COVID-19 Treatment at a Glance.
As coronavirus disease 2019 (COVID-19) spreads across the world, the ongoing clinical trials are leading to a big race worldwide to develop a treatment that will help control the pandemic. Unfortunately, COVID-19 does not have any known effective treatment with reliable study results yet. In this pandemic, there is not a lot of time to develop a new specific agent because of the rapid spread of the disease. The process of developing a vaccine is long and requires hard work. Although the pathophysiology of the disease is not fully understood, some of the proposed treatment alternatives are based on old evidence and some have been used with the idea that they might work owing to their mechanism of action. The efficacy, reliability, and safety of the currently available treatment alternatives are therefore a matter of debate. Currently, the main therapies used in the treatment of COVID-19 are antiviral drugs and chloroquine/hydroxychloroquine. Other proposed options include tocilizumab, convalescent plasma, and steroids, but the mainstay of the treatment in intensive care units remains supportive therapies.


Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphism and circulating osteocalcin.
Osteocalcin, the most abundant noncollagenous protein in bone, is a marker of bone turnover in normal and disease states. Its synthesis is induced by calcitriol, the active hormonal form of vitamin D, through the vitamin D receptor and a specific vitamin D-responsive element in the osteocalcin gene promoter. Serum concentrations of osteocalcin are under strong genetic influence. To ascertain whether variability in circulating osteocalcin levels may reflect allelic variation in the vitamin D receptor gene, we have analyzed the relationship between frequent restriction fragment length polymorphisms (RFLPs, detected by endonucleases Bsm I, EcoRV, and Apa I) that define human vitamin D receptor alleles and serum osteocalcin in a cohort of normal subjects. In 91 Caucasian subjects, RFLPs in the vitamin D receptor gene predicted circulating osteocalcin levels (P less than 0.0001) independent of age or menopause effects. Since the osteocalcin gene and the vitamin D receptor gene are encoded on different chromosomes, the interaction between these two genes occurs in trans. Thus, common alleles of this trans-acting factor, the vitamin D receptor, are functionally different and contribute to "normal" physiological variability in osteocalcin levels. Preliminary analysis in monozygotic and dizygotic twin pairs indicates that the greater diversity in lumbar spine density between the dizygotic pairs can be explained by divergence in vitamin D receptor alleles. Variations in this receptor and other transacting factor genes may confound physiological studies of regulation of target genes and will need to be considered in future human and animal studies. This approach to genetic analysis provides a paradigm for the study of functional variation in trans-acting factors and the role such variation may play in the generation and evolution of physiological diversity.


The MBE growth and optimization of high performance terahertz frequency quantum cascade lasers.
The technique of molecular beam epitaxy has recently been used to demonstrate the growth of terahertz frequency GaAs/AlGaAs quantum cascade lasers (QCL) with Watt-level optical output powers. In this paper, we discuss the critical importance of achieving accurate layer thicknesses and alloy compositions during growth, and demonstrate that precise growth control as well as run-to-run growth reproducibility is possible. We also discuss the importance of minimizing background doping level in maximizing QCL performance. By selecting high-performance active region designs, and optimizing the injection doping level and device fabrication, we demonstrate total optical (two-facet) output powers as high as 1.56 W.


Selection To Increase Expression, Not Sequence Diversity, Precedes Gene Family Origin and Expansion in Rattlesnake Venom.
Gene duplication is the primary mechanism leading to new genes and phenotypic novelty, but the proximate evolutionary processes underlying gene family origin, maintenance, and expansion are poorly understood. Although sub- and neofunctionalization provide clear long-term advantages, selection does not act with foresight, and unless a redundant gene copy provides an immediate fitness advantage, the copy will most likely be lost. Many models for the evolution of genes immediately following duplication have been proposed, but the robustness and applicability of these models is unclear because of the lack of data at the population level. We used qPCR, protein expression data, genome sequencing, and hybrid enrichment to test three competing models that differ in whether selection favoring the spread of duplicates acts primarily on expression level or sequence diversity for specific toxin-encoding loci in the eastern diamondback rattlesnake (Crotalus adamanteus). We sampled 178 individuals and identified significant inter- and intrapopulation variation in copy number, demonstrated that copy number was significantly and positively correlated with protein expression, and found little to no sequence variation across paralogs in all populations. Collectively, these results demonstrate that selection for increased expression, not sequence diversity, was the proximate evolutionary process underlying gene family origin and expansion, providing data needed to resolve the debate over which evolutionary processes govern the fates of gene copies immediately following duplication.


Cardiorespiratory fitness and visceral fat are key determinants of serum fibroblast growth factor 21 concentration in Japanese men.
Fibroblast growth factor-21 (FGF21) is an important metabolic regulator suggested to improve glucose metabolism and prevent dyslipidemia. An FGF21-resistant state that increases circulating FGF21 has been reported in obese patients. Although regular exercise prevents metabolic disease, the relationship of the fitness level to serum FGF21 level and body fat distribution in humans remains poorly understood. The objective of the study was to determine the relationship among the serum FGF21 concentration, cardiorespiratory fitness (CRF) level, and visceral fat area (VFA). Serum FGF21 was measured by an ELISA in 166 middle-aged and elderly Japanese men (aged 30-79 y) and 25 untrained and 21 endurance-trained young men (aged 19-29 y). CRF was assessed by measuring the peak oxygen uptake (VO2peak) and VFA by magnetic resonance imaging. In the middle-aged and elderly subjects, the serum FGF21 level correlated with the VO2peak (r = -0.355, P < .001) and VFA (r = 0.487, P < .001). Stepwise multiple regression analysis showed VFA to be most strongly associated with the serum FGF21 level (β = .360, P < .001), and VO2peak was also an independent predictor of the serum FGF21 level (β = -.174, P = .019). Furthermore, the proportion of subjects with an FGF21 level below the limit of detection was significantly higher among the endurance-trained than among the untrained young men (71.4% vs 24.0%, P = .001), and the VO2peak and VFA were independently associated with an undetectable FGF21 level (P < .05). CRF and VFA are key determinants of the circulating FGF21 concentration.


Temporal Irreversibility of Large-Scale Brain Dynamics in Alzheimer's Disease.
Healthy brain dynamics can be understood as the emergence of a complex system far from thermodynamic equilibrium. Brain dynamics are temporally irreversible and thus establish a preferred direction in time (i.e., arrow of time). However, little is known about how the time-reversal symmetry of spontaneous brain activity is affected by Alzheimer's disease (AD). We hypothesized that the level of irreversibility would be compromised in AD, signaling a fundamental shift in the collective properties of brain activity toward equilibrium dynamics. We investigated the irreversibility from resting-state fMRI and EEG data in male and female human patients with AD and elderly healthy control subjects (HCs). We quantified the level of irreversibility and, thus, proximity to nonequilibrium dynamics by comparing forward and backward time series through time-shifted correlations. AD was associated with a breakdown of temporal irreversibility at the global, local, and network levels, and at multiple oscillatory frequency bands. At the local level, temporoparietal and frontal regions were affected by AD. The limbic, frontoparietal, default mode, and salience networks were the most compromised at the network level. The temporal reversibility was associated with cognitive decline in AD and gray matter volume in HCs. The irreversibility of brain dynamics provided higher accuracy and more distinctive information than classical neurocognitive measures when differentiating AD from control subjects. Findings were validated using an out-of-sample cohort. Present results offer new evidence regarding pathophysiological links between the entropy generation rate of brain dynamics and the clinical presentation of AD, opening new avenues for dementia characterization at different levels.SIGNIFICANCE STATEMENT By assessing the irreversibility of large-scale dynamics across multiple brain signals, we provide a precise signature capable of distinguishing Alzheimer's disease (AD) at the global, local, and network levels and different oscillatory regimes. Irreversibility of limbic, frontoparietal, default-mode, and salience networks was the most compromised by AD compared with more sensory-motor networks. Moreover, the time-irreversibility properties associated with cognitive decline and atrophy outperformed and complemented classical neurocognitive markers of AD in predictive classification performance. Findings were generalized and replicated with an out-of-sample validation procedure. We provide novel multilevel evidence of reduced irreversibility in AD brain dynamics that has the potential to open new avenues for understating neurodegeneration in terms of the temporal asymmetry of brain dynamics.


Efficacy of praziquantel against Schistosoma haematobium infection in children.
A study was performed to determine the efficacy of praziquantel (PZQ) against Schistosoma haematobium. Children (n = 592) infected with S. haematobium received either a single treatment with PZQ (40 mg/kg) or two or three treatments with PZQ at three-week intervals after the initial treatment and efficacy was monitored for nine weeks. Cure rates at three-weeks post-treatment were low (< 50%), suggesting either that worms are killed very slowly or, more likely, that eggs continue to be released from tissues after worm death. Interestingly, a single dose of PZQ showed high efficacy (cure rate > 83% and egg reduction rate > 98%) when assessed from six weeks post-treatment onward. There were no significant differences in cure rates or intensity of infection between the three cohorts at any point in the study, despite the different treatment regimens. Since children were in contact with transmission sites during the study period, the results suggest good efficacy of PZQ against all stages of S. haematobium, including the immature worms.


ImmunoNodes - graphical development of complex immunoinformatics workflows.
Immunoinformatics has become a crucial part in biomedical research. Yet many immunoinformatics tools have command line interfaces only and can be difficult to install. Web-based immunoinformatics tools, on the other hand, are difficult to integrate with other tools, which is typically required for the complex analysis and prediction pipelines required for advanced applications. We present ImmunoNodes, an immunoinformatics toolbox that is fully integrated into the visual workflow environment KNIME. By dragging and dropping tools and connecting them to indicate the data flow through the pipeline, it is possible to construct very complex workflows without the need for coding. ImmunoNodes allows users to build complex workflows with an easy to use and intuitive interface with a few clicks on any desktop computer.


Introduction of enteral food increases plasma GLP-2 and decreases GLP-2 receptor mRNA abundance during pig development.
Glucagon-like peptide 2 (GLP-2) may mediate in part the rapid growth effects of luminal nutrients in the small intestine of newborns. The objectives of this study were to determine plasma GLP-2 concentrations and small intestinal GLP-2 receptor (GLP-2R) mRNA abundance (measured by reverse transcription polymerase chain reaction) during pre- and postnatal development and the relationship between these variables and small intestinal growth in enterally and parenterally fed fetal and newborn pigs (premature and term-delivered, 92 and 100% gestation, respectively). Plasma GLP-2 concentrations increased before birth, peaked in suckling 1-d-old pigs (87 +/- 14 pmol/L, P < 0.05), decreased with weaning-related anorexia (34 +/- 5 pmol/L, P < 0.05) and increased when normal food intake resumed (81 +/- 9 pmol/L, P < 0.05). Plasma GLP-2 concentrations were increased 1 d after enteral infusion of colostrum in fetal pigs at 92% gestation compared with untreated controls (59 +/- 11 vs. 7 +/- 2 pmol/L, P < 0.05). In newborn pigs, plasma GLP-2 was increased 2-6 d after the enteral administration of a milk diet, compared with the parenteral infusion of elemental nutrients, but the time course of the response was delayed in premature newborn pigs. Small intestinal GLP-2R mRNA abundance was highest at birth and decreased with enteral food intake in fetal, suckling and weaned pigs (P < 0.05). In contrast, enteral feeding increased (P < 0.05) relative small intestinal weight and/or villous heights in these pigs. We conclude that the introduction of enteral feeding transiently increases plasma GLP-2 concentrations and decreases small intestinal GLP-2R mRNA levels during pig development. GLP-2 may play a role in the growth of the small intestine around birth and weaning via a response to enteral nutrition.


Whole-body MRI including diffusion-weighted MRI compared with 5-HTP PET/CT in the detection of neuroendocrine tumors.
We wanted to explore if whole-body magnetic resonance imaging (MRI) including diffusion-weighted (DW) and liver-specific contrast agent-enhanced imaging could be valuable in lesion detection of neuroendocrine tumors (NET). [11C]-5-Hydroxytryptophan positron emission tomography/computed tomography (5-HTP PET/CT) was used for comparison. Twenty-one patients with NET were investigated with whole-body MRI, including DW imaging (DWI) and contrast-enhanced imaging of the liver, and whole-body 5-HTP PET/CT. Seven additional patients underwent upper abdomen MRI including DWI, liver-specific contrast agent-enhanced imaging, and 5-HTP PET/CT. There was a patient-based concordance of 61% and a lesion-based concordance of 53% between the modalities. MRI showed good concordance with PET in detecting bone metastases but was less sensitive in detecting metastases in mediastinal lymph nodes. MRI detected more liver metastases than 5-HTP PET/CT. Whole-body MRI with DWI did not detect all NET lesions found with whole-body 5-HTP PET/CT. Our findings indicate that MRI of the liver including liver-specific contrast agent-enhanced imaging and DWI could be a useful complement to whole-body 5-HTP PET/CT.


WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus.
The ErbB-4 receptor protein-tyrosine kinase is proteolytically processed by membrane proteases in response to the ligand or 12-O-tetradecanoylphorbol-13-acetate stimulation resulting in the cytoplasmic fragment translocating to the cell nucleus. The WW domain-containing co-transcriptional activator Yes-associated protein (YAP) associates physically with the full-length ErbB-4 receptor and functionally with the ErbB-4 cytoplasmic fragment in the nucleus. The YAP.ErbB4 complex is mediated by the first WW domain of YAP and the most carboxyl-terminal PPXY motif of ErbB-4. In human tissues, we documented the expression of YAP1 with a single WW domain and YAP2 with two WW domains. It is known that the COOH-terminal fragment of ErbB4 does not have transcriptional activity by itself; however, we show here that in the presence of YAP its transcriptional activity is revealed. There is a difference in the extent of transactivation activity among YAP isoforms: YAP2 is the stronger activator compared with YAP1. This transactivation is abolished by mutations that abrogate the YAP.ErbB4 complex formation. The unphosphorylatable mutation that increases the nuclear localization of YAP increases transcription activity. The COOH-terminal fragment of ErbB-4 and full-length YAP2 overexpressed in cells partially co-localize to the nucleus. Our data indicate that YAP is a potential signaling partner of the full-length ErbB4 receptor at the membrane and of the COOH-terminal fragment of ErbB-4 that translocates to the nucleus to regulate transcription.


Point prevalence survey for tick-borne pathogens in military working dogs, shelter animals, and pet populations in northern Colombia.
Based on the high tick-borne pathogen results from a 2011 surveillance study in three Colombian cities, an in-depth point prevalence survey was conducted to determine the seroprevalence of tick-borne pathogens at a specific point in time in 70 working dogs, 101 shelter dogs, and 47 client-owned dogs in Barranquilla, Colombia. Of the 218 serum samples, 163 (74%) were positive for Ehrlichia canis and 116 (53%) for Anaplasma platys. Exposure to tick-borne pathogens was highest in shelter and working dogs where more than 90% of the samples were seropositive or positive on polymerase chain reaction for one or more organisms as compared to 51% in client-owned animals. Surveillance for exposure to tick-borne pathogens provides vital information necessary to protect and conserve the health of local humans and animals, deployed military service members, and working dogs in various parts of the world. This study and resultant data demonstrate the value of following a broad-based surveillance study with a more specific, focused analysis in an area of concern. This area?s high levels of exposure warrant emphasis by medical planners and advisors on precautionary measures for military dogs, Special Operations Forces personnel, and the local public.


Potential health-related behaviors for pre-school and school-aged children during COVID-19 lockdown: A narrative review.
As a consequence of the COVID-19 pandemic, different measures have been implemented by governments from each affected country. Such measures usually involve restrictions on the movement of citizens, and have had a profound effect on usual activities and timetables. As a result of school closures and strict restrictions regarding going outside home, children have been one of the most disadvantaged population groups during the lockdown period. We therefore aimed to investigate potential health risk behaviors amongst isolated pre-school and school-aged children. We retrieved relevant articles from MEDLINE, Web of Science, PsycInfo, and Scopus databases to describe identified health-related behaviors (i.e. screen exposure, environmental influence, physical activity and fitness, sedentariness, sleep patterns, eating habits, psychological response, body composition, and injuries) in relation to social isolation and social deprivation of children without previous illness or conditions. This review depicts the potential health-related behaviors according to related literature, and put the focus on future short and long-term sequels of social isolation. Socio-affective complications and insufficient physical activity are underscored as two of the main concerns, particularly among socio-economic deprived children. Both issues could be effectively addressed with either adequate parental or community guidance.


Associations of advanced glycation end-products with cognitive functions in individuals with and without type 2 diabetes: the maastricht study.
Advanced glycation end-products (AGEs) are thought to be involved in the pathogenesis of Alzheimer's disease. AGEs are products resulting from nonenzymatic chemical reactions between reduced sugars and proteins, which accumulate during natural aging, and their accumulation is accelerated in hyperglycemic conditions such as type 2 diabetes mellitus. The objective of the study was to examine associations between AGEs and cognitive functions. This study was performed as part of the Maastricht Study, a population-based cohort study in which, by design, 215 participants (28.1%) had type 2 diabetes mellitus. We examined associations of skin autofluorescence (SAF) (n = 764), an overall estimate of skin AGEs, and specific plasma protein-bound AGEs (n = 781) with performance on tests for global cognitive functioning, information processing speed, verbal memory (immediate and delayed word recall), and response inhibition. After adjustment for demographics, diabetes, smoking, alcohol, waist circumference, total cholesterol/high-density lipoprotein cholesterol ratio, triglycerides, and lipid-lowering medication use, higher SAF was significantly associated with worse delayed word recall (regression coefficient, b = -0.44; P = .04), and response inhibition (b = 0.03; P = .04). After further adjustment for systolic blood pressure, cardiovascular disease, estimated glomerular filtration rate, and depression, associations were attenuated (delayed word recall, b = -0.38, P = .07; response inhibition, b = 0.02, P = .07). Higher pentosidine levels were associated with worse global cognitive functioning (b = -0.61; P = .04) after full adjustment, but other plasma AGEs were not. Associations did not differ between individuals with and without diabetes. We found inverse associations of SAF (a noninvasive marker for tissue AGEs) with cognitive performance, which were attenuated after adjustment for vascular risk factors and depression.


Interleukin-6 expression by interactions between gynecologic cancer cells and human mesenchymal stem cells promotes epithelial-mesenchymal transition.
Epithelial-to-mesenchymal transition (EMT) facilitates the invasion and metastasis of cancer cells. EMT seems to be mediated by the interaction between cancer cells and human mesenchymal stem cells (hMSCs) in the tumor microenvironment. The present study is intended to identify specific cytokines as potent inducers of EMT associated hMSCs-tumor interactions. We used ovarian cancer cell lines (SKOV-3 and IGROV-1), endometrial cancer cell line (Ishikawa) and hMSCs (bone marrow MSC, amniotic membrane MSC and decidua MSC). The expressions of EMT markers (E-cadherin, Snail, Twist and N-cadherin) were analyzed using quantitative RT-PCR, immunofluorescence and western blot analysis. Matrix metalloproteinases (MMP-2 and MMP-9), Matrigel invasion assay, and wound healing assay were used to analyze cell migration and invasion. Gynecologic cancer cells directly co-cultured with hMSCs had contact-dependent altered morphology and growth patterns. IL-6 was elevated in all co-cultures using a human cytokine array. After IL-6 treatment of cancer cell lines, RT-PCR and western blot analysis indicated a decrease in an epithelial marker and an increase in mesenchymal markers. Also, cancer cells with IL-6 significantly increase in MMP-2 and MMP-9 and significantly enhance the migration ability compared to untreated cells (P<0.05), as shown by wound healing assay. On Matrigel invasion assay, treated cells displayed significantly increased invasiveness compared to untreated cancer cells. Gyneocologic cancer cells exposed to IL-6 acquired mesenchymal properties that facilitated metastasis and invasion by promoting EMT. The present study suggests that IL-6 of the tumor microenvironment has a critical role in oncogenic EMT.


[Semiologic considerations and clinical significance of magnetic resonance in 11 intracranial aneurysms].
The author's experience with high-field Magnetic Resonance (Signa, 1.5 T, G.E.) in 11 cases of intracranial aneurysms (6 presenting as space lesion and 5 with symptoms of rupture) is reported. Spin-echo, gradient-echo and GRASS (fast-scan or flip-angle) sequences have been used and results compared with those of CT-scan and angiography. Magnetic Resonance findings, relating to blood flow and oxidation of haemoglobin (within the lumen, in the wall and at the periphery of the aneurysm) were interpreted from the point of diagnosis and surgical planning. The authors concluded that Magnetic Resonance should be considered as a routine investigation for intracranial aneurysms particularly when it is suspected that they might be voluminous and/or thrombosed.


Effect of inulin and glycerol supplementation on physicochemical properties of probiotic frozen yogurt.
The present study was designed to investigate the effects of inulin and glycerol supplementation on physicochemical properties of probiotic frozen yogurt. Frozen yogurt was prepared with different types of probiotic (Lactobacillus acidophilus and Bifidobacterium lactis) along with yogurt starter culture (Streptococcus thermophilus and Lactobacillus bulgaricus). The frozen yogurt mixture was supplemented with inulin (2%, 4%, and 6%) and glycerol (1%, 2%, 3%, and 4%). The results showed that inulin 4% and 6% supplementation increased the overrun by 3% and 5% and the glass transition temperature by 3.3% and 2.8%, and decreased the hardness by 7% and 11%, respectively. Inulin supplementation did not have a significant effect on ice crystal size (p > 0.05). Glycerol supplementation increased the stickiness from 2.4% to 18.7%, and decreased the hardness from 8.0% to 14.5% and the glass transition temperature from 2.4% to 34.5%, respectively. Glycerol supplementation did not have a significant effect on overrun or melting rate (p > 0.05).


Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships.
The glycolytic enzyme glucokinase plays an important role in the regulation of insulin secretion and recent studies have shown that mutations in the human glucokinase gene are a common cause of an autosomal dominant form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM) that has an onset often during childhood. The majority of the mutations that have been identified are missense mutations that result in the synthesis of a glucokinase molecule with an altered amino acid sequence. To characterize the effect of these mutations on the catalytic properties of human beta-cell glucokinase, we have expressed native and mutant forms of this protein in Escherichia coli. All of the missense mutations show changes in enzyme activity including a decrease in Vmax and/or increase in Km for glucose. Using a model for the three-dimensional structure of human glucokinase based on the crystal structure of the related enzyme yeast hexokinase B, the mutations map primarily to two regions of the protein. One group of mutations is located in the active site cleft separating the two domains of the enzyme as well as in surface loops leading into this cleft. These mutations usually result in large reductions in enzyme activity. The second group of mutations is located far from the active site in a region that is predicted to undergo a substrate-induced conformational change that results in closure of the active site cleft. These mutations show a small approximately 2-fold reduction in Vmax and a 5- to 10-fold increase in Km for glucose. The characterization of mutations in glucokinase that are associated with a distinct and readily recognizable form of NIDDM has led to the identification of key amino acids involved in glucokinase catalysis and localized functionally important regions of the glucokinase molecule.


Aspergillus flavus Promoted the Growth of Soybean and Sunflower Seedlings at Elevated Temperature.
The current climate changes in the form of global warming are one of the leading threats to agricultural crops (including soybean and sunflower). To enable the crops to cope with the heat stress, innovative steps are needed to be taken as soon as possible. Fungal endophytes are known to secrete secondary metabolites that promote the growth of host plants under stress conditions. Therefore, we have isolated endophytic fungus from Euphorbia indica (a wild desert plant) and tested it for plant growth promoting activities. The culture filtrate of the fungal strains exhibited the presence of secondary metabolites. Higher amounts of indole acetic acid (IAA), salicylic acid (SA), flavonoids, and phenolics have been found in the culture filtrate. The 18S rDNA sequence homology and phylogenetic analysis revealed that the isolate is Aspergillus flavus. Soybean and sunflower seedlings were inoculated with the identified A. flavus. The A. flavus-associated seedlings along with the control (without A. flavus) were monitored for thermal stress resistance in a growth chamber, operated at 25°C and 40°C. Control seedlings exposed to high temperature stress had higher levels of abscisic acid (ABA), proline, and lower levels of phenols, flavonoids, catalase, and ascorbic acid oxidase. Similarly, a higher reduction in chlorophyll, root-shoot length, and dry weight has been noticed in the control seedlings. The results suggested the usefulness of A. flavus in host plant growth promotion under heat stress conditions.


Risk of stroke after chiropractic spinal manipulation in medicare B beneficiaries aged 66 to 99 years with neck pain.
The purpose of this study was to quantify risk of stroke after chiropractic spinal manipulation, as compared to evaluation by a primary care physician, for Medicare beneficiaries aged 66 to 99 years with neck pain. This is a retrospective cohort analysis of a 100% sample of annualized Medicare claims data on 1 157 475 beneficiaries aged 66 to 99 years with an office visit to either a chiropractor or primary care physician for neck pain. We compared hazard of vertebrobasilar stroke and any stroke at 7 and 30 days after office visit using a Cox proportional hazards model. We used direct adjusted survival curves to estimate cumulative probability of stroke up to 30 days for the 2 cohorts. The proportion of subjects with stroke of any type in the chiropractic cohort was 1.2 per 1000 at 7 days and 5.1 per 1000 at 30 days. In the primary care cohort, the proportion of subjects with stroke of any type was 1.4 per 1000 at 7 days and 2.8 per 1000 at 30 days. In the chiropractic cohort, the adjusted risk of stroke was significantly lower at 7 days as compared to the primary care cohort (hazard ratio, 0.39; 95% confidence interval, 0.33-0.45), but at 30 days, a slight elevation in risk was observed for the chiropractic cohort (hazard ratio, 1.10; 95% confidence interval, 1.01-1.19). Among Medicare B beneficiaries aged 66 to 99 years with neck pain, incidence of vertebrobasilar stroke was extremely low. Small differences in risk between patients who saw a chiropractor and those who saw a primary care physician are probably not clinically significant.


Routinization, within-occupation task changes and long-run employment dynamics.
The present study adds to the literature on routinization and employment by capturing within-occupation task changes over the period 1980-2010. The main contributions are the measurement of such changes and the combination of two data sources on occupational task content for the United States: the Dictionary of Occupational Titles (DOT) and the Occupational Information Network (O*NET). We show that within-occupation reorientation away from routine tasks: i) accounts for 1/3 of the decline in routine-task use; ii) accelerated in the 1990s, decelerated in the 2000s but with significant convergence across occupations; and iii) allowed workers to escape the employment and wage decline, conditional on the initial level of routine-task intensity. The latter finding suggests that task reorientation is a key channel through which labour markets adapt to various forms of labour-saving technological change.


Cardiovascular and renal action of platelet-activating factor in anesthetized dogs.
Platelet-activating factor (PAF) has hypotensive effects similar to those of antihypertensive polar renomedullary lipid (APRL), a potent endogenous hypotensive lipid. In this study the cardiovascular and renal effects of PAF were characterized in anesthetized dogs. Intravenous infusion of PAF at 0.1 micrograms/kg/min for 1 hour caused marked reduction in arterial blood pressure and cardiac output and was accompanied by minimal changes in heart rate. Concomitantly, renal blood flow, glomerular filtration rate, urine flow, and fractional excretion of Na+ and K+ fell significantly. Plasma renin activity was greatly stimulated (11.9 +/- 1.66 vs 3.26 +/- 0.45 ng/angiotensin I/ml/hr for the placebo group). There were no significant alterations in any of these parameters following PAF at a lower dose (0.03 micrograms/kg/min for 1 hour). In a separate study, PAF at 0.1 micrograms/kg/min for 20 minutes produced a decrease in left ventricular myocardial contractile force, concomitant with bradycardia and hypotension, which indicated the presence of a negative inotropic activity. It is concluded that systemic administration of PAF has a deleterious effect on kidney function due to arterial hypotension and diminished cardiac output.


Beta-arrestin-2 regulates the development of allergic asthma.
Asthma is a chronic inflammatory disorder of the airways that is coordinated by Th2 cells in both human asthmatics and animal models of allergic asthma. Migration of Th2 cells to the lung is key to their inflammatory function and is regulated in large part by chemokine receptors, members of the seven-membrane-spanning receptor family. It has been reported recently that T cells lacking beta-arrestin-2, a G protein-coupled receptor regulatory protein, demonstrate impaired migration in vitro. Here we show that allergen-sensitized mice having a targeted deletion of the beta-arrestin-2 gene do not accumulate T lymphocytes in their airways, nor do they demonstrate other physiological and inflammatory features characteristic of asthma. In contrast, the airway inflammatory response to LPS, an event not coordinated by Th2 cells, is fully functional in mice lacking beta-arrestin-2. beta-arrestin-2-deficient mice demonstrate OVA-specific IgE responses, but have defective macrophage-derived chemokine-mediated CD4+ T cell migration to the lung. This report provides the first evidence that beta-arrestin-2 is required for the manifestation of allergic asthma. Because beta-arrestin-2 regulates the development of allergic inflammation at a proximal step in the inflammatory cascade, novel therapies focused on this protein may prove useful in the treatment of asthma.


Effects of Individuals' Cultural Orientations and Trust in Government Health Communication Sources on Behavioral Intentions During a Pandemic: A Cross-Country Study.
Public health messages disseminated by trusted government authorities are likely to have more influence over individuals' intentions and behaviors. However, individuals worldwide have different levels of trust in government authorities, which leads to varying levels of compliance intentions. Additionally, these trust levels may vary during major public crises, such as pandemics. Based on a COVID-19 pandemic communication survey (N = 3,065) disseminated throughout six countries (Australia, Finland, Italy, South Korea, Sweden, and the United States), this study examined the association among trust in distinct government sources, cultural orientations, and health behavioral intentions. Findings indicated that trust in official health communication sources at four governmental levels (i.e. national government, the head of the national government, the national health authority, and the chief representative of the national health authority) was related to vaccination intentions and other behavioral compliance intentions (i.e. willingness to prevent COVID-19 infection in other ways). Meanwhile, these direct associations were mediated by the cultural orientations of power distance and uncertainty avoidance. Findings also revealed that the direct association of trust in government sources and the indirect relationship through the above cultural orientations varied by country. This study offers insight into the important role of credible sources and individuals' cultural orientations in the domain of health communication aimed at influencing behavioral intentions.


Distinct roles for the NF-kappaB1 and c-Rel transcription factors in the differentiation and survival of plasmacytoid and conventional dendritic cells activated by TLR-9 signals.
Reticuloendotheliosis viral oncogene homolog/nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (Rel/NF-kappaB) activation is a ubiquitous outcome of engaging Toll-like receptors (TLRs), yet the cell-type-specific functions of this pathway in response to particular microbial signals remain poorly defined. Here we show that NF-kappaB1 and C-Rel, Rel/NF-kappaB proteins induced in conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) by cytosine-phosphate-guanosine (CpG) DNA, a TLR-9 ligand, serve markedly different functions in these DC subsets. With the exception of impaired interleukin-12 (IL-12) production, cultured Nfkb1(-/-)C-Rel(-/-) cDCs responded relatively normally to CpG DNA. In contrast, CpG-treated Nfkb1(-/-)C-Rel(-/-) pDCs, which were still able to produce type I interferon and regulated on activation normal T-cell expressed and secreted (RANTES), but not IL-6 or IL-12, failed to acquire an activated dendritic phenotype and underwent apoptosis. Although the TLR-9-mediated death of Nfkb1(-/-)C-Rel(-/-) pDCs, which coincided with a failure to up-regulate the prosurvival proteins B-cell lymphoma apoptosis regulator xL (Bcl-x(L)) and A1, was blocked by Bcl-2 transgene expression, this inhibition of apoptosis still failed to rescue the differentiation defects. This indicated that these NF-kappaB transcription factors independently regulate TLR-9-mediated pDC morphogenesis and survival. Collectively, these findings establish that NF-kappaB1 and c-Rel, while largely dispensable for TLR-9-induced cDC activation, are critical for regulating differentiation and survival programs during pDC activation.


Safer tattooing interventions in prisons: a systematic review and call to action.
Worldwide more than ten million people are detained at any given time. Between 5 and 60% of people experiencing incarceration report receipt of a tattoo in prison - mostly clandestine, which is associated with risks of blood-borne infections (BBIs). Although safer tattooing techniques are effective in preventing BBI transmission and available to the general population, there is limited knowledge about the impact of safer tattooing strategies in prisons in terms of health outcomes, changes in knowledge and behaviors, and best practice models for implementation. The objective of this research was to identify and review safer tattooing interventions. We conducted a systematic review of the literature. Studies of all design types were included if they were published until 27 June 2018, the population was incarcerated adults, they reported quantitative outcomes, and were published in English, French, or Spanish. Of 55 papers retrieved from the initial search, no peer-reviewed article was identified. One paper from the grey literature described a multi-site pilot project in Canada. Its evaluation suggested that the project was effective in enhancing knowledge of incarcerated people and prison staff on standard precautions, had the potential to reduce harm, provided vocational opportunities, and was feasible although enhancements were needed to improve implementation issues and efficiency. Although access to preventive services, including to safer tattooing interventions, is a human right and recommended by United Nations agencies as part of a comprehensive package of harm reduction interventions in prisons, this review identified only a few promising strategies for safer tattooing interventions in carceral settings. We call upon governments, criminal justice authorities, non-governmental organizations, and academic institutions to implement safer tattooing projects that adhere to the following guiding principles: i) integration of methodologically-rigorous implementation research; ii) involvement of key stakeholders (incarcerated people, prison authorities, research partners) in the project design, implementation, and research; iii) integration into a comprehensive package of BBI prevention, treatment, and care, using a stepwise approach that considers local resources and acceptability; and iv) publication and dissemination of findings, and scaling up efforts. CRD42017072502 .


Neural effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253.
The single nucleotide polymorphism rs10503253 within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2 has been identified as genome-wide significant for schizophrenia (SZ). This gene is of unknown function but has been implicated in multiple neurodevelopmental disorders that impact upon cognition, leading us to hypothesize that an effect on brain structure and function underlying cognitive processes may be part of the mechanism by which CMSD1 increases illness risk. To test this hypothesis, we investigated this CSMD1 variant in vivo in healthy participants in a magnetic resonance imaging (MRI) study comprised of both fMRI of spatial working memory (N = 50) and a voxel-based morphometry investigation of grey and white matter (WM) volume (N = 150). Analyses of these data indicated that the risk "A" allele was associated with comparatively reduced cortical activations in BA18, that is, middle occipital gyrus and cuneus; posterior brain regions that support maintenance processes during performance of a spatial working memory task. Conversely, there was an absence of significant structural differences in brain volume (i.e., grey or WM). In accordance with previous evidence, these data suggest that CSMD1 may mediate brain function related to cognitive processes (i.e., executive function); with the relatively deleterious effects of the identified "A" risk allele on brain activity possibly constituting part of the mechanism by which CSMD1 increases schizophrenia risk.


Redox-mediated activation of ATG3 promotes ATG8 lipidation and autophagy progression in Chlamydomonas reinhardtii.
Autophagy is one of the main degradative pathways used by eukaryotic organisms to eliminate useless or damaged intracellular material to maintain cellular homeostasis under stress conditions. Mounting evidence indicates a strong interplay between the generation of ROS and the activation of autophagy. Although a tight redox regulation of autophagy has been shown in several organisms, including microalgae, the molecular mechanisms underlying this control remain poorly understood. In this study, we have performed an in-depth in vitro and in vivo redox characterization of ATG3, an E2-activating enzyme involved in ATG8 lipidation and autophagosome formation, from two evolutionary distant unicellular model organisms: the green microalga Chlamydomonas (Chlamydomonas reinhardtii) and the budding yeast Saccharomyces cerevisiae. Our results indicated that ATG3 activity from both organisms is subjected to redox regulation since these proteins require reducing equivalents to transfer ATG8 to the phospholipid phosphatidylethanolamine. We established the catalytic Cys of ATG3 as a redox target in algal and yeast proteins and showed that the oxidoreductase thioredoxin efficiently reduces ATG3. Moreover, in vivo studies revealed that the redox state of ATG3 from Chlamydomonas undergoes profound changes under autophagy-activating stress conditions, such as the absence of photoprotective carotenoids, the inhibition of fatty acid synthesis, or high light irradiance. Thus, our results indicate that the redox-mediated activation of ATG3 regulates ATG8 lipidation under oxidative stress conditions in this model microalga.


Efficacy of Bioindexing for Graft-Transmissible Citrus Pathogens in Mixed Infections.
Biological indexing for graft-transmissible pathogens of citrus in the presence of additional pathogens was investigated. The probability for symptom expression, the efficacy of the bio-indexing tests, and the number of citrus indicators required for pathogen detection were statistically evaluated. Multiple infections did not preclude symptom expression or reduce the diagnostic efficacy of the primary indexing hosts for Citrus tristeza virus (CTV), Citrus psorosis virus (CPsV), and Citrus tatter leaf virus (Apple stem grooving virus). Symptoms of Citrus vein enation virus (CVEV) and the diagnostic efficacy of Mexican lime were suppressed by the T30 group CTV isolates, but not by other CTV isolates tested. CPsV suppressed symptom expression and diagnostic efficiency of Dweet tangor and sweet orange for concave gum. The application of alternate bioassay hosts for indexing was also investigated. Dweet tangor, sweet orange, and Citrus excelsa are not typically used for bioindexing of CVEV, however, Dweet tangor and C. excelsa detected CVEV in single infections, whereas in sweet orange, CVEV was detected only when CPsV, concave gum, or citrus viroids were present. CTV was readily detected using the alternative indicator C. excelsa, whereas only shock reacting CPsV isolates were effectively indexed by Mexican lime.


Dielectrophoresis of lambda-DNA using 3D carbon electrodes.
Carbon electrodes have recently been introduced as an alternative to metal electrodes and insulator structures for dielectrophoretic applications. Here, an experimental and theoretical study employing an array of 3D carbon electrodes contained in a microfluidic channel for the dielectrophoretic manipulation of DNA is presented. First evidence that carbon-electrode DEP can be used for the manipulation and trapping of biomolecules such as DNA is reported. In particular, the dielectrophoretic response of λ-DNA (48.5 kbp) under various frequencies and flow conditions necessary for retention of λ-DNA are studied. Negative DEP is observed at frequencies above 75 kHz and positive DEP is present in the range below 75 kHz and down to 5 kHz. We further implement a theoretical model to capture the experimental findings in sufficient detail. Our theoretical considerations based on reported scaling laws for linear and supercoiled DNA further suggest that carbon-electrode DEP devices could be employed in future analytical applications such as DNA preconcentration and fractionation.


The new cardiac surgery patient: defying previous expectations.
Studies conducted before 1999 of patients who had coronary artery bypass graft surgery (CABG) have shown a tendency toward increasing preoperative risk factors. This study examines whether this trend of increasing risk in patients who have cardiac surgery has continued since 1999 and whether its effect on mortality and morbidity has changed. We prospectively collected data for 2754 patients who had cardiac surgery, divided them into 4 cohorts based on the year of operation (2000-2003) and analyzed the data according to 56 predefined preoperative, operative and postoperative variables. There were no significant changes in most preoperative risk factors over time, except for significant decreases in the proportion of elective (p = 0.016) and emergency/salvage operations (p < 0.001) and increases in urgent procedures and in the number of patients with congestive heart failure (CHF) (p < 0.001). The proportion of CABG procedures decreased significantly, whereas the proportion of valve, CABG plus valve, and non-CABG surgeries increased. A significant increase in multiarterial graft use and a decrease in off-pump coronary artery bypass procedures were observed. Postoperative complication rates did not change during the 4 years except for a significant decrease in wound infections. No significant changes in overall mortality and mortality across types of procedure were observed. Median observed/expected ratios for expected length of stay in hospital and risk of mortality did not change significantly over time. Patients' risk factors, except for CHF, did not change from 2000 to 2003. Despite more complicated procedures, the postoperative complication rates did not change except for a decrease in wound infections. These results suggest that the assumption of an inexorably increasing patient risk profile should be re-evaluated.


Cellular mechanisms of endotoxin-induced myocardial depression in rabbits.
We investigated the mechanisms by which endotoxic shock induces intrinsic myocardial depression by studying cardiac myocytes isolated from 10 anesthetized instrumented rabbits given 172 +/- 42 (mean +/- SD) micrograms/kg IV endotoxin. Left ventricular (LV) depression developed 4 +/- 1 hours after endotoxin administration, with a 15 +/- 4% increase in LV internal end-systolic diameter, measured with sonomicrometers at a matched LV end-systolic pressure of 65 +/- 10 mm Hg. Normal LV pressure, arterial PO2, and pH were maintained to minimize confounding effects of ischemia, hypoxia, and acidosis. Cardiac myocytes from endotoxin-exposed rabbits had less unloaded cell shortening and lower peak rates of cell shortening (-dL/dt) and lengthening (+dL/dt) at [Ca2+] levels ranging from 0.5 to 16 mM when compared with myocytes isolated from normal rabbits or rabbits undergoing an identical protocol but without exposure to endotoxin. At 2 mM [Ca2+], cell shortening was depressed by approximately 25% because of a decrease in action potential duration (207 +/- 70 versus 375 +/- 64 milliseconds). In contrast, there was only mild impairment of sarcoplasmic reticulum (SR) function. When myocytes were restimulated after rest periods of 4 to 480 seconds, the decrement in cell shortening (rest decay), peak -dL/dt and peak +dL/dt, and the recovery from rest decay were similar in myocytes from endotoxin-treated and normal rabbits. There was a greater decrement in cell shortening in the second beat of postrest recovery in myocytes from endotoxin-treated rabbits than in normal myocytes. This was partly due to a 12% decrement in action potential duration with rest decay, which did not occur in normal myocytes. The SR Ca2+ content assessed by contractures in 10 mM caffeine was similar in the two groups. We conclude that endotoxic shock produces a LV depression in vivo that persists in isolated myocytes studied in vitro. This intrinsic myocardial depression is largely related to endotoxin-mediated sarcolemmal alterations, which shorten action potential duration, and is not due to alterations in SR function.


Sexual risk reduction interventions for patients attending sexual health clinics: a mixed-methods feasibility study.
Sexually transmitted infections (STIs) continue to represent a major public health challenge. There is evidence that behavioural interventions to reduce risky sexual behaviours can reduce STI rates in patients attending sexual health (SH) services. However, it is not known if these interventions are effective when implemented at scale in SH settings in England. The study (Santé) had two main objectives - (1) to develop and pilot a package of evidence-based sexual risk reduction interventions that can be delivered through SH services and (2) to assess the feasibility of conducting a randomised controlled trial (RCT) to determine effectiveness against usual care. The project was a multistage, mixed-methods study, with developmental and pilot RCT phases. Preparatory work included a systematic review, an analysis of national surveillance data, the development of a triage algorithm, and interviews and surveys with SH staff and patients to identify, select and adapt interventions. A pilot cluster RCT was planned for eight SH clinics; the intervention would be offered in four clinics, with qualitative and process evaluation to assess feasibility and acceptability. Four clinics acted as controls; in all clinics, participants would be consented to a 6-week follow-up STI screen. SH clinics in England. Young people (aged 16-25 years), and men who have sex with men. A three-part intervention package - (1) a triage tool to score patients as being at high or low risk of STI using routine data, (2) a study-designed web page with tailored SH information for all patients, regardless of risk and (3) a brief one-to-one session based on motivational interviewing for high-risk patients. The three outcomes were (1) the acceptability of the intervention to patients and SH providers, (2) the feasibility of delivering the interventions within existing resources and (3) the feasibility of obtaining follow-up data on STI diagnoses (primary outcome in a full trial). We identified 33 relevant trials from the systematic review, including videos, peer support, digital and brief one-to-one sessions. Patients and SH providers showed preferences for one-to-one and digital interventions, and providers indicated that these intervention types could feasibly be implemented in their settings. There were no appropriate digital interventions that could be adapted in time for the pilot; therefore, we created a placeholder for the purposes of the pilot. The intervention package was piloted in two SH settings, rather than the planned four. Several barriers were found to intervention implementation, including a lack of trained staff time and clinic space. The intervention package was theoretically acceptable, but we observed poor engagement. We recruited patients from six clinics for the follow-up, rather than eight. The completion rate for follow-up was lower than anticipated (16% vs. 46%). Fewer clinics were included in the pilot than planned, limiting the ability to make strong conclusions on the feasibility of the RCT. We were unable to conclude whether or not a definitive RCT would be feasible because of challenges in implementation of a pilot, but have laid the groundwork for future research in the area. Current Controlled Trials ISRCTN16738765. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 12. See the NIHR Journals Library website for further project information.


Tensional stress generation in gelatinous fibres: a review and possible mechanism based on cell-wall structure and composition.
Gelatinous fibres are specialized fibres, distinguished by the presence of an inner, gelatinous cell-wall layer. In recent years, they have attracted increasing interest since their walls have a desirable chemical composition (low lignin, low pentosan, and high cellulose contents) for applications such as saccharification and biofuel production, and they have interesting mechanical properties, being capable of generating high tensional stress. However, the unique character of gelatinous layer has not yet been widely recognized. The first part of this review presents a model of gelatinous-fibre organization and stresses the unique character of the gelatinous layer as a separate type of cell-wall layer, different from either primary or secondary wall layers. The second part discusses major current models of tensional stress generation by these fibres and presents a novel unifying model based on recent advances in knowledge of gelatinous wall structure. Understanding this mechanism could potentially lead to novel biomimetic developments in material sciences.


The History of Mental Health Services in Modern England: Practitioner Memories and the Direction of Future Research.
Writing the recent history of mental health services requires a conscious departure from the historiographical tropes of the nineteenth and twentieth centuries which have emphasised the experience of those identified (and legally defined) as lunatics and the social, cultural, political, medical and institutional context of their treatment. A historical narrative structured around rights (to health and liberty) is now complicated by the rise of new organising categories such as 'costs', 'risks', 'needs' and 'values'. This paper, drawing on insights from a series of witness seminars attended by historians, clinicians and policymakers, proposes a programme of research to place modern mental health services in England and Wales in a richer historical context. Historians should recognise the fragmentation of the concepts of mental illness and mental health need, acknowledge the relationship between critiques of psychiatry and developments in other intellectual spheres, place the experience of the service user in the context of wider socio-economic and political change, understand the impacts of the social perception of 'risk' and of moral panic on mental health policy, relate the politics of mental health policy and resources to the general determinants of institutional change in British central and local government, and explore the sociological and institutional complexity of the evolving mental health professions and their relationships with each other and with their clients. While this is no small challenge, it is perhaps the only way to avoid the perpetuation of 'single-issue mythologies' in describing and accounting for change.


Two subclasses of odorant-binding proteins in Spodoptera exigua display structural conservation and functional divergence.
Although many studies on lepidopteran pheromone-binding proteins (PBPs)/ general odorant-binding proteins (GOBPs) have been reported, the functional differentiation within and between the two odorant-binding protein (OBP) subclasses is still elusive. Here we conducted a comparative study on three SexiPBPs and two SexiGOBPs in Spodoptera exigua. Results showed that all five SexiPBP/GOBP genes have the same intron numbers and conserved exon/intron splice sites. Reverse transcription PCR results showed that these five SexiPBP/GOBPs were primarily expressed in antennae of both sexes and some were also detected in other tissues. Further, quantitative real-time PCR showed that five SexiPBP/GOBPs had different sex-biased expression patterns, with PBP1 being highly male-biased (5.96-fold difference) and PBP3 slightly female-biased (2.43-fold difference), while PBP2 and two GOBPs were approximately sex-equivalent (the absolute value<1.90-fold difference). Binding assays showed that all three SexiPBPs could bind all six sex pheromone components, but SexiPBP1 had much higher affinities [dissociation constant (Ki ) <1.10 μM] than did the other two SexiPBPs (Ki >1.20 μM). Very intriguingly, SexiGOBP2 displayed even stronger binding to five sex pheromone components (Ki <0.40 μM) than SexiPBP1. In contrast, SexiGOBP1 only exhibited weak binding to three alcohol-pheromone components. Similar results were obtained for tested pheromone analogues. In addition, each of SexiPBP/GOBPs selectively bound some plant odorants with considerable affinities (Ki <10.0 μM). Taken together, of the three SexiPBPs, SexiPBP1 may play the most important role in female sex pheromone reception, and additionally all three SexiPBPs can detect some plant odorants, while SexiGOBP2 may be involved in the detection of female sex pheromones in addition to plant odorants. The results strongly suggest functional differentiation within and between the two OBP sub-classes.


Zinc deficiency in anorexia nervosa.
Adolescents with anorexia nervosa were evaluated for clinical and biochemical evidence of zinc deficiency. To assess whether these patients would benefit from zinc supplementation, a double-blind, randomized, controlled trial was conducted. The mean zinc intake of the anorexic group calculated on the basis of three-day dietary records was 7.7 +/- 5.2 mg/day, which is significantly below the recommended daily allowance of 15 mg for adolescents (p less than 0.001). The mean urinary zinc excretion in the anorexic group was 257.1 +/- 212.7 micrograms/24 hours compared to 749.9 +/- 897.8 micrograms/24 hours in the control group (p less than 0.005). This result suggests that the zinc status of anorexia nervosa patients may be compromised due to an inadequate zinc intake. Zinc supplementation (50 mg elemental zinc/day) was followed by a decrease in the level of depression and anxiety as assessed by the Zung Depression Scale (p less than 0.05) and the State-Trait Anxiety Inventory (p less than 0.05), respectively. Our data suggest that individuals with anorexia nervosa may be at risk for zinc deficiency and may respond favorably after zinc supplementation.


Manumycin A induces apoptosis in malignant pleural mesothelioma through regulation of Sp1 and activation of the mitochondria-related apoptotic pathway.
Manumycin A (Manu A) is a natural product isolated from Streptomyces parvulus and has been reported to have anti-carcinogenic and anti-biotic properties. However, neither its molecular mechanism nor its molecular targets are well understood. Thus, the aim of the present study was to explore the possibility that Manu A has cancer preventive and chemotherapeutic effects on malignant pleural mesothelioma (MPM) through regulation of Sp1 and induction of mitochondrial cell death pathway. Manu A inhibited the cell viability of MSTO-211H and H28 cells in a concentration‑dependent manner as determined by MTS assay. IC50 values were calculated as 8.3 and 4.3 µM in the MSTO-311H and H28 cells following 48 h incubation, respectively. Manu A induced a significant increase in apoptotic indices as shown by DAPI staining, Annexin V assay, multi-caspase activity and mitochondrial membrane potential assay. The downregulation of Sp1 mRNA and protein expression by Manu A led to apoptosis by suppressing Sp1-regulated proteins (cyclin D1, Mcl-1 and survivin). Manu A decreased the protein levels of BID, Bcl-xL and PARP while it increased Bax levels. Manu A caused depolarization of the mitochondrial membrane with induction of CHOP, DR4 and DR5. Our results demonstrated that Manu A exerted anticancer effects by inducing apoptosis via inhibition of the Sp1-related signaling pathway in human MPM.


Dynamic expression of Lgr5, a Wnt target gene, in the developing and mature mouse cochlea.
The Wnt signaling pathway is a recurring theme in tissue development and homeostasis. Its specific roles during inner ear development are just emerging, but few studies have characterized Wnt target genes. Lgr5, a member of the G protein-coupled receptor family, is a Wnt target in the gastrointestinal and integumentary systems. Although its function is unknown, its deficiency leads to perinatal lethality due to gastrointestinal distension. In this study, we used a knock-in reporter mouse to examine the spatiotemporal expression of Lgr5 in the cochlear duct during embryonic and postnatal periods. In the embryonic day 15.5 (E15.5) cochlear duct, Lgr5-EGFP is expressed in the floor epithelium and overlapped with the prosensory markers Sox2, Jagged1, and p27(Kip1). Nascent hair cells and supporting cells in the apical turn of the E18.5 cochlear duct express Lgr5-EGFP, which becomes downregulated in hair cells and subsets of supporting cells in more mature stages. In situ hybridization experiments validated the reporter expression, which gradually decreases until the second postnatal week. Only the third row of Deiters' cells expresses Lgr5-EGFP in the mature organ of Corti. Normal cochlear development was observed in Lgr5(EGFP/EGFP) and Lgr5(EGFP/+) mice, which exhibited normal auditory thresholds. The expression pattern of Lgr5 contrasts with another Wnt target gene, Axin2, a feedback inhibitor of the Wnt pathway. Robust Axin2 expression was found in cells surrounding the embryonic cochlear duct and becomes restricted to tympanic border cells below the basilar membrane in the postnatal cochlea. Both Lgr5 and Axin2 act as Wnt targets in the cochlea because purified Wnt3a promoted and Wnt antagonist suppressed their expression. Their differential expression among cell populations highlights the dynamic but complex distribution of Wnt-activated cells in and around the embryonic and postnatal cochlea.


Optical structure factor measurements of soot particles in a prmixed flame.
We have measured the scattered-light intensity as a function of the scattering angle for light scattered from soot particles in a premixed methane/oxygen flame. This yields the optical structure factor for the soot particles. We find that the structure factor shows the soot particles to have a morphology consistent with a fractal interpretation with a fractal dimension in the 1.6 </= D </= 1.8 range and a radius of gyration that increases with the height above the burner. The structure factor may also show the effect of the finite monomer size of the soot clusters.


The Application of Pureed Butter Beans and a Combination of Inulin and Rebaudioside A for the Replacement of Fat and Sucrose in Sponge Cake: Sensory and Physicochemical Analysis.
Determining minimum levels of fat and sucrose needed for the sensory acceptance of sponge cake while increasing the nutritional quality was the main objective of this study. Sponge cakes with 0, 25, 50 and 75% sucrose replacement (SR) using a combination of inulin and Rebaudioside A (Reb A) were prepared. Sensory acceptance testing (SAT) was carried out on samples. Following experimental results, four more samples were prepared where fat was replaced sequentially (0, 25, 50 and 75%) in sucrose-replaced sponge cakes using pureed butter beans (Pbb) as a replacer. Fat-replaced samples were investigated using sensory (hedonic and intensity) and physicochemical analysis. Texture liking and overall acceptability (OA) were the only hedonic sensory parameters significantly affected after a 50% SR in sponge cake (p < 0.05). A 25% SR had no significant impact on any hedonic sensory properties and samples were just as accepted as the control sucrose sample. A 30% SR was chosen for further experiments. After a 50% fat replacement (FR), no significant differences were found between 30% sucrose-replaced sponge cake samples in relation to all sensory (hedonic and intensity) parameters investigated. Flavour and aroma intensity attributes such as buttery and sweet and, subsequently, liking and OA of samples were negatively affected after a 75% FR (p < 0.05). Instrumental texture properties (hardness and chewiness (N)) did not discriminate between samples with increasing levels of FR using Pbb. Moisture content increased significantly with FR (p < 0.05). A simultaneous reduction in fat (42%) and sucrose was achieved (28%) in sponge cake samples without negatively affecting OA. Optimised samples contained significantly more dietary fibre (p < 0.05).


A systematic review on robotic coronary artery bypass graft surgery.
Robotic-assisted coronary artery bypass graft surgery (CABG) has been performed over the past decade. Despite encouraging results from selected centres, there is a paucity of robust clinical data to establish its clinical safety and efficacy. The present systematic review aimed to identify all relevant clinical data on robotic CABG. The primary endpoint was perioperative mortality, and secondary endpoints included perioperative morbidities, anastomotic complications, and long-term survival. Electronic searches were performed using three online databases from their dates of inception to 2016. Relevant studies fulfilling the predefined search criteria were categorized according to surgical techniques as (I) totally endoscopic coronary artery bypass without cardiopulmonary bypass (TECAB off-pump); (II) TECAB on-pump; and robotic-assisted mammary artery harvesting followed by minimally invasive direct coronary artery bypass (robotic MIDCAB). The present systematic review identified 44 studies that fulfilled the study selection criteria, including nine studies in the TECAB off-pump group and 16 studies in the robotic MIDCAB group. Statistical analysis reported a pooled mortality of 1.7% for the TECAB off-pump group and 1.0% for the robotic MIDCAB group. Intraoperative details such as the number and location of grafts performed, operative times and conversion rates, as well as postoperative secondary endpoints such as morbidities, anastomotic complications and long-term outcomes were also summarized for both techniques. A number of technical, logistic and cost-related issues continue to hinder the popularization of the robotic CABG procedure. Current clinical evidence is limited by a lack of randomized controlled trials, heterogeneous definition of techniques and complications, as well as a lack of robust clinical follow-up with routine angiography. Nonetheless, the present systematic review reported acceptable perioperative mortality rates for selected patients at specialized centres. These results should be considered as a useful benchmark for future studies, until further data is reported in the form of randomized trials.


Neighbourhoods matter too: the association between neighbourhood socioeconomic position, population density and breast, prostate and lung cancer incidence in Denmark between 2004 and 2008.
Previous studies have shown that cancer incidence is related to a number of individual factors, including socioeconomic status. The aim of this study was to refine the current knowledge about indicators associated with cancer incidence by evaluating the influence of neighbourhood characteristics on breast, prostate and lung cancer incidence in Denmark. All women aged 30-83 years were followed for breast cancer between 2004 and 2008, men between 50 and 83 years were followed for prostate cancer and both sexes between ages 50 and 83 were followed for lung cancer. Registry data obtained from Statistics Denmark included age, sex, availability of breast cancer screening, marital status, education, disposable income and occupational socioeconomic status on the individual level and population density and neighbourhood socioeconomic status (the proportion of unemployed) on the parish level. Frailty modelling with individuals on the first level and parishes on the second level was conducted. A significantly lower HR of breast cancer was found in areas with low population density (HR=0.93; CI 0.88 to 0.99), while neighbourhood unemployment had no effect. Inhabitants of lower unemployment areas had a higher risk of prostate cancer (HR=1.14; CI 1.08 to 1.21) compared with those in higher unemployment areas, whereas population density had no effect. Risk of lung cancer was lower in areas with lowest population density (HR=0.80; CI 0.74 to 0.85) and lowest in areas with lowest unemployment (HR=0.88; CI 0.84 to 0.92). In addition to individual-level factors, characteristics on the neighbourhood level also have an influence on breast, prostate and lung cancer incidence.


A hermetically sealed, fluid-filled surgical enclosure for microgravity.
Expeditionary spaceflight is fraught with significant risks to human health, including trauma and other emergency medical events. To address several of the basic challenges of surgical care in reduced gravity, we are developing the Aqueous Immersion Surgical System (AISS), an optically clear enclosure pressurized by a fluid medium. The AISS is designed to prevent contamination of the spacecraft with blood and tissue debris, reduce intraoperative blood loss, and maintain visualization of the operative field. An early prototype of the AISS was tested in reduced gravity during parabolic flight. A clear, aqueous field was created in a watertight chamber containing a mock vascular network. Hemorrhage was simulated by severing several of the analogue vessels. Experiments were performed to evaluate the benefits of surrounding a surgical cavity with fluid medium, as compared to an air environment, with respect to maintaining a clear view and achieving hemostasis. Qualitative evaluation of audio and video recorded during parabolic flight confirm AISS capacity to maintain visualization of the surgical field during a hemorrhage situation and staunch bleeding by raising interchamber pressure. Evaluation of the AISS in reduced gravity corroborates observations in the literature regarding the difficulty in maintaining visualization of the surgical field when performing procedures in an air environment. By immersing the surgical field in fluid we were able to apply suction directly to the hemorrhage and also achieve hemostasis.


The control of wing kinematics and flight forces in fruit flies (Drosophila spp.).
By simultaneously measuring flight forces and stroke kinematics in several species of fruit flies in the genus Drosophila, we have investigated the relationship between wing motion and aerodynamic force production. We induced tethered flies to vary their production of total flight force by presenting them with a vertically oscillating visual background within a closed-loop flight arena. In response to the visual motion, flies modulated their flight force by changing the translational velocity of their wings, which they accomplished via changes in both stroke amplitude and stroke frequency. Changes in wing velocity could not, however, account for all the modulation in flight force, indicating that the mean force coefficient of the wings also increases with increasing force production. The mean force coefficients were always greater than those expected under steady-state conditions under a variety of assumptions, verifying that force production in Drosophila spp. must involve non-steady-state mechanisms. The subtle changes in kinematics and force production within individual flight sequences demonstrate that flies possess a flexible control system for flight maneuvers in which they can independently control the stroke amplitude, stroke frequency and force coefficient of their wings. By studying four different-sized species, we examined the effects of absolute body size on the production and control of aerodynamic forces. With decreasing body size, the mean angular wing velocity that is required to support the body weight increases. This change is due almost entirely to an increase in stroke frequency, whereas mean stroke amplitude was similar in all four species. Despite the elevated stroke frequency and angular wing velocity, the translational velocity of the wings in small flies decreases with the reduction in absolute wing length. To compensate for their small size, D. nikananu must use higher mean force coefficients than their larger relatives.


Comparison of paclitaxel-, sirolimus-, and zotarolimus-eluting stents in patients with acute ST-segment elevation myocardial infarction and metabolic syndrome.
The purpose of the present study was to compare the efficacy and safety of paclitaxel-eluting stent (PES), sirolimus-eluting stent (SES), and zotarolimus-eluting stent (ZES) in primary percutaneous coronary intervention (PCI) for acute ST-segment elevation myocardial infarction (STEMI) with metabolic syndrome (MS). Using data from Korea Acute Myocardial Infarction Registry (KAMIR; November 2005-December 2007), a total of 1,768 MS patients with STEMI who underwent primary PCI were enrolled: The PES group was 634, SES group, 906, and ZES group, 228. The primary endpoint was major adverse cardiac event (all-cause death, re-myocardial infarction, target lesion revascularization) during 12 months follow-up. At 12 months, the cumulative incidence of primary endpoint in the PES, SES, and ZES groups was 10.9%, 9.1%, and 11.0%, respectively (P=0.086). Incidence of death, recurrent myocardial infarction, or target lesion revascularization did not differ among the 3 groups. There were 7 episodes of acute (0.3% in PES group, 0.4% in SES group, and 0.4% in ZES group, respectively, P=0.773) and 18 episodes of cumulative stent thrombosis including late stent thrombosis (0.9% in PES group, 1.0% in SES group, and 1.3% in ZES group, respectively, P=0.448). Implantation of SES, PES, and ZES in MS patients with STEMI undergoing primary PCI provided comparable clinical outcomes in patients enrolled in KAMIR.


Rapid synthesis of lipid nanoparticles containing hydrophobic inorganic nanoparticles.
A straightforward "bottom-up" synthesis is described for efficient entrapment of inorganic hydrophobic nanoparticles (HNPs) consisting of iron oxide, gold, or quantum dots within the hydrophobic core of lipid nanoparticles (LNPs). These LNPs consist of hydrophobic "core" lipids such as triolein surrounded by a monolayer of amphipathic "surface" lipids, such as phosphatidylcholine and polyethylene-glycol-lipid. It is shown that rapid, controlled mixing of HNPs, core lipids and surface lipids in an organic solvent with an aqueous phase resulted in stable, monodisperse LNPs containing HNPs (LNP-HNP). This method allows 40-fold more hydrophobic iron oxide nanoparticles (IONPs) to be entrapped within an LNP than previous methods and can be readily extended to encapsulate other HNPs. The LNP-HNP diameter can be modulated over the range of 35-150 nm by varying the flow rate during particle synthesis or by varying the core-to-surface lipid ratio. LNP-IONPs can be generated using a variety of "core" lipids, including other triglycerides as well as cholesteryl-palmitate and tocopherol. Finally, it is shown that LNP-IONPs are accumulated in the liver, resulting in enhanced contrast for in vivo MRI. It is concluded that the bottom-up approach for encapsulating HNPs within LNPs has advantages of homogeneity, reproducibility and stability required for biomedical applications.


Multiple-image encryption by wavelength multiplexing.
We introduce the technique of wavelength multiplexing into a double random-phase encoding system to achieve multiple-image encryption. Each primary image is first encrypted by the double phase encoding method and then superposed to yield the final enciphered image. We analyze the minimum separation between two adjacent multiplexing wavelengths through cross talk and the multiplexing capacity through the correlation coefficient. Computer simulations are performed to demonstrate the concept. This technique can be used for hiding multiple images as well.


Efficacy and response time to sertraline versus fluoxetine in the treatment of unipolar major depressive disorder.
Few studies have compared the treatment efficacy of the 2 selective serotonin reuptake inhibitors sertraline and fluoxetine. A randomized, single-blind, parallel-group study of 10 weeks' duration comparing the efficacy of sertraline, 50 mg/day; sertraline, 100 mg/day; and fluoxetine, 20 mg/day, was conducted in 44 psychiatric outpatients with DSM-IV unipolar major depressive disorder. Antidepressant dosages were doubled at 6 weeks for subjects who had not achieved remission. Primary outcome measurements included the 21-item Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impressions-Improvement scale (CGI-I), with scores of < or = 7 on the HAM-D and < or = 2 on the CGI-I representing a positive treatment response, i.e., remission. At 4 weeks, significant differences in rate of positive treatment response were noted, with 0% for sertraline, 50 mg; 46% for sertraline, 100 mg; and 31% for fluoxetine, 20 mg (p = .023). At 6 weeks, positive treatment response rates were 21%, 43%, and 31% for subjects taking 50 mg of sertraline, those taking 100 mg of sertraline, and those taking 20 mg of fluoxetine, respectively, with treatment groups no longer differing significantly from each other. In subjects for whom antidepressant dose was doubled at week 6, response rates at week 10 (4 weeks on increased dose) were 40% for sertraline, 100 mg; 43% for sertraline, 200 mg; and 55% for fluoxetine, 40 mg. Subjects taking sertraline, 100 mg, and fluoxetine, 20 mg, demonstrated an earlier treatment response compared with subjects taking sertraline, 50 mg. For patients without a positive response at 6 weeks, an increased antidepressant dose resulted in remission for a substantial proportion of patients when assessed 4 weeks later.


Characterisation of bovine leukocyte Ig-like receptors.
Leukocyte Immunoglobulin-like receptors (LILR) are innate immune receptors involved in regulating both innate and adaptive immune functions. LILR show more interspecies conservation than the closely related Killer Ig-like receptors, and homologues have been identified in rodents, primates, seals and chickens. The murine equivalents, paired Ig-like receptors (PIR), contain two additional immunoglobulin domains, but show strong sequence and functional similarities to human LILR. The bovine genome was recently sequenced, with preliminary annotations indicating that LILR were present in this species. We therefore sought to identify and characterize novel LILR within the Bos taurus genome, compare these phylogenetically with LILR from other species and determine whether they were expressed in vivo. Twenty six potential bovine LILR were initially identified using BLAST and BLAT software. Phylogenetic analysis constructed using the neighbour-joining method, incorporating pairwise deletion and confidence limits estimated from 1000 replicates using bootstrapping, indicated that 16 of these represent novel bovine LILR. Protein structures defined using protein BLAST predict that the bovine LILR family comprises seven putative inhibitory, four activating and five soluble receptors. Preliminary expression analysis was performed by mapping the predicted sequences with raw data from total transcript sequence generated using Genome Analyzer IIx (Illumina) to provide evidence that all 16 of these receptors are expressed in vivo. The bovine receptor family appears to contain receptors which resemble the six domain rodent PIR as well as the four domain LILR found in other species.


Lipoprotein (a) and coronary heart disease: a prospective case-control study in a general population sample of middle aged men.
To examine the association between the serum lipoprotein (a) concentration and subsequent coronary heart disease. Prospective case-control study based on a six year follow up of a general population sample of men aged 50 at baseline in 1983-4. Serum samples were frozen at the time of the baseline examination and kept at -70 degrees C for six years, after which the lipoprotein (a) concentrations in the samples were measured in cases and controls. City of Gothenburg, Sweden. 26 Men, from a general population sample of 776 men, who had sustained a myocardial infarction or died of coronary heart disease during the six years and 109 randomly selected controls from the same sample who had remained free of myocardial infarction. In neither cases nor controls was there a history of myocardial infarction at baseline. Proportion of myocardial infarction or deaths from coronary heart disease, or both, in relation to the serum lipoprotein (a) concentration. Men who suffered coronary heart disease had significantly higher serum lipoprotein (a) concentrations than controls (mean difference 105 mg/l; 95% confidence interval 18 to 192 mg/l). Men with the highest fifth of serum lipoprotein (a) concentrations (cut off point 365 mg/l) suffered a coronary heart disease rate which was more than twice that of men with the lowest four fifths of concentrations. Logistic regression analysis showed the serum lipoprotein (a) concentration to be significantly associated with coronary heart disease independently of other risk factors. The serum lipoprotein (a) concentration in middle aged men is an independent risk factor for subsequent myocardial infarction or death from coronary heart disease.


EEG theta and beta power spectra in adolescents with ADHD versus adolescents with ASD + ADHD.
Attention problems are common in youngsters with attention deficit hyperactivity disorder (ADHD) as well as in adolescents with combined autism spectrum disorder (ASD) and ADHD. However, it is unknown whether there is psychophysiological overlap and/or a difference in electroencephalogram (EEG) power spectra between ADHD and comorbid ASD and ADHD (ASD + ADHD), on and off stimulant medication. To explore potential differences and overlap, measures of theta and beta power in adolescents diagnosed with ADHD (n = 33) versus adolescents with combined ASD + ADHD (n = 20), categorized by stimulant medication use (57 % of the total sample), were compared. EEG measures were acquired in three conditions: (1) resting state, eyes closed (2) resting state, eyes open and (3) during an oddball task. In addition, performance on the d2 attention test was analyzed. Adolescents with ADHD displayed more absolute theta activity than adolescents with ASD + ADHD during the eyes open and task conditions, independent of stimulant medication use. In addition, only the adolescents with ADHD showed an association between diminished attention test performance and increased theta in the eyes open condition. Results of the current study suggest that although there is behavioral overlap between ADHD characteristics in adolescents with ADHD and adolescents with combined ASD + ADHD, the underlying psychophysiological mechanisms may be different. Adolescents with ASD + ADHD exhibited fewer of the EEG physiological signs usually associated with ADHD, although there was an overlap in attentional problems between the groups. This may indicate that treatments developed for ADHD work differently in some adolescents with ASD + ADHD and adolescents with ADHD only.


Infection of Manila clams Ruditapes philippinarum from Galicia (NW Spain) with a Mikrocytos-like parasite.
The name 'microcells' is frequently used to refer to small-sized unicellular stages of molluscan parasites of the genera Bonamia (Rhizaria, Haplosporidia) and Mikrocytos (Rhizaria). Histological examination of Manila clams Ruditapes philippinarum revealed microcells in the connective tissue of adductor muscle, foot, mantle, gills, siphon and visceral mass. The clams had been collected from 4 beds on the coast of Galicia, Spain. The prevalence of these microcells ranged from 73 to 93% in surface clams and from 3 to 33% in buried clams. However, the detection of brown ring disease signs in clams from every bed prevented us from making the assumption that the microcells alone were responsible for clam mortality. PCR assays using primer pairs designed to detect Bonamia spp. and haplosporidians gave negative results, whereas positive results were obtained with primers for the genus Mikrocytos. A consensus sequence of 1670 bp of the ribosomal gene complex of the microcells was obtained. It contained a section of the 18S region, the whole first internal transcribed spacer, the 5.8S region, the second internal transcribed spacer and a section of the 28S region. Comparison of this sequence with those of M. mackini infecting Crassostrea gigas and Mikrocytos sp. infecting Ostrea edulis showed that the microcells of Galician clams were the most divergent among the compared parasites. This is the first report of a Mikrocytos-like parasite infecting Manila clams. Care must be taken to avoid the spread of this parasite through Manila clam transfers.


Combining phylogeography with distribution modeling: multiple Pleistocene range expansions in a parthenogenetic gecko from the Australian arid zone.
Phylogenetic and geographic evidence suggest that many parthenogenetic organisms have evolved recently and have spread rapidly. These patterns play a critical role in our understanding of the relative merits of sexual versus asexual reproductive modes, yet their interpretation is often hampered by a lack of detail. Here we present a detailed phylogeographic study of a vertebrate parthenogen, the Australian gecko Heteronotia binoei, in combination with statistical and biophysical modeling of its distribution during the last glacial maximum. Parthenogenetic H. binoei occur in the Australian arid zone and have the widest range of any known vertebrate parthenogen. They are broadly sympatric with their sexual counterparts, from which they arose via hybridization. We have applied nested clade phylogeographic, effective migration, and mismatch distribution analyses to mitochondrial DNA (mtDNA) sequences obtained for 319 individuals sampled throughout the known geographic ranges of two parthenogenetic mitochondrial lineages. These analyses provide strong evidence for past range expansion events from west to east across the arid zone, and for continuing eastward range expansion. Parthenogen formation and range expansion events date to the late Pleistocene, with one lineage expanding from the northwest of its present range around 240,000 years ago and the second lineage expanding from the far west around 70,000 years ago. Statistical and biophysical distribution models support these inferences of recent range expansion, with suitable climatic conditions during the last glacial maximum most likely limited to parts of the arid zone north and west of much of the current ranges of these lineages. Combination of phylogeographic analyses and distribution modeling allowed considerably stronger inferences of the history of this complex than either would in isolation, illustrating the power of combining complementary analytical approaches.


Functional Analysis of a MATE Gene OsFRDL2 Revealed its Involvement in Al-Induced Secretion of Citrate, but a Lower Contribution to Al Tolerance in Rice.
The multidrug and toxic compound extrusion (MATE) transporters represent a large transporter family in plants, but the role of most genes in this family has not been examined. We functionally characterized a MATE family member, OsFRDL2, in rice (Oryza sativa). OsFRDL2 showed an efflux transport activity for citrate when it was expressed in both Xenopus oocytes and cultured tobacco cells. OsFRDL2 was mainly expressed in the roots and its expression was not induced by iron (Fe) deficiency, but it was rapidly up-regulated by aluminum (Al). Furthermore, the expression of OsFRDL2 was regulated by ART1, a C2H2-type zinc-finger transcription factor for Al tolerance. OsFRDL2 protein was localized at unidentified vesicles in the cytosol, but not co-localized with either mitochondria or peroxisomes when expressed in both onion epidermal cells and cultured tobacco cells. Knockout of OsFRDL2 decreased Al-induced secretion of citrate from the roots, but did not affect the internal citrate concentration. The Al-induced inhibition of root elongation was similar between the OsFRDL2 knockout line and its wild-type rice. Knockout of OsFRDL2 did not affect the translocation of Fe from the roots to the shoots. A double mutant between osfrdl2 and osfrdl4 or osfrdl1 did not further decrease the Al-induced citrate secretion and Fe translocation compared with the single mutant. Collectively, our results indicate that although OsFRDL2 is involved in the Al-induced secretion of citrate, its contribution to high Al tolerance is relatively small in rice.


Exercise ability after Mustard's operation.
Twenty children who were well six to 12 years after undergoing Mustard's operation for transposition of the great arteries were studied. Each child performed a graded maximal treadmill test with measurements of gas exchange and oxygen saturation, and had electrocardiography carried out. Nineteen were also catheterised, and oxygen consumption was measured so that pulmonary and systemic flow could be calculated. Compared with 20 age and size matched controls, seven of the patients had normal exercise tolerance (as judged by a maximal oxygen consumption of greater than 40 ml/kg/min), 10 showed a moderate reduction (30-39 ml/kg/min), and three were more seriously limited. None of the patients with normal exercise tolerance had obstruction of venous return but six of those with mild impairment of exercise ability had partial or complete obstruction of one or both of the vena cavas. More severe limitation was associated with pulmonary vascular disease and fixed ventricular outflow tract obstruction. Formal exercise testing of apparently well children who have undergone Mustard's operation identifies those with haemodynamic abnormalities that may require intervention.


Cytotoxicity and Anti-inflammatory Activity of Flavonoid Derivatives Targeting NF-kappaB.
Nuclear factor-kappaB (NF-kappaB) has been reported to regulate various genes involved in cancer and inflammation. Accordingly, drugs inhibiting NF-kappaB may possess both anti-inflammatory and anticancer properties. So there is a need to discover novel compounds which should not only be a potential lead but also less toxic and cost effective. The aim of the study was to develop new synthetic anti-inflammatory and cytotoxic agents targeting NF-kappaB. Test compounds were synthesized and characterized by UV, IR, 1H-NMR, 13C-NMR and mass spectrometry. The synthesized compounds were evaluated for in vitro cytotoxicity by MTT assay against various cancer cell lines and in vivo anti-inflammatory in carrageenan-induced paw edema model. Selected compounds were subjected to cell cycle analysis using propidium iodide. Docking study was done into an active site of NF-kappaB using Auto Dock 4.2. Three series of compounds were synthesized and characterized by various spectroscopic techniques. The test compounds (10b), (1c) and (2c) were found to be the most potent anti-inflammatory agents, whereas compounds such as (10b), (6b), (4b), (2b), (6a), (4a), (5c) and (3c) have shown promising cytotoxicity in different cancer cell lines, followed by cell cycle analysis of selected compounds ((10b) and (4b)). The free energy of binding of ligands was in the range between -6.47 to -12.50.Kcal/ mole. compound (10b) was found to be the most potent as both anti-inflammatory and cytotoxic agents. In silico approach was in good tune with the wet lab experiments. The promising compounds have shown to induce cell cycle arrest at G2/M Phase.


Floating wetland islands as a method of nitrogen mass reduction: results of a 1 year test.
Floating wetland islands (FWIs) were tested in Pasco County, Florida, as a method of reducing total nitrogen (TN) in reclaimed water during reservoir storage. The Pasco County Master Reuse System (PCMRS) is a regional reclaimed-water transmission and distribution system providing wastewater effluent disposal for the county. Total daily mass loading from reclaimed water is limited by nitrogen content in the PCMRS watershed. To test TN reduction efficacy, 20 FWIs were constructed, installed, and monitored in a lined pond receiving PCMRS reclaimed water. In total, 149 m2 of FWIs were installed, distributed as a connected network covering 1,122 m2, or 7% of pond area. Pond hydraulic residence time averaged 15.7 days. Treatment performance was assessed during three consecutive periods: establishment (first 6 months of grow-in), performance (8 months immediately following grow-in), and control (3 months after the FWIs were removed from the pond). The FWIs enhanced pond nitrogen removal capacity by 32%. The primary effect of the FWIs was to decrease organic nitrogen in the pond outflow. By evaluating the difference between the performance and control periods, an incremental TN removal rate for the FWIs was calculated to be 4.2 kg N/m2 FWI per year.


Challenging pancreatic cancer-prone pedigrees: a nosologic dilemma.
Our objective is to describe 11 pancreatic cancer (PC)-prone families, none of which are consonant with known hereditary cancer syndromes, in an attempt to portray familial aggregations of this disease that might be encountered in a clinical practice setting. We selected 11 families containing two or more first- and/or second-degree relatives affected with PC from a registry of 200 PC-prone kindreds. Each proband and/or key relative(s) was interviewed and completed a detailed family history questionnaire (after providing informed consent) that allowed us to extend the pedigree as far as possible with retrieval of primary medical and pathology documents, whenever available. All of the 11 families show PC features that merit clinical attention and raise questions as to whether this familial clustering could be due to "chance" alone, exposure to certain common environmental factors, such as cigarette smoking, and/or polygenic, multifactorial, or Mendelian inherited factors. It is estimated that about 5% of PC may have a primary hereditary etiology. Because of early death, reduced penetrance, and often profuse phenotypic and genotypic heterogeneity, particularly with respect to variable age of onset and association with diverse patterns of cancer at different anatomic sites, the pedigrees require extension for ultimate diagnosis. Physician knowledge about PC's natural history and syndrome delineation should ultimately foster earlier diagnoses and possibly prevention of this disease. These high-risk patients may provide a source of DNA for formal linkage analysis in the search for culprit cancer-prone susceptibility loci.