Cirrhosis is the primary risk factor for the development of hepatocellular carcinoma (HCC), yet the mechanisms by which cirrhosis predisposes to carcinogenesis are poorly understood. Using a mouse model that recapitulates many aspects of the pathophysiology of human liver disease, we explored the mechanisms by which changes in the liver microenvironment induce dysplasia and HCC. Hepatic expression of platelet-derived growth factor-c (PDGF-C) induces progressive fibrosis, chronic inflammation, neoangiogenesis, and sinusoidal congestion, as well as global changes in gene expression. Using reporter mice, immunofluorescence, immunohistochemistry and liver cell isolation, we demonstrate that receptors for PDGF-CC are localized on hepatic stellate cells (HSCs), which proliferate, and transform into myofibroblast-like cells that deposit extracellular matrix (ECM) and lead to production of growth factors and cytokines. We demonstrate induction of cytokines genes at two months, and stromal cell-derived hepatocyte growth factors that coincide with the onset of dysplasia at four months. Our results support a paracrine signaling model wherein hepatocyte-derived PDGF-C stimulates widespread HSC activation throughout the liver leading to chronic inflammation, liver injury, and architectural changes. These complex changes to the liver microenvironment precede the development of HCC. Further, increased PDGF-CC levels were observed in livers of patients with non-alcoholic fatty steatohepatitis (NASH) and correlate with the stage of disease, suggesting a role for this growth factor in chronic liver disease in humans. PDGF-C transgenic mice provide a unique model for the in vivo study of tumor-stromal interactions in the liver.
PDGF; hepatocellular carcinoma; stromal cell; microenvironment
Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10-7) in SOX2OT and rs17030795 (P=5.84×10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10-6) between CUL3 and FAM124B and rs1886797 (P=8.05×10-6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4×10-6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
anorexia nervosa; eating disorders; GWAS; genome-wide association study; body mass index; metabolic
Adherence to prevention, care, and treatment recommendations among people living with HIV (PLHIV) is a critical challenge. Yet good clinical outcomes depend on consistent, high adherence to antiretroviral therapy (ART) regimens. Mobile phones offer a promising means to improve patient adherence and health outcomes. However, limited information exists on the impact that mobile phones for health (mHealth) programs have on ART adherence or the behavior change processes through which such interventions may improve patient health, particularly among ongoing clients enrolled in large public sector HIV service delivery programs and key populations such as men who have sex with men (MSM) and female sex workers (FSW).
Our aim is to evaluate an mHealth intervention where text message reminders are used as supportive tools for health providers and as motivators and reminders for ART clients to adhere to treatment and remain linked to care in Ghana. Using an implementation science framework, we seek to: (1) evaluate mHealth intervention effects on patient adherence and health outcomes, (2) examine the delivery of the mHealth intervention for improving HIV care and treatment, and (3) assess the cost-effectiveness of the mHealth intervention.
The 36-month study will use a facility cluster randomized controlled design (intervention vs standard of care) for evaluating the impact of mHealth on HIV care and treatment. Specifically, we will look at ART adherence, HIV viral load, retention in care, and condom use at 6 and 12-month follow-up. In addition, participant adoption and satisfaction with the program will be measured. This robust methodology will be complemented by qualitative interviews to obtain feedback on the motivational qualities of the program and benefits and challenges of delivery, especially for key populations. Cost-effectiveness will be assessed using incremental cost-effectiveness ratios, with health effects expressed in terms of viral load suppression and costs of resources used for the intervention.
This study and protocol was fully funded, but it was terminated prior to review from ethics boards and study implementation.
This cluster-RCT would have provided insights into the health effects, motivational qualities, and cost-effectiveness of mHealth interventions for PLHIV in public sector settings. We are seeking funding from alternate sources to implement the trial.
implementation science; mobile phones; mHealth; HIV; AIDS; HIV care and treatment; cluster-RCT; Ghana
Objective. To investigate the effects of sitting Tai Chi on muscle strength, balance control, and quality of life (QOL) among survivors with spinal cord injuries (SCI). Methods. Eleven SCI survivors participated in the sitting Tai Chi training (90 minutes/session, 2 times/week for 12 weeks) and eight SCI survivors acted as controls. Dynamic sitting balance was evaluated using limits of stability test and a sequential weight shifting test in sitting. Handgrip strength was also tested using a hand-held dynamometer. QOL was measured using the World Health Organization's Quality of Life Scale. Results. Tai Chi practitioners achieved significant improvements in their reaction time (P = 0.042); maximum excursion (P = 0.016); and directional control (P = 0.025) in the limits of stability test after training. In the sequential weight shifting test, they significantly improved their total time to sequentially hit the 12 targets (P = 0.035). Significant improvement in handgrip strength was also found among the Tai Chi practitioners (P = 0.049). However, no significant within and between-group differences were found in the QOL outcomes (P > 0.05). Conclusions. Twelve weeks of sitting Tai Chi training could improve the dynamic sitting balance and handgrip strength, but not QOL, of the SCI survivors.
Motility is a fundamental part of cellular life and survival, including for Plasmodium parasites – single‐celled protozoan pathogens responsible for human malaria. The motile life cycle forms achieve motility, called gliding, via the activity of an internal actomyosin motor. Although gliding is based on the well‐studied system of actin and myosin, its core biomechanics are not completely understood. Currently accepted models suggest it results from a specifically organized cellular motor that produces a rearward directional force. When linked to surface‐bound adhesins, this force is passaged to the cell posterior, propelling the parasite forwards. Gliding motility is observed in all three life cycle stages of Plasmodium: sporozoites, merozoites and ookinetes. However, it is only the ookinetes – formed inside the midgut of infected mosquitoes – that display continuous gliding without the necessity of host cell entry. This makes them ideal candidates for invasion‐free biomechanical analysis. Here we apply a plate‐based imaging approach to study ookinete motion in three‐dimensional (3D) space to understand Plasmodium cell motility and how movement facilitates midgut colonization. Using single‐cell tracking and numerical analysis of parasite motion in 3D, our analysis demonstrates that ookinetes move with a conserved left‐handed helical trajectory. Investigation of cell morphology suggests this trajectory may be based on the ookinete subpellicular cytoskeleton, with complementary whole and subcellular electron microscopy showing that, like their motion paths, ookinetes share a conserved left‐handed corkscrew shape and underlying twisted microtubular architecture. Through comparisons of 3D movement between wild‐type ookinetes and a cytoskeleton‐knockout mutant we demonstrate that perturbation of cell shape changes motion from helical to broadly linear. Therefore, while the precise linkages between cellular architecture and actomyosin motor organization remain unknown, our analysis suggests that the molecular basis of cell shape may, in addition to motor force, be a key adaptive strategy for malaria parasite dissemination and, as such, transmission.
This analysis explored the effect of timing, sequencing, and change in preconception health across adolescence and young adulthood on racial/ethnic disparities in birth weight in a diverse national cohort of young adult women.
Data came from Waves I (1994–1995), III (2001–2002), and IV (2007–2008) of the National Longitudinal Study of Adolescent Health. Eligibility was restricted to all singleton live births to female non-Hispanic White, non-Hispanic Black, Mexican-origin Latina, or Asian/Pacific Islander participants (n=3014) occurring between the Wave III (ages 18–26 years) and IV (ages 24–32 years) interviews. Birth weight was categorized into low (<2500 grams), normal (2500–4000 grams), and macrosomic (>4000 grams). Preconception health indicators were cigarette smoking, heavy alcohol consumption, overweight or obesity, and inadequate physical activity, measured in adolescence (Wave I, ages 11–19 years) and early adulthood (Wave III) and combined into 4-category variables to capture the timing and sequencing of exposure.
Measures of preconception health did not explain the Black-White disparity in low birth weight, which increased after adjustment for confounders (odds ratio [OR]=2.17, 95% confidence interval [CI]: 1.33–3.53) and effect modification by overweight/obesity (OR=3.58, 95%CI: 1.65–7.78). A positive association between adult-onset overweight/obesity and macrosomia was modified by race (OR=3.83, 95%CI: 1.02–14.36 for Black women).
This longitudinal analysis provides new evidence on preconception health and racial/ethnic disparities in birth weight. Specifically, it indicates that interventions focused on prevention of overweight/obesity and maintenance of healthy weight during the transition to adulthood, especially among Black females, may be warranted.
The lytic cycles of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are induced in cell culture by sodium butyrate (NaB), a short-chain fatty acid (SCFA) histone deacetylase (HDAC) inhibitor. Valproic acid (VPA), another SCFA and an HDAC inhibitor, induces the lytic cycle of KSHV but blocks EBV lytic reactivation. To explore the hypothesis that structural differences between NaB and VPA account for their functional effects on the two related viruses, we investigated the capacity of 16 structurally related short- and medium-chain fatty acids to promote or prevent lytic cycle reactivation. SCFAs differentially affected EBV and KSHV reactivation. KSHV was reactivated by all SCFAs that are HDAC inhibitors, including phenylbutyrate. However, several fatty acid HDAC inhibitors, such as isobutyrate and phenylbutyrate, did not reactivate EBV. Reactivation of KSHV lytic transcripts could not be blocked completely by any fatty acid tested. In contrast, several medium-chain fatty acids inhibited lytic activation of EBV. Fatty acids that blocked EBV reactivation were more lipophilic than those that activated EBV. VPA blocked activation of the BZLF1 promoter by NaB but did not block the transcriptional function of ZEBRA. VPA also blocked activation of the DNA damage response that accompanies EBV lytic cycle activation. Properties of SCFAs in addition to their effects on chromatin are likely to explain activation or repression of EBV. We concluded that fatty acids stimulate the two related human gammaherpesviruses to enter the lytic cycle through different pathways.
IMPORTANCE Lytic reactivation of EBV and KSHV is needed for persistence of these viruses and plays a role in carcinogenesis. Our direct comparison highlights the mechanistic differences in lytic reactivation between related human oncogenic gammaherpesviruses. Our findings have therapeutic implications, as fatty acids are found in the diet and produced by the human microbiota. Small-molecule inducers of the lytic cycle are desired for oncolytic therapy. Inhibition of viral reactivation, alternatively, may prove useful in cancer treatment. Overall, our findings contribute to the understanding of pathways that control the latent-to-lytic switch and identify naturally occurring molecules that may regulate this process.
Heme oxygenase-1 (HO-1) is an inducible, detoxifying enzyme that is critical for limiting oxidative stress, inflammation, and cellular injury within the CNS and other tissues. Here, we demonstrate a deficiency of HO-1 expression in the brains of HIV-infected individuals. This HO-1 deficiency correlated with cognitive dysfunction, HIV replication in the CNS, and neuroimmune activation. In vitro analysis of HO-1 expression in HIV-infected macrophages, a primary CNS HIV reservoir along with microglia, demonstrated a decrease in HO-1 as HIV replication increased. HO-1 deficiency correlated with increased culture supernatant glutamate and neurotoxicity, suggesting a link among HIV infection, macrophage HO-1 deficiency, and neurodegeneration. HO-1 siRNA knockdown and HO enzymatic inhibition in HIV-infected macrophages increased supernatant glutamate and neurotoxicity. In contrast, increasing HO-1 expression through siRNA derepression or with nonselective pharmacologic inducers, including the CNS-penetrating drug dimethyl fumarate (DMF), decreased supernatant glutamate and neurotoxicity. Furthermore, IFN-γ, which is increased in CNS HIV infection, reduced HO-1 expression in cultured human astrocytes and macrophages. These findings indicate that HO-1 is a protective host factor against HIV-mediated neurodegeneration and suggest that HO-1 deficiency contributes to this degeneration. Furthermore, these results suggest that HO-1 induction in the CNS of HIV-infected patients on antiretroviral therapy could potentially protect against neurodegeneration and associated cognitive dysfunction.
The quadrivalent HPV vaccination was approved for use in males ages 9 to 26 in 2009 and recommended for routine administration in 2011. The purpose of this study was to uncover predictable commonalities amongst parents who chose to vaccinate their 11–17 year old sons against HPV.
We compiled data from a U.S. national sample of 779 parents with sons 11–17 years old using a web-based survey to gather information about behavioral and sociodemographic factors which predicted receipt of 1 or more HPV vaccine doses based on parental report. Predictors were first modeled individually for univariable associations. Significant predictors (p<0.10) were combined in a multivariable model.
In the adjusted model, independent predictors included receipt of flu vaccination, health insurance coverage and sexual health topic discussions with sons. Sons who had received a flu shot in the last two years more frequently received at least one dose of the vaccine (OR 1.82; 95% CI 1.45–2.26). Sons covered by private health insurance had decreased odds of HPV vaccination (OR 0.56 95% CI 0.37–0.83). Lastly, parents who had discussed sexual health topics with their sons were more likely to vaccinate (OR 1.61; 95% CI 1.37–1.89).
Male vaccination rates in the U.S. have increased, but males continue to be under-immunized. Utilization of health care is an important factor in HPV vaccine uptake; therefore, health care providers should use every contact as an opportunity to vaccinate. Communication about sexual health topics may provide a forum for parents and health care providers to have conversations about HPV vaccination as those more comfortable discussing these topics may also be more comfortable discussing HPV vaccination.
Animal studies indicate gonadal hormones at puberty have an effect on the development of masculine and feminine traits. However, it is unknown whether similar processes occur in humans. We examined whether women with anorexia nervosa (AN), who often experience primary amenorrhea, exhibit attenuated feminization in their psychological characteristics in adulthood due to the decrease/absence of gonadal hormones at puberty. Women with AN were compared on a number of psychological characteristics using General Linear Models based on the presence/absence of primary amenorrhea. Although women with primary amenorrhea exhibited lower anxiety scores than those without primary amenorrhea, in general, results did not provide evidence of attenuated feminization in women with AN with primary amenorrhea. Future research should utilize novel techniques and direct hormone measurement to explore the effects of pubertal gonadal hormones on masculine and feminine traits.
Organizational effects; sex differences; amenorrhea; pubertal timing; anorexia nervosa
The purpose of this study was to determine if third-year medical students participating in a mandatory 12-week simulation course perceived improvement in decision-making, communication, and teamwork skills. Students participated in or observed 24 acute emergency scenarios. At 4-week intervals, students completed 0-10 point Likert scale questionnaires evaluating the curriculum and role of team leader. Linear contrasts were used to examine changes in outcomes. P-values were Bonferroni-corrected for multiple pairwise comparisons. Student evaluations (n = 96) demonstrated increases from week 4 to 12 in educational value (p = 0.006), decision-making (p < 0.001), communication (p = 0.02), teamwork (p = 0.01), confidence in management (p < 0.001), and translation to clinical experience (p < 0.001). Regarding the team leader role, students reported a decrease in stress (p = 0.001) and increase in ability to facilitate team function (p < 0.001) and awareness of team building (p = <0.001). Ratings demonstrate a positive impact of simulation on both clinical management skills and team leadership skills. A simulation curriculum can enhance the ability to manage acute clinical problems and translates well to the clinical experience. These positive perceptions increase as the exposure to simulation increases.
medical education; simulation; communication skills
Research examining changes in eating disorder symptoms across adolescence suggests an increase in disordered eating from early to late adolescence. However, relevant studies have largely been cross-sectional in nature and most have not examined the changes in the attitudinal symptoms of eating disorders (e.g., weight concerns). This longitudinal study aimed to address gaps in the available data by examining the developmental trajectories of disordered eating in females from preadolescence into young adulthood.
Participants were 745 same-sex female twins from the Minnesota Twin Family Study. Disordered eating was assessed using the Total Score, Body Dissatisfaction subscale, Weight Preoccupation subscale, and a combined Binge Eating and Compensatory Behavior subscale from the Minnesota Eating Behavior Survey assessed at the ages of 11, 14, 18, 21, and 25. Several latent growth models were fit to the data to identify the trajectory that most accurately captures the changes in disordered eating symptoms from 11 to 25 years.
The best-fitting models for overall levels of disordered eating, body dissatisfaction, and weight preoccupation showed an increase in from 11 through 25 years. In contrast, bulimic behaviors increased to age of 18 and then stabilized to age of 25.
The findings expanded upon extant research by investigating longitudinal, symptom specific, within-person changes and showing an increase in cognitive symptoms into young adulthood and the stability of disordered eating behaviors past late adolescence.
disordered eating; longitudinal; developmental; growth curve
Women with bulimia nervosa (BN) frequently have co-occurring alcohol use disorders (AUDs). Studies of shared genetic transmission of these disorders have been mixed. Personality heterogeneity among individuals with BN may explain discrepant findings. Cluster analysis has characterized women with BN in groups on the basis of personality profiles. One group, the Dysregulated cluster, characterized largely by behavioural disinhibition and emotional dysregulation may be more closely linked etiologically to AUDs. This study examined whether genetic associations between BN and AUDs are the strongest among the Dysregulated cluster. Symptoms of BN and AUDs were assessed in female twins at ages 17 and 25 years from the Minnesota Twin Family Study. Personality clusters were defined using the Multidimensional Personality Questionnaire. Twin moderation models suggested small-to-moderate common genetic transmission between BN and AUDs. However, shared genetic effects did not differ by personality cluster. Findings suggest that personality clusters are unlikely to account for inconsistent findings regarding their shared aetiology.
bulimia nervosa; alcohol use disorders; personality
Diabetic nephropathy (DN) is a major complication of diabetes and the leading cause of end‐stage renal disease. DN is characterized by changes in kidney structure and function but the underlying genetic and molecular factors are poorly understood. We used a mouse diversity panel to explore the genetic basis of DN traits in mice carrying the Ins2 Akita mutation. Twenty‐eight Akita strains were generated by breeding this panel to DBA/2.Akita mice. Male F1 diabetic and nondiabetic littermates were evaluated for DN‐related traits. Urine albumin‐to‐creatinine ratios (ACRs), volume and cystatin C as well as blood urea nitrogen and lipoprotein levels varied significantly among the diabetic strains. For most Akita strains, ACR values increased 2‐ to 6‐fold over euglycemic control values. However, six strains exhibited changes in ACR exceeding 10‐fold with two strains (NOD/ShiLt and CBA) showing 50‐ to 83‐ fold increases. These increases are larger than previously reported among available DN mouse models establishing these strains as useful for additional studies of renal function. ACRs correlated with cystatin C (P = 0.0286), a measure of hyperfiltration and an interstitial tubular marker associated with DN onset in humans suggesting that tubule damage as well as podocyte‐stress contributed to reduced kidney function assessed by ACR. Although large changes were seen for ACRs, severe nephropathology was absent. However, glomerular hypertrophy and collagen IV content were found to vary significantly among strains suggesting a genetic basis for early onset features of DN. Our results define the range of DN phenotypes that occur among common inbred strains of mice.
Diabetic nephropathy (DN) is characterized by changes in kidney structure and function but the underlying genetic and molecular factors are poorly understood. We used a mouse diversity panel to explore the genetic basis of DN traits in mice carrying the Ins2 Akita mutation. Twenty‐eight Akita strains on different genetic backgrounds were evaluated for DN‐related traits and the results define the range of DN phenotypes that occur among common inbred strains of mice.
Akita; Animal models; Albuminuria; Diabetic nephropathy; Genetics
Resurgent sodium currents contribute to the regeneration of action potentials and enhanced neuronal excitability. Tetrodotoxin-sensitive (TTX-S) resurgent currents have been described in many different neuron populations, including cerebellar and dorsal root ganglia (DRG) neurons. In most cases, sodium channel Nav1.6 is the major contributor to these TTX-S resurgent currents. Here we report a novel TTX-resistant (TTX-R) resurgent current recorded from rat DRG neurons. The TTX-R resurgent currents are similar to classic TTX-S resurgent currents in many respects, but not all. As with TTX-S resurgent currents, they are activated by membrane repolarization, inhibited by lidocaine, and enhanced by a peptide-mimetic of the β4 sodium channel subunit intracellular domain. However, the TTX-R resurgent currents exhibit much slower kinetics, occur at more depolarized voltages, and are sensitive to the Nav1.8 blocker A803467. Moreover, coimmunoprecipitation experiments from rat DRG lysates indicate the endogenous sodium channel β4 subunits associate with Nav1.8 in DRG neurons. These results suggest that slow TTX-R resurgent currents in DRG neurons are mediated by Nav1.8 and are generated by the same mechanism underlying TTX-S resurgent currents. We also show that both TTX-S and TTX-R resurgent currents in DRG neurons are enhanced by inflammatory mediators. Furthermore, the β4 peptide increased excitability of small DRG neurons in the presence of TTX. We propose that these slow TTX-R resurgent currents contribute to the membrane excitability of nociceptive DRG neurons under normal conditions and that enhancement of both types of resurgent currents by inflammatory mediators could contribute to sensory neuronal hyperexcitability associated with inflammatory pain.
action potential; hyperexcitability; nociceptor; resurgent sodium current; sodium current; voltage clamp
The optical properties of human whole blood and blood plasma with and
without Y2O3 and
Nd3+:Y2O3 nanoparticles are characterized
in the near infrared region at 808 nm using a double integrating sphere
technique. Using experimentally measured quantities of diffuse reflectance and
diffuse transmittance, a computational analysis was conducted utilizing the
Kubelka-Munk, the Inverse Adding Doubling, and Magic Light Kubelka-Munk and
Monte Carlo Methods to determine optical properties of the absorption and
scattering coefficients. Room temperature absorption and emission spectra were
also acquired of Nd3+:Y2O3 nanoparticles
elucidating their utility as biological markers. The emission spectra of
Nd3+:Y2O3 were taken by exciting the
nanoparticles before and after entering the whole blood sample. The emission
from the 4F3/2→4I11/2
manifold transition of Nd3+:Y2O3 nanoparticles
readily propagates through the blood sample at excitation of 808 nm and exhibits
a shift in relative intensities of the peaks due to differences in scattering.
At 808 nm, in both whole blood and plasma samples, a direct relationship was
found with absorption coefficient and Y2O3 nanoparticle
concentration. Results for the whole blood indicate a small inverse relationship
with Y2O3 nanoparticle concentration and scattering
coefficient and in contrast a direct relation for the plasma.
Lasers; Blood; Nanoparticles; Optical properties
This study evaluated the effectiveness of an atrial septal defect (ASD) with veno-venous extracorporeal membrane oxygenation (vvECMO) as a bridge to transplantation. Sheep (56 ± 3 kg; n = 7) underwent a right sided thoracotomy to create the ASD (diameter = 1 cm) and place instrumentation and a pulmonary artery (PA) occluder. After recovery, animals were placed on ECMO, and the PA was constricted to generate a two-fold rise in right ventricular systolic pressure. Sheep were then maintained for 60 hours on ECMO, and data were collected hourly. Five sheep survived 60 hours. One sheep died due to a circuit clot extending into the RV, and another died presumably due to an arrhythmia. Mean right ventricular pressure (mRVP) was 19±3 mmHg at baseline, averaged 27±7 mmHg over the experiment, but was not statistically significant (p = 0.27) due to one sheep without an increase. Cardiac output (CO) was 6.8±1.2 L/min at baseline, averaged 6.0±1.0 L/min during the experiment, and was statistically unchanged (p = 0.34). Average arterial oxygen saturation and pCO2 over the experiment were 96.8 ± 1.4% and 31.8 ± 3.4 mmHg, respectively. In conclusion, an ASD combined with vvECMO maintains normal systemic hemodynamics and arterial blood gases during a long-term increase in right ventricular afterload.
right ventricular failure; pulmonary failure; ECLS; lung transplant; septostomy
Neuronal damage in HIV-associated Neurocognitive Disorders (HAND) has been linked to inflammation induced by soluble factors released by HIV-infected, and non-infected, activated macrophages/microglia (HIV M/M) in the brain. It has been suggested that aberrant neuronal cell cycle activation determines cell fate in response to these toxic factors. We have previously shown increased expression of cell cycle proteins such as E2F1 and phosphorylated pRb in HAND midfrontal cortex in vivo and in primary neurons exposed to HIV M/M supernatants in vitro. In addition, we also demonstrated have previously shown that MDMx (also referred to as MDM4), a negative regulator of E2F1, was decreased in the brain in a primate model of HIV-induced CNS neurodegeneration. Thus, we hypothesized that MDMx provides indirect neuroprotection from HIV-induced neurodegeneration in our in vitro model. In this report, we found significant reductions in MDMx protein levels in the mid-frontal cortex of patients with HAND. In addition, treatment of primary rat neuroglial cultures with HIV M/M led to NMDA receptor- and calpain-dependent degradation of MDMx and decreased neuronal survival, while overexpression of MDMx conferred partial protection from HIV M/M toxicity in vitro. Further, our results demonstrate that MDMx is a novel and direct calpain substrate. Finally, blocking MDMx activity led to neuronal death in vitro in the absence of toxic stimulus, which was reversed by calpain inhibition. Overall, our results indicate that MDMx plays a pro-survival role in neurons, and that strategies to stabilize and/or induce MDMx can provide neuroprotection in HAND and in other neurodegenerative diseases where calpain activation contributes to neuropathogenesis.
Calpain; caspase; HIV-associated neurocognitive disorder; MDMx; neuron; neuroprotection
The aims of this paper are to examine the relationship between psychological trauma symptoms and Type 2 diabetes prevalence, glucose control, and treatment modality among 3,776 American Indians in Phase V of the Strong Heart Family Study.
This cross-sectional analysis measured psychological trauma symptoms using the National Anxiety Disorder Screening Day instrument, diabetes by American Diabetes Association criteria, and treatment modality by four categories: no medication, oral medication only, insulin only, or both oral medication and insulin. We used binary logistic regression to evaluate the association between psychological trauma symptoms and diabetes prevalence. We used ordinary least squares regression to evaluate the association between psychological trauma symptoms and glucose control. We used binary logistic regression to model the association of psychological trauma symptoms with treatment modality.
Neither diabetes prevalence (22-31%; p = 0.19) nor control (8.0-8.6; p = 0.25) varied significantly by psychological trauma symptoms categories. However, diabetes treatment modality was associated with psychological trauma symptoms categories, as people with greater burden used either no medication, or both oral and insulin medications (odds ratio = 3.1, p < 0.001).
The positive relationship between treatment modality and psychological trauma symptoms suggests future research investigate patient and provider treatment decision making.
diabetes treatment modality; American Indians; psychological trauma symptoms
Bioaccessibility is a growing area of research in the field of risk assessment. As polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants, they are the toxicants of focus to establish cancer risks in humans. Orally ingested PAHs also cause toxicity and even affect the pharmacokinetic behavior of some therapeutic agents. Toward this end, bioaccessibility is being used as a tool to assess the risk of PAHs via dietary exposures.
This review covers some in vitro bioaccessibility models for PAHs that have been used for the past one-and-a-half decade. This review also considers the factors that influence bioaccessibility and debates the merits and limitations of using a bioaccessibility concept for estimating risk from ingestion of PAH-contaminated soil and food. Finally, the authors discuss the implications of bioaccessibility for PAH-induced toxicity and cancers in the context of risk assessment.
So far, much of the focus on PAH bioaccessibility is centered on soil as a preferential matrix. However, ingestion of PAHs through diet far exceeds the amount accidentally ingested through soil. Therefore, bioaccessibility could be exploited as a tool to assess the relative risk of various dietary ingredients tainted with PAHs. While bioaccessibility is a promising approach for assessing PAH risk arising from various types of contaminated soils, none of the models proposed appears to be valid. Bioaccessibility values, derived from in vitro studies, still require validation from in vivo studies.
bioaccessibility; bioavailability; colon cancer; colon extended physiologically based extraction test; in vitro digestion; polycyclic aromatic hydrocarbons
High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in gliomagenesis such that BSG is considered a distinct disease from glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the brainstem gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in glioma. Ectopic expression of Pax3 in normal brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced brainstem gliomagenesis.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-014-0134-6) contains supplementary material, which is available to authorized users.
Brainstem Glioma; Pax3; DIPG; ACVR1
Medulloblastoma (MB) is the most common malignant brain tumor in children. While aggressive surgery, radiation, and chemotherapy have improved outcomes, survivors suffer severe long-term side effects, and many patients still succumb to their disease. For patients whose tumors are driven by mutations in the Sonic hedgehog (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated MBs do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH-associated MB. One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPCs). We previously identified a population of TPCs in tumors from patched mutant mice, a model for SHH-dependent MB. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G2/M phases of the cell cycle. Here, we show that CD15+ cells progress more rapidly through the cell cycle than CD15- cells and contain an increased proportion of cells in G2/M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora and Polo-like kinases, key regulators of G2/M, induces cell cycle arrest, apoptosis and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived MB xenografts are also sensitive to Aurora and Polo-like kinase inhibitors. Our findings suggest that targeting G2/M regulators may represent a novel approach for treatment of human MB.
Medulloblastoma; Cancer stem cell; Aurora kinase; Polo-like kinase; Hedgehog
Background. Uterine inversion is a rare, but life threatening, obstetrical emergency which occurs when the uterine fundus collapses into the endometrial cavity. Various conservative and surgical therapies have been outlined in the literature for the management of uterine inversions. Case. We present a case of a chronic, recurrent uterine inversion, which was diagnosed following spontaneous vaginal delivery and recurred seven weeks later. The uterine inversion was likely due to a leiomyoma. This late-presenting, chronic, recurring uterine inversion was treated with a vaginal hysterectomy. Conclusion. Uterine inversions can occur in both acute and chronic phases. Persistent vaginal bleeding with the appearance of a prolapsing fibroid should prompt further investigation for uterine inversion and may require surgical therapy. A vaginal hysterectomy may be an appropriate management option in select populations and may be considered in women who do not desire to maintain reproductive function.
Lipoproteins are the major agonists of Wolbachia-dependent inflammatory pathogenesis in filariasis and a validated target for drug discovery. Here we characterise the abundance, localisation and serology of the Wolbachia lipoproteins: Wolbachia peptidoglycan associated lipoprotein and the Type IV Secretion System component, VirB6.
We used proteomics to confirm lipoprotein presence and relative abundance; fractionation, immunoblotting and confocal and electron immuno-microscopy for localisation and ELISA for serological analysis.
Proteomic analysis of Brugia malayi adult female protein extracts confirmed the presence of two lipoproteins, previously predicted through bioinformatics: Wolbachia peptidoglycan associated lipoprotein (wBmPAL) and the Type IV Secretion System component, VirB6 (wBmVirB6). wBmPAL was among the most abundant Wolbachia proteins present in an extract of adult female worms with wBmVirB6 only detected at a much lower abundance. This differential abundance was reflected in the immunogold-labelling, which showed wBmPAL localised at numerous sites within the bacterial membranes, whereas wBmVirB6 was present as a single cluster on each bacterial cell and also located within the bacterial membranes. Immunoblotting of fractionated extracts confirmed the localisation of wBmPAL to membranes and its absence from cytosolic fractions of C6/36 mosquito cells infected with wAlbB. In whole worm mounts, antibody labelling of both lipoproteins were associated with Wolbachia. Serological analysis showed that both proteins were immunogenic and raised antibody responses in the majority of individuals infected with Wuchereria bancrofti.
Two Wolbachia lipoproteins, wBmPAL and wBmVirB6, are present in extracts of Brugia malayi with wBmPAL among the most abundant of Wolbachia proteins. Both lipoproteins localised to bacterial membranes with wBmVirB6 present as a single cluster suggesting a single Type IV Secretory System on each Wolbachia cell.
Wolbachia; Lipoprotein; Peptidoglycan associated lipoprotein; Type IV Secretion System VirB6; Brugia malayi; Aedes albopictus
Prior studies exploring gene-environment interactions (GxE) in the development of youth conduct problems (CP) have focused almost exclusively on single risk experiences, despite research indicating that the presence of other risk factors and/or the absence of protective factors can accentuate the influence of a given risk factor on CP. The goal of the current study was to fill this gap in the literature, evaluating whether risky and protective aspects of parenting might combine to jointly moderate the etiology of CP.
The sample consisted of 500 child twin pairs from the Michigan State University Twin Registry (MSUTR). Child CP was assessed using multiple informant reports. Maternal warmth and directiveness were assessed via videotaped dyadic interactions between mothers and each of their twins.
Biometric GxE analyses revealed that directiveness and warmth did appear to jointly moderate the etiology of CP. In particular, shared environmental influences were accentuated by colder, less directive or “less engaged” mothering, while genetic influences were strongest when the child was experiencing warmer, more directive or “more authoritative” mothering.
Such findings serve to highlight the synergistic effects of risky and protective experiences on child outcomes. They also provide additional empirical support for the bioecological form of GxE which postulates that, in some cases, genetic influences may be most strongly expressed in the presence of low risk environments.
child conduct problems; maternal directiveness or control; maternal warmth; GxE