Control of prostaglandin stereochemistry at the 15-carbon by cyclooxygenases-1 and -2. A critical role for serine 530 and valine 349.
Prostaglandin synthesis by cyclooxygenases-1 and -2 (COX-1 and COX-2) involves an initial oxygenation of arachidonic acid at C-11, followed by endoperoxide and cyclopentane ring formation, and then a second reaction with molecular oxygen in the S configuration at C-15. The resulting 15S-hydroxyl group of prostaglandins is crucial for their bioactivity. Using human COX-1 and human and murine COX-2, we have identified two amino acids located in the oxygenase active site that control the stereochemistry at C-15. The most crucial determinant is Ser-530, the residue that is acetylated by aspirin. In COX-2, site-directed mutagenesis of Ser-530 to methionine, threonine, or valine produced highly active enzymes that formed 82-95% 15R-configuration prostaglandins; these have the opposite stereochemistry at C-15 to the natural products. In COX-1, the corresponding Ser-530 mutations inactivated the enzyme. The second residue, Val-349, exerts a more subtle influence. When Val-349 was replaced by isoleucine, the mutant COX-1 and COX-2 enzymes formed 41 and 65% 15R-prostaglandins, respectively. This change was highly specific for isoleucine, as mutations of Val-349 to alanine, leucine, asparagine, or threonine did not alter or only slightly altered (< or =13%) the S-configuration at C-15. These results establish a previously unrecognized role for Ser-530 and Val-349 in maintaining the correct S stereochemistry of the carbon-15 hydroxyl group during prostaglandin synthesis. The findings may also explain the absolute conservation of Ser-530, the target of aspirin, throughout the families of cyclooxygenase enzymes.


Commemorating two centuries of iodine research: an interdisciplinary overview of current research.
Iodine was discovered as a novel element in 1811 during the Napoleonic Wars. To celebrate the bicentennial anniversary of this event we reflect on the history and highlight the many facets of iodine research that have evolved since its discovery. Iodine has an impact on many aspects of life on Earth as well as on human civilization. It is accumulated in high concentrations by marine algae, which are the origin of strong iodine fluxes into the coastal atmosphere which influence climatic processes, and dissolved iodine is considered a biophilic element in marine sediments. Iodine is central to thyroid function in vertebrates, with paramount implications for human health. Iodine can exist in a wide range of oxidation states and it features a diverse supramolecular chemistry. Iodine is amenable to several analytical techniques, and iodine compounds have found widespread use in organic synthesis. Elemental iodine is produced on an industrial scale and has found a wide range of applications in innovative materials, including semiconductors--in particular, in solar cells.


Cross-sectional study evaluating burden and depressive symptoms in family carers of persons with age-related macular degeneration in Australia.
We aimed to analyse the degree of carer burden and depressive symptoms in family carers of persons with age-related macular degeneration (AMD) and explore the factors independently associated with carer burden and depressive symptoms. Cross-sectional study using self-administered and interviewer-administered surveys, involving 96 family carer-care recipient pairs. Participants were identified from tertiary ophthalmology clinics in Sydney, Australia, as well as the Macular Disease Foundation of Australia database. Logistic regression, Pearson and Spearman correlation analyses were used to investigate associations of explanatory factors (family caregiving experience, carer fatigue, carer quality of life and care-recipient level of dependency) with study outcomes-carer burden and depressive symptoms. Over one in two family carers reported experiencing mild or moderate-severe burden. More than one in five and more than one in three family carers experienced depressive symptoms and substantial fatigue, respectively. High level of care-recipient dependency was associated with greater odds of moderate-severe and mild carer burden, multivariable-adjusted OR 8.42 (95% CI 1.88 to 37.60) and OR 4.26 (95% CI 1.35 to 13.43), respectively. High levels of fatigue were associated with threefold greater odds of the carer experiencing depressive symptoms, multivariable-adjusted OR 3.47 (95% CI 1.00 to 12.05). A substantial degree of morbidity is observed in family carers during the caregiving experience for patients with AMD. Level of dependency on the family carer and fatigue were independently associated with family carer burden and depressive symptoms. The trial registration number is ACTRN12616001461482. The results presented in this paper are Pre-results stage.


Generation of the volatile spiroketals conophthorin and chalcogran by fungal spores on polyunsaturated fatty acids common to almonds and pistachios.
The spiroketal (E)-conophthorin has recently been reported as a semiochemical of the navel orangeworm moth, a major insect pest of California pistachios and almonds. Conophthorin and the isomeric spiroketal chalcogran are most commonly known as semiochemicals of several scolytid beetles. Conophthorin is both an insect- and plant-produced semiochemical widely recognized as a nonhost plant volatile from the bark of several angiosperm species. Chalcogran is the principal aggregation pheromone component of the six-spined spruce bark beetle. Recent research has shown conophthorin is produced by almonds undergoing hull-split, and both spiroketals are produced by mechanically damaged almonds. To better understand the origin of these spiroketals, the volatile emissions of orchard fungal spores on fatty acids common to both pistachios and almonds were evaluated. The volatile emission for the first 13 days of spores placed on a fatty acid was monitored. The spores investigated were Aspergillus flavus (atoxigenic), A. flavus (toxigenic), Aspergillus niger, Aspergillus parasiticus, Penicillium glabrum, and Rhizopus stolonifer. The fatty acids used as growth media were palmitic, oleic, linoleic, and linolenic. Spores on linoleic acid produced both spiroketals, those on linolenic acid produced only chalcogran, and those on palmitic and oleic acid did not produce either spiroketal. This is the first report of the spiroketals conophthorin and chalcogran from a fungal source.


Noise analysis of genome-scale protein synthesis using a discrete computational model of translation.
Noise in genetic networks has been the subject of extensive experimental and computational studies. However, very few of these studies have considered noise properties using mechanistic models that account for the discrete movement of ribosomes and RNA polymerases along their corresponding templates (messenger RNA (mRNA) and DNA). The large size of these systems, which scales with the number of genes, mRNA copies, codons per mRNA, and ribosomes, is responsible for some of the challenges. Additionally, one should be able to describe the dynamics of ribosome exchange between the free ribosome pool and those bound to mRNAs, as well as how mRNA species compete for ribosomes. We developed an efficient algorithm for stochastic simulations that addresses these issues and used it to study the contribution and trade-offs of noise to translation properties (rates, time delays, and rate-limiting steps). The algorithm scales linearly with the number of mRNA copies, which allowed us to study the importance of genome-scale competition between mRNAs for the same ribosomes. We determined that noise is minimized under conditions maximizing the specific synthesis rate. Moreover, sensitivity analysis of the stochastic system revealed the importance of the elongation rate in the resultant noise, whereas the translation initiation rate constant was more closely related to the average protein synthesis rate. We observed significant differences between our results and the noise properties of the most commonly used translation models. Overall, our studies demonstrate that the use of full mechanistic models is essential for the study of noise in translation and transcription.


Thrombotic Microangiopathy Syndrome in a Basic Underwater Demolition/SEAL Student.
Thrombotic microangiopathy (TMA) syndromes represent a spectrum of illnesses that share common clinical and pathologic features of microangiopathic hemolytic anemia, thrombocytopenia, and organ injury from pathologic small-vessel thrombosis. At least nine primary TMA syndromes have been described and classified based on common probable etiologies, diagnostic criteria, and treatments. The most recognized of the TMA syndromes include thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). Advanced laboratory techniques are required to distinguish between these syndromes; however, all patients should initially be treated with plasma exchange for presumed ADAMTS13 deficiency-mediated TMA. The authors present a case of a TMA syndrome in a Navy SEAL (Sea, Air, Land) candidate.


Characterization and analysis of the transcriptome in Gymnocypris selincuoensis on the Qinghai-Tibetan Plateau using single-molecule long-read sequencing and RNA-seq.
The lakes on the Qinghai-Tibet Plateau (QTP) are the largest and highest lake group in the world. Gymnocypris selincuoensis is the only cyprinid fish living in lake Selincuo, the largest lake on QTP. However, its genetic resource is still blank, limiting studies on molecular and genetic analysis. In this study, the transcriptome of G. selincuoensis was first generated by using PacBio Iso-Seq and Illumina RNA-seq. A full-length (FL) transcriptome with 75,435 transcripts was obtained by Iso-Seq with N50 length of 3,870 bp. Among all transcripts, 75,016 were annotated to public databases, 64,710 contain complete open reading frames and 2,811 were long non-coding RNAs. Based on all- vs.-all BLAST, 2,069 alternative splicing events were detected, and 80% of them were validated by reverse transcription polymerase chain reaction (RT-PCR). Tissue gene expression atlas showed that the number of detected expressed transcripts ranged from 37,397 in brain to 19,914 in muscle, with 10,488 transcripts detected in all seven tissues. Comparative genomic analysis with other cyprinid fishes identified 77 orthologous genes with potential positive selection (Ka/Ks > 0.3). A total of 56,696 perfect simple sequence repeats were identified from FL transcripts. Our results provide valuable genetic resources for further studies on adaptive evolution, gene expression and population genetics in G. selincuoensis and other congeneric fishes.


The effect of race on provider decisions to test for illicit drug use in the peripartum setting.
Testing for illicit drugs may expose women who test positive to severe legal and social consequences. It is unknown whether racial disparities in drug testing practices underlie observed disparities in legal and social consequences of positive tests. Using administrative hospital and birth certificate data, we analyzed factors associated with both receipt and results of illicit drug testing among women with live births during 2002-2003. We assessed the independent association of race and other sociodemographic factors with both receipt of a drug test by the mother or her newborn infant and positive maternal or neonatal toxicology results, after controlling for obstetrical conditions and birth outcomes associated with maternal substance abuse. Of the 8487 women with live births, 244 mother-newborn pairs (3%) were tested for illicit drug use. Black women and their newborns were 1.5 times more likely to be tested for illicit drugs as nonblack women in multivariable analysis. However, race was not independently associated with a positive result. We identified racial differences in rates of testing for illicit drug use between black and nonblack women. We found equivalent positivity rates among tested black and nonblack women. The prevalence of drug use among untested women is unknown, however, so although tested women had equivalent rates of substance use detected, whether black and nonblack substance users are equally likely to be identified in the course of peripartum care remains uncertain.


Evidence of Allergic Reactions and Cardiopulmonary Impairments among Traders Operating from Foodstuff Warehouses.
Background. Foodstuff traders operating from warehouses (FTFW) are potentially exposed to dangerous rodenticides/pesticides that may have adverse effects on cardiopulmonary function. Methods. Fifty consenting male foodstuff traders, comprising 15 traders (21-63 years) operating outside warehouses and 35 FTFW (20-64 years), were randomly recruited at Ogbete Market, Enugu, in a cross-sectional observational study of spirometric and electrocardiographic parameters. Seventeen FTFW (21-57 years) participated in focus group discussions. Qualitative and quantitative data were analysed thematically and with independent t-test and Pearson correlation coefficient at p < 0.05, respectively. Results. Most FTFW experienced respiratory symptoms, especially dry cough (97.1%) and wheezing (31.4%) with significant reductions in forced vital capacity (FVC) (t = -2.654; p = 0.011), forced expiratory volume in one second (FEV1) (t = -2.240; p = 0.030), maximum expiratory flow rate (FEF200-1200) (t = -1.148; p = -0.047), and forced end-expiratory flow (FEF75-85) (t = -1.11; p = 0.007). The maximum mid-expiratory flow (FEF25-75) was marginally decreased (p > 0.05) with a significantly prolonged (p < 0.05) QTc interval. Conclusion. Allergic response was evident in the FTFW. Significant decrease in FVC may negatively impact lung flow rates and explains the marginal decrease in FEF25-75, which implies a relative limitation in airflow of peripheral/distal airways and elastic recoil of the lungs. This is consistent with obstructive pulmonary disease; a significant decrease in FEF75-85/FEV1 supports this conclusion. Significant decrease in FEF200-1200 indicates abnormalities in the large airways/larynx just as significantly prolonged ventricular repolarization suggests cardiac arrhythmias.


Parathyroidectomy is safe and improves symptoms in elderly patients with primary hyperparathyroidism (PHPT).
Parathyroidectomy for primary hyperparathyroidism (PHPT) is curative in over 95% of cases. Although PHPT affects up to 2% of the elderly population, whose life expectancy may be a decade or more, such patients may be denied surgery because of perceived risk. This study investigates the outcomes of surgery for PHPT in the elderly. Consecutive patients with PHPT treated at a tertiary referral centre over 5 years. A prospective database recorded clinical, biochemical and pathological information. Pasieka's parathyroid symptom scores were obtained pre-operatively and post-operatively, from a recent subgroup of 70 consecutive patients. Deaths during follow-up were identified using the NHS Strategic Tracing Service. Statistical analysis was performed with spss v12.0. Between November 2002 and October 2007, 224 patients (17-89 years) underwent surgery for PHPT. In the subgroup comprising patients aged >75 years there was a significantly greater proportion of women (47/56 vs. 52/81, P < 0.05). Pre-operative indices of these patients were similar to younger patients, as were proportions undergoing minimally invasive parathyroidectomy (n = 134) or bilateral neck exploration (n = 90). Patients >75 years had a longer hospital stay (1.6 vs. 0.8 days, P = 0.003). Pasieka's symptom scores improved significantly at 3-6 months postoperatively in all age groups. During a minimum median follow-up of 22 months, there were seven patients with persistent/recurrent disease. Median 2-year survival of those aged 60-74 and those over 75 ranged from 85-90%. Parathyroidectomy is safe in the elderly and is associated with a significant improvement in symptoms. As survival after operation is similar to younger patients, surgery should be considered in all elderly patients with PHPT.


SpSoxB1, a maternally encoded transcription factor asymmetrically distributed among early sea urchin blastomeres.
We have identified a Sox family transcription factor, SpSoxB1, that is asymmetrically distributed among blastomeres of the sea urchin embryo during cleavage, beginning at 4th cleavage. SpSoxB1 interacts with a cis element that is essential for transcription of SpAN, a gene that is activated cell autonomously and expressed asymmetrically along the animal-vegetal axis. In vitro translated SpSoxB1 forms a specific complex with this cis element whose mobility is identical to that formed by a protein in nuclear extracts. An anti-SpSoxB1 rabbit polyclonal antiserum specifically supershifts this DNA-protein complex and recognizes a single protein on immunoblots of nuclear proteins that comigrates with in vitro translated SpSoxB1. Developmental immunoblots of total proteins at selected early developmental stages, as well as EMSA of egg and 16-cell stage proteins, show that SpSoxB1 is present at low levels in unfertilized eggs and progressively accumulates during cleavage. SpSoxB1 maternal transcripts are uniformly distributed in the unfertilized egg and the protein accumulates to similar, high concentrations in all nuclei of 4- and 8-cell embryos. However, at fourth cleavage, the micromeres, which are partitioned by asymmetric division of the vegetal 4 blastomeres, have reduced nuclear levels of the protein, while high levels persist in their sister macromeres and in the mesomeres. During cleavage, the uniform maternal SpSoxB1 transcript distribution is replaced by a zygotic nonvegetal pattern that reinforces the asymmetric SpSoxB1 protein distribution and reflects the corresponding domain of SpAN mRNA accumulation at early blastula stage ( approximately 150 cells). The vegetal region lacking nuclear SpSoxB1 gradually expands so that, after blastula stage, only cells in differentiating ectoderm accumulate this protein in their nuclei. The results reported here support a model in which SpSoxB1 is a major regulator of the initial phase of asymmetric transcription of SpAN in the nonvegetal domain by virtue of its distribution at 4th cleavage and is subsequently an important spatial determinant of expression in the early blastula. This factor is the earliest known spatially restricted regulator of transcription along the animal-vegetal axis of the sea urchin embryo.


A high resolution hydrodynamic model system suitable for novel harmful algal bloom modelling in areas of complex coastline and topography.
Fjordic coastlines provide sheltered locations for finfish and shellfish aquaculture, and are often subject to harmful algal blooms (HABs) some of which develop offshore and are then advected to impact nearshore aquaculture. Numerical models are a potentially important tool for providing early warning of such HAB events. However, the complex topography of fjordic shelf regions is a significant challenge to modelling. This is frequently compounded by complex bathymetry and local weather patterns. Existing structured grid models do not provide the resolution needed to represent these coastlines in their wider shelf context. In a number of locations advectively transported blooms of the ichthyotoxic dinoflagellate Karenia mikimotoi are of particular concern for the finfish industry. Here were present a novel hydrodynamic model of the coastal waters to the west of Scotland that is based on unstructured finite volume methodology, providing a sufficiently high resolution hydrodynamical structure to realistically simulate the transport of particles (such as K. mikimotoi cells) within nearshore waters where aquaculture sites are sited. Model-observation comparisons reveal close correspondence of tidal elevations for major semidiurnal and diurnal tidal constituents. The thermohaline structure of the model and its current fields are also in good agreement with a number of existing observational datasets. Simulations of the transport of Lagrangian drifting buoys, along with the incorporation of an individual-based biological model, based on a bloom of K. mikimotoi, demonstrate that unstructured grid models have considerable potential for HAB prediction in Scotland and in complex topographical regions elsewhere.


Adrenomedullin as a novel antimigration factor of vascular smooth muscle cells.
The present study investigated the effect of adrenomedullin, a novel vasorelaxant peptide, on the migration of cultured rat vascular smooth muscle cells (SMCs) by using the Boyden-chamber method. Fetal calf serum (FCS) and platelet-derived growth factor (PDGF)-BB strongly stimulated SMC migration. Adrenomedullin clearly inhibited SMC migration stimulated with 5% and 10% FCS in a concentration-dependent manner. The migration induced by 10 and 25 ng/mL PDGF-BB was also inhibited by adrenomedullin in a concentration-dependent manner. Inhibition by adrenomedullin of FCS- and PDGF-induced SMC migration was paralleled by an increase in the cellular level of cAMP. In fact, the percent increase in cAMP level was strongly correlated with the percent decrease in migration activity of SMCs after treatment with adrenomedullin. 8-Bromo cAMP, a cAMP analogue, reproduced the inhibition by adrenomedullin of FCS- and PDGF-induced SMC migration. An activator of adenylate cyclase, forskolin, also reduced FCS- and PDGF-induced SMC migration. These data indicate that adrenomedullin inhibits the migration of SMCs stimulated with FCS and PDGF, probably through a cAMP-dependent process. On the basis of these results and the finding that adrenomedullin is synthesized in and secreted from vascular endothelial cells, adrenomedullin may play a role as a local antimigration factor in some pathophysiological states.


Yellow NIR dye: π-fused bisbenzoBODIPYs with electron-withdrawing groups.
Bicyclo[2.2.2]octadiene-fused (BCOD-fused) bis(benzoborondipyrromethene)s (bisbenzoBODIPYs) bearing electron-withdrawing groups such as fluorine and cyano groups were prepared either by incorporating tetrafluoroisoindole moieties into BODIPY chromophores or by introducing cyano or ethoxycarbonyl groups at the 3,5-positions. The BCOD-fused bisbenzoBODIPYs were quantitatively converted to the corresponding benzene-fused bisbenzoBODIPYs by a retro-Diels-Alder reaction. The π-fused bisbenzoBODIPYs were found to have intense absorption in the near-infrared region and not to have any strong absorption bands in the visible region. Moreover, the bisbenzoBODIPYs were stable under atmospheric conditions.


A Vulnerability Assessment of Fish and Invertebrates to Climate Change on the Northeast U.S. Continental Shelf.
Climate change and decadal variability are impacting marine fish and invertebrate species worldwide and these impacts will continue for the foreseeable future. Quantitative approaches have been developed to examine climate impacts on productivity, abundance, and distribution of various marine fish and invertebrate species. However, it is difficult to apply these approaches to large numbers of species owing to the lack of mechanistic understanding sufficient for quantitative analyses, as well as the lack of scientific infrastructure to support these more detailed studies. Vulnerability assessments provide a framework for evaluating climate impacts over a broad range of species with existing information. These methods combine the exposure of a species to a stressor (climate change and decadal variability) and the sensitivity of species to the stressor. These two components are then combined to estimate an overall vulnerability. Quantitative data are used when available, but qualitative information and expert opinion are used when quantitative data is lacking. Here we conduct a climate vulnerability assessment on 82 fish and invertebrate species in the Northeast U.S. Shelf including exploited, forage, and protected species. We define climate vulnerability as the extent to which abundance or productivity of a species in the region could be impacted by climate change and decadal variability. We find that the overall climate vulnerability is high to very high for approximately half the species assessed; diadromous and benthic invertebrate species exhibit the greatest vulnerability. In addition, the majority of species included in the assessment have a high potential for a change in distribution in response to projected changes in climate. Negative effects of climate change are expected for approximately half of the species assessed, but some species are expected to be positively affected (e.g., increase in productivity or move into the region). These results will inform research and management activities related to understanding and adapting marine fisheries management and conservation to climate change and decadal variability.


Measurement of cell thickness in infrared spectrophotometry.
It is shown that the usual expression for measuring the cell thickness d(a) of an empty cell, namely, d(a) = lambda(1)lambda(2)N/2(lambda(2) - lambda(1)), where N is the number of fringes over the wavelength range lambda(1) and lambda(2), may only be applied under particular conditions of cell and wall thickness and spectrophotometer characteristics. This is done by first deriving the expression for the transmission coefficient of a cell taking into account all the four surfaces at which a discontinuity in the refractive index occurs (while in deriving the above formula only two such surfaces are considered). Then, by examining the spectrophotometer characteristics, we investigate what amount of the information contained in the variation of transmission coefficient with wavelength is actually recorded by the instrument. Formulas are developed for different situations, in which only cell thickness, both cell and wall thickness, and finally only wall thickness, may be measured by counting the number of fringes over a wavelength interval. The equation mentined at the beginning is only valid for the first of these cases.


Evidence of a critical leucite particle size for microcracking in dental porcelains.
The leucite particles in dental porcelains are often partially encircled by microcracks that are the result of the thermal expansion mismatch between leucite and the surrounding glass matrix. Although the magnitude of the stress at the particle-matrix interface is independent of the particle size (Selsing, 1961), Davidge and Green (1968) showed experimentally that there is a critical particle size below which microcracking is absent. The critical particle size is explained by a Griffith-type energy balance criterion: Below the critical size, the stress magnitude may be sufficient to cause cracking, but there is insufficient strain energy for the creation of the new surfaces of the microcrack. The purpose of the present study was to determine whether the mean leucite particle size of a dental porcelain influences the degree of microcracking in the porcelain. Microcrack density, leucite particle surface area per unit volume, and leucite mean volume-surface diameter, D3,2, were determined by quantitative stereology on 10 specimens each of 6 dental porcelains and Component No. 1 of the Weinstein et al. patent (US Patent 3,052,982, 1962). The fraction of leucite particles with microcracks around them, f(mc), was estimated for each porcelain from the microcrack density and the leucite surface area. Using the equations of Selsing (1961) and Davidge and Green (1968), we calculated the critical particle diameter, Dc, for leucite to be 4 microm. The porcelains were partitioned according to whether their mean leucite particle diameters, D3,2, fell above or below Dc, and their values of f(mc) were analyzed by a permutation test with random re-sampling. The porcelains with mean leucite particle diameters below Dc had a significantly lower fraction of cracked particles compared with the porcelains with mean leucite particle diameters above Dc (p < 0.05). This study provides evidence that microcracking in dental porcelain can be minimized by a reduction of the mean leucite particle diameter to less than 4 microm.


Effects of vitamin C supplementation on blood pressure: a meta-analysis of randomized controlled trials.
In observational studies, increased vitamin C intake, vitamin C supplementation, and higher blood concentrations of vitamin C are associated with lower blood pressure (BP). However, evidence for blood pressure-lowering effects of vitamin C in clinical trials is inconsistent. The objective was to conduct a systematic review and meta-analysis of clinical trials that examined the effects of vitamin C supplementation on BP. We searched Medline, EMBASE, and Central databases from 1966 to 2011. Prespecified inclusion criteria were as follows: 1) use of a randomized controlled trial design; 2) trial reported effects on systolic BP (SBP) or diastolic BP (DBP) or both; 3) trial used oral vitamin C and concurrent control groups; and 4) trial had a minimum duration of 2 wk. BP effects were pooled by random-effects models, with trials weighted by inverse variance. Twenty-nine trials met eligibility criteria for the primary analysis. The median dose was 500 mg/d, the median duration was 8 wk, and trial sizes ranged from 10 to 120 participants. The pooled changes in SBP and DBP were -3.84 mm Hg (95% CI: -5.29, -2.38 mm Hg; P < 0.01) and -1.48 mm Hg (95% CI: -2.86, -0.10 mm Hg; P = 0.04), respectively. In trials in hypertensive participants, corresponding reductions in SBP and DBP were -4.85 mm Hg (P < 0.01) and -1.67 mm Hg (P = 0.17). After the inclusion of 9 trials with imputed BP effects, BP effects were attenuated but remained significant. In short-term trials, vitamin C supplementation reduced SBP and DBP. Long-term trials on the effects of vitamin C supplementation on BP and clinical events are needed.


The cardiac care bridge program: design of a randomized trial of nurse-coordinated transitional care in older hospitalized cardiac patients at high risk of readmission and mortality.
After hospitalization for cardiac disease, older patients are at high risk of readmission and death. Although geriatric conditions increase this risk, treatment of older cardiac patients is limited to the management of cardiac diseases. The aim of this study is to investigate if unplanned hospital readmission and mortality can be reduced by the Cardiac Care Bridge transitional care program (CCB program) that integrates case management, disease management and home-based cardiac rehabilitation. In a randomized trial on patient level, 500 eligible patients ≥ 70 years and at high risk of readmission and mortality will be enrolled in six hospitals in the Netherlands. Included patients will receive a Comprehensive Geriatric Assessment (CGA) at admission. Randomization with stratified blocks will be used with pre-stratification by study site and cognitive status based on the Mini-Mental State Examination (15-23 vs ≥ 24). Patients enrolled in the intervention group will receive a CGA-based integrated care plan, a face-to-face handover with the community care registered nurse (CCRN) before discharge and four home visits post-discharge. The CCRNs collaborate with physical therapists, who will perform home-based cardiac rehabilitation and with a pharmacist who advices the CCRNs in medication management The control group will receive care as usual. The primary outcome is the incidence of first all-cause unplanned readmission or mortality within 6 months post-randomization. Secondary outcomes at three, six and 12 months after randomization are physical functioning, functional capacity, depression, anxiety, medication adherence, health-related quality of life, healthcare utilization and care giver burden. This study will provide new knowledge on the effectiveness of the integration of geriatric and cardiac care. NTR6316 . Date of registration: April 6, 2017.


Determination of the local structure of CsBi4-xPbxTe6 (x = 0, 0.5) by X-ray absorption spectroscopy.
We have studied the local structure and valence electronic unoccupied states of thermoelectric CsBi4Te6 and superconducting CsBi3.5Pb0.5Te6 (Tc ∼ 3 K) by extended X-ray absorption fine structure (EXAFS) and X-ray absorption near edge structure (XANES) measurements. The Bi-L3 edge EXAFS reveals wide Bi-Te distance distribution for both compounds indicating complex atomic arrangements in the studied system. The mean square relative displacements (MSRDs) of the Bi-Te bond distances appear largely increased in Pb substituted system due to larger overall local disorder, however, one of the Bi-Te bonds shows a reduced disorder. On the other hand, the Bi-L3 edge XANES is hardly affected by Pb substitution while the Te-L1 edge XANES reveals increased density of unoccupied Te 5p states. This suggests that the carriers introduced by the Pb substitution in CsBi4-xPbxTe6 preferentially goes on Te sites. Similarly, the Cs-L3 edge XANES also shows small changes due to Pb-substitution and reduced local disorder indicated by the reduced width of the Cs-L3 edge white line. We have also shown that the X-ray photoemission spectroscopy (XPS) measurements on various electronic core levels are in a qualitative agreement with the XANES results. These findings are consistent with carrier doping and a reduced disorder in one direction to be likely factors to drive the thermoelectric CsBi4Te6 into a bulk superconductor by Pb-substitution in CsBi4-xPbxTe6.


Prevention Of Skeletal Related Events In Multiple Myeloma: Focus On The RANK-L Pathway In The Treatment Of Multiple Myeloma.
More than 90% of patients with multiple myeloma (MM) have osteolytic bone lesions which increase the risk of skeletal-related events (SRE). The cytokine milieu in the bone marrow microenvironment (BMME) of MM plays a key role in myeloma bone disease by impairing the balance between osteoclastogenesis and osteoblastogenesis. This is orchestrated by the malignant plasma cell (MPC) with the ultimate outcome of MPC proliferation and survival at the expense of excess osteoclast activation resulting in osteolytic bone lesions. Prevention of SRE is currently accomplished by the inhibition of osteoclasts. Bisphosphonates (BPs) are pyrophosphate analogues that cause apoptosis of osteoclasts and have been proven to prevent and delay SRE. Denosumab, a fully humanized monoclonal antibody that binds and inhibits receptor activator of nuclear factor-ĸB ligand (RANKL), a key molecule in the BMME crucial for osteoclastogenesis, is also approved for the prevention of SRE in MM. The addition of BPs and denosumab to standard MM treatment affords a survival benefit for patients with MM. Specifically, the addition of denosumab to standard MM treatments results in superior PFS compared to BPs, highlighting the key role of the RANKL pathway in MM. This review focuses on the pathophysiology of myeloma bone disease as well as on the importance of targeting the RANK-L pathway for the treatment of MM and prevention of SRE.


Astlingen - a benchmark for real time control (RTC).
This contribution serves two purposes. (1) It presents an updated version of the Astlingen example developed by the working group 'Integral Real Time Control' of the German Water Association (DWA), which serves as a benchmark example for the setup and evaluation of real time control strategies. As this benchmark is also intended for educational use, it demonstrates a simple RTC algorithm, illustrating the main concepts of RTC of drainage system. (2) The paper also encourages the preliminary analysis of the potential feasibility and benefit of a temporal increase of inflow to the wastewater treatment plant (WWTP) before analysing the WWTP behaviour in detail. For the present example, RTC within the sewer system alone led to almost the same reduction of overflow volume as permitting the inflow to the WWTP to be increased for 6 h within any 24 h, if at all permitted.


Energetics and dynamics of the non-natural fluorescent 4AP:DAP base pair.
The fluorescent non-natural 4-aminophthalimide (4AP) base, when paired to the complementary 2,4-diaminopyrimidine (DAP) nucleobase, is accommodated in a B-DNA duplex being efficiently recognized and incorporated by DNA polymerases. To complement the experimental studies and rationalize the impact of the above non-natural bases on the structure, stability and dynamics of nucleic acid structures, we performed quantum mechanics (QM) calculations along with classical molecular dynamics (MD) simulations. QM calculations were initially focused on the geometry and energetics of the 4AP:DAP non-natural pair and of H-bonded base pairs between 4AP and all the natural bases in their classical Watson-Crick geometries. The QM calculations indicate that the 4AP:DAP pair, despite the fact that it can form 3 H-bonds in a classic Watson-Crick geometry, has a stability comparable to the A:T pair. Then, we extended the study to reverse Watson-Crick geometries, characteristic of parallel strands. MD simulations were carried out on two 13-mer DNA duplexes, featuring a central 4AP:DAP or A:T pair, respectively. No major structural deformation of the duplex was observed during the MD simulation. Snapshots from the MD simulations were subjected to QM calculations to investigate the 4AP:DAP interaction energy when embedded into a duplex structure, and to investigate the impact of the two non-natural bases on the stacking interactions with adjacent bases in the DNA duplex. We found a slight increase in stacking interactions involving the 4AP:DAP pair, counterbalanced by a moderate decrease in H-bonding interactions of the 4AP:DAP and of the adjacent base pairs in the duplex. The results of our study are in agreement with experimental data and complement them by providing an insight into which factors contribute positively and which factors contribute negatively to the structural compatibility of the fluorescent 4AP:DAP pair with a B-DNA structure.


Susceptibility of lamivudine-resistant hepatitis B virus to other reverse transcriptase inhibitors.
The emergence of resistant hepatitis B virus (HBV), with mutations in the YMDD motif of the polymerase gene after treatment with lamivudine, is becoming an important clinical problem. In this study, susceptibility of wild-type and lamivudine-resistant HBV M552I, M552V, and L528M/M552V mutants to other reverse transcriptase inhibitors was investigated by transient transfection of full-length HBV DNA into human hepatoma cells. HBV DNA replication was monitored by Southern blot hybridization, which showed the presence of a single-stranded band (representative of the HBV replicative intermediates) in the drug-free, wild-type HBV-transfected cells. This band was diminished in the samples of wild-type HBV DNA treated with either lamivudine, adefovir, or lobucavir. The band intensities from the lamivudine-resistant mutants were not decreased by treatment with lamivudine, but were decreased by the treatments with adefovir or lobucavir. In contrast, penciclovir and nevirapine did not diminish the intensity of the single-stranded band of wild-type HBV or the lamivudine-resistant mutants. These results demonstrate that lamivudine-resistant HBV is susceptible to adefovir and lobucavir. Lamivudine-resistant HBV should be treated with adefovir or lobucavir, and combination therapy with lamivudine and adefovir/lobucavir may prevent the emergence of lamivudine-resistant HBV.


Virulence genes and intimin types of Shiga-toxin-producing Escherichia coli isolated from cattle and beef products in Argentina.
A total of 153 Shiga-toxin-producing Escherichia coli (STEC) isolates from feces of cattle and beef products (hamburgers and ground beef) in Argentina were characterized in this study. PCR showed that 22 (14%) isolates carried stx1 genes, 113 (74%) possessed stx2 genes and 18 (12%) both stx1 and stx2. Intimin (eae), enterohemolysin (ehxA), and STEC autoagglutinating adhesin (saa) virulence genes were detected in 36 (24%), 70 (46%) and in 34 (22%) of the isolates, respectively. None of 34 saa-positive isolates carried the gene eae, and 31 were ehxA-positive. Fourteen (7 of serotype O26:H11 and 4 of serotype O5:H-) isolates had intimin b1, 16 isolates possessed intimin g1 (11 of serotype O145:H- and 5 of serotype O157:H7), 5 isolates had intimin type e1 (4 of serotypes O103:H- and O103:H2), and one isolate O111:H- showed intimin type q/g2. Although the 153 STEC isolates belonged to 63 different seropathotypes, only 12 accounted for 58% of isolates. Seropathotype ONT:H- stx2 (18 isolates) was the most common, followed by O171:H2 stx2 (12 isolates), etc. The majority (84%) of STEC isolates belonged to serotypes previously found in human STEC and 56% to serotypes associated with STEC isolated from patients with hemolytic uremic syndrome (HUS). Thus, this study confirms that cattle are a major reservoir of STEC pathogenic for humans. To our knowledge, this is the first study that described the presence of saa gene in STEC of serotypes O20:H19, O39:H49, O74:H28, O79:H19, O116:H21, O120:H19, O141:H7, O141:H8, O174:H21, and ONT:H21. The serotypes O120:H19 and O185:H7 were not previously reported in bovine STEC.


SISCOM in children with tuberous sclerosis complex-related epilepsy.
Identification of a single epileptogenic focus in patients with tuberous sclerosis complex is a challenge. Noninvasive imaging modalities, including subtraction ictal single-photon emission computed tomography coregistered to magnetic resonance imaging (SISCOM), have been used to determine the dominant epileptogenic focus for surgical resection. We assessed whether complete resection of SISCOM hyperperfusion abnormality correlates with seizure-free outcome in 6 children with tuberous sclerosis complex-related epilepsy. The median seizure onset age was 4 months (range 1 day to 16 months). The age at surgery ranged from 8 months to 13 years. A dominant SISCOM hyperperfusion focus was identified in 5 patients with multiple tubers. SISCOM provided additional localizing information for epilepsy surgery in 3 patients with nonlocalizing or discordant electrophysiologic and neuroimaging findings. At a minimum of 2 years' follow-up, 3 patients were free of seizures overall. Freedom from seizures was associated with complete resection of SISCOM abnormality in 2 patients. These findings demonstrate that SISCOM can be useful in identifying the epileptogenic zone and in guiding the location and extent of epilepsy surgery in children with tuberous sclerosis complex and multifocal abnormalities. In children with tuberous sclerosis complex and intractable epilepsy, complete resection of the SISCOM hyperperfusion abnormality is associated with freedom from seizures.


Direct Isosurface Ray Casting of NURBS-Based Isogeometric Analysis.
In NURBS-based isogeometric analysis, the basis functions of a 3D model's geometric description also form the basis for the solution space of variational formulations of partial differential equations. In order to visualize the results of a NURBS-based isogeometric analysis, we developed a novel GPU-based multi-pass isosurface visualization technique which performs directly on an equivalent rational Bézier representation without the need for discretization or approximation. Our approach utilizes rasterization to generate a list of intervals along the ray that each potentially contain boundary or isosurface intersections. Depth-sorting this list for each ray allows us to proceed in front-to-back order and enables early ray termination. We detect multiple intersections of a ray with the higher-order surface of the model using a sampling-based root-isolation method. The model's surfaces and the isosurfaces always appear smooth, independent of the zoom level due to our pixel-precise processing scheme. Our adaptive sampling strategy minimizes costs for point evaluations and intersection computations. The implementation shows that the proposed approach interactively visualizes volume meshes containing hundreds of thousands of Bézier elements on current graphics hardware. A comparison to a GPU-based ray casting implementation using spatial data structures indicates that our approach generally performs significantly faster while being more accurate.


Spontaneous perforation of common bile duct in infants.
Two infants with spontaneous perforation of the common bile duct are described. One presented with mild jaundice, dark urine, acholic stools, and hydroceles, the other with bilateral inguinal hernia. In both the diagnosis was unsuspected until bile-stained ascites was discovered. Both eventually developed bile-staining of the scrotum. Neither was acutely ill. The 131I-Rose Bengal faecal excretion test showed reduced faecal excretion at 8% and 12% of the injected dose with 16-5 and 17%/dl of the dose being recovered in the ascitic fluid 48 hours after intravenous injection. The ascitic:plasma ratio of isotope at that time was 32:1 and 28:1. Operative cholangiography in both showed a perforation at the junction of the cystic duct and common bile duct with no contrast entering the duodenum. Cholecystenterostomy using a Roux-en-Y loop of jejunum produced a rapid sustained recovery and is suggested as the treatment of choice. This condition should be considered in the differential diagnosis of obstructive jaundice in infancy since early surgical correction is necessary.


A new biofilm-associated colicin with increased efficiency against biofilm bacteria.
Formation of bacterial biofilm communities leads to profound physiological modifications and increased physical and metabolic exchanges between bacteria. It was previously shown that bioactive molecules produced within the biofilm environment contribute to bacterial interactions. Here we describe new pore-forming colicin R, specifically produced in biofilms formed by the natural isolate Escherichia coli ROAR029 but that cannot be detected under planktonic culture conditions. We demonstrate that an increased SOS stress response within mature biofilms induces SOS-dependent colicin R expression. We provide evidence that colicin R displays increased activity against E. coli strains that have a reduced lipopolysaccharide length, such as the pathogenic enteroaggregative E. coli LF82 clinical isolate, therefore pointing to lipopolysaccharide size as an important determinant for resistance to colicins. We show that colicin R toxicity toward E. coli LF82 is increased under biofilm conditions compared with planktonic susceptibility and that release of colicin R confers a strong competitive advantage in mixed biofilms by rapidly outcompeting sensitive neighboring bacteria. This work identifies the first biofilm-associated colicin that preferentially targets biofilm bacteria. Furthermore, it indicates that the study of antagonistic molecules produced in biofilm and multispecies contexts could reveal unsuspected, ecologically relevant bacterial interactions influencing population dynamics in natural environments.


Spinocerebellar ataxia type 6.
We report a 39-year-old woman with spinocerebellar ataxia type 6. She presented with ataxia and a 3-year history of progressive ataxia and recurrent falls. There was no relevant family history. Genetic tests revealed an expanded allele of 24 CAG repeats at the spinocerebellar ataxia type 6 locus. This appears to be the first case reported in Hong Kong. As genetic testing becomes more widely available and clinical awareness increases, more such patients are expected to be diagnosed.


The impact of adopting EHRs: how losing connectivity affects clinical reasoning.
As electronic health records (EHRs) are adopted by teaching hospitals, educators must examine how this change impacts trainee development. We investigate this influence by studying clinician experiences of a hospital's move from paper charts to an EHR. We ask: how does each chart modality present conceptions of time and data interconnections? How do these conceptions affect clinical reasoning? This two-phase, longitudinal study employed constructivist grounded theory. Data were collected at a paediatric teaching hospital before (Phase 1), during and after (Phase 2) the transition from a paper chart to an EHR system. Data collection consisted of field observations (146 hours involving 300 health care providers, 22 patients and 32 patient family members), think-aloud (n = 13) and think-after (n = 11) sessions, interviews (n = 39) and document retrieval (n = 392). Theories of rhetorical genre studies and visual rhetoric informed analysis. In the paper flowsheet, clinicians recorded and viewed patient data in chronologically organised displays that emphasised data interconnections. In the EHR flowsheet, clinicians viewed and recorded individual data points that were largely chronologically and contextually isolated. Clinicians reported that this change resulted in: (i) not knowing the patient's evolving status; (ii) increased cognitive workload, and (iii) loss of clinical reasoning support mechanisms. Understanding how patient data are interconnected is essential to clinical reasoning. The use of EHRs supports this goal because the EHR is a tool for collecting dispersed data; however, these collections often deconstruct data interconnections. Where the paper flowsheet emphasises chronology and interconnectedness, the EHR flowsheet emphasises individual data values that are largely independent of time and other patient data. To prepare trainees to work with EHRs, the ways of thinking and acting that were implicitly learned through the use of paper charts must be made explicit. To support clinical reasoning, medical educators should provide lessons in connectivity – the chronologically framed data interconnections upon which clinicians rely to provide patient care.


Effects of phytoplankton blooms on fluxes and emissions of greenhouse gases in a eutrophic lake.
Lakes are important sources of greenhouse gases (GHGs) to the atmosphere. Factors controlling CO2, CH4 and N2O fluxes include eutrophication and warming, but the integrated influence of climate-warming-driven stratification, oxygen loss and resultant changes in bloom characteristics on GHGs are not well understood. Here we assessed the influence of contrasting meteorological conditions on stratification and phytoplankton bloom composition in a eutrophic lake, and tested for associated changes in GHGs inventories in both the shallow and deep waters, over three seasons (2010-2012). Atmospheric heatwaves had one of the most dramatic effects on GHGs. Indeed, cyanobacterial blooms that developed in response to heatwave events in 2012 enhanced both sedimentary CH4 concentrations (reaching up to 1mM) and emissions to the atmosphere (up to 8 mmol m-2 d-1). That summer, CH4 contributed 52% of the integrated warming potential of GHGs produced in the lake (in CO2 equivalents) as compared to between 34 and 39% in years without cyanobacterial blooms. High CH4 accumulation and subsequent emission in 2012 were preceded by CO2 and N2O consumption and under-saturation at the lake surface (uptakes at -30 mmol m-2 d-1 and -1.6 µmol m-2 d-1, respectively). Fall overturn presented a large efflux of N2O and CH4, particularly from the littoral zone after the cyanobacterial bloom. We provide evidence that, despite cooling observed at depth during hot summers, CH4 emissions increased via stronger stratification and surface warming, resulting in enhanced cyanobacterial biomass deposition and intensified bottom water anoxia. Our results, supported by recent literature reports, suggests a novel interplay between climate change effects on lake hydrodynamics that impacts both bloom characteristics and GHGs production in shallow eutrophic lakes. Given global trends of warming and enrichment, these interactive effects should be considered to more accurately predict the future global role of lakes in GHG emissions.


Sleep, aging, and lifespan in Drosophila.
Epidemiological studies in humans suggest that a decrease in daily sleep duration is associated with reduced lifespan, but this issue remains controversial. Other studies in humans also show that both sleep quantity and sleep quality decrease with age. Drosophila melanogaster is a useful model to study aging and sleep, and inheriting mutations affecting the potassium current Shaker results in flies that sleep less and have a shorter lifespan. However, whether the link between short sleep and reduced longevity exists also in wild-type flies is unknown. Similarly, it is unknown whether such a link depends on sleep amount per se, rather than on other factors such as waking activity. Also, sleep quality has been shown to decrease in old flies, but it remains unclear whether aging-related sleep fragmentation is a generalized phenomenon. We compared 3 short sleeping mutant lines (Hk1, HkY and Hk2) carrying a mutation in Hyperkinetic, which codes for the beta subunit of the Shaker channel, to wild-type siblings throughout their entire lifespan (all flies kept at 20 degrees C). Hk1 and HkY mutants were short sleeping relative to wild-type controls from day 3 after eclosure, and Hk2 flies became short sleepers about two weeks later. All 3 Hk mutant lines had reduced lifespan relative to wild-type flies. Total sleep time showed a trend to increase in all lines with age, but the effect was most pronounced in Hk1 and HkY flies. In both mutant and wild-type lines sleep quality did not decay with age, but the strong preference for sleep at night declined starting in "middle age". Using Cox regression analysis we found that in Hk1 and HkY mutants and their control lines there was a negative relationship between total sleep amount during the first 2 and 4 weeks of age and hazard (individual risk of death), while no association was found in Hk2 flies and their wild-type controls. Hk1 and HkY mutants and their control lines also showed an association between total daily wake activity over the first 2 and 4 weeks of age and hazard. However, when both sleep duration and wake activity were used in the same regression, the effects of activity were much reduced, while most of the sleep effects remained significant. Finally, Hk1 flies and wild-type siblings were also tested at 25 degrees C, and results were similar to those at 20 degrees C. Namely, Hk1 mutants were short sleeping, hyperactive, and short lived relative to controls, and sleep quality in both groups did not decrease with age. Different Hk mutations affect the sleep phenotype, and do so in an age-dependent manner. In 4 of the 6 lines tested sleep associates significantly with lifespan variation even after any effect of activity is removed, but activity does not associate significantly with lifespan after the effects of sleep are removed. Thus, in addition to environmental factors and genetic background, sleep may also affect longevity. Sleep quality does not necessarily decay as flies age, suggesting that aging-related sleep fragmentation may also depend on many factors, including genetic background and rearing conditions.


Prevalence of Fusobacterium necrophorum in tonsils from patients with chronic tonsillitis.
There was a high prevalence of Fusobacterium necrophorum (FN) in patients with chronic tonsillitis in the age group 15-23 years. This indicates that FN might play an important role in the pathogenesis of chronic tonsillitis in this age group, which is also the age group in which chronic or recurrent tonsillitis is most common. The role of FN in patients with acute and chronic tonsillitis is unclear. Thus, this study investigated the occurrence of FN in tonsils of patients with chronic tonsillitis. The aim of the study was to determine the prevalence of FN in patients that underwent tonsillectomy due to chronic tonsillitis. This study also investigated if FN was found at different areas in the tonsils. One hundred and twenty-six consecutive patients undergoing tonsillectomy due to chronic tonsillitis were included from the ENT clinics at Sunderby Hospital and Gällivare Hospital, Sweden. Both children and adults were included to encompass various age groups (age =2-57 years). Culture swabs were taken from three different levels of the tonsils - the surface, the crypts, and the inner core of the tonsils. Selective agar plates for detecting FN were used for culture. Culture was also made for detecting β-hemolytic streptococci, Haemophilus influenzae, and Arcanobacterium. FN was the most common pathogen (19%). The highest prevalence of FN was found in the age group 15-23 years (in 34% of the patients). FN was detected both at the surface and in the core of the tonsils. Furthermore, in the few patients where FN was not detected in all three areas, FN was always detected at the tonsillar surface, in spite of being an anaerobic bacterium. Streptococci group G and C also occurred most frequently (30%) in the same age group as FN (15-23 years), whereas Streptococci group A was more evenly spread among the age groups.


High-throughput variation detection and genotyping using microarrays.
The genetic dissection of complex traits may ultimately require a large number of SNPs to be genotyped in multiple individuals who exhibit phenotypic variation in a trait of interest. Microarray technology can enable rapid genotyping of variation specific to study samples. To facilitate their use, we have developed an automated statistical method (ABACUS) to analyze microarray hybridization data and applied this method to Affymetrix Variation Detection Arrays (VDAs). ABACUS provides a quality score to individual genotypes, allowing investigators to focus their attention on sites that give accurate information. We have applied ABACUS to an experiment encompassing 32 autosomal and eight X-linked genomic regions, each consisting of approximately 50 kb of unique sequence spanning a 100-kb region, in 40 humans. At sufficiently high-quality scores, we are able to read approximately 80% of all sites. To assess the accuracy of SNP detection, 108 of 108 SNPs have been experimentally confirmed; an additional 371 SNPs have been confirmed electronically. To access the accuracy of diploid genotypes at segregating autosomal sites, we confirmed 1515 of 1515 homozygous calls, and 420 of 423 (99.29%) heterozygotes. In replicate experiments, consisting of independent amplification of identical samples followed by hybridization to distinct microarrays of the same design, genotyping is highly repeatable. In an autosomal replicate experiment, 813,295 of 813,295 genotypes are called identically (including 351 heterozygotes); at an X-linked locus in males (haploid), 841,236 of 841,236 sites are called identically.


Breast-feeding and Vitamin D Supplementation Rates in the Ochsner Health System.
Breast-feeding imparts many benefits to both mothers and infants. Because of these numerous recognized benefits, there has been an effort to increase breast-feeding rates nationwide; increasing breast-feeding rates was one of the goals of the U.S. Department of Health and Human Services' Healthy People 2010 initiative. This study examined the breast-feeding rate at the Ochsner Clinic Foundation by conducting a retrospective chart review of patients aged 0-12 months who visited any branch of the Ochsner hospital system. Our results indicate that the rate of initiation of breast-feeding for children followed at the Ochsner Clinic Foundation is 66.3%. However, as breast-feeding rates rise, there is concern that there may be a resurgence of rickets, a disease caused by the deficiency of vitamin D. Currently the American Academy of Pediatrics recommends that exclusively breast-fed infants receive vitamin D supplementation starting within the first 2 months of life. We have therefore initiated a clinical trial to determine whether vitamin D supplementation is required to prevent rickets in breast-fed children. In the course of conducting this study, we have gathered additional data regarding the patterns of breast-feeding and of vitamin D supplementation for babies born at Ochsner.


The Host Immune Response to Tissue-Engineered Organs: Current Problems and Future Directions.
As the global health burden of chronic disease increases, end-stage organ failure has become a costly and intractable problem. De novo organ creation is one of the long-term goals of the medical community. One of the promising avenues is that of tissue engineering: the use of biomaterials to create cells, structures, or even whole organs. Tissue engineering has emerged from its nascent stage, with several proof-of-principle trials performed across various tissue types. As tissue engineering moves from the realm of case trials to broader clinical study, three major questions have emerged: (1) Can the production of biological scaffolds be scaled up accordingly to meet current and future demands without generating an unfavorable immune response? (2) Are biological scaffolds plus or minus the inclusion of cells replaced by scar tissue or native functional tissue? (3) Can tissue-engineered organs be grown in children and adolescents given the different immune profiles of children? In this review, we highlight current research in the immunological response to tissue-engineered biomaterials, cells, and whole organs and address the answers to these questions.


A new human lung adenocarcinoma cell line harboring the EML4-ALK fusion gene.
The echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was identified in patients with non-small cell lung cancer. To the best of our knowledge, there are only three cell lines harboring the EML4-ALK fusion gene, which have contributed to the development of therapeutic strategies. Therefore, we tried to establish a new lung cancer cell line harboring EML4-ALK. A 61-year-old Japanese female presented with chest discomfort. She was diagnosed with left lung adenocarcinoma with T4N3M1 Stage IV. Although she was treated with chemotherapy, her disease progressed with massive pleural effusion. Because the EML4-ALK rearrangement was found in a biopsied specimen using fluorescence in situ hybridization, she was treated with crizotinib. She did well for 3 months. Tumor cells were obtained from the malignant pleural effusion before treatment with crizotinib. Cells continued to proliferate substantially for several weeks. The cell line was designated ABC-11. The EML4-ALK fusion protein and genes were identified in ABC-11 cells using fluorescence in situ hybridization and immunohistochemistry, respectively. ABC-11 cells were sensitive to crizotinib and next-generation ALK inhibitors (ceritinib and AP26113), as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Phosphorylated ALK protein and its downstream signaling were suppressed by treatment with crizotinib in western blotting. Furthermore, we could transplant ABC-11 cells subcutaneously into BALB/c nu/nu mice. We successfully established a new lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. This cell line could contribute to future research of EML4-ALK-positive lung cancer both in vivo and in vitro.


Cooperative coordination as a social behavior : Experiments with an animal model.
Coordinating behavior is widespread in contexts that include courtship, aggression, and cooperation for shared outcomes. The social significance of cooperative coordination (CC) is usually downplayed by learning theorists, evolutionary biologists, and game theorists in favor of an individual behavior → outcome perspective predicated on maximizing payoffs for all participants. To more closely model CC as it occurs under free-ranging conditions, pairs of rats were rewarded for coordinated shuttling within a shared chamber with unrestricted social interaction. Results show that animals learned to work together with sensitivity to the task and type of partner. Moreover, social interaction and coordination influenced both consumption of the reward solution immediately following a session and preference for cooperation, suggesting that affective states and incentives related to cooperation extend beyond the outcomes obtained. These results support field studies by showing not only how cooperation is performed but also the importance of considering how the behavior of cooperating affects outcomes and preference for cooperating.


Neuropsychological performance 10 years after immunization in infancy with thimerosal-containing vaccines.
Thimerosal, a mercury compound used as a preservative in vaccines administered during infancy, has been suspected to affect neuropsychological development. We compared the neuropsychological performance, 10 years after vaccination, of 2 groups of children exposed randomly to different amounts of thimerosal through immunization. Children who were enrolled in an efficacy trial of pertussis vaccines in 1992-1993 were contacted in 2003. Two groups of children were identified, according to thimerosal content in vaccines assigned randomly in the first year of life (cumulative ethylmercury intake of 62.5 or 137.5 microg), and were compared with respect to neuropsychological outcomes. Eleven standardized neuropsychological tests, for a total of 24 outcomes, were administered to children during school hours. Mean scores of neuropsychological tests in the domains of memory and learning, attention, executive functions, visuospatial functions, language, and motor skills were compared according to thimerosal exposure and gender. Standard regression coefficients obtained through multivariate linear regression analyses were used as a measure of effect. Nearly 70% of the invited subjects participated in the neuropsychological assessment (N = 1403). Among the 24 neuropsychological outcomes that were evaluated, only 2 were significantly associated with thimerosal exposure. Girls with higher thimerosal intake had lower mean scores in the finger-tapping test with the dominant hand and in the Boston Naming Test. Given the large number of statistical comparisons performed, the few associations found between thimerosal exposure and neuropsychological development might be attributable to chance. The associations found, although statistically significant, were based on small differences in mean test scores, and their clinical relevance remains to be determined.


Inhibition of soluble epoxide hydrolase preserves cardiomyocytes: role of STAT3 signaling.
Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs), primarily 14,15-EET. EETs are derived from arachidonic acid via P-450 epoxygenases and are cardioprotective. We tested the hypothesis that sEH deficiency and pharmacological inhibition elicit tolerance to ischemia via EET-mediated STAT3 signaling in vitro and in vivo. In addition, the relevance of single nucleotide polymorphisms (SNPs) of EPHX2 (the gene encoding sEH) on tolerance to oxygen and glucose deprivation and reoxygenation and glucose repletion (OGD/RGR) was assessed in male C57BL\6J (WT) or sEH knockout (sEHKO) cardiomyocytes by using transactivator of transcription (TAT)-mediated transduction with sEH mutant proteins. Cell death and hydrolase activity was lower in Arg287Gln EPHX2 mutants vs. nontransduced controls. Excess 14,15-EET and SEH inhibition did not improve cell survival in Arg287Gln mutants. In WT cells, the putative EET receptor antagonist, 14,15-EEZE, abolished the effect of 14,15-EET and sEH inhibition. Cotreatment with 14,15-EET and SEH inhibition did not provide increased protection. In vitro, STAT3 inhibition blocked 14,15-EET cytoprotection, but not the effect of SEH inhibition. However, STAT3 small interfering RNA (siRNA) abolished cytoprotection by 14,15-EET and sEH inhibition, but cells pretreated with JAK2 siRNA remained protected. In vivo, STAT3 inhibition abolished 14,15-EET-mediated infarct size reduction. In summary, the Arg287Gln mutation is associated with improved tolerance against ischemia in vitro, and inhibition of sEH preserves cardiomyocyte viability following OGD/RGR via an EET-dependent mechanism. In vivo and in vitro, 14,15-EET-mediated protection is mediated in part by STAT3.


Low birth weight in Mexico: new evidence from a multi-site postpartum hospital survey.
To identify factors related to cases of low birth weight among a sample of Mexican women. The present analysis utilizes data from a post partum survey of 565 women implemented in eight different social security hospitals in western Mexico during 2001. Women giving birth to low weight infants (2.5 kgs) were oversampled and make up half of the sample. A series of logistic regression equations are presented that estimate the risk of low birth weight. Study findings indicate that, although behavioral factors appear to be highly significant in predicting the odds of low birth weight, socioeconomic and sociodemographic factors were found to be important in determining utilization of prenatal care. The key role of behavioral characteristics in determining low birth weight risk and the role of socioeconomic and sociodemographic factors in determining prenatal care usage highlights the need to improve prenatal care utilization by disadvantaged populations.


Role of Massed Versus Distributed Practice in Learning Novel Foreign Language Utterances.
The current study compared the role of massed versus distributed practice in learning novel foreign language utterances. Fifty healthy native English-speaking participants were randomly assigned to either massed or distributed practice groups. All participants practiced eight novel French utterances 25 times each for a total of 200 times, with the spacing of practice sessions differing between the two groups. Both the groups completed an immediate retention as well as a delayed retention test. Participants' learning was evaluated based on phonetic accuracy and naturalness of the French utterances. The findings revealed that participants involved in distributed practice demonstrated better learning over participants involved in massed practice. Future research should aim to extrapolate these findings in treating speech disorders.


Seroprevalence following the second wave of Pandemic 2009 H1N1 influenza in Pittsburgh, PA, USA.
In April 2009, a new pandemic strain of influenza infected thousands of persons in Mexico and the United States and spread rapidly worldwide. During the ensuing summer months, cases ebbed in the Northern Hemisphere while the Southern Hemisphere experienced a typical influenza season dominated by the novel strain. In the fall, a second wave of pandemic H1N1 swept through the United States, peaking in most parts of the country by mid October and returning to baseline levels by early December. The objective was to determine the seroprevalence of antibodies against the pandemic 2009 H1N1 influenza strain by decade of birth among Pittsburgh-area residents. Anonymous blood samples were obtained from clinical laboratories and categorized by decade of birth from 1920-2009. Using hemagglutination-inhibition assays, approximately 100 samples per decade (n = 846) were tested from blood samples drawn on hospital and clinic patients in mid-November and early December 2009. Age specific seroprevalences against pandemic H1N1 (A/California/7/2009) were measured and compared to seroprevalences against H1N1 strains that had previously circulated in the population in 2007, 1957, and 1918. (A/Brisbane/59/2007, A/Denver/1/1957, and A/South Carolina/1/1918). Stored serum samples from healthy, young adults from 2008 were used as a control group (n = 100). Seroprevalences against pandemic 2009 H1N1 influenza varied by age group, with children age 10-19 years having the highest seroprevalence (45%), and persons age 70-79 years having the lowest (5%). The baseline seroprevalence among control samples from 18-24 year-olds was 6%. Overall seroprevalence against pandemic H1N1 across all age groups was approximately 21%. After the peak of the second wave of 2009 H1N1, HAI seroprevalence results suggest that 21% of persons in the Pittsburgh area had become infected and developed immunity. Extrapolating to the entire US population, we estimate that at least 63 million persons became infected in 2009. As was observed among clinical cases, this sero-epidemiological study revealed highest infection rates among school-age children.


Twelve months fixed duration WHO multidrug therapy for multibacillary leprosy: incidence of relapses in Agra field based cohort study.
The reported low relapse rates after 24 months multidrug therapy (MDT) for multibacillary leprosy (MB) led to the recommendation of reducing duration of therapy to 12 months. However, only a few reports exist on long term follow up data after 12 months fixed duration therapy (FDT). The present study was done to assess the incidence of relapse in MB leprosy patients after 12 months treatment. The leprosy patients detected in field surveys during 2001-2006 in Agra district, Uttar Pradesh, India, were put on WHO-MDT and followed up for treatment completion, relapse, reactions and development of disability. The assessment was done clinically by following up the patients until January 2011. Data collected were analyzed for risk and survival analysis. The incidence of relapse was found to be 1.97/100 person years of follow up. The incidence of relapse by age (34 yr vs >34 yr), sex (male vs female), delay in detection (<36 months vs >36 months) and smear status (smear +ve vs -ve) was not found to be significantly different but patients with no nerve involvement were observed to have significantly higher relapses than those with three or more nerve involvement (P<0.05). Similarly, borderline-borderline and BB with reaction (BB/BBR) patients were observed to have significantly high relapses than among those with borderline tuberculoid or BT with reaction (BT/BTR) or borderline lipromatous/lepromatous/neuritic (BL/LL/N) type of leprosy (P<0.01). From the observations in the study, it can be suggested that relapses occur in 12 months FDT and almost as much as reported in 24 months FDT for MB leprosy. Although, early relapses may be due to insufficient treatment, late relapses may be due to persistent dormant mycobacteria. However, a study relating to immunological response of treatment and change in immunological profile relating to the occurrence of relapses and its clinical correlates may suggest better information on causes of relapses.


Altered biomarkers of mucosal immunity and reduced vaginal Lactobacillus concentrations in sexually active female adolescents.
Genital secretions collected from adult women exhibit in vitro activity against herpes simplex virus (HSV) and Escherichia coli (E. coli), but prior studies have not investigated this endogenous antimicrobial activity or its mediators in adolescent females. Anti-HSV and anti-E.coli activity were quantified from cervicovaginal lavage (CVL) specimens collected from 20 sexually active adolescent females (15-18 years). Soluble immune mediators that may influence this activity were measured in CVL, and concentrations of Lactobacillus jensenii and crispatus were quantified by PCR from vaginal swabs. Results for adolescents were compared to those obtained from 54 healthy, premenopausal adult women. Relative to specimens collected from adults, CVL collected from adolescent subjects had significantly reduced activity against E. coli and diminished concentrations of protein, IgG, and IgA but significantly increased anti-HSV activity and concentrations of interleukin (IL)-1α, IL-6 and IL-1 receptor antagonist. Vaginal swabs collected from adolescent subjects had comparable concentrations of L. crispatus but significantly reduced concentrations of L. jensenii, relative to adult swabs. Biomarkers of genital mucosal innate immunity may differ substantially between sexually active adolescents and adult women. These findings warrant further study and may have significant implications for prevention of sexually transmitted infections in adolescent females.


Professional values and reported behaviours of doctors in the USA and UK: quantitative survey.
BACKGROUND The authors aimed to determine US and UK doctors' professional values and reported behaviours, and the extent to which these vary with the context of care. METHOD 1891 US and 1078 UK doctors completed the survey (64.4% and 40.3% response rate respectively). Multivariate logistic regression was used to compare responses to identical questions in the two surveys. RESULTS UK doctors were more likely to have developed practice guidelines (82.8% UK vs 49.6% US, p<0.001) and to have taken part in a formal medical error-reduction programme (70.9% UK vs 55.7% US, p<0.001). US doctors were more likely to agree about the need for periodic recertification (completely agree 23.4% UK vs 53.9% US, p<0.001). Nearly a fifth of doctors had direct experience of an impaired or incompetent colleague in the previous 3 years. Where the doctor had not reported the colleague to relevant authorities, reasons included thinking that someone else was taking care of the problem, believing that nothing would happen as a result, or fear of retribution. UK doctors were more likely than US doctors to agree that significant medical errors should always be disclosed to patients. More US doctors reported that they had not disclosed an error to a patient because they were afraid of being sued. DISCUSSION The context of care may influence both how professional values are expressed and the extent to which behaviours are in line with stated values. Doctors have an important responsibility to develop their healthcare systems in ways which will support good professional behaviour.


A closer look at the Medicare part D low-income benchmark premium: how low can it go?
This issue brief explains how the Medicare Part D low income benchmark premium is calculated, what factors influence the level of the low-income benchmark premium in any given year, and the implications of the benchmark amount for Medicare drug plans and beneficiaries as it changes from year to year. The paper provides a simplified, two-year example of how the low-income benchmark premium is calculated in order to illustrate the key factors that influence it.


The role of nurse practitioners in hypertension care.
1. Two groups of hypertensive patients, randomly assigned to either physician or nurse practitioner care, were compared, after two years of follow up, with respect to diastolic blood pressure reduction and utilization and costs of medical services. In addition, satisfaction with hypertension are was evaluated. 2. There was no statistical difference in mean diastolic blood pressure reduction between the physician and nurse practitioner groups. 3. Patients in the nurse practitioner group made more visits for hypertension care than those in the physician group; thus, even though the cost per nurse practitioner visit was lower than the cost per physician visit, the total annual cost of care per patient was higher in the nurse practitioner group. 4. Patients followed by nurse practitioners were very satisfied with their care. 5. Nurse practitioners provide excellent hypertension care and thereby save valuable physician time.


Turn-amplitude analysis as a diagnostic test for myofascial syndrome in patients with chronic pelvic pain.
Myofascial pain syndrome of the pelvic floor (MPSPF) is a common disease in the context of chronic pelvic pain (CPP); however, there is currently no gold-standard test to diagnose it. To validate the turns-amplitude analysis (TAA) as a diagnostic test for MPSPF in patients with CPP. A case-control study was performed, and patients were consecutively sampled within a specified period of time. A total of 128 patients were included: 64 patients with CPP (32 men and 32 women) and 64 control patients (32 men and 32 women). The same operator conducted all tests. Electromyography of the TAA is based on the collection of motor unit potentials that measure the number of changes in the signal and the mean amplitude of the changes. The electromyogram transfers the data to a graphical point cloud, which enables the patient's results to be compared with the results of the healthy subjects. In patients and control subjects, the sensitivity and specificity of the proposed diagnostic test showed a marked clinical significance: the sensitivity was 83%, and the specificity was 100%. A positive predictive value of 1 (95% CI 1 to 1) and a negative predictive value of 0.85 (95% CI 0.77 to 0.93) were observed. TAA is a reliable diagnostic test to detect MPSPF. Further studies are needed to reproduce these results.


DHEA promotes osteoblast differentiation by regulating the expression of osteoblast-related genes and Foxp3(+) regulatory T cells.
Several studies have reported that dehydroepiandrosterone (DHEA) promotes osteoblast proliferation and inhibits osteoblast apoptosis and that DHEA inhibits osteoclast maturation. However, whether DHEA regulates osteoblast differentiation remains unclear. The present study first examined the effect of DHEA on bone morphology in vivo. DHEA was found to increase bone volume (BV), bone mineral density (BMD), and the number of trabeculae in bone (Th.N) and it was found to decrease trabecular spacing in bone (Th.sp) in ovariectomized (OVX) mice. Next, the effect of DHEA on osteoblast differentiation was examined in vitro and osteoblastogenesis-related marker genes, such as Runx2, Osterix, Collagen1, and Osteocalcin, were also detected. DHEA increased osteoblast production in mesenchymal stem cells (MSCs) cultured in osteoblastogenic medium, and DHEA increased the expression of Runx2 and osterix, thereby increasing the expression of osteocalcin and collagen1. Immune cells and bone interact, so changes in immune cells were detected in vivo. DHEA increased the number of Foxp3(+) regulatory T cells (Tregs) in the spleen but it did not affect CTLA-4 or IL-10. When MSCs were treated with DHEA in the presence of Tregs, alkaline phosphatase (ALP) activity increased. Osteoblasts and adipocytes are both generated by MSCs. If osteoblast differentiation increases, adipocyte differentiation will decrease, and the reverse also holds true. DHEA was found to increase the number of adipocytes in osteoblastogenic medium but it had no effect on the number of adipocytes and expression of PPARγ mRNA in adipogenic medium. This finding suggests that osteoblasts may be involved in adipocyte production. In conclusion, the current results suggest that DHEA can improve postmenopausal osteoporosis (PMO) by up-regulating osteoblast differentiation via the up-regulation of the expression of osteoblastogenesis-related genes and via an increase in Foxp3(+) Tregs.


How many and which ant species are being accidentally moved around the world?
Human transportation facilitates the dispersal of exotic ants, but few studies have quantified the magnitude and geography of these movements. We used several non-parametric indexes to estimate the number of species successfully introduced to or established in new regions. We also compared their source biogeographic realms to assess the importance of the geographical origin in determining the likelihood of establishment after introduction. Data on exotic ants derive from studies of three temperate regions. Our results suggest that the numbers of introduced or established ants may be much larger than the numbers so far documented. Ants introduced or established in new regions tend to arrive from the same or neighbouring realms, as would be expected if exotic species tend to match climates and if arrival/establishment is dependent upon higher trade rates from neighbouring countries.


A decade of viral mutations and associated drug resistance in a population of HIV-1+ Puerto Ricans: 2002-2011.
Puerto Rico has one of the highest rates of HIV/AIDS seen for any US state or territory, and antiretroviral therapy has been a mainstay of efforts to mitigate the HIV/AIDS public health burden on the island. We studied the evolutionary dynamics of HIV-1 mutation and antiretroviral drug resistance in Puerto Rico by monitoring the population frequency of resistance-associated mutations from 2002 to 2011. Whole blood samples from 4,475 patients were analyzed using the TRUGENE HIV-1 Genotyping Kit and OpenGene DNA Sequencing System in the Immunoretrovirus Research Laboratory at Universidad Central del Caribe. Results show that 64.0% of female and 62.9% of male patients had HIV-1 mutations that confer resistance to at least one antiretroviral medication. L63P and M184V were the dominant mutations observed for the protease (PRO) and reverse transcriptase (RT) encoding genes, respectively. Specific resistance mutations, along with their associated drug resistance profiles, can be seen to form temporal clusters that reveal a steadily changing landscape of resistance trends over time. Both women and men showed resistance mutations for an average of 4.8 drugs over the 10-year period, further underscoring the strong selective pressure exerted by antiretrovirals along with the rapid adaptive response of HIV. Nevertheless, both female and male patients showed a precipitous decrease for overall drug resistance, and for PRO mutations in particular, over the entire course of the study, with the most rapid decrease in frequency seen after 2006. The reduced HIV-1 mutation and drug resistance trends that we observed are consistent with previous reports from multi-year studies conducted around the world. Reduced resistance can be attributed to the use of more efficacious antiretroviral drug therapy, including the introduction of multi-drug combination therapies, which limited the ability of the virus to mount rapid adaptive responses to antiretroviral selection pressure.


Antagonistic Interactions and Clutch-Dependent Sensitivity Induce Variable Responses to Ocean Acidification and Warming in Squid (Doryteuthis pealeii) Embryos and Paralarvae.
Ocean acidification (OA) and warming seas are significant concerns for coastal systems and species. The Atlantic longfin squid, Doryteuthis pealeii, a core component of the Northwest Atlantic trophic web, has demonstrated impacts, such as reduced growth and delayed development, under high chronic exposure to acidification (2200 ppm), but the combined effects of OA and warming have not been explored in this species. In this study, D. pealeii egg capsules were reared under a combination of several acidification levels (400, 2200, and 3500 ppm) and temperatures (20 and 27°C). Hatchlings were measured for a range of metrics [dorsal mantle length (DML), yolk sac volume (YV), malformation, and hatching success] in three trials over the 2016 breeding season (May - October). Although notable resistance to stressors was seen, highlighting variability within and between clutches, reduced DML and malformation of the embryos occurred at the highest OA exposure. Surprisingly, increased temperatures did not appear to exacerbate OA impacts, although responses were variable. Time to hatching, which increased with acidification, decreased much more drastically under warming and, further, decreased or removed delays caused by acidification. Hatching success, while variable by clutch, showed consistent patterns of greater late stage loss of embryos under acidification and greater early stage loss under warming, highlighting the potential difference in timing between these stressors for this system, i.e., that acidification stress builds up and causes impacts over time within the egg capsule as the embryos grow and respire. High OA-exposed hatchlings from the warmer conditions often showed reduced impacts compared to those reared in ambient temperatures. This may be due to the increased developmental rate and subsequently reduced OA exposure time of embryos in the higher temperature treatment. These results indicate a substantive potential plasticity to multiple stressors during the embryonic development of this species of squid, but do not predict how this species would fare under these future ocean scenarios.


Tie2-expressing monocytes (TEMs): novel targets and vehicles of anticancer therapy?
There is a growing interest in understanding the complex interactions between bone marrow-derived myeloid-lineage cells and angiogenesis in tumors. Such interest has been revived recently by the observation that tumor-infiltrating myeloid cells convey proangiogenic programs that can counteract the activity of antiangiogenic drugs in mouse tumor models. Among myeloid cells, Tie2-expressing monocytes (TEMs) appear to have nonredundant function in promoting tumor angiogenesis and growth in mouse models. The identification and functional characterization of TEMs in mice and humans may provide novel molecular targets for anticancer therapy. Moreover, TEMs may be exploited to deliver antitumor drugs specifically to the tumor microenvironment.


Occupational and environmental medicine in a family medicine residency.
Well-rounded instruction in occupational medicine as part of family medicine residency training is feasible through a program that balances a longitudinal curriculum of monthly occupational and environmental medicine (OEM) lectures, community-based OEM patient care, and worksite assessment. Such training would help equip family medicine residents to integrate occupational medicine into their practices, which, in light of a shortage of board-certified practitioners in OEM, would help fill community needs. The Intern-Resident Training Committee of Carson City Hospital in rural Michigan established both learner and institutional goals and objectives for such a program of instruction. A learner-needs assessment found appreciable interest among the residents for occupational medicine training. In addition, results of a survey of the occupational health community suggested there is inadequate coverage of OEM in medical schools and residencies. Furthermore, a focus group of occupational health managers revealed that clarity of communication and standardization of reporting were paramount concerns. Instruments for standardized OEM history and for OEM case management were developed for use within the residency continuity clinic. The curriculum was implemented with a variety of teaching strategies, including worksite assessment. Practice-based, case-oriented instruction was subsequently phased into the program as residents assumed responsibility for managing cases under the supervision of family medicine preceptors knowledgeable in OEM. An occupational medicine rotation was developed that included focused clinical exposure to OEM patients and studies that would lead to eligibility for a certificate of additional qualification in occupational medicine. Learner evaluations included chart reviews and patient satisfaction surveys. Program evaluations included interviews with occupational health managers. The residents were judged by their preceptors to have performed well. The responses of the health managers and the patients were positive. This program in occupational medicine was found to be educationally sound with demonstrated community benefit and patient satisfaction. Further, it is cost-effective, requiring no external funding.


Characterizing cell-cell interactions induced spatial organization of cell phenotypes: application to density-dependent protein nucleocytoplasmic distribution.
Cell-cell interactions play an important role in spatial organization (pattern formation) during the development of multicellular organisms. An understanding of these biological roles requires identifying cell phenotypes that are regulated by cell-cell interactions and characterizing the spatial organizations of the phenotypes. However, conventional methods for assaying cell-cell interactions are mainly applicable at a cell population level. These measures are incapable of elucidating the spatial organizations of the phenotypes, resulting in an incomplete view of cell-cell interactions. To overcome this issue, we developed an automated image-based method to investigate cell-cell interactions based on spatial localizations of cells. We demonstrated this method in cultured cells using cell density-dependent nucleocytoplasmic distribution of β-catenin and aryl hydrocarbon receptor as the phenotype. This novel method was validated by comparing with a conventional population-based method, and proved to be more sensitive and reliable. The application of the method characterized how the phenotypes were spatially organized in a population of cultured cells. We further showed that the spatial organization was governed by cell density and was protein-specific. This automated method is very simple, and will be applicable to study cell-cell interactions in different systems from prokaryotic colonies to multicellular organisms. We envision that the ability to extract and interpret how cell-cell interactions determine the spatial organization of a cell phenotype will provide new insights into biology that may be missed by traditional population-averaged studies.


The Reliability of Swipe/Wipe Classification and Directionality Determination Methods in Bloodstain Pattern Analysis.
Swipe and wipe are types of transfer patterns commonly encountered at bloodied scenes. So far, there have been little published data on the reliability of evaluating these patterns. In this study, 36 bloodstain patterns were randomly assigned to 12 analysts in three separate trials, and the analysts were required to evaluate the pattern type and directionality. The results revealed that correct classifications of patterns type were problematic, with an overall error rate of 32%. Wipes created from wet bloodstains were the most difficult to identify due to the absence of signs of alteration. The directionality of swipes made with a gloved finger had a 100% success rate; however, for swipes made with cloth, the analysts mistook the direction in nearly every case, which is of significant concern, considering these are common patterns at crime scenes. This study suggested there is a need for revising the current protocols for interpretation of these pattern types.


Experimental validation of an inverse fluorescence Monte Carlo model to extract concentrations of metabolically relevant fluorophores from turbid phantoms and a murine tumor model.
An inverse Monte Carlo based model has been developed to extract intrinsic fluorescence from turbid media. The goal of this work was to experimentally validate the model to extract intrinsic fluorescence of three biologically meaningful fluorophores related to metabolism from turbid media containing absorbers and scatterers. Experimental studies were first carried out on tissue-mimicking phantoms that contained individual fluorophores and their combinations, across multiple absorption, scattering, and fluorophore concentrations. The model was then tested in a murine tumor model to determine both the kinetics of fluorophore uptake as well as overall tissue fluorophore concentration through extraction of the intrinsic fluorescence of an exogenous contrast agent that reports on glucose uptake. Results show the model can be used to recover the true intrinsic fluorescence spectrum with high accuracy (R(2)=0.988) as well as accurately compute fluorophore concentration in both single and multiple fluorophores phantoms when appropriate calibration standards are available. In the murine tumor, the model-corrected intrinsic fluorescence could be used to differentiate drug dose injections between different groups. A strong linear correlation was observed between the extracted intrinsic fluorescence intensity and injected drug dose, compared with the distorted turbid tissue fluorescence.


Pandemic potential of a strain of influenza A (H1N1): early findings.
A novel influenza A (H1N1) virus has spread rapidly across the globe. Judging its pandemic potential is difficult with limited data, but nevertheless essential to inform appropriate health responses. By analyzing the outbreak in Mexico, early data on international spread, and viral genetic diversity, we make an early assessment of transmissibility and severity. Our estimates suggest that 23,000 (range 6000 to 32,000) individuals had been infected in Mexico by late April, giving an estimated case fatality ratio (CFR) of 0.4% (range: 0.3 to 1.8%) based on confirmed and suspected deaths reported to that time. In a community outbreak in the small community of La Gloria, Veracruz, no deaths were attributed to infection, giving an upper 95% bound on CFR of 0.6%. Thus, although substantial uncertainty remains, clinical severity appears less than that seen in the 1918 influenza pandemic but comparable with that seen in the 1957 pandemic. Clinical attack rates in children in La Gloria were twice that in adults (<15 years of age: 61%; >/=15 years: 29%). Three different epidemiological analyses gave basic reproduction number (R0) estimates in the range of 1.4 to 1.6, whereas a genetic analysis gave a central estimate of 1.2. This range of values is consistent with 14 to 73 generations of human-to-human transmission having occurred in Mexico to late April. Transmissibility is therefore substantially higher than that of seasonal flu, and comparable with lower estimates of R0 obtained from previous influenza pandemics.


Is there sufficient evidence to support the long-term efficacy of mineral trioxide aggregate (MTA) for endodontic therapy in primary teeth?
Several papers have been published to illustrate the effectiveness of mineral trioxide aggregate (MTA) as a pulpotomy medicament. Most of these reports do not offer a critical assessment on the data quality. Therefore, this review evaluated whether the currently available evidence is of an appropriate quality to support the long-term effectiveness of MTA as a pulpotomy medicament in primary molars using a standardized assessment criterion. A comprehensive literature search of human clinical outcome studies, which employed MTA as a pulpotomy medicament in primary teeth, was conducted using the MEDLINE database. Two independent observers rated these articles using the standardized assessment criteria. Furthermore, based on the initial sample mentioned in the individual studies and the sample included for the final analysis, the drop-out rates were calculated. Twenty-two studies were included for quality assessment with an excellent interobserver agreement. None of the 22 studies obtained grade A, four studies attained grade B1, five were graded B2 and 13 received grade C. Based on the assessment criteria employed, there was no evidence that MTA was better than present materials and techniques as a pulpotomy medicament. Furthermore, given the low quality of data, it is highly desirable to establish standard requisites for conducting and reporting on pulp therapy studies in primary teeth so as to benefit both researchers and clinicians to produce high-quality studies that are comparable and to prevent the misuse of clinical material and resources.