Nocturnal Cough and Sleep Quality to Assess Asthma Control and Predict Attacks.
Objective markers for asthma, that can be measured without extra patient effort, could mitigate current shortcomings in asthma monitoring. We investigated whether smartphone-recorded nocturnal cough and sleep quality can be utilized for the detection of periods with uncontrolled asthma or meaningful changes in asthma control and for the prediction of asthma attacks. We analyzed questionnaire and sensor data of 79 adults with asthma. Data were collected in situ for 29 days by means of a smartphone. Sleep quality and nocturnal cough frequencies were measured every night with the Pittsburgh Sleep Quality Index and by manually annotating coughs from smartphone audio recordings. Primary endpoint was asthma control assessed with a weekly version of the Asthma Control Test. Secondary endpoint was self-reported asthma attacks. Mixed-effects regression analyses showed that nocturnal cough and sleep quality were statistically significantly associated with asthma control on a between- and within-patient level (p < 0.05). Decision trees indicated that sleep quality was more useful for detecting weeks with uncontrolled asthma (balanced accuracy (BAC) 68% vs 61%; Δ sensitivity -12%; Δ specificity -2%), while nocturnal cough better detected weeks with asthma control deteriorations (BAC 71% vs 56%; Δ sensitivity 3%; Δ specificity -34%). Cut-offs using both markers predicted asthma attacks up to five days ahead with BACs between 70% and 75% (sensitivities 75 - 88% and specificities 57 - 72%). Nocturnal cough and sleep quality have useful properties as markers for asthma control and seem to have prognostic value for the early detection of asthma attacks. Due to the limited study duration per patient and the pragmatic nature of the study, future research is needed to comprehensively evaluate and externally validate the performance of both biomarkers and their utility for asthma self-management.


Phytoestrogen-Rich Dietary Supplements in Anti-Atherosclerotic Therapy in Postmenopausal Women.
Cardiovascular diseases remain the leading cause of morbidity and mortality among postmenopausal women in western societies. There are still no specific and highly efficient methods of preservation of women's vascular health in modern preventive medicine. For many years physicians have assumed that hormone replacement therapy prevents the development of atherosclerosis in menopausal women. However, the results of the largest international trials involving thousands of women have completely destroyed this hope. The modern perspective for the development of effective and safe drugs to enhance the quality of life and to prevent atherosclerosis progression in postmenopausal women may be the use of phytoestrogens, the substances of plant origin possessing estrogen- like effects, and possibly providing anti-atherosclerotic and anti-climacteric action. Phytoestrogens are often considered as a possible alternative to hormone replacement therapy, since they are believed to alleviate some symptoms of menopause. However, until now there is no exact evidence to consider phytoestrogens as the substances that protect women from atherosclerosis. It should be noted that the data from clinical studies with inconsistent results are mainly inconsistent per se, as most of the studies have serious limitations due to the study design and the participants' compliance. Nevertheless, there is a substantial evidence that phytoestrogens have the potential to address several conditions and diseases associated with the menopausal transition. Phytoestrogens, at least, can potentially reduce atherosclerosis and atherosclerosis-related diseases through multiple mechanisms, by regulating serum lipid metabolism, arterial vessels, cytokine levels, and coagulation/fibrinolysis system. However, a skepticism exists concerning the true potential of phytoestrogens to beneficially modify these processes. An analysis of findings from supplementing the diet with phytoestrogens has failed, in general, to confirm them as the agents responsible for beneficial cardiovascular effects. Fortunalely, now there is a growing interest to the use of phytoestrogens for primary prevention of cardiovascular disease in postmenopausal women. Clinical and epidemiologic data indicate that phytoestrogens possess anti-atherosclerotic effects and may be used to prevent and treat cardiovascular diseases, and that adding phytoestrogens to the diet can contribute to the health of postmenopausal women. This review discusses the effects of phytoestrogens possibly beneficial for cardiovascular health, and how these effects could retard the progression of atherosclerosis, as well as the areas that need further investigation.


Patient use of email for health care communication purposes across 14 European countries: an analysis of users according to demographic and health-related factors.
The use of the Internet for health purposes is growing steadily, yet the use of asynchronous communication tools for health care purposes remains undeveloped. The introduction of email as a method of communication in health care has the potential to impact on both patients and health care professionals. This study aims to describe the characteristics of people who have sent or received an email to or from their doctor, nurse, or health care organization, by country and in relation to demographics, health care resource use, and health status factors. We conducted a secondary analysis of data (N=14,000) collected from the online Citizens and Information Communication Technology for Health survey, a project undertaken in 2011 by the Institute for Prospective Technology Studies of the European Commission's Joint Research Centre. The survey was developed to understand and characterize European citizens' use of information communication technologies for health. Descriptive and statistical analyses of association were used to interpret the data. Denmark reported the highest level of emails sent/received (507/1000, 50.70%). The lowest level reported was by participants in France (187/1000, 18.70%). Men used email communication for health care more than women, as did respondents in the 16-24 age group and those educated to tertiary level or still within the education system. As self-reported health state worsens, the proportion of people reporting having sent or received an email within the context of health care increases. Email use, poor health, multimorbidity, and number of visits to a physician are positively correlated. The use of email communication within the context of European health care is extremely varied. The relationship between high email use, poor health, doctor visits, and multimorbidity is especially pertinent: provision of asynchronous communication for such groups is favored by policymakers. Low reported email use by country may not necessarily reflect low interest in using email for health care: local health policies and technical infrastructures may be significant factors in the delay in implementation of alternative forms of routine health communication.


Cystic fibrosis in adults: diagnostic and therapeutic aspects.
Once considered a childhood disease, cystic fibrosis is now also a disease of adults. Increased longevity has resulted in the aging of the cystic fibrosis population. The consequent age-related medical problems among adults with cystic fibrosis have increased medical care needs. These needs are being met by a growing number of non-pediatric pulmonologists and other non-pediatric specialists. The objective of this review was to summarize the current knowledge about diagnosis and treatment in adult cystic fibrosis. In most cases, the diagnosis is suggested by manifestations of chronic sinopulmonary disease and exocrine pancreatic insufficiency. The diagnosis is confirmed by a positive sweat test result. Adult patients may, however, present pancreatic sufficiency and atypical clinical features, sometimes in combination with normal or borderline sweat test results. In such cases, identifying cystic fibrosis mutations and measuring nasal potential difference can have diagnostic utility. The standard therapeutic approach to pulmonary disease includes the use of antibiotics, airway clearance, exercise, mucolytics, bronchodilators, oxygen therapy, anti-inflammatory agents and nutritional support. Appropriate application of these therapies results in most cystic fibrosis patients surviving into adulthood with an acceptable quality of life.


Hybrid technique to bail out an unsuccessful transfemoral TAVR attempt.
The most common route to perform transcatheter aortic valve replacement (TAVR) is via the transfemoral access. The success of this technique hinges on the successful passage of guidewires across the stenosed aortic valve. Although this is possible in the majority of cases, this case illustrates an occasional anomaly. In this report, we describe a novel hybrid technique involving a transseptal access as well as the formation of a continuous arteriovenous loop to complete the procedure successfully. This technique also has an additional advantage as it maintains the feasibility of performing the procedure under local anaesthesia and conscious sedation.


Long-term outcomes of laser iridotomy in Vietnamese patients with primary angle closure.
To investigate the long-term outcomes of laser peripheral iridotomy (LPI) on controlling intraocular pressure (IOP) and progression of angle closure in Vietnamese. Medical charts of Vietnamese patients who were diagnosed as having primary angle-closure suspect (PACS), primary angle closure (PAC) or primary angle-closure glaucoma (PACG), and who had received LPI at least 10 years prior, in a single private practice were reviewed. The main outcomes included use of further treatments after LPI, progression rate to another classification category and ocular characteristics associated with progression. 359 patients with a mean follow-up period of 11.8 ± 1.6 years after the LPI were included in this study. The proportion of patients who required additional therapies (medical, laser or surgical) to control IOP were 7.1, 42.4 and 100% in the PACS, PAC and PACG groups, respectively. Fifty-three patients with PACS (22.2%) progressed to PAC; nine patients with PACS (3.8%) progressed to PACG; and five PAC patients (5.2%) progressed to PACG. Cataract surgery was a significant factor associated with PACS eyes without progression (p=0.019). Further medications, laser or surgery are frequently required to control IOP after LPI for eyes with PAC, especially for eyes with PACG. Lens extraction seems to play a protective role in PACS eyes. Close follow-up after LPI remains necessary to prevent progression of disease.


Effects of Kinesio tape on lower limb muscle strength, hop test, and vertical jump performances: a meta-analysis.
To date, published systematic reviews concerning the effects of Kinesio Taping (KT) on muscle strength have not analysed facilitatory and inhibitory applications separately. As a result, their results could be substantially affected by clinical heterogeneity. This meta-analysis was conducted to determine the effectiveness of using a facilitatory application of KT for lower limb muscle strength and functional performance (distance in a single-leg hop and vertical jump height) in individuals without disabilities and in those with musculoskeletal conditions (muscle fatigue, chronic musculoskeletal diseases, and post-operative orthopaedic conditions). Searches were conducted on six major electronic databases. Randomised controlled trials that used facilitatory KT were included. Standardised mean differences (SMDs) were calculated and random-effects models were used for analysis. Thirty-seven randomised controlled trials were included. KT was superior to controls for improving lower limb muscle strength in individuals with muscle fatigue (short-term effect, pooled SMD = 0.53, 95% CI = 0.09 to 0.96; long-term effect, pooled SMD = 0.61, 95% CI = 0.12 to 1.11) and in individuals with chronic musculoskeletal diseases (pooled SMD = 1.24, 95% CI = 0.33 to 2.16) with large effect sizes. The use of KT in populations without disabilities was not supported. There is insufficient evidence for the effect of KT on functional performance in individuals with musculoskeletal conditions. Contrary to prior research, the existing evidence shows that KT can improve lower limb muscle strength in individuals with muscle fatigue and chronic musculoskeletal diseases. The effect sizes produced in this meta-analysis show that KT may be superior to some existing treatments for these conditions. In addition, this study suggests that practitioners may wish to avoid the use of KT in individuals without disabilities. PROSPERO registration number CRD42017075490 , registered on 21 November 2017.


Interplay between local GABAergic interneurons and relay neurons generates gamma oscillations in the rat olfactory bulb.
Olfactory stimuli have been known for a long time to elicit oscillations in olfactory brain areas. In the olfactory bulb (OB), odors trigger synchronous oscillatory activity that is believed to arise from the coherent and rhythmic discharges of large numbers of neurons. These oscillations are known to take part in encoding of sensory information before their transfer to higher subcortical and cortical areas. To characterize the cellular mechanisms underlying gamma (30-80 Hz) local field potential (LFP) oscillations, we simultaneously recorded multiunit discharges, intracellular responses, and LFP in rat OB slices. We showed that a single and brief electrical stimulation of olfactory nerve elicited LFP oscillations in the mitral cell body layer lasting >1 sec. Both action potentials and subthreshold oscillations of mitral/tufted cells, the bulbar output neurons, were precisely synchronized with LFP oscillations. This synchronization arises from the interaction between output neurons and granule cells, the main population of local circuit inhibitory interneurons, through dendrodendritic synapses. Interestingly enough, the synchronization exerted by reciprocal synaptic interactions did not require action potentials initiated in granule cell somata. Finally, local application of a GABA(A) receptor antagonist at the mitral cell and external plexiform layers confirmed the exclusive role of the granule cell reciprocal synapses in generating the evoked oscillations. We concluded that interneurons located in the granule cell layer generate synaptic activity capable of synchronizing activity of output neurons by interacting with both their subthreshold and spiking activity.


Comparison of two staining and evaluation methods used for computerized human sperm morphology evaluations.
The purpose of the study was to analyse the agreement between computer analysed (Hamilton Thorne, IVOS Dimensions Version 3) normal sperm morphology and values obtained from 97 slides stained according to the Papanicolaou and Diff-Quik method. Liquefied semen samples were washed once by centrifugation and air dried smears on slides were made, which were stained according to the Papanicolaou and Diff-Quik method and analysed by computer. The paired t-test was used to assess whether any bias existed between the two methods. The limits of agreement were calculated using the Bland and Altman approach and a modification of this approach (mean-dependent limits). A significant bias of 1.6% was obtained in favour of higher normal sperm morphology percentages when using the Diff-Quik method. The standard limits of agreement were -13.4% to 16.6%, whereas the mean-dependent limits of agreement were 1.6% [5.8 + 0.6 (mean percentage normal morphology)]. Statistically, the Diff-Quik and Papanicolaou staining methods produce different normal sperm morphology profiles. These inherent differences may, therefore, require the establishment of new normal sperm morphology thresholds for male fertility, based on clinical data, when using the Diff-Quik staining method in conjunction with computerized analysis.


Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina.
Which drug is most effective as a first-line treatment for stable angina is not known. To compare the relative efficacy and tolerability of treatment with beta-blockers, calcium antagonists, and long-acting nitrates for patients who have stable angina. We identified English-language studies published between 1966 and 1997 by searching the MEDLINE and EMBASE databases and reviewing the bibliographies of identified articles to locate additional relevant studies. Randomized or crossover studies comparing antianginal drugs from 2 or 3 different classes (beta-blockers, calcium antagonists, and long-acting nitrates) lasting at least 1 week were reviewed. Studies were selected if they reported at least 1 of the following outcomes: cardiac death, myocardial infarction, study withdrawal due to adverse events, angina frequency, nitroglycerin use, or exercise duration. Ninety (63%) of 143 identified studies met the inclusion criteria. Two independent reviewers extracted data from selected articles, settling any differences by consensus. Outcome data were extracted a third time by 1 of the investigators. We combined results using odds ratios (ORs) for discrete data and mean differences for continuous data. Studies of calcium antagonists were grouped by duration and type of drug (nifedipine vs nonnifedipine). Rates of cardiac death and myocardial infarction were not significantly different for treatment with beta-blockers vs calcium antagonists (OR, 0.97; 95% confidence interval [CI], 0.67-1.38; P = .79). There were 0.31 (95% CI, 0.00-0.62; P = .05) fewer episodes of angina per week with beta-blockers than with calcium antagonists. beta-Blockers were discontinued because of adverse events less often than were calcium antagonists (OR, 0.72; 95% CI, 0.60-0.86; P<.001). The differences between beta-blockers and calcium antagonists were most striking for nifedipine (OR for adverse events with beta-blockers vs nifedipine, 0.60; 95% CI, 0.47-0.77). Too few trials compared nitrates with calcium antagonists or beta-blockers to draw firm conclusions about relative efficacy. beta-Blockers provide similar clinical outcomes and are associated with fewer adverse events than calcium antagonists in randomized trials of patients who have stable angina.


[Updates on extracorporeal life support in the world and challenges in Turkey].
Extracorporeal life support (ECLS) is instituted for the management of life threatening pulmonary or cardiac failure (or both), when no other form of treatment has been or is likely to be successful. It has being used in developed countries for many years. ECLS has come into practice for a while in Turkey, in order to ECLS recommendations. However, most of them are postcardiotomy cases. However, this therapeutic option has more indications including its reason that brought it into practice. All equipment of the system has being changed with the developing technology. The aim of this paper is to point out this modality, to introduce equipment, and to give information about organization and management to bring this therapeutic option in Turkey in order.


The Inverse Relationship Between Labral Size and Acetabular Coverage: Does It Protect the Cartilage in the Dysplastic Hip?
The aims of this study were to confirm the relationship between osseous coverage and labral size and to investigate the severity of intra-articular damage in borderline dysplastic hips in correlation to labral size. Patients treated with primary hip arthroscopy for symptomatic labral tears between 2010 and 2018 were considered for this study. Patients were included if they had preoperative radiographic measures and intraoperative assessments of the labra and cartilage. The study group was divided into borderline dysplastic and nondysplastic groups via 3 measurements: lateral center edge angle (LCEA), acetabular index (Ax), and anterior center edge angle (ACEA). Undercoverage was defined as LCEA ≤ 25°, Ax ≥ 10°, and ACEA ≤ 20°. The labrum was measured in four quadrants: anterosuperior (AS), anteroinferior (AI), posterosuperior (PS), and posteroinferior (PI). Additionally, to assess cartilage damage in borderline dysplastic hips, hips with average labral size in the top quartile were compared to hips with average labral size in the bottom quartile. A total of 1765 hips (1589 patients) were included in the study. The mean LCEA, Ax, and ACEA between the borderline dysplastic and nondysplastic groups were significantly different (P < .001). According to the Ax classification, there was significant evidence that borderline dysplastic hips had larger labra (P < .05). Among the dysplastic group, there was significantly more cartilage damage according to the Outerbridge classifications along both the acetabulum and femoral head in hips with labra in the upper quartile (P =.011 and .005, respectively). An inverse relationship may exist between acetabular depth and labral size. Additionally, specifically in borderline dysplastic hips, a relatively large labrum correlates with worse intra-articular damage compared to borderline dysplastic hips with a relatively small labrum. Larger labral size may indicate a higher degree of instability in patients with borderline dysplasia. Level III, case-control study.


Policymaker, please consider your needs carefully: does outcomes research in relapsed or refractory multiple myeloma reduce policymaker uncertainty regarding value for money of bortezomib?
Dutch policy regulations require outcomes research for the assessment of appropriate drug use and cost-effectiveness after 4 years of temporary reimbursement. We investigated whether outcomes research reduced policymaker uncertainty regarding the question whether the costs are worth public funding. Our cohort study included 139 patients with relapsed/refractory multiple myeloma who were treated outside of a clinical study; 72 received bortezomib and 67 did not receive bortezomib. Detailed data were retrospectively collected from medical records in 38% of Dutch hospitals. All patients received second-line treatment; 65%, 40%, and 14%, received three, four, or five or more lines of therapy. Neither a specific treatment sequence nor an appropriate comparator could be identified because of large variation in regimes. Kaplan-Meier curves showed an increased overall survival (mean [median] 29.5 [33.2] vs. 28.0 [21.6] months) for patients treated with bortezomib (Wilcoxon P = 0.01). Total mean costs were €81,626 (range €17,793-€229,783) and €52,760 (range €748-€179,571) for patients receiving bortezomib and patients not receiving bortezomib, respectively. Patients treated with bortezomib, however, were not comparable to other patients despite attempts to correct for confounding. Therefore, it was impossible to develop a feasible model to obtain a valid incremental cost-effectiveness estimate. It was possible to develop evidence on bortezomib's use, effects, and costs in everyday practice. Much uncertainty, however, remained regarding its cost-effectiveness. Policymakers should carefully consider whether outcomes research sufficiently decreases uncertainty or whether other options (e.g., finance- and/or outcomes-based risk-sharing arrangements) are more appropriate to ensure sufficient value for money of expensive drugs.


High incidence of hepatocellular carcinomas induced by a choline deficient L-amino acid defined diet in rats.
The carcinogenicities of a choline deficient L-amino acid defined (CDAA) diet and a semipurified choline deficient diet were comparatively examined. A total of 60 male Fischer 344 rats, 6 weeks old, were divided into 5 experimental groups each consisting of 12 rats. Group 1 received the CDAA diet chronically to the end of the 52-week experiment while Group 2 was given the same diet for the first 24 weeks and then a basal diet for the following 28 weeks. Groups 3, 4, and 5 received a choline supplemented L-amino acid defined diet, the semipurified choline deficient diet, and a semipurified choline supplemented diet, respectively, throughout the experimental period. All surviving rats were subjected to complete macroscopic examination at Week 52. Histopathologically diagnosed hepatocellular carcinomas were induced in Group 1 at an incidence of 100%; multiple metastatic nodules were seen in the lungs of one of the animals. Hepatocellular carcinomas were also induced in Group 4 rats at a significantly lower incidence of 20%. No hepatocellular carcinomas were observed in rats in Groups 2, 3, and 4. The results indicate that the CDAA diet exerts more potent carcinogenicity for the livers of rats than does the semipurified choline deficient diet. However, limited exposure for 24 weeks may have not been sufficient for hepatocellular carcinoma induction by the CDAA diet at Week 52 although a high incidence of hyperplastic nodules and slight cirrhosis were evidence of persistent lesions.


Refined crystal structures of guanine nucleotide complexes of adenylosuccinate synthetase from Escherichia coli.
Structures of adenylosuccinate synthetase from Escherichia coli complexed with guanosine-5'-(beta,gamma-imido) triphosphate and guanosine-5'-(beta,gamma-methylene)triphosphate in the presence and the absence of Mg2+ have been refined to R-factors below 0.2 against data to a nominal resolution of 2.7 A. Asp333 of the synthetase hydrogen bonds to the exocyclic 2-amino and endocyclic N1 groups of the guanine nucleotide base, whereas the hydroxyl of Ser414 and the backbone amide of Lys331 hydrogen bond to the 6-oxo position. The side chains of Lys331 and Pro417 pack against opposite faces of the guanine nucleotide base. The synthetase recognizes neither the N7 position of guanine nucleotides nor the ribose group. Electron density for the guanine-5'-(beta,gamma-imido) triphosphate complex is consistent with a mixture of the triphosphate nucleoside and its hydrolyzed diphosphate nucleoside bound to the active site. The base, ribose, and alpha-phosphate positions overlap, but the beta-phosphates occupy different binding sites. The binding of guanosine-5'-(beta,gamma-methylene)triphosphate to the active site is comparable with that of guanosine-5'-(beta, gamma-imido)triphosphate. No electron density, however, for the corresponding diphosphate nucleoside is observed. In addition, electron density for bound Mg2+ is absent in these nucleotide complexes. The guanine nucleotide complexes of the synthetase are compared with complexes of other GTP-binding proteins and to a preliminary structure of the complex of GDP, IMP, Mg2+, and succinate with the synthetase. The enzyme, under conditions reported here, does not undergo a conformational change in response to the binding of guanine nucleotides, and minimally IMP and/or Mg2+ must be present in order to facilitate the complete recognition of the guanine nucleotide by the synthetase.


Lemon grass (Cymbopogon citratus) essential oil as a potent anti-inflammatory and antifungal drugs.
Volatile oils obtained from lemon grass [Cymbopogon citratus (DC.) Stapf, Poaceae family] are used in traditional medicine as remedies for the treatment of various diseases. In the present study, lemon grass essential oil (LGEO) was evaluated for its in vivo topical and oral anti-inflammatory effects, and for its in vitro antifungal activity using both liquid and vapor phases. The chemical profile of LGEO as determined by gas chromatography-mass spectrometry analysis revealed two major components: geranial (42.2%), and neral (31.5%). The antifungal activity of LGEO was evaluated against several pathogenic yeasts and filamentous fungi using disc diffusion and vapor diffusion methods. LGEO exhibited promising antifungal effect against Candida albicans, C. tropicalis, and Aspergillus niger, with different inhibition zone diameters (IZDs) (35-90 mm). IZD increased with increasing oil volume. Significantly, higher anti-Candida activity was observed in the vapor phase. For the evaluation of the anti-inflammatory effect, LGEO (10 mg/kg, administered orally) significantly reduced carrageenan-induced paw edema with a similar effect to that observed for oral diclofenac (50 mg/kg), which was used as the positive control. Oral administration of LGEO showed dose-dependent anti-inflammatory activity. In addition, topical application of LGEO in vivo resulted in a potent anti-inflammatory effect, as demonstrated by using the mouse model of croton oil-induced ear edema. To our knowledge, this is the first such report to be published. The topical application of LGEO at doses of 5 and 10 µL/ear significantly reduced acute ear edema induced by croton oil in 62.5 and 75% of the mice, respectively. In addition, histological analysis clearly confirmed that LGEO inhibits the skin inflammatory response in animal models. RESULTS of the present study indicate that LGEO has a noteworthy potential for the development of drugs for the treatment of fungal infections and skin inflammation that should be explored in future studies.


From the Viscera to First Impressions: Phase-Dependent Cardio-Visual Signals Bias the Perceived Trustworthiness of Faces.
When we see new people, we rapidly form first impressions. Whereas past research has focused on the role of morphological or emotional cues, we asked whether transient visceral states bias the impressions we form. Across three studies (N = 94 university students), we investigated how fluctuations of bodily states, driven by the interoceptive impact of cardiac signals, influence the perceived trustworthiness of faces. Participants less often chose faces presented in synchrony with their own cardiac systole as more trustworthy than faces presented out of synchrony. Participants also explicitly judged faces presented in synchrony with their cardiac systole as less trustworthy. Finally, the presentation of faces in synchrony with participants' cardiac diastole did not modulate participants' perceptions of the faces' trustworthiness, suggesting that the systolic phase is necessary for such interoceptive effects. These findings highlight the role of phasic interoceptive information in the processing of social information and provide a mechanistic account of the role of visceroception for social perception.


Amygdalohippocampal MR volume measurements in the early stages of Alzheimer disease.
To evaluate the accuracy of hippocampal and amygdala volume measurements in diagnosing patients in the early stages of Alzheimer disease. Measurements of the hippocampal formation, amygdala, amygdalohippocampal complex (the two measurements summed), caudate nucleus, and ventricles, normalized for total intracranial volume, were obtained on coronal sections (1.5 T, 400/13 [repetition time/echo time], 5 mm) of 13 patients in the mild (minimental status > or = 21) and five patients in the moderate stages of Alzheimer disease (10 < minimental status < 21), and eight age-matched control subjects. For patients with a minimental status score of 21 or greater, atrophy was significant for the amygdala and hippocampal formation (-36% and -25% for amygdala/total intracranial volume and hippocampal formation/total intracranial volume, respectively), but not for the caudate nucleus. No significant ventricular enlargement was found. For patients with a minimental status score less than 21, atrophy was more severe in all structures studied (amygdala/total intracranial volume, -40%; hippocampal formation/total intracranial volume, -45%; caudate nucleus/total intracranial volume, -21%), and ventricles were enlarged (63%). No overlap was found between Alzheimer disease and control values for the amygdalohippocampal volume, even in the mild stages of the disease. In Alzheimer disease patients, hippocampal formation volumes correlated with the minimental status. Hippocampal and amygdala atrophy is marked and significant in the mild stages of Alzheimer disease. Volumetric measurements of the amygdala and the amygdalohippocampal complex appear more accurate than those of the hippocampal formation alone in distinguishing patients with Alzheimer disease.


Fast density matrix-based partitioning of the energy over the atoms in a molecule consistent with the Hirshfeld-I partitioning of the electron density.
For the Hirshfeld-I atom in the molecule (AIM) model, associated single-atom energies and interaction energies at the Hartree-Fock level are efficiently determined in one-electron Hilbert space. In contrast to most other approaches, the energy terms are fully consistent with the partitioning of the underlying one-electron density matrix (1DM). Starting from the Hirshfeld-I AIM model for the electron density, the molecular 1DM is partitioned with a previously introduced double-atom scheme (Vanfleteren et al., J Chem Phys 2010, 132, 164111). Single-atom density matrices are constructed from the atomic and bond contributions of the double-atom scheme. As the Hartree-Fock energy can be expressed solely in terms of the 1DM, the partitioning of the latter over the AIM naturally leads to a corresponding partitioning of the Hartree-Fock energy. When the size of the molecule or the molecular basis set does not grow too large, the method shows considerable computational advantages compared with other approaches that require cumbersome numerical integration of the molecular energy integrals weighted by atomic weight functions.


Emergency stabilization of the pelvic ring: Clinical comparison between three different techniques.
Emergency devices for pelvic ring stabilization include circumferential sheets, pelvic binders, and c-clamps. Our knowledge of the outcome of these techniques is currently based on limited information. Using the dataset of the German Pelvic Trauma Registry, demographic and injury-associated characteristics as well as the outcome of pelvic fracture patients after sheet, binder, and c-clamp treatment was compared. Outcome parameters included transfusion requirement of packed red blood cells, length of hospital stay, mortality, and incidence of lethal pelvic bleeding. Two hundred seven of 6137 (3.4%) patients documented in the German Pelvic Trauma Registry between April 30th 2004 and January 19th 2012 were treated by sheets, binders, or c-clamps. In most cases, c-clamps (69%) were used, followed by sheets (16%), and binders (15%). The median age was significantly lower in patients treated with binders than in patients treated with sheets or c-clamps (26 vs. 47 vs. 42 years, p=0.01). Sheet wrapping was associated with a significantly higher incidence of lethal pelvic bleeding compared to binder or c-clamp stabilization (23% vs. 4% vs. 8%). No significant differences between the study groups were found in sex, fracture type, blood haemoglobin concentration, arterial blood pressure, Injury Severity Score, the incidence of additional pelvic packing and arterial embolization, need of red blood cell transfusion, length of hospitalisation, and mortality. The data suggest that emergency stabilization of the pelvic ring by binders and c-clamps is associated with a lower incidence of lethal pelvic bleeding compared to sheet wrapping. Level III.


A general-purpose mechanism of visual feature association in visual word identification and beyond.
As writing systems are a relatively novel invention (slightly over 5 kya),1 they could not have influenced the evolution of our species. Instead, reading might recycle evolutionary older mechanisms that originally supported other tasks2,3 and preceded the emergence of written language. Accordingly, it has been shown that baboons and pigeons can be trained to distinguish words from nonwords based on orthographic regularities in letter co-occurrence.4,5 This suggests that part of what is usually considered reading-specific processing could be performed by domain-general visual mechanisms. Here, we tested this hypothesis in humans: if the reading system relies on domain-general visual mechanisms, some of the effects that are often found with orthographic material should also be observable with non-orthographic visual stimuli. We performed three experiments using the same exact design but with visual stimuli that progressively departed from orthographic material. Subjects were passively familiarized with a set of composite visual items and tested in an oddball paradigm for their ability to detect novel stimuli. Participants showed robust sensitivity to the co-occurrence of features ("bigram" coding) with strings of letter-like symbols but also with made-up 3D objects and sinusoidal gratings. This suggests that the processing mechanisms involved in the visual recognition of novel words also support the recognition of other novel visual objects. These mechanisms would allow the visual system to capture statistical regularities in the visual environment.6-9 We hope that this work will inspire models of reading that, although addressing its unique aspects, place it within the broader context of vision.


Asymmetrical nonscalp aplasia cutis congenita: a case report.
Aplasia cutis congenita or congenital absence of the skin is a rare and serious congenital disease; its etiopathogenesis remains unclear. In this condition, localized or widespread areas of skin are absent at birth. A newborn suffering from an unusual aplasia cutis congenita located asymmetrically on the nonscalp, without blistering, was presented. This patient was completely healed with conservative treatment.


Massive and parallel expression profiling using microarrayed single-cell sequencing.
Single-cell transcriptome analysis overcomes problems inherently associated with averaging gene expression measurements in bulk analysis. However, single-cell analysis is currently challenging in terms of cost, throughput and robustness. Here, we present a method enabling massive microarray-based barcoding of expression patterns in single cells, termed MASC-seq. This technology enables both imaging and high-throughput single-cell analysis, characterizing thousands of single-cell transcriptomes per day at a low cost (0.13 USD/cell), which is two orders of magnitude less than commercially available systems. Our novel approach provides data in a rapid and simple way. Therefore, MASC-seq has the potential to accelerate the study of subtle clonal dynamics and help provide critical insights into disease development and other biological processes.


SPORTS1.0: A Tool for Annotating and Profiling Non-coding RNAs Optimized for rRNA- and tRNA-derived Small RNAs.
High-throughput RNA-seq has revolutionized the process of small RNA (sRNA) discovery, leading to a rapid expansion of sRNA categories. In addition to the previously well-characterized sRNAs such as microRNAs (miRNAs), piwi-interacting RNAs (piRNAs), and small nucleolar RNA (snoRNAs), recent emerging studies have spotlighted on tRNA-derived sRNAs (tsRNAs) and rRNA-derived sRNAs (rsRNAs) as new categories of sRNAs that bear versatile functions. Since existing software and pipelines for sRNA annotation are mostly focused on analyzing miRNAs or piRNAs, here we developed the sRNA annotation pipelineoptimized for rRNA- and tRNA-derived sRNAs (SPORTS1.0). SPORTS1.0 is optimized for analyzing tsRNAs and rsRNAs from sRNA-seq data, in addition to its capacity to annotate canonical sRNAs such as miRNAs and piRNAs. Moreover, SPORTS1.0 can predict potential RNA modification sites based on nucleotide mismatches within sRNAs. SPORTS1.0 is precompiled to annotate sRNAs for a wide range of 68 species across bacteria, yeast, plant, and animal kingdoms, while additional species for analyses could be readily expanded upon end users' input. For demonstration, by analyzing sRNA datasets using SPORTS1.0, we reveal that distinct signatures are present in tsRNAs and rsRNAs from different mouse cell types. We also find that compared to other sRNA species, tsRNAs bear the highest mismatch rate, which is consistent with their highly modified nature. SPORTS1.0 is an open-source software and can be publically accessed at https://github.com/junchaoshi/sports1.0.


Kia kaua te reo e rite ki te moa, ka ngaro: do not let the language suffer the same fate as the moa.
More than a third of the world's languages are currently classified as endangered and more than half are expected to go extinct by 2100. Strategies aimed at revitalizing endangered languages have been implemented in numerous countries, with varying degrees of success. Here, we develop a new model regarding language transmission by dividing the population into defined proficiency categories and dynamically quantifying transition rates between categories. The model can predict changes in proficiency levels over time and, ultimately, whether a given endangered language is on a long-term trajectory towards extinction or recovery. We calibrate the model using data from Wales and show that the model predicts that the Welsh language will thrive in the long term. We then apply the model to te reo Māori, the indigenous language of New Zealand, as a case study. Initial conditions for this model are estimated using New Zealand census data. We modify the model to describe a country, such as New Zealand, where the endangered language is associated with a particular subpopulation representing the indigenous people. We conclude that, with current learning rates, te reo Māori is on a pathway towards extinction, but identify strategies that could help restore it to an upward trajectory.


[Validation of the Adolescent Victimization through Mobile Phone and Internet Scale].
To validate the adolescent victimization through mobile phone and internet scale (CYBVIC) through analysis of its psychometric properties. A cross-sectional study was conducted in which two independent samples of adolescents aged 11-19, both male and female, participated. The first sample was comprised of 1 934 Spanish adolescents, and the second sample, 1 483 Mexican adolescents. An exploratory factor analysis of the scale was done with the first sample and a confirmatory factor analysis with the second. Multigroup and reliability analyses, as well as an analysis of the correlation of the scale's dimensions with various external variables related to psychological adjustment (depressive symptomatology, perceived stress, loneliness, satisfaction with life, and traditional victimization), were also conducted. Results. Two factors, called cybmóvil [cyber mobile] and cybinternet [cyber internet], were found, which together explained 52% of the variance. These factors were consistent with the original hypothesis. The confirmatory factor analysis showed the model's adequate fit to two correlated factors. The data indicated the factorial invariance of the questionnaire between the Spanish and Mexican samples. The reliability analysis confirmed that the scale has sufficient internal consistency. Significant correlations were found between the cybmóvil/cybinternet factors and the external variables with which they were related. The CYBVIC scale has adequate psychometric properties and can be used as a valid and reliable measure in new research, which could expand knowledge about the growing international problem of cyberbullying among adolescents.


Aedes aegypti from temperate regions of South America are highly competent to transmit dengue virus.
Aedes aegypti is extensively spread throughout South America where it has been responsible for large dengue epidemics during the last decades. Intriguingly, dengue transmission has not been reported in Uruguay and is essentially prevalent in subtropical northern Argentina which borders Uruguay. We assessed vector competence for dengue virus (DENV) of Ae. aegypti populations collected in subtropical Argentina (Corrientes) as well as temperate Uruguay (Salto) and Argentina (Buenos Aires) in 2012 using experimental oral infections with DENV-2. Mosquitoes were incubated at 28 °C and examined at 14 and 21 days p.i. to access viral dissemination and transmission. Batches of the Buenos Aires mosquitoes were also incubated at 15 °C and 20 °C. Although mosquitoes from temperate Uruguay and Argentina were competent to transmit DENV, those from subtropical Argentina were more susceptible, displaying the highest virus titters in the head and presenting the highest dissemination of infection and transmission efficiency rates when incubated at 28 °C. Interestingly, infectious viral particles could be detected in saliva of mosquitoes from Buenos Aires exposed to 15 °C and 20 °C. There is a potential risk of establishing DENV transmission in Uruguay and for the spread of dengue outbreaks to other parts of subtropical and temperate Argentina, notably during spring and summer periods.


Measuring preferences for health care interventions using conjoint analysis: an application to HIV testing.
To examine preferences for HIV test methods using conjoint analysis, a method used to measure economic preferences (utilities). Self-administered surveys at four publicly funded HIV testing locations in San Francisco, California, between November 1999 and February 2000 (n = 365, 96 percent response rate). We defined six important attributes of HIV tests and their levels (location, price, ease of collection, timeliness/accuracy, privacy/anonymity, and counseling). A fractional factorial design was used to develop scenarios that consisted of combinations of attribute levels. Respondents were asked 11 questions about whether they would choose "Test A or B" based on these scenarios. We used random effects probit models to estimate utilities for testing attributes. Since price was included as an attribute, we were able to estimate willingness to pay, which provides a standardized measure for use in economic evaluations. We used extensive analyses to examine the reliability and validity of the results, including analyses of: (1) preference consistency, (2) willingness to trade among attributes, and (3) consistency with theoretical predictions. Respondents most preferred tests that were accurate/timely and private/anonymous, whereas they had relatively lower preferences for in-person counseling. Respondents were willing to pay an additional $35 for immediate, highly accurate results; however, they had a strong disutility for receiving immediate but less accurate results. By using conjoint analysis to analyze new combinations of attributes, we found that respondents would most prefer instant, highly accurate home tests, even though they are not currently available in the U.S. Respondents were willing to pay $39 for a highly accurate, instant home test. The method of conjoint analysis enabled us to estimate utilities for specific attributes of HIV tests as well as the overall utility obtained from various HIV tests, including tests that are under consideration but not yet available. Conjoint analysis offers an approach that can be useful for measuring and understanding the value of other health care goods, services, and interventions.


A new and frequent human T-cell leukemia virus indeterminate Western blot pattern: epidemiological determinants and PCR results in central African inhabitants.
Human T-cell leukemia virus (HTLV) indeterminate Western blot (WB) serological patterns are frequently observed in plasma/serum from persons living in intertropical areas. In the framework of ongoing projects on HTLV-1/2 and related viruses in Central Africa, we systematically analyzed plasma from villagers living in South Cameroon by WB. The group included 1,968 individuals (mean age, 44 years; age range, 5 to 90 years; 978 women/990 men), both Bantus (1,165) and Pygmies (803). Plasma samples were tested by WB analysis (MPD HTLV Blot 2.4) and interpreted according to the manufacturer's instructions. Only clear bands were considered in the analysis. Among the 1,968 plasma samples, 38 (1.93%) were HTLV-1, 13 (0.66%) were HTLV-2, and 6 (0.3%) were HTLV WB seropositive. Furthermore, 1,292 (65.65%) samples were WB sero-indeterminate, including 104 (5.28%) with an HTLV-1 Gag-indeterminate pattern (HGIP) and 68 (3.45%) with a peculiar yet unreported pattern exhibiting mostly a strong shifted GD21 and a p28. The other 619 (31.45%) samples were either WB negative or exhibited other patterns, mostly with unique p19 or p24 bands. DNA, extracted from peripheral blood buffy coat, was subjected to PCR using several primer pairs known to detect HTLV-1/2/3/4. Most DNAs from HTLV-1- and HTLV-seropositive individuals were PCR positive. In contrast, all the others, from persons with HTLV-2, HGIP, new WB, and other indeterminate patterns, were PCR negative. Epidemiological determinant analysis of the persons with this new peculiar WB pattern revealed that seroprevalence was independent from age, sex, or ethnicity, thus resembling the indeterminate profile HGIP rather than HTLV-1. Moreover, this new pattern persists over time.


Mutations in SEPT9 cause hereditary neuralgic amyotrophy.
Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant recurrent neuropathy affecting the brachial plexus. HNA is triggered by environmental factors such as infection or parturition. We report three mutations in the gene septin 9 (SEPT9) in six families with HNA linked to chromosome 17q25. HNA is the first monogenetic disease caused by mutations in a gene of the septin family. Septins are implicated in formation of the cytoskeleton, cell division and tumorigenesis.


Light-responsive expression atlas reveals the effects of light quality and intensity in Kalanchoë fedtschenkoi, a plant with crassulacean acid metabolism.
Crassulacean acid metabolism (CAM), a specialized mode of photosynthesis, enables plant adaptation to water-limited environments and improves photosynthetic efficiency via an inorganic carbon-concentrating mechanism. Kalanchoë fedtschenkoi is an obligate CAM model featuring a relatively small genome and easy stable transformation. However, the molecular responses to light quality and intensity in CAM plants remain understudied. Here we present a genome-wide expression atlas of K. fedtschenkoi plants grown under 12 h/12 h photoperiod with different light quality (blue, red, far-red, white light) and intensity (0, 150, 440, and 1,000 μmol m-2 s-1) based on RNA sequencing performed for mature leaf samples collected at dawn (2 h before the light period) and dusk (2 h before the dark period). An eFP web browser was created for easy access of the gene expression data. Based on the expression atlas, we constructed a light-responsive co-expression network to reveal the potential regulatory relationships in K. fedtschenkoi. Measurements of leaf titratable acidity, soluble sugar, and starch turnover provided metabolic indicators of the magnitude of CAM under the different light treatments and were used to provide biological context for the expression dataset. Furthermore, CAM-related subnetworks were highlighted to showcase genes relevant to CAM pathway, circadian clock, and stomatal movement. In comparison with white light, monochrome blue/red/far-red light treatments repressed the expression of several CAM-related genes at dusk, along with a major reduction in acid accumulation. Increasing light intensity from an intermediate level (440 μmol m-2 s-1) of white light to a high light treatment (1,000 μmol m-2 s-1) increased expression of several genes involved in dark CO2 fixation and malate transport at dawn, along with an increase in organic acid accumulation. This study provides a useful genomics resource for investigating the molecular mechanism underlying the light regulation of physiology and metabolism in CAM plants. Our results support the hypothesis that both light intensity and light quality can modulate the CAM pathway through regulation of CAM-related genes in K. fedtschenkoi.


Testing the role of circadian genes in conferring risk for psychiatric disorders.
Disturbed sleep and disrupted circadian rhythms are a common feature of psychiatric disorders, and many groups have postulated an association between genetic variants in circadian clock genes and psychiatric disorders. Using summary data from the association analyses of the Psychiatric Genomics Consortia (PGC) for schizophrenia, bipolar disorder and major depressive disorder, we evaluated the evidence that common SNPs in genes encoding components of the molecular clock influence risk to psychiatric disorders. Initially, gene-based and SNP P-values were analyzed for 21 core circadian genes. Subsequently, an expanded list of genes linked to control of circadian rhythms was analyzed. After correcting for multiple comparisons, none of the circadian genes were significantly associated with any of the three disorders. Several genes previously implicated in the etiology of psychiatric disorders harbored no SNPs significant at the nominal level of P < 0.05, and none of the the variants identified in candidate studies of clock genes that were included in the PGC datasets were significant after correction for multiple testing. There was no evidence of an enrichment of associations in genes linked to control of circadian rhythms in human cells. Our results suggest that genes encoding components of the molecular clock are not good candidates for harboring common variants that increase risk to bipolar disorder, schizophrenia, or major depressive disorder.


Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins.
Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P=0.002. Replication was sought in two additional cohorts (N=670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.


Raman signal enhancement in deep spectroscopy of turbid media.
A new, passive method for enhancing spontaneous Raman signals for the spectroscopic investigation of turbid media is presented. The main areas to benefit are transmission Raman and spatially offset Raman spectroscopy approaches for deep probing of turbid media. The enhancement, which is typically several fold, is achieved using a multilayer dielectric optical element, such as a bandpass filter, placed within the laser beam over the sample. This element prevents loss of the photons that re-emerge from the medium at the critical point where the laser beam enters the sample, the point where major photon loss occurs. This leads to a substantial increase of the coupling of laser radiation into the sample and consequently an enhanced laser photon-medium interaction process. The method utilizes the angular dependence of dielectric optical elements on impacting photon direction with its transmission spectral profile shifting to the blue with increase in the deviation of photons away from normal incidence. This feature enables it to act as a unidirectional mirror passing a semi-collimated laser beam through unhindered from one side, and at the other side, reflecting photons emerging from the sample at random directions back into it with no restrictions to the detected Raman signal. With substantial restrictions to the spectral range, the concept can also be applied to conventional backscattering Raman spectroscopy. The use of additional reflective elements around the sample to enhance the Raman signal further is also discussed. The increased signal strength yields higher signal quality, a feature important in many applications. Potential uses include sensitive noninvasive disease diagnosis in vivo, security screening, and quality control of pharmaceutical products. The concept is also applicable in an analogous manner to other types of analytical methods such as fluorescence or near-infrared (NIR) absorption spectroscopy of turbid media or it can be used to enhance the effectiveness of the coupling of laser radiation into tissue in applications such as photodynamic therapy for cancer treatment.


Lineage-specific transcriptional regulation of DICER by MITF in melanocytes.
DICER is a central regulator of microRNA maturation. However, little is known about mechanisms regulating its expression in development or disease. While profiling miRNA expression in differentiating melanocytes, two populations were observed: some upregulated at the pre-miRNA stage, and others upregulated as mature miRNAs (with stable pre-miRNA levels). Conversion of pre-miRNAs to fully processed miRNAs appeared to be dependent upon stimulation of DICER expression--an event found to occur via direct transcriptional targeting of DICER by the melanocyte master transcriptional regulator MITF. MITF binds and activates a conserved regulatory element upstream of DICER's transcriptional start site upon melanocyte differentiation. Targeted KO of DICER is lethal to melanocytes, at least partly via DICER-dependent processing of the pre-miRNA-17 approximately 92 cluster thus targeting BIM, a known proapoptotic regulator of melanocyte survival. These observations highlight a central mechanism underlying lineage-specific miRNA regulation which could exist for other cell types during development.


Usefulness of Plasmodium falciparum-specific rapid diagnostic tests for assessment of parasite clearance and detection of recurrent infections after artemisinin-based combination therapy.
Rapid diagnostic test (RDT) is an important tool for parasite-based malaria diagnosis. High specificity of RDTs to distinguish an active Plasmodium falciparum infection from residual antigens from a previous infection is crucial in endemic areas where residents are repeatedly exposed to malaria. The efficiency of two RDTs based on histidine-rich protein 2 (HRP2) and lactate dehydrogenase (LDH) antigens were studied and compared with two microscopy techniques (Giemsa and acridine orange-stained blood smears) and real-time polymerase chain reaction (PCR) for assessment of initial clearance and detection of recurrent P. falciparum infections after artemisinin-based combination therapy (ACT) in a moderately high endemic area of rural Tanzania. In this exploratory study 53 children < five years with uncomplicated P. falciparum malaria infection were followed up on nine occasions, i.e., day 1, 2, 3, 7, 14, 21, 28, 35 and 42, after initiation of artemether-lumefantrine treatment. At each visit capillary blood samples was collected for the HRP2 and LDH-based RDTs, Giemsa and acridine orange-stained blood smears for microscopy and real-time PCR. Assessment of clearance times and detection of recurrent P. falciparum infections were done for all diagnostic methods. The median clearance times were 28 (range seven to >42) and seven (two to 14) days for HRP2 and LDH-based RDTs, two (one to seven) and two (one to 14) days for Giemsa and acridine orange-stained blood smear and two (one to 28) days for real-time PCR. RDT specificity against Giemsa-stained blood smear microscopy was 21% for HRP2 on day 14, reaching 87% on day 42, and ≥96% from day 14 to 42 for LDH. There was no significant correlation between parasite density at enrolment and duration of HRP2 positivity (r = 0.13, p = 0.34). Recurrent malaria infections occurred in ten (19%) children. The HRP2 and LDH-based RDTs did not detect eight and two of the recurrent infections, respectively. The LDH-based RDT was superior to HRP2-based for monitoring of treatment outcome and detection of recurrent infections after ACT in this moderately high transmission setting. The results may have implications for the choice of RDT devices in similar transmission settings for improved malaria case management. Clinicaltrials.gov, NCT01843764.


Ir- and Ru-doped layered double hydroxides as affordable heterogeneous catalysts for electrochemical water oxidation.
Three M-doped LDHs (M = noble metal active site, LDH = layered double hydroxides; Ir-1, Ir-ZnAl; Ru, Ru-ZnAl; Ir-2, Ir-MgAl), containing small amounts of M (ca. 2 mol% and even <1 mol% for Ru and Ir, respectively), were prepared by following simple and established synthetic procedures. Their characterization indicates that M atoms are effectively incorporated into the brucite-like layers of LDH, without phase segregation. The resulting materials catalyse electrochemical water oxidation (WO), when immobilized in carbon paste electrodes, with performances that exceed those of the benchmark system IrO2, as probed by linear sweep voltammetry (LSV). Some of these catalysts undergo continuous activation upon chronoamperometric and chronopotentiometric treatments over several hours. The crystalline structure of all of them is preserved during electrocatalytic experiments, and no significant leaching of noble metal in solution is detected. The results herein reported highlight the remarkable potential of these doped M-LDHs and confirm that dispersing Ir and Ru centers in layered and cheap inorganic materials results in easily accessible metal centers, providing highly active catalysts, while minimizing the utilization of noble metals.


Low-cost high-performance fiber-optic pH sensor based on thin-core fiber modal interferometer.
A new fiber-optic pH sensor based on a thin-core fiber modal interferometer with electrostatic self-assembled nanocoating is presented. After inserting a segment of thin-core fiber into a standard single-mode fiber, high-order cladding modes are excited and interfere with the core mode to form an in-fiber modal interferometer. The side surface of the sensor is then deposited with poly(allylamine hydrochloride) and poly(acrylic acid) nanocoating by electrostatic self-assembly technique. A fast and linear response is obtained in either acid or alkali solution (in the pH range 2.5 to 10) with resolution of 0.013 pH unit.


5-Iodo-3-ethoxypyrazoles: an entry point to new chemical entities.
Our program, which has focused on the preparation of new pyrazole derivatives, has led us to report here an original and simplified preparation of ethyl 3-ethoxy-1H-pyrazole-4-carboxylate. This is based on the reaction of hydrazine monohydrochloride and diethyl 2-(ethoxymethylene)malonate. Further transformations of this key compound allowed the preparation of the two possible iodinated isomers, namely, 3-ethoxy-4-iodo- and 3-ethoxy-5-iodo-1H-pyrazole. These compounds have opened the way to a quick access to many original pyrazole series. As an illustration, we report here on the selectivity of N-arylation, by using the Lam and Cham method, the C4- and C5-arylation of some of these 3-ethoxypyrazole derivatives by using the Suzuki-Miyaura reaction, and C5-benzylation reactions by means of the Negishi reaction. This was followed by hydrolysis of the ethoxy group, which led to the corresponding pyrazol-3-one derivatives. As a conclusion of this work, we conducted an investigation into the regiochemistry of the condensation between diethyl 2-(ethoxymethylene)malonate and the hydrochloride salts of methyl, benzyl, or phenyl hydrazine.


Emotion regulation and positive affect in the context of salivary alpha-amylase response to pain in children with cancer.
Children with cancer routinely undergo painful medical procedures invoking strong physiological stress responses. Resilience to this pain may be conferred through resources such as emotion regulation strategies and positive affect. This study measured dispositional positive affect in children with cancer (N = 73) and randomly assigned participants to one of three emotion regulation strategy conditions (distraction, reappraisal, or reassurance). Children applied their assigned strategy during an experimental pain procedure (the cold pressor task [CPT]) and provided saliva samples before, immediately after, and 15 min after the CPT. Saliva samples were later assayed for salivary alpha amylase (sAA)-a surrogate marker for autonomic/sympathetic nervous system activity and regulation. Children in the reassurance group had sAA levels that continued to rise after completion of the CPT compared to children in the distraction (b = -1.68, P = 0.021) and reappraisal conditions (b = -1.24, P = 0.084). Furthermore, dispositional positive affect moderated the effect of condition such that children in the reassurance group with lower levels of positive affect had sAA levels that continued to rise after completion of the CPT (dy/dx = 1.56, P = 0.027), whereas children in the reassurance condition with higher levels of positive affect did not exhibit this rise (P > 0.05). Specific emotion regulation strategies, such as distraction and reappraisal, may attenuate the stress response to pain in pediatric patients with cancer, and positive affect may confer resilience in response to pain even with use of less effective coping strategies such as reassurance.


Changes in blood pressure and related autonomic function during cervical traction in healthy women.
Cervical traction is a physical therapy procedure frequently used to treat cervical disk lesions, cervical spondylosis, and cervical facet joint lesions. We have observed rare cases of side effects in elderly patients, but not in women younger than 30 years.In this pilot study, 96 young women were randomly divided into 3 groups to study the effect of cervical traction with different traction weights on blood pressure, heart rate, heart rate variability, and correlated autonomic adjustment. Cervical traction weight used was 10% of the patient's body weight in group A (n=32), 20% in group B (n=32), and 30% in group C (n=32). Assessments of blood pressure, heart rate, heart rate variability, percentage of high- and low-frequency signals, and low-frequency/high-frequency ratio were performed before, during, and 20 minutes after traction. We found that systolic blood pressure, diastolic blood pressure, and heart rate variability elevated during cervical traction and returned nearly to original levels immediately after traction in group C, but not in groups A or B. There were no significant changes in heart rate, percentage of high- or low-frequency signals, and low-frequency/high-frequency ratio in all 3 groups during or after cervical traction.Cervical traction with a traction weight approximately 10% to 20% of body weight can be safely provided without significant compromise of cardiovascular function. However, heavy traction weight (30% of body weight) should be avoided, especially for a patient with cardiovascular disease.


Proteomic analysis of the copper resistance of Streptococcus pneumoniae.
Streptococcus pneumoniae is a Gram-positive bacterial pathogen causing a variety of diseases, including otitis media, bacteraemia and meningitis. Although copper is an essential trace metal for bacterial growth, high intracellular levels of free-copper are toxic. Copper resistance has emerged as an important virulence determinant of microbial pathogens. In this study, we determined the minimum inhibition concentration of copper for the growth inhibition of S. pneumoniae. Two-dimensional-electrophoresis coupled with mass spectrometry was applied to identify proteins involved in copper resistance of S. pneumoniae. In total, forty-four proteins with more than 1.5-fold alteration in expression (p < 0.05) were identified. Quantitative reverse transcription PCR was used to confirm the proteomic results. Bioinformatics analysis showed that the differentially expressed proteins were mainly involved in the cell wall biosynthesis, protein biosynthesis, purine biosynthesis, pyrimidine biosynthesis, primary metabolic process, and the nitrogen compound metabolic process. Many up-regulated proteins in response to the copper treatment directly or indirectly participated in the cell wall biosynthesis, indicating that the cell wall is a critical determinant in copper resistance of S. pneumoniae.


GRASr2 evaluation of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances used as flavoring ingredients.
This publication is the 1st in a series of publications by the Expert Panel of the Flavor and Extract Manufacturers Assoc. summarizing the Panel's 3rd re-evaluation of Generally Recognized as Safe (GRAS) status referred to as the GRASr2 program. In 2011, the Panel initiated a comprehensive program to re-evaluate the safety of more than 2700 flavor ingredients that have previously met the criteria for GRAS status under conditions of intended use as flavor ingredients. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics, and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances as flavoring ingredients are evaluated. The group of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances was reaffirmed as GRAS (GRASr2) based, in part, on their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic studies and the lack of significant genotoxic and mutagenic potential.


Degradation of nano-scale cathodes: a new paradigm for selecting low-temperature solid oxide cell materials.
Oxygen electrodes have been able to meet area specific resistance targets for solid oxide cell operating temperatures as low as ∼500 °C, but their stability over expected device operation times of up to 50 000 h is unknown. Achieving good performance at such temperatures requires mixed ionically and electronically-conducting electrodes with nano-scale structure that makes the electrode susceptible to particle coarsening and, as a result, electrode resistance degradation. Here we describe accelerated life testing of nanostructured Sm0.5Sr0.5CoO3-Ce0.9Gd0.1O2 electrodes combining impedance spectroscopy and microstructural evaluation. Measured electrochemical performance degradation is accurately fitted using a coarsening model that is then used to predict cell operating conditions where required performance and long-term stability are both achieved. A new electrode material figure of merit based on both performance and stability metrics is proposed. An implication is that cation diffusion, which determines the coarsening rate, must be considered along with oxygen transport kinetics in the selection of optimal electrode materials.


How alcohol industry organisations mislead the public about alcohol and cancer.
Alcohol consumption increases the risk of several types of cancer, including several common cancers. As part of their corporate social responsibility activities, the alcohol industry (AI) disseminates information about alcohol and cancer. We examined the information on this which the AI disseminates to the public through its 'social aspects and public relations organizations' and related bodies. The aim of the study was to determine its comprehensiveness and accuracy. Qualitative analysis of websites and documents from 27 AI organisations. All text relating to cancer was extracted and analysed thematically. Most of the organisations were found to disseminate misrepresentations of the evidence about the association between alcohol and cancer. Three main industry strategies were identified: (i) denial/omission: denying, omitting or disputing the evidence that alcohol consumption increases cancer risk; (ii) distortion: mentioning cancer, but misrepresenting the risk; and (iii) distraction: focussing discussion away from the independent effects of alcohol on common cancers. Breast cancer and colorectal cancer appeared to be a particular focus for this misrepresentation. The AI appears to be engaged in the extensive misrepresentation of evidence about the alcohol-related risk of cancer. These activities have parallels with those of the tobacco industry. This finding is important because the industry is involved in developing alcohol policy in many countries, and in disseminating health information to the public, including schoolchildren. Policymakers, academics, public health and other practitioners should reconsider the appropriateness of their relationships to these AI bodies.


H2O2 acts on cellular membranes to generate ceramide signaling and initiate apoptosis in tracheobronchial epithelial cells.
Hydrogen peroxide (H2O2) is an inflammatory oxidant which contributes to the pathogenesis of chronic diseases such as lung injury of the respiratory tract, atherosclerosis and cancer. The mechanisms and target sites of this reactive oxidant are mainly unknown. So far there are opposing reports as to whether reactive oxidants inhibit or promote apoptosis. We activated the death pathway in primary tracheobronchial epithelial (TBE) cells with H2O2 (20-200 microM) and observed the morphological changes, DNA laddering patterns, and DNA fragmentation associated with apoptosis. Elevation of ceramide with exogenous ceramide analogs was sufficient for apoptosis induction with the same characteristics and in the same time frame. H2O2 induced rapid sphingomyelin hydrolysis to ceramide, the elevation of which paralleled the induction of apoptosis. Furthermore, H2O2 acted directly on TBE cells membrane preparations devoid of nuclei, stimulating sphingomyelin hydrolysis through a neutral Mg2+ dependent sphingomyelinase (SMase). These data suggest that the formation of ceramide from sphingomyelin in the plasma membrane is a key event in H2O2-induced apoptosis in tracheobronchial epithelial cells.


Total energy expenditure during arduous wildfire suppression.
The purpose of this investigation was to determine the total energy expenditure (TEE) by using the doubly labeled water (DLW) methodology during 5 d of wildfire suppression in Montana, California, Florida, Washington, and Idaho. Seventeen wildland firefighters (from three Interagency Hot Shot crews, N = 8 men, height = 177 +/- 7 cm, weight = 74.6 +/- 6.4 kg, age = 24.5 +/- 1.8 yr; N = 9 women, height = 170 +/- 7 cm, weight = 65.2 +/- 8.0 kg, age = 25.0 +/- 1.3 yr) served as subjects. Before wildland fire suppression, each subject was given an oral dose of 2H2O and H218O (approximately 0.23 g 2H2O.kg estimated TBW-1 and 0.39 g H218O.kg estimated TBW-1). Urine samples were collected between 0400 and 0600 daily. TEE was calculated using the two-point method for days 1-3 and 1-5, with the TEE for days 4-5 calculated by extrapolation. Urine samples from other crew members not participating in the DLW protocol were collected at the same times and used to adjust calculations of isotopic elimination for background shifts. TEE was 17.4 +/- 3.7 and 17.5 +/- 6.9 MJ.d-1 during days 1-3 and 4-5, respectively. The energy expenditure associated with physical activity (EEA) was 8.8 +/- 3.0 and 8.9 +/- 6.1 MJ.d-1 for days 1-3 and 4-5, respectively. The current data demonstrate consistently high daily energy expenditure in the wildland firefighter. These data also demonstrate that the doubly labeled water methodology is an appropriate methodology for the measure of TEE during unpredictable field operations if adjustments are made for changes in background enrichment and elevated water turnover.


Optimization of Cannula Visibility during Ultrasound-Guided Subclavian Vein Catheterization, via a Longitudinal Approach, by Implementing Echogenic Technology.
Objective. One limitation of ultrasound-guided vascular access is the technical challenge of visualizing the cannula during insertion into the vessel. We hypothesized that the use of an echogenic vascular cannula (EC) would improve visualization when compared with a nonechogenic vascular cannula (NEC) during real-time ultrasound-guided subclavian vein (SCV) cannulation in the ICU. Material and Methods. Eighty mechanically ventilated patients were prospectively enrolled in a randomized study that was conducted in a medical-surgical ICU. Forty patients underwent EC and 40 patients were randomized to NEC. The procedure was ultrasound-guided SCV cannulation via the infraclavicular approach on the longitudinal axis. Results. The EC group exhibited increased cannula visibility as compared to the NEC group (92%±3% versus 85 ± 7%, resp., P < 0.01). There was strong agreement between the procedure operators and independent observers (k = 0.9, 95% confidence intervals assessed by bootstrap analysis = 0.87 to 0.93; P < 0.01). Access time (12.1 s ± 6.5 versus 18.9 s ± 10.9) and the perceived technical difficulty of the ultrasound method (4.5 ± 1.5 versus 7.5 ± 1.5) were both decreased in the EC group compared to the NEC group (P < 0.05). Conclusions. Echogenic technology significantly improved cannula visibility and decreased access time and technical complexity optimizing thus real-time ultrasound-guided SCV cannulation via a longitudinal approach.


Evaluating a bilingual patient navigation program for uninsured women with abnormal screening tests for breast and cervical cancer: implications for future navigator research.
The DuPage Patient Navigation Collaborative evaluated the Patient Navigation Research Program (PNRP) model for uninsured women receiving free breast or cervical cancer screening through the Illinois Breast and Cervical Cancer Program in DuPage County, Illinois. We used medical records review and patient surveys of 477 women to compare median follow-up times with external Illinois Breast and Cervical Cancer Program and Chicago PNRP benchmarks of performance. We examined the extent to which we mitigated community-defined timeliness risk factors for delayed follow-up, with a focus on Spanish-speaking participants. Median follow-up time (29.0 days for breast and 56.5 days for cervical screening abnormalities) compared favorably to external benchmarks. Spanish-speaking patients had lower health literacy, lower patient activation, and more health care system distrust than did English-speaking patients, but despite the prevalence of timeliness risk factors, we observed no differences in likelihood of delayed (> 60 days) follow-up by language. Our successful replication and scaling of the PNRP navigation model to DuPage County illustrates a promising approach for future navigator research.


Correlation between uncoupled conductance-based integrate-and-fire neurons due to common and synchronous presynaptic firing.
We investigate the firing characteristics of conductance-based integrate-and-fire neurons and the correlation of firing for uncoupled pairs of neurons as a result of common input and synchronous firing of multiple synaptic inputs. Analytical approximations are derived for the moments of the steady state potential and the effective time constant. We show that postsynaptic firing barely depends on the correlation between inhibitory inputs; only the inhibitory firing rate matters. In contrast, both the degree of synchrony and the firing rate of excitatory inputs are relevant. A coefficient of variation CV > 1 can be attained with low inhibitory firing rates and (Poisson-modulated) synchronized excitatory synaptic input, where both the number of presynaptic neurons in synchronous firing assemblies and the synchronous firing rate should be sufficiently large. The correlation in firing of a pair of uncoupled neurons due to common excitatory input is initially increased for increasing firing rates of independent inhibitory inputs but decreases for large inhibitory firing rates. Common inhibitory input to a pair of uncoupled neurons barely induces correlated firing, but amplifies the effect of common excitation. Synchronous firing assemblies in the common input further enhance the correlation and are essential to attain experimentally observed correlation values. Since uncorrelated common input (i.e., common input by neurons, which do not fire in synchrony) cannot induce sufficient postsynaptic correlation, we conclude that lateral couplings are essential to establish clusters of synchronously firing neurons.


Advanced penile carcinoma.
In the United States penile carcinoma is an uncommon malignancy that represents only 0.4% of all male malignancies and 2% to 4% of genitourinary malignancies. Of penile cancer cases 30% are diagnosed with advanced disease. Improved understanding of the natural history, appropriate and accurate staging, and tailored, less morbid lymphadenectomy have led to improved survival and decreased the adverse effects of therapy. However, the management of advanced penile carcinoma remains a challenge to urological, medical and radiation oncologists. The rarity and paucity of well designed clinical studies of medical and/or surgical therapy for advanced penile cancer have hampered progress in the treatment of this disease. However, there is clear evidence that identifies active chemotherapy and radiation treatments. This review aims to provide the treating physician with an overview of available data for surgical, chemotherapeutic and radiation treatments, and provide guidelines for appropriate patient selection for these therapies. We performed a detailed review of the available literature regarding advanced penile carcinoma to include its etiology, epidemiology, natural history, staging classification and treatment. Penile carcinoma typically spreads along an echelon of nodal pathways that permits fairly accurate staging. Prognosis correlates well with clinical nodal status and grade, and the TNM classification developed by the UICC should be uniformly used by clinicians. Treatment recommendations are tightly associated with disease stage. Although tailored lymphadenectomy as currently recommended has greatly decreased morbidity, improved staging accuracy and improved treatment results, controversies still exist regarding the need for lymphadenectomy in patients with impalpable lymph node (cN0) disease, and the role and timing of pelvic lymphadenectomy. There is evidence of modest activity for chemotherapy in advanced penile carcinoma. Active agents include cisplatin, bleomycin and methotrexate. Combination chemotherapy regimens with promising activity and toxicity profiles include cisplatin and 5-fluorouracil, and vincristine, bleomycin and methotrexate. Radiation in combination with surgery and/or chemotherapy in advanced disease have also demonstrated activity. The natural history of penile carcinoma and its proclivity to spread via regional lymphatics has been well defined. This understanding has led to the development of effective locoregional treatment strategies. Penile carcinoma is sensitive to radiation and certain chemotherapeutic agents. A threshold volume of nodal metastases is associated with significant mortality. The optimal application of these strategies remains to be determined. Improvements in survival and quality of life likely require the incorporation of multiple modalities into the treatment of advanced penile carcinoma. A multi-institutional, international effort is essential to perform appropriately powered clinical trials to advance the standard of care in this rare disease.


The Effect of Acute Caffeine Ingestion on Tactical Performance of Professional Soccer Players.
In soccer, physical, tactical, and decision-making processes are highly important facets of successful performance. Caffeine has well established effects for promoting both physical and cognitive performance, but the translation of such benefits specifically for soccer match play is not well established. This study examined the effects of acute caffeine ingestion on tactical performance during small-sided games (SSG) in professional soccer players. Nineteen soccer players (22 ± 4 years) underwent a randomized, counterbalanced, crossover, double-blind placebo-controlled trial. The protocol consisted of 5 bouts of 5-min SSG with 3 players plus a goalkeeper in each team (3 + GK × 3 + GK) with each SSG separated by 1 min rest intervals. Tactical performance was assessed using the system of tactical assessment in soccer (FUT-SAT). Prior to each experimental trial, participants ingested caffeine (5 mg·kg-1) or a placebo 60 min before the protocol. Overall, caffeine ingestion resulted in an increased ball possession time when compared to the placebo. When the offensive and defensive core principles were analyzed, the results were equivocal. Caffeine resulted in positive effects on some tactical decisions during the protocol, but it was deleterious or promoted no observed effect on other of the core tactical principles. Caffeine ingestion resulted in less offensive (during SSG3) and defensive (SSG 2, SSG3, and SSG4) errors. Caffeine ingestion also resulted in higher total offensive success during SSG 1 and SSG2, but it was detrimental during SSG3. Additionally, total defensive success was lower for the caffeine conditions during SSG 2 and SSG5 when compared to the placebo. In conclusion, caffeine influenced aspects of tactical decisions in soccer, resulting in fewer offensive and defensive errors, although it may be deleterious considering other tactical parameters. Future studies may clarify the effects of caffeine ingestion on specific decision-making parameters in soccer.


Electroacupuncture for fatigue, sleep, and psychological distress in breast cancer patients with aromatase inhibitor-related arthralgia: a randomized trial.
Although fatigue, sleep disturbance, depression, and anxiety are associated with pain in breast cancer patients, it is unknown whether acupuncture can decrease these comorbid symptoms in cancer patients with pain. The objective of this study was to evaluate the effect of electroacupuncture (EA) on fatigue, sleep, and psychological distress in breast cancer survivors who experience joint pain related to aromatase inhibitors (AIs). The authors performed a randomized controlled trial of an 8-week course of EA compared with a waitlist control (WLC) group and a sham acupuncture (SA) group in postmenopausal women with breast cancer who self-reported joint pain attributable to AIs. Fatigue, sleep disturbance, anxiety, and depression were measured using the Brief Fatigue Inventory (BFI), the Pittsburgh Sleep Quality Index (PSQI), and the Hospital Anxiety and Depression Scale (HADS). The effects of EA and SA versus WLC on these outcomes were evaluated using mixed-effects models. Of the 67 randomly assigned patients, baseline pain interference was associated with fatigue (Pearson correlation coefficient [r]=0.75; P < .001), sleep disturbance (r=0.38; P=.0026), and depression (r=0.58; P < .001). Compared with the WLC condition, EA produced significant improvements in fatigue (P=.0095), anxiety (P=.044), and depression (P=.015) and a nonsignificant improvement in sleep disturbance (P=.058) during the 12-week intervention and follow-up period. In contrast, SA did not produce significant reductions in fatigue or anxiety symptoms but did produce a significant improvement in depression compared with the WLC condition (P=.0088). Compared with usual care, EA produced significant improvements in fatigue, anxiety, and depression; whereas SA improved only depression in women experiencing AI-related arthralgia.


Influence of practice schedules and attention on skill development and retention.
Focus of attention during dual-tasks and practice schedules are important components of motor skill performance and learning; often studied in isolation. The current study required participants to complete a simple key-pressing task under a blocked or random practice schedule. To manipulate attention, participants reported their finger position (i.e., skill-focused attention) or the pitch of an auditory tone (i.e., extraneous attention) while performing two variations of a dual-task key-pressing task. Analyses were conducted at baseline, 10 min and 24h after acquisition. The results revealed that participants in a blocked schedule, extraneous focus condition had significantly faster movement times during retention compared to a blocked schedule, skill focus condition. Furthermore, greatest improvements from baseline to immediate and delayed retention were evident for an extraneous attention compared to the skill-focused attention, regardless of practice schedule. A discussion of the unique benefits an extraneous focus of attention may have on the learning process during dual-task conditions is presented.


The digital surgeon: How big data, automation, and artificial intelligence will change surgical practice.
Exponential growth in computing power, data storage, and sensing technology has led to a world in which we can both capture and analyze incredible amounts of data. The evolution of machine learning has further advanced the ability of computers to develop insights from massive data sets that are beyond the capacity of human analysis. The convergence of computational power, data storage, connectivity, and Artificial Intelligence (AI) has led to health technologies that, to date, have focused on diagnostic areas such as radiology and pathology. The question remains how the digital revolution will translate in the realm of surgery. There are three main areas where the authors believe that AI could impact surgery in the near future: enhancement of training modalities, cognitive enhancement of the surgeon, and procedural automation. While the promise of Big Data, AI, and Automation is high, there have been unanticipated missteps in the use of such technologies that are worth considering as we evaluate how such technologies could/should be adopted in surgical practice. Surgeons must be prepared to adopt smarter training modalities, supervise the learning of machines that can enhance cognitive function, and ultimately oversee autonomous surgery without allowing for a decay in the surgeon's operating skills.


Antigen-specific T cell phenotyping microarrays using grating coupled surface plasmon resonance imaging and surface plasmon coupled emission.
The circulating population of peripheral T lymphocytes obtained from a blood sample can provide a large amount of information about an individual's medical status and history. Recent evidence indicates that the detection and functional characterization of antigen-specific T cell subsets within the circulating population may provide a diagnostic indicator of disease and has the potential to predict an individual's response to therapy. In this report, a microarray detection platform that combines grating-coupled surface plasmon resonance imaging (GCSPRI) and grating-coupled surface plasmon coupled emission (SPCE) fluorescence detection modalities were used to detect and characterize CD4(+) T cells. The microspot regions of interest (ROIs) printed on the array consisted of immobilized antibodies or peptide loaded MHC monomers (p/MHC) as T cell capture ligands mixed with additional antibodies as cytokine capture ligands covalently bound to the surface of a corrugated gold sensor chip. Using optimized parameters, an unlabeled influenza peptide reactive T cell clone could be detected at a frequency of 0.1% in a mixed T cell sample using GCSPRI. Additionally, after cell binding was quantified, differential TH1 cytokine secretion patterns from a T cell clone cultured under TH1 or TH2 inducing conditions was detected using an SPCE fluorescence based assay. Differences in the secretion patterns of 3 cytokines, characteristic of the inducing conditions, indicated that differences were a consequence of the functional status of the captured cells. A dual mode GCSPRI/SPCE assay can provide a rapid, high content T cell screening/characterization tool that is useful for diagnosing disease, evaluating vaccination efficacy, or assessing responses to immunotherapeutics.


Hydrogen Sulfide--Mechanisms of Toxicity and Development of an Antidote.
Hydrogen sulfide is a highly toxic gas-second only to carbon monoxide as a cause of inhalational deaths. Its mechanism of toxicity is only partially known, and no specific therapy exists for sulfide poisoning. We show in several cell types, including human inducible pluripotent stem cell (hiPSC)-derived neurons, that sulfide inhibited complex IV of the mitochondrial respiratory chain and induced apoptosis. Sulfide increased hydroxyl radical production in isolated mouse heart mitochondria and F2-isoprostanes in brains and hearts of mice. The vitamin B12 analog cobinamide reversed the cellular toxicity of sulfide, and rescued Drosophila melanogaster and mice from lethal exposures of hydrogen sulfide gas. Cobinamide worked through two distinct mechanisms: direct reversal of complex IV inhibition and neutralization of sulfide-generated reactive oxygen species. We conclude that sulfide produces a high degree of oxidative stress in cells and tissues, and that cobinamide has promise as a first specific treatment for sulfide poisoning.


Effects of angiotensin II on human endothelial cells survival signalling pathways and its angiogenic response.
Reduced capillary density (rarefaction) is an early event of cardiovascular disease. The PI-3K-Akt pathway is a key player in anti-endothelial cells (ECs) apoptosis. VEGF is a key growth factor for angiogenesis. We investigated the effect of Angiotensin II (Ang II) on ECs survival signalling and angiogenesis in vitro. We found that Ang II had a biphasic effect on Akt phosphorylation by western blotting analysis. Low concentration Ang II caused a dose-dependent increase in Akt phosphorylation, while high concentration of Ang II led to a decrease of Akt phosphorylation. This effect was negative regulated by its type II receptor. Ang II 10(-4) M induced ECs apoptosis by its type II receptor was completely blocked by VEGF. Cell viability was increased by Ang II 10(-6) M and decreased by Ang II 10(-4) M. It was further decreased by pre-treatment with PI-3K/Akt inhibitor LY294002, but unaffected by p38-MAPK inhibitor SB202190. Ang II 10(-4) M reduced ECs' proliferation and vascular tube length, which were in part regulated by type II receptor. Our findings support a dose-dependent role of Ang II in effect on ECs survival and angiogenesis by PI-3K/Akt pathway. The anti-angiogenic effect of Ang II was mediated by its type II receptor.


Physical Activity Promotion in Business and Industry: Evidence, Context, and Recommendations for a National Plan.
The contemporary workplace setting is in need of interventions that effectively promote higher levels of occupational and habitual physical activity. It is the purpose of this paper to outline an evidence-based approach to promote physical activity in the business and industry sector in support of a National Physical Activity Plan. Comprehensive literature searches identified systematic reviews, comprehensive reviews, and consensus documents on the impact of physical activity interventions in the business and industry sector. A framework for action and priority recommendations for practice and research were generated. Comprehensive, multicomponent worksite programs that include physical activity components generate significant improvements in health, reduce absenteeism and sick leave, and can generate a positive financial return. Specific evidence-based physical activity interventions are presented. Recommendations for practice include implementing comprehensive, multicomponent programs that make physical activity interventions possible, simple, rewarding and relevant in the context of a social-ecological model. The business and industry sector has significant opportunities to improve physical activity among employees, their dependents, and the community at-large and to reap important benefits related to worker health and business performance.


Antiviral protein APOBEC3G localizes to ribonucleoprotein complexes found in P bodies and stress granules.
Members of the APOBEC (apolipoprotein B mRNA-editing enzyme catalytic polypeptide 1-like) family of cytidine deaminases inhibit host cell genome invasion by exogenous retroviruses and endogenous retrotransposons. Because these enzymes can edit DNA or RNA and potentially mutate cellular targets, their activities are presumably regulated; for instance, APOBEC3G (A3G) recruitment into high-molecular-weight ribonucleoprotein (RNP) complexes has been shown to suppress its enzymatic activity. We used tandem affinity purification together with mass spectrometry (MS) to identify protein components within A3G-containing RNPs. We report that numerous cellular RNA-binding proteins with diverse roles in RNA function, metabolism, and fate determination are present in A3G RNPs but that most interactions with A3G are mediated via binding to shared RNAs. Confocal microscopy demonstrated that substantial quantities of A3G localize to cytoplasmic microdomains that are known as P bodies and stress granules (SGs) and are established sites of RNA storage and metabolism. Indeed, subjecting cells to stress induces the rapid redistribution of A3G and a number of P-body proteins to SGs. Among these proteins are Argonaute 1 (Ago1) and Argonaute 2 (Ago2), factors that are important for RNA silencing and whose interactions with A3G are resistant to RNase treatment. Together, these findings reveal that A3G associates with RNPs that are found throughout the cytosol as well as in discrete microdomains. We also speculate that the interplay between A3G, RNA-silencing pathways, and cellular sites of RNA metabolism may contribute to A3G's role as an inhibitor of retroelement mobility and as a possible regulator of cellular RNA function.