Angiovision: Aortic stent-graft placement by augmented angionavigation

The endovascular treatment of abdominal aortic aneurysm (EVAR - EndoVascular Aneurism Repair) has become an alternative therapy to conventional open surgery. The objective of Angiovision project was to contribute to the improvement of EVAR procedures in terms of accuracy and customization of the interventional strategy. Our approach was mainly based on the use of patient-specific data, computer-aided endovascular navigation and numerical simulation. We proposed a new FEM-based patient-specific simulation solution to estimate the deformations caused by the introduction of stiff endovascular devices. We developed and implemented an original endovascular navigation system to augment the intraoperative fluoroscopy with the visualization of deformed preoperative aorto-iliac structure, and related information concerning vessel wall (calcifications), as well as stent-graft virtual deployment. The proposed solution, that requires only lightweight computer equipment, can be used in a standard operating room in order to optimize device placement (from a single angle of incidence). Evaluation is currently under way.     

β-Globin Sleeping Beauty Transposon Reduces Red Blood Cell Sickling in a Patient-Derived CD34+-Based In Vitro Model

The ultimate goal of gene therapy for sickle cell anemia (SCA) is an improved phenotype for the patient. In this study, we utilized bone marrow from a sickle cell patient as a model of disease in an in vitro setting for the hyperactive Sleeping Beauty transposon gene therapy system. We demonstrated that mature sickle red blood cells containing hemoglobin-S and sickling in response to metabisulfite can be generated in vitro from SCA bone marrow. These cells showed the characteristic morphology and kinetics of hemoglobin-S polymerization, which we quantified using video microscopy and imaging cytometry. Using video assessment, we showed that delivery of an IHK-β^T87Q antisickling globin gene by Sleeping Beauty via nucleofection improves metrics of sickling, decreasing percent sickled from 53.2 ± 2.2% to 43.9 ± 2.0%, increasing the median time to sickling from 8.5 to 9.6 min and decreasing the maximum rate of sickling from 2.3 x 10^-3 sickling cells/total cells/sec in controls to 1.26 x 10^-3 sickling cells/total cells/sec in the IHK-β^T87Q-globin group (p < 0.001). Using imaging cytometry, the percentage of elongated sickled cells decreased from 34.8 ± 4.5% to 29.5 ± 3.0% in control versus treated (p < 0.05). These results support the potential use of Sleeping Beauty as a clinical gene therapy vector and provide a useful tool for studying sickle red blood cells in vitro.     

Economic Recession and Emergence of an HIV-1 Outbreak among Drug Injectors in Athens Metropolitan Area: A Longitudinal Study

Background

During 2011, a dramatic increase (1600%) of reported HIV-1 infections among injecting drug users (IDUs) was noted in Athens, Greece. We herein assess the potential causal pathways associated with this outbreak.

Methods

Our study employed high resolution HIV-1 phylogenetic and phylogeographic analyses. We examined also longitudinal data of ecological variables such as the annual growth of gross domestic product (GDP) of Greece in association with HIV-1 and HCV sentinel prevalence in IDUs, unemployment and homelessness rates and HIV transmission networks in Athens IDUs before and during economic recession (2008–2012).

Results

IDU isolates sampled in 2011 and 2012 suggested transmission networks in 94.6% and 92.7% of the cases in striking contrast with the sporadic networking (5%) during 1998–2009. The geographic origin of most HIV-1 isolates was consistent with the recently documented migratory waves in Greece. The decline in GDP was inversely correlated with annual prevalence rates of HIV and HCV and with unemployment and homelessness rates in IDUs (all p<0.001). The slope of anti-HCV prevalence in the sentinel populations of IDUs and in “new” drug injectors was found 120 and 1.9-fold (p = 0.007, p = 0.08 respectively) higher in 2008–2012 (economic recession) compared with 2002–2006. The median (25th, 75th) size of transmission networks were 34 (12, 58) and 2 (2, 2) (p = 0.057) in 2008–2012 and 1998–2007, respectively. The coverage of harm reduction services was low throughout the study period.

Conclusions

Scaling-up harm reduction services and addressing social and structural factors related to the current economic crisis should be urgently considered in environments where HIV-1 outbreaks may occur.     

HIV Viremia and T-Cell Activation Differentially Affect the Performance of Glomerular Filtration Rate Equations Based on Creatinine and Cystatin C

Background

Serum creatinine and cystatin C are used as markers of glomerular filtration rate (GFR). The performance of these GFR markers relative to exogenously measured GFR (mGFR) in HIV-positive individuals is not well established.

Methods

We assessed the performance of the chronic kidney disease epidemiology collaboration equations based on serum concentrations of creatinine (eGFR_cr), cystatin C (eGFR_cys) and both biomarkers combined (eGFR_cr-cys) in 187 HIV-positive and 98 HIV-negative participants. Measured GFR was calculated by plasma iohexol clearance. Bias and accuracy were defined as the difference between eGFR and mGFR and the percentage of eGFR observations within 30% of mGFR, respectively. Activated CD4 and CD8 T-cells (CD38+ HLA-DR+) were measured by flow cytometry.

Results

The median mGFR was >100 ml/min/1.73 m² in both groups. All equations tended to be less accurate in HIV-positive than in HIV-negative subjects, with eGFR_cr-cys being the most accurate overall. In the HIV-positive group, eGFR_cys was significantly less accurate and more biased than eGFR_cr and eGFR_{cr_cys}. Additionally eGFR_cys bias and accuracy were strongly associated with use of antiretroviral therapy, HIV RNA suppression, and percentages of activated CD4 or CD8 T-cells. Hepatitis C seropositivity was associated with larger eGFR_cys bias in both HIV-positive and HIV-negative groups. In contrast, eGFR_cr accuracy and bias were not associated with HIV-related factors, T-cell activation, or hepatitis C.

Conclusions

The performance of eGFR_cys relative to mGFR was strongly correlated with HIV treatment factors and markers of T-cell activation, which may limit its usefulness as a GFR marker in this population.     

Calcium ions and osteoclastogenesis initiate the induction of bone formation by coral‐derived macroporous constructs

Coral-derived calcium carbonate/hydroxyapatite macroporous constructs of the genus Goniopora with limited hydrothermal conversion to hydroxyapatite (7% HA/CC) initiate the induction of bone formation. Which are the molecular signals that initiate pattern formation and the induction of bone formation? To evaluate the role of released calcium ions and osteoclastogenesis, 7% HA/CC was pre-loaded with either 500 μg of the calcium channel blocker, verapamil hydrochloride, or 240 μg of the osteoclast inhibitor, biphosphonate zoledronate, and implanted in the rectus abdominis muscle of six adult Chacma baboons Papio ursinus. Generated tissues on days 15, 60 and 90 were analysed by histomorphometry and qRT-PCR. On day 15, up-regulation of type IV collagen characterized all the implanted constructs correlating with vascular invasion. Zoledronate-treated specimens showed an important delay in tissue patterning and morphogenesis with limited bone formation. Osteoclastic inhibition yielded minimal, if any, bone formation by induction. 7% HA/CC pre-loaded with the Ca⁺⁺ channel blocker verapamil hydrochloride strongly inhibited the induction of bone formation. Down-regulation of bone morphogenetic protein-2 (BMP-2) together with up-regulation of Noggin genes correlated with limited bone formation in 7% HA/CC pre-loaded with either verapamil or zoledronate, indicating that the induction of bone formation by coral-derived macroporous constructs is via the BMPs pathway. The spontaneous induction of bone formation is initiated by a local peak of Ca⁺⁺ activating stem cell differentiation and the induction of bone formation.     

The CRHR1 gene,trauma exposure,and alcoholism risk: a test of G × E effects

The corticotropin‐releasing hormone type I receptor (CRHR1) gene has been implicated in the liability for neuropsychiatric disorders, particularly under conditions of stress. On the basis of the hypothesized effects of CRHR1 variation on stress reactivity, measures of adulthood traumatic stress exposure were analyzed for their interaction with CRHR1 haplotypes and single‐nucleotide polymorphisms (SNPs) in predicting the risk for alcoholism. Phenotypic data on 2533 non‐related Caucasian individuals (1167 alcoholics and 1366 controls) were culled from the publically available Study of Addiction: Genetics and Environment genome‐wide association study. Genotypes were available for 19 tag SNPs. Logistic regression models examined the interaction between CRHR1 haplotypes/SNPs and adulthood traumatic stress exposure in predicting alcoholism risk. Two haplotype blocks spanned CRHR1. Haplotype analyses identified one haplotype in the proximal block 1 (P = 0.029) and two haplotypes in the distal block 2 (P = 0.026, 0.042) that showed nominally significant (corrected P < 0.025) genotype × traumatic stress interactive effects on the likelihood of developing alcoholism. The block 1 haplotype effect was driven by SNPs rs110402 (P = 0.019) and rs242924 (P = 0.019). In block 2, rs17689966 (P = 0.018) showed significant and rs173365 (P = 0.026) showed nominally significant, gene × environment (G × E) effects on alcoholism status. This study extends the literature on the interplay between CRHR1 variation and alcoholism, in the context of exposure to traumatic stress. These findings are consistent with the hypothesized role of the extra hypothalamic corticotropin‐releasing factor system dysregulation in the initiation and maintenance of alcoholism. Molecular and experimental studies are needed to more fully understand the mechanisms of risk and protection conferred by genetic variation at the identified loci .     

Genetic variation in oxytocin rs2740210 and early adversity associated with postpartum depression and breastfeeding duration

Mothers vary in duration of breastfeeding. These individual differences are related to a variety of demographic and individual maternal factors including maternal hormones, mood and early experiences. However, little is known about the role of genetic factors. We studied single‐nucleotide polymorphisms (SNPs) in the OXT peptide gene (rs2740210; rs4813627) and the OXT receptor gene (OXTR rs237885) in two samples of mothers from the Maternal adversity, Vulnerability and Neurodevelopment study (MAVAN), a multicenter (Hamilton and Montreal, Canada) study following mothers and their children from pregnancy until 7 years of age. Data from the Hamilton site was the primary sample (n = 201) and data from Montreal was the replication sample (n = 151). Breastfeeding duration, maternal mood (measured by the CES‐D scale) and early life adversity (measured by the CTQ scale) were established during 12 months postpartum. In our primary sample, polymorphisms in OXT rs2740210, but not the other SNPs, interacted with early life adversity to predict variation in breastfeeding duration (overall F_8,125 = 2.361, P = 0.021; interaction effect b = ?8.12, t = ?2.3, P = 0.023) and depression (overall F_8,118 = 5.751, P ≤ 0.001; interaction effect b = 6.06, t = 3.13, P = 0.002). A moderated mediation model showed that higher levels of depression mediated the inverse relation of high levels of early life adversity to breastfeeding duration, but only in women possessing the CC genotype [effect a′ = ?3.3401, 95% confidence interval (CI) = ?7.9466 to ?0.0015] of the OXT SNP and not in women with the AA/AC genotype (a′ = ?1.2942, ns). The latter findings (moderated mediation model) were replicated in our Montreal sample (a′ = ?0.277, 95% CI = ?0.7987 to ?0.0348 for CC; a′ = ?0.1820, ns for AA/AC) .     

Association study of 37 genes related to serotonin and dopamine neurotransmission and neurotrophic factors in cocaine dependence

Cocaine dependence is a neuropsychiatric disorder in which both environmental and genetic factors are involved. Several processes, that include reward and neuroadaptations, mediate the transition from use to dependence. In this regard, dopamine and serotonin neurotransmission systems are clearly involved in reward and other cocaine‐related effects, whereas neurotrophic factors may be responsible for neuroadaptations associated with cocaine dependence. We examined the contribution to cocaine dependence of 37 genes related to the dopaminergic and serotoninergic systems, neurotrophic factors and their receptors through a case–control association study with 319 single nucleotide polymorphisms selected according to genetic coverage criteria in 432 cocaine‐dependent patients and 482 sex‐matched unrelated controls. Single marker analyses provided evidence for association of the serotonin receptor HTR2A with cocaine dependence [rs6561333; nominal P‐value adjusted for age = 1.9e?04, odds ratio = 1.72 (1.29–2.30)]. When patients were subdivided according to the presence or absence of psychotic symptoms, we confirmed the association between cocaine dependence and HTR2A in both subgroups of patients. Our data show additional evidence for the involvement of the serotoninergic system in the genetic susceptibility to cocaine dependence.     

Neuropsychological effects of the CSMD1 genome‐wide associated schizophrenia risk variant rs10503253

The single‐nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains‐1 (CSMD1) gene on 8p23.2, was recently identified as genome‐wide significant for schizophrenia (SZ), but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non‐carriers of the risk ‘A’ allele on measures of neuropsychological performance typically impaired in SZ (general cognitive ability, episodic and working memory and attentional control) in independent samples of Irish patients (n = 387) and controls (n = 171) and German patients (205) and controls (n = 533). Across these groups, the risk ‘A’ allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified ‘A’ risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with SZ risk.