Atypical audiovisual speech integration in infants at risk for autism

The language difficulties often seen in individuals with autism might stem from an inability to integrate audiovisual information, a skill important for language development. We investigated whether 9-month-old siblings of older children with autism, who are at an increased risk of developing autism, are able to integrate audiovisual speech cues. We used an eye-tracker to record where infants looked when shown a screen displaying two faces of the same model, where one face is articulating/ba/and the other/ga/, with one face congruent with the syllable sound being presented simultaneously, the other face incongruent. This method was successful in showing that infants at low risk can integrate audiovisual speech: they looked for the same amount of time at the mouths in both the fusible visual/ga/− audio/ba/and the congruent visual/ba/− audio/ba/displays, indicating that the auditory and visual streams fuse into a McGurk-type of syllabic percept in the incongruent condition. It also showed that low-risk infants could perceive a mismatch between auditory and visual cues: they looked longer at the mouth in the mismatched, non-fusible visual/ba/− audio/ga/display compared with the congruent visual/ga/− audio/ga/display, demonstrating that they perceive an uncommon, and therefore interesting, speech-like percept when looking at the incongruent mouth (repeated ANOVA: displays x fusion/mismatch conditions interaction: F(1,16) = 17.153, p = 0.001). The looking behaviour of high-risk infants did not differ according to the type of display, suggesting difficulties in matching auditory and visual information (repeated ANOVA, displays x conditions interaction: F(1,25) = 0.09, p = 0.767), in contrast to low-risk infants (repeated ANOVA: displays x conditions x low/high-risk groups interaction: F(1,41) = 4.466, p = 0.041). In some cases this reduced ability might lead to the poor communication skills characteristic of autism

Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin A-4 phosphate

BACKGROUND: This study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD). METHODS: Prospective, interventional, dose-escalation clinical trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly intravenous infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and physical examinations, electrocardiogram, routine laboratory tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiography, optical coherence tomography, and best corrected visual acuity (BCVA). RESULTS: The most common adverse events were elevated blood pressure (46.7%), QTc prolongation (23.3%), elevated temperature (13.3%), and headache (10%), followed by nausea and eye injection (6.7%). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was reduction of the excess foveal thickness by 24.15% at end of treatment period and by 43.75% at end of the two-month follow-up (p = 0.674 and 0.161, respectively). BCVA remained stable throughout the treatment and follow-up periods. CONCLUSIONS: The safety profile of intravenous CA4P was consistent with that reported in oncology trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current standard-of-care therapy

Enhancement of the anti-tumour effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine

The ability of the bioreductive drugs AQ4N and tirapazamine to enhance the anti-tumour effect of cyclophosphamide was assessed in three murine tumour models. In male BDF mice implanted with the T50/80 mammary carcinoma, AQ4N (50–150 mg kg−1) in combination with cyclophosphamide (100 mg kg−1) produced an effect equivalent to a single 200 mg kg−1dose of cyclophosphamide. Tirapazamine (25 mg kg−1) in combination with cyclophosphamide (100 mg kg−1) produced an effect equivalent to a single 150 mg kg−1dose of cyclophosphamide. In C3H mice implanted with the SCCVII or RIF-1 tumours, enhancement of tumour cell killing was found with both drugs in combination with cyclophosphamide (50–200 mg kg−1); AQ4N (50–200 mg kg−1) produced a more effective combination than tirapazamine (12.5–50 mg kg−1). Unlike tirapazamine, which showed a significant increase in toxicity to bone marrow cells, the combination of AQ4N (100 mg kg−1) 6 h prior to cyclophosphamide (100 mg kg−1) resulted in no additional toxicity towards bone marrow cells compared to that caused by cyclophosphamide alone. In conclusion, AQ4N gave a superior anti-tumour effect compared to tirapazamine when administered with a single dose of cyclophosphamide (100 mg kg−1). © 2000 Cancer Research Campaig

Conceptualising production, productivity and technology in pharmacy practice: a novel framework for policy, education and research.

CONTEXT AND BACKGROUND: People and health systems worldwide face serious challenges due to shifting disease demographics, rising population demands and weaknesses in healthcare provision, including capacity shortages and lack of impact of healthcare services. These multiple challenges, linked with the global push to achieve universal health coverage, have made apparent the importance of investing in workforce development to improve population health and economic well-being. In relation to medicines, health systems face challenges in terms of access to needed medicines, optimising medicines use and reducing risk. In 2017, the International Pharmaceutical Federation (FIP) published global policy on workforce development ('the Nanjing Statements') that describe an envisioned future for professional education and training. The documents make clear that expanding the pharmacy workforce benefits patients, and continually improving education and training produces better clinical outcomes. AIMS AND PURPOSE: The opportunities for harnessing new technologies in pharmacy practice have been relatively ignored. This paper presents a conceptual framework for analysing production methods, productivity and technology in pharmacy practice that differentiates between dispensing and pharmaceutical care services. We outline a framework that may be employed to study the relationship between pharmacy practice and productivity, shaped by educational and technological inputs. METHOD AND RESULTS: The analysis is performed from the point of view of health systems economics. In relation to pharmaceutical care (patient-oriented practice), pharmacists are service providers; however, their primary purpose is not to deliver consultations, but to maximise the quantum of health gain they secure. Our analysis demonstrates that 'technology shock' is clearly beneficial compared with orthodox notions of productivity or incremental gain implementations. Additionally, the whole process of providing professional services using 'pharmaceutical care technologies' is governed by local institutional frames, suggesting that activities may be structured differently in different places and countries. DISCUSSION AND CONCLUSION: Addressing problems with medication use with the development of a pharmaceutical workforce that is sufficient in quantity and competence is a long-term issue. As a result of this analysis, there emerges a challenge about the profession's relationship with existing and emerging technical innovations. Our novel framework is designed to facilitate policy, education and research by providing an analytical approach to service delivery. By using this approach, the profession could develop examples of good practice in both developed and developing countries worldwide

Perturbation with Intrabodies Reveals That Calpain Cleavage Is Required for Degradation of Huntingtin Exon 1

Background: Proteolytic processing of mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD), is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD. Methodology/Principal Findings: We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1) clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of soluble mHDx-1 by increasing clearance. While proteasome and macroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1-accelerated mHDx-1 clearance does not rely on these processes. In contrast, a calpain inhibitor or an inhibitor of lysosomal pH block Happ1-mediated acceleration of mHDx-1 clearance. These results suggest that mHDx-1 is cleaved by calpain, likely followed by lysosomal degradation and this process regulates the turnover rate of mHDx-1. Sequence analysis identifies amino acid (AA) 15 as a potential calpain cleavage site. Calpain cleavage of recombinant mHDx-1 in vitro yields fragments of sizes corresponding to this prediction. Moreover, when the site is blocked by binding of another intrabody, V_L12.3, turnover of soluble mHDx-1 in living cells is blocked. Conclusions/Significance: These results indicate that calpain-mediated removal of the 15 N-terminal AAs is required for the degradation of mHDx-1, a finding that may have therapeutic implications

A MIQE-Compliant Real-Time PCR Assay for Aspergillus Detection

PMCID: PMC3393739This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Analysis of factors influencing the ultrasonic fetal weight estimation

Objective: The aim of our study was the evaluation of sonographic fetal weight estimation taking into consideration 9 of the most important factors of influence on the precision of the estimation. Methods: We analyzed 820 singleton pregnancies from 22 to 42 weeks of gestational age. We evaluated 9 different factors that potentially influence the precision of sonographic weight estimation ( time interval between estimation and delivery, experts vs. less experienced investigator, fetal gender, gestational age, fetal weight, maternal BMI, amniotic fluid index, presentation of the fetus, location of the placenta). Finally, we compared the results of the fetal weight estimation of the fetuses with poor scanning conditions to those presenting good scanning conditions. Results: Of the 9 evaluated factors that may influence accuracy of fetal weight estimation, only a short interval between sonographic weight estimation and delivery (0-7 vs. 8-14 days) had a statistically significant impact. Conclusion: Of all known factors of influence, only a time interval of more than 7 days between estimation and delivery had a negative impact on the estimation

The magic nature of 132Sn explored through the single-particle states of 133Sn

Atomic nuclei have a shell structure where nuclei with 'magic numbers' of neutrons and protons are analogous to the noble gases in atomic physics. Only ten nuclei with the standard magic numbers of both neutrons and protons have so far been observed. The nuclear shell model is founded on the precept that neutrons and protons can move as independent particles in orbitals with discrete quantum numbers, subject to a mean field generated by all the other nucleons. Knowledge of the properties of single-particle states outside nuclear shell closures in exotic nuclei is important for a fundamental understanding of nuclear structure and nucleosynthesis (for example the r-process, which is responsible for the production of about half of the heavy elements). However, as a result of their short lifetimes, there is a paucity of knowledge about the nature of single-particle states outside exotic doubly magic nuclei. Here we measure the single-particle character of the levels in 133Sn that lie outside the double shell closure present at the short-lived nucleus 132Sn. We use an inverse kinematics technique that involves the transfer of a single nucleon to the nucleus. The purity of the measured single-particle states clearly illustrates the magic nature of 132Sn.Comment: 19 pages, 5 figures and 4 table

Massive migration from the steppe is a source for Indo-European languages in Europe

We generated genome-wide data from 69 Europeans who lived between 8,000-3,000 years ago by enriching ancient DNA libraries for a target set of almost four hundred thousand polymorphisms. Enrichment of these positions decreases the sequencing required for genome-wide ancient DNA analysis by a median of around 250-fold, allowing us to study an order of magnitude more individuals than previous studies and to obtain new insights about the past. We show that the populations of western and far eastern Europe followed opposite trajectories between 8,000-5,000 years ago. At the beginning of the Neolithic period in Europe, ~8,000-7,000 years ago, closely related groups of early farmers appeared in Germany, Hungary, and Spain, different from indigenous hunter-gatherers, whereas Russia was inhabited by a distinctive population of hunter-gatherers with high affinity to a ~24,000 year old Siberian6 . By ~6,000-5,000 years ago, a resurgence of hunter-gatherer ancestry had occurred throughout much of Europe, but in Russia, the Yamnaya steppe herders of this time were descended not only from the preceding eastern European hunter-gatherers, but from a population of Near Eastern ancestry. Western and Eastern Europe came into contact ~4,500 years ago, as the Late Neolithic Corded Ware people from Germany traced ~3/4 of their ancestry to the Yamnaya, documenting a massive migration into the heartland of Europe from its eastern periphery. This steppe ancestry persisted in all sampled central Europeans until at least ~3,000 years ago, and is ubiquitous in present-day Europeans. These results provide support for the theory of a steppe origin of at least some of the Indo-European languages of Europe

International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible