Synthese und trägerarme Radiofluorierung von A2A-Adenosin-Rezeptorliganden für die Positronen-Emissions-Tomographie

The A$_{2A}$ adenosine receptor (A$_{2A}$AR) localized in the brain has important roles in the regulationof glutamate and dopamine release. In several brain disorders like Parkinson`s disease theexpression profile of A$_{2A}$AR is altered which can be sensitively detected with the aid ofcorresponding radioligands for the positron emission tomography (PET). Therefore, the aim ofthe present study was to develop a potent and selective A$_{2A}$AR ligand radiolabeled with nocarrier-added (n.c.a.) [$^{18}$F]fluoride. A series of A$_{2A}$AR antagonists containing the benzothiazole as lead structure were preparedfor this project. Starting from 4-methoxy-7-morpholinobenzo[d]thiazol-2-amine, eight differentpotential radioligands were synthesized. In in vitro experiments the affinity and subtypeselectivity of different ligands for the A$_{2A}$AR and the complementary A$_{1}$ adenosine receptor(A$_{1}$AR) were determined. These experiments showed that 4-(fluormethyl)-4-hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)piperidine-1-carboxamide represented the mostpromising candidate. In a second step, various labelling precursors bearing different leavinggroups at the 1° hydroxyl function (mesylate, tosylate, nosylate), and different protectinggroups at the 3° hydroxyl function (THP, acetyl, Boc), and at the carboxamide nitrogen (POM,Boc) were prepared.The target ligand and the corresponding precursors were synthesized in sufficient amountsand purities and were characterized by appropriate physicochemical methods. Binding studiesrevealed a high affinity of 4-(fluormethyl)-4-hydroxy-N-(4-methoxy-7-morpholinobenzo[d]-thiazol-2-yl)piperidine-1-carboxamide for the A$_{2A}$AR (K$_{i}$ 0.7 nM and 2.1 nM) in combination witha high selectivity over the A$_{1}$AR (K$_{i}$ >> 1 $\mu$M). First radiofluorination experiments revealedincompatibility of the acetyl and THP protecting groups to the basic labelling conditions andresulted in dehydration. Therefore, alternative protection group strategies were developed toovercome these obstacles. The use of cyclic sulfites proved to be successful and the product4-([$^{18}$F]fluormethyl)-4-hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)piperidine-1-carboxamide was obtained after HPLC separation in 7$\pm$3 % radiochemical yields. Firstautoradiographic studies showed a highly affine and selective binding exclusively at thestriatum on rat brain slices with a low unspecific binding. Further in vivo studies will show, ifthis new ligand is suitable for in vivo PET-imaging

Izzivi in odzivi na ranljivost druzin na podrocju predsolske vzgoje

Problems in vulnerable families are multilayered and include the intersection of physical, psychosocial and other forms of distress. The multidimensional nature of the problems of these families is closely linked to the fact that there are many institutions in the field of education, social welfare, health care and others, in which treatment and support are not satisfactory or adapted to their needs. The article presents the partial results of a large-scale qualitative research study, results that refer to the position of vulnerable families in the context of preschool education. The study examined how vulnerability is experienced by parents of preschool children, how the expert workers in the preschools involved in the study responded to the parents’ vulnerability, and how they cooperated with experts from other services outside the preschool. A qualitative research method was used in the study. Data was collected partly through semi-structured interviews with various expert workers employed in two preschools, as well as with the parents of children in the preschools; the interviews were conducted individually and in focus groups. Using thematic analysis (Braun & Clarke, 2006), we have identified four representative themes: amongst parents, the two recurring themes can be subsumed under the headings “from door to door” and “adaptation/flexibility”, and amongst experts, under the headings “powerlessness/incompetence/lack of information” and “power/innovation/sensitivity”. The study finds that the ability to effectively contend with vulnerability presumes a reconceptualisation of the attitude of institutional preschool education towards the family, including a change in the professional role of preschool teachers. (DIPF/Orig.

Ridinilazole: A novel therapy for Clostridium difficile infection

Clostridium difficile infection (CDI) is the leading cause of infectious healthcare-associated diarrhoea. Recurrent CDI increases disease morbidity and mortality, posing a high burden to patients and a growing economic burden to the healthcare system. Thus, there exists a significant unmet and increasing medical need for new therapies for CDI. This review aims to provide a concise summary of CDI in general and a specific update on ridinilazole (formerly SMT19969), a novel antibacterial currently under development for the treatment of CDI. Owing to its highly targeted spectrum of activity and ability to spare the normal gut microbiota, ridinilazole provides significant advantages over metronidazole and vancomycin, the mainstay antibiotics for CDI. Ridinilazole is bactericidal against . C. difficile and exhibits a prolonged post-antibiotic effect. Furthermore, treatment with ridinilazole results in decreased toxin production. A phase 1 trial demonstrated that oral ridinilazole is well tolerated and specifically targets clostridia whilst sparing other faecal bacteria. Phase 2 and 3 trials will hopefully further our understanding of the clinical utility of ridinilazole for the treatment of CDI

Follow-Up Analysis of Genome-Wide Association Data Identifies Novel Loci for Type 1 Diabetes

OBJECTIVE—Two recent genome-wide association (GWA) studies have revealed novel loci for type 1 diabetes, a common multifactorial disease with a strong genetic component. To fully utilize the GWA data that we had obtained by genotyping 563 type 1 diabetes probands and 1,146 control subjects, as well as 483 case subject–parent trios, using the Illumina HumanHap550 BeadChip, we designed a full stage 2 study to capture other possible association signals

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Purpose We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. Methods We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. Results These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. Conclusion These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis

The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated to torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with TOR1A-AMC5 have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with fetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71% with higher mortality in males. Death occurred at a median age of 1.2 months (1 week - 9 years) due to respiratory failure, cardiac arrest, or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival

The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival

Teachers’ emotional expression in interaction with students of different ages

Emotions are an integral part of “classroom life” and are experienced in teacher-student interactions quite often (Hosotani & Imai-Matsumura, 2011). The present study focuses on teachers’ emotions in classrooms. Its purpose is to establish which emotions are expressed by teachers in their interactions with students, the triggering situations of the two most frequent emotions, and their level of intensity and suitability. Teachers’ emotions were observed by students of primary education during their practical experience work, in grades one to five. They used a scheme constructed for observing different aspects of emotions. The observations of 108 teachers in 93 primary schools from various Slovenian regions were gathered. The results show that primary school teachers express various pleasant and unpleasant emotions, with unpleasant emotions prevailing. The average frequency of teachers’ emotion expression decreased from grade one to five. Anger was the most frequently expressed emotion (N= 261), followed by joy (N = 151). Teachers’ anger and joy were triggered in different situations: anger predominantly when students lacked discipline and joy predominantly in situations of students’ academic achievement. The intensity of expressed anger and joy was moderate in all five grades, while the assessed suitability of these two emotions was high. (DIPF/Orig.