Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model.

The phosphoinositide-3-kinase (PI3K) family plays a major role in cell signaling and is predominant in leukocytes. Gain-of-function (GOF) mutations in the PIK3CD gene lead to the development of activated PI3Kδ syndrome (APDS), a rare primary immunodeficiency disorder. A subset of APDS patients also displays neurodevelopmental delay symptoms, suggesting a potential role of PIK3CD in cognitive and behavioural function. However, the extent and nature of the neurodevelopmental deficits has not been previously quantified. Here, we assessed the cognitive functions of two APDS patients, and investigated the causal role of the PIK3CD GOF mutation in neurological deficits using a murine model of this disease. We used p110δE1020K knock-in mice, harbouring the most common APDS mutation in patients. We found that APDS patients present with visuomotor deficits, exacerbated by autism spectrum disorder comorbidity, whereas p110δE1020K mice exhibited impairments in motor behaviour, learning and repetitive behaviour patterning. Our data indicate that PIK3CD GOF mutations increase the risk for neurodevelopmental deficits, supporting previous findings on the interplay between the nervous and the immune system. Further, our results validate the knock-in mouse model, and offer an objective assessment tool for patients that could be incorporated in diagnosis and in the evaluation of treatments

Expectations, perceptions, and physiotherapy predict prolonged sick leave in subacute low back pain

<p>Abstract</p> <p>Background</p> <p>Brief intervention programs for subacute low back pain (LBP) result in significant reduction of sick leave compared to treatment as usual. Although effective, a substantial proportion of the patients do not return to work. This study investigates predictors of return to work in LBP patients participating in a randomized controlled trial comparing a brief intervention program (BI) with BI and physical exercise.</p> <p>Methods</p> <p>Predictors for not returning to work was examined in 246 patients sick listed 8-12 weeks for low back pain. The patients had participated in a randomized controlled trial, with BI (n = 122) and BI + physical exercise (n = 124). There were no significant differences between the two intervention groups on return to work. The groups were therefore merged in the analyses of predictors. Multiple logistic regression analysis was used to identify predictors for non return to work at 3, 12, and 24 months of follow-up.</p> <p>Results</p> <p>At 3 months of follow-up, the strongest predictors for not returning to work were pain intensity while resting (OR = 5.6; CI = 1.7-19), the perception of constant back strain when working (OR = 4.1; CI = 1.5-12), negative expectations for return to work (OR = 4.2; CI = 1.7-10), and having been to a physiotherapist prior to participation in the trial (OR = 3.3; CI = 1.3-8.3). At 12 months, perceived reduced ability to walk far due to the complaints (OR = 2.6; CI = 1.3-5.4), pain during activities (OR = 2.4; CI = 1.1-5.1), and having been to a physiotherapist prior to participation in the trial (OR = 2.1; CI = 1.1-4.3) were the strongest predictors for non return to work. At 24 months age below 41 years (OR = 2.9; CI = 1.4-6.0) was the only significant predictor for non return to work.</p> <p>Conclusion</p> <p>It appears that return to work is highly dependant on individual and cognitive factors. Patients not returning to work after the interventions were characterized by negative expectations, perceptions about pain and disability, and previous physiotherapy treatment. This is the first study reporting that previous treatment by physiotherapists is a risk factor for long-term sick leave. This has not been reported before and is an interesting finding that deserves more scrutiny.</p

Generic mechanism for generating a liquid-liquid phase transition

Recent experimental results indicate that phosphorus, a single-component system, can have two liquid phases: a high-density liquid (HDL) and a low-density liquid (LDL) phase. A first-order transition between two liquids of different densities is consistent with experimental data for a variety of materials, including single-component systems such as water, silica and carbon. Molecular dynamics simulations of very specific models for supercooled water, liquid carbon and supercooled silica, predict a LDL-HDL critical point, but a coherent and general interpretation of the LDL-HDL transition is lacking. Here we show that the presence of a LDL and a HDL can be directly related to an interaction potential with an attractive part and two characteristic short-range repulsive distances. This kind of interaction is common to other single-component materials in the liquid state (in particular liquid metals), and such potentials are often used to decribe systems that exhibit a density anomaly. However, our results show that the LDL and HDL phases can occur in systems with no density anomaly. Our results therefore present an experimental challenge to uncover a liquid-liquid transition in systems like liquid metals, regardless of the presence of the density anomaly.Comment: 5 pages, 3 ps Fig

Anti-müllerian hormone is not associated with cardiometabolic risk factors in adolescent females

&lt;p&gt;Objectives: Epidemiological evidence for associations of Anti-Müllerian hormone (AMH) with cardiometabolic risk factors is lacking. Existing evidence comes from small studies in select adult populations, and findings are conflicting. We aimed to assess whether AMH is associated with cardiometabolic risk factors in a general population of adolescent females.&lt;/p&gt; &lt;p&gt;Methods: AMH, fasting insulin, glucose, HDLc, LDLc, triglycerides and C-reactive protein (CRP) were measured at a mean age 15.5 years in 1,308 female participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Multivariable linear regression was used to examine associations of AMH with these cardiometabolic outcomes.&lt;/p&gt; &lt;p&gt;Results: AMH values ranged from 0.16–35.84 ng/ml and median AMH was 3.57 ng/ml (IQR: 2.41, 5.49). For females classified as post-pubertal (n = 848) at the time of assessment median (IQR) AMH was 3.81 ng/ml (2.55, 5.82) compared with 3.25 ng/ml (2.23, 5.05) in those classed as early pubertal (n = 460, P≤0.001). After adjusting for birth weight, gestational age, pubertal stage, age, ethnicity, socioeconomic position, adiposity and use of hormonal contraceptives, there were no associations with any of the cardiometabolic outcomes. For example fasting insulin changed by 0% per doubling of AMH (95%CI: −3%,+2%) p = 0.70, with identical results if HOMA-IR was used. Results were similar after additional adjustment for smoking, physical activity and age at menarche, after exclusion of 3% of females with the highest AMH values, after excluding those that had not started menarche and after excluding those using hormonal contraceptives.&lt;/p&gt; &lt;p&gt;Conclusion: Our results suggest that in healthy adolescent females, AMH is not associated with cardiometabolic risk factors.&lt;/p&gt

Impaired neutralising antibody formation and high transduction efficacy after isolated hepatic perfusion with adenoviral vectors

Local adenoviral gene transfer can be performed by means of isolated hepatic perfusion (IHP). This methodology is a very effective and safe way to deliver adenoviral vectors. We studied the immune response after IHP, A decreased neutralising antibody formation was observed, offering possibilities for further research in the field of gene therapy in isolated perfusion settings

Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods: We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results: We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions: We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD

Ecosystem restoration strengthens pollination network resilience and function.

Land degradation results in declining biodiversity and the disruption of ecosystem functioning worldwide, particularly in the tropics. Vegetation restoration is a common tool used to mitigate these impacts and increasingly aims to restore ecosystem functions rather than species diversity. However, evidence from community experiments on the effect of restoration practices on ecosystem functions is scarce. Pollination is an important ecosystem function and the global decline in pollinators attenuates the resistance of natural areas and agro-environments to disturbances. Thus, the ability of pollination functions to resist or recover from disturbance (that is, the functional resilience) may be critical for ensuring a successful restoration process. Here we report the use of a community field experiment to investigate the effects of vegetation restoration, specifically the removal of exotic shrubs, on pollination. We analyse 64 plant-pollinator networks and the reproductive performance of the ten most abundant plant species across four restored and four unrestored, disturbed mountaintop communities. Ecosystem restoration resulted in a marked increase in pollinator species, visits to flowers and interaction diversity. Interactions in restored networks were more generalized than in unrestored networks, indicating a higher functional redundancy in restored communities. Shifts in interaction patterns had direct and positive effects on pollination, especially on the relative and total fruit production of native plants. Pollinator limitation was prevalent at unrestored sites only, where the proportion of flowers producing fruit increased with pollinator visitation, approaching the higher levels seen in restored plant communities. Our results show that vegetation restoration can improve pollination, suggesting that the degradation of ecosystem functions is at least partially reversible. The degree of recovery may depend on the state of degradation before restoration intervention and the proximity to pollinator source populations in the surrounding landscape. We demonstrate that network structure is a suitable indicator for pollination quality, highlighting the usefulness of interaction networks in environmental management

Copy number variation in Williams-Beuren syndrome: suitable diagnostic strategy for developing countries

<p>Abstract</p> <p>Background</p> <p>Williams-Beuren syndrome (WBS; OMIM 194050) is caused by a hemizygous contiguous gene microdeletion at 7q11.23. Supravalvular aortic stenosis (SVAS), mental retardation, and overfriendliness comprise typical symptoms of WBS. Although fluorescence in situ hybridization (FISH) is considered the gold standard technique, the microsatellite DNA markers and multiplex ligation-dependent probe amplification (MLPA) could be used for to confirm the diagnosis of WBS.</p> <p>Results</p> <p>We have evaluated a total cohort of 88 patients with a suspicion clinical diagnosis of WBS using a collection of five markers (D7S1870, D7S489, D7S613, D7S2476, and D7S489_A) and a commercial MLPA kit (P029). The microdeletion was present in 64 (72.7%) patients and absent in 24 (27.3%) patients. The parental origin of deletion was maternal in 36 of 64 patients (56.3%) paternal in 28 of 64 patients (43.7%). The deletion size was 1.55 Mb in 57 of 64 patients (89.1%) and 1.84 Mb in 7 of 64 patients (10.9%). The results were concordant using both techniques, except for four patients whose microsatellite markers were uninformative. There were no clinical differences in relation to either the size or parental origin of the deletion.</p> <p>Conclusion</p> <p>MLPA was considered a faster and more economical method in a single assay, whereas the microsatellite markers could determine both the size and parental origin of the deletion in WBS. The microsatellite marker and MLPA techniques are effective in deletion detection in WBS, and both methods provide a useful diagnostic strategy mainly for developing countries.</p