The B-box family gene STO (BBX24) in Arabidopsis thaliana regulates flowering time in different pathways.
Flowering at the appropriate time is crucial for reproductive success and is strongly influenced by various pathways such as photoperiod, circadian clock, FRIGIDA and vernalization. Although each separate pathway has been extensively studied, much less is known about the interactions between them. In this study we have investigated the relationship between the photoperiod/circadian clock gene and FRIGIDA/FLC by characterizing the function of the B-box STO gene family. STO has two B-box Zn-finger domains but lacks the CCT domain. Its expression is controlled by circadian rhythm and is affected by environmental factors and phytohormones. Loss and gain of function mutants show diversiform phenotypes from seed germination to flowering. The sto-1 mutant flowers later than the wild type (WT) under short day growth conditions, while over-expression of STO causes early flowering both in long and short days. STO over-expression not only reduces FLC expression level but it also activates FT and SOC1 expression. It also does not rely on the other B-box gene CO or change the circadian clock system to activate FT and SOC1. Furthermore, the STO activation of FT and SOC1 expression is independent of the repression of FLC; rather STO and FLC compete with each other to regulate downstream genes. Our results indicate that photoperiod and the circadian clock pathway gene STO can affect the key flowering time genes FLC and FT/SOC1 separately, and reveals a novel perspective to the mechanism of flowering regulation.


Designing Talbot array illuminators with phase-space optics.
The problem of designing Talbot array illuminators is revisited in the context of phase-space optics. It is shown that for Talbot array illuminators with optimum compression ratio the construction of phase-only grating profiles can be simplified significantly by using phase-space representations of optical signals. Based on the Wigner distribution function a graphical procedure is derived for obtaining the complete design of the array generator for a given compression ratio. The application of phase-space optics to other classes of Talbot array illuminators, and its use as part of numerical optimization algorithms, is considered as well.


A chloroplast DNA phylogeny of lilacs (Syringa, Oleaceae): plastome groups show a strong correlation with crossing groups.
Phylogenetic relationships and genomic compatibility were compared for 60 accessions of Syringa using chloroplast DNA (cpDNA) and nuclear ribosomal DNA (rDNA) markers. A total of 669 cpDNA variants, 653 of which were potentially phylogenetically informative, was detected using 22 restriction enzymes. Phylogenetic analyses reveal four strongly supported plastome groups that correspond to four genetically incompatible crossing groups. Relationships of the four plastome groups (I(II(III,IV))) correlate well with the infrageneric classification except for ser. Syringa and Pinnatifoliae. Group I, which includes subg. Ligustrina, forms a basal lineage within Syringa. Group II includes ser. Syringa and Pinnatifoliae and the two series have high compatibility and low sequence divergence. Group III consists of three well-defined species groups of ser. Pubescentes. Group IV comprises all members of ser. Villosae and has the lowest interspecific cpDNA sequence divergences. Comparison of cpDNA sequence divergence with crossability data indicates that hybrids have not been successfully generated between species with divergence greater than 0.7%. Hybrid barriers are strong among the four major plastome groups, which have sequence divergence estimates ranging from 1.096 to 1.962%. In contrast, fully fertile hybrids occur between species pairs with sequence divergence below 0.4%. Three regions of the plastome have length variants of greater than 100 bp, and these indels identify 12 different plastome types that correlate with phylogenetic trees produced from cpDNA restriction site data. Biparentally inherited nuclear rDNA and maternally inherited cpDNA length variants enable the identification of the specific parentage of several lilac hybrids.


Evaluation of the Role and Impact of Ambulatory Clinical Pharmacists in an Academic Comprehensive Cancer Center.
In recent years, there has been significant growth of ambulatory oncology pharmacy, yet there is a paucity of published studies on the clinical activities and impact of ambulatory oncology clinical pharmacists. At Duke Cancer Center, dedicated pharmacist services are embedded in specialized outpatient oncology areas. Pharmacists document their clinical and administrative activities in the electronic health record. The primary objective of this study is to quantify and assess ambulatory oncology pharmacist interventions in clinics in a large academic comprehensive cancer center. For the purposes of this single-center, retrospective, descriptive study, pharmacist interventions were collected, quantified, and described over a 6-month period from July 1 to December 31, 2015. The study evaluated the perceived contribution and impact of a pharmacist on patient care in ambulatory oncology clinics via a survey that was distributed to providers and nurses. In the 6-month time period, there were 5,091 interventions spanning 3,967 patient encounters between nine ambulatory oncology clinic pharmacists. The average time per encounter in the 6-month time frame was 22.4 minutes. There were 92 respondents to the survey (61.7% response rate). Overall, responses showed that the clinical pharmacists add value to patient care and are integral members of the team. Although previous studies have described pharmacist activities in outpatient oncology clinics, this study showed a larger number and variety of clinical pharmacist activities in outpatient cancer clinics to improve patient care. Future directions include conducting prospective, controlled studies to link pharmacist activities to tangible outcomes.


Educating nursing home staff on fracture prevention: a cluster randomised trial.
to assess whether specialist osteoporosis nurses delivering training to care home staff can reduce fractures and improve the prescription of treatments to reduce fractures versus usual care. pragmatic cluster randomised controlled trial (RCT) with randomisation at the Primary Care Organisation (PCO) level. care homes (residential, nursing and EMI) across England and Wales within PCOs. all 300 PCOs in England and Wales were invited to take part. Of these, 58 agreed to participate and gained ethical approval in time to start the study: 29 clusters were randomised to the intervention group and 29 to the control. specialist osteoporosis nurses undertaking short training sessions with care home staff emphase the importance of fracture and fall prevention and train staff on how to identify those residents at high risk of fracture. Residents' risk of fracture and falls was reported to general practitioners (GPs) of patients along with treatment recommendations. primary outcome measures were total fractures over the past 12 months and total hip fractures over past the 12 months. Secondary outcome measures were total home falls, number of residents sustaining a fall, number of residents prescribed bisphosphonates, number of residents prescribed calcium and vitamin D and number of residents wearing hip protectors. All outcomes were measured at the care home level. of the 230 care homes randomised data were collected from 209 of these containing 5,637 residents. There were no differences between the groups in the incidence rate ratios (IRRs) for total fractures (IRR = 0.94 [0.71, 1.26] P = 0.70) or total hip fractures (IRR = 0.86 [0.63, 1.18] P = 0.36). No differences were found between groups for home falls or hip protector use. A significant increase in bisphosphonate prescription was seen in the intervention group over the control group (IRR = 1.50 [1.00, 2.24] P = 0.05). Calcium and vitamin D prescription was significantly increased in the intervention group over the control group (IRR = 1.64 [1.23, 2.18] P<0.01). the intervention significantly increased the prescription of bisphosphonates and calcium/vitamin D, but was not associated with a significant effect on the rate of falls or fractures.


Effect of age and the APOE gene on metabolite concentrations in the posterior cingulate cortex.
Proton magnetic resonance spectroscopy (1H-MRS) has provided valuable information about the neurochemical profile of Alzheimer's disease (AD). However, its clinical utility has been limited in part by the lack of consistent information on how metabolite concentrations vary in the normal aging brain and in carriers of apolipoprotein E (APOE) ε4, an established risk gene for AD. We quantified metabolites within an 8cm3 voxel within the posterior cingulate cortex (PCC)/precuneus in 30 younger (20-40 years) and 151 cognitively healthy older individuals (60-85 years). All 1H-MRS scans were performed at 3T using the short-echo SPECIAL sequence and analyzed with LCModel. The effect of APOE was assessed in a sub-set of 130 volunteers. Older participants had significantly higher myo-inositol and creatine, and significantly lower glutathione and glutamate than younger participants. There was no significant effect of APOE or an interaction between APOE and age on the metabolite profile. Our data suggest that creatine, a commonly used reference metabolite in 1H-MRS studies, does not remain stable across adulthood within this region and therefore may not be a suitable reference in studies involving a broad age-range. Increases in creatine and myo-inositol may reflect age-related glial proliferation; decreases in glutamate and glutathione suggest a decline in synaptic and antioxidant efficiency. Our findings inform longitudinal clinical studies by characterizing age-related metabolite changes in a non-clinical sample.


The Role of the TGF-β Superfamily in Myocardial Infarction.
The members of the transforming growth factor β (TGF-β) superfamily are essential regulators of cell differentiation, phenotype and function, and have been implicated in the pathogenesis of many diseases. Myocardial infarction is associated with induction of several members of the superfamily, including TGF-β1, TGF-β2, TGF-β3, bone morphogenetic protein (BMP)-2, BMP-4, BMP-10, growth differentiation factor (GDF)-8, GDF-11 and activin A. This manuscript reviews our current knowledge on the patterns and mechanisms of regulation and activation of TGF-β superfamily members in the infarcted heart, and discusses their cellular actions and downstream signaling mechanisms. In the infarcted heart, TGF-β isoforms modulate cardiomyocyte survival and hypertrophic responses, critically regulate immune cell function, activate fibroblasts, and stimulate a matrix-preserving program. BMP subfamily members have been suggested to exert both pro- and anti-inflammatory actions and may regulate fibrosis. Members of the GDF subfamily may also modulate survival and hypertrophy of cardiomyocytes and regulate inflammation. Important actions of TGF-β superfamily members may be mediated through activation of Smad-dependent or non-Smad pathways. The critical role of TGF-β signaling cascades in cardiac repair, remodeling, fibrosis, and regeneration may suggest attractive therapeutic targets for myocardial infarction patients. However, the pleiotropic, cell-specific, and context-dependent actions of TGF-β superfamily members pose major challenges in therapeutic translation.


A Monte Carlo investigation of lung brachytherapy treatment planning.
Iodine-125 ((125)I) and Caesium-131 ((131)Cs) brachytherapy have been used in conjunction with sublobar resection to reduce the local recurrence of stage I non-small cell lung cancer compared with resection alone. Treatment planning for this procedure is typically performed using only a seed activity nomogram or look-up table to determine seed strand spacing for the implanted mesh. Since the post-implant seed geometry is difficult to predict, the nomogram is calculated using the TG-43 formalism for seeds in a planar geometry. In this work, the EGSnrc user-code BrachyDose is used to recalculate nomograms using a variety of tissue models for (125)I and (131)Cs seeds. Calculated prescription doses are compared to those calculated using TG-43. Additionally, patient CT and contour data are used to generate virtual implants to study the effects that post-implant deformation and patient-specific tissue heterogeneity have on perturbing nomogram-derived dose distributions. Differences of up to 25% in calculated prescription dose are found between TG-43 and Monte Carlo calculations with the TG-43 formalism underestimating prescription doses in general. Differences between the TG-43 formalism and Monte Carlo calculated prescription doses are greater for (125)I than for (131)Cs seeds. Dose distributions are found to change significantly based on implant deformation and tissues surrounding implants for patient-specific virtual implants. Results suggest that accounting for seed grid deformation and the effects of non-water media, at least approximately, are likely required to reliably predict dose distributions in lung brachytherapy patients.


Effect of exercise and environmental terrain on development of the digital cushion and bony structures of the bovine foot.
To determine whether exercise on alternative terrain affects the development of the digital cushion and bony structures of the bovine foot. 20 weaned bull calves. Two-month-old calves were randomly allocated to an exercise or control group. For 4 months, the control group was maintained in grass paddocks, and the exercise group was maintained in a 0.8-km lane with a mixed terrain of dirt, stones (0.32- to 0.95-cm pea gravel and 5-cm crusher run), and grass. Water and food for the exercise group were located at opposite ends of the lane; calves were fed twice daily, which ensured they walked 3.2 km/d. Pedometers were applied to all calves to measure distance traveled. All calves were slaughtered at 6 months of age. The right forefeet and hind feet were harvested for MRI and CT evaluation. Control calves walked a mean of 1.1 km daily, whereas the exercised calves walked a mean of 3.2 km daily. Mean digital cushion volume and surface area were 25,335 mm(3) and 15,647 mm(2), respectively, for the exercised calves and 17,026 mm(3) and 12,745 mm(2), respectively, for the control calves. When weight was controlled, mean digital cushion volume and surface area for the exercise group were increased by 37.10% and 18.25%, respectively, from those for the control group. Results indicated that exercise on alternative terrain increased the volume and surface area of the digital cushion of the feet of dairy calves, which should make them less susceptible to lameness.


Ciclopirox ethanolamine preserves the immature state of human HSCs by mediating intracellular iron content.
Culture conditions in which hematopoietic stem cells (HSCs) can be expanded for clinical benefit are highly sought after. To elucidate regulatory mechanisms governing the maintenance and propagation of human HSCs ex vivo, we screened libraries of annotated small molecules in human cord blood cells using an optimized assay for detection of functional HSCs during culture. We found that the antifungal agent ciclopirox ethanolamine (CPX) selectively supported immature CD34+CD90+ cells during culture and enhanced their long-term in vivo repopulation capacity. Purified HSCs treated with CPX showed a reduced cell division rate and an enrichment of HSC-specific gene expression patterns. Mechanistically, we found that the HSC stimulating effect of CPX was directly mediated by chelation of the intracellular iron pool, which in turn affected iron-dependent proteins and enzymes mediating cellular metabolism and respiration. Our findings unveil a significant impact of iron homeostasis in regulation of human HSCs, with important implications for both basic HSC biology and clinical hematology.


Affinity purification and characterization of a cutinase from the fungal plant pathogen Monilinia fructicola (Wint.) honey.
Trifluoromethyl ketones (TFK) are potent inhibitors of a variety of serine hydrolases. The TFK inhibitor, 3-(4-mercaptobutylthio)-1,1,1-trifluoro-2-propanone (MBTFP), was found to competitively inhibit cutinase activity (I50 = 9.4 x 10(-3)) from the fungal plant pathogen Monilinia fructicola and to serve as an effective affinity ligand for the purification of cutinases from culture filtrates. The TFK inhibitors, 3-n-octylthio-1,1,1-trifluoro-2-propanone (OTFP) and 3-n-pentylthio-1,1,1-trifluoro-2-propanone (PTFP), also inhibited cutinase activity with I50 values of 1.6 x 10(-6) and 2.3 x 10(-4) M, respectively. Buffer containing OTFP was the strongest eluant for cutinases of M. fructicola and provided the best purification factor and yield, although buffers containing OTFP, detergent, and salt were found to be effective for eluting cutinases bound to MBTFP-Sepharose. Buffer containing 0.5% Triton X-100 also selectively eluted cutinases from the affinity column. Two-dimensional electrophoretic analysis by SDS-PAGE and isoelectric focusing of the affinity-purified cutinase fraction indicated activity associated with proteins of pI 8.2 and molecular masses of approximately 18.6 and 20.8 kDa. These proteins hydrolyzed [3H]cutin and artificial substrates such as p-nitrophenylbutyrate and related esters, typical of other cutinases, but differ from previously characterized cutinases in molecular mass. The two low-molecular-weight proteins resolved by 2-D gel electrophoresis were subjected to in-gel digestion with Lys-C and the resulting peptide fragments were separated by Microbore-HPLC. The amino acid sequences of several internal peptide fragments had high homology with cutinase sequences from other fungi, particularly the plant pathogen Botrytis cinerea. Our study illustrates the potential of TFK ligands for the affinity purification of cutinases and indicates that the cutinases from M. fructicola have novel features warranting further study.


Computational prediction of protein aggregation: Advances in proteomics, conformation-specific algorithms and biotechnological applications.
Protein aggregation is a widespread phenomenon that stems from the establishment of non-native intermolecular contacts resulting in protein precipitation. Despite its deleterious impact on fitness, protein aggregation is a generic property of polypeptide chains, indissociable from protein structure and function. Protein aggregation is behind the onset of neurodegenerative disorders and one of the serious obstacles in the production of protein-based therapeutics. The development of computational tools opened a new avenue to rationalize this phenomenon, enabling prediction of the aggregation propensity of individual proteins as well as proteome-wide analysis. These studies spotted aggregation as a major force driving protein evolution. Actual algorithms work on both protein sequences and structures, some of them accounting also for conformational fluctuations around the native state and the protein microenvironment. This toolbox allows to delineate conformation-specific routines to assist in the identification of aggregation-prone regions and to guide the optimization of more soluble and stable biotherapeutics. Here we review how the advent of predictive tools has change the way we think and address protein aggregation.


L-Carnitine in the treatment of fatigue in adult celiac disease patients: a pilot study.
Fatigue is common in celiac disease. L-Carnitine blood levels are low in untreated celiac disease. L-Carnitine therapy was shown to improve muscular fatigue in several diseases. To evaluate the effect of L-carnitine treatment in fatigue in adult celiac patients. Randomised double-blind versus placebo parallel study. Thirty celiac disease patients received 2 g daily, 180 days (L-carnitine group) and 30 were assigned to the placebo group (P group). The patients underwent clinical investigation and questionnaires (Scott-Huskisson Visual Analogue Scale for Asthenia, Verbal Scale for Asthenia, Zung Depression Scale, SF-36 Health Status Survey, EuroQoL). OCTN2 levels, the specific carnitine transporter, were detected in intestinal tissue. Fatigue measured by Scott-Huskisson Visual Analogue Scale for Asthenia was significantly reduced in the L-carnitine group compared with the placebo group (p=0.0021). OCTN2 was decreased in celiac patients when compared to normal subjects (-134.67% in jejunum), and increased after diet in both celiac disease treatments. The other scales used did not show any significant difference between the two celiac disease treatment groups. L-Carnitine therapy is safe and effective in ameliorating fatigue in celiac disease. Since L-carnitine is involved in muscle energy production its decreased absorption due to OCTN2 reduction might explain muscular symptoms in celiac disease patients. The diet-induced OCTN2 increase, improving carnitine absorption, might explain the L-carnitine treatment efficacy.


Health and nutrition content claims on Australian fast-food websites.
To determine the extent that Australian fast-food websites contain nutrition content and health claims, and whether these claims are compliant with the new provisions of the Australia New Zealand Food Standards Code ('the Code'). Systematic content analysis of all web pages to identify nutrition content and health claims. Nutrition information panels were used to determine whether products with claims met Nutrient Profiling Scoring Criteria (NPSC) and qualifying criteria, and to compare them with the Code to determine compliance. Australian websites of forty-four fast-food chains including meals, bakery, ice cream, beverage and salad chains. Any products marketed on the websites using health or nutrition content claims. Of the forty-four fast-food websites, twenty (45 %) had at least one claim. A total of 2094 claims were identified on 371 products, including 1515 nutrition content (72 %) and 579 health claims (28 %). Five fast-food products with health (5 %) and 157 products with nutrition content claims (43 %) did not meet the requirements of the Code to allow them to carry such claims. New provisions in the Code came into effect in January 2016 after a 3-year transition. Food regulatory agencies should review fast-food websites to ensure compliance with the qualifying criteria for nutrition content and health claim regulations. This would prevent consumers from viewing unhealthy foods as healthier choices. Healthy choices could be facilitated by applying NPSC to nutrition content claims. Fast-food chains should be educated on the requirements of the Code regarding claims.


Double-ion imprinted polymer @magnetic nanoparticles modified screen printed carbon electrode for simultaneous analysis of cerium and gadolinium ions.
A typical, reproducible, and rugged screen printed carbon electrode, modified with dual-ion imprinted beads, was fabricated employing the "surface grafting from" approach. For this, the acyl chloride functionalized magnetic nanoparticles were first immobilized and chemically attached with a typical functional monomer (but-2-enedioic acid bis-[(2-amino-ethyl)-amide]) on the electrode surface. This was subsequently subjected to the thermal polymerization in the presence of template ions (Ce(IV) and Gd(III)), cross-linker (ethylene glycol dimethacrylate), initiator (AIBN), and multiwalled carbon nanotubes. The modified sensor was used for the simultaneous analysis of both template ions in aqueous, blood serum, and waste-water samples, using differential pulse anodic stripping voltammetry which revealed two oxidation peaks for respective templates with resolution as much as 950 mV, without any cross reactivity, interferences and false-positives. The detection limits realized by the proposed sensor, under optimized conditions, were found to be as low as 0.07 ng mL(-1) for Ce(IV) and 0.19 ng mL(-1) for Gd(III) (S/N=3) that could eventually be helpful for lanthanide estimation at stringent levels.


Improvement of Thermal Stability of BCG Vaccine
Thermal stability (TS) is a part of the BCG vaccine characterization by which the consistency of process in BCG vaccine production could be confirmed. To enhance the TS of the vaccine, some prevalent stabilizers in different concentrations were added to the final formulation of BCG bulk prior to Freeze-drying process. We found a formulation more effective than the current stabilizer for retaining the higher viability of lyophilized BCG vaccine produced by Pasteur Institute of Iran. In the design of experiments using Taguchi method, lactose, trehalose, glucose, dextran, and monosodium glutamate were added to the final formulation of BCG bulk prior to freeze-drying process. Viability of the samples was determined by counting the colony forming unit. Maximum signal-to-noise ratio equal to maximum TS and viability was obtained by adding lactose, dextran, and glutamate in defined concentrations. Adding the stabilizers had a significant impact on TS of BCG vaccine to meet the quality requirements.


Intrapancreatic accessory spleen.
An asymptomatic 79-year-old woman, with incidental finding on abdominal ultrasound of a solid nodule in the tail of the pancreas. Magnetic resonance imaging showed a 12mm solid tumor. The suggested diagnosis was pancreatic neuroendocrine tumor. The pathological examination showed an intrapancreatic splenic tissue. This is a rare ectopic location of spleen tissue and it should be considered in the differential diagnosis of pancreatic solid tumors.


The effects of lauromacrogol on thyroid tissue in rabbits. Is this a safe option for the treatment of nodular thyroid disease?
The effects of lauromacrogol as a sclerosing agent were evaluated on rabbit thyroid tissue. Twelve rabbits were divided into two equal groups. Intra-thyroid injections of 0.1 ml lauromacrogol were administered in the study group and 0.1 ml physiologic serum in the control group. The blood levels of free T3, free T4, TSH, postoperative adhesions and histopathologic differences of the thyroid tissues were evaluated. The values of serum free T3, free T4 and TSH levels did not differ significantly (p>0.05), but the free T3 levels were significantly different in the inter-group analysis (p=0.020). Postoperative macroscopic adhesion scores did not differ significantly (p>0.05). In the histopathologic evaluation, the inflammation and fibrosis scores were significantly higher in the study group (p=0.003). In our study, we found two important outcomes. Firstly, tests of thyroid function were not significantly different between the control and study groups. This important finding suggests lauromacrogol can be safely used without the risk of hypothyroidism or hyperthyroidism. Secondly, the Erlich-Hunt Model histopathologic evaluation results revealed that inflammation and fibrosis were significantly increased in the study group. This finding shows lauromacrogol can be effectively used to treat thyroid nodules by means of fibrosis. Lauromacrogol causes fibrosis in thyroid tissue without significant perithyroidal adhesion formation and functional differences. Treatment of nodular thyroid disease with lauromacrogol may be safe. Lauromacrogol, Nodule, Thyroid.


[Joint correction for motion artifacts and off-resonance artifacts in multi-shot diffusion magnetic resonance imaging].
Aiming at motion artifacts and off-resonance artifacts in multi-shot diffusion magnetic resonance imaging (MRI), we proposed a joint correction method in this paper to correct the two kinds of artifacts simultaneously without additional acquisition of navigation data and field map. We utilized the proposed method using multi-shot variable density spiral sequence to acquire MRI data and used auto-focusing technique for image deblurring. We also used direct method or iterative method to correct motion induced phase errors in the process of deblurring. In vivo MRI experiments demonstrated that the proposed method could effectively suppress motion artifacts and off-resonance artifacts and achieve images with fine structures. In addition, the scan time was not increased in applying the proposed method.


Subsite-based alterations in miR-21, miR-125b, and miR-203 in squamous cell carcinoma of the oral cavity and correlation to important target proteins.
MicroRNAs (miRNAs) are small noncoding RNA molecules with an essential role in regulation of gene expression. miRNA expression profiles differ between tumor and normal control tissue in many types of cancers and miRNA profiling is seen as a promising field for finding new diagnostic and prognostic tools. In this study, we have analyzed expression of three miRNAs, miR-21, miR-125b, and miR-203, and their potential target proteins p53 and p63, known to be deregulated in squamous cell carcinoma of the head and neck (SCCHN), in two distinct and one mixed subsite in squamous cell carcinoma in the oral cavity. We demonstrate that levels of miRNA differ between tumors of different subsites with tongue tumors showing significant deregulation of all three miRNAs, whereas gingival tumors only showed significant downregulation of miR-125b and the mixed group of tumors in tongue/floor of the mouth showed significant deregulation of miR-21 and miR-125b. In the whole group of oral squamous cell carcinoma (SCC), a significant negative correlation was seen between miR-125b and p53 as well as a significant correlation between TP53 mutation status and miR-125b. The present data once again emphasize the need to take subsite into consideration when analyzing oral SCC and clearly show that data from in vitro studies cannot be transferred directly to the in vivo situation.


Optically computed optical coherence tomography for volumetric imaging.
We describe an innovative optically computed optical coherence tomography (OC-OCT) technology. The OC-OCT system performs depth resolved imaging by computing the Fourier transform of the interferometric spectra optically. The OC-OCT system modulates the interferometric spectra with Fourier basis function projected to a spatial light modulator and detects the modulated signal without spectral discrimination. The novel, to the best of our knowledge, optical computation strategy enables volumetric OCT imaging without performing mechanical scanning and without the need for Fourier transform in a computer.


Patterns of spatial genetic structuring in a hydropsychid caddisfly (Cheumatopsyche sp. AV1) from southeastern Australia.
We assessed levels of mitochondrial genetic spatial structuring in the hydropsychid caddisfly Cheumatopsyche sp. AV1 in southeastern New South Wales, Australia. No significant spatial structuring was detected within or between catchments using analysis of molecular variance, and nested clade contingency analysis suggested no strong relationship between haplotypes and geographical location, at any clade level. However, tests for association among haplotypes incorporating geographical distance in the nested clade analysis, revealed patterns of historical range expansion and recent restricted gene flow. Most likely, population fragmentation preceded range expansion, although subsequent recontact and gene flow among the previously sundered populations has apparently obscured the geographical signature of the former fragmentation. Taken together, our analyses suggest that a number of populations fragmented during the Pleistocene evolved in isolation for a time and subsequently expanded into secondary contact. Since expansion, there has apparently been substantial (albeit somewhat restricted) dispersal and gene flow of adult female Cheumatopsyche sp. AV1, throughout the study area.


Photothermal Effect and Multi-Modality Imaging of Up-Conversion Nanomaterial Doped with Gold Nanoparticles.
Two key concerns exist in contemporary cancer chemotherapy in clinics: limited therapeutic efficiency and substantial side effects in patients. In recent years, researchers have been investigating revolutionary cancer treatment techniques and photo-thermal therapy (PTT) has been proposed by many scholars. A drug for photothermal cancer treatment was synthesized using the hydrothermal method, which has a high light-to-heat conversion efficiency. It may also be utilized as a clear multi-modality bioimaging platform for photoacoustic imaging (PAI), computed tomography (CT), and magnetic resonance imaging (MRI). When compared to single-modality imaging, multi-modality imaging delivers far more thorough and precise details for cancer diagnosis. Furthermore, gold-doped upconverting nanoparticles (UCNPs) have an exceptionally high target recognition for tumor cells. The gold-doped UCNPs, in particular, are non-toxic to normal tissues, endowing the as-prepared medications with outstanding therapeutic efficacy but exceptionally low side effects. These findings may encourage the creation of fresh effective imaging-guided approaches to meet the goal of photothermal cancer therapy.


The Economic Burden of Breast Cancer in Korea from 2007-2010.
This study estimates the socioeconomic cost and burden for breast cancer patients in Korea between 2007 and 2010. This study used a prevalence-based approach to estimate the cost of breast cancer. Breast cancer patients were defined as those who were hospitalized or have visited an outpatient clinic during the period from 2007 to 2010. The socioeconomic costs of breast cancer were subdivided into two costs: direct and indirect. From 2007 to 2010, the prevalence of treated breast cancer increased from 7.9% to 20.4%. The total socioeconomic costs incurred by breast cancer increased by approximately 40.7% from US $668.49 million in 2007 to US $940.75 million in 2010. The direct medical care costs for 2010 were 1.4 times greater (US $399.22 million) than for 2007 (US $278.71 million). The direct non-medical costs rose from US $50.69 million in 2007 to US $75.83 million in 2010, a 49.6% increase. Regarding the economic burden of breast cancer, the total indirect costs were US $339.09 million in 2007 and increased by 37.3% to US $465.70 million in 2010. In the sensitivity analysis, with the annual discount rate for each year ranging from 0%-5%, the costs increased 1.1-1.2 times. Due to the growing incidence of breast cancer, the annual prevalence and related costs are increasing. We must strive to reduce the socioeconomic burden of breast cancer through preventive measures and early screening.


iATTRACT: simultaneous global and local interface optimization for protein-protein docking refinement.
Protein-protein interactions are abundant in the cell but to date structural data for a large number of complexes is lacking. Computational docking methods can complement experiments by providing structural models of complexes based on structures of the individual partners. A major caveat for docking success is accounting for protein flexibility. Especially, interface residues undergo significant conformational changes upon binding. This limits the performance of docking methods that keep partner structures rigid or allow limited flexibility. A new docking refinement approach, iATTRACT, has been developed which combines simultaneous full interface flexibility and rigid body optimizations during docking energy minimization. It employs an atomistic molecular mechanics force field for intermolecular interface interactions and a structure-based force field for intramolecular contributions. The approach was systematically evaluated on a large protein-protein docking benchmark, starting from an enriched decoy set of rigidly docked protein-protein complexes deviating by up to 15 Å from the native structure at the interface. Large improvements in sampling and slight but significant improvements in scoring/discrimination of near native docking solutions were observed. Complexes with initial deviations at the interface of up to 5.5 Å were refined to significantly better agreement with the native structure. Improvements in the fraction of native contacts were especially favorable, yielding increases of up to 70%.


Transfer RNA Bound to MnmH Protein Is Enriched with Geranylated tRNA--A Possible Intermediate in Its Selenation?
The wobble nucleoside 5-methylaminomethyl-2-thio-uridine (mnm5s2U) is present in bacterial tRNAs specific for Lys and Glu and 5-carboxymethylaminomethyl-2-thio-uridine (cmnm5s2U) in tRNA specific for Gln. The sulfur of (c)mnm5s2U may be exchanged by selenium (Se)-a reaction catalyzed by the selenophosphate-dependent tRNA 2-selenouridine synthase encoded by the mnmH (ybbB, selU, sufY) gene. The MnmH protein has a rhodanese domain containing one catalytic Cys (C97) and a P-loop domain containing a Walker A motif, which is a potential nucleotide binding site. We have earlier isolated a mutant of Salmonella enterica, serovar Typhimurium with an alteration in the rhodanese domain of the MnmH protein (G67E) mediating the formation of modified nucleosides having a geranyl (ge)-group (C10H17-fragment) attached to the s2 group of mnm5s2U and of cmnm5s2U in tRNA. To further characterize the structural requirements to increase the geranylation activity, we here report the analysis of 39 independently isolated mutants catalyzing the formation of mnm5ges2U. All these mutants have amino acid substitutions in the rhodanese domain demonstrating that this domain is pivotal to increase the geranylation activity. The wild type form of MnmH+ also possesses geranyltransferase activity in vitro although only a small amount of the geranyl derivatives of (c)mnm5s2U is detected in vivo. The selenation activity in vivo has an absolute requirement for the catalytic Cys97 in the rhodanese domain whereas the geranylation activity does not. Clearly, MnmH has two distinct enzymatic activities for which the rhodanese domain is pivotal. An intact Walker motif in the P-loop domain is required for the geranylation activity implying that it is the binding site for geranylpyrophosphate (GePP), which is the donor molecule in vitro in the geranyltransfer reaction. Purified MnmH from wild type and from the MnmH(G67E) mutant have bound tRNA, which is enriched with geranylated tRNA. This in conjunction with earlier published data, suggests that this bound geranylated tRNA may be an intermediate in the selenation of the tRNA.


Quantifying the Risks of Asparagine Deamidation and Aspartate Isomerization in Biopharmaceuticals by Computing Reaction Free-Energy Surfaces.
Early identification of asparagine deamidation and aspartate isomerization degradation sites can facilitate the successful development of biopharmaceuticals. Several knowledge-based models have been proposed to assess these degradation risks. In this study, we propose a physics-based approach to identify the degradation sites on the basis of the free-energy barriers along the prechemical conformational step and the chemical reaction pathway. These contributions are estimated from classical and quantum mechanics/molecular mechanics molecular dynamics simulations. The computed barriers are compared to those for reference reactions in water within GNG and GDG sequence motifs in peptides (which demonstrate the highest degradation rates). Two major factors decreasing the degradation rates relative to the reference reactions are steric hindrance toward accessing reactive conformations and replacement of water by less polar side chains in the solvation shell of transition states. Among the potential degradation sites in the complementarity-determining region of trastuzumab and between two DK sites in glial cell-derived neurotropic factor, this method identified N30T, N55G, D102G, and D95K, respectively, in agreement with experiments. This approach can be incorporated in early computational screening of chemical degradation sites in biopharmaceuticals.


Macroautophagy Proteins Assist Epstein Barr Virus Production and Get Incorporated Into the Virus Particles.
Epstein Barr virus (EBV) persists as a latent herpes virus infection in the majority of the adult human population. The virus can reactivate from this latent infection into lytic replication for virus particle production. Here, we report that autophagic membranes, which engulf cytoplasmic constituents during macroautophagy and transport them to lysosomal degradation, are stabilized by lytic EBV replication in infected epithelial and B cells. Inhibition of autophagic membrane formation compromises infectious particle production and leads to the accumulation of viral DNA in the cytosol. Vice versa, pharmacological stimulation of autophagic membrane formation enhances infectious virus production. Atg8/LC3, an essential macroautophagy protein and substrate anchor on autophagic membranes, was found in virus preparations, suggesting that EBV recruits Atg8/LC3 coupled membranes to its envelope in the cytosol. Our data indicate that EBV subverts macroautophagy and uses autophagic membranes for efficient envelope acquisition during lytic infection.


Depressed height gain of children associated with intrauterine exposure to polycyclic aromatic hydrocarbons (PAH) and heavy metals: the cohort prospective study.
Fetal exposure to environmental toxicants may program the development of children and have long-lasting health impacts. The study tested the hypothesis that depressed height gain in childhood is associated with prenatal exposure to airborne polycyclic aromatic hydrocarbons (PAH) and heavy metals (lead and mercury). The study sample comprised 379 children born to non-smoking mothers among whom a total of 2011 height measurements were carried out over the 9-year follow-up period. Prenatal airborne PAH exposure was assessed by personal air monitoring of the mother in the second trimester of pregnancy and heavy metals were measured in cord blood. At the age of 3 residential air monitoring was done to evaluate the level of airborne PAH, and at the age 5 the levels of heavy metals were measured in capillary blood. The effect estimates of prenatal PAH exposure on height growth over the follow-up were adjusted in the General Estimated Equation (GEE) models for a wide set of relevant covariates. Prenatal exposure to airborne PAH showed a significant negative association with height growth, which was significantly decreased by 1.1cm at PAH level above 34.7 ng/m(3) (coeff.=-1.07, p=0.040). While prenatal lead exposure was not significantly associated with height restriction, the effect of mercury was inversely related to cord blood mercury concentration above 1.2 μg/L (coeff.=-1.21, p=0.020), The observed negative impact of prenatal PAH exposure on height gain in childhood was mainly mediated by shorter birth length related to maternal PAH exposure during pregnancy. The height gain deficit associated with prenatal mercury exposure was not seen at birth, but the height growth was significantly slower at later age.


Higher prevalence of non-skeletal comorbidity related to X-linked hypophosphataemia: a UK parallel cohort study using CPRD.
X-Linked hypophosphataemic rickets (XLH) is a rare multi-systemic disease of mineral homeostasis that has a prominent skeletal phenotype. The aim of this study was to describe additional comorbidities in XLH patients compared with general population controls. The Clinical Practice Research Datalink (CPRD) GOLD was used to identify a cohort of XLH patients (1995-2016), along with a non-XLH cohort matched (1 : 4) on age, sex and GP practice. Using the CALIBER portal, phenotyping algorithms were used to identify the first diagnosis (and associated age) of 273 comorbid conditions during patient follow-up. Fifteen major disease categories were used and the proportion of patients having ≥1 diagnosis was compared between cohorts for each category and condition. Main analyses were repeated according to the Index of Multiple Deprivation (IMD). There were 64 and 256 patients in the XLH and non-XLH cohorts, respectively. There was increased prevalence of endocrine [OR 3.46 (95% CI: 1.44, 8.31)] and neurological [OR 3.01 (95% CI: 1.41, 6.44)] disorders among XLH patients. Across all specific comorbidities, four were at least twice as likely to be present in XLH cases, but only depression met the Bonferroni threshold: OR 2.95 (95% CI: 1.47, 5.92). Distribution of IMD among XLH cases indicated greater deprivation than the general population. We describe a higher risk of mental illness in XLH patients compared with matched controls, and greater than expected deprivation. These findings may have implications for clinical practice guidelines and decisions around health and social care provision for these patients.


Thermistors coated with molecularly imprinted nanoparticles for the electrical detection of peptides and proteins.
In this communication, molecularly imprinted nanoparticles (nanoMIPs) that are produced by solid-phase synthesis are functionalised onto thermistors via dip-coating. These thermistors are soldered onto a printed-circuit board to facilitate electrical detection. Subsequently, these are inserted into a home-made thermal device that can measure the selective binding of biomolecules to the nanoMIP layer via monitoring the thermal resistance (Rth) at the solid-liquid interface. This thermal analysis technique, referred to as the Heat-Transfer Method, has previously been used for detection of proteins with MIP-based binders. While offering the advantages of low-cost and label free analysis, this method is limited by the high noise on the feedback loop and not being commercially available. These disadvantages can be overcome by the use of thermistors, which offer superior temperature sensitivity compared to thermocouples, and its electrical read-out can be easily integrated into portable devices. To our knowledge, this is the first report where MIPs are directly integrated onto thermistors for detection purposes. Measurements were conducted with an epitope of epidermal growth factor receptor (EGFR) and trypsin, where the electrical resistance was correlated to the biomolecule concentration. For both EGFR and trypsin, an enhanced signal to noise ratio for the electrical measurements was observed compared to previous analysis that was based on thermal resistance. The sensitivity of the sensors in buffered solution was in the nanomolar range, which is compatible with physiologically relevant concentrations. Upon exposure of the nanoMIP for EGFR towards pepsin no significant change in the resistance was yielded, establishing the selectivity of the developed sensor platform. Besides the enhanced sensitivity, the use of thermistors will enable miniaturisation of the device and has potential for in vivo measurements since specified electrochemical measurements are compatible with human use. To highlight the versatility of the nanoMIPs, this work should be extended to a set of biomolecules with various structures, with the possibility of extending this to an array format.


Sodium bicarbonate-based hydration prevents contrast-induced nephropathy: a meta-analysis.
Contrast-induced nephropathy is the leading cause of in-hospital acute renal failure. This side effect of contrast agents leads to increased morbidity, mortality, and health costs. Ensuring adequate hydration prior to contrast exposure is highly effective at preventing this complication, although the optimal hydration strategy to prevent contrast-induced nephropathy still remains an unresolved issue. Former meta-analyses and several recent studies have shown conflicting results regarding the protective effect of sodium bicarbonate. The objective of this study was to assess the effectiveness of normal saline versus sodium bicarbonate for prevention of contrast-induced nephropathy. The study searched MEDLINE, EMBASE, Cochrane databases, International Pharmaceutical Abstracts database, ISI Web of Science (until 15 December 2008), and conference proceedings for randomized controlled trials that compared normal saline with sodium bicarbonate-based hydration regimen regarding contrast-induced nephropathy. Random-effects models were used to calculate summary odds ratios. A total of 17 trials including 2,633 subjects were pooled. Pre-procedural hydration with sodium bicarbonate was associated with a significant decrease in the rate of contrast-induced nephropathy (odds ratios 0.52; 95% confidence interval 0.34-0.80, P = 0.003). Number needed to treat to prevent one case of contrast-induced nephropathy was 16 (95% confidence interval 10-34). No significant differences in the rates of post-procedure hemodialysis (P = 0.20) or death (P = 0.53) was observed. Sodium bicarbonate-based hydration was found to be superior to normal saline in prevention of contrast-induced nephropathy in this updated meta-analysis.


Effective medium equivalent to a symmetric multilayer at oblique incidence.
It is shown that a multilayer with repeated symmetric unit structure is equivalent to a homogeneous and optically biaxial medium for obliquely incident light, the three principal axes being normal to the plane of incidence, normal to the film plane, and normal to the other two. Unit thickness dependence and incident angle dependence of the dielectric tensor and the effective thickness are calculated using exact formulas. It is found that, at small unit structure thickness, the equivalent medium is almost uniaxial, the optical axis being normal to the film, and the effective thickness is very close to the mechanical one. Absorbing films are also envisaged and the domain of validity (in terms of unit structure thickness) of the uniaxial equivalent medium is defined by numerical examples.


Detection of specific IgE-secreting cells with an enzyme-linked immunospot assay.
An in vitro assay system for monitoring the induction of human allergen-specific IgE synthesis with an enzyme-linked immunospot assay is described. IgE-secreting cells, responding specifically to short ragweed pollen allergens. Amb a V and Amb a VI, were directly enumerated after the coculture of high-density, resting B cells with either autologous T cells or allergen-specific T-cell clones from the peripheral blood of two ragweed-allergic individuals. Both T-cell clones were type 2-like T helper cells (TH2) as determined by reverse transcription polymerase chain reaction. The IgE-producing cells were detected on a nitrocellulose-based paper disc coated with antigen after treatment with biotinylated, anti-human IgE and avidin-peroxidase conjugate. We demonstrated the induction of Amb a V- or Amb a VI-specific IgE synthesis from either peripheral blood B cells or purified resting B cells. Specific IgE-secreting B cells could be detected only when T cells were present in the culture, providing that they were not separated by a membrane. The addition of interleukin-4 had an enhancing effect on the overall numbers of IgE-secreting cells and allergen-specific T cells and a synergistic effect in the coculture of B cells and an autoreactive T-cell line. These results suggest that cognate interaction T and B cells is required for the de novo induction of IgE responses. This in vitro system could thus provide a useful model for analysis of the molecular and cellular mechanisms that regulate the allergen-specific IgE responses in human beings.


Towards socio-material approaches in simulation-based education: lessons from complexity theory.
Review studies of simulation-based education (SBE) consistently point out that theory-driven research is lacking. The literature to date is dominated by discourses of fidelity and authenticity - creating the 'real' - with a strong focus on the developing of clinical procedural skills. Little of this writing incorporates the theory and research proliferating in professional studies more broadly, which show how professional learning is embodied, relational and situated in social - material relations. A key concern for medical educators concerns how to better prepare students for the unpredictable and dynamic ambiguity of professional practice; this has stimulated the movement towards socio-material theories in education that address precisely this question. Among the various socio-material theories that are informing new developments in professional education, complexity theory has been of particular importance for medical educators interested in updating current practices. This paper outlines key elements of complexity theory, illustrated with examples from empirical study, to argue its particular relevance for improving SBE. Complexity theory can make visible important material dynamics, and their problematic consequences, that are not often noticed in simulated experiences in medical training. It also offers conceptual tools that can be put to practical use. This paper focuses on concepts of emergence, attunement, disturbance and experimentation. These suggest useful new approaches for designing simulated settings and scenarios, and for effective pedagogies before, during and following simulation sessions. Socio-material approaches such as complexity theory are spreading through research and practice in many aspects of professional education across disciplines. Here, we argue for the transformative potential of complexity theory in medical education using simulation as our focus. Complexity tools open questions about the socio-material contradictions inherent in SBE, draw attention to important material dynamics of emergence, and suggest practical educative ways to expand and deepen student learning.


The human SWI/SNF complex associates with RUNX1 to control transcription of hematopoietic target genes.
The acute myeloid leukemia 1 (AML1, RUNX1) transcription factor is a key regulator of hematopoietic differentiation that forms multi-protein complexes with co-regulatory proteins. These complexes are assembled at target gene promoters in nuclear microenvironments to mediate phenotypic gene expression and chromatin-related epigenetic modifications. Here, immunofluorescence microscopy and biochemical assays are used to show that RUNX1 associates with the human ATP-dependent SWI/SNF chromatin remodeling complex. The SWI/SNF subunits BRG1 and INI1 bind in vivo to RUNX1 target gene promoters (e.g., GMCSF, IL3, MCSF-R, MIP, and p21). These interactions correlate with histone modifications characteristic of active chromatin, including acetylated H4 and dimethylated H3 lysine 4. Downregulation of RUNX1 by RNA interference diminishes the binding of BRG1 and INI1 at selected target genes. Taken together, our findings indicate that RUNX1 interacts with the human SWI/SNF complex to control hematopoietic-specific gene expression.


Association between genetic variants in DNA and histone methylation and telomere length.
Telomere length, a biomarker of aging and age-related diseases, exhibits wide variation between individuals. Common genetic variation may explain some of the individual differences in telomere length. To date, however, only a few genetic variants have been identified in the previous genome-wide association studies. As emerging data suggest epigenetic regulation of telomere length, we investigated 72 single nucleotide polymorphisms (SNPs) in 46 genes that involve DNA and histone methylation as well as telomerase and telomere-binding proteins and DNA damage response. Genotyping and quantification of telomere length were performed in blood samples from 989 non-Hispanic white participants of the Sister Study, a prospective cohort of women aged 35-74 years. The association of each SNP with logarithmically-transformed relative telomere length was estimated using multivariate linear regression. Six SNPs were associated with relative telomere length in blood cells with p-values<0.05 (uncorrected for multiple comparisons). The minor alleles of BHMT rs3733890 G>A (p = 0.041), MTRR rs2966952 C>T (p = 0.002) and EHMT2 rs558702 G>A (p = 0.008) were associated with shorter telomeres, while minor alleles of ATM rs1801516 G>A (p = 0.031), MTR rs1805087 A>G (p = 0.038) and PRMT8 rs12299470 G>A (p = 0.019) were associated with longer telomeres. Five of these SNPs are located in genes coding for proteins involved in DNA and histone methylation. Our results are consistent with recent findings that chromatin structure is epigenetically regulated and may influence the genomic integrity of telomeric region and telomere length maintenance. Larger studies with greater coverage of the genes implicated in DNA methylation and histone modifications are warranted to replicate these findings.


Vocal cord paralysis in the Shy-Drager syndrome.
Eight out of 12 unselected patients with Shy-Drager syndrome were found to have severe bilateral paresis of vocal cord abduction by fibre-optic laryngoscopy. This commonly presented as increased snoring followed by episodes of inspiratory and expiratory stridor and sometimes by sleep apnoea. Respiratory failure eventually developed in four cases and was reversed by tracheostomy. In another patient tracheostomy relieved severe attacks of sleep apnoea. This complication was not necessarily associated with advanced disease, and it should be considered in all patients with Shy-Drager syndrome as appropriate treatment can lead to a useful extension of life.


The Quest for Value in Canadian Healthcare: The Applied Value in Healthcare Framework.
The exponential rise in healthcare costs in developed nations has sharpened the need for greater "value" in healthcare. Porter's (2010) seminal work is one of the most cited definitions and equation for value-based care. The pursuit of greater value in our healthcare system is of paramount importance, yet translating value-based healthcare (VBHC) into a framework that can be effectively utilized in the Canadian system remains a challenge. To address this challenge, we propose that VBHC can be adapted to fit the Canadian healthcare system through (1) visionary leadership for and conceptualization of VBHC at the federal government level and (2) thoughtful application of VBHC at the provincial government level. Our applied value in healthcare framework serves as a platform from which VBHC initiatives, programs and outcome measures can be systematically organized and executed within provincial healthcare systems. This methodical approach could support both provincial ministries and their health systems in pursuit of VBHC and provide the basis for explicit measurement of VBHC success, thereby helping to address the pressing issue of sustainability of the Canadian healthcare system while optimizing patient-centred outcomes of care.


Isoniazid- and rifampicin-induced oxidative hepatic injury--protection by N-acetylcysteine.
The role of N-acetylcysteine (NAC), a glutathione (GSH) precursor, was investigated in protection against isoniazid- (INH) and rifampicin- (RIF) induced oxidative hepatic injury in young Wistar rats. The hepatotoxic dose of INH and RIF was 50 mg kg(-1) day(-1) each and the hepatoprotective dose of NAC was 100 mg kg(-1) day(-1). All drugs were administered intraperitoneally (i.p.) in sterile water (4.0 ml kg(-1) day(-1)) over a period of 3 weeks. Status of oxidative/antioxidative profiles was the mechanistic approach to assess the hepatotoxicity and/or hepatoprotection. The oxidative injury in INH-RIF co-exposed animals was closely associated with significant decline of GSH and related thiols, as well as with compromised antioxidant enzyme system. The oxidative stress was further supported by increased lipid peroxidation observed in these animals. The co-administration of NAC prevented the induction of oxidative stress in INH-RIF co-exposed animals. The amelioration of oxidative stress by NAC was faithfully reflected as normal morphology in these animals, except the presence of mild degree of portal triaditis in one animal co-exposed to INH-RIF and NAC. In contrast, the animals co-exposed to INH-RIF alone showed histological lesions which ranged from intralobular inflammation to patchy necrosis. These results suggest that INH-RIF-induced oxidative injury can be prevented by supporting the cellular antioxidant defense mechanism by NAC.


The Role of Spatial Statistics in the Control and Elimination of Neglected Tropical Diseases in Sub-Saharan Africa: A Focus on Human African Trypanosomiasis, Schistosomiasis and Lymphatic Filariasis.
Disease control and elimination programmes can benefit greatly from accurate information on the spatial variability of disease risk, particularly when risk is highly spatially heterogeneous. Due to advances in statistical methodology, coupled with the increased availability of geospatial technology, this information is becoming increasingly accessible. In this chapter we describe recent advancements in spatial methods associated with the analysis of disease data measured at the point-level and demonstrate their application to the control and elimination of neglected tropical diseases (NTDs). We further provide information on spatially referenced data sources and software that can be used to create NTD risk maps, concentrating on those that can be freely obtained. Examples relating to three NTDs affecting populations in sub-Saharan Africa are presented throughout the chapter, i.e., human African trypanosomiasis, schistosomiasis and lymphatic filariasis. These three diseases, with differing routes of transmission, control methods and level of spatial heterogeneity, demonstrate the flexibility and applicability of the methods described.


Noncanonical Wnt signaling regulates midline convergence of organ primordia during zebrafish development.
Several components of noncanonical Wnt signaling pathways are involved in the control of convergence and extension (CE) movements during zebrafish and Xenopus gastrulation. However, the complexity of these pathways and the wide patterns of expression and activity displayed by some of their components immediately suggest additional morphogenetic roles beyond the control of CE. Here we show that the key modular intracellular mediator Dishevelled, through a specific activation of RhoA GTPase, controls the process of convergence of endoderm and organ precursors toward the embryonic midline in the zebrafish embryo. We also show that three Wnt noncanonical ligands wnt4a, silberblick/wnt11, and wnt11-related regulate this process by acting in a largely redundant way. The same ligands are also required, nonredundantly, to control specific aspects of CE that involve interaction of Dishevelled with mediators different from that of RhoA GTPase. Overall, our results uncover a late, previously unexpected role of noncanonical Wnt signaling in the control of midline assembly of organ precursors during vertebrate embryo development.


What explains black-white differences in survival in idiopathic dilated cardiomyopathy? The Washington, DC, Dilated Cardiomyopathy Study.
We have found race to be an independent predictor of mortality in a preliminary analysis of data from an ongoing study of patients with idiopathic dilated cardiomyopathy. Our previous, analyses, however, were based on only 12 to 24 months of follow-up. In the present analysis, which is based on up to 5 years of follow-up, we extended our earlier observations and examined whether other socioeconomic factors account for the association with race. A total of 128 patients from five Washington, DC, area hospitals were included in the analysis. One hundred three (80.5%) of the patients were black and 25 (19.5%) were white. The black patients were less likely to have private health insurance, less educated on average, and more likely to have a household income < or = $15,000. No racial differences were found in cardiac medication usage, with the exception of beta blockers and antiarrhythmics. The cumulated survival among black patients at 12 and 60 months was 71.5% and 39.1%, respectively, compared with 92% and 31.4% among whites. Age, ventricular arrhythmias, and ejection fraction were significant predictors of survival in univariate analysis. The univariate association with black race was of borderline significance. In multivariable analysis using the proportional hazards model, age and ejection fraction were significant independent predictors of survival. The association with ventricular arrhythmias was of borderline significance. The association with black race, which was statistically nonsignificant, was diminished even further by adjustment for income and type of health insurance. Thus, the previously reported association with black race may be accounted for by socioeconomic factors related to access to health care.


A DFT+U study of the catalytic degradation of 1,2-dichloroethane over CeO2.
The catalytic degradation of 1,2-dichloroethane (DCE) at CeO2(111) was investigated using periodic density functional theory calculations corrected by on-site Coulomb interactions. From thorough calculations of possible elementary steps, we are able to identify the lowest energy reaction pathway for the catalytic oxidation of DCE at CeO2(111). It proceeds via two successive C-Cl bond breaking processes to form adsorbed CH2CH2 species, and after further dehydrogenation and C-C bond scission, the surface species are finally oxidized to CO2 and H2O. The surface oxygen vacancies were found to be important for the catalytic decomposition of DCE, by providing the adsorption sites, as well as for charge transfer to favor C-Cl bond breaking. We are also able to illustrate the effect of H2O on the catalytic activity of CeO2(111) for DCE oxidation.


Impact of Interstitial Ni on the Thermoelectric Properties of the Half-Heusler TiNiSn.
TiNiSn is an intensively studied half-Heusler alloy that shows great potential for waste heat recovery. Here, we report on the structures and thermoelectric properties of a series of metal-rich TiNi1+ySn compositions prepared via solid-state reactions and hot pressing. A general relation between the amount of interstitial Ni and lattice parameter is determined from neutron powder diffraction. High-resolution synchrotron X-ray powder diffraction reveals the occurrence of strain broadening upon hot pressing, which is attributed to the metastable arrangement of interstitial Ni. Hall measurements confirm that interstitial Ni causes weak n-type doping and a reduction in carrier mobility, which limits the power factor to 2.5-3 mW m-1 K-2 for these samples. The thermal conductivity was modelled within the Callaway approximation and is quantitively linked to the amount of interstitial Ni, resulting in a predicted value of 12.7 W m-1 K-1 at 323 K for stoichiometric TiNiSn. Interstitial Ni leads to a reduction of the thermal band gap and moves the peak ZT = 0.4 to lower temperatures, thus offering the possibility to engineer a broad ZT plateau. This work adds further insight into the impact of small amounts of interstitial Ni on the thermal and electrical transport of TiNiSn.


The drop-jump video screening test: retention of improvement in neuromuscular control in female volleyball players.
A valgus lower limb alignment is commonly documented during noncontact anterior cruciate ligament injuries. We previously developed a videographic drop-jump test to measure overall lower limb alignment in the coronal plane as a screening tool to detect such an abnormal (valgus) position on landing. A neuromuscular retraining program developed for female athletes was shown to be effective in improving lower limb alignment on this test immediately after completion of training. What remained unknown was whether these improvements would be retained for longer periods of time. Therefore, this study was undertaken to determine if these improvements in overall lower limb alignment would be retained up to 1 year after the training. Sixteen competitive, experienced female high-school volleyball players underwent the video drop-jump test and then completed the neuromuscular retraining program. The program consisted of a dynamic warm-up, jump training, speed and agility drills, strength training, and static stretching and was performed 3 times a week for 6 weeks. The athletes repeated the drop-jump test immediately upon completion of training and then 3- and 12-months later. Significant improvements were found in the mean normalized knee separation distance between the pre and posttrained values for all test sessions (p < 0.01). Immediately after training, 11 athletes (69%) displayed significant improvements in the mean normalized knee separation distance that were retained 12 months later. Five athletes failed to improve. The video drop-jump test, although not a risk indicator for a knee ligament injury, provides a cost-effective general assessment of lower limb position and depicts athletes who have poor control on landing and acceleration into a vertical jump.


PCSK9 is a critical regulator of the innate immune response and septic shock outcome.
A decrease in the activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases the amount of low-density lipoprotein (LDL) receptors on liver cells and, therefore, LDL clearance. The clearance of lipids from pathogens is related to endogenous lipid clearance; thus, PCSK9 may also regulate removal of pathogen lipids such as lipopolysaccharide (LPS). Compared to controls, Pcsk9 knockout mice displayed decreases in inflammatory cytokine production and in other physiological responses to LPS. In human liver cells, PCSK9 inhibited LPS uptake, a necessary step in systemic clearance and detoxification. Pharmacological inhibition of PCSK9 improved survival and inflammation in murine polymicrobial peritonitis. Human PCSK9 loss-of-function genetic variants were associated with improved survival in septic shock patients and a decrease in inflammatory cytokine response both in septic shock patients and in healthy volunteers after LPS administration. The PCSK9 effect was abrogated in LDL receptor (LDLR) knockout mice and in humans who are homozygous for an LDLR variant that is resistant to PCSK9. Together, our results show that reduced PCSK9 function is associated with increased pathogen lipid clearance via the LDLR, a decreased inflammatory response, and improved septic shock outcome.


Energy and protein intake increases with an electronic bedside spoken meal ordering system compared to a paper menu in hospital patients.
Electronic bedside spoken meal ordering systems (BMOS) have the potential to improve patient dietary intakes, but there are few published evaluation studies. The aim of this study was to determine changes in the dietary intake and satisfaction of hospital patients, as well as the role of the Nutrition Assistant (NA), associated with the implementation of an electronic BMOS compared to a paper menu. This study evaluated the effect of a BMOS compared to a paper menu at a 210-bed tertiary private hospital in Sydney during 2011-2012. Patient dietary intake, patient satisfaction and changes in NA role were the key outcomes measured. Dietary intake was estimated from observational recordings and photographs of meal trays (before and after patient intake) over two 48 h periods. Patient satisfaction was measured through written surveys, and the NA role was compared through a review of work schedules, observation, time recordings of patient contact, written surveys and structured interviews. Baseline data were collected across five wards from 54 patients (75% response rate) whilst using the paper menu service, and after BMOS was introduced across the same five wards, from 65 patients (95% response rate). Paper menu and BMOS cohorts' demographics, self-reported health, appetite, weight, body mass index, dietary requirements, and overall foodservice satisfaction remained consistent. However, 80% of patients preferred the BMOS, and importantly mean daily energy and protein intakes increased significantly (paper menu versus BMOS): 6273 kJ versus 8273 kJ and 66 g versus 83 g protein; both p < 0.05. No additional time was required for the NA role, however direct patient interaction increased significantly (p < 0.05), and patient awareness of the NA and their role increased with the BMOS. The utilisation of a BMOS improved patient energy and protein intake. These results are most likely due to an enhancement of existing NA work processes, enabling more NA time with patients, facilitating an increase in patient participation and satisfaction with the service.


Electroencephalography correlates of spatial working memory deficits in attention-deficit/hyperactivity disorder: vigilance, encoding, and maintenance.
In the current study we sought to dissociate the component processes of working memory (WM) (vigilance, encoding and maintenance) that may be differentially impaired in attention-deficit/ hyperactivity disorder (ADHD). We collected electroencephalographic (EEG) data from 52 children with ADHD and 47 typically developing (TD) children, ages 7-14 years, while they performed a spatial Sternberg working memory task. We used independent component analysis and time-frequency analysis to identify midoccipital alpha (8-12 Hz) to evaluate encoding processes and frontal midline theta (4-7 Hz) to evaluate maintenance processes. We tested for effects of task difficulty and cue processing to evaluate vigilance. Children with ADHD showed attenuated alpha band event-related desynchronization (ERD) during encoding. This effect was more pronounced when task difficulty was low (consistent with impaired vigilance) and was predictive of memory task performance and symptom severity. Correlated with alpha ERD during encoding were alpha power increases during the maintenance period (relative to baseline), suggesting a compensatory effort. Consistent with this interpretation, midfrontal theta power increases during maintenance were stronger in ADHD and in high-load memory conditions. Furthermore, children with ADHD exhibited a maturational lag in development of posterior alpha power whereas age-related changes in frontal theta power deviated from the TD pattern. Last, subjects with ADHD showed age-independent attenuation of evoked responses to warning cues, suggesting low vigilance. Combined, these three EEG measures predicted diagnosis with 70% accuracy. We conclude that the interplay of impaired vigilance and encoding in ADHD may compromise maintenance and lead to impaired WM performance in this group.


Eligibility and subsequent burden of cardiovascular disease of four strategies for blood pressure-lowering treatment: a retrospective cohort study.
Worldwide treatment recommendations for lowering blood pressure continue to be guided predominantly by blood pressure thresholds, despite strong evidence that the benefits of blood pressure reduction are observed in patients across the blood pressure spectrum. In this study, we aimed to investigate the implications of alternative strategies for offering blood pressure treatment, using the UK as an illustrative example. We did a retrospective cohort study in primary care patients aged 30-79 years without cardiovascular disease, using data from the UK's Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality. We assessed and compared four different strategies to determine eligibility for treatment: using 2011 UK National Institute for Health and Care Excellence (NICE) guideline, or proposed 2019 NICE guideline, or blood pressure alone (threshold ≥140/90 mm Hg), or predicted 10-year cardiovascular risk alone (QRISK2 score ≥10%). Patients were followed up until the earliest occurrence of a cardiovascular disease diagnosis, death, or end of follow-up period (March 31, 2016). For each strategy, we estimated the proportion of patients eligible for treatment and number of cardiovascular events that could be prevented with treatment. We then estimated eligibility and number of events that would occur during 10 years in the UK general population. Between Jan 1, 2011, and March 31, 2016, 1 222 670 patients in the cohort were followed up for a median of 4·3 years (IQR 2·5-5·2). 271 963 (22·2%) patients were eligible for treatment under the 2011 NICE guideline, 327 429 (26·8%) under the proposed 2019 NICE guideline, 481 859 (39·4%) on the basis of a blood pressure threshold of 140/90 mm Hg or higher, and 357 840 (29·3%) on the basis of a QRISK2 threshold of 10% or higher. During follow-up, 32 183 patients were diagnosed with cardiovascular disease (overall rate 7·1 per 1000 person-years, 95% CI 7·0-7·2). Cardiovascular event rates in patients eligible for each strategy were 15·2 per 1000 person-years (95% CI 15·0-15·5) under the 2011 NICE guideline, 14·9 (14·7-15·1) under the proposed 2019 NICE guideline, 11·4 (11·3-11·6) with blood pressure threshold alone, and 16·9 (16·7-17·1) with QRISK2 threshold alone. Scaled to the UK population, we estimated that 233 152 events would be avoided under the 2011 NICE guideline (28 patients needed to treat for 10 years to avoid one event), 270 233 under the 2019 NICE guideline (29 patients), 301 523 using a blood pressure threshold (38 patients), and 322 921 using QRISK2 threshold (27 patients). A cardiovascular risk-based strategy (QRISK2 ≥10%) could prevent over a third more cardiovascular disease events than the 2011 NICE guideline and a fifth more than the 2019 NICE guideline, with similar efficiency regarding number treated per event avoided. National Institute for Health Research.


There Is Something in the Air: Testing the Efficacy of a new Olfactory Stress Relief Method (AromaStick®).
In recent years, aromatherapy has become increasingly popular for clinical treatment and therapeutic management of both acute and chronic stress. It targets distinct and unique neurobiological characteristics of the olfactory system, which is tightly linked to emotions and information processing as well as the autonomous nervous system. Yet, depending on the mode of application, aromatherapeutic interventions show varying degrees of therapeutic effectiveness. In a series of five experiments, the effects of a new mode of aromatherapeutic application (inhaler) was investigated, which is specifically designed to directly stimulate the olfactory system and to reduce the activity of the sympathetic nervous system. Overall, the application of the inhaler showed consistent and large psychological and physiological effects. It also clearly outperformed other stress management techniques, like progressive muscle relaxation, Bach flowers or passive resting periods (natural control). The effects occurred shortly after very few inhalations, drastically reduced stress related biomarkers (i.e. blood pressure, heart rate and cortisol) and considerably enhanced well-being. Copyright © 2015 John Wiley & Sons, Ltd.


Normal laboratory reference intervals among healthy adults screened for a HIV pre-exposure prophylaxis clinical trial in Botswana.
Accurate clinical laboratory reference values derived from a local or regional population base are required to correctly interpret laboratory results. In Botswana, most reference intervals used to date are not standardized across clinical laboratories and are based on values derived from populations in the United States or Western Europe. We measured 14 hematologic and biochemical parameters of healthy young adults screened for participation in the Botswana HIV Pre-exposure Prophylaxis Study using tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) (TDF2 Study). Reference intervals were calculated using standard methods, stratified by gender, and compared with the site-derived reference values used for the TDF2 study (BOTUSA ranges), the Division of AIDS (DAIDS) Grading Table for Adverse Events, the Botswana public health laboratories, and other regional references. Out of 2533 screened participants, 1786 met eligibility criteria for participation in study and were included in the analysis. Our reference values were comparable to those of the Botswana public health system except for amylase, blood urea nitrogen (BUN), phosphate, total and direct bilirubin. Compared to our reference values, BOTUSA reference ranges would have classified participants as out of range for some analytes, with amylase (50.8%) and creatinine (32.0%) producing the highest out of range values. Applying the DAIDS toxicity grading system to the values would have resulted in 45 and 18 participants as having severe or life threatening values for amylase and hemoglobin, respectively. Our reference values illustrate the differences in hematological and biochemical analyte ranges between African and Western populations. Thus, the use of western-derived reference laboratory values to screen a group of Batswana adults resulted in many healthy people being classified as having out-of-range blood analytes. The need to establish accurate local or regional reference values is apparent and we hope our results can be used to that end in Botswana.


High-resolution linkage map and chromosome-scale genome assembly for cassava (Manihot esculenta Crantz) from 10 populations.
Cassava (Manihot esculenta Crantz) is a major staple crop in Africa, Asia, and South America, and its starchy roots provide nourishment for 800 million people worldwide. Although native to South America, cassava was brought to Africa 400-500 years ago and is now widely cultivated across sub-Saharan Africa, but it is subject to biotic and abiotic stresses. To assist in the rapid identification of markers for pathogen resistance and crop traits, and to accelerate breeding programs, we generated a framework map for M. esculenta Crantz from reduced representation sequencing [genotyping-by-sequencing (GBS)]. The composite 2412-cM map integrates 10 biparental maps (comprising 3480 meioses) and organizes 22,403 genetic markers on 18 chromosomes, in agreement with the observed karyotype. We used the map to anchor 71.9% of the draft genome assembly and 90.7% of the predicted protein-coding genes. The chromosome-anchored genome sequence will be useful for breeding improvement by assisting in the rapid identification of markers linked to important traits, and in providing a framework for genomic selection-enhanced breeding of this important crop.


MtSNPscore: a combined evidence approach for assessing cumulative impact of mitochondrial variations in disease.
Human mitochondrial DNA (mtDNA) variations have been implicated in a broad spectrum of diseases. With over 3000 mtDNA variations reported across databases, establishing pathogenicity of variations in mtDNA is a major challenge. We have designed and developed a comprehensive weighted scoring system (MtSNPscore) for identification of mtDNA variations that can impact pathogenicity and would likely be associated with disease. The criteria for pathogenicity include information available in the literature, predictions made by various in silico tools and frequency of variation in normal and patient datasets. The scoring scheme also assigns scores to patients and normal individuals to estimate the cumulative impact of variations. The method has been implemented in an automated pipeline and has been tested on Indian ataxia dataset (92 individuals), sequenced in this study, and other publicly available mtSNP dataset comprising of 576 mitochondrial genomes of Japanese individuals from six different groups, namely, patients with Parkinson's disease, patients with Alzheimer's disease, young obese males, young non-obese males, and type-2 diabetes patients with or without severe vascular involvement. MtSNPscore, for analysis can extract information from variation data or from mitochondrial DNA sequences. It has a web-interface http://bioinformatics.ccmb.res.in/cgi-bin/snpscore/Mtsnpscore.pl that provides flexibility to update/modify the parameters for estimating pathogenicity. Analysis of ataxia and mtSNP data suggests that rare variants comprise the largest part of disease associated variations. MtSNPscore predicted possible role of eight and 79 novel variations in ataxia and mtSNP datasets, respectively, in disease etiology. Analysis of cumulative scores of patient and normal data resulted in Matthews Correlation Coefficient (MCC) of ~0.5 and accuracy of ~0.7 suggesting that the method may also predict involvement of mtDNA variation in diseases. We have developed a novel and comprehensive method for evaluation of mitochondrial variation and their involvement in disease. Our method has the most comprehensive set of parameters to assess mtDNA variations and overcomes the undesired bias generated as a result of better-studied diseases and genes. These variations can be prioritized for functional assays to confirm their pathogenic status.


The environmental and economic sustainability of carbon capture and storage.
For carbon capture and storage (CCS) to be a truly effective option in our efforts to mitigate climate change, it must be sustainable. That means that CCS must deliver consistent environmental and social benefits which exceed its costs of capital, energy and operation; it must be protective of the environment and human health over the long term; and it must be suitable for deployment on a significant scale. CCS is one of the more expensive and technically challenging carbon emissions abatement options available, and CCS must first and foremost be considered in the context of the other things that can be done to reduce emissions, as a part of an overall optimally efficient, sustainable and economic mitigation plan. This elevates the analysis beyond a simple comparison of the cost per tonne of CO(2) abated--there are inherent tradeoffs with a range of other factors (such as water, NOx, SOx, biodiversity, energy, and human health and safety, among others) which must also be considered if we are to achieve truly sustainable mitigation. The full life-cycle cost of CCS must be considered in the context of the overall social, environmental and economic benefits which it creates, and the costs associated with environmental and social risks it presents. Such analysis reveals that all CCS is not created equal. There is a wide range of technological options available which can be used in a variety of industries and applications-indeed CCS is not applicable to every industry. Stationary fossil-fuel powered energy and large scale petroleum industry operations are two examples of industries which could benefit from CCS. Capturing and geo-sequestering CO(2) entrained in natural gas can be economic and sustainable at relatively low carbon prices, and in many jurisdictions makes financial sense for operators to deploy now, if suitable secure disposal reservoirs are available close by. Retrofitting existing coal-fired power plants, however, is more expensive and technically challenging, and the economic sustainability of post-combustion capture retrofit needs to be compared on a portfolio basis to the relative overall net benefit of CCS on new-build plants, where energy efficiency can be optimised as a first step, and locations can be selected with sequestration sites in mind. Examples from the natural gas processing, liquefied natural gas (LNG), and coal-fired power generation sectors, illustrate that there is currently a wide range of financial costs for CCS, depending on how and where it is applied, but equally, environmental and social benefits of emissions reduction can be considerable. Some CCS applications are far more economic and sustainable than others. CCS must be considered in the context of the other things that a business can do to eliminate emissions, such as far-reaching efforts to improve energy efficiency.


Characteristics associated with virologic failure in high-risk HIV-positive participants with prior failure: a post hoc analysis of ACTG 5251.
Patients with prior virologic failure (VF) are at an increased risk of subsequent failure, emergence of resistance, and death. This analysis identifies outcomes and correlates of VF in a high-risk population. A5251 was designed to evaluate an enhanced adherence counseling intervention delivered by nurses from a central call site on virologic suppression. Due to slow enrollment, the study was closed prematurely and revised study endpoints were evaluated (week 24 VF (HIV-1 RNA ≥200 copies/ml) and non-perfect adherence (<100% self-reported using both the ACTG adherence questionnaire and visual analog scale (VAS)). Fifty-nine participants were enrolled, 43 (73%) black non-Hispanic and 23 (39%) women. Median prior antiretroviral regimen changes were three and the co-morbidity in this population was higher than typical for HIV clinical trials. At week 24 (n = 41), 24 (59%) failed to reach virologic suppression (HIV-1 RNA <200 copies/ml) and 25 (63%) reported non-perfect adherence. Higher depression (CES-D10) and adverse illness perceptions (IPQ-B) were associated with week 24 non-adherence. Early clinical assessments (week 12 HIV-RNA ≥200 copies/mL and non-perfect adherence) as well as higher depression and adverse illness perceptions were associated with week 24 VF. In this high-risk population, the proportion of participants with suboptimal adherence and VF was unacceptably high. Interventions to address this treatment gap are clearly needed. Depression and a higher illness perception score, failure to achieve virologic suppression by week 12, and less than perfect adherence could be used to target individuals for early interventions in treatment-experienced, high-risk individuals at high risk for VF.


Tumor angiogenesis and endothelial cell modulatory factors.
Angiogenesis is the ability of preexisting vasculature to send out capillary sprouts leading to the formation of new vasculature. It is now a well-accepted idea that progression of solid tumors is intrinsically dependent on angiogenesis for growth of the primary tumor and metastatic lesions. Investigations into tumor angiogenesis have focused on inhibition of tumor neovasculature as yet another possible mechanism for impairing tumor progression. Numerous studies have characterized cellular and molecular factors important to vascular formation and development and have led to the identification and understanding of requisite interactions between endothelium, angiogenic cytokines, and the supporting matrix. These studies have also led to the identification of cytokines involved in the proteolytic disruption of the basement membrane, the migration of endothelial cells, and the proliferation and formation of neoendothelium into functional vasculature. As therapies based on antiangiogenic strategies continue to evolve and clinical trials are conducted, these agents may become an important part of the arsenal against tumor proliferation, especially given their favorable toxicity profile. This review discusses the angiogenic cytokines which have been most intensely studied and the receptors they act upon. Additionally, we discuss select proteases and their importance in the development of neovasculature. A better understanding of these components will help in the development of novel therapeutic strategies.


Apoprotein B-48 is a constant finding in very low density lipoproteins of humans.
The results of this study indicate that very low density lipoprotein (VLDL) from the plasma of fasting normolipidemic or slightly hypertriglyceridemic subjects contains two apo B species. In SDS gel electrophoresis, the VLDL shows the presence of a major band corresponding to low density lipoprotein (LDL) apo B (apo B-100) and a minor band with the appropriate mobility of the lymph chylomicron apo B (apo B-48). The reactivity of monoclonal antibodies directed against opportunely selected human apo B suggests that the protein with the lower molecular weight corresponds to apo B-48. This finding was confirmed by using immunoadsorbants and affinity chromatography with monoclonal antibodies that react only with apo B-100. Through this method, VLDL were separated into two fractions: one that had only apo B-100 and one with both apo B-100 and apo B-48. Hepatic and intestinal VLDL may constitute different particles. The ratio of apo B-100 to apo B-48 in VLDL decreased as the mass of fasting plasma VLDL increased. This may improve our understanding of the metabolism of triglyceride-rich lipoproteins. The investigation of the new subspecies of apo B may be relevant in understanding the atherogenetic process and better defining the hyperlipidemic states.


Cortical concentrations of corticotropin-releasing hormone and its receptor in Alzheimer type dementia and major depression.
Corticotropin-releasing hormone-immunoreactivity (CRH-IR) and CRH receptors (binding capacity and affinity) were measured in postmortem cortical areas from depressed subjects, two groups of senile dementia of the Alzheimer type (SDAT), and age-, sex-, and postmortem-delay-matched controls. No difference in CRH-IR and CRH receptor status between depressed subjects and controls was noted. CRH-IR was decreased in all cortical areas in SDAT, with a corresponding increase in CRH receptor binding capacity (with no change in affinity) in occipital cortex. No effects of postmortem delay were seen. It is suggested that the increase in CRH receptor numbers in SDAT is related to the degree of distribution of pathological involvement in specific regions.


The short-term blood biocompatibility of poly(hydroxyethyl methacrylate-co-methyl methacrylate) in an in vitro flow system measured by digital videomicroscopy.
An in vitro flow system for short-term blood biocompatibility testing of solution-castable polymeric biomaterials was developed. This system was relatively free of artefacts resulting from blood contact with materials other than the test material itself. In conjunction with epifluorescence videomicroscopy and digital image processing, this method provided a high resolution, quantitative, continuous analysis of platelet adhesion, aggregation, thrombus formation, and embolization on the biomaterial surface. This system was well suited for performing biochemical assays on post-contact blood for assessment of platelet activation and release as additional measures of the thrombogenicity of the test material. This method for biomaterials evaluation in vitro was demonstrated by a detailed examination of copolymers of hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA). Videomicroscopic analysis of fluorescently labelled platelets adhering per unit area of the polymer surface after 5 min of flow at a wall shear rate of 500 s-1 showed a dramatic decrease with increasing HEMA fraction in the polymer. The release of serotonin and thromboxane A2 by platelets decreased with increasing HEMA fraction. Reflection interference contrast microscopy was used to examine focal contacts of platelets on the copolymer surfaces as a qualitative measure of the platelet-surface interaction. A polymer-dependent gradation in contact extent and morphology was observed, ranging from large contacts on P(MMA) to none on P(HEMA).


Temporal phenotypic features distinguish polarized macrophages in vitro.
Macrophages are important in vascular inflammation and environmental factors influence macrophage plasticity. Macrophage transitions into pro-inflammatory (M1) or anti-inflammatory (M2) states have been defined predominately by measuring cytokines in culture media (CM). However, temporal relationships between cellular and secreted cytokines have not been established. We measured phenotypic markers and cytokines in cellular and CM of murine bone marrow-derived macrophages at multiple time points following stimulation with IFN-γ + LPS (M1), IL-4 (M2a) or IL-10 (M2c). Cytokines/proteins in M1-polarized macrophages exhibited two distinct temporal patterns; an early (0.5-3 h), transient increase in cellular cytokines (GM-CSF, KC-GRO, MIP-2, IP-10 and MIP-1β) and a delayed (3-6 h) response that was more sustained [IL-3, regulated on activation normal T cell expressed and secreted (RANTES), and tissue inhibitor of metalloproteinases 1 (TIMP-1)]. M2a-related cytokine/cell markers (IGF-1, Fizz1 and Ym1) were progressively (3-24 h) increased post-stimulation. In addition, novel patterns were observed. First, and unexpectedly, cellular pro-inflammatory chemokines, MCP-1 and MCP-3 but not MCP-5, were comparably increased in M1 and M2a macrophages. Second, Vegfr1 mRNA was decreased in M1 and increased in M2a macrophages. Finally, VEGF-A was increased in the CM of M1 cultures and strikingly reduced in M2a coinciding with increased Vegfr1 expression, suggesting decreased VEGF-A in M2a CM was secondary to increased soluble VEGFR1. In conclusion, macrophage cytokine production and marker expression were temporally regulated and relative levels compared across polarizing conditions were highly dependent upon the timing and location (cellular versus CM) of the sample collection. For most cytokines, cellular production preceded increases in the CM suggesting that cellular regulatory pathways should be studied within 6 h of stimulation. The divergent polarization-dependent expression of Vegfr1 may be essential to controlling VEGF potentially regulating angiogenesis and inflammatory cell infiltration in the vascular niche. The current study expands the repertoire of cytokines produced by polarized macrophages and provides insights into the dynamic regulation of macrophage polarization and resulting cytokines, proteins and gene expression that influence vascular inflammation.


Fast CNN Stereo Depth Estimation through Embedded GPU Devices.
Current CNN-based stereo depth estimation models can barely run under real-time constraints on embedded graphic processing unit (GPU) devices. Moreover, state-of-the-art evaluations usually do not consider model optimization techniques, being that it is unknown what is the current potential on embedded GPU devices. In this work, we evaluate two state-of-the-art models on three different embedded GPU devices, with and without optimization methods, presenting performance results that illustrate the actual capabilities of embedded GPU devices for stereo depth estimation. More importantly, based on our evaluation, we propose the use of a U-Net like architecture for postprocessing the cost-volume, instead of a typical sequence of 3D convolutions, drastically augmenting the runtime speed of current models. In our experiments, we achieve real-time inference speed, in the range of 5-32 ms, for 1216 × 368 input stereo images on the Jetson TX2, Jetson Xavier, and Jetson Nano embedded devices.