De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome.

Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.

Comparing resonant photon tunneling via cavity modes and Tamm plasmon polariton modes in metal-coated Bragg mirrors.

Resonant photon tunneling was investigated experimentally in multilayer structures containing a high-contrast (TiO(2)/SiO(2)) Bragg mirror capped with a semitransparent gold film. Transmission via a fundamental cavity resonance was compared with transmission via the Tamm plasmon polariton resonance that appears at the interface between a metal film and a one-dimensional photonic bandgap structure. The Tamm-plasmon-mediated transmission exhibits a smaller dependence on the angle and polarization of the incident light for similar values of peak transmission, resonance wavelength, and finesse. Implications for transparent electrical contacts based on resonant tunneling structures are discussed.

Functional renormalization group approach to the singlet-triplet transition in quantum dots.

We present a functional renormalization group approach to the zero bias transport properties of a quantum dot with two different orbitals and in the presence of Hund's coupling. Tuning the energy separation of the orbital states, the quantum dot can be driven through a singlet-triplet transition. Our approach, based on the approach by Karrasch et al (2006 Phys. Rev. B 73 235337), which we apply to spin-dependent interactions, recovers the key characteristics of the quantum dot transport properties with very little numerical effort. We present results on the conductance in the vicinity of the transition and compare our results both with previous numerical renormalization group results and with predictions of the perturbative renormalization group.

Art therapy improves experienced quality of life among women undergoing treatment for breast cancer: a randomized controlled study.

Women with breast cancer are naturally exposed to strain related to diagnosis and treatment, and this influences their experienced quality of life (QoL). The present paper reports the effect, with regard to QoL aspects, of an art therapy intervention among 41 women undergoing radiotherapy treatment for breast cancer. The women were randomized to an intervention group with individual art therapy sessions for 1 h/week (n = 20), or to a control group (n = 21). The WHOQOL-BREF and EORTC Quality of Life Questionnaire-BR23, were used for QoL assessment, and administrated on three measurement occasions, before the start of radiotherapy and 2 and 6 months later. The results indicate an overall improvement in QoL aspects among women in the intervention group. A significant increase in total health, total QoL, physical health and psychological health was observed in the art therapy group. A significant positive difference within the art therapy group was also seen, concerning future perspectives, body image and systemic therapy side effects. The present study provides strong support for the use of art therapy to improve QoL for women undergoing radiotherapy treatment for breast cancer.

A new radiological index for assessing asphericity of the femoral head in cam impingement.

Femoroacetabular cam impingement is thought to be a cause of premature osteoarthritis of the hip. The presence of cam malformation was determined in 2803 standardised anteroposterior (AP) pelvic radiographs from the Copenhagen Osteoarthritis Study by measuring the alpha (alpha) angle and the triangular index, a new measure of asphericity of the femoral head. In addition, the alpha-angle and the triangular index were assessed on the AP and lateral hip radiographs of 82 men and 82 women randomly selected from patients scheduled for total hip replacement (THR). The influence of varying femoral rotation on the alpha angle and the triangular index was also determined in femoral specimens under experimental conditions. From the 2803 radiographs the mean AP alpha-angle was 55 degrees (30 degrees to 100 degrees ) in men and 45 degrees (34 degrees to 108 degrees ) in women. Approximately 6% of men and 2% of women had cam malformation. The alpha-angle and triangular index were highly inter-related. Of those patients scheduled for THR, 36 men (44%) and 28 women (35%) had cam malformation identifiable on the AP radiographs. The triangular index proved to be more reliable in detecting cam malformation when the hip was held in varying degrees of rotation. The combination of the alpha-angle and the triangular index will allow examination of historical radiographs for epidemiological purposes in following the natural history of the cam deformity.

Language problems in poor readers.

In recent definitions of dyslexia there is agreement on the following: dyslexia is a language (-based) disorder restricted to difficulties in phonological processing abilities. This causes primary problems in word decoding and spelling, and, as a consequence, also in reading comprehension. This is in accordance with the widely accepted reading model, which regards decoding as a prerequisite for reading comprehension. In this paper, we will discuss the relevance of these definitions, and the reading model they are based on, using data from a longitudinal study of readers who were diagnosed as being language-impaired when they were pre-schoolers. This group will be compared with a control group having no history of language impairments and also with groups of adolescent and adult dyslexics.

Reading and writing development: report from an ongoing longitudinal study of language-disordered and normal groups from pre-school to adolescence.

This interim report provides information on an ongoing longitudinal study of 115 subjects, 78 language-disordered children and 39 children with no known language disorders as a control group. This follow-up study reports on a subgroup of the original subjects, 90 adolescents who completed a questionnaire, and 48 of the 90 who have been administered a full test battery compiled by the authors. Ongoing analyses indicate that early language problems are slow to resolve, persisting in one linguistic form or another in these adolescents who are now age 18 and about to leave school.

Identification and characterization of genomic nucleosome-positioning sequences.

Positioned nucleosomes are believed to play important roles in transcriptional regulation and for the organization of chromatin in cell nuclei. Here, we have isolated the DNA segments in the mouse genome that form the most stable nucleosomes yet characterized. In separate molecules we find phased runs of three to four adenine nucleotides, extensive CA repeats, and in a few cases phased TATA tetranucleotides. The latter forms the most stable nucleosome yet characterized. One sequence with CAG repeats was also found. By fluorescence in situ hydridization the selected sequences are shown to be localized at the centromeric regions of mouse metaphase chromosomes.

Pharmacy in Iceland.

OBJECTIVE: To summarize the practice of pharmacy in Iceland. DATA SOURCES: Human resources were the primary sources of data for this publication. Personal observation by Cleary is the basis of this publication. DATA EXTRACTION AND SYNTHESIS: Data on areas related to Icelandic history, practice of pharmacy, Icelandic health system, and the European Economic Community and Education were obtained through interviews. Information is presented to give an appreciation of pharmacy practice in a Nordic country. CONCLUSIONS: Pharmacy education and practice is progressive and flourishing in Iceland's National Health Service. Clinical pharmacy services are in their infancy; however, the potential for growth is immense. The Fulbright experience was educational and beneficial for all parties involved.

Heart rate control and aversive stimulation.

College students were required to train heart rate control (heart rate increase and decrease) with visual feedback for three sessions in a within-person design. In the second and third sessions a test period was added when electric shocks were delivered during half in the trials. Subjects had been grouped in advance in an Aware and an Unaware group on the basis of the Automatic Perception Questionnaire (APQ). The results contradicted some findings by other authors which claim that biofeedback can be used to ameliorate subjective effects of aversive stimulation. Alternative interpretations of the discrepant findings were discussed in terms of expectancy effects that may influence autonomically Aware subjects more strongly than Unaware subjects.

Physiological response patterns during "intake" and "rejection" tasks.

Two 2-min tasks, one requiring outer-directed attention (intake task), the other a mental arithmetic task (rejection task) were presented to 20 subjects. According to Lacey the distinguishing feature of the response to intake tasks are cardiac deceleration and blood pressure decreases. None of these responses was obtained. Some variables, however, were only affected by one of the tasks; the intake task led to a decreased hand (skin) blood flow and an increased hand vascular resistance, whereas a heart rate acceleration and increased forearm (muscle) blood flow and decreased forearm vascular resistance were observed during the rejection task. Blood pressure, respiration rate and skin conductance were similarly affected by the two tasks. Inconsistencies among previous studies of the response to the two types of tasks were discussed and found to be partially explained by methodological differences.

The effects of controlled muscle tension on performance and learning of heart-rate control.

Thirty female subjects were divided in three groups and instructed in group I to increase their HRs with the aid of continuous feedback of performance, while they tensed their right forearm muscles 20% of maximal voluntary contraction. In the last session only feedback was used, Group II were trained with feedback only. Group III for the first two sessions tensed their muscles only, and in the last session trained HR increases with feedback only. Group I was superior in HR performance in the first two sessions. In the third session they deteriorated significantly and could not be distinguished from the other two groups. The results were interpreted in terms of relations between somatic and autonomic events and transfer between different states of somatic involvement during learning. Electrodermal activity and respiration were included as control variables.