2 is an intermediate in the regulation of DA release by the
classical neurotransmitters glutamate and GABA, as well as other neuromodulators,
including cannabinoids. However, modulatory actions of H2O2 occur in other regions and cell types, as well, consistent
with the widespread expression of KATP and other H2O2-sensitive channels throughout the CNS.
Brain slices; dorsal striatum; fast-scan cyclic
voltammetry; fluorescence imaging; transmitter release; review
Intracranial self-stimulation (ICSS) is an operant procedure in which responding is maintained by electrical brain stimulation. Stimulation frequency can be rapidly varied to maintain a wide range of baseline response rates, and drugs effects can be simultaneously evaluated on both low ICSS rates maintained by low stimulation frequencies and high ICSS rates maintained by high stimulation frequencies. ICSS “facilitation” denotes drug-induced increases in low ICSS rates and is often interpreted as an abuse-related effect, whereas ICSS “depression” denotes decreases in high ICSS rates and may indicate abuse-limiting effects. This study examined the roles of drug efficacy and of prior mu agonist exposure as determinants of mu agonist effects on ICSS in rats with electrodes implanted in the medial forebrain bundle. The high-, intermediate- and low-efficacy mu agonists methadone, fentanyl and nalbuphine were tested during escalating regimens of morphine exposure (Vehicle, 3.2, 18 mg/kg/day). During vehicle treatment, methadone and fentanyl primarily depressed ICSS, whereas nalbuphine produced weak facilitation that was not dose-dependent. Chronic morphine produced tolerance to ICSS depression and increased expression of ICSS facilitation. These results suggest that mu agonist exposure increases expression of abuse-related ICSS facilitation by mu agonists with a broad range of efficacies at mu receptors.
Drug abuse; Methadone; Fentanyl; Nalbuphine; Chronic morphine; Tolerance; Intracranial self-stimulation; Rat
The failure of antibiotic therapies to clear Pseudomonas aeruginosa lung infection, the key mortality factor for cystic fibrosis (CF) patients, is partly attributed to the high tolerance of P. aeruginosa biofilms. Mannitol has previously been found to restore aminoglycoside sensitivity in Escherichia coli by generating a proton-motive force (PMF), suggesting a potential new strategy to improve antibiotic therapy and reduce disease progression in CF. Here, we used the commonly prescribed aminoglycoside tobramycin to select for P. aeruginosa persister cells during biofilm growth. Incubation with mannitol (10–40 mM) increased tobramycin sensitivity of persister cells up to 1,000-fold. Addition of mannitol to pre-grown biofilms was able to revert the persister phenotype and improve the efficacy of tobramycin. This effect was blocked by the addition of a PMF inhibitor or in a P. aeruginosa mutant strain unable to metabolise mannitol. Addition of glucose and NaCl at high osmolarity also improved the efficacy of tobramycin although to a lesser extent compared to mannitol. Therefore, the primary effect of mannitol in reverting biofilm associated persister cells appears to be an active, physiological response, associated with a minor contribution of osmotic stress. Mannitol was tested against clinically relevant strains, showing that biofilms containing a subpopulation of persister cells are better killed in the presence of mannitol, but a clinical strain with a high resistance to tobramycin was not affected by mannitol. Overall, these results suggest that in addition to improvements in lung function by facilitating mucus clearance in CF, mannitol also affects antibiotic sensitivity in biofilms and does so through an active, physiological response.
In this study, combinatorial libraries were used in conjunction with ultra-high throughput sequencing to comprehensively determine the impact of each of the 19 possible amino acid substitutions at each residue position in the TEM-1β-lactamase enzyme. The libraries were introduced into E. coli and mutants were selected for ampicillin resistance. The selected colonies were pooled and subjected to ultra-high throughput sequencing to reveal the sequence preferences at each position. The depth of sequencing provided a clear, statistically significant picture of what amino acids are favored for ampicillin hydrolysis for all 263 positions of the enzyme in one experiment. Although the enzyme is generally tolerant of amino acid substitutions, several surface positions far from the active site are sensitive to substitutions suggesting a role for these residues in enzyme stability, solubility or catalysis. In addition, information on the frequency of substitutions was used to identify mutations that increase enzyme thermodynamic stability. Finally, a comparison of sequence requirements based on the mutagenesis results versus those inferred from sequence conservation in an alignment of 156 class A β-lactamases reveals significant differences in that several residues in TEM-1 do not tolerate substitutions and yet extensive variation is observed in the alignment, and vice versa. An analysis of the TEM-1 and other class A structures suggests residues that vary in the alignment may nevertheless make unique, but important, interactions within individual enzymes.
Visual information is crucial for goal-directed reaching. A number of studies have recently shown that motion in particular is an important source of information for the visuomotor system. For example, when reaching a stationary object, movement of the background can influence the trajectory of the hand, even when the background motion is irrelevant to the object and task. This manual following response may be a compensatory response to changes in body position, but the underlying mechanism remains unclear. Here we tested whether visual motion area MT+ is necessary to generate the manual following response. We found that stimulation of MT+ with transcranial magnetic stimulation significantly reduced a strong manual following response. MT+ is therefore necessary for generating the manual following response, indicating that it plays a crucial role in guiding goal-directed reaching movements by taking into account background motion in scenes.
action; localization; manual following response; perception; pointing; TMS; visuomotor
B. pseudomallei BPSL1549 has been overexpressed in E. coli, purified and crystallized.
Burkholderia pseudomallei BPSL1549, a putative protein of unknown function, has been overexpressed in Escherichia coli, purified and subsequently crystallized by the hanging-drop vapour-diffusion method using PEG as a precipitant to give crystals with overall dimensions of 0.15 × 0.15 × 0.1 mm. Native data were collected to 1.47 Å resolution at the European Synchrotron Radiation Facility (ESRF). The crystals belonged to space group P212121, with unit-cell parameters a = 37.1, b = 45.4, c = 111.9 Å and with a single polypeptide chain in the asymmetric unit.
Burkholderia pseudomallei; pathogens; BPSL1549
Summary: GWASTools is an R/Bioconductor package for quality control and analysis of genome-wide association studies (GWAS). GWASTools brings the interactive capability and extensive statistical libraries of R to GWAS. Data are stored in NetCDF format to accommodate extremely large datasets that cannot fit within R’s memory limits. The documentation includes instructions for converting data from multiple formats, including variants called from sequencing. GWASTools provides a convenient interface for linking genotypes and intensity data with sample and single nucleotide polymorphism annotation.
Availability and implementation: GWASTools is implemented in R and is available from Bioconductor (http://www.bioconductor.org). An extensive vignette detailing a recommended work flow is included.
Oxide-bridged phenylmorphans were conceptualized as topologically distinct, structurally rigid ligands with 3-dimensional shapes that could not be appreciably modified on interaction with opioid receptors. An enantiomer of the N-phenethyl-substituted ortho-f isomer was found to have high affinity for the μ-receptor (Ki = 7 nM) and was about four times more potent than naloxone as an antagonist. In order to examine the effect of introduction of a small amount of flexibility into these molecules, we have replaced the rigid 5-membered oxide ring with a more flexible 6-membered carbon ring. Synthesis of the new N-phenethyl-substituted tricyclic N-substituted-2,3,4,9,10,10a-hexahydro-1H-1,4a-(epiminoethano)phenanthren-6- and 8-ols resulted in a two carbon-bridged relative of the f-isomers, the dihydrofuran ring was replaced by a cyclohexene ring. The carbocyclic compounds had much higher affinity and greater selectivity for the μ-receptor than the f-oxide-bridged phenylmorphans. They were also much more potent μ-antagonists, with activities comparable to naltrexone in the [35S]GTPγS assay.
Synthesis; opioid receptor binding and efficacy; N-substituted-2,3,4,9,10,10a-hexahydro-1H-1,4a-(epiminoethano)phenanthren-6- and 8-ols; f-oxide-bridged phenylmorphans; opioid antagonist
With the long-term goal of developing a gene-based treatment for osteoarthritis (OA), we performed studies to evaluate the equine joint as a model for AAV-mediated gene transfer to large, weight-bearing human joints. A self-complementary AAV2 vector containing the coding regions for human interleukin-1 receptor antagonist (hIL-1Ra) or green fluorescent protein (GFP) was packaged in AAV capsid serotypes 1, 2, 5, 8 and 9. Following infection of human and equine synovial fibroblasts in culture, we found that both were only receptive to transduction with AAV1, 2 and 5. For these serotypes, however, transgene expression from the equine cells was consistently at least 10-fold higher. Analyses of AAV surface receptor molecules and intracellular trafficking of vector genomes implicate enhanced viral uptake by the equine cells. Following delivery of 1 × 1011 vector genomes of serotypes 2, 5 and 8 into the forelimb joints of the horse, all three enabled hIL-1Ra expression at biologically relevant levels and effectively transduced the same cell types, primarily synovial fibroblasts and, to a lesser degree, chondrocytes in articular cartilage. These results provide optimism that AAV vectors can be effectively adapted for gene delivery to large human joints affected by OA.
Osteoarthritis; Self-complementary Adeno-Associated Virus; Interleukin-1 Receptor Antagonist; Synovium; Cartilage; Equine
To determine if higher levels of partial pressure of arterial oxygen are associated with in-hospital mortality and poor neurologic status at hospital discharge in patients treated with mild therapeutic hypothermia after sudden cardiac arrest.
Retrospective analysis of a prospective cohort study
A total of 170 consecutive patients treated with therapeutic hypothermia in the cardiovascular care unit of an academic tertiary care hospital.
Measurements and Main Results
Of 170 patients, 77 (45.2%) survived to hospital discharge. Survivors had a significantly lower maximum partial pressure of arterial oxygen(198 mmHg, IQR 152.5–282) measured in the first 24 hours following cardiac arrest compared to nonsurvivors (254 mmHg, IQR 172–363, p = .022). A multivariable analysis including age, time to return of spontaneous circulation, the presence of shock, bystander CPR, and initial rhythm revealed that higher levels of the partial pressure of arterial oxygen were significantly associated with increased in-hospital mortality (odds ratio 1.439, 95% confidence interval 1.028–2.015, p = 0.034) and poor neurologic status at hospital discharge (odds ratio 1.485, 95% confidence interval 1.032–2.136, p = 0.033).
Higher levels of the maximum measured partial pressure of arterial oxygen are associated with increased in-hospital mortality and poor neurologic status on hospital discharge in patients treated with mild therapeutic hypothermia after sudden cardiac arrest.
therapeutic hypothermia; hyperoxia; sudden cardiac arrest; cerebral performance category; mortality; neurological outcomes
Protein acetylation is an essential mechanism in regulating transcriptional and inflammatory events. Studies have shown that nonselective histone deacetylase (HDAC) inhibitors can protect the retina from ischemic injury in rats. However, the role of specific HDAC isoforms in retinal degenerative processes remains obscure. The purpose of this study was to investigate the role of HDAC2 isoform in a mouse model of ischemic retinal injury.
Localization of HDAC2 in mice retinas was evaluated by immunohistochemical analyses. To investigate whether selective reduction in HDAC2 activity can protect the retina from ischemic injury, Hdac2+/− mice were utilized. Electroretinographic (ERG) and morphometric analyses were used to assess retinal function and morphology.
Our results demonstrated that HDAC2 is primarily localized in nuclei in inner nuclear and retinal ganglion cell layers, and HDAC2 activity accounted for approximately 35% of the total activities of HDAC1, 2, 3, and 6 in the retina. In wild-type mice, ERG a- and b-waves from ischemic eyes were significantly reduced when compared to pre-ischemia baseline values. Morphometric examination of these eyes revealed significant degeneration of inner retinal layers. In Hdac2+/− mice, ERG a- and b-waves from ischemic eyes were significantly greater than those measured in ischemic eyes from wild-type mice. Morphologic measurements demonstrated that Hdac2+/− mice exhibit significantly less retinal degeneration than wild-type mice.
This study demonstrated that suppressing HDAC2 expression can effectively reduce ischemic retinal injury. Our results support the idea that the development of selective HDAC2 inhibitors may provide an efficacious treatment for ischemic retinal injury.
This study displayed the localization of HDAC2 in the inner retina and demonstrated that HDAC2 appears to be a key isoform involved in ischemic retinal degeneration. Furthermore, suppressing HDAC2 expression can effectively reduce ischemic retinal injury.
HDAC2; ischemia; retinal degeneration; neuroprotection
Higher circulating insulin-like growth factor I (IGF-1) levels have been associated with higher mammographic density among women in some, but not all studies. Also, few studies have examined the association between mammographic density and circulating growth hormone (GH) in premenopausal women. We conducted a cross-sectional study among 783 premenopausal women and 436 postmenopausal women who were controls in breast cancer case–control studies nested in the Nurses' Health Study (NHS) and NHSII. Participants provided blood samples in 1989–1990 (NHS) or in 1996–1999 (NHSII), and mammograms were obtained near the time of blood draw. Generalized linear models were used to assess the associations of IGF-1, IGF-binding protein-3 (IGFBP-3), IGF-1:IGFBP-3 ratio, and GH with percent mammographic density, total dense area, and total non-dense area. Models were adjusted for potential confounders including age and body mass index (BMI), among others. We also assessed whether the associations varied by age or BMI. In both pre- and postmenopausal women, percent mammographic density was not associated with plasma levels of IGF-1, IG-FBP-3, or the IGF-1:IGFBP-3 ratio. In addition, GH was not associated with percent density among premenopausal women in the NHSII. Similarly, total dense area and non-dense area were not significantly associated with any of these analytes. In postmenopausal women, IGF-1 was associated with higher percent mammographic density among women with BMI <25 kg/m2, but not among overweight/obese women. Overall, plasma IGF-1, IGFBP-3, and GH levels were not associated with mammographic density in a sample of premenopausal and postmenopausal women.
Insulin-like growth factor 1; Insulin-like growth factor-binding protein-3; Mammographic density; Breast cancer
The recent identification of nonprimate hepaciviruses in dogs and then in horses prompted us to look for pegiviruses (GB virus-like viruses) in these species. Although none were detected in canines, we found widespread natural infection of horses by a novel pegivirus. Unique genomic features and phylogenetic analyses confirmed that the tentatively named equine pegivirus (EPgV) represents a novel species within the Pegivirus genus. We also determined that EPgV causes persistent viremia whereas its clinical significance is undetermined.