A neural basis for the effect of candidate appearance on election outcomes.
Election outcomes correlate with judgments based on a candidate's visual appearance, suggesting that the attributions viewers make based on appearance, so-called thin-slice judgments, influence voting. Yet, it is not known whether the effect of appearance on voting is more strongly influenced by positive or negative attributions, nor which neural mechanisms subserve this effect. We conducted two independent brain imaging studies to address this question. In Study 1, images of losing candidates elicited greater activation in the insula and ventral anterior cingulate than images of winning candidates. Winning candidates elicited no differential activation at all. This suggests that negative attributions from appearance exert greater influence on voting than do positive. We further tested this hypothesis in Study 2 by asking a separate group of participants to judge which unfamiliar candidate in a pair looked more attractive, competent, deceitful and threatening. When negative attribution processing was enhanced (specifically, under judgment of threat), images of losing candidates again elicited greater activation in the insula and ventral anterior cingulate. Together, these findings support the view that negative attributions play a critical role in mediating the effects of appearance on voter decisions, an effect that may be of special importance when other information is absent.


Mucosal IL-12 inhibits airway reactivity to methacholine and respiratory failure in murine asthma.
The worldwide incidence, prevalence, and fatality rates from asthma are increasing despite currently available therapeutic modalities. Systemic administration of interleukin (IL)-12 has been shown to inhibit airway reactivity in murine models of asthma, but the required dosage is high and may be toxic. This study tested the hypothesis that IL-12 administered directly into the lungs is more effective in inhibiting airway reactivity than systemically administered IL-12, allowing lower doses to be used. A low dose (10 ng) of IL-12 was delivered either intratracheally (mucosal delivery) or intraperitoneally (systemic delivery) at the time of ragweed (RW) challenge in mice sensitized to RW. Basal airway resistance and airway reactivity to methacholine were measured 3 days after RW challenge. Compared to phosphate-buffered saline (PBS) challenge of RW sensitized mice, RW challenge increased basal resistance and the slope of the methacholine dose-response curve. Methacholine challenge of RW-challenged mice also induced premature respiratory failure (respiratory rate < 150/min, tidal volume < 0.15 mL) in some animals. Administration of mucosal or systemic IL-12 at the time of RW challenge decreased basal airway resistance. However, only mucosal IL-12 decreased airway reactivity and inhibited respiratory failure during methacholine challenge. These findings indicate that mucosal delivery of a low dose of IL-12 is more effective than systemic IL-12 in inhibiting airway reactivity and respiratory failure in a mouse model of asthma.


Effectiveness of small- and large-scale Nature-Based Solutions for flood mitigation: The case of Ayutthaya, Thailand.
There is growing evidence that traditional response to floods and flood-related disaster is no longer achieving desirable results. Nature-Based Solutions (NBS) represent a relatively new response towards disaster risk reduction, water security, and resilience to climate change, which has a potential to be more effective and sustainable than traditional measures. However, in practice, these measures are still being applied at a slow rate while traditional grey infrastructure remains as a preferred choice. This can be attributed to several barriers which range from political and governance to social and technological/technical. More generally, there is a lack of sufficient knowledge base to accelerate their wider acceptance and uptake. The present work provides contribution in this direction and addresses the question of effectiveness of different types of NBS (i.e., small- and large-scale NBS) and their hybrid combinations with grey infrastructure. The work has been applied on the case of Ayutthaya, Thailand. The results suggest that the effectiveness of small-scale NBS is limited to smaller rainfall events whereas the larger (or extreme) events necessitate combinations of different kinds of measures with different scales of implementation (i.e., hybrid measures).


Clinical impact of molecular genetic diagnosis, genetic counseling, and management of hereditary cancer. Part I: Studies of cancer in families.
Hereditary cancer represents approximately 5-10% of the total cancer burden and may account for 60,000 to 120,000 new cancer occurrences this year in the United States. New developments in molecular genetics and the cloning of cancer-prone genes have intensely fueled interest in dealing with hereditary forms of cancer. The authors provide an algorithm that depicts the process for the identification, study, and DNA-based genetic counseling of families being investigated under a research proposal at the Hereditary Cancer Institute of Creighton University School of Medicine. They have studied 56 hereditary nonpolyposis colorectal carcinoma families; in 18 of them, associated genomic mutations have been identified in affected members. DNA-based genetic counseling has been provided for seven of these families. The authors have also evaluated 131 hereditary breast-ovarian carcinoma families. BRCA1 and BRCA2 mutation searches have been performed for 76 of these families; BRCA1 mutations were found in 38 families and BRCA2 mutations in 9. The study of cancer-prone families is a powerful approach to cancer control, particularly when the germ-line mutation is identified in the family and individuals at high risk can be tested, once they provide informed consent, and receive DNA-based genetic counseling. Discovery of the germ-line mutation for cancer proneness provides an unparalleled opportunity to predict patients' life-time risk for cancer of specific anatomic sites, inclusive of a pattern of multiple primaries. Surveillance and management protocols, when melded to the particular syndrome's natural history, can be life-saving.


Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity.
Apoptosis can be triggered by members of the Bcl-2 protein family, such as Bim, that share only the BH3 domain with this family. Gene targeting in mice revealed important physiological roles for Bim. Lymphoid and myeloid cells accumulated, T cell development was perturbed, and most older mice accumulated plasma cells and succumbed to autoimmune kidney disease. Lymphocytes were refractory to apoptotic stimuli such as cytokine deprivation, calcium ion flux, and microtubule perturbation but not to others. Thus, Bim is required for hematopoietic homeostasis and as a barrier to autoimmunity. Moreover, particular death stimuli appear to activate apoptosis through distinct BH3-only proteins.


Study of Urine Composition of Patients With Recurrent Nephrolithiasis in Lorestan, Iran.
Nephrolithiasis is one of the most common urinary tract diseases. After the first episode of urinary calculus, the risk of recurrence is nearly 40% to 50% at 5 years. Nephrolithiasis is a systemic disease that is associated with some metabolic disorders. This study aimed to provide a picture of the frequency of metabolic abnormalities in patients with nephrolithiasis from west part of Iran. Patients with recurrent urinary tract calculi referred to the Nephrology-Urology Clinics in Khorramabad city were recruited. After collection of demographic data of all the patients, 24-hour urine and blood samples were taken to measure biochemical factors. Of the 232 participants, 125 were males and 107 were females. Hyperoxaluria was seen in 93 (40.1%) of the participants, hypercalciuria in 55 (23.7%), hypocitraturia in 58 (25%), and hyperuricosuria in 33 (14.9%). Hyperoxaluria in the males was significantly more frequent than in the female patients. There were no significant differences between the two groups in other urinary metabolic disorders. Patients with nephrolithiasis from Lorestan province may have metabolic characteristics varying from those of regions; ethnicity may be a possible reason. Variation of dietary regimens, such as the amount of meat or vegetable in the diet that can change oxalate, calcium, or citrate of urine, might have influenced the results. Time of sampling is another factor. Population-specific studies are helpful to health care providers for preventive planning for nephrolithiasis.


Adaptive loss of ultraviolet-sensitive/violet-sensitive (UVS/VS) cone opsin in the blind mole rat (Spalax ehrenbergi).
In previous studies, fully functional rod and long-wavelength-sensitive (LWS) cone photopigments have been isolated from the eye of the subterranean blind mole rat (Spalax ehrenbergi superspecies). Spalax possesses subcutaneous atrophied eyes and lacks any ability to respond to visual images. By contrast this animal retains the ability to entrain circadian rhythms of locomotor behaviour to environmental light cues. As this is the only known function of the eye, the rod and LWS photopigments are thought to mediate this response. Most mammals are dichromats possessing, in addition to a single rod photopigment, two classes of cone photopigment, LWS and ultraviolet-sensitive/violet-sensitive (UVS/VS) with differing spectral sensitivities which mediate colour vision. In this paper we explore whether Spalax is a dichromat and has the potential to use colour discrimination for photoentrainment. Using immunocytochemistry and molecular approaches we demonstrate that Spalax is a LWS monochromat. Spalax lacks a functional UVS/VS cone photopigment due to the accumulation of several deleterious mutational changes that have rendered the gene nonfunctional. Using phylogenetic analysis we show that the loss of this class of photoreceptor is likely to have arisen from the visual ecology of this species, and is not an artefact of having an ancestor which lacked a functional UVS/VS cone photopigment. We conclude that colour discrimination is not a prerequisite for photoentrainment in this species.


High-quality genome sequences of uncultured microbes by assembly of read clouds.
Although shotgun metagenomic sequencing of microbiome samples enables partial reconstruction of strain-level community structure, obtaining high-quality microbial genome drafts without isolation and culture remains difficult. Here, we present an application of read clouds, short-read sequences tagged with long-range information, to microbiome samples. We present Athena, a de novo assembler that uses read clouds to improve metagenomic assemblies. We applied this approach to sequence stool samples from two healthy individuals and compared it with existing short-read and synthetic long-read metagenomic sequencing techniques. Read-cloud metagenomic sequencing and Athena assembly produced the most comprehensive individual genome drafts with high contiguity (>200-kb N50, fewer than ten contigs), even for bacteria with relatively low (20×) raw short-read-sequence coverage. We also sequenced a complex marine-sediment sample and generated 24 intermediate-quality genome drafts (>70% complete, <10% contaminated), nine of which were complete (>90% complete, <5% contaminated). Our approach allows for culture-free generation of high-quality microbial genome drafts by using a single shotgun experiment.


Characterization of the protective effects of cardiotrophin-1 against non-ischemic death stimuli in adult cardiomyocytes.
The aim of this study was to investigate the cytoprotective effects of CT-1 against non-ischemic death stimuli in adult cardiomyocytes. Primary cultures of cardiomyocytes isolated from adult rats were stimulated with either angiotensin II (Ang II) or H(2)O(2) in the presence or absence of CT-1. Cell death was determined by trypan blue exclusion, cell viability by MTT assay and apoptosis by TUNEL-Annexin-V staining. Intracellular pathways were analyzed by the employment of chemical inhibitors and by the assessment of signalling intermediates phosphorylation by Western blot analysis. CT-1 reduced (p<0.01) total cell death and apoptosis induced by either Ang II or H(2)O(2), and increased (p<0.01) cell viability in cardiomyocytes exposed to these stimuli. These effects of CT-1 were abolished in the presence of antibodies specific for gp130 or LIFR and did not require RNA or protein synthesis. Both Wortmannin and PD98059 abolished protective effects of CT-1 against H(2)O(2), whereas only Wortmannin inhibited protection against Ang II. In both cases, Akt kinase activation and Bad phosphorylation were observed. These findings suggest that CT-1 protects adult cardiomyocytes against Ang II- and oxidative stress-induced cell death, via gp130/LIFR and by means of the PI3K/Akt and the p42/44 MAPK intracellular cascades.


Ultrastructural organization of human corneal nerves.
Although the human cornea is densely innervated, observations of the nerve fiber distribution and ultrastructure are scarce. This study aimed to provide a detailed electron microscopic analysis of nerve fibers in the central and peripheral human cornea. Samples from seven fresh corneas, obtained from the eyes of persons with melanoma, were processed for light and electron microscopic examinations. Both frontal and cross-sections were studied. Furthermore, serial ultrathin sections from the mid-epithelium to the anterior stroma were used. Unmyelinated nerve fiber bundles (as many as 30 nerve fibers and cross-section as large as 20 micrometers) run parallel to the stromal collagen fibers. Nerve fibers contain clear, dense cored and dense vesicles and are ensheathed by thin rims of Schwann cell protrusions and amorphic matrix. Some nerve fibers invaginate the cytoplasm of keratocytes. After passing through Bowman's membrane, bundles of straight fibers (cross-section 0.1 to 0.5 micrometers) and single-beaded nerve fibers, which both lack Schwann cell ensheathment, run parallel in an alternating manner. Beaded nerve fibers, containing many mitochondria and glycogen (cross-section as large as 2 micrometers), turn upward and invaginate both basal and wing cells. Except for the presence of myelinated nerve fibers in the peripheral stroma, no differences in the central cornea were observed. Nerve fibers invaginating epithelial cells and keratocytes suggest that both cell types are directly innervated. The presence of vesicles, mitochondria, and glycogen in stromal and epithelial nerve fibers suggest that classical and peptidergic transmitters, probably of sensory origin, innervate the human cornea. Peptidergic transmitters in nerve fibers may be involved in neuroimmunomodulation of the cornea.


Cancer patients undergoing chemotherapy show adequate serological response to vaccinations against influenza virus and Streptococcus pneumoniae.
Cancer patients receiving chemotherapy are prone to develop infections that might postpone treatment and lead to complications. The aim of our study was to investigate whether a heterogeneous population of patients with solid tumors and malignant lymphoma undergoing chemotherapy would respond serologically to vaccination against influenza and pneumococcal disease. There are no established routines in oncology departments in Norway regarding vaccination of these patients. The study included 35 cancer patients with median age 53 yr (range 20-74) and 38 controls with median age 57 yr (range 43-75). The chemotherapy regimens used were mild or moderately immunosuppressive. After one vaccination, 25 patients (72%) and 34 controls (87%) were serologically protected against two or three influenza strains. A higher proportion of patients with solid tumors (81%) than lymphoma (38%) achieved protection. Age, months on chemotherapy, and curative versus palliative treatment did not influence responses to vaccination. After vaccination with a 23-valent polysaccharide vaccine against pneumococci, most patients and controls achieved protective serum levels of antibodies against the different serotypes, with the exception that fewer patients were protected against serotype 4. The responses in controls were, however, generally stronger to all serotypes. Tumor type did not influence this vaccination response. We conclude that our cancer patients achieved adequate responses to influenza virus and Streptococcus pneumoniae. These are not live vaccines and are therefore safe for immunocompromised patients. Routine vaccinations against influenza virus and Streptococcus pneumoniae should be considered in cancer patients undergoing mild to moderately immunosuppressive chemotherapy.


A Review of the Role of the Intestinal Microbiota in Age-Related Macular Degeneration.
Blindness from age-related macular degeneration (AMD) is an escalating problem, yet AMD pathogenesis is incompletely understood and treatments are limited. The intestinal microbiota is highly influential in ocular and extraocular diseases with inflammatory components, such as AMD. This article reviews data supporting the role of the intestinal microbiota in AMD pathogenesis. Multiple groups have found an intestinal dysbiosis in advanced AMD. There is growing evidence that environmental factors associated with AMD progression potentially work through the intestinal microbiota. A high-fat diet in apo-E-/- mice exacerbated wet and dry AMD features, presumably through changes in the intestinal microbiome, though other independent mechanisms related to lipid metabolism are also likely at play. AREDS supplementation reversed some adverse intestinal microbial changes in AMD patients. Part of the mechanism of intestinal microbial effects on retinal disease progression is via microbiota-induced microglial activation. The microbiota are at the intersection of genetics and AMD. Higher genetic risk was associated with lower intestinal bacterial diversity in AMD. Microbiota-induced metabolite production and gene expression occur in pathways important in AMD pathogenesis. These studies suggest a crucial link between the intestinal microbiota and AMD pathogenesis, thus providing a novel potential therapeutic target. Thus, the need for large longitudinal studies in patients and germ-free or gnotobiotic animal models has never been more pressing.


RecG and UvsW catalyse robust DNA rewinding critical for stalled DNA replication fork rescue.
Helicases that both unwind and rewind DNA have central roles in DNA repair and genetic recombination. In contrast to unwinding, DNA rewinding by helicases has proved difficult to characterize biochemically because of its thermodynamically downhill nature. Here we use single-molecule assays to mechanically destabilize a DNA molecule and follow, in real time, unwinding and rewinding by two DNA repair helicases, bacteriophage T4 UvsW and Escherichia coli RecG. We find that both enzymes are robust rewinding enzymes, which can work against opposing forces as large as 35 pN, revealing their active character. The generation of work during the rewinding reaction allows them to couple rewinding to DNA unwinding and/or protein displacement reactions central to the rescue of stalled DNA replication forks. The overall results support a general mechanism for monomeric rewinding enzymes.


Transcriptional regulation of the T cell antigen receptor zeta subunit: identification of a tissue-restricted promoter.
The cell surface expression of T cell antigen receptors (TCR) is regulated in part by the limiting synthesis of the zeta subunit. Utilizing fragments from the 5' region of the human zeta gene, two discrete regions that promote transcription were characterized. Both of these elements are located within 125 bases of the most 3' site of transcription initiation. The more proximal (3') promoter exhibits activity in lymphoid as well as nonlymphoid cells. In contrast, the more distal (5') promoter element functions in a tissue-restricted fashion. The tissue-specific promoter is localized to a 29-base fragment. The sequence of this region is remarkable for a stretch of 11 consecutive purines that are required for activity. This element constitutes the only known tissue-specific promoter for an invariant TCR subunit. Consistent with the unique role served by the zeta subunit in assembly of the TCR, this study demonstrates that the expression of the zeta gene is regulated in a fashion distinct from other TCR components.


Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) and cirrhosis of the liver: A case report and literature review.
Patients with cirrhosis of the liver usually present with a small shrunken liver and a large spleen. The presence of an unusually huge liver should prompt the treating doctor to look for another cause, as this may be treatable and improve the patient's outcome. In South Africa tuberculosis and lymphoma in the presence of HIV infection should be excluded. Sinus histiocytosis with massive lymphadenopathy and cirrhosis is a rare combination and has not been reported before in the literature. This case is intended to make clinicians aware of this rare combination of diseases.


Data Portal for the Library of Integrated Network-based Cellular Signatures (LINCS) program: integrated access to diverse large-scale cellular perturbation response data.
The Library of Integrated Network-based Cellular Signatures (LINCS) program is a national consortium funded by the NIH to generate a diverse and extensive reference library of cell-based perturbation-response signatures, along with novel data analytics tools to improve our understanding of human diseases at the systems level. In contrast to other large-scale data generation efforts, LINCS Data and Signature Generation Centers (DSGCs) employ a wide range of assay technologies cataloging diverse cellular responses. Integration of, and unified access to LINCS data has therefore been particularly challenging. The Big Data to Knowledge (BD2K) LINCS Data Coordination and Integration Center (DCIC) has developed data standards specifications, data processing pipelines, and a suite of end-user software tools to integrate and annotate LINCS-generated data, to make LINCS signatures searchable and usable for different types of users. Here, we describe the LINCS Data Portal (LDP) (http://lincsportal.ccs.miami.edu/), a unified web interface to access datasets generated by the LINCS DSGCs, and its underlying database, LINCS Data Registry (LDR). LINCS data served on the LDP contains extensive metadata and curated annotations. We highlight the features of the LDP user interface that is designed to enable search, browsing, exploration, download and analysis of LINCS data and related curated content.


Restricted Sequence Variation in Streptococcus pyogenes Penicillin Binding Proteins.
A recent clinical report has linked Streptococcus pyogenes β-lactam antibiotic resistance to mutation in the penicillin binding protein (PBP) PBP2x. To determine whether this is an isolated case or reflects a broader prevalence of mutations that might confer reduced β-lactam susceptibility, we investigated the relative frequency of PBP sequence variation within a global database of 9,667 S. pyogenes isolates. We found that mutations in S. pyogenes PBPs (PBP2x, PBP1a, PBP1b, and PBP2a) occur infrequently across this global database, with fewer than 3 amino acid changes differing between >99% of the global population. Only 4 of the 9,667 strains contained mutations near transpeptidase active sites of PBP2x or PBP1a. The reported PBP2x T553K substitution was not identified. These findings are in contrast to those of 2,520 S. pneumococcus sequences where PBP mutations are relatively frequent and are often located in key β-lactam binding pockets. These data, combined with the general lack of penicillin resistance reported in S. pyogenes worldwide, suggests that extensive, unknown constraints restrict S. pyogenes PBP sequence plasticity. Our findings imply that while heavy antibiotic pressure may select for mutations in the PBPs, there is currently no evidence of such mutations becoming fixed in the S. pyogenes population or that mutations are being sequentially acquired in the PBPs.IMPORTANCE β-Lactam antibiotics are the first-line therapeutic option for Streptococcus pyogenes infections. Despite the global high prevalence of S. pyogenes infections and widespread use of β-lactams worldwide, reports of resistance to β-lactam antibiotics, such as penicillin, have been incredibly rare. Recently, β-lactam resistance, as defined by clinical breakpoints, was detected in two clinical S. pyogenes isolates with accompanying mutations in the active site of the penicillin binding protein PBP2x, raising concerns that β-lactam resistance will become more widespread. We screened a global database of S. pyogenes genome sequences to investigate the frequency of PBP mutations, identifying that PBP mutations are uncommon relative to those of Streptococcus pneumoniae These findings support clinical observations that β-lactam resistance is rare in S. pyogenes and suggest that there are considerable constraints on S. pyogenes PBP sequence variation.


Chemical Composition, but Not Specific Surface Area, Affects Calcium Retention of Nanostructured Calcium Compounds in Growing Rats.
Background: Low dietary calcium intake and bioavailability may adversely affect bone health. Reducing the size of calcium compounds increases their specific surface area (SSA, expressed as m2/g) and may increase calcium dissolution and bioavailability.Objective: We investigated the influence of SSA and chemical composition on the bioavailability of calcium and compared in vitro calcium dissolution with in vivo absorption.Methods: Calcium dissolution was measured in 0.1 M phosphoric acid, whereas color and pH changes of foods were assessed as indicators for potential sensory performance. Calcium absorption, retention, and fractional retention were measured over a 5-d balance study in growing Sprague-Dawley male rats after 21 d of feeding. Femoral and vertebral bone mineral density (BMD) and extensive tissue histology were assessed at study end. The influence of SSA on calcium bioavailability was assessed by comparing the groups fed pure calcium carbonate (CaCO3) with increasing SSAs of 3, 36, and 64 m2/g (CaCO3_3, CaCO3_36 and CaCO3_64), whereas chemical composition was assessed by comparing the smallest CaCO3_64, a 50:50 wt:wt percent solution mixture of CaCO3 and hydroxyapatite_94, and pure hydroxyapatite_100.Results: In vivo, fractional calcium retention from hydroxyapatite_100 (mean ± SEM: 54.86% ± 0.95%/5 d) was significantly greater than from CaCO3_64 (49.66% ± 1.15%/5 d) (P = 0.044). Increasing SSA of the pure CaCO3 did not significantly improve calcium retention. Across all 5 groups, there were no significant differences in BMD or tissue calcification by histology. In vitro calcium dissolution did not correlate with SSA or calcium absorption. In selected food matrixes, hydroxyapatite_100 caused less color change and/or smaller pH increase than did the other calcium compounds.Conclusions: Our findings suggest that chemical composition rather than SSA is a predictor of nanostructured calcium bioavailability and that in vitro dissolution of nanostructured calcium does not predict in vivo absorption. Although its phosphorus content may limit use in some populations, nanostructured hydroxyapatite may be a promising calcium compound for food fortification.


The Ischemic Stroke Genetics Study (ISGS) Protocol.
The molecular basis for the genetic risk of ischemic stroke is likely to be multigenic and influenced by environmental factors. Several small case-control studies have suggested associations between ischemic stroke and polymorphisms of genes that code for coagulation cascade proteins and platelet receptors. Our aim is to investigate potential associations between hemostatic gene polymorphisms and ischemic stroke, with particular emphasis on detailed characterization of the phenotype. The Ischemic Stroke Genetic Study is a prospective, multicenter genetic association study in adults with recent first-ever ischemic stroke confirmed with computed tomography or magnetic resonance imaging. Patients are evaluated at academic medical centers in the United States and compared with sex- and age-matched controls. Stroke subtypes are determined by central blinded adjudication using standardized, validated mechanistic and syndromic classification systems. The panel of genes to be tested for polymorphisms includes beta-fibrinogen and platelet glycoprotein Ia, Iba, and IIb/IIIa. Immortalized cell lines are created to allow for time- and cost-efficient testing of additional candidate genes in the future. The study is designed to minimize survival bias and to allow for exploring associations between specific polymorphisms and individual subtypes of ischemic stroke. The data set will also permit the study of genetic determinants of stroke outcome. Having cell lines will permit testing of future candidate risk factor genes.


Preventive zinc supplementation in developing countries: impact on mortality and morbidity due to diarrhea, pneumonia and malaria.
Zinc deficiency is commonly prevalent in children in developing countries and plays a role in decreased immunity and increased risk of infection. Preventive zinc supplementation in healthy children can reduce mortality due to common causes like diarrhea, pneumonia and malaria. The main objective was to determine all-cause mortality and cause-specific mortality and morbidity in children under five in developing countries for preventive zinc supplementation. DATA SOURCES/ REVIEW METHODS: A literature search was carried out on PubMed, the Cochrane Library and the WHO regional databases to identify RCTs on zinc supplementation for greater than 3 months in children less than 5 years of age in developing countries and its effect on mortality was analyzed. The effect of preventive zinc supplementation on mortality was given in eight trials, while cause specific mortality data was given in five of these eight trials. Zinc supplementation alone was associated with a statistically insignificant 9% (RR = 0.91; 95% CI: 0.82, 1.01) reduction in all cause mortality in the intervention group as compared to controls using a random effect model. The impact on diarrhea-specific mortality of zinc alone was a non-significant 18% reduction (RR = 0.82; 95% CI: 0.64, 1.05) and 15% for pneumonia-specific mortality (RR = 0.85; 95% CI: 0.65, 1.11). The incidence of diarrhea showed a 13% reduction with preventive zinc supplementation (RR = 0.87; 95% CI: 0.81, 0.94) and a 19% reduction in pneumonia morbidity (RR = 0.81; 95% CI: 0.73, 0.90). Keeping in mind the direction of effect of zinc supplementation in reducing diarrhea and pneumonia related morbidity and mortality; we considered all the outcomes for selection of effectiveness estimate for inclusion in the LiST model. After application of the CHERG rules with consideration to quality of evidence and rule # 6, we used the most conservative estimates as a surrogate for mortality. We, therefore, conclude that zinc supplementation in children is associated with a reduction in diarrhea mortality of 13% and pneumonia mortality of 15% for inclusion in the LiST tool. Preventive zinc supplementation had no effect on malaria specific mortality (RR = 0.90; 95% CI: 0.77, 1.06) or incidence of malaria (RR = 0.92; 95 % CI 0.82-1.04). Zinc supplementation results in reductions in diarrhea and pneumonia mortality.


Secondary iris-claw anterior chamber lens implantation in patients with aphakia without capsular support.
To evaluate the efficacy, predictability, safety and complications of secondary iris-claw intraocular lens (IOL) implantation in aphakic eyes without capsular support. Retrospective, non-comparative, interventional case series of 128 aphakic eyes, which consecutively underwent secondary iris-claw Artisan IOL (Ophtec BV) implantation, were included. Manifest refraction, uncorrected visual acuity, best-spectacle corrected visual acuity, biomicroscopy, tonometry, funduscopy and central endothelial cell count (cECC) were evaluated before surgery, and at yearly intervals up to 5 years. Minimum follow-up time was 1 year. One hundred twenty-eight eyes were treated. Mean age was 54.55 years (range, 1-98 years). Mean follow-up was 41.8 months (SD 23.63). Mean preoperative logarithm of the minimum angle of resolution BSCVA and spherical equivalent (SE) were 0.67 ((SD) 0.53) and 9.63 D (SD 5.50), respectively. One year postoperatively, mean logarithm of the minimum angle of resolution best-spectacle corrected visual acuity improved to 0.52 (SD 0.46) (p<0.05), and remained stable up to 5 years. One year postoperatively, mean SE was -0.52 (SD 2.21) (p<0.05). Mean SE progressively decreased during the 1st year, and remained stable thereafter (p<0.05). Mean preoperative cECC was 2237.47 (SD 793.33) cells/mm(2). cECC showed a slight, though statistically significant, decrease over the years (p=0.05). Main complications were: 2 pupillary block; 3 transient increase in intraocular pressure; 1 IOL replacement; 2 penetrating keratoplasty and 4 cystoid macular oedema. Iris-claw IOL implantation in aphakic eyes is an effective, predictable and safe procedure in the first 5 years of follow-up. However, a longer follow-up is required to demonstrate its long-term safety.


Sound focusing in rooms: the time-reversal approach.
New perspectives in audible range acoustics, such as virtual sound space creation and active noise control, rely on the ability of the rendering system to recreate precisely a desired sound field. This ability to control sound in a given volume of a room is directly linked to the capacity to focus acoustical energy both in space and time. However, sound focusing in rooms remains a complicated problem, essentially because of the multiple reflections on obstacles and walls occurring during propagation. In this paper, the technique of time-reversal focusing, well known in ultrasound, is experimentally applied to audible range acoustics. Compared to classical focusing techniques such as delay law focusing, time reversal appears to considerably improve quality of both temporal and spatial focusing. This so-called super-resolution phenomenon is due to the ability of time reversal to take into account all of the different sound paths between the emitting antenna and the focal point, thus creating an adaptive spatial and temporal matched filter for the considered propagation medium. Experiments emphasize the strong robustness of time-reversal focusing towards small modifications in the medium, such as people in motion or temperature variations. Sound focusing through walls using the time-reversal approach is also experimentally demonstrated.


Evaluation of antral follicle count and ovarian morphology in crossbred beef cows: investigation of influence of stage of the estrous cycle, age, and birth weight.
Depletion of the ovarian reserve is associated with reproductive senescence in mammalian females, and there is a positive relationship between the size of the ovarian reserve and the number of antral follicles on the surface of the ovary. Therefore, we conducted a series of experiments to investigate the influence of stage of the estrous cycle, age, and birth weight on antral follicle counts (AFC) in beef cows and heifers. Pairs of ovaries were collected from crossbred beef cows at slaughter (n = 72) or at necropsy (n = 333; 0 to 11 yr of age); all visible antral follicles were counted, the ovaries were weighed, and stage of the estrous cycle was estimated based on ovarian morphology. There was no influence of estimated stage of the estrous cycle on AFC (P = 0.36). There was a small but positive effect of birth weight on AFC [AFC = -1.7 + 0.31(birth weight); P = 0.007, r(2) = 0.05]. When antral follicle counts were regressed on age, there was a quadratic effect of age such that AFC increased until 5 yr of age and decreased thereafter [AFC = 12.9 + 9.0(yr) - 0.86(yr(2)); P < 0.001, r(2) = 0.22]. In a third experiment, crossbred beef heifers (n = 406; 353 to 463 d of age) at 3 locations were subjected to ovarian ultrasonography on unknown day of the estrous cycle. Heifers were classified as low AFC (<15 follicle, n = 84) or high AFC (>24 follicles, n = 178). Whereas estimated stage of the estrous cycle did not influence AFC (P = 0.62), heifers classified as low AFC had smaller ovaries (P = 0.001), decreased birth weight (P = 0.003), and a decreased heifer pregnancy rate (P = 0.05) compared with heifers in the high AFC group. From these results, we conclude that AFC in beef cows and heifers is influenced by birth weight and age but not by stage of the estrous cycle. In beef cows, the number of antral follicles increases to 5 yr of age and then begins to decline. This may indicate that a decrease in fertility due to decline of the ovarian reserve may begin earlier than previously thought in beef cows.


Intense mixing of lower thermocline water on the crest of the Mid-Atlantic Ridge.
Buoyancy exchange between the deep and the upper ocean, which is essential for maintaining global ocean circulation, mainly occurs through turbulent mixing. This mixing is thought to result primarily from instability of the oceanic internal wave field, but internal waves tend to radiate energy away from the regions in which they are generated rather than dissipate it locally as turbulence and the resulting distribution of turbulent mixing remains unknown. Another, more direct, mixing mechanism involves the generation of turbulence as strong flows pass through narrow passages in topography, but the amount of turbulence generated at such locations remains poorly quantified owing to a lack of direct measurements. Here we present observations from the crest of the Mid-Atlantic Ridge in the subtropical North Atlantic Ocean that suggest that passages in rift valleys and ridge-flank canyons provide the most energetic sites for oceanic turbulence. Our measurements show that diffusivities as large as 0.03 m2 s(-1) characterize the mixing downstream of a sill in a well-stratified boundary layer, with mixing levels remaining of the order of 10(-4) m2 s(-1) at the base of the main thermocline. These mixing rates are significantly higher than the diffusivities of the order of 10(-5) m2 s(-1) that characterize much of the global thermocline and the abyssal ocean. Our estimates suggest that overflows associated with narrow passages on the Mid-Atlantic Ridge in the North Atlantic Ocean produce as much buoyancy flux as has previously been estimated for the entire Romanche fracture zone, a large strait in the Mid-Atlantic Ridge that connects the North and South Atlantic basins. This flux is equivalent to the interior mixing that occurs in the entire North Atlantic basin at the depth of the passages, suggesting that turbulence generated in narrow passages on mid-ocean ridges may be important for buoyancy flux at the global scale.


Circulating galectin-1 delineates response to bevacizumab in melanoma patients and reprograms endothelial cell biology.
Blockade of vascular endothelial growth factor (VEGF) signaling with bevacizumab, a humanized anti-VEGF monoclonal antibody (mAb), or with receptor tyrosine kinase inhibitors, has improved progression-free survival and, in some indications, overall survival across several types of cancers by interrupting tumor angiogenesis. However, the clinical benefit conferred by these therapies is variable, and tumors from treated patients eventually reinitiate growth. Previously we demonstrated, in mouse tumor models, that galectin-1 (Gal1), an endogenous glycan-binding protein, preserves angiogenesis in anti-VEGF-resistant tumors by co-opting the VEGF receptor (VEGFR)2 signaling pathway in the absence of VEGF. However, the relevance of these findings in clinical settings is uncertain. Here, we explored, in a cohort of melanoma patients from AVAST-M, a multicenter, open-label, randomized controlled phase 3 trial of adjuvant bevacizumab versus standard surveillance, the role of circulating plasma Gal1 as part of a compensatory mechanism that orchestrates endothelial cell programs in bevacizumab-treated melanoma patients. We found that increasing Gal1 levels over time in patients in the bevacizumab arm, but not in the observation arm, significantly increased their risks of recurrence and death. Remarkably, plasma Gal1 was functionally active as it was able to reprogram endothelial cell biology, promoting migration, tubulogenesis, and VEGFR2 phosphorylation. These effects were prevented by blockade of Gal1 using a newly developed fully human anti-Gal1 neutralizing mAb. Thus, using samples from a large-scale clinical trial from stage II and III melanoma patients, we validated the clinical relevance of Gal1 as a potential mechanism of resistance to bevacizumab treatment.


Output from VIP cells of the mammalian central clock regulates daily physiological rhythms.
The suprachiasmatic nucleus (SCN) circadian clock is critical for optimising daily cycles in mammalian physiology and behaviour. The roles of the various SCN cell types in communicating timing information to downstream physiological systems remain incompletely understood, however. In particular, while vasoactive intestinal polypeptide (VIP) signalling is essential for SCN function and whole animal circadian rhythmicity, the specific contributions of VIP cell output to physiological control remains uncertain. Here we reveal a key role for SCN VIP cells in central clock output. Using multielectrode recording and optogenetic manipulations, we show that VIP neurons provide coordinated daily waves of GABAergic input to target cells across the paraventricular hypothalamus and ventral thalamus, supressing their activity during the mid to late day. Using chemogenetic manipulation, we further demonstrate specific roles for this circuitry in the daily control of heart rate and corticosterone secretion, collectively establishing SCN VIP cells as influential regulators of physiological timing.


How does provider and patient awareness of high-risk status for lower-extremity amputation influence foot-care practice?
To assess whether patients with diabetes at high risk for lower extremity amputation received more intensive medical care or self-care instruction and to determine the association between foot care and risk of lower-extremity amputation. Patients with diabetes were seen at he Seattle Veterans Affairs Medical Center (VAMC) between October 1984 and April 1987; 67 patients were seen for initial non-traumatic amputation, and 236 consecutive control subjects were seen for non-traumatic but medically necessary surgery unrelated to diabetes. Data collection included patient interview and medical record review. High-risk status, defined as presence of peripheral neuropathy, peripheral vascular disease, or or prior foot ulcer, was temporally fixed at 2 years before study enrollment. Peripheral neuropathy, peripheral vascular disease, and prior foot ulcer were independently associated with risk of lower-extremity amputation: peripheral neuropathy odds ratio (OR) = 1.4 (95% confidence interval (CI) 0.7-2.7), peripheral vascular disease OR = 2.6 (95% CI 1.5-4.5), and prior foot ulcer OR = 10.9 (95% CI 4.6-25.5). Patients with a prior foot ulcer were significantly more likely to have seen a podiatrist and to have received outpatient diabetes education at the Seattle VAMC; their providers were more likely to prescribe clipping toenails, regular foot washing, and elevating feet during the day (chi 1(2) for proportions P < 0.05). However, for patients with a history of peripheral neuropathy or peripheral vascular disease, there was no statistically significant increase in medical care (podiatry visits, outpatient diabetes education) or self-care instruction (clip nails, elevate feet, or self-monitor blood glucose) compared with patients without either of these two conditions (chi 1(2) for proportions P > 0.20). When clinicians were aware of a patient's very elevated risk for lower-extremity amputation (evidenced by prior history of foot ulcer), they were more likely to prescribe preventive foot-care behaviors, but awareness of other risk factors (peripheral neuropathy or peripheral vascular disease) did not necessarily increase preventive care. Physicians and patients should receive periodic education and reinforcement of diabetes management skills to modify care delivered to individuals at highest risk for lower-extremity amputation.


The Colorado-retinopathy of prematurity model (CO-ROP): postnatal weight gain screening algorithm.
To describe a novel retinopathy of prematurity (ROP) screening model incorporating birth weight, gestational age, and postnatal weight gain that maintains sensitivity but improves specificity in detecting all grades of ROP compared to current 2013 screening guidelines. The medical records of 499 neonates from a single tertiary referral center who met the 2013 screening guidelines for ROP were retrospectively reviewed. Weekly weights were analyzed using standard logistic regression to determine the age at which the weekly net weight gain best predicted the development of ROP, which was designated as the postnatal weight gain criterion. The 2013 birth weight and gestational age criteria were included in an "and" fashion to form the CO-ROP model. Sensitivities and specificities in detecting high grade (type 1 and 2) and all grades of ROP were calculated. The CO-ROP model screens infants with a gestational age at birth of ≤30 weeks and birth weight of ≤1500 g and net weight gain of ≤650 g between birth and 1 month of age. In our cohort, CO-ROP had a sensitivity of 100% (95% CI, 92.1%-100.0%) for high-grade (type 1 and 2) ROP and 96.4% (95% CI, 92.3%-98.7%) for all grades of ROP. It would reduce the number of infants screened by 23.7% compared to 2013 guidelines. Calibrating the model to detect only high-grade ROP would result in a 45.9% reduction in the total number of infants screened. CO-ROP is a simple model that maintains a statistically similar sensitivity in detecting all grades of ROP while significantly reducing the total number of required ROP screenings compared to 2013 guidelines. The study had a small sample size but shows promise for future research and clinical efforts.


Quantitative GSTP1 hypermethylation in bodily fluids of patients with prostate cancer.
To further determine the value of real-time quantitative methylation-specific polymerase chain reaction (MSP) of GSTP1 as a molecular tool for the detection of prostate adenocarcinoma. Recent studies have shown a high frequency (more than 90%) of GSTP1 gene promotor methylation in prostate adenocarcinoma and a lower frequency in DNA from serum and urine. Tissue samples from 69 patients with early-stage prostate adenocarcinoma and 31 patients with benign prostatic hyperplasia were collected. Matched urine and plasma specimens were obtained preoperatively. After sodium-bisulfite treatment, extracted DNA was analyzed for GSTP1 promoter hypermethylation both by conventional and real-time quantitative MSP. In tissue samples, GSTP1 hypermethylation was detected in 63 (91.3%) of the 69 patients with cancer and in 9 (29%) of the 31 patients with benign prostatic hyperplasia. Conventional MSP detected GSTP1 hypermethylation in a larger number of urine and plasma samples than did real-time quantitative MSP (53.6% versus 31.9%, overall). In all positive bodily fluids, the paired tumor was also confirmed to be methylated. GSTP1 hypermethylation was detected by both MSP methods in only one urine sample (3.2%) from a patient with benign prostatic hyperplasia. Although not quantitative, conventional MSP is currently more sensitive than real-time quantitative MSP in the detection of GSTP1 hypermethylation in bodily fluids from patients with prostate cancer with clinically localized disease. The value of quantitative determinations in monitoring and risk assessment remains to be further explored.


Incidence, Risk Factors, and Outcomes of Patients Who Develop Mucosal Barrier Injury-Laboratory Confirmed Bloodstream Infections in the First 100 Days After Allogeneic Hematopoietic Stem Cell Transplant.
Patients undergoing hematopoietic stem cell transplant (HSCT) are at risk for bloodstream infection (BSI) secondary to translocation of bacteria through the injured mucosa, termed mucosal barrier injury-laboratory confirmed bloodstream infection (MBI-LCBI), in addition to BSI secondary to indwelling catheters and infection at other sites (BSI-other). To determine the incidence, timing, risk factors, and outcomes of patients who develop MBI-LCBI in the first 100 days after HSCT. A case-cohort retrospective analysis was performed using data from the Center for International Blood and Marrow Transplant Research database on 16 875 consecutive pediatric and adult patients receiving a first allogeneic HSCT from January 1, 2009, to December 31, 2016. Patients were classified into 4 categories: MBI-LCBI (1481 [8.8%]), MBI-LCBI and BSI-other (698 [4.1%]), BSI-other only (2928 [17.4%]), and controls with no BSI (11 768 [69.7%]). Statistical analysis was performed from April 5 to July 17, 2018. Demographic characteristics and outcomes, including overall survival, chronic graft-vs-host disease, and transplant-related mortality (only for patients with malignant disease), were compared among groups. Of the 16 875 patients in the study (9737 [57.7%] male; median [range] age, 47 [0.04-82] years) 13 686 (81.1%) underwent HSCT for a malignant neoplasm, and 3189 (18.9%) underwent HSCT for a nonmalignant condition. The cumulative incidence of MBI-LCBI was 13% (99% CI, 12%-13%) by day 100, and the cumulative incidence of BSI-other was 21% (99% CI, 21%-22%) by day 100. Median (range) time from transplant to first MBI-LCBI was 8 (<1 to 98) days vs 29 (<1 to 100) days for BSI-other. Multivariable analysis revealed an increased risk of MBI-LCBI with poor Karnofsky/Lansky performance status (hazard ratio [HR], 1.21 [99% CI, 1.04-1.41]), cord blood grafts (HR, 2.89 [99% CI, 1.97-4.24]), myeloablative conditioning (HR, 1.46 [99% CI, 1.19-1.78]), and posttransplant cyclophosphamide graft-vs-host disease prophylaxis (HR, 1.85 [99% CI, 1.38-2.48]). One-year mortality was significantly higher for patients with MBI-LCBI (HR, 1.81 [99% CI, 1.56-2.12]), BSI-other (HR, 1.81 [99% CI, 1.60-2.06]), and MBI-LCBI plus BSI-other (HR, 2.65 [99% CI, 2.17-3.24]) compared with controls. Infection was more commonly reported as a cause of death for patients with MBI-LCBI (139 of 740 [18.8%]), BSI (251 of 1537 [16.3%]), and MBI-LCBI plus BSI (94 of 435 [21.6%]) than for controls (566 of 4740 [11.9%]). In this cohort study, MBI-LCBI, in addition to any BSIs, were associated with significant morbidity and mortality after HSCT. Further investigation into risk reduction should be a clinical and scientific priority in this patient population.


Multilayered regulation of autophagy by the Atg1 kinase orchestrates spatial and temporal control of autophagosome formation.
Autophagy is a conserved intracellular degradation pathway exerting various cytoprotective and homeostatic functions by using de novo double-membrane vesicle (autophagosome) formation to target a wide range of cytoplasmic material for vacuolar/lysosomal degradation. The Atg1 kinase is one of its key regulators, coordinating a complex signaling program to orchestrate autophagosome formation. Combining in vitro reconstitution and cell-based approaches, we demonstrate that Atg1 is activated by lipidated Atg8 (Atg8-PE), stimulating substrate phosphorylation along the growing autophagosomal membrane. Atg1-dependent phosphorylation of Atg13 triggers Atg1 complex dissociation, enabling rapid turnover of Atg1 complex subunits at the pre-autophagosomal structure (PAS). Moreover, Atg1 recruitment by Atg8-PE self-regulates Atg8-PE levels in the growing autophagosomal membrane by phosphorylating and thus inhibiting the Atg8-specific E2 and E3. Our work uncovers the molecular basis for positive and negative feedback imposed by Atg1 and how opposing phosphorylation and dephosphorylation events underlie the spatiotemporal regulation of autophagy.


Contributions of two cytosolic glutamine synthetase isozymes to ammonium assimilation in Arabidopsis roots.
Glutamine synthetase (GS) catalyzes a reaction that incorporates ammonium into glutamate and yields glutamine in the cytosol and chloroplasts. Although the enzymatic characteristics of the GS1 isozymes are well known, their physiological functions in ammonium assimilation and regulation in roots remain unclear. In this study we show evidence that two cytosolic GS1 isozymes (GLN1;2 and GLN1;3) contribute to ammonium assimilation in Arabidopsis roots. Arabidopsis T-DNA insertion lines for GLN1;2 and GLN1;3 (i.e. gln1;2 and gln1;3 single-mutants), the gln1;2:gln1;3 double-mutant, and the wild-type accession (Col-0) were grown in hydroponic culture with variable concentrations of ammonium to compare their growth, and their content of nitrogen, carbon, ammonium, and amino acids. GLN1;2 and GLN1;3 promoter-dependent green fluorescent protein was observed under conditions with or without ammonium supply. Loss of GLN1;2 caused significant suppression of plant growth and glutamine biosynthesis under ammonium-replete conditions. In contrast, loss of GLN1;3 caused slight defects in growth and Gln biosynthesis that were only visible based on a comparison of the gln1;2 single- and gln1;2:gln1;3 double-mutants. GLN1;2, being the most abundantly expressed GS1 isozyme, markedly increased following ammonium supply and its promoter activity was localized at the cortex and epidermis, while GLN1;3 showed only low expression at the pericycle, suggesting their different physiological contributions to ammonium assimilation in roots. The GLN1;2 promoter-deletion analysis identified regulatory sequences required for controlling ammonium-responsive gene expression of GLN1;2 in Arabidopsis roots. These results shed light on GLN1 isozyme-specific regulatory mechanisms in Arabidopsis that allow adaptation to an ammonium-replete environment.


Rates of hospitalized bacterial infection associated with juvenile idiopathic arthritis and its treatment.
To compare the incidence of hospitalized bacterial infections among children with and children without juvenile idiopathic arthritis (JIA) and to examine the effects of selected medications. Using national Medicaid data from 2000 through 2005, we identified a cohort of children with JIA and a comparator cohort of children with attention deficit hyperactivity disorder (ADHD). Exposures to methotrexate (MTX), TNF inhibitors, and oral glucocorticoids (GCs) were determined using pharmacy claims. Patients hospitalized with bacterial infections were identified using coded discharge diagnoses. We calculated adjusted hazard ratios (HR(adj) ) to compare infection incidence rates while adjusting for relevant covariates. We identified 8,479 JIA patients with 13,003 person-years of followup; 36% took MTX and 16% took TNF inhibitors. Compared with ADHD patients, JIA patients who were not currently taking MTX or TNF inhibitors had an increased rate of infection (HR(adj) 2.0 [95% confidence interval (95% CI) 1.5, 2.5]). Among JIA patients not receiving TNF inhibitor therapy, MTX users had a similar rate of infection as those not currently taking MTX (HR(adj) 1.2 [95% CI 0.9, 1.7]). TNF inhibitor use (irrespective of MTX) resulted in a similar rate of infection as use of MTX without a TNF inhibitor (HR(adj) 1.2 [95% CI 0.8, 1.8]). Use of high-dose GCs (≥10 mg/day of prednisone or equivalent) increased the rate of infection as compared with no GC use, after adjustment for MTX and TNF inhibitor use (HR(adj) 3.1 [95% CI 2.0, 4.7]). Children with JIA had an increased rate of infection compared to children with ADHD. Among children with JIA, the rate of infection was not increased with MTX or TNF inhibitor use, but was significantly increased with high-dose GC use.


A new method using insert-based systems (IBS) to improve cell behavior study on flexible and rigid biomaterials.
In vitro studies about biomaterials biological properties are essential screening tests. Yet cell cultures encounter difficulties related to cell retention on material surface or to the observation of both faces of permeable materials. The objective of the present study was to develop a reliable in vitro method to study cell behavior on rigid and flexible/permeable biomaterials elaborating two specific insert-based systems (IBS-R and IBS-F respectively). IBS-R was designed as a specific cylindrical polytetrafluoroethylene (PTFE) system to evaluate attachment, proliferation and morphology of human gingival fibroblasts (HGFs) on grade V titanium and lithium disilicate glass-ceramic discs characteristics of dental prostheses. The number of cells, their covering on discs and their morphology were determined from MTS assays and microscopic fluorescent images after 24, 48 and 72 h. IBS-F was developed as a two components system to study HGFs behavior on guided bone regeneration polyester membranes. The viability and the membrane barrier effect were evaluated by metabolic MTS assays and by scanning electron microscopy. IBS-R and IBS-F were shown to promote (1) easy and rapid handling; (2) cell retention on biomaterial surface; (3) accurate evaluation of the cellular proliferation, spreading and viability; (4) use of non-toxic material. Moreover IBS-F allowed the study of the cell migration through degradable membranes, with an access to both faces of the biomaterial and to the bottom of culture wells for medium changing.


The stiff man and stiff man plus syndromes.
Rigidity in the setting of continuous motor unit activity at rest can be caused by a variety of central and peripheral conditions. A central origin is suggested by the presence of painful reflex spasms. Focal spinal lesions and infective causes are relatively easily excluded through imaging, microbiological and serological studies. There then remain a group of patients who may have the classical 'stiff-man syndrome' or a related syndrome. When strict diagnostic criteria are used, patients with the stiff man syndrome uniformly have axial rigidity, and about 90% are found to have antibodies against glutamic acid decarboxylase. Treatment response and prognosis are excellent. Stiff persons with 'plus' signs, particularly those with rigidity of a distal limb, are unlikely to have the classical stiff man syndrome. They have a poorer treatment response and prognosis. Some have a paraneoplastic aetiology, while a non-malignant autoimmune basis seems likely in others. Those in whom post-mortem pathology findings are available usually are seen to have had an encephalomyelitis with prominent involvement of the grey matter. Clinically, stiff persons with 'plus' signs may be divided into three groups according to the aggressiveness of the pathology and its relative distribution. Encephalomyelitis with rigidity follows a relentless subacute course, leading to death within 3 years. Chronic cases may present with predominantly brainstem involvement, including generalised myoclonus (the 'jerking stiff person syndrome') or spinal cord involvement, dominated by stiffness and spasm in one or more limbs (the 'stiff limb syndrome').


Complementary and alternative medicine whole systems research: beyond identification of inadequacies of the RCT.
Complementary and alternative medicine (CAM) often consists of whole systems of care (such as naturopathic medicine or traditional Chinese medicine (TCM)) that combine a wide range of modalities to provide individualised treatment. The complexity of these interventions and their potential synergistic effect requires innovative evaluative approaches. Model validity, which encompasses the need for research to adequately address the unique healing theory and therapeutic context of the intervention, is central to whole systems research (WSR). Classical randomised controlled trials (RCTs) are limited in their ability to address this need. Therefore, we propose a mixed methods approach that includes a range of relevant and holistic outcome measures. As the individual components of most whole systems are inseparable, complementary and synergistic, WSR must not focus only on the "active" ingredients of a system. An emerging WSR framework must be non-hierarchical, cyclical, flexible and adaptive, as knowledge creation is continuous, evolutionary and necessitates a continuous interplay between research methods and "phases" of knowledge. Finally, WSR must hold qualitative and quantitative research methods in equal esteem to realize their unique research contribution. Whole systems are complex and therefore no one method can adequately capture the meaning, process and outcomes of these interventions.


Mechanisms of multiphase reactive flow using biogenically calcite-functionalized micromodels.
Dissolution of carbonate minerals in porous media is important to many instances of subsurface flow, including geological carbon dioxide (CO2) sequestration, karst formation, and crude-oil reservoir stimulation and acidizing. Of particular interest, geological CO2 storage in deep carbonate reservoirs presents a significant long-term opportunity to mitigate atmospheric carbon emissions. The reactivity of carbonate reservoirs, however, may negatively impact storage formation integrity and hence jeopardize sequestered CO2 storage security. In this work, we develop a novel biogenically calcite-functionalized microvisual device to study the fundamental pore-scale reactive transport dynamics in carbonate formations. Importantly, we discover a new microscale mechanism that dictates the overall behavior of the reactive transport phenomenon, where the reaction product, CO2, due to carbonate rock dissolution forms a separate, protective phase that engulfs the carbonate rock grain and reduces further dissolution. The presence of the separate, protective CO2 phase determines overall dissolution patterns in the storage reservoir and leads to formation of preferential leakage paths. We scale these results using nondimensional numbers to demonstrate their influence on industrial CO2 storage security, safety, and capacity.


Hematologic response of fish to changes in gas or hydrostatic pressure.
Hematologic changes were studied in fingering salmon after rapid decompression from combined or independent exposure to gas and hydrostatic pressure. After decompression, fingerling salmon saturated with excess gas under pressure (10.1-40.6 m of seawater) suffered a decrease in thrombocyte counts and fibrinogen, prolonged prothrombin (PT) times, and increased fibrinolytic activity, plasma proteins, and erythrocyte counts in proportion to severity of the dive. After decompression, fingerling salmon exposed to increased pressure experienced an increase in thrombocyte counts and available fibrinogen, shortened PT times, increased erythrocyte counts, and decreased plasma protein levels. It appeared that pressure causes activation of the blood coagulation system of fish. This activation may predispose the fish to increased susceptibility to bubble-induced diffuse intravascular coagulation after rapid decompression. Furthermore, hemoconcentration after decompression may be a pressure-related phenomenon and not a response to bubble-induced anoxia.


Ossification of the posterior longitudinal ligament in non-Asians: demographic, clinical, and radiographic findings in 43 patients.
Ossification of the posterior longitudinal ligament (OPLL) is a disorder afflicting as many as 2% of East Asians. However, reports of OPLL in non-Asians have been sporadic in the medical literature. This study describes clinical and radiographic findings with OPLL in non-Asians at a tertiary care center treating a diverse multiethnic population. Over a 6-year period, 43 patients not of East Asian descent presented to an urban tertiary medical center with OPLL. Patient data, including ethnicity, spinal cord function, Nurick grade, radiographic findings, OPLL subtype, and degree of cervical stenosis, were recorded. The average patient age was 59 years (range 32-92 years) with 18 women and 25 men. There were 22 Caucasian patients, 17 Hispanic patients, and 4 Black patients. With respect to the radiographic findings, OPLL morphology was continuous in 19, segmental in 17, mixed in 6, and other in 1. Average canal diameter was 7.6 mm (range 4.2-9.0 mm) at the most stenotic points. The mean Nurick grade was 2.95 at presentation, but 7 of the patients had OPLL identified incidentally and with early or minimal symptoms and signs of myelopathy. Ossification of the posterior longitudinal ligament in non-Asians demonstrates similar demographic and radiographic characteristics as in East Asians. The representation of different ethnic groups mirrors the demographics of the medical center population in general, showing no specific predilection for particular ethnic groups. Surgical decompression in appropriately selected patients results in similar rates of improvement when compared with the Japanese literature.


Persistence and spatial autocorrelation of clones of Erysiphe necator overwintering as mycelium in dormant buds in an isolated vineyard in northern Italy.
The population structure of the grape powdery mildew fungus, Erysiphe necator (formerly Uncinula necator), has been hypothesized to vary from being clonal to highly diverse and recombining. We report here on the structure of an E. necator population sampled during a 4-year period from an isolated vineyard in northern Italy (Voghera, Pavia Province). We obtained 54 isolates of E. necator that overwintered asexually as mycelium in grapevine buds and caused severe symptoms on the emerging shoots, known as flag shoots. All isolates were genotyped for mating type, four multilocus polymerase chain reaction (PCR)-based markers (a total of 64 loci were scored), and two single-copy loci designed to identify genetic subgroups in E. necator. All isolates had the same mating type and single-locus alleles that correlate to isolates from flag shoots in other areas. Only 2 of the 64 loci scored from multilocus markers were polymorphic; 46 of the 54 isolates had the same multilocus haplotype. Seven isolates had a second haplotype that was recovered over 3 years, and only a single isolate was found with a third haplotype. Both variant haplotypes differed from the main clonal haplotype by single loci. Spatial autocorrelation analyses showed that vines with flag shoots were not aggregated within years, but they were aggregated between consecutive years. These results demonstrate that this subpopulation of E. necator on flag shoots is composed of a single clonal lineage that has persisted for at least 4 years. We speculate that the lack of diversity in the flag shoot subpopulation in this vineyard is the result of restricted immigration from surrounding areas and genetic drift operating through founder effects and periodic bottlenecks. We propose a model that integrates epidemiology and population genetics to explain the variation observed in genetic structure of E. necator flag shoot subpopulations from different vineyards or viticultural regions.


Menhaden oil decreases high-fat diet-induced markers of hepatic damage, steatosis, inflammation, and fibrosis in obese Ldlr-/- mice.
The frequency of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with obesity in the United States. NASH is progressive and characterized by hepatic damage, inflammation, fibrosis, and oxidative stress. Because C20-22 (n-3) PUFA are established regulators of lipid metabolism and inflammation, we tested the hypothesis that C20-22 (n-3) PUFA in menhaden oil (MO) prevent high-fat (HF) diet-induced fatty liver disease in mice. Wild-type (WT) and Ldlr(-/-) C57BL/6J mice were fed the following diets for 12 wk: nonpurified (NP), HF with lard (60% of energy from fat), HF-high-cholesterol with olive oil (HFHC-OO; 54.4% of energy from fat, 0.5% cholesterol), or HFHC-OO supplemented with MO (HFHC-MO). When compared with the NP diet, the HF and HFHC-OO diets induced hepatosteatosis and hepatic damage [elevated plasma alanine aminotransferase (ALT) and aspartate aminotransferases] and elevated hepatic expression of markers of inflammation (monocyte chemoattractant protein-1), fibrosis (procollagen 1α1), and oxidative stress (heme oxygenase-1) (P ≤ 0.05). Hepatic damage (i.e., ALT) correlated (r = 0.74, P < 0.05) with quantitatively higher (>140%, P < 0.05) hepatic cholesterol in Ldlr(-/-) mice fed the HFHC-OO diet than WT mice fed the HF or HFHC-OO diets. Plasma and hepatic markers of liver damage, steatosis, inflammation, and fibrosis, but not oxidative stress, were lower in WT and Ldlr(-/-) mice fed the HFHC-MO diet compared with the HFHC-OO diet (P < 0.05). In conclusion, MO [C20-22 (n-3) PUFA at 2% of energy] decreases many, but not all, HF diet-induced markers of fatty liver disease in mice.


A database of global marine commercial, small-scale, illegal and unreported fisheries catch 1950-2014.
Global fisheries landings data from a range of public sources was harmonised and mapped to 30-min spatial cells based on the distribution of the reported taxa and the fishing fleets involved. This data was extended to include the associated fishing gear used, as well as estimates of illegal, unregulated and unreported catch (IUU) and discards at sea. Expressed as catch rates, these results also separated small-scale fisheries from other fishing operations. The dataset covers 1950 to 2014 inclusive. Mapped catch allows study of the impacts of fisheries on habitats and fauna, on overlap with the diets of marine birds and mammals, and on the related use of fuels and release of greenhouse gases. The fine-scale spatial data can be aggregated to the exclusive economic zone claims of countries and will allow study of the value of landed marine products to their economies and food security, and to those of their trading partners.


Expectations and experiences of eHealth in primary care: a qualitative practice-based investigation.
(1) To assess expectations and experiences of a new eHealth service by patients and staff in three primary care settings; (2) to ascertain attitudes to a range of future, primary care-oriented eHealth services. Qualitative case study. Three UK general practices introducing an eHealth service for booking patient appointments. Ninety patients purposively selected from users and non-users of the new service and 28 staff (clinicians, management and administrative staff). Actual patient use of the service was lower than stated intention. Patients and staff felt that more active promotion of the service would have resulted in more use. Low usage did not result in a negative assessment of the service by most staff. Different patient groupings were identified with characteristics that may be used as predictors of eHealth service use and indicators of training needs. GPs and patients expressed opposing viewpoints on a range of future eHealth services. Take-up of eHealth services may be lower than expected. To overcome patient barriers, factors that may narrow the intention-behaviour gap such as level of service promotion, GP endorsement, and usage by different patient groups, should be investigated. For clinician barriers, the eHealth evidence base needs strengthening, while for primary care practices, a learning process including staff training needs to be instituted. The differing views of patients and GPs about components of eHealth means that policymakers need to plan for a lengthy political process to obtain agreement on contentious issues if they are to achieve successful eHealth services.


Live-cell video microscopy of fungal pathogen phagocytosis.
Phagocytic clearance of fungal pathogens, and microorganisms more generally, may be considered to consist of four distinct stages: (i) migration of phagocytes to the site where pathogens are located; (ii) recognition of pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs); (iii) engulfment of microorganisms bound to the phagocyte cell membrane, and (iv) processing of engulfed cells within maturing phagosomes and digestion of the ingested particle. Studies that assess phagocytosis in its entirety are informative but are limited in that they do not normally break the process down into migration, engulfment and phagosome maturation, which may be affected differentially. Furthermore, such studies assess uptake as a single event, rather than as a continuous dynamic process. We have recently developed advanced live-cell imaging technologies, and have combined these with genetic functional analysis of both pathogen and host cells to create a cross-disciplinary platform for the analysis of innate immune cell function and fungal pathogenesis. These studies have revealed novel aspects of phagocytosis that could only be observed using systematic temporal analysis of the molecular and cellular interactions between human phagocytes and fungal pathogens and infectious microorganisms more generally. For example, we have begun to define the following: (a) the components of the cell surface required for each stage of the process of recognition, engulfment and killing of fungal cells; (b) how surface geometry influences the efficiency of macrophage uptake and killing of yeast and hyphal cells; and how engulfment leads to alteration of the cell cycle and behavior of macrophages. In contrast to single time point snapshots, live-cell video microscopy enables a wide variety of host cells and pathogens to be studied as continuous sequences over lengthy time periods, providing spatial and temporal information on a broad range of dynamic processes, including cell migration, replication and vesicular trafficking. Here we describe in detail how to prepare host and fungal cells, and to conduct the video microscopy experiments. These methods can provide a user-guide for future studies with other phagocytes and microorganisms.


Application of medical cannabis in unstable angina and coronary artery disease: A case report.
First discovered in 1990, the endocannabinoid system (ECS) was initially shown to have an intimate relationship with central areas of the nervous system associated with pain, reward, and motivation. Recently, however, the ECS has been extensively implicated in the cardiovascular system with contractility, heart rate, blood pressure, and vasodilation. Emerging data demonstrate modulation of the ECS plays an essential role in cardio metabolic risk, atherosclerosis, and can even limit damage to cardiomyocytes during ischemic events. This case describes a 63-year-old man who presented to a primary care physician for a medical cannabis (MC) consult due to unstable angina (UA) not relieved by morphine or cardiac medications; having failed all first- and second-line polypharmaceutical therapies. The patient reported frequent, unprovoked, angina and exertional dyspnea. Having a complex cardiac history, the patient first presented 22 years ago after a suspected myocardial infarction. He re-presented in 2010 and underwent stent placement at that time for inoperable triple-vessel coronary artery disease (CAD) which was identified via percutaneous transluminal coronary angioplasty. UA developed on follow-up and, despite medical management over the past 6 years, became progressively debilitating. In conjunction with his standard cardiac care, patient had a gradual lessening of UA-related pain, including frequency and character, after using an edible form of MC (1:1 cannabidiol:Δ9-tetrahydrocannabinol). Following continued treatment, he ceased long-term morphine treatment and described the pain as no longer crippling. As demonstrated by his exercise tolerance tests, the patient experienced an improved functional capacity and reported an increase in his daily functioning, and overall activity. This case uniquely highlights MC in possibly reducing the character, quality, and frequency of UA, whereas concordantly improving functional cardiac capacity in a patient with CAD. Additional case reports are necessary to verify this.


Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: detection of high order gene-gene interaction.
There have been many reports regarding the association between renin-angiotensin system (RAS) gene polymorphisms and coronary artery disease (CAD) or acute myocardial infarction (AMI), but the results are inconsistent. In the present study, we used several new approaches with multilocus data to reappraise this issue in a large and relatively homogeneous Taiwanese population. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with documented coronary artery disease and 519 without) between 1996 and 2003 were recruited. Angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen gene; and A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In single-locus analyses, no locus was associated with CAD, history of AMI and three-vessel CAD, either with or without adjustment for conventional CAD risk factors. For multilocus analyses, we recreated a balanced population, with the controls individually matched to the cases regarding the conventional CAD risk factors. We found that the angiotensinogen gene haplotype profile was significantly different between the cases and controls (chi2=31.6, P=0.030) in haplotype analyses. Furthermore, significant three-locus (G-217A, M235T and I/D) gene-gene interactions were detected by multifactor-dimensionality reduction method (highest cross-validation consistency 10.0, lowest prediction error 40.56%, P=0.017) and many even higher order gene-gene interactions by multilocus genotype disequilibrium tests (16 genotype disequilibria exclusively found in the controls, all of which included at least two genes among AGT, ACE and AT1R genes). Our study is the first to demonstrate epistatic, high-order, gene-gene interactions between RAS gene polymorphisms and CAD. These results are compatible with the concept of multilocus and multi-gene effects in complex diseases that would be missed with conventional approaches.


Opposite modulation of opiate withdrawal behaviors on microinfusion of a protein kinase A inhibitor versus activator into the locus coeruleus or periaqueductal gray.
Chronic opiate administration upregulates the cAMP pathway in the locus coeruleus (LC). This adaptation is thought to increase the electrical excitability of LC neurons and contribute to the dramatic increase in LC firing induced by opioid receptor antagonists in opiate-dependent animals. The goal of the present study was to evaluate directly a role of the cAMP pathway in opiate withdrawal behaviors by studying, in vivo, whether withdrawal is influenced by intra-LC infusion of compounds known to activate or inhibit protein kinase A (PKA). Infusions into amygdala or periaqueductal gray (PAG) were studied for comparison. In one series of experiments the effect of intra-LC, intra-amygdala, or intra-PAG infusions of the PKA inhibitor Rp-cAMPS on naloxone-precipitated withdrawal from morphine was examined. Intra-LC infusions of Rp-cAMPS significantly attenuated several prominent behavioral signs of morphine withdrawal. Intra-PAG infusions of Rp-cAMPS also significantly attenuated opiate withdrawal behaviors, although different behaviors were affected. In contrast, intra-amygdala infusions of Rp-cAMPS were without significant effect. In a second series of experiments the effect of intra-LC or intra-PAG infusions of the PKA activator Sp-cAMPS on behavior in nondependent drug-naive animals was determined. Sp-cAMPS infusions into either brain region induced a quasi-withdrawal syndrome, but the observed behaviors differed between the two groups. Analysis of the phosphorylation state of tyrosine hydroxylase, a well characterized substrate for PKA, confirmed the ability of Rp-cAMPS and Sp-cAMPS to inhibit and activate, respectively, PKA activity in vivo. Together, these data provide direct evidence for involvement of the cAMP-PKA system in the LC, as well as in the PAG, in opiate withdrawal and withdrawal-related behaviors.


A Systematic Review of Surgical Randomized Controlled Trials: Part 2. Funding Source, Conflict of Interest, and Sample Size in Plastic Surgery.
The authors examined industry support, conflict of interest, and sample size in plastic surgery randomized controlled trials that compared surgical interventions. They hypothesized that industry-funded trials demonstrate statistically significant outcomes more often, and randomized controlled trials with small sample sizes report statistically significant results more frequently. An electronic search identified randomized controlled trials published between 2000 and 2013. Independent reviewers assessed manuscripts and performed data extraction. Funding source, conflict of interest, primary outcome direction, and sample size were examined. Chi-squared and independent-samples t tests were used in the analysis. The search identified 173 randomized controlled trials, of which 100 (58 percent) did not acknowledge funding status. A relationship between funding source and trial outcome direction was not observed. Both funding status and conflict of interest reporting improved over time. Only 24 percent (six of 25) of industry-funded randomized controlled trials reported authors to have independent control of data and manuscript contents. The mean number of patients randomized was 73 per trial (median, 43, minimum, 3, maximum, 936). Small trials were not found to be positive more often than large trials (p = 0.87). Randomized controlled trials with small sample size were common; however, this provides great opportunity for the field to engage in further collaboration and produce larger, more definitive trials. Reporting of trial funding and conflict of interest is historically poor, but it greatly improved over the study period. Underreporting at author and journal levels remains a limitation when assessing the relationship between funding source and trial outcomes. Improved reporting and manuscript control should be goals that both authors and journals can actively achieve.


Optimality and evolution of transcriptionally regulated gene expression.
How transcriptionally regulated gene expression evolves under natural selection is an open question. The cost and benefit of gene expression are the driving factors. While the former can be determined by gratuitous induction, the latter is difficult to measure directly. We addressed this problem by decoupling the regulatory and metabolic function of the Escherichia coli lac system, using an inducer that cannot be metabolized and a carbon source that does not induce. Growth rate measurements directly identified the induced expression level that maximizes the metabolism benefits minus the protein production costs, without relying on models. Using these results, we established a controlled mismatch between sensing and metabolism, resulting in sub-optimal transcriptional regulation with the potential to improve by evolution. Next, we tested the evolutionary response by serial transfer. Constant environments showed cells evolving to the predicted expression optimum. Phenotypes with decreased expression emerged several hundred generations later than phenotypes with increased expression, indicating a higher genetic accessibility of the latter. Environments alternating between low and high expression demands resulted in overall rather than differential changes in expression, which is explained by the concave shape of the cross-environmental tradeoff curve that limits the selective advantage of altering the regulatory response. This work indicates that the decoupling of regulatory and metabolic functions allows one to directly measure the costs and benefits that underlie the natural selection of gene regulation. Regulated gene expression is shown to evolve within several hundreds of generations to optima that are predicted by these costs and benefits. The results provide a step towards a quantitative understanding of the adaptive origins of regulatory systems.


Quantification of insect genome divergence.
The recent sequencing of twelve insect genomes has enabled us to quantify their divergence using synteny conservation and sequence identity of single-copy orthologs. Protein identity correlates well with synteny and is about three times more conserved, an observation consistent with comparisons among vertebrates. The observed distribution of the lengths of synteny blocks follows a power law and differs from the expectations of the currently accepted random breakage model. Our results show that there is only limited selection for conservation of gene order and reveal a few hundred genes, proximity among which seems to be vital.


A ten-year review of lower extremity burns in diabetics: small burns that lead to major problems.
Diabetes mellitus with its resulting neurovascular changes may lead to an increased risk of burns and impaired wound healing. The purpose of this article is to review 10 years of experience with foot and lower leg burns in patients with diabetes at a single adult burn center. Patients with lower extremity burns and diabetes mellitus, between May 1999 and December 2009, were identified in the Trauma Registry of the American College of Surgeons database, and their charts were reviewed for data related to their outcomes. Sixty-eight diabetic patients, 87% male, with a mean age of 54 years, sustained foot or lower extremity burns with 37 having burns resulting from insensate feet. The pathogenesis included walking on a hot or very cold surface (8), soaking feet in hot water (22), warming feet on or near something hot such as a heater (13), or spilling hot water (7). The majority of patients were taking insulin (59.6%) or oral hyperglycemic medications (34.6%). Blood sugar levels were not well controlled (mean glucose, 215.8 mg/dl; mean hemoglobin A1c, 9.08%). Renal disease was common with admission serum blood urea nitrogen (27.5 mg/dl) and creatinine (2.21 mg/dl), and 13 were on dialysis preinjury. Cardiovascular problems were common with 39 (57%) having hypertension or cardiac disease, 3 having peripheral vascular disease, and 9, previous amputations. The mean burn size was 4.2% TBSA (range, 0.5-15%) with 57% being full thickness. Despite the small burn, the mean length of stay was 15.2 days (range, 1-95), with 5.65 days per 1% TBSA. Inability to heal these wounds was evident in 19 patients requiring readmission (one required 10 operative procedures). At least one patient sustained more than one burn. There were 62 complications with 30 episodes of infection (cellulitis, 28; osteomyelitis, 4; deep plantar infections, 2; ruptured Achilles tendon, 1) and 3 deaths. Eleven patients needed amputations (7 below-knee amputations, 4 transmetatarsal amputations, and 20 toe amputations) with several needing revisions or higher amputations. Patients with diabetes have an increased risk for lower extremity complications, but the risk of burns is not well known. The majority of lower extremity burns result from intentional exposure to sources of heat without recognition for the risk of burns. Once a burn occurs, morbidity and cost to the patient and society are severe. Prevention programs should be initiated to make diabetic patients and their doctors aware of the significant risk for burns.


Curvilinear relations between age and hemostatic parameters in Chinese.
The role of hemostatic factors in the pathogenesis of cardiovascular disease has gained much attention recently. Information about hemostatic factors, and their age patterns is sparse for orientals. With the data collected in the Cardiovascular Disease Risk Factor Two-township Study in Taiwan, this study shows that, in general, the older the age, the stronger the tendency toward thrombosis. With advancing age, prothrombin time, activated partial thromboplastin time, and antithrombin-III level decreased steadily; but mean values of fibrinogen, factor VIIc, and factor VIIIc increased. Gender differences in the age patterns of the above factors are carefully described. Curvilinear relations between hemostatic factors and age were demonstrated for adults aged 18 and above for all hemostatic factors studied. This curvilinearity should be taken into consideration when adjusting for the effect of age in data analysis to avoid residual confounding, particularly when the age range of the study subjects is wide.


Cryostat setup for measuring spectral and electrical properties of light-emitting diodes at junction temperatures from 81 K to 297 K.
We introduce a cryostat setup for measuring fundamental optical and electrical properties of light-emitting diodes (LEDs). With the setup, the cryostat pressure and the LED properties of the forward voltage, junction temperature, and electroluminescence spectrum are monitored with temperature steps less than 1.5 K, over the junction temperature range of 81-297 K. We applied the setup to commercial yellow AlGaInP and blue InGaN LEDs. At cryogenic temperatures, the fine structure of the electroluminescence spectra became resolved. For the yellow LED, we observed the phonon replica at 2.094 eV that was located 87 meV below the peak energy at the junction temperature of 81 K. For the blue LED, we observed the cascade phonon replicas at 2.599 eV, 2.510 eV, and 2.422 eV with the energy interval of 89 meV. For both LED types, the forward voltage increased sharply toward the lower temperatures due to the increased resistivity of materials in the LED components. We found significant differences between the temperature dependent behaviors of the forward voltages, spectral peak energies, and bandgap energies of LEDs obtained from the Varshni formula. We also noted a sharp pressure peak at 180-185 K arising from the solid-vapor phase transition of water when the base level of the cryostat pressure was approximately 0.4 mPa.


Spatial symmetry groups as sensorimotor guidelines.
While some aspects of neuroanatomical organization are related to packing and access rather than to function, other aspects of anatomical/physiological organization are directly related to function. The mathematics of symmetry groups can be used to determine logical structure in projections and to relate it to function. This paper reviews two studies of the symmetry groups of vestibular projections that are related to the spatial functions of the vestibular complex, including gaze, posture, and movement. These logical structures have been determined by finding symmetry groups of two vestibular projections directly from physiological and anatomical data. Logical structures in vestibular projections are distinct from mapping properties such as the ability to maintain two- and three-dimensional coordinate systems; rather, they provide anatomical/physiological foundations for these mapping properties. The symmetry group of the direct projection from the semicircular canal primary afferents to neck motor neurons is that of the cube (O, the octahedral group), which can serve as a discrete skeleton for coordinate systems in three-dimensional space. The symmetry group of the canal projection from the secondary vestibular afferents to the inferior olive and thence to the cerebellar uvula-nodulus is that of the square (D8), which can support coordinates for the horizontal plane. While the mathematical relationship between these symmetry groups and functions of the vestibular complex are clear, these studies open a larger question: what is the causal logic by which neural centers and their intrinsic organization affect each other and behavior? The relationship of vestibular projection symmetry groups to spatial function make them ideal projections for investigating this causal logic. The symmetry group results are discussed in relationship to possible ways they communicate spatial structure to other neural centers and format spatial functions such as body movements. These two projection symmetry groups suggest that all vestibular projections may have symmetry groups significantly related to function, perhaps all to spatial function.


Analysis of factors regulating erythrocyte deformability.
Using a laser diffraction technique, we have studied factors that influence the deformability of erythrocytes. Variations in suspending medium osmolality and applied shear stress were employed to isolate the individual contributions to whole cell deformability of internal viscosity, surface area-to-volume ratio, and viscoelastic properties of the membrane. An experimental system was devised in which normal cells were modified in vitro to induce specific alterations in each factor. Measurements of deformability as a function of medium osmolality showed characteristic behavior of the modified cells. Reduced surface area-to-volume ratio was detected by an exaggeration of the normal decrease in deformability as medium osmolality was decreased. In contrast, increased internal viscosity was detected by an increase in deformability as osmolality was decreased. Finally, decreased membrane flexibility was detected by reduced deformation at low shear stress. These methods of analysis were applied to cells from patients with hereditary spherocytosis, hereditary pyropoikilocytosis, and hemoglobin CC disease to define the basis of reduced deformability. Hereditary spherocytes showed the combined effects of reduced surface area and increased internal viscosity. Hereditary pyropoikilocytes revealed the effects of severely reduced surface area-to-volume ratio. Hemoglobin CC cells showed only the effects of high internal viscosity. An increase in the membrane shear modulus (decreased membrane deformability) was not evident in these disorders.


Music-induced Mood Biases Decision Strategies during the Ultimatum Game.
Recently, an increasing attempt has been made to understand the influence of mood on socioeconomic decision-making. We tested in this study whether an unpleasant mood would lead to unfavorable decisions more frequently than a pleasant mood, and whether decisions under different moods can be explained in different ways. Healthy volunteers were assigned to either a pleasant or unpleasant mood group and listened to musical excerpts to induce pleasant or unpleasant mood. Both groups completed the ultimatum game as a responder with an unacquainted partner who was actually a confederate. The proposer's offers were made in six different ratios of split (1:9, 2:8, 3:7, 4:6, 5:5, 6:4) in a preprogramed manner unbeknownst to the participants. After the completion of the task as a responder, the participant rated subjectively perceived fairness and emotional feelings about each split of offer. The statistical results showed that the unpleasant mood group rejected unfair offers more often compared to the pleasant mood group. Self-reported ratings of perceived fairness and emotional feelings did not statistically differ between the two groups. Interestingly, however, only in the unpleasant mood group, rejection rates of unfair offers were negatively correlated with perceived fairness. Both the pleasant and unpleasant mood groups showed a negative correlation between rejection rates of unfair offers and self-reported happiness. These results suggest a possibility that different decision strategies operate under different mood during a socioeconomic exchange.


Building an environmentally accountable medical curriculum through international collaboration.
Global environmental change is associated with significant health threats. The medical profession can address this challenge through advocacy, health system adaptation and workforce preparedness. Stewardship of health systems with attention to their environmental impacts can contribute to mitigation of and adaptation to negative health impacts of environmental change. Medical schools have an integral role in training doctors who understand the interdependence of ecosystems and human health. Yet integrating environmental perspectives into busy medical curricula is not a simple task. At the 2016 Association for Medical Education in Europe conference, medical educators, students and clinicians from six continents discussed these challenges in a participatory workshop. Here we reflect on emerging themes from the workshop and how to plan for curricular change. Firstly, we outline recent developments in environmental health and associated medical education. Secondly, we reflect on our process and outcomes during this innovative approach to international collaboration. Thirdly, we present learning objectives which cover core content for environmentally accountable medical curricula, developed through a reflective process of international collaboration integrating current literature and the workshop outcomes. International collaboration can bring together diverse perspectives and provide critical insights for the inclusion of environmental health into basic education for medical practitioners.


GenPhyloData: realistic simulation of gene family evolution.
PrIME-GenPhyloData is a suite of tools for creating realistic simulated phylogenetic trees, in particular for families of homologous genes. It supports generation of trees based on a birth-death process and--perhaps more interestingly--also supports generation of gene family trees guided by a known (synthetic or biological) species tree while accounting for events such as gene duplication, gene loss, and lateral gene transfer (LGT). The suite also supports a wide range of branch rate models enabling relaxation of the molecular clock. Simulated data created with PrIME-GenPhyloData can be used for benchmarking phylogenetic approaches, or for characterizing models or model parameters with respect to biological data. The concept of tree-in-tree evolution can also be used to model, for instance, biogeography or host-parasite co-evolution.