Hypoalbuminemia accelerates erythrocyte membrane lipid peroxidation in chronic hemodialysis patients.
Persistent hypoalbuminemia is a long-term poor prognostic factor in chronic hemodialysis patients. We investigated the correlation between the degree of peroxidation of erythrocyte membrane lipids, erythrocyte alpha tocopherol content, erythrocyte glutathione peroxidase activity and serum albumin concentration in twelve patients with uremia not undergoing hemodialysis and fifteen patients on maintenance hemodialysis. The glutathione peroxidase activity in erythrocytes was higher in patients of uremia not undergoing hemodialysis than in chronic hemodialysis patients. A significant negative correlation was observed between the erythrocyte alpha tocopherol content and the degree of erythrocyte membrane lipid peroxidation in chronic hemodialysis patients. There was a statistically significant difference in the degree of erythrocyte membrane lipid peroxidation between patients with chronic hemodialysis-associated hypoalbuminemia and chronic hemodialysis patients having normal serum albumin levels. This study suggested that serum albumin inhibits peroxidation of erythrocyte membrane lipids and that hemodialysis induces recovery of serum reductivity. We conclude that persistent hypoalbuminemia worsens the serum antioxidant activity in chronic hemodialysis patients and may contribute to increased oxidative cell damage.


Cystic artery pseudoaneurysm following acute necrotising pancreatitis.
Cystic artery pseudoaneurysm is a rare pathology. Of the 20 cases reported so far, chronic cholecystitis and iatrogenic biliary injury form the majority of causes. Currently, there is no published report of such pseudoaneurysms caused secondary to pancreatitis, hence the management in such a scenario is unclear. We hereby present the first such report of cystic artery pseudoaneurysm occurring as a sequel of acute necrotising pancreatitis. A 33-year-old man who recovered from a recent attack of acute pancreatitis was readmitted for melena and fever. Computed tomography of abdomen revealed blood in the gall bladder with pericholecystic blush and resolving pancreatic necrosis. Percutaneous transarterial embolisation of the cystic artery was done. This stabilised the patient but persistent sepsis and clinical deterioration warranted a surgical exploration and cholecystostomy. Hence, transarterial embolisation followed by surgery in selected cases can be an ideal management protocol.


Mesangial cell apoptosis induced by stimulation of the adenosine A3 receptor: signaling and apoptotic events.
Mesangial cell apoptosis has been proposed as a means of resolution of glomerular hypercellularity in proliferative forms of glomerular disease. We previously demonstrated that adenosine causes mesangial cell apoptosis by stimulating the A3-type adenosine receptor. This is a G protein-coupled receptor shown to activate kinases involved in apoptotic signaling. In this work, we assessed changes in phosphorylation of the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK)1/2 and in levels of specific pro- and antiapoptotic proteins following exposure of mesangial cells to the A3 adenosine receptor agonist N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA). Cultured mesangial cells were incubated with IB-MECA for 30 minutes and 6, 24, and 48 hours. IB-MECA was used at a concentration (30 microM) that induces a reproducible degree of mesangial cell apoptosis. Changes in ERK1/2 phosphorylation and in protein levels of Bcl-2, Bax, and caspase 3 were assessed by Western blot analysis. IB-MECA markedly increased phosphorylation of ERK1/2. This effect peaked at 5 minutes, dissipated by 20 minutes, and was abolished by the inhibitor of ERK phosphorylation, compound U0126, in a dose-dependent manner. This inhibitor had no effect on the extent of IB-MECA-induced apoptosis. Bcl-2 levels progressively declined, whereas those of Bax and activated caspase 3 increased. These observations indicate that stimulation of the A3-type adenosine receptor causes mesangial cell apoptosis via mechanisms independent of ERK activation. The observations also point to an imbalance in the expression of antiapoptotic (Bcl-2) and proapoptotic (Bax, caspase 3) proteins as a potential mechanism underlying adenosine-induced mesangial cell apoptosis.


A new microphone system for near whispering.
A new microphone system was developed to monitor the human voice near the microphone in a noisy environment. The system is equipped with two special functions in addition to the usual microphone functions: reduction of air-blow effects by the mouth and focused reception to a sound source. A wind filter was developed to reduce the air-blow effects from the mouth during speaking. This filter is a plate perforated by an array of small holes; the method used to design the filter is also presented. To achieve focused reception, four microphones were used in conjunction with a new signal-processing method. The proposed signal-processing method effectively increases the directivity in the desired direction. Additionally, it provides the system with focusing on the source since the source is located adjacent to the system. A prototype of the proposed system was fabricated and subjected to performance tests. The results showed that air-blow effects can be reduced by up to 20 dB and the directional gain is more than 4 dB. The proposed microphone system shows such good performance that it can be used in mobile phones for whispering communication.


Angiotensin II receptor content within the circumventricular organs increases after experimental hydrocephalus in rats.
Hydrocephalus is known to cause various endocrinological abnormalities. These abnormalities are either though a direct effect on anterior hypothalamus or pituitary gland. However almost nothing is known about the effects of hydrocephalus on the intrinsic angiotensin system of the brain. The aim of this study is to investigate the effect of hydrocephalus on neurotransmitter-rich circumventricular organ systems. Such an effect was investigated by means of angiotensin receptor content in subfornical organ (SFO), organum vasculosum lamina terminalis (OVLT), area postrema (AP) and the median eminence (ME). Experimental hydrocephalus was created in rats by the intracisternal kaolin injection method as described by Shapiro et al. The receptor content was measured at 4-6 weeks by in-vitro autoradiography method as described by Israel et al. Angiotensin II receptor content in hydrocephalic animals was found to be statistically increased in SFO, OVLT and ME but not in AP when compared with the normal animals. Receptor content was found to have increased by 182.4% at SFO, 76.7% at ME, 7.7% at AP and 22.1% at OVLT after kaolin injection. These findings may indicate the possible role of CVO's on pathological conditions such as hydrocephalus.


Functional parathyroid cyst: a rare cause of malignant hypercalcemia with primary hyperparathyroidism-a case report and review of the literature.
Parathyroid cysts are rare lesions found in the neck and anterior mediastinum. They are often nonfunctional (>90%) and rarely in the functional form. This paper discusses a case of severe hypercalcemia (23 mg/dL) secondary to a rare functional parathyroid cyst. The patient was later found to have a hemorrhagic cyst with compression of the right recurrent laryngeal nerve. Preoperative diagnosis of the lesion was parathyroid carcinoma. However, reexploration of the parathyroid mass along with microscopic study confirmed the diagnosis of a parathyroid cyst. Following cystectomy, the patient restored her baseline functional status with preservation of the right recurrent laryngeal nerve. Postoperative followup three years later showed no evidence of cyst recurrence. This paper illustrates the rare presentation of parathyroid functional cysts with severe hypercalcemia and primary hyperparathyroidism. Physicians should be aware of the presence of hemorrhage, inflammation, and compressive symptoms in these cysts which mimic parathyroid carcinoma. These patients should be managed with aggressive medical and surgical intervention.


Diffusion MRI and spectroscopy in Rasmussen's encephalitis.
The purpose of this study was to evaluate the diffusion MRI and proton MR spectroscopy findings in a rare disorder, Rasmussen's encephalitis. Diffusion MRI studies of 3 cases of Rasmussen's encephalitis were performed using the echo-planar trace sequence (TR=5700 ms, TE=139.03 ms). The gradient-echo diffusion sequence, PSIF (TR=21.6 ms, TE=5 ms), which is a reverse FISP sequence, and proton MR spectroscopy (TR=1500 ms, TE=40 ms) were applied in two patients. The trace sequence revealed high apparent diffusion coefficient values at the diseased regions (1.21+/-0.13 x 10(-3) mm2/s), compared with normal parenchymal values in 12 control cases (0.84+/-0.09 x 10(-3) mm2/s), indicating increased motion of water molecules (disintegration of the tissue) in these regions. The PSIF sequence revealed pixel value differences between the two hemispheres. Proton MR spectroscopy revealed decreased N-acetyl aspartate peaks, compared with five control cases.


A study of children with learning disabilities and sensorimotor problems or let's not throw the baby out with the bathwater.
The 1986 position statement by the Board of Trustees fo the Council for Learning Disabilities called for a moratorium on the measurement and training of perceptual and perceptual-motor function as a part of services for children with learning disabilities (LD). Estimates in the literature, however, indicate that approximately 13% of children with LD exhibit motor deficits. Such children with motor or perceptual-motor problems are of ten referred to occupational therapy and found to have sensory integrative (SI) dysfunction; subsequently, they are treated with techniques aimed at remediating perceptual or sensorimotor dysfunction. Because the results of research concerned with the efficacy fo sensorimotor therapy are inconclusive and incomplete at this time, the position statement may be premature. Occupational therapists, however, must be aware of the statement and respond appropriately. In order to respond, they must have a better understanding of the nature of this subgroup of children with LD who have motor problems. the purpose fo this study was to assist in the definition of this population. Eighty children with LD between 5 years and 8 years 11 months were examined. They had been referred for occupational therapy at six centres in Southern Ontario. Results indicated that these children were similar to other children with LD in terms of gender and IQ distribution, developmental history, and academic achievement. The study population, however, tended to have less generalized emotional/behavioral disorder than the general population with LD. As expected, these children also had major deficits in gross and fine motor performance. A focus of the paper is on the importance of sensorimotor deficit for learning and self-concept in the child. Implications for both the position statement and practice and research in occupational therapy are discussed.


Quantum fidelity measures for mixed states.
Applications of quantum technology often require fidelities to quantify performance. These provide a fundamental yardstick for the comparison of two quantum states. While this is straightforward in the case of pure states, it is much more subtle for the more general case of mixed quantum states often found in practice. A large number of different proposals exist. In this review, we summarize the required properties of a quantum fidelity measure, and compare them, to determine which properties each of the different measures has. We show that there are large classes of measures that satisfy all the required properties of a fidelity measure, just as there are many norms of Hilbert space operators, and many measures of entropy. We compare these fidelities, with detailed proofs of their properties. We also summarize briefly the applications of these measures in teleportation, quantum memories and quantum computers, quantum communications, and quantum phase-space simulations.


Medical strategies for treatment of castration resistant prostate cancer (CRPC) docetaxel resistant.
Current landscape of treatment of castration-resistant prostate cancer (CRPC) has recently changed. Cabazitaxel, a new taxane with potential antineoplastic activity, has been approved by Food and Drug Administration (FDA) after docetaxel failure. In a phase III trial, cabazitaxel showed increased overall survival (OS) compared with mitoxantrone (15.1 vs. 12.7 mo, HR 0.70, 95% CI 0.59-0.83, p < 0.0001). Furthermore, chemotherapy is not the only strategy available: several studies have shown as CRPC remains dependent on androgen receptor function for growth. Abiraterone acetate, an irreversible inhibitor of CYP17, has also been approved by FDA after docetaxel failure. In a phase III trial comparing abiraterone acetate to placebo, abiraterone showed improvement in OS (14.8 vs. 10.4 mo, HR 0.65, 95% CI 0.54-0.77; p < 0.0001). This review will discuss current options and the ongoing trials for second-line treatment of CRPC including chemotherapy, hormonal therapies, antiangiogenetic and immune strategies.


Effect of inspiratory muscle fatigue on perception of effort during loaded breathing.
The present study examined the relationship between the intensity of the sense of effort during inspiratory threshold loading and the severity of inspiratory muscle fatigue. Studies were performed on normal subjects in whom the magnitude of airway pressure developed (Pm) and the duty cycle of breathing (TI/TT) were constrained to achieve a pressure-time integral (i.e., Pm/Pmax X TI/TT) 24% of maximum. In separate trials, the same pressure-time index (24%) was achieved using two widely different patterns of pressure magnitude and duty cycle to allow the effects of changes in the pattern of inspiratory muscle contraction on sensation and fatigue to be assessed. The intensity of the sense of effort was assessed using a category (Borg) scale. The severity of inspiratory muscle fatigue was assessed both from changes in the centroid frequency of the diaphragm electromyogram and from changes in the maximum static inspiratory pressure. Loaded breathing produced inspiratory muscle fatigue and a progressive increase in the sense of effort over time in all subjects. The rate at which the inspiratory muscles fatigued was the same with the two patterns of loading. In contrast, the rate of growth in the intensity of the sense of effort varied significantly as a function of the pattern of loaded breathing. The sense of effort increased at a faster rate with the high pressure-short duty cycle pattern of contraction as compared with the low pressure-long duty cycle pattern. As a result, the intensity of the sense of effort was not uniquely related to the severity of inspiratory muscle fatigue.(ABSTRACT TRUNCATED AT 250 WORDS)


EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma.
We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. We recruited 55 eligible participants from September 2010 to August 2012. mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. ACTRN12609000643279.


Blunted Hypercapnic Respiratory Drive Response in Subjects With Late-Onset Pompe Disease.
Patients with late-onset Pompe disease develop progressive hypercapnic respiratory failure that can be disproportionate to the respiratory muscle compromise and/or thoracic restriction. Although recent studies have reported the presence of a blunted hypercapnic respiratory response in some subjects with neuromuscular disorders and chronic hypercapnia, no study has evaluated the integrity of the respiratory drive in subjects with late-onset Pompe disease. Thus, we endeavor to determine the CO2 rebreathing response in subjects with late-onset Pompe disease. Respiratory muscle strength was assessed by measuring the maximum inspiratory pressure, and the maximum expiratory pressure. The maximum inspiratory pressure reflects the strength of the diaphragm and other inspiratory muscles, whereas the maximum expiratory pressure reflects the strength of the abdominal muscles and other expiratory muscles. We studied the hypercapnic drive response (measured as the ratio of the change in airway-occlusion pressure 0.1 s after the start of inspiration and end-tidal PCO2 in 13 subjects with late-onset Pompe disease and 51 healthy controls. Overall inspiratory muscle strength was within normal limits or slightly diminished in the late-onset Pompe disease group. Five subjects (38.5%) were chronically hypercapnic, and 9 (69.2%) had an increased breath-holding time. Compared with controls, the change in airway-occlusion pressure 0.1 s/change in end-tidal CO2 pressure slope (hypercapnic respiratory drive) was lower in the late-onset Pompe disease group (median 0.050 [interquartile range 0.027-0.118] vs 0.183 [0.153-0.233], P < .001). Nine subjects (69.2%) had a blunted change in airway-occlusion pressure 0.1 s/change in end-tidal carbon dioxide pressure slope. Subjects with late-onset Pompe disease had an impaired hypercapnic respiratory drive response. The clinical impact of this phenomenon in this subject subset deserves further investigation.


Time-resolved influences of functional DAT1 and COMT variants on visual perception and post-processing.
Dopamine plays an important role in orienting and the regulation of selective attention to relevant stimulus characteristics. Thus, we examined the influences of functional variants related to dopamine inactivation in the dopamine transporter (DAT1) and catechol-O-methyltransferase genes (COMT) on the time-course of visual processing in a contingent negative variation (CNV) task. 64-channel EEG recordings were obtained from 195 healthy adolescents of a community-based sample during a continuous performance task (A-X version). Early and late CNV as well as preceding visual evoked potential components were assessed. Significant additive main effects of DAT1 and COMT on the occipito-temporal early CNV were observed. In addition, there was a trend towards an interaction between the two polymorphisms. Source analysis showed early CNV generators in the ventral visual stream and in frontal regions. There was a strong negative correlation between occipito-temporal visual post-processing and the frontal early CNV component. The early CNV time interval 500-1000 ms after the visual cue was specifically affected while the preceding visual perception stages were not influenced. Late visual potentials allow the genomic imaging of dopamine inactivation effects on visual post-processing. The same specific time-interval has been found to be affected by DAT1 and COMT during motor post-processing but not motor preparation. We propose the hypothesis that similar dopaminergic mechanisms modulate working memory encoding in both the visual and motor and perhaps other systems.


Discovery of divided RdRp sequences and a hitherto unknown genomic complexity in fungal viruses.
By identifying variations in viral RNA genomes, cutting-edge metagenome technology has potential to reshape current concepts about the evolution of RNA viruses. This technology, however, cannot process low-homology genomic regions properly, leaving the true diversity of RNA viruses unappreciated. To overcome this technological limitation, we applied an advanced method, Fragmented and Primer-Ligated Double-stranded (ds) RNA Sequencing (FLDS), to screen RNA viruses from 155 fungal isolates, which allowed us to obtain complete viral genomes in a homology-independent manner. We created a high-quality catalog of 19 RNA viruses (12 viral species) that infect Aspergillus isolates. Among them, nine viruses were not detectable by the conventional methodology involving agarose gel electrophoresis of dsRNA, a hallmark of RNA virus infections. Segmented genome structures were determined in 42 per cent of the viruses. Some RNA viruses had novel genome architectures; one contained a dual methyltransferase domain and another had a separated RNA-dependent RNA polymerase (RdRp) gene. A virus from a different fungal taxon (Pyricularia) had an RdRp sequence that was separated on different segments, suggesting that a divided RdRp is widely present among fungal viruses, despite the belief that all RNA viruses encode RdRp as a single gene. These findings illustrate the previously hidden diversity and evolution of RNA viruses, and prompt reconsideration of the structural plasticity of RdRp.


Career intentions of medical students in the UK: a national, cross-sectional study (AIMS study).
To determine current UK medical students' career intentions after graduation and on completing the Foundation Programme (FP), and to ascertain the motivations behind these intentions. Cross-sectional, mixed-methods survey of UK medical students, using a non-random sampling method. All 44 UK medical schools recognised by the General Medical Council. All UK medical students were eligible to participate. The study sample consisted of 10 486 participants, approximately 25.50% of the medical student population. Career intentions of medical students postgraduation and post-FP, motivations behind these career intentions, characterising the medical student population and correlating demographic factors and propensity to leave the National Health Service (NHS). The majority of participating students (8806/10 486, 83.98%) planned to complete both years of the FP after graduation, with under half of these students (4294/8806, 48.76%) intending to pursue specialty training thereafter. A subanalysis of career intentions after the FP by year of study revealed a significant decrease in students' intentions to enter specialty training as they advanced through medical school. Approximately a third of surveyed students (3392/10 486, 32.35%) intended to emigrate to practise medicine, with 42.57% (n=1444) of those students not planning to return. In total, 2.89% of students intended to leave medicine altogether (n=303). Remuneration, work-life balance and working conditions were identified as important factors in decision-making regarding emigration and leaving the profession. Subgroup analyses based on gender, type of schooling, fee type and educational background were performed. Only 17.26% of surveyed students were satisfied or very satisfied with the overall prospect of working in the NHS. The Ascertaining the career Intentions of UK Medical Students study highlights UK students' views and career intentions, revealing a concerning proportion of those surveyed considering alternative careers or emigration. Addressing factors such as remuneration, work-life balance and working conditions may increase retention of doctors and improve workforce planning efforts.


Strong-field ionization and coulomb explosion of chlorine weakly bound to small water clusters.
Clusters exhibit an enhancement in ionization rates under intense, ultrafast laser pulses compared to their molecular/atomic counterparts. Studies of ionization enhancement of weakly bound molecules to clusters have not been previously characterized and quantified. We demonstrate that weakly bound ClO to (H(2)O)(n) (n = 1-12) clusters and weakly bound HCl to (H(2)O)(n) (n = 1-12) clusters produce high atomic charge states of chlorine via Coulomb explosion. Density functional theory (DFT) was used to qualitatively compare the interaction energy of ClO with respect to the number of water molecules as well as HCl with respect to the number of water molecules. The chlorine ion signal intensity for each atomic charge state was observed to be dependent on the molecule-cluster bond strength. The observed ionization enhancement was quantified using semiclassical tunneling theory, and it was found that the Cl(3+-5+) and O(2+) charge states are enhanced in ionization. Possible mechanisms of ionization enhancement are explored for weakly bound chlorine species.


Evidence for involvement of IgA1 hinge glycopeptide in the IgA1-IgA1 interaction in IgA nephropathy.
The study was performed to investigate the role of the IgA1 hinge region in the IgA1-IgA1 interaction, which was observed previously in IgA nephropathy. The competitive inhibition assays of the IgA1-IgA1 binding were performed using the following candidates for inhibitors: native IgA1 hinge glycopeptide (nHGP), IgA1, IgA2, and IgG. The IgA1-IgA1 binding was definitely inhibited by the nHGP and the IgA1 (maximum of percent inhibition: 66.1 and 60.5%, respectively). There was no obvious inhibition in the IgA2 and the IgG. The inhibition curves of the nHGP and the IgA1 were significantly different from that of the IgG (P < 0.01, respectively). Furthermore, to reveal the detailed binding sites in the interaction, the same inhibition assays were performed using the following substances composing the IgA1 hinge glycopeptide: galactose (Gal), N-acetyl-galactosamine (GalNAc), Gal beta 1-3GalNAc, sialic acid, tetrapeptide PTPS, and synthesized hinge proline-rich peptide PVPSTPPTPSPSTPPTPSPS (sHP). sHP, Gal beta 1-3GalNAc, Gal, and GalNAc inhibited the binding (69.3, 34.1, 14.9, 14.6%, respectively). No obvious inhibition was observed in sialic acid and tetrapeptide PTPS. The inhibition curve of sHP was significantly different from that of the PTPS (P < 0.05). Those of Gal beta 1-3GalNAc, Gal, and GalNAc were also significantly different from that of sialic acid (P < 0.05, respectively). These results suggested that the IgA1-IgA1 interaction could be mediated by the core structure including the peptide and the sugars, except for sialic acid in the hinge region, resulting in the formation of the circulating macromolecular IgA1 in IgA nephropathy.


When punishment pays.
Explaining cooperation in groups remains a key problem because reciprocity breaks down between more than two. Punishing individuals who contribute little provides a potential answer but changes the dilemma to why pay the costs of punishing which, like cooperation itself, provides a public good. Nevertheless, people are observed to punish others in behavioural economic games, posing a problem for existing theory which highlights the difficulty in explaining the spread and persistence of punishment. Here, I consider the apparent mismatch between theory and evidence and show by means of instructive analysis and simulation how much of the experimental evidence for punishment comes from scenarios in which punishers may expect to obtain a net benefit from punishing free-riders. In repeated games within groups, punishment works by imposing costs on defectors so that it pays them to switch to cooperating. Both punishers and non-punishers then benefit from the resulting increase in cooperation, hence investing in punishment can constitute a social dilemma. However, I show the conditions in which the benefits of increased cooperation are so great that they more than offset the costs of punishing, thereby removing the temptation to free-ride on others' investments and making punishment explicable in terms of direct self-interest. Crucially, this is because of the leveraging effect imposed in typical studies whereby people can pay a small cost to inflict a heavy loss on a punished individual. In contrast to previous models suggesting punishment is disadvantaged when rare, I show it can invade until it comes into a producer-scrounger equilibrium with non-punishers. I conclude that adding punishment to an iterated public goods game can solve the problem of achieving cooperation by removing the social dilemma.


Macromolecular crowding effects on coupled folding and binding.
Replica exchange molecular dynamics simulations are performed on the protein complex pKID-KIX to understand the effects of macromolecular crowding on coupled folding and binding events. A structure-based protein model at the residue level is adopted for the two proteins to include intramolecular conformational flexibility, while crowding macromolecules are represented as spherical particles. The interactions between crowders and protein residues can be either purely repulsive or a combination of short-range repulsion and intermediate-range attraction. Consistent with previous studies on rigid-body protein binding in the presence of spherical crowders, we find that the complex formation is stabilized by repulsive protein-crowder interactions and destabilized by sufficiently strong attractive protein-crowder interactions. Competition between stabilizing repulsive and destabilizing attractive interactions is quantitatively captured by a previous theoretical model developed for describing the change in the binding free energy of rigid proteins in a crowded environment. We find that protein flexibility has little effect on the thermodynamics of the pKID-KIX binding (with respect to bulk) for repulsive and weakly attractive protein-crowder interactions. For strong protein-crowder attractive interactions, the destabilizing effect due to crowding is attenuated by protein flexibility. Interestingly, the mechanism of coupled folding and binding observed in bulk remains unchanged under highly crowded conditions over a broad range of protein-crowder interaction strengths. Also, strong protein-crowder attractive interactions can significantly stabilize intermediate states involving partial contact between pKID and KIX domains.


A tension between genuine care and other duties: Swedish nursing students' views of their future work.
There is a current need for nurses to take on new roles due to changing health care policies, economic cut-backs and shortage of staff. It is therefore important to study nursing students' view of their future profession. The theoretical framework was contemporary theories of competence development, which has shown that people's understanding of their work is expressed in their actions. The aim of this study was to describe nursing students' understanding of their future professional role in health care. A purposeful sample of 12 nursing students wrote narratives. The texts were condensed in five steps using the Empirical Phenomenological Psychological Method. The essence of the students' view of their future work was A tension between genuine nursing care and other duties. Four themes constituted this essence: professional status, working conditions and stress, evidence-based nursing contra holistic care, teamwork, co-operation and disrespect, and intensive care instead of geriatrics. This study highlights pedagogic and practical problems that need to be constructively addressed. The nursing students' eagerness to care in a holistic way needs to be acknowledged and used in a fruitful way. This core function of nursing needs to be integrated with up-to-date nursing research.


Effect of self-measurement of blood pressure on adherence to treatment in patients with mild-to-moderate hypertension.
Poor adherence to treatment is one of the major problems in the treatment of hypertension. Self blood pressure measurement may help patients to improve their adherence to treatment. In this prospective, randomized, controlled study coordinated by a university hospital, a total of 228 mild-to-moderate hypertensive patients were randomized to either a group that performed self-measurements at home in addition to office blood pressure measurements [the self-pressure group (n = 114)] or a group that only underwent office blood pressure measurement [the office pressure group (n = 114)]. Patients were followed for 1 year in which treatment was adjusted, if necessary, at each visit to the physician's office according to the achieved blood pressure. Adherence to treatment was assessed by means of medication event monitoring system TrackCaps. Median adherence was slightly greater in patients from the self-pressure group than in those from the office pressure group (92.3 vs. 90.9%; P = 0.043). Although identical among both groups, in the week directly after each visit to the physician's office, adherence [71.4% (interquartile range 71-79%)] was significantly lower (P < 0.001) than that at the last 7 days prior to each visit [100% (interquartile range 90-100%)]. On the remaining days between the visits, patients from the self-pressure group displayed a modestly better adherence than patients from the office pressure group (97.6 vs. 97.0%; P = 0.024). Although self-blood pressure measurement as an adjunct to office blood pressure measurement led to somewhat better adherence to treatment in this study, the difference was only small and not clinically significant. The time relative to a visit to the doctor seems to be a more important predictor of adherence.


Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data.
Meta-analysis is increasingly used as a key source of evidence synthesis to inform clinical practice. The theory and statistical foundations of meta-analysis continually evolve, providing solutions to many new and challenging problems. In practice, most meta-analyses are performed in general statistical packages or dedicated meta-analysis programs. Herein, we introduce Meta-Analyst, a novel, powerful, intuitive, and free meta-analysis program for the meta-analysis of a variety of problems. Meta-Analyst is implemented in C# atop of the Microsoft .NET framework, and features a graphical user interface. The software performs several meta-analysis and meta-regression models for binary and continuous outcomes, as well as analyses for diagnostic and prognostic test studies in the frequentist and Bayesian frameworks. Moreover, Meta-Analyst includes a flexible tool to edit and customize generated meta-analysis graphs (e.g., forest plots) and provides output in many formats (images, Adobe PDF, Microsoft Word-ready RTF). The software architecture employed allows for rapid changes to be made to either the Graphical User Interface (GUI) or to the analytic modules.We verified the numerical precision of Meta-Analyst by comparing its output with that from standard meta-analysis routines in Stata over a large database of 11,803 meta-analyses of binary outcome data, and 6,881 meta-analyses of continuous outcome data from the Cochrane Library of Systematic Reviews. Results from analyses of diagnostic and prognostic test studies have been verified in a limited number of meta-analyses versus MetaDisc and MetaTest. Bayesian statistical analyses use the OpenBUGS calculation engine (and are thus as accurate as the standalone OpenBUGS software). We have developed and validated a new program for conducting meta-analyses that combines the advantages of existing software for this task.


Epidemiology of fibromyalgia.
Chronic widespread pain, the cardinal symptom of fibromyalgia (FM), is common in the general population, with comparable prevalence rates of 7.3% to 12.9% across different countries. The prevalence of FM in the general population was reported to range from 0.5% to 5% and up to 15.7% in the clinic. The common association of FM with other rheumatic disorders, chronic viral infections, and systemic illnesses has been well documented in several studies. Up to 65% of patients with systemic lupus erythematosus meet the criteria for FM. FM is considered a member of the family of functional somatic syndromes. These syndromes are very common and share a similar phenomenology, epidemiologic characteristics, high rates of occurrence, a common pathogenesis, and similar management strategies. A high prevalence of FM was demonstrated among relatives of patients with FM and it may be attributed to genetic and environmental factors.


Editorial: Cardiovascular Complications at One Year After SARS-CoV-2 Infection are Independent of Underlying Cardiovascular Risk Factors or Severity of COVID-19.
The consequences of SARS-CoV-2 infection include short-term, long-term, mild, and severe clinical symptoms. The cardiovascular system, including endothelial cells, vascular smooth muscle cells, and cardiac myocytes, are important targets for SARS-CoV-2. In February 2022, the findings from a large US cohort of individuals diagnosed with COVID-19 and two sets of control cohorts evaluated the risk and 12-month cardiovascular disease burden. Individuals who had COVID-19 had a 72% increased risk of heart failure, a 63% increased risk of myocardial infarction, and a 52% increased risk of ischemic stroke compared with controls. These results were independent of gender, race, age, and other cardiovascular risk factors, including diabetes, obesity, hypertension, hyperlipidemia, and chronic kidney disease. As of 25 April 2022, the World Health Organization (WHO) reported that more than 80 million people in the US, more than 22 million people in the UK, and more than 505 million people worldwide were infected with SARS-CoV-2. This Editorial aims to present what is currently known about the cardiovascular outcomes at one year following SARS-CoV-2 infection and highlights that primary care physicians should be mindful of the COVID-19 infection status of their patients when evaluating cardiovascular health.


[AVOID COMMON MISTAKES IN REALIZATION OF A ELECTROCARDIOGRAM].
The electrocardiogram (ECG) is a noninvasive technique to perform simple, economical, reproducible and provides valuable information that can be used to make the diagnosis of the patient and to guide clinical decisions. It is a diagnostic test used frequently as it can be done quickly, since it is done with a laptop and generally is always possible implementation in any field either primary care, specialty outpatient care. The diagnosis made by the ECG is considered valid in clinical practice, but is only effective if the electrodes are placed in the correct anatomical locations, if the hoses are properly attached to the electrodes, the registry maintains a good quality (the filters are used appropriate, interference and electrical noise are avoided) and ECG compares made by the same registration system (ECG 5 or 10 lead) for determining evolutionary changes (to determine changes in the ST segment during myocardial ischemia or assess the changes caused by reperfusion therapies). To review the most common errors in electrocardiography, which are related to inappropriate placements of shunts, cross or exchange of patch cords limb leads, records of poor quality and comparisons of ECG serials made with different acquisition systems (10 vs 5 lead). We make the recommendations to prevent and avoid these scams that can lead to diagnosis and treatment with adverse outcomes for the patient.


Subtelomeric demethylation deregulated hTERT expression, telomerase activity, and telomere length in four nasopharyngeal carcinoma cell lines.
Global DNA hypomethylation, in particular that of the gene promoter sequence in gene hypermethylation, is a well-known characteristic of human cancer. Subtelomeres are enriched CpG islands; methylation is believed to be a potential epigenetic regulator. However, regulation on the telomere length remains largely unknown. To demonstrate this correlation, four nasopharyngeal carcinoma cell lines (CNE, CNE1, CNE2, 5-8F) were treated for 72 hours with 0, 1, or 2.5 μM of the demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC). Subtelomeric (D4Z4) level methylation was evaluated with a bisulfite assay, the human telomerase catalytic subunit (hTERT) expression was assayed by reverse transcription-polymerase chain reaction, the telomerase activity was detected using a telomeric repeat amplification protocol assay, and the telomere length was measured by Southern blot terminal restriction fragment analysis. There was significant demethylation following 5-aza-dC treatment, and a strongly repressed hTERT expression decreased the telomerase activity and remarkably shortened telomeres. Thus, partial subtelomeric methylation does not repress hTERT expression; conversely, demethylation may downregulate hTERT expression and shorten telomeres.


Emerging coexistence of three PMQR genes on a multiple resistance plasmid with a new surrounding genetic structure of qnrS2 in E. coli in China.
Quinolones are commonly used for treatment of infections by bacteria of the Enterobacteriaceae family. However, the rising resistance to quinolones worldwide poses a major clinical and public health risk. This study aimed to characterise a novel multiple resistance plasmid carrying three plasmid-mediated quinolone resistance genes in Escherichia coli clinical stain RJ749. MICs of ceftriaxone, cefepime, ceftazidime, ciprofloxacin, and levofloxacin for RJ749 and transconjugant c749 were determined by the Etest method. Conjugation was performed using sodium azide-resistant E. coli J53 strain as a recipient. The quinolone resistance-determining regions of gyrA, gyrB, parC, and parE were PCR-amplified. RJ749 was highly resistant to quinolones, while c749 showed low-level resistance. S1-nuclease pulsed-field gel electrophoresis revealed that RJ749 and c749 both harboured a plasmid. PCR presented chromosomal mutation sites of the quinolone resistance-determining region, which mediated quinolone resistance. The c749 genome comprised a single plasmid, pRJ749, with a multiple resistance region, including three plasmid-mediated quinolone resistance (PMQR) genes (aac (6')-Ib-cr, qnrS2, and oqxAB) and ten acquired resistance genes. One of the genes, qnrS2, was shown for the first time to be flanked by two IS26s. Three IS26-mediated circular molecules carrying the PMQR genes were detected. We revealed the coexistence of three PMQR genes on a multiple resistance plasmid and a new surrounding genetic structure of qnrS2 flanked by IS26 elements. IS26 plays an important role in horizontal spread of quinolone resistance.


An investigation of self-assessment bias in mental health providers.
Previous research has consistently found self-assessment bias (an overly positive assessment of personal performance) to be present in a wide variety of work situations. The present investigation extended this area of research with a multi-disciplinary sample of mental health professionals. Respondents were asked to: (a) compare their own overall clinical skills and performance to others in their profession, and (b) indicate the percentage of their clients who improved, remained the same, or deteriorated as a result of treatment with them. Results indicated that 25% of mental health professionals viewed their skill to be at the 90th percentile when compared to their peers, and none viewed themselves as below average. Further, when compared to the published literature, clinicians tended to overestimate their rates of client improvement and underestimate their rates of client deterioration. The implications of this self-assessment bias for improvement of psychotherapy outcomes are discussed.


The long-run effects of noncommunicable disease shocks.
The health shocks literature typically does not take into account the temporal patterns of loss since the time of the shock. This limits understanding of the long-run impact of health shocks and the capacity of individuals to cope over time. This study estimates the dynamic effects of a noncommunicable disease shock on the economic well-being of working-age individuals in China up to 6 years after onset. We find that after a period of temporal loss, individuals and their families can insure consumption against the average noncommunicable disease shock over the long-run. We observe significant heterogeneity according to the persistence of the disease, value of household wealth, and health insurance status. Individuals with consistent onset, with below median wealth, and without health insurance are least equipped to smooth consumption over the long-term.


Design of Deep Eutectic Systems: A Simple Approach for Preselecting Eutectic Mixture Constituents.
Eutectic systems offer a wide range of new (green) designer solvents for diverse applications. However, due to the large pool of possible compounds, selecting compounds that form eutectic systems is not straightforward. In this study, a simple approach for preselecting possible candidates from a pool of substances sharing the same chemical functionality was presented. First, the melting entropy of single compounds was correlated with their molecular structure to calculate their melting enthalpy. Subsequently, the eutectic temperature of the screened binary systems was qualitatively predicted, and the systems were ordered according to the depth of the eutectic temperature. The approach was demonstrated for six hydrophobic eutectic systems composed of L-menthol and monocarboxylic acids with linear and cyclic structures. It was found that the melting entropy of compounds sharing the same functionality could be well correlated with their molecular structures. As a result, when the two acids had a similar melting temperature, the melting enthalpy of a rigid acid was found to be lower than that of a flexible acid. It was demonstrated that compounds with more rigid molecular structures could form deeper eutectics. The proposed approach could decrease the experimental efforts required to design deep eutectic solvents, particularly when the melting enthalpy of pure components is not available.


Familial resemblance for coronary heart disease risk: the HERITAGE Family Study.
The objective of this study was to quantify familial resemblance for coronary heart disease risk in 260 Black and 427 White participants in the HERITAGE Family Study. Coronary heart disease risk was estimated using a coronary heart disease risk index (CHDRI) computed from the revised Framingham Heart Study algorithm, based on age, LDL-cholesterol, HDL-cholesterol, blood pressure, diabetes, and smoking status. Using a familial correlation model to test hypotheses regarding familial aggregation, significant familial resemblance was detected in both Blacks and Whites. There were significant sibling correlations in both Blacks and Whites, while spouse correlations were significant only in the White sample. The maximal heritabilities, which have to be interpreted cautiously in light of negligible parent-offspring correlations, were 34% and 53% in Whites and Blacks, respectively. Thus, the maximal heritability, which includes both genetic and non-genetic sources of variation, is higher in Blacks than Whites, and explains a significant proportion of the total phenotypic variance. The results indicate that risk of coronary heart disease runs along family lines, and common environmental effects are important in explaining the observed familial resemblance.


Long-term cryoconservation and stability of vitamin C in serum samples of the European prospective investigation into cancer and nutrition.
Plasma vitamin C level may be associated with risk of some chronic diseases. The rapid degradability of vitamin C in biological samples necessitates its stabilization with metaphosphoric acid or similar agents. However, in most cohort studies, prospectively collected biological samples are not treated with stabilizing agents before long-term frozen storage and it is not known whether vitamin C can be properly measured in such samples. The objective of this study was to determine the degree of vitamin C degradation in plasma samples stored without stabilization for 7 to 11 years at -196 degrees C. Spearman's correlation coefficients indicate a moderate correlation between baseline and final plasma vitamin C levels in both men (r = 0.57, P < 0.0001) and women (r = 0.52, P < 0.0001). Samples were also categorized based on low or high baseline levels of plasma vitamin C, with the latter category showing the highest rate of loss per year of frozen storage in men (1.96 micromol/L, P value for difference <0.0001; percent loss 24.6%) and women (2.35 micromol/L, P value for difference <0.0001; percent loss 24.2%), as determined by multiple regression analysis adjusted for smoking status, age, and body mass index. In men, both baseline and final plasma vitamin C values were lower in smokers than never smokers, but for both men and women the rate of vitamin C loss during storage was not significantly different between smokers and never smokers. The results of this study show that vitamin C can be measured with reasonable reliability in plasma samples frozen for long periods of time without addition of any stabilizing agents.


[Quantum pharmacology: state of scientific research].
In the article literature data and own investigations are summarized. Quantum pharmacology is defined as science which uses methods of theoretical chemistry and quantum mechanics as well as a computer modeling for studying drug molecular structure, mechanisms of drug interactions to understand primary pharmacological reactions. Main investigations in quantum pharmacology have been carried out in these arias: 1. Study of drug molecular structure. 2. Quantitative structure-activity relationship study (QSAR). 3. Investigations of mechanisms of drugs action. 4. Pharmacophores study. 5. De novo drug design. 6. Study of protein-ligand interactions for description of reactions between drugs and biomolecules of organism. 7. Investigations of primary mechanisms of drugs action. Study of quantum-pharmacological properties of captopril-inhibitor of angiotensineconverting enzyme showed that its molecule belongs to group of soft reagents, that's why this substance will interact with soft alkaline substances-amino acids, unsaturated and aromatic compounds. Quantum-pharmacological investigations will favour the discovery of new effective drugs for treatment of different diseases.


Bicycle use for transport in an Australian and a Belgian city: associations with built-environment attributes.
The walkability attributes of neighborhood environments (residential density, land use mixture, and connectedness of streets) have been found to be associated with higher rates of walking. However, relatively less is known about the associations of walkability attributes with bicycle use for transport. We examined the relationships between adults' bicycle use for transport and measures of neighborhood walkability in two settings: an Australian city (Adelaide) with low rates of bicycle use and a Belgian city (Ghent) with high rates of bicycle use. A total of 2,159 and 382 participants were recruited in Adelaide and Ghent, respectively. A walkability index was derived from objectively measured data in Adelaide, while a similar index was derived from perceived measures in Ghent. Logistic regression models were employed to examine associations of bicycle use with different levels of walkability. There were higher rates of bicycle ownership for Ghent compared to Adelaide participants (96% versus 61%), and there was a higher prevalence of bicycle use for transport for Ghent compared to Adelaide participants (50% vs. 14%). Despite the large differences in bicycle ownership and use, living in a high-walkable neighborhood was associated with significantly higher odds of bicycle use for transport in both cities, after adjusting for relevant confounding factors. Built-environment innovations that are increasingly being advocated by health authorities and transport planners, primarily to promote higher rates of walking for transport, should also impact positively on bicycle use.


Clinically aggressive diffuse capillary telangiectasia of the brain stem: a clinical radiologic-pathologic case study.
Capillary malformations or telangiectasias of the brain usually exhibit a benign clinical course, although occassionally they may be associated with mild to moderate symptomatology of uncertain origin. We report a case of an exceptionally aggressive capillary telangiectasia in a child, which was associated with progressive neurologic deterioration resulting in death.


Dissociating Bottom-Up and Top-Down Mechanisms in the Cortico-Limbic System during Emotion Processing.
The cortico-limbic system is critically involved in emotional responses and resulting adaptive behaviors. Within this circuit, complementary regions are believed to be involved in either the appraisal or the regulation of affective state. However, the respective contribution of these bottom-up and top-down mechanisms during emotion processing remains to be clarified. We used a new functional magnetic resonance imaging (fMRI) paradigm varying 3 parameters: emotional valence, emotional congruency, and allocation of attention, to distinguish the functional variation in activity and connectivity between amygdala, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). Bottom-up appraisal of negative compared with positive stimuli led to a greater amygdala response and stronger functional interaction between amygdala and both dorsal ACC and DLPFC. Top-down resolution of emotional conflict was associated with increased activity within ACC and higher functional connectivity between this structure, and both the amygdala and DLPFC. Finally, increased top-down attentional control caused greater engagement of the DLPFC, accompanied by increased connectivity between DLPFC and dorsal ACC. This novel task provides an efficient tool for exploring bottom-up and top-down processes underlying emotion and may be particularly helpful for investigating the neurofunctional underpinnings of psychiatric disorders.


Maximum Entropy Based Non-Negative Optoacoustic Tomographic Image Reconstruction.
Optoacoustic (photoacoustic) tomography is aimed at reconstructing maps of the initial pressure rise induced by the absorption of light pulses in tissue. In practice, due to inaccurate assumptions in the forward model, noise, and other experimental factors, the images are often afflicted by artifacts, occasionally manifested as negative values. The aim of this work is to develop an inversion method which reduces the occurrence of negative values and improves the quantitative performance of optoacoustic imaging. We present a novel method for optoacoustic tomography based on an entropy maximization algorithm, which uses logarithmic regularization for attaining non-negative reconstructions. The reconstruction image quality is further improved using structural prior-based fluence correction. We report the performance achieved by the entropy maximization scheme on numerical simulation, experimental phantoms, and in-vivo samples. The proposed algorithm demonstrates superior reconstruction performance by delivering non-negative pixel values with no visible distortion of anatomical structures. Our method can enable quantitative optoacoustic imaging, and has the potential to improve preclinical and translational imaging applications.


[Gestational trophoblastic diseases. Classification, epidemiology and genetic data].
Gestational trophoblastic diseases amalgamate several entities with a common denominator which is a hypersecretion of hCG: complete mole, invasive or not, partial mole or triploid syndrome, gestational trophoblastic carcinoma and trophoblastic carcinoma from the implantation site. These entities differ by their origins, their morphology, their evolution and their treatments. Complete moles are diploid and in 80% of cases, chromosomes are only from paternal origin (diandry or dispermy). Their evolution is unpredictable whatever the molecular biology or cytogenetical methods are. Partial moles, generally triploid, are much more frequent (10-20% of miscarriages) than the number of cases diagnosed during the pregnancy. In 85% of cases, two sets of chromosomes are of paternal origin. The gestational trophoblastic carcinoma is diploid and its genetic material comes from both parents. This probably excludes a direct filiation between complete mole and gestational trophoblastic carcinoma. The trophoblastic tumor from the implantation site comes from the trophoblast of the implantation site which explain why its evolution and its prognosis are totally distinct from the previous one. In this report, we successively discuss the natural history of gestational trophoblastic diseases, their epidemiology and the genetic data explaining their origins.


Development of a Tunable, Narrow-Linewidth, CW 2.066-mum Ho:YLF Laser for Remote Sensing of Atmospheric CO(2) and H(2)O.
A smoothly tunable, narrow-linewidth, cw, 32-mW, 2.066-mum Ho:YLF laser was constructed and used for the first time in preliminary spectroscopic measurements of atmospheric CO(2) and H(2)O. The laser was constructed with a 4.5-mm-long, TE-cooled, codoped 5% Tm and 0.5% Ho yttrium lithium fluoride crystal (cut at Brewster's angle) pumped by an Ar(+)-pumped 500-mW Ti:sapphire laser operating at 792 nm. Intracavity etalons were used to reduce the laser linewidth to approximately 0.025 cm(-1) (0.75 GHz), and the laser wavelength was continuously and smoothly tunable over approximately 6 cm(-1) (180 GHz). The Ho:YLF laser was used to perform spectroscopic measurements on molecular CO(2) in a laboratory absorption cell and to measure the concentration of CO(2) and water vapor in the atmosphere with an initial accuracy of approximately 5-10%. The measurement uncertainty was found to be due to several noise sources, including the effect of asymmetric intensity of the laser modes within the laser linewidth, fluctuations caused by atmospheric turbulence and laser beam/target movement, and background spectral shifts.


Crystal structure of a Pseudomonas malonate decarboxylase holoenzyme hetero-tetramer.
Pseudomonas species and other aerobic bacteria have a biotin-independent malonate decarboxylase that is crucial for their utilization of malonate as the sole carbon and energy source. The malonate decarboxylase holoenzyme contains four subunits, having an acyl-carrier protein (MdcC subunit) with a distinct prosthetic group, as well as decarboxylase (MdcD-MdcE) and acyl-carrier protein transferase (MdcA) catalytic activities. Here we report the crystal structure of a Pseudomonas malonate decarboxylase hetero-tetramer, as well as biochemical and functional studies based on the structural information. We observe a malonate molecule in the active site of MdcA and we also determine the structure of malonate decarboxylase with CoA in the active site of MdcD-MdcE. Both structures provide molecular insights into malonate decarboxylase catalysis. Mutations in the hetero-tetramer interface can abolish holoenzyme formation. Mutations in the hetero-tetramer interface and the active sites can abolish Pseudomonas aeruginosa growth in a defined medium with malonate as the sole carbon source.Some aerobic bacteria contain a biotin-independent malonate decarboxylase (MDC), which allows them to use malonate as the sole carbon source. Here, the authors present the crystal structure of a Pseudomonas MDC and give insights into its catalytic mechanism and function.


Bone morphogenetic protein-7 regulates Snail signaling in carbon tetrachloride-induced fibrosis in the rat liver.
The aim of this study was to explore the molecular mechanism of the bone morphogenetic protein-7 (BMP-7) downregulation of Snail-mediated E-cadherin repression and mesenchymal-epithelial transition (MET) induction, since little is presently known about this issue. In this study, our aim was to elucidate the underlying mechanism by which cells acquire liver fibrosis characteristics after epithelial-mesenchymal transition (EMT). Cell cultures were exposed to Snail alone or in the presence of BMP-7; control cultures were exposed to medium only. The expression of the mRNA encoding α-smooth muscle actin (α-SMA), Snail and E-cadherin in rat liver epithelial cells was determined by real-time quantitative PCR (RT-PCR) and the main results were confirmed by ELISA. Cell differentiation was determined by analysis of the expression of α-SMA, Snail and E-cadherin by western blotting and co-immunoprecipitation. We demonstrated Snail-induced upregulation of mRNAs encoding α-SMA and downregulation of mRNAs encoding E-cadherin in rat liver epithelial cells when compared with unstimulated cells, and confirmed these results at the protein level. BMP-7 downregulated Snail-induced α-SMA and upregulated E-cadherin release compared with untreated and Snail-treated cells. In summary, we demonstrated that BMP-7 induces MET through decreased downregulation of Snail. In addition, Snail1 directly regulates Nanog promoter activity. Notch signaling is also involved in this process.


Optimizing brain tumor resection. High-field interventional MR imaging.
High-field strength iMRI guidance is an effective tool for brain tumor resection. Although its use lengthens the average time for a craniotomy, the reward is a more extensive tumor excision compared with conventional neurosurgery without an increased risk to the patient (Table 4). Although intraoperative patient transfer into and out of the magnet is cumbersome, the possibility for complete resection, especially for a low-grade glioma, makes the effort worthwhile. The cost and technical support required for this system presently limits its use to only a few sites worldwide. As with any technology, further refinements will make this system less expensive and more attainable. Practical consideration aside, high-field strength iMRI is presently [table: see text] the most effective tool available for brain tumor resection. Because of its novelty, future studies are necessary to determine if this technology lowers the incidence of and extends the duration to tumor recurrence as the preliminary data in children suggests. These are the ultimate measures of efficacy for any brain tumor treatment. Based on the rapid advancement of technology, will today's high-field strength interventional magnet become tomorrow's low-field system? Very high-field strength designs may improve diagnostic capabilities through higher resolution, but their interventional applications may be hindered by increased sensitivity for clinically insignificant abnormalities and decreased specificity for clinically relevant lesions. As new technology is developed, clinicians must continue to explore and refine the existing high-field strength iMRI to make it cost-effective and widely applicable.


Estimation of the risk of death during the first year after acute myocardial infarction from systolic time intervals during the first week.
Patients who survived for the first seven days after acute myocardial infarction were followed up for a further 51 weeks. During these 51 weeks there were 123 deaths and 477 eventual survivors. Approximately half of the deaths occurred during the first 3 weeks of follow up. The deaths were predicted with 75% sensitivity and 73% specificity by a discriminant analysis based upon six variables seen during the first 7 days; predictions of death and survival were 55% and 92% accurate respectively. These six variables were, in ascending order of prognostic importance, the occurrence of bundle branch blocks, the administration of a diuretic, the age of the patient, the presence of diabetes mellitus, a previous myocardial infarction, and the ratio of the measured left ventricular pre-ejection and ejection periods. Many other monitored variables, although univariately associated with death, contributed nothing further to the multivariate assessment of mortality risk.


GenSoFNN: a generic self-organizing fuzzy neural network.
Existing neural fuzzy (neuro-fuzzy) networks proposed in the literature can be broadly classified into two groups. The first group is essentially fuzzy systems with self-tuning capabilities and requires an initial rule base to be specified prior to training. The second group of neural fuzzy networks, on the other hand, is able to automatically formulate the fuzzy rules from the numerical training data. No initial rule base needs to be specified prior to training. A cluster analysis is first performed on the training data and the fuzzy rules are subsequently derived through the proper connections of these computed clusters. However, most existing neural fuzzy systems (whether they belong to the first or second group) encountered one or more of the following major problems. They are (1) inconsistent rule-base; (2) heuristically defined node operations; (3) susceptibility to noisy training data and the stability-plasticity dilemma; and (4) needs for prior knowledge such as the number of clusters to be computed. Hence, a novel neural fuzzy system that is immune to the above-mentioned deficiencies is proposed in this paper. This new neural fuzzy system is named the generic self-organizing fuzzy neural network (GenSoFNN). The GenSoFNN network has strong noise tolerance capability by employing a new clustering technique known as discrete incremental clustering (DIC). The fuzzy rule base of the GenSoFNN network is consistent and compact as GenSoFNN has built-in mechanisms to identify and prune redundant and/or obsolete rules. Extensive simulations were conducted using the proposed GenSoFNN network and its performance is encouraging when benchmarked against other neural and neural fuzzy systems.


Intracellular pH of mitogen-stimulated lymphocytes.
Mitogenic stimulation of mouse lymphocytes results in two sequential intracellular alkalinizations. The first shift of intracellular pH from 7.18 to 7.35 coincides with early biochemical events following mitogenic stimulation. The second alkalinization begins 12 hours after stimulation and rises in parallel with the rate of thymidine incorporation. The results suggest that intracellular alkalinization following stimulation may play a key role in the enhancement of cellular activation and mitogenesis.


Short communication: The antilipogenic effect of trans-10,cis-12 conjugated linoleic acid in bovine mammary epithelial cells is associated with proteasome activity and ATP production.
Proteasomes play a widespread role in the control of protein abundance via degrading ubiquitinated proteins. Activity of proteasomes is regulated by constitutive ATPases that respond to intracellular concentrations of ATP. Although recent data suggest a role of proteasomes in fatty acid metabolism, whether lipogenic activity in mammary cells is responsive to ATP concentrations and proteasome activity is unknown. To investigate whether proteasomes play a role in milk fat depression induced by trans-10,cis-12 conjugated linoleic acid (t10,c12 CLA), a bovine mammary epithelial cell line was treated with t10,c12 CLA for 24 h before analysis of lipogenic protein abundance. Western blot analysis of inactive sterol response element-binding protein-1 (pSREBP1) and active (nSREBP1) fragments indicated a decrease in abundance induced by exogenous t10,c12 CLA. At 150 nM t10,c12 CLA, abundance of both pSREBP1 and nSREBP1 was lowest, and decreased from basal levels by 16 and 64%, respectively. Exogenous t10,c12 CLA had no effect on abundance of peroxisome proliferator-activated receptor-gamma (PPARγ), but at 150 and 300 nM it decreased abundance of SREBF chaperone (SCAP). Inhibition of proteasome activity via incubation with MG-132 (a proteasome inhibitor) alone had no effect on pSREBP1, nSREBP1, PPARγ, or SCAP abundance. However, when cells were pre-incubated with MG-132, treatment with t10,c12 CLA reduced pSREBP1 (∼27%) and nSREBP1 (∼41%) abundance without affecting PPARγ or SCAP. Compared with the control, exogenous t10,c12 CLA increased ATP concentrations, and MG-132 alone had no effect. However, ATP concentration decreased markedly in cells incubated with both MG-132 and t10,c12 CLA. Combined with the alteration of SCAP and nSREBP1, the increase of ATP concentrations with t10,c12 CLA suggested that this fatty acid influenced the function of the SREBP1-SCAP complex through altering proteasome activity. Collectively, the current data highlight a role of proteasomes and intracellular ATP concentrations in the antilipogenic effect induced by t10,c12 CLA that leads to milk fat depression.


Adverse effects associated with high-dose olanzapine therapy in patients admitted to inpatient psychiatric care.
In 2012, Danish psychiatrist raised concerns regarding the use of high-dose olanzapine in the treatment of patients. The present study was part of an audit carried out by the Mental Health Services of the Capitol Region of Denmark regarding this topic. Objective. To assess the potential risks associated with high-dose olanzapine treatment (> 40 mg daily) in inpatient psychiatric units. The study was an observational case series based on review of patient charts. The main inclusion criterion was treatment with at least one daily dose > 40 mg olanzapine during the index admission in the period between 1st of January and 15th of March 2012. Six additional criteria were applied in order to target the subgroup of patients most likely to have experienced an adverse event due to treatment with olanzapine. The physician order entry system and the central patient register containing patient specific information about diagnoses and treatments were used for identification of study population. The 91 patients included in the study received maximum daily doses of olanzapine ranging from 45 to 160 mg and in 25% of patients, the total antipsychotic load exceeded 2000 mg of chlorpromazine equivalents. Extrapyramidal symptoms and sedation were the most frequent adverse events with frequencies of 27% and 25%, respectively. Furthermore, other well-known adverse events such as weight gain (14%), hypotension (2%), neuroleptic malignant syndrome (2%) and corrected QT-interval (QTc) prolongation (1%) were also observed in some patients. Five patients died and in two of these cases, olanzapine was concluded to be a possible contributing cause of death. Increased frequency of extrapyramidal symptoms and sedation as well as severe toxicity was observed in patients treated with up to 160 mg olanzapine per day. In order to prevent harmful outcomes, the clinicians should be ready to act appropriately if toxic effects of olanzapine occur. Treatment cessation should be immediate if serious adverse events such as neuroleptic malignant syndrome arise.


Effectiveness of percutaneous transforaminal adhesiolysis in patients with lumbar neuroforaminal spinal stenosis.
Lumbar foraminal spinal stenosis (LFSS) is a narrowing of the bony exit of a nerve root, which causes mechanical compression of spinal nerve roots. Low back pain and/or leg pain, and possibly neurogenic claudication, may result due to mechanical neural compression. Transforaminal epidural steroid injections (TFESIs) are commonly used for treating LFSS. Patients refractory to TFESIs may benefit from percutaneous epidural adhesiolysis. Our intent was to assess transforaminal adhesiolysis (TFA) as treatment for LFSS, analyzing patient response by severity of stenosis and evaluating the short-term effectiveness of TFA. Prospective study. Following IRB approval, 35 patients with LFSS were enrolled, all of whom underwent magnetic resonance imaging (MRI) of the lumbar spine. Sagittal MRI views were evaluated to grade the severity of LFSS. TFA was routinely conducted in the operating room. One hour after the procedure, each patient received 6 mL of 10% sodium chloride, infused over 30 minutes, with monitoring. Posttreatment outcomes were determined at 2 weeks and 3 months using a 5-point patient satisfaction scale. To test predictive value, patients were stratified by response (improvement versus no improvement). Improvement (defined as little pain, moderate pain, or no pain) was observed in 25 patients (71.4%) at 2 weeks and in 22 patients (62.8%) at 3 months following the procedure. Among patients showing improvement, those with Grade 3 spinal stenosis outnumbered those with Grade 2. At the 3-month follow-up, no statistically significant correlations between pain relief and the grade of LFSS was evident. Secondary outcomes were not measured and the follow-up period was relatively brief. Short-term results indicate that percutaneous TFA is an effective treatment for LFSS, although therapeutic outcomes and the severity of LFSS showed no correlation.


Microbial transformation from normal oral microbiota to acute endodontic infections.
Endodontic infections are a leading cause of oro-facial pain and tooth loss in western countries, and may lead to severe life-threatening infections. These infections are polymicrobial with high bacterial diversity. Understanding the spatial transition of microbiota from normal oral cavities through the infected root canal to the acute periapical abscess can improve our knowledge of the pathogenesis of endodontic infections and lead to more effective treatment. We obtained samples from the oral cavity, infected root canal and periapical abscess of 8 patients (5 with localized and 3 with systemic infections). Microbial populations in these samples were analyzed using next-generation sequencing of 16S rRNA amplicons. Bioinformatics tools and statistical tests with rigorous criteria were used to elucidate the spatial transition of the microbiota from normal to diseased sites. On average, 10,000 partial 16S rRNA gene sequences were obtained from each sample. All sequences fell into 11 different bacterial phyla. The microbial diversity in root canal and abscess samples was significantly lower than in the oral samples. Streptococcus was the most abundant genus in oral cavities while Prevotella and Fusobacterium were most abundant in diseased samples. The microbiota community structures of root canal and abscess samples were, however, more similar to each other than to the oral cavity microbiota. Using rigorous criteria and novel bioinformatics tools, we found that Granulicatella adiacens, Eubacterium yurii, Prevotella melaninogenica, Prevotella salivae, Streptococcus mitis, and Atopobium rimae were over-represented in diseased samples. We used a novel approach and high-throughput methodologies to characterize the microbiota associated normal and diseased oral sites in the same individuals.


Belief in astrology inventory: development and validation.
After the paper by Mayo, White, and Eysenck in 1978, a considerable number of papers studied the so-called sun-sign-effect predicted by astrology: people born with the sun in a positive sign are supposed to be extraverted, and those with the sun in a negative sign are supposed to be introverted. In these papers, researchers used ad hoc questionnaires with a few questions related to belief, knowledge, experience, or attitude toward astrology. However, an appropriate inventory with known psychometric properties has yet to be developed to assess the belief in astrology. In the present paper, the Belief in Astrology Inventory is presented with some psychometric data. The participants were 743 undergraduates studying Psychology and Social Sciences at a university in Spain. Correlation of scores on Belief in Astrology and Extraversion was small but significant (r = .22; r2 = .04) for positive sun-sign participants. This value accounts for negligible common variance. Women had significandy higher scores on the inventory than men.


Quantitative proteomics to characterize specific histone H2A proteolysis in chronic lymphocytic leukemia and the myeloid THP-1 cell line.
Proteome studies on hematological malignancies contribute to the understanding of the disease mechanism and to the identification of new biomarker candidates. With the isobaric tag for relative and absolute quantitation (iTRAQ) method we analyzed the protein expression between B-cells of healthy people and chronic lymphocytic leukemia (CLL) B-cells. CLL is the most common lymphoid cancer of the blood and is characterized by a variable clinical course. By comparing samples of patients with an aggressive vs. indolent disease, we identified a limited list of differentially regulated proteins. The enhanced sensitivity attributed to the iTRAQ labels led to the discovery of a previously reported but still not clarified proteolytic product of histone H2A (cH2A) which we further investigated in light of the suggested functional properties of this modification. In the exploratory proteome study the Histone H2A peptide was up-regulated in CLL samples but a more specific and sensitive screening of a larger patient cohort indicated that cH2A is of myeloid origin. Our subsequent quantitative analysis led to a more profound characterization of the clipping in acute monocytic leukemia THP-1 cells subjected to induced differentiation.


Sexual and reproductive health risk behaviours among South African university students: results from a representative campus-wide survey.
Among South African university students, HIV prevalence is lower than in age-peers, but at 3.8% it is not negligible. We examined prevalence of factors potentially associated with HIV risk, focusing on partnership characteristics and consistent condom use. We hypothesised that contraceptive-related factors, for example, desire to prevent pregnancy and not using hormonal contraceptives, would be positively associated with consistent condom use. Data were drawn from a representative interviewer-administered survey of 2nd to 4th year students conducted during registration at a university campus in KwaZulu-Natal. Of 576 students, 218 (83 women, 135 men) reported vaginal intercourse in the past 2 months. Of these, 7% of women and 43% of men reported past-year concurrent partnerships, and 24% knew/ suspected partner non-monogamy. Although reported condom use at last intercourse was 90%, 2-month consistent use was 53% (women) and 73% (men). Reported hormonal contraception use was low (women: 36.8%; men: 16.7%), and 68% used condoms for dual protection. In gender-stratified multivariable analyses, consistent condom use was higher for men who reported their partner did not use (vs. used) hormonal contraception (aOR = 5.84; 95%CI = 2.71, 12.57; p < 0.001) and who reported using condoms for dual protection (vs. single protection) (aOR = 2.46; 95%CI = 1.43, 4.25; p = 0.001). No contraception-related factors were associated with consistent condom use among women. Sexual partnership characteristics potentially place sexually active university students at high HIV risk and should be investigated further. Among men, but not women, contraceptive concerns were associated with consistent condom use. Promoting condoms for dual protection may resonate with students and should be continued.


Increased glomerular thromboxane synthesis as a possible cause of proteinuria in experimental nephrosis.
Altered glomerular metabolism of arachidonic acid (AA) has already been demonstrated in experimental nephrotoxic nephritis. The enhanced synthesis of thromboxane A2 (TxA2) in isolated glomeruli that has been found may mediate changes in renal hemodynamics. The objectives of this investigation were: to check whether glomerular AA metabolism is also altered in a model of glomerulopathy in which no leukocyte infiltration or platelet deposition could be demonstrated; to establish a correlation between the altered AA metabolism and proteinuria; and to explore whether the alteration of the prostaglandin (PG) pathway found in isolated glomeruli is an in vitro artifact or reflects a modification in vivo. We used a model of glomerular damage characterized by heavy and persistent proteinuria, which was induced in the rat by a single intravenous injection of adriamycin. At light microscopy, minimal glomerular abnormalities were found in this model. Electron microscopy showed profound alterations of glomerular epithelial cells with extensive fusion of foot processes and signs of epithelial cell activation. Electron microscopy of numerous glomeruli showed no platelet deposition or macrophage and leukocyte infiltration in this model. Isolated glomeruli from nephrotic rats studied 14 or 30 d after a single intravenous injection of adriamycin (7.5 mg/kg) when animals were heavily proteinuric generated significantly more TxB2, the stable breakdown product of TxA2, than normal glomeruli. No significant changes were found in the other major AA metabolites formed through cyclooxygenase. Urinary excretion of immunoreactive TxB2 was also significantly higher in nephrotic than in normal animals. Administration of a selective Tx synthetase inhibitor, UK-38,485, from day 14 to day 18 after adriamycin resulted in a significant reduction of proteinuria compared with pretreatment values. Glomerular synthesis and urinary excretion of TxB2 were normal during the UK-38,485 treatment. Additional experiments showed that elevated glomerular synthesis and urinary excretion of TxB2 were not a consequence of increased substrate availability. Maximal stimulation of the renin-angiotensin axis with furosemide increased glomerular TxB2 synthesis in normal rats, which was significantly lower than in nephrotic animals. Finally, experiments using a unilateral model of adriamycin nephrosis indicated that the enhancement of glomerular TxB2 synthesis is not simply a consequence of the nephrotic syndrome. We conclude that: there is an abnormality of glomerular AA metabolism in nephritic syndrome, which leads to increased TxA2 production; the increased Tx generation correlates with protein excretion and might be responsible for altering the glomerular basement membrane permeability to protein; and the alteration found in isolated glomeruli probably reflects a modification in vivo, in that urinary excretion of immunoreactive TxB2 is also consistently increased in adriamycin nephrosis.


Herbal remedies: adverse effects and drug interactions.
A growing number of Americans are using herbal products for preventive and therapeutic purposes. The manufacturers of these products are not required to submit proof of safety and efficacy to the U.S. Food and Drug Administration before marketing. For this reason, the adverse effects and drug interactions associated with herbal remedies are largely unknown. Ginkgo biloba extract, advertised as improving cognitive functioning, has been reported to cause spontaneous bleeding, and it may interact with anticoagulants and antiplatelet agents. St. John's wort, promoted as a treatment for depression, may have monoamine oxidase-inhibiting effects or may cause increased levels of serotonin, dopamine and norepinephrine. Although St. John's wort probably does not interact with foods that contain tyramine, it should not be used with prescription antidepressants. Ephedrine-containing herbal products have been associated with adverse cardiovascular events, seizures and even death. Ginseng, widely used for its purported physical and mental effects, is generally well tolerated, but it has been implicated as a cause of decreased response to warfarin. Physicians must be alert for adverse effects and drug interactions associated with herbal remedies, and they should ask all patients about the use of these products.


[Pulse-therapy with glucocorticoids and cyclophosphamide in the treatment of thromboangiitis obliterans].
Effectiveness of glucocorticoid and cyclophosphamide pulse-therapy was studied in patients with thrombangitis abliterans (TA). We examined 28 males. All of them were treated with antiplatelet agents and vasodilators in standard doses. In addition, 16 patients received a standard three-day scheme of a glucocorticoid and cyclophosphamide pulse-therapy. The examination of the patients was carried out before the treatment and in a month. Estimation of clinical activity was made according to the BVAS index, serum levels of C-reactive protein (CRP) and von Willebrand factor antigen (VWF-Ag), ESR. Before the start of the treatment there were no significant differences in the values of BVAS, ESR and CRP between the groups. In a month, BVAS index, concentrations, the rate of high serum levels of CRP and frequency of amputations were significantly reduced in patients treated with pulse-therapy. So, this pulse-therapy has a considerable anti-inflammatory effect and decreases frequency of amputations in thrombangiitis obliterans.


Glucocorticoid receptors in sheep brain tissues during development.
In this study we describe changes in the number of glucocorticoid binding sites that occur in cytosols of pituitary, hypothalamic, and hippocampal tissue obtained from fetal, newborn, and adult sheep. We observed specific, saturable binding of [3H]triamcinolone acetonide by cytosols of all three tissues. There were both age-related and tissue-related differences in the number of binding sites observed. By midgestation (70 days) significant quantities of binding sites were present in pituitary and brain tissues, and the number remained relatively constant throughout gestation and in the neonatal period. The number of binding sites declined markedly in cytosols from adult tissues. At all ages there were more binding sites present in pituitary cytosols than in cytosols of hypothalamus and hippocampus. The sucrose density gradient profile of the radioactive ligand-binding site complex is characteristic of a glucocorticoid receptor. Thus, by midgestation at least a portion of the biochemical machinery mediating glucocorticoid effects is present in the fetal pituitary and in specific brain tissues considered important in the modulation of ACTH secretion by corticosteroids.


COVID-19 in Relation to Alzheimer's Disease: Mendelian Randomization Analyses Add to Multiple Lines of Evidence.
The potential link between COVID-19 and Alzheimer's disease (AD) has been an intriguing topic in the global pandemic. Whether the susceptibility and severity of COVID-19 affects the onset and progression of AD is of great concern. Clinical studies suggested an increased risk of AD occurrence or cognitive deficit after COVID-19. Basic research found that severe COVID-19 induced changes resembling AD. Evidence synthesis should always take into account diverse study designs, both traditional and novel. The recent study by Ding et al. aimed to investigate the association of COVID-19 with AD using a non-overlapping two-sample Mendelian randomization analysis.


Oxidative stress triggers the amyloidogenic pathway in human vascular smooth muscle cells.
Cerebral amyloid angiopathy, associated to most cases of Alzheimer's disease (AD), is characterized by the deposition of amyloid ss-peptide (Ass) in brain vessels, although the origin of the vascular amyloid deposits is still controversial: neuronal versus vascular. In the present work, we demonstrate that primary cultures of human cerebral vascular smooth muscle cells (HC-VSMCs) have all the secretases involved in amyloid ss-protein precursor (APP) cleavage and produce Ass(1-40) and Ass(1-42). Oxidative stress, a key factor in the etiology and pathophysiology of AD, up-regulates ss-site APP cleaving enzyme 1 (BACE1) expression, as well as Ass(1-40) and Ass(1-42) secretion in HC-VSMCs. This process is mediated by c-Jun N-terminal Kinase and p38 MAPK signaling and appears restricted to BACE1 regulation as no changes in the other secretases were observed. In conclusion, oxidative stress-mediated up-regulation of the amyloidogenic pathway in human cerebral vascular smooth muscle cells may contribute to the overall cerebrovascular amyloid angiopathy observed in AD patients.


Assessing Field-Specific Risk of Soybean Sudden Death Syndrome Using Satellite Imagery in Iowa.
Moderate resolution imaging spectroradiometer (MODIS) satellite imagery from 2004 to 2013 were used to assess the field-specific risks of soybean sudden death syndrome (SDS) caused by Fusarium virguliforme in Iowa. Fields with a high frequency of significant decrease (>10%) of the normalized difference vegetation index (NDVI) observed in late July to middle August on historical imagery were hypothetically considered as high SDS risk. These high-risk fields had higher slopes and shorter distances to flowlines, e.g., creeks and drainages, particularly in the Des Moines lobe. Field data in 2014 showed a significantly higher SDS level in the high-risk fields than fields selected without considering NDVI information. On average, low-risk fields had 10 times lower F. virguliforme soil density, determined by quantitative polymerase chain reaction, compared with other surveyed fields. Ordinal logistic regression identified positive correlations between SDS and slope, June NDVI, and May maximum temperature, but high June maximum temperature hindered SDS. A modeled SDS risk map showed a clear trend of potential disease occurrences across Iowa. Landsat imagery was analyzed similarly, to discuss the ability to utilize higher spatial resolution data. The results demonstrated the great potential of both MODIS and Landsat imagery for SDS field-specific risk assessment.


A luciferase-based budding assay for Ebola virus.
The VP40 matrix protein of Ebola virus (EBOV) is capable of budding from mammalian cells as a virus-like particle (VLP) and is the major protein involved in virus egress. A functional budding assay has been developed based upon this characteristic of VP40 to assess the contributions of VP40 sequences as well as host proteins to the budding process. This well-defined assay has been modified for potential use in a high-throughput format in which the detection and quantification of firefly luciferase protein in VLPs represents a direct measure of VP40 budding efficiency. Luciferase was found to be incorporated into budding VP40 VLPs. Furthermore, co-expression of EBOV glycoprotein (GP) enhances release of VLPs containing VP40 and luciferase. In contrast, when luciferase is co-expressed with a budding deficient mutant of VP40, luciferase levels in the VLP fraction decrease significantly. This assay represents a promising high-throughput approach to identify inhibitors of EBOV budding.


Barriers to following the supine sleep recommendation among mothers at four centers for the Women, Infants, and Children Program.
The risk for sudden infant death syndrome in black infants is twice that of white infants, and their parents are less likely to place them in the supine position for sleep. We previously identified barriers for parents to follow recommendations for sleep position. Our objective with this study was to quantify these barriers, particularly among low-income, primarily black mothers. We conducted face-to-face interviews with 671 mothers, 64% of whom were black, who attended Women, Infants, and Children Program centers in Boston, Massachusetts, Dallas, Texas, Los Angeles, California, and New Haven, Connecticut. We used univariate analyses to quantify factors that were associated with choice of sleeping position and multivariate logistic regression to calculate adjusted odds ratios for the 2 outcome variables: "ever" (meaning usually, sometimes, or last night) put infant in the prone position for sleep and "usually" put infant in the supine position to sleep. Fifty-nine percent of mothers reported supine, 25% side, 15% prone, and 1% other as the usual position. Thirty-four percent reported that they ever placed infants in the prone position. Seventy-two percent said that a nurse, 53% a doctor, and 38% a female friend or relative provided source of advice. Only 42% reported that a nurse, only 36% a doctor, and only 15% a female friend or relative recommended the supine position for sleep. When a female friend or relative recommended the prone position, mothers were more likely ever to place their infants in the prone position and less likely usually to choose supine compared with those who received no advice from friends or relatives. When a doctor or a nurse recommended a nonsupine position, the mothers were less likely to choose supine compared with those who received no advice from a doctor or a nurse. Mothers who trusted the opinion of a doctor or a nurse about infant sleeping position were more likely to place their infants in the supine position. Half of the mothers believed that infants were more likely to choke when supine, and they were less likely to place their infants supine. Mothers who believed that infants are more comfortable in the prone position (36%) were more likely to place their infants prone. Twenty-nine percent believed that having their infants sleep with an adult helps prevent sudden infant death syndrome, and only 43% believed that sudden infant death syndrome is related to sleeping position. We identified specific barriers to placing infants in the supine position for sleep (lack of or wrong advice, lack of trust in providers, knowledge and concerns about safety and comfort) in low-income, primarily black mothers that should be considered when designing interventions to get more infants onto their back for sleep.


A hands-on experience of the voice of customer analysis in maternity care from Iran.
The purpose of this paper is to describe the use of voice of customer (VoC) analysis in a maternity care case study, where the aim was to identify the most important requirements of women giving birth and to determine targets for the improvement of maternity care in Fayazbakhsh Hospital in Tehran, Iran. The tools of VoC analysis were used to identify: the main customer segment of maternity care; the most important of women's needs and requirements; the level of maternal satisfaction with delivered services at the study hospital and at a competitor; the nature of women's of requirements (termed Kano levels: assumed, expected, and unexpected); and the priorities of the study hospital for meeting these requirements. Women identified the well-being of mother and baby as the most important requirements. Women's satisfaction with the services was, with a few exceptions, low to moderate. Services related to most of the maternal requirements were ranked better in the competitor hospital than the study hospital. The results form a solid basis for achieving improvements in the processes of care for mothers and babies. The paper presents a systematic approach to VoC analysis in health care settings as a basis for clinical process improvement initiatives.


A Critical Test of the Electrostatic Contribution to Catalysis with Noncanonical Amino Acids in Ketosteroid Isomerase.
The vibrational Stark effect (VSE) has been used to measure the electric field in the active site of ketosteroid isomerase (KSI). These measured fields correlate with ΔG(⧧) in a series of conventional mutants, yielding an estimate for the electrostatic contribution to catalysis (Fried et al. Science 2014, 346, 1510-1513). In this work we test this result with much more conservative variants in which individual Tyr residues in the active site are replaced by 3-chlorotyrosine via amber suppression. The electric fields sensed at the position of the carbonyl bond involved in charge displacement during catalysis were characterized using the VSE, where the field sensitivity has been calibrated by vibrational Stark spectroscopy, solvatochromism, and MD simulations. A linear relationship is observed between the electric field and ΔG(⧧) that interpolates between wild-type and more drastic conventional mutations, reinforcing the evaluation of the electrostatic contribution to catalysis in KSI. A simplified model and calculation are developed to estimate changes in the electric field accompanying changes in the extended hydrogen-bond network in the active site. The results are consistent with a model in which the O-H group of a key active site tyrosine functions by imposing a static electrostatic potential onto the carbonyl bond. The model suggests that the contribution to catalysis from the active site hydrogen bonds is of similar weight to the distal interactions from the rest of the protein. A similar linear correlation was also observed between the proton affinity of KSI's active site and the catalytic rate, suggesting a direct connection between the strength of the H-bond and the electric field it exerts.


Development of the macular circulation.
The development of the primate retinal vasculature has been investigated in fetal monkeys (M. mulatta) during the latter half of gestation. Vascularization is found to be retarded in the region of the macula. The macula is found to become completely encircled by a network of primitive capillaries which then proliferate centripetally towards the presumptive fovea. These encircling vessels normally cease to proliferate before reaching the center of the fovea, and the resulting central avascular zone and centripetal pattern of vessels persist thereafter in the mature macula. The superficial peripapillary network of capillaries, like the outer vascular net, is found to be derived from the inner network of vessels.