Notes

[Comparative evaluation of the particular microstructure regarding combined biological materials manufactured on the basis of acrylic plastic].
Umbilical cord blood transplantation (UCBT) has been used to treat malignant and non-malignant diseases. UCBT offers the advantages of easy procurement and acceptable partial HLA mismatches, but also shows delayed hematopoietic and immunological recoveries. We postulated that an intrabone (IB) infusion of cord blood could provide a faster short- and long-term engraftment in a pediatric population with malignant and non-malignant hematologic diseases. We conducted this phase I-II single arm, exploratory clinical trial (NCT01711788) from 2012 to 2016 in a single center. Fifteen patients aged from 1.9 to 16.4 years received an IB UCBT. Median time to neutrophils and platelet recoveries were 18 days (range 13-36 days) and 42 days (range 26-107 days), respectively. Rate of severe acute GVH grade was low, with only one patient with grade III aGVH. Relapse occurred in 5 patients (38.5%) and TRM occurred in 1 patient. This leads to 6 years EFS and OS of 66.7% and 80% respectively. In conclusion, IB UCBT is safe and well-tolerated in children and hematological recovery compared similarly to the results obtained with IV UCBT.Considering the immense societal and personal costs and suffering associated with multiple drug use or "polytoxicomania", better understanding of environmental and genetic causes is crucial. While previous studies focused on single risk factors and selected drugs, effects of early-accumulated environmental risks on polytoxicomania were never addressed. Similarly, evidence of genetic susceptibility to particular drugs is abundant, while genetic predisposition to polytoxicomania is unexplored. We exploited the GRAS data collection, comprising information on N~2000 deep-phenotyped schizophrenia patients, to investigate effects of early-life environmental risk accumulation on polytoxicomania and additionally provide first genetic insight. Preadult accumulation of environmental risks (physical or sexual abuse, urbanicity, migration, cannabis, alcohol) was strongly associated with lifetime polytoxicomania (p  = 1.5 × 10-45; OR = 31.4), preadult polytoxicomania with OR = 226.6 (p = 1.0 × 10-33) and adult polytoxicomania with OR = 17.5 (p = 3.4 × 10-24). Parallel accessibility of genetic data from GRAS patients and N~2100 controls for genome-wide association (GWAS) and phenotype-based genetic association studies (PGAS) permitted the creation of a novel multiple GWAS-PGAS approach. this website This approach yielded 41 intuitively interesting SNPs, potentially conferring liability to preadult polytoxicomania, which await replication upon availability of suitable deep-phenotyped cohorts anywhere world-wide. Concisely, juvenile environmental risk accumulation, including cannabis and alcohol as starter/gateway drugs, strongly predicts polytoxicomania during adolescence and adulthood. This pivotal message should launch more effective sociopolitical measures to prevent this deleterious psychiatric condition.Childhood maltreatment is considered a risk factor for substance use disorders (SUD), but this is largely based on retrospective self-reports that are subject to recall bias, designs that do not control for familial confounding, or both. The specific contribution of childhood maltreatment to SUD risk thus remains unclear. Here, we evaluated this contribution in a prospective cohort with objectively recorded childhood maltreatment, using a design that allows controlling for familial confounding. We used medical records and registers to study 525 young adults (20-37 years) with prospectively and objectively documented severe maltreatment exposure, 1979 clinical controls (unexposed former child and adolescent psychiatry patients), 1388 matched healthy controls; and their siblings and cousins. We examined the association between maltreatment and SUD using Cox regression models in the population, as well as stratified within siblings in the same family. SUD risk was significantly increased with childhood maltreatment exposure (crude HR 6.61, 95% CI 5.81-7.53; HR adjusted for sex, birthyear, externalizing problems, parents' SUD and socioeconomic factors 3.50, 95% CI 2.95, 4.16). An approximately threefold elevated SUD risk remained when comparing exposed individuals with their unexposed siblings (adjusted HR 3.12, 95% CI 2.21, 4.42). We provide estimates of the association between childhood maltreatment and SUD accounting for possible confounds of both recall bias and familial factors. When familial confounding is controlled for, SUD risk attributable to severe childhood maltreatment is decreased, but nevertheless considerable. These findings establish a specific contribution of childhood maltreatment to SUD, underscoring the need for SUD prevention in young people exposed to maltreatment.Carbamazepine (CBZ)-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are strongly associated with the HLA-B*1502 allele. Screening HLA-B*1502 before CBZ administration might prevent CBZ-induced SJS/TEN by enabling clinicians to prescribe alternative therapy for positive patients. Similar to other Southeastern Asian countries, HLA-B*1502 is highly prevalent in Indonesia. Therefore, we assessed the economic value of HLA-B*1502 screening before CBZ prescription to patients with epilepsy in Indonesia. A generic cost-effectiveness model and decision support tool, developed to enable users to perform an initial cost-effectiveness analysis from a healthcare provider/payer perspective, were used to assess the value of HLA-B*1502 genotyping. The incremental cost-effectiveness ratio of adopting universal HLA-B*1502 screening was 656,444,671 Indonesian Rupiah (IDR)/quality-adjusted life year (QALY) gained for patients compared with 2,634,975,574 IDR/QALY gained for providing valproic acid (alternative drug) without screening. Thus, neither HLA-B*1502 screening nor substitution with VPA meets the Indonesian threshold for cost effectiveness. However, the improved outcomes with this test in other Asian countries may inform the desirability of implementation in Indonesia even with suboptimal cost-effectiveness.Selective serotonin reuptake inhibitors (SSRIs) are prescribed both to patients with schizophrenia and bipolar disorder. Previous studies have shown associations between SSRI treatment and cardiometabolic alterations. The aim of the present study was to investigate genetic variants associated with cardiometabolic adverse effects in patients treated with SSRIs in a naturalistic setting, using a genome-wide cross-sectional approach in a genetically homogeneous sample. We included and genotyped 1981 individuals with schizophrenia or bipolar disorder, of whom 1180 had information available on the outcomes low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein cholesterol (HDL-cholesterol), triglycerides, and body mass index (BMI) and investigated interactions between SNPs and SSRI use (N = 246) by conducting a genome-wide GxE analysis. We report 13 genome-wide significant interaction effects of SNPs and SSRI serum concentrations on LDL-cholesterol, HDL-cholesterol, and BMI, located in four distinct genomic loci. This study provides new insight into the pharmacogenetics of SSRI but warrants replication in independent populations.The classification of life forms into a hierarchical system (taxonomy) and the application of names to this hierarchy (nomenclature) is at a turning point in microbiology. The unprecedented availability of genome sequences means that a taxonomy can be built upon a comprehensive evolutionary framework, a longstanding goal of taxonomists. However, there is resistance to adopting a single framework to preserve taxonomic freedom, and ever increasing numbers of genomes derived from uncultured prokaryotes threaten to overwhelm current nomenclatural practices, which are based on characterised isolates. The challenge ahead then is to reach a consensus on the taxonomic framework and to adapt and scale the existing nomenclatural code, or create a new code, to systematically incorporate uncultured taxa into the chosen framework.Sulfate-reducing bacteria Candidatus Desulforudis audaxviator (CDA) were originally discovered in deep fracture fluids accessed via South African gold mines and have since been found in geographically widespread deep subsurface locations. In order to constrain models for subsurface microbial evolution, we compared CDA genomes from Africa, North America and Eurasia using single cell genomics. Unexpectedly, 126 partial single amplified genomes from the three continents, a complete genome from of an isolate from Eurasia, and metagenome-assembled genomes from Africa and Eurasia shared >99.2% average nucleotide identity, low frequency of SNP's, and near-perfectly conserved prophages and CRISPRs. Our analyses reject sample cross-contamination, recent natural dispersal, and unusually strong purifying selection as likely explanations for these unexpected results. We therefore conclude that the analyzed CDA populations underwent only minimal evolution since their physical separation, potentially as far back as the breakup of Pangea between 165 and 55 Ma ago. High-fidelity DNA replication and repair mechanisms are the most plausible explanation for the highly conserved genome of CDA. CDA presents a stark contrast to the current model organisms in microbial evolutionary studies, which often develop adaptive traits over far shorter periods of time.As an excitatory transmitter system, the glutamatergic transmitter system controls excitability and conductivity of neurons. Since both cardiomyocytes and neurons are excitable cells, we hypothesized that cardiomyocytes may also be regulated by a similar system. Here, we have demonstrated that atrial cardiomyocytes have an intrinsic glutamatergic transmitter system, which regulates the generation and propagation of action potentials. First, there are abundant vesicles containing glutamate beneath the plasma membrane of rat atrial cardiomyocytes. Second, rat atrial cardiomyocytes express key elements of the glutamatergic transmitter system, such as the glutamate metabolic enzyme, ionotropic glutamate receptors (iGluRs), and glutamate transporters. Third, iGluR agonists evoke iGluR-gated currents and decrease the threshold of electrical excitability in rat atrial cardiomyocytes. Fourth, iGluR antagonists strikingly attenuate the conduction velocity of electrical impulses in rat atrial myocardium both in vitro and in vivo. Knockdown of GRIA3 or GRIN1, two highly expressed iGluR subtypes in atria, drastically decreased the excitatory firing rate and slowed down the electrical conduction velocity in cultured human induced pluripotent stem cell (iPSC)-derived atrial cardiomyocyte monolayers. Finally, iGluR antagonists effectively prevent and terminate atrial fibrillation in a rat isolated heart model. In addition, the key elements of the glutamatergic transmitter system are also present and show electrophysiological functions in human atrial cardiomyocytes. In conclusion, our data reveal an intrinsic glutamatergic transmitter system directly modulating excitability and conductivity of atrial cardiomyocytes through controlling iGluR-gated currents. Manipulation of this system may open potential new avenues for therapeutic intervention of cardiac arrhythmias.
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