Spreader events and the limitations of projected networks for capturing dynamics on multipartite networks.
Many systems of scientific interest can be conceptualized as multipartite networks. Examples include the spread of sexually transmitted infections, scientific collaborations, human friendships, product recommendation systems, and metabolic networks. In practice, these systems are often studied after projection onto a single class of nodes, losing crucial information. Here, we address a significant knowledge gap by comparing transmission dynamics on temporal multipartite networks and on their time-aggregated unipartite projections to determine the impact of the lost information on our ability to predict the systems' dynamics. We show that the dynamics of transmission models can be dramatically dissimilar on multipartite networks and on their projections at three levels: final outcome, the magnitude of the variability from realization to realization, and overall shape of the temporal trajectory. We find that the ratio of the number of nodes to the number of active edges over the time-aggregation scale determines the ability of projected networks to capture the dynamics on the multipartite network. Finally, we explore which properties of a multipartite network are crucial in generating synthetic networks that better reproduce the dynamical behavior observed in real multipartite networks.


Evaluation of a surgical supervision model in three African countries-protocol for a prospective mixed-methods controlled pilot trial.
District-level hospitals (DLHs) can play an important role in the delivery of essential surgical services for rural populations in sub-Saharan Africa if adequately prepared and supported. This article describes the protocol for the evaluation of the Scaling up Safe Surgery for District and Rural Populations in Africa (SURG-Africa) project which aims to strengthen the capacity in district-level hospitals (DLHs) in Malawi, Tanzania and Zambia to deliver safe, quality surgery. The intervention comprises a programme of quarterly supervisory visits to surgically active district-level hospitals by specialists from referral hospitals and the establishment of a mobile phone-based consultation network. The overall objective is to test and refine the model with a view to scaling up to national level. This mixed-methods controlled pilot trial will test the feasibility of the proposed supervision model in making quality-assured surgery available at DLHs. Firstly, the study will conduct a quantitative assessment of surgical service delivery at district facilities, looking at hospital preparedness, capacity and productivity, and how these are affected by the intervention. Secondly, the study will monitor changes in referral patterns from DLHs to a higher level of care as a result of the intervention. Data on utilisation of the mobile based-support network will also be collected. The analysis will compare changes over time and between intervention and control hospitals. The third element of the study will involve a qualitative assessment to obtain a better understanding of the functionality of DLH surgical systems and how these have been influenced by the intervention. It will also provide further information on feasibility, impact and sustainability of the supervision model. We seek to test a model of district-level capacity building through regular supervision by specialists and mobile phone technology-supported consultations to make safe surgical services more accessible, equitable and sustainable for rural populations in the target countries. The results of this study will provide robust evidence to inform and guide local actors in the national scale-up of the supervision model. Lessons learned will be transferred to the wider region.


A novel tumor grading scheme for chromophobe renal cell carcinoma: prognostic utility and comparison with Fuhrman nuclear grade.
Chromophobe renal cell carcinoma (RCC) is a histologic subtype of RCC that portends a favorable prognosis. It is controversial whether the Fuhrman nuclear grade of chromophobe RCC has prognostic utility. Irregular nuclei, prominent nucleoli, and nuclear pleomorphism are inherently present in chromophobe RCC. Hence, the Fuhrman nuclear grade is higher even though the majority of these tumors have a favorable outcome. In this study, the prognostic utility of a novel 3-tiered tumor grading system in which the innate nuclear atypia of chromophobe RCC was discounted, herein referred to as chromophobe tumor grade from a series of 124 chromophobe RCC, was compared with Fuhrman nuclear grade. Chromophobe tumor grade is based on the assessment of geographic nuclear crowding and anaplasia. The Fuhrman nuclear grade distribution between the tumors was grade 1 (1%), grade 2 (19%), grade 3 (74%), and grade 4 (6%), whereas the chromophobe tumor grade distribution was grade 1 (74%), grade 2 (16%), and grade 3 (10%). Neither Fuhrman nuclear grade nor chromophobe tumor grade was significantly associated with patient's age or sex and chromophobe RCC cell types, but both showed a significant association with tumor size. Both Fuhrman nuclear grade and chromophobe tumor grade showed statistically significant positive associations with broad alveolar growth, necrosis, vascular invasion, and with pathologic stage; however, all these associations tended to be dictated by tumors with sarcomatoid change. When tumors with sarcomatoid change were excluded, a strong positive association persisted between chromophobe tumor grade and pathologic stage. In contrast, there was no such association between Fuhrman nuclear grade and stage in nonsarcomatoid chromophobe RCCs. Characterizing aggressive chromophobe RCC with aggressive behavior with the time from surgery to first occurrence of metastasis, local recurrence, or death owing to disease, we found that both Fuhrman nuclear grade and chromophobe tumor grade were highly associated with adverse outcome. However, as with the pathologic stage, only a significant association between chromophobe tumor grade and outcome was retained among nonsarcomatoid chromophobe RCCs. Multivariable Cox regression analysis also tended to support chromophobe tumor grade rather than Fuhrman nuclear grade as an independent predictor of adverse outcome, controlling for other univariably significant risk factors [estimated relative hazard=3.68 (P=0.026) vs. 1.86 (P=0.42)]. In conclusion, the novel chromophobe tumor grading system proposed herewith provides superior prognostic value to that of the Fuhrman nuclear grade in chromophobe RCC and will potentially help stratify patients of chromophobe RCC who are at a greater risk of disease progression.


Observation of Flat Frequency Bands at Open Edges and Antiphase Boundary Seams in Topological Mechanical Metamaterials.
Motivated by the recent theoretical studies on a two-dimensional (2D) chiral Hamiltonian based on the Su-Schrieffer-Heeger chains [L. Zhu, E. Prodan, and K. H. Ahn, Phys. Rev. B 99, 041117(R) (2019)PRBMDO2469-995010.1103/PhysRevB.99.041117], we experimentally and computationally demonstrate that topological flat frequency bands can occur at open edges of 2D planar metamaterials and at antiphase boundary seams of ring-shaped or tubular metamaterials. Specifically, using mechanical systems made of magnetically coupled spinners, we reveal that the presence of the edge or seam bands that are flat in the entire projected reciprocal space follows the predictions based on topological winding numbers. The edge-to-edge distance sensitively controls the flatness of the edge bands and the localization of excitations, consistent with the theoretical analysis. The analog of the fractional charge state is observed. Possible realizations of flat bands in a large class of metamaterials, including photonic crystals and electronic metamaterials, are discussed.


Inhibition of HIV-1 Env-Mediated Cell-Cell Fusion by Lectins, Peptide T-20, and Neutralizing Antibodies.
Broadly cross-reactive, neutralizing human monoclonal antibodies, including 2F5, 2G12, 4E10 and IgG1 b12, can inhibit HIV-1 infection in vitro at very low concentrations. We examined the ability of these antibodies to inhibit cell-cell fusion between Clone69TRevEnv cells induced to express the viral envelope proteins, gp120/gp41 (Env), and highly CD4-positive SupT1 cells. The cells were loaded with green and red-orange cytoplasmic fluorophores, and fusion was monitored by fluorescence microscopy. Cell-cell fusion was inhibited completely by the carbohydrate binding proteins (CBPs), Hippeastrum hybrid (Amaryllis) agglutinin (HHA), and Galanthus nivalis (Snowdrop) agglutinin (GNA), and by the peptide, T-20, at relatively low concentrations. Anti-gp120 and anti-gp41 antibodies, at concentrations much higher than those required for neutralization, were not particularly effective in inhibiting fusion. Monoclonal antibodies b12, m14 IgG and 2G12 had moderate inhibitory activity; the IC(50) of 2G12 was about 80 µg/ml. Antibodies 4E10 and 2F5 had no inhibitory activity at the concentrations tested. These observations raise concerns about the ability of neutralizing antibodies to inhibit the spread of viral genetic material from infected cells to uninfected cells via cell-cell fusion. The interaction of gp120/gp41 with cell membrane CD4 may be different in cell-cell and virus-cell membrane fusion reactions, and may explain the differential effects of antibodies in these two systems. The fluorescence assay described here may be useful in high throughput screening of potential HIV fusion inhibitors.


Solid-state nanocasting synthesis of ordered mesoporous CoNx-carbon catalysts for highly efficient hydrogenation of nitro compounds.
Selective catalytic hydrogenation of nitro compounds (NCs) is an attractive challenge with significant research being focused on the development of cobalt (Co)-based nanocatalysts. Herein, in order to achieve high activity and selectivity for the catalytic hydrogenation of NCs and identify the essential active Co-containing sites, a facile solid-state nanocasting approach is developed for the controllable synthesis of CoNx-doped ordered mesoporous carbon materials (denoted as CoNx-OMCs). Compared with the previous nanocasting synthesis of mesoporous catalysts, the current method requires no solvent and relies on melting and interfacial chemical interactions between silica and the precursors for loading and casting, and chemical coordination among the precursors for the formation and dispersion of the active sites. The resulting CoNx-OMCs possess high surface areas (∼941 m2 g-1), ordered mesopores (∼4.0 nm), high N content (∼6.8 wt%) and abundant CoNx sites and fine metallic Co nanoparticles. With molecular H2 as the reducing agent, the optimized catalyst delivers very attractive catalytic activities (100% conversions), selectivities (close to 100% selectivities) and stability (no obvious performance decay after cycling) in the hydrogenation of a series of NCs carrying diverse groups in aqueous solutions under mild conditions. A comparative study clearly reveals that the CoNx sites, not the metallic Co nanoparticles, are the key active sites for the hydrogenation of NCs. The CoNx sites are found to preferentially adsorb nitro groups, thus activating them and promoting their reduction. A detailed study reveals that the high catalytic performance relies on the synergistic cooperation of the catalyst composition and structure, which are tuneable by adjusting the synthetic conditions.


An integrated approach to modeling resource utilization for rural communities in developing countries.
Resource consumption in developing countries has been the focus of a considerable amount of research. What has been understudied however, has been the feedback affects of resource consumption on resource availability to both households and communities. Heavy reliance on natural resources and intensive smallholder agriculture common to many rural communities in developing countries has forced people to fulfill short-term needs to the detriment of long-term ecological and livelihood sustainability. This paper introduces a conceptual framework to examine how individuals and households fulfill daily caloric needs and the aggregate effects on resource availability and consumption. Data were collected from a large number of published case studies of rural land-use dynamics, growth and yield models, and human livelihoods were reviewed from scientific journals, reports published by NGOs, and government reports. Using inputs defined by the user, the model tracks annual fuelwood and agricultural land use based on meeting individual energy demands. A case-study-based analysis was patterned after smallholder agriculturalists at the family and community level. Three scenarios are presented in this paper using data from Uganda to illustrate the application of this model.


Cutaneous activation of rage in nonsystemic vasculitic and diabetic neuropathy.
We asked whether the receptor of advanced glycation end products (RAGE) is related to dermal inflammation in nonsystemic vasculitic neuropathy (NSVN) and diabetic neuropathy (DN) and whether its presence in skin is comparable to that in sural nerve biopsies. We immunoreacted skin biopsy samples from 17 NSVN and 7 DN patients who had also undergone sural nerve biopsy, and 14 healthy controls with antibodies to advanced glycation end products (AGE), RAGE, T-cells, and macrophages. AGE and RAGE immunoreactivity were present in vessels of nerve biopsies from NSVN and DN. AGE and RAGE were increased in dermal endothelial cells and T-cells of NSVN and DN patients compared with controls. Dermal RAGE is increased in NSVN and DN, supporting the concept of a role of the RAGE pathway in the pathophysiology of dermal inflammation and skin denervation in NSVN and DN.


Ecosystem feedbacks and nitrogen fixation in boreal forests.
Biological feedback mechanisms regulate fundamental ecosystem processes and potentially regulate ecosystem productivity. To date, no studies have documented the down-regulation of terrestrial nitrogen (N) fixation via an ecosystem-level feedback mechanism. Herein, we demonstrate such a feedback in boreal forests. Rapid cycling of N in early secondary succession forests yielded greater throughfall N deposition, which in turn decreased N fixation by cyanobacterial associates in feather moss carpets that reside on the forest floor. The forest canopy exerts a tight control on biotic N input at a period of high productivity.


Rapamycin inhibits fibronectin-induced migration of the human arterial smooth muscle line (E47) through the mammalian target of rapamycin.
The matrix protein fibronectin (FN) is a potent agoinst of vascular smooth muscle cell (SMC) migration. The role of rapamycin and the mammalian target of rapamycin (mTOR) in matrix protein-induced migration has not yet been defined. In these studies, we found that rapamycin (10 nM) markedly diminished chemotaxis of E47 cells (a cell line derived from human atherosclerotic plaques) and rat aortic SMCs toward FN as well as type I collagen and laminin; however, a period of preincubation >20 h was required. Subsequently, we showed that treatment with FN induced a rapid activation of mTOR as well as its downstream effector, S6 kinase (S6K). Moreover, FN-induced activation of both proteins was inhibited by preincubation with rapamycin for only 30 min. We then explored the upstream signaling pathway through which FN might mediate mTOR activation. A blocking antibody to alpha(v)beta(3) inhibited FN-induced mTOR/S6K activation as well as E47 cell chemotaxis, implicating alpha(v)beta(3) as the integrin receptor responsible for initiating FN-induced migration. Moreover, preincubation of E47 cells with wortmannin or LY-294002 blocked FN-induced mTOR/S6K activation, demonstrating that phosphatidylinositol 3-kinase (PI3K) plays a critical role in this rapamycin-sensitive signaling pathway. It has been previously suggested that rapamycin's effect on migration maybe related to enhancement of p27(kip1). However, treatment of E47 cells with rapamycin did not alter the level of p27(kip1) in the presence or absence of FN. Taken together, our data demonstrate that rapamycin inhibits FN-induced SMC migration through a pathway that involves at least alpha(v)beta(3)-integrin, PI3K, mTOR, and S6K.


A cystic hepatic lesion: when to worry?
A 16-year old female presented to hospital with abdominal pain. Features on computed tomography raised the possibility of biliary cystadenoma or cystadenocarcinoma. She underwent a liver resection, and histopathology confirmed a serous biliary cystadenoma. This case is presented to highlight the radiological features of this uncommon pre-malignant condition as well as to summarize a management algorithm for cystic liver lesions.


The "special effect" of case mixing on word identification: neuropsychological and transcranial magnetic stimulation studies dissociating case mixing from contrast reduction.
We present neuropsychological and transcranial magnetic stimulation (TMS) evidence with normal readers, that the effects of case mixing and contrast reduction on word identification are qualitatively different. Lesions and TMS applied to the right parietal lobe selectively disrupted the identification of mixed relative to single-case stimuli. Bilateral lesions and TMS applied to the occipital cortex selectively disrupted the identification of low-contrast words. These data suggest that different visual distortions (case mixing, contrast reduction) exert different effects on reading, modulated by contrasting brain regions. Case mixing is a "special" distortion and involves the recruitment of processes that are functionally distinct, and dependent on different regions in the brain, from those required to deal with contrast reduction.


Genetic diversity of the malaria vaccine candidate Plasmodium falciparum merozoite surface protein-3 in a hypoendemic transmission environment.
The N-terminal domain of Plasmodium falciparum merozoite surface protein-3 (PfMSP3) has been excluded from malaria vaccine development largely because of genetic diversity concerns. However, no study to date has followed N-terminal diversity over time. This study describes PfMSP3 variation in a hypoendemic longitudinal cohort in the Peruvian Amazon over the 2003-2006 transmission seasons. Polymerase chain reaction was used to amplify the N-terminal domain in 630 distinct P. falciparum infections, which were allele-typed by size and also screened for sequence variation using a new high-throughput technique, denaturing high performance liquid chromatography. PfMSP3 allele frequencies fluctuated significantly over the 4-year period, but sequence variation was very limited, with only 10 mutations being identified of 630 infections screened. The sequence of the PfMSP3 N-terminal domain is relatively stable over time in this setting, and further studies of its status as a vaccine candidate are therefore warranted.


The Arabidopsis thaliana proteome harbors undiscovered multi-domain molecules with functional guanylyl cyclase catalytic centers.
Second messengers link external cues to complex physiological responses. One such messenger, 3',5'-cyclic guanosine monophosphate (cGMP), has been shown to play a key role in many physiological responses in plants. However, in higher plants, guanylyl cyclases (GCs), enzymes that generate cGMP from guanosine-5'-triphosphate (GTP) have remained elusive until recently. GC search motifs constructed from the alignment of known GCs catalytic centers form vertebrates and lower eukaryotes have led to the identification of a number of plant GCs that have been characterized in vitro and in vivo.Presentation of the hypothesis. Recently characterized GCs in Arabidopsis thaliana contributed to the development of search parameters that can identify novel candidate GCs in plants. We hypothesize that there are still a substantial number (> 40) of multi-domain molecules with potentially functional GC catalytic centers in plants that remain to be discovered and characterized. The hypothesis can be tested, firstly, by computational methods constructing 3D models of selected GC candidates using available crystal structures as templates. Homology modeling must include substrate docking that can provide support for the structural feasibility of the GC catalytic centers in those candidates. Secondly, recombinant peptides containing the GC domain need to be tested in in vitro GC assays such as the enzyme-linked immune-sorbent assay (ELISA) and/or in mass spectrometry based cGMP assays. In addition, quantification of in vivo cGMP transients with fluorescent cGMP-reporter assays in wild-type or selected mutants will help to elucidate the biological role of novel GCs. Implications of the hypothesis. If it turns out that plants do harbor a large number of functional GC domains as part of multi-domain enzymes, then major new insights will be gained into the complex signal transduction pathways that link cGMP to fundamental processes such as ion transport and homeostasis, biotic and abiotic stress responses as well as cGMP-dependent responses to hormones.


Conformational control of the binding of diatomic gases to cytochrome c'.
The cytochromes c' (CYTcp) are found in denitrifying, methanotrophic and photosynthetic bacteria. These proteins are able to form stable adducts with CO and NO but not with O2. The binding of NO to CYTcp currently provides the best structural model for the NO activation mechanism of soluble guanylate cyclase. Ligand binding in CYTcps has been shown to be highly dependent on residues in both the proximal and distal heme pockets. Group 1 CYTcps typically have a phenylalanine residue positioned close to the distal face of heme, while for group 2, this residue is typically leucine. We have structurally, spectroscopically and kinetically characterised the CYTcp from Shewanella frigidimarina (SFCP), a protein that has a distal phenylalanine residue and a lysine in the proximal pocket in place of the more common arginine. Each monomer of the SFCP dimer folds as a 4-alpha-helical bundle in a similar manner to CYTcps previously characterised. SFCP exhibits biphasic binding kinetics for both NO and CO as a result of the high level of steric hindrance from the aromatic side chain of residue Phe 16. The binding of distal ligands is thus controlled by the conformation of the phenylalanine ring. Only a proximal 5-coordinate NO adduct, confirmed by structural data, is observed with no detectable hexacoordinate distal NO adduct.


Rural-urban dimensions of the perception of malaria severity and practice of malaria preventive measures: insight from the 2018 Nigeria Demographic and Health Survey.
Morbidities and mortalities caused by malaria are still a serious issue in Nigeria, with the country accounting for 25% of malaria morbidities and 24% of malaria mortalities globally in 2018. Treated bed nets reduce the incidence of malaria, but not all Nigerians use them. This study aimed to examine the factors associated with treated bed net usage, including perceived severity of malaria, and the rural-urban differences in the relationship between socio-demographic factors and use of treated bed nets in Nigeria. The analytic sample size comprised 40,693 women aged 15-49 years. Poisson regression and bivariable and multivariable analyses were used to test the study hypothesis that women who agreed that malaria could potentially lead to death would be more likely to adopt malaria preventive measures, including treated bed net use. About 48% of the women slept under a treated mosquito net the night before the survey. Those who perceived that malaria could lead to death had a higher likelihood of using a treated bed net in the urban, rural and combined samples. However, in the multivariable model, the association between perceived malaria severity and use of a treated bed net was only significant for rural women (APR=0.964, 95% CI: 0.933, 0.996). The results unexpectedly suggest that rural Nigerian women who perceive malaria to be severe have a lower likelihood of using treated bed nets. Also, rural-urban variations in the relationship between the socio-demographic variables and use of treated bed nets were observed. Policies should consider the observed rural-urban dichotomy in the influence of perceived severity of malaria and other socio-demographic factors on women's use of treated bed nets in Nigeria.


Characterization of Fast-Scan Cyclic Voltammetric Electrodes Using Paraffin as an Effective Sealant with In Vitro and In Vivo Applications.
Fast-scan cyclic voltammetry (FSCV) is a powerful technique for measuring sub-second changes in neurotransmitter levels. A great time-limiting factor in the use of FSCV is the production of high-quality recording electrodes; common recording electrodes consist of cylindrical carbon fiber encased in borosilicate glass. When the borosilicate is heated and pulled, the molten glass ideally forms a tight seal around the carbon fiber cylinder. It is often difficult, however, to guarantee a perfect seal between the glass and carbon. Indeed, much of the time spent creating electrodes is in an effort to find a good seal. Even though epoxy resins can be useful in this regard, they are irreversible (seals are permanent), wasteful (epoxy cannot be reused once hardener is added), hazardous (hardeners are often caustic), and require curing. Herein we characterize paraffin as an electrode sealant for FSCV microelectrodes. Paraffin boasts the advantages of near-immediate curing times, simplicity in use, long shelf-life and stable waterproof seals capable of withstanding extended cycling. Borosilicate electrode tips were left intact or broken and dipped in paraffin embedding wax. Excess wax was removed from the carbon surface with xyelenes or by repeated cycling at an extended waveform (-0.4 to 1.4V, 400 V/s, 60 Hz). Then, the waveform was switched to a standard waveform (-0.4 to 1.3V, 400 V/s, 10 Hz) and cycled until stable. Wax-sealing does not inhibit electrode sensitivity, as electrodes detected linear changes in dopamine before and after wax (then xylenes) exposure. Paraffin seals are intact after 11 days of implantation in the mouse, and still capable of measuring transient changes in in vivo dopamine. From this it is clear that paraffin wax is an effective sealant for FSCV electrodes that provides a convenient substitute to epoxy sealants.


Long-term climate sensitivity of grazer performance: a cross-site study.
Climate change will affect grasslands in a number of ways, but the consequences of a warmer, drier world for grazers is uncertain. Predicting future grazer performance is complex since climate change affects both the quantity and quality of forage through a combination of processes that occur over a range of time scales. To better predict the consequences of climate change for grazer performance, a dataset was compiled of over a quarter million bison weights distributed across 22 US herds that span a large range of climates. Patterns of bison body mass among sites, age classes, and sexes were analyzed with respect to differences in geographic patterns of climate and interannual variation in climate. While short-term effects of climate variability are likely to depend on the magnitude and timing of precipitation during the year, grazers will be negatively affected by sustained hotter, drier conditions most likely associated with reductions in forage quality. Short-term, little effect of high temperatures on bison performance is observed, which suggests that the long-term effects of higher temperatures are likely to accrue over time as nitrogen availability in grasslands is reduced and forage quality declines. If relationships observed for bison are general for cattle, the economic consequences of higher temperatures due to decreased weight gain in US cattle could be on the order of US$1B per 1°C increase in temperature. Long-term monitoring of forage quality as well as native and domesticated grazer performance is recommended to better understand climate change effects on grazers.


Wettability alteration in a functional capillary tube for visual quantitative point of care testing.
Capillarity is an extremely common physical-chemical phenomenon related to wettability in nature, which has wide theoretical and practical interest. Herein, we reported a facile sensing device based on capillary force change in a vertical capillary tube. In this height-based capillary sensor (HCS), the inner surface of the capillary tube was modified with a layer of molecules with wetting responsibility based on the well-known simple surface chemistry. With targets in different concentrations, the wettability of the surface modified with responsive molecules would produce different changes. The responsive surfaces would change the capillary force of the vertical capillary tube, and result in different column heights. Like a thermometer, H+ and phenol have been quantified visually based on the height of the liquid inside the capillary tube.


Primary localised pleural neurofibroma: expanding the spectrum of spindle cell tumours of the pleura.
Primary localised pleural neoplasms are a rare group of thoracic tumours, with solitary fibrous tumour representing the most frequently encountered entity. Two cases of localised pleural neurofibromas involving the pleura are described. The patients were both female: 78 and 29 years of age. In the former a pleural-based lesion was identified on a chest radiograph after she presented with shoulder pain. The second patient was known to have neurofibromatosis type I, and the pleural lesion was found incidentally during excision of a metastatic malignant peripheral nerve sheath tumour of the lung. Both tumours were localised and composed histologically of bland neoplastic spindle cells embedded in a loose collagenous matrix. There was variable immunoreactivity for S100 and CD34, while ultrastructure examination in the two cases showed a mixture of nerve sheath cell types. To the best of the authors' knowledge, localised neurofibromas have not been previously reported within the pleura. The presence of a bland spindle cell pleural neoplasm immunoreactive for CD34 may potentially be mistaken for a solitary fibrous tumour. While distinction is usually achieved on close attention to the histological features, staining with S100 protein, especially in small biopsies, should be considered to exclude a neurofibroma.


The emerging role of endoscopic ultrasound-guided core biopsy for the evaluation of solid pancreatic masses.
Pancreatic ductal adenocarcinoma is a lethal cancer with a 5-year survival rate of less than 5%. Surgical resection is the only curative treatment but only 20% are eligible for resection at the time of diagnosis. Early detection of cancer is of paramount importance in the management. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the preferred modality for obtaining tissue diagnosis of pancreatic masses. However, the diagnostic accuracy of EUS-FNA may be limited by several factors like availability of onsite cytopathology, adequacy of tissue core for histology, location of the mass, presence of underlying chronic pancreatitis, and experience of the endoscopist. Modern oncology is focusing on personalizing treatment based on tissue analysis of genetic aberrations and molecular biomarkers which are now available. Core tissue also aids in the diagnosis of disease entities like lymphoma, metastatic tumors, neuroendocrine tumors and autoimmune pancreatitis whose diagnosis rely on preserved tissue architecture and immunohistochemistry. Making accurate diagnosis of solid pancreatic masses is critical to avoid unnecessary resections in patients with benign lesions like focal lesions of chronic pancreatitis and autoimmune pancreatitis which mimic cancer. To overcome the limitations of FNA and to obtain adequate core tissue, a Tru-Cut biopsy needle was developed which met with variable success due to stiffness, cumbersome operation and technical failure using it in the duodenum/pancreatic head. More recently fine needle biopsy needles, with reverse bevel technology have become available in different sizes (19, 22, 25-gauge). The aim of this article was to review the emerging role of core biopsy needles in acquiring tissue in solid pancreatic masses and discuss its potential role in personalized medicine.


The genome sequence of Desulfatibacillum alkenivorans AK-01: a blueprint for anaerobic alkane oxidation.
Desulfatibacillum alkenivorans AK-01 serves as a model organism for anaerobic alkane biodegradation because of its distinctive biochemistry and metabolic versatility. The D. alkenivorans genome provides a blueprint for understanding the genetic systems involved in alkane metabolism including substrate activation, CoA ligation, carbon-skeleton rearrangement and decarboxylation. Genomic analysis suggested a route to regenerate the fumarate needed for alkane activation via methylmalonyl-CoA and predicted the capability for syntrophic alkane metabolism, which was experimentally verified. Pathways involved in the oxidation of alkanes, alcohols, organic acids and n-saturated fatty acids coupled to sulfate reduction and the ability to grow chemolithoautotrophically were predicted. A complement of genes for motility and oxygen detoxification suggests that D. alkenivorans may be physiologically adapted to a wide range of environmental conditions. The D. alkenivorans genome serves as a platform for further study of anaerobic, hydrocarbon-oxidizing microorganisms and their roles in bioremediation, energy recovery and global carbon cycling.


The use of heart rate variability measures as indicators of autonomic nervous modulation must be careful in patients after orthotopic heart transplantation.
The precise relation between heart rate variability (HRV) and autonomic re-innervation has not been established explicitly in patients after orthotopic heart transplantation (OHT), but can be inferred from the fact that the HRV is reduced immediately after OHT and may increase gradually with time. The aim of this study was to investigate the residual HRV in patients about 1-2 years after OHT, as compared with patients after coronary artery bypass graft (CABG) surgery. Thirteen patients who had received OHT and 14 patients who had received CABG surgery were recruited. HRV analysis was performed and the HRV measures in supine position were compared between these two groups of patients. We found that the mean (mRRI), standard deviation and coefficient of variation of RR intervals, total power, very low frequency power (VLFP), low frequency power, high frequency power (HFP), normalized VLFP (nVLFP) and low-/high-frequency power ratio in the OHT group were all significantly decreased, while the heart rate (HR) and normalized HFP (nHFP) were significantly increased, as compared with the CABG group. The decrease in HRV was more severe in the VLFP region. A smaller nVLFP and a greater nHFP were associated with a smaller mRRI and a larger HR in the OHT patients. The slope of the power law relation of HRV became positive in OHT patients, instead of negative in CABG patients. We conclude that patients after OHT have residual HRV which were characterized by severely depressed time and frequency domain HRV, increased HR and nHFP, decreased nVLFP, and positive slope of the power-law relation of HRV. The use of nHFP as the indicator of vagal modulation and the use of nVLFP as the indicator of renin-angiotensin modulation, thermoregulation and vagal withdrawal must be careful in the OHT patients.


Putidaredoxin-cytochrome p450cam interaction. Spin state of the heme iron modulates putidaredoxin structure.
During the monooxygenase reaction catalyzed by cytochrome P450cam (P450cam), a ternary complex of P450cam, reduced putidaredoxin, and d-camphor is formed as an obligatory reaction intermediate. When ligands such as CO, NO, and O2 bind to the heme iron of P450cam in the intermediate complex, the EPR spectrum of reduced putidaredoxin with a characteristic signal at 346 millitesla at 77 K changed into a spectrum having a new signal at 348 millitesla. The experiment with O2 was carried out by employing a mutant P450cam with Asp251 --> Asn or Gly where the rate of electron transfer from putidaredoxin to oxyferrous P450cam is considerably reduced. Such a ligand-induced EPR spectral change of putidaredoxin was also shown in situ in Pseudomonas putida. Mutations introduced into the neighborhood of the iron-sulfur cluster of putidaredoxin revealed that a Ser44 --> Gly mutation mimicked the ligand-induced spectral change of putidaredoxin. Arg109 and Arg112, which are in the putative putidaredoxin binding site of P450cam, were essential for the spectral changes of putidaredoxin in the complex. These results indicate that a change in the P450cam active site that is the consequence of an altered spin state is transmitted to putidaredoxin within the ternary complex and produces a conformational change of the 2Fe-2S active center.


Presence of ATG triplets in 5' untranslated regions of eukaryotic cDNAs correlates with a 'weak' context of the start codon.
The context of the start codon (typically, AUG) and the features of the 5' Untranslated Regions (5' UTRs) are important for understanding translation regulation in eukaryotic mRNAs and for accurate prediction of the coding region in genomic and cDNA sequences. The presence of AUG triplets in 5' UTRs (upstream AUGs) might effect the initiation rate and, in the context of gene prediction, could reduce the accuracy of the identification of the authentic start. To reveal potential connections between the presence of upstream AUGs and other features of 5' UTRs, such as their length and the start codon context, we undertook a systematic analysis of the available eukaryotic 5' UTR sequences. We show that a large fraction of 5' UTRs in the available cDNA sequences, 15-53% depending on the organism, contain upstream ATGs. A negative correlation was observed between the information content of the translation start signal and the length of the 5' UTR. Similarly, a negative correlation exists between the 'strength' of the start context and the number of upstream ATGs. Typically, cDNAs containing long 5' UTRs with multiple upstream ATGs have a 'weak' start context, and in contrast, cDNAs containing short 5' UTRs without ATGs have 'strong' starts. These counter-intuitive results may be interpreted in terms of upstream AUGs having an important role in the regulation of translation efficiency by ensuring low basal translation level via double negative control and creating the potential for additional regulatory mechanisms. One of such mechanisms, supported by experimental studies of some mRNAs, includes removal of the AUG-containing portion of the 5' UTR by alternative splicing. An ATG_ EVALUATOR program is available upon request or at www.itba.mi.cnr.it/webgene. email@example.com, email@example.com.


Crisis at Guy's Hospital (1880) and the nature of nursing work.
This historical study aims to refine understanding of the nature of nursing work. The study focuses on the 1880 crisis at Guy's Hospital in London to examine the nature and meaning of nursing work, particularly the concept of nursing work as many 'little things.' In this paper, an examination of Margaret Lonsdale's writing offers an original contribution to our understanding of the ways in which nursing work differs from medical practice. In this way, we use the late-nineteenth-century controversy at Guy's Hospital as a prism through which to examine the contested nature of nursing work. Lonsdale's ideas are corroborated by examination of writings by nurse leaders Florence Nightingale and Eva Luckes. Luckes, in particular, elaborated what was meant by nursing as the performance of a thousand little things, which are specific to nursing work. While physicians had been performing much of what was considered to be nursing work, nurses developed some of these and other interventions into a unique body of work characterized by meticulous attention to significant details. Some implications regarding current nursing practice are discussed.


Residential Exposure to Pesticide During Childhood and Childhood Cancers: A Meta-Analysis.
There is an increasing concern about chronic low-level pesticide exposure during childhood and its influence on childhood cancers. In this meta-analysis, we aimed to examine associations between residential childhood pesticide exposures and childhood cancers. We searched all observational studies published in PubMed before February 2014 and reviewed reference sections of articles derived from searches. The literature search yielded 277 studies that met inclusion criteria. Sixteen studies were included in the meta-analysis. We calculated effect sizes and 95% confidence intervals (CIs) by using a random effect model with inverse variance weights. We found that childhood exposure to indoor but not outdoor residential insecticides was associated with a significant increase in risk of childhood leukemia (odds ratio [OR] = 1.47; 95% CI, 1.26-1.72; I(2) = 30%) and childhood lymphomas (OR = 1.43; 95% CI, 1.15-1.78; I(2) = 0%). A significant increase in risk of leukemia was also associated with herbicide exposure (OR = 1.26; 95% CI, 1.10-1.44; I(2) = 0%). Also observed was a positive but not statistically significant association between childhood home pesticide or herbicide exposure and childhood brain tumors. The small number of studies included in the analysis represents a major limitation of the current analysis. Results from this meta-analysis indicated that children exposed to indoor insecticides would have a higher risk of childhood hematopoietic cancers. Additional research is needed to confirm the association between residential indoor pesticide exposures and childhood cancers. Meanwhile, preventive measures should be considered to reduce children's exposure to pesticides at home.


A Review of the Key Considerations in Mental Health Services Research: A Focus on Low-Income Children and Families.
Children have been particularly vulnerable to the economic challenges of the past decade, with half (45 to 51%) of children under the age of 18 living in a low-income home and nearly 22% of those living in poverty. Low-income children are overrepresented in a range of statistics on psychosocial maladjustment issues, but their families are less likely than other socioeconomic groups to participate in mental health services and intervention research. Thus, this review asserts that substantive advances in mental health services and intervention research with low income families must move beyond a between-group, deficit-focused perspective to a more nuanced contemplation of how to: 1) Operationalize the "income" in low-income families; 2) Disentangle the interrelationship of low income, race, and ethnicity; and 3) Optimize recruitment, engagement and retention efforts via sensitivity to the culture of low-income status. Examples of mental health services and intervention research with low-income families will be discussed, and a summary, conclusions, and directions for future research are discussed in the context of these recommendations.


Cost Analysis of a Randomized Trial of Getting to Outcomes Implementation Support of CHOICE in Boys and Girls Clubs in Southern California.
Costs of supporting prevention program implementation are not well known. This study estimates the societal costs of implementing CHOICE, a voluntary after-school alcohol and other drug prevention program for adolescents, in Boys and Girls Clubs (BGCs) across Southern California with and without an implementation support system called Getting To Outcomes© (GTO). This article uses micro-costing methods to estimate the cost of the CHOICE program and GTO support. Labor and expense data were obtained from logs kept by the BGC staff and by the GTO technical assistance (TA) staff, and staff time was valued based on Bureau of Labor Statistics estimates. From the societal perspective, the cost of implementing CHOICE at BGCs over the 2-year study period was $27 per attendee when CHOICE was offered by itself (all costs incurred by the BGCs) and $177 per attendee when CHOICE was offered with GTO implementation support ($67 cost to the BGCs; $110 to the entity funding GTO). These results were most sensitive to assumptions as to the number of times CHOICE was offered per year. Adding GTO implementation support to CHOICE increased the cost per attendee by approximately $150. For this additional cost, there was evidence that the CHOICE program was offered with more fidelity and offered more often after the 2-year intervention ended. If the long-term benefits of this better and continued implementation are found to exceed these additional costs, GTO could be an attractive structure to support evidence-based substance misuse prevention programs. Trial Registration. This project is registered at ClinicalTrials.gov with number NCT02135991 (URL: https://clinicaltrials.gov/show/NCT02135991). The trial was registered May 12, 2014.


Unbalancing the phosphatidylinositol-4,5-bisphosphate-cofilin interaction impairs cell steering.
Cofilin is a key player in actin dynamics during cell migration. Its activity is regulated by (de)phosphorylation, pH, and binding to phosphatidylinositol-4,5-bisphosphate [PI(4,5)P(2)]. Here, we here use a human cofilin-1 (D122K) mutant with increased binding affinity for PI(4,5)P(2) and slower release from the plasma membrane to study the role of the PI(4,5)P(2)-cofilin interaction in migrating cells. In fibroblasts in a background of endogenous cofilin, D122K cofilin expression negatively affects cell turning frequency. In carcinoma cells with down-regulated endogenous cofilin, D122K cofilin neither rescues the drastic morphological defects nor restores the effects in cell turning capacity, unlike what has been reported for wild-type cofilin. In cofilin knockdown cells, D122K cofilin expression promotes outgrowth of an existing lamellipod in response to epidermal growth factor (EGF) but does not result in initiation of new lamellipodia. This indicates that, next to phospho- and pH regulation, the normal release kinetics of cofilin from PI(4,5)P(2) is crucial as a local activation switch for lamellipodia initiation and as a signal for migrating cells to change direction in response to external stimuli. Our results demonstrate that the PI(4,5)P(2) regulatory mechanism, that is governed by EGF-dependent phospholipase C activation, is a determinant for the spatial and temporal control of cofilin activation required for lamellipodia initiation.


A phase I study of carboplatin and etoposide administered in conjunction with dipyridamole, prochlorperazine and cyclosporine A.
In recognition of the variety of available chemotherapeutic modulating agents and their potential to enhance the efficacy of platinum-based therapy, we embarked upon a phase I study to investigate the feasibility of combining fixed doses of carboplatinum (CBDCA) and etoposide (VP-16) with 24-h concurrent infusions of dipyridamole (DP), prochlorperazine (PCZ) and cyclosporine A (CSA) administered in escalating doses. Patients received intravenous VP-16 (200 mg/m2) and CBDCA (300 mg/m2), each over 30 min, starting at hour 6 of the modulator infusions. Resistance modulators were escalated sequentially to determine their respective maximally tolerated doses (MTDs). The pharmacokinetics (PK) of VP-16, CBDCA, and the three drug resistance (DR) modifiers were studied in eight patients. A total of 59 patients were entered on study. The MTD was established at DP 5 mg/kg per day, PCZ 24 mg/h, and CSA 9.5 mg/kg per day. Dose-limiting toxicities included hypotension and severe sedation, presumably related to PCZ. No objective responses were seen. PK studies were performed when PCZ and DP doses were 24 mg/h and 3.3 mg/kg, and the CSA dose was either 8.5 mg/kg (five patients) or 9.5 mg/kg (three patients). The median clearance of VP-16 was 0.96 l/h per m2 (range 0.8-1.5 l/h per m2), which is lower than for VP-16 alone and similar to previously reported effects of CSA on VP-16 elimination. The median measured CBDCA AUC was 3.0 mg/ml x min (range 2.4-4.8 mg/ml x min). CBDCA AUC predicted by the Calvert formula using measured creatinine clearance underestimated the actual AUC in seven of the eight patients, in one case by as much as twofold. The median end of infusion PCZ and total DP plasma concentrations were 1.2 microM (range 0.5-2.2 microM) and 4.4 microM (range 1.3-5.9 microM), respectively, consistent with in vitro resistance modulatory levels. However, free DP was only 0.02 microM (range 0.004-0.04 microM). The median CSA level at 24 h of 1450 microg/l (range 1075-1640 microg/l) is in agreement with concentrations required for partial DR reversal in vitro, although it is much lower than levels achieved in our previous phase I study of CBDCA + CSA alone using similar doses of CSA. The CSA dose on the current trial was escalated beyond the MTD for the previous phase I study, suggesting that there may be an interaction between CSA and one of the other modulators. These results demonstrate that in vitro DR-reversing levels of two of the three agents used in this study can be achieved in vivo, and that this combination of DR modulators has significant effects on the pharmacokinetics of VP-16.


In vitro interaction of tubulin with the photoreceptor cGMP phosphodiesterase gamma-subunit.
The alpha and beta tubulins compose the microtubule cytoskeleton which is involved in many cellular processes such as vesicular transport. The photoreceptor cells in the retina are neurons specialized for phototransduction. Here we report a novel interaction between tubulin and the photoreceptor cGMP phosphodiesterase (PDE6) gamma subunit (PDE gamma). The specificity and molecular details of the PDE gamma:tubulin interaction were analyzed through the experiments of pull down, microtubule co-sedimentation, and NMR spectroscopy. The tubulin-interacting site was identified to be in the PDE gamma C-terminal I67-G85 region, and the interaction interface appeared to be distinct from those with the other PDE gamma targets in phototransduction. We also observed that PDE gamma interacted with tubulin in a GTP-dependent manner. Our findings offer implications for non-phototransduction role(s) of PDE gamma in the photoreceptor neurons.


Vascular Injury Is a Major Cause of Lung Injury After Balloon Pulmonary Angioplasty in Patients With Chronic Thromboembolic Pulmonary Hypertension.
Balloon pulmonary angioplasty (BPA) has become an alternative treatment for inoperable patients with chronic thromboembolic pulmonary hypertension. Lung injury (LI) is a major complication of BPA and may attenuate the benefits of BPA. Therefore, we conducted a retrospective study to evaluate the association between patient and procedural characteristics and LI in patients with chronic thromboembolic pulmonary hypertension. We reviewed 76 patients with chronic thromboembolic pulmonary hypertension who underwent BPA and multidetector computed tomography scanning pre- and post-BPA procedures. We performed BPA on 1247 vessels during 297 BPA procedures and reviewed 594 multidetector computed tomography scans. By comparing pre- and post-BPA multidetector computed tomography images, we diagnosed LI as follows: newly appeared ground-glass opacity, consolidation, and pleural effusion. LI was detected using multidetector computed tomography scans during 138 procedures (47%), and mechanical ventilation was required during 40 procedures (13%). Angiographic findings of extravasation with or without simultaneous clinical symptoms (BPA-related vascular injury) occurred during 50 procedures (17%). In mixed-effect logistic regression models, the BPA-related vascular injury was an independent predictor of LI after BPA, odds ratio, 20.1 (6.43-63.1). High mean pulmonary artery pressure before BPA procedure and BPA-related vascular injury were independent predictors of mechanical ventilation after BPA, odds ratio, 1.13 (1.03-1.24) and 10.8 (3.77-30.9), respectively. Vascular injury during BPA could be a triggering factor of LI after BPA, and its severity could be exacerbated by a high pulmonary artery pressure.


Characterization of single heat-activated Bacillus spores using laser tweezers Raman spectroscopy.
Heat activation of dormant bacterial spores is a short treatment at a sublethal temperature that potentiates and synchronizes spore germination. In this paper, laser tweezers Raman spectroscopy (LTRS) was used to study the heat activation of single spores of Bacillus cereus and Bacillus subtilis. We measured the Raman spectra of single spores without treatment, during heat activation at 65 degrees C (B. cereus) or 70 degrees C (B. subtilis), and following heat activation and cooling to 25 degrees C. Principle component analysis (PCA) was applied to discriminate among the three groups of spores based on their Raman spectra. The results indicated that: (1) there are large changes in the Raman bands of Ca-DPA and protein for both B. cereus and B. subtilis spores during heat activation, indicative of changes in spore core state and partial protein denaturation at the heat activation temperatures; (2) these spectral changes become smaller once the heated spores are cooled, consistent with heat activation being reversible; (3) minor spectral differences between untreated and heat-activated and cooled spores can be discriminated by PCA based on non-polarized and polarized Raman spectra; and (4) analysis based on polarized Raman spectra reveals that partial denaturation of protein during heat activation is mainly observed in the vertically polarized component.


Quarantine and testing strategies to ameliorate transmission due to travel during the COVID-19 pandemic: a modelling study.
Numerous countries have imposed strict travel restrictions during the COVID-19 pandemic, contributing to a large socioeconomic burden. The long quarantines that have been applied to contacts of cases may be excessive for travel policy. We developed an approach to evaluate imminent countrywide COVID-19 infections after 0-14-day quarantine and testing. We identified the minimum travel quarantine duration such that the infection rate within the destination country did not increase compared to a travel ban, defining this minimum quarantine as "sufficient." We present a generalised analytical framework and a specific case study of the epidemic situation on November 21, 2021, for application to 26 European countries. For most origin-destination country pairs, a three-day or shorter quarantine with RT-PCR or antigen testing on exit suffices. Adaptation to the European Union traffic-light risk stratification provided a simplified policy tool. Our analytical approach provides guidance for travel policy during all phases of pandemic diseases. For nearly half of origin-destination country pairs analysed, travel can be permitted in the absence of quarantine and testing. For the majority of pairs requiring controls, a short quarantine with testing could be as effective as a complete travel ban. The estimated travel quarantine durations are substantially shorter than those specified for traced contacts. EasyJet (JPT and APG), the Elihu endowment (JPT), the Burnett and Stender families' endowment (APG), the Notsew Orm Sands Foundation (JPT and APG), the National Institutes of Health (MCF), Canadian Institutes of Health Research (SMM) and Natural Sciences and Engineering Research Council of Canada EIDM-MfPH (SMM).


Efficacy of text-message reminders on paediatric malaria treatment adherence and their post-treatment return to health facilities in Kenya: a randomized controlled trial.
Short Message Service (SMS) reminders have been suggested as a potential intervention for improving adherence to medications and health facility attendance. An open-label, randomized, controlled trial to test the efficacy of automated SMS reminders in improving adherence to artemether-lumefantrine (AL) and post-treatment attendance in comparison with standard care was conducted at four health facilities in western Kenya. Children below five years of age with uncomplicated malaria were randomized to intervention (SMS reminders) or control groups. Within each study group they were further randomized to three categories, which determined the timing of home visits to measure adherence to complete AL course and to individual AL doses. A sub-set of caregivers was advised to return to the facility on day 3 and all were advised to return after 28 days. The primary outcomes were adherence to medication and return on day 3. The primary analysis was by intention-to-treat. Between 9 June, 2014 and 26 February, 2016, 1677 children were enrolled. Of 562 children visited at home on day 3, all AL doses were completed for 97.6% (282/289) of children in the control and 97.8% (267/273) in the intervention group (OR = 1.10; 95% CI = 0.37-3.33; p = 0.860). When correct timing in taking each dose was considered a criteria for adherence, 72.3% (209/289) were adherent in the control and 69.2% (189/273) in the intervention group (OR = 0.82; 95% CI = 0.56-1.19; p = 0.302). Sending SMS reminders significantly increased odds of children returning to the facility on day 3 (81.4 vs 74.0%; OR = 1.55; 95% CI = 1.15-2.08; p = 0.004) and on day 28 (63.4 vs 52.5%; OR = 1.58; 95% CI = 1.30-1.92; p < 0.001). In this efficacy trial, SMS reminders increased post-treatment return to the health facility, but had no effect on AL adherence which was high in both control and intervention groups. Further effectiveness studies under the real world conditions are needed to determine the optimum role of SMS reminders. Trial registration ISRCTN39512726.


Inbreeding coefficients and runs of homozygosity islands in Brazilian water buffalo.
Characterization of autozygosity is relevant to monitor genetic diversity and manage inbreeding levels in breeding programs. Identification of autozygosity hotspots can unravel genomic regions targeted by selection for economically important traits and can help identify candidate genes for selection. In this study, we estimated the inbreeding levels of a Brazilian population of Murrah buffalo undergoing selection for milk production traits, particularly milk yield. We also studied the distribution of runs of homozygosity (ROH) islands and identified putative genes and quantitative trait loci (QTL) under selection. We genotyped 422 Murrah buffalo for 51,611 SNP; 350 of these had ROH longer than 10 Mb, indicating the occurrence of inbreeding in the last 5 generations. The mean length of the ROH per animal was 4.28 ± 1.85 Mb. Inbreeding coefficients were calculated from the genomic relationship matrix, the pedigree, and the ROH, with estimates varying between 0.242 and 0.035. Inbreeding estimates from the pedigree had a low correlation with the genomic estimates, and estimates from the genomic relationship matrix were much higher than those from the pedigree or the ROH. Signatures of selection were identified in 6 genomic regions, located on chromosomes 1, 2, 3, 5, 16, and 18, encompassing a total of 190 genes and 174 QTL. Many of the genes (e.g., APRT and ACSF3) and QTL identified are related to milk production traits, such as milk yield, milk fat yield and percentage, and milk protein yield and percentage. Other genes are associated with reproduction and immune response traits as well as morphological aspects of the buffalo species. Inbreeding levels in this population are still low but are increasing due to selection and should be managed to avoid future losses due to inbreeding depression. The proximity of genes linked to milk production traits with genes associated with reproduction and immune system traits suggests the need to include these latter genes in the breeding program to avoid negatively affecting them due to selection for production traits.


Crank fore-aft position alters the distribution of work over the push and pull phase during synchronous recumbent handcycling of able-bodied participants.
The objective of the current study was to investigate the effect of four different crank fore-aft positions on elbow flexion and shoulder protraction, the consequent propulsion kinetics and the physiological responses during handcycling. Twelve able-bodied male participants volunteered in this study. Crank fore-aft positions were standardised at 94%, 97%, 100% and 103% of the participants' arm length. Two submaximal 3 min trials were performed at a fixed cadence (70 rpm), in a recumbent handcyle attached to an ergometer at two fixed power outputs (30W and 60W). Elbow flexion, shoulder protraction, propulsion kinetics and physiological responses of the participants were continuously measured. As crank fore-aft distance increased, a decrease in elbow flexion (42±4, 37±3, 33±3, 29±3°) and an increase shoulder protraction was observed (29±5, 31±5, 34±5, 36±5°). The percentage of work done in the pull phase increased as well (62±7, 65±7, 67±6, 69±8%, at 60W), which was in line with an increased peak torque during the pull phase (8.8±1.6, 9.0±1.4, 9.4±1.5, 9.7±1.4Nm, at 60W) and reduced peak torque during the push phase (6.0±0.9, 5.6±0.9,5.6±0.9, 5.4±1.0Nm, in 60W condition). Despite these changes in work distribution, there were no significant changes in gross mechanical efficiency (15.7±0.8, 16.2±1.1, 15.8±0.9, 15.6±1.0%, at 60W). The same patterns were observed in the 30W condition. From a biomechanical perspective the crank position closest to the trunk (94%) seems to be advantageous, because it evens the load over the push and pull phase, which reduces speed fluctuations, without causing an increase in whole body energy expenditure and hence a decrease of gross mechanical efficiency. These findings may help handcyclists to optimize their recumbent handcycle configuration.


Warfarin: A double-edged sword.
Warfarin is the commonest anticoagulant used in today's practice; it has a very narrow therapeutics window. Under and overdosing results in various life-threatening complications. Warfarin-related nephropathy (WRN) is a rare cause of acute kidney injury (AKI) in patients on long-term anticoagulation, as a result of supratherapeutic anticoagulation. Warfarin causes AKI by inducing glomerular hemorrhage with subsequent tubular obstruction by red blood cell (RBC) casts. WRN has been associated with irreversible kidney injury and increased risk of mortality. Despite a better understanding of pathophysiology and histopathology of WRN, its preventive measures and clinical outcome are not well known. We report here the case of a 62-year-old male, who was on a long-term warfarin therapy due to chronic atrial fibrillation with a history of old ischemic stroke and dilated cardiomyopathy. He was presented with AKI and his renal biopsy was suggestive of WRN. He was managed by withholding warfarin for a few days until the therapeutic range of international normalized ratio was achieved and steroids and N-acetylcysteine (NAC) recovered. WRN is a diagnosis of exclusion; other causes of AKI must be ruled out. Renal biopsy is the gold standard for diagnosis. Patients on chronic anticoagulant therapy should be monitored periodically for the therapeutic range of anticoagulants, deterioration of renal function, and hematuria.


Psychological predictors of weight loss after bariatric surgery: a review of the recent research.
Morbid obesity is the fastest growing BMI group in the U.S. and the prevalence of morbid obesity worldwide has never been higher. Bariatric surgery is the most effective treatment for severe forms of obesity especially with regard to a sustained long-term weight loss. Psychological factors are thought to play an important role for maintaining the surgical weight loss. However, results from prior research examining preoperative psychological predictors of weight loss outcome are inconsistent. The aim of this article was to review more recent literature on psychological predictors of surgical weight loss. We searched PubMed, PsycInfo and Web of Science, for original prospective studies with a sample size >30 and at least one year follow-up, using a combination of search terms such as 'bariatric surgery', 'morbid obesity', 'psychological predictors', and 'weight loss'. Only studies published after 2003 were included. 19 eligible studies were identified. Psychological predictors of surgical weight loss investigated in the reviewed studies include cognitive function, personality, psychiatric disorder, and eating behaviour. In general, recent research remains inconsistent, but the findings suggest that pre-surgical cognitive function, personality, mental health, composite psychological variables and binge eating may predict post-surgical weight loss to the extent that these factors influence post-operative eating behaviour.


Label-free detection of cell-contractile activity with lipid nanotubes.
Surface-bound self-assembled lipid nanotubes (LNTs) made of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) were used to visualize the contractile activity of spreading cells. The interaction of cells with LNTs resulted in the nucleation of new nanotubes, directed toward the cell center, from existing ones. This process depended on cell generated forces and required acto-myosin mediated contractility. The dynamics of de novo generation of LNTs upon cell spreading was captured using optical microscopy on fluorescently labeled nanotubes and revealed characteristic fingerprints for different cell types such as fibroblasts, endothelial and melanoma cells. Additionally, the method was applied to detect the effect of a specific inhibitor on the generation of cellular forces. The mechanism of the LNT-cell interaction and the potential applications are discussed.


Responses to projected changes in climate and UV-B at the species level.
Environmental manipulation experiments showed that species respond individualistically to each environmental-change variable. The greatest responses of plants were generally to nutrient, particularly nitrogen, addition. Summer warming experiments showed that woody plant responses were dominant and that mosses and lichens became less abundant. Responses to warming were controlled by moisture availability and snow cover. Many invertebrates increased population growth in response to summer warming, as long as desiccation was not induced. CO2 and UV-B enrichment experiments showed that plant and animal responses were small. However, some microorganisms and species of fungi were sensitive to increased UV-B and some intensive mutagenic actions could, perhaps, lead to unexpected epidemic outbreaks. Tundra soil heating, CO2 enrichment and amendment with mineral nutrients generally accelerated microbial activity. Algae are likely to dominate cyanobacteria in milder climates. Expected increases in winter freeze-thaw cycles leading to ice-crust formation are likely to severely reduce winter survival rate and disrupt the population dynamics of many terrestrial animals. A deeper snow cover is likely to restrict access to winter pastures by reindeer/caribou and their ability to flee from predators while any earlier onset of the snow-free period is likely to stimulate increased plant growth. Initial species responses to climate change might occur at the sub-species level: an Arctic plant or animal species with high genetic/racial diversity has proved an ability to adapt to different environmental conditions in the past and is likely to do so also in the future. Indigenous knowledge, air photographs, satellite images and monitoring show that changes in the distributions of some species are already occurring: Arctic vegetation is becoming more shrubby and more productive, there have been recent changes in the ranges of caribou, and "new" species of insects and birds previously associated with areas south of the treeline have been recorded. In contrast, almost all Arctic breeding bird species are declining and models predict further quite dramatic reductions of the populations of tundra birds due to warming. Species-climate response surface models predict potential future ranges of current Arctic species that are often markedly reduced and displaced northwards in response to warming. In contrast, invertebrates and microorganisms are very likely to quickly expand their ranges northwards into the Arctic.


Fiber and penton base capsid modifications yield diminished adenovirus type 5 transduction and proinflammatory gene expression with retention of antigen-specific humoral immunity.
Fiber and penton base capsid proteins of adenovirus type 5 (Ad5) mediate a well-characterized two-step entry pathway in permissive tissue culture cell lines. Fiber binds with high affinity to the cell surface coxsackievirus-and-adenovirus receptor (CAR), and penton base facilitates viral internalization by binding alphav integrins through an RGD motif. In vivo, the entry pathway is complicated by interactions of capsid proteins with additional cell surface molecules and blood factors. When administered systemically in mice, adenovirus vectors (Adv) localize primarily to hepatic tissue, resulting in efficient gene transduction and potent activation of the host antiviral immune response. The goal of the present study was to detarget Adv uptake through fiber and penton base capsid protein manipulations and determine how detargeted vectors influence transduction efficiency, inflammatory activation, and activation of the adaptive arm of the immune system. By manipulating fiber and the penton base, we have generated highly detargeted vectors (up to 1,200-fold reduction in transgene expression in vivo) with reduced macrophage stimulatory activity in vitro and in vivo. In spite of the diminished transduction and macrophage activation, the detargeted vectors induce strong neutralizing immunity as well as efficient antitransgene antibody. Three of the modified vectors produce antitransgene humoral immunity at levels that exceed or are equal to that seen with an unmodified Ad5-based vector. The fiber-pseudotyped and penton base constructs with RGD deleted have attributes that could be important enhancements in a number of vaccine applications.


In vivo efficiency of targeted norfloxacin against persistent, isoniazid-insensitive, Mycobacterium bovis BCG present in the physiologically hypoxic mouse liver.
Persistence of Mycobacterium tuberculosis is a hypoxia-inducible state in which the bacteria are phenotypically insensitive to currently available antituberculous drugs. In humans, persistent M. tuberculosis is found in granulomatous lesions, either inside macrophages or in necrotic tissue, where the partial oxygen pressure (pO(2)) is very low. Persistent bacteria can remain silent for decades before overt tuberculosis develops. Due to insensitivity to classical drugs, M. tuberculosis persistence prevents rapid and definitive clearance of bacteria. Consequently, therapeutic molecules are required that are both active against persistent bacilli and able to reach their intramacrophagic location. In contrast to its native form, norfloxacin is active in vivo against Mycobacterium bovis BCG present in the lungs when temporarily linked to a macromolecular carrier targeted to macrophages. To study the efficiency of this macromolecular prodrug targeted to persistent mycobacteria confined inside macrophages, we established a short-term in vivo model based on the physiological pO(2) differences between lungs, spleen and liver. Whereas lungs and spleen are well oxygenated, the liver has a low pO(2) due to its portal irrigation. Therefore, studying mycobacteria in the liver yields information about in vivo persistent bacilli exposed to low pO(2). To our knowledge, no similar short-term in vivo model has been published to date. Using this model, we demonstrated the insensitivity to isoniazid of M. bovis BCG present in hypoxic sites, and showed that norfloxacin given as a mannosylated macrophage-targeted prodrug was able to kill these isoniazid-insensitive mycobacteria. This demonstrates that intracellular persistent mycobacteria are amenable to antibiotic treatment.


Quantitative electroencephalographic abnormalities in fibromyalgia patients.
There is increasing acceptance that pain in fibromyalgia (FM) is a result of dysfunctional sensory processing in the spinal cord and brain, and a number of recent imaging studies have demonstrated abnormal central mechanisms. The objective of this report is to statistically compare quantitative electroencephalogram (qEEG) measures in 85 FM patients with age and gender matched controls in a normative database. A statistically significant sample (minimum 60 seconds from each subject) of artifact-free EEG data exhibiting a minimum split-half reliability ratio of 0.95 and test-retest reliability ratio of 0.90 was used as the threshold for acceptable data inclusion. FM subject EEG data was compared to EEGs of age and gender matched healthy subjects in the Lifespan Normative Database and analyzed using NeuroGuide 2.0 software. Analyses were based on spectral absolute power, relative power and coherence. Clinical evaluations included the Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Inventory and Fischer dolorimetry for pain pressure thresholds. Based on Z-statistic findings, the EEGs from FM subjects differed from matched controls in the normative database in three features: (1) reduced EEG spectral absolute power in the frontal International 10-20 EEG measurement sites, particularly in the low- to mid-frequency EEG spectral segments; (2) elevated spectral relative power of high frequency components in frontal/central EEG measurement sites; and (3) widespread hypocoherence, particularly in low- to mid-frequency EEG spectral segments, in the frontal EEG measurement sites. A consistent and significant negative correlation was found between pain severity and the magnitude of the EEG abnormalities. No relationship between EEG findings and medicine use was found. It is concluded that qEEG analysis reveals significant differences between FM patients compared to age and gender matched healthy controls in a normative database, and has the potential to be a clinically useful tool for assessing brain function in FM patients.


Melanin: the biophysiology of oral melanocytes and physiological oral pigmentation.
The presence of melanocytes in the oral epithelium is a well-established fact, but their physiological functions are not well defined. Melanin provides protection from environmental stressors such as ultraviolet radiation and reactive oxygen species; and melanocytes function as stress-sensors having the capacity both to react to and to produce a variety of microenvironmental cytokines and growth factors, modulating immune, inflammatory and antibacterial responses. Melanocytes also act as neuroendocrine cells producing local neurotransmitters including acetylcholine, catecholamines and opioids, and hormones of the melanocortin system such as proopiomelanocortin, adrenocorticotropic hormone and α-melanocyte stimulating hormone, that participate in intracellular and in intercellular signalling pathways, thus contributing to tissue homeostasis.There is a wide range of normal variation in melanin pigmentation of the oral mucosa. In general, darker skinned persons more frequently have oral melanin pigmentation than light-skinned persons. Variations in oral physiological pigmentation are genetically determined unless associated with some underlying disease.In this article, we discuss some aspects of the biophysiology of oral melanocytes, of the functions of melanin, and of physiological oral pigmentation.


Protocol for a randomized, placebo-controlled, double-blind clinical trial investigating sacral neuromodulation for neurogenic lower urinary tract dysfunction.
Sacral neuromodulation has become a well-established and widely accepted treatment for refractory non-neurogenic lower urinary tract dysfunction, but its value in patients with a neurological cause is unclear. Although there is evidence indicating that sacral neuromodulation may be effective and safe for treating neurogenic lower urinary tract dysfunction, the number of investigated patients is low and there is a lack of randomized controlled trials. This study is a prospective, randomized, placebo-controlled, double-blind multicenter trial including 4 sacral neuromodulation referral centers in Switzerland. Patients with refractory neurogenic lower urinary tract dysfunction are enrolled. After minimally invasive bilateral tined lead placement into the sacral foramina S3 and/or S4, patients undergo prolonged sacral neuromodulation testing for 3-6 weeks. In case of successful (defined as improvement of at least 50% in key bladder diary variables (i.e. number of voids and/or number of leakages, post void residual) compared to baseline values) prolonged sacral neuromodulation testing, the neuromodulator is implanted in the upper buttock. After a 2 months post-implantation phase when the neuromodulator is turned ON to optimize the effectiveness of neuromodulation using sub-sensory threshold stimulation, the patients are randomized in a 1:1 allocation in sacral neuromodulation ON or OFF. At the end of the 2 months double-blind sacral neuromodulation phase, the patients have a neuro-urological re-evaluation, unblinding takes place, and the neuromodulator is turned ON in all patients. The primary outcome measure is success of sacral neuromodulation, secondary outcome measures are adverse events, urodynamic parameters, questionnaires, and costs of sacral neuromodulation. It is of utmost importance to know whether the minimally invasive and completely reversible sacral neuromodulation would be a valuable treatment option for patients with refractory neurogenic lower urinary tract dysfunction. If this type of treatment is effective in the neurological population, it would revolutionize the management of neurogenic lower urinary tract dysfunction. http://www.clinicaltrials.gov; Identifier: NCT02165774.


Comparative in vitro bioactivities of tea extracts from six species of Ardisia and their effect on growth inhibition of HepG2 cells.
Ardisia species, notably A. compressa, are used in some regions of the world as food or in traditional medicine for prevention and treatment of certain health conditions including liver disease. We investigated the chemical composition and relative anticancer potential of six Ardisia species [A. japonica (AJ), A. escallonioides (AES), A. mamillata (AM), A. compressa (AC), A. crenata (ACR), and A. elliptica (AE)]. Antioxidant capacity, DNA human topoisomerase II catalytic inhibition, and cytotoxicity on human liver cancer cells (HepG2) were determined in vitro in tea extracts of the 6 Ardisia species evaluated. Selected pure phenolic compounds present in Ardisia species were also evaluated. AC showed the highest topoisomerase II catalytic inhibition (IC(50)=12 microg/ml) and cytotoxicity (IC(50)=117 microg/ml) against HepG2 cells, followed by ACR and AJ. Total polyphenols ranged from 21 to 72 mg equivalents of gallic acid (GA)/g solid extract (SE). LC-MS analysis revealed the presence of GA, quercetin derivatives, ardisenone, ardisiaquinone, ardisianone, bergenin, norbergenin, and embelin. However, neither total polyphenol concentration nor antioxidant capacity correlated with anticancer capacity. Significant HepG2 cytotoxicity was also achieved by bergenin (IC(50)=18 microM) and embelin (IC(50)=120 microM). AC, bergenin, embelin, and quercetin showed a tendency to accumulate cells in the G1 phase and reduced G2/M leading to apoptosis. Although the mechanism is not entirely clear, AC, ACR, and AJ are the Ardisia species with the greatest anticancer potential against liver cancer cells in vitro and deserve further investigation.


Faking good: self-enhancement in medical school applicants.
The problem of dissimulation by applicants when self-report tests of personality are used for job selection has received considerable attention in non-medical contexts. Personality testing is not yet widely used in medical student selection, but this may change in the light of recent research demonstrating significant relationships between personality and performance in medical school. This study therefore aimed to assess the extent of self-enhancement in a sample of medical school applicants. A within-subjects design compared personality test scores collected in 2007 for 83 newly enrolled medical students with scores for the same students obtained on the same personality test administered during the selection process 4 months previously. Five factors of personality were measured using the International Personality Item Pool and mean differences in scores were assessed using paired t-tests. At the time of selection, the personality scores of successful applicants were similar to those of candidates who were not accepted (n=271). Once selected, the medical students achieved significantly lower scores on four of the five personality factors (conscientiousness, extroversion, openness to experience, agreeableness) and higher scores on the fifth factor (neuroticism). Of the selected students, 62.7% appeared to have 'faked good' on at least one of the five factors measured. Applicants to medical school are likely to dissimulate when completing self-report tests of personality used for selection. The authors review the evidence as to whether such dissimulation reduces construct and predictive validity and summarise methods used to reduce self-enhancement in applicant samples.


Muscle creatine kinase sequence elements regulating skeletal and cardiac muscle expression in transgenic mice.
Muscle creatine kinase (MCK) is expressed at high levels only in skeletal and cardiac muscle tissues. Previous in vitro transfection studies of skeletal muscle myoblasts and fibroblasts had identified two MCK enhancer elements and one proximal promoter element, each of which exhibited expression only in differentiated skeletal muscle. In this study, we have identified several regions of the mouse MCK gene that are responsible for tissue-specific expression in transgenic mice. A fusion gene containing 3,300 nucleotides of MCK 5' sequence exhibited chloramphenicol acetyltransferase activity levels that were more than 10(4)-fold higher in skeletal muscle than in other, nonmuscle tissues such as kidney, liver, and spleen. Expression in cardiac muscle was also greater than in these nonmuscle tissues by 2 to 3 orders of magnitude. Progressive 5' deletions from nucleotide -3300 resulted in reduced expression of the transgene, and one of these resulted in a preferential decrease in expression in cardiac tissue relative to that in skeletal muscle. Of the two enhancer sequences analyzed, only one directed high-level expression in both skeletal and cardiac muscle. The other enhancer activated expression only in skeletal muscle. These data reveal a complex set of cis-acting sequences that have differential effects on MCK expression in skeletal and cardiac muscle.


Rapid detection of fetal aneuploidies by quantitative fluorescent-polymerase chain reaction for prenatal diagnosis in the Turkish population.
Prenatal diagnosis is testing for diseases or conditions in a fetus or embryo before it is born. It employs a variety of techniques to determine the health and condition of an unborn fetus. The main goal of this process is to perform prenatal diagnosis at the earliest possible stage of gestation. In this regard, quantitative fluorescent-polymerase chain reaction (QF-PCR), a novel technique that is fast and reliable, was employed to detect aneuploidies (13, 18, 21, X and Y) without the need of the time-consuming culturing process. The QF-PCR method can detect five different chromosome aneuploidies with 98.6% accuracy. In this study, 1874 amniotic fluid samples of pregnant subjects, who were referred to the Department of Medical Biology and Genetics, Adana, Turkey (molecular biology section), were analyzed with the QF-PCR technique by employing 27 short tandem repeat (STR) markers to detect chromosomes 13, 18, 21, X and Y aneuploidies. We detected 31 subjects (1.7%) with aneuploidies or euploidies out of the 1874 subjects. The average age of the pregnant subjects was 32 (range: 14-49). Abnormal karyotypes detected were as follows: 47,XX,+21 (19.4%, 6/31), 47,XY,+21 (48.4%, 15/31), 48,XXX,+21 (3.2%, 1/31), 69,XXX (3.2%, 1/31), 47,XY,+13 (3.2%, 1/31), 47,XXY (9.6%, 3/31), 47,XXX (9.6%, 3/31) and 45,X (3.2%, 1/31). Moreover, some STR markers were found to be more specific to the Turkish population. In conclusion, QF-PCR can be regarded as an alternative method of conventional cytogenetic analysis as it is a rapid and reliable method; however, in most cases it is required to be supported or validated with conventional cytogenetic karyotyping and some STR markers employed for QF-PCR can be more informative for a given population.


The effect of cap lamp lighting on postural control and stability.
Researchers at the National Institute for Occupational Safety and Health (NIOSH) are conducting mine illumination research with the objective of improving miner safety. Slips, trips, and falls (STFs) are the second leading accident class (18.1%, n = 2,374) of nonfatal lost-time injuries at underground mines (MSHA, 2005-2009). Factors contributing to STFs include recognition of hazards as well as postural balance and age. Improved lighting may enable better hazard recognition and reduce the impact of postural balance and age. Previous research has shown that cap lamp technology that used light-emitting diodes (LEDs) has improved hazard detection. This study was an initial investigation to determine if cap lamp lighting significantly influences measures of static postural stability (displacement and velocity of center of pressure). Results of this investigation showed no significant differences in the balance measures of interest between cap lamps tested. However, balance was shown to significantly decline (p < 0.05) when tested in an underground coal mine compared to the laboratory testing condition. Relevance to industry: Underground coal mine workers wear cap lamps on their hard hats as their primary light source to illuminate nearby areas where their vision is directed. Proper illumination may improve miner safety by improving their STF hazard recognition and balance.


Impact of a Multi-Strategy Community Intervention to Reduce Maternal and Child Health Inequalities in India: A Qualitative Study in Haryana.
A multi-strategy community intervention, known as National Rural Health Mission (NRHM), was implemented in India from 2005 to 2012. By improving the availability of and access to better-quality healthcare, the aim was to reduce maternal and child health (MCH) inequalities. This study was planned to explore the perceptions and beliefs of stakeholders about extent of implementation and effectiveness of NRHM's health sector plans in improving MCH status and reducing inequalities. A total of 33 in-depth interviews (n = 33) with program managers, community representatives, mothers and 8 focus group discussions (n = 42) with health service providers were conducted from September to December 2013, in Haryana, post NRHM. Using NVivo software (version 9), an inductive applied thematic analysis was done based upon grounded theory, program theory of change and a framework approach. Almost all the participants reported that there was an improvement in overall health infrastructure through an increased availability of accredited social health activists, free ambulance services, and free treatment facilities in rural areas. This had increased the demand and utilization of MCH services, especially for those related to institutional delivery, even by the poor families. Service providers felt that acute shortage of human resources was a major health system level barrier. District-specific individual, community, and socio-political level barriers were also observed. Overall program managers, service providers and community representatives believed that NRHM had a role in improving MCH outcomes and in reduction of geographical and socioeconomic inequalities, through improvement in accessibility, availability and affordability of the MCH services in the rural areas and for the poor. Any reduction in gender-based inequalities, however, was linked to the adoption of small family sizes and an increase in educational levels.


Relationship Between Decentration and Induced Corneal Higher-Order Aberrations Following Small-Incision Lenticule Extraction Procedure.
To investigate the amount of lenticule decentration following small-incision lenticule extraction (SMILE) by using the Keratron Scout tangential topography difference map, and the relationship between the magnitudes of total decentration and induced corneal higher-order aberrations (HOAs). This retrospective observational case series study analyzed decentration values obtained from the Keratron Scout tangential topography difference map of 360 eyes (360 patients) that underwent SMILE. Root mean square total HOAs, third order coma aberration, fourth order spherical aberration, as well as individual coefficients for vertical and horizontal coma were measured preoperatively and 3-months postoperatively. Simple linear regression analysis and piecewise regression models were used to determine the relationship between the magnitudes of total decentration and induced corneal HOAs. The mean total decentration distance from the corneal vertex was 0.36 ± 0.22 mm (range, 0.02-1.27 mm). There were significant differences in total HOAs, coma, vertical and horizontal comas, and spherical aberration between preoperative and 3-month postoperative assessments. Significant relationships between the magnitudes of total decentration and induced corneal HOAs were noted. Subgroup analysis according to the degree of total decentration (group I, total decentered displacement ≤0.335 mm; and group II, total decentered displacement >0.335 mm) revealed that induced changes in total HOAs, coma, vertical coma, and spherical aberration were significantly larger in group II than in group I. A minimal degree of decentration was closely related to a smaller induction of corneal HOAs. Efforts to optimize centration are critical for achieving better surgical outcomes in SMILE.


Analysis of the dispersion compensation of acousto-optic deflectors used for multiphoton imaging.
The acousto-optic deflector (AOD) is highly preferred in laser scanning microscopy for its fast scanning ability and random-addressing capability. However, its application in two-photon microscopy is frustrated by the dispersion of the AOD, which results in beam distortion and pulse lengthening. We report the analysis of simultaneous compensation for the angular dispersion and temporal dispersion of the AOD by merely introducing a single dispersive element such as a prism or a grating. Besides serving as a scanner, the AOD is also a part of the compressor pair by integrating the dispersive nature of the AO interaction. This compensation principle is effective for both one-dimensional (1-D) AOD and two-dimensional (2-D) AOD scanning. Switching from a 1-D to a 2-D system requires proper optical alignment with the compensation element, but does not involve any new components. Analytical expressions are given to illustrate the working principle and to help with understanding the design of the system. Fluorescence images of beads and cells are shown to demonstrate the performance of two-photon microscopy when applying this compensated 2-D AOD as scanner.


Telomere length is an independent prognostic marker in MDS but not in de novo AML.
Telomere dysfunction is implicated in the generation of large-scale genomic rearrangements that drive progression to malignancy. In this study we used high-resolution single telomere length analysis (STELA) to examine the potential role of telomere dysfunction in 80 myelodysplastic syndrome (MDS) and 95 de novo acute myeloid leukaemia (AML) patients. Despite the MDS cohort being older, they had significantly longer telomeres than the AML cohort (P < 0·0001) where telomere length was also significantly shorter in younger AML patients (age <60 years) (P = 0·02) and in FLT3 internal tandem duplication-mutated AML patients (P = 0·03). Using a previously determined telomere length threshold for telomere dysfunction (3·81 kb) did not provide prognostic resolution in AML [Hazard ratio (HR) = 0·68, P = 0·2]. In contrast, the same length threshold was highly prognostic for overall survival in the MDS cohort (HR = 5·0, P < 0·0001). Furthermore, this telomere length threshold was an independent parameter in multivariate analysis when adjusted for age, gender, cytogenetic risk group, number of cytopenias and International Prognostic Scoring System (IPSS) score (HR = 2·27, P < 0·0001). Therefore, telomere length should be assessed in a larger prospective study to confirm its prognostic role in MDS with a view to integrating this variable into a revised IPSS.


Are familial factors underlying the association between socioeconomic position and prescription medicine? A register-based study on Danish twins.
Although well established, the association between socioeconomic position and health and health behaviour is not clearly understood, and it has been speculated that familial factors, for example, dispositional factors or exposures in the rearing environment, may be underlying the association. The objective was to compare prescription fillings within twin pairs who are partly or fully genetically identical and share childhood exposures. Twin cohort study. Denmark. Data from the Danish Twin Registry were linked to registers in Statistics Denmark and the Danish Registry of Medicinal Product statistics. A total of 8582 monozygotic (MZ) and 15 788 dizygotic same sex (DZSS) twins were included. Number of prescription fillings during follow-up (1995-2005) was analysed according to education and income. Results of unpaired and intrapair analyses were compared. An inverse social gradient in filling of prescriptions for all-purpose and system-specific drugs was observed in the unpaired analyses. In the intrapair analyses, associations were attenuated some in DZSS and more in MZ twins. Filling of drugs targeting the nervous system was still strongly associated with income in the intrapair analyses. Familial factors seem to account for part of the observed social inequality in filling of prescription medicine.


Molecular basis and species specificity of high affinity binding of vasoactive intestinal polypeptide by the rat secretin receptor.
The affinity and specificity of the binding interaction between ligands and their receptors are key for appropriate hormonal regulation of target tissues. However, it is now apparent that vasoactive intestinal polypeptide (VIP) binds to the rat secretin receptor with similar affinity to that for its natural ligand, secretin (Holtmann et al., 1995). In this report, we establish that this is not a characteristic of the human secretin receptor, and use rat-human secretin receptor chimeras, site mutants and truncated receptor constructs to establish the molecular basis for this unusual binding interaction. Of note, isolated N-terminal domains of the rat secretin and the VIP receptors are capable of high affinity binding of VIP. In the recently recognized secretin family of receptors, this domain has six conserved cysteine residues and disulfide bonds that are likely important to achieve the complex conformation critical for this binding. A single acidic residue (Asp98) present in the rat secretin receptor appears to be critical, because a site-mutant changing this to the polar, but uncharged residue present in that position in the human receptor (Asn) eliminates the high affinity binding of VIP. Of interest, a previously identified critical basic residue in VIP (Lys15) provides a candidate for charge-pairing with this residue, potentially aligning the peptide ligand in a nonproductive orientation within this receptor.


Triptans and troponin: a case report.
This case report describes for the first time acute coronary syndrome in a 67-year old patient after oral intake of naratriptan for migraine. So far in the literature, only sumatriptan, zolmitriptan and frovatriptan have been described to cause acute coronary syndromes. A 67-year old Swiss woman with thoracic pain after intake of 2.5 mg naratriptan presented with T-wave inversions in the ECG and a positive troponin-T at our hospital. Coronary angiography showed normal coronary arteries. Naratriptan-induced coronary vasospasms were thought to have caused the acute coronary syndrome.Triptans should not be prescribed in patients with pre-existing coronary heart disease. However, triptans can also cause acute coronary syndromes in patients without coronary heart disease--as described in our case report. Severe or persistent thoracic pain after intake of triptans should therefore be investigated accordingly.


Impact of an Inpatient Psychiatric Unit on Pediatric Emergency Mental Health Care.
Mental health complaints are a frequent presentation to the pediatric emergency department (PED). It is unclear if having an on-site inpatient pediatric psychiatric unit impacts pediatric mental health care in the acute setting. The objective of this study was to compare PED mental health care between a pediatric tertiary care center with an associated inpatient child psychiatric unit (PAPED) and one that does not (NOPED) with the hypothesis that children have longer lengths of stay (LOS) at the PED without an inpatient unit. This was a retrospective, observational study of all mental health presentations aged 1 to 18 years to 2 tertiary care PEDs from March 2012 to June 2013 with a final mental health diagnosis International Classification of Diseases, Ninth Revision code. A total of 1409 patient encounters comprised the study group. The PAPED had a significantly higher rate of admission 41.3% versus 18.8% (P < 0.0001). The LOS was significantly longer at the NOPED compared with the PAPED with a visit of 15.6 versus 6.3, respectively (P < 0.0001). When LOS was stratified for disposition, patients requiring admission from the NOPED had a significantly longer LOS of 33.4 compared with an emergency department LOS of 8.1 at the PAPED (P < 0.0001). Mental health care in the PED seems to be affected by having an associated inpatient child psychiatric unit. Further research needs to address this growing problem and ways to utilize community resources to develop safe outpatient plans and divert admission if possible.