Robust vessel segmentation in fundus images.
One of the most common modalities to examine the human eye is the eye-fundus photograph. The evaluation of fundus photographs is carried out by medical experts during time-consuming visual inspection. Our aim is to accelerate this process using computer aided diagnosis. As a first step, it is necessary to segment structures in the images for tissue differentiation. As the eye is the only organ, where the vasculature can be imaged in an in vivo and noninterventional way without using expensive scanners, the vessel tree is one of the most interesting and important structures to analyze. The quality and resolution of fundus images are rapidly increasing. Thus, segmentation methods need to be adapted to the new challenges of high resolutions. In this paper, we present a method to reduce calculation time, achieve high accuracy, and increase sensitivity compared to the original Frangi method. This method contains approaches to avoid potential problems like specular reflexes of thick vessels. The proposed method is evaluated using the STARE and DRIVE databases and we propose a new high resolution fundus database to compare it to the state-of-the-art algorithms. The results show an average accuracy above 94% and low computational needs. This outperforms state-of-the-art methods.


Evaluation of four serological techniques to determine the seroprevalence of Neospora caninum in foxes (Vulpes vulpes) and coyotes (Canis latrans) on Prince Edward Island, Canada.
The objectives of this study were (1) to evaluate the performance and agreement of serological assays (ELISA, IFAT, Neospora caninum agglutination test and immunoblot) using reference sera and field sera from foxes and coyotes and (2) to estimate the N. caninum seroprevalence in foxes and coyotes on Prince Edward Island, Canada. With fox and coyote reference sera the test performance of the ELISA, IFAT and IB was excellent (100% sensitivity and specificity). NAT showed a low sensitivity (50%). Serum was collected from 201 coyotes and 271 foxes. The seroprevalence observed in the different assays ranged from 0.5 to 14.0% in coyotes and 1.1 to 34.8% in foxes. The seroprevalence, when taking more than one test positive as cut-off value was 3.3 and 1.1% for coyotes and foxes, respectively. From the N. caninum-positive group, all coyotes were older than 3 years. Agreement among assays (measured as prevalence-adjusted bias-adjusted kappa) using the field sera ranged from 0.17 to 0.97. Best agreement was observed between ELISA and IFAT, poor agreement was observed between NAT and the other assays. Positive agreement was moderate to poor among all assays utilized in this study. Although the seroprevalence observed was low, N. caninum antibodies are present in foxes and coyotes on Prince Edward Island (PEI) and their role in the N. caninum epidemiology needs further study.


A, B and C in Uganda: the roles of abstinence, monogamy and condom use in HIV decline.
Uganda is often cited as a role model in the fight against HIV/AIDS because of its success in reducing both prevalence and incidence of HIV infection since the late 1980s. Although an increase in sexual abstinence has been highlighted as a primary cause of the declines, large increases have also been recorded in monogamy and condom use. The extent to which each of these factors actually influenced the overall decline in Uganda's HIV rates has become a highly charged political issue in the United States, leading to restrictions on how US development funding for combatting HIV is allocated. The Alan Guttmacher Institute investigated changes that occurred in abstinence, monogamy and condom use in Uganda in the 1990s, using nationally representative data from Uganda's Demographic and Health Surveys of 1988 (women only), 1995 and 2000 (women and men), and national-level findings from two surveys by the Global Programme on AIDS in 1989 and 1995 (women and men). Reduction of infection risk by lowering numbers or types of partners among people with more than one relationship was not covered. Here we reprint the chapter on "Implications" from the AGI report, a commentary on the lessons that can and cannot be taken from the data, published in a 2003 Guttmacher Report on Public Policy.


The single dominant medial row perforator DIEP flap in breast reconstruction: three-dimensional perforasome and clinical results.
Successful outcomes with the deep inferior epigastric artery perforator (DIEP) flap are heavily dependent on identifying the largest perforators. The purpose of this study was to describe the vascular anatomy (location, size, zones of perfusion, and variations) of the single most dominant deep inferior epigastric artery perforator and to report a clinical series based on this flap. Eleven abdominal flaps were harvested from fresh adult cadavers, and measurements were combined with clinical measurements from 16 patients. Details such as perforator size, location, type, and zones of perfusion were documented for all flaps and clinical outcomes for all patients. A total of 36 flaps were dissected with an average perforator location within a 3-cm radius of the umbilicus and an average perforator size greater than 1.8 mm. Computed tomographic scans of the cadaver abdominal flaps demonstrated consistent perfusion in zones I and II and half of zones III and IV. Clinical results showed partial flap necrosis in one patient and fat necrosis of less than 5 percent in three patients, all of which occurred in the distal portion of zone III. The deep inferior epigastric artery medial row perforators near the umbilicus were found to be the largest perforators in the entire deep inferior epigastric artery system and abdomen. The single dominant medial row perforator has a maximal vascularity in zones I and II, and less in zones III an IV. The authors recommend that half of zone III and all of zone IV be discarded to avoid the risks of partial flap loss and fat necrosis.


Purification of carbon nanotubes by high temperature chlorine gas treatment.
Carbon nanotubes (CNTs) have a tremendous amount of potential to become useful components for future practical applications that may become a part of everyday life. While the sp(2) carbon itself is a rather chemically inert material, the issue of residual metal nanoparticle catalysts remains a prominent barrier in the utilization of CNTs in many areas due to the strong influence of these metallic impurities on the redox chemistry of biomarkers. Even with a standard purification procedure, CNTs have been shown to still contain residual metal nanoparticle catalysts. As such, presented in this paper is an improved purification technique for treating the CNTs with the highly reactive Cl2 gas at an elevated temperature of 1000 °C for 10 min, which would result in the vaporization of the metallic impurities as MxCly, leading to a large decrease in the amount of metallic nanoparticle impurities within the CNTs. By means of electrochemistry and X-ray fluorescence analysis, we demonstrate that the behaviour of such Cl2 treated CNTs showed a significant shift towards that of high purity CNTs, with a dramatic decrease in the influence of the residual metallic impurities on the electrochemical behaviour of CNTs. Therefore it is suggested that the Cl2 treatment of carbon nanotubes is a highly promising route towards the production of pure CNTs.


Targeted assemblies of cas1 suggest CRISPR-Cas's response to soil warming.
There is an increasing interest in the clustered regularly interspaced short palindromic repeats CRISPR-associated protein (CRISPR-Cas) system to reveal potential virus-host dynamics. The universal and most conserved Cas protein, cas1 is an ideal marker to elucidate CRISPR-Cas ecology. We constructed eight Hidden Markov Models (HMMs) and assembled cas1 directly from metagenomes by a targeted-gene assembler, Xander, to improve detection capacity and resolve the diverse CRISPR-Cas systems. The eight HMMs were first validated by recovering all 17 cas1 subtypes from the simulated metagenome generated from 91 prokaryotic genomes across 11 phyla. We challenged the targeted method with 48 metagenomes from a tallgrass prairie in Central Oklahoma recovering 3394 cas1. Among those, 88 were near full length, 5 times more than in de-novo assemblies from the Oklahoma metagenomes. To validate the host assignment by cas1, the targeted-assembled cas1 was mapped to the de-novo assembled contigs. All the phylum assignments of those mapped contigs were assigned independent of CRISPR-Cas genes on the same contigs and consistent with the host taxonomies predicted by the mapped cas1. We then investigated whether 8 years of soil warming altered cas1 prevalence within the communities. A shift in microbial abundances was observed during the year with the biggest temperature differential (mean 4.16 °C above ambient). cas1 prevalence increased and even in the phyla with decreased microbial abundances over the next 3 years, suggesting increasing virus-host interactions in response to soil warming. This targeted method provides an alternative means to effectively mine cas1 from metagenomes and uncover the host communities.


The efficacy of early language intervention in mainstream school settings: a randomized controlled trial.
Oral language skills are a critical foundation for literacy and more generally for educational success. The current study shows that oral language skills can be improved by providing suitable additional help to children with language difficulties in the early stages of formal education. We conducted a randomized controlled trial with 394 children in England, comparing a 30-week oral language intervention programme starting in nursery (N = 132) with a 20-week version of the same programme starting in Reception (N = 133). The intervention groups were compared to an untreated waiting control group (N = 129). The programmes were delivered by trained teaching assistants (TAs) working in the children's schools/nurseries. All testers were blind to group allocation. Both the 20- and 30-week programmes produced improvements on primary outcome measures of oral language skill compared to the untreated control group. Effect sizes were small to moderate (20-week programme: d = .21; 30-week programme: d = .30) immediately following the intervention and were maintained at follow-up 6 months later. The difference in improvement between the 20-week and 30-week programmes was not statistically significant. Neither programme produced statistically significant improvements in children's early word reading or reading comprehension skills (secondary outcome measures). This study provides further evidence that oral language interventions can be delivered successfully by trained TAs to children with oral language difficulties in nursery and Reception classes. The methods evaluated have potentially important policy implications for early education.


Metal-free ribonucleotide reduction powered by a DOPA radical in Mycoplasma pathogens.
Ribonucleotide reductase (RNR) catalyses the only known de novo pathway for the production of all four deoxyribonucleotides that are required for DNA synthesis1,2. It is essential for all organisms that use DNA as their genetic material and is a current drug target3,4. Since the discovery that iron is required for function in the aerobic, class I RNR found in all eukaryotes and many bacteria, a dinuclear metal site has been viewed as necessary to generate and stabilize the catalytic radical that is essential for RNR activity5-7. Here we describe a group of RNR proteins in Mollicutes-including Mycoplasma pathogens-that possess a metal-independent stable radical residing on a modified tyrosyl residue. Structural, biochemical and spectroscopic characterization reveal a stable 3,4-dihydroxyphenylalanine (DOPA) radical species that directly supports ribonucleotide reduction in vitro and in vivo. This observation overturns the presumed requirement for a dinuclear metal site in aerobic ribonucleotide reductase. The metal-independent radical requires new mechanisms for radical generation and stabilization, processes that are targeted by RNR inhibitors. It is possible that this RNR variant provides an advantage under metal starvation induced by the immune system. Organisms that encode this type of RNR-some of which are developing resistance to antibiotics-are involved in diseases of the respiratory, urinary and genital tracts. Further characterization of this RNR family and its mechanism of cofactor generation will provide insight into new enzymatic chemistry and be of value in devising strategies to combat the pathogens that utilize it. We propose that this RNR subclass is denoted class Ie.


Synergism between oral paracetamol and nefopam in a murine model of postoperative pain.
The use of paracetamol or nefopam for postoperative pain control is limited by the need of high doses associated with unwanted effects. Previous works suggest positive interactions between both compounds that may be exploited to obtain potentiation of antinociception. Mechanical and heat antinociception induced by oral doses of paracetamol, nefopam or their combination was studied by isobolographic analysis in a murine model of postsurgical pain. The effective doses that produced 50% antinociception (ED50 ) were calculated from the log dose-response curves for each compound. Subsequently, the effects of ED8.7 s, ED12.5 s, ED17.5 s and ED35 s of nefopam and paracetamol combined were assessed. Oral paracetamol induced dose-dependent relief of postoperative sensitivity and showed higher efficacy reducing mechanical hypersensitivity (ED50 177.3 ± 15.4 mg/kg) than heat hyperalgesia (ED50 278.6 ± 43 mg/kg). Oral nefopam induced dose-dependent antinociception with similar efficacy for mechanical and heat hypersensitivity (ED50 s 5.42 ± 0.81 vs. 5.83 ± 0.72). Combinations of increasing isoeffective doses revealed that combined ED17.5 s (85.76 mg/kg paracetamol and 1.9 mg/kg nefopam) and ED35 s (132.67 mg/kg and 3.73 mg/kg) showed synergistic effects leading to 75% and 90% mechanical antinociception, respectively. These mixtures were defined by interaction indexes of 0.43 and 0.41 and ratios 45:1 and 35:1 paracetamol:nefopam, respectively. The same combinations showed additive effects for the inhibition of incisional thermal hyperalgesia. This work describes a synergistic antinociceptive interaction between low doses of nefopam and paracetamol for the treatment of postoperative hypersensitivity to peripheral stimuli. The promising results obtained on reflexive nociceptive responses of young male mice subjected to plantar surgery highlight the interest of further research evaluating the effects of this mixture on the affective-motivational component of pain and in females and additional age groups. Confirmation of pain-relieving efficacy and safety of this oral combination clinically available in European and Asian countries could provide a useful tool for postsurgical pain management. Early postoperative pain is currently undertreated and has been recognized as a relevant source of chronic postsurgical pain. Oral efficient treatments could facilitate fast-track surgeries and patient recovery at home. Here, we identify in a mouse model of postoperative pain a potent synergistic oral combination consisting of low paracetamol and nefopam doses that provides relief of postsurgical hypersensitivity to mechanical and thermal stimuli. Oral multimodal paracetamol-nefopam mixtures represent a potential clinically available pharmacological strategy for the relief of incisional sensitivity and the promotion of patient recovery.


Oxidative Stress Parameters, Selenium Levels, DNA Damage, and Phthalate Levels in Plastic Workers.
Di(2-ethylhexyl)phthalate (DEHP) is the most widely used phthalate. DEHP is highly used in PVC floorings and PVC windows and carpeting. The objective of this study was to determine sex hormone levels, oxidative stress parameters, selenium levels, DNA damage, and phthalate levels in plastics workers (n = 24, age = 20-58 years) working in the production of rubber mechanical goods and exposed to DEHP in workplace. The control group (n = 29, age = 25-54, all male) was selected from age-matched healthy adults. Antioxidant parameters and DNA damage were determined by spectrophotometry. Selenium levels were determined by atomic absorption spectroscopy. Plasma hormone levels were measured by chemiluminescence microparticle immunoassay. Plasma phthalate levels were determined by high-pressure liquid chromatography. Plastic workers had lower serum testosterone and free T4 levels and higher follicle-stimulating hormone levels vs. controls. Liver enzyme activities were markedly higher in workers vs. controls. There were also increases in plasma glutathione peroxidase levels and marked decreases in plasma selenium and erythrocyte total glutathione levels in plastics workers (P < 0.05 vs. control). Plasma 8-hydroxy-2'-deoxyguanosine levels were 14-fold higher in plastics workers than in controls. Plasma DEHP and mono(2-ethylhexyl)phthalate were also markedly higher in workers vs. controls. The results of this study show that occupational exposure to DEHP may lead to disturbances in sex hormones, increased liver problems, higher oxidative stress and DNA damage levels, and lower trace element concentrations in workers. More comprehensive and mechanistic studies with higher numbers of subjects are needed to show the unwanted effects of occupational exposure to DEHP.


Beta-lactone probes identify a papain-like peptide ligase in Arabidopsis thaliana.
New activity-based probes are essential for expanding studies on the hundreds of serine and cysteine proteases encoded by the genome of Arabidopsis thaliana. To monitor protease activities in plant extracts, we generated biotinylated peptides containing a beta-lactone reactive group. These probes cause strong labeling in leaf proteomes. Unexpectedly, labeling was detected at the N terminus of PsbP, nonproteolytic protein of photosystem II. Inhibitor studies and reverse genetics led to the discovery that this unusual modification is mediated by a single plant-specific, papain-like protease called RD21. In cellular extracts, RD21 accepts both beta-lactone probes and peptides as donor molecules and ligates them, probably through a thioester intermediate, to unmodified N termini of acceptor proteins.


Nrf2-regulated redox signaling in brain endothelial cells adapted to physiological oxygen levels: Consequences for sulforaphane mediated protection against hypoxia-reoxygenation.
Ischemic stroke is associated with a surge in reactive oxygen species generation during reperfusion. The narrow therapeutic window for the delivery of intravenous thrombolysis and endovascular thrombectomy limits therapeutic options for patients. Thus, understanding the mechanisms regulating neurovascular redox defenses are key for improved clinical translation. Our previous studies in a rodent model of ischemic stroke established that activation of Nrf2 defense enzymes by pretreatment with sulforaphane (SFN) affords protection against neurovascular and neurological deficits. We here further investigate SFN mediated protection in mouse brain microvascular endothelial cells (bEnd.3) adapted long-term (5 days) to hyperoxic (18 kPa) and normoxic (5 kPa) O2 levels. Using an O2-sensitive phosphorescent nanoparticle probe, we measured an intracellular O2 level of 3.4 ± 0.1 kPa in bEnd 3 cells cultured under 5 kPa O2. Induction of HO-1 and GCLM by SFN (2.5 μM) was significantly attenuated in cells adapted to 5 kPa O2, despite nuclear accumulation of Nrf2. To simulate ischemic stroke, bEnd.3 cells were adapted to 18 or 5 kPa O2 and subjected to hypoxia (1 kPa O2, 1 h) and reoxygenation. In cells adapted to 18 kPa O2, reoxygenation induced free radical generation was abrogated by PEG-SOD and significantly attenuated by pretreatment with SFN (2.5 μM). Silencing Nrf2 transcription abrogated HO-1 and NQO1 induction and led to a significant increase in reoxygenation induced free radical generation. Notably, reoxygenation induced oxidative stress, assayed using the luminescence probe L-012 and fluorescence probes MitoSOX™ Red and FeRhoNox™-1, was diminished in cells cultured under 5 kPa O2, indicating an altered redox phenotype in brain microvascular cells adapted to physiological normoxia. As redox and other intracellular signaling pathways are critically affected by O2, the development of antioxidant therapies targeting the Keap1-Nrf2 defense pathway in treatment of ischemia-reperfusion injury in stroke, coronary and renal disease will require in vitro studies conducted under well-defined O2 levels.


Development and evaluation of a custom bait design based on 469 single-copy protein-coding genes for exon capture of isopods (Philosciidae: Haloniscus).
Transcriptome-based exon capture approaches, along with next-generation sequencing, are allowing for the rapid and cost-effective production of extensive and informative phylogenomic datasets from non-model organisms for phylogenetics and population genetics research. These approaches generally employ a reference genome to infer the intron-exon structure of targeted loci and preferentially select longer exons. However, in the absence of an existing and well-annotated genome, we applied this exon capture method directly, without initially identifying intron-exon boundaries for bait design, to a group of highly diverse Haloniscus (Philosciidae), paraplatyarthrid and armadillid isopods, and examined the performance of our methods and bait design for phylogenetic inference. Here, we identified an isopod-specific set of single-copy protein-coding loci, and a custom bait design to capture targeted regions from 469 genes, and analysed the resulting sequence data with a mapping approach and newly-created post-processing scripts. We effectively recovered a large and informative dataset comprising both short (<100 bp) and longer (>300 bp) exons, with high uniformity in sequencing depth. We were also able to successfully capture exon data from up to 16-year-old museum specimens along with more distantly related outgroup taxa, and efficiently pool multiple samples prior to capture. Our well-resolved phylogenies highlight the overall utility of this methodological approach and custom bait design, which offer enormous potential for application to future isopod, as well as broader crustacean, molecular studies.


Integral role of integrins in Th17 development.
A lineage of CD4+ T cells known as Th17 cells, which are derived by exposure of naive CD4+ T cells to IL-6 and TGF-β, have been implicated in several autoimmune diseases. In this issue of the JCI, studies by Acharya et al. and Melton et al. show that TGF-β is activated at the DC/CD4+ T cell synapse by αv integrins and that this activation is required for Th17 differentiation and autoimmunity in the central nervous system. Thus, these studies offer a potential therapeutic target in fighting autoimmune diseases.


Oral prosthodontic rehabilitation for traumatic sports injuries.
Sports injuries to the mouth and oral cavity may be treated with a variety of prosthetic treatment methods. These may include a temporary removable appliance, especially when adjacent teeth are unrestored and free of caries. Other traditional forms of prosthetic rehabilitation can range from conventional clasped removable partial dentures to traditional fixed prosthesis. The use of clip bar overdentures has demonstrated their clinical acceptability, especially for athletes involved in contact sports. The optimal treatment for patients suffering tooth loss, however, is the use of the osseointegrated implant. This concept, developed and refined by P.I. Branemark, permits successful replacement of single as well as multiple lost teeth. Criteria for patient selection must be evaluated carefully, especially for immediate fixture placement in sockets of avulsed teeth. Professional athletes in high-impact contact sports should receive a resilient prosthesis and protective appliance to use during the sport season, followed by a screw-retained nonremovable prosthesis to be used in the off season. Considering all forms of prosthodontic treatment available to patients with missing teeth, the use of osseointegrated implants currently appears to be the most biologically conservative approach. Retrospective studies document the effectiveness of the treatment of partially edentulous jaws, results similar or better than those reported for fully edentulous patients indicate the effectiveness of the Branemark method of osseointegration.


Body mass predicts isotope enrichment in herbivorous mammals.
Carbon isotopic signatures recorded in vertebrate tissues derive from ingested food and thus reflect ecologies and ecosystems. For almost two decades, most carbon isotope-based ecological interpretations of extant and extinct herbivorous mammals have used a single diet-bioapatite enrichment value (14‰). Assuming this single value applies to all herbivorous mammals, from tiny monkeys to giant elephants, it overlooks potential effects of distinct physiological and metabolic processes on carbon fractionation. By analysing a never before assessed herbivorous group spanning a broad range of body masses-sloths-we discovered considerable variation in diet-bioapatite δ13C enrichment among mammals. Statistical tests (ordinary least squares, quantile, robust regressions, Akaike information criterion model tests) document independence from phylogeny, and a previously unrecognized strong and significant correlation of δ13C enrichment with body mass for all mammalian herbivores. A single-factor body mass model outperforms all other single-factor or more complex combinatorial models evaluated, including for physiological variables (metabolic rate and body temperature proxies), and indicates that body mass alone predicts δ13C enrichment. These analyses, spanning more than 5 orders of magnitude of body sizes, yield a size-dependent prediction of isotopic enrichment across Mammalia and for distinct digestive physiologies, permitting reconstruction of foregut versus hindgut fermentation for fossils and refined mean annual palaeoprecipitation estimates based on δ13C of mammalian bioapatite.


Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa.
MK-7655 is a novel inhibitor of class A and C β-lactamases. We investigated its potential to protect imipenem. Chequerboard MICs were determined by CLSI agar dilution: (i) for Enterobacteriaceae with carbapenemases; (ii) for Enterobacteriaceae with carbapenem resistance contingent on combinations of impermeability together with an extended-spectrum β-lactamase or AmpC enzyme; and (iii) for Pseudomonas aeruginosa and other non-fermenters. At a concentration of 4 mg/L, MK-7655 reduced imipenem MICs for Enterobacteriaceae with KPC carbapenemases from 16-64 mg/L to 0.12-1 mg/L. Synergy also was seen for Enterobacteriaceae with impermeability-mediated carbapenem resistance, with weaker synergy seen for isolates with the OXA-48 enzyme. On the other hand, MK-7655 failed to potentiate imipenem against Enterobacteriaceae with metallo-carbapenemases. In the case of P. aeruginosa, where endogenous AmpC confers slight protection versus imipenem, 4 mg/L MK-7655 reduced the MIC of imipenem for all isolates, except those with metallo-carbapenemases: the MICs of imipenem fell from 1-2 mg/L to 0.25-0.5 mg/L for imipenem-susceptible P. aeruginosa and from 16-64 mg/L to 1-4 mg/L for OprD-deficient strains. No potentiation was seen for chryseobacteria or for Stenotrophomonas maltophilia. MK-7655 potentiated imipenem against Enterobacteriaceae with KPC carbapenemases or combinations of β-lactamase and impermeability, but not those with metallo-carbapenemases. It augmented the activity of imipenem against P. aeruginosa in general and OprD mutants in particular.


ATF3 Protects against LPS-Induced Inflammation in Mice via Inhibiting HMGB1 Expression.
Lipopolysaccharide (LPS) triggers innate immunity mainly via TLR4 signaling. ATF3 is a negative regulator of TLR4 signaling. HMGB1 plays a critical role in the final step of sepsis. However, the mechanisms of ATF3 and the role of HMGB1 in regulating innate immunity-induced sepsis are incompletely understood. In this study, we found that serum HMGB1 levels were 10-fold higher in patients with sepsis than normal controls. We further demonstrated that ATF3 gene knockout in mice subjected to LPS-induced endotoxemia correlates with an increase in the mortality rate and the elevated expression of IL-6, TNF- α , NO, MCP-1, and HMGB1 in the lung tissues or serum. The biochemical effects of ATF3 were observed in in vitro macrophages and blocked by ATF3 siRNA treatment. We have also shown that adeno-associated virus-mediated ATF3 gene transfer protected ATF3 knockout mice from LPS-induced mortality. In addition, ATF3 knockdown increased LPS-induced release of HMGB1. In conclusion, upregulation of ATF3 contributes to the reduced release of inflammatory molecules, especially HMGB1, which induced lung injury and increased the survival rate of mice after LPS challenge. Therefore, suppressing LPS-induced inflammation with ATF3 induction or ATF3 mimetics may be an important strategy for sepsis therapy.


Fertility trend and pattern in a rural area of South Africa in the context of HIV/AIDS.
Little is known about the dynamics of fertility transition in South Africa, though recent studies have begun to shed light on demographic changes in the country. This study presents trends and patterns of fertility observed in a rural South African population. Various demographic and statistical techniques were used to examine fertility patterns in a population of 21,847 women in a rural KwaZulu-Natal (KZN) demographic surveillance area. These are compared with patterns seen in another South African rural population under demographic surveillance, and with data from the 1998 South Africa Demographic and Health Survey. Findings are interpreted in light of contraceptive use patterns and HIV prevalence in the population. In South Africa, the end of the fertility transition is now in sight. In rural KZN, where national fertility levels are highest, fertility has declined rapidly for about two decades and would have reached below replacement level in 2003. While fertility has declined rapidly among all women over age 18 years, fertility levels among adolescents have not changed in decades. Although most adolescents in rural KZN were sexually active (60%), few had ever used contraception (200%). High HIV seroprevalence appears to explain a small part of the fertility decline (12%); however, this effect is likely to grow in the near future as the HIV/AIDS epidemic continues in South Africa. If the current trends continue in the future, below replacement fertility, together with high mortality due to AIDS, it could soon lead to negative natural population growth in rural South Africa.


Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects.
Magnetic resonance imaging (MRI) studies of schizophrenic patients have revealed structural brain abnormalities, with low volumes of gray matter in the left posterior superior temporal gyrus and in medial temporal lobe structures. However, the specificity to schizophrenia and the roles of chronic morbidity and neuroleptic treatment in these abnormalities remain unclear. Magnetic resonance (1.5-T) scans were obtained from 33 patients with first-episode psychosis and 18 age-matched normal comparison subjects, all right-handed. Sixteen of the patients were diagnosed with affective disorder and 17 with schizophrenia. Quantitative volumetric analysis showed that the patients with first-episode schizophrenia had significantly smaller gray matter volume in the left posterior superior temporal gyrus than did the patients with first-episode affective psychosis or the comparison subjects, with a significant left-less-than-right asymmetry. The schizophrenic patients also showed a smaller gray matter volume of the left posterior amygdala-hippocampal complex than the comparison subjects. Both the patients with schizophrenia and those with affective psychosis had significant left-less-than-right asymmetry of the posterior amygdala-hippocampal complex. These findings suggest that temporal lobe abnormalities are present at the first hospitalization for schizophrenia and that low volume of the left posterior superior temporal gyrus gray matter is specific to schizophrenia compared with affective disorder.


Time Slices: What Is the Duration of a Percept?
We experience the world as a seamless stream of percepts. However, intriguing illusions and recent experiments suggest that the world is not continuously translated into conscious perception. Instead, perception seems to operate in a discrete manner, just like movies appear continuous although they consist of discrete images. To explain how the temporal resolution of human vision can be fast compared to sluggish conscious perception, we propose a novel conceptual framework in which features of objects, such as their color, are quasi-continuously and unconsciously analyzed with high temporal resolution. Like other features, temporal features, such as duration, are coded as quantitative labels. When unconscious processing is "completed," all features are simultaneously rendered conscious at discrete moments in time, sometimes even hundreds of milliseconds after stimuli were presented.


Do steatosis and steatohepatitis impact on sustained virological response (SVR) rates in patients receiving pegylated interferon and ribavirin for chronic hepatitis C infection?
The impact of steatosis on treatment response in chronic hepatitis C infection is controversial. The aim of this study was to determine whether steatosis +/- steatohepatitis on pre-treatment liver biopsy influenced sustained virological response (HCV RNA negative 6 months after completing therapy) in patients with chronic hepatitis C infection treated with pegylated interferon-alpha and ribavirin. One hundred and seventy-nine patients, median age 46 years (interquartile range 40-52), treated between 2001 and 2005. Histological evidence of steatosis was present in 93 patients (52%) and steatohepatitis in 33 patients (18%), 31 patients (17.3%) were cirrhotic. There were 106 (59%) responders, who were similar to non-responders in respect to gender, age, and pre-treatment ALT. On univariate analysis, infection with genotype 2 or 3 was associated with sustained virological response (odds ratio 6.5 (95% CI, 3.3-12.5); P < 0.0001), whereas cirrhosis and patient weight were associated with a reduced response (odds ratios 0.23 (95% CI, 0.11-0.48); P < 0.0001, and 0.97 (95% CI, 0.95-0.99); P < 0.01, respectively); steatohepatitis but not steatosis impacted on the likelihood of achieving sustained virological response (odds ratio 0.37 (95% CI, 0.17-0.77); P = 0.009, and P = 0.18, respectively). Multivariate analysis revealed that infection with genotype 1 or 4 (odds ratio 0.09 (95% CI, 0.03-0.32); P < 0.001) and pre-treatment weight (odds ratio 0.94 (95% CI, 0.90-0.98); P = 0.002) were the only variables associated independently with sustained virological response. In chronic hepatitis C infection, although steatosis was associated with steatohepatitis, neither was shown to affect sustained virological response, which was influenced by genotype, patient weight and the presence of cirrhosis.


Quality of antiepileptic drugs in sub-Saharan Africa: A study in Gabon, Kenya, and Madagascar.
Epilepsy is a major public health issue in low- and middle-income countries, where the availability and accessibility of quality treatment remain important issues, the severity of which may be aggravated by poor quality antiepileptic drugs (AEDs). The primary objective of this study was to measure the quality of AEDs in rural and urban areas in 3 African countries. This cross-sectional study was carried out in Gabon, Kenya, and Madagascar. Both official and unofficial supply chains in urban and rural areas were investigated. Samples of oral AEDs were collected in areas where a patient could buy or obtain them. Pharmacological analytical procedures and Medicine Quality Assessment Reporting Guidelines were used to assess quality. In total, 102 batches, representing 3782 units of AEDs, were sampled. Overall, 32.3% of the tablets were of poor quality, but no significant difference was observed across sites: 26.5% in Gabon, 37.0% in Kenya, and 34.1% in Madagascar (P = .7). The highest proportions of substandard medications were found in the carbamazepine (38.7%; 95% confidence interval [CI] 21.8-57.8) and phenytoin (83.3%; 95% CI 35.8-99.5) batches, which were mainly flawed by their failure to dissolve. Sodium valproate was the AED with the poorest quality (32.1%; 95% CI 15.8-42.3). The phenobarbital (94.1%; 95% CI 80.3-99.2) and diazepam (100.0%) batches were of better quality. The prevalence of substandard quality medications increased in samples supplied by public facilities (odds ratio [OR] 9.9; 95% CI 1.2-84.1; P < .04) and manufacturers located in China (OR 119.8; 95% CI 8.7-1651.9; P < .001). The prevalence of AEDs of bad quality increased when they were stored improperly (OR 5.4; 95% CI 1.2-24.1; P < .03). No counterfeiting was observed. However, inadequate AED storage conditions are likely to lead to ineffective and possibly dangerous AEDs, even when good-quality AEDs are initially imported.


Correlates and Predictors of Stigmatization of Patients With Mental Illness Among Nursing Students.
The purpose of the current study was to explore knowledge of, attitudes about, and perception of stigma among nursing students in relation to mental illness, and to identify the predictors of stigma toward patients with mental illness based on nursing students' characteristics, knowledge, and attitude. A cross-sectional survey was conducted on 169 participants from a university in Jordan. The regression model predicted a relatively moderate proportion of variance in stigma perception. Significant predictors in the model were family income, father's educational level, and experience with mental health patients. Findings of the current study showed that undergraduate nursing students who had experience with patients with mental illness hold relatively positive perceptions toward mental health patients. Enhancing the content of nursing curriculum regarding issues related to patients with mental illness could help students develop better assessment skills, have more positive attitudes, and gain more accurate knowledge about mental illness. [Journal of Psychosocial Nursing and Mental Health Services, 57(1), 43-51.].


Asthma management in accident and emergency and the BTS guidelines--a study of the impact of clinical audit.
To determine whether the care of asthma patients in accident and emergency Departments (A&E) is improved by clinical audit of asthma management. The quality of care during continuous cycles of clinical audit was compared with that one year later, after an audit programme had ended and most of the medical staff had changed. This was done by a retrospective case notes review of all asthma cases (n = 79) in April and May 1993, compared to the same months (n = 93) in 1994. The quality of care was higher during the audit in a number of areas, as determined by conformity to the British Thoracic Society (BTS) guidelines. Comparing the management of episodes for the earlier to the later study periods, the significant differences were: the ability to complete a sentence in one breath was recorded in 63% and 33% of episodes; a nebuliser was given when indicated in 97% and 88%; when indicated a chest x ray was ordered in 73% and 43%; and arterial blood gases were measured in 73% and 33% of episodes. The initial assessment and management of asthma was better when the audit was in progress. However, in both study periods some areas of care did not receive the attention recommended in the BTS guidelines, these were all areas which would have influenced asthma control after discharge.


Dimethylaluminium aldiminophenolates: synthesis, characterization and ring-opening polymerization behavior towards lactides.
The stoichiometric reaction of the salicylaldimine derivatives (L1-L12) with trimethylaluminium afforded the corresponding dimethylaluminium aldiminophenolates (C1-C12), which were fully characterized by NMR spectroscopy and elemental analysis. The molecular structures of the representative complexes C1, C6, and C8 were determined by the single-crystal X-ray diffraction, which revealed distorted tetrahedral geometry at aluminium. Activation of the dimethylaluminium aldiminophenolates for the ring-opening polymerization required one equivalent of BnOH. On the basis of the polymerization results for L-lactide, D-lactide or rac-lactide, higher efficiency was observed for the ROP of D-lactide, and the nature of the ligands present significantly affected the observed catalytic activities and the properties of the resultant polylactides.


Clinicopathologic features of incident and subsequent tumors in patients with multiple primary cutaneous melanomas.
0.6-12.7% of patients with primary cutaneous melanoma will develop additional melanomas. Pathologic features of tumors in patients with multiple primary cutaneous melanomas have not been well described. In this large, international, multicenter, case-control study, we compared the clinicopathologic features of a subsequent melanoma with the preceding (usually the first) melanoma in patients with multiple primary cutaneous melanomas, and with those of melanomas in patients with single primary cutaneous melanomas. Multiple primary melanoma (cases) and single primary invasive melanoma (controls) patients from the Genes, Environment and Melanoma (GEM) study were included if their tumors were available for pathologic review and confirmed as melanoma. Clinicopathologic characteristics of invasive subsequent and first melanomas in cases and invasive single melanomas in controls were compared. A total of 473 pairs comprising a subsequent and a first melanoma and 1,989 single melanomas were reviewed. Forward stepwise regression modeling in 395 pairs with complete data showed that, compared with first melanomas, subsequent melanomas were more commonly contiguous with a dysplastic nevus, more prevalent on the head/neck and legs than other sites, and thinner. Compared with single primary melanomas, subsequent melanomas were more likely to be associated with a contiguous dysplastic nevus, more prevalent on the head/neck and legs, and thinner. The same differences were observed when subsequent melanomas were compared with single melanomas. First melanomas were more likely than single melanomas to have associated solar elastosis and no observed mitoses. Thinner subsequent than first melanomas suggest earlier diagnosis, perhaps due to closer clinical scrutiny. The association of subsequent melanomas with dysplastic nevi is consistent with the latter being risk factors or risk markers for melanoma.


Brain metastasis in renal cancer patients: metastatic pattern, tumour-associated macrophages and chemokine/chemoreceptor expression.
The mechanisms of brain metastasis in renal cell cancer (RCC) patients are poorly understood. Chemokine and chemokine receptor expression may contribute to the predilection of RCC for brain metastasis by recruitment of monocytes/macrophages and by control or induction of vascular permeability of the blood-brain barrier. Frequency and patterns of brain metastasis were determined in 246 patients with metastatic RCC at autopsy. Expression of CXCR4, CCL7 (MCP-3), CCR2 and CD68(+) tumour-associated macrophages (TAMs) were analysed in a separate series of 333 primary RCC and in 48 brain metastases using immunohistochemistry. Fifteen percent of 246 patients with metastasising RCC had brain metastasis. High CXCR4 expression levels were found in primary RCC and brain metastases (85.7% and 91.7%, respectively). CCR2 (52.1%) and CCL7 expression (75%) in cancer cells of brain metastases was more frequent compared with primary tumours (15.5% and 16.7%, respectively; P<0.0001 each). The density of CD68(+) TAMs was similar in primary RCC and brain metastases. However, TAMs were more frequently CCR2-positive in brain metastases than in primary RCC (P<0.001). Our data demonstrate that the monocyte-specific chemokine CCL7 and its receptor CCR2 are expressed in tumour cells of RCC. We conclude that monocyte recruitment by CCR2 contributes to brain metastasis of RCC.


DNA methylation in individuals with anorexia nervosa and in matched normal-eater controls: A genome-wide study.
Evidence associates anorexia nervosa (AN) with epigenetic alterations that could contribute to illness risk or entrenchment. We investigated the extent to which AN is associated with a distinct methylation profile compared to that seen in normal-eater women. Genome-wide methylation profiles, obtained using DNA from whole blood, were determined in 29 women currently ill with AN (10 with AN-restrictive type, 19 with AN-binge/purge type) and 15 normal-weight, normal-eater control women, using 450 K Illumina bead arrays. Regardless of type, AN patients showed higher and less-variable global methylation patterns than controls. False Discovery Rate corrected comparisons identified 14 probes that were hypermethylated in women with AN relative to levels obtained in normal-eater controls, representing genes thought to be associated with histone acetylation, RNA modification, cholesterol storage and lipid transport, and dopamine and glutamate signaling. Age of onset was significantly associated with differential methylation in gene pathways involved in development of the brain and spinal cord, while chronicity of illness was significantly linked to differential methylation in pathways involved with synaptogenesis, neurocognitive deficits, anxiety, altered social functioning, and bowel, kidney, liver and immune function. Although pre-existing differences cannot be ruled out, our findings are consistent with the idea of secondary alterations in methylation at genomic regions pertaining to social-emotional impairments and physical sequelae that are commonly seen in AN patients. Further investigation is needed to establish the clinical relevance of the affected genes in AN, and, importantly, reversibility of effects observed with nutritional rehabilitation and treatment.


Proximity-induced superconductivity in DNA.
Conductivity measurements on double-stranded DNA molecules deposited by a combing process across a submicron slit between rhenium/carbon metallic contacts reveal conduction to be ohmic between room temperature and 1 kelvin. The resistance per molecule is less than 100 kilohm and varies weakly with temperature. Below the superconducting transition temperature (1 kelvin) of the contacts, proximity-induced superconductivity is observed. These results imply that DNA molecules can be conducting down to millikelvin temperature and that phase coherence is maintained over several hundred nanometers.


A genome-wide linkage study of autism spectrum disorder and the broad autism phenotype in extended pedigrees.
Although several genetic variants for autism spectrum disorder (ASD) have now been identified, these largely occur sporadically or are de novo. Much less progress has been made in identifying inherited variants, even though the disorder itself is familial in the majority of cases. The objective of this study was to identify chromosomal regions that harbor inherited variants increasing the risk for ASD using an approach that examined both ASD and the broad autism phenotype (BAP) among a unique sample of extended pedigrees. ASD and BAP were assessed using standardized tools in 28 pedigrees from Canada and the USA, each with at least three ASD-diagnosed individuals from two nuclear families. Genome-wide linkage analysis was performed using the posterior probability of linkage (PPL) statistic, a quasi-Bayesian method that provides strength of evidence for or against linkage in an essentially model-free manner, with outcomes on the probability scale. The results confirm appreciable interfamilial heterogeneity as well as a high level of intrafamilial heterogeneity. Both ASD and combined ASD/BAP specific loci are apparent. Inclusion of subclinical phenotypes such as BAP should be more widely employed in genetic studies of ASD as a way of identifying inherited genetic variants for the disorder. Moreover, the results underscore the need for approaches to identifying genetic risk factors in extended pedigrees that are robust to high levels of inter/intrafamilial locus and allelic heterogeneity.


Window-level rate control for smooth picture quality and smooth buffer occupancy.
In rate control, smooth picture quality and smooth buffer occupancy are both important but contrary to each other at a given bit rate. How to get a good tradeoff between them was not devoted much attention previously. To deal with this problem, a theoretical window model is proposed in this paper, in which several adjacent frames grouped as a window are considered together. The smoothness of both picture quality and buffer occupancy can be gracefully achieved by regulating the size of the window. To illustrate the usage of window model, a window-level rate control algorithm cooperated with the traditional ρ-domain rate-distortion model is further introduced. In experiments, we first show how the proposed window model achieves the tradeoff between picture quality smoothness and buffer smoothness, and then demonstrate the significant PSNR improvement, accuracy of bit control and consistency of visual quality of the proposed window-level rate control algorithm.


Tris(1,10-phenanthroline-κ(2) N,N')nickel(II) hexa-oxido-μ-peroxido-disulfate-(VI) N,N-dimethyl-formamide disolvate monohydrate.
The asymmetric unit of the title complex, [Ni(C12H8N2)3]S2O8·2C3H7NO·H2O, consists of a complex [Ni(phen)3](2+) cation and one isolated pds anion, with two DMF mol-ecules and one water mol-ecule as solvates (where phen is 1,10-phenanthroline, pds is the hexa-oxido-μ-peroxoido-di-sulf-ate dianion and DMF is dimethyl-formamide). The [Ni(phen)3](2+) cation is regular, with an almost ideal Ni(II) bond-valence sum of 2.07 v.u. The group, as well as the water solvent mol-ecule, are well behaved in terms of crystallographic order, but the remaining three mol-ecules in the structure display different kinds of disorder, viz. the two DMF mol-ecules mimic a twofold splitting and the pds anion has both S atoms clamped at well-determined positions but with a not-too-well-defined central part. These peculiar behaviours are a consequence of the hydrogen-bonding inter-actions: the outermost SO3 parts of the pds anion are heavily connected to the complex cations via C-H⋯O hydrogen bonding, generating an [Ni(phen)3]pds network and providing for the stability of the terminal pds sites. Also, the water solvent mol-ecule is strongly bound to the structure (being a donor of two strong bonds and an acceptor of one) and is accordingly perfectly ordered. The peroxide O atoms in the pds middle region, instead, appear as much less restrained into their sites, which may explain their tendency to disorder. The cation-anion network leaves large embedded holes, amounting to about 28% of the total crystal volume, which are occupied by the DMF mol-ecules. The latter are weakly inter-acting with the rest of the structure, which renders them much more labile and, accordingly, prone to disorder.


Physical activity and osteoarthritis: a consensus study to harmonise self-reporting methods of physical activity across international cohorts.
Physical activity (PA) is increasingly recognised as an important factor within studies of osteoarthritis (OA). However, subjective methods used to assess PA are highly variable and have not been developed for use within studies of OA, which creates difficulties when comparing and interpreting PA data in OA research. The aim of this study was, therefore, to gain expert agreement on the appropriate methods to harmonise PA data among existing population cohorts to enable the investigation of the association of PA and OA. The definition of PA in an OA context and methods of harmonization were established via an international expert consensus meeting and modified Delphi exercise using a geographically diverse committee selected on the basis of individual expertise in physical activity, exercise medicine, and OA. Agreement was met for all aims of study: (1) The use of Metabolic Equivalent of Task (MET) minutes per week (MET-min/week) as a method for harmonising PA variables among cohorts; (2) The determination of methods for treating missing components of MET-min/week calculation; a value will be produced from comparable activities within a representative cohort; (3) Exclusion of the domain of occupation from total MET-min/week; (4) The need for a specific measure of joint loading of an activity in addition to intensity and time, in studies of diseases, such as OA. This study has developed a systematic method to classify and harmonise PA in existing OA cohorts. It also provides minimum requirements for future studies intending to include subjective PA measures.


Inter-individual variability of stone marten behavioral responses to a highway.
Efforts to reduce the negative impacts of roads on wildlife may be hindered if individuals within the population vary widely in their responses to roads and mitigation strategies ignore this variability. This knowledge is particularly important for medium-sized carnivores as they are vulnerable to road mortality, while also known to use available road passages (e.g., drainage culverts) for safely crossing highways. Our goal in this study was to assess whether this apparently contradictory pattern of high road-kill numbers associated with a regular use of road passages is attributable to the variation in behavioral responses toward the highway between individuals. We investigated the responses of seven radio-tracked stone martens (Martes foina) to a highway by measuring their utilization distribution, response turning angles and highway crossing patterns. We compared the observed responses to simulated movement parameterized by the observed space use and movement characteristics of each individual, but naïve to the presence of the highway. Our results suggested that martens demonstrate a diversity of responses to the highway, including attraction, indifference, or avoidance. Martens also varied in their highway crossing patterns, with some crossing repeatedly at the same location (often coincident with highway passages). We suspect that the response variability derives from the individual's familiarity of the landscape, including their awareness of highway passage locations. Because of these variable yet potentially attributable responses, we support the use of exclusionary fencing to guide transient (e.g., dispersers) individuals to existing passages to reduce the road-kill risk.


The role of social support in the association between gambling, poor health and health risk-taking.
Studies have shown that gambling is associated with poor health and health risk-taking behaviour. However, little is known about those factors that can influence the association between gambling, health risk-taking and health. Using a population-based School Health Promotion Study of eighth- and ninth-grade Finnish boys and girls (N = 62,956), we investigated the relationships between gambling frequency, health risk-taking and poor health as well as whether social support from parents, friends and school staff could mediate these associations. Path analysis was used to discover direct and indirect effects of health, health risk-taking and gambling. Social support from parents and school staff decreased gambling among boys and girls, whereas among boys support from friends increased gambling. However, the role of social support as a mediator was very weak. Overall poor health and health risk-taking were associated with increased gambling. CONCLUSIONS GAMBLING SHOULD BE CONSIDERED AN IMPORTANT PUBLIC HEALTH ISSUE BECAUSE IT CLUSTERS WITH OTHER UNHEALTHY BEHAVIOUR PATTERNS INTERVENTIONS CONCERNING ADOLESCENT GAMBLING SHOULD ALSO TAKE OTHER SIMULTANEOUS RISK-TAKING INTO CONSIDERATION ALSO SOCIAL SUPPORT FROM PARENTS AND SCHOOL SHOULD BE NOTED WHEN TRYING TO DECREASE ADOLESCENTS' GAMBLING.


Decreased phospholipase A2 activity in plasma and liver in uncontrolled diabetes mellitus. A defect in the early steps of prostaglandin synthesis?
Arachidonic acid metabolites and prostaglandins participate in numerous physiologic functions. An enzyme important in the control of prostaglandin production is phospholipase A2. In this study, we have investigated the changes in plasma and hepatic phospholipase A2 activity in diabetes mellitus. In uncontrolled diabetic patients, the postheparin plasma phospholipase A2 level was 18.7 +/- 4.1 U/ml; this value was significantly different from the enzyme activities in control subjects (106 +/- 9.8 U/ml) and in controlled diabetic patients (87 +/- 7.3 U/ml). In the streptozocin-induced diabetic rat model, the postheparin plasma phospholipase A2 level (1.9 +/- 0.45 U/ml) was also decreased when compared with normal (9.4 +/- 1.6 U/ml) and controlled diabetic rats (7.0 +/- 1.3 U/ml). The total hepatic enzyme activity in the uncontrolled diabetic rats was only 21.6% of that seen in control rats. Subcellular fraction studies demonstrated that the enzyme activity is decreased in all fractions in the liver. Liver perfusion studies showed that the heparin-releasable phospholipase A2 activity in the perfusate was significantly decreased in the diabetic rats when compared with control and controlled diabetic animals. We conclude that postheparin plasma and hepatic phospholipase A2 activities are decreased in uncontrolled diabetes mellitus, that the low plasma activity is related to decreased release from the liver, and that the alterations in phospholipase A2 activity in plasma and liver are restored to normal by controlling the diabetic status.


In vitro cytokine profiles as indicators of relapse activity and clinical course in multiple sclerosis.
In vitro production of tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10 and oligoclonal IgG (IgG OB) was evaluated in the aim to investigate their profile in correlation with multiple sclerosis (MS) clinical activity and clinical course. Whole blood stimulation with lipopolysaccharide or concanavalin A was performed in 61 patients presenting with relapsing-remitting, relapsing-progressive or chronic progressive MS; treatments received were: none, azathioprine (AZA), cyclosporin, cyclophosphamide, subcutaneous interferon-beta 1a (IFN-beta 1a) and corticosteroids (CST). The cinetics of cytokine production showed that (i) in the absence of treatment, TNF-alpha and IL-6 dropped respectively after and during the periods surrounding relapse, while IL-4 was increasing before and IL-10 after relapse; (ii) with AZA, TNF-alpha and IL-6 lowered before exacerbation, IL-4 prolonged high levels after and IL-10 before relapse; (iii) with IFN-beta 1a, IL-10 was already increasing before relapse, and TNF-alpha was higher after relapse. When cytokine levels were analysed independently from MS clinical activity, the use of AZA inhibited IgG OB and TNF-alpha synthesis (P = 0.002) but increased IL-4 (P = 0.0024), whereas IFN-beta 1a stimulated TNF-alpha and inhibited IgG OB and IL-4 production. CST inhibited TNF-alpha, IL-6, IL-4 and IgG OB synthesis. This study stresses both the weight of clinical parameters and of methodology used in results obtained in cytokine analysis in MS.


The evolution of mobile apps for asthma: an updated systematic assessment of content and tools.
Interest in mobile apps that support long-term conditions such as asthma is matched by recognition of the importance of the quality and safety of apps intended for patient use. We assessed how changes over a 2-year period affected the clinical suitability of apps providing self-management information and tools for people with asthma by updating a review first performed in 2011. Systematic content assessment of all apps for iOS and Android examining the comprehensiveness of asthma information, consistency with the evidence base for asthma self-management and adherence to best practice principles for trustworthy content, comparing the quality of apps available in 2011 to those released since. Between 2011 and 2013, numbers of asthma apps more than doubled from 93 to 191, despite withdrawal of 25% (n = 23/93) of existing apps. Newer apps were no more likely than those available in 2011 to include comprehensive information, such as the use of action plans, or offer guidance consistent with evidence; 13% (n = 19/147) of all apps, and 39% (n = 9/23) of those intended to manage acute asthma, recommended self-care procedures unsupported by evidence. Despite increases in the numbers of apps targeting specific skills, such as acute asthma management (n = 12 to 23) and inhaler technique (from n = 2 to 12), the proportion consistent with guidelines (17%, n = 4/23) and inhaler instructions (25%, n = 3/12), respectively, was low, and most apps provided only either basic information about asthma (50%, n = 75/147) or simple diary functions (24%, n = 36/147). In addition to persisting questions about clinical quality and safety, dynamic aspects of app turnover and feature evolution affect the suitability of asthma apps for use in routine care. The findings underline the need for coordinated quality assurance processes that can adapt to changing clinical and information governance-related risks, ensure compliance with the evidence base and reflect local variations in clinical practice. It is unclear if substantial clinical benefits can be realized from a landscape dominated by low quality generic information apps and tools that do not adhere to accepted medical practice.


Fractalkine preferentially mediates arrest and migration of CD16+ monocytes.
CD16+ monocytes represent 5-10% of peripheral blood monocytes in normal individuals and are dramatically expanded in several pathological conditions including sepsis, human immunodeficiency virus 1 infection, and cancer. CD16+ monocytes produce high levels of proinflammatory cytokines and may represent dendritic cell precursors in vivo. The mechanisms that mediate the recruitment of CD16+ monocytes into tissues remain unknown. Here we investigate molecular mechanisms of CD16+ monocyte trafficking and show that migration of CD16+ and CD16- monocytes is mediated by distinct combinations of adhesion molecules and chemokine receptors. In contrast to CD16- monocytes, CD16+ monocytes expressed high CX3CR1 and CXCR4 but low CCR2 and CD62L levels and underwent efficient transendothelial migration in response to fractalkine (FKN; FKN/CX3CL1) and stromal-derived factor 1 alpha (CXCL12) but not monocyte chemoattractant protein 1 (CCL2). CD16+ monocytes arrested on cell surface-expressed FKN under flow with higher frequency compared with CD16- monocytes. These results demonstrate that FKN preferentially mediates arrest and migration of CD16+ monocytes and suggest that recruitment of this proinflammatory monocyte subset to vessel walls via the CX3CR1-FKN pathway may contribute to vascular and tissue injury during pathological conditions.


Alternative models for allozyme-associated heterosis in the marine bivalve Spisula ovalis.
Correlations between allozyme heterozygosity and fitness-related traits, especially growth, have been documented in natural populations of marine bivalves. However, no consistent pattern has been exhibited, because heterotic effects on size vary with age and individual growth parameters are generally unknown. No consensus has emerged on the genetic basis of allozyme-associated heterosis. The species studied here, Spisula ovalis, displays annual shell growth lines, which allows us to compute individual age and growth dynamics over the whole life span. Our morphological study was coupled to a protein electrophoresis study at seven polymorphic loci. While the maximum size gained is not related to heterozygosity, the age at half maximum size, t1/2, is significantly negatively correlated with heterozygosity, indicating an heterotic effect on initial growth. The correlation between heterozygosity and size is expected to vanish when age increases, due to the form of the growth function. This decreasing correlation is consistent with previous studies. We compare the relative performances of five linear models to analyze the genetic basis of heterosis. Surprisingly, the largest part of variance in t1/2 is due to additive effects, the overdominant components being much weaker. Heterosis is therefore due to general genomic effects rather than to local overdominance restricted to allozymes or small neighboring chromosomal segments. A significant dependence of individual heterotic contributions of the enzyme loci upon expected heterozygosities, rather than metabolic function, further supports the hypothesis of enzymes acting as markers. General genomic effects can hold only if allozyme heterozygosity is positively correlated with heterozygosity at fitness-related genes scattered throughout the genome. This hypothesis is supported here by heterozygosity correlations between enzymatic loci.


Threshold-varying integrate-and-fire model reproduces distributions of spontaneous blink intervals.
Spontaneous blinking is one of the most frequent human behaviours. While attentionally guided blinking may benefit human survival, the function of spontaneous frequent blinking in cognitive processes is poorly understood. To model human spontaneous blinking, we proposed a leaky integrate-and-fire model with a variable threshold which is assumed to represent physiological fluctuations during cognitive tasks. The proposed model is capable of reproducing bimodal, normal, and widespread peak-less distributions of inter-blink intervals as well as the more common popular positively skewed distributions. For bimodal distributions, the temporal positions of the two peaks depend on the baseline and the amplitude of the fluctuating threshold function. Parameters that reproduce experimentally derived bimodal distributions suggest that relatively slow oscillations (0.11-0.25 Hz) govern blink elicitations. The results also suggest that changes in blink rates would reflect fluctuations of threshold regulated by human internal states.


Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8.
Antibody 10E8 targets the membrane-proximal external region (MPER) of HIV-1 gp41, neutralizes >97% of HIV-1 isolates, and lacks the auto-reactivity often associated with MPER-directed antibodies. The developmental pathway of 10E8 might therefore serve as a promising template for vaccine design, but samples from time-of-infection-often used to infer the B cell record-are unavailable. In this study, we used crystallography, next-generation sequencing (NGS), and functional assessments to infer the 10E8 developmental pathway from a single time point. Mutational analysis indicated somatic hypermutation of the 2nd-heavy chain-complementarity determining region (CDR H2) to be critical for neutralization, and structures of 10E8 variants with V-gene regions reverted to genomic origin for heavy-and-light chains or heavy chain-only showed structural differences >2 Å relative to mature 10E8 in the CDR H2 and H3. To understand these developmental changes, we used bioinformatic sieving, maximum likelihood, and parsimony analyses of immunoglobulin transcripts to identify 10E8-lineage members, to infer the 10E8-unmutated common ancestor (UCA), and to calculate 10E8-developmental intermediates. We were assisted in this analysis by the preservation of a critical D-gene segment, which was unmutated in most 10E8-lineage sequences. UCA and early intermediates weakly bound a 26-residue-MPER peptide, whereas HIV-1 neutralization and epitope recognition in liposomes were only observed with late intermediates. Antibody 10E8 thus develops from a UCA with weak MPER affinity and substantial differences in CDR H2 and H3 from the mature 10E8; only after extensive somatic hypermutation do 10E8-lineage members gain recognition in the context of membrane and HIV-1 neutralization.


Structural mass spectrometry decodes domain interaction and dynamics of the full-length Human Histone Deacetylase 2.
Human Histone Deacetylase 2 (HDAC2) belongs to a conserved enzyme superfamily that regulates deacetylation inside cells. HDAC2 is a drug target as it is known to be upregulated in cancers and neurodegenerative disorders. It consists of globular deacetylase and C-terminus intrinsically-disordered domains [1-3]. To date, there is no full-length structure of HDAC2 available due to the high intrinsic flexibility of its C-terminal domain. The intrinsically-disordered domain, however, is known to be important for the enzymatic function of HDAC2 [1, 4]. Here we combine several structural Mass Spectrometry (MS) methodologies such as denaturing, native, ion mobility and chemical crosslinking, alongside biochemical assays and molecular modelling to study the structure and dynamics of the full-length HDAC2 for the first time. We show that MS can easily dissect heterogeneity inherent within the protein sample and at the same time probe the structural arrangement of the different conformers present. Activity assays combined with data from MS and molecular modelling suggest how the structural dynamics of the C-terminal domain, and its interactions with the catalytic domain, regulate the activity of this enzyme.


Biodegradable synthetic polymers for tissue engineering.
This paper reviews biodegradable synthetic polymers focusing on their potential in tissue engineering applications. The major classes of polymers are briefly discussed with regard to synthesis, properties and biodegradability, and known degradation modes and products are indicated based on studies reported in the literature. A vast majority of biodegradable polymers studied belongs to the polyester family, which includes polyglycolides and polylactides. Some disadvantages of these polymers in tissue engineering applications are their poor biocompatibility, release of acidic degradation products, poor processability and loss of mechanical properties very early during degradation. Other degradable polymers such as polyorthoesters, polyanhydrides, polyphosphazenes, and polyurethanes are also discussed and their advantages and disadvantages summarised. With advancements in tissue engineering it has become necessary to develop polymers that meet more demanding requirements. Recent work has focused on developing injectable polymer compositions based on poly (propylene fumarate) and poly (anhydrides) to meet these requirements in orthopaedic tissue engineering. Polyurethanes have received recent attention for development of degradable polymers because of their great potential in tailoring polymer structure to achieve mechanical properties and biodegradability to suit a variety of applications.


Culture, compassion and clinical neglect: probity in the NHS after Mid Staffordshire.
Speaking of the public response to the deaths of children at the Bristol Royal Infirmary before 2001, the BMJ commented that the NHS would be 'all changed, changed utterly'. Today, two inquiries into the Mid Staffordshire Foundation Trust suggest nothing changed at all. Many patients died as a result of their care and the stories of indifference and neglect there are harrowing. Yet Bristol and Mid Staffordshire are not isolated reports. In 2011, the Health Services Ombudsman reported on the care of elderly and frail patients in the NHS and found a failure to recognise their humanity and individuality and to respond to them with sensitivity, compassion and professionalism. Likewise, the Care Quality Commission and Healthcare Commission received complaints from patients and relatives about the quality of nursing care. These included patients not being fed, patients left in soiled bedding, poor hygiene practices, and general disregard for privacy and dignity. Why is there such tolerance of poor clinical standards? We need a better understanding of the circumstances that can lead to these outcomes and how best to respond to them. We discuss the findings of these and other reports and consider whether attention should be devoted to managing individual behaviour, or focus on the systemic influences which predispose hospital staff to behave in this way. Lastly, we consider whether we should look further afield to cognitive psychology to better understand how clinicians and managers make decisions?


Primary oral soft tissue angiosarcoma of the cheek: a case report and literature review.
Angiosarcoma is a rare and aggressive malignant tumor that has a poor prognosis. It represents less than 1% of all malignancies occurring in the oral cavity and salivary glands. We present a 35-year-old male with angiosarcoma of the cheek following traumatic injury and a review of the current literature.


3D Lung-on-Chip Model Based on Biomimetically Microcurved Culture Membranes.
A comparatively straightforward approach to accomplish more physiological realism in organ-on-a-chip (OoC) models is through substrate geometry. There is increasing evidence that the strongly, microscale curved surfaces that epithelial or endothelial cells experience when lining small body lumens, such as the alveoli or blood vessels, impact their behavior. However, the most commonly used cell culture substrates for modeling of these human tissue barriers in OoCs, ion track-etched porous membranes, provide only flat surfaces. Here, we propose a more realistic culture environment for alveolar cells based on biomimetically microcurved track-etched membranes. They recreate the mainly spherical geometry of the cells' native microenvironment. In this feasibility study, the membranes were given the shape of hexagonally arrayed hemispherical microwells by an innovative combination of three-dimensional (3D) microfilm (thermo)forming and ion track technology. Integrated in microfluidic chips, they separated a top from a bottom cell culture chamber. The microcurved membranes were seeded by infusion with primary human alveolar epithelial cells. Despite the pronounced topology, the cells fully lined the alveoli-like microwell structures on the membranes' top side. The confluent curved epithelial cell monolayers could be cultured successfully at the air-liquid interface for 14 days. Similarly, the top and bottom sides of the microcurved membranes were seeded with cells from the Calu-3 lung epithelial cell line and human lung microvascular endothelial cells, respectively. Thereby, the latter lined the interalveolar septum-like interspace between the microwells in a network-type fashion, as in the natural counterpart. The coculture was maintained for 11 days. The presented 3D lung-on-a-chip model might set the stage for other (micro)anatomically inspired membrane-based OoCs in the future.


A 3-year study of patients with tinnitus and jaw muscle tenderness.
Objective: This study evaluated three-year results of treatment with an interocclusal appliance in 89 tinnitus patients with jaw muscle tenderness. Methods: Subjective tinnitus severity was recorded using a visual analog scale (VAS). The number of tender muscles was registered. The patients were followed annually. After three years, 64 patients were examined (72%). Results: Tinnitus severity at baseline was high (mean VAS value 68.3). After one year, the VAS values were substantially lower (mean 37.4; p < 0.001). During the following two years, there were no significant changes in VAS values. The mean number of tender muscles decreased from seven to two after one year and remained at this number for up to three years. Conclusion: In many tinnitus patients with signs of temporomandibular disorders (TMDs), intraoral splint therapy reduced tinnitus severity and jaw muscle symptoms. The favorable results after one year remained for up to three years without significant changes.


Comprehensive Lifestyle Improvement Program for Prostate Cancer (CLIPP): Protocol for a Feasibility and Exploratory Efficacy Study in Men on Androgen Deprivation Therapy.
Androgen deprivation therapy (ADT) for prostate cancer is associated with adverse cardiometabolic effects such as reduced libido, hot flashes, metabolic syndrome, diabetes, myocardial infarction, and stroke. This reduces quality of life and potentially increases mortality. Several large clinical trials have demonstrated improvements in cardiometabolic risk with comprehensive multimodality lifestyle modification. However, there is a lack of data for such interventions in men on ADT for prostate cancer, and existing studies have used non-standardized interventions or lacked data on metabolic risk factors. The Comprehensive Lifestyle Improvement Project for Prostate Cancer (CLIPP) is designed to address these gaps by using an intervention modeled on the Diabetes Prevention Program, a standardized multicomponent intervention with demonstrated effectiveness in reducing cardiometabolic risk factors that has been successfully adapted for multiple disease types including breast cancer. A single-arm unblinded clinical trial will be conducted to determine the feasibility of conducting a 24-week comprehensive lifestyle modification intervention that targets weight loss and increased physical activity modeled on the Diabetes Prevention Program in 30 men on ADT for prostate cancer. Secondary aims are to determine the effect of the intervention on cardiometabolic markers and quality of life. The tertiary aim is to determine the effect of the intervention on markers of inflammation and angiogenesis, important mechanisms for prostate cancer progression. Participants will be recruited from the University of Arizona Cancer Center and the surrounding community. The intervention will be delivered weekly in person and over the phone for 16 weeks. For Weeks 16-24, participants receive weekly phone calls from the study health coach to motivate them to continue their lifestyle modification. Questionnaire and biological data are collected at baseline, 12 weeks, and 24 weeks. Body composition using dual-energy x-ray absorptiometry scans will be performed at baseline and end of study. Based on a sample size of 30, the two-sided 95% confidence interval will not be wider than 0.373 standard deviations for the adherence rate and will not be wider than 0.374 for the retention rate. In addition, the study will have a power of 80% to detect a change of 0.47 standard deviations from baseline for each of the markers investigated in the secondary and tertiary aims assuming a within-subject correlation of 0.20 at a significance level of 5%. The recruitment period is from October 2018 to April 2019. The aim of CLIPP is to determine the feasibility of conducting a Diabetes Prevention Program-style comprehensive lifestyle modification intervention in men with ADT for prostate cancer and its effects on cardiometabolic adverse effects, quality of life, as well as markers of inflammation and angiogenesis. Results will inform the development of future clinical trials in this population. DERR1-10.2196/12579.


Sjögren-like syndrome after bone marrow transplantation.
To study the incidence of dry eye in Sjögren-like syndrome, graft-versus-host disease (GVHD) in hematological patients undergoing bone marrow transplantation (BMT). Prospective, cross-sectional study in twenty-six patients that were planned for BMT (group I). Twenty-nine patients undergoing BMT before study were classified as group II no GVHD (9), and group III with GVHD (20). Thirty-two normal subjects were controls. All subjects were examined by slit lamp biomicroscopy and had their tear samples analyzed about tear osmolarity. They were also evaluated for aqueous tear production by phenol red thread test, Schirmer test without anesthesia, tear film stability by tear break-up time (TBUT), and rose bengal staining 2 weeks before BMT (for group I) as well as 6 weeks, 3 months, and 6 months after BMT. The patients with GVHD were followed up 1 month later. Main outcome measures were amount of tear production, tear film stability, and dry eye symptoms. Average aqueous tear production in group III was less than control and group II (p < 0.001). Mean TBUT in group III was faster than control (p < 0.001) and group I before BMT (p = 0.001). Mean score of rose bengal staining in group III was more than control and group I before BMT (p < 0.001). Keratoconjunctivitis sicca and red eye developed in 27.5%, and 20% of group III, with incidence of dry eye by Schirmer test without anesthesia (67.5%). This compares with group II having incidence of dry eye of 16.7%. However, 42.3% of group I before BMT had dry eye compared with 9.4% in the controls (p < 0.001). Trend of dry eye in patients with BMT and GVHD were higher than no-GVHD group. Doctors should be aware of ocular symptoms and signs of dry eye in patients with BMT and follow-up for proper management.


Serum IgG antibody levels to periodontal microbiota are associated with incident Alzheimer disease.
Periodontitis and Alzheimer disease (AD) are associated with systemic inflammation. This research studied serum IgG to periodontal microbiota as possible predictors of incident AD. Using a case-cohort study design, 219 subjects (110 incident AD cases and 109 controls without incident cognitive impairment at last follow-up), matched on race-ethnicity, were drawn from the Washington Heights-Inwood Columbia Aging Project (WHICAP), a cohort of longitudinally followed northern Manhattan residents aged >65 years. Mean follow-up was five years (SD 2.6). In baseline sera, serum IgG levels were determined for bacteria known to be positively or negatively associated with periodontitis (Porphyromonas gingivalis, Tannerella forsythia, Actinobacillus actinomycetemcomitans Y4, Treponema denticola, Campylobacter rectus, Eubacterium nodatum, and Actinomyces naeslundii genospecies-2). In all analyses, we used antibody threshold levels shown to correlate with presence of moderate-severe periodontitis. Mean age was 72 years (SD 6.9) for controls, and 79 years (SD 4.6) for cases (p<0.001). Non-Hispanic Whites comprised 26%, non-Hispanic Blacks 27%, and Hispanics 48% of the sample. In a model adjusting for baseline age, sex, education, diabetes mellitus, hypertension, smoking, prior history of stroke, and apolipoprotein E genotype, high anti-A. naeslundii titer (>640 ng/ml, present in 10% of subjects) was associated with increased risk of AD (HR = 2.0, 95%CI: 1.1-3.8). This association was stronger after adjusting for other significant titers (HR = 3.1, 95%CI: 1.5-6.4). In this model, high anti-E. nodatum IgG (>1755 ng/ml; 19% of subjects) was associated with lower risk of AD (HR = 0.5, 95%CI: 0.2-0.9). Serum IgG levels to common periodontal microbiota are associated with risk for developing incident AD.


Additive, modular functionalization of reactive self-assembled monolayers: toward the fabrication of multilevel optical storage media.
We report a novel strategy based on iterative microcontact printing, which provides additive, modular functionalization of reactive SAMs by different functional molecules. We demonstrate that after printing the molecules form an interpenetrating network at the SAM surface preserving their individual properties. We exploited the process by fabricating new optical storage media that consist of a multilevel TAG.


Nonstandard Lumbar Region in Predicting Fracture Risk.
Femoral neck (FN) bone mineral density (BMD) is the most commonly used skeletal site to estimate fracture risk. The role of lumbar spine (LS) BMD in fracture risk prediction is less clear due to osteophytes that spuriously increase LS BMD, particularly at lower levels. The aim of this study was to compare fracture predictive ability of upper L1-L2 BMD with standard L2-L4 BMD and assess whether the addition of either LS site could improve fracture prediction over FN BMD. This study comprised a prospective cohort of 3016 women and men over 60 yr from the Dubbo Osteoporosis Epidemiology Study followed up for occurrence of minimal trauma fractures from 1989 to 2014. Dual-energy X-ray absorptiometry was used to measure BMD at L1-L2, L2-L4, and FN at baseline. Fracture risks were estimated using Cox proportional hazards models separately for each site. Predictive performances were compared using receiver operating characteristic curve analyses. There were 565 women and 179 men with a minimal trauma fracture during a mean of 11 ± 7 yr. L1-L2 BMD T-score was significantly lower than L2-L4 T-score in both genders (p < 0.0001). L1-L2 and L2-L4 BMD models had a similar fracture predictive ability. LS BMD was better than FN BMD in predicting vertebral fracture risk in women [area under the curve 0.73 (95% confidence interval, 0.68-0.79) vs 0.68 (95% confidence interval, 0.62-0.74), but FN was superior for hip fractures prediction in both women and men. The addition of L1-L2 or L2-L4 to FN BMD in women increased overall and vertebral predictive power compared with FN BMD alone by 1% and 4%, respectively (p < 0.05). In an elderly population, L1-L2 is as good as but not better than L2-L4 site in predicting fracture risk. The addition of LS BMD to FN BMD provided a modest additional benefit in overall fracture risk. Further studies in individuals with spinal degenerative disease are needed.


Confocal laser scanning microscopy of peritoneal catheter surfaces.
Surface topography of used (in situ > 12 months) and unused CAPD catheters was studied by scanning electronmicroscopy (SEM) and confocal laser scanning microscopy (CLSM). Microbial biofilm was observed on all used catheters. Disruption and removal of the attached biofilm revealed extensive pitting of the catheter surface and scoring within the catheter pores. Similar, though less extensive, surface defects were present in unused catheters. Examination by CLSM, with software specific to the determination of surface topography, showed used catheters to have a surface microrugosity greater than that of unused catheters (p < 0.0005). Adherence studies with radiolabelled Staphylococcus epidermidis demonstrated increased adherence to used than to unused catheters (p < 0.0005) after 48 h. However, when catheters were pre-treated with spent dialysate there was a substantial reduction in bacterial adherence to either catheter and no significant difference in adherence to used and unused catheters. Surface microrugosity of CAPD catheters increases during use but is unlikely to be an important factor in bacterial adherence in vivo.


Airway Inflammation and Lung Function in Sickle Cell Disease.
Rationale: Asthma is a common comorbid condition in sickle cell disease (SCD). However, obstructive lung disease is prevalent in SCD, independent of a diagnosis of asthma. It is speculated that the heightened state of inflammation in SCD, involving pathways distinct from allergic asthma, may underlie the SCD-specific obstructive disease. Objective: The objective of the study was to compare airway and systemic inflammatory markers between SCD patients with pulmonary manifestations and patients with allergic asthma, and correlate the discriminating inflammatory markers with clinical measures of pulmonary disease. Materials and Methods: In a pilot translational study conducted at the Children's Hospital at Montefiore, 15 patients with SCD, and history of asthma, airway obstruction, or airway hyper-reactivity, and 15 control patients with allergic asthma 6-21 years of age were recruited. Inflammatory markers, including peripheral blood T helper cell subsets, serum and exhaled breath condensate (EBC) cytokines and chemokines of the Th-1/Th-17, Th-2, and monocytic pathways, and serum cysteinyl leukotrienes B4 (LTB4), were quantified, compared between the study groups, and correlated with atopic sensitization, pulmonary function tests, and markers of hemolysis. Results: White blood cells (P < 0.05) and monocytes (P < 0.001) were elevated in the SCD group, while atopic characteristics were higher in the control asthma group. Tumor necrosis factor-alpha (P < 0.01), interferon gamma inducible protein (IP)-10 (P < 0.05), and interleukin-4 (P < 0.01) in serum and monocyte chemotactic protein (MCP)-1 in EBC were higher in the SCD group (P ≤ 0.05). Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) in patients with SCD inversely correlated with serum IP-10 and LTB4 levels. Conclusions: Compared with atopic asthmatic patients, inflammatory markers involving Th-1, Th-2, and monocytic pathways were higher in the SCD group, among which Th-1 measures correlated with pulmonary function deficits.


Macrophage migration inhibitory factor increases atrial arrhythmogenesis through CD74 signaling.
Macrophage migration inhibitory factor (MIF), a pleiotropic inflammatory cytokine, is highly expressed in patients with atrial fibrillation (AF). CD74 (major histocompatibility complex, class II invariant chain) is the main receptor for MIF. However, the role of the MIF/CD74 axis in atrial arrhythmogenesis is unclear. In this study, we investigated the effects of MIF/CD74 signaling on atrial electrophysiological characteristics and determined its underlying mechanisms. Confocal fluorescence microscopy, patch clamp, and western blot analysis were used to study calcium homeostasis, ionic currents, and calcium-related signaling in MIF-treated HL-1 atrial cardiomyocytes with or without anti-CD74 neutralized antibodies treatment. Furthermore, electrocardiographic telemetry recording and echocardiography were obtained from mice treated with MIF. Compared with controls, MIF-treated HL-1 myocytes had increased calcium transients, sarcoplasmic reticulum (SR) calcium content, Na+/Ca2+ exchanger (NCX) efflux rate, calcium leak, transient outward potassium current, and ultra-rapid delayed rectifier potassium current. Furthermore, MIF could induce expression of SR Ca2+ATPase, NCX, phosphorylation of ryanodine receptor 2 (RyR2), and activation of calcium/calmodulin kinase II (CaMKII) when compared with control cells. MIF-mediated electrical dysregulation and CaMKII-RyR2 signaling activation were attenuated through blocking of CD74. Moreover, MIF-injected mice had lesser left atrium fractional shortening, greater atrial fibrosis, and atrial ectopic beats than control (nonspecific immunoglobulin treated) or MIF combined with anti-CD74 neutralized antibody-treated mice. Consequently, our study on MIF/CD74 signaling has pointed out a new potential therapeutic intervention of AF patients with MIF elevation.


Survival of Verwey transition in gadolinium-doped ultrasmall magnetite nanoparticles.
We have demonstrated that the Verwey transition, which is highly sensitive to impurities, survives in anisotropic Gd-doped magnetite nanoparticles. Transmission electron microscopy analysis shows that the nanoparticles are uniformly distributed. X-ray photoelectron spectroscopy and EDS mapping analysis confirm Gd-doping on the nanoparticles. The Verwey transition of the Gd-doped magnetite nanoparticles is robust and the temperature dependence of the magnetic moment (zero field cooling and field cooling) shows the same behaviour as that of the Verwey transition in bulk magnetite, at a lower transition temperature (∼110 K). In addition, irregularly shaped nanoparticles do not show the Verwey transition whereas square-shaped nanoparticles show the transition. Mössbauer spectral analysis shows that the slope of the magnetic hyperfine field and the electric quadrupole splitting change at the same temperature, meaning that the Verwey transition occurs at ∼110 K. These results would provide new insights into understanding the Verwey transition in nano-sized materials.


Stacking-enriched magneto-transport properties of few-layer graphenes.
The quantum Hall effects in sliding bilayer graphene and a AAB-stacked trilayer system are investigated using the Kubo formula and a generalized tight-binding model. The various stacking configurations can greatly diversify the magnetic quantization and thus create rich and unique transport properties. The quantum conductivities are very sensitive to the Fermi energy and magnetic-field strength. The diverse features cover the specific non-integer conductivities, the integer conductivities with distinct steps, the splitting-created reduction and complexity of quantum conductivity, a vanishing or non-zero conductivity at the neutral point, and the well-like, staircase, composite, and abnormal plateau structures in the field dependencies. Such stacking-dependent characteristics mainly originate from the crossing, anticrossing and splitting Landau-level energy spectra and three kinds of quantized modes.


Comparison of the physicochemical properties of type I and type II iodothyronine 5'-deiodinase.
The 5'-deiodination of thyroxine is catalyzed by two enzymes which differ in their tissue distribution, substrate specificities, sensitivity to the inhibitor, propylthiouracil, and response to thyroid status. By using the affinity label, N-bromoacetyl-L-thyroxine, both isoenzymes have been found to have substrate binding subunits of approximately 27 kDa. In this study, we compared the substrate binding subunits and hydrodynamic properties of the type I and the type II isozymes using the affinity label, N-bromoacetyl-L-thyroxine, to identify the enzymes. High resolution sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that the substrate binding subunit of the type I enzyme had an Mr of 27,000, while that of the type II enzyme had a slightly higher Mr of 29,000. This difference was not accounted for by glycosylation. Partial staphylococcal V8-protease digests of the substrate binding subunit of the type I enzyme yielded fragments of 14.6, 13.7, and 7.0 kDa, while V8-protease digests of the substrate binding subunit for the type II enzyme produced fragments of 28.0, 25.1, 19.0, 9.5, 7.2, and 5.8 kDa. Unique cyanogen bromide fragmentation patterns were also observed for the two substrate binding subunits. Sedimentation coefficients of the detergent-soluble type I and type II holoenzymes were 3.67 and 5.22 S, respectively, as determined by sucrose density centrifugation. The type I enzyme behaved as a globular protein, whereas the type II enzyme showed sedimentation properties typical of asymmetric integral membrane proteins. The Stokes radii were 3.78 and 4.97 nm, respectively. From these data, the calculated Mr for detergent-solubilized type I 5'-iodothyronine deiodinase was 55,400 and for the type II enzyme was 198,700. These data indicate that the two isozymes of iodothyronine 5'-deiodinase are multimeric, differ in holoenzyme size and subunit composition, and that their substrate binding subunits are distinct.


Temporal studies into attachment, VE-cadherin perturbation, and paracellular migration of human umbilical mesenchymal stem cells across umbilical vein endothelial monolayers.
Mesenchymal stem cells from Wharton's jelly of human umbilical cords (WJ-MSC) are a valuable alternate source of stem cells. Their role in situ and whether they can interact and cross intact endothelial monolayers requires elucidation. The aim of this study was to investigate the dynamic interactions between WJ-MSC and human umbilical vein endothelial cells (HUVEC), including attachment, transit times, extravasation pathway, and the effects of WJ-MSC on junctional vascular endothelial (VE)-cadherin. HUVEC were grown to near confluence in endothelial media and to full confluence in mixed media before the addition of PKH26-labelled WJ-MSC. Time lapse fluorescence microscopy showed stem cells undergoing membrane blebbing followed by amoeboid movement on HUVEC monolayers before rounding up and changing shape toward the spindle-shaped morphology during/after transmigration to subendothelial positions. Cells demonstrated a time lag of 60 min before paracellular extravasation, confirmed by confocal microscopy. Forty-six percent of attached cells crossed in the first 2 h. By 16 h, a majority of cells had transmigrated with >96% of cells crossing by 22 h. There were concomitant changes in endothelial junctional VE-cadherin with statistically significant increases in discontinuous staining at 2 h, return to control values at 16 h, even as from 22 h onward HUVEC displayed increased percentage of junctions with continuous staining and upregulation of protein. Our data suggests that WJ-MSC crosses the endothelial barrier through the paracellular pathway and can influence junctional organization of HUVEC with discreet perturbation of VE-cadherin preceding transmigration followed by upregulation once the adluminal side is reached. The latter may reflect a perivascular support function of WJ-MSC in the umbilical cord.