Effects of a front-of-package disclosure on accuracy in assessing children's drink ingredients: two randomised controlled experiments with US caregivers of young children.
Test effects of a standardised front-of-package (FOP) disclosure statement (indicating added sugar, non-nutritive sweetener (NNS) and juice content) on accuracy in assessing ingredients and perceived healthfulness of children's drinks. In two randomised controlled experiments, the same participants viewed drink packages and indicated if products contained added sugar or NNS and percent juice and rated drink healthfulness. Experiment 1 (E1) included novel (non-US) children's drinks with a) product claims only (control), b) claims and disclosure, or c) disclosure only. Experiment 2 (E2) included existing children's drinks (with claims) with a) no disclosure (control) or b) disclosure. Both experiments evaluated sweetened (fruit drink and flavoured water) and unsweetened (100 % juice and juice/water blend) drinks. Potential individual differences (education level and race/ethnicity) in effects were explored. Online survey. Six hundred and forty-eight US caregivers of young children (1-5 years). FOP disclosures significantly increased accuracy for most ingredients and drink types, including identifying presence or absence of NNS in sweetened drinks, no added sugar in juice/water blends, and actual percent juice in fruit drinks and juice/water blends in both experiments. Disclosures also increased recognition that the novel 100 % juice and juice/water blend did not contain NNS or added sugar (E1) and existing sweetened drinks contained added sugar (E2). Disclosures reduced perceived healthfulness of sweetened drinks but did not increase unsweetened drink healthfulness ratings. Some differences by participant socio-demographic characteristics require additional research. FOP disclosures on children's drink packages can increase caregivers' understanding of product ingredients and aid in selecting healthier children's drinks.


Vasoactive Therapy in Systemic Sclerosis: Real-life Therapeutic Practice in More Than 3000 Patients.
Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry. The data of 3248 patients with SSc were analyzed. Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005. These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.


Cognitive findings after transient global amnesia: role of prefrontal cortex.
The aim of this study is to verify, after recovery, the presence of specific patterns of cognitive dysfunctions in Transient Global Amnesia (TGA). Fourteen patients with the diagnosis of TGA were submitted to a battery of neuropsychological tests and compared to a matched control group. We found significant qualitative and quantitative differences between TGA patients and controls in the California Verbal Learning Test (CLVT) and Rey-Osterrieth Complex Figure Test. Our data support the presence of selective cognitive dysfunctions after the clinical recovery. Moreover, for Verbal Fluency, Digit Span Backward, and Number of Clusters in the CVLT short-term memory test, the relation resulted as positively related with the temporal interval from the TGA episode. Reduction of categorical learning, attention, and qualitative alterations of spatial strategy seem to postulate a planning defect due to a prefrontal impairment.


p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies.
The mechanisms of tumorigenesis of adrenocortical neoplasms have not been elucidated as yet. However, loss of heterozygosity at chromosomal locus 17p has been consistently observed in adrenocortical cancer. p53 is a recessive tumor suppressor gene located on chromosome 17p. Mutations in the p53 gene play an important role in the tumorigenesis of diverse types of human neoplasms including breast and colon cancers. More than 90% of all mutations discovered in such tumors have been detected in 4 hot spot areas that lie between exons 5 and 8. In contrast to wild-type p53, mutant p53 accumulates intracellularly and can be easily detected by immunohistochemistry. We therefore investigated the frequency of p53 mutations in human adrenocortical neoplasms using molecular biology and immunohistochemistry techniques. Five patients with adrenocortical adenomas (5 female; ages 39-72 yr), 11 patients with adrenocortical carcinomas (8 female, 3 male; ages 15-50 yr), and two adrenocortical tumor cell lines were studied. After DNA extraction from frozen tumor tissue or paraffin-embedded material, exons 5 through 8 were amplified using the polymerase chain reaction and directly sequenced by the dideoxy termination method. Immunohistochemistry was performed on paraffin-embedded tumor specimens obtained during adrenalectomy using a monoclonal antibody reacting with both wild-type and mutant p53. Prevalence of mutations was adenomas, 0/5, carcinomas, 3/11, and adrenocortical cell lines, 2/2. Single point mutations were detected in 3 cases (exons 5, 6, and 7, respectively), and rearrangements of exon 7/8 and 8 were found in 2 cases. Immunohistochemistry detected strong nuclear and/or cytoplasmic p53 immunoreactivity in all adrenocortical carcinomas with point mutations of the p53 gene but not in adenomas and carcinomas with the wild-type sequence or with deletion/rearrangement of the p53 gene. We conclude that p53 plays a role in the tumorigenesis of adrenocortical carcinomas but is of less importance to benign adenomas.


Findings of the first ANZICS conference on the role of intensive care in Rapid Response Teams.
Rapid Response Teams (RRTs) are specialised teams introduced into hospitals to improve the outcomes of deteriorating ward patients. Although Rapid Response Systems (RRSs) were developed by the intensive care unit (ICU) community, there is variability in their delivery, and consultant involvement, supervision and leadership appears to be relatively infrequent. In July 2014, the Australian and New Zealand Intensive Care Society (ANZICS) convened the first conference on the role of intensive care medicine in RRTs in Australia and New Zealand. The conference explored RRSs in the broader role of patient safety, resourcing and staffing of RRTs, effect on ICU workload, different RRT models, the outcomes of RRT patients and original research projects in the area of RRSs. Issues around education and training of both ICU registrars and nurses were examined, and the role of team training explored. Measures to assess the effectiveness of the RRS and RRT at the level of health system and hospital, team performance and team effectiveness were discussed, and the need to develop a bi-national ANZICS RRT patient database was presented. Strategies to prevent patient deterioration in the 'pre-RRT' period were discussed, including education of ward nurses and doctors, as well as an overarching governance structure. The role of the ICU in deteriorating ward patients was debated and an integrated model of acute care presented. This article summarises the findings of the conference and presents recommendations on the role of intensive care medicine in RRTs in Australia and New Zealand.


The association of in-hospital guideline adherence and longitudinal postdischarge mortality in older patients with non-ST-segment elevation myocardial infarction.
Prior work has demonstrated that adherence to American College of Cardiology/American Heart Association guideline recommendations is associated with decreased in-hospital mortality in non-ST-segment elevation myocardial infarction (NSTEMI) patients; however, it is unknown whether this association persists after hospital discharge in older, real-world populations. We evaluated 32,646 NSTEMI patients ≥65 years treated at 243 US hospitals participating in CRUSADE from 2003 to 2006, linked to Medicare longitudinal claims data (followed to January 1, 2010). Hospital composite adherence examined the use of 13 individual American College of Cardiology/American Heart Association Class IA guideline-recommended interventions. Among patients who survived to hospital discharge, we used Cox proportional hazards modeling to examine the association between hospital composite adherence and 1- and 3-year mortality conditional on surviving initial hospitalization and adjusting for patient baseline clinical factors and hospital characteristics. The overall median composite guideline adherence to all 13 interventions was 77.4% with median (25th, 75th percentiles) hospital adherence ranging from 66.7% (61.9%, 70.1%) in the lowest adherence quartile to 85.8% (83.7%, 88.7%) in the highest adherence quartiles. Overall survival at 1 and 3 years was 80.0% and 62.8%, respectively. Relative to patients treated at the lowest adherence hospitals, those treated at the highest had similar adjusted mortality risk at 1 year but significantly lower 3-year mortality risk (adjusted hazard ratio [95% CI] 0.90 [0.82-0.99]). For every 10% increase in adherence to all 13 hospital composite therapies, there was a 5% reduction in 3-year mortality risk (0.95 [0.91-0.98]). Use of guideline-based therapies during acute hospitalization for NSTEMI was associated with significant decreases in mortality up to 3 years post-hospital discharge.


SMURF: Genomic mapping of fungal secondary metabolite clusters.
Fungi produce an impressive array of secondary metabolites (SMs) including mycotoxins, antibiotics and pharmaceuticals. The genes responsible for their biosynthesis, export, and transcriptional regulation are often found in contiguous gene clusters. To facilitate annotation of these clusters in sequenced fungal genomes, we developed the web-based software SMURF (www.jcvi.org/smurf/) to systematically predict clustered SM genes based on their genomic context and domain content. We applied SMURF to catalog putative clusters in 27 publicly available fungal genomes. Comparison with genetically characterized clusters from six fungal species showed that SMURF accurately recovered all clusters and detected additional potential clusters. Subsequent comparative analysis revealed the striking biosynthetic capacity and variability of the fungal SM pathways and the correlation between unicellularity and the absence of SMs. Further genetics studies are needed to experimentally confirm these clusters.


Colonic preservation reduces need for parenteral therapy, increases incidence of renal stones, but does not change high prevalence of gall stones in patients with a short bowel.
Forty six patients with less than 200 cm of normal jejunum and no functioning colon were compared with 38 patients with similar jejunal lengths in continuity with a functioning colon. Women predominated (67%), and the most common diagnosis in each group was Crohn's disease (33 of 46 no colon, 16 of 38 with colon). All patients without a colon and less than 85 cm of jejunum and all those with a colon and less than 45 cm jejunum needed long term parenteral nutrition. Six months after the last resection 12 of 17 patients with less than 100 cm jejunum and no colon needed intravenous supplements compared with 7 of 21 with a colon. Between 6 months and 2 years, little change occurred in the nutritional/fluid requirements in either group, though there was weight gain. Of 71 patients assessed clinically at a median of 5 years, none with more than 50 cm of jejunum and a colon needed parenteral supplements. Most (25 of 27) of those without a colon who did not need parenteral supplements required oral electrolyte replacement compared with few (4 of 27) with a colon. None of the patients without a colon developed symptomatic renal stones compared with 9 of 38 (24%) with a colon (p < 0.001). Stone analysis in three patients showed calcium oxalate. Gall stone prevalence was high but equal in the two groups--43% of those without and 44% of those with a colon.


MicroRNA-139 modulates Alzheimer's-associated pathogenesis in SAMP8 mice by targeting cannabinoid receptor type 2.
Alzheimer's disease (AD) is a neurodegenerative disorder, and is the most common type of dementia in the elderly population. Growing evidence indicates that microRNAs (miRNAs) play a crucial role in neuroinflammation associated with AD progression. In this study, we analyzed the expression of microRNA-139 (miR-139) as well as the learning and memory function in AD. We observed that the miR-139 expression was significantly higher in the hippocampus of aged senescence accelerated mouse prone 8 (SAMP8) mice (2.92 ± 0.13) than in the control mice (1.49 ± 0.08). Likewise, the overexpression of miR-139 by means of hippocampal injection impaired the hippocampus-dependent learning and memory formation. In contrast, the downregulation of miR-139 in mice improved learning and memory function in the mice. The level of cannabinoid receptor type 2 (CB2), a potential target gene of miR-139, was inversely correlated with the miR-139 expression in primary hippocampal cells. Furthermore, we demonstrated that miR-139 inversely modulated the responses to proinflammatory stimuli. Together, our findings demonstrate that miR-139 exerts a pathogenic effect in AD by modulating CB2-meditated neuroinflammatory processes.


Displacement and strain of the median nerve at the wrist.
Median nerve displacement and strain in the carpal tunnel region were measured as functions of wrist position and carpal tunnel pressure in 5 cadaver forearms during simulated active finger flexion. The positions of spherical stainless-steel markers embedded within the median nerve and flexor digitorum superficialis of the long finger were measured in 3 dimensions by a radiographic direct linear transformation technique. Each limb was tested in 3 wrist positions (60 degrees extension, neutral, and 60 degrees flexion) and 4 carpal tunnel pressures (0, 30, 60, and 90 mmHg). Carpal tunnel pressure was controlled with a balloon angiocatheter inserted deep to the flexor digitorum profundus. The ratio of median nerve to flexor tendon excursion was linear and was affected by wrist position but not carpal tunnel pressure. Patterns of strain in the median nerve proximal to the flexor retinaculum were different from those of strain within the carpal tunnel. Nerve strains were affected by wrist position, but carpal tunnel pressure had no effect. The hydrostatic pressure effect associated with carpal tunnel syndrome does not appear to influence median nerve kinetics or kinematics for the wrist positions studied.


High-throughput identification of viral termini and packaging mechanisms in virome datasets using PhageTermVirome.
Viruses that infect bacteria (phages) are increasingly recognized for their importance in diverse ecosystems but identifying and annotating them in large-scale sequence datasets is still challenging. Although efficient scalable virus identification tools are emerging, defining the exact ends (termini) of phage genomes is still particularly difficult. The proper identification of termini is crucial, as it helps in characterizing the packaging mechanism of bacteriophages and provides information on various aspects of phage biology. Here, we introduce PhageTermVirome (PTV) as a tool for the easy and rapid high-throughput determination of phage termini and packaging mechanisms using modern large-scale metagenomics datasets. We successfully tested the PTV algorithm on a mock virome dataset and then used it on two real virome datasets to achieve the rapid identification of more than 100 phage termini and packaging mechanisms, with just a few hours of computing time. Because PTV allows the identification of free fully formed viral particles (by recognition of termini present only in encapsidated DNA), it can also complement other virus identification softwares to predict the true viral origin of contigs in viral metagenomics datasets. PTV is a novel and unique tool for high-throughput characterization of phage genomes, including phage termini identification and characterization of genome packaging mechanisms. This software should help researchers better visualize, map and study the virosphere. PTV is freely available for downloading and installation at https://gitlab.pasteur.fr/vlegrand/ptv .


Joint modeling of multiple social networks to elucidate primate social dynamics: I. maximum entropy principle and network-based interactions.
In a complex behavioral system, such as an animal society, the dynamics of the system as a whole represent the synergistic interaction among multiple aspects of the society. We constructed multiple single-behavior social networks for the purpose of approximating from multiple aspects a single complex behavioral system of interest: rhesus macaque society. Instead of analyzing these networks individually, we describe a new method for jointly analyzing them in order to gain comprehensive understanding about the system dynamics as a whole. This method of jointly modeling multiple networks becomes valuable analytical tool for studying the complex nature of the interaction among multiple aspects of any system. Here we develop a bottom-up, iterative modeling approach based upon the maximum entropy principle. This principle is applied to a multi-dimensional link-based distributional framework, which is derived by jointly transforming the multiple directed behavioral social network data, for extracting patterns of synergistic inter-behavioral relationships. Using a rhesus macaque group as a model system, we jointly modeled and analyzed four different social behavioral networks at two different time points (one stable and one unstable) from a rhesus macaque group housed at the California National Primate Research Center (CNPRC). We report and discuss the inter-behavioral dynamics uncovered by our joint modeling approach with respect to social stability.


The neurobiology of D-amino acid oxidase and its involvement in schizophrenia.
D-amino acid oxidase (DAO) is a flavoenzyme that metabolizes certain D-amino acids, notably the endogenous N-methyl D-aspartate receptor (NMDAR) co-agonist, D-serine. As such, it has the potential to modulate the function of NMDAR and to contribute to the widely hypothesized involvement of NMDAR signalling in schizophrenia. Three lines of evidence now provide support for this possibility: DAO shows genetic associations with the disorder in several, although not all, studies; the expression and activity of DAO are increased in schizophrenia; and DAO inactivation in rodents produces behavioural and biochemical effects, suggestive of potential therapeutic benefits. However, several key issues remain unclear. These include the regional, cellular and subcellular localization of DAO, the physiological importance of DAO and its substrates other than D-serine, as well as the causes and consequences of elevated DAO in schizophrenia. Herein, we critically review the neurobiology of DAO, its involvement in schizophrenia, and the therapeutic value of DAO inhibition. This review also highlights issues that have a broader relevance beyond DAO itself: how should we weigh up convergent and cumulatively impressive, but individually inconclusive, pieces of evidence regarding the role that a given gene may have in the aetiology, pathophysiology and pharmacotherapy of schizophrenia?


Reformulating time-dependent density functional theory with non-orthogonal localized molecular orbitals.
Time-dependent density functional theory (TDDFT) has broad application in the study of electronic response, excitation and transport. To extend such application to large and complex systems, we develop a reformulation of TDDFT equations in terms of non-orthogonal localized molecular orbitals (NOLMOs). NOLMO is the most localized representation of electronic degrees of freedom and has been used in ground state calculations. In atomic orbital (AO) representation, the sparsity of NOLMO is transferred to the coefficient matrix of molecular orbitals (MOs). Its novel use in TDDFT here leads to a very simple form of time propagation equations which can be solved with linear-scaling effort. We have tested the method for several long-chain saturated and conjugated molecular systems within the self-consistent charge density-functional tight-binding method (SCC-DFTB) and demonstrated its accuracy. This opens up pathways for TDDFT applications to large bio- and nano-systems.


Anaortic off-pump coronary artery bypass grafting in the elderly and very elderly.
Elderly patients undergoing surgical revascularisation may disproportionately benefit from avoiding manipulation of the ascending aorta and cardiopulmonary bypass. In this multi-centre observational study, we sought to determine the 30-day outcomes of anaortic off-pump coronary artery bypass (OPCAB) in an elderly and very-elderly population. Data were prospectively collected for all patients aged >70 years old (y) undergoing anaortic OPCAB at three hospitals between January 2002 and October 2011. Analysis was carried out on two age sub-groups (70-79 y vs. ≥80 y). Multiple logistic regression was used to identify predictors of post-operative 30-day mortality. In total, 1135 patients >70 years underwent anaortic OPCAB - 817 (72%) patients were aged 70-79 y while 318 (28%) were aged ≥80 y. The rate of mortality and morbidity for both groups was low: 30-day mortality (70-79 y: 1.8%; ≥80 y: 2.8%) or permanent stroke (70-79 y: 0.2%; ≥80 y: 0.9%). Chronic lung disease, a history of previous myocardial infarction and left main disease were independent predictors of 30-day mortality. OPCAB is associated with low rates of 30-day mortality and peri-operative stroke in this elderly and very elderly patient cohort. Anaortic OPCAB can provide excellent short-term post-operative outcomes and may give the elderly and very elderly population the opportunity to benefit from surgical coronary revascularisation.


Optimizing therapy for iron overload in the myelodysplastic syndromes: recent developments.
The myelodysplastic syndromes (MDS) are characterized by cytopenias and risk of progression to acute myeloid leukaemia (AML). Most MDS patients eventually require transfusion of red blood cells for anaemia, placing them at risk of transfusional iron overload. In β-thalassaemia major, transfusional iron overload leads to organ dysfunction and death; however, with iron chelation therapy, organ function is improved, and survival improved to near normal and correlated with the degree of compliance with chelation. In lower-risk MDS, several nonrandomized studies suggest an adverse effect of iron overload on survival and that lowering iron with chelation may minimize this impact. Emerging data indicate that chelation may improve organ function, particularly hepatic function, and a minority of patients may have improvement in cell counts and decreased transfusion requirements. While guidelines for MDS generally recommend chelation in selected lower-risk patients, data from nonrandomized trials suggest iron overload may impact adversely on the outcome of higher-risk MDS and stem cell transplantation (SCT). This effect may be due to increased transplant-related mortality, infection and AML progression, and preliminary data suggest that lowering iron may be beneficial in this patient group. Other areas of active and future investigation include optimizing the monitoring of iron overload using imaging such as T2* MRI and measures of labile iron and oxidative stress; correlating new methods of measuring iron to clinical outcomes; clarifying the contribution of different cellular and extracellular iron pools to iron toxicity; optimizing chelation by using agents that access the appropriate iron pools to minimize the relevant clinical consequences in individual patients; and incorporating measures of quality of life and co-morbidities into clinical trials of chelation in MDS. It should be noted that chelation is costly and potentially toxic, and in MDS should be initiated after weighing potential risks and benefits for each patient until more definitive data are available. In this review, data on the impact of iron overload in MDS and SCT are discussed; for example, several noncontrolled studies show inferior survival in patients with iron overload in these clinical settings, including an increase in transplant-related mortality and infection risk. Possible mechanisms of iron toxicity include oxidative stress, which can damage cellular components, and the documented impact of lowering iron on organ function with measures such as iron chelation therapy includes an improvement in elevated liver transaminases. Lowering iron also appears to improve survival in both lower-risk MDS and SCT in nonrandomized studies. Selected aspects of iron metabolism, transport, storage and distribution that may be amenable to future intervention and improved removal of iron from important cellular sites are discussed, as are attempts to quantify quality of life and the importance of co-morbidities in measures to treat MDS, including chelation therapy.


Geoengineering, news media and metaphors: Framing the controversial.
We analyze how metaphors are used in presenting and debating novel technologies that could influence the climate and thereby also future climate change policies. We show that metaphors strengthen a policy-related storyline, while metaphors are rarer in purely descriptive accounts. The choice of metaphor frames the technologies. War metaphors are used equally in arguments that are for, against and neutral with respect to the further development of geoengineering, but differences arise in the use of metaphors related to controllability, health and mechanisms. Controllability metaphors are often used in justifying further research and development of good governance practices, whereas health metaphors tend to be used against the very idea of geoengineering by portraying technological interventions in the climate as an emblematic case of an unacceptable development. These findings suggest that metaphors are early indications of restrictions in the interpretative flexibility that influences future governance of geoengineering and geoengineering research.


Virus transmission during orthopedic surgery on patients with COVID-19 - a brief narrative review.
Background and purpose - COVID-19 is among the most impactful pandemics that the society has experienced. Orthopedic surgery involves procedures generating droplets and aerosols and there is concern amongst surgeons that otherwise rational precautionary principles are being set aside due to lack of scientific evidence and a shortage of personal protective equipment (PPE). This narrative review attempts to translate relevant knowledge into practical recommendations for healthcare workers involved in orthopedic surgery on patients with known or suspected COVID-19.Patients and methods - We unsystematically searched in PubMed, reference lists, and the WHO's web page for relevant publications concerning problems associated with the PPE used in perioperative practice when a patient is COVID-19 positive or suspected to be. A specific search for literature regarding COVID-19 was extended to include publications from the SARS epidemic in 2002/3.Results - Transmission of infectious viruses from patient to surgeon during surgery is possible, but does not appear to be a considerable problem in clinical practice. Seal-leakage is a problem with surgical masks. Due to the lack of studies and reports, the possibility of transmission of SARS-CoV-2 from patient to surgeon during droplet- and aerosol-generating procedures is unknown.Interpretation - Surgical masks should be used only in combination with a widely covering visor and when a respirator (N95, FFP2, P3) is not made available. Furthermore, basic measures to reduce shedding of droplets and aerosols during surgery and correct and consistent use of personal protective equipment is important.


Design of a minimal silencer for the silent mating-type locus HML of Saccharomyces cerevisiae.
The silent mating-type loci HML and HMR of Saccharomyces cerevisiae contain mating-type information that is permanently repressed. This silencing is mediated by flanking sequence elements, the E- and I-silencers. They contain combinations of binding sites for the proteins Rap1, Abf1 and Sum1 as well as for the origin recognition complex (ORC). Together, they recruit other silencing factors, foremost the repressive Sir2/Sir3/Sir4 complex, to establish heterochromatin-like structures at the HM loci. However, the HM silencers exhibit considerable functional redundancy, which has hampered the identification of further silencing factors. In this study, we constructed a synthetic HML-E silencer (HML-SS ΔI) that lacked this redundancy. It consisted solely of Rap1 and ORC-binding sites and the D2 element, a Sum1-binding site. All three elements were crucial for minimal HML silencing, and mutations in these elements led to a loss of Sir3 recruitment. The silencer was sensitive to a mutation in RAP1, rap1-12, but less sensitive to orc mutations or sum1Δ. Moreover, deletions of SIR1 and DOT1 lead to complete derepression of the HML-SS ΔI silencer. This fully functional, minimal HML-E silencer will therefore be useful to identify novel factors involved in HML silencing.


Monoclonal antibodies as probes of the distribution of ZP-2, the major sulfated glycoprotein of the murine zona pellucida.
Three sulfated glycoproteins (ZP-1, ZP-2, and ZP-3) make up the zona pellucida, an extracellular glycocalyx that surrounds mouse oocytes. We have produced five monoclonal antibodies specific to the zona. All five immunoprecipitated ZP-2, and in addition, two of the antibodies immunoprecipitated ZP-3. This suggests the presence of either a common antigenic site or one made up in part by each of the two glycoproteins. The monoclonal antibodies bound to approximately 1.3 X 10(8) binding sites per ovulated mouse egg which represents 2% of the total number of ZP-2 molecules present in the zona. ZP-2 appeared to be present throughout the zona and indirect immunofluorescence revealed a fibrous pattern with no evidence of localization. Furthermore, this pattern of distribution, which was identical for all five monoclones, remained constant after fertilization at the two-cell embryo stage. Laser photobleaching demonstrated that ZP-2 is stably integrated in the extracellular matrix of the zona pellucida. No mouse tissue other than the ovary contained ZP-2 and ZP-2 is antigenically distinct from other previously described extracellular matrix proteins.


Information on death certificates: cause for concern?
To assess the frequency with which the cause of death on death certificates included the relevant details requested of certifying doctors, especially in deaths due to malignant disease, but also including certain other deaths where specific information would be expected to be included. Consecutive series of certificates attributing death to malignancy, pneumonia, an acute cerebrovascular event, and renal failure were inspected and compared with the categories identified in the International Classification of Disease. Review of clinical notes and of laboratory data was used to determine the number of cases in which detailed histological diagnoses were available. A histological diagnosis was available in 79.1% of cases of deaths due to malignancy, but was recorded on only 23.6% of certificates. Haematologists performed best (69.6%) and general surgeons worst (2.8%). The sites of primary tumours were recorded in detail in only 23 of 89 cases of tumours of the large bowel (22/36), lung (1/35) and stomach (0/18). In cases of pneumonia the causative organism was recorded in only 4 of 330. In cases of an acute cerebrovascular event one of 70 was recorded as being due to haemorrhage. A distinction between cerebral or precerebral arterial occlusion (embolism/thrombosis) and cerebral haemorrhage was not recorded in any of the other cases. In cases of renal failure a cause was not recorded in 75 of 95. Despite consistent encouragement to record all relevant details on death certificates this study shows that doctors fail to do so in most cases. Such a failure diminishes information available to the Office of Population Censuses and Surveys, affecting mortality statistics and gives further cause for concern about standards of certification. Means by which the standard of certification might be improved are discussed, including screening of certificates by a medically qualified person prior to registration.


Correlation between total nitrite/nitrate concentrations and monoamine oxidase (types A and B) and semicarbazide-sensitive amine oxidase enzymatic activities in human mesenteric arteries from non-diabetic and type 2 diabetic patients.
The aim of this study was to determine the correlation between total nitrite/nitrate concentrations (NOx) and the kinetic parameters of monoamine oxidase enzymes (MAO-A and MAO-B) and semicarbazide-sensitive amine oxidase (SSAO) in human mesenteric arteries. Arteries were from non-diabetic and type 2 diabetic patients with sigmoid or rectum carcinoma for whom surgery was the first option and who were not exposed to neo-adjuvant therapy. Segments of human inferior mesenteric arteries from non-diabetic (61.1 ± 8.9 years old, 7 males and 5 females, N = 12) and type 2 diabetic patients (65.8 ± 6.2 years old, 8 males and 4 females, N = 12) were used to determine NOx concentrations and the kinetic parameters of MAO-A, MAO-B and SSAO by the Griess reaction and by radiochemical assay, respectively. The NOx concentrations in arteries from diabetic patients did not differ significantly from those of the non-diabetic group (10.28 ± 4.61 vs 10.71 ± 4.32 nmol/mg protein, respectively). In the non-diabetic group, there was a positive correlation between NOx concentrations and MAO-B parameters: Km (r = 0.612, P = 0.034) and Vmax (r = 0.593, P = 0.042), and a negative correlation with the SSAO parameters: Km (r = -0.625, P = 0.029) and Vmax (r = -0.754, P = 0.005). However, in the diabetic group no correlation was found between NOx concentrations and the three kinetic parameters of the enzymes. These results suggest an important function of sympathetic nerves and vascular NOx concentrations in arteries of non-diabetic patients. Thus, these results confirm the importance of a balance between oxidants and antioxidants in the maintenance of vascular homeostasis to prevent oxidative stress.


Functional genomics: applying calcium imaging and RNA interference to Drosophila cell lines to identify new roles for gene products.
The selective knockdown of genes using RNA interference, and the analysis of the resultant phenotype using calcium imaging, is proving to be a powerful combination for discovering new genes involved in calcium signalling. This technical note describes the application of this approach to the Drosophila S2 cell line and its derivatives.


Bead-based screening in chemical biology and drug discovery.
High-throughput screening is an important component of the drug discovery process. The screening of libraries containing hundreds of thousands of compounds requires assays amenable to miniaturisation and automization. Combinatorial chemistry holds a unique promise to deliver structurally diverse libraries for early drug discovery. Among the various library forms, the one-bead-one-compound (OBOC) library, where each bead carries many copies of a single compound, holds the greatest potential for the rapid identification of novel hits against emerging drug targets. However, this potential has not yet been fully realized due to a number of technical obstacles. In this feature article, we review the progress that has been made in bead-based library screening and its application to the discovery of bioactive compounds. We identify the key challenges of this approach and highlight key steps needed for making a greater impact in the field.


Sturge-Weber syndrome: a favourable surgical outcome in a case with contralateral seizure onset and myoclonic-astatic seizures.
Sturge-Weber syndrome is a neurocutaneous disorder classically characterized by the presence of facial port-wine stain and ipsilateral leptomeningeal angiomatosis. It is often associated with refractory epilepsy which requires surgical treatment. We present a case of a patient who initially presented with partial seizures of temporo-occipital origin, ipsilateral to the pial angiomatosis. During the course of the disease, the patient developed medically refractory epilepsy with partial seizures originating predominantly from the contralateral temporo-occipital area as well as myoclonic and myoclonic-astatic seizures. Resection of the occipital and temporal lobe affected by the pial angioma resulted in favourable outcome. Bilateral dysfunction observed in Sturge-Weber syndrome may result in an increased capability of focal discharges to generate synchronous epileptiform activity leading to an increased incidence of generalised seizures, most probably via a mechanism of secondary bilateral synchrony. [Published with video sequences].


Mid-gestational gene expression profile in placenta and link to pregnancy complications.
Despite the importance of placenta in mediating rapid physiological changes in pregnancy, data on temporal dynamics of placental gene expression are limited. We completed the first transcriptome profiling of human placental gene expression dynamics (GeneChips, Affymetrix®; ~47,000 transcripts) from early to mid-gestation (n = 10; gestational weeks 5-18) and report 154 genes with significant transcriptional changes (ANOVA, FDR P<0.1). TaqMan RT-qPCR analysis (n = 43; gestational weeks 5-41) confirmed a significant (ANOVA and t-test, FDR P<0.05) mid-gestational peak of placental gene expression for BMP5, CCNG2, CDH11, FST, GATM, GPR183, ITGBL1, PLAGL1, SLC16A10 and STC1, followed by sharp decrease in mRNA levels at term (t-test, FDR P<0.05). We hypothesized that normal course of late pregnancy may be affected when genes characteristic to mid-gestation placenta remain highly expressed until term, and analyzed their expression in term placentas from normal and complicated pregnancies [preeclampsia (PE), n = 12; gestational diabetes mellitus (GDM), n = 12; small- and large-for-gestational-age newborns (SGA, LGA), n = 12+12]. STC1 (stanniocalcin 1) exhibited increased mRNA levels in all studied complications, with the most significant effect in PE- and SGA-groups (t-test, FDR P<0.05). In post-partum maternal plasma, the highest STC1 hormone levels (ELISA, n = 129) were found in women who had developed PE and delivered a SGA newborn (median 731 vs 418 pg/ml in controls; ANCOVA, P = 0.00048). Significantly higher expression (t-test, FDR P<0.05) of CCNG2 and LYPD6 accompanied with enhanced immunostaining of the protein was detected in placental sections of PE and GDM cases (n = 15). Our study demonstrates the importance of temporal dynamics of placental transcriptional regulation across three trimesters of gestation. Interestingly, many genes with high expression in mid-gestation placenta have also been implicated in adult complex disease, promoting the discussion on the role of placenta in developmental programming. The discovery of elevated maternal plasma STC1 in pregnancy complications warrants further investigations of its potential as a biomarker.


Is primitive neuroectodermal tumor of the kidney a distinct entity?
Primitive neuroectodermal tumors (PNETs) constitute a family of neoplasms of presumed neuroectodermal origin, most often presenting as bone or soft tissue masses in the trunk or axial skeleton in adolescents and young adults. As a soft tissue neoplasm, PNET arising in the kidney has not been well described, with only three cases previously reported. Four patients with PNET of the kidney were diagnosed and treated at St. Jude Children's Research Hospital. The authors reviewed the clinical, radiologic, and pathologic features and outcomes of these cases and of those previously described. The authors' patients were age 4-20 years. They presented with unilateral renal masses and metastatic disease in the lymph nodes (three patients), lungs (three patients), bone (two patients), liver (one patient), and bone marrow (one patient). Treatment included surgery, radiotherapy, and multiagent chemotherapy. Three of the patients died of progressive disease within 14 months of diagnosis. Features and outcomes were similar to those of the three previously reported cases. PNET of the kidney appears to be a distinct entity. Although rare, it must be included in the differential diagnosis of renal tumors in children and young adults. Patients usually present with advanced disease and show poor response to combined-modality therapy.


Influence of type D personality on job stress and job satisfaction in clinical nurses: the mediating effects of compassion fatigue, burnout, and compassion satisfaction.
To test a hypothetical path model evaluating the influence of type D personality on job stress and job satisfaction and to identify the mediating effects of compassion fatigue, burnout, and compassion satisfaction among clinical nurses in South Korea. Personalities susceptible to stress, compassion fatigue, and burnout in clinical nurses have negative effects on the job stress and job satisfaction. A correlational, cross-sectional design was used. A convenience sample of 875 clinical nurses was recruited between December 2014 - February 2015. The structured questionnaires included the Type D personality scale-14, Professional Quality of Life, job stress, job satisfaction, and general characteristics. To test the hypothetical path model, we performed a path analysis by using the AMOS 18·0 program. Based on the path model, type D personality was significantly associated with compassion fatigue, burnout, and compassion satisfaction in our study subjects. Type D personality was significantly associated with job stress and job satisfaction via the effect of burnout, compassion satisfaction, and job stress. Since type D personality is associated with job stress and job satisfaction, identifying personalities vulnerable to stress would help to address job stress and to enhance job satisfaction when nurses have a high level of compassion fatigue and burnout and a low level of compassion satisfaction. The development of interventions that can reduce negative affect and social inhibition of nurses with type D personality and investigation of methods to decrease their compassion fatigue and burnout and to increase compassion satisfaction should be encouraged.


Nocturnal assisted ventilation using bilevel positive airway pressure: the effect of expiratory positive airway pressure.
Increasing expiratory positive airway pressure (EPAP) has theoretical advantages during overnight nasal ventilation. We wanted to evaluate the effect of the addition of EPAP upon the control of nocturnal hypoventilation. Seven patients with neuromuscular/skeletal (NMS) disorder (mean +/- SD forced vital capacity (FVC) 1.06 +/- 0.28 l, arterial oxygen tension (PaO2) 9.1 +/- 0.6 kPa, and arterial carbon dioxide tension (PaCO2) 6.9 +/- 0.9 kPa), and seven patients with chronic obstructive pulmonary disease (COPD) (FEV1 0.46 +/- 0.14 l, PaO2 6.2 +/- 0.6 kPa, and PaCO2 8.4 +/- 1.1 kPa) all underwent full polysomnography on two nights during bilevel positive airway pressure (BiPAP) ventilation, with and without the addition of expiratory positive airway pressure, which was matched to the level of dynamic positive end-expiratory pressure (PEEP) or set at a minimum value of 5 cmH2O. In the group with neuromuscular/skeletal disorders the maximum transcutaneous carbon dioxide tension (PtcCO2) overnight was lower (inspiratory positive airway pressure (IPAP) 8.1 +/- 1.4 kPa, IPAP/EPAP 7.3 +/- 0.9 kPa) and the minimum level of arterial oxygen saturation (SaO2 min) increased (IPAP 77.1 +/- 6.7%, IPAP/EPAP 83.6 +/- 4.2%) when expiratory positive airway pressure was added. There were no differences in mean PtcCO2 or mean oxygen saturation, but sleep quality was worse (non-rapid eye movement (non-REM) sleep IPAP 266 +/- 44 min, IPAP/EPAP 226 +/- 32 min). In the patients with COPD, expiratory positive airway pressure conferred no advantage.(ABSTRACT TRUNCATED AT 250 WORDS)


Molecular analysis of phyllodes tumors reveals distinct changes in the epithelial and stromal components.
Phyllodes tumors are fibroepithelial mammary lesions that tend to behave in a benign fashion but may undergo sarcomatous transformation. A study of clonality in these tumors has suggested that the epithelial component is polyclonal, but the stroma is monoclonal, and thus forms the neoplastic component of the lesion. In this study microsatellites on chromosome 1q and chromosome 3p were assessed for allelic imbalance (AI) in 47 phyllodes tumors; in all cases stroma and epithelium were analyzed separately. Ten of 42 (24%) phyllodes tumors showed AI at one or more markers on 3p, and 14 of 46 (30%) showed AI on chromosome 1. Five tumors had changes in both the epithelium and stroma. Eight tumors had changes only detectable in the stroma and eight, changes in the epithelium only. Three tumors exhibited low-level microsatellite instability in the epithelium but not in the stroma. The results show that AI on 3p and 1q does occur in phyllodes tumors and that it can occur in both the stroma and epithelium, sometimes as independent genetic events. These unexpected findings throw into doubt the classical view that phyllodes tumors are simply stromal neoplasms and raise questions about the nature of stromal and epithelial interactions in these tumors.


Optimal fluoroscopic viewing angles of right-sided heart structures in patients with tricuspid regurgitation based on multislice computed tomography.
This study sought to analyse multislice computed tomography (MSCT) data of patients with tricuspid regurgitation and to report the variability of fluoroscopic viewing angles for several right-sided heart structures, as well as chamber views of the right heart in order to determine the optimal fluoroscopic viewing angles of six right-sided heart structures and right-heart chamber views. The MSCT data of 44 patients with mild to severe tricuspid regurgitation (TR) were retrospectively analysed. For each patient, we determined the optimal fluoroscopic viewing angles of the annulus/orifice en face view of the tricuspid valve, atrial septum, superior vena cava (SVC), inferior vena cava (IVC), coronary sinus (CS) and pulmonary valve. In this TR patient cohort, the average fluoroscopic viewing angle for the en face view of the tricuspid valve annulus was LAO 54-CAUD 15; RAO 10-CAUD 66 for the SVC orifice; LAO 27-CRA 59 for the IVC orifice; RAO 28-CRA 19 for the CS orifice; RAO 33-CAUD 33 for the atrial septum and LAO 13-CAUD 52 for the pulmonary valve annulus. The average viewing angle for right-heart chamber views was LAO 55-CAUD 15 for the one-chamber view; RAO 59-CAUD 54 for the two-chamber view; RAO 27-CRA 19 for the three-chamber view and LAO 5-CRA 60 for the four-chamber view. MSCT can provide patient-specific fluoroscopic viewing angles of right-sided heart structures. This information may facilitate transcatheter right-heart interventions.


WMAXC: a weighted maximum clique method for identifying condition-specific sub-network.
Sub-networks can expose complex patterns in an entire bio-molecular network by extracting interactions that depend on temporal or condition-specific contexts. When genes interact with each other during cellular processes, they may form differential co-expression patterns with other genes across different cell states. The identification of condition-specific sub-networks is of great importance in investigating how a living cell adapts to environmental changes. In this work, we propose the weighted MAXimum clique (WMAXC) method to identify a condition-specific sub-network. WMAXC first proposes scoring functions that jointly measure condition-specific changes to both individual genes and gene-gene co-expressions. It then employs a weaker formula of a general maximum clique problem and relates the maximum scored clique of a weighted graph to the optimization of a quadratic objective function under sparsity constraints. We combine a continuous genetic algorithm and a projection procedure to obtain a single optimal sub-network that maximizes the objective function (scoring function) over the standard simplex (sparsity constraints). We applied the WMAXC method to both simulated data and real data sets of ovarian and prostate cancer. Compared with previous methods, WMAXC selected a large fraction of cancer-related genes, which were enriched in cancer-related pathways. The results demonstrated that our method efficiently captured a subset of genes relevant under the investigated condition.


Feasibility of engaging "Village Doctors" in the Community-based Integrated Management of Childhood Illness (C-IMCI): experience from rural Bangladesh.
Informal health care providers particularly "village doctors" are the first point of care for under-five childhood illnesses in rural Bangladesh. We engaged village doctors as part of the Multi-Country Evaluation (MCE) of Integrated Management of Childhood Illness (IMCI) and assessed their management of sick under-five children before and after a modified IMCI training, supplemented with ongoing monitoring and supportive supervision. In 2003-2004, 144 village doctors across 131 IMCI intervention villages in Matlab Bangladesh participated in a two-day IMCI training; 135 of which completed pre- and post-training evaluation tests. In 2007, 38 IMCI-trained village doctors completed an end-of-project knowledge retention test. Village doctor prescription practices for sick under-five children were examined through household surveys, and routine monitoring visits. In-depth interviews were done with mothers seeking care from village doctors. Village doctors' knowledge on the assessment and management of childhood illnesses improved significantly after training; knowledge of danger signs of pneumonia and severe pneumonia increased from 39% to 78% (P < 0.0001) and from 17% to 47% (P < 0.0001) respectively. Knowledge on the correct management of severe pneumonia increased from 62% to 84% (P < 0.0001), and diarrhoea management improved from 65% to 82% (P = 0.0005). Village doctors retained this knowledge over three years except for home management of pneumonia. No significant differences were observed in prescribing practices for diarrhoea and pneumonia management between trained and untrained village doctors. Village doctors were accessible to communities; 76% had cell phones; almost all attended home calls, and did not charge consultation fees. Nearly all (91%) received incentives from pharmaceutical representatives. Village doctors have the capacity to learn and retain knowledge on the appropriate management of under-five illnesses. Training alone did not improve inappropriate antibiotic prescription practices. Intensive monitoring and efforts to target key actors including pharmaceutical companies, which influence village doctors dispensing practices, and implementation of mechanisms to track and regulate these providers are necessary for future engagement in management of under-five childhood illnesses.


Huperzine-A in capsules and tablets for treating patients with Alzheimer disease.
To compare the efficacy and safety between huperzine-A (Hup) in capsules and tablets for treating patients with Alzheimer disease (AD). Using multicenter, prospective, double-blind, double-mimic, parallel, positive controlled and randomized methods, 60 patients meeting with the NINCDS-ARDRA criteria of AD were divided into 2 equal groups. Patients in the capsule group received 4 capsules of Hup (each contains 50 micrograms) and 4 tablets of placebo (lactose and starch inside); while the tablet group received 4 tablets of Hup (each contains 50 micrograms) and 4 capsules of placebo, p.o., twice a day for 60 d. All the patients were evaluated with a lot of related ranting scales, and physiological and laboratory examination. There were significant differences (P < 0.01) on all the psychological evaluations between 'before' and 'after' the 60-d trial of 2 groups, but there was no significant difference between 2 groups by group t test (P > 0.05). The changes of oxygen free radicals in 2 groups showed marked improvement. No severe side effect besides moderate to mild nausea was found in both groups. There is equal efficacy and safety between Hup in capsule and tablet for treating patients with AD, and Hup can reduce the pathological changes of the oxygen free radicals in the plasma and erythrocytes of patients with AD.


Linear array of InAs APDs operating at 2 µm.
A linear array of avalanche photodiodes (APDs) comprising of 128 pixels was fabricated from InAs. The uniformity of the dark currents and avalanche gain was investigated at 77, 200 K and room temperature. The array shows highly uniform results apart from some defective pixels at the edge of the arrays. At 200 K and at a wavelength of 2.04 µm, we obtained an unmultiplied responsivity of 0.61 A/W at 0 V, along with a gain of 8.5 at a bias of 10 V.


Wogonin mitigates nonalcoholic fatty liver disease via enhancing PPARα/AdipoR2, in vivo and in vitro.
Wogonin has been reported to attenuate hyperglycemia in diabetic mice via anti-adipogenic effect on adipocytes. The potential therapeutic role of wogonin in nonalcoholic fatty liver disease (NAFLD) remains obscure. The aim of the present study was to explore the protective effect of wogonin on NAFLD mice and cultured NCTC 1469 cells exposed to palmitate. Wogonin supplementation significantly improved metabolic parameters in NAFLD mice, including body weight, blood glucose, insulin resistance, adiponectin, blood lipids, aminotransferases and hepatic histopathology. Further research in liver tissues from NAFLD mice and NCTC 1469 cells stressed by lipotoxicity showed wogonin treatment reduced inflammatory response by lowering interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), alleviated oxidative stress by preventing the accumulation of oxidative product malondialdehyde (MDA) and strengthening the anti-oxidative capacity of glutathione (GSH), Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPX). In addition, wogonin repaired the lipotoxicity-induced decline of peroxisome proliferator- activated receptor α (PPARα) and adiponectin receptor 2 (AdipoR2) in hepatocytes, in vivo and in vitro. Knock-down of PPARα abolished the protective effect of wogonin on NCTC 1469 cells, including the up-regulation of AdipoR2. Taken together, the current study demonstrated wogonin might be a potential therapeutic agent for NAFLD via up-regulation of hepatic PPARα/AdipoR2.


Beyond borders-international database collaboration in thoracic surgery.
Thoracic surgery databases continue to emerge as pillars for institutional quality improvement and research endeavors. This paper reviews the current state of the largest thoracic surgery databases: the Thoracic Surgeons General Thoracic Surgery Database (STS-GTSD) and the European Society of Thoracic Surgery Database (ESTSD). In addition, we utilize these as a platform to evaluate the role and key ingredients for successful international database collaborations. Ultimately, collaborative efforts among large databases unify research efforts, foster cohesion, serve as benchmarks for quality improvement locally, nationally and internationally, promote comparative innovation, and ultimately improve patient outcomes.


Interactions of monocyte subpopulations generated from cord blood CD34(+) hematopoietic progenitors with tumor cells: assessment of antitumor potential.
Monocytes and their subsets (CD14(++)CD16(+) and CD14(+)CD16(-)) generated from cord blood CD34(+) progenitor cells were used for determination of their capacity to interact with tumor cells in vitro and in vivo. The studies in vitro included adhesion to human umbilical vein endothelial cells, cytotoxicity, production of toxic mediators: reactive oxygen and nitrogen intermediates (ROI and RNI, respectively), and finally their effect on transplantable human tumor growth in nonobese diabetic severe combined immunodeficient mice. The CD14(++)CD16(+) subset exhibited an increased adherence to human umbilical vein endothelial cells and cytotoxicity toward tumor cells in vitro. CD14(+)CD16(-) monocytes showed a higher production of reactive oxygen and nitrogen intermediates after stimulation with tumor cells, and more pronounced inhibition of tumor growth in vivo. The results revealed significant differences in the behavior of CD14(++)CD16(+) and CD14(+)CD16(-) monocyte subsets toward tumor cells, thus providing further evidence that CD34(+) cell-derived monocytes differ in this respect from blood monocytes. The protocol for generation of monocytes with antitumor reactivity described here may be useful to obtain monocytes from CD34(+) progenitor cells of cancer patients. This might offer a basis for a novel approach for various forms of cellular immunotherapy of cancer.


Reliability of audiometric thresholds obtained with insert earphones when used by certified audiometric technicians.
Clinical audiologists and audiometric equipment manufacturers have embraced the clinical use of insert earphones; however, their use in audiometric testing in occupational hearing loss prevention programs has been limited. This study was undertaken to research whether certified audiometric technicians without practical hands-on training could reliably use insert earphones when compared to a clinically experienced audiologist. Hearing thresholds were obtained on 60 human ears by six certified audiometric technicians using insert earphones for the first time. Technician-acquired audiometric thresholds were compared to thresholds obtained under the same conditions by a clinical audiologist experienced in the use of the insert earphones. Statistical analyses of audiometric thresholds were performed to investigate the relationships between audiometric threshold values at each frequency obtained by certified technicians vs. the audiologist. These relationships were examined for the group as a whole as well as when ear tip size and earphone insertion depth varied between the audiologist and the technicians. No significant differences (p > .01) were found between mean group thresholds at any of the test frequencies (500-8000 Hz). Mean group thresholds differed by < 1.2 dB. Pearson Product-Moment correlation (PPMC) coefficients suggested that thresholds obtained by the audiometric technician were highly correlated with those obtained by the audiologist. There were no significant threshold differences (p > .01) even when the audiologist and technicians varied in their selection of ear tip size or in the amount of insertion depth achieved. This study suggests that CAOHC-certified audiometric technicians can reliably use insert earphones without practical training when testing in quiet environments by reading the earphone package directions provided by the manufacturer.


Estrogen Protects Neurotransmission Transcriptome During Status Epilepticus.
Women with epilepsy commonly have premature onset of menopause. The decrease in estrogen levels is associated with increased occurrence of neurodegenerative processes and cognitive decline. Previously, we found that estradiol (E2) replacement in ovariectomized (OVX) female rats significantly reduced the seizure-related damage in the sensitive hilar region of hippocampal dentate gyrus (DG). However, the complex mechanisms by which E2 empowers the genomic fabrics of neurotransmission to resist damaging effects of status epilepticus (SE) are still unclear. We determined the protective effects of the estradiol replacement against kainic acid-induced SE-associated transcriptomic alterations in the DG of OVX rats. Without E2 replacement, SE altered expression of 44% of the DG genes. SE affected all major functional pathways, including apoptosis (61%), Alzheimer's disease (47%), cell cycle (59%), long-term potentiation (62%), and depression (55%), as well as synaptic vesicle cycle (62%), glutamatergic (53%), GABAergic (49%), cholinergic (52%), dopaminergic (55%), and serotonergic (49%) neurotransmission. However, in rats with E2 replacement the percentage of significantly affected genes after SE was reduced to the average 11% (from 8% for apoptosis to 32% for GABAergic synapse). Interestingly, while SE down-regulated most of the synaptic receptor genes in oil-injected females it had little effect on these receptors after E2-replacement. Our novel Pathway Protection analysis indicated that the E2-replacement prevented SE-related damage from 50% for GABA to 75% for dopaminergic transmission. The 15% synergistic expression between genes involved in estrogen signaling (ESG) and neurotransmission explains why low E2 levels result in down-regulation of neurotransmission. Interestingly, in animals with E2-replacement, SE switched 131 synergistically expressed ESG-neurotransmission gene pairs into antagonistically expressed gene pairs. Thus, the ESG pathway acts like a buffer against SE-induced alteration of neurotransmission that may contribute to the E2-mediated maintenance of brain function after the SE injury in postmenopausal women. We also show that the long-term potentiation is lost in OVX rats following SE but not in those with E2 replacement. The electrophysiological findings in OVX female rats with SE are corroborated by the high percentage of long-term potentiation regulated genes (62%) in oil-injected while only 13% of genes were regulated following SE in E2-replaced rats.


Direct antibody access to the HIV-1 membrane-proximal external region positively correlates with neutralization sensitivity.
On the prereceptor-engaged HIV-1 envelope glycoprotein (Env) spike, epitope access by the membrane-proximal external region (MPER)-directed broadly neutralizing antibodies 2F5 and 4E10 remains unresolved. Data on binding to cell surface Env and entry data using primary isolates suggest inaccessibility of the 2F5 and 4E10 epitopes on the viral spike prior to receptor engagement, but trimer gel shift analysis and slow kinetics of shedding induced by 2F5 and 4E10 indicate otherwise. Therefore, it remains unclear if the epitopes themselves are formed in their antibody-bound state (or at least sampled) prior to receptor/coreceptor engagement or if receptor interactions both expose and form the MPER epitopes, presumably in the putative prefusion transitional intermediate. Here, we performed antibody-virus "washout experiments" using both lab-adapted and a panel of clade B primary isolates to analyze MPER accessibility. The neutralization activity of 2F5 and 4E10 against lab-adapted viruses and sensitive and moderately resistant viruses was largely unaffected by relatively rapid antibody-virus washing, suggesting direct interaction with the "static" spike. However, for more neutralization-resistant viruses, the 2F5 and 4E10 antibodies could neutralize only under the "no antibody-virus wash" conditions, implying that the MPER epitopes were not accessible prior to receptor engagement. Accessibility in the washout conditions could be precisely predicted by the relative resistance to neutralization in a standard neutralization format. These data are consistent with a model in which the local MPER antibody epitope conformations may be sampled on the native spike but are occluded to antibody by local steric or distal quaternary constraints adopted by highly resistant HIV-1 isolates.


Caffeine as a Probable Factor for Increased Risk of OAB Development in Elderly People.
This study was conducted to compare overactive bladder (OAB) prevalence among people greater than 60 years of age who intake various doses of caffeine, as well as those who abstain from caffeine. A randomized observational study was carried out in Vladivostok Gerontological Hospital. A total of 1,098 retired people greater than 60 years of age (659 women and 439 men, average age 67.1 years) took part in the study. They were admitted to the in-patient department with the purpose of annual physical examination performed in accordance with the order of the Ministry of Public Health of the Russian Federation. People over age 60, who at the moment of examination were in satisfactory health condition, were included into the study. People in which OAB had been detected or who used to take antimuscarinic were excluded from the study. Assessment tools for examining the patients' lower urinary tract condition were as follows: OAB-q SF, urination diaries, and uroflowmetry. In the course of the experiment conducted, we found that 1/3 of people, both men and women greater than 60 years of age, who did not previously seek medical advice due to urination troubles, had symptoms of detrusor overactivity. These symptoms were moderate and did not bother patients too much in most cases (63.4%). It was also found that most patients consumed no more than 300mg caffeine with beverages per day, with 30% and 10% of patients suffering from OAB or severe detrusor overactivity, respectively. At the same time, almost 50% of patients taking more than 300 mg of caffeine per day suffer from OAB. 48.1% of people over 60 years of age suffering from overactive detrusor symptoms consume greater than 300 mg caffeine daily, which is significantly higher than that of their peers who do not intake excessive amounts of caffeine.


The 'Fit for Life' exercise programme: improving the physical health of people with a mental illness.
People with a mental illness have very poor physical health parameters when compared to the general population. This paper outlines an exercise programme developed to improve overall fitness and curb weight gain. Seventy-two mental health service inpatients completed the general or individualised gym exercise programme within 12 weeks. Baseline and end of course physical health parameters were recorded, along with test results on a number of fitness, strength and agility tasks. No statistically significant differences were found between average pre and post programme weight scores, and weight did not increase over time. Significant differences were found on strength and agility tasks, and a decrease was observed in average resting and post exercise heart rates. Average blood pressure did not change, but the number of baseline readings indicating hypertension reduced from 14 to 8 people. The exercise programme was successful in improving the physical capacity of the individuals who participated.


Excitatory and inhibitory synapses in neuropeptide Y-expressing striatal interneurons.
Although rare, interneurons are pivotal in governing striatal output by extensive axonal arborizations synapsing on medium spiny neurons. Using a genetically modified mouse strain in which a green fluorescent protein (GFP) is driven to be expressed under control of the neuropeptide Y (NPY) promoter, we identified NPY interneurons and compared them with striatal principal neurons. We found that the bacteria artificial chromosome (BAC)-npy mouse expresses GFP with high fidelity in the striatum to the endogenous expression of NPY. Patch-clamp analysis from NPY neurons showed a heterogeneous population of striatal interneurons. In the majority of cells, we observed spontaneous firing of action potentials in extracellular recordings. On membrane rupture, most NPY interneurons could be classified as low-threshold spiking interneurons and had high-input resistance. Voltage-clamp recordings showed that both GABA and glutamate gated ion channels mediate synaptic inputs onto these striatal interneurons. AMPA receptor-mediated spontaneous excitatory postsynaptic currents (sEPSCs) were small in amplitude and infrequent in NPY neurons. Evoked EPSCs did not show short-term plasticity but some rectification. Evoked N-methyl-d-aspartate (NMDA) EPSCs had fast decay kinetics and were poorly sensitive to an NR2B subunit containing NMDA receptor blocker. Spontaneous inhibitory postsynaptic currents (sIPSCs) were mediated by GABA(A) receptors and were quite similar among all striatal neurons studied. On the contrary, evoked IPSCs decayed faster in NPY neurons than in other striatal neurons. These data report for the first time specific properties of synaptic transmission to NPY striatal interneurons.


Brain stem responses to speech in younger and older adults.
This experiment was designed to evaluate whether neural encoding of speech features at the brain stem level is altered in the aging auditory system. In addition, the effect of minimal peripheral hearing loss on the auditory brain stem response (ABR) evoked by speech stimuli and interactions with aging were examined. Speech-evoked ABRs (S-ABRs) were recorded using a synthetic 40-msec /da/ stimulus from both ears of participants in two groups: normal-hearing younger adults (n = 19) and normal-hearing older adults (n = 18). Latencies and amplitude for S-ABR peaks representing neural responses to the onset and offset of the speech syllable as well as a sustained frequency following response to the vowel content were analyzed. The role of hearing threshold differences between groups and the reduced overall stimulus level on the S-ABR were also examined. In addition, click-evoked ABRs (C-ABRs) were obtained from all participants, and age-group differences in the neural response to both types of stimuli at the brain stem level were compared. S-ABR latencies, amplitudes, and sustained response mean data were obtained for younger adults and older adults. Older adults were found to have significantly smaller C-ABRs with longer latencies, despite all latencies falling within normal limits. Older adults also had significantly smaller onset and offset responses for the S-ABR, with significantly delayed offset latencies in response to this synthetic consonant-vowel syllable. Many of the C-ABR and S-ABR variables were found to significantly correlate with high-frequency audiometric thresholds, and few of the group differences remained significant when this was taken into account. The remaining significant S-ABR effects were decreased amplitude at the onset and significantly delayed offset responses in the older group. These effects were different from those of simply decreasing the overall stimulus level, which caused significant shifts in latency across the entire S-ABR. Results of this study partially supported the hypothesis of age-related differences in neural processing of speech at the brain stem level. There were significant delays in the timing of the offset portion of the S-ABR in older listeners compared with their younger counterparts, even after accounting for the differences in peripheral hearing threshold between groups. There were also significant reductions in amplitude of the S-ABR at the onset. These results are consistent with a reduction in neural synchrony in older adults to transient components of both speech and nonspeech sounds. However, sustained components of the S-ABR, which follow the harmonic components of the syllable, showed group differences but were not significant after adjusting for peripheral hearing loss, suggesting that they may be more affected by hearing sensitivity and other peripheral changes. These results support further investigation into the ability of the aging auditory system to encode temporal cues at the brain stem level, particularly the response to speech stimulus offset and its relationship to speech perception and temporal processing abilities.


The acute treatment of episodic and chronic migraine in the USA.
Understanding the patterns of acute treatment of migraine in the population is a necessary step in evaluating treatment in relation to guidelines, and in improving care. Herein we assess the specific medication used for the acute treatment of migraine and chronic migraine (CM) in the population. We identified 24 000 headache sufferers, drawn from over 165 000 individuals representative of the US population. This sample has been followed with annual surveys using validated questionnaires. As part of the survey, subjects were asked to report the specific medications currently used for their most severe headaches, dose, and number of days per month using medication. Complete responses were obtained from 14 540 individuals, including 9128 with episodic migraine and 503 with CM. For episodic migraine, specific treatment was used by 19.2% of subjects (triptans 18.7%; compounds with ergotamine 0.5%). A total of 11.1% routinely used opiates, whereas 6% used compounds with barbiturates. For CM, 22% used migraine-specific treatment, whereas 34.3% used opiates and barbiturates. Non-prescribed medications were frequently used in both groups. Opiates were more commonly used by those with CM [odds ratio (OR) 2.12, 95% confidence interval (CI) 1.69, 2.65], as were butalbital-containing compounds (OR 2.46, 95% CI 1.88, 3.22). The minority of migraineurs in the USA use specific medication, and one-fifth use opiates or barbiturates. For CM, > 34% use opiates or barbiturates. Accordingly, a sizable proportion use medications that are not firstline according to the US Headache Consortium Guidelines.


A novel high-throughput assay for islet respiration reveals uncoupling of rodent and human islets.
The pancreatic beta cell is unique in its response to nutrient by increased fuel oxidation. Recent studies have demonstrated that oxygen consumption rate (OCR) may be a valuable predictor of islet quality and long term nutrient responsiveness. To date, high-throughput and user-friendly assays for islet respiration are lacking. The aim of this study was to develop such an assay and to examine bioenergetic efficiency of rodent and human islets. The XF24 respirometer platform was adapted to islets by the development of a 24-well plate specifically designed to confine islets. The islet plate generated data with low inter-well variability and enabled stable measurement of oxygen consumption for hours. The F1F0 ATP synthase blocker oligomycin was used to assess uncoupling while rotenone together with myxothiazol/antimycin was used to measure the level of non-mitochondrial respiration. The use of oligomycin in islets was validated by reversing its effect in the presence of the uncoupler FCCP. Respiratory leak averaged to 59% and 49% of basal OCR in islets from C57Bl6/J and FVB/N mice, respectively. In comparison, respiratory leak of INS-1 cells and C2C12 myotubes was measured to 38% and 23% respectively. Islets from a cohort of human donors showed a respiratory leak of 38%, significantly lower than mouse islets. The assay for islet respiration presented here provides a novel tool that can be used to study islet mitochondrial function in a relatively high-throughput manner. The data obtained in this study shows that rodent islets are less bioenergetically efficient than human islets as well as INS1 cells.


Altered Pre-mRNA Splicing Caused by a Novel Intronic Mutation c.1443+5G>A in the Dihydropyrimidinase (DPYS) Gene.
Dihydropyrimidinase (DHP) deficiency is an autosomal recessive disease caused by mutations in the DPYS gene. Patients present with highly elevated levels of dihydrouracil and dihydrothymine in their urine, blood and cerebrospinal fluid. The analysis of the effect of mutations in DPYS on pre-mRNA splicing is hampered by the fact that DHP is primarily expressed in liver and kidney cells. The minigene approach can detect mRNA splicing aberrations using cells that do not express the endogenous mRNA. We have used a minigene-based approach to analyze the effects of a presumptive pre-mRNA splicing mutation in two newly identified Chinese pediatric patients with DHP deficiency. Mutation analysis of DPYS showed that both patients were compound heterozygous for a novel intronic mutation c.1443+5G>A in intron 8 and a previously described missense mutation c.1001A>G (p.Q334R) in exon 6. Wild-type and the mutated minigene constructs, containing exons 7, 8 and 9 of DPYS, yielded different splicing products after expression in HEK293 cells. The c.1443+5G>A mutation resulted in altered pre-mRNA splicing of the DPYS minigene construct with full skipping of exon 8. Analysis of the DHP crystal structure showed that the deletion of exon 8 severely affects folding, stability and homooligomerization of the enzyme as well as disruption of the catalytic site. Thus, the analysis suggests that the c.1443+5G>A mutation results in aberrant splicing of the pre-mRNA encoding DHP, underlying the DHP deficiency in two unrelated Chinese patients.


Aspects of endowment: a query theory of value construction.
How do people judge the monetary value of objects? One clue is provided by the typical endowment study (D. Kahneman, J. L. Knetsch, & R. H. Thaler, 1991), in which participants are randomly given either a good, such as a coffee mug, that they may later sell ("sellers") or a choice between the good and amounts of cash ("choosers"). Sellers typically demand at least twice as much as choosers, inconsistent with economic theory. This result is usually explained by an increased weighting of losses, or loss aversion. The authors provide a memory-based account of endowment, suggesting that people construct values by posing a series of queries whose order differs for sellers and choosers. Because of output interference, these queries retrieve different aspects of the object and the medium of exchange, producing different valuations. The authors show that the content and structure of the recalled aspects differ for selling and choosing and that these aspects predict valuations. Merely altering the order in which queries are posed can eliminate the endowment effect, and changing the order of queries can produce endowment-like effects without ownership.


The association between serum cathepsin L and mortality in older adults.
Research suggests that the protease cathepsin L is causally involved in atherosclerosis. However, data on cathepsin L as a risk marker are lacking. Therefore, we investigated associations between circulating cathepsin L and cardiovascular mortality. Two independent community-based cohorts were used: Uppsala Longitudinal Study of Adult Men (ULSAM); n = 776; mean age 77 years; baseline 1997-2001; 185 cardiovascular deaths during 9.7 years follow-up, and Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS); n = 993; 50% women; mean age 70 years; baseline 2001-2004; 42 cardiovascular deaths during 10.0 years follow-up. Higher serum cathepsin L was associated with an increased risk for cardiovascular mortality in age- and sex-adjusted models in both cohorts (ULSAM: hazard ratio (HR) for 1-standard deviation (SD) increase, 1.17 [95% CI, 1.01-1.34], p = 0.032 PIVUS: HR 1.35 [95% CI, 1.07-1.72], p = 0.013). When merging the cohorts, these associations were independent of inflammatory markers and cardiovascular risk factors, but non-significant adjusting for kidney function. Individuals with a combination of elevated cathepsin L and increased inflammation, kidney dysfunction, or prevalent cardiovascular disease had a markedly increased risk, while no increased risk was associated with elevated cathepsin L, in the absence of these disease states. An association between higher serum cathepsin L and increased risk of cardiovascular mortality was found in two independent cohorts. Impaired kidney function appears to be an important moderator or mediator of these associations. Further studies are needed to delineate the underlying mechanisms and to evaluate whether the measurement of cathepsin L might have clinical utility.


Perceptual grouping and distance estimates in typical and atypical development: comparing performance across perception, drawing and construction tasks.
Perceptual grouping is a pre-attentive process which serves to group local elements into global wholes, based on shared properties. One effect of perceptual grouping is to distort the ability to estimate the distance between two elements. In this study, biases in distance estimates, caused by four types of perceptual grouping, were measured across three tasks, a perception, a drawing and a construction task in both typical development (TD: Experiment 1) and in individuals with Williams syndrome (WS: Experiment 2). In Experiment 1, perceptual grouping distorted distance estimates across all three tasks. Interestingly, the effect of grouping by luminance was in the opposite direction to the effects of the remaining grouping types. We relate this to differences in the ability to inhibit perceptual grouping effects on distance estimates. Additive distorting influences were also observed in the drawing and the construction task, which are explained in terms of the points of reference employed in each task. Experiment 2 demonstrated that the above distortion effects are also observed in WS. Given the known deficit in the ability to use perceptual grouping in WS, this suggests a dissociation between the pre-attentive influence of and the attentive deployment of perceptual grouping in WS. The typical distortion in relation to drawing and construction points towards the presence of some typical location coding strategies in WS. The performance of the WS group differed from the TD participants on two counts. First, the pattern of overall distance estimates (averaged across interior and exterior distances) across the four perceptual grouping types, differed between groups. Second, the distorting influence of perceptual grouping was strongest for grouping by shape similarity in WS, which contrasts to a strength in grouping by proximity observed in the TD participants.


Physical inactivity prevalence and trends among Mexican adults: results from the National Health and Nutrition Survey (ENSANUT) 2006 and 2012.
Lifestyles such as unhealthy diets and the lack of physical activity have been contributed to the increased prevalence of obesity. In 2012, the world health organization published the first global recommendation for physical activity and health. People who do not meet at least 150 minutes of moderate-to-vigorous physical activity are considered to be physically inactive. The prevalence of physical inactivity worldwide is 31%, however there is insufficient data from prevalence and trends of physical inactivity in Mexican population. The purposes of this study are to describe the physical inactivity prevalence and recent trends in Mexican adults and to examine the association between physical inactivity with biologic and sociodemographic characteristics. Representative samples of 17,183 and 10,729 adults (aged 20 to 69 years) who participated in the National Health and Nutrition Survey (ENSANUT) in 2006 and 2012, respectively. Moderate-to-vigorous physical activity (MVPA) was assessed using the short form version of the International Physical Activity Questionnaire (IPAQ), which was administered in face-to-face interviews. Self-reported IPAQ MVPA levels were adjusted using an equation derived from a previous validation study. Participants were considered inactive if they engaged in <150-minutes/week of moderate physical activity or <75 minutes/week of vigorous physical activity according to WHO classification criteria. The prevalence of physical inactivity was significantly higher in 2012 (19.4%, 95% CI: 18.1, 20.7) than in 2006 (13.4%, 95% CI: 12.5, 14.5). Adults in the obese category, 60-69 age group, and those in the highest socioeconomic status tertile were more likely to be physically inactive. The proportion of the Mexican adult population who do not meet the minimum WHO physical activity criteria has increased by 6% points between 2006 and 2012. Given the increasing prevalence of obesity, the aging of the population, and the shift in socioeconomic status in Mexico, physical inactivity could continue to increase in the coming years unless effective public health interventions are implemented.


Context- and Output Layer-Dependent Long-Term Ensemble Plasticity in a Sensory Circuit.
Sensory information is translated into ensemble representations by various populations of projection neurons in brain circuits. The dynamics of ensemble representations formed by distinct channels of output neurons in diverse behavioral contexts remains largely unknown. We studied the two output neuron layers in the olfactory bulb (OB), mitral and tufted cells, using chronic two-photon calcium imaging in awake mice. Both output populations displayed similar odor response profiles. During passive sensory experience, both populations showed reorganization of ensemble odor representations yet stable pattern separation across days. Intriguingly, during active odor discrimination learning, mitral but not tufted cells exhibited improved pattern separation, although both populations showed reorganization of ensemble representations. An olfactory circuitry model suggests that cortical feedback on OB interneurons can trigger both forms of plasticity. In conclusion, we show that different OB output layers display unique context-dependent long-term ensemble plasticity, allowing parallel transfer of non-redundant sensory information to downstream centers. VIDEO ABSTRACT.


Vitamin D supplementation for treatment of seasonal affective symptoms in healthcare professionals: a double-blind randomised placebo-controlled trial.
Low serum 25-hydroxyvitamin D levels (25(OH)D) have been associated with a higher likelihood of seasonal affective disorder (SAD) and poor mental well-being, yet firm evidence for either remains lacking. Thus, vitamin D supplementation may alleviate symptoms associated with SAD. This study was a randomized, single-centre, double-blind, placebo-controlled trial including healthcare professionals employed in psychiatric and somatic hospitals. 3345 healthcare professionals were invited to participate, 50 participants were screened, and 34 were able to complete the study. The main inclusion criterion was 8 points or more on question no. 2 of the Seasonal Pattern Assessment Questionnaire (SPAQ-SAD). During a 3-month period, the participants received a daily dose of 70 μg vitamin D or placebo. The primary outcome was the sum of the self-reported questionnaire Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders (SIGH-SAD). The secondary outcome was World Health Organization-Five Well-Being Index (WHO-5) of the healthcare professionals during the winter period and the exploratory outcome measures were weight, waist circumference, blood pressure, absenteeism from work and 25(OH)D. There were no significant between-group differences in SIGH-SAD sums at 12 weeks (p = 0.7 (CI: - 3.27 to 4.81)). However, there was a significant improvement of primary SIGH-SAD over time from inclusion (autumn-winter) to the completion of the study (winter-spring) for all participants. The secondary and exploratory outcome measures were all insignificant between groups.The sums of the SIGH-SAD at 12 weeks were not significantly different [p = 0.701 (CI: 4.81-3.27)] between the groups. There was, however, a significant improvement in primary SIGH-SAD sums over time from inclusion (autumn-winter) to the completion of the study (winter-spring) in both groups. The secondary and explorative outcome measures were not significantly different between groups. There were no significant between-group differences in the primary (SIGH-SAD) and secondary (WH0-5) as well as the exploratory outcome measures (weight, waist circumference, blood pressure, absenteeism from work and 25(OH)D. Thus, the study failed to demonstrate an effect of vitamin D on SAD symptoms, but our findings may be limited by confounders. Furthermore, the study was underpowered and did not allow us to assess the ability of vitamin D to improve mood in those with low 25(OH)D. ( http://www.clinicaltrials.gov registration number: NCT01462058).


The triple role of rongalite in aminosulfonylation of aryldiazonium tetrafluoroborates: synthesis of N-aminosulfonamides via a radical coupling reaction.
A simple and convenient method for N-aminosulfonamide synthesis from the cross-coupling of aryldiazonium tetrafluoroborates and rongalite under metal-free, oxidant-free, and room-temperature conditions is reported. This method does not require an external amine source, with the aryldiazonium tetrafluoroborates participating as both an aryl radical and a potential amine source in the transformation. Mechanistic studies revealed that rongalite could act as a radical initiator, a sulfur dioxide surrogate and a reducing reagent simultaneously in this reaction.


Systematic Literature Review of Health Impact Assessments in Low and Middle-Income Countries.
Health Impact Assessments (HIAs) motivate effective measures for safeguarding public health. There is consensus that HIAs in low and middle-income countries (LMICs) are lacking, but no study systematically focuses on those that have been successfully conducted across all regions of the world, nor do they highlight factors that may enable or hinder their implementation. Our objectives are to (1) systematically review, geographically map, and characterize HIA activity in LMICs; and (2) apply a process evaluation method to identify factors which are important to improve HIA implementation in LMICs. A systematic review of peer-reviewed HIAs in 156 LMICs was performed in Scopus, Medline, Web of Science, Sociological abstracts, and LILACs (Latin American and Caribbean Health Sciences) databases. The search used PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and covered HIAs across all type of interventions, topics, and health outcomes. HIAs were included if they reported a clear intervention and health outcome to be assessed. No time restriction was applied, and grey literature was not included. The eligible studies were subjected to six process evaluation criteria. The search yielded 3178 hits and 57 studies were retained. HIAs were conducted in 26 out of 156 countries. There was an unequal distribution of HIAs across regions and within LMICs countries. The leading topics of HIA in LMICs were air pollution, development projects, and urban transport planning. Most of the HIAs reported quantitative approaches (72%), focused on air pollution (46%), appraised policies (60%), and were conducted at the city level (36%). The process evaluation showed important variations in the way HIAs have been conducted and low uniformity in the reporting of six criteria. No study reported the time, money, and staff used to perform HIAs. Only 12% of HIAs were based on participatory approaches; 92% of HIAs considered multiple outcomes; and 61% of HIAs provided recommendations and fostered cross-national collaboration. The limited transparency in process, weak participation, and inconsistent delivery of recommendations were potential limitations to HIA implementation in low and middle-income countries. Scaling and improving HIA implementation in low and middle-income countries in the upcoming years will depend on expanding geographically by increasing HIA governance, adapting models and tools in quantitative methods, and adopting better reporting practices.


Barriers to excellent end-of-life care for patients with dementia.
While great strides have been made recently in improving end-of-life care in the United States, people with dementia often die with inadequate pain control, with feeding tubes in place, and without the benefits of hospice care. In this paper, we discuss the most important and persistent challenges to providing excellent end-of-life care for patients with dementia, including dementia not being viewed as a terminal illness; the nature of the course and treatment decisions in advanced dementia; assessment and management of symptoms; the caregiver experience and bereavement; and health systems issues. We suggest approaches for overcoming these barriers in the domains of education, clinical practice, and public policy. As the population ages, general internists increasingly will be called upon to provide primary care for a growing number of patients dying with dementia. There are great opportunities to improve end-of-life care for this vulnerable and underserved population.


Crosstalk and error analysis of fat layer on continuous wave near-infrared spectroscopy measurements.
Accurate estimation of concentration changes in muscles by continuous wave near-IR spectroscopy for muscle measurements suffers from underestimation and crosstalk problems due to the presence of superficial skin and fat layers. Underestimation error is basically caused by a homogeneous medium assumption in the calculations leading to the partial volume effect. The homogeneous medium assumption and wavelength dependence of mean partial path length in the muscle layer cause the crosstalk. We investigate underestimation errors and crosstalk by Monte Carlo simulations with a three layered (skin-fat-muscle) tissue model for a two-wavelength system where the choice of first wavelength is in the 675- to 775-nm range and the second wavelength is in the 825- to 900-nm range. Means of absolute underestimation errors and crosstalk over the considered wavelength pairs are found to be higher for greater fat thicknesses. Estimation errors of concentration changes for Hb and HbO(2) are calculated to be close for an ischemia type protocol where both Hb and HbO(2) are assumed to have equal magnitude but opposite concentration changes. The minimum estimation errors are found for the 700825- and 725825-nm pairs for this protocol.


Effect of NCB-02, atorvastatin and placebo on endothelial function, oxidative stress and inflammatory markers in patients with type 2 diabetes mellitus: a randomized, parallel-group, placebo-controlled, 8-week study.
Hyperglycaemia leads to increased oxidative stress resulting in endothelial dysfunction. ACE inhibitors, antioxidants and HMG-CoA reductase inhibitors (statins) have been shown to improve endothelial function. The aim of this study was to compare the effects of NCB-02 (a standardized preparation of curcuminoids), atorvastatin and placebo on endothelial function and its biomarkers in patients with type 2 diabetes mellitus. A total of 72 patients with type 2 diabetes were randomized to receive NCB-02 (two capsules containing curcumin 150 mg twice daily), atorvastatin 10 mg once daily or placebo for 8 weeks. Endothelial function assessment was performed at baseline and post-treatment using digital volume plethysmography (salbutamol [albuterol] challenge test) to measure change in reflective index, an indicator of arterial vascular tone. Blood samples were similarly collected at baseline and post-treatment for estimations of malondialdehyde, endothelin-1 (ET-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNFalpha). Pre-and post-treatment safety assessments were also conducted. ANOVA and paired t-test evaluations were used for comparison. A total of 67 patients completed the study. At baseline, there was no significant difference in the various parameters tested. In all three groups, the change in reflective index at baseline was <6% as assessed by the salbutamol challenge test, indicating the presence of endothelial dysfunction. Compared with baseline, there was a significant improvement in endothelial function after treatment with atorvastatin (mean +/- SD: -3.63 +/- 3.17% vs -8.95 +/- 6.80%, respectively) and NCB-02 (-2.69 +/- 3.02% vs -8.19 +/- 5.73%, respectively). Similarly, patients receiving atorvastatin or NCB-02 showed significant reductions in the levels of malondialdehyde, ET-1, IL-6 and TNFalpha. No significant improvements were obtained in patients administered placebo. NCB-02 had a favourable effect, comparable to that of atorvastatin, on endothelial dysfunction in association with reductions in inflammatory cytokines and markers of oxidative stress. Further studies are needed to evaluate the potential long-term effects of NCB-02 and its combination with other herbal antioxidants.


The development of anti-heat stress clothing for construction workers in hot and humid weather.
The purpose of this study was to develop anti-heat stress clothing for construction workers in hot and humid weather. Following DeJonge's functional clothing design process, the design situation was explored, including clothing fabric heat/moisture transporting properties and UV protection and the aspects of clothing ergonomic design (mobility, convenience, and safety). The problem structure was derived from the results of the surveys in three local construction sites, which agreed well with the task requirements and observations. Specifications were consequently described and 30 commercially available fabrics were identified and tested. Fabric testing data and design considerations were inputted in S-smart system to predict the thermal functional performance of the clothing. A new uniform prototype was developed and evaluated. The results of all measurements suggest that the new uniform which incorporated fabrics with superior heat/moisture transporting properties and loose-fitting design could reduce the workers' heat stress and improve their comfort and work performance. Practitioner Summary: The construction workers' uniform currently used in Hong Kong during summer was unsatisfactory. Following DeJonge's functional clothing design process, an anti-heat stress uniform was developed by testing 30 fabrics and predicting clothing thermal functional performance using S-smart system. The new uniform could reduce the workers' heat stress and improve their comfort and work performance.