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Purpose of review Virtually all viruses have evolved molecular instruments to circumvent cell mechanisms that may hamper their replication, dissemination, or persistence. Among these is p53, a key gatekeeper for cell division and survival that also regulates innate immune responses. This review summarizes the strategies used by different viruses and discusses the mechanisms deployed by SARS-CoV to target p53 activities. Recent findings We propose a typology for the strategies used by different viruses to address p53 functions: hit and run (e.g. IAV, ZIKV), hide and seek (e.g. HIV1), kidnap and exploit (e.g. EBV, HSV1), dominate and suppress (e.g. HR HPV). We discuss the mechanisms by which SARS nsp3 protein targets p53 for degradation and we speculate on the significance for Covid-19 pathogenesis and risk of cancer. Summary p53 may operate as an intracellular antiviral defense mechanism. To circumvent it, SARS viruses adopt a kidnap and exploit strategy also shared by several viruses with transforming potential. This raises the question of whether SARS infections may make cells permissive to oncogenic DNA damage.

Saliva is a complex secretion consisting of 99% of water and remaining 1% of organic and inorganic molecules. Sucrose and starches are the predominant dietary carbohydrates in modern societies. Among all the foods consumed by children, chocolates and biscuits are the most common. Therefore this present in vivo study was conducted to assess the acidogenic effect of commercially available biscuits on salivary pH among 10 to 15 years old children. Study Design used in the study was In Vivo clinical study (Pilot Trail). The population collected in the survey was children between the age group of 10 - 15 years old children. 4 Groups were considered and 10 in each group. Group 1: Hide and Seek, Group 2: Good Day, Group 3: Dream and Cream, Group 4: Oreo. Sampling method used in the study was conducted as simple random sampling. Ethical approval of the study was obtained from Saveetha Institutional Review Board. Informed consent of the children were obtained from the parents. Descriptive statistics were expressed by means of mean and standard deviation. Shapiro Wilks test used to test the normality of the data set. Kruskal Wallis test was used to find the difference in mean Salivary pH between the groups and within the groups at Baseline, Immediate and after 15 min, 30 mins. A statistically significant difference in mean Salivary pH was observed between the groups at Immediate and after 30 mins (p

This research aims to analyze the main characters in Hide and Seek movie as the characters who have psychopathic problem and Dissociative Identity Disorder. In relation to which, the writer studied Hide and Seek movie as the unit of analysis. Psychopathic problems viewed from Sigmund Freud’s psychoanalysis concepts are used for the review of related literature theories or concepts of the research. Therefore, the method of the research is descriptive qualitative, which tries to explain about the intrinsic elements of the movie; such as characterization and the scenes of the movie, then followed by analyzing them through Sigmund Freud’s psychoanalysis. Through observations of the scenes and the behavior of the main characters the writer reveals David and Emily have been identified to have psychopathic characters such as manipulative, parasitical, deceitful, power hungry, less empathy, often lie, shallow affect and poor behavioral control. In addition, the causes of such character are trauma and stress viewed from Sigmund Freud’s psychoanalysis theory

Gopal and Rao’s editorial made me reflect on five important UK reports published in the past year, generating controversy about institutional and structural racism.1 The UK government commissioned Public Health England (PHE) to report on inequalities in covid-19, including ethnicity.2 The report was criticised for having no recommendations and no reference to extensive public consultations by PHE. A second report including the consultations with more than …

Squamous cell carcinoma is the second most common malignancy of the skin after basal cell carcinoma and mainly found in sun-exposed areas such as the face. This mostly locally destructive malignancy may show invasive growth and insidious mechanisms of dissemination such as perineural invasion. Periorbital squamous cell carcinoma is associated with perineural invasion in up to 14 % of cases. Specifically in this region, the proximity to cranial nerves and therefore the associated risk of progression to the central nervous system are associated with poor prognosis. The clinically concealed character of this entity often leads to a delay in diagnosis and consequently makes complete resection and reconstruction demanding. Careful clinical evaluation often hints at perineural invasion before obtaining histology. Aside from presenting five challenging cases, this work analyzes risk factors, clinical as well as histological features, and treatment options for periorbital squamous cell carcinoma with perineural invasion.

Wolff-Parkinson-White (WPW) syndrome is an uncommon form of cardiac preexcitation due to an underlying structural accessory pathway, which may lead to potentially lethal arrhythmias. Classic electrocardiogram (ECG) findings of WPW include short PR interval, slurred upstroke of the QRS complex, and prolonged QRS duration. However, in intermittent preexcitation, a rare variant in contrast to continuous preexcitation, these findings are not always present, thus masking a diagnosis of WPW syndrome. Consequently, this may adversely affect or delay the appropriate treatment of short-term tachyarrhythmias and long-term definitive therapies for this syndrome. The emergency physician should promptly obtain an ECG after the termination of any tachyarrhythmia, and maintain a high index of suspicion for intermittent preexcitation with typical WPW ECG findings which were not present on prior studies. The authors present a case of a 17-year-old female diagnosed with an intermittent preexcitation variant of WPW syndrome after a case of successfully treated symptomatic supraventricular tachycardia (SVT).

The role of somatic SMAD3 mutations in melorheostosis pathogenesis, In the current issue of JEM, Kang et al. (https://doi.org/10.1084/jem.20191499) describe somatic mutations in the SMAD3 gene causing endosteal melorheostosis. Using osteoblast models, the identified mutations are demonstrated to exert a gain-of-function mechanism, augmenting transforming growth factor (TGF) β signaling. These findings provide further insights into the genetic etiology of melorheostosis and consolidate the importance of the TGFβ pathway in skeletal disorders.

Background Early defibrillation is a critical link in the chain of survival. Public access defibrillation (PAD) programmes utilising automated external defibrillators (AEDs) aim to decrease the time-to-first-shock, and improve survival from out-of-hospital cardiac arrest. Effective use of PADs requires rapid location of the device, facilitated by adequate signage. We aimed to therefore assess the quality of signage for PADs in the community. Method From April 2017 to January 2018 we surveyed community PADs available for public use on the ‘Save a Life’ AED locator mobile application in and around Southampton, UK. Location and signage characteristics were collected, and the distance from the furthest sign to the AED was measured. Results Researchers evaluated 201 separate PADs. All devices visited were included in the final analysis. No signage at all was present for 135 (67.2%) devices. Only 15/201 (7.5%) AEDs had signage at a distance from AED itself. In only 5 of these cases (2.5%) was signage mounted more than 5.0 m from the AED. When signage was present, 46 used 2008 ILCOR signage and 15 used 2006 Resuscitation Council (UK) signage. Signage visibility was partially or severely obstructed at 27/66 (40.9%) sites. None of the 45 GP surgeries surveyed used exterior signage or an exterior 24/7 access box. Conclusions Current signage of PADs is poor and limits the device effectiveness by impeding public awareness and location of AEDs. Recommendations should promote visible signage within the operational radius of each AED.

BACKGROUND: Half of inflammatory myofibroblastic tumors (IMTs) regardless of anatomic location harbor ALK gene rearrangements and overexpress ALK protein. The wide application of next generation sequencing (NGS) and the clinical benefit to tyrosine kinase inhibitors have opened new opportunities for investigation of ALK-negative IMT. DESIGN: In this study we investigate a series of pediatric and adult thoracic IMT for abnormalities in a wide spectrum of actionable kinases, by applying a variety of molecular and NGS techniques, including FISH, targeted RNA sequencing and NanoString. RESULTS: There were 33 thoracic IMTs, with a mean age of 37, including 5 children. Tumors showed a monomorphic spindle cell phenotype, except one with epithelioid morphology and moderate to severe atypia. By IHC, 24 cases were ALK positive, of which by FISH, 19 showed ALK rearrangements and 1 RET gene rearrangement. RNA sequencing was performed in the remaining 4 cases lacking ALK abnormalities by FISH, revealing ALK fusions in 3 cases, involving TMP4 and EML4 genes. NanoString was performed in the remaining case, revealing ALK-alternative transcription initiation (ALK(ATI)). Nine cases lacking ALK abnormalities were further tested by FISH or targeted RNA sequencing, revealing ROS1 rearrangement in 6 cases and ETV6-NTRK3 fusion in 3, respectively. CONCLUSIONS: By employing a battery of complementary molecular techniques, all thoracic IMTs harbored a tyrosine kinase abnormality, with 30% outside the ALK kinase, including gene fusions involving ROS1, NTRK3, and RET. We also describe for the first time ALK(ATI)-induced ALK oncogenic activation is involved in the pathogenesis of IMTs.

With 40% of the world population at risk, infections with dengue virus (DENV) constitute a serious threat to public health. While there is no antiviral therapy available against this potentially lethal disease, the efficacy of the only approved vaccine is not optimal and its safety has been recently questioned. In order to develop better vaccines based on attenuated and/or chimeric viruses, one must consider how the human immune system is engaged during DENV infection. The activation of the innate immunity through the detection of viruses by cellular sensors is the first line of defence against those pathogens. This triggers a cascade of events which establishes an antiviral state at the cell level and leads to a global immunological response. However, DENV has evolved to interfere with the innate immune signalling at multiple levels, hence dampening antiviral responses and favouring viral replication and dissemination. This review elaborates on the interplay between DENV and the innate immune system. A special focus is given on the viral countermeasure mechanisms reported over the last decade which should be taken into consideration during vaccine development.

The enhanced ability of cancer stem cells (CSCs) to give rise to new tumors suggests that these cells may also have an advantage in evading immune detection and elimination. This tumor-forming ability, combined with the known plasticity of the immune system, which can play both protumorigenic and antitumorigenic roles, has motivated investigations into the interaction between CSCs and the immune system. Herein, we review the interplay between host immunity and CSCs by examining the immune-related mechanisms that favor CSCs and the CSC-mediated expansion of protumorigenic immune cells. Furthermore, we discuss immune cells, such as natural killer cells, that preferentially target CSCs and the strategies used by CSCs to evade immune detection and destruction. An increased understanding of these interactions and the pathways that regulate them may allow us to harness immune system components to create new adjuvant therapies that eradicate CSCs and improve patient survival.

Background: The etiology of stroke remains unknown over 25% of cases. Stroke with Large Vessel Occlusion (LVO) treated with endovascular treatment (EVT) and complete recanalization are a good group to analyze efficiency of diagnosis studies. After hospitalization the percentage and clinical impact of hidden atrial fibrillation (AF) diagnosis in embolic strokes of unknown source are uncertain. Methods: We reviewed patients treated with EVT from 2010 to 2016. We evaluated percentage of cases with new clinical diagnosis of atrial fibrillation during long-term follow-up in several etiologic subgroups. We analyze several epidemiologic variables, functional recovery and other relevant pathologies. Results: A total of 514 patients with complete cardiac diagnosis tests treated with EVT were analyzed over 3,9 years of follow-up. The etiology of stroke was unknown in 123 patients (23,9%). During follow-up were diagnosed 8% of patients with new atrial fibrillation/flutter in unknown etiology subgroup (3% in atherothrombotic and none in unusual subgroup). Half of them presented minor cardiologic symptoms but none of them had presented a new stroke. Variables significant associated to new finding of AF were >6 supraventricular extrasystoles or tachycardia in 24Holter test and severe auricular dilatation evaluated by means echocardiography during hospitalization (p:0.004). Only 2% patients were studied with long-term heart rhythm recorder. Other new diagnoses in follow-up of EVT were malignant neoplasm (7%) and delayed seizures (6%). Conclusions: The findings of atrial fibrillation in follow-up of patients treated with EVT with complete cardiac diagnosis tests are infrequent. The recurrence of stroke seems rare in follow-up, however we must select patients for catch atrial fibrillation by means long-term heart recorder systems according to signs of auricular impairment.

Worldwide land cover and land use change rapidly due to biophysical and complex socio-economic and political factors. These changes are directly affecting both local and global biodiversity and impeding the ability of agricultural landscapes to provide essential ecosystem services. These changes are particularly evident in sub-Saharan Africa, which is experiencing a rapid transformation in rural and urban areas as a consequence of urbanisation and population growth while simultaneously being the continent in most urgent need for increasing agricultural production and most threatened by climate change and pest outbreaks. There is growing need for alternative agricultural practices that conserve biodiversity and natural regulatory processes in order to meet the rising demands for food and dietary diversity, to mitigate climate change, and to restore degraded landscapes. To better understand the potential of current agricultural landscapes to provide essential ecosystem services, insight is required into the historic trajectories of farming systems, their drivers, and how these drivers shaped current landscapes in terms of composition and structure, as well as the impact they have on ecosystem services. These insights can contribute to informing the design of more sustainable cereal-based agroecosystems for the smallholder multifunctional subsistence agriculture. Ethiopia is now the second most populated country in Africa with more than 100 million people and a population growth rate of 3% per year. In Ethiopia, cereals are the major staple crops with maize ranking second after teff (Eragrostis tef) in acreage and first in total production and productivity. In the Hawassa area, in the Rift Valley of Ethiopia, maize (Zea mays) productivity fluctuates widely, and that is caused in part by infestation by maize stemborers. Adults stemborer are nocturnal moths which disperse by flight, while the larval stages have a wide range of host plants. Current recommended pest management practices for stemborers only focus on the plot level and do not take into account the entire farming system or the composition of the surrounding landscape context. Yet farming systems and the associated management practices and landscape contexts are crucial for understanding the population dynamics of stemborers, their natural enemies, and the resulting pest pressure. In Hawassa, there is an ongoing transformation of farming systems, and these changes are influenced by institutional and socio-economic drivers, such as land tenure regulation, market access, and population growth. It is unclear how these drivers influence the dynamics of farming systems and ultimately shape agricultural landscapes and their potential for the provision of food, feed, and energy. The general objective of my work was to identify stemborer management strategies at the field, farm, and landscape levels for a more sustainable intensification of maize-based production systems that would (i) limit stemborer incidence, (ii) maintain or improve soil fertility, and (iii) improve fodder production for livestock. In particular, I studied how trajectories of farming systems have shaped current agricultural landscapes and assessed the implications for maize stemborer pest pressure and the potential for biocontrol. I quantified the relations between stemborer abundance, farming practices, and maize yields at the plot level and analysed the impact of landscape factors on stemborers and the abundance of their natural enemy. This brings new insight that can inform effective farming practices for increased maize production and stemborer suppression at multiple spatial scales. In Chapter 2, I assessed how the ongoing expansion of arable land and urban areas is affecting the availability of common resources, such as forest and grazing land, and the availability of biomass for food, feed, and energy. By combining data from (i) farm household surveys, (ii) focus group discussions with farmers, (iii) statistical typology of trajectories of change in farming systems, (iv) remote sensing, and (v) secondary data analysis, I showed that the current farming systems in Hawassa result from the combined effects of past policies, population growth, access to market, urbanisation, and biophysical characteristics. This work has revealed, among other things, that farm sizes declined rapidly over the past four decades and that farmers responded to this constraint by adopting three main livelihood strategies: consolidation, diversification, and specialisation. These trajectories combined with urbanisation led to more fragmented and more complex landscapes. In Chapter 3, I assessed how the changes in land use and landscape composition and structure in the Hawassa region influenced the capacity of the landscape to support communities of the natural enemy of maize stemborers: Busseola fusca (Fuller). Natural enemies were sampled in maize fields adjacent to simple hedgerows, complex hedgerows, enset (Ensete ventricosum) fields, and khat (Catha edulis) fields at 1, 10, and 30 m using pitfalls and yellow pan traps in 2014 and 2015. The landscape analysis indicated that landscapes in the study area have changed over time from maize-dominated to more diverse small-scale and fragmented agroecosystems with a higher proportion of perennial crops. In maize fields adjacent to enset and complex hedgerows, I found a higher abundance of predators (mostly ants and rove beetles) than in maize fields adjacent to khat and simple hedgerows, and the influence of border type decreases with distance from the border. The abundance of parasitoids and parasitic flies were not influenced by border type. I concluded that in terms of biocontrol service, the changes observed in landscape composition and structure may have influenced the capacity of the landscape to support populations of natural enemies of stemborers in different ways. On the one hand, smaller field sizes have resulted in more field borders that may support relatively high predator densities; on the other hand, the area of khat increased, and the area of enset decreased, which may have had a negative effect on predator densities. In Chapter 4, I investigated how farmers’ management practices at the field scale and landscape context affect maize stemborer infestation levels and maize productivity. Maize infestation levels, yield, and biomass production were assessed in 33 farmer fields managed according to local practices. When considering field level factors only, plant density was positively related to stemborer infestation level. During high infestation events, the length of tunnelling, a proxy of infestation and plant damage, was positively associated with the date of planting and negatively associated with the botanical diversity of hedges. However, the proportion of maize crops in the surrounding landscape was strongly positively associated with the length of tunnelling at 100, 500, 1000, and 1500 m radii. The findings reveal that the landscape context overrides farmers’ management practices in explaining maize infestation levels but also indicate that maize is tolerant to low and medium infestation levels of stemborers. The push-pull system, a stimulo-deterrent cropping strategy consisting of intercropping cereals with legumes and surrounding by fodder grasses, is considered a promising crop diversification strategy for smallholder farmers in Africa as it may contribute to maize stemborer Busseola fusca (Fuller) suppression while improving soil fertility and providing feed for livestock. In Chapter 5, I investigated the performance of different push-pull systems in terms of stemborer suppression, predator abundance, and maize productivity in different landscape settings. Within each landscape (simple, intermediate, and complex), experimental plots were established on four representative smallholder farms. At each farm we used a split-plot factorial design with main plots surrounded or not by Napier grass and subplots consisting of sole maize, maize-bean, or maize-Desmodium. I assessed stemborer infestation levels and maize grain and stover yields for two years; I also assessed natural enemy abundance and egg predation at two maize development stages in the second year. I demonstrated that the push-pull system was effective in reducing stemborer infestation only in the intermediate complexity landscape, where subplots with sole maize had higher stemborer infestation levels compared to maize-bean or maize-Desmodium. In the simple landscape, which was dominated by maize, all treatments had high stemborer infestation levels irrespective of within-field crop diversity; the presence of Napier grass was associated with higher predator abundance, while egg predation rates were the highest in the maize-bean intercrop. In the complex landscape, infestation levels were low in all treatments. I found no significant difference between the two push crops tested - Desmodium or bean - suggesting that beans can be used as push crop in push-pull systems with the additional advantage of increasing egg predation rate and being a common maize-bean farmers’ practice. However, there was no significant yield differences between the sub-systems nor between the three landscapes. Thus, the benefits of the push-pull system mostly come from the companion crops (bean, Desmodium, and Napier) rather than from stemborer suppression per se. Agricultural landscapes in the Hawassa area went through important transformations over the last 40 years due to the combined effects of national, regional, and local level drivers (agricultural policies, commodity prices, and infrastructures), regional/local level factors (population density and urbanisation), farmers’ livelihood assets, and unexpected climate events. The area of maize monocultures declined and was progressively replaced by perennial crops, such as enset (food crop) and khat (cash crop). In addition, population growth and the expansion of urbanised areas have reduced the availability of land and led to more fragmentation of the croplands, with a potential positive benefit for the biocontrol of maize stemborers. Although the push-pull system is a promising crop diversification strategy for smallholder farmers in Africa, its adoption can be limited in land-constrained farming systems, most likely due the farmers’ reluctance to replace food crops, such as common bean, with fodder crops. In addition, the development of Napier grass can be hampered when nitrogen is a limiting factor. Therefore, there is a need for developing push-pull systems that use locally available plants. Napier grass could be planted as part of hedgerows to avoid hampering mechanical work of fields. In general, increasing plant diversity of hedgerows and their density can contribute to increasing natural enemy abundance and decreasing maize infestation levels. In addition, the intentional management of hedgerows could also consider adding plants and trees that are multifunctional (e.g. botanicals, feed for livestock, erosion control, carbon storage, beneficials for soil fauna). Above all, given the overriding influence of landscape context over field level management practices and the multifunctional nature of smallholder farming systems, the design of sustainable agroecosystems requires a context-specific and strongly integrative (social, economic and, environmental objectives) approach. Taking maize stemborer pressure as an entry point, I showed that the infestation cannot be explained by field level factors only. Tackling maize infestation issues requires a landscape approach for sustainable pest management. Landscape composition, in particular, could either impact the pest abundance directly by affecting its dispersal, mortality, or reproduction or indirectly by affecting its natural enemies. Yet a landscape design which aims not only at the ecological control of maize stemborers but also addresses other farming constraints (i.e. soil fertility, fodder availability) and aim at maintaining moisture to avoid crop failure (by using cover crops, increasing rainfall infiltration) and diverse farming systems to increase nutrition and income diversity for smallholder farmers. Diversified farming systems which promote the conservation of natural enemies seem to be an ecologically sound solution, but more research is needed to understand and maximise the efficiency of existing mixed cropping systems. A systems approach to agriculture production such as agroecology could be the best option to respond to the requirements of the multifunctional small-scale subsistence agriculture in Africa.

Purpose In vivo tau-PET tracer retention in the anterior temporal lobe of patients with semantic variant primary progressive aphasia (SV PPA) has consistently been reported. This is unexpected as the majority of these patients have frontotemporal lobar degeneration TDP (FTLD-TDP). Methods We conducted an in vitro [18F]AV1451 autoradiography binding study in five cases with a clinical diagnosis of SV PPA constituting the range of pathologies (i.e., three FTLD-TDP, one Alzheimer’s disease (AD), and one Pick’s disease (PiD)). Binding was compared with two controls without neurodegeneration, two typical AD, one corticobasal syndrome with underlying AD, and one frontotemporal dementia behavioral variant with FTLD-TDP. The effect of blocking with the authentic reference material and with the MAO-B inhibitor deprenyl was assessed. Immunohistochemistry was performed on adjacent cryosections. Results Absence of specific [18F]AV1451 binding was observed for all three SV PPA FTLD-TDP cases. The absence of binding in controls as well as the successful blocking with authentic AV1451 in cases with tauopathy demonstrated specificity of the [18F]AV1451 signal for tau. The specific [18F]AV1451 binding was highest in AD, followed by PiD. This binding colocalized with the respective tau lesions and could not be blocked by deprenyl. Similar pilot findings were obtained with [18F]THK5351. Conclusion In vitro autoradiography showed no [18F]AV1451 binding in SV PPA due to FTLD-TDP, while specific binding was present in SV PPA due to AD and PiD. The discrepancy between in vitro and in vivo findings remains to be explained. The discordance is not related to [18F]AV1451 idiosyncrasies as [18F]THK5351 findings were similar. Electronic supplementary material The online version of this article (10.1007/s00259-019-04631-x) contains supplementary material, which is available to authorized users.

The ability to integrate inside the host genome lays a strong foundation for HIV to play hide and seek with the host's immune surveillance mechanisms. Present anti-viral therapies, although successful in suppressing the virus to a certain level, fail to wipe it out completely. However, recent approaches in modifying stem cells and enabling them to give rise to potent/resistant T-cells against HIV holds immense hope for eradication of the virus from the host. In this review, we will briefly discuss previous landmark studies on engineering stem cells or T-cells that have been explored for therapeutic efficacy against HIV. We will also analyze potential benefits and pitfalls of some studies done recently and will share our opinion on emerging trends.

In its trope of playing with the past as a kind of game, The Devil’s Arithmetic by Jane Yolen wavers between conviction in young readers’ ability to confront the traumatic past and anxiety about the uncensored model of exposure that the novel is often thought to epitomize. Role-play emerges as this Holocaust text’s central modality of concomitantly pretending to know and not know, expose and conceal, hide and seek the truth without real danger or risk.

A 51-year-old woman with a previous history of rheumatoid arthritis experienced painless progressive visual loss in the left eye for 3 weeks. Fundus examination revealed optic disk pallor in her left eye. Magnetic resonance imaging of the brain and orbits showed enhancement of the pachymeninges and hypersignal at the left optic nerve. Meningeal biopsy was performed. Immunohistochemical staining for IgG4 revealed several IgG4-positive plasma cells, which in some areas reached the number of 50 cells/high-power field. In this case, the clinical and histopathological features of the patient met diagnostic criteria for rheumatoid arthritis and IgG4-related disease, respectively. Rheumatoid arthritis sometimes occurs with abundant IgG4 plasma cells and fulfills the histological diagnostic criteria for IgG4-related disease. This case demonstrates that overlapping features of IgG4-RD and rheumatoid arthritis may present in a single patient.

Linked activity schedules were used to establish appropriate game play in children with autism during a game of hide-and-seek. All 6 participants demonstrated acquisition of appropriate play skills in the presence of the activity schedules and maintained responding during subsequent phases. When the schedules were removed, responding decreased to baseline levels, demonstrating that the schedules controlled responding. Implications for future research on the use of activity schedules to teach social behavior are discussed.

The development of paediatric medicines can be challenging since this is a diverse patient population with specific needs. For example, the toxicity of excipients may differ in children compared to adults and children have different taste preferences. Acceptable palatability of oral paediatric medicinal products is of great importance to facilitate patient adherence. This has been recognised by regulatory authorities and so is becoming a key aspect of paediatric pharmaceutical development studies. Many active pharmaceutical ingredients (APIs) have aversive taste characteristics and so it is necessary to utilise taste masking techniques to improve the palatability of paediatric oral formulations. The aim of this review is to provide an overview of different approaches to taste masking APIs in paediatric oral dosage forms, with a focus on the tolerability of excipients used. In addition, where possible, the provision of examples of some marketed products is made.

This chapter begins with an introduction to the overall subject matter covered in this chapter. This is followed by a brief description of the light-capturing pigment in microscopic marine bacteria. Next, a description of marine organisms that carry living light is provided, with particular attention to blue light-beaming ostracods, luminous deep-sea sharks, and the discovery of a precious molecule from a special kind of light-emitting jellyfish, which turned out to be a Nobel Prize-winning discovery that revolutionized the field of medical research. This is followed by a description of fishes that play hide and seek and marine creatures that mimic. Next are gelatinous creatures, particularly the bumpy jellyfish in deep sea and the highly venomous mysterious creature, known as the box jellyfish. Special emphasis is given to the treatment for box jellyfish sting victims. Discussions on jellyfishes are wound up with the ecosystem impact of jellyfish explosion. The topics addressed next include a special kind of dangerous fish known as lionfish , which poses a grave threat to fish populations and coral reef ecosystems; deep-sea vampire squid, which has the ability to thrive in the oxygen minimum zone, where other marine creatures shudder to enter; and the giant squid and colossal squid. The chapter winds up with discussions on the difficult life at submarine canyons and deep-sea trenches as well as the role of dead whales in providing a deep-sea living legacy.

There are 3-4 million new hepatitis C virus (HCV) infections yearly. The extensive inter-genotypic sequence diversity of envelope proteins E1 and E2 of HCV and shielding of important epitopes by hypervariable region 1 (HVR1) of E2 are believed to be major hindrances to developing universally protective HCV vaccines. Using cultured viruses expressing the E1/E2 complex of isolates H77 (genotype 1a), J6 (2a), or S52 (3a), with and without HVR1, we tested HVR1-mediated neutralization occlusion in vitro against a panel of 12 well-characterized human monoclonal antibodies (HMAbs) targeting diverse E1, E2, and E1/E2 epitopes. Surprisingly, HVR1-mediated protection was greatest for S52, followed by J6 and then H77. HCV pulldown experiments showed that this phenomenon was caused by epitope shielding. Moreover, by regression analysis of HMAb binding and neutralization titer of HCV we found a strong correlation for HVR1-deleted viruses, but not for parental viruses retaining HVR1. The inter-genotype neutralization sensitivity of the parental viruses to HMAbs AR2A, AR3A, AR4A, AR5A, HC84.26, and HC33.4 varied greatly (>24- to >130-fold differences in IC50-values). However, except for AR5A, these differences decreased to less than 6.0-fold when comparing the corresponding HVR1-deleted viruses. Importantly, this simplified pattern of neutralization sensitivity in the absence of HVR1 was also demonstrated in a panel of HVR1-deleted viruses of genotypes 1a, 2a, 2b, 3a, 5a, and 6a, although for all HMAbs, except AR4A, an outlier was observed. Finally, unique amino acid residues in HCV E2 could explain these outliers in the tested cases of AR5A and HC84.26. Conclusion: HVR1 adds complexity to HCV neutralization by shielding a diverse array of unexpectedly cross-genotype-conserved E1/E2 epitopes. Thus, an HVR1-deleted antigen could be a better HCV vaccine immunogen.

Breast cancer treatment is improving due to the introduction of new drugs, guided by molecular testing of the primary tumour for mutations/oncogenic drivers (e.g. HER2 gene amplification). However, tumour tissue is not always available for molecular analysis, intra-tumoural heterogeneity is common and the "cancer genome" is known to evolve with time, particularly following treatment as resistance develops. After resection, those patients with only residual micrometastases are likely to be cured but those with radiologically detectable overt disease are not. Thus, the discovery of blood test(s) that could (1) alert clinicians to early primary or recurrent disease and (2) monitor response to treatment could impact significantly on mortality. Towards this, we and others have focused on molecular profiling of circulating nucleic acids isolated from plasma, both cell-free DNA (cfDNA) and microRNAs, and the relationship of these to circulating tumour cells (CTCs). This review considers the utility of each as circulating biomarkers in breast cancer with particular emphasis on the bioinformatic tools available to support molecular profiling.

A logical relationship exists among six general problems that people face in life. Using hope about something for its subjective probability, its expected likelihood, the problems form a series where the method of assessing hope changes in a simple manner from one problem to the next. The central hypothesis is that human beings exploit this. Brain structures and predispositions have evolved accordingly, leading to the hemispheres having different predispositions. The hemispheres are effectively joined at 5 months. Infants will then find that they engage in two unrelated activities. Typical infants label the activities in detail, using visual images, as part of gaining control over them. Hypotheses are: (a) autistic children fail labelling at the start, and hence they encounter uncontrolled competition between the hemispheres; (b) with some, serotonin abnormality impairs sensory information processing and hence the labelling; (c) with some, a delay in myelination from autoimmune effects disrupts labelling; (d) the likelihood of this 'delay autism' is reduced by long chain omega oils; (e) self-pressuring, which underlies taking on challenges and play like Hide and Seek, brings relief from the competition by raising the influence of one side; (f) the same left-right competition occurs in confused episodes and schizophrenia in vulnerable people who encounter pressures to use both hemispheres at the same time; (g) some symptoms raise the influence on one side ideationally. This leads to coherent theories of autism and schizophrenia. In both competition between the hemispheres is relieved primarily by self-pressuring, which raises influence on one side.

The success of highly active antiretroviral therapy (HAART) for HIV-1 infection has sparked interest in mechanisms by which the virus can persist despite effectively suppressive therapy. Latent HIV-1 reservoirs established early during infection not only prevent sterilizing immunity but also represent a major obstacle to virus eradication. When HIV-1 gains a foothold in the immunologic memory or in certain inaccessible compartments of the human body, it cannot be easily purged by HAART and is able to replenish systemic infection on treatment interruption. Because latently infected cells are indistinguishable from uninfected cells, deliberate activation of latent infection combined with intensified HAART seems to be the best strategy to combat latent infection. Initial hypothesis-driven clinical trials did not achieve their ultimate goal, although they provided valuable insight for the design of future eradication protocols. A more detailed understanding of the basic mechanisms underlying the establishment and long-term maintenance of HIV-1 reservoirs will be critical in developing new eradication approaches.

During the pre-erythrocytic asymptomatic phase of malarial infection, sporozoites develop transiently inside less than 100 hepatocytes that subsequently release thousands of merozoites. Killing of these hepatocytes by cytotoxic T cells (CTLs) confers protection to subsequent malarial infection, suggesting that this bottleneck phase in the parasite life cycle can be targeted by vaccination. During natural transmission, although some CTLs are generated in the skin draining lymph nodes, they are unable to eliminate the parasite, suggesting that the liver is important for the sporozoite to escape immune surveillance. The contribution of the organ to this process is unclear. Based on the known ability of several hepatic antigen-presenting cells (APCs) to induce primary activation of CD8 T cells and tolerance, malarial antigens presented by both infected hepatocytes and/or hepatic cross-presenting APCs should result in tolerance. However, our latest model predicts that due to the low frequency of infected hepatocytes, some T cells recognizing sporozoite epitopes with high affinity should differentiate into CTLs. In this review, we discuss two possible models to explain why CTLs generated in the liver and skin draining lymph nodes are unable to eliminate the parasite: (1) sporozoites harness the tolerogenic property of the liver; (2) CTLs are not tolerized but fail to detect infected cells due to sparse infection of hepatocytes and the very short liver stage. We propose that while malaria sporozoites might use the ability of the liver to tolerize both naive and effector cells, they have also developed strategies to decrease the probability of encounter between CTLs and infected liver cells. Thus, we predict that to achieve protection, vaccination strategies should aim to boost intrahepatic activation and/or increase the chance of encounter between sporozoite-specific CTLs and infected hepatocytes.

The horse, and the complexly diverse and international equine industry of which it is the foundation, are under constant threat from a variety of viral diseases (Table 1), which not only has a significant impact on animal welfare throughout the world, but also maintains a persistent economic burden on the industry. In the 21st century, where international transportation of horses for competition, sale and breeding is commonplace, and in a rapidly changing environment that is breaking down barriers for the geographical confinement of infectious agents, the role of the equine veterinary practitioner in the control of viral disease is also changing. The identification and diagnosis of any infectious disease must not only serve as the basis for appropriate therapeutic intervention at the individual or group level, but must also be considered an imperative step for appropriate disease control, quarantine and prevention, and for national disease surveillance. In order to achieve these measures, however, practitioners must have at their disposal readily accessible, reliable and affordable diagnostic tests that can provide results within a time frame that is both compliant with the demands of daily practice and allows prompt and appropriate intervention.

TLR7 is an innate signaling receptor that recognizes single-stranded viral RNA and is activated by viruses that cause persistent infections. We show that TLR7 signaling dictates either clearance or establishment of life-long chronic infection by lymphocytic choriomeningitis virus (LCMV) Cl 13 but does not affect clearance of the acute LCMV Armstrong 53b strain. TLR7−/− mice infected with LCMV Cl 13 remained viremic throughout life from defects in the adaptive anti-viral immune response, notably diminished T cell function, exacerbated T cell exhaustion, decreased plasma cell maturation, and negligible anti-viral antibody production. Adoptive transfer of TLR7+/+ LCMV immune memory cells that enhance clearance of persistent LCMV Cl 13 infection in TLR7+/+ mice fail to purge LCMV Cl 13 infection in TLR7−/− mice, demonstrating that a TLR7-deficient environment renders anti-viral responses ineffective. Therefore, methods that promote TLR7 signaling are promising treatment strategies for chronic viral infections.

This paper is based on a study aimed at understanding the perceptions of men to induced abortion and contraceptive use within marriage in rural Zimbabwe. Two qualitative methods were combined. Men were found to view abortion not as a reproductive health problem for women. Instead, they described abortion as a sign of illicit sexual activity and contraceptive use as a strategy married women use to conceal their involvement in extramarital sexual activity. Men felt anxious and vulnerable for lack of control over women. In the absence of verbal communication on sexual matters, women and men resort to what are called here ‘hide-and-seek’ strategies, where women acquire and use contraceptives secretly while men search for evidence of such use. It is concluded that promoting women’s sexual and reproductive health requires both short- and long-term strategies. The short-term strategy would entail providing women with reproductive technology they can use without risking violence. The long-term strategy would entail understanding men’s concerns and the way these are manifested. In turn this requires the use of methodologies that encourage dialogue with research participants, in order to capture their deep meanings and experiences.

Locally acquired zoonotic hepatitis E virus (HEV) has ‘arrived’ in developed countries [1,2]. Of considerable concern, and eloquently and thoroughly described by Dreier and Juhl [3], HEV has found its way into the blood supply. The numbers of viraemic donors are worryingly high in a number of developed countries, particularly in Germany. HEV is considered by many as the ‘new kid on the block’. Is this true? A few years ago, when my colleagues and I described locally acquired hepatitis E as an ‘emerging infection’ in developed countries, we almost certainly made an error [1]. The evidence suggests that HEV is an ancient virus, and biological time-clock studies show that HEV diverged into its four genotypes several hundred years ago [4]. It would be more accurate to describe locally acquired hepatitis E in developed countries as a disease that is ‘emerging in human consciousness’. How long has HEV been in the blood supply in developed countries such as Germany? No one knows for sure (yet). My best guess is that HEV has been in the blood supply ever since the advent of blood transfusion. I have been studying locally acquired, zoonotic HEV for over 10 years. Although I am not a virologist, HEV strikes me as an unusual virus, for two reasons. Firstly, although exposure to zoonotic HEV occurs in all age groups, including children, it appears to cause clinically evident hepatitis mainly in middle aged/elderly males [2]. The reason for this observation is not known, but I cannot think of another virus that behaves in such a manner. Nor can any of the very eminent virologists that I have talked to about this issue over the years. The second reason that I think that HEV is unusual is that it is a virus which likes to hide from human scrutiny. HEV has been playing ‘hide and seek’ with us humans for centuries. It has, until very recently, been winning this ‘game’. I realize that virologists would never ever think about a virus in such human terms. However, I am not a virologist, I am a clinical gastroenterologist. I would ask forbearance of virologist readers, and allow me to explain what I mean.

International audience; 1/ The disruption of host-finding cues has been proposed as a key mechanism underlying the lower damage caused by phytophagous insects in mixed forests. We tested this hypothesis by investigating the distribution of pine processionary moth Thaumetopoea pityocampa (Denis & Schiffer-Müller) (Lepidoptera) infestation at the edges of pure stands of Pinus pinaster (AÏton) at some distance from nonhost trees (Experiment 1) or bordered in part by a broadleaved hedgerow (Experiment 2). 2/An ‘edge effect' was demonstrated, with trees at the edge of the stand being more heavily infested than those at the interior of the stand. 3/ The presence of a nonhost broadleaved hedgerow in front of the edge of the pine stand resulted in lower T. pityocampa infestation. There were significantly fewer T. pityocampa nests behind the hedgerow than on the exposed part of the edge. The presence of the hedgerow did not dilute or repel T. pityocampa infestation further into the pine stand, although it decreased the infestation of T. pityocampa throughout the pine stand. The decrease in T. pityocampa infestation behind the hedgerow was greater when the broadleaved hedgerow was taller than the pine trees. 4/These results highlight the benefits of using nonhost tree species on the edge of monospecific forest stands to reduce insect damage. This approach could be promoted as an innovative forest pest management method.

Submitted for publication November 17, 2011 Accepted for publication November 17, 2011 From the Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center, Boston, Massachusetts. Address correspondence to Dr. Elliot Sternthal, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center, 88 East Newton Street, Evans 201, Boston, MA 02118. E-mail: Elliot.sternthal@bmc.org. Copyright © 2011 AACE. Abbreviations: DPP-4 = dipeptidyl-peptidase-4; GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagonlike peptide-1

“Hide and seek” with antineutrophil cytoplasmic antibodies Matteo Alicandri-Ciufelli, MD, Gabriele Molteni, MD⁎, Maria Teresa Mascia, MD, Elisabetta Genovese, MD, Livio Presutti, MD Department of Otolaryngology-Head and Neck Surgery, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy Department of Rheumatology, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy Received 19 April 2009

This paper reports on two XMM-Newton observations of the Seyfert 1 Galaxy H0557-385 obtained in 2006, which show the source at an historical low flux state, more than a factor of 10 lower than a previous XMM-Newton look in 2002. The low flux spectrum presents a strong Fe Kalpha line associated to a Compton reflection continuum. An additional spectral line around 6.6 keV is required to fit Kalpha emission from Fe XXV. The spectral curvature below 6 keV implies obscuration by neutral gas with a column density of 8*10^{23}cm^{-2} partially covering the primary emission, which still contributes for a few percent of the soft X-ray emission. Absorption by ionised material on the line of sight is required to fit the deep trough below 1 keV. The comparison of the two spectral states shows that the flux transition is to be ascribed entirely to intervening line-of-sight clouds with high column density., 5 pages, accepted for publication on MNRAS Letters

Deep-sequencing of lymphoid tissue samples from patients infected with HIV who were undergoing suppressive antiretroviral therapy reveals ongoing replication in lymphoid tissues and replenishment of the latent reservoir.

As part of the most important contributions to the understanding of viral immunity, Michael Oldstone recounts his pioneering work on lymphocytic choriomeningitis virus.

Despite many peer-reviewed works that draw on tobacco industry documents that have now been made public, questions remain about how complete a picture has emerged. We present a conceptual framework that identifies and evaluates tobacco industry efforts to conceal information. Widespread document destruction like that in recent litigation in Australia is just one of more than a dozen tobacco industry efforts to prevent access, or at least timely access, to documents. Industry efforts range from small, locally employed initiatives to company-wide tactics. Some efforts, such as using "oral only" procedures, scrambling telephone lines, or involving lawyers in scientific projects, are preemptive. Others seek to deal with already existing documents by invoking bogus claims of legal privilege, stipulating "read then destroy" for memos, and rewriting problematic memos. That evidence of concealment has, in fact, been found in tobacco company archives attests to the futility of attempting to control the flow of millions of pieces of paper among tens of tbousands of employees. However, researchers have yet to reveal the full story: We know of the industry's failures in concealing information, but not its successes. The industry's objective is not destruction of information per se, but prevention of public disclosure of that information. Exposing the tobacco industry's many approaches to concealment provides greater insight into companies' intentions and potential means for stripping away that concealment.

Introduction 1. The Symptoms of Truth: A Historical Search 2. Hide and Seek: Medicine and 'Somatization' 3. The Vital and the Social 4. Does Psychosomatics Exist? An Introduction 5. The Dispersion of Psychosomatics 6. Interpreting the Bodily Sign 7. Interpreting the Signs of Embodiment 8. Who is the Subject of Somatic Pathology?