Association between Longitudinal Cerebrospinal Fluid Alzheimer's Biomarkers and the Lifestyle for Brain Health (LIBRA) Index: Findings from the European Prevention of Alzheimer's Dementia Cohort Study (EPAD LCS).

BACKGROUND: In the absence of preventative pharmacological interventions for Alzheimer's Disease dementia, there is a growing interest in modifiable risk factors associated with AD. Such risk factors are thought to contribute up to 40% of the risk of dementia. The Lifestyle for Brain Health (LIBRA) index, a dementia risk score which focuses exclusively on modifiable factors, has been found to be associated with increased risk of dementia and cognitive decline. It is currently unclear how the LIBRA index relates to cerebrospinal fluid (CSF) biomarkers of Alzheimer's Disease. OBJECTIVES: To examine the association between LIBRA index scores and trajectories of phospho-tau 181 and total tau in the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS), and to examine whether these trajectories differ between participants with high and low CSF amyloid-beta 1-42 (Aß42). DESIGN: Analysis of CSF biomarker and LIBRA index scores from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study. SETTING: The European Prevention of Alzheimer's Dementia Longitudinal Cohort Study is a multi-centre, pan-European study. MEASUREMENTS: Cerebrospinal fluid samples were taken by lumbar puncture and analysed using electrochemiluminescence. LIBRA index scores were calculated from self-reported variables, questionnaires, and physiological measurements. RESULT: In the total sample (n = 1715; mean age = 66.0, 56.4% female), there were no significant associations between LIBRA scores (mean = 0.73 points) and rate of change in cerebrospinal fluid biomarkers. In participants with high Aß, reflecting less deposition in the brain, (n = 1134), LIBRA scores were significantly associated with the rate of change in total tau, where higher LIBRA scores (denoting higher dementia risk) were associated with increases in t-tau. There were no significant associations between LIBRA scores and change in cerebrospinal biomarkers in participants with low Aß. CONCLUSION: We found an association between modifiable risk factors and total tau accumulation in participants without dementia and without Aß accumulation. This suggests that increasing levels of total tau may be driven by factors other than Aß accumulation and highlights the need for developing and examining tau-targeting drugs in Alzheimer's Disease development.

Nasal chondromesenchymal hamartoma: an update.

OBJECTIVE: Nasal chondromesenchymal hamartoma is a rare pathology that can present with a myriad of symptoms to ENT, maxillofacial and ophthalmology departments. This study reviewed the literature on nasal chondromesenchymal hamartoma as well as adding three new cases to the reported literature. METHOD: This study was an up-to-date review of the world literature with the addition of three new cases to provide the most comprehensive review to date. RESULTS: A total of 56 patients with nasal chondromesenchymal hamartoma were identified, ranging from children to adults. Nasal symptoms and ocular symptoms were most common, and surgical resection was the most frequent treatment modality. CONCLUSION: This study advocates for increased awareness of the condition associations for nasal chondromesenchymal hamartoma, multi-specialty treatment and the role for the ENT surgeon in treatment of the condition.

Spatiotemporal sensitivity of mesoderm specification to FGFR signalling in the Drosophila embryo.

Development of the Drosophila embryonic mesoderm is controlled through both internal and external inputs to the mesoderm. One such factor is Heartless (Htl), a Fibroblast Growth Factor Receptor (FGFR) expressed in the mesoderm. Although Htl has been extensively studied, the dynamics of its action are poorly understood after the initial phases of mesoderm formation and spreading. To begin to address this challenge, we have developed an optogenetic version of the FGFR Heartless in Drosophila (Opto-htl). Opto-htl enables us to activate the FGFR pathway in selective spatial (~ 35 µm section from one of the lateral sides of the embryo) and temporal domains (ranging from 40 min to 14 h) during embryogenesis. Importantly, the effects can be tuned by the intensity of light-activation, making this approach significantly more flexible than other genetic approaches. We performed controlled perturbations to the FGFR pathway to define the contribution of Htl signalling to the formation of the developing embryonic heart and somatic muscles. We find a direct correlation between Htl signalling dosage and number of Tinman-positive heart cells specified. Opto-htl activation favours the specification of Tinman positive cardioblasts and eliminates Eve-positive DA1 muscles. This effect is seen to increase progressively with increasing light intensity. Therefore, fine tuning of phenotypic responses to varied Htl signalling dosage can be achieved more conveniently than with other genetic approaches. Overall, Opto-htl is a powerful new tool for dissecting the role of FGFR signalling during development.

Psychological interventions for acute psychiatric inpatients with schizophrenia-spectrum disorders: A systematic review and meta-analysis.

BACKGROUND: Acute inpatient psychiatric wards are important yet challenging environments in which to implement psychological interventions for people with schizophrenia-spectrum disorders. No meta-analysis to date has evaluated whether psychological interventions are effective in this context. METHODS: We systematically searched Embase, Medline and PsycInfo databases for randomised controlled trials (RCTs) of psychological interventions implemented in acute inpatient psychiatric settings with individuals with schizophrenia-spectrum disorders. We conducted random effects meta-analyses of between-groups outcomes at post-intervention and relapse/re-hospitalisation rates by follow-up. RESULTS: Twenty-nine trials were suitable for meta-analysis. Psychological interventions improved post-intervention positive symptoms, social functioning and treatment compliance and reduced the risk of relapse/ re-hospitalisation, relative to control conditions. Analyses of specific intervention effects found positive effects of psychoeducation on several key outcomes (power > 80%) and preliminary evidence for positive effects of acceptance and commitment therapy (ACT), cognitive behaviour therapy (CBT) and metacognitive training (MCT) on some outcomes (power < 80%). CONCLUSION: Psychological interventions can be helpful for acute inpatients with schizophrenia-spectrum disorders. However, risk of bias was often high or unclear, and some analyses were underpowered. Further research should use more rigorous RCT designs and publish meta-analysable data on positive symptoms, general psychopathology, relapse/ re-hospitalisation, social functioning and treatment compliance.

Molecular action of pyriproxyfen: Role of the Methoprene-tolerant protein in the pyriproxyfen-induced sterilization of adult female mosquitoes.

Exposure of adult mosquitoes to pyriproxyfen (PPF), an analog of insect juvenile hormone (JH), has shown promise to effectively sterilize female mosquitoes. However, the underlying mechanisms of the PPF-induced decrease in mosquito fecundity are largely unknown. We performed a comprehensive study to dissect the mode of PPF action in Aedes aegypti mosquitoes. Exposure to PPF prompted the overgrowth of primary follicles in sugar-fed Ae. aegypti females but blocked the development of primary follicles at Christopher's Stage III after blood feeding. Secondary follicles were precociously activated in PPF-treated mosquitoes. Moreover, PPF substantially altered the expression of many genes that are essential for mosquito physiology and oocyte development in the fat body and ovary. In particular, many metabolic genes were differentially expressed in response to PPF treatment, thereby affecting the mobilization and utilization of energy reserves. Furthermore, PPF treatment on the previtellogenic female adults considerably modified mosquito responses to JH and 20-hydroxyecdysone (20E), two major hormones that govern mosquito reproduction. Krüppel homolog 1, a JH-inducible transcriptional regulator, showed consistently elevated expression after PPF exposure. Conversely, PPF upregulated the expression of several key players of the 20E regulatory cascades, including HR3 and E75A, in the previtellogenic stage. After blood-feeding, the expression of these 20E response genes was significantly weaker in PPF-treated mosquitoes than the solvent-treated control groups. RNAi-mediated knockdown of the Methoprene-tolerant (Met) protein, the JH receptor, partially rescued the impaired follicular development after PPF exposure and substantially increased the hatching of the eggs produced by PPF-treated female mosquitoes. Thus, the results suggested that PPF relied on Met to exert its sterilizing effects on female mosquitoes. In summary, this study finds that PPF exposure disturbs normal hormonal responses and metabolism in Ae. aegypti, shedding light on the molecular targets and the downstream signaling pathways activated by PPF.

Shaping Organs: Shared Structural Principles Across Kingdoms.

Development encapsulates the morphogenesis of an organism from a single fertilized cell to a functional adult. A critical part of development is the specification of organ forms. Beyond the molecular control of morphogenesis, shape in essence entails structural constraints and thus mechanics. Revisiting recent results in biophysics and development, and comparing animal and plant model systems, we derive key overarching principles behind the formation of organs across kingdoms. In particular, we highlight how growing organs are active rather than passive systems and how such behavior plays a role in shaping the organ. We discuss the importance of considering different scales in understanding how organs form. Such an integrative view of organ development generates new questions while calling for more cross-fertilization between scientific fields and model system communities.

Human immunodeficiency disease in new diagnoses of head and neck squamous cell cancer: are we testing?

BACKGROUND: Human immunodeficiency virus infected patients have a three-fold increased risk of head and neck squamous cell carcinoma. The British HIV Association recommends human immunodeficiency virus testing in all new diagnoses of head and neck squamous cell carcinoma. OBJECTIVES: This observational study aimed to examine the current routine practice of human immunodeficiency virus testing in patients with newly diagnosed head and neck squamous cell carcinoma, and to address the importance of this test in promoting the early diagnosis and treatment of human immunodeficiency virus. METHODS: All head and neck cancer multidisciplinary teams in England were questioned on their protocol for human immunodeficiency virus testing in new diagnoses of head and neck squamous cell carcinoma. RESULTS: Only 1 out of 30 hospitals leading head and neck multidisciplinary teams (3.3 per cent) routinely offered human immunodeficiency virus testing in this high-risk patient group. CONCLUSION: This observational study highlights that head and neck specialists are not aware of, and are consequently not complying with, routine human immunodeficiency virus testing as recommended by the British HIV Association guidelines.

Shaping the zebrafish myotome by intertissue friction and active stress.

Organ formation is an inherently biophysical process, requiring large-scale tissue deformations. Yet, understanding how complex organ shape emerges during development remains a major challenge. During zebrafish embryogenesis, large muscle segments, called myotomes, acquire a characteristic chevron morphology, which is believed to aid swimming. Myotome shape can be altered by perturbing muscle cell differentiation or the interaction between myotomes and surrounding tissues during morphogenesis. To disentangle the mechanisms contributing to shape formation of the myotome, we combine single-cell resolution live imaging with quantitative image analysis and theoretical modeling. We find that, soon after segmentation from the presomitic mesoderm, the future myotome spreads across the underlying tissues. The mechanical coupling between the future myotome and the surrounding tissues appears to spatially vary, effectively resulting in spatially heterogeneous friction. Using a vertex model combined with experimental validation, we show that the interplay of tissue spreading and friction is sufficient to drive the initial phase of chevron shape formation. However, local anisotropic stresses, generated during muscle cell differentiation, are necessary to reach the acute angle of the chevron in wild-type embryos. Finally, tissue plasticity is required for formation and maintenance of the chevron shape, which is mediated by orientated cellular rearrangements. Our work sheds light on how a spatiotemporal sequence of local cellular events can have a nonlocal and irreversible mechanical impact at the tissue scale, leading to robust organ shaping.

Generation of Amelx-iCre Mice Supports Ameloblast-Specific Role for Stim1.

The identification and targeting of the molecular pathways regulating amelogenesis is an ongoing challenge in dental research, and progress has been restricted by the limited number of genetic tools available to study gene function in ameloblasts. Here, we generated 4 transgenic Cre-driver mouse lines that express improved Cre (iCre)-recombinase from the locus of the mouse ameloblast-specific gene amelogenin X (Amelx-iCre) with a large (250-kb) bacterial artificial chromosome DNA vector. All 4 Amelx-iCre transgenic lines were bred with ROSA26 reporter mice to characterize the iCre developmental pattern with the LacZ gene encoding ß-galactosidase enzyme activity assay and Cre protein immunohistochemistry. From the 4 generated transgenic lines, 2 were selected for further analysis because they expressed a high amount of Cre recombinase exclusively in ameloblasts and showed developmental stage- and cell-specific ß-galactosidase activity mimicking the endogenous amelogenin expression. To test the functionality of the selected transgenic models, we bred the 2 Amelx-iCre mice lines with stromal interaction molecule 1 (Stim1) floxed mice to generate ameloblast-specific Stim1 conditional knockout mice (Stim1 cKO). STIM1 protein serves as one of the main calcium sensors in ameloblasts and plays a major role in enamel mineralization and ameloblast differentiation. Amelx-iCre mice displayed exclusive CRE-mediated recombination in incisor and molar ameloblasts. Stim1 cKO mice showed a severely defected enamel phenotype, including reduced structural integrity concomitant with increased attrition and smaller teeth. The phenotype and genotype of the Amelx-iCre/Stim1 cKO showed significant differences with the previously reported Ker14-Cre/Stim1 cKO, highlighting the need for cell- and stage-specific Cre lines for an accurate phenotype-genotype comparison. Furthermore, our model has the advantage of carrying the entire Amelx gene locus rather than being limited to an Amelx partial promoter construct, which greatly enhances the stability and the specificity of our Cre expression. As such, the Amelx-iCre transgenic lines that we developed may serve as a powerful tool for targeting ameloblast-specific gene expression in future investigations.

Videolaryngoscope-assisted flexible intubation tracheal tube exchange in a patient with a difficult airway.

An 88-year-old woman presented with acute airway obstruction caused by a large retrothyroid bleed following anterior neck trauma. Her airway was secured in the operating theatre with an awake nasal flexible optical bronchoscope tracheal intubation using an Intubating Laryngeal Mask Airway tracheal tube. Haemostasis was achieved following surgical ligation and the patient was transferred to the critical care unit. Postoperatively, a large leak around the tracheal tube was noted and a decision was made to change to an orotracheal tube with a subglottic drainage port. Our exchange technique required two experienced operators. The first operator used videolaryngoscopy with a hyperangulated blade to establish an optimal view of the larynx. The second operator placed an airway exchange catheter through the existing nasal tracheal tube to ensure airway control. The trachea was then intubated orally using a flexible optical bronchoscope observed under direct vision using the videolaryngoscope. The technique combined several simple and well-documented approaches, but importantly, the airway remained secure and visible throughout the procedure.

Isl1 mediates mesenchymal expansion in the developing external genitalia via regulation of Bmp4, Fgf10 and Wnt5a.

Genital malformations are among the most common human birth defects, and both genetic and environmental factors can contribute to these malformations. Development of the external genitalia in mammals relies on complex signaling networks, and disruption of these signaling pathways can lead to genital defects. Islet-1 (ISL1), a member of the LIM/Homeobox family of transcription factors, has been identified as a major susceptibility gene for classic bladder exstrophy in humans, a common form of the bladder exstrophy-epispadias complex (BEEC), and is implicated in a role in urinary tract development. We report that deletion of Isl1 from the genital mesenchyme in mice led to hypoplasia of the genital tubercle and prepuce, with an ectopic urethral opening and epispadias-like phenotype. These mice also developed hydroureter and hydronephrosis. Identification of ISL1 transcriptional targets via ChIP-Seq and expression analyses revealed that Isl1 regulates several important signaling pathways during embryonic genital development, including the BMP, WNT, and FGF cascades. An essential function of Isl1 during development of the external genitalia is to induce Bmp4-mediated apoptosis in the genital mesenchyme. Together, these studies demonstrate that Isl1 plays a critical role during development of the external genitalia and forms the basis for a greater understanding of the molecular mechanisms underlying the pathogenesis of BEEC and urinary tract defects in humans.

A global bibliometric analysis of otolaryngology: Head and neck surgery literature.

OBJECTIVE: Bibliometrics uses analysis of content and citations of journal articles to quantify trends in published data. We aim to use bibliometric analysis to identify the global contribution by country to the ENT surgical literature over a 5-year period. DATA SOURCE: The top 20 countries for number of articles published in surgery and the 11 English-language otolaryngology surgical journals with the highest impact factors (IF) were included. Numbers of scientific articles per year (2009-2013) per country for each journal were identified through PubMed. As a marker of quality, a mean IF for each country was calculated, using number of articles and journal IF. These data were compared against population, GDP and dollars spent on research. RESULTS: In total, 10 574 articles were included. The USA was the largest contributor, with 4462 articles published over 5 years. The second largest was the UK (1215 articles). Spain's mean IF was 2.136, followed by Taiwan (2.110). The Netherlands (19.7) and the UK (18.9) had the highest number of publications per million population. When considering overall research spending per country, Greece had the most cost-effective publication output. The least cost-effective country was Japan. India, Greece and Japan had the greatest increase in publication quality. CONCLUSIONS: Bibliometric analysis can be used to identify not only major centres of English-language ENT surgical research, such as the USA and UK but centres that are producing high-quality data, such as Spain, and cost-effective research, such as the UK. It can also highlight areas of increasing success in ENT research.

Interactions between sleep, movement and other non-movement behaviours in the pathogenesis of childhood obesity.

Research examining the health effects of physical activity, sedentary behaviour and sleep on different health outcomes has largely been conducted independently or in isolation of the other behaviours. However, the fact that time is finite (i.e. 24 h) suggests that the debate on whether or not the influence of a single behaviour is independent of another one is conceptually incorrect. Time spent in one behaviour should naturally depend on the composition of the rest of the day. Recent evidence using more appropriate analytical approaches to deal with this methodological issue shows that the combination of sleep, movement and non-movement behaviours matters and all components of the 24-h movement continuum should be targeted to enhance health and prevent childhood obesity. The objective of this review is to discuss research investigating how combinations of physical activity, sedentary behaviour and sleep are related to childhood obesity. Emerging statistical approaches (e.g. compositional data analysis) that can provide a good understanding of the best 'cocktail' of behaviours associated with lower adiposity and improved health are also discussed. Finally, future research directions are provided. Collectively, it becomes clearer that guidelines and public health interventions should target all movement behaviours synergistically to optimize health of children and youth around the world.

Australian consensus guidelines for the safe handling of monoclonal antibodies for cancer treatment by healthcare personnel.

These consensus guidelines provide recommendations for the safe handling of monoclonal antibodies. Definitive recommendations are given for the minimum safe handling requirements to protect healthcare personnel. The seven recommendations cover: (i) appropriate determinants for evaluating occupational exposure risk; (ii) occupational risk level compared with other hazardous and non-hazardous drugs; (iii) stratification of risk based on healthcare personnel factors; (iv) waste products; (v) interventions and safeguards; (vi) operational and clinical factors and (vii) handling recommendations. The seventh recommendation includes a risk assessment model and flow chart for institutions to consider and evaluate clinical and operational factors unique to individual healthcare services. These guidelines specifically evaluated monoclonal antibodies used in the Australian cancer clinical practice setting; however, the principles may be applicable to monoclonal antibodies used in non-cancer settings. The guidelines are only applicable to parenterally administered agents.

A comparison of the effectiveness of physical activity and sedentary behaviour interventions in reducing sedentary time in adults: a systematic review and meta-analysis of controlled trials.

The objective of this study was to systematically review the literature and compare the effectiveness of controlled interventions with a focus on physical activity (PA) and/or sedentary behaviours (SBs) for reducing sedentary time in adults. Six electronic databases were searched to identify all studies that examined the effects of interventions that targeted PA and/or SBs and that reported on changes in SBs (sedentary, sitting or television time). A qualitative synthesis was performed for all studies, and meta-analyses conducted among studies with mean differences (min/d) of sedentary time. PROSPERO: CRD42014006535. Sixty-five controlled studies met inclusion criteria; 33 were used in the meta-analyses. Interventions with a focus on PA or that included a PA and SB component produced less consistent findings and generally resulted in modest reductions in sedentary time (PA: standardized mean differences [SMD] = -0.22 [95% confidence interval {CI}: -0.35, -0.10], PA+SB: SMD= -0.37 [95% CI: -0.69, -0.05]). Moderate quality evidence from the randomized controlled trial meta-analysis coupled with the qualitative synthesis provides consistent evidence that large and clinically meaningful reductions in sedentary time can be expected from interventions with a focus on reducing SBs (SMD= -1.28 [95% CI: -1.68, -0.87] ). There is evidence to support the need for interventions to include a component focused on reducing SBs in order to generate clinically meaningful reductions in sedentary time.

A case of conservatively managed invasive ceruminoma and a review of the literature.

Ceruminomas are rare tumours arising from the apocrine sweat glands of the ear canal. We present a case of a malignant ceruminoma, which was managed with local surgical excision only rather than the wider clearance more commonly undertaken with these invasive neoplasms. We present the clinical case, histological analysis, and clinical progression for this patient and review the literature on this uncommon pathology.

The outcome of surgical treatment for peri-acetabular metastases.

We reviewed the outcome of patients who had been treated operatively for symptomatic peri-acetabular metastases and present an algorithm to guide treatment. The records of 81 patients who had been treated operatively for symptomatic peri-acetabular metastases between 1987 and 2010 were identified. There were 27 men and 54 women with a mean age of 61 years (15 to 87). The diagnosis, size of lesion, degree of pelvic continuity, type of reconstruction, World Health Organization performance status, survival time, pain, mobility and complications including implant failure were recorded in each case. The overall patient survivorship at five years was 5%. The longest lived patient survived 16 years from the date of diagnosis. The mean survival was 23 months (< 1 to 16 years) and the median was 15 months. At follow-up 14 patients remained alive. Two cementoplasties failed because of local disease progression. Three Harrington rods broke: one patient needed a subsequent Girdlestone procedure. One 'ice-cream cone' prosthesis dislocated and was subsequently revised without further problems. We recommend the 'ice-cream cone' for pelvic discontinuity and Harrington rod reconstruction for severe bone loss. Smaller defects can be safely managed using standard revision hip techniques.