Public health responses to HIV epidemics have long relied on epidemiological modelling analyses to help prospectively project and retrospectively estimate the impact, cost-effectiveness, affordability, and investment returns of interventions, and to help plan the design of evaluations. But translating model output into policy decisions and implementation on the ground is challenged by the differences in background and expectations of modellers and decision-makers. As part of the PLoS Medicine Collection “Investigating the Impact of Treatment on New HIV Infections”—which focuses on the contribution of modelling to current issues in HIV prevention—we present here principles of “best practice” for the construction, reporting, and interpretation of HIV epidemiological models for public health decision-making on all aspects of HIV. Aimed at both those who conduct modelling research and those who use modelling results, we hope that the principles described here will become a shared resource that facilitates constructive discussions about the policy implications that emerge from HIV epidemiology modelling results, and that promotes joint understanding between modellers and decision-makers about when modelling is useful as a tool in quantifying HIV epidemiological outcomes and improving prevention programming.
While the enhanced permeability and retention effect may promote the preferential accumulation of nanoparticles into well-vascularized primary tumors, it is ineffective in the case of metastases hidden within a large population of normal cells. Due to their small size, high dispersion to organs, and low vascularization, metastatic tumors are less accessible to targeted nanoparticles. To tackle these challenges, we designed a nanoparticle for vascular targeting based on an αvβ3 integrin-targeted nanochain particle composed of four iron oxide nanospheres chemically linked in a linear assembly. The chain-shaped nanoparticles enabled enhanced ‘sensing’ of the tumor-associated remodeling of the vascular bed offering increased likelihood of specific recognition of metastatic tumors. Compared to spherical nanoparticles, the chain-shaped nanoparticles resulted in superior targeting of αvβ3 integrin due to geometrically enhanced multivalent docking. We performed multimodal in vivo imaging (Fluorescence Molecular Tomography and Magnetic Resonance Imaging) in a non-invasive and quantitative manner, which showed that the nanoparticles targeted metastases in the liver and lungs with high specificity in a highly aggressive breast tumor model in mice.
Iron oxide nanoparticle; nanochain; metastasis; integrin targeting; magnetic resonance imaging
We describe an automated computerized scheme to identify pulmonary fissures depicted in chest computed tomography (CT) examinations from a novel perspective. Whereas CT images can be regarded as a cloud of points, the underlying idea is to search for surface-like structures in the three dimensional (3D) Euclidean space by using an efficient plane fitting algorithm. The proposed plane fitting operation is performed in a number of small spherical lung sub-volumes to detect small planar patches. Using a simple clustering criterion based on their spatial coherence and surface area, the identified planar patches, assumed to represent fissures, are classified into different types of fissures, namely left oblique, right oblique and right horizontal fissures. The performance of the developed scheme was assessed by comparing with a manually created “reference standard” and the results obtained by a previously developed approach on a dataset of 30 lung CT examinations. The experiments show that the average discrepancy is around 1.0 mm in comparison with the reference standard, while the corresponding maximum discrepancy is 20.5 mm. In addition, 94% of the fissure voxels identified by the computerized scheme are within 3 mm of the fissures in the reference standard. As compared to a previously developed approach, we also found that the newly developed scheme had a smaller discrepancy with the standard reference. In efficiency, it takes approximately 8 minutes to identify the fissures in a chest CT examination on a typical PC. The developed scheme demonstrates a reasonable performance in terms of accuracy, robustness, and computational efficiency.
pulmonary fissure; segmentation; surface detection; plane fitting; clustering
In sexual conflict, aggressive males frequently diminish the long-term reproductive success of females in efforts to gain a short-term advantage over rival males. This short-term advantage can selectively favour high-exploitation males. However, just as the over-exploitation of resources can lead to local extinction, the over-exploitation of females in the form of harassment by aggressive males can yield similar consequences resulting in reduced female fecundity, increased female mortality and overall decline in mating activity. This outcome may often be prevented by selection acting at multiple levels of biological organization. Directional selection favouring aggressive exploitation within groups can be balanced by directional selection amongst groups opposing exploitation. Such between-group selection has recently been demonstrated in laboratory studies of water striders, where the conditional dispersal of individuals increased variation amongst groups and influenced the balance of selection toward reduced male aggression. This multilevel selection (MLS) framework also provides predictive value when investigating natural populations differing in their relative strength of selection within versus among groups. For water striders, the consequences of local exploitation cause fitness differences between groups, favouring less aggressive males. Inconsistently flowing ephemeral streams consist of isolated pools that prevent aggressive male water striders from escaping the consequences of local exploitation. We, therefore, predicted that inconsistently flowing ephemeral streams would favour the evolution of less aggressive males than would perennial streams, which allow aggressive males to move more freely and to escape the group-level costs of their aggression. Comparing two neighbouring streams during the mating season, we found that males dispersed naturally between pools at much higher rates in the perennial stream than in the ephemeral stream. As predicted, we found that males from the perennial stream were significantly more aggressive than those from the ephemeral stream. We also found that dispersers were significantly more aggressive than non-dispersers within each stream. These field results illustrate the relevance of the MLS framework in our understanding of the evolution of sexual conflict.
multilevel selection; group selection; tragedy of the commons; water strider; sexual conflict; altruism; Aquarius remigis
This study aims to describe the trends in and determinants of six month mortality and loss to follow up (LTFU) during 2005–2009 in 13 outpatient clinics in Vietnam.
Data were obtained from clinical records of 3,449 Vietnamese HIV/AIDS patients aged 18 years or older who initiated ART between 1 January 2005 and 31 December 2009. Mantel-Haenszel chi-square test, log rank test were conducted to examine the trends of baseline characteristics, six month mortality and LTFU. Cox proportional hazards regression models were performed to compute hazard ratio (HR) and 95% Confidence Interval (CI).
Though there was a declining trend, the incidence of six month mortality and LTFU remained as high as 6% and 15%, respectively. Characteristics associated with six month mortality were gender (HR females versus males 0.54, 95%CI: 0.34–0.85), years of initiation (HR 2009 versus 2005 0.54, 95%CI: 0.41–0.80), low baseline CD4 (HR 350–500 cells/mm3 versus <50 cells/mm3 0.26, 95%CI: 0.18–0.52), low baseline BMI (one unit increase: HR 0.96, 95%CI: 0.94–0.97), co-infection with TB (HR 1.61, 95%CI: 1.46–1.95), history of injecting drugs (HR 1.58, 95%CI: 1.31–1.78). Characteristics associated with LTFU were younger age (one year younger: HR 0.97, 95%CI: 0.95–0.98), males (HR females versus males 0.82, 95%CI: 0.63–0.95), and poor adherence (HR 0.55, 95%CI: 0.13–0.87).
To reduce early mortality, special attention is required to ensure timely access to ART services, particularly for patients at higher risk. Patients at risk for LTFU after ART initiation should be targeted through enhancing treatment counselling and improving patient tracing system at ART clinics.
Migration is a fundamental trait in humans and animals. Recent studies investigated the effect of migration on the evolution of cooperation, showing that contingent migration favors cooperation in spatial structures. In those studies, only local migration to immediate neighbors was considered, while long-range migration has not been considered yet, partly because the long-range migration has been generally regarded as harmful for cooperation as it would bring the population to a well-mixed state that favors defection. Here, we studied the effects of adaptive long-range migration on the evolution of cooperation through agent-based simulations of a spatial Prisoner's Dilemma game where individuals can jump to a farther site if they are surrounded by more defectors. Our results show that adaptive long-range migration strongly promotes cooperation, especially under conditions where the temptation to defect is considerably high. These findings demonstrate the significance of adaptive long-range migration for the evolution of cooperation.
Combination antiretroviral therapy (cART) has greatly improved the life expectancy of people living with HIV (PLHIV). Our study aims to project the life expectancy of PLHIV in a resource-rich setting in the context of the currently available antiretroviral treatments.
Patient antiretroviral treatment data were sourced from an observational cohort of 3,434 predominantly male (94.2%) PLHIV in Australia over the period 1997–2010. These data were analysed in a computer simulation model to calculate the distribution of time until exhaustion of all treatment options and expected effect on mortality. Standardised mortality ratios were used to simulate expected survival before and after treatment exhaustion.
We estimated that the median time until exhaustion of currently available treatment options is 45.5 years (IQR 34.0–61.0 years). However, 10% of PLHIV are expected to exhaust all currently available cART options after just 25.6 years. PLHIV who start currently available cART regimens at age 20 years are expected to live to a median age of 67.4 (IQR 53.2–77.7) years. This is a substantial improvement on no cART (27.7 [IQR 23.8–32.0] years) but is still substantially less than the median general population mortality age (82.2 [IQR 74.0–87.8] years). The life expectancy gap between PLHIV and the general population is greatest for those infected at younger ages.
As treatment options are exhausted, a substantial difference in life expectancy between PLHIV and the general population could be expected even in resource-rich settings, particularly for people who acquire HIV at a younger age or who are currently highly treatment experienced.
antiretroviral therapy; HIV; life expectancy; survival
We report the imaging of β-cyclodextrin/benzoic acid binding at 14T using hyperpolarized 13C magnetic resonance (MR). Benzoic acid was polarized using a dynamic nuclear polarization (DNP) approach and combined with β-cyclodextrin in aqueous solution. As anticipated, decreases in the spin-lattice relaxation constant (T1) were observed with decreases in the ligand/ receptor ratio. The calculated log K was approximately 1.7, similar to previously reported binding constants. Hyperpolarized [1-13C] benzoic acid was used to interrogate solutions of variable β-cyclodextrin concentration, with the mixtures imaged at 14T using a 3D frequency-selective MR sequence. Differences in β-cyclodextrin concentration were easily visualized. These results suggest that hyperpolarized 13C MR could be used in vivo to determine the presence, and density of receptors for a given ligand-receptor pair.
This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk).
Prospective, multicenter study.
459 patients with posterior uveal melanoma were enrolled from 12 independent centers.
Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP to the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and to chromosome 3 status.
Main Outcome Measures
Patients were managed for their primary tumor and monitored for metastasis.
The GEP assay successfully classified 446/459 (97.2%) cases. The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 (1.1%) class 1 cases and 44 (25.9%) class 2 cases (log rank test, P<10−14). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54/260 (20.8%) tumors were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log rank test, P=0.0001). Using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P=0.2). At three years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P=0.001) and 0.38 (P=0.004) over chromosome 3 status.
The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.
Unless repaired, DNA damage can drive mutagenesis or cell death. DNA repair proteins may therefore be used as biomarkers in disease etiology or therapeutic response prediction. Thus, the accurate determination of DNA repair protein expression and genotype is of fundamental importance. Among DNA repair proteins involved in base excision repair, apurinic/apyrimidinic endonuclease 1 (APE1) is the major endonuclease in mammals and plays important roles in transcriptional regulation and modulating stress responses. Here, we present a novel approach involving LC-MS/MS with isotope-dilution to positively identify and accurately quantify APE1 in human cells and mouse tissue. A completely 15N-labeled full-length human APE1 was produced and used as an internal standard. Fourteen tryptic peptides of both human APE1 (hAPE1) and 15N-labeled hAPE1 were identified following trypsin digestion. These peptides matched the theoretical peptides expected from trypsin digestion and provided a statistically significant protein score that would unequivocally identify hAPE1. Using the developed methodology, APE1 was positively identified and quantified in nuclear and cytoplasmic extracts of multiple human cell lines and mouse liver using selected-reaction monitoring of typical mass transitions of the tryptic peptides. We also show that the methodology can be applied to the identification of hAPE1 variants found in the human population. The results describe a novel approach for the accurate measurement of wild-type and variant forms of hAPE1 in vivo, and ultimately for defining the role of this protein in disease development and treatment responses.
The outflow tract myocardium and other regions corresponding to the location of the major coronary vessels of the developing chicken heart, display a high level of hypoxia as assessed by the hypoxia indicator EF5. The EF5 positive tissues were also specifically positive for nuclear-localized hypoxia inducible factor-1 alpha (HIF-1α), the oxygen-sensitive component of the hypoxia inducible factor-1 (HIF-1) heterodimer. This led to our hypothesis that there is a “template” of hypoxic tissue that determines the stereotyped pattern of the major coronary vessels. In this study we disturbed this template by altering ambient oxygen levels (hypoxia 15%; hyperoxia 75-40%) during the early phases of avian coronary vessel development, in order to alter tissue hypoxia, HIF-1α protein expression and its downstream target genes without high mortality. We also altered HIF-1α gene expression in the embryonic outflow tract cardiomyocytes by injecting an adenovirus containing a constitutively active form of HIF-1α (AdCA5). We assayed for coronary anomalies using anti-alpha-smooth muscle actin immunohistology. When incubated under abnormal oxygen levels or injected with a low titer of the AdCA5, coronary arteries displayed deviations from their normal proximal connections to the aorta. These deviations were similar to known clinical anomalies of coronary arteries. These findings indicated that developing coronary vessels may be subject to a level of regulation that is dependent on differential oxygen levels within cardiac tissues and subsequent HIF-1 regulation of gene expression.
Methadone maintenance treatment (MMT) has been scaled up by the Chinese government alongside persistent compulsory drug user detention, but the extent to which detention interferes with MMT is unknown. The study systematically reviews Chinese MMT retention rates, reasons for drop out, and behavioural changes.
Chinese and English databases of literature are searched for studies reporting retention rates, drug use and sexual behaviours among MMT participants in China between 2004 and 2013. The estimates are summarized through a systematic review and meta-analysis.
A total of 74 studies representing 43,263 individuals are included in this analysis. About a third of MMT participants drop out during the first three months of treatment (retention rate 69.0% (95% CI 57.7-78.4%)). Police arrest and detention in compulsory rehabilitation was the most common cause of drop out, accounting for 22.2% of all those not retained. Among retained participants, changing unsafe drug use behaviours was more effective than changing unsafe sexual behaviours. At 12 months following MMT initiation, 24.6% (15.7-33.5%) of MMT participants had a positive urine test, 9.3% (4.7-17.8%) injected drugs and only 1.1% (0.4-3.0%) sold sex for drugs. These correspond to 0.002 (<0.001-0.011), 0.045 (0.004-0.114) and 0.209 (0.076-0.580) times lower odds than baseline. However, MMT participants did not have substantial changes in condom use rates.
MMT is effective in drug users in China but participant retention is poor, substantially related to compulsory detention. Reforming the compulsory drug user detention system may improve MMT retention and effectiveness.
HIV prevalence is low in the Middle East and North Africa (MENA) region, though the risk or potential for further spread in the future is not well understood. Behavioral surveys are limited in this region and when available have serious limitations in assessing the risk of HIV acquisition. We demonstrate the potential use of herpes simplex virus-2 (HSV-2) seroprevalence as a marker for HIV risk within MENA.
We designed a mathematical model to assess whether HSV-2 prevalence can be predictive of future HIV spread. We also conducted a systematic literature review of HSV-2 seroprevalence studies within MENA.
We found that HSV-2 prevalence data are rather limited in this region. Prevalence is typically low among the general population but high in established core groups prone to sexually transmitted infections such as men who have sex with men and female sex workers. Our model predicts that if HSV-2 prevalence is low and stable, then the risk of future HIV epidemics is low. However, expanding or high HSV-2 prevalence (greater than about 20%), implies a risk for a considerable HIV epidemic. Based on available HSV-2 prevalence data, it is not likely that the general population in MENA is experiencing or will experience such a considerable HIV epidemic. Nevertheless, the risk for concentrated HIV epidemics among several high-risk core groups is high.
HSV-2 prevalence surveys provide a useful mechanism for identifying and corroborating populations at risk for HIV within MENA. HSV-2 serology offers an effective tool for probing hidden risk behaviors in a region where quality behavioral data are limited.
Sexually transmitted infections; genital herpes; epidemiology; mathematical modeling; review; Middle East and North Africa
We reviewed the epidemiology of HIV and selected sexually transmitted infections (STIs) among female sex workers (FSWs) in WHO-defined Europe. There were three objectives: (1) to assess the prevalence of HIV and STIs (chlamydia, syphilis and gonorrhoea); (2) to describe structural and individual-level risk factors associated with prevalence and (3) to examine the relationship between structural-level factors and national estimates of HIV prevalence among FSWs.
A systematic search of published and unpublished literature measuring HIV/STIs and risk factors among FSWs, identified through electronic databases published since 2005. ‘Best’ estimates of HIV prevalence were calculated from the systematic review to provide national level estimates of HIV. Associations between HIV prevalence and selected structural-level indicators were assessed using linear regression models.
Of the 1993 papers identified in the search, 73 peer-reviewed and grey literature documents were identified as meeting our criteria of which 63 papers provided unique estimates of HIV and STI prevalence and nine reported multivariate risk factors for HIV/STI among FSWs.
HIV in Europe remains low among FSWs who do not inject drugs (<1%), but STIs are high, particularly syphilis in the East and gonorrhoea. FSWs experience high levels of violence and structural risk factors associated with HIV, including lack of access to services and working on the street. Linear regression models showed HIV among FSWs to link with injecting drug use and imprisonment.
Findings show that HIV prevention interventions should be nested inside strategies that address the social welfare of sex workers, highlighting in turn the need to target the social determinants of health and inequality, including regarding access to services, experience of violence and migration. Future epidemiological and intervention studies of HIV among vulnerable populations need to better systematically delineate how microenvironmental and macroenvironmental factors combine to increase or reduce HIV/STI risk.
To determine if plasma levels of follistatin-like protein 1 (FSTL-1), a pro-inflammatory protein produced by mesenchymal tissue, including cardiac myocytes, correlate with the development of Kawasaki disease (KD) and coronary artery aneurysms (CAA).
FSTL-1 plasma levels were measured serially by ELISA in 48 patients with KD at time of diagnosis and, when available, 2 weeks, 6 weeks and 6 months following onset of disease. These were compared with 23 controls. Data were analyzed using Generalized Estimating Equations.
Plasma FSTL-1 levels were elevated in patients with acute KD as compared with controls (p=0.0086). FSTL-1 levels remained significantly elevated at 2 weeks after disease onset but returned to control levels by 6 months. Seven patients with CAA had significantly higher FSTL-1 levels at the time of diagnosis than those who did not develop aneurysms (p=0.0018). Sensitivity and specificity for CAA at a specific FSTL-1 cutpoint (178ng/ml) was 85% and 71%.
Plasma levels of FSTL-1 are elevated in acute KD and may predict cardiac morbidity in this disease. These results suggest a possible role for FSTL-1 in the formation of coronary artery aneurysms.
The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR), which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0) of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1) or induce parasite clearance (PRR >1) with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally) in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a feasible task.
Optimal phototransduction requires separation of the avascular photoreceptor layer from the adjacent vascularized inner retina and choroid. Breakdown of peri-photoreceptor vascular demarcation leads to retinal angiomatous proliferation or choroidal neovascularization, two variants of vascular invasion of the photoreceptor layer in age-related macular degeneration (AMD), the leading cause of irreversible blindness in industrialized nations. Here we show that sFLT-1, an endogenous inhibitor of vascular endothelial growth factor A (VEGF-A), is synthesized by photoreceptors and retinal pigment epithelium (RPE), and is decreased in human AMD. Suppression of sFLT-1 by antibodies, adeno-associated virus-mediated RNA interference, or Cre/lox-mediated gene ablation either in the photoreceptor layer or RPE frees VEGF-A and abolishes photoreceptor avascularity. These findings help explain the vascular zoning of the retina, which is critical for vision, and advance two transgenic murine models of AMD with spontaneous vascular invasion early in life.
The inner surface of the vertebrate eye is lined with a multilayered structure known as the retina. The bottom layer of the retina is composed of rods and cones—neurons that are directly sensitive to light—and is called the photoreceptor layer. Rods function primarily in dim light and provide black-and-white vision, while cones support daytime vision and are responsible for colour perception. Unlike the upper layers of the retina, the photoreceptor layer does not contain blood vessels: oxygen and nutrients are instead provided by a structure just underneath the retina called the choroid.
The eye relies on the rods and cones converting light into electrical signals, and the photoreceptor layer must remain free of blood vessels for this process to work properly. If blood vessels extend into the photoreceptor layer from rest of the retina (which is above it) or the choroid (below), they can disrupt the retina and give rise to a condition called age-related macular degeneration, which is a leading cause of irreversible blindness in adults.
Within the eye, the development of new blood vessels from pre-existing vessels is stimulated by a protein known as vascular endothelial growth factor A (VEGF-A), while an inhibitor protein called sFLT-1 prevents the growth of new blood vessels in the other tissues of the eye like the cornea. However, it has not been clear what keeps the photoreceptor layer (and also the cells that support the photoreceptor layer) free of blood vessels, and what happens to disrupt this process of vascular demarcation in age-related macular degeneration.
Now, Luo et al. reveal that cells in the photoreceptor layer produce sFLT-1, and that the levels of this protein are indeed reduced in people with age-related macular degeneration. Using genetic and pharmacological methods, they show that a reduction in sFLT-1 triggers blood vessels to grow into the photoreceptor layer from above or below. Luo et al. also report two new genetic mouse models in which blood vessels form spontaneously in the photoreceptor layer at an early age, which should prove useful for further research into age-related macular degeneration.
age-related macular degeneration; photoreceptor metabolism; retinal vasculature; soluble VEGF receptor-1; vascular demarcation; transgenic model; Human; Mouse
Apurinic/apyrimidinic endonuclease 1 (APE1) is the predominant AP site repair enzyme in mammals. APE1 also maintains 3′–5′ exonuclease and 3′-repair activities, and regulates transcription factor DNA binding through its REF-1 function. Since complete or severe APE1 deficiency leads to embryonic lethality and cell death, it has been hypothesized that APE1 protein variants with slightly impaired function will contribute to disease etiology. Our data indicate that except for the endometrial cancer-associated APE1 variant R237C, the polymorphic variants Q51H, I64V and D148E, the rare population variants G241R, P311S and A317V, and the tumor-associated variant P112L exhibit normal thermodynamic stability of protein folding; abasic endonuclease, 3′–5′ exonuclease and REF-1 activities; coordination during the early steps of base excision repair; and intracellular distribution when expressed exogenously in HeLa cells. The R237C mutant displayed reduced AP-DNA complex stability, 3′–5′ exonuclease activity and 3′-damage processing. Re-sequencing of the exonic regions of APE1 uncovered no novel amino acid substitutions in the 60 cancer cell lines of the NCI-60 panel, or in HeLa or T98G cancer cell lines; only the common D148E and Q51H variants were observed. Our results indicate that APE1 missense mutations are seemingly rare and that the cancer-associated R237C variant may represent a reduced-function susceptibility allele.
To investigated the effect of Granulocyte-colony stimulating factor (G-CSF) on expression of proteins that regulate apoptosis in newborn piglet brain following cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA).
The newborn piglets were assigned to three groups: 1/DHCA (30 min of DHCA, 1hr of low-flow CPB), 2/DHCA with prior injection of G-CSF (17µg/kg 2hrs before CPB) and 3/sham-operated. After 2hrs of post-bypass recovery the frontal cortex, striatum and hippocampus were dissected. The expression of proteins was measured by gel electrophoresis or protein arrays. Data are presented in arbitrary units. Statistical analysis was performed using one way ANOVA. p<0.05 was considered significant.
In the frontal cortex, only Fas-L expression was significantly lower in G-CSF group when compared with DHCA group. In the hippocampus, G-CSF increased Bcl-2 (54.3±6.4 vs. 32.3±2.2, p=0.001) and pAkt (141.4±19 vs. 95.9±21.1, p=0.047) when compared to DHCA group. Caspase-3, Bax, Fas, Fas-L, DR6 and pJAK2 levels were unchanged. The Bcl-2/Bax ratio was 0.33 for DHCA and 0.93 for G-CSF groups (p=0.02). In the striatum, when compared to DHCA group, G-CSF group had higher levels of Bcl-2 (50.3±7.4 vs. 31.8±3.8, p=0.01), pAkt (132.7±12.3 vs. 14±1.34, p=2.3×106), pJAK2 (126±17.4 vs.77.9±13.6, p=0.011), and lower Caspase-3 (12.8±5.0 vs. 32.2±11.5, p=0.033), Fas (390±31 vs. 581±74, p=0.038), Fas-L (20.5±11.5 vs. 57.8±15.6, p=0.04) and DR6 (57.4± 4.4 vs. 108.8±13.4, p=0.007). The Bcl-2/Bax ratio was 0.25 for DHCA and 0.44 for G-CSF groups (p=0.046).
In the piglet model of hypoxic brain injury, G-CSF decreases pro-apoptotic signaling, particularly in the striatum.
G-CSF; DHCA; apoptosis; newborn brain
Multiple different surgical techniques have previously been described to address long head of the biceps tendinopathy. Subpectoral biceps tenodesis has proven to be an effective procedure to relieve pain and maintain function. We describe a surgical technique for subpectoral biceps tenodesis using a single double-loaded suture anchor implant. Advantages of this procedure include the ease of implant placement and the freedom this technique affords to perform the anchor placement without direct visualization of the docking site.
Activation-induced deaminase (AID) initiates diversity of immunoglobulin genes through deamination of cytosine to uracil. Two opposing models have been proposed for the deamination of DNA or RNA by AID. Although most data support DNA deamination, there is no physical evidence of uracil residues in immunoglobulin genes. Here we demonstrate their presence by determining the sensitivity of DNA to digestion with uracil DNA glycosylase (UNG) and abasic endonuclease. Using several methods of detection, we identified uracil residues in the variable and switch regions. Uracil residues were generated within 24 h of B cell stimulation, were present on both DNA strands and were found to replace mainly cytosine bases. Our data provide direct evidence for the model that AID functions by deaminating cytosine residues in DNA.
Decomposition of water and fat in Magnetic Resonance Imaging (MRI) is important for biomedical research and clinical applications. In this paper, we propose a two-phased approach for the three-point water-fat decomposition problem. Our contribution consists of two components: (1) a background-masked Markov Random Field (MRF) energy model to formulate the local smoothness of field inhomogeneity; (2) a new Iterated Conditional Modes (ICM) algorithm accounting for high-performance optimization of the MRF energy model. The MRF energy model is integrated with background masking to prevent error propagation of background estimates as well as improve efficiency. The central component of our new ICM algorithm is the Stability Tracking (ST) mechanism intended to dynamically track iterative stability on pixels so that computation per iteration is performed only on instable pixels. The ST mechanism significantly improves the efficiency of ICM. We also develop a median-based initialization algorithm to provide good initial guesses for ICM iterations, and an adaptive gradient-based scheme for parametric configuration of the MRF model. We evaluate the robust of our approach with high-resolution mouse datasets acquired from 7-Tesla MRI.
Background masking; field inhomogeneity; MRF; iterated conditional modes(ICM); magnetic resonance imaging(MRI); Markov random field(MRF); median value initialization; stability tracking; water/fat
Needle-syringe exchange programs (NSPs) have been substantially rolled-out in China since 2002. Limited studies reported effectiveness of NSPs in a Chinese setting. This study aimed to assess the association between accessibility to NSPs and drug-use risk behaviors of IDUs by investigating primary (self-reported) data of IDUs recruited from NSP sites, community settings and mandatory detoxification centers (MDCs) in Hunan province, China.
A cross-sectional survey was conducted in Hunan province in 2010. IDU recruits participated in a face-to-face interview to provide information related to their ability to access NSPs, demographic characteristics, and injecting behaviors in the past 30 days.
Of the total 402 participants, 35%, 14% and 51% participants indicated low, medium and high ability to access NSPs in the past 30 days, respectively. A significantly higher proportion of IDUs (77.3%) from the high-access group reported ≤2 injecting episodes per day compared with medium- (46.3%) and low-access (58.8%) groups. Only 29.0% of high-access IDUs re-used syringes before disposal in the past 30 days, significantly lower than those in the medium- (43.1%) and low-access (41.3%) groups. Reported levels of needle/syringe sharing decreased significantly as the ability to access NSPs increased (16.3%, 12.7% and 2.5% in the low, medium and high access groups, respectively). Ninety percent of IDUs recruited from MDCs had low ability to access NSPs.
Increased NSP accessibility is associated with decreased levels of injecting frequency, repetitive use and sharing of injecting equipment among Chinese IDUs. Mandatory detention of IDUs remains as a major barrier for IDUs to access NSPs in China.
Human illness due to Camplyobacter jejuni infection is closely associated with consumption of poultry products. We previously demonstrated a 50 % shift in allele frequency (phase variation) in contingency gene Cj1139 (wlaN) during passage of C. jejuni NCTC11168 populations through Ross 308 broiler chickens. We hypothesized that phase variation in contingency genes during chicken passage could promote subsequent colonization and disease in humans. To test this hypothesis, we passaged C. jejuni strains NCTC11168, 33292, 81-176, KanR4 and CamR2 through broiler chickens and analysed the ability of passaged and non-passaged populations to colonize C57BL6 IL-10-deficient mice, our model for human colonization and disease. We utilized fragment analysis and nucleotide sequence analysis to measure phase variation in contingency genes. Passage through the chicken reservoir promoted phase variation in five specific contingency genes, and these ‘successful’ populations colonized mice. When phase variation did not occur in these same five contingency genes during chicken passage, these ‘unsuccessful’ populations failed to colonize mice. Phase variation during chicken passage generated small insertions or deletions (indels) in the homopolymeric tract (HT) in contingency genes. Single-colony isolates of C. jejuni strain KanR4 carrying an allele of contingency gene Cj0170 with a10G HT colonized mice at high frequency and caused disease symptoms, whereas single-colony isolates carrying the 9G allele failed to colonize mice. Supporting results were observed for the successful 9G allele of Cj0045 in strain 33292. These data suggest that phase variation in Cj0170 and Cj0045 is strongly associated with mouse colonization and disease, and that the chicken reservoir can play an active role in natural selection, phase variation and disease.