Respiratory Health Effects of Exposure to Ambient Particulate Matter and Bioaerosols.
Researchers have been studying the respiratory health effects of ambient air pollution for more than 70 years. While air pollution as a whole can include gaseous, solid, and liquid constituents, this article focuses only on the solid and liquid fractions, termed particulate matter (PM). Although PM may contain anthropogenic, geogenic, and/or biogenic fractions, in this article, particles that originate from microbial, fungal, animal, or plant sources are distinguished from PM as bioaerosols. Many advances have been made toward understanding which particle and exposure characteristics most influence deposition and clearance processes in the respiratory tract. These characteristics include particle size, shape, charge, and composition as well as the exposure concentration and dose rate. Exposure to particles has been directly associated with the exacerbation and, under certain circumstances, onset of respiratory disease. The circumstances of exposure leading to disease are dependent on stressors such as human activity level and changing particle composition in the environment. Historically, researchers assumed that bioaerosols were too large to be inhaled into the deep lung, and thus, not applicable for study in conjunction with PM2.5 (the 2.5-μm and below size fraction that can reach the deep lung); however, this concept is beginning to be challenged. While there is extensive research on the health effects of PM and bioaerosols independent of each other, only limited work has been performed on their coexposure. Studying these two particle types as dual stressors to the respiratory system may aid in more thoroughly understanding the etiology of respiratory injury and disease. © 2020 American Physiological Society. Compr Physiol 10:1-20, 2020.


Fifty years of vascular surgery in australia and new zealand.
Over the 50 years that vascular surgery has been practised in Australia and New Zealand there have been major advances and refinements of surgical techniques, particularly with the advent of endovascular surgery, spurred on especially with the introduction of endovascular aortic aneurysm stent grafting. At the same time, there has been a revolution in medical imaging, with the introduction of ultrasound, computed tomography scanning and magnetic resonance scanning. Vascular surgery in Australia and New Zealand was initially an interest of either general or cardiothoracic surgeons, but was recognized as a subspecialty of general surgery with the formation of the Section of Vascular Surgery within the Division of General Surgery of the Royal Australasian College of Surgeons in 1972. In 1981, a 2-year training programme in vascular surgery was established and in 1983 an Australian and New Zealand Chapter of the International Society for Cardiovascular Surgery was formed. In 1995, vascular surgery was recognized as a specialty in its own right with the formation of the Division of Vascular Surgery within the College. There has been a separate examination for Fellowship of the Royal Australasian College of Surgeons (Vascular) since 1997. In 2001, the Chapter changed its name to The Australian and New Zealand Society for Vascular Surgery and in 2002 it amalgamated with and took over the functions of the Division of Vascular Surgery, which was formally dissolved.


Clinical and neuroinflammatory responses to meningoencephalitis in substance P receptor knockout mice.
Human African trypanosomiasis, also known as sleeping sickness, affects the CNS at the late stage of the disease. Untreated the disease is invariably fatal, and melarsoprol, the only available and effective treatment for CNS disease, is associated in up to 10% of cases with a severe post-treatment reactive encephalopathy (PTRE), which can itself cause death. We used a reproducible mouse model of the PTRE to investigate the pathogenesis and treatment of this condition. Mice infected with Trypanosoma brucei brucei and treated subcuratively with diminazene aceturate develop a severe meningoencephalitis that closely resembles PTRE. We previously reported that substance P plays an important role in PTRE. We investigated the effect of disrupting the gene encoding for the NK1 receptor in mice on the clinical and neuroinflammatory response in this model. After induction of PTRE, NK1-/- mice showed a significant reduction in clinical impairment compared with NK1+/+ mice, but the severity of the neuroinflammatory response was significantly greater in NK1-/- mice. To explore the mechanisms of this dissociated phenotype, we treated infected NK1-/- mice with antagonists to NK2 and NK3 receptors, either singly or in combination. While none of these antagonist treatments altered the clinical score, combined treatment with the NK2 and NK3 antagonists significantly reduced the neuroinflammatory grading score in the NK1-/- mice. Thus, the clinical and neuroinflammatory responses to parasite invasion can be mediated by different pathways, and, importantly, the neuroinflammatory response is altered by alternative tachykinin receptor usage. These findings could be exploited to develop novel anti-inflammatory therapies in Human African trypanosomiasis by modulating the NK1 receptor as well as the parasite.


Description and cohort characterization of the Longevity Study: learning from our elders.
The purpose of this article is to describe the Longevity Study: Learning From Our Elders, a research program on healthy aging that began in 2007 at the Center for Healthy Aging at Banner Sun Health Research Institute. As of June 2015, 1139 participants (age range of 50-110 years) completed baseline assessments with the majority living in the Sun Cities retirement communities northwest of Phoenix, Arizona but expanding throughout the state. The registry includes over 830 currently active participants with 450 aged 80 years and older, 188 aged 90 and older, and 27 centenarians. Data from in-person interviews at the Center for Healthy Aging in Sun City or in the participants' residences which includes sociodemographic, medical, cognitive, physical and psychosocial variables have been collected since the study's inception. This paper outlines some of the key demographic and clinical characteristics of the Longevity Study, its progress, and future directions. It also reflects on how exceptional aging individuals function psychosocially, cognitively and physically, particularly among individuals aged 85 and older.


Selective-area growth of periodic nanopyramid light-emitting diode arrays on GaN/sapphire templates patterned by multiple-exposure colloidal lithography.
Gallium nitride-based nanopyramid light-emitting diodes are a promising technology to achieve highly efficient solid-state lighting and beyond. Here, periodic nanopyramid light-emitting diode arrays on gallium nitride/sapphire templates were fabricated by selective-area metalorganic chemical vapor deposition and multiple-exposure colloidal lithography. The electric field intensity distribution of incident light going through polystyrene microspheres and photoresist are simulated using finite-different time-domain method. Nitrogen as the carrier gas and a low V/III ratio (ratio of molar flow rate of group-V to group-III sources) are found to be important in order to form gallium nitride nanopyramid. In addition, a broad yellow emission in photoluminescence and cathodoluminescence spectra were observed. This phenomena showed the potential of nanopyramid light-emitting diodes to realize long wavelength visible emissions.


Genomic surveillance of enterovirus associated with aseptic meningitis cases in southern Spain, 2015-2018.
New circulating Enterovirus (EV) strains often emerge through recombination. Upsurges of recombinant non-polio enteroviruses (NPEVs) associated with neurologic manifestations such as EVA71 or Echovirus 30 (E30) are a growing public health concern in Europe. Only a few complete genomes of EVs circulating in Spain are available in public databases, making it difficult to address the emergence of recombinant EVs, understand their evolutionary relatedness and the possible implication in human disease. We have used metagenomic (untargeted) NGS to generate full-length EV genomes from CSF samples of EV-positive aseptic meningitis cases in Southern Spain between 2015 and 2018. Our analyses reveal the co-circulation of multiple Enterovirus B (EV-B) types (E6, E11, E13 and E30), including a novel E13 recombinant form. We observed a genetic turnover where emergent lineages (C1 for E6 and I [tentatively proposed in this study] for E30) replaced previous lineages circulating in Spain, some concomitant with outbreaks in other parts of Europe. Metagenomic sequencing provides an effective approach for the analysis of EV genomes directly from PCR-positive CSF samples. The detection of a novel, disease-associated, recombinant form emphasizes the importance of genomic surveillance to monitor spread and evolution of EVs.


Real Time Spectroscopic Ellipsometry Analysis of First Stage CuIn1-xGaxSe₂ Growth: Indium-Gallium Selenide Co-Evaporation.
Real time spectroscopic ellipsometry (RTSE) has been applied for in-situ monitoring of the first stage of copper indium-gallium diselenide (CIGS) thin film deposition by the three-stage co-evaporation process used for fabrication of high efficiency thin film photovoltaic (PV) devices. The first stage entails the growth of indium-gallium selenide (In1-xGax)₂Se₃ (IGS) on a substrate of Mo-coated soda lime glass maintained at a temperature of 400 °C. This is a critical stage of CIGS deposition because a large fraction of the final film thickness is deposited, and as a result precise compositional control is desired in order to achieve the optimum performance of the resulting CIGS solar cell. RTSE is sensitive to monolayer level film growth processes and can provide accurate measurements of bulk and surface roughness layer thicknesses. These in turn enable accurate measurements of the bulk layer optical response in the form of the complex dielectric function ε = ε₁ - iε₂, spectra. Here, RTSE has been used to obtain the (ε₁, ε₂) spectra at the measurement temperature of 400 °C for IGS thin films of different Ga contents (x) deduced from different ranges of accumulated bulk layer thickness during the deposition process. Applying an analytical expression in common for each of the (ε₁, ε₂) spectra of these IGS films, oscillator parameters have been obtained in the best fits and these parameters in turn have been fitted with polynomials in x. From the resulting database of polynomial coefficients, the (ε₁, ε₂) spectra can be generated for any composition of IGS from the single parameter, x. The results have served as an RTSE fingerprint for IGS composition and have provided further structural information beyond simply thicknesses, for example information related to film density and grain size. The deduced IGS structural evolution and the (ε₁, ε₂) spectra have been interpreted as well in relation to observations from scanning electron microscopy, X-ray diffractometry and energy-dispersive X-ray spectroscopy profiling analyses. Overall the structural, optical and compositional analysis possible by RTSE has assisted in understanding the growth and properties of three stage CIGS absorbers for solar cells and shows future promise for enhancing cell performance through monitoring and control.


HPTN 062: A Pilot Randomized Controlled Trial Exploring the Effect of a Motivational-Interviewing Intervention on Sexual Behavior among Individuals with Acute HIV Infection in Lilongwe, Malawi.
We pilot tested a Motivational Interviewing (MI) -based counseling intervention for individuals with Acute HIV Infection (AHI) to reduce risky sexual behavior in Lilongwe, Malawi. Twenty-eight individuals diagnosed with AHI were randomized to receive either brief education alone, or the brief education plus the MI-based intervention, called Uphungu Wanga. Participants in Uphungu Wanga received four sessions delivered on the day of diagnosis, three days later and at weeks 1 and 2 with a booster session at week 8; participants were followed for 24 weeks from diagnosis. An interviewer administered quantitative questionnaire was conducted at baseline and at weeks 2, 4, 8, 12, 16, 20 and 24. Semi-structured qualitative interviews (SSI) were conducted at weeks 2, 8, 12, and 24. The majority of participants in both arms reported rapid and sustained behavior change following diagnosis with AHI. Very few participants reported having sex without a condom after diagnosis. Participants reported a trend towards fewer sex partners and abstaining from sex during study follow-up. Participants in the MI-based arm provided concrete examples of risk reduction strategies in the SSIs while those in the brief education arm primarily described reducing risk behavior, suggesting that the MI-based group may have acquired more risk reduction skills. Individuals in both study arms reduced risky sexual behaviors after diagnosis with AHI. We found few major differences between study arms during the 6-month follow up period in self-reported sexual behaviors therefore a MI-based intervention may not be needed to trigger behavior change following AHI. However, comparing the MI-based intervention to repeated brief education sessions made it difficult to assess the potential benefit of an MI-based intervention in a setting where standard counseling often consists of one post-test session. Nevertheless, provision of counseling immediately following diagnosis with HIV to support behavior change should remain a priority. ClinicalTrials.gov NCT01197027.


Development and implementation of a pharmacist-managed outpatient parenteral antimicrobial therapy program.
The development and implementation of a pharmacist-managed outpatient parenteral antimicrobial therapy (OPAT) program in a county teaching hospital are described. A pharmacist-managed OPAT program was developed and implemented at a county teaching hospital to provide consistent evaluation, approval, and monitoring of patients requiring OPAT for the treatment of infection. The developmental and implementation stages of the OPAT program included (1) a needs assessment, (2) the identification of resources necessary for program operation, (3) delineation of general OPAT program operations and activities of individual OPAT clinicians, (4) the development of patient selection criteria, including a plan of care algorithm, and (5) acquisition of administrative support to approve the program. In this program, the OPAT pharmacist plays an integral role in the management and oversight of OPAT patients, working under a collaborative agreement with infectious diseases physicians. The OPAT pharmacist assists with appropriate patient and regimen selection, confirmation of orders on discharge, assuring that laboratory tests for safety surveillance are performed and evaluated, performing routine monitoring for adverse events and line complications, and assuring the removal of the vascular access device upon the completion of OPAT. The OPAT program provides structured monitoring, patient follow-up, and led to improvements in patient outcome with minimization of treatment and line-related adverse events.


Comparative genomics of Alternaria species provides insights into the pathogenic lifestyle of Alternaria brassicae - a pathogen of the Brassicaceae family.
Alternaria brassicae, a necrotrophic pathogen, causes Alternaria Leaf Spot, one of the economically important diseases of Brassica crops. Many other Alternaria spp. such as A. brassicicola and A. alternata are known to cause secondary infections in the A. brassicae-infected Brassicas. The genome architecture, pathogenicity factors, and determinants of host-specificity of A. brassicae are unknown. In this study, we annotated and characterised the recently announced genome assembly of A. brassicae and compared it with other Alternaria spp. to gain insights into its pathogenic lifestyle. We also sequenced the genomes of two A. alternata isolates that were co-infecting B. juncea using Nanopore MinION sequencing for additional comparative analyses within the Alternaria genus. Genome alignments within the Alternaria spp. revealed high levels of synteny between most chromosomes with some intrachromosomal rearrangements. We show for the first time that the genome of A. brassicae, a large-spored Alternaria species, contains a dispensable chromosome. We identified 460 A. brassicae-specific genes, which included many secreted proteins and effectors. Furthermore, we have identified the gene clusters responsible for the production of Destruxin-B, a known pathogenicity factor of A. brassicae. The study provides a perspective into the unique and shared repertoire of genes within the Alternaria genus and identifies genes that could be contributing to the pathogenic lifestyle of A. brassicae.


Stability and structure of mixed-ligand metal ion complexes that contain Ni2+, Cu2+, or Zn2+, and Histamine, as well as adenosine 5'-triphosphate (ATP4-) or uridine 5'-triphosphate (UTP(4-): an intricate network of equilibria.
With a view on protein-nucleic acid interactions in the presence of metal ions we studied the "simple" mixed-ligand model systems containing histamine (Ha), the metal ions Ni(2+), Cu(2+), or Zn(2+) (M(2+)), and the nucleotides adenosine 5'-triphosphate (ATP(4-)) or uridine 5'-triphosphate (UTP(4-)), which will both be referred to as nucleoside 5'-triphosphate (NTP(4-)). The stability constants of the ternary M(NTP)(Ha)(2-) complexes were determined in aqueous solution by potentiometric pH titrations. We show for both ternary-complex types, M(ATP)(Ha)(2-) and M(UTP)(Ha)(2-), that intramolecular stacking between the nucleobase and the imidazole residue occurs and that the stacking intensity is approximately the same for a given M(2+) in both types of complexes: The formation degree of the intramolecular stacks is estimated to be 20 to 50%. Consequently, in protein-nucleic acid interactions imidazole-nucleobase stacks may well be of relevance. Furthermore, the well-known formation of macrochelates in binary M(2+) complexes of purine nucleotides, that is, the phosphate-coordinated M(2+) interacts with N7, is confirmed for the M(ATP)(2-) complexes. It is concluded that upon formation of the mixed-ligand complexes the M(2+)-N7 bond is broken and the energy needed for this process corresponds to the stability differences determined for the M(UTP)(Ha)(2-) and M(ATP)(Ha)(2-) complexes. It is, therefore, possible to calculate from these stability differences of the ternary complexes the formation degrees of the binary macrochelates: The closed forms amount to (65±10)%, (75±8)%, and (31±14) % for Ni(ATP)(2-), Cu(ATP)(2-), and Zn(ATP)(2-), respectively, and these percentages agree excellently with previous results obtained by different methods, confirming thus the internal validity of the data and the arguments used in the evaluation processes. Based on the overall results it is suggested that M(ATP)(2-) species, when bound to an enzyme, may exist in a closed macrochelated form only, if no enzyme groups coordinate directly to the metal ion.


Order-of-magnitude polymerization-shrinkage suppression of volume gratings recorded in nanoparticle-polymer composites.
We demonstrate substantial shrinkage suppression of nanoparticle-polymer composite transmission gratings by use of the step-growth polymerization mechanism. It is shown that the polymerization shrinkage can be reduced as low as 0.3% at the nanoparticle concentration of 35 vol. % by which the refractive index modulation and the material sensitivity are maximized to be 8x10(-3) and 1014 cm/J, respectively, in the green. Our results offer a noticeable advance in the development of holographic data storage materials.


Maternal and paternal occupational exposure to agricultural work and the risk of anencephaly.
To evaluate the association between parental occupational exposure to agricultural work and the risk of anencephaly in three Mexican states. A paired case control study (1:1) was done based on records of the Epidemiological Surveillance System of Neural Tube Defects in Mexico; 151 cases of anencephaly of more than 20 weeks' gestation were selected between March 2000 and February 2001. Controls were selected from the same maternity services as those of the cases and were born alive without congenital malformations. Information was obtained from both parents by means of a general questionnaire, a food frequency questionnaire, and a specific questionnaire on occupational exposure to pesticides. Exposures were analysed with emphasis on the three months before and one month after the last menstruation periods (acute risk period (ARP)), as well as exposure prior to the above mentioned period (non-acute risk period (NARP)). The children of mothers who worked in agriculture in the ARP had a greater risk of anencephaly (OR = 4.57, 95% CI 1.05 to 19.96). The risk of fathers having a child with anencephaly was greater in those who applied pesticides irrespective of whether it was done in the ARP or the NARP (OR = 2.50, 95% CI 0.73 to 8.64; and OR = 2.03, 95% CI 0.58 to 7.08, respectively). These results support the hypothesis of the effect of maternal exposure to agricultural work on anencephaly and suggest that exposure of the father to pesticides in the periconceptional period or prior to this can also increase the risk of having an anencephalic child.


Community health nursing vision for 2020: shaping the future.
As health care is shifting from hospital to community, community health nurses (CHNs) are directly affected. This descriptive qualitative study sought to understand priority issues currently facing CHNs, explore development of a national vision for community health nursing, and develop recommendations to shape the future of the profession moving toward the year 2020. Focus groups and key informant interviews were conducted across Canada. Five key themes were identified: community health nursing in crisis now, a flawed health care system, responding to the public, vision for the future, and CHNs as solution makers. Key recommendations include developing a common definition and vision of community health nursing, collaborating on an aggressive plan to shift to a primary health care system, developing a comprehensive social marketing strategy, refocusing basic baccalaureate education, enhancing the capacity of community health researchers and knowledge in community health nursing, and establishing a community health nursing center of excellence.


Variability and agreement of frailty measures and risk of falls, hospital admissions and mortality in TILDA.
Little is known about the within-person variability of different frailty instruments, their agreement over time, and whether use of repeat assessments could improve the strength of associations with adverse health outcomes. Repeat measurements recorded in 2010-2011 (Wave 1) and 2012 (Wave 2) from The Irish Longitudinal Study on Ageing (TILDA) were used to classify individuals with frailty using the frailty phenotype (FP) and frailty index (FI). Within-person variability and agreement of frailty classifications were assessed using ANOVA and kappa (K) statistics, respectively. Associations of each frailty measure (wave 1, wave 2, or mean of both waves) with risk of falls, hospitalisations and all-cause mortality were assessed using logistic regression. Among 7455 individuals (mean age 64.7 [SD 9.9] years), within-person SD was 0.664 units (95% CI 0.654-0.671) for FP and 2 health deficits (SD 0.050 [0.048-0.051]) for FI. Agreement of frailty was modest for both measures, but higher for FI (K 0.600 [0.584-0.615]) than FP (K 0.370 [0.348-0.401]). The odds ratios (ORs) for all-cause mortality were higher for frailty assessed using the mean of two versus single measurements for FI (ORs for mortality 3.5 [2.6-4.9] vs. 2.7 [1.9-3.4], respectively) and FP (ORs for mortality 6.9 [4.6-10.3] vs. 4.0 [2.8-5.635], respectively). Frailty scores based on single measurements had substantial within-person variability, but the agreement in classification of frailty was higher for FI than FP. Frailty assessed using the mean of two or more measurements recorded at separate visits was more strongly associated with adverse health outcomes than those recorded at a single visit.


[Acute delirium in decompensated schizophrenia and bipolar disorder].
Acute delirium is common in decompensated schizophrenia and bipolar disor- der: more 50% in two years after the first episode of schizophrenia and 90% of patients with a diagnosis of bipolar disorder. Early signs precede in more 50% of cases the delirious exacerbation of 6 months. These non-specific signs are a change in the mood, an increase of anxiety, sleep and food disorders and suicidal ideation. After this prodromal phase, a persecutory delusion and hallucinations are often present in decompensated schizophrenia. In decompensated bipolar disorder, the delusional syndrome is congruent with the mood. The care should be the earliest possible. The treatment by antipsychotic or mood stabilizer must be increased or re-introduced and maintained during a long time in order to prevent a relapse. In parallel, a psychosocial care must be instituted.


Fructose, insulin resistance, and metabolic dyslipidemia.
Obesity and type 2 diabetes are occurring at epidemic rates in the United States and many parts of the world. The "obesity epidemic" appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in the amount of dietary fructose consumption from high intake of sucrose and high fructose corn syrup, a common sweetener used in the food industry. A high flux of fructose to the liver, the main organ capable of metabolizing this simple carbohydrate, perturbs glucose metabolism and glucose uptake pathways, and leads to a significantly enhanced rate of de novo lipogenesis and triglyceride (TG) synthesis, driven by the high flux of glycerol and acyl portions of TG molecules from fructose catabolism. These metabolic disturbances appear to underlie the induction of insulin resistance commonly observed with high fructose feeding in both humans and animal models. Fructose-induced insulin resistant states are commonly characterized by a profound metabolic dyslipidemia, which appears to result from hepatic and intestinal overproduction of atherogenic lipoprotein particles. Thus, emerging evidence from recent epidemiological and biochemical studies clearly suggests that the high dietary intake of fructose has rapidly become an important causative factor in the development of the metabolic syndrome. There is an urgent need for increased public awareness of the risks associated with high fructose consumption and greater efforts should be made to curb the supplementation of packaged foods with high fructose additives. The present review will discuss the trends in fructose consumption, the metabolic consequences of increased fructose intake, and the molecular mechanisms leading to fructose-induced lipogenesis, insulin resistance and metabolic dyslipidemia.


Mechanism of porphyrin-induced sonodynamic effect: possible role of hyperthermia.
The biological effects of ultrasound have been investigated vigorously for various applications including the thermal coagulation of tissues, the opening of tight junctions, and localized gene or drug introduction. The synergistic cell killing effect of ultrasound and porphyrin derivatives, the so-called sonodynamic effect, holds promise for cancer treatment. Although several models to explain the sonodynamic effect have been proposed, its exact mechanism, especially in vivo, remains unknown. We examined the effect of a porphyrin derivative, protoporphyrin IX, on ultrasound-induced killing of HeLa cells. In some experiments, the intracellular protoporphyrin IX concentration was increased by 5-aminolevulinic acid treatment of the cells. Although extracellular protoporphyrin IX showed an enhanced cell killing effect by microbubble-enhanced ultrasound, intracellular protoporphyrin IX did not. On the other hand, intracellular protoporphyrin IX enhanced the cell killing effect of hyperthermia, which can be produced by ultrasound exposure, in a moderately acidic environment (pH 6.6). Because porphyrin derivatives are generally imported into the intracellular component in vivo, our results suggest that hyperthermia caused by ultrasound may play an important role in the sonodynamic effect induced by porphyrin derivatives.


Genital ulcer disease in central Australia: predictors of testing and outcomes.
To identify factors associated with the uptake and outcome of testing for infectious causes of genital ulcer disease (GUD) in central Australia. Prospective investigation of GUD cases in central Australia from February 2002 to August 2003. Data were collected from primary health care clinics in remote indigenous communities of Central Australia. During the study period, 134 cases of GUD were reported and investigated. Of these cases, 71 (53%) were in women (age range 14-75, median 28) and 63 (47%) in men (14-63, median 28). Testing for syphilis was undertaken for 111 (82.8%) cases, 75 (56%) were tested for herpes simplex virus infection, and 82 (61.2%) for donovanosis. Testing for at least one of the three sexually transmissible pathogens of interest was undertaken in 128 (95.5%) cases, while 99 (73.9%) were tested for two pathogens and 41 (30.6%) for all three agents. Of subjects tested, 19.8% had new syphilis infection, 51% had herpes simplex virus infection and 7% had donovanosis. In 19 of 41 (46.3%) subjects fully investigated no cause for genital ulceration was found. This study provides the first quantitative description of GUD diagnosis in central Australia. Logistic constraints limited the systematic application of diagnostic tests. Current treatment protocols may need to be reassessed in light of the higher than expected detection of genital herpes as a cause of GUD.


Transient sexual precocity and ovarian cysts.
Nine girls presenting under the age of 7 years with unsustained sexual precocity are described. Large ovarian cysts were detected by ultrasound in three and laparotomy in one. In two girls the symptoms resolved after surgical removal of the cyst; the other seven had spontaneous remission of symptoms, but in two of these transient breast development and bleeding recurred: further ovarian cyst formation was found in one of these patients. Endocrine studies performed before resolution of the cysts showed raised plasma oestradiol concentrations (64 to 440 pmol/l) in three girls and no appreciable rise in plasma luteinising hormone after gonadotrophin releasing hormone stimulation in two. We conclude that ovarian cyst formation with spontaneous resolution may cause transient sexual precocity in girls, and that ultrasound examination is an effective means of diagnosing and following these patients.


Growth characteristics of two strains of bovine virus diarrhoea virus.
The replication cycles of a cytopathogenic and a non-cytopathogenic strain of bovine virus diarrhoea virus (BVDV) were similar in kinetics and the tendency of cell-free infectivity to exceed the titre of cell-associated, but differed in virus yield per cell. Actinomycin D enhanced the yield of the non-cytopathogenic strain and depressed that of the cytopathogenic strain.


Secretome of pleural effusions associated with non-small cell lung cancer (NSCLC) and malignant mesothelioma: therapeutic implications.
We compared the secretome of metastatic (non-small cell lung cancer (NSCLC)) and primary (mesothelioma) malignant pleural effusions, benign effusions and the published plasma profile of patients receiving chimeric antigen receptor T cells (CAR-T), to determine factors unique to neoplasia in pleural effusion (PE) and those accompanying an efficacious peripheral anti-tumor immune response. Cryopreserved cell-free PE fluid from 101 NSCLC patients, 8 mesothelioma and 13 with benign PE was assayed for a panel of 40 cytokines/chemokines using the Luminex system. Profiles of benign and malignant PE were dominated by high concentrations of sIL-6Rα, CCL2/MCP1, CXCL10/IP10, IL-6, TGFβ1, CCL22/MDC, CXCL8/IL-8 and IL-10. Malignant PE contained significantly higher (p < 0.01, Bonferroni-corrected) concentrations of MIP1β, CCL22/MDC, CX3CL1/fractalkine, IFNα2, IFNγ, VEGF, IL-1α and FGF2. When grouped by function, mesothelioma PE had lower effector cytokines than NSCLC PE. Comparing NSCLC PE and published plasma levels of CAR-T recipients, both were dominated by sIL-6Rα and IL-6 but NSCLC PE had more VEGF, FGF2 and TNFα, and less IL-2, IL-4, IL-13, IL-15, MIP1α and IFNγ. An immunosuppressive, wound-healing environment characterizes both benign and malignant PE. A dampened effector response (IFNα2, IFNγ, MIP1α, TNFα and TNFβ) was detected in NSCLC PE, but not mesothelioma or benign PE. The data indicate that immune effectors are present in NSCLC PE and suggest that the IL-6/sIL-6Rα axis is a central driver of the immunosuppressive, tumor-supportive pleural environment. A combination localized antibody-based immunotherapy with or without cellular therapy may be justified in this uniformly fatal condition.


A density functional theory insight towards the rational design of ionic liquids for SO2 capture.
A systematic density functional theory (DFT) analysis has been carried out to obtain information at the molecular level on the key parameters related to efficient SO2 capture by ionic liquids (ILs). A set of 55 ILs, for which high gas solubility is expected, has been selected. SO2 solubility of ILs was firstly predicted based on the COSMO-RS (Conductor-like Screening Model for Real Solvents) method, which provides a good prediction of gas solubility data in ILs without prior experimental knowledge of the compounds' features. Then, interactions between SO2 and ILs were deeply analyzed through DFT simulations. This work provides valuable information about required factors at the molecular level to provide high SO2 solubility in ILs, which is crucial for further implementation of these materials in the future. In our opinion, systematic research on ILs for SO2 capture increases our knowledge about those factors which could be controlled at the molecular level, providing an approach for the rational design of task-specific ILs.


People with epilepsy and intellectual disability: More than a sum of two conditions.
Around 25% of people with Intellectual Disability (PwID) have comorbid epilepsy with seizures in up to two-thirds being drug-resistant. Little is known of the general characteristics and prescribing practices to this population. Describe and compare characteristics of two cohorts of PwID and epilepsy in two different countries to inform clinical practice better. An explorative, retrospective, case-note review in a specialist ID community service in England and in an expert center for PwID and epilepsy in the Netherlands was conducted. Information on ID severity, medical/behavioral/psychiatric/neurodevelopmental/genetic comorbidities, psychotropic, and antiepileptic drugs (AEDs) for each cohort was collected. The English cohort consisted of 167 people (98 males; age range 18-73 years; mild/moderate ID- 35%) and the Dutch cohort of 189 people (111 males; age range 18-85 years; mild/moderate ID - 51%). The two cohorts were comparable in their baseline characteristics. The Dutch had higher rates of physical comorbidity, but less mental or behavioral disorders and were more likely to be on anti-psychotic medication. The mean dosages between three most common AEDs prescribed were similar. The most frequently prescribed drug in both centers is valproate. Three-quarters of the Dutch were on three or more AEDs compared to a third in the English cohort. Structured description of the characteristics, differences, and commonalities of PwID, treatment, and services of both countries is presented. This is the first real-world study to reveal unique characteristics of managing epilepsy for a complex ID population. In particular, it highlights the considerable comorbid psychiatric burden and psychotropic prescribing.


Vitamin D receptor regulates TGF-β signalling in systemic sclerosis.
Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily. Its ligand, 1,25-(OH)2D, is a metabolically active hormone derived from vitamin D3. The levels of vitamin D3 are decreased in patients with systemic sclerosis (SSc). Here, we aimed to analyse the role of VDR signalling in fibrosis. VDR expression was analysed in SSc skin, experimental fibrosis and human fibroblasts. VDR signalling was modulated by siRNA and with the selective agonist paricalcitol. The effects of VDR on Smad signalling were analysed by reporter assays, target gene analyses and coimmunoprecipitation. The effects of paricalcitol were evaluated in the models of bleomycin-induced fibrosis and fibrosis induced by overexpression of a constitutively active transforming growth factor-β (TGF-β) receptor I (TBRI(CA)). VDR expression was decreased in fibroblasts of SSc patients and murine models of SSc in a TGF-β-dependent manner. Knockdown of VDR enhanced the sensitivity of fibroblasts towards TGF-β. In contrast, activation of VDR by paricalcitol reduced the stimulatory effects of TGF-β on fibroblasts and inhibited collagen release and myofibroblast differentiation. Paricalcitol stimulated the formation of complexes between VDR and phosphorylated Smad3 in fibroblasts to inhibit Smad-dependent transcription. Preventive and therapeutic treatment with paricalcitol exerted potent antifibrotic effects and ameliorated bleomycin- as well as TBRI(CA)-induced fibrosis. We characterise VDR as a negative regulator of TGF-β/Smad signalling. Impaired VDR signalling with reduced expression of VDR and decreased levels of its ligand may thus contribute to hyperactive TGF-β signalling and aberrant fibroblast activation in SSc.


A Machine Learning Approach to Predict Gene Regulatory Networks in Seed Development in Arabidopsis.
Gene regulatory networks (GRNs) provide a representation of relationships between regulators and their target genes. Several methods for GRN inference, both unsupervised and supervised, have been developed to date. Because regulatory relationships consistently reprogram in diverse tissues or under different conditions, GRNs inferred without specific biological contexts are of limited applicability. In this report, a machine learning approach is presented to predict GRNs specific to developing Arabidopsis thaliana embryos. We developed the Beacon GRN inference tool to predict GRNs occurring during seed development in Arabidopsis based on a support vector machine (SVM) model. We developed both global and local inference models and compared their performance, demonstrating that local models are generally superior for our application. Using both the expression levels of the genes expressed in developing embryos and prior known regulatory relationships, GRNs were predicted for specific embryonic developmental stages. The targets that are strongly positively correlated with their regulators are mostly expressed at the beginning of seed development. Potential direct targets were identified based on a match between the promoter regions of these inferred targets and the cis elements recognized by specific regulators. Our analysis also provides evidence for previously unknown inhibitory effects of three positive regulators of gene expression. The Beacon GRN inference tool provides a valuable model system for context-specific GRN inference and is freely available at https://github.com/BeaconProjectAtVirginiaTech/beacon_network_inference.git.


Ethically difficult situations in hemodialysis care - Nurses' narratives.
Providing nursing care for patients with end-stage renal disease entails dealing with existential issues which may sometimes lead not only to ethical problems but also conflicts within the team. A previous study shows that physicians felt irresolute, torn and unconfirmed when ethical dilemmas arose. This study, conducted in the same dialysis care unit, aimed to illuminate registered nurses' experiences of being in ethically difficult situations that give rise to a troubled conscience. This study has a phenomenological hermeneutic approach. Narrative interviews were carried out with 10 registered nurses working in dialysis care. The study was approved by the Ethics Committee of the Faculty of Medicine, Umeå University. One theme, 'Calling for a deliberative dialogue', and six sub-themes emerged: 'Dealing with patients' ambiguity', 'Responding to patients' reluctance', 'Acting against patients' will', 'Acting against one's moral convictions', 'Lacking involvement with patients and relatives' and 'Being trapped in feelings of guilt'. In ethically difficult situations, the registered nurses tried, but failed, to open up a dialogue with the physicians about ethical concerns and their uncertainty. They felt alone, uncertain and sometimes had to act against their conscience. In ethical dilemmas, personal and professional integrity is at stake. Mistrusting their own moral integrity may turn professionals from moral actors into victims of circumstances. To counteract such a risk, professionals and patients need to continuously deliberate on their feelings, views and experiences, in an atmosphere of togetherness and trust.


Role of propolis on oxidative stress in fish brain.
Cypermethrin causes its neurotoxic effect through voltage-dependent sodium channels and integral protein ATPases in the neuronal membrane. Brain and nerve damage are often associated with low residual level of pesticides. In vitro and in vivo studies have also shown that pesticides cause free radical-mediated tissue damage in brain. Propolis has antioxidant properties. The main chemical classes found in propolis are flavonoids and phenolics. Bioflavonoids are antioxidant molecules that play important roles in scavenging free radicals, which are produced in neurodegenerative diseases and aging. To determine the protective role of propolis, rainbow trouts were treated with cypermethrin, followed by biochemical analyses of brain tissue. Fish were divided into four groups: control, propolis-treated, cypermethrin-treated, and cypermethrin + propolis-treated. In fish brains, catalase (CAT) activity decreased (P ≤ 0.001) and malondialdehyde (MDA) level increased (P ≤ 0.001) in cypermethrin-treated group compared to control group. In cypermethrin + propolis-treated group CAT activity increased (P ≤ 0.001) and MDA level decreased (P ≤ 0.001) compared to cypermethrin group. The results demonstrated that the negative effects, observed as a result of cypermethrin treatment, could be reversed by adding supplementary propolis. Propolis may improve some biochemical markers associated with oxidative stress in fish brain, after exposure to cypermethrin.


Amplitude modulation drive to rectangular-plate linear ultrasonic motors with vibrators dimensions 8 mm x 2.16 mm X 1 mm.
In this paper, to exploit the contribution from not only the stators but also from other parts of miniature ultrasonic motors, an amplitude modulation drive is proposed to drive a miniature linear ultrasonic motor consisting of two rectangular piezoelectric ceramic plates. Using finite-element software, the first longitudinal and second lateral-bending frequencies of the vibrator are shown to be very close when its dimensions are 8 mm x 2.16 mm x 1 mm. So one single frequency power should be able to drive the motor. However, in practice the motor is found to be hard to move with a single frequency power because of its small vibration amplitudes and big frequency difference between its longitudinal and bending resonance, which is induced by the boundary condition variation. To drive the motor effectively, an amplitude modulation drive is used by superimposing two signals with nearly the same frequencies, around the resonant frequency of the vibrators of the linear motor. When the amplitude modulation frequency is close to the resonant frequency of the vibrator's surroundings, experimental results show that the linear motor can move back and forward with a maximum thrust force (over 0.016 N) and a maximum velocity (over 50 mm/s).


Comparison of accelerated T1-weighted whole-brain structural-imaging protocols.
Imaging in neuroscience, clinical research and pharmaceutical trials often employs the 3D magnetisation-prepared rapid gradient-echo (MPRAGE) sequence to obtain structural T1-weighted images with high spatial resolution of the human brain. Typical research and clinical routine MPRAGE protocols with ~1mm isotropic resolution require data acquisition time in the range of 5-10min and often use only moderate two-fold acceleration factor for parallel imaging. Recent advances in MRI hardware and acquisition methodology promise improved leverage of the MR signal and more benign artefact properties in particular when employing increased acceleration factors in clinical routine and research. In this study, we examined four variants of a four-fold-accelerated MPRAGE protocol (2D-GRAPPA, CAIPIRINHA, CAIPIRINHA elliptical, and segmented MPRAGE) and compared clinical readings, basic image quality metrics (SNR, CNR), and automated brain tissue segmentation for morphological assessments of brain structures. The results were benchmarked against a widely-used two-fold-accelerated 3T ADNI MPRAGE protocol that served as reference in this study. 22 healthy subjects (age=20-44yrs.) were imaged with all MPRAGE variants in a single session. An experienced reader rated all images of clinically useful image quality. CAIPIRINHA MPRAGE scans were perceived on average to be of identical value for reading as the reference ADNI-2 protocol. SNR and CNR measurements exhibited the theoretically expected performance at the four-fold acceleration. The results of this study demonstrate that the four-fold accelerated protocols introduce systematic biases in the segmentation results of some brain structures compared to the reference ADNI-2 protocol. Furthermore, results suggest that the increased noise levels in the accelerated protocols play an important role in introducing these biases, at least under the present study conditions.


VEGF-Targeted Multispectral Optoacoustic Tomography and Fluorescence Molecular Imaging in Human Carotid Atherosclerotic Plaques.
Vulnerable atherosclerotic carotid plaques are prone to rupture, resulting in ischemic strokes. In contrast to radiological imaging techniques, molecular imaging techniques have the potential to assess plaque vulnerability by visualizing diseases-specific biomarkers. A risk factor for rupture is intra-plaque neovascularization, which is characterized by overexpression of vascular endothelial growth factor-A (VEGF-A). Here, we study if administration of bevacizumab-800CW, a near-infrared tracer targeting VEGF-A, is safe and if molecular assessment of atherosclerotic carotid plaques in vivo is possible using multispectral optoacoustic tomography (MSOT). Healthy volunteers and patients with symptomatic carotid artery stenosis scheduled for carotid artery endarterectomy were imaged with MSOT. Secondly, patients were imaged two days after intravenous administration of 4.5 bevacizumab-800CW. Ex vivo fluorescence molecular imaging of the surgically removed plaque specimen was performed and correlated with histopathology. In this first-in-human MSOT and fluorescence molecular imaging study, we show that administration of 4.5 mg bevacizumab-800CW appeared to be safe in five patients and accumulated in the carotid atherosclerotic plaque. Although we could visualize the carotid bifurcation area in all subjects using MSOT, bevacizumab-800CW-resolved signal could not be detected with MSOT in the patients. Future studies should evaluate tracer safety, higher doses of bevacizumab-800CW or develop dedicated contrast agents for carotid atherosclerotic plaque assessment using MSOT.


The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.
We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.


Association between MGMT promoter methylation and non-small cell lung cancer: a meta-analysis.
O(6)-methylguanine-DNA methyltransferase (MGMT) is one of most important DNA repair enzyme against common carcinogens such as alkylate and tobacco. Aberrant promoter methylation of the gene is frequently observed in non-small cell lung cancer (NSCLC). However, the importance of epigenetic inactivation of the gene in NSCLC published in the literature showed inconsistence. We quantified the association between MGMT promoter methylation and NSCLC using a meta-analysis method. We systematically reviewed studies of MGMT promoter methylation and NSCLC in PubMed, EMBASE, Ovid, ISI Web of Science, Elsevier and CNKI databases and quantified the association between MGMT promoter methylation and NSCLC using meta-analysis method. Odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated to evaluate the strength of association. Potential sources of heterogeneity were assessed by subgroup analysis and meta-regression. A total of 18 studies from 2001 to 2011, with 1, 160 tumor tissues and 970 controls, were involved in the meta-analysis. The frequencies of MGMT promote methylation ranged from 1.5% to 70.0% (median, 26.1%) in NSCLC tissue and 0.0% to 55.0% (median, 2.4%) in non-cancerous control, respectively. The summary of OR was 4.43 (95% CI: 2.85, 6.89) in the random-effects model. With stratification by potential source of heterogeneity, the OR was 20.45 (95% CI: 5.83, 71.73) in heterogeneous control subgroup, while it was 4.16 (95% CI: 3.02, 5.72) in the autologous control subgroup. The OR was 5.31 (95% CI: 3.00, 9.41) in MSP subgroup and 3.06 (95% CI: 1.75, 5.33) in Q-MSP subgroup. This meta-analysis identified a strong association between methylation of MGMT gene and NSCLC. Prospective studies should be required to confirm the results in the future.


International Collegium of Rehabilitative Audiology (ICRA) recommendations for the construction of multilingual speech tests. ICRA Working Group on Multilingual Speech Tests.
To provide guidelines for the development of two types of closed-set speech-perception tests that can be applied and interpreted in the same way across languages. The guidelines cover the digit triplet and the matrix sentence tests that are most commonly used to test speech recognition in noise. They were developed by a working group on Multilingual Speech Tests of the International Collegium of Rehabilitative Audiology (ICRA). The recommendations are based on reviews of existing evaluations of the digit triplet and matrix tests as well as on the research experience of members of the ICRA Working Group. They represent the results of a consensus process. The resulting recommendations deal with: Test design and word selection; Talker characteristics; Audio recording and stimulus preparation; Masking noise; Test administration; and Test validation. By following these guidelines for the development of any new test of this kind, clinicians and researchers working in any language will be able to perform tests whose results can be compared and combined in cross-language studies.


Cyclin A overexpression in carcinoma of the renal pelvis and ureter including dysplasia: immunohistochemical findings in relation to prognosis.
Several in vitro studies have shown that cyclin A gene alteration in the cell cycle plays an important role in carcinogenesis. We immunohistochemically examined the expression of cyclin A protein in 120 patients with transitional cell carcinoma (TCC) of the renal pelvis and ureter, including adjacent dysplastic lesions to determine their significance for the tumor behavior and patient prognosis. Cyclin A immunostaining of the nucleus was observed in 29 tumors (24.2%). Furthermore, 17 cyclin A-positive tumors (58.6%) had dysplastic lesions positive for cyclin A antibody. The prevalence of cases exhibiting cyclin A staining was higher in the high grade (P < 0.01) and invasive tumors (P < 0.05) than in the other types of tumors. In the selected 117 cases, patients whose TCCs expressed a high level of cyclin A protein had a significantly poorer prognosis than those without cyclin A expression (P < 0.01). These in vivo findings provide the first evidence for frequent and redundant cyclin A protein overexpression in TCC and suggest that cyclin A overexpression is related to the tumor behavior and patient prognosis. In addition, our observations indicate that overexpression of cyclin A may be one of the early events, at least in some cases, in the carcinogenesis of TCC.


There is no association between the serotonin receptor gene and bipolar I disorder in the Korean population.
Despite the close relationship between the functional polymorphism C(-1019)G (rs6295) of the serotonergic 1A receptor (5-HT1A) and mood, few studies have investigated the relationship between rs6295 and bipolar disorder. In this study, we aimed to investigate whether rs6295 is associated with clinical prognosis and treatment response in patients with bipolar I disorder acute manic episodes. One hundred twenty-eight patients with bipolar I disorder and one hundred sixty-eight healthy controls were recruited. Associations between patients with bipolar I disorder and healthy controls were compared. In addition, age at onset, number of admissions, and treatment response, including response rate, mean changes in manic symptoms, number of anti-manic agents and the total dosage of mood stabilizers for acute manic symptoms were compared between the rs6295 GG and CG+ CC groups in patients with bipolar I disorder. We conducted a separate subgroup analysis according to gender. There were no differences in frequency between patients and controls. In patients with bipolar disorder, clinical prognosis and treatment response were no different between GG and CG+ CC groups. However, in a subgroup analysis according to gender, male, but not female, patients in the GG group had a longer duration of illness and a greater number of both previous episodes and psychiatric ward admissions than did the GC+ CC group. Further studies should investigate the relationship between 5-HT1A polymorphisms and bipolar disorder in terms of mood episode and gender.


Simultaneous acquisition of perfusion image and dynamic MR angiography using time-encoded pseudo-continuous ASL.
Both dynamic magnetic resonance angiography (4D-MRA) and perfusion imaging can be acquired by using arterial spin labeling (ASL). While 4D-MRA highlights large vessel pathology, such as stenosis or collateral blood flow patterns, perfusion imaging provides information on the microvascular status. Therefore, a complete picture of the cerebral hemodynamic condition could be obtained by combining the two techniques. Here, we propose a novel technique for simultaneous acquisition of 4D-MRA and perfusion imaging using time-encoded pseudo-continuous arterial spin labeling. The time-encoded pseudo-continuous arterial spin labeling module consisted of a first subbolus that was optimized for perfusion imaging by using a labeling duration of 1800 ms, whereas the other six subboli of 130 ms were used for encoding the passage of the labeled spins through the arterial system for 4D-MRA acquisition. After the entire labeling module, a multishot 3D turbo-field echo-planar-imaging readout was executed for the 4D-MRA acquisition, immediately followed by a single-shot, multislice echo-planar-imaging readout for perfusion imaging. The optimal excitation flip angle for the 3D turbo-field echo-planar-imaging readout was investigated by evaluating the image quality of the 4D-MRA and perfusion images as well as the accuracy of the estimated cerebral blood flow values. When using 36 excitation radiofrequency pulses with flip angles of 5 or 7.5°, the saturation effects of the 3D turbo-field echo-planar-imaging readout on the perfusion images were relatively moderate and after correction, there were no statistically significant differences between the obtained cerebral blood flow values and those from traditional time-encoded pseudo-continuous arterial spin labeling. This study demonstrated that simultaneous acquisition of 4D-MRA and perfusion images can be achieved by using time-encoded pseudo-continuous arterial spin labeling. Magn Reson Med 79:2676-2684, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Health care priority setting: principles, practice and challenges.
BACKGROUND: Health organizations the world over are required to set priorities and allocate resources within the constraint of limited funding. However, decision makers may not be well equipped to make explicit rationing decisions and as such often rely on historical or political resource allocation processes. One economic approach to priority setting which has gained momentum in practice over the last three decades is program budgeting and marginal analysis (PBMA). METHODS: This paper presents a detailed step by step guide for carrying out a priority setting process based on the PBMA framework. This guide is based on the authors' experience in using this approach primarily in the UK and Canada, but as well draws on a growing literature of PBMA studies in various countries. RESULTS: At the core of the PBMA approach is an advisory panel charged with making recommendations for resource re-allocation. The process can be supported by a range of 'hard' and 'soft' evidence, and requires that decision making criteria are defined and weighted in an explicit manner. Evaluating the process of PBMA using an ethical framework, and noting important challenges to such activity including that of organizational behavior, are shown to be important aspects of developing a comprehensive approach to priority setting in health care. CONCLUSION: Although not without challenges, international experience with PBMA over the last three decades would indicate that this approach has the potential to make substantial improvement on commonly relied upon historical and political decision making processes. In setting out a step by step guide for PBMA, as is done in this paper, implementation by decision makers should be facilitated.


A study on the direct and indirect costs of multiple sclerosis based on expanded disability status scale score in khuzestan, iran.
Multiple sclerosis is a common and chronic neurologic disorder. This disorder imposes physical, economic, and psychosocial burden on individuals, their families and society. This study aims to analyze the costs of multiple sclerosis disease based on the severity of disability. We performed a cross-sectional cost of illness study. This study was conducted in 332 patients of Khuzestan province of Iran. Data were included: Patient's characteristics, disability status, medical, and nonmedical costs and were gathered by using the questionnaire during 3 months period. Costs analysis was performed in the basis of expanded disability status scale (EDSS). Data were analyzed by using SPSS 18 software. Mean age of the patients was 33.5 (standard deviation [SD]: 9.1) and 70.5% of patients were female. Mean EDSS score of the patients was 2.2 (SD: 1.6). Most patients (92.1%) had relapsing remitting multiple sclerosis (MS) form of the disease. Costs mean per patients was 8.6 ± 7.9 million Rial. The direct and indirect costs were 93.1% and 6.9% of total costs, respectively. The major cost of the disease belongs to the pharmaceutical treatment (22% of costs). The majority costs (approximately 62%) attributed to EDSS of 6-7 and >7. Furthermore, there was strong significant relationship between cost of illness and disability severity of patients (P < 0.05). Cost mean per MS patients was relatively high. Furthermore, the results showed that cost of disease had positive and significant relationships with EDSS score that is, progression of disability increase costs of patients.


Interaction of γ-glutamyltranspeptidase with ibuprofen-S-acyl-glutathione in vitro and in vivo in human.
Ibuprofen is metabolized to chemically reactive acyl glucuronide and S-acyl-CoA metabolites that are proposed to transacylate glutathione (GSH) forming ibuprofen-S-acyl-GSH (I-SG) in vivo. Herein, we report the detection of novel metabolites of ibuprofen, namely ibuprofen-N-acyl-cysteinylglycine (I-N-CG), ibuprofen-N-acyl-cysteine (I-N-C), and the mercapturic acid conjugate, ibuprofen-S-acyl-N-acetylcysteine (I-S-NAC), in urine from an ibuprofen-dosed volunteer. Thus, analysis of ibuprofen-dosed (Advil, 800 mg, Pfizer, Madison, NJ) human urine extracts by sensitive liquid chromatography tandem mass spectrometric detection resulted in the identification of I-N-CG, I-N-C, and I-S-NAC derivatives as minor metabolites (6.0, 1.7, and 0.2 µg excreted 10-hours postadministration, respectively). I-N-CG is proposed to be formed from the degradation of I-SG by γ-glutamyltranspeptidase (γ-GT)-mediated cleavage of the γ-glutamyl group, leading to an unstable ibuprofen-S-acyl-cysteinylglycine (I-S-CG) intermediate that undergoes spontaneous S to N intramolecular rearrangement. Then, dipeptidase-mediated cleavage of glycine from I-N-CG leads to the formation of I-N-C. Treatment of racemic I-SG (100 µM) in vitro with commercially available bovine kidney γ-GT (0.1 units/ml) in buffer at pH 7.4 and 37°C resulted in its complete degradation, yielding (R)- and (S)-I-N-CG after 15 minutes of incubation. In vitro enzyme kinetic studies with bovine kidney γ-GT incubated separately with (R)- and (S)-I-SG isomers revealed no enantioselective degradation. Results from these studies provided evidence that ibuprofen is metabolized in human to reactive transacylating-type intermediates that react with GSH, forming I-SG thioester that, following degradation by γ-GT and dipeptidase enzymes and following S to N intramolecular rearrangement, leads to the urinary excretion of the I-N-CG and I-N-C amide-linked conjugates, respectively.


Difference in the risk of serious infections in patients with rheumatoid arthritis treated with adalimumab, infliximab and etanercept: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry.
Tumour necrosis factor (TNF)-inhibiting therapy increases the risk of serious infections in rheumatoid arthritis (RA). However, it is not clear whether this risk differs between TNF inhibitors. To analyse whether the risk of serious infections in patients with RA treated with an anti-TNF inhibitor is different for adalimumab, infliximab and etanercept. Data from the Dutch RA monitoring registry were used. Incidence rates were calculated from the observed number of first serious infections and follow-up time up to 5 years. A Cox proportional hazards model with time-to-first-serious infection was used to estimate risk differences among the anti-TNF treatment groups, with correction for confounders. The unadjusted incidence rate of a first serious infection in patients with RA per 100 patient-years was 2.61 (95% CI 2.21 to 3.00) for adalimumab, 3.86 (95% CI 3.33 to 4.40) for infliximab and 1.66 (95% CI 1.09 to 2.23) for etanercept. Age, year of starting anti-TNF therapy, comorbidities at baseline and disease activity score 28 over time were included as confounders. No difference in risk for serious infections was found between adalimumab and infliximab with an adjusted HR (adjHR) of 0.90 (95% CI 0.55 to 1.48). The risk of serious infections was significantly lower in etanercept than in both infliximab (adjHR=0.49 (95% CI 0.29 to 0.83)) and adalimumab (adjHR=0.55 (95% CI 0.44 to 0.67)). The risk of serious infections in patients with RA treated with adalimumab or infliximab was similar, while the risk of serious infections in patients with RA treated with etanercept was lower than with both adalimumab and infliximab.


Bone mineral density reductions after tenofovir disoproxil fumarate initiation and changes in phosphaturia: a secondary analysis of ACTG A5224s.
It is unknown if the greater reductions in bone mineral density (BMD) associated with initiation of tenofovir disoproxil fumarate compared with abacavir in previously untreated HIV-infected participants in the ACTG A5224s clinical trial were associated with potentially worsening tenofovir-related phosphaturia. We correlated changes in BMD at the hip and spine with changes in phosphaturia [transtubular reabsorption of phosphorus (TRP) and tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR)] from entry through week 96 in those initiating tenofovir ( n = 134) versus abacavir ( n = 135) with efavirenz or atazanavir/ritonavir in A5224s. We also correlated changes in BMD with tenofovir AUC measured between weeks 4 and 24. Changes in TRP and TmP/GFR through week 96 between the tenofovir and abacavir arms were not significantly different (both P ≥ 0.70) and did not differ with use of efavirenz versus atazanavir/ritonavir. There were no significant correlations between changes in either TRP or TmP/GFR and with either hip or spine BMD in the tenofovir arms. Tenofovir AUC was significantly correlated with changes in hip BMD, but not spine BMD, at week 24 ( r = -0.22, P = 0.028) and week 48 ( r = -0.26, P = 0.010), but not at week 96 ( r = -0.14, P = 0.18). Changes in phosphaturia were not different between the tenofovir and abacavir arms in A5224s. Changes in hip and spine BMD with tenofovir were not related to changes in phosphaturia. However, tenofovir exposure was weakly associated with changes in hip BMD through week 48.


Overexpression of cyclin D1 and cyclin E in 1,2-dimethylhydrazine dihydrochloride-induced rat colon carcinogenesis.
Deregulation of G1 cyclins has been reported in several human and rodent tumors including colon cancer. To investigate the expression pattern of G1 cyclins in 1,2- dimethyl-hydrazine dihydrochloride (DMH)-induced rat colon carcinogenesis, we studied the expression of cyclin D1 and cyclin E by quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis and immunohistochemistry (IHC). The mRNA level of cyclin D1 was increased 1.2-fold in adenocarcinomas but not significantly in adenomas, when compared with normal rat colonic mucosa (p<0.05). The cyclin E mRNA level was increased 2.7-fold in adenomas and 3.3-fold in adenocarcinomas (p<0.05). The PCNA mRNA level was also increased 1.9-fold in adenomas and 1.8-fold in adenocarcinomas (p<0.05). Immunohistochemical staining revealed exclusive nuclear staining of the neoplastic cells for cyclin D1, cyclin E and PCNA. Cyclin D1 expression was detected in 56.3% of the adenomas and in 61.5% of the adenocarcinomas examined, whereas cyclin E expression was detected in 87.5% of the adenomas and in 92.3% of the adenocarcinomas. Overall, cyclin D1, cyclin E and PCNA expression was significantly increased at both the mRNA and protein levels in normal colonic mucosa, adenomas and adenocarcinomas, but there was no significant difference in the degree of expression of these genes in adenomas and adenocarcinomas. Our results indicate that the overexpression of cyclin D1 and cyclin E may play an important role during the multistage process of rat colon carcinogenesis, at a relatively early stage, and may disturb cell-cycle control in benign adenomas, and thereafter, participate in tumor progression.


Perspectives on the genetic improvement of health- and nutrition-related traits in pea.
Pea (Pisum sativum L.) is a widely grown pulse crop that is a source of protein, starch and micronutrients in both human diets and livestock feeds. There is currently a strong global focus on making agriculture and food production systems more sustainable, and pea has one of the smallest carbon footprints of all crops. Multiple genetic loci have been identified that influence pea seed protein content, but protein composition is also important nutritionally. Studies have previously identified gene families encoding individual seed protein classes, now documented in a reference pea genome assembly. Much is also known about loci affecting starch metabolism in pea, with research especially focusing on improving concentrations of resistant starch, which has a positive effect on maintaining blood glucose homeostasis. Diversity in natural germplasm for micronutrient concentrations and mineral hyperaccumulation mutants have been discovered, with quantitative trait loci on multiple linkage groups identified for seed micronutrient concentrations. Antinutrients, which affect nutrient bioavailability, must also be considered; mutants in which the concentrations of important antinutrients including phytate and trypsin inhibitors are reduced have already been discovered. Current knowledge on the genetics of nutritional traits in pea will greatly assist with crop improvement for specific end uses, and further identification of genes involved will help advance our knowledge of the control of the synthesis of seed compounds.


Expression and role of GLUT-1, MCT-1, and MCT-4 in malignant pleural mesothelioma.
Malignant cells supply their energy needs through increased glucose consumption, producing large quantities of lactic acid via glycolysis. Glucose transporters (GLUTs) and monocarboxylate transporters (MCTs) are therefore commonly up-regulated in human malignancies to mediate glucose influx and lactic acid efflux, respectively. However, their roles in malignant pleural mesothelioma (MPM) have not been fully elucidated. Here, we evaluated GLUT-1, MCT-1, and MCT-4 expression in human MPM and reactive mesothelial hyperplasia (RMH) and elucidated their biological role in vitro. GLUT-1, MCT-1, and MCT-4 expression was determined in human MPM (n = 35) and RMH (n = 20) specimens by immunohistochemistry and in frozen tissue, and MPM cell lines, by real-time reverse transcription-polymerase chain reaction and western blot analysis. GLUT-1, MCT-1, and MCT-4 functions in MPM were evaluated by transfection with small interfering RNA. Immunohistochemical analysis revealed higher levels of GLUT-1, MCT-1, and MCT-4 in MPM than in RMH. Additionally, GLUT-1, MCT-1, and MCT-4 mRNA levels were higher in MPM than in non-neoplastic mesothelial cell lines. The siRNA-mediated knockdown of GLUT-1 or MCT-1 significantly suppressed tumor cell proliferation, and MCT-1 silencing inhibited invasion and induced apoptosis. Taken together, these results indicate that combined application of GLUT-1, MCT-1, and MCT-4 immunohistochemistry might be useful in differentiating MPM from RMH and suggest that MCT-1plays an important biological role.


Octreotide long-acting repeatable for the treatment of chronic macular edema in uveitis.
To report on the efficacy of the somatostatin analog octreotide long-acting repeatable (LAR), in the treatment of uveitic chronic macular edema (CME). Case series, retrospective analysis. In 20 patients, 20 episodes of recurrent CME during otherwise quiescent uveitis were treated with intramuscular octreotide LAR injections. Patients were included if CME control with acetazolamide or systemic and periocular steroids had failed during previous CME episodes or if contraindications existed for persistent use of these therapies. Mean outcome points were CME and visual acuity changes. Correlation of prognostic factors with these outcomes was analyzed. The included CME episodes occurred 7.6 +/- 1.4 years after onset of uveitis. Octreotide LAR treatment started 7.0 +/- 7.3 months after diagnosis of CME. CME decreased in 70% of episodes, after 2.7 +/- 1.3 months of treatment. After arrest of successful treatment, CME recurred instantly (27.2%) or within six months (36.4%). In 36.4% of successfully treated episodes, CME was absent for more than one year. A probable prognostic factor for success was the duration of CME before treatment. Octreotide LAR had an edema-reducing effect in 70% of treated CME episodes. Successful response was related to duration of CME before start of treatment. The early recurrence of CME (63.6%) after arrest of octreotide LAR advocates a long-term treatment in recent episodes of macular edema in otherwise quiescent uveitis.


Single-Cell Analyses of Colon and Blood Reveal Distinct Immune Cell Signatures of Ulcerative Colitis and Crohn's Disease.
Studies are needed to determine the mechanisms of mucosal dysregulation in patients with inflammatory bowel diseases (IBDs) and differences in inflammatory responses of patients with ulcerative colitis (UC) vs Crohn's disease (CD). We used mass cytometry (CyTOF) to characterize and compare immune cell populations in the mucosa and blood from patients with IBD and without IBD (controls) at single-cell resolution. We performed CyTOF analysis of colonic mucosa samples (n = 87) and peripheral blood mononuclear cells (n = 85) from patients with active or inactive UC or CD and controls. We also performed single-cell RNA sequencing, flow cytometry, and RNA in situ hybridization analyses to validate key findings. We used random forest modeling to identify differences in signatures across subject groups. Compared with controls, colonic mucosa samples from patients with IBD had increased abundances of HLA-DR+CD38+ T cells, including T-regulatory cells that produce inflammatory cytokines; CXCR3+ plasmablasts; and IL1B+ macrophages and monocytes. Colonic mucosa samples from patients with UC were characterized by expansion of IL17A+ CD161+ effector memory T cells and IL17A+ T-regulatory cells; expansion of HLA-DR+CD56+ granulocytes; and reductions in type 3 innate lymphoid cells. Mucosal samples from patients with active CD were characterized by IL1B+HLA-DR+CD38+ T cells, IL1B+TNF+IFNG+ naïve B cells, IL1B+ dendritic cells (DCs), and IL1B+ plasmacytoid DCs. Peripheral blood mononuclear cells from patients with active CD differed from those of active UC in that the peripheral blood mononuclear cells from patients with CD had increased IL1B+ T-regulatory cells, IL1B+ DCs and IL1B+ plasmacytoid DCs, IL1B+ monocytes, and fewer group 1 innate lymphoid cells. Random forest modeling differentiated active UC from active CD in colonic mucosa and blood samples; top discriminating features included many of the cellular populations identified above. We used single-cell technologies to identify immune cell populations specific to mucosa and blood samples from patients with active or inactive CD and UC and controls. This information might be used to develop therapies that target specific cell populations in patients with different types of IBD.


Cytosolic chaperonin-containing t-complex polypeptide 1 changes the content of a particular subunit species concomitant with substrate binding and folding activities during the cell cycle.
The chaperonin-containing t-complex polypeptide 1 (CCT) is a cytosolic molecular chaperone composed of eight subunits that assists in the folding of actin, tubulin and other cytosolic proteins. We show here that the content of particular subunits of CCT within mammalian cells decreases concomitantly with the reduction of chaperone activity during cell cycle arrest at M phase. CCT recovers chaperone activity upon resumption of these subunits after release from M phase arrest or during arrest at S phase. The levels of alpha, delta and zeta-1 subunits decreased more rapidly than the other subunits during M phase arrest by colcemid treatment and recovered after release from the arrest. Gel filtration chromatography or native (nondenaturing) PAGE analysis followed by immunoblotting indicated that the alpha and delta subunit content in the 700- to 900-kDa CCT complex was appreciably lower in the M phase cells than in asynchronous cells. In vivo, the CCT complex of M-phase-arrested cells was found to bind lower amounts of tubulin than that of asynchronous cells. In vitro, the CCT complex of M phase-arrested cells was less active in binding and folding denatured actin than that of asynchronous cells. On the other hand, the CCT complex of asynchronous cells (a mixture of various phases of cell cycle) exhibited lower alpha and delta subunit content and lower chaperone activity than that of S-phase-arrested cells obtained by excess thymidine treatment. In addition, turnover (synthesis and degradation) rates of the alpha and delta subunits in vivo were more rapid than those of most other subunits. These results suggest that the content of alpha and delta subunits of CCT reduces from the complete active complex in S phase cells to incomplete inactive complex in M phase cells.


Role of autophagy genetic variants for the risk of Candida infections.
Candida albicans can cause candidemia in neutropenic and critically ill patients and oropharyngeal candidiasis in human immunodeficiency virus (HIV)-positive patients with low CD4(+) counts. Because all patients at risk do not develop Candida infections, it is possible that a patient's genetic background might play a role in his or her susceptibility to infection. Autophagy mediates pathogen clearance and modulation of inflammation. Our aim was to assess the effect of genetic variations in the ATG16L1 and IRGM autophagy genes on the susceptibility of patients with candidemia and oropharyngeal candidiasis. We assessed genetic variations in the ATG16L1 and IRGM genes in a cohort of candidemia patients of both African and European origin. In addition, we evaluated the effect of these polymorphisms on the susceptibility to oropharyngeal candidiasis of an HIV-positive cohort from Tanzania. Functional studies have been performed to assess the effect of the ATG16L1 and IRGM genetic variants on both in vitro and in vivo cytokine production. The results indicate that ATG16L1 variants modulate production of tumor necrosis factor-alpha, but not other cytokines, while no effects were seen in the presence of IRGM polymorphisms. In addition, no significant associations between the single-nucleotide polymorphisms in the ATG16L1 and IRGM genetic variants and the incidence of candidemia or oropharyngeal candidiasis were identified. Despite moderate effects on the modulation of proinflammatory cytokine production, genetic variation in the autophagy genes ATG16L1 and IRGM has a minor impact on the susceptibility to both mucosal and systemic Candida infections.


Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children.
The effects on long-term outcome in childhood acute lymphoblastic leukaemia (ALL) of the duration and the intensity of maintenance chemotherapy need to be assessed reliably. With this objective the Childhood ALL Collaborative Group coordinated a worldwide overview of all randomised trials that began before 1987. Individual patient data were sought for about 3900 children in trials of longer vs shorter maintenance (eg, 3 vs 2 years), 3700 in trials of intensive "reinduction" chemotherapy during maintenance, and 4400 in trials of various other questions, including 1300 in trials of pulses of vincristine and prednisone (VP) during maintenance. Analyses were of survival in first remission, overall survival, and cause-specific mortality. Deaths during remission were increased by longer maintenance (2.7 percent vs 1.2 percent), VP pulses (4.0 vs 3.2 percent), and intensive reinduction (4.8 percent vs 3.3 percent), but these increases were counterbalanced by reductions in relapses. Total events (relapse or death) were significantly reduced by longer maintenance (23.3 percent vs 27.6 percent), VP pulses (31.2 percent vs 40.4 percent) and intensive reinduction (27.8 percent vs 35.8 percent) (each 2p<0.001). Many of those who relapsed were successfully re-treated, however, and only for intensive reinduction was overall survival significantly improved (18.5 percent vs 22.3 percent; 2p=0.01). Intensive reinduction chemotherapy in these trials produced an absolute improvement of about 4 percent in long-term survival; if the extra deaths in remission had been avoided, this would have been a 5 percent benefit. Further improvements in survival seem more likely to be obtained with intensive treatment than with longer low-level maintenance.


Neutering increases the risk of obesity in male dogs but not in bitches - A cross-sectional study of dog- and owner-related risk factors for obesity in Danish companion dogs.
Knowledge of risk factors for canine obesity is an important pre-requisite of effective preventative strategies. This study aimed to investigate risk factors for canine obesity in adult companion dogs across Zealand, Denmark. Client-owned dogs (>2 years of age and without chronic illness) were recruited and examined at eight companion animal veterinary practices in areas with varying socio-economic characteristics. The body condition score (BCS) of the dogs was examined by two investigators based on a 9-point scoring scheme. Dog owners answered a questionnaire that had prompts regarding: 1) dog characteristics, including neuter status, 2) owner characteristics, 3) feeding and exercise practices and 4) the owners' attachment to the dog. The effect of these factors on BCS and the risk of being heavy/obese (BCS scores 7-9) were analysed in two separate analyses. A total of 268 dogs were included in the analysis, of which 20.5% were found to be heavy/obese. The average BCS was 5.46. In terms of dog characteristics, neutering dramatically increased both BCS and the risk of being heavy/obese in male dogs but not in bitches. BCS and the risk of being heavy/obese increased in senior bitches and decreased in senior male dogs. The risk of being heavy/obese was higher in dogs with overweight and obese owners. Regarding feeding and exercise practices, providing only one meal per day increased BCS and risk of being heavy/obese. Treats during relaxation increased the risk of dogs being heavy/obese. It also increased the dogs' BCS, but only if the owners were overweight or obese. An increased duration of daily walking increased the risk of the dog being heavy/obese, but only if the owner was overweight or obese. Allowing the dog to run free in the garden/property decreased the risk of the dog being heavy/obese. The owners' attachment to the dog was not associated with the dogs' BCS or dogs' being heavy/obese. An important and novel finding was that neutering increased the risk of being overweight or obese for male dogs while bitches were at risk irrespective of neuter status. Furthermore, a complex interaction between owners' weight status, feeding practices and the risk of dogs being overweight or obese was found, which stresses the need to consider companion animal obesity from a One Health perspective in future prospective studies. Finally, this study was unable to confirm that canine obesity is a product of owners being too attached to their dogs.


Ten Years of Messaging about the Affordable Care Act in Advertising and News Media: Lessons for Policy and Politics.
Messaging about the Affordable Care Act (ACA) has seemingly produced a variety of outcomes: millions of Americans gained access to health insurance, yet much of the US public remains confused about major components of the law, and there remain stark and persistent political divides in support of the law. Our analysis of the volume and content of ACA-related media (including both ads and news) helps explain these phenomena, with three conclusions. First, the information environment around the ACA has been complex and competitive, with messaging originating from diverse sponsors with multiple objectives. Second, partisan cues in news and political ads are abundant, likely contributing to the crystallized politically polarized opinion about the law. Third, partisan discussions of the ACA in political ads have shifted in volume, direction, and tone over the decade, presenting divergent views regarding which party is accountable for the law's successes (or failures). We offer evidence for each of these conclusions from longitudinal analyses of the volume and content of ACA messaging, also referencing studies that have linked these messages to attitudes and behavior. We conclude with implications for health communication, political science, and the future outlook for health reform.


Full-frame video stabilization with motion inpainting.
Video stabilization is an important video enhancement technology which aims at removing annoying shaky motion from videos. We propose a practical and robust approach of video stabilization that produces full-frame stabilized videos with good visual quality. While most previous methods end up with producing smaller size stabilized videos, our completion method can produce full-frame videos by naturally filling in missing image parts by locally aligning image data of neighboring frames. To achieve this, motion inpainting is proposed to enforce spatial and temporal consistency of the completion in both static and dynamic image areas. In addition, image quality in the stabilized video is enhanced with a new practical deblurring algorithm. Instead of estimating point spread functions, our method transfers and interpolates sharper image pixels of neighboring frames to increase the sharpness of the frame. The proposed video completion and deblurring methods enabled us to develop a complete video stabilizer which can naturally keep the original image quality in the stabilized videos. The effectiveness of our method is confirmed by extensive experiments over a wide variety of videos.


Effect of arginase inhibition on ischemia-reperfusion injury in patients with coronary artery disease with and without diabetes mellitus.
Arginase competes with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in coronary artery disease (CAD) and diabetes mellitus may reduce nitric oxide bioavailability contributing to endothelial dysfunction and ischemia-reperfusion injury. Arginase inhibition reduces infarct size in animal models. Therefore the aim of the current study was to investigate if arginase inhibition protects from endothelial dysfunction induced by ischemia-reperfusion in patients with CAD with or without type 2 diabetes ( NCT02009527). Male patients with CAD (n = 12) or CAD + type 2 diabetes (n = 12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and after 20 min ischemia-reperfusion during intra-arterial infusion of the arginase inhibitor (Nω-hydroxy-nor-L-arginine, 0.1 mg/min) or saline. The forearm ischemia-reperfusion was well tolerated. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Ischemia-reperfusion decreased FMD in patients with CAD from 12.7±5.2% to 7.9±4.0% during saline administration (P<0.05). Nω-hydroxy-nor-L-arginine administration prevented the decrease in FMD in the CAD group (10.3±4.3% at baseline vs. 11.5±3.6% at reperfusion). Ischemia-reperfusion did not significantly reduce FMD in patients with CAD + type 2 diabetes. However, FMD at reperfusion was higher following nor-NOHA than following saline administration in both groups (P<0.01). Endothelium-independent vasodilatation did not differ between the occasions. Inhibition of arginase protects against endothelial dysfunction caused by ischemia-reperfusion in patients with CAD. Arginase inhibition may thereby be a promising therapeutic strategy in the treatment of ischemia-reperfusion injury.


Adaptation of soil microbial growth to temperature: Using a tropical elevation gradient to predict future changes.
Terrestrial biogeochemical feedbacks to the climate are strongly modulated by the temperature response of soil microorganisms. Tropical forests, in particular, exert a major influence on global climate because they are the most productive terrestrial ecosystem. We used an elevation gradient across tropical forest in the Andes (a gradient of 20°C mean annual temperature, MAT), to test whether soil bacterial and fungal community growth responses are adapted to long-term temperature differences. We evaluated the temperature dependency of soil bacterial and fungal growth using the leucine- and acetate-incorporation methods, respectively, and determined indices for the temperature response of growth: Q10 (temperature sensitivity over a given 10oC range) and Tmin (the minimum temperature for growth). For both bacterial and fungal communities, increased MAT (decreased elevation) resulted in increases in Q10 and Tmin of growth. Across a MAT range from 6°C to 26°C, the Q10 and Tmin varied for bacterial growth (Q10-20 = 2.4 to 3.5; Tmin = -8°C to -1.5°C) and fungal growth (Q10-20 = 2.6 to 3.6; Tmin = -6°C to -1°C). Thus, bacteria and fungi did not differ significantly in their growth temperature responses with changes in MAT. Our findings indicate that across natural temperature gradients, each increase in MAT by 1°C results in increases in Tmin of microbial growth by approximately 0.3°C and Q10-20 by 0.05, consistent with long-term temperature adaptation of soil microbial communities. A 2°C warming would increase microbial activity across a MAT gradient of 6°C to 26°C by 28% to 15%, respectively, and temperature adaptation of microbial communities would further increase activity by 1.2% to 0.3%. The impact of warming on microbial activity, and the related impact on soil carbon cycling, is thus greater in regions with lower MAT. These results can be used to predict future changes in the temperature response of microbial activity over different levels of warming and over large temperature ranges, extending to tropical regions.


Dietary patterns are associated with cognitive function in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort.
Identifying factors that contribute to the preservation of cognitive function is imperative to maintaining quality of life in advanced years. Of modifiable risk factors, diet quality has emerged as a promising candidate to make an impact on cognition. The objective of this study was to evaluate associations between empirically derived dietary patterns and cognitive function. This study included 18 080 black and white participants aged 45 years and older from the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Principal component analysis on data from the Block98 FFQ yielded five dietary patterns: convenience, plant-based, sweets/fats, Southern, and alcohol/salads. Incident cognitive impairment was defined as shifting from intact cognitive status (score >4) at first assessment to impaired cognitive status (score ≤4) at latest assessment, measured by the Six-Item Screener. Learning, memory and executive function were evaluated with the Word List Learning, Word List Delayed Recall, and animal fluency assessments. In fully adjusted models, greater consumption of the alcohol/salads pattern was associated with lower odds of incident cognitive impairment (highest quintile (Q5) v. lowest quintile (Q1): OR 0·68; 95 % CI 0·56, 0·84; P for trend 0·0005). Greater consumption of the alcohol/salads pattern was associated with higher scores on all domain-specific assessments and greater consumption of the plant-based pattern was associated with higher scores in learning and memory. Greater consumption of the Southern pattern was associated with lower scores on each domain-specific assessment (all P < 0·05). In conclusion, dietary patterns including plant-based foods and alcohol intake were associated with higher cognitive scores, and a pattern including fried food and processed meat typical of a Southern diet was associated with lower scores.


Tailored Behavioral Intervention Among Blacks With Metabolic Syndrome and Sleep Apnea: Results of the MetSO Trial.
To assess effectiveness of a culturally and linguistically tailored telephone-delivered intervention to increase adherence to physician-recommended evaluation and treatment of obstructive sleep apnea (OSA) among blacks. In a two-arm randomized controlled trial, we evaluated effectiveness of the tailored intervention among blacks with metabolic syndrome, relative to those in an attention control arm (n = 380; mean age = 58 ± 13; female = 71%). The intervention was designed to enhance adherence using culturally and linguistically tailored OSA health messages delivered by a trained health educator based on patients' readiness to change and unique barriers preventing desired behavior changes. Analysis showed 69.4% of the patients in the intervention arm attended initial consultation with a sleep specialist, compared to 36.7% in the control arm; 74.7% of those in the intervention arm and 66.7% in the control arm completed diagnostic evaluation; and 86.4% in the intervention arm and 88.9% in the control arm adhered to PAP treatment based on subjective report. Logistic regression analyses adjusting for sociodemographic factors indicated patients in the intervention arm were 3.17 times more likely to attend initial consultation, compared to those in the control arm. Adjusted models revealed no significant differences between the two arms regarding adherence to OSA evaluation or treatment. The intervention was successful in promoting importance of sleep consultation and evaluation of OSA among blacks, while there was no significant group difference in laboratory-based evaluation and treatment adherence rates. It seems that the fundamental barrier to OSA care in that population may be the importance of seeking OSA care.


In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity.
Cytokine-induced killer (CIK) cells are ex vivo-expanded T lymphocytes expressing both natural killer (NK)- and T-cell markers. CIK cells are cytotoxic against autologous and allogeneic tumors. We previously showed that adoptive transfer of allogeneic CIK cells in a murine model caused minimal graft-versus-host disease (GVHD). However, the precise mechanism of reduced GVHD is not fully understood. Therefore, we evaluated the trafficking and survival of luciferase-expressing CIK cells in an allogeneic bone marrow transplant model. The initial trafficking patterns of CIK cells were similar to conventional T cells that induced GVHD; however, CIK cells infiltrated GVHD target tissues much less and transiently. CIK cells accumulated and persisted in tumor sites, resulting in tumor eradication. We evaluated different properties of CIK cells compared with conventional T cells, demonstrating a slower division rate of CIK cells, higher susceptibility to apoptosis, persistent increased expression of interferon gamma (IFN-gamma), and reduced acquisition of homing molecules required for entry of cells into inflamed GVHD target organs that lack expression of NKG2D ligands recognized by CIK cells. Due to these properties, allogeneic CIK cells had reduced expansion and caused less tissue damage. We conclude that CIK cells have the potential to separate graft-versus-tumor effects from GVHD.


The role of cardiopulmonary sympathetic afferents in blood volume homoeostasis in the non-human primate.
1. Four Macaca fascicularis monkeys were bilaterally sympathectomized by removing the thoracic sympathetic chain from the middle cervical ganglion to the T-6 sympathetic ganglion. This was done chronically, allowing adequate recovery time. While under light pentobarbital anaesthesia, the animals were then subjected to blood volume expansions with isotonic, isooncotic dextran or to head-out immersions. Seven immersions and seven volume expansions were carried out. 2. With immersion, there were significant increases in blood pressure, central venous pressure, urine flow, sodium excretion, potassium excretion, glomerular filtration rate, percentage of filtered sodium excreted and free water clearance. Although blood pressure and central venous pressure initially increased during the first immersion period, heart rate continued to increase with the immersion, while blood pressure and central venous pressure remained constant. Volume expansion caused an increase in central venous pressure, urine flow, sodium and potassium excretion, osmolar clearance, free water clearance, percentage of filtered sodium excreted and glomerular filtration rate. 3. Since these results with both the immersions and volume expansions were not qualitatively different from those observed in control animals, it is concluded that cardiopulmonary sympathetic afferents are not necessary for the renal response to head-out immersion or blood volume expansion in the non-human primate.


Electronic structure changes during the surface-assisted formation of a graphene nanoribbon.
High conductivity and a tunability of the band gap make quasi-one-dimensional graphene nanoribbons (GNRs) highly interesting materials for the use in field effect transistors. Especially bottom-up fabricated GNRs possess well-defined edges which is important for the electronic structure and accordingly the band gap. In this study we investigate the formation of a sub-nanometer wide armchair GNR generated on a Au(111) surface. The on-surface synthesis is thermally activated and involves an intermediate non-aromatic polymer in which the molecular precursor forms polyanthrylene chains. Employing angle-resolved two-photon photoemission in combination with density functional theory calculations we find that the polymer exhibits two dispersing states which we attribute to the valence and the conduction band, respectively. While the band gap of the non-aromatic polymer obtained in this way is relatively large, namely 5.25 ± 0.06 eV, the gap of the corresponding aromatic GNR is strongly reduced which we attribute to the different degree of electron delocalization in the two systems.