Cultural Competence and Humility in Infectious Diseases Clinical Practice and Research.
Infectious diseases as a specialty is tilted toward social justice, and practitioners are frequently on the front lines of the battle against health inequity in practices that are diverse and sometimes cross international borders. Whether caring for patients living with the human immunodeficiency virus, tuberculosis, or Ebola, infectious diseases practitioners often interact with those at the margins of societies (eg, racial/ethnic/sexual/gender minorities), who disproportionately bear the brunt of these conditions. Therefore, cultural barriers between providers and patients are often salient in the infectious diseases context. In this article, we discuss cultural competence broadly, to include not only the knowledge and the skills needed at both the organizational and the individual levels to provide culturally appropriate care, but also to include "cultural humility"-a lifelong process of learning, self-reflection, and self-critique. To enhance the quality and the impact of our practices, we must prioritize cultural competence and humility and be mindful of the role of culture in the patient-provider-system interactions, in our larger healthcare systems, and in our research agendas and workforce development.


Barrett's oesophagus: epidemiology, cancer risk and implications for management.
Although endoscopic surveillance of patients with Barrett's oesophagus has been widely implemented, its effectiveness is debateable. The recently reported low annual oesophageal adenocarcinoma risk in population studies, the failure to identify most Barrett's patients at risk of disease progression, the poor adherence to surveillance and biopsy protocols, and the significant risk of misclassification of dysplasia all tend to undermine the effectiveness of current management, in particular, endoscopic surveillance programmes, to prevent or improve the outcomes of patients with oesophageal adenocarcinoma. The ongoing increase in incidence of Barrett's oesophagus and consequent growth of the surveillance population, together with the associated discomfort and costs of endoscopic surveillance, demand improved techniques for accurately determining individual risk of oesophageal adenocarcinoma. More accurate techniques are needed to run efficient surveillance programmes in the coming decades. In this review, we will discuss the current knowledge on the epidemiology of Barrett's oesophagus, and the challenging epidemiological dilemmas that need to be addressed when assessing the current screening and surveillance strategies.


Effects of Mobile Phones on Children's and Adolescents' Health: A Commentary.
The use of digital technology has grown rapidly during the last couple of decades. During use, mobile phones and cordless phones emit radiofrequency (RF) radiation. No previous generation has been exposed during childhood and adolescence to this kind of radiation. The brain is the main target organ for RF emissions from the handheld wireless phone. An evaluation of the scientific evidence on the brain tumor risk was made in May 2011 by the International Agency for Research on Cancer at World Health Organization. The scientific panel reached the conclusion that RF radiation from devices that emit nonionizing RF radiation in the frequency range 30 kHz-300 GHz is a Group 2B, that is, a "possible" human carcinogen. With respect to health implications of digital (wireless) technologies, it is of importance that neurological diseases, physiological addiction, cognition, sleep, and behavioral problems are considered in addition to cancer. Well-being needs to be carefully evaluated as an effect of changed behavior in children and adolescents through their interactions with modern digital technologies.


Extruded dielectric sample tubes of complex cross section for EPR signal enhancement of aqueous samples.
This paper builds on the work of Mett and Hyde (2003) and Sidabras et al. (2005) where multiple flat aqueous sample cells placed perpendicular to electric fields in microwave cavities were used to reduce the RF losses and increase the EPR signal. In this work, we present three novel sample holders for loop-gap resonators (LGRs) and cylindrical cavity geometries. Two sample holders have been commissioned and built by polytetrafluoroethylene (PTFE) extrusion techniques: a 1mm O.D. capillary with a septum down the middle, named DoubleDee, and a 3.5mm O.D. star shaped sample holder, named AquaStar. Simulations and experimental results at X-band show that the EPR signal intensity increases by factors of 1.43 and 3.87 in the DoubleDee and AquaStar respectively, over the current TPX 0.9mm O.D. sample tube in a two-loop-one-gap LGR. Finally, combining the insight gained from the constructed sample holders and finite-element solutions, a third multi-lumen sample holder for a cylindrical TE011 cavity is optimized, named AquaSun, where simulations show an EPR signal intensity increase by a factor of 8.2 over a standard 1mm capillary.


Performance assessment of the modified-hybrid optical neural network filter.
We present in detail the recorded results of the modified-hybrid optical neural network (M-HONN) filter during a full series of tests to examine its robustness and overall performance for object recognition tasks. We test the M-HONN filter for its detectability and peak sharpness with within-class distortion of the input object, its discrimination ability between an in-class and out-of-class object, and its performance with cluttered images of the true-class object. The M-HONN filter is found to exhibit good detectability, an ability to maintain its correlation-peak sharpness throughout the recorded tests, good discrimination ability, and an ability to detect the true-class object within cluttered input images. Additionally we observe the M-HONN filter's performance within the tests in comparison with the constrained-hybrid optical neural network filter for the first three series of tests and the synthetic discriminant function-maximum average correlation height filter for the fourth set of tests.


Coiled coil protein origami: from modular design principles towards biotechnological applications.
The design of new protein folds represents a grand challenge for synthetic, chemical and structural biology. Due to the good understanding of the principles governing its pairing specificity, coiled coil (CC) peptide secondary structure elements can be exploited for the construction of modular protein assemblies acting as a proxy for the straightforward complementarity of DNA modules. The prerequisite for the successful translation of the modular assembly strategy pioneered by DNA nanotechnology to protein design is the availability of orthogonal building modules: a collection of peptides that assemble into CCs only with their predetermined partners. Modular CC-based protein structures can self-assemble from multiple polypeptide chains whose pairing is determined by the interaction pattern of the constituent building blocks. Orthogonal CC sets can however also be used for the design of more complex coiled coil protein origami (CCPO) structures. CCPOs are based on multiple CC modules concatenated into a single polypeptide chain that folds into a polyhedral protein cage as the peptide segments assemble into CC dimers. The CCPO strategy has hitherto led to successful de novo design of protein cages in the shape of a tetrahedron, square pyramid and triangular prism. Recent advances in the design of CC modules and design principles have enabled the construction of CCPOs that self-assemble in vivo without any apparent toxicity to human cells or animals, opening the path towards therapeutic applications. The CCPO platform therefore has potential for diverse applications in biomedicine and biotechnology, from drug delivery to molecular cages.


Fractionation of copper, nickel, and zinc in metal-spiked sewage sludge.
The enrichment or spiking of sewage sludge with heavy metals for experimental purposes is a fairly widely used, although sometimes controversial, technique. A study was undertaken, using a sequential fractionation scheme, to assess the degree of incorporation of Cu, Ni, and Zn into sewage sludge samples spiked with these metals and incubated for 6 mo. For all three metals, substantial proportions of the metals were incorporated into the sludge matrix, particularly as evidenced by their occurrence in the oxide-bound, organic-bound, and residual fractions. In particular, for Cu very little of the added copper remained in the sludge supernatant solution after 6 mo of incubation and, apart from at the highest level of Cu addition, there was very little difference in the fractional distribution of Cu between the Cu-spiked and non-Cu-spiked sludges. For Ni and Zn, however, although there was substantial incorporation of these metals into the sludge, the higher levels of Ni and Zn addition resulted in greater proportions of the metals in the most soluble fractions (soluble, exchangeable, specifically sorbed) compared with nonspiked sludges. The fractionation data for Ni also showed that large additions of Cu and Zn can affect the fractional distribution of Ni in the sludge. The drying of sewage sludge prior to analysis was shown to increase metal solubility in the sludge samples, and the potential implications of this finding for the prediction of sludge metal bioavailability are discussed.


Label-free multidimensional information acquisition from optogenetically engineered cells using a graphene transistor.
The optogenetic technique, which allows the manipulation of cellular activity patterns in space and time by light, has transformed the field of neuroscience. However, acquiring multidimensional optogenetic information remains challenging despite the fact that several cellular information detection methods have been proposed. Herein, we present a new method to acquire label-free multidimensional information from optogenetically engineered cells using a graphene transistor. Using a graphene film to form a strong densely packed layer with cells, the cellular action potentials were characterized as light-activated transistor conductance signals, which quantified the multidimensional optogenetic information. Based on this approach, some important cellular optogenetic information, including electrophysiological state, cell concentration, expression levels of opsin and response to variable light intensity, were also precisely detected. Furthermore, the graphene transistor was also used to distinguish cells expressing different channelrhodopsin-2 variants. Our study offers a general detection method of multidimensional optogenetic information for extending the applications of the optogenetic technique and provides a novel sensor for the development of future biological prosthetic devices.


BigBrain 3D atlas of cortical layers: Cortical and laminar thickness gradients diverge in sensory and motor cortices.
Histological atlases of the cerebral cortex, such as those made famous by Brodmann and von Economo, are invaluable for understanding human brain microstructure and its relationship with functional organization in the brain. However, these existing atlases are limited to small numbers of manually annotated samples from a single cerebral hemisphere, measured from 2D histological sections. We present the first whole-brain quantitative 3D laminar atlas of the human cerebral cortex. It was derived from a 3D histological atlas of the human brain at 20-micrometer isotropic resolution (BigBrain), using a convolutional neural network to segment, automatically, the cortical layers in both hemispheres. Our approach overcomes many of the historical challenges with measurement of histological thickness in 2D, and the resultant laminar atlas provides an unprecedented level of precision and detail. We utilized this BigBrain cortical atlas to test whether previously reported thickness gradients, as measured by MRI in sensory and motor processing cortices, were present in a histological atlas of cortical thickness and which cortical layers were contributing to these gradients. Cortical thickness increased across sensory processing hierarchies, primarily driven by layers III, V, and VI. In contrast, motor-frontal cortices showed the opposite pattern, with decreases in total and pyramidal layer thickness from motor to frontal association cortices. These findings illustrate how this laminar atlas will provide a link between single-neuron morphology, mesoscale cortical layering, macroscopic cortical thickness, and, ultimately, functional neuroanatomy.


Innate and adaptive immunity in bacteria: mechanisms of programmed genetic variation to fight bacteriophages.
Bacteria are constantly challenged by bacteriophages (viruses that infect bacteria), the most abundant microorganism on earth. Bacteria have evolved a variety of immunity mechanisms to resist bacteriophage infection. In response, bacteriophages can evolve counter-resistance mechanisms and launch a 'virus versus host' evolutionary arms race. In this context, rapid evolution is fundamental for the survival of the bacterial cell. Programmed genetic variation mechanisms at loci involved in immunity against bacteriophages generate diversity at a much faster rate than random point mutation and enable bacteria to quickly adapt and repel infection. Diversity-generating retroelements (DGRs) and phase variation mechanisms enhance the generic (innate) immune response against bacteriophages. On the other hand, the integration of small bacteriophage sequences in CRISPR loci provide bacteria with a virus-specific and sequence-specific adaptive immune response. Therefore, although using different molecular mechanisms, both prokaryotes and higher organisms rely on programmed genetic variation to increase genetic diversity and fight rapidly evolving infectious agents.


Interactions between motor exploration and reinforcement learning.
Motor exploration, a trial-and-error process in search for better motor outcomes, is known to serve a critical role in motor learning. This is particularly relevant during reinforcement learning, where actions leading to a successful outcome are reinforced while unsuccessful actions are avoided. Although early on motor exploration is beneficial to finding the correct solution, maintaining high levels of exploration later in the learning process might be deleterious. Whether and how the level of exploration changes over the course of reinforcement learning, however, remains poorly understood. Here we evaluated temporal changes in motor exploration while healthy participants learned a reinforcement-based motor task. We defined exploration as the magnitude of trial-to-trial change in movements as a function of whether the preceding trial resulted in success or failure. Participants were required to find the optimal finger-pointing direction using binary feedback of success or failure. We found that the magnitude of exploration gradually increased over time when participants were learning the task. Conversely, exploration remained low in participants who were unable to correctly adjust their pointing direction. Interestingly, exploration remained elevated when participants underwent a second training session, which was associated with faster relearning. These results indicate that the motor system may flexibly upregulate the extent of exploration during reinforcement learning as if acquiring a specific strategy to facilitate subsequent learning. Also, our findings showed that exploration affects reinforcement learning and vice versa, indicating an interactive relationship between them. Reinforcement-based tasks could be used as primers to increase exploratory behavior leading to more efficient subsequent learning.NEW & NOTEWORTHY Motor exploration, the ability to search for the correct actions, is critical to learning motor skills. Despite this, whether and how the level of exploration changes over the course of training remains poorly understood. We showed that exploration increased and remained high throughout training of a reinforcement-based motor task. Interestingly, elevated exploration persisted and facilitated subsequent learning. These results suggest that the motor system upregulates exploration as if learning a strategy to facilitate subsequent learning.


Cytokine-based therapy in psoriasis.
Psoriasis and psoriatic arthritis are chronic inflammatory diseases of unknown etiology, affecting 2-3% of the world population. Initially, psoriasis was thought to be a hyper-proliferation disorder of keratinocytes only, but as time passed, the role of immune system became more evident and now both diseases are considered autoimmune disorders. In last few years, the discovery of interleukin (IL)-23/Th17 axis in pathophysiology of psoriatic diseases shifts the cytokine paradigm from Th1 to Th17 cytokines, focused mainly on IL-17 and IL-22. Therapeutic experiences strongly support the use of cytokine antagonists as an important modality in the treatment of psoriatic arthritis and plaque psoriasis. Studies examining these therapeutic agents which target different steps of the psoriatic inflammatory cascade have also shown significant efficacy. The relatively new IL-23/Th17 axis in psoriatic diseases got more importance with the success of ustekinumab, a new monoclonal antibody against IL-12 and IL-23. In IL-17 and IL-22 knock-out and transgenic mouse models, it has been found that recombinant IL-23 fails to produce epidermal hyperplasia which resembles psoriasis. Also, some success in animal models of psoriasis was found with anti IL-17A and anti IL-22. More studies are needed to validate the efficacy and safety of these cytokine antagonists in psoriatic diseases. Using a historical perspective and a chess game as an analogy, the main objective of this review is to summarize the central role of some of these cytokines in psoriasis pathophysiology and to develop a strategic approach to new therapeutic weapons within the armamentarium of psoriasis treatment.


Multiple norovirus infections in a birth cohort in a Peruvian Periurban community.
Human noroviruses are among the most common enteropathogens globally, and are a leading cause of infant diarrhea in developing countries. However, data measuring the impact of norovirus at the community level are sparse. We followed a birth cohort of children to estimate norovirus infection and diarrhea incidence in a Peruvian community. Stool samples from diarrheal episodes and randomly selected nondiarrheal samples were tested by polymerase chain reaction for norovirus genogroup and genotype. Excretion duration and rotavirus coinfection were evaluated in a subset of episodes. Two hundred twenty and 189 children were followed to 1 and 2 years of age, respectively. By 1 year, 80% (95% confidence interval [CI], 75%-85%) experienced at least 1 norovirus infection and by 2 years, 71% (95% CI, 65%-77%) had at least 1 episode of norovirus-associated diarrhea. Genogroup II (GII) infections were 3 times more frequent than genogroup 1 (GI) infections. Eighteen genotypes were found; GII genotype 4 accounted for 41%. Median excretion duration was 34.5 days for GII vs 8.5 days for GI infection (P = .0006). Repeat infections by the same genogroup were common, but repeat infections by the same genotype were rare. Mean length-for-age z score at 12 months was lower among children with prior norovirus infection compared to uninfected children (coefficient: -0.33 [95% CI, -.65 to -.01]; P = .04); the effect persisted at 24 months. Norovirus infection occurs early in life and children experience serial infections with multiple genotypes, suggesting genotype-specific immunity. An effective vaccine would have a substantial impact on morbidity, but may need to target multiple genotypes.


Maternal menopause as a predictor of anti-Mullerian hormone level and antral follicle count in daughters during reproductive age.
Is the ovarian reserve in a woman at a given age associated with her mother's age at menopause? We demonstrated a significant, positive association between age at maternal menopause and serum anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) in daughters. The rate of decline in serum-AMH level and AFC is also associated with age at maternal menopause. The association between menopausal age in mothers and daughters has been established through several epidemiological studies. This paper shows that early maternal menopause is related to an advanced depletion of the ovarian reserve and that late maternal menopause is related to a delayed depletion. Cross-sectional data were obtained from a prospective cohort study of 863 women. The study comprised 527 participants from this prospective cohort whose mothers' age at natural menopause was known. Participants were recruited from female health care workers aged 20-40 years employed at Copenhagen University Hospital, Rigshospitalet, and were enrolled in the study between September 2008 and February 2010. The response rate was 52.1%. Endocrine and ovarian parameters related to reproductive ageing (AMH and AFC) were assessed by serum AMH analyses and transvaginal ovarian sonography on cycle Day 2-5. Data on reproductive history, including age at natural maternal menopause, were obtained through an internet-based questionnaire. We used an analysis of covariance model with serum-AMH and AFC as outcomes, age as the quantitative predictor and onset of maternal menopause as the categorical predictor, with further adjustments for BMI, use of oral contraceptives, participants' smoking habits and prenatal smoking exposure. We found a significant effect of age at maternal menopause on both serum AMH levels (P < 0.001) and AFC (P = 0.005). Median serum-AMH concentration declined by 8.6% per year [95% confidence interval (CI): 6.4-10.8%, P < 0.001] in the group with early maternal menopausal age (≤ 45 years), by 6.8% per year (95% CI: 5.0-8.6%, P < 0.001) in the group with normal maternal menopausal age (46-54 years) and by 4.2% per year (95% CI: 2.0-6.4%, P < 0.001) in the group with late maternal menopausal age (≥ 55 years). Median AFC declined by 5.8% per year (95% CI: 4.0-7.5%, P < 0.001) in the group with early maternal menopausal age (≤ 45 years), by 4.7% per year (95% CI: 3.3-6.1%, P < 0.001) in the group with normal maternal menopausal age (46-54 years) and by 3.2% per year (95% CI: 1.4-4.9%, P < 0.001) in the group with late maternal age (≥ 55 years) at menopause. Information on 'age at maternal menopause' was obtained retrospectively and may be prone to recall bias and digit preference. The study population consisted of health care workers, which implies a potential selection bias. Finally, the cross-sectional nature of the data limits the generalizability. This study was co-financed by PhD scholarships where funding was covered by the Danish Agency for Science, Technology and Innovation, Copenhagen Graduate School of Health Science (CGSHS) and the Fertility Clinic at Copenhagen University Hospital, Rigshopitalet. No competing interests are declared.


Hypoxia-induced SETX links replication stress with the unfolded protein response.
Tumour hypoxia is associated with poor patient prognosis and therapy resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. Therefore, suggesting that, SETX plays a role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we propose that the mechanism of SETX induction in hypoxia is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.


How has the prevalence of cigarette smoking changed among Australian adults? Trends in smoking prevalence between 1980 and 2001.
To examine trends in the prevalence of cigarette smoking between 1980 and 2001 among several different sociodemographic groups within the Australian population. National cross sectional surveys conducted by face to face interview every 3 years from 1980. Respondents were classified into five age groups and the occupation of respondents in the workforce were classified into one of upper or lower white collar or upper or lower blue collar. Prevalence of smoking at least weekly. The prevalence of smoking in 2001 was lower than that found in 1980 and this was true for all sociodemographic groups. Among adults smoking prevalence decreased from 35% in 1980 to 23% in 2001. The differential in smoking prevalence between men and women decreased between 1980 and 2001. Although smoking was more common among younger Australians (<24 years) than older Australians throughout the study, the differential between age groups reduced. For all years except 1980, the proportion of smokers among upper white collar workers was significantly lower than in all other occupation groups. There had been a continual decline in the prevalence of smoking among the Australian population since 1980. This decline had occurred across both sexes and in all age and occupation groups. Much of the decline in smoking prevalence between 1998 and 2001 was among blue collar worker group.


The molecular identity of the mitochondrial Ca2+ sequestration system.
There is ample evidence to suggest that a dramatic decrease in mitochondrial Ca(2+) retention may contribute to the cell death associated with stroke, excitotoxicity, ischemia and reperfusion, and neurodegenerative diseases. Mitochondria from all studied tissues can accumulate and store Ca(2+) , but the maximum Ca(2+) storage capacity varies widely and exhibits striking tissue specificity. There is currently no explanation for this fact. Precipitation of Ca(2+) and phosphate in the mitochondrial matrix has been suggested to be the major form of storage of accumulated Ca(2+) in mitochondria. How this precipitate is formed is not known. The molecular identity of almost all proteins involved in Ca(2+) transport, storage and formation of the permeability transition pore is also unknown. This review summarizes studies aimed at identifying these proteins, and describes the properties of a known mitochondrial protein that may be involved in Ca(2+) transport and the structure of the permeability transition pore.


Prevalence and clinical implications of cyclin D1 expression in diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program.
Cyclin D1 expression has been reported in a subset of patients with diffuse large B-cell leukemia (DLBCL), but studies have been few and generally small, and they have demonstrated no obvious clinical implications attributable to cyclin D1 expression. The authors reviewed 1435 patients who were diagnosed with DLBCL as part of the International DLBCL rituximab with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) Consortium Program and performed clinical, immunohistochemical, and genetic analyses with a focus on cyclin D1. All patients who were cyclin D1-positive according to immunohistochemistry were also assessed for rearrangements of the cyclin D1 gene (CCND1) using fluorescence in situ hybridization. Gene expression profiling was performed to compare patients who had DLBCL with and without cyclin D1 expression. In total, 30 patients (2.1%) who had DLBCL that expressed cyclin D1 and lacked CCND1 gene rearrangements were identified. Patients with cyclin D1-positive DLBCL had a median age of 57 years (range, 16.0-82.6 years). There were 23 males and 7 females. Twelve patients (40%) had bulky disease. None of them expressed CD5. Two patients expressed cyclin D2. Gene expression profiling indicated that 17 tumors were of the germinal center type, and 13 were of the activated B-cell type. Genetic aberrations of B-cell leukemia/lymphoma 2 (BCL2), BCL6, v-myc avian myelocytomatosis viral oncogene homolog (MYC), mouse double minute 2 oncogene E3 ubiquitin protein ligase (MDM2), MDM4, and tumor protein 53 (TP53) were rare or absent. Gene expression profiling did not reveal any striking differences with respect to cyclin D1 in DLBCL. Compared with patients who had cyclin D1-negative DLBCL, men were more commonly affected with cyclin D1-positive DLBCL, and they were significantly younger. There were no other significant differences in clinical presentation, pathologic features, overall survival, or progression-free survival between these two subgroups of patients with DLBCL.


Undernutrition among Kenyan children: contribution of child, maternal and household factors.
To examine the contribution of selected child-, maternal- and household-related factors to child undernutrition across two different age groups of Kenyan under-5s. Demographic and Health Survey data, multistage stratified cluster sampling methodology. Rural and urban areas of Kenya. A total of 1851 children between the ages of 0 and 24 months and 1942 children between the ages of 25 and 59 months in Kenya. Thirty per cent of the younger children were stunted, 13 % were underweight and 8 % were wasted. Forty per cent of the older children were stunted, 17 % were underweight and 4 % were wasted. Longer breast-feeding duration, small birth size, childhood diarrhoea and/or cough, poor maternal nutritional status and urban residence were associated with higher odds of at least one form of undernutrition, while female gender, large birth size, up-to-date immunization, higher maternal age at first birth, BMI and education level at the time of the survey and higher household wealth were each associated with lower odds of at least one form of undernutrition among Kenyan children. The more proximal child factors had the strongest impact on the younger group of children while the intermediate and more distal maternal and household factors had the strongest impact on child undernutrition among the older group of children. The present analysis identifies determinants of undernutrition among two age groups of Kenyan pre-school children and demonstrates that the contribution of child, maternal and household factors on children's nutritional status varies with children's age.


One-year patency control and risk analysis of eSVS®-mesh-supported coronary saphenous vein grafts.
The eSVS® external venous nitinol mesh (Kips Bay Medical, Minneapolis, USA) was designed to improve long-term patency of coronary saphenous vein grafts (SVG) by preventing pressure-induced wall stress and reactive neo-intimal hyperplasia. We present one-year-patency rates of meshed SVGs assessed by coronary computed tomographic angiography (cCTA). Data from consecutive patients receiving an eSVS® meshed coronary bypass SVG from 06/2010 to 06/2011 were prospectively collected and analysed post-hoc. Patient characteristics, coronary artery disease, SVG quality, surgery (including number of anastomoses and transit time flow-measurement: TTFM), postoperative course and graft patency by cCTA were recorded. Potential risk factors for meshed graft occlusion were evaluated. 22 patients received an eSVS® mesh (18 isolated CABG, 4 combined with aortic valve replacement). Three patients died prior to the one-year follow-up and were excluded. All 19 surviving patients (mean age 70.4 ± 9.5 years, 3 female) completed a cCTA of all grafts at 12 ± 0.1 months after surgery including 21 meshed SVGs (33 distal anastomoses), 7 unmeshed SVGs (13 distal anastomoses) and 22 arterial grafts (30 distal anastomoses). Mesh application was safe with patent grafts (by intraoperative TTFM) and perioperative course uneventful in all patients. The average graft/anastomosis number per patient was 2.6 ± 0.5/3.7 ± 0.8. Patency was unrestricted in all arterial and unmeshed SVGs (cCTA). Meshed SVG patency was 85 % (n = 28/33) for distal anastomoses and 76 % (n = 16/21) among meshed SVGs. Four SVGs with single distal anastomosis to the right coronary were completely occluded. One sequential graft to the left coronary was occluded between proximal and first distal anastomosis (see Fig. 1). Patency was independent of target site, coronary run-off, SVG quality and sequential distal grafting. All patients were asymptomatic. The overall one-year patency rate of eSVS® meshed SVGs/anastomoses was 76 %/85 %. Surgical implantation is safe independently of target site, run-off, vein quality and sequential distal anastomoses. However, graft patency of meshed veins (76 %) was inferior to non-meshed (100 %) or arterial grafts (100 %). Thus our mid-term data do not sustain the concept of improving vein graft patency by external reinforcing with the eSVS® mesh. Further long-term follow-up is warranted.


Gastric neuroendocrine neoplasm with late liver metastasis.
Gastric neuroendocrine neoplasms (GNENs) are classified into three types according to their aetiology. We present a clinical case of a female patient of 66 years and a well-differentiated (grade 2), type 3 GNEN with late liver metastasis (LM). The patient underwent surgical excision of a gastric lesion at 50 years of age, without any type of follow-up. Sixteen years later, she was found to have a neuroendocrine tumour (NET) metastatic to the liver. The histological review of the gastric lesion previously removed confirmed that it was a NET measuring 8 mm, pT1NxMx (Ki67 = 4%). 68Ga-DOTANOC PET/CT reported two LM and a possible pancreatic tumour/gastric adenopathy. Biopsies of the lesion were repeatedly inconclusive. She had a high chromogranin A, normal gastrin levels and negative anti-parietal cell and intrinsic factor antibodies, which is suggestive of type 3 GNEN. She underwent total gastrectomy and liver segmentectomies (segment IV and VII) with proven metastasis in two perigastric lymph nodes and both with hepatic lesions (Ki67 = 5%), yet no evidence of local recurrence. A 68Ga-DOTANOC PET/CT was performed 3 months after surgery, showing no tumour lesions and normalisation of CgA. Two years after surgery, the patient had no evidence of disease. This case illustrates a rare situation, being a type 3, well-differentiated (grade 2) GNEN, with late LM. Despite this, it was possible to perform surgery with curative intent, which is crucial in these cases, as systemic therapies have limited efficacy. We emphasise the need for extended follow-up in these patients. GNENs have a very heterogeneous biological behaviour.Clinical distinction between the three types of GNEN is essential to plan the correct management strategy.LMs are rare and more common in type 3 and grade 3 GNEN.Adequate follow-up is crucial for detection of disease recurrence.Curative intent surgery is the optimal therapy for patients with limited and resectable LM, especially in well-differentiated tumours (grade 1 and 2).


A study of meningiomas in South Africa: investigating a correlation between clinical presentation, histopathology and genetic markers.
To determine whether there are certain genetic markers which correlate with particular clinical characteristics of meningiomas including multiplicity, recurrence and calvarial erosion. Thirty-eight South African-born patients with meningiomas were recruited for this study. At surgery, blood and tumour specimens were obtained for histopathological, cytogenetic and molecular analysis. Loss of heterozygosity (LOH) on chromosomes 1p and 22q were investigated and the NF2 gene on 22q12.2 was screened for disease-causing mutations. The commonest tumour locations were convexity (25%) and parasagittal (21%). The histology results showed that 86.8% of the patients had Grade I tumours and the remainder had Grade II tumours. A pathogenic nonsense mutation, R341X in the NF2 gene was found in only one patient. LOH on each of chromosomes 1p and 22q was observed in 44.7% of patients, but in different individuals. Significant associations were found between having specific tumour characteristics and both male gender (p-value = 0.0059) and 22q LOH (p-value = 0.0425). We estimated that having 22q LOH makes an individual approximately four times more likely to develop a tumour that exhibits multiplicity, recurrence or calvarial erosion (OR = 4.8; 95% CI: 1.2-23.4). Adjusting for gender strengthened this effect (OR = 6.1; 95% CI: 1.1-48.7). Our data indicate that male patients and patients with a meningioma that has 22q LOH are more likely to develop tumours exhibiting multiplicity, recurrence or calvarial erosion. We recommend that this subset of patients should be followed up more closely. Further study is needed to determine the benefit of adjuvant radiation therapy in this scenario.


Smartphone integrated optoelectrowetting (SiOEW) for on-chip sample processing and microscopic detection of water quality.
With the increasing capabilities and ubiquity of smartphones and their associated digital cameras, this study presents a smartphone integrated optoelectrowetting (SiOEW) device as a simple, portable tool capable of on-chip water sample preparation and microscopic detection of the target cells in water samples, which significantly reduce the detection time and the labor cost required for water quality monitoring. A commercially available smartphone is used as a low-intensity portable light source to perform optoelectrowetting (OEW)-based microfluidic operations such as droplet transportation, merging, mixing, and immobilization on a hydrophobic detection zone. Furthermore, a built-in smartphone camera allows on-chip microscopic detection of water quality with a 45× magnification. We have experimentally demonstrated that the SiOEW platform is able not only to automate the sample processing of marine water including the target algae cells (Amphiprora sp.) and staining reagents fluorescein diacetate (FDA) and 5-chloromethylfluorescein diacetate (CMFDA), but also detect the fluorescence signals emitted from the target cells in water samples and count their populations. Using the smartphone, the collected information (e.g. the location of the water sample collected and the time it was detected, the number of the target cells, etc.) can be rapidly and wirelessly shared with a central host such as an environmental regulation agency for real-time monitoring and further management of water quality.


Serotonergic control of phenylephrine-induced cyclic 3,5'-adenosine monophosphate and inositol phosphates formation in rat hippocampus.
Chemical lesion of serotonergic afferents to the hippocampus resulted in a potentiation of phenylephrine (PHE) stimulation of cyclic AMP (cAMP) formation in rat hippocampal slices. The concentration-response curve of the alpha-1-agonist in lesioned rats was shifted markedly to the left with the peak increase occurring at a concentration 200 times lower (500 nM) than that required to raise cAMP to the same extent in slices of the sham-operated controls. Adenylate cyclase activity measured on crude homogenate preparations was increased by the lesion, too. The alpha-1 antagonist WB-4101 (dimethyloxyphenoxy-ethylamino-methyl benzo-1,4-dioxan) was the most potent inhibitor of PHE in lesioned rats with an IC50 of 125 nM, 110 times lower than that of prazosin (14 microM); yohimbine and propranolol, respectively, alpha-2 and beta-antagonists caused inhibition only at very high concentrations. Serotonin (10 microM) induced a marked rightward shift in the concentration response of PHE in lesioned rats, without any effect of its own on the cAMP level. PHE stimulated inositol phosphates accumulation in hippocampal slices in a concentration-dependent manner with an EC50 of 20 microM. Chemical lesion of the serotonergic median raphe nuclei caused a significant reduction of PHEs maximal effect on inositol phosphate accumulation by 50% with no change detectable in the EC50. The results imply that both second messenger responses to PHE stimulation are modulated by serotonin. Whether cAMP and phosphatidylinositol-4,5-bisphosphate generated second messengers act in a cooperative manner, or independently, is discussed.


Effect of Nanometric Lactobacillus plantarum in Kimchi on Dextran Sulfate Sodium-Induced Colitis in Mice.
Nanometric Lactobacillus plantarum (nLp) is a processed form of Lab. plantarum derived from kimchi and is 0.5-1.0 μm in size. This study was undertaken to determine the effect of nLp and kimchi plus nLp (K-nLp) on a dextran sulfate sodium (DSS)-induced mouse model of colitis. Animals fed nLp or K-nLp had longer colons, but lower colon weights per unit length than DSS controls. In addition, nLp- or K-nLp-fed animals showed lower levels of proinflammatory cytokines and inflammatory genes in serum and in colon tissues, lower populations of total bacteria, but higher populations of lactic acid bacteria in feces, and lower activities of fecal β-glucosidase and β-glucuronidase. Furthermore, these suppressive activities of nLp on colitis were equivalent to or higher than those of naive Lab. plantarum. Consequently, nLp was found to exhibit anticolitic effects, and the addition of nLp to kimchi was found to enhance the protective activity of kimchi against DSS-induced colitis. These results suggest that nLp might be an effective substitute for live probiotics and be useful as a functional ingredient with the anticolitic activity by the probiotic and food processing industries.


Tissue engineering of human cartilage in bioreactors using single and composite cell-seeded scaffolds.
Chondrocytes isolated from human fetal epiphyseal cartilage were seeded under mixed conditions into 15-mm-diameter polyglycolic acid (PGA) scaffolds and cultured in recirculation column bioreactors to generate cartilage constructs. After seeding, the cell distributions in thick (4.75 mm) and thin (2.15 mm) PGA disks were nonuniform, with higher cell densities accumulating near the top surfaces. Composite scaffolds were developed by suturing together two thin PGA disks after seeding to manipulate the initial cell distribution before bioreactor culture. The effect of medium flow direction in the bioreactors, including periodic reversal of medium flow, was also investigated. The quality of the tissue-engineered cartilage was assessed after 5 weeks of culture in terms of the tissue wet weight, glycosaminoglycan (GAG), total collagen and collagen type II contents, histological analysis of cell, GAG and collagen distributions, and immunohistochemical analysis of collagen types I and II. Significant enhancement in construct quality was achieved using composite scaffolds compared with single PGA disks. Operation of the bioreactors with periodic medium flow reversal instead of unidirectional flow yielded further improvements in tissue weight and GAG and collagen contents with the composite scaffolds. At harvest, the constructs contained GAG concentrations similar to those measured in ex vivo human adult articular cartilage; however, total collagen and collagen type II levels were substantially lower than those in adult tissue. This study demonstrates that the location of regions of high cell density in the scaffold coupled with application of dynamic bioreactor operating conditions has a significant influence on the quality of tissue-engineered cartilage.


Characterization of the Interaction Domains between the Phosphoprotein and the Nucleoprotein of Human Metapneumovirus.
Human metapneumovirus (HMPV) causes severe respiratory diseases in young children. The HMPV RNA genome is encapsidated by the viral nucleoprotein (N), forming an RNA-N complex (NNuc), which serves as the template for genome replication and mRNA transcription by the RNA-dependent RNA polymerase (RdRp). The RdRp is formed by the association of the large polymerase subunit (L), which has RNA polymerase, capping, and methyltransferase activities, and the tetrameric phosphoprotein (P). P plays a central role in the RdRp complex by binding to NNuc and L, allowing the attachment of the L polymerase to the NNuc template. During infection these proteins concentrate in cytoplasmic inclusion bodies (IBs) where viral RNA synthesis occurs. By analogy to the closely related pneumovirus respiratory syncytial virus (RSV), it is likely that the formation of IBs depends on the interaction between HMPV P and NNuc, which has not been demonstrated yet. Here, we finely characterized the binding P-NNuc interaction domains by using recombinant proteins, combined with a functional assay for the polymerase complex activity, and the study of the recruitment of these proteins to IBs by immunofluorescence. We show that the last 6 C-terminal residues of HMPV P are necessary and sufficient for binding to NNuc and that P binds to the N-terminal domain of N (NNTD), and we identified conserved N residues critical for the interaction. Our results allowed us to propose a structural model for the HMPV P-NNuc interaction. IMPORTANCE Human metapneumovirus (HMPV) is a leading cause of severe respiratory infections in children but also affects human populations of all ages worldwide. Currently, no vaccine or efficient antiviral treatments are available for this pneumovirus. A better understanding of the molecular mechanisms involved in viral replication could help the design or discovery of specific antiviral compounds. In this work, we have investigated the interaction between two major viral proteins involved in HMPV RNA synthesis, the N and P proteins. We finely characterized their domains of interaction and identified a pocket on the surface of the N protein, a potential target of choice for the design of compounds interfering with N-P complexes and inhibiting viral replication.


The Role of the Brainstem in Generating and Modulating Tinnitus.
Purpose The purpose of this work is to present a perspective article summarizing ideas pertaining to the brainstem's role in generating and modulating tinnitus. It is organized in 4 sections: Part 1, the role of the brainstem as a tinnitus generator; Part 2, the role of the brainstem in modulating tinnitus; Part 3, the role of the brainstem in nonauditory comorbid conditions associated with tinnitus; and Part 4, clinical implications. In Part 1, well-established neurophysiological models are discussed providing the framework of evidence that auditory brainstem nuclei play a role in generating tinnitus. In Part 2, ideas are presented explaining modulatory effects on tinnitus related to underlying pathways originating from or projecting to brainstem auditory and nonauditory nuclei. This section addresses multiple phenomena including somatic-related, attention-mediated, and emotion-mediated changes in the tinnitus percept. In Part 3, the role of the brainstem in common nonauditory comorbidities that occur in patients with tinnitus is discussed. Part 4 presents clinical implications of these new ideas related to the brainstem's involvement in generating and modulating tinnitus. Impact Knowledge of the brainstem's involvement in generating and modulating tinnitus provides a context for health care professionals to understand the temporal relationship between tinnitus and common nonauditory comorbid conditions.


Treatment with grass allergen peptides improves symptoms of grass pollen-induced allergic rhinoconjunctivitis.
Synthetic peptide immunoregulatory epitopes are a new class of immunotherapy to treat allergic rhinoconjunctivitis (ARC). Grass allergen peptides, comprising 7 synthetic T-cell epitopes derived from Cyn d 1, Lol p 5, Dac g 5, Hol l 5, and Phl p 5, is investigated for treatment of grass pollen-induced ARC. We sought to evaluate the efficacy, safety, and tolerability of intradermally administered grass allergen peptides. A multicenter, randomized, double-blind, placebo-controlled study evaluated 3 regimens of grass allergen peptides versus placebo in patients with grass pollen-induced allergy (18-65 years). After a 4-day baseline challenge to rye grass in the environmental exposure unit (EEU), subjects were randomized to receive grass allergen peptides at 6 nmol at 2-week intervals for a total of 8 doses (8x6Q2W), grass allergen peptides at 12 nmol at 4-week intervals for a total of 4 doses (4x12Q4W), or grass allergen peptides at 12 nmol at 2-week intervals for a total of 8 doses (8x12Q2W) or placebo and treated before the grass pollen season. The primary efficacy end point was change from baseline in total rhinoconjunctivitis symptom score across days 2 to 4 of a 4-day posttreatment challenge (PTC) in the EEU after the grass pollen season. Secondary efficacy end points and safety were also assessed. Two hundred eighty-two subjects were randomized. Significantly greater improvement (reduction of total rhinoconjunctivitis symptom score from baseline to PTC) occurred across days 2 to 4 with grass allergen peptide 8x6Q2W versus placebo (-5.4 vs -3.8, respectively; P = .0346). Greater improvement at PTC also occurred for grass allergen peptide 8x6Q2W versus placebo (P = .0403) in patients with more symptomatic ARC. No safety signals were detected. Grass allergen peptide 8x6Q2W significantly improved ARC symptoms after rye grass allergen challenge in an EEU with an acceptable safety profile.


The immunoreceptor tyrosine-based activation motif (ITAM) -related factors are increased in synovial tissue and vasculature of rheumatoid arthritic joints.
The immunoreceptor tyrosine-based activation motif (ITAM) pathway provides osteoclast co-stimulatory signals and regulates proliferation, survival and differentiation of effector immune cells. In the osteoclast, the receptors Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Osteoclast Associated Receptor (OSCAR) and their respective adaptor proteins, DAP12 and FcRγ mediate ITAM signals and induce calcium signaling and the crucial transcription factor, NFATc1. In rheumatoid arthritis (RA), OSCAR expression by monocytes is inversely correlated with disease activity. Additionally, serum levels of OSCAR are reduced in RA patients versus healthy controls suggesting that expression and secretion or cleavage of soluble (s) OSCAR is immune modulated. Recent data suggest that endothelial cells may also be a source of OSCAR. ITAM receptors, their adaptor proteins, and NFATc1 and cathepsin K were detected in human synovial tissues by immunohistochemistry. Synovial tissues from patients with active RA were compared with tissue from patients in remission, osteoarthritis (OA) patients and healthy individuals. OSCAR was measured by immunoassay in synovial fluids recovered from active RA and OA patients. Endothelial cells were cultured with or without 5 ng/mL TNF-α or IL-1β over 72 hours. Temporal expression of OSCAR mRNA was assessed by qRT PCR and OSCAR protein in the supernatant was measured by ELISA. Significantly higher (P < 0.05) NFATc1-positive inflammatory cell aggregates were found in active RA tissues than in healthy synovial tissue. Similarly, the percentage of OSCAR, FcRγ, DAP12 and TREM2 positive cells was significantly higher in active RA tissues compared to the healthy synovial tissue. Notably, OSCAR was strongly expressed in the microvasculature of the active RA tissues (9/9), inactive RA (8/9) weakly in OA (4/9) but only in the lumen of healthy synovial tissue (0/8). OSCAR levels were detected in synovial fluids from both RA (47 to 152 ng/mL) and OA (112 to 145 ng/mL) patients. Moreover, OSCAR mRNA expression and soluble OSCAR release was stimulated by TNF-α and IL1-β in cultured endothelial cells. Increased levels of ITAM related factors were present in synovial tissue from active RA joints compared to OA and healthy joints. OSCAR was strongly expressed by the vasculature of active RA patients and membrane bound and soluble OSCAR was stimulated by inflammatory mediators in endothelial cells in vitro.


Risky business: factor analysis of survey data - assessing the probability of incorrect dimensionalisation.
This paper undertakes a systematic assessment of the extent to which factor analysis the correct number of latent dimensions (factors) when applied to ordered-categorical survey items (so-called Likert items). We simulate 2400 data sets of uni-dimensional Likert items that vary systematically over a range of conditions such as the underlying population distribution, the number of items, the level of random error, and characteristics of items and item-sets. Each of these datasets is factor analysed in a variety of ways that are frequently used in the extant literature, or that are recommended in current methodological texts. These include exploratory factor retention heuristics such as Kaiser's criterion, Parallel Analysis and a non-graphical scree test, and (for exploratory and confirmatory analyses) evaluations of model fit. These analyses are conducted on the basis of Pearson and polychoric correlations. We find that, irrespective of the particular mode of analysis, factor analysis applied to ordered-categorical survey data very often leads to over-dimensionalisation. The magnitude of this risk depends on the specific way in which factor analysis is conducted, the number of items, the properties of the set of items, and the underlying population distribution. The paper concludes with a discussion of the consequences of over-dimensionalisation, and a brief mention of alternative modes of analysis that are much less prone to such problems.


A single mutation in arrestin-2 prevents ERK1/2 activation by reducing c-Raf1 binding.
Arrestins regulate the signaling and trafficking of G protein-coupled receptors (GPCRs). GPCR complexes with both nonvisual arrestins channel signaling to G protein-independent pathways, one of which is the activation of extracellular signal regulated kinase 1/2 (ERK1/2). Here we used alanine-scanning mutagenesis of residues on the nonreceptor-binding surface conserved between arrestin-2 and arrestin-3. We show that an Arg307Ala mutation significantly reduced arrestin-2 binding to c-Raf1, whereas the binding of the mutant to active phosphorylated receptor and downstream kinases MEK1 and ERK2 was not affected. In contrast to wild-type arrestin-2, the Arg307Ala mutant failed to rescue arrestin-dependent ERK1/2 activation via β2-adrenergic receptor in arrestin-2/3 double knockout mouse embryonic fibroblasts. Thus, Arg307 plays a specific role in arrestin-2 binding to c-Raf1 and is indispensable in the productive scaffolding of c-Raf1-MEK1-ERK1/2 signaling cascade. Arg307Ala mutation specifically eliminates arrestin-2 signaling through ERK, which makes arrestin-2-Arg307Ala the first signaling-biased arrestin mutant constructed. In the crystal structure the side chain of homologous arrestin-3 residue Lys308 points in a different direction. Alanine substitution of Lys308 does not significantly affect c-Raf1 binding to arrestin-3 and its ability to promote ERK1/2 activation, suggesting that the two nonvisual arrestins perform the same function via distinct molecular mechanisms.


Consequences of protein supplementation for anorexia, expression of immunity and plasma leptin concentrations in parasitized ewes of two breeds.
The periparturient relaxation of immunity (PPRI) against parasites in ewes has a nutritional basis. We investigated whether ewes experience a reduction in food intake (anorexia) during PPRI and if the magnitude of anorexia is affected by host production potential and dietary protein supplementation. We also investigated whether nematode infection is linked to plasma leptin concentrations in periparturient ewes. The experiment was a 2 x 2 x 2 factorial design. Two breeds of twin-bearing/lactating ewes (Greyface cross, G (n 32) and Scottish Blackface, B (n 32)) were used. Half of the ewes were trickle infected with 30,000 larvae of the abomasal parasite Teladorsagia circumcincta per week and the other half were not. During the experiment, all ewes had ad libitum access to a low-protein diet that provided less protein than the recommended allowance. In addition, half of the ewes received a protein supplement that resulted in protein intakes that exceeded recommendations. Nematode infection resulted in a breakdown of immunity to parasites and a reduction in food intake in both breeds. The breeds differed in the extent of PPRI (G ewes having higher faecal egg counts than B ewes), but not in the magnitude of anorexia. Protein supplementation resulted in a reduction in faecal egg counts, but had no effect on the magnitude of anorexia. Plasma leptin concentrations changed significantly over time, but were not affected by protein supplementation or infection. It is concluded that infection with T. circumcincta in periparturient ewes results in anorexia that is not alleviated by protein supplementation and seems unrelated to plasma leptin concentrations.


New Detection Paradigms to Improve Wireless Sensor Network Performance under Jamming Attacks.
In this work, two new self-tuning collaborative-based mechanisms for jamming detection are proposed. These techniques are named (i) Connected Mechanism and (ii) Extended Mechanism. The first one detects jamming by comparing the performance parameters with respect to directly connected neighbors by interchanging packets with performance metric information, whereas the latter, jamming detection relays comparing defined zones of nodes related with a collector node, and using information of this collector detects a possible affected zone. The effectiveness of these techniques were tested in simulated environment of a quadrangular grid of 7 × 7, each node delivering 10 packets/sec, and defining as collector node, the one in the lower left corner of the grid. The jammer node is sending packets under reactive jamming. The mechanism was implemented and tested in AODV (Ad hoc On Demand Distance Vector), DSR (Dynamic Source Routing), and MPH (Multi-Parent Hierarchical), named AODV-M, DSR-M and MPH-M, respectively. Results reveal that the proposed techniques increase the accurate of the detected zone, reducing the detection of the affected zone up to 15% for AODV-M and DSR-M and up to 4% using the MPH-M protocol.


Pharmacotherapy in bronchiolitis at discharge from emergency departments within the Pediatric Emergency Research Networks: a retrospective analysis.
Clinical guidelines advise against pharmacotherapy in bronchiolitis. However, little is known about global variation in prescribing practices for bronchiolitis at discharge from emergency departments. We aimed to evaluate global variation in prescribing practice (ie, inhaled salbutamol, or oral or inhaled corticosteroids) for infants with bronchiolitis at discharge from emergency departments. We did a planned secondary analysis of a multinational, retrospective cohort study of the Pediatric Emergency Research Networks. Previously healthy infants (aged <12 months) who were discharged with bronchiolitis between Jan 1 and Dec 31, 2013 from 38 emergency departments in Australia and New Zealand, Canada, Spain and Portugal, the UK and Ireland, and the USA were included. The primary outcome was pharmacotherapy prescription at discharge from the emergency department. Secondary outcomes were revisits to the emergency department or hospitalisations for bronchiolitis within 21 days of discharge. Of 1566 infants discharged from the emergency department, 317 (20%) were prescribed pharmacotherapy. Corticosteroid prescriptions were infrequent, ranging from 0% (0 of 68 infants) in Spain and Portugal to 6% (25 of 452) in the USA. Salbutamol prescriptions ranged from 5% (22 of 432) in the UK and Ireland to 32% (146 of 452) in the USA. Compared with the UK and Ireland, the odds of prescription of pharmacotherapy were increased in Spain and Portugal (odds ratio [OR] 9·22, 95% CI 1·70-49·96), the USA (8·20, 2·79-24·11), Canada (5·17, 1·61-16·67), and Australia and New Zealand (1·21, 0·36-4·10). After adjustment for clustering by site, pharmacotherapy at discharge was associated with older age (per 1 month increase; OR 1·23, 95% CI 1·16-1·30), oxygen saturation (per 1% decrease from 100%; 1·09, 1·01-1·18), chest retractions (1·88, 1·26-2·79), network (p=0·00050), and site (p<0·00090). 303 (19%) of 1566 infants returned to the emergency department and 129 (43%) of 303 were hospitalised. Discharge pharmacotherapy was not associated with revisits (p=0·55) or subsequent hospitalisations (p=0·50). Use of ineffective medications in infants with bronchiolitis at discharge from emergency departments is common, with large differences in prescribing practices between countries and emergency departments. Enhanced knowledge translation and deprescribing efforts are needed to optimise and unify the management of bronchiolitis. None.


The children of teenage mothers: patterns of early childbearing in two generations.
Twenty years after a mostly black group of Baltimore women became adolescent mothers, the majority of their first-born children had not become adolescent parents, a finding that challenges the popular belief that the offspring of teenage mothers are themselves destined to become adolescent parents. Almost all of the offspring had had intercourse by age 19. About half of the young women had experienced a pregnancy before that age, and approximately one-third of the young men reported having impregnated a partner before age 19. The Baltimore youths were just as likely to have had a live birth before age 19 as were the children of teenage mothers in a national sample of urban blacks, and both of these groups were more likely to have done so than were the children of older mothers in the national sample. In the Baltimore sample, maternal welfare experience only increased a daughter's likelihood of early childbearing if welfare was received during her teenage years. Within the Baltimore sample, a direct comparison of the daughters who became adolescent mothers with their own mothers at a comparable age reveals that the daughters have bleaker educational and financial prospects than their mothers had, and are less likely to ever have married. These results suggest that today's teenage parents may be less likely than were previous cohorts of adolescent mothers to overcome the handicaps of early childbearing. This trend could portend the growth of an urban underclass, even though only a minority of the offspring of teenage mothers go on to become adolescent parents.


International students of speech and language therapy in the UK: do we meet their needs?
Informal evidence suggests that many Speech and Language Therapy (SLT) students from outside of the UK and/or Republic of Ireland who come to the UK either do not return to their home country on qualification or do not practise as SLTs in the public sector. Many factors may contribute to this situation. Concern that it may result in part from a poor match between UK SLT education and the demands of the role in other countries led the Royal College of Speech and Language Therapists (RCSLT) to fund a study of international SLT students' experiences of UK qualifying courses. To discover and describe the experiences, views and expectations of current and past international students studying SLT in the UK and past international students' experiences, views and expectations of practising as SLTS, both inside and outside the UK. To consider the implications of the findings for (1) international students planning to work as SLTs; (2) UK SLT students planning to practise outside the UK; and (3) all those involved in SLT education: educational institutions; supervising SLTs; RCSLT. The study involved distributing 166 postal questionnaires (some directly to (ex)students and some to their Higher Education Institutes, or HEIs) and carrying out 23 interviews, with both current students and those qualifying since May 1994. Quantitative analysis was carried out using SPSS using descriptive statistics. Qualitative analysis used content and thematic analyses. Seventy-one questionnaires were received from current and past students, representing a minimum response rate of 43%. (It was not possible to verify exactly how many questionnaires were distributed by HEIs.) The results describe the diverse range of respondents' experiences of studying and working in the UK, their views of working in their home countries and the UK, and their suggestions about strategies that might be adopted to support them further. The results revealed that students come from a wide diversity of countries, with resulting differences in their experiences. However, there were some commonalities in the perceived advantages and disadvantages of working at home and in the UK. The suggestions for change included practical ideas for change both before and after qualification as an SLT. These included courses about the organization of health, education and social services in the UK, adaptations of course delivery and course work to include cross-cultural/linguistic work and 'home-based' projects. Implications of the findings and strategies for home as well as international SLT students are discussed.


Contact lens use and its compliance for care among healthcare workers in Pakistan.
Poor care and hygiene of contact lens (CL) results in eye problems and infections. Healthcare workers have an important role in advocating correct lens care. To determine the practices of CL care and the adverse consequences of poor CL care among healthcare workers. A cross-sectional study in one public and three private sector hospitals in Karachi, Pakistan, in 2009-2010. We questioned 500 healthcare workers of all ages and both sexes, who wore CL, about compliance with advice on care and any complications due to improper hygiene practices. Ethical approval was obtained. Chi-square tests were used to determine significance and p-value less than 0.05 was considered statistically significant. Of the total CL users, 385 (77%) were females. Most (75%) respondents wore CL to correct myopia, whereas 54% wore CL only occasionally. Surprisingly, only 24% knew the CL cleaning protocol. Lens solution was changed daily by 33% of users and after more than 2 weeks by 42%. Although 412 (82%) participants practised reasonable hand hygiene before inserting CL, 88 (18%) did not. Infection and eye dryness were statistically significantly (P < 0.01) associated with sex, hand-washing, and frequency of CL use. Noncompliance with the CL protocol was common among healthcare workers in our society. This behavior calls for targeted health education and awareness programs for healthcare workers.


A prospective randomized double-blind controlled trial to evaluate the efficacy of an analgesic epidural paste following lumbar decompressive surgery.
Pain control can often be improved by local (as opposed to systemic) application of analgesic and/or anesthetic medication. The purpose of this study was to evaluate the efficacy of a single-dose epidural analgesic "paste" in the control of postoperative pain in patients who have undergone lumbar decompressive surgery. Sixty patients undergoing routine elective lumbar decompressive surgery were randomized in a double-blind fashion to one of two groups: those receiving active paste or placebo paste. The paste was applied to the exposed dura at the time of surgery, just prior to wound closure. Patients received follow-up care in the hospital and at home for 3 months postsurgery. Several outcome measures were studied to ascertain differences in pain control and to ensure comparability between groups. Patients who received active paste demonstrated significantly lower pain scores compared with those who received placebo paste for up to 6 weeks postoperatively. General health perception indexed by the Short Form 36 was also significantly better in patients who received active paste for up to 6 weeks. In-hospital and outpatient oral narcotic consumption was significantly lower in the active paste-treated group. Inpatient straight leg raising scores were improved in those patients who received active compared with control paste. Application of an analgesic paste directly to the epidural space during lumbar decompressive surgery significantly improves postoperative pain control, reduces prescribed analgesic drug consumption, and improves overall health perception for up to 6 weeks following surgery. The authors conclude that this postoperative pain control strategy is both effective and safe and may provide a new standard of pain management in patients undergoing lumbar discectomy or laminectomy.


Lentinula edodes-derived polysaccharide rejuvenates mice in terms of immune responses and gut microbiota.
Aging is characterized by impaired immunity and unbalanced gut microbiota. Prebiotics have the capability to prevent or reverse age-related declines in health by modulating gut microbiota. Mushroom polysaccharides have been suggested to be potential prebiotics. However, their effects on the immunity and gut microbiota in aged mice have not been determined. This study firstly assessed the effects of a heteropolysaccharide L2 isolated from the fruit body of L. edodes on the immune response of aged mice, and then compared the composition of fecal microbiota in adult (N), old (O) and L2-treated old (Oa) mice using the high-throughput pyrosequencing technique. The results showed that L2 can restore the age-attenuated immune responses by increasing cytokine levels in peripheral blood. Moreover, L2 can partly reverse the age-altered composition of gut microbiota. The Euclidean distances (De) among 3 groups (N, O and Oa) are determined to be De(O, N) = 0.19, De(O, Oa) = 0.20, and De(N, Oa) = 0.10, i.e. there is a marked reduction in the distance from 0.19 to 0.1 by L2. This suggests the beneficial effects of L2 on enhancing immunity and improving gut health.


Phenotype refinement strengthens the association of AHR and CYP1A1 genotype with caffeine consumption.
Two genetic loci, one in the cytochrome P450 1A1 (CYP1A1) and 1A2 (CYP1A2) gene region (rs2472297) and one near the aryl-hydrocarbon receptor (AHR) gene (rs6968865), have been associated with habitual caffeine consumption. We sought to establish whether a more refined and comprehensive assessment of caffeine consumption would provide stronger evidence of association, and whether a combined allelic score comprising these two variants would further strengthen the association. We used data from between 4,460 and 7,520 women in the Avon Longitudinal Study of Parents and Children, a longitudinal birth cohort based in the United Kingdom. Self-report data on coffee, tea and cola consumption (including consumption of decaffeinated drinks) were available at multiple time points. Both genotypes were individually associated with total caffeine consumption, and with coffee and tea consumption. There was no association with cola consumption, possibly due to low levels of consumption in this sample. There was also no association with measures of decaffeinated drink consumption, indicating that the observed association is most likely mediated via caffeine. The association was strengthened when a combined allelic score was used, accounting for up to 1.28% of phenotypic variance. This was not associated with potential confounders of observational association. A combined allelic score accounts for sufficient phenotypic variance in caffeine consumption that this may be useful in Mendelian randomization studies. Future studies may therefore be able to use this combined allelic score to explore causal effects of habitual caffeine consumption on health outcomes.


7,8- and 5,8-Linoleate diol synthases support the heterolytic scission of oxygen-oxygen bonds by different amide residues.
Linoleate diol synthases (LDS) are fungal dioxygenase-cytochrome P450 fusion enzymes. They oxidize 18:2n-6 sequentially to 8R-hydroperoxylinoleic acid (8R-HPODE) and 7S,8S- or 5S,8R-dihydroxylinoleic acids (DiHODE) by intramolecular oxygen transfer. The P450 domains contain a conserved sequence, Ala-Asn-Gln-Xaa-Gln, presumably located in the I-helices. The Asn938Leu replacement of 7,8-LDS of Gaeumannomyces graminis virtually abolished and the Asn938Asp and Asn938Gln replacements reduced the hydroperoxide isomerase activity. Gln941Leu and Gln941Glu substitutions had little effects. Replacements of the homologous Asn(887) and Gln(890) residues of 5,8-LDS of Aspergillus fumigatus yielded the opposite results. Asn887Leu and Asn887Gln of 5,8-LDS retained 5,8-DiHODE as the main metabolite with an increased formation of 6,8- and 8,11-DiHODE, whereas Gln890Leu almost abolished the 5,8-LDS activity. Replacement of Gln(890) with Glu also retained 5,8-DiHODE as the main product, but shifted oxygenation from C-5 to C-7 and C-11 and to formation of epoxyalcohols by homolytic scission of 8R-HPODE. P450 hydroxylases usually contain an "acid-alcohol" pair in the I-helices for the heterolytic scission of O2 and formation of compound I (Por(+) Fe(IV)=O) and water. The function of the acid-alcohol pair appears to be replaced by two different amide residues, Asn(938) of 7,8-LDS and Gln(890) of 5,8-LDS, for heterolysis of 8R-HPODE to generate compound I.


Betulinic Acid Kills Colon Cancer Stem Cells.
Cancer stem cells (CSCs) are considered to be the origin of cancer and it is suggested that they are resistant to chemotherapy. Current therapies fail to eradicate CSCs and therefore selecting a resistant cell subset that is able to facilitate tumor recurrences. Betulinic acid (BetA) is a broad acting natural compound, shown to induce cell death via the inhibition of the stearoyl-CoA- desaturase (SCD- 1). This enzyme converts saturated fatty acids into unsaturated fatty acids and is over-expressed in tumor cells. Here we show that BetA induces rapid cell death in all colon CSCs tested and is able to affect the CSCs directly as shown, via the loss of clonogenic capacity. Similar results were observed with inhibition of SCD-1, suggesting that SCD-1 activity is indeed a vulnerable link in colon CSCs and can be considered an ideal target for therapy in colon cancer.


The long-term risks and complications of bovine-derived xenografts: A case series.
The frequency of dental implant related surgeries that involve soft tissue and bone augmentation procedures has increased significantly. Bovine-derived substitutes have been by far the most commonly used xenografts in dentistry. Albeit literature is replete with clinical studies in favor of bovine-derived graft materials, bibliographical data reporting on risks and clinical complications is scarce. Clinical impression and concern for patient safety led to the report we have provided. The aim of the present case series was to raise awareness on the long-term risks and late clinical complications of bovine-derived graft materials. Patients were referred to a private practice due to bone augmentation complications. Demographics, significant medical and dental findings are reported. Complications included sinus and maxillary bone pathoses, displacement of the graft materials, oroantral communications, implant failure, foreign body reactions, encapsulation, chronic inflammation, soft tissue fenestrations and associated cysts. Bovine-derived graft materials were not biodegradable. Resolution of the associated lesions and symptoms was achieved after the removal of the bone graft materials. The surgical removal of the xenograft materials may require advanced clinical skills because of the different configurations clinicians might encounter of the non-resorbed and migrated particles. The authors' concern is that patient morbidity may not be reduced with xenografts, due to the inherent risks and associated complications. Clinicians seeking to provide functional and esthetic outcomes should be aware of the complications of the bovine-derived graft materials. The long-term safety of xenografts and their potential association with disease are valid concerns.


Fitness costs of synonymous mutations in the rpsT gene can be compensated by restoring mRNA base pairing.
We previously reported that the distribution of fitness effects for non-synonymous and synonymous mutations in Salmonella typhimurium ribosomal proteins S20 and L1 are similar, suggesting that fitness constraints are present at the level of mRNA. Here we explore the hypothesis that synonymous mutations confer their fitness-reducing effect by alterating the secondary structure of the mRNA. To this end, we constructed a set of synonymous substitutions in the rpsT gene, encoding ribosomal protein S20, that are located in predicted paired regions in the mRNA and measured their effect on bacterial fitness. Our results show that for 3/9 cases tested, the reduced fitness conferred by a synonymous mutation could be fully or partly restored by introducing a second synonymous substitution that restore base pairing in a mRNA stem. In addition, random mutations in predicted paired regions had larger fitness effects than those in unpaired regions. Finally, we did not observe any correlation between fitness effects of the synonymous mutations and their rarity. These results suggest that for ribosomal protein S20, the deleterious effects of synonymous mutations are not generally due to codon usage effects, but that mRNA secondary structure is a major fitness constraint.


Identification of phlebotomine sand flies using one MALDI-TOF MS reference database and two mass spectrometer systems.
Rapid, accurate and high-throughput identification of vector arthropods is of paramount importance in surveillance programmes that are becoming more common due to the changing geographic occurrence and extent of many arthropod-borne diseases. Protein profiling by MALDI-TOF mass spectrometry fulfils these requirements for identification, and reference databases have recently been established for several vector taxa, mostly with specimens from laboratory colonies. We established and validated a reference database containing 20 phlebotomine sand fly (Diptera: Psychodidae, Phlebotominae) species by using specimens from colonies or field-collections that had been stored for various periods of time. Identical biomarker mass patterns ('superspectra') were obtained with colony- or field-derived specimens of the same species. In the validation study, high quality spectra (i.e. more than 30 evaluable masses) were obtained with all fresh insects from colonies, and with 55/59 insects deep-frozen (liquid nitrogen/-80 °C) for up to 25 years. In contrast, only 36/52 specimens stored in ethanol could be identified. This resulted in an overall sensitivity of 87 % (140/161); specificity was 100 %. Duration of storage impaired data counts in the high mass range, and thus cluster analyses of closely related specimens might reflect their storage conditions rather than phenotypic distinctness. A major drawback of MALDI-TOF MS is the restricted availability of in-house databases and the fact that mass spectrometers from 2 companies (Bruker, Shimadzu) are widely being used. We have analysed fingerprints of phlebotomine sand flies obtained by automatic routine procedure on a Bruker instrument by using our database and the software established on a Shimadzu system. The sensitivity with 312 specimens from 8 sand fly species from laboratory colonies when evaluating only high quality spectra was 98.3 %; the specificity was 100 %. The corresponding diagnostic values with 55 field-collected specimens from 4 species were 94.7 % and 97.4 %, respectively. A centralized high-quality database (created by expert taxonomists and experienced users of mass spectrometers) that is easily amenable to customer-oriented identification services is a highly desirable resource. As shown in the present work, spectra obtained from different specimens with different instruments can be analysed using a centralized database, which should be available in the near future via an online platform in a cost-efficient manner.


Community-Based Prevalence of Genital Human Papilloma Virus (HPV) Infection: a Systematic Review and Meta-Analysis
Introduction: Cervical cancer probably represents the best-studied human cancer caused by a viral infection and the causal association of this preventable cancer with human papilloma virus (HPV) is well established. Worldwide there is a scarcity of data regarding HPV prevalence with vast differences existing among populations. Objective: The aim of this meta-analysis was to determine the community-based HPV prevalence estimates among asymptomatic women from urban and rural set ups and in participants of cancer screening clinics. Study design: Systematic review and meta-analysis. Methods: PubMed-Medline, CINAHL, Scopus, and Google scholar were systematically searched for studies providing prevalence data for HPV infection among asymptomatic women between 1986 and 2016. Results: The final analysis included 32 studies comprising a population of 224,320 asymptomatic women. The overall pooled HPV prevalence was 11% (95% confidence interval (CI), 9%-12%). The pooled HPV prevalence of 11% (95% CI, 9%-11%) was observed among women attending cervical cancer screening clinics. The pooled HPV prevalences were 10% (95% CI 8%-12%) and 11% (95% CI 4%-18%) from urban and rural areas respectively, indicating higher infection rates among the rural women with the least access to cancer screening and cancer care. Conclusion: The prevalence rates in this systematic quantitative review provide a reliable estimate of the burden of HPV infection among asymptomatic women from developed as well as developing nations. Rural women and women attending cervical cancer screening programmes feature higher genital HPV prevalences compared to their urban counterparts.


Quantifying the health benefits of primary care physician supply in the United States.
This analysis addresses the question, Would increasing the number of primary care physicians improve health outcomes in the United States? A search of the PubMed database for articles containing "primary care physician supply" or "primary care supply" in the title, published between 1985 and 2005, identified 17 studies, and 10 met all inclusion criteria. Results were reanalyzed to assess primary care effect size and the predicted effect on health outcomes of a one-unit increase in primary care physicians per 10,000 population. Primary care physician supply was associated with improved health outcomes, including all-cause, cancer, heart disease, stroke, and infant mortality; low birth weight; life expectancy; and self-rated health. This relationship held regardless of the year (1980-1995) or level of analysis (state, county, metropolitan statistical area (MSA), and non-MSA levels). Pooled results for all-cause mortality suggest that an increase of one primary care physician per 10,000 population was associated with an average mortality reduction of 5.3 percent, or 49 per 100,000 per year.


Miniature battery foreign bodies in auditory and nasal cavities.
A series of cases involving button batteries lodged in the ear or nasal cavity is presented. All produced tissue destruction. Injuries were generally severe, and included tympanic membrane perforation (three patients) or total destruction (three), marked necrosis of dermis of the external ear canal with exposed bone (seven), documented further impairment of hearing (three), destruction of ossicles (two), facial nerve paralysis and chondritis (one), nasal septal perforation (one), and superficial burns of nasal mucosa (one). Otic and nasal drops must be withheld as they provide an external electrolyte bath for the battery, enhancing leakage and generation of an external current, with subsequent tissue electrolysis and hydroxide formation. Instead, batteries lodged in the ear or nose must be removed promptly.


Forced dimerization increases the activity of ΔEGFR/EGFRvIII and enhances its oncogenicity.
Delta epidermal growth factor receptor (ΔEGFR), an in-frame deletion mutant of the extracellular ligand-binding domain, which occurs in about 30% of glioblastoma, is a potent oncogene that promotes tumor growth and progression. The signaling of ΔEGFR is ligand-independent and low intensity, allowing it to evade the normal mechanisms of internalization and degradation by the endocytic machinery and hence is persistent. The basis of the oncogenic potential of ΔEGFR remains incompletely understood, including whether dimerization plays an important role in its signal and whether its oncogenic potential is dependent on its relatively low intensity, when compared with the acutely activated wild-type receptor. To examine these two important questions, we have generated a chimeric ΔEGFR that allows forced dimerization via domains derived from variants of the FKBP12 protein that are brought together by FK506 derivatives. Forced dimerization of chimeric ΔEGFR significantly increased the intensity of its signal, as measured by receptor phosphorylation levels, suggesting that the naturally occurring ΔEGFR does not form strong or stable dimers as part of its low level signal. Interestingly, the increased activity of dimerized, chimeric ΔEGFR did not promote receptor internalization, implying that reduced rate of endocytic downregulation of ΔEGFR is an inherent characteristic. Significantly, forced dimerization enhanced the oncogenic signal of the receptor, implying that the ΔEGFR is a potent oncogene despite, not because of its low intensity.


The effect of 6-week zinc supplement and weight training on the blood lipids of the sedentaries and athletes.
In this study, we aimed to investigate the effect of 6 weeks of zinc supplementation and weight training on blood lipids of sedentary and athletes. Research group consists of total 40 males; 20 athletes who do regularly physical exercises and 20 sedentary volunteers. The volunteers were divided into four groups. These groups were constituted in that way: the first group is a natural sedentary group which called control group as well (S); the second group is another sedentary group which is supplied with only zinc (Z+S); the third group is training group which composing of athletes and is supplied with zinc (Z+T); the fourth group is the natural training group or athletes (T). From the beginning of the study to the end of 6-weeks of training, the participants gave blood samples before and after every application order to measure the total cholesterol, LDL cholesterol and HDL cholesterol and the levels of Triglyceride. This study identifies that the values of the total cholesterol, LDL cholesterol and Triglyceride of the groups which were supplied with zinc supplement decreased, whereas the levels of HDL cholesterol increased in these groups. Consequently, this work demonstrates that the 6-weeks zinc supplement and training can make a significant contribution to the performance by changing positively the levels of blood lipid.


Cultural childbirth practices and beliefs in Zambia.
Zambia, one of the world's poorest countries, also has one of the highest maternal mortality rates in the world. Most pregnant women in Zambia (96%) attend antenatal care, while 53% deliver at home. This may be related to socio-economic and cultural factors, but cultural childbirth practices and beliefs in Zambia have been little documented. The aim of this study was to explore cultural childbirth practices and beliefs in Zambia as related by women accompanying labouring women to maternity units. These social support women were also interviewed about their views on providing companionship to labouring women. Thirty-six women accompanying labouring women to urban and rural maternity units in Zambia were interviewed A thematic guide with closed and open-ended questions was used. EPI INFO, an epidemiological statistical software package, was used to analyse the quantitative data; qualitative data were analysed using content analysis. Eighteen of the women considered themselves to be mbusas, or traditional birth assistants and the rest said that they followed labouring women to maternity units. Those who considered themselves traditional birth assistants advised childbearing women on appropriate cultural childbirth practices and assisted with deliveries at home. They also advised women on the use of traditional medicine, for example, to widen the birth canal and to precipitate labour. If something went wrong during labour, they relied on traditional beliefs and witchcraft to explain the mishap and expected the woman in labour to confess her purported 'bad' behaviour. Twelve of the women were in favour of providing support to labouring women in maternity units and learning about childbirth care from midwives. These social support women, including those who considered themselves as mbusas, lacked understanding of the causes of obstetric complications during childbirth, and had inadequate knowledge of the appropriate management of labour. Culturally-specific knowledge from this study should be used to guide policy-makers and health planners in the future development of safe motherhood initiatives in developing countries. Midwives have a unique opportunity to ensure that care given during childbirth is clinically safe and culturally sensitive.


Unilateral cerebral cortical encephalitis with epilepsy: a possible special phenotype of MOG antibody-associated disorders.
Myelin oligodendrocyte glycoprotein (MOG) antibody-related encephalomyelitis is an increasingly recognized entity with heterogeneity in phenotype. Among all clinical phenotypes, encephalitis restricted to cerebral cortex might be most easily ignored and under-estimated type. Here, we described two cases of cerebral cortical encephalitis with MOG seropositivity to facilitate the awareness of the manifestations of the disease. In case 1, the patient presented with headaches and fevers turned out to have elevated CSF cells and cerebral cortical FLAIR hyperintense lesions in brain MRI. He was treated as intracranial infection during his first and second admission and fully resolved when discharged. During the patient's third admission, the patient experienced a seizure, and we found cerebral cortical FLAIR hyperintensity again and MOG antibody was positive in the serum. Therefore, we considered the patient suffered from MOG antibody encephalitis. In case 2, the patient also had headache, fever, and experienced a seizure. MOG antibody was positive in the serum and brain MRI showed cortical hyperintense lesions. Both the patients were young man, response well to corticosteroids and recovered completely. The two cases suggested that encephalitis, especially benign recurrent unilateral cerebral cortical encephalitis with epilepsy, might be a special phenotype of MOG antibody-associated disorders.


Polarization selective computer-generated holograms realized in glass by femtosecond laser induced nanogratings.
We demonstrate polarization selective computer-generated holograms (PSCGH) for visible light operation fabricated in glass by a femtosecond laser. For this purpose we create arrays of tailored microwaveplates by controlling the laser formation of nanogratings embedded in fused silica. A birefringent cell-oriented encoding method adapted to the characteristics of the physical writing process is proposed and implemented. According to this method, each cell contains a micro-waveplate with controlled phase retardation and orientation. A detour of each microwaveplate, combined with the orientation of its principal optical axis, simultaneously realizes a different phase function for each polarization. PSCGH's are attractive for integration with other free-space and guided-wave devices embedded in glass.


Oral azacitidine (CC-486) in combination with lenalidomide and dexamethasone in advanced, lenalidomide-refractory multiple myeloma (ROAR study).
In preclinical studies, oral azacitidine (CC-486), a hypomethylating agent, has been shown to have a direct anti-MM effect and in vitro anti-MM synergism when combined with lenalidomide (LEN). We present a phase 1b, single center, 3 × 3 dose escalation study with planned expansion at maximum tolerated dose (MTD), which assessed the safety and efficacy of combining CC-486 with LEN (25 mg d1-21/28) and dexamethasone (DEX) (40 mg weekly) in patients with relapsed/refractory MM who had previously failed LEN. Twenty-four patients were enrolled. The MTD of CC-486 was 150 mg d1-21; recommended expansion dose was 100 mg d1-21. Adverse events were predictable and manageable. ORR was 37.5%; clinical benefit rate was 50%. Median OS was 10.3 m; median PFS was 2.6 m. Correlative proteomics demonstrated that higher MM tumor cell cereblon expression (pretreatment, C1D5) was associated with superior PFS/OS. CC-486, LEN and DEX produced meaningful clinical responses in heavily treated LEN refractory MM patients. Proteomics may have utility in predicting clinical outcomes.


Catalytic degradation of phenols by recyclable CVD graphene films.
Ferrous ion-based catalysts have been widely employed to oxidatively destruct the major industrial pollutants such as phenolic compounds through advanced oxidation processes (AOPs). These agents, however, inevitably show several drawbacks including the need for pH adjustment and further purification steps to remove residual salts. Here we report the use of a chemical vapour deposition (CVD) graphene film as a novel metal-free catalyst for the AOP-based degradation of phenols in aqueous solution, which does not require additional steps for salt removal nor external energy to activate the process. We have also verified that the catalytic activity is strongly dependent on the surface area of the graphene film and the degradation efficiency can be markedly improved by exploiting an array of multiple graphene films. Finally, the recyclability of the graphene film has been validated by performing repetitive degradation tests to ensure its practical use.


Is there a relationship between time-lapse parameters and embryo sex?
To study if it is possible to identify embryo sex from embryo cleavage timings. Retrospective and observational study. University-affiliated private fertility center. Women undergoing preimplantion genetic diagnosis. INTERVENTION[S): All biopsied embryos were cultured in an Embryoscope incubator with time-lapse technology. Cleavage timing from insemination to day 3 and all kinetic parameters that have been described in previous studies by our group. The study included 421 embryos from our Compressive Chromosome Screening program, conducted from January 2012 to December 2012. Embryos were grouped according to their sex: male (176 embryos) and female (161 embryos). Chromosomal abnormal rate was similar for the two groups (male 62.5%, female 58.4%). When morphokinetic parameters were separated in different quartiles and grouped, we found statistical differences between male or female embryos. By logistic regression analysis we found that two specific kinetic variables were relevant: second synchrony (>2 hours) and timing of morula formation (80.8-90.9 hours). With the use of these parameters, we propose an algorithm with four different categories reflecting the range from 71% to 42% in the likelihood of an embryo being female. Embryo development was affected by embryo sex, and the sex ratio could be affected by the embryo selection method for transfer based on kinetic parameters.


TXNDC5 protects synovial fibroblasts of rheumatoid arthritis from the detrimental effects of endoplasmic reticulum stress.
TXNDC5 is an endoplasmic reticulum (ER)-resident chaperone that protects the endothelium from secondary effects of ER stress. Previous studies by the current authors identified TXNDC5 as a key pathological factor in promoting the inflammatory phenotype of fibroblast-like synoviocytes (FLSs) from rheumatoid arthritis (RA). However, its activity in RA FLSs under ER stress remains unclear. The current study found that TXNDC5 is responsive to ER stress in RA FLSs since its expression was induced by ER stress at both the endogenous and secretory level. A functional study indicated that silencing TXNDC5 reduced the viability of RA FLSs more markedly in the presence of ER stressors. In contrast, rhTXNDC5 attenuated a decrease in cell viability as a result of ER stress. Moreover, silencing TXNDC5 attenuated the induction of IL-6 and IL-8 from RA FLSs in response to ER stress. In addition, rhTXNDC5 induced a greater increase in VEGF production during ER stress. These findings confirm the pro-survival and pro-inflammation roles of TXNDC5 under ER stress in RA FLSs. TXNDC5 appears to act as a mediator linking ER stress and inflammation of RA.


Serum bicarbonate: can it be a marker of metformin induced acidosis in geriatrics?
Metformin is an oral antidiabetic agent, widely used in the treatment of type 2 diabetes mellitus. The serious side effect of metformin therapy is lactic acidosis. Contraindications for metformin therapy include renal insufficiency. A cut off value of 60 ml/min in creatinine clearance is suggested. Hundred type 2 diabetics receiving metformin as monotherapy or in combination with insulin/other oral antidiabetic agents, were enrolled in the study. Patients were on metformin for atleast one month prior to being enrolled. Patients' demographic data were taken. Baseline serum creatinine and bicarbonate were estimated. Creatinine clearance (Clcr ml/ min) was calculated. Patients were grouped into group 1-4 depending upon the doses of metformin they received. Patients were again grouped based on their Clcr as groupA (Clcr < 60 ml/min), group B (Clcr > 60.01 ml/min). Data was analysed using student's t test. Out of 100 patients 52 were males, 48 females. Mean age and SD of males and females were 69.92 +/- 6.95 and 66.85 +/- 5.72 respectively. Comparison of mean bicarbonate level in different doses of metformin did not show any statistical significance. But comparison of bicarbonate levels based on Clcr were highly statistically significant (p = 0.0084). In three patients whose bicarbonate level was very low (15, 16.4 and 19.2 mmol/L), doses of metformin was reduced and after one month their bicarbonate levels returned to normal (27.4, 25.6 and 26.2 mmol/L). Hence serum bicarbonate can be a marker to assess metformin induced acidosis in geriatrics patients with low creatinine clearance.