Correlations Between Clinical Judgement and Learning Style Preferences of Nursing Students in the Simulation Room.
Health care educators account for variables affecting patient safety and are responsible for developing the highly complex process of education planning. Clinical judgement is a multidimensional process, which may be affected by learning styles. The aim was to explore three specific hypotheses to test correlations between nursing students' team achievements in clinical judgement and emotional, sociological and physiological learning style preferences. A descriptive cross-sectional study was conducted with Swedish university nursing students in 2012-2013. Convenience sampling was used with 60 teams with 173 nursing students in the final semester of a three-year Bachelor of Science in nursing programme. Data collection included questionnaires of personal characteristics, learning style preferences, determined by the Dunn and Dunn Productivity Environmental Preference Survey, and videotaped complex nursing simulation scenarios. Comparison with Lasater Clinical Judgement Rubric and Non-parametric analyses were performed. Three significant correlations were found between the team achievements and the students' learning style preferences: significant negative correlation with 'Structure' and 'Kinesthetic' at the individual level, and positive correlation with the 'Tactile' variable. No significant correlations with students' 'Motivation', 'Persistence', 'Wish to learn alone' and 'Wish for an authoritative person present' were seen. There were multiple complex interactions between the tested learning style preferences and the team achievements of clinical judgement in the simulation room, which provides important information for the becoming nurses. Several factors may have influenced the results that should be acknowledged when designing further research. We suggest conducting mixed methods to determine further relationships between team achievements, learning style preferences, cognitive learning outcomes and group processes.


Genome-wide data substantiate Holocene gene flow from India to Australia.
The Australian continent holds some of the earliest archaeological evidence for the expansion of modern humans out of Africa, with initial occupation at least 40,000 y ago. It is commonly assumed that Australia remained largely isolated following initial colonization, but the genetic history of Australians has not been explored in detail to address this issue. Here, we analyze large-scale genotyping data from aboriginal Australians, New Guineans, island Southeast Asians and Indians. We find an ancient association between Australia, New Guinea, and the Mamanwa (a Negrito group from the Philippines), with divergence times for these groups estimated at 36,000 y ago, and supporting the view that these populations represent the descendants of an early "southern route" migration out of Africa, whereas other populations in the region arrived later by a separate dispersal. We also detect a signal indicative of substantial gene flow between the Indian populations and Australia well before European contact, contrary to the prevailing view that there was no contact between Australia and the rest of the world. We estimate this gene flow to have occurred during the Holocene, 4,230 y ago. This is also approximately when changes in tool technology, food processing, and the dingo appear in the Australian archaeological record, suggesting that these may be related to the migration from India.


Copper coordination polymers based on single-chain or sheet structures involving dinuclear and tetranuclear copper(II) units: synthesis, structures, and magnetostructural correlations.
Reactions between the potentially pentadentate (N(2)O(3)), trianionic double Schiff-base ligand 2,6-bis[[(2-hydroxyethyl)imino]methyl]-4-methylphenol (H(3)L) and Cu(CH(3)CO(2))(2) or Cu(ClO(4))(2), in the presence of NaN(3), give novel coordination polymers with chain {[Cu(2)(H(2)L)(N(3))(3)](2).H(2)O}(n) (1) or sheet [Cu(2)(H(2)L)(N(3))(3)](n) (2) and [Cu(2)(HL)(N(3))](n)[ClO(4)](n) (3) structures, respectively. These clusters are comprised of repeating dinuclear units (1) or their dimers (2 and 3). In these compounds, H(3)L acts as a tridentate (N(2)O) monoanionic (1), tetradentate (ON(2)O) monoanionic (2), or pentadentate (O(3)N(2)) dianionic (3) ligand. Compound [Cu(2)(HL)(N(3))(2)(H(2)O)].0.5CH(3)OH (4) formed from the reaction of Cu(CH(3)CO(2))(2) with H(3)L under reflux, which did not afford crystals suitable for X-ray studies. X-ray structure determinations have revealed that the basic building block in 1-3 comprises two copper centers bridged through one mu-phenolate O atom from H(2)L(-) or HL(2-) and one mu-azido(N1,N1) ion. Compounds 1-3 unveil three different ways in which this Cu(2) basic unit may be organized in the crystalline phase at the supramolecular level through a variety of bridging interactions involving additional azide ligands or alkoxide groups from the side arms of the ligand H(3)L. Bulk magnetization measurements have served to demonstrate that the magnetic interactions are completely dominated by the strong antiferromagnetic coupling occurring within the Cu(2) building block, with coupling constants ranging from 330 to 560 cm(-1) (in the H = -JS(1)S(2) convention). These results together have been incorporated with data from the few related copper dimers reported exhibiting the same bridging pattern into a study aimed at extracting possible magnetostructural correlations within this Cu(2) unit. An earlier predicted correlation between J and the angle formed by the phenoxide bridge and the Cu(2) core has been identified for the first time.


Topological Analysis of the Brainstem of the Australian Lungfish Neoceratodus forsteri.
This paper presents a survey of the cell masses in the brainstem of the Australian lungfish Neoceratodus forsteri, based ontransversely cut Bodian-stained serial sections, supplemented by immunohistochemical data from the recent literature. This study is intended to serve a double purpose. First it concludes and completes a series of publications on the structure of the brainstem in representative species of all groups of anamniote vertebrates. Within the framework of this comparative program the cell masses in the brainstem and their positional relations are analyzed in the light of the Herrick-Johnston concept, according to which the brainstem nuclei are arranged in four longitudinal, functional zones or columns, the boundaries of which are marked by ventricular sulci. The procedure employed in this analysis essentially involves two steps: first, the cell masses and large individual cells are projected upon the ventricular surface, and next, the ventricular surface is flattened out, that is, subjected to a one-to-one continuous topological transformation [J Comp Neurol. 1974;156:255-267]. The second purpose of the present paper is to complement our mapping of the longitudinal zonal arrangement of the cell masses in the brainstem of Neoceratoduswith a subdivision in transversely oriented neural segments. Five longitudinal rhombencephalic sulci - the sulcus medianus inferior, the sulcus intermedius ventralis, the sulcus limitans, the sulcus intermedius dorsalis and the sulcus medianus superior - and four longitudinal mesencephalic sulci - the sulcus tegmentalis medialis, the sulcus tegmentalis lateralis, the sulcus subtectalis and the sulcus lateralis mesencephali - could be distinguished. Two obliquely oriented grooves, present in the isthmic region - the sulcus isthmi dorsalis and ventralis - deviate from the overall longitudinal pattern of the other sulci. Although in Neoceratodus most neuronal perikarya are situated within a diffuse periventricular gray, 45 cell masses could be delineated. Ten of these are primary efferent or motor nuclei, eight are primary afferent or sensory centers, six are considered to be components of the reticular formation and the remaining 21 may be interpreted as "relay" nuclei. The topological analysis showed that in most of the rhombencephalon the gray matter is arranged in four longitudinal zones or areas, termed area ventralis, area intermedioventralis, area intermediodorsalis and area dorsalis. The sulcus intermedius ventralis, the sulcus limitans, and the sulcus intermedius dorsalis mark the boundaries between these morphological entities. These longitudinal zones coincide largely, but not entirely, with the functional columns of Herrick and Johnston. The most obvious incongruity is that the area intermediodorsalis contains, in addition to the viscerosensory nucleus of the solitary tract, several general somatosensory and special somatosensory centers. The isthmus region does not exhibit a clear morphological zonal pattern. The mesencephalon is divisible into a ventral, primarily motor zone and a dorsal somatosensory zone. The boundary between these zones is marked by the sulcus tegmentalis lateralis, which may be considered as an isolated rostral extremity of the sulcus limitans. The results of this study are summarized in a "classical" topological map, as well as in a "modernized" version of this map, in which neuromere borders are indicated.


Re-revision Anterior Cruciate Ligament Reconstruction: An Evaluation From the Norwegian Knee Ligament Registry.
To identify the rate of re-revision anterior cruciate ligament reconstruction (ACLR) to estimate the influence of patient-related factors on the risk of re-revision ACLR. The secondary aim of the study was to report the intra-articular findings and patient-related factors at the time of revision ACLR and to compare these with the findings in a matched controlled group of primary ACLR. Patients with primary ACLR without a subsequent need of revision and patients with a revision ACLR identified in the Norwegian Knee Ligament Registry from June 2004 through September 2016 were included. Using age at operation, sex, activity at injury, and year of ACLR as covariates, a propensity score matched control group of primary ACLR patients for the revision ACLR patients was identified. For the revision ACLR patients, re-revision ACLR rates at 1, 2, 5, and 8 years were estimated with Kaplan-Meier analysis; the hazard ratio for a re-revision ACLR was estimated using a multivariable Cox regression model. The cumulative estimated proportion of patients undergoing a re-revision ACLR at 1, 2, 5, and 8 years after the original revision ACLR was 0.4%, 3.0%, 6.5%, and 9.0% respectively. There was no significant difference between the control and revision ACLR groups regarding cartilage injury (P = .72) or associated ligament injury (P = .17). Revision ACLR patients did have fewer meniscal injuries (P < .001). There were no intraoperative findings or surgical techniques identified as a predictor for a higher risk of re-revision ACLR. Based on a review of a large ligament reconstruction registry,one can expect 9% of patients to undergo a re-revision ALCR at 8 years of follow up. Revision ACLR did not have an increase in cartilage injuries or associated ligament injuries and had significantly fewer meniscal injuries compared with a primary ACLR control group. Level III, retrospective comparative study.


Delayed progression of a murine retrovirus-induced acquired immunodeficiency syndrome in X-linked immunodeficient mice.
The murine acquired immunodeficiency syndrome (MAIDS) caused by defective LP-BM5 murine leukemia virus (MuLV) is a disease that shows severe immunodeficiency with abnormal lymphoproliferation, and hypergammaglobulinemia in susceptible C57BL/6 (B6) mice. To examine the cellular mechanisms of development of MAIDS, we injected LP-BM5 MuLV intraperitoneally into B6 mice bearing the X chromosome-linked immunodeficiency (xid). xid mice lack functionally mature B cells including Ly-1 B cells (also known as B-1 cells). All B6 mice died by 20 wk after LP-BM5 MuLV inoculation. In marked contrast, xid mice have continued to survive without any sign of MAIDS-related symptoms till at least 20 wk after the inoculation. The delayed progression of MAIDS in xid mice appears to depend on xid mutation, according to our experiments using both sexes of (B6.xid x B6)F1 and (B6 x B6.xid)F1 mice. Furthermore, Ly-1 B cells, enriched by a FACS, were shown to integrate the defective genome and appeared to be a major virus-infected B cell population. Our data corroborate that Ly-1 B cells play an important role in the induction and progression of MAIDS.


Molecular chaperone function for myocilin.
Myocilin is thought to be a stress response protein, but its exact molecular functions have not been established. Studies were conducted to see whether myocilin can act as a general molecular chaperone. Myocilin was isolated and purified from porcine trabecular meshwork (TM) cell culture media. Its ability to protect citrate synthase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and the restriction endonuclease DrdI from thermal inactivation was evaluated. Light scattering was used to evaluate thermally induced aggregation of citrate synthase. Myocilin induction was assessed after exposure of TM cells to several types of stress treatments. Levels of extracellular myocilin expressed by TM cells were increased in response to mechanical stretch, heat shock, TNFα, or IL-1α. Myocilin protected citrate synthase activity against thermal inactivation for 5 minutes at 55°C in a concentration-dependent manner, with nearly full protection of 1.5 μM citrate synthase in the presence of 650 nM myocilin. Myocilin significantly reduced thermal aggregation of citrate synthase to levels 36% to 44% of control levels. Myocilin also protected GAPDH from thermal inactivation for 10 minutes at 45°C. Myocilin at 18 nM was more effective than 1 μM bovine serum albumin at protecting DrdI from thermal inactivation. Myocilin is induced in response to several cellular stresses and displays general molecular chaperone activity by protecting DrdI, citrate synthase, and GAPDH from thermal inactivation. Myocilin also suppresses the thermal aggregation of citrate synthase. One function of myocilin may be to serve as a molecular chaperone.


[Study of apoptosis and mitosis mechanisms in the eye. Experimental model of gestational toxic syndrome].
To improve knowledge of the mechanisms of cellular differentiation and proliferation during retinal development, by studying cellular and molecular damage in a rat model of prenatal ethanol exposure. Female, juvenile Wistar rats (200g body weight) and their offspring were divided into two groups, which were fed a liquid diet: 1) ethanol-exposed group (5% ethanol weight/vol as 35% of daily total calories) and 2) isocaloric control group (maltose/dextrin as 35% of daily total calories). Eyeballs were obtained at 21 days of gestation, embedded in paraffin, and immunodetection procedures performed on apoptotic (TUNEL) and mitotic profiles, which were observed and photographed using a confocal microscope. Analysis of the microphotographs revealed a statistically significant increase of apoptotic profiles and a decrease in mitotic profiles in the ethanol exposed group compared to controls (p<0.05). Ganglion cells and photoreceptors showed more changes than other retinal cell phenotypes. These findings suggest that abnormalities in the differentiation and proliferation processes of the retina were caused by the alcohol exposure. Alcohol abuse during pregnancy alters development of the visual system by inducing developmental changes in the mitotic and apoptotic processes of the retina. These latter changes may be the result of changes in the expression of regulatory genes as well as the result of alteration in signalling pathways for both differentiation-proliferation and apoptotic events.


Bats and Coronaviruses.
Bats are speculated to be reservoirs of several emerging viruses including coronaviruses (CoVs) that cause serious disease in humans and agricultural animals. These include CoVs that cause severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), porcine epidemic diarrhea (PED) and severe acute diarrhea syndrome (SADS). Bats that are naturally infected or experimentally infected do not demonstrate clinical signs of disease. These observations have allowed researchers to speculate that bats are the likely reservoirs or ancestral hosts for several CoVs. In this review, we follow the CoV outbreaks that are speculated to have originated in bats. We review studies that have allowed researchers to identify unique adaptation in bats that may allow them to harbor CoVs without severe disease. We speculate about future studies that are critical to identify how bats can harbor multiple strains of CoVs and factors that enable these viruses to "jump" from bats to other mammals. We hope that this review will enable readers to identify gaps in knowledge that currently exist and initiate a dialogue amongst bat researchers to share resources to overcome present limitations.


Pain Management in Abdominal Wall Reconstruction.
In abdominal wall reconstruction, adequate pain control and minimization of narcotic consumption are essential to improving patient outcomes and satisfaction. Previous studies have examined the role of individual strategies, such as neuraxial analgesia and multimodal analgesia. However, there has not been a study that examined all potential determinants of postoperative narcotic requirements, including intraoperative strategies. Consecutive patients who underwent abdominal wall reconstruction were reviewed. Preoperative factors (chronic preoperative narcotic usage, indication for abdominal wall reconstruction, administration of neuraxial analgesia), intraoperative factors (intraoperative narcotics administered, method of mesh fixation), and postoperative factors (multimodal analgesia, complications) were collected. The main outcomes were daily amount of opioids used and length of hospital stay. Ninety-three patients were included in the study. Patients who had an epidural required lower doses of opioids postoperatively, while those on chronic preoperative opioids, those whose mesh was fixated using transfascial sutures, and those who received large doses of opioids intraoperatively required higher doses of postoperative opioids. Hospital length of stay was longer in patients who received transfascially sutured mesh and those on chronic opioids preoperatively. This study provides potential strategies to improve pain control and minimize narcotic consumption postoperatively in patients undergoing abdominal wall reconstruction. Intraoperative administration of opioids should be minimized to avoid the development of tolerance. Epidural analgesia reduces postoperative narcotic requirement and may be especially beneficial in patients at highest risk for postoperative pain, including those on chronic opioids, and those in whom transfascial sutures are used for mesh fixation.


Electromyographic assessment of spasmodic dysphonia patients prior to botulinum toxin injection.
Electromyographic (EMG) evidence of inappropriate muscle activity (IMA) in the cricothyroid (CT) and vocalis (V) (thyroarytenoid) muscles was correlated with clinical voice measures in 32 patients with spasmodic dysphonia (SD). Subjective voice rating and quantified fluency and laryngeal diadochokinesis measures were obtained prior to botulinum toxin (Botox) injection into the V muscles. Pre-Botox EMG was performed using a monopolar needle electrode. Each muscle was sequentially examined at rest, during vocal click, scale, sustained "E" at different pitches, and repeated "E" voicings for brief periods. A three point EMG severity scale was used to grade the amount of IMA seen in each muscle. EMG evaluation showed no evidence of lower motor neuron involvement but did reveal IMA in 81.3% of the subjects. There were no significant correlations for the patients between different EMG-based IMA severity scales and the measures of voice quality and sound production. EMG did discriminate between predominantly adductor and abductor SD pattern types, but could not correctly differentiate a mixed SD group. Those patients with adductor SD displayed IMA in the V and CT muscles, while those with abductor SD displayed more IMA in the CT than the V muscles. Sequential EMG assessment of CT and V IMA in SD did not predict clinical severity or outcome following Botox injection into the V muscles.


Infective Endocarditis in French West Indies: A 13-Year Observational Study.
We conducted an observational study to describe the characteristics of infective endocarditis (IE) in French West Indies (FWI) and to identify variables associated with in-hospital case fatality. The records of the patients admitted for IE to the University Hospital of Martinique between 2000 and 2012 were collected using an electronic case report form. Only Duke-Li definite cases were considered for this analysis. Variables associated with in-hospital mortality were tested using univariate logistic regression analysis. The analysis included 201 patients (median age 58 years, sex ratio: two males to one female). There was no previously known heart disease in 45.8%, a prosthetic valve in 21.4%, and previously known native valve disease in 32.8% of the cases. Community-acquired IE represented 59.7% of all cases, health-care-associated IE represented 38.3% and injection-drug-use-acquired IE represented 1.5%. Locations of IE were distributed as follows: 42.3% were mitral valve IE, 34.8% were aortic valve IE, and 7% were right-sided IE. Microorganisms recovered from blood cultures included 30.4% streptococci, 28.9% staphylococci, and 5% enterococci. Blood cultures were negative in 20.9% of the cases. Surgical treatment was performed in 53% of the patients. In-hospital case fatality rate was 19%. Advanced age, Staphylococcus aureus IE, and health-care-associated IE were associated with in-hospital case fatality. The epidemiological and microbiological profile of IE in FWI is in between those observed in developed countries and developing countries: patients were younger, blood cultures were more frequently negative, and IE due to group D streptococci and enterococci were less common than in industrialized countries.


Mechanism of membrane nanotube formation by molecular motors.
Membrane nanotubes are ubiquitous in eukaryotic cells due to their involvement in the communication between many different membrane compartments. They are very dynamical structures, which are generally extended along the microtubule network. One possible mechanism of tube formation involves the action of molecular motors, which can generate the necessary force to pull the tubes along the cytoskeleton tracks. However, it has not been possible so far to image in living organisms simultaneously both tube formation and the molecular motors involved in the process. The reasons for this are mainly technological. To overcome these limitations and to elucidate in detail the mechanism of tube formation, many experiments have been developed over the last years in cell-free environments. In the present review, we present the results, which have been obtained in vitro either in cell extracts or with purified and artificial components. In particular, we will focus on a biomimetic system, which involves Giant Unilamellar Vesicles, kinesin-1 motors and microtubules in the presence of ATP. We present both theoretical and experimental results based on fluorescence microscopy that elucidate the dynamics of membrane tube formation, growth and stalling.


Fine-Tuning the Nanostructured Titanium Oxide Surface for Selective Biological Response.
Cardiovascular diseases are a pre-eminent global cause of mortality in the modern world. Typically, surgical intervention with implantable medical devices such as cardiovascular stents is deployed to reinstate unobstructed blood flow. Unfortunately, existing stent materials frequently induce restenosis and thrombosis, necessitating the development of superior biomaterials. These biomaterials should inhibit platelet adhesion (mitigating stent-induced thrombosis) and smooth muscle cell proliferation (minimizing restenosis) while enhancing endothelial cell proliferation at the same time. To optimize the surface properties of Ti6Al4V medical implants, we investigated two surface treatment procedures: gaseous plasma treatment and hydrothermal treatment. We analyzed these modified surfaces through scanning electron microscopy (SEM), water contact angle analysis (WCA), X-ray photoelectron spectroscopy (XPS), and X-ray diffraction (XRD) analysis. Additionally, we assessed in vitro biological responses, including platelet adhesion and activation, as well as endothelial and smooth muscle cell proliferation. Herein, we report the influence of pre/post oxygen plasma treatment on titanium oxide layer formation via a hydrothermal technique. Our results indicate that alterations in the titanium oxide layer and surface nanotopography significantly influence cell interactions. This work offers promising insights into designing multifunctional biomaterial surfaces that selectively promote specific cell types' proliferation─which is a crucial advancement in next-generation vascular implants.


Chiral electron transport: scattering through helical potentials.
We present a model for the transmission of spin-polarized electrons through oriented chiral molecules, where the chiral structure is represented by a helix. The scattering potential contains a confining term and a spin-orbit contribution that is responsible for the spin-dependent scattering of electrons by the molecular target. The differential scattering cross section is calculated for right- and left-handed helices and for arbitrary electron spin polarizations. We apply our model to explain chiral effects in the intensity of photoemitted polarized electrons transmitted through thin organic layers. These are molecular interfaces that exhibit spin-selective scattering with surprisingly large asymmetry factors as well as a number of remarkable magnetic properties. In our model, differences in intensity are generated by the preferential transmission of electron beams whose polarization is oriented in the same direction as the sense of advance of the helix. This model can be easily extended to the Landauer regime of conductance where conductance is due to elastic scattering, so that we can consider the conductance of chiral molecular junctions.


Use of the ecosystem services concept in ecological risk assessment of chemicals.
The reason for expressing ecological protection goals in terms of ecosystem services is to make a connection between ecosystems and what people get out of them in terms of marketed goods and nonmarketed welfare. Here our focus will be on how the ecosystem services framework is and can be applied to the ecological risk assessment (ERA) of chemicals. We provide 2 contrasting examples of how the ecosystem services framework is currently being applied in regulatory risk assessment, and we discuss the challenges and knowledge gaps that need to be addressed if such a framework is to substantially improve ERAs and their ability to inform management decisions. We make the point that formulating protection goals in terms of ecosystem services only makes sense if they can be used in managing environmental impacts and if they are useful in informing the risk assessments behind these. Ecosystem services can make a contribution to management by connecting ecosystem structure and process to what is valued, and analyzing risk in this context is a way of making risk assessment more policy- and value-relevant. Using an ecosystem services framework to its fullest potential to support ERA will require the successful development of a suite of coupled Valuation Methods, Ecological Production Functions, and Mechanistic Effect Models that will require the establishment of strong multidisciplinary collaborations among ecologists, computer scientists, social scientists, and possibly others. In addition, buy-in from environmental decision makers and other stakeholders will be crucial. Some progress is being made on the research front, and the implementation of new legislation is providing incentives for developing risk assessment outputs that are much more directly related to environmental protection goals than those used currently.


Potentiation of luteolin cytotoxicity by flavonols fisetin and quercetin in human chronic lymphocytic leukemia cell lines.
Despite numerous studies chronic lymphocytic leukemia (CLL) still remains an incurable disease. Therefore, all new compounds and novel strategies which are able to eradicate CLL cells should be considered as valuable clues for a potential future remedy against this malignancy. In the present study, the cytotoxic profiles of natural flavonoids were described in two human CLL cell lines, HG-3 and EHEB, indicating the flavone luteolin as the most potent flavonoid with half-maximal inhibitory constants (IC50) of 37 μM and 26 μM, respectively. Luteolin significantly increased the apoptotic cell population in both cell lines by increasing the activities of caspases-3 and -9 and triggering the intrinsic apoptotic pathway. Two flavonols, fisetin and quercetin, were somewhat less efficient in suppressing cellular viability, whereas baicalein, chrysin, (+)-catechin and hesperetin exerted only a small or no response at doses as high as 100 μM. Both fisetin and quercetin were able to augment the cytotoxic activity of luteolin in both cell lines by reducing the IC50 values up to four fold. As a result of this, luteolin displayed cytotoxicity activity already at low micromolar concentrations that could potentially be physiologically achievable through oral ingestion. No other tested flavonoids were capable of sensitizing CLL cells to luteolin pointing to a specific binding of fisetin and quercetin to the cellular targets which interfere with the signaling pathways induced by luteolin. Although further molecular studies to unravel this potentiating mechanism are certainly needed, this phenomenon could contribute to future remedies for prevention and treatment of chronic lymphocytic leukemia.


Increased Artemis levels confer radioresistance to both high and low LET radiation exposures.
Artemis has a defined role in V(D)J recombination and has been implicated in the repair of radiation induced double-strand breaks. However the exact function(s) of Artemis in DNA repair and its preferred substrate(s) in vivo remain undefined. Our previous work suggests that Artemis is important for the repair of complex DNA damage like that inflicted by high Linear Energy Transfer (LET) radiation. To establish the contribution of Artemis in repairing DNA damage caused by various radiation qualities, we evaluated the effect of over-expressing Artemis on cell survival, DNA repair, and cell cycle arrest after exposure to high and low LET radiation. Our data reveal that Artemis over-expression confers marked radioprotection against both types of radiation, although the radioprotective effect was greater following high LET radiation. Inhibitor studies reveal that the radioprotection imparted by Artemis is primarily dependent on DNA-PK activity, and to a lesser extent on ATM kinase activity. Together, these data suggest a DNA-PK dependent role for Artemis in the repair of complex DNA damage. These findings indicate that Artemis levels significantly influence radiation toxicity in human cells and suggest that Artemis inhibition could be a practical target for adjuvant cancer therapies.


Identification of trabecular excrescences, novel microanatomical structures, present in bone in osteoarthropathies.
It is widely held that bone architecture is finely regulated in accordance with homeostatic requirements. Aberrant remodelling (hyperdensification and/or cyst formation in the immediately subchondral region) has previously been described in bone underlying cartilage in arthropathies. The present study examined the trabecular architecture of samples of bone, initially in the severe osteoarthropathy of alkaptonuria, but subsequently in osteoarthritis using a combination of light microscopy, 3D scanning electron microscopy and quantitative backscattered electron scanning electron microscopy. We report an extraordinary and previously unrecognised bone phenotype in both disorders, including novel microanatomical structures. The underlying subchondral trabecular bone contained idiosyncratic architecture. Trabecular surfaces had numerous outgrowths that we have termed "trabecular excrescences", of which three distinct types were recognised. The first type arose from incomplete resorption of branching secondary trabeculae arising from the deposition of immature (woven) bone in prior marrow space. These were characterised by very deeply scalloped surfaces and rugged edges. The second type had arisen in a similar way but been smoothed over by new bone deposition. The third type, which resembled coarse stucco, probably arises from resting surfaces that had been focally reactivated. These were poorly integrated with the prior trabecular wall. We propose that these distinctive microanatomical structures are indicative of abnormal osteoclast/osteoblast modelling in osteoarthropathies, possibly secondary to altered mechanical loading or other aberrant signalling. Identification of the mechanisms underlying the formation of trabecular excrescences will contribute to a better understanding of the role of aberrant bone remodelling in arthropathies and development of new therapeutic strategies.


Phase II trial of postoperative adjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II and IIIA non-small-cell lung cancer: promising long-term results of the Radiation Therapy Oncology Group--RTOG 9705.
To determine the overall survival, progression-free survival, and toxicity associated with concurrent paclitaxel/carboplatin and thoracic radiotherapy for completely resected patients with stage II and IIIA non-small-cell lung cancer (NSCLC). Eighty-eight eligible patients had surgical resection for pathologic stage II or IIIA disease and received postoperative paclitaxel and carboplatin. Concurrent thoracic radiotherapy at 50.4 Gy in 28 fractions for 6 weeks (1.8 Gy/d, 5 days/wk) was given during cycles 1 and 2. A boost of 10.8 Gy in six fractions was given for extracapsular nodal extension or T3 lesions. Treatment compliance was acceptable, with 93% compliance for radiation therapy and 86% for chemotherapy completion. The median duration of follow-up was 56.7 months (range, 17 to 61 months). The median overall survival time was 56.3 months, with 1-, 2-, and 3-year survival rates of 86%, 70%, and 61%, respectively. The 1-, 2-, and 3- year progression-free survival rates were 70%, 57%, and 50%, respectively. Brain metastasis occurred as the sole site of first failure in 11%, and 9% failed in other metastatic sites as first failure. Of the 43 patients who died, the cause of death was the treated cancer in 31 (35%). Local failure was a component of first failure in 15% of patients. Toxicities were acceptable. An overall survival comparison to Eastern Cooperative Oncology Group 3590 is favorable. The mature results of this trial suggest an improved overall and progression-free survival in this group of resected NSCLC patients, compared with previously reported trials. A phase III trial comparing this treatment regimen with standard therapy seems warranted.


Polyphasic characterization of Xanthomonas axonopodis pv. allii associated with outbreaks of bacterial blight on three Allium species in the Mascarene archipelago.
Based on the number of new reports during the last two decades, bacterial blight of onion (Allium cepa) is considered an emerging disease. The causal agent, Xanthomonas axonopodis pv. allii, is pathogenic to several Allium species after inoculation, but outbreaks worldwide have been primarily reported on onion. We describe a unique epidemiological situation in Réunion Island, France, with concomitant outbreaks on three Allium species, onion, leek (A. porrum), and garlic (A. sativum). There was no host specialization within Allium spp. among strains associated with the three host species. Based on amplified fragment length polymorphism (AFLP) and restriction fragment length polymorphism, strains associated with these outbreaks in Réunion Island were highly related genetically to strains isolated from diseased plant samples and contaminated seed lots in the neighboring island of Mauritius, where the disease has occurred since 1984. All AFLP haplotypes were identified as X. axonopodis pv. allii based on polymerase chain reaction analysis using specific primers, biochemical tests, and/or pathogenicity tests. Two genetically related groups of strains (A and B) that can be distinguished by AFLP, differential utilization of three carbon sources, and xanthomonadin pigment production were detected initially after establishment of the pathogen. In less than 10 years after the establishment of the pathogen there was nearly an extinction of group A strains in Réunion Island, suggesting differences in fitness between strains in the two groups.


A host-protein based assay to differentiate between bacterial and viral infections in preschool children (OPPORTUNITY): a double-blind, multicentre, validation study.
A physician is frequently unable to distinguish bacterial from viral infections. ImmunoXpert is a novel assay combining three proteins: tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma induced protein-10 (IP-10), and C-reactive protein (CRP). We aimed to externally validate the diagnostic accuracy of this assay in differentiating between bacterial and viral infections and to compare this test with commonly used biomarkers. In this prospective, double-blind, international, multicentre study, we recruited children aged 2-60 months with lower respiratory tract infection or clinical presentation of fever without source at four hospitals in the Netherlands and two hospitals in Israel. A panel of three experienced paediatricians adjudicated a reference standard diagnosis for all patients (ie, bacterial or viral infection) using all available clinical and laboratory information, including a 28-day follow-up assessment. The panel was masked to the assay results. We identified majority diagnosis when two of three panel members agreed on a diagnosis and unanimous diagnosis when all three panel members agreed on the diagnosis. We calculated the diagnostic performance (ie, sensitivity, specificity, positive predictive value, and negative predictive value) of the index test in differentiating between bacterial (index test positive) and viral (index test negative) infection by comparing the test classification with the reference standard outcome. Between Oct 16, 2013 and March 1, 2015, we recruited 777 children, of whom 577 (mean age 21 months, 56% male) were assessed. The majority of the panel diagnosed 71 cases as bacterial infections and 435 as viral infections. In another 71 patients there was an inconclusive panel diagnosis. The assay distinguished bacterial from viral infections with a sensitivity of 86·7% (95% CI 75·8-93·1), a specificity of 91·1% (87·9-93·6), a positive predictive value of 60·5% (49·9-70·1), and a negative predictive value of 97·8% (95·6-98·9). In the more clear cases with unanimous panel diagnosis (n=354), sensitivity was 87·8% (74·5-94·7), specificity 93·0% (89·6-95·3), positive predictive value 62·1% (49·2-73·4), and negative predictive value 98·3% (96·1-99·3). This external validation study shows the diagnostic value of a three-host protein-based assay to differentiate between bacterial and viral infections in children with lower respiratory tract infection or fever without source. This diagnostic based on CRP, TRAIL, and IP-10 has the potential to reduce antibiotic misuse in young children. MeMed Diagnostics.


Pneumonia identification using statistical feature selection.
This paper describes a natural language processing system for the task of pneumonia identification. Based on the information extracted from the narrative reports associated with a patient, the task is to identify whether or not the patient is positive for pneumonia. A binary classifier was employed to identify pneumonia from a dataset of multiple types of clinical notes created for 426 patients during their stay in the intensive care unit. For this purpose, three types of features were considered: (1) word n-grams, (2) Unified Medical Language System (UMLS) concepts, and (3) assertion values associated with pneumonia expressions. System performance was greatly increased by a feature selection approach which uses statistical significance testing to rank features based on their association with the two categories of pneumonia identification. Besides testing our system on the entire cohort of 426 patients (unrestricted dataset), we also used a smaller subset of 236 patients (restricted dataset). The performance of the system was compared with the results of a baseline previously proposed for these two datasets. The best results achieved by the system (85.71 and 81.67 F1-measure) are significantly better than the baseline results (50.70 and 49.10 F1-measure) on the restricted and unrestricted datasets, respectively. Using a statistical feature selection approach that allows the feature extractor to consider only the most informative features from the feature space significantly improves the performance over a baseline that uses all the features from the same feature space. Extracting the assertion value for pneumonia expressions further improves the system performance.


Magnesium sulfate induces translocation of protein kinase C isoenzymes alpha and delta in myometrial cells from pregnant women.
The purpose of this study was to determine the effect of magnesium sulfate on protein kinase C (PKC) translocation in myometrial cells from pregnant women. Myometrium was obtained at the time of cesarean delivery from women at term before labor. Cultured myometrial cells were treated with magnesium sulfate (3, 5, and 10 mmol/L), oxytocin (0.1 micromol/L), or 12-O-tetradecanoylphorbol-13-acetate (TPA, 0.1 micromol/L). The translocation of PKC isozymes alpha (calcium dependent) and delta (calcium independent) from cytosol to membrane fractions was assessed with use of Western blot analysis. In unexposed control cells, the majority of PKC alpha and delta was located in the cytosol fraction. Exposure to magnesium sulfate for 60 minutes induced translocation of both PKC alpha and delta at concentrations as low as 5 and 3 mmol/L, respectively. The magnitude of magnesium sulfate induced translocation for PKC delta is similar to that seen after oxytocin or TPA exposure but less for PKC alpha. Exposure to oxytocin for 30 minutes and 60 minutes induced translocation of PKC alpha and delta, respectively. Exposure to TPA for 5 and 30 minutes induced translocation of PKC alpha and PKC delta, respectively. In calcium-free media, only TPA induced translocation of these two isoenzymes. Magnesium sulfate stimulates PKC translocation in cultured myometrial cells from pregnant women. Magnesium sulfate and oxytocin require extracellular calcium to induce translocation of both PKC alpha and delta.


Host country responses to non-communicable diseases amongst Syrian refugees: a review.
Since the beginning of the Syrian conflict in 2011, Jordan, Lebanon and Turkey have hosted large refugee populations, with a high pre-conflict burden of non-communicable diseases (NCDs). We aimed to describe the ways in which these three host country health systems have provided NCD services to Syrian refugees over time, and to highlight the successes and challenges they encountered. We conducted a descriptive review of the academic and grey literature, published between March 2011 and March 2017, using PubMed and Google searches complemented with documents provided by relevant stakeholders. Forty-one articles and reports met our search criteria. Despite the scarcity of systematic population-level data, these documents highlight the high burden of reported NCDs among Syrian refugees, especially amongst older adults. The three host countries utilized different approaches to the design, delivery and financing of NCD services for these refugees. In Jordan and Lebanon, Ministries of Health and the United Nations High Commissioner for Refugees (UNHCR) coordinate a diverse group of health care providers to deliver health services to Syrian refugees at a subsidized cost. In Turkey, however, services are provided solely by the Disaster and Emergency Management Presidency (AFAD), a Turkish governmental agency, with no cost to patients for primary or secondary care. Access to NCD services varied both within and between countries, with no data available from Turkey. The cost of NCD treatment is the primary barrier to accessing healthcare, with high out-of-pocket payments required for medications and secondary and tertiary care services, despite the availability of free or subsidized primary health services. Financial impediments led refugees to adopt coping strategies, including returning to Syria to seek treatment, with associated frequent treatment interruptions. These gaps were compounded by health system related barriers such as complex referral systems, lack of effective guidance on navigating the health system, limited health facility capacity and suboptimal NCD health education. As funding shortages for refugee services continue, innovative service delivery models are needed to create responsive and sustainable solutions to the NCD burden among refugees in host countries.


Inhibition and facilitation of afferent information by the caudate nucleus.
Stimulation of the caudate nucleus modifies inputs to the visual system of the cat. The modification of such sensory information is similar to the modification seen on stimulation of the thalamus and brain stem reticular formation. Preliminary stimulation of the caudate nucleus at different intervals prior to the afferent input may have facilitatory or inhibitory effects on both evoked potentials and unitary responses of the visual cortex.


Determinants of fracture risk in osteoporosis.
Osteoporosis is a major public health issue, with fragility fractures of the hip, vertebrae, and distal radius considered the most important consequences. These lead to increased morbidity, mortality, hospital care, and dependency. The risk factors for the development of fragility fractures are numerous and involve genetic and environmental influences, as well as an interaction between the two. In this review, the recent literature examining genetic factors, possible candidate genes, the evolving area of intrauterine fetal programming, and anthropometric and environmental factors will be reviewed.


Tunable photoluminescence and SERS behaviour of additively manufactured Au nanoparticle patterns.
The ability to tune the localised surface plasmon resonance (LSPR) behaviour of metal nanostructures has great importance for many optical sensor applications such as metal (plasmon) enhanced fluorescence spectroscopy and surface-enhanced Raman scattering (SERS). In this paper, we used Aerosol Direct Writing (ADW) to selectively deposit fine gold nanoparticles (AuNPs) patterns. A low-temperature thermal post-treatment (below 200 °C) provides enough energy to merge and transform AuNPs into larger features significantly different from non-thermally treated samples. The optical behaviour of non-treated and thermally treated AuNP films was investigated by photoluminescence (PL) spectroscopy. The PL measurements showed a red-shift, compared to bulk gold, using 488 nm and 514 nm laser excitation, and a blue-shift using 633 nm laser excitation. The thermal post-treatment leads to a further blue-shift compared to non-treated samples in the presence of both 514 and 633 nm laser. Finally, the AuNPs patterns were employed as a SERS-active substrate to detect low-concentrated (10-8 M) rhodamine B. This method's ability to selectively deposit 3D gold nanostructures and tune their optical behaviour through a low-temperature thermal treatment allows optimisation of the optical response and enhancement of the Raman signal for specific bio-analytes.


A shot through the window.
At issue in this case was whether an unusual window defect seen in two of the crime scene photographs was due to a bullet and if so, if that same bullet fatally wounded the victim. The window appeared to have been cracked prior to the apparent shot through it. A .22 bullet recovered from autopsy, when examined only by light microscopy, failed to show associated glass fragments. A previously cracked test window was shot a number of times with .22 caliber bullets near the cracks in an effort to simulate the window defect seen in the crime scene photographs. Several of the defects produced by the test window shots appeared similar to the crime scene window defect. The .22 bullet taken from the victim and several of the test bullets (collected by a cotton box) were examined by scanning electron microscopy/energy dispersive X-ray spectroscopy. The test bullets showed glass particles on and embedded in their surfaces. Particles of similar size and composition were found embedded in the surface of the bullet from the victim. The bullet likely struck the window prior to hitting the victim. It was apparent by the morphology of some of the mushroomed test .22 bullets that they hit the window crack. These bullets showed that the glass on one side of a crack often fails before the other side during the strike. Aggregations of powdered glass on many of the mushroomed surfaces of the .22 bullets suggest that as the bullet mushrooms during impact on the window surface, the glass in contact with the bullet powderizes and coats the mushroomed surface of the bullet with a layer of fine glass particles.


Modeling self-assembly processes driven by nonbonded interactions in soft materials.
This Centennial Feature Article provides an overview of research in the general area of self-assembly modeling, with particular emphasis on the self-assembly of molecules into soft nanoscale structures where the driving force for assembly is provided by nonbonded interactions (hydrogen bonds and electrostatics). The models have been developed at many different levels of theory, going all the way from simple analytical models of packing effects to atomistic descriptions using molecular dynamics methods. In between these limits are mean-field and coarse-grained models, including models for DNA, peptides, and lipids that can be used to describe the assembly of hybrid (amphiphilic) materials. Several recent applications to specific systems are discussed, including the description of peptide amphiphile assembly to make cylindrical micelles, the assembly and melting of DNA hairpins, the use of DNA tethers to assemble nanoparticles into aggregates and crystalline structures, and the use of coarse-grained lipid models to make lamellar and high-curvature phases. These examples demonstrate the difficulties associated with brute force atomistic methods, and they also show the opportunities (but uncertainties and ambiguities) associated with simpler models such as coarse-grained models. The examples also demonstrate the usefulness of successful modeling methods in the design of new materials, including an understanding of the relationship between structure and function.


Outcomes and Complications of Radiological Gastrostomy vs. Percutaneous Endoscopic Gastrostomy for Enteral Feeding: An Updated Systematic Review and Meta-Analysis.
Percutaneous endoscopic gastrostomy (PEG) and percutaneous radiological gastrostomy (PRG) are commonly utilized to establish access to enteral nutrition. However, data comparing the outcomes of PEG vs. PRG are conflicting. Therefore, we aimed to conduct an updated systemic review and meta-analysis comparing PRG and PEG outcomes. Medline, Embase, and Cochrane library databases were searched until February 24, 2023. Primary outcomes included 30-day mortality, tube leakage, tube dislodgement, perforation, and peritonitis. Secondary outcomes included bleeding, infectious complications, and aspiration pneumonia. All analyses were conducted using Comprehensive Meta-Analysis Software. The initial search revealed 872 studies. Of these, 43 of these studies met our inclusion criteria and were included in the final meta-analysis. Of 471,208 total patients, 194,399 received PRG and 276,809 received PEG. PRG was associated with higher odds of 30-day mortality when compared to PEG (odds ratio (OR): 1.205, 95% confidence interval (CI): 1.015 - 1.430, I2 = 55%). In addition, tube leakage and tube dislodgement were higher in the PRG group than in PEG (OR: 2.231, 95% CI: 1.184 - 4.2 and OR: 2.602, 95% CI: 1.911 - 3.541, respectively). Perforation, peritonitis, bleeding, and infectious complications were higher with PRG than PEG. PEG is associated with lower 30-day mortality, tube leakage, and tube dislodgement rates than PRG.


A nonsynonymous mutation in the WFS1 gene in a Finnish family with age-related hearing impairment.
Wolfram syndrome (WS) is caused by recessive mutations in the Wolfram syndrome 1 (WFS1) gene. Sensorineural hearing impairment (HI) is a frequent feature in WS and, furthermore, certain mutations in WFS1 cause nonsyndromic dominantly inherited low-frequency sensorineural HI. These two phenotypes are clinically distinct indicating that WFS1 is a reasonable candidate for genetic studies in patients with other phenotypes of HI. Here we have investigated, whether the variation in WFS1 has a pathogenic role in age-related hearing impairment (ARHI). WFS1 gene was investigated in a population sample of 518 Finnish adults born in 1938-1949 and representing variable hearing phenotypes. Identified variants were evaluated with respect to pathogenic potential. A rare mutation predicted to be pathogenic was found in a family with many members with impaired hearing. Twenty members were recruited to a segregation study and a detailed clinical examination. Heterozygous p.Tyr528His variant segregated completely with late-onset HI in which hearing deteriorated first at high frequencies and progressed to mid and low frequencies later in life. We report the first mutation in the WFS1 gene causing late-onset HI with audiogram configurations typical for ARHI. Monogenic forms of ARHI are rare and our results add WFS1 to the short list of such genes.


DNA interactions of non-chelating tinidazole-based coordination compounds and their structural, redox and cytotoxic properties.
Novel tinidazole (tnz) coordination compounds of different geometries were synthesised, whose respective solid-state packing appears to be driven by inter- and intramolecular lone pairπ interactions. The copper(ii) compounds exhibit interesting redox properties originating from both the tnz and the metal ions. These complexes interact with DNA through two distinct ways, namely via electrostatic interactions or/and groove binding, and they can mediate the generation of ROS that damage the biomolecule. Cytotoxic studies revealed an interesting activity of the dinuclear compound [Cu(tnz)2(μ-Cl)Cl]27, which is further more efficient towards cancer cells, compared with normal cells.


Alexithymia and health-related quality of life in patients with dizziness.
Alexithymia is a personality trait characterized by deficits in regulating, experiencing and verbalizing emotions and has been assumed to be associated with a tendency to express emotional arousal through somatization. Although such a tendency is often observed in patients with dizziness, the exact relationship of alexithymia to dizziness is not yet known. The aim of this study was to examine alexithymic characteristics in patients with dizziness and its relation to health-related quality of life (HRQoL). We assessed 208 patients from an interdisciplinary center for vertigo and balance disorders for characteristics of alexithymia (20-item Toronto Alexithymia Scale), HRQoL (Short-Form 12 Health Survey, SF-12), dizziness (Dizziness Handicap Inventory), depression and anxiety (Hospital Anxiety and Depression Scale). Hierarchical regression analyses were used to evaluate the relationship between alexithymia, dizziness and HRQoL. We found that difficulties in identifying and describing feelings, two important factors of alexithymia, were significantly related to more severe symptoms of dizziness. More pronounced alexithymic characteristics were associated with lower HRQoL, especially in the mental dimension of the SF-12. The results remained significant after controlling for possibly confounding variables such as socioeconomic status and depression. These findings contribute to a better understanding of affect regulation in patients with dizziness, which is important for the development of psychotherapeutic interventions suitable for alexithymic patients with dizziness.


The flight path of the phoenix--the visible trace of invisible elements in human vision.
How features are attributed to objects is one of the most puzzling issues in the neurosciences. A deeply entrenched view is that features are perceived at the locations where they are presented. Here, we show that features in motion displays can be systematically attributed from one location to another although the elements possessing the features are invisible. Furthermore, features can be integrated across locations. Feature mislocalizations are usually treated as errors and limits of the visual system. On the contrary, we show that the nonretinotopic feature attributions, reported herein, follow rules of grouping precisely suggesting that they reflect a fundamental computational strategy and not errors of visual processing.


An evaluation of the level of satisfaction with a dedicated inpatient venepuncture service at a rehabilitation centre.
The purpose of this prospective observational study was to determine the levels of satisfaction of the three main 'customers' of a dedicated inpatient venepuncture service at a rehabilitation centre, namely the patients, medical staff and nursing staff. The venepuncture service was delivered by two part-time nurses. One hundred and six patients, 14 medical staff and 35 nurses participated in the study. Three purpose-designed surveys were administered to investigate levels of satisfaction. High degrees of satisfaction were reported by all three 'customer' groups. Patients were highly satisfied with the interpersonal skills of the venepuncture nurses and their ability to obtain blood on the first pass, medical staff agreed that a dedicated venepuncture service gave them more time to spend in patient care, and nursing staff believed that a dedicated venepuncture service caused less disruption to patients' daily schedule.


Role of nitric oxide in resveratrol-induced renal protective effects of ischemic preconditioning.
Resveratrol, a natural antioxidant and polyphenol found in red wine and grapes, has been found to pharmacologically precondition the heart through upregulation of nitric oxide (NO). This study was designed to explore the involvement of NO in the renoprotective effect of resveratrol in renal ischemic preconditioning in rat kidney. Ischemic preconditioning was induced by three cycles 2-minutes of ischemia followed by 5 minutes of reperfusion before 45 minutes of prolonged ischemia. Resveratrol was given 1 hour before the surgical procedures. Ischemic preconditioning and resveratrol treatment significantly improved the renal dysfunction, decrease in total NO levels, and oxidative stress induced by 45 minutes of ischemia followed by 24 hours of reperfusion. Histopatholgic examination of the kidneys of ischemic/reperfusion rats revealed severe renal damage, which was attenuated in both preconditioned and resveratrol-treated animals. Preconditioning and resveratrol administration led to a marked increase in NO levels in kidney. Renoprotective effects of resveratrol were abolished when animals were pretreated with NG-nitro-L-arginine methyl ester, a nonspecific NO synthase inhibitor. These findings demonstrate an important contributory role of NO in the protection afforded by resveratrol in renal ischemic preconditioning. It is now well established that brief periods of ischemia followed by reperfusion render a variety of tissues tolerant to subsequent ischemia/reperfusion-induced injury. This phenomenon, referred to as ischemic preconditioning, was first demonstrated in the dog myocardium. The potential for clinical application of such a powerful protective phenomenon has generated enormous interest in identifying the underlying intracellular signaling pathways, with the ultimate aim of pharmacologically exploiting these mechanisms to develop therapeutic strategies that can enhance tolerance to ischemia/reperfusion injury in patients. This study explored the possible involvement of nitric oxide in renal ischemic preconditioning.


Blue-conversion of organic dyes produces artifacts in multicolor fluorescence imaging.
Multicolor fluorescence imaging is a powerful tool visualizing the spatiotemporal relationship among biomolecules. Here, we report that commonly employed organic dyes exhibit a blue-conversion phenomenon, which can produce severe multicolor image artifacts leading to false-positive colocalization by invading predefined spectral windows, as demonstrated in the case study using EGFR and Tensin2. These multicolor image artifacts become much critical in localization-based superresolution microscopy as the blue-converted dyes are photoactivatable. We provide a practical guideline for the use of organic dyes for multicolor imaging to prevent artifacts derived by blue-conversion.


Microtissue size and hypoxia in HTS with 3D cultures.
The three microenvironmental factors that characterize 3D cultures include: first, chemical and/or biochemical composition, second, spatial and temporal dimensions, and third, force and/or substrate physical properties. Although these factors have been studied individually, their interdependence and synergistic interactions have not been well appreciated. We make this case by illustrating how microtissue size (spatial) and hypoxia (chemical) can be used in the formation of physiologically more relevant constructs (or not) for cell-based high-throughput screening (HTS) in drug discovery. We further show how transcriptomic and/or proteomic results from heterogeneously sized microtissues and scaffold architectures that deliberately control hypoxia can misrepresent and represent in vivo conditions, respectively. We offer guidance, depending on HTS objectives, for rational 3D culture platform choice for better emulation of in vivo conditions.


The use of recombinant luteinizing hormone in patients undergoing assisted reproductive techniques with advanced reproductive age: a systematic review and meta-analysis.
To evaluate the effect of recombinant LH in assisted reproduction technology (ART) cycles in patients of advanced reproductive age. A systematic review and meta-analysis. Published randomized controlled clinical trials comparing recombinant LH plus recombinant FSH versus recombinant FSH only in patients of advanced reproductive age. Patients 35 years and older undergoing assisted reproduction. Recombinant LH plus recombinant FSH controlled ovarian hyperstimulation (COH) versus recombinant FSH stimulation only in assisted reproduction cycles. Implantation and clinical pregnancy. Seven trials were identified that met inclusion criteria and comprised 902 assisted reproduction technology cycles. No differences in serum E(2) on the day of hCG administration were reported in any trials. Two trials reported lower oocyte yield and one trial reported lower metaphase II oocyte yield in the recombinant LH-supplemented group. One trial reported higher fertilization rates in the recombinant LH-supplemented group. In a fixed effect model, implantation was higher in the recombinant LH-supplemented group (odds ratio 1.36, 95% confidence interval 1.05-1.78). Similarly, clinical pregnancy was increased in the recombinant LH-supplemented group (odds ratio 1.37, 95% confidence interval 1.03-1.83). The addition of recombinant LH to ART cycles may improve implantation and clinical pregnancy in patients of advanced reproductive age.


Assessment of changes in formations of non-forest woody vegetation in southern Denmark based on airborne LiDAR.
LiDAR (Light Detection and Ranging) is a remote sensing technology that uses light in the form of pulses to measure the range between a sensor and the Earth's surface. Recent increase in availability of airborne LiDAR scanning (ALS) data providing national coverage with high point densities has opened a wide range of possibilities for monitoring landscape elements and their changes at broad geographical extent. We assessed the dynamics of the spatial extent of non-forest woody vegetation (NFW) in a study area of approx. 2500 km2 in southern Jutland, Denmark, based on two acquisitions of ALS data for 2006 and 2014 in combination with other spatial data. Our results show a net-increase (4.8%) in the total area of NFW. Furthermore, this net change comprises of both areas with a decrease and areas with an increase of NFW. An accuracy assessment based on visual interpretation of aerial photos indicates high accuracy (>95%) in the delineation of NFW without changes during the study period. For NFW that changed between 2006 and 2014, accuracies were lower (90 and 82% in removed and new features, respectively), which is probably due to lower point densities of the 2006 ALS data (0.5 pts./m2) compared to the 2014 data (4-5 pts./m2). We conclude that ALS data, if combined with other spatial data, in principle are highly suitable for detailed assessment of changes in landscape features, such as formations of NFW at broad geographical extent. However, in change assessment based on multi-temporal ALS data with different point densities errors occur, particularly when examining small or narrow NFW objects.


Cannabinoids in Chronic Non-Cancer Pain: A Systematic Review and Meta-Analysis.
For patients with chronic, non-cancer pain, traditional pain-relieving medications include opioids, which have shown benefits but are associated with increased risks of addiction and adverse effects. Medical cannabis has emerged as a treatment alternative for managing these patients and there has been a rise in the number of randomized clinical trials in recent years; therefore, a systematic review of the evidence was warranted. To analyze the evidence surrounding the benefits and harms of medical cannabinoids in the treatment of chronic, non-cancer-related pain. Systematic review with meta-analysis. Medline, Embase, CINAHL, SCOPUS, Google Scholar, and Cochrane Databases. English language randomized clinical trials of cannabinoids for the treatment of chronic, non-cancer-related pain. Study quality was assessed using the Cochrane risk of bias tool. All stages were conducted independently by a team of 6 reviewers. Data were pooled through meta-analysis with different durations of treatment (2 weeks, 2 months, 6 months) and stratified by route of administration (smoked, oromucosal, oral), conditions, and type of cannabinoids. Patient-reported pain and adverse events (AEs). Thirty-six trials (4006 participants) were included, examining smoked cannabis (4 trials), oromucosal cannabis sprays (14 trials), and oral cannabinoids (18 trials). Compared with placebo, cannabinoids showed a significant reduction in pain which was greatest with treatment duration of 2 to 8 weeks (weighted mean difference on a 0-10 pain visual analogue scale -0.68, 95% confidence interval [CI], -0.96 to -0.40, I 2 = 8%, P < .00001; n = 16 trials). When stratified by route of administration, pain condition, and type of cannabinoids, oral cannabinoids had a larger reduction in pain compared with placebo relative to oromucosal and smoked formulations but the difference was not significant (P[interaction] > .05 in all the 3 durations of treatment); cannabinoids had a smaller reduction in pain due to multiple sclerosis compared with placebo relative to other neuropathic pain (P[interaction] = .05) within 2 weeks and the difference was not significant relative to pain due to rheumatic arthritis; nabilone had a greater reduction in pain compared with placebo relative to other types of cannabinoids longer than 2 weeks of treatment but the difference was not significant (P[interaction] > .05). Serious AEs were rare, and similar across the cannabinoid (74 out of 2176, 3.4%) and placebo groups (53 out of 1640, 3.2%). There was an increased risk of non-serious AEs with cannabinoids compared with placebo. There was moderate evidence to support cannabinoids in treating chronic, non-cancer pain at 2 weeks. Similar results were observed at later time points, but the confidence in effect is low. There is little evidence that cannabinoids increase the risk of experiencing serious AEs, although non-serious AEs may be common in the short-term period following use.


Epoetin Alfa and Outcomes in Dialysis amid Regulatory and Payment Reform.
Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anemia in patients with CKD, including those receiving dialysis, although clinical trials have identified risks associated with ESA use. We evaluated the effects of changes in dialysis payment policies and product labeling instituted in 2011 on mortality and major cardiovascular events across the United States dialysis population in an open cohort study of patients on dialysis from January 1, 2005, through December 31, 2012, with Medicare as primary payer. We compared observed rates of death and major cardiovascular events in 2011 and 2012 with expected rates calculated on the basis of rates in 2005-2010, accounting for differences in patient characteristics and influenza virulence. An abrupt decline in erythropoietin dosing and hemoglobin concentration began in late 2010. Observed rates of all-cause mortality, cardiovascular mortality, and myocardial infarction in 2011 and 2012 were consistent with expected rates. During 2012, observed rates of stroke, venous thromboembolic disease (VTE), and heart failure were lower than expected (absolute deviation from trend per 100 patient-years [95% confidence interval]: -0.24 [-0.08 to -0.37] for stroke, -2.43 [-1.35 to -3.70] for VTE, and -0.77 [-0.28 to -1.27] for heart failure), although non-ESA-related changes in practice and Medicare payment penalties for rehospitalization may have confounded the results. This initial evidence suggests that action taken to mitigate risks associated with ESA use and changes in payment policy did not result in a relative increase in death or major cardiovascular events and may reflect improvements in stroke, VTE, and heart failure.


The Role of PTEN in Innate and Adaptive Immunity.
The lipid and protein phosphatase and tensin homolog (PTEN) controls the differentiation and activation of multiple immune cells. PTEN acts downstream from T- and B-cell receptors, costimulatory molecules, cytokine receptors, integrins, and also growth factor receptors. Loss of PTEN activity in human and mice is associated with cellular and humoral immune dysfunction, lymphoid hyperplasia, and autoimmunity. Although most patients with PTEN hamartoma tumor syndrome (PHTS) have no immunological symptoms, a subclinical immune dysfunction is present in many, and clinical immunodeficiency in few. Comparison of the immune phenotype caused by PTEN haploinsufficiency in PHTS, phosphoinositide 3-kinase (PI3K) gain-of-function in activated PI3K syndrome, and mice with conditional biallelic Pten deletion suggests a threshold model in which coordinated activity of several phosphatases control the PI3K signaling in a cell-type-specific manner. Emerging evidence highlights the role of PTEN in polygenic autoimmune disorders, infection, and the immunological response to cancer. Targeting the PI3K axis is an emerging therapeutic avenue.


An Epstein-Barr virus transforming protein associates with vimentin in lymphocytes.
The Epstein-Barr virus (EBV) latent infection membrane protein (LMP) is likely to be an important mediator of EBV-induced cell proliferation, since it is one of the few proteins encoded by the virus in latent infection and since production of this protein in Rat-1 cells results in their conversion to a fully transformed phenotype. LMP was previously noted to localize to patches at the cell periphery. In this paper we examine the basis of LMP patching in EBV-infected, transformed lymphocytes. Our data indicate that LMP is associated with the cytoskeletal protein vimentin. Although LMP is fully soluble in isotonic Triton X-100 buffer, only 50% of it is extracted from cells in this solution. The rest remains bound to the cytoskeleton. LMP undergoes phosphorylation, and phosphorylated LMP is preferentially associated with the cytoskeleton. As judged by both immunofluorescence and immunoelectron microscopy, the vimentin network in EBV-transformed lymphocytes or EBV-infected Burkitt tumor lymphocytes is abnormal. Vimentin and LMP often colocalize in a single patch near the plasma membrane. In response to Colcemid treatment of EBV-infected cells, vimentin reorganizes into perinuclear rings, as it does in uninfected cells. LMP is associated with these perinuclear rings. Vimentin (or a vimentin-associated protein) may be a transducer of an LMP transmembrane effect in lymphoproliferation.


Multiple perspectives on symptom interpretation in primary care research.
Assessment and management of symptoms is a main task in primary care. Symptoms may be defined as 'any subjective evidence of a health problem as perceived by the patient'. In other words, symptoms do not appear as such; symptoms are rather the result of an interpretation process. We aim to discuss different perspectives on symptom interpretation as presented in the disciplines of biomedicine, psychology and anthropology and the possible implications for our understanding of research on symptoms in relation to prevalence and diagnosis in the general population and in primary care. Symptom experiences are embedded in a complex interplay between biological, psychological and cultural factors. From a biomedical perspective, symptoms are seen as possible indicators of disease and are characterized by parameters related to seriousness (e.g. appearance, severity, impact and temporal aspects). However, such symptom characteristics are rarely unambiguous, but merely indicate disease probability. In addition, the GP's interpretation of presenting symptoms will also be influenced by other factors. From a psychological perspective, factors affecting interpretation are in focus (e.g. internal frame of reference, attention to sensations, illness perception and susceptibility to suggestion). These individual factors cannot stand alone either, but are influenced by the surroundings. Anthropological research suggests that personal experiences and culture form a continuous feedback relationship which influence when and how sensations are understood as symptoms of disease and acted upon. The different approaches to symptom interpretation imply that we need to be cautious and conscious when interpreting survey findings that are based on symptom prevalence in the general population or in primary care. These findings will reflect a variety of interpretations of sensations, which are not equivalent to expressions of underlying disease. Furthermore, if diagnosis of disease is based exclusively on the presence of specific symptom characteristics, we may risk reinforcing a dualistic approach, including medicalisation of normal phenomena and devaluation of medically unexplained symptoms. Future research in primary care could gain from exploring symptoms as a generic phenomenon and raised awareness of symptom complexity.


Application of solar disinfection for treatment of contaminated public water supply in a developing country: field observations.
A sustainable and low-cost point-of-use household drinking water solar disinfection (SODIS) technology was successfully applied to treat microbiologically contaminated water. Field experiments were conducted to determine the efficiency of SODIS and evaluate the potential benefits and limitations of SODIS under local climatic conditions in Karachi, Pakistan. In order to enhance the efficiency of SODIS, the application of physical interventions were also investigated. Twenty per cent of the total samples met drinking water guidelines under strong sunlight weather conditions, showing that SODIS is effective for complete disinfection under specific conditions. Physical interventions, including black-backed and reflecting rear surfaces in the batch reactors, enhanced SODIS performance. Microbial regrowth was also investigated and found to be more controlled in reactors with reflective and black-backed surfaces. The transfer of plasticizer di(2-ethylhexyl)phthalate (DEHP) released from the bottle material polyethylene terephthalate (PET) under SODIS conditions was also investigated. The maximum DEHP concentration in SODIS-treated water was 0.38 μg/L less than the value of 0.71 μg/L reported in a previous study and well below the WHO drinking-quality guideline value. Thus SODIS-treated water can successfully be used by the people living in squatter settlements of mega-cities, such as Karachi, with some limitations.


Tunable band offsets in the BP/P4O10 van der Waals heterostructure: first-principles calculations.
The structural and electronic properties of the black phosphorus/phosphorus pentoxide (BP/P4O10) van der Waals (vdW) heterostructure are investigated theoretically by first-principles calculations. The BP/P4O10 vdW heterostructure is a direct bandgap semiconductor with intrinsic type-II band alignment thus facilitating separation of photoexcited charge carriers. A transition from semiconducting to metallic is predicted under a positive electric field and the transition of type-II to type-I band alignment occurs under a negative electric field in the BP/P4O10 vdW heterostructure. Moreover, the bandgap can be modulated by adjusting the interlayer distance. The results indicate that the band offsets of the BP/P4O10 vdW heterostructure are tunable, consequently boding well for application to nanoelectronics and optoelectronics.


Multipath ultrasonic gas flow-meter based on multiple reference waves.
Several technologies can be used in ultrasonic gas flow-meters, such as transit-time, Doppler, cross-correlation and etc. In applications, the approach based on measuring transit-time has demonstrated its advantages and become more popular. Among those techniques which can be applied to determine time-of-flight (TOF) of ultrasonic waves, including threshold detection, cross correlation algorithm and other digital signal processing algorithms, cross correlation algorithm has more advantages when the received ultrasonic signal is severely disturbed by the noise. However, the reference wave for cross correlation computation has great influence on the precise measurement of TOF. In the applications of the multipath flow-meters, selection of the reference wave becomes even more complicated. Based on the analysis of the impact factors that will introduce noise and waveform distortion of ultrasonic waves, an averaging method is proposed to determine the reference wave in this paper. In the multipath ultrasonic gas flow-meter, the analysis of each path of ultrasound needs its own reference wave. In case study, a six-path ultrasonic gas flow-meter has been designed and tested with air flow through the pipeline. The results demonstrate that the flow rate accuracy and the repeatability of the TOF are significantly improved by using averaging reference wave, compared with that using random reference wave.


Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution.
The distribution of adipose tissue thickness, fat cell weight (FCW), and number (FCN) were studied in four regions in randomly selected middle-aged men and women and in 930 obese individuals. Both the obese and the randomly selected men were found to have the largest adipose tissue thickness in the abdominal region. Women, however, showed a relative preponderance for the gluteal and femoral regions. FCW increased with expanding body fat up to a maximal size of approximately 0.7-0.8 micrograms/cell in each region. After this increase in FCW, a more rapid increase in FCN was found. For the same degree of relative overweight, men had higher triglyceride, fasting glucose, and insulin levels; higher sums of glucose and insulin levels during an oral glucose tolerance test; and higher blood pressure. Furthermore, elevated fasting glucose levels (greater than 7.4 mM) occurred twice as often in the males. These differences between males and females persisted even after body fat matching. A male risk profile was seen in women characterized by abdominal obesity (high waist/hip circumference ratio) as compared to women with the typical peripheral obesity. Stepwise multiple regression analyses in both women and men showed the obesity complications to be associated in a first step to waist/hip circumference or body fat and in a second to abdominal fat cell size. It may thus be concluded that: (a) In both obese and nonobese subjects, regional differences exist between the sexes with regard to adipose tissue distribution. (b) Moderate expansion of body fat is mainly due to FCW enlargement, which is subsequently followed by increased FCN. (c) Men and women with a male abdominal type of obesity are more susceptible to the effect of excess body fat on lipid and carbohydrate metabolism.


Treatment effects produced by preorthodontic trainer appliance in patients with class II division I malocclusion.
The aim of the present study was to evaluate cephalometrically the treatment effects of preorthodontic trainer on dentoskeletal components in individuals showing class II division I malocclusion. This study comprised of 50 class II div. I patients (20 test patients and 30 controls) in the age group of 8-12 years. The test group was treated with a preorthodontic trainer for a period of 15 months. Standardized lateral cephalograms of both groups were taken before and after the treatment period. The cephalograms were then evaluated to determine the skeletal and dental changes in the course of treatment and then compared with the normative growth data to eliminate the possible growth effects. The readings were tabulated and subjected to statistical analysis. The results of the study after excluding the changes due to growth showed reduction in ANB and OP-SN values, indicating a significant reduction in the skeletal class II relationship. An upward cant of the occlusal plane in the treatment group was noted, probably due to the forward rotation of mandible. A significant increase in the vertical dimensions of the face in general and the mandible in particular was observed with the use of preorthodontic trainer. A significant reduction in the overjet and an increase in the inclination of mandibular incisor (L1-NB deg) were noted in the treatment group when compared with control group. It can be concluded that class II corrections can be achieved with the preorthodontic trainer appliance, which appears to have mostly dentoalveolar effects with smaller but significant skeletal effects.


P73 regulates cisplatin-induced apoptosis in ovarian cancer cells via a calcium/calpain-dependent mechanism.
P73 is important in drug-induced apoptosis in some cancer cells, yet its role in the regulation of chemosensitivity in ovarian cancer (OVCA) is poorly understood. Furthermore, if and how the deregulation of p73-mediated apoptosis confers resistance to cisplatin (CDDP) treatment is unclear. Here we demonstrate that TAp73α over-expression enhanced CDDP-induced PARP cleavage and apoptosis in both chemosensitive (OV2008 and A2780s) and their resistant counterparts (C13* and A2780cp) and another chemoresistant OVCA cells (Hey); in contrast, the effect of ΔNp73α over-expression was variable. P73α downregulation attenuated CDDP-induced PUMA and NOXA upregulation and apoptosis in OV2008 cells. CDDP decreased p73α steady-state protein levels in OV2008, but not in C13*, although the mRNA expression was identical. CDDP-induced p73α downregulation was mediated by a calpain-dependent pathway. CDDP induced calpain activation and enhanced its cytoplasmic interaction and co-localization with p73α in OV2008, but not C13* cells. CDDP increased the intracellular calcium concentration ([Ca(2+)](i)) in OV2008 but not C13* whereas cyclopiazonic acid (CPA), a Ca(2+)-ATPase inhibitor, caused this response and calpain activation, p73α processing and apoptosis in both cell types. CDDP-induced [Ca(2+)](i) increase in OV2008 cells was not effected by the elimination of extracellular Ca(2+), but this was attenuated by the depletion of internal Ca(2+) store, indicating that mobilization of intracellular Ca(2+]) stores was potentially involved. These findings demonstrate that p73α and its regulation by the Ca(2+)-mediated calpain pathway are involved in CDDP-induced apoptosis in OVCA cells and that dysregulation of Ca(2+)/calpain/p73 signaling may in part be the pathophysiology of CDDP resistance. Understanding the cellular and molecular mechanisms of chemoresistance will direct the development of effective strategies for the treatment of chemoresistant OVCA.


Profiling of generic anti-phosphopeptide antibodies and kinases with peptide microarrays using radioactive and fluorescence-based assays.
Kinases represent one of the largest enzyme families and key regulatory proteins in the cell. Only a small subset of these enzymes has been characterised so far. We have prepared different types of phosphopeptide and peptide microarrays displaying peptides deduced from annotated human phosphorylation sites and cytoplasmic domains of all annotated human membrane proteins. This approach was enabled by fully-automated high throughput micro-scale synthesis of peptides by the SPOT technology combined with chemo-selective immobilisation on modified glass slides. The phosphopeptide microarrays displaying 2923 peptides in total have been used for the characterisation of commercially available generic anti-phosphopeptide antibodies. This enabled us to detect Abl kinase activity on a microarray with anti-phosphotyrosine antibodies yielding results comparable to those obtained from a radioactive assay. More than 13 000 peptides deposited on six glass slides were used to profile casein kinase 2 (CK2) using a radioactive assay, since no generic antibody for the reliable detection of serine or threonine phosphorylation could be identified. All previously identified substrates were detected in the microarray experiment. In order to confirm whether substrates on the microarray are substrates in solution phase assays, more than 700 peptides were synthesised and tested with CK2 in a solution phase assay. All substrates identified in the solution phase assay were also detected on the microarray.


A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding.
Antibody treatment is currently the only available countermeasure for botulism, a fatal illness caused by flaccid paralysis of muscles due to botulinum neurotoxin (BoNT) intoxication. Among the seven major serotypes of BoNT/A-G, BoNT/A poses the most serious threat to humans because of its high potency and long duration of action. Prior to entering neurons and blocking neurotransmitter release, BoNT/A recognizes motoneurons via a dual-receptor binding process in which it engages both the neuron surface polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Previously, we identified a potent neutralizing antitoxin against BoNT/A1 termed ciA-C2, derived from a camelid heavy-chain-only antibody (VHH). In this study, we demonstrate that ciA-C2 prevents BoNT/A1 intoxication by inhibiting its binding to neuronal receptor SV2. Furthermore, we determined the crystal structure of ciA-C2 in complex with the receptor-binding domain of BoNT/A1 (HCA1) at 1.68 Å resolution. The structure revealed that ciA-C2 partially occupies the SV2-binding site on HCA1, causing direct interference of HCA1 interaction with both the N-glycan and peptide-moiety of SV2. Interestingly, this neutralization mechanism is similar to that of a monoclonal antibody in clinical trials, despite that ciA-C2 is more than 10-times smaller. Taken together, these results enlighten our understanding of BoNT/A1 interactions with its neuronal receptor, and further demonstrate that inhibiting toxin binding to the host receptor is an efficient countermeasure strategy.


Attention deficit hyperactivity disorder among inmates in Bergen Prison.
The aim of this study was to investigate whether clinical findings are consistent with research indicating a high prevalence of attention deficit hyperactivity disorder (ADHD) among prison inmates. Forty-three male inmates who were referred for ADHD assessment at the health service in Bergen prison participated. Although most of them reported symptoms in accordance with ADHD both in childhood and adulthood, only 35% of the referred inmates fulfilled the criteria for ADHD when a comprehensive assessment was conducted. The results emphasize the importance of a comprehensive assessment when diagnosing ADHD among prison inmates.


Intersensory selective attention and temporal orienting operate in parallel and are instantiated in spatially distinct sensory and motor cortices.
Knowledge about the sensory modality in which a forthcoming event might occur permits anticipatory intersensory attention. Information as to when exactly an event occurs enables temporal orienting. Intersensory and temporal attention mechanisms are often deployed simultaneously, but as yet it is unknown whether these processes operate interactively or in parallel. In this human electroencephalography study, we manipulated intersensory attention and temporal orienting in the same paradigm. A continuous stream of bisensory visuo-tactile inputs was presented, and a preceding auditory cue indicated to which modality participants should attend (visual or tactile). Temporal orienting was manipulated blockwise by presenting stimuli either at regular or irregular intervals. Using linear beamforming, we examined neural oscillations at virtual channels in sensory and motor cortices. Both attentional processes simultaneously modulated the power of anticipatory delta- and beta-band oscillations, as well as delta-band phase coherence. Modulations in sensory cortices reflected intersensory attention, indicative of modality-specific gating mechanisms. Modulations in motor and partly in somatosensory cortex reflected temporal orienting, indicative of a supramodal preparatory mechanism. We found no evidence for interactions between intersensory attention and temporal orienting, suggesting that these two mechanisms act in parallel and largely independent of each other in sensory and motor cortices.


B-Hπ: a nonclassical hydrogen bond or dispersion contact?
Close B-Hπ contacts have recently been observed in crystallographic structures of Ir-dithiolene-phosphine complexes containing boron hydride cluster. This finding was interpreted using quantum chemical calculations as a new type of electrostatically driven nonclassical hydrogen bonding. However, such an explanation contradicts the wealth of evidence for unique noncovalent interactions of boron hydrides. Moreover, care must be exercised when computational methods are used to interpret new phenomena. Therefore, here, we cautiously examine the B-Hπ interaction by means of advanced quantum chemistry and disprove the claimed attractive electrostatic nature and rather define it as a nonspecific dispersion-driven contact. In summary, we present evidence that the crystallographically observed B-Hπ contacts do not constitute a novel type of hydrogen bonding of boron hydride clusters.


Effects of research complexity and competition on the incidence and growth of coauthorship in biomedicine.
Investigations into the factors behind coauthorship growth in biomedical research have mostly focused on specific disciplines or journals, and have rarely controlled for factors in combination or considered changes in their effects over time. Observers often attribute the growth to the increasing complexity or competition (or both) of research practices, but few attempts have been made to parse the contributions of these two likely causes. We aimed to assess the effects of complexity and competition on the incidence and growth of coauthorship, using a sample of the biomedical literature spanning multiple journals and disciplines. Article-level bibliographic data from PubMed were combined with publicly available bibliometric data from Web of Science and SCImago over the years 1999-2007. We selected four predictors of coauthorship were selected, two (study type, topical scope of the study) associated with complexity and two (financial support for the project, popularity of the publishing journal) associated with competition. A negative binomial regression model was used to estimate the effects of each predictor on coauthorship incidence and growth. A second, mixed-effect model included the journal as a random effect. Coauthorship increased at about one author per article per decade. Clinical trials, supported research, and research of broader scope produced articles with more authors, while review articles credited fewer; and more popular journals published higher-authorship articles. Incidence and growth rates varied widely across journals and were themselves uncorrelated. Most effects remained statistically discernible after controlling for the publishing journal. The effects of complexity-associated factors held constant or diminished over time, while competition-related effects strengthened. These trends were similar in size but not discernible from subject-specific subdata. Coauthorship incidence rates are multifactorial and vary with factors associated with both complexity and competition. Coauthorship growth is likewise multifactorial and increasingly associated with research competition.


Induction of STAT3-related genes in fast degenerating cone photoreceptors of cpfl1 mice.
Cone dystrophies are genetic diseases characterized by loss of cone photoreceptor function and severe impairment of daylight vision. Loss of function is accompanied by a progressive degeneration of cones limiting potential therapeutic interventions. In this study we combined microarray-based gene-expression analysis with electroretinography and immunohistochemistry to characterize the pathological processes in the cone photoreceptor function loss 1 (cpfl1) mouse model. The cpfl1-mouse is a naturally arising mouse mutant with a loss-of-function mutation in the cone-specific Pde6c gene. Cpfl1-mice displayed normal rod-specific light responses while cone-specific responses were strongly diminished. Despite the lack of a general retinal degeneration, the cone-specific functional defect resulted in a marked activation of GFAP, a hallmark of Müller-cell gliosis. Microarray-based network-analysis confirmed activation of Müller-glia-specific transcripts. Unexpectedly, we found up-regulation of the cytokine LIF and the anti-apoptotic transcription factor STAT3 in cpfl1 cone photoreceptors. We postulate that STAT3-related pathways are induced in cpfl1 cone photoreceptors to counteract degeneration.


Using neural networks as an aid in the determination of disease status: comparison of clinical diagnosis to neural-network predictions in a pedigree with autosomal dominant limb-girdle muscular dystrophy.
Studies of the genetics of certain inherited diseases require expertise in the determination of disease status even for single-locus traits. For example, in the diagnosis of autosomal dominant limb-girdle muscular dystrophy (LGMD1A), it is not always possible to make a clear-cut determination of disease, because of variability in the diagnostic criteria, age at onset, and differential presentation of disease. Mapping such diseases is greatly simplified if the data present a homogeneous genetic trait and if disease status can be reliably determined. Here, we present an approach to determination of disease status, using methods of artificial neural-network analysis. The method entails "training" an artificial neural network, with input facts (based on diagnostic criteria) and related results (based on disease diagnosis). The network contains weight factors connecting input "neurons" to output "neurons," and these connections are adjusted until the network can reliably produce the appropriate outputs for the given input facts. The trained network can be "tested" with a second set of facts, in which the outcomes are known but not provided to the network, to see how well the training has worked. The method was applied to members of a pedigree with LGMD1A, now mapped to chromosome 5q. We used diagnostic criteria and disease status to train a neural network to classify individuals as "affected" or "not affected." The trained network reproduced the disease diagnosis of all individuals of known phenotype, with 98% reliability. This approach defined an appropriate choice of clinical factors for determination of disease status. Additionally, it provided insight into disease classification of those considered to have an "unknown" phenotype on the basis of standard clinical diagnostic methods.