Eosinophils are recruited to sites of inflammation via the action of a number of chemical mediators, including PAF, leukotrienes, eotaxins, ECF-A and histamine. Although many of the cell-surface receptors for these mediators have been identified, histamine-driven chemotaxis has not been conclusively attributed to any of the three known histamine receptor subtypes, suggesting the possibility of a 4th histamine-responsive receptor on eosinophils. We have identified and cloned a novel G protein-coupled receptor (GPCR), termed Pfi-013, from an IL-5 stimulated eosinophil cDNA library which is homologous to the human histamine H3 receptor, both at the sequence and gene structure level. Expression data indicates that Pfi-013 is predominantly expressed in peripheral blood leukocytes, with lower expression levels in spleen, testis and colon. Ligand-binding studies using Pfi-013 expressed in HEK-293Galpha15 cells, demonstrates specific binding to histamine with a Kd of 3.28 +/- 0.76 nM and possesses a unique rank order of potency against known histaminergic compounds in a competitive ligand-binding assay (histamine > clobenpropit > iodophenpropit > thioperamide > R-alpha-methylhistamine > cimetidine > pyrilamine). We have therefore termed this receptor human histamine H4. Chemotaxis studies on isolated human eosinophils have confirmed that histamine is chemotactic and that agonists of the known histamine receptors (H1, H2, and H3) do not induce such a response. Furthermore, studies employing histamine-receptor antagonists have shown an inhibition of chemotaxis only by the H3 antagonists clobenpropit and thioperamide. Since these compounds are also antagonists of hH4 we postulate that the receptor mediating histaminergic chemotaxis is this novel histamine H4 receptor.

Two functionally related genes, FOXP2 and CNTNAP2, influence language abilities in families with rare syndromic and common nonsyndromic forms of impaired language, respectively. We investigated whether these genes are associated with component phenotypes of dyslexia and measures of sequential motor ability. Quantitative transmission disequilibrium testing (QTDT) and linear association modeling were used to evaluate associations with measures of phonological memory (nonword repetition, NWR), expressive language (sentence repetition), reading (real word reading efficiency, RWRE; word attack, WATT), and timed sequential motor activities (rapid alternating place of articulation, RAPA; finger succession in the dominant hand, FS-D) in 188 family trios with a child with dyslexia. Consistent with a prior study of language impairment, QTDT in dyslexia showed evidence of CNTNAP2 single nucleotide polymorphism (SNP) association with NWR. For FOXP2, we provide the first evidence for SNP association with component phenotypes of dyslexia, specifically NWR and RWRE but not WATT. In addition, FOXP2 SNP associations with both RAPA and FS-D were observed. Our results confirm the role of CNTNAP2 in NWR in a dyslexia sample and motivate new questions about the effects of FOXP2 in neurodevelopmental disorders.

In 10 cases of 2p15p16.1 microdeletions reported worldwide to date, shared phenotypes included growth retardation, craniofacial and skeletal dysmorphic traits, internal organ defects, intellectual disability, nonverbal or low verbal status, abnormal muscle tone, and gross motor delays. The size of the deletions ranged from 0.3 to 5.7 Mb, where the smallest deletion involved the BCL11A, PAPOLG, and REL genes. Here we report on an 11-year-old male with a heterozygous de novo 0.2 Mb deletion containing a single gene, BCL11A, and a phenotype characterized by childhood apraxia of speech and dysarthria in the presence of general oral and gross motor dyspraxia and hypotonia as well as expressive language and mild intellectual delays. BCL11A is situated within the dyslexia susceptibility candidate region 3 (DYX3) candidate region on chromosome 2. The present case is the first to involve a single gene within the microdeletion region and a phenotype restricted to a subset of the traits observed in other cases with more extensive deletions.

Background: Physical exercise has a positive effect on cognitive performance and quality of life (QoL). One reason for this is the upregulation of brain-derived neurotrophic factor, which improves brain plasticity. Intermittent hypoxia promotes first the proliferation of endogenous neuroprogenitors which leads to an increased number of newborn neurons and second the expression of brain-derived neurotrophic factor in the adult hippocampus. Intermittent hypoxia may, therefore, support synaptic plasticity, the process of learning and provoke antidepressant-like effects. Hence, intermittent hypoxia might also lead to improved cognitive functioning and QoL. Objective: This study aims to evaluate to what extent physical activity with preceded intermittent hypoxic training is more effective than solely strength-endurance training on cognitive performance and QoL. Methods: 34 retired people aged between 60 and 70 years were randomly assigned to a control group or intervention group. Contrarily to the control group, which was supplied with a placebo air mixture, the intervention group was supplied with an intermittent hypoxic training prior to a strength-endurance exercise program. The cognitive performance of individuals was examined using the d2 test and the Number Combination Test (ZVT) both before and after the exercise program. We assessed QoL with the Medical Outcomes Study Short-Form 36-Item Health Survey (SF-12) and Pittsburgh Sleep Quality Index (PSQI) and the strength-endurance capacity using the Spring test. Results: Regarding the d2 test, a time × group effect was observed. Speed of cognitive performance in seconds was measured using ZVT. Here, no interaction effect was discovered. An interaction effect was not found in the Physical Component Summary scores (SF-12). Regarding the Mental Component Summary, an interaction effect just failed to become statistically significant. Furthermore, we determined sleep quality with the PSQI. Here, an interaction effect was observed. The analysis of the strength-endurance test revealed no interaction effects. Conclusion: The data of the current study suggest that an additional intermittent hypoxic training combined with physical exercise augments the positive effects of exercise on cognitive performance and QoL in elderly humans.