Reading the unique DNA methylation landscape of the brain: Non-CpG methylation,hydroxymethylation, and MeCP2

DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non-CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system.     

Serological Responses of Raccoons and Striped Skunks to Ontario Rabies Vaccine Bait in West Virginia during 2012–2016

Since the 1990s, oral rabies vaccination (ORV) has been used successfully to halt the westward spread of the raccoon rabies virus (RV) variant from the eastern continental USA. Elimination of raccoon RV from the eastern USA has proven challenging across targeted raccoon (Procyon lotor) and striped skunk (Mephitis mephitis) populations impacted by raccoon RV. Field trial evaluations of the Ontario Rabies Vaccine Bait (ONRAB) were initiated to expand ORV products available to meet the rabies management goal of raccoon RV elimination. This study describes the continuation of a 2011 trial in West Virginia. Our objective was to evaluate raccoon and skunk response to ORV occurring in West Virginia for an additional two years (2012–2013) at 75 baits/km² followed by three years (2014–2016) of evaluation at 300 baits/km². We measured the change in rabies virus-neutralizing antibody (RVNA) seroprevalence in targeted wildlife populations by comparing levels pre- and post-ORV during each year of study. The increase in bait density from 75/km² to 300/km² corresponded to an increase in average post-ORV seroprevalence for raccoon and skunk populations. Raccoon population RVNA levels increased from 53% (300/565, 95% CI: 50–57%) to 82.0% (596/727, 95% CI: 79–85%) during this study, and skunk population RVNA levels increased from 11% (8/72, 95% CI: 6–20%) to 39% (51/130, 95% CI: 31–48%). The RVNA seroprevalence pre-ORV demonstrated an increasing trend across study years for both bait densities and species, indicating that multiple years of ORV may be necessary to achieve and maintain RVNA seroprevalence in target wildlife populations for the control and elimination of raccoon RV in the eastern USA.     

Vers un rapprochement du syndrome de Klinefelter et de la psychopathie en psychiatrie légale

Klinefelter syndrome (KS) (47,XXY) is the most common aneuploidy (1/650) of sexual chromosome among male (0,1 à 0,2 % of male population) (Hong and Reiss, 2014). Because its large physical phenotypic variability (high tall, sparse hairiness, gynecomastia), this syndrome is largely underdiagnosed (less than 25 % of affected persons) (Samango-Sprouse et al., 2018). Nevertheless, cognitive variability is smaller. Normal to low average total IQ, low verbal IQ, social problems and high levels of psychiatric comorbidities including early aggressiveness are commonly described (Hong and Reiss, 2014). In Denmark, higher risks of committing sexual crime and arson (compared to criminal controls) was recently reported (Stochholm et al., 2012). Quite a few clinically relevant cases reports scattered in the literature, suggests the presence of a pattern of a specific subtype of KS inpatients among forensic population (Bénézech, 1975). However, very few studies provide quantitative or qualitative pertaining to robust results. KS well-documented neurobiological (van Rijn, 2018) (e.g. low levels of testosterone), neuropsychological (Bénézech, 1975; Hong and Reiss, 2014; Samango-Sprouse et al., 2018; Savic, 2012; Seara-Cardoso et al., 2016; Senon, 2005; Stochholm et al., 2012; van Rijn, 2018; van Rijn et al., 2008; van Rijn et al., 2018; van Rijn et al., 2014; van Rijn et al., 2012) [29] (e.g. alterations of both complex cerebral — attention, empathy — and behavioral regulation functions - inhibition, mental flexibility, emotional response modulation, control of own actions) and neuroanatomical (Hong and Reiss, 2014; Itti et al., 2003; Savic, 2012; van Rijn et al., 2008; van Rijn et al., 2012) [29] (e.g. limbic system and temporal lobe abnormal volume, hemispheric specialization shortcoming) features may be helpful to understand comorbid symptoms psychopathology. Numbers of recent studies conduct on KS pediatric or adult population provide interesting results on conduct, anxiety, psychotic and autism spectrum disorders. In addition, some authors use genetic and epigenetic specific features of sex chromosome aneuploidies (e.g. X genes neurodevelopmental role; imprinting) in order to clarify genotype-phenotype links of comorbid symptoms (Bruining et al., 2011; Zitzmann et al., 2004;). With Belgian colleagues from the Social Defense Research Center (CRDS, Tournai, Belgium), we are currently recruiting KS inpatients from security hospitals or psychiatric units in Belgium and France. We aim to assess psychopathic traits with the Psychopathy Checklist Revised (PCL-R, Hare) (Hare, 2003). Our first results concerning 3 KS males outline that PCL-R is useful for the characterization of clinical phenotype among KS forensic sample. While three of them present psychopathic traits, two of them present categorical double diagnose “psychopathy-KS” (total PCL-R score > = 30/40 (Delannoy et al., 2017)). Moreover, dimensional analysis support our hypothesis of a higher prevalence of “explosive profile” in comparison to other psychopathic profiles in our sample (Delannoy et al., 2017). The present article summarizes historic background (e.g. “psychopathy” disappearance of mental disorder reference classification schemes, “crime chromosome” (Bénézech, 1975)) and current context argues (e.g. French psychiatrists court experts widely refer to psychopathy concept despite a lack of consensual definition (Senon, 2005), weak knowledge and training of PCL-R and its related biopsychological recent findings (Blair, 2013; de Oliveira-Souza et al., 2008; Dotterer et al., 2017; Glenn and Raine, 2014; Hosking et al., 2017; Korponay et al., 2017; Pham, 1995; Pham, 2005; Raine, 2008; Raine et al., 2003); stigma and discrimination apprehensions of KS and psychopath) that motivate our research project. Finally, we discuss the advantages of our research protocol on KS participants assessed with PCL-R, such as tackling stigma and discrimination, better understanding psychopathology, and clarifying murky interactions of biological, psychological and social factors entangled in the development of these two fascinating troubles.     

Epitope load identifies kidney transplant recipients at risk of allosensitization following minimization of immunosuppression

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Preparation and tumor affinity testing of the radioiodinated tetrahydroisoquinoline derivative [123I]TIC(OH) for targeting prostate cancer.

This work describes the synthesis and tumor affinity testing of 8-[123I]iodo-l-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid [ITIC(OH)], a cyclic non-naturally occurring amino acid as an imaging probe for prostate cancer. Parameters for labelling were optimized with regard to the amount of precursor, the temperature and time. Thereafter, ITIC(OH) was evaluated in terms of its uptake in primary human PC-3 and DU-145 prostate cancer cells, followed by analysis of the underlying mechanisms of the radioactivity accumulation in tumor cells. No-carrier-added ITIC(OH) was obtained in 80+/-15% radiochemical yield and >98% radiochemical purity by a one-step radioiodination, using IODO-GEN as oxidant. The total synthesis time was less than 30 min, and compatible with a clinical routine production. ITIC(OH) accumulated intensively in primary human prostate cancer cells. The radioactivity incorporation in tumor following a 10-min incubation at 37 degrees C/pH 7.4 varied from 35% to 58% of the total loaded activity per 10(6) tumor cells (355-540 cpm/1000 cells). Inhibition experiments revealed that ITIC(OH) was taken up into tumor by an active transport different from the common amino acid carrier systems, including the sodium-dependent system A and B+,0, and the sodium-independent L- and ASC-type transporter. In contrast, the cellular incorporation was dependent on the membrane potential and correlated with the activity of the mitochondria. In conclusion, the specific and high-level accumulation of ITIC(OH) in human prostate carcinoma cells, indicates that the new radiopharmaceutical is a good candidate for further in vivo investigations to ascertain its potential as an imaging probe for prostate cancer by SPET.     

PDT in clinics: indications, results, and markets.

Photodynamic therapy (PDT) is based on the selective light activation of an exogenously given drug to patients. PDT acts mainly on cell membranes either of neovascular endothelial cells or of cancer cells leading to cancer cell death. Six drugs are now marketed based on clinical assays in various indications, which showed a clear cost efficiency as compared to other classical procedures. PDT is easy to handle and can be performed in medical installations fitting the conditions of health care in developing countries. Its cost effectiveness could represent an appropriate solution to the increasing number of cancers of various origin. However despite all the clinical results now available, PDT development remains slow. The reasons for this situation include cost of development, intellectual property, and competition between pharmaceutical companies.     

A new bioabsorbable sleeve for lung staple-line reinforcement (FOREseal™): report of a three-center phase II clinical trial

Objective: To investigate on the feasibility, safety, and effectiveness of a new bioabsorbable material for lung staple-line reinforcement. Methods: This prospective open trial included 66 patients (mean age of 56 ± 17 years) who underwent various types of lung resection using staplers with knitted calcium alginate sleeves for buttressing (FOREseal™, Laboratoires Brothier, Nanterre, France) at three academic centers: 29 lobectomies, 22 emphysema surgeries, 15 wedge resections or lung biopsies. Intraoperative air leakage was assessed at a mean respiratory peak pressure of 30 cmH₂O, and rated as grade 1, 2, or 3. Persistent air leakage in the postoperative course, as well as any relevant event, was assessed daily. The follow-up period was of 6 months. Results: No technical problem linked to the device occurred. Hemostasis of the cutting edges was completed in all patients. Fifty-six percent of the patients had no intraoperative air leak and 27.3% had grade 1 leaks. Mean postoperative air leaks and thoracic drainage times were 1.9 ± 2.3 days and 6 ± 5.3 days, respectively. In-hospital mortality was nil. There was no empyema. Mean hospital stay was 9.1 ± 6.6 days. At follow-up, one patient underwent lung transplantation, and pathology of the explanted specimen showed the absence of device-related foreign-body inflammation. One patient complained from metalloptysis, and another one, with a metastatic invasive aspergillosis, developed an infectious recurrence that required reoperation. Conclusions: FOREseal is an ergonomic, safe, and promising new material instead of nonabsorbable materials and xenomaterials for staple-line reinforcement. A randomized comparative study is now in progress.