Improved forecasts of influenza-associated hospitalization rates with Google Search Trends.
Reliable forecasts of influenza-associated hospitalizations during seasonal outbreaks can help health systems better prepare for patient surges. Within the USA, public health surveillance systems collect and distribute near real-time weekly hospitalization rates, a key observational metric that makes real-time forecast of this outcome possible. In this paper, we describe a method to forecast hospitalization rates using a population level transmission model in combination with a data assimilation technique. Using this method, we generated retrospective forecasts of hospitalization rates for five age groups and the overall population during five seasons in the USA and quantified forecast accuracy for both near-term and seasonal targets. Additionally, we describe methods to correct for under-reporting of hospitalization rates (backcast) and to estimate hospitalization rates from publicly available online search trends data (nowcast). Forecasts based on surveillance rates alone were reasonably accurate in predicting peak hospitalization rates (within ± 25% of the actual peak rate, three weeks before peak). The error in predicting rates one to four weeks ahead, remained constant for the duration of the seasons, even during periods of increased influenza incidence. An improvement in forecast quality across all age groups, seasons and targets was observed when backcasts and nowcasts supplemented surveillance data. These results suggest that the model-inference framework can provide reasonably accurate real-time forecasts of influenza hospitalizations; backcasts and nowcasts offer a way to improve system tolerance to observational errors.


When sounds become actions: higher-order representation of newly learned action sounds in the human motor system.
In the absence of visual information, our brain is able to recognize the actions of others by representing their sounds as a motor event. Previous studies have provided evidence for a somatotopic activation of the listener's motor cortex during perception of the sound of highly familiar motor acts. The present experiments studied (a) how the motor system is activated by action-related sounds that are newly acquired and (b) whether these sounds are represented with reference to extrinsic features related to action goals rather than with respect to lower-level intrinsic parameters related to the specific movements. TMS was used to measure the correspondence between auditory and motor codes in the listener's motor system. We compared the corticomotor excitability in response to the presentation of auditory stimuli void of previous motor meaning before and after a short training period in which these stimuli were associated with voluntary actions. Novel cross-modal representations became manifest very rapidly. By disentangling the representation of the muscle from that of the action's goal, we further showed that passive listening to newly learnt action-related sounds activated a precise motor representation that depended on the variable contexts to which the individual was exposed during testing. Our results suggest that the human brain embodies a higher-order audio-visuo-motor representation of perceived actions, which is muscle-independent and corresponds to the goals of the action.


Theoretical study of benzonitrile clusters in the gas phase and their adsorption onto a Au(111) surface.
We made theoretical calculations for a benzonitrile molecule and its clusters in the gas phase and as adsorbed on the Au(111) surface, to explain the observation by scanning tunneling microscope, that is, the trimer formation of cyanophenyl porphyrins adsorbed onto the Au(111) surface. With regard to the gas-phase species, ab initio calculations showed that (1) the benzonitrile dimer has a single stable structure that is planar and antiparallel; (2) the trimer has two isoenergetic stable structures, that is, a planar and cyclic structure and an antiparallel and nonplanar one; (3) the clusters are more stable, at low temperatures, than the monomer. For the adsorbed species, we made quantum mechanical/molecular mechanical calculations in which the interaction between the adsorbates and the surface is evaluated in a molecular-mechanical way by using analytical potential functions and an image charge model. Because the stable structures were found to be similar to those in the gas phase, the cluster formation of adsorbed cyanophenyl porphyrins was attributed to the interaction between cyanophenyl groups, which is barely affected by adsorbate-surface interaction. It was also found that the adsorbed cyclic benzonitrile trimer is more stable than the monomer and the dimer because the relative stability is dependent on enthalpy alone. We therefore concluded that the preferential formation of trimers by the adsorbed cyanophenyl porphyrins is due to the negligible contribution of entropy to the relative stability of the adsorbed species and that the adsorption hardly changes the situation found in the gas phase.


Molecular complexity of the major urinary protein system of the Norway rat, Rattus norvegicus.
Major urinary proteins (MUP) are the major component of the urinary protein fraction in house mice (Mus spp.) and rats (Rattus spp.). The structure, polymorphism and functions of these lipocalins have been well described in the western European house mouse (Mus musculus domesticus), clarifying their role in semiochemical communication. The complexity of these roles in the mouse raises the question of similar functions in other rodents, including the Norway rat, Rattus norvegicus. Norway rats express MUPs in urine but information about specific MUP isoform sequences and functions is limited. In this study, we present a detailed molecular characterization of the MUP proteoforms expressed in the urine of two laboratory strains, Wistar Han and Brown Norway, and wild caught animals, using a combination of manual gene annotation, intact protein mass spectrometry and bottom-up mass spectrometry-based proteomic approaches. Cluster analysis shows the existence of only 10 predicted mup genes. Further, detailed sequencing of the urinary MUP isoforms reveals a less complex pattern of primary sequence polymorphism in the rat than the mouse. However, unlike the mouse, rat MUPs exhibit added complexity in the form of post-translational modifications, including the phosphorylation of Ser4 in some isoforms, and exoproteolytic trimming of specific isoforms. Our results raise the possibility that urinary MUPs may have different roles in rat chemical communication than those they play in the house mouse. Shotgun proteomics data are available via ProteomExchange with identifier PXD013986.


Association of diabetes mellitus and dementia: the Rotterdam Study.
Dementia and non-insulin-dependent diabetes mellitus (NIDDM) are highly prevalent disorders in the elderly. Diabetes has repeatedly been reported to affect cognition, but its relation with dementia is uncertain. We therefore studied the association between diabetes and dementia in the Rotterdam Study, a large population-based study in the elderly. Of 6330 participants, aged 55 to 99 years old, complete information on diabetes and presence of dementia was available. Diabetes was diagnosed as use of anti-diabetes medication or random or post-load serum glucose over 11 mmol/1. Dementia was diagnosed through a stepped approach, including a sensitive screening of all participants and a comprehensive diagnostic work-up. Diabetes was present in 724 (11.4%) subjects. Of the 265 dementia patients 59 (22.3%) had diabetes. Multiple logistic regression analyses, adjusting for age and sex differences, revealed a positive association between diabetes and dementia (odds ratio: 1.3, 95% confidence interval 1.0-1.9). In particular, strong associations were found between dementia and diabetes treated with insulin (odds ratio: 3.2, 95% confidence interval: 1.4-7.5) The relation was strongest with vascular dementia but was also observed with Alzheimer's disease. These associations were independent of educational attainment, smoking, body mass index, atherosclerosis, blood pressure and antihypertensive drug treatment, and could not be explained by clinical cerebra infarctions. The results suggest that NIDDM is associated with dementia. Alzheimer's disease may be more frequent in elderly diabetic patients treated with insulin.


Three large, functioning cystic parathyroid adenomas.
To report a very rare case of 3 large, functioning cystic parathyroid adenomas causing primary hyperparathyroidism. We present the history, clinical findings, laboratory test results, radiologic findings, endocrine workup results, intraoperative surgical challenges, and surgical pathology report of the study patient. We review the literature and discuss the importance of intraoperative parathyroid hormone (PTH) measurement in such cases. A 79-year-old woman presented with primary hyperparathyroidism and elevated levels of calcium and PTH. Localization studies confirmed the presence of a large right upper parathyroid adenoma. On exploration, a very large cystic parathyroid gland was identified at that location. Because intraoperative PTH levels remained elevated, further exploration was pursued, which revealed 2 more large cystic glands on the left side that were resected. This resulted in an adequate but slow PTH drop. The right lower gland appeared normal. On follow-up 4 days and 6 weeks after surgery, the calcium and PTH levels had normalized. This case highlights the aspects of intraoperative PTH use and underscores the need to exclude multigland disease even in the setting of a very large parathyroid cyst with concordant localization studies.


First quarter century of laparoscopic liver resection.
The beginnings of laparoscopic liver resection (LLR) were at the start of the 1990s, with the initial reports being published in 1991 and 1992. These were followed by reports of left lateral sectionectomy in 1996. In the years following, the procedures of LLR were expanded to hemi-hepatectomy, sectionectomy, segmentectomy and partial resection of posterosuperior segments, as well as the parenchymal preserving limited anatomical resection and modified anatomical (extended and/or combining limited) resection procedures. This expanded range of LLR procedures, mimicking the expansion of open liver resection in the past, was related to advances in both technology (instrumentation) and technical skill with conceptual changes. During this period of remarkable development, two international consensus conferences were held (2008 in Louisville, KY, United States, and 2014 in Morioka, Japan), providing up-to-date summarizations of the status and perspective of LLR. The advantages of LLR have become clear, and include reduced intraoperative bleeding, shorter hospital stay, and - especially for cirrhotic patients-lower incidence of complications (e.g., postoperative ascites and liver failure). In this paper, we review and discuss the developments of LLR in operative procedures (extent and style of liver resections) during the first quarter century since its inception, from the aspect of relationships with technological/technical developments with conceptual changes.


Multicenter, double-blind study of intravenous milrinone for patients with acute heart failure in Japan. Japan Intravenous Milrinone Investigators.
Milrinone is a phosphodiesterase F-III inhibitor with positive inotropic and vasodilating activities. We investigated the hemodynamic response and pharmacokinetics of intravenous milrinone in patients with acute heart failure. Double-blind studies: a prospective, multicenter, double-blind, dose-finding study and a placebo-controlled, double-blind, comparative study. Patients with acute heart failure (pulmonary artery occlusion pressure of > or = 18 mm Hg), who were hospitalized in the cardiac care units of 33 institutes in Japan, were entered into the study. Fifty-four patients with acute or decompensated heart failure in the dose-finding study and 52 patients in the placebo-controlled, double-blind, comparative study. The present multicenter study consisted of a double-blind, dose-finding study (50-micrograms/kg intravenous loading dose, followed by 0.25, 0.5, or 0.75 microgram/kg/min of a continuous infusion of milrinone for 6 hrs, n = 54), and a placebo-controlled, double-blind, comparative study (50-micrograms/kg loading dose, followed by 0.5 microgram/kg/min of a continuous infusion of milrinone vs. placebo treatment, n = 52). We investigated the effects on cardiovascular hemodynamics, subjective symptoms, physical findings, and the pharmacokinetics of intravenous milrinone in a total of 106 patients with acute heart failure. In the double-blind, dose-finding study, dose-dependent inotropic/vasodilating hemodynamic effects were documented for percent changes in cardiac index (+21.2%, +25.8%, and +30.9%, respectively) and pulmonary artery occlusion pressure (-12.8%, -17.0%, -41.3%, respectively) vs. plasma drug concentration at the equilibrium state (6 hrs after starting continuous infusion; 97 +/- 13, 197 +/- 22, and 284 +/- 28 ng/mL, respectively). Throughout the 6-hr infusion period, subjective symptoms were improved in 40%, 46.2%, and 70% of patients, respectively, for the three continuous infusion rates (0.25, 0.5, and 0.75 microgram/kg/min). In the placebo-controlled, double-blind, comparative study, the milrinone group exhibited marked improvement in cardiovascular hemodynamics (pulmonary artery occlusion pressure: from 26 +/- 6 to 15 +/- 3 mm Hg; cardiac index: from 2.6 +/- 0.9 to 3.3 +/- 1.1 L/min/m2) within 15 mins after starting drug administration. However, the placebo group showed no significant hemodynamic changes. Subjective symptoms and physical findings of acute heart failure improved in 47.6% and 40%, respectively, of patients within 60 mins after starting milrinone. The placebo group, however, showed no improvement providing inotropic/vasodilating (both 0%). Continuous infusion of milrinone (0.25 to 0.75 microgram/kg/min) after a 50-micrograms/kg loading dose is effective for inotropic/vasodilating hemodynamic support in patients with acute or decompensated heart failure.


A point mutation within conserved region VI of herpes simplex virus type 1 DNA polymerase confers altered drug sensitivity and enhances replication fidelity.
Herpes simplex virus type 1 (HSV-1) DNA polymerase contains several conserved regions within the polymerase domain. The conserved regions I, II, III, V, and VII have been shown to have functional roles in the interaction with deoxynucleoside triphosphates (dNTPs) and DNA. However, the role of conserved region VI in DNA replication has remained unclear due, in part, to the lack of a well-characterized region VI mutant. In this report, recombinant viruses containing a point mutation (L774F) within the conserved region VI were constructed. These recombinant viruses were more susceptible to aphidicolin and resistant to both foscarnet and acyclovir, compared to the wild-type KOS strain. Marker transfer experiments demonstrated that the L774F mutation conferred the altered drug sensitivities. Furthermore, mutagenesis assays demonstrated that L774F recombinant viruses containing the supF marker gene, which was integrated within the thymidine kinase locus (tk), exhibited increased fidelity of DNA replication. These data indicate that conserved region VI, together with other conserved regions, forms the polymerase active site, has a role in the interaction with deoxyribonucleotides, and regulates DNA replication fidelity. The possible effect of the L774F mutation in altering the polymerase structure and activity is discussed.


The hidden challenges in role transitions and how leadership coaching can help new leaders find solid ground.
Leadership coaching is becoming an increasingly important intervention that helps individual nurse executives and managers develop and use the best of their strengths, gifts, and talents. As the need for leadership in nursing becomes urgent and brave souls move into the positions of greater authority and potential impact, they will face challenges as they move up in rank. This article identifies the hidden and often-overlooked challenges that are faced by new leaders as they transition into roles of increased responsibility, and it demonstrates how leadership coaching can help new leaders make successful transitions. As the current health care crisis creates opportunity for new leaders, those who opt for promotions and lateral shifts encounter both expected and surprising challenges. The expected challenges include mastering new content skills, learning new organizational structures, and getting to know new teams. The less obvious stressors include issues of self-esteem, assertiveness, self-consciousness, self-criticism, perfectionism, new boundaries, changing identities, and finding one's own leadership style. These important issues are often kept out of conscious awareness and overlooked at great cost to the individual leader and her institution. Leadership coaching can provide support and practical strategies for managing and overcoming these hidden challenges.


Oral health-related quality of life in Germany.
The prevalence of impaired oral health-related quality of life (OHRQoL) in Germany is unknown. The aim was to determine the OHRQoL distribution in the population and to derive population-based norms. OHRQoL was measured using the German version of the Oral Health Impact Profile (OHIP-G, 53 items) which was administered in a personal interview to 2050 subjects (response proportion: 60%) 16-79 yr of age. Subjects were sampled using a multistage sampling technique in a national survey. Prevalence was calculated for any impairment on the item (OHIP answer categories ranging from 'hardly ever' to 'very often') and for frequent problems (categories 'fairly often' and 'very often'). Norms for the OHIP-G summary score (sum of all item responses in the English-language OHIP, range 0-196) were described by percentiles. Past-month prevalence of any impairment in OHRQoL ranged from 13% to 46% across all items. Frequent problems were rare (</= 6% for all items). Among subjects without dentures, 50% of the population had >/= 5 OHIP-G score points and 10% had >/= 38 points. For subjects with removable dentures the scores were 15 and 60 points, respectively, and for subjects with complete dentures, 23 and 85 points, respectively. The results provide the first overview of impaired OHRQoL in Germany.


Analysis of the expression of neurokinin B, kisspeptin, and their cognate receptors NK3R and KISS1R in the human female genital tract.
To investigate the presence of neurokinin B (NKB)/NK(3) receptor (NK(3)R) and kisspeptin/KISS1 receptor (KISS1R) messenger RNA (mRNA) and proteins throughout the human female genital tract. In vitro study. Academic research laboratories and academic hospitals. Fifteen reproductive-age women and 16 postmenopausal women provided fresh samples of uterus, ovary, or oviduct, and 12 women provided archival samples of endometrium or oviduct. Fresh and archival samples of uterus, ovary, and oviduct obtained from reproductive-age and postmenopausal women. Results of reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry to investigate the pattern of expression of NKB/NK(3)R and kisspeptin/KISS1R in target tissues. Expression of the genes encoding NKB (TAC3) and NK(3)R (TACR3), and kisspeptin (KISS1) and its receptor (KISS1R) was found in the uterus, ovary, and oviduct. Both NKB and NK(3)R immunoreactivity was detected in the endometrium, the oviduct, and the ovary, with marked expression in endometrial and oviductal epithelial cells, where intense coexpression of kisspeptin and KISS1R was also detected. Positive staining for NKB and NK(3)R was found in the myometrium where, in contrast, kisspeptin and KISS1R were absent. NKB/NK(3)R and kisspeptin/KISS1R are present in female peripheral reproductive tissues with colocalization of both systems in some non-neuronal cell populations of the human female genital tract. Our findings are compatible with a potential modulatory role of NKB and kisspeptin at peripheral reproductive tissues.


Comparison of Effects of Low- versus High-Dose Heparin on Access-Site Complications during Transradial Coronary Angiography: A Double-Blind Randomized Study.
Although heparin is highly effective in reducing the rate of radial artery occlusion after transradial catheterization, the optimal heparin dose is still controversial. The aim of this study was to evaluate the efficacy and safety of two different heparin doses during transradial coronary angiography. 490 consecutive patients undergoing transradial coronary angiography were prospectively enrolled into this double-blind randomized trial. A total of 202 patients enrolled in the low-dose (LD; 2,500 U of heparin) group and 202 patients enrolled in the high-dose (HD; 5,000 U of heparin) group were included in the final analysis. The primary endpoint of the study was radial artery occlusion. Bleeding and hematomas were the secondary outcome measures. At day 7, radial artery occlusion occurred in 5.9% of the patients in the LD group and in 5.4% of the patients in the HD group (p = 0.83). Bleeding during deflation of the transradial band occurred in 6.4% of the patients in the LD group and in 18.3% of the patients in the HD group; the difference was statistically significant (p < 0.001). Higher-dose heparin was found to be an independent predictor of bleeding (p = 0.007). A lower dose of heparin (i.e. 2,500 U) decreases bleeding during transradial band deflation without an increase in radial artery occlusion.


The development of multisensory speech perception continues into the late childhood years.
Observing a speaker's articulations substantially improves the intelligibility of spoken speech, especially under noisy listening conditions. This multisensory integration of speech inputs is crucial to effective communication. Appropriate development of this ability has major implications for children in classroom and social settings, and deficits in it have been linked to a number of neurodevelopmental disorders, especially autism. It is clear from structural imaging studies that there is a prolonged maturational course within regions of the perisylvian cortex that persists into late childhood, and these regions have been firmly established as being crucial to speech and language functions. Given this protracted maturational timeframe, we reasoned that multisensory speech processing might well show a similarly protracted developmental course. Previous work in adults has shown that audiovisual enhancement in word recognition is most apparent within a restricted range of signal-to-noise ratios (SNRs). Here, we investigated when these properties emerge during childhood by testing multisensory speech recognition abilities in typically developing children aged between 5 and 14 years, and comparing them with those of adults. By parametrically varying SNRs, we found that children benefited significantly less from observing visual articulations, displaying considerably less audiovisual enhancement. The findings suggest that improvement in the ability to recognize speech-in-noise and in audiovisual integration during speech perception continues quite late into the childhood years. The implication is that a considerable amount of multisensory learning remains to be achieved during the later schooling years, and that explicit efforts to accommodate this learning may well be warranted.


Synthesis of novel ZnV₂O₄ hierarchical nanospheres and their applications as electrochemical supercapacitor and hydrogen storage material.
Hierarchical nanostructures (Hs) have recently garnered enormous attention due to their remarkable performances in catalysis, electronic devices, energy storage and conversion. Considering the advantage of hierarchical nanostructures, we have formulated a facile and template free method to synthesize novel hierarchical nanospheres (NHNs) of ZnV2O4. Both zinc and vanadium are earth abundant, relatively economical and can offer several oxidation states, which can render a broad range of redox reactions favorable for electrochemical energy storage applications. Keeping these points in mind, we investigated for the first time the electrochemical supercapacitor performance of NHNs. The electrochemical measurements were performed in 2 M KOH solution. The measured specific capacitance of ZnV2O4 electrode is 360 F/g at 1 A/g with good stability and retention capacity of 89% after 1000 cycles. Moreover, the hydrogen storage properties of NHNs were measured at 473, 573, and 623 K with an absorption of 1.76, 2.03, and 2.49 wt %. respectively. These studies pave the way to consider ZnV2O4 as prospective material for energy storage applications.


Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells.
Cyclooxygenase-2 (COX-2) is upregulated in pulmonary artery smooth muscle cells (PASMCs) during hypoxia and may play a protective role in the response of the lung to hypoxia. Selective COX-2 inhibition may have detrimental pulmonary vascular consequences during hypoxia. To investigate the role of COX-2 in the pulmonary vascular response to hypoxia, we subjected wild-type and COX-2-deficient mice to a model of chronic normobaric hypoxia. COX-2-null mice developed severe pulmonary hypertension with exaggerated elevation of right ventricular systolic pressure, significant right ventricular hypertrophy, and striking vascular remodeling after hypoxia. Pulmonary vascular remodeling in COX-2-deficient mice was characterized by PASMC hypertrophy but not increased proliferation. Furthermore, COX-2-deficient mice had significant upregulation of the endothelin-1 receptor (ET(A)) in the lung after hypoxia. Similarly, selective pharmacological inhibition of COX-2 in wild-type mice exacerbated hypoxia-induced pulmonary hypertension and resulted in PASMC hypertrophy and increased ET(A) receptor expression in pulmonary arterioles. The absence of COX-2 in vascular smooth muscle cells during hypoxia in vitro augmented traction forces and enhanced contractility of an extracellular matrix. Treatment of COX-2-deficient PASMCs with iloprost, a prostaglandin I(2) analog, and prostaglandin E(2) abrogated the potent contractile response to hypoxia and restored the wild-type phenotype. Our findings reveal that hypoxia-induced pulmonary hypertension and vascular remodeling are exacerbated in the absence of COX-2 with enhanced ET(A) receptor expression and increased PASMC hypertrophy. COX-2-deficient PASMCs have a maladaptive response to hypoxia manifested by exaggerated contractility, which may be rescued by either COX-2-derived prostaglandin I(2) or prostaglandin E(2).


Neuropsychological functioning, illness perception, mood and quality of life in chronic fatigue syndrome, autoimmune thyroid disease and healthy participants.
This study attempted to longitudinally investigate neuropsychological function, illness representations, self-esteem, mood and quality of life (QoL) in individuals with chronic fatigue syndrome (CFS) and compared them with both healthy participants and a clinical comparison group of individuals with autoimmune thyroid disease (AITD). Neuropsychological evaluation was administered at two time points, five weeks apart. Twenty-one individuals with CFS, 20 individuals with AITD and 21 healthy participants were matched for age, pre-morbid intelligence, education level and socio-economic status (SES). All groups also completed measures of illness perceptions, mood, self-esteem and QoL at both time points. The CFS group showed significantly greater impairment on measures of immediate and delayed memory, attention and visuo-constructional ability, and reported significantly higher levels of anxiety and depression. After controlling for the effects of mood, the CFS group still demonstrated significant impairment in attention. The CFS group also reported significantly lower self-reported QoL than the AITD and healthy participants. In terms of illness perceptions, the AITD group believed that their condition would last longer, that they had more treatment control over their condition, and reported less concern than the CFS group. These results suggest that the primary cognitive impairment in CFS is attention and that this is not secondary to affective status. The lower treatment control perceptions and greater illness concerns that CFS patients report may be causally related to their affective status.


Alcohol consumption, alcohol dependence and related harms in Spain, and the effect of treatment-based interventions on alcohol dependence.
Alcohol consumption in Spain has traditionally followed the Mediterranean drinking pattern, featuring daily drinking with meals, beer as the preferred beverage, and comparatively little drinking to intoxication. Alcohol dependence (AD), one of the most detrimental disorders caused by alcohol, was prevalent in 0.2% of women and 1.2% of men, corresponding to 31,200 women and 186,000 men in Spain with AD in 2005 in the age group of 15 to 64 year. These prevalence estimates of alcohol dependence are likely underestimated due to limitations in the World Mental Health Survey which cannot be fully corrected for; however, the estimates of AD for Spain represent the most accurate and up to date estimates available. Alcohol creates a significant health burden in Spain with 11.3 premature deaths in women per 100,000 aged 15 to 64 years, and 40.9 premature deaths in men per 100,000 in the same age group were due to alcohol consumption (data for 2004). This amounts to 8.4% of all female deaths and 12.3% of all the male deaths in this age group being attributable to alcohol consumption. A large percentage of these harms were due to heavy alcohol consumption and AD. AD is undertreated in Spain, with less than 10% of all people with AD treated. For those who are treated, psychotherapy is the most utilized form of treatment to avoid relapse. If 40% of AD patients in Spain were treated with pharmacological treatment (the most effective treatment method), 2.2% of female and 6.2% of male deaths due to AD would be prevented within one year. Thus by increasing treatment rates is an important means of reducing the alcohol-attributable mortality and health burden in Spain.


Photocurrent enhancement of SnO2 nanowires through Au-nanoparticles decoration.
It is found that the sensitivity of photoresponse of SnO(2) nanowires can be enhanced by metallic particles decoration. The underlying mechanism is attributed to the formation of the Schottky junction on nanowires surface in the vicinity of metallic nanoparticles. The increment in the barrier height and width of space charge region due to the existence of Schottky junction increases the surface electric field and enhances the spatial separation effect, which then prolongs the lifetime of photoinduced electron and consequently increases the photoresponse gain. The result shown here provides an alternative route for enhancing the photoresponse of semiconductor nanostructures, which should be useful for creating highly sensitive photodetectors.


Sensory deprivation alters aggrecan and perineuronal net expression in the mouse barrel cortex.
An important role for the neural extracellular matrix in modulating cortical activity-dependent synaptic plasticity has been established by a number of recent studies. However, identification of the critical molecular components of the neural matrix that mediate these processes is far from complete. Of particular interest is the perineuronal net (PN), an extracellular matrix component found surrounding the cell body and proximal neurites of a subset of neurons. Because of the apposition of the PN to synapses and expression of this structure coincident with the close of the critical period, it has been hypothesized that nets could play uniquely important roles in synapse stabilization and maturation. Interestingly, previous work has also shown that expression of PNs is dependent on appropriate sensory stimulation in the visual system. Here, we investigated whether PNs in the mouse barrel cortex are expressed in an activity-dependent manner by manipulating sensory input through whisker trimming. Importantly, this manipulation did not lead to a global loss of PNs but instead led to a specific decrease in PNs, detected with the antibody Cat-315, in layer IV of the barrel cortex. In addition, we identified a key activity-regulated component of PNs is the proteoglycan aggrecan. We also demonstrate that these Cat-315-positive neurons virtually all also express parvalbumin. Together, these data are in support of an important role for aggrecan in the activity-dependent formation of PNs on parvalbumin-expressing cells and suggest a role for expression of these nets in regulating the close of the critical period.


The cholinergic hypothesis of Alzheimer's disease: a review of progress.
Alzheimer's disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer's disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer's disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no "cure" for Alzheimer's disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer's disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.


Assessment of mitral annular velocities by speckle tracking echocardiography versus tissue Doppler imaging: validation, feasibility, and reproducibility.
Mitral annular velocity may be measured angle independently by speckle tracking echocardiography (STE), in contrast with tissue Doppler imaging (TDI). The purpose of the current study was to compare STE and TDI, with respect to 1) the accuracy of velocity measurements in a moving phantom, 2) the feasibility and reproducibility of measurement of mitral annular velocities in a clinical setting, and 3) the estimation of left ventricular filling pressures using mitral annular velocities. The velocity of a moving phantom, using different angles of insonation, and mitral annular velocities of 80 nonselected patients and 50 healthy volunteers were determined using TDI and STE. A subgroup of 20 patients was studied during right-sided heart catheterization. When the motion direction of the phantom was parallel to the ultrasound beam, both TDI and STE determined velocities accurately. With increasing angle of insonation, TDI-derived velocity decreased, whereas STE-derived velocity remained unchanged. The feasibility of mitral annular velocities measured by TDI and STE was comparable (98% vs 95%, P = not significant). Although for both techniques correlations between measured mitral annular velocities at repeated examinations were good, the test-retest variability of mitral annular velocities by TDI was higher. E/Em ratio by STE correlated better to pulmonary capillary wedge pressure (R(2) = 0.51, P < .001) compared with E/Em ratio derived from TDI (R(2) = 0.35, P < .01), although the difference in correlation was not statistically significant because of the limited sample size. Tissue velocities can be accurately determined by STE in a moving phantom and are angle independent, in contrast with TDI measurements. Furthermore, STE is a feasible and better reproducible method for the assessment of mitral annular velocities in a clinical setting.


Structural coloration of transmission light through self-aligned and complementary plasmonic nanostructures.
Structural coloration of natural surfaces often originates from the change of reflected colors depending on the viewing or illumination angle. Recently, the structural coloration of nanoplasmonic structures has attracted a great deal of attention due to high compactness, robust stability and high color-tunability, as well as high sensitivity to the incidence angle. Here we report complementary plasmonic structures (CPS) for transmission structural coloration by tailoring a single spectral peak depending on the incidence angle of light. The CPS features self-aligned silver nanohole and nanodisk arrays, supported by dielectric nanopillar arrays of hydrogen silsesquioxane. Unlike the conventional hybridized nanostructures of plasmonic nanohole and nanodisk arrays, the nanodisks of CPS effectively attenuate undesired spectral peaks of nanoholes by exploiting an extinction peak of nanodisks, serving as a spectral suppressor. As a result, a single transmission spectral peak becomes red-shifted from 736 nm to 843 nm as the incidence angle varies from 0° to 30°. This unique configuration provides a new direction for tunable filters that can be utilized for compact multispectral or hyperspectral imaging applications.


Culture, gaze and the neural processing of fear expressions.
The direction of others' eye gaze has important influences on how we perceive their emotional expressions. Here, we examined differences in neural activation to direct- versus averted-gaze fear faces as a function of culture of the participant (Japanese versus US Caucasian), culture of the stimulus face (Japanese versus US Caucasian), and the relation between the two. We employed a previously validated paradigm to examine differences in neural activation in response to rapidly presented direct- versus averted-fear expressions, finding clear evidence for a culturally determined role of gaze in the processing of fear. Greater neural responsivity was apparent to averted- versus direct-gaze fear in several regions related to face and emotion processing, including bilateral amygdalae, when posed on same-culture faces, whereas greater response to direct- versus averted-gaze fear was apparent in these same regions when posed on other-culture faces. We also found preliminary evidence for intercultural variation including differential responses across participants to Japanese versus US Caucasian stimuli, and to a lesser degree differences in how Japanese and US Caucasian participants responded to these stimuli. These findings reveal a meaningful role of culture in the processing of eye gaze and emotion, and highlight their interactive influences in neural processing.


[Lifetime medical expenditures of smokers and nonsmokers].
The aim of this study was to examine which of the two groups have higher lifetime medical expenditures; male smokers or male nonsmokers. We conducted this investigation using a Japanese single cohort database to calculate long-term medical expenditures and 95% confidence intervals. We first constructed life tables for male smokers and male nonsmokers from the age of 40 years after analyzing their mortality rates. Next, we calculated the average annual medical expenditures of each of the two groups, categorized into survivors and deceased. Finally, we calculated long-term medical expenditures and performed sensitivity analyses. The results showed that although smokers had generally higher annual medical expenditures than nonsmokers, the former's lifetime medical expenditure was slightly lower than the latter's because of a shorter life expectancy that resulted from a higher mortality rate. Sensitivity analyses did not reverse the order of the two lifetime medical expenditures. In conclusion, although smoking may not result in an increase in lifetime medical expenditures, it is associated with diseases, decreased life expectancy, lower quality of life (QOL), and generally higher annual medical expenditures. It is crucial to promote further tobacco control strategically by maximizing the use of available data.


Direct observation and validation of fluorescein tear film break-up patterns by using a dual thermal-fluorescent imaging system.
The fluorescein tear film break-up test is a common tear film stability test for dry eye diagnosis. This test requires applying fluorescein sodium drops to a tear film to observe the tear film break-up. However, this test is limited by using the fluorescein sodium drops, which can induce reflex tearing and reduce the reliability of the diagnosis results. This paper proposes that tear film evaporation accelerates on the fluorescein tear film break-up area (FTBA), resulting in a lower temperature area (LTA) on the tear film. A dual modality system was established to capture the thermal and fluorescent image of fluorescein-stain tear films for 48 participants. Observations showed that the LTA and FTBA were highly correlated in their location (r = 0.82) and size (r = 0.91). This is first study to show that the FTBA and LTA are essentially the same region. This study demonstrated the feasibility of using the noncontact thermograph method to evaluate tear film stability without using a fluorescein sodium drop.


Prediction of adult height in growth-hormone-treated children with growth hormone deficiency.
Several studies have searched for factors that significantly influence adult height (AH) of children with GH deficiency (GHD) who have been treated with biosynthetic GH, but a prediction model for AH has not yet been presented. Our objective was to develop models for prediction of AH, using information available at the start of GH treatment or after 1 yr of treatment. For this retrospective study, data were collected from the National Registry of Growth Hormone Treatment in Children, which contained data of Dutch children treated with GH. Patients included males born before 1985 and females born before 1987 with either diagnosis of GHD (syndromes, tumors, and other diseases were excluded) or a maximal GH response during provocation tests of less than 11 ng/ml, treated with biosynthetic GH for at least 1 yr. To be able to use the complete group of 342 children for the development of the models, multiple imputation was used for missing values. We assessed AH sd scores (SDS). Each prediction model contained both target height SDS and current height SDS. The change in height SDS during the first year proved an important predictor for AH. In all models, addition of GH dose was not significant. The percent explained variance, after correction for overfitting, ranged from 37% (prepubertal children, prediction at start) to 60% (pubertal children, prediction after 1 yr). The presented prediction models give accurate predictions of AH for children with GHD at start and after 1 yr of GH treatment. They are useful tools in the treatment of these children.


Risk factors for anal cancer in persons infected with HIV: a nested case-control study in the Swiss HIV Cohort Study.
Although persons infected with human immunodeficiency virus (HIV), particularly men who have sex with men, are at excess risk for anal cancer, it has been difficult to disentangle the influences of anal exposure to human papillomavirus (HPV) infection, immunodeficiency, and combined antiretroviral therapy. A case-control study that included 59 anal cancer cases and 295 individually matched controls was nested in the Swiss HIV Cohort Study (1988-2011). In a subset of 41 cases and 114 controls, HPV antibodies were tested. A majority of anal cancer cases (73%) were men who have sex with men. Current smoking was significantly associated with anal cancer (odds ratio (OR) = 2.59, 95% confidence interval (CI): 1.25, 5.34), as were antibodies against L1 (OR = 4.52, 95% CI: 2.00, 10.20) and E6 (OR = ∞, 95% CI: 4.64, ∞) of HPV16, as well as low CD4+ cell counts, whether measured at nadir (OR per 100-cell/μL decrease = 1.53, 95% CI: 1.18, 2.00) or at cancer diagnosis (OR per 100-cell/μL decrease = 1.24, 95% CI: 1.08, 1.42). However, the influence of CD4+ cell counts appeared to be strongest 6-7 years prior to anal cancer diagnosis (OR for <200 vs. ≥500 cells/μL = 14.0, 95% CI: 3.85, 50.9). Smoking cessation and avoidance of even moderate levels of immunosuppression appear to be important in reducing long-term anal cancer risks.


Pay in the British NHS: a local solution for a national service?
An important component of the reforms of the British National Health Service (NHS) has been devolution of a previously highly centralised pay bargaining system to the local provider level. As the wage bill is by far the single largest item of health care expenditure, the implications of this change may be far-reaching. This article surveys the available theory and evidence from an economic perspective. It reviews the development of pay determination mechanisms in the NHS and the extent to which local pay has been adopted since the reforms were introduced. It then considers the theory of local pay and general evidence on local pay variations in the UK, before turning to the available evidence on local labour markets in the health care sectors of the UK and USA. It concludes with a discussion of the policy and research implications of current developments on local pay bargaining in the NHS. In particular, it suggests that judgements over the success or failure of local pay bargaining will concern: first, whether the weakened monopsony position of the NHS at national level results in higher pay for the more powerful employee groups; second, whether fragmentation of bargaining weakens the negotiating and lobbying power of national trade unions and professional organisations; third, whether competition between providers leads to higher or lower costs; and fourth, whether any efficiency gains from local bargaining outweight the higher transaction costs involved.


The effects of physiological arousal on cognitive and psychomotor performance among individuals with high and low anxiety sensitivity.
Information-processing models of anxiety posit that anxiety pathology is associated with processing biases that consume cognitive resources and may detract from one's ability to process environmental stimuli. Previous research has consistently indicated that high anxiety has a negative impact on cognitive and psychomotor performance. Anxiety sensitivity, or the fear of anxiety and anxiety-related arousal sensations, is an anxiety vulnerability factor that has been shown to play a role in the development and maintenance of panic attacks and panic disorder. However, relatively little is known regarding the potential impact of anxiety sensitivity on performance. In the present study, 105 college students who scored either high (≥ 24) or low (≤ 14) on the Anxiety Sensitivity Index were randomly assigned to complete a series of arousal-induction tasks or no activity, followed immediately by three cognitive and psychomotor performance tasks: digit span - backward, math fluency, and grooved pegboard. Results indicated that participants with high anxiety sensitivity performed comparably to individuals with low anxiety sensitivity on each task, regardless of arousal level.


In vitro antibody response to tetanus in the MIMIC system is a representative measure of vaccine immunogenicity.
In response to the recurrent failure of animal vaccine protection studies to accurately predict human trial results, we have developed a fully human modular immune in vitroconstruct (MIMIC) to serve as a preliminary screen for efficacy testing of potential vaccine formulations. To validate the potential of this approach, we monitored the in vitro-generated tetanus (TT)-specific antibody levels in a cohort of donors before and after receiving tetanus vaccination. Purified CD4_T cell and B cell populations were combined with autologous tetanus vaccine-pulsed dendritic cells to generate specific antibody. Enumeration of TT-specific IgG antibody-secreting cells by ELISPOT displayed a significant increase in the magnitude of this population after vaccination. The relative magnitudes of the in vitro-generated TT-specific antibody response before and after vaccination largely recapitulated the TT-specific IgG serum titer profiles measured in the same individuals. These findings provide evidence that the MIMIC system can be a rapid and representative in vitro method for measuring vaccine immunogenicity via induction of the memory B cell response.


Marine viruses: the beneficial side of a threat.
Marine viruses are ubiquitous, extremely diverse, and outnumber any form of life in the sea. Despite their ecological importance, viruses in marine environments have been largely ignored by the academic community, and only those that have caused substantial economic losses have received more attention. Fortunately, our current understanding on marine viruses has advanced considerably during the last decades. These advances have opened new and exciting research opportunities as several unique structural and genetic characteristics of marine viruses have shown to possess an immense potential for various biotechnological applications. Here, a condensed overview of the possibilities of using the enormous potential offered by marine viruses to develop innovative products in industries as pharmaceuticals, environmental remediation, cosmetics, material sciences, and several others, is presented. The importance of marine viruses to biotechnology should not be underestimated.


Strong, Water-Durable, and Wet-Resilient Cellulose Nanofibril-Stabilized Foams from Oven Drying.
Porous materials from cellulose nanofibrils (CNFs) have been prepared using Pickering foams from aqueous dispersions. Stable wet foams were first produced using surface-modified CNFs as stabilizing particles. To better maintain the homogeneous pore structure of the foam after drying, the foams were dried in an oven on a liquid-filled porous ceramic frit. The cell structure was studied by scanning electron microscopy and liquid porosimetry, the mechanical properties were studied by compression testing, and the liquid absorption capacity was determined both with liquid porosimetry and by soaking in water. By controlling the charge density of the CNFs, it was possible to prepare dry foams with different densities, the lowest density being 6 kg m(-3), that is, a porosity of 99.6%. For a foam with a density of 200 kg m(-3), the compressive Young's modulus was 50 MPa and the energy absorption to 70% strain was 2.3 MJ m(-3). The use of chemically modified CNFs made it possible to prepare cross-linked foams with water-durable and wet-resilient properties. These foams absorbed liquid up to 34 times their own weight and were able to release this liquid under compression and to reabsorb the same amount when the pressure was released.


Perspectives of Health Care Providers Regarding Emergency Department Care of Children and Youth with Autism Spectrum Disorder.
This study aimed to characterize the perspectives of health professionals who care for children with autism spectrum disorder (ASD) in the emergency department (ED) and to determine what strategies could optimize care. Ten physicians and twelve nurses were interviewed individually. Questions related to experiences, processes, clinical decision-making and outcomes of children with ASD recently seen in the ED. Interviews were audio recorded, transcribed, and analyzed using a qualitative framework. Participants identified factors that facilitated effective care, including communication strategies, parental involvement and teamwork. Barriers identified included child characteristics, the ED environment, and competing demands. Recommendations included additional staff training and stakeholder engagement. However, making accommodations was often described as being at odds with how the ED functioned, with implications for future service planning.


Ten-year follow-up of a DOCK8-deficient child with features of systemic lupus erythematosus.
Dedicator of cytokinesis 8 (DOCK8) deficiency is an innate error of adaptive immunity characterized by recurrent infections with viruses, bacteria, and fungi, typically high serum levels of immunoglobulin E, eosinophilia, and a progressive deterioration of T- and B-cell-mediated immunity. DOCK8 mutations are the second most common cause of hyper-immunoglobulin E syndromes (HIES). We report a case of DOCK8 deficiency associated with systemic lupus erythematosus (SLE). Association of SLE with HIES is very rare; to our knowledge, this is the sixth such case reported in the literature. A 10-year-old girl of consanguineous parents was followed in our clinic because of HIES since early childhood. She developed SLE with purpuric and necrotic skin lesions, diffuse arthritis, and glomerulonephritis. These autoimmune features were corroborated by the presence of antinuclear, anti-DNA, and antiphospholipid antibodies. The combination of HIES and autoimmunity makes treatment difficult, because the use of immunosuppressive drugs needed for SLE may worsen existing symptoms caused by the immunodeficiency. Our observation is the first case of association of SLE with HIES in the literature where the primary immune disease is genetically documented and labeled as DOCK8 deficiency.


Safety of live-attenuated influenza vaccination in cystic fibrosis.
Given the improved efficacy of the nasal live-attenuated influenza virus vaccine (LAIV) compared with the injectable vaccine in children, we aimed to determine its safety in individuals with cystic fibrosis (CF). A cohort of 168 study participants, aged 2 to 18 years with CF, vaccinated with LAIV between October 1, 2012, and January 30, 2013, was followed prospectively for 56 days after initial vaccination in 3 pediatric CF clinics across the province of Quebec. Days 0 to 28 post-LAIV were considered the at-risk period for all outcomes of interest, and days 29 to 56 post-LAIV were considered the non-at-risk period. Incident respiratory deteriorations were defined as an unscheduled medical visit, hospitalization, or a new course of oral antibiotics for respiratory complaints. Using a self-controlled design, incidence rate ratios (IRR) were used to compare at-risk and non-at-risk periods. Comparing at-risk to non-at-risk periods, there was no significant increase in the rate of incident respiratory deteriorations (IRR, 0.72; 95% confidence interval, 0.11-4.27) or all-cause hospitalizations (IRR, 1.16; 95% confidence interval, 0.30-4.81). A greater proportion of participants reported experiencing at least 1 minor respiratory and/or systemic adverse event after immunization during the at-risk period compared with the non-at-risk period (77% vs 54%, respectively). During the first week after LAIV, 13 of 168 (8%) children reported some wheezing, with the vast majority, 9 of 13 (69%), on the day of vaccination. There was no increased risk of respiratory deterioration or all-cause hospitalization associated with LAIV in our study population. LAIV seems well tolerated in children and adolescents with CF.


An in-vitro study of ginsenoside Rb1-induced teratogenicity using a whole rat embryo culture model.
Ginseng is a commonly used herbal medicine worldwide. However, there is limited information regarding its effects on the developing embryo. The effect of ginsenoside on the developing embryo during the critical period of organogenesis was investigated using a whole rat embryo culture model. Embryos were exposed to various concentrations of ginsenoside Rb(1) and scored for growth and differentiation at the end of the culture period. Median total morphological scores in embryos exposed to 30 micro g/ml of ginsenoside Rb(1) was significantly lower (P < 0.05) than that in control embryos (35 versus 45). Morphological scores for flexion, forelimb and hindlimb were also significantly reduced. The median total morphological scores further decreased to 28 when the concentration of ginsenoside Rb(1) was increased to 50 micro g/ml. At this concentration, the embryonic crown-rump length and somite number were also significantly reduced compared with control embryos (2.8 versus 3.0 mm and 16.0 versus 21.0, respectively). Our study has demonstrated that ginsenoside exerts direct teratogenic effects on rat embryos. Until more is known about the effects of ginsenoside in women of reproductive age, we suggest its use should be treated with caution.


Functional activity within the frontal eye fields, posterior parietal cortex, and cerebellar vermis significantly correlates to symmetrical vergence peak velocity: an ROI-based, fMRI study of vergence training.
Convergence insufficiency (CI) is a prevalent binocular vision disorder with symptoms that include double/blurred vision, eyestrain, and headaches when engaged in reading or other near work. Randomized clinical trials support that Office-Based Vergence and Accommodative Therapy with home reinforcement leads to a sustained reduction in patient symptoms. However, the underlying neurophysiological basis for treatment is unknown. Functional activity and vergence eye movements were quantified from seven binocularly normal controls (BNC) and four CI patients before and after 18 h of vergence training. An fMRI conventional block design of sustained fixation vs. vergence eye movements stimulated activity in the frontal eye fields (FEF), the posterior parietal cortex (PPC), and the cerebellar vermis (CV). Comparing the CI patients' baseline measurements to the post-vergence training data sets with a paired t-test revealed the following: (1) the percent change in the BOLD signal in the FEF, PPC, and CV significantly increased (p < 0.02), (2) the peak velocity from 4° symmetrical convergence step responses increased (p < 0.01) and (3) patient symptoms assessed using the CI Symptom Survey (CISS) improved (p < 0.05). CI patient measurements after vergence training were more similar to levels observed within BNC. A regression analysis revealed the peak velocity from BNC and CI subjects before and after vergence training was significantly correlated to the percent BOLD signal change within the FEF, PPC, and CV (r = 0.6; p < 0.05). Results have clinical implications for understanding the behavioral and neurophysiological changes after vergence training in patients with CI, which may lead to the sustained reduction in visual symptoms.


A multi-centre evaluation of oral cancer in Southern and Western Nigeria: an African oral pathology research consortium initiative.
Oral cancer is a leading cause of cancer deaths among African populations. Lack of standard cancer registries and under-reporting has inaccurately depicted its magnitude in Nigeria. Development of multi-centre collaborative oral pathology networks such as the African Oral Pathology Research Consortium (AOPRC) facilitates skill and expertise exchange and fosters a robust and systematic investigation of oral diseases across Africa. In this descriptive cross-sectional study, we have leveraged the auspices of the AOPRC to examine the burden of oral cancer in Nigeria, using a multi-centre approach. Data from 4 major tertiary health institutions in Western and Southern Nigeria was generated using a standardized data extraction format and analysed using the SPSS data analysis software (version 20.0; SPSS Inc. Chicago, IL). Of the 162 cases examined across the 4 centres, we observed that oral squamous cell carcinomas (OSCC) occurred mostly in the 6th and 7th decades of life and maxillary were more frequent than mandibular OSCC lesions. Regional variations were observed both for location, age group and gender distribution. Significant regional differences was found between poorly, moderately and well differentiated OSCC (p value = 0.0071). A multi-centre collaborative oral pathology research approach is an effective way to achieve better insight into the patterns and distribution of various oral diseases in men of African descent. The wider outlook for AOPRC is to employ similar approaches to drive intensive oral pathology research targeted at addressing the current morbidity and mortality of various oral diseases across Africa.


Measuring leprosy stigma--a preliminary review of the leprosy literature.
A literature review was conducted to review work done to date on measuring stigma related to leprosy. References were obtained through a PubMed (Medline) search and through examining relevant bibliographies. Twelve papers were selected that addressed the issue of measurement of stigma and that contained a sample of the instrument used. Three unpublished studies were also included in the review. Studies that attempt to measure stigma can be broadly categorized in two groups, a) studies that assess the effects of stigma on the person affected, and b) surveys that assess community attitudes and/or practices. The study and questionnaire characteristics of the studies in both categories are described and compared. The studies reviewed indicate that leprosy stigma is still a global phenomenon, occurring in both endemic and non-endemic countries. The consequences of stigma affect individuals as well as the effectiveness of leprosy control activities. Despite enormous cultural diversity, the areas of life affected are remarkably similar. They included mobility, interpersonal relationships, marriage, employment, leisure activities, and attendance at social and religious functions. This suggests that development of a standard stigma scale for leprosy may be possible. Data obtained with such an instrument would useful in situational analysis, advocacy work, monitoring and evaluation of interventions against stigma, and research to better understand stigma and its determinants.


Iron and folic acid supplements and reduced early neonatal deaths in Indonesia.
To examine the relationship between antenatal care, iron and folic acid supplementation and tetanus toxoid vaccination during pregnancy in Indonesia and the risk of early neonatal death (death in days 0-6 of life). We analysed pooled data on neonatal survival in singleton infants born in the 5 years before each of the Indonesian demographic and health surveys of 1994, 1997 and 2002-2003. Only the most recently born infant of each mother was included. Multivariate Cox proportional hazards models were used to identify factors linked to early neonatal death. Of the 40 576 infants included, 442 experienced early neonatal death. After adjustment, the risk of early neonatal death was significantly reduced for infants of mothers who received either any form of antenatal care (hazard ratio, HR: 0.48; 95% confidence interval, CI: 0.31-0.73), any quantity of iron and folic acid (HR: 0.53; 95% CI: 0.36-0.77) or >or= 2 tetanus toxoid injections (HR: 0.66; 95% CI: 0.48-0.92). When we analysed different combinations of these measures, iron and folic acid supplementation provided the main protective effect: early neonatal deaths were still significantly reduced among infants whose mothers received iron and folic acid supplements but no other form of antenatal care (HR: 0.10; 95% CI: 0.01-0.67), or the supplements but < 2 tetanus toxoid injections (HR: 0.46; 95% CI: 0.29-0.73). Subsequent analysis showed that 20% of early neonatal deaths in Indonesia could be attributed to a lack of iron and folic acid supplementation during pregnancy. Iron and folic acid supplementation during pregnancy in Indonesia significantly reduced the risk of early neonatal death and could also do so in other low- and middle-income countries.


Phase-shifting technique for improving the imaging capacity of sparse-aperture optical interferometers.
We describe the principle of a multiaperture interferometer that uses a phase-shifting technique and is suitable for quick snapshot imaging of astrophysical objects at extreme angular resolution through Fourier inversion. A few advantages of the proposed design are highlighted, among which are radiometric efficiency, field of view equivalent to those of Fizeau interferometers, and a preliminary calibration procedure allowing characterization of instrumental errors. For large telescope numbers, the proposed design also results in considerable simplification of the optical and mechanical design. Numerical simulations suggest that it should be possible to couple hundreds of telescopes on a single 4K × 4K detector array, using only conventional optical components or emerging technologies.


Applying cusum-based methods for the detection of outbreaks of Ross River virus disease in Western Australia.
The automated monitoring of routinely collected disease surveillance data has the potential to ensure that important changes in disease incidence are promptly recognised. However, few studies have established whether the signals produced by automated monitoring methods correspond with events considered by epidemiologists to be of public health importance. This study investigates the correspondence between retrospective epidemiological evaluation of notifications of Ross River virus (RRv) disease in Western Australia, and the signals produced by two cumulative sum (cusum)-based automated monitoring methods. RRv disease case notification data between 1991 and 2004 were assessed retrospectively by two experienced epidemiologists, and the timing of identified outbreaks was compared with signals generated from two different types of cusum-based automated monitoring algorithms; the three Early Aberration Reporting System (EARS) cusum algorithms (C1, C2 and C3), and a negative binomial cusum. We found the negative binomial cusum to have a significantly greater area under the receiver operator characteristic curve when compared with the EARS algorithms, suggesting that the negative binomial cusum has a greater level of agreement with epidemiological opinion than the EARS algorithms with respect to the existence of outbreaks of RRv disease, particularly at low false alarm rates. However, the performance of individual EARS and negative binomial cusum algorithms were not significantly different when timeliness was also incorporated into the area under the curve analyses. Our retrospective analysis of historical data suggests that, compared with the EARS algorithms, the negative binomial cusum provides greater sensitivity for the detection of outbreaks of RRv disease at low false alarm levels, and decreased timeliness early in the outbreak period. Prospective studies are required to investigate the potential usefulness of these algorithms in practice.


Acoustical and perceptual influence of duplex stringing in grand pianos.
This study investigates the acoustical and perceptual influence of the string parts outside the speaking length in grand pianos (front and rear duplex strings). Acoustical measurements on a grand piano in concert condition were conducted, measuring the fundamental frequencies of all main and duplex strings in the four octaves D4-C8. Considerable deviations from the nominal harmonic relations between the rear duplex and main string frequencies, as described by the manufacturer in a patent, were observed. Generally the rear duplex strings were tuned higher than the nominal harmonic relations with average and median deviations approaching +50 cent. Single keys reached +190 and -100 cent. The spread in deviation from harmonic relations within trichords was also substantial with average and median values around 25 cent, occasionally reaching 60 cent. Contributions from both front and rear duplex strings were observed in the bridge motion and sound. The audibility of the duplex strings was studied in an ABX listening test. Complete dampening of the front duplex was clearly perceptible both for an experiment group consisting of musicians and a control group with naive subjects. The contribution from the rear duplex could also be perceived, but less pronounced.


Modulation of viability of live cells by focused ion-beam exposure.
Introduction of membrane-impermeant substances into living cells is the key method to understand contemporary cellular processes by investigating cellular responses and phenotypes. Here, we performed gold ion beam exposure into live cells by using the focused ion beam implantation method, which was originally developed to precisely control semiconductor device performances. We evaluated the viability of the gold-irradiated cells by measuring the concentration of adenosine triphosphate (ATP), which is an intracellular energy source produced in the mitochondrial membrane. The viability of the irradiated cells was found to be 20% higher than that of the unirradiated control cells. The atoms might promote the energy generating processes within the mitochondrion. Our results suggest that the viability of living cells can be modulated by accurately controlling the dopant atom numbers. Our technique may be considered as a potential tool in life and medical sciences to quantitatively elucidate the dose-dependent effects of dopants.


[Telemedicine with digital video transport system].
The growth of technology based on internet protocol has affected on the informatics and automatic controls of medical fields. The aim of this study was to establish the telemedical educational system by developing the high quality image transfer using the DVTS (digital video transmission system) on the high-speed internet network. Using telemedicine, we were able to send surgical images not only to domestic areas but also to international area. Moreover, we could discuss the condition of surgical procedures in the operation room and seminar room. The Korean-Japan cable network (KJCN) was structured in the submarine between Busan and Fukuoka. On the other hand, the Korea advanced research network (KOREN) was used to connect between Busan and Seoul. To link the image between the Hanyang University Hospital in Seoul and Kyushu University Hospital in Japan, we started teleconference system and recorded image-streaming system with DVTS on the circumstance with IPv4 network. Two operative cases were transmitted successfully. We could keep enough bandwidth of 60 Mbps for two-line transmission. The quality of transmitted moving image had no frame loss with the rate 30 per second. The sound was also clear and the time delay was less than 0.3 sec. Our study has demonstrated the feasibility of domestic and international telemedicine. We have established an international medical network with high-quality video transmission over internet protocol. It is easy to perform, reliable, and also economical. Thus, it will be a promising tool in remote medicine for worldwide telemedical communication in the future.


Demographic, behavioral, and psychosocial correlates of using the website component of a worksite physical activity and healthy nutrition promotion program: a longitudinal study.
Internet-delivered behavior change programs have the potential to reach a large population. However, low participation levels and high levels of attrition are often observed. The worksite could be a setting suitable for reaching and retaining large numbers of people, but little is known about reach and use of Internet-delivered health promotion programs in the worksite setting. This study aimed (1) to gain more insight in the use of the website component of a worksite behavior change intervention and (2) to identify demographic, behavioral, and psychosocial factors associated with website use. The study was an observational study among participants from 5 workplaces in a cluster randomized controlled trial. At baseline, all participants visited a study website to fill out the baseline questionnaire. Then a physical health check was done followed by face-to-face advice. After this contact, all participants received an email to promote visiting the website to view their health check results and the personal advice based on the baseline questionnaire. In the subsequent period, only participants in the intervention group received monthly email messages to promote website visits and were offered additional Web-based tools (self-monitors and a food frequency questionnaire [FFQ] assessing saturated fat intake) to support their behavior change. Website use was monitored by website statistics registering website access. Complete data were available for 726 employees. Logistic regression analyses were conducted to identify characteristics of employees who visited and used the website. In total, 43% of the participants visited the website after the email to promote website visits. Participants who were insufficiently physically active were less likely to visit the website (odds ratio [OR] 0.63, 95% confidence interval [CI] 0.45-0.88), whereas individuals with an elevated total cholesterol level visited the website more often (OR 1.44, 95% CI 1.05-1.98). The monthly emails in the intervention group resulted in higher website use during a 3-month period (18% versus 5% in the reference group, OR 3.96, 95% CI 2.30-6.82). Participants with a positive attitude toward increasing physical activity were less likely to visit the website (OR 0.54, 95% CI 0.31-0.93) or to use the self-monitor and FFQ (OR 0.50, 95% CI 0.25-0.99). Female workers visited the website more often to monitor their behavior and to receive advice on fat intake (OR 2.36, 95% CI 1.14-4.90). Almost half of the participants used the website component of a worksite behavior change program. Monthly emails were a prompt to visit the website, but website use remained low. More women than men used the website to obtain personalized advice for behavior change. No consistently higher participation was found among those with healthier behaviors. This health promotion program did not provide an indication that healthier subjects are more susceptible to health promotion. ISRCTN52854353; http://www.controlled-trials.com/ISRCTN52854353 (Archived by WebCite at http://www.webcitation.org/5smxIncB1).


The influence of streptozotocin-induced diabetes mellitus on fluid and electrolyte handling in rats.
Intakes and urine outputs of fluid and electrolytes were measured daily in rats before, and for 3 weeks after, induction of diabetes by intraperitoneal injection of streptozotocin (STZ; 60 mg/kg); control animals received saline. Water intakes and urine outputs were increased on and after the first day after injection with STZ; after a transient period of negative water balance, fluid intakes and urine outputs increased in parallel. Food intake was reduced for the first 3 days after injection of STZ but thereafter there was a steady increase. On the final experimental day, the food intake of the diabetic group was 60% greater than that of the control group. Urinary electrolyte excretion was increased after injection of STZ; at the end of the experiment, the increase in urinary sodium excretion was similar to the increase in intake but the increase in urinary potassium excretion was less. On day 21 after injection of STZ plasma sodium concentration and packed cell volume were significantly reduced in the diabetic group but plasma potassium concentration was not. There was a difference between the measured osmolality and the calculated osmolarity of the plasma of the diabetic animals which was not seen in the controls. This difference was not due to pseudohyponatraemia, but was probably due to the presence of unidentified solutes, since there was a significant gap between the urinary osmolal and osmolar excretion in the diabetic animals that was not present in the control animals.


Antigenic variation of Borrelia hermsii.
At least 24 different serotypes were detected in populations of Borrelia hermsii that originated from a single organism. These serotypes were identified by staining with specific fluoresceinated antisera prepared against cloned populations of living organisms of each type. In the order of decreasing frequency, the 10 types more often encountered were 7, which was clearly dominant, and 2, 17, 24, 13, 2, 1, 21, 11, and 12. Each of the 24 types were shown to change to 7 or more other serotypes. Spirochetemia in mice was persistent, and relapses occurred when the concentration of organisms was sufficient for detection by visual means. After mice were inoculated with a single organism, peak spirochetemia usually occurred on day 4, after which clearance of organisms occurred, and an apparently pure population was replaced by a mixed population consisting of as many as seven variants. These types persisted for 2-3 d before being replaced by other types. Conversions occurred constantly and were independent of relapses. The rate of conversion in mice treated with cyclophosphamide to delay antibody production was comparable to that of controls. Spontaneous conversion was clearly demonstrated in tubes of fortified Kelly's medium inoculated with a single organism of type 7 or 21. 11 different variants appeared in eight cultures of type 21 by the time growth had reached 4 X 10(6)-10(7) organisms/ml. The rate of spontaneous change was estimated to be or approximately 10(-4)-10(-3) per cell per generation.


Gynecologic cancers in pregnancy: guidelines based on a third international consensus meeting.
We aimed to provide comprehensive protocols and promote effective management of pregnant women with gynecological cancers. New insights and more experience have been gained since the previous guidelines were published in 2014. Members of the International Network on Cancer, Infertility and Pregnancy (INCIP), in collaboration with other international experts, reviewed existing literature on their respective areas of expertise. Summaries were subsequently merged into a manuscript that served as a basis for discussion during the consensus meeting. Treatment of gynecological cancers during pregnancy is attainable if management is achieved by collaboration of a multidisciplinary team of health care providers. This allows further optimization of maternal treatment, while considering fetal development and providing psychological support and long-term follow-up of the infants. Nonionizing imaging procedures are preferred diagnostic procedures, but limited ionizing imaging methods can be allowed if indispensable for treatment plans. In contrast to other cancers, standard surgery for gynecological cancers often needs to be adapted according to cancer type and gestational age. Most standard regimens of chemotherapy can be administered after 14 weeks gestational age but are not recommended beyond 35 weeks. C-section is recommended for most cervical and vulvar cancers, whereas vaginal delivery is allowed in most ovarian cancers. Breast-feeding should be avoided with ongoing chemotherapeutic, endocrine or targeted treatment. More studies that focus on the long-term toxic effects of gynecologic cancer treatments are needed to provide a full understanding of their fetal impact. In particular, data on targeted therapies that are becoming standard of care in certain gynecological malignancies is still limited. Furthermore, more studies aimed at the definition of the exact prognosis of patients after antenatal cancer treatment are warranted. Participation in existing registries (www.cancerinpregnancy.org) and the creation of national tumor boards with multidisciplinary teams of care providers (supplementary Box S1, available at Annals of Oncology online) is encouraged.


Sleep classification from wrist-worn accelerometer data using random forests.
Accurate and low-cost sleep measurement tools are needed in both clinical and epidemiological research. To this end, wearable accelerometers are widely used as they are both low in price and provide reasonably accurate estimates of movement. Techniques to classify sleep from the high-resolution accelerometer data primarily rely on heuristic algorithms. In this paper, we explore the potential of detecting sleep using Random forests. Models were trained using data from three different studies where 134 adult participants (70 with sleep disorder and 64 good healthy sleepers) wore an accelerometer on their wrist during a one-night polysomnography recording in the clinic. The Random forests were able to distinguish sleep-wake states with an F1 score of 73.93% on a previously unseen test set of 24 participants. Detecting when the accelerometer is not worn was also successful using machine learning ([Formula: see text]), and when combined with our sleep detection models on day-time data provide a sleep estimate that is correlated with self-reported habitual nap behaviour ([Formula: see text]). These Random forest models have been made open-source to aid further research. In line with literature, sleep stage classification turned out to be difficult using only accelerometer data.


Trabecular metal tibial knee component still stable at 10 years.
Background and purpose - Total knee replacement (TKR) in younger patients using cemented components has shown inferior results, mainly due to aseptic loosening. Excellent clinical results have been reported with components made of trabecular metal (TM). In a previous report, we have shown stabilization of the TM tibial implants for up to 5 years. In this study, we compared the clinical and RSA results of these uncemented implants with those of cemented implants. Patients and methods - 41 patients (47 knees) aged ≤ 60 years underwent TKR. 22 patients (26 knees) received an uncemented monoblock cruciate-retaining (CR) tibial component (TM) and 19 patients (21 knees) received a cemented NexGen Option CR tibial component. Follow-up examination was done at 10 years, and 16 patients (19 knees) with TM tibial components and 17 patients (18 knees) with cemented tibial components remained for analysis. Results - 1 of 19 TM implants was revised for infection, 2 of 18 cemented components were revised for knee instability, and no revisions were done for loosening. Both types of tibial components migrated in the first 3 months, the TM group to a greater extent than the cemented group. After 3 months, both groups were stable during the next 10 years. Interpretation - The patterns of migration for uncemented TM implants and cemented tibial implants over the first 10 years indicate that they have a good long-term prognosis regarding fixation.


Penicillin Detection by Tobacco Mosaic Virus-Assisted Colorimetric Biosensors.
The presentation of enzymes on viral scaffolds has beneficial effects such as an increased enzyme loading and a prolonged reusability in comparison to conventional immobilization platforms. Here, we used modified tobacco mosaic virus (TMV) nanorods as enzyme carriers in penicillin G detection for the first time. Penicillinase enzymes were conjugated with streptavidin and coupled to TMV rods by use of a bifunctional biotin-linker. Penicillinase-decorated TMV particles were characterized extensively in halochromic dye-based biosensing. Acidometric analyte detection was performed with bromcresol purple as pH indicator and spectrophotometry. The TMV-assisted sensors exhibited increased enzyme loading and strongly improved reusability, and higher analysis rates compared to layouts without viral adapters. They extended the half-life of the sensors from 4 - 6 days to 5 weeks and thus allowed an at least 8-fold longer use of the sensors. Using a commercial budget-priced penicillinase preparation, a detection limit of 100 µM penicillin was obtained. Initial experiments also indicate that the system may be transferred to label-free detection layouts.


Diabetes mellitus type 2 is associated with higher levels of myeloperoxidase.
Diabetes mellitus type 2 is linked to augmented endothelial dysfunction and accelerated atherosclerosis. Myeloperoxidase plays an important role in the initiation, progression, and the complications of atherosclerosis. We investigated whether myeloperoxidase levels are increased in diabetic patients. We compared baseline plasma myeloperoxidase levels in diabetic and nondiabetic patients with mild, stable anginal complaints (Canadian Cardiovascular Society I-II/IV) and performed multivariate linear regression analyses to adjust for possible confounding factors. A total of 440 patients were recruited from the outpatient clinic of cardiology, 268 patients with and 172 without diabetes mellitus type 2. Levels of myeloperoxidase were significantly higher in diabetic patients (median, 141 pM; interquartile range, 115-171 pM) than in nondiabetic patients (median, 126 pM; interquartile range, 105-167 pM) (P=0.01). Diabetes mellitus type 2, age in years, current smoking status, presence of hypercholesterolemia, and use of calcium antagonists and ACE inhibitors were associated with logarithmically transformed myeloperoxidase levels. Of these variables, diabetes mellitus type 2 (beta 0.096, SE 0.038, P=0.01); age (beta 0.01, SE 0.002, P<0.001), and current smoking (beta 0.166, SE 0.05, P=0.001) remained independently associated with myeloperoxidase levels in multivariate analysis. The linear regression coefficient of diabetes mellitus type 2 in relation to myeloperoxidase was 0.092 in univariate linear regression and 0.078 after adjusting for age, current smoking, and use of ACE inhibitors and calcium antagonists. Diabetes mellitus type 2 is associated with mildly increased levels of myeloperoxidase, independent of other clinical variables. This association may contribute to the accelerated progression of atherosclerosis in diabetics.


Fruits and vegetables protect against the genotoxicity of heterocyclic aromatic amines activated by human xenobiotic-metabolizing enzymes expressed in immortal mammalian cells.
Heterocyclic aromatic amines (HAAs) can be formed during the cooking of meat and fish at elevated temperatures and are associated with an increased risk for cancer. On the other hand, epidemiological findings suggest that foods rich in fruits and vegetables can protect against cancer. In the present study three teas, two wines, and the juices of 15 fruits and 11 vegetables were investigated for their protective effect against the genotoxic effects of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). To closely mimic the enzymatic activation of these HAAs in humans, genetically engineered V79 Chinese hamster fibroblasts were employed that express human cytochrome P450-dependent monooxygenase (hCYP) 1A2 (responsible for the first step of enzymatic activation) and human N(O)-acetyltransferase (hNAT) 2*4 or human sulfotransferase (hSULT)1A1*1 (responsible for the second step of enzymatic activation): V79-hCYP1A2-hNAT2*4 for IQ activation and V79-hCYP1A2-hSULT1A1*1 for PhIP activation. HAA genotoxicity was determined by use of the comet assay. Black, green and rooibos tea moderately reduced the genotoxicity of IQ (IC(50)=0.8-0.9%), whereas red and white wine were less active. From the fruit juices, sweet cherry juice exhibited the highest inhibitory effect on IQ genotoxicity (IC(50)=0.17%), followed by juices from kiwi fruit, plum and blueberry (IC(50)=0.48-0.71%). The juices from watermelon, blackberry, strawberry, black currant, and Red delicious apple showed moderate suppression, whereas sour cherry, grapefruit, red currant, and pineapple juices were only weakly active. Granny Smith apple juice and orange juice proved inactive. Of the vegetable juices, strong inhibition of IQ genotoxicity was only seen with spinach and onion juices (IC(50)=0.42-0.54%). Broccoli, cauliflower, beetroot, sweet pepper, tomato, chard, and red-cabbage juices suppressed IQ genotoxicity only moderately, whereas cucumber juice was ineffective. In most cases, fruits and vegetables inhibited PhIP genotoxicity less strongly than IQ genotoxicity. As one possible mechanism of antigenotoxicity, the inhibition of activating enzymes was studied either indirectly with diagnostic substrates or directly by measuring CYP1A2 inhibition. Only sour cherry, blueberry, and black currant juices suppressed the first step of HAA enzymatic activation, whereas most plant-derived beverages inhibited the second step.


Predictive outcomes of revision total hip replacement--a consecutive series of 1176 patients with a minimum 10-year follow-up.
The burden of revision total hip replacement (THR) surgery is increasing. With an increasing life expectancy and younger age of primary surgery this trend is set to continue. There are few data on the long-term outcome of revision THR. This retrospective study of 1176 consecutive revision THRs with a minimum 10-year follow-up from a University Teaching Hospital was undertaken to review implant survival and patient reported outcomes. Mean follow-up was 11 years with implant survival at 10 years of 82% (CI: 80-85). Implant survival varied between 58% (unexplained pain) to 84% (aseptic loosening) depending on the indication for revision surgery. Positive predictors of survival were age greater than 70 at the time of surgery (p=0.011), revision for aseptic loosening (p<0.01) and revision of both components or just the acetabular component (p<0.01). At the last review, mean Oxford Hip Score (OHS) was 34 (SD: 11.3) and 92% of the living patients with unrevised hips were satisfied with the outcome of revision surgery. This long term study has demonstrated that positive predictors of survival and outcome of revision THR surgery are age greater than 70 years, revision for aseptic loosening and component revision. This should aid surgeons in their counselling of patients prior to surgery.


Norepinephrine-containing neurons: changes in spontaneous discharge patterns during sleeping and waking.
Norepinephrine-containing neurons of the locus coeruleus of the cat were recorded with microelectrodes during unrestrained sleeping and waking. The recorded neurons were subsequently defined by combined fluorescence histochemistry of catecholamines and production of microlesions at recording sites. These pontine units show homogeneous changes in discharge patterns with respect to sleep stages, firing slowly during drowsy periods and slow wave sleep and firing in rapid bursts during paradoxical sleep. These data provide a direct correlation between the activity of defined catecholamine-containing neurons and the spontaneous occurrence of sleep stages.


Experimental and theoretical studies of hydroxyl-induced magnetism in TiO nanoclusters.
A main challenge in understanding the defect ferromagnetism in dilute magnetic oxides is the direct experimental verification of the presence of a particular kind of defect and distinguishing its magnetic contributions from other defects. The magnetic effect of hydroxyls on TiO nanoclusters has been studied by measuring the evolution of the magnetic moment as a function of moisture exposure time, which increases the hydroxyl concentration. Our combined experiment and density-functional theory (DFT) calculations show that as dissociative water adsorption transforms oxygen vacancies into hydroxyls, the magnetic moment shows a significant increase. DFT calculations show that the magnetic moment created by hydroxyls arises from 3d orbitals of neighboring Ti sites predominantly from the top and second monolayers. The two nonequivalent hydroxyls contribute differently to the magnetic moment, which decreases as the separation of hydroxyls increases. This work illustrates the essential interplay among defect structure, local structural relaxation, charge redistribution, and magnetism. The microscopic differentiation and clarification of the specific roles of each kind of intrinsic defect is critical for the future applications of dilute magnetic oxides in spintronic or other multifunctional materials.


High-level porcine endothelial cell expression of alpha(1,2)-fucosyltransferase reduces human monocyte adhesion and activation.
Monocyte binding to and activation by human endothelium requires a number of interactions, including those involving sialylated endothelial cell ligands. As porcine endothelial cell transfection with alpha(1,2)-fucosyltransferase has been shown to reduce terminal sialylation, we investigated whether high-level expression of alpha(1,2)-fucosyltransferase by porcine endothelium would reduce human monocyte adhesion and functional activation. Purified human monocytes were labeled with 51Cr, and measured for adherence to human or porcine endothelial cell monolayers in the presence of either medium or monoclonal antibodies against monocyte lectins or sialylated endothelial cell ligands. Monocyte production of prostaglandin E2 (PGE2) and interleukin-1beta (IL-1beta) was measured by enzyme-linked immunosorbent assay, using supernatants collected from cultures performed between human monocytes and human or porcine endothelial cell monolayers. Finally, monocyte adhesion and activation were measured after culture with a porcine endothelial cell line transfected with alpha(1,2)-fucosyltransferase, expressing reduced surface expression of terminal Gal alpha(1,3)-Gal and sialic acid residues. Human monocytes adhered by 50% higher levels to porcine endothelium than to human endothelium. This increased level of adherence was associated with augmented monocyte activation, as defined by 3.3-fold higher levels of PGE2 production and 7.3-fold higher levels of IL-1beta production. Monoclonal antibodies against CD62L (L-selectin) on monocytes or CD15s (sialylated Lewis X) on porcine endothelium reduced monocyte adhesion by 38% and 52%, respectively. Porcine endothelial cell transfection with alpha(1,2)-fucosyltransferase reduced terminal sialic acid expression by 65%, monocyte adherence by 50%, and the production of PGE2 and IL-1beta by 67% and 38%, respectively. Together, these results demonstrate that human monocytes use surface lectins to bind to sialylated carbohydrate structures on porcine endothelium, and indicate that reduction in porcine endothelial cell surface expression of terminally sialylated structures by high-level alpha(1,2)-fucosyltransferase activity reduces monocyte adherence and activation.


Left atrial wall thickness variability measured by CT scans in patients undergoing pulmonary vein isolation.
Successful catheter ablation of atrial fibrillation (AF) requires the creation of transmural lesions in the left atrium (LA). In addition, cardiac perforation is more likely to occur in areas of thin walls. The LA wall thickness is thus relevant both for procedural efficacy and safety. This study sought to evaluate the regional LA wall thickness in patients with AF. The LA muscular wall thickness (excluding fat) was measured by 64 slice cardiac computed tomography (CT) in 60 patients with persistent AF prior to catheter ablation procedures. Measurements were performed in all patients at 12 distinct LA locations, including 3 at the roof (right, middle left), 3 at the floor (right, middle, left), 4 at the posterior wall (right, middle, middle-superior, left), 1 at the left lateral ridge (LLR), and 1 at the mitral isthmus. There was a large range of LA wall thickness (average thickness 1.89 ± 0.48 mm, range 0.5-3.5 mm). In addition, there were significant regional differences in LA wall thickness. In particular, the LA roof was significantly thicker than the posterior wall and floor (P < 0.001), the LLR was significantly thicker than most regions (P < 0.04), and the mitral isthmus was also significantly thicker than the posterior wall (P < 0.001) and floor (P < 0.001). In patients with persistent AF, there is inter- and intra-patient variability in the thickness of the LA muscular wall. In most patients, however, the roof, mitral isthmus, and the ridge between the pulmonary veins and appendage are thicker compared to the posterior wall and floor.


Iloprost, a prostacyclin analogue, stimulates meiotic maturation and early embryonic development in pigs.
Oviduct fluid contains various cytokines and growth factors that enhance the embryo development during the preimplantation period. In hatched embryos, prostacyclin (PGI(2)) improves implantation, but its role during oocyte maturation and early embryo development remains contentious. Therefore, in the present study, we examined the effects of a PGI(2) analogue (iloprost) on meiotic maturation and early embryonic development in pigs, as well on the structural integrity, mitochondrial membrane potential and apoptosis in blastocysts. First, meiotic maturation in pig oocytes was examined in the presence of increasing concentrations of iloprost (1, 5 and 10 muM). After IVM, a higher proportion of iloprost-treated compared with untreated oocytes was in MII (90.0% v. 65.7%, respectively; P < 0.05). In addition, protein kinase A activity increased in iloprost-treated oocytes, indicating increased intracellular cAMP concentrations. After 22 h iloprost treatment (44 h total incubation time), western blotting demonstrated increased expression of extracellular signal-regulated kinase (ERK) 1/2, phosphorylated (p-) ERK1/2, cAMP response element-binding protein (CREB), p-CREB and cyclo-oxygenase-2, indicating activation of the mitogen-activated protein kinase and PGI(2) pathways. In addition, the frequency of polyspermy decreased in iloprost-treated oocytes (19.9%) compared with control (35.8%), whereas the rate of blastocyst formation increased (P < 0.05). Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) showed that the number of nuclei containing fragmented DNA at the blastocyst stage decreased in the iloprost-treated group compared with control (1.2% v. 3.6%, respectively). In conclusion, iloprost appears to play a direct role in porcine oocyte maturation by enhancing blastocyst structure and survival.