Achieving standardised reporting of suicide in Australia: rationale and program for change.
Suicide and intentional self-harm are issues of major importance in public health and public policy, with rates widely used as progress indicators in these areas. Accurate statistics are vital for appropriately targeted prevention strategies and research, costing of suicide and to combat associated stigma. Underreporting of Australian suicide rates probably grew from 2002 to 2006; Australian Bureau of Statistics (ABS) suicide data were at least 11% or 16% undercounted (depending on case definitions) in 2004. In coronial cases with undetermined intent for 2005 to 2007, intentional self-harm was found in 39%. Systemic reasons for undercounting include: (i) absence of a central authority for producing mortality data; (ii) inconsistent coronial processes for determining intent, as a result of inadequate information inputs, suicide stigma, and high standards of proof; (iii) collection and coding methods that are problematic for data stakeholders; and (iv) lack of systemic resourcing, training and shared expertise. Revision of data after coronial case closure, beginning with ABS deaths registered in 2007, is planned and will reduce undercounting. Other reasons for undercounting, such as missing or ambiguous information (eg, single-vehicle road crashes, drowning), differential ascertainment (eg, between jurisdictions), or lack of recorded information on groups such as Indigenous people and gay, lesbian, bisexual and transgender people require separate responses. A systemic coordinated program should address current inaccuracies, and social stigma about suicide and self-harm must be tackled if widespread underreporting is to stop.


The metabolic epicenter of supratentorial gliomas: a 1H-MRSI study.
Assessing the impact of glioma location on prognosis remains elusive. We approached the problem using multivoxel proton magnetic resonance spectroscopic imaging (1H-MRSI) to define a tumor "metabolic epicenter", and examined the relationship of metabolic epicenter location to survival and histopathological grade. We studied 54 consecutive patients with a supratentorial glioma (astrocytoma or oligodendroglioma, WHO grades II-IV). The metabolic epicenter in each tumor was defined as the 1H-MRSI voxel containing maximum intra-tumoral choline on preoperative imaging. Tumor location was considered the X-Y-Z coordinate position, in a standardized stereotactic space, of the metabolic epicenter. Correlation between epicenter location and survival or grade was assessed. Metabolic epicenter location correlated significantly with patient survival for all tumors (r2 = 0.30, p = 0.0002) and astrocytomas alone (r2 = 0.32, p = 0.005). A predictive model based on both metabolic epicenter location and histopathological grade accounted for 70% of the variability in survival, substantially improving on histology alone to predict survival. Location also correlated significantly with grade (r2 = 0.25, p = 0.001): higher grade tumors had a metabolic epicenter closer to the midpoint of the brain. The concept of the metabolic epicenter eliminates several problems related to existing methods of classifying glioma location. The location of the metabolic epicenter is strongly correlated with overall survival and histopathological grade, suggesting that it reflects biological factors underlying glioma growth and malignant dedifferentiation. These findings may be clinically relevant to predicting patterns of local glioma recurrence, and in planning resective surgery or radiotherapy.


[Reinfarction after thrombolytic therapy. Results obtained with readministration of thrombolytic agent in 3 patients].
From 1985 to 1990, 120 patients within 6h after the onset of acute myocardial infarction were submitted to thrombolytic treatment. In 4 patients, there were clinical and electrocardiographic (ECG) changes of reinfarction. Three of them were undergone to a second thrombolytic therapy with streptokinase (SK). Two had infarction of the inferior wall, and one on the anterior wall. The patients were managed with the same SK dosage as in the first episode and the same protocol of infusion. All 3 patients, after new SK infusion showed evidence of myocardial reperfusion with relief of pain and improvement of the ECG. One patient, 24h after retreatment, had another reinfarction treated with emergency angioplasty of the right coronary artery, which was totally occluded. One patient (case n. 2), presented haematoma of right arm after punction of the subclavian vein and the other two patients did not show any serious intecorrence related to the new thrombolytic treatment. All of them were found alive over one year of follow-up.


De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability.
High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD). This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28). A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations. Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.


Correlated motions in the U1 snRNA stem/loop 2:U1A RBD1 complex.
The complex formed by U1A RBD1 and the U1 snRNA stem/loop II is noted for its high affinity and exquisite specificity. Here, that complex is investigated by 5 ns molecular dynamics simulations and analyzed by reorientational eigenmode dynamics to determine the dynamic properties of the RNA:protein interface that could contribute to the binding mechanism. The analysis shows that there is extensive correlation between motions of the RNA and protein, involving 7 of the 10 RNA loop nucleotides, the protein beta-sheet surface, two of its loops, and its C-terminal tripeptide sequence. Order parameters of these regions of the complex are uniformly high, indicating restricted motion. However, several regions of both RNA and protein retain local flexibility, notably three nucleotides of the RNA loop and one loop of RBD1 that does not contact RNA. The highly correlated motions involving both molecules reflect the intricate network of interactions that characterize this complex and could account in part for the thermodynamic coupling observed for complex formation.


Studies on the stabilized ubisemiquinone species in the succinate-cytochrome c reductase segment of the intact mitochondrial membrane system.
1. Evidence is presented for the presence of a stable ubisemiquinone pair in the vicinity of iron-sulphur centre S-3, based on its thermodynamic and spin relaxation properties. 2. These semiquinones are coupled by dipolar interaction; quantitative analysis of the signals of the spin-coupled semiquinones (at pH 7.4) gives midpoint redox potentials E1 (oxidized to semiquinone state) and E2 (semiquinone to fully reduced state) of 140 and 80mV, respectively, for individual ubiquinones. 3. Values of pKS (pK of the semiquinone form) below 6.5 and pKR (pK of the fully reduced ubiquinone) of about 8.0 or above were estimated from the pH-dependence of the midpoint potentials of the spin coupled signals. Thus the ubisemiquinone associated with succinate dehydrogenase (designated as SQS) functions mostly in the anionic form of the physiological pH range. 4. Theonyltrifluoroacetone, a specific inhibitor of the succinate-ubiquinone reductase segment of the respiratory chain, destabilized the intermediate redox state; thus it quenches both the g = 2.00 signal and ubisemiquinone (SQS) and split signals from the spin coupled pair. This inhibitor has no significant effect on another bound ubisemiquinone species present in the cytochrome bc1 region (designated as SQC). 5. The possible function and location of these stabilized ubisemiquinone species were discussed in connection with Site-II energy transduction.


Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B-cell responses with age.
T cell-dependent B-cell responses decline with age, suggesting defective CD4 T-cell function. CD4 memory T cells from individuals older than 65 y displayed increased and sustained transcription of the dual-specific phosphatase 4 (DUSP4) that shortened expression of CD40-ligand (CD40L) and inducible T-cell costimulator (ICOS) (both P < 0.001) and decreased production of IL-4, IL-17A, and IL-21 (all P < 0.001) after in vitro activation. In vivo after influenza vaccination, activated CD4 T cells from elderly individuals had increased DUSP4 transcription (P = 0.002), which inversely correlated with the expression of CD40L (r = 0.65, P = 0.002), ICOS (r = 0.57, P = 0.008), and IL-4 (r = 0.66, P = 0.001). In CD4 KO mice reconstituted with DUSP4 OT-II T cells, DUSP4 had a negative effect on the expansion of antigen-specific B cells (P = 0.003) and the production of ova-specific antibodies (P = 0.03) after immunization. Silencing of DUSP4 in memory CD4 T cells improved CD40L (P < 0.001), IL-4 (P = 0.007), and IL-21 (P = 0.04) expression significantly more in the elderly than young adults. Consequently, the ability of CD4 memory T cells to support B-cell differentiation that was impaired in the elderly (P = 0.004) was restored. Our data suggest that increased DUSP4 expression in activated T cells in the elderly in part accounts for defective adaptive immune responses.


World Health Organization collaborative study to calibrate the 3rd International Standard for Hepatitis C virus RNA nucleic acid amplification technology (NAT)-based assays.
A collaborative study was undertaken to evaluate a replacement World Health Organization International Standard for hepatitis C virus (HCV) RNA for nucleic acid amplification technology (NAT)-based assays. The candidate preparations were calibrated in International Units (IUs). Three new candidate preparations were produced from a single bulk containing anti-HCV-negative, genotype 1a HCV RNA-positive plasma. Two samples were lyophilized (coded Sample 2 and Sample 3), whilst a third (Sample 4) contained liquid/frozen material. The samples were distributed together with the 2(nd) International Standard (Sample 1, NIBSC code 96/798) for evaluation by thirty-three laboratories, from fourteen countries. The panel of samples were assayed on four separate occasions. Stability studies were performed for the lyophilized samples by accelerated thermal degradation. Participants returned data from a wide range of commercial and in-house quantitative and qualitative assays. Twenty-five data sets were returned for quantitative assays and fourteen for qualitative assays. Excellent agreement was observed between laboratories and assay methods. The mean relative potencies of Samples 2-4 were 5·19, 5·41 and 5·70 log(10) IU/ml, respectively, when compared against the 2(nd) International Standard. Samples 2 and 3 demonstrated stability of a similar order to the previous standards. Based upon the results of the collaborative study, Sample 2 (code number 06/100) was established as the 3rd International Standard for HCV RNA with an assigned unitage of 5·19 log(10) IU/ml. Each vial contains the equivalent of 0·5 ml of material; each vial contains 4·89 log(10) IU of HCV RNA.


Thinking styles and cognitive development.
Using R. J. Sternberg's (1988, 1997) theory of thinking styles and W. G. Perry's (1970) theory of cognitive development, the author investigated the nature of thinking styles as they relate to cognitive development. Eighty-two Hong Kong university students (44 male, 38 female) responded to the Thinking Styles Inventory (R. J. Sternberg & R. K. Wagner, 1992) and the Zhang Cognitive Development Inventory (L. F. Zhang, 1997). Statistical analyses provided varying degrees of support for the prediction of an overlap between the thinking style and cognitive development constructs. In general, students who reasoned at a higher cognitive developmental level tended to use a wider range of thinking styles than students who reasoned at a lower cognitive developmental level. Implications of results are discussed in relation to education and research.


Genotypically determined ancestry across an infertile population: ovarian reserve and response parameters are not influenced by continental origin.
To evaluate the relationship between genetic ethnicity using ancestry informative markers (AIMs) and ovarian reserve and response parameters as evidenced by FSH, antimüllerian hormone (AMH), basal antral follicle count (BAFC), and total oocyte yield in IVF. Retrospective. Academic medical center. A total of 2,508 infertile patients undergoing IVF at a single center. Patients were genotyped for 32 AIMs and analyzed for differences in allele frequencies. A validated Bayesian clustering algorithm was then used to assign individuals into one of four ethnic populations: European, African, Central/South Asian, or East Asian. FSH, AMH, BAFC, and oocyte yield variation. After controlling for age and body mass index, genetic ethnicity had no impact on AMH, BAFC, and oocyte yield. FSH was found to be lower in patients of Central/South Asian ancestry (6.46 ng/mL vs. 6.97 ng/mL); however, the absolute difference is of little clinical significance. Subgroup analyses of 1,327 patients restricted to those with limited genetic admixture as determined by AIMs indicated that FSH, AMH, BAFC, and oocyte yield were equivalent. When determining ethnicity using AIMs, ethnic background does not have an impact on markers of ovarian reserve or ovarian response. Specifically, no differences were found in AMH, BAFC, or oocyte yield relative to genotypic ethnicity. Using AIMs rather than self-reported ethnicity allows for elimination of reporting biases and nonreporting of ethnicity, which can confound data. Based upon these data, specific recommendations for ovarian reserve testing should thus be made based on other factors besides ethnic background.


Draft genome sequence of the biocontrol bacterium Pseudomonas putida B001, an oligotrophic bacterium that induces systemic resistance to plant diseases.
Pseudomonas putida B001 is a rhizobacterium that was isolated on the basis of its abilities to grow under low-nutrient conditions and induce systemic resistance against bacterial, fungal, and viral diseases of plants. Here we report the draft genome sequence and automatic annotation of strain B001. Comparison of this sequence to the sequenced genome of P. putida KT2440 points to a subset of gene functions that may be related to the defense-inducing functions of B001.


Age and African-American race impact the validity and reliability of the asthma control test in persistent asthmatics.
The Asthma Control Test (ACT) is widely used to assess asthma control, yet the validity and reliability of the test have not been specifically evaluated in adolescents or African-Americans. We conducted a prospective psychometric study of the ACT in African-American (AA) and non-African-American (nAA) adolescents with persistent asthma, with emphasis on the clinical utility of the test for medical decision making. Participants completed the ACT and performed spirometry. A physician conducted a guidelines-based assessment of asthma control, blinded to the ACT score. Study procedures were repeated 6-8 weeks later. The ACT-based asthma control assessment was compared to physician assessment. For baseline and follow-up visits, internal consistency, as measured using Cronbach's alpha, was 0.80 and 0.81 in AA teens and 0.80 and 0.83 in nAA teens. Intraclass correlation coefficients were 0.59 and 0.76 in AA and nAA teens, respectively, with stable asthma control over time. Agreement between ACT and physician assessment was moderate in AA teens and fair in nAA teens. An ACT score of ≤19 showed reduced sensitivity for not well controlled asthma in both groups, while a score of ≤21 had the greatest area under the ROC curve. ACT scores were marginally responsive to change in control status. Concerns for the ACT's ability to detect uncontrolled asthma in adolescents emphasizes the need for a more comprehensive evaluation of asthma control in clinical settings. A higher threshold ACT score to define not well controlled asthma may be needed if the ACT is to be used for medical decision making. ClinicalTrials.gov: NCT02671643 , NCT02662413 .


Health-related quality of life and strain in caregivers of Australians with Parkinson's disease: an observational study.
The relationship between health-related quality of life (HRQoL) in people with Parkinson's disease and their caregivers is little understood and any effects on caregiver strain remain unclear. This paper examines these relationships in an Australian sample. Using the generic EuroQol (EQ-5D) and disease-specific Parkinson's Disease Questionnaire-39 Item (PDQ-39), HRQoL was evaluated in a sample of 97 people with PD and their caregivers. Caregiver strain was assessed using the Modified Caregiver Strain Index. Associations were evaluated between: (i) caregiver and care-recipient HRQoL; (ii) caregiver HRQoL and caregiver strain, and; (iii) between caregiver strain and care-recipient HRQoL. No statistically significant relationships were found between caregiver and care-recipient HRQoL, or between caregiver HRQoL and caregiver strain. Although this Australian sample of caregivers experienced relatively good HRQoL and moderately low strain, a significant correlation was found between HRQoL of people with PD and caregiver strain (rho 0.43, p < .001). Poor HRQoL in people with PD is associated with higher strain in caregivers. Therapy interventions may target problems reported as most troublesome by people with PD, with potential to reduce strain on the caregiver.


A fidelity assay using "dideoxy" DNA sequencing: a measurement of sequence dependence and frequency of forming 5-bromouracil X guanine base mispairs.
DNA replication fidelity has been assayed by using a modified DNA sequencing reaction. In one experimental approach, dideoxycytidine 5'-triphosphate (ddCTP) was used as a chain terminator during replication of M13 phage DNA by the large fragment of DNA polymerase I. The deoxyribonucleotide analogue BrdUTP was used to compete against ddCTP-induced chain terminations as an assay for B X G base mispairing (B represents bromodeoxyuridine when the analogue is present as a base pair or base mispair). By comparing BrdUTP to dCTP for competition against ddCTP, an average misincorporation frequency for BrdUMP of 0.2% was found. A similar average misincorporation frequency has been measured previously for the incorporation of radioactively labeled BrdUMP and dCMP into the synthetic template-primer poly-[d(G,T)] X oligo(dA). The advantage of the sequencing method is that an error frequency is determined for each template guanine in a defined DNA sequence, thus providing information on the effect of neighboring base sequences on fidelity. Misincorporation frequencies varied no more than 5-fold among 50 template guanines tested. The approach used here is not limited for use with nucleotide analogues but is generally applicable in determining misincorporation frequencies and sequence specificities for any deoxynucleoside triphosphate substrate. In a second experimental approach, base mispairing between bromouracil and guanine was demonstrated directly by using 5-bromodideoxyuridine 5'-triphosphate (BrddUTP). A comparison of chain terminations attributable to BrddUTP and to dideoxythymidine 5'-triphosphate (ddTTP) revealed that B X A and T X A base pairs formed at about the same rate, whereas B X G mispairs occurred 4-10 times more frequently than T X G. The elevation in the frequency of B X G over T X G mispairs is consistent with the mutagenic behavior of the base analogue.


The Evolution of Lactation in Mammalian Species.
Lactation is a defining characteristic of all mammals, and, indeed, mammals draw their name from mammae, or mammary glands. The evolution of mammary glands has been the subject of debate since Charles Darwin. The purpose of this brief review is not to examine all past theories of mammary evolution but to consider the evolution of the mammary gland in relation to (1) modern paleobiology, giving special attention to the mammaliaforms which had many mammalian features, including delayed tooth development suggestive of milk intake. (2) Comparative aspects of mammary development in monotremes, marsupials, and eutherians, which reveal the close developmental relation of mammary glands to other skin glands and hair follicles. (3) The evolution of caseins, which are now known to derive from secretory calcium-binding phosphoproteins, which have a long history in regulating biomineralization. (4) The evolution of lipid secretion, and especially the evolutionary incorporation of immune system components (such as xanthine oxidoreductase) into the fat globule membrane. (5) The evolution of lactose synthesis, and especially the synthesis of the wide array of oligosaccharides found in some milks, including monotremes, marsupials, caniform carnivores, and humans.


Effect of degradable and escape protein and roughage type on performance and carcass characteristics of finishing yearling steers.
We evaluated protein sources for finishing steers in two randomized complete block design experiments. Experiment 1 used 144 steers (334 kg) with 2 x 3 factorially arranged treatments. Basal diets contained .9% urea or 5.6% soybean meal (SBM) and were either not supplemented or supplemented with additional protein (2%) from blood meal-corn gluten meal (BMCG) or SBM. Steers fed urea-containing diets consumed 4.6% (P < .10) more feed than those fed SBM-supplemented basal diets. On the basis of carcass weights, steers fed diets containing SBM as the basal protein source were 3.8% (P < .10) more efficient than those fed urea-containing diets; supplying additional SBM improved gain efficiency (G/F) 4.3% (P < .10) compared with BMCG. In Exp. 2, 384 steers (367 kg) were fed diets containing 1.0% urea (DM basis) and 10% roughage as either sorghum silage (four diets) or alfalfa hay (two diets). Additional protein was either not provided or provided (2%) as SBM, sunflower meal (SFM), or a 50:50 (N basis) SBM:SFM blend in silage-containing diets; for diets containing alfalfa, additional protein was either not provided or provided (2%) as SBM. Averaged across roughage source, added SBM tended (P = .16) to increase ADG. Dressing percent decreased (P = .09) with added SBM but was higher (P = .04) with alfalfa as roughage source. Feeding alfalfa vs sorghum silage as the roughage source increased carcass adjusted ADG 4.3% (P = .06) and G/F 4.8% (P = .02). Supplementing high-grain diets with SBM enhanced diet utilization, but BMCG was of little value.


[Assessment of microhaemodynamics and oxygenation in tissues after the vestibuloplasty with the use of a free dermal autograft in patients after the reconstructive jaw surgery with the use of the revascularized autografts].
Purpose of the study: to study the features of microhaemodynamics and oxygenation in soft tissues in the area of the plastically reconstructed jaw after the vestibuloplasty. The study included 40 patients aged 20 to 65 (21 males and 19 females). The patients were divided into two groups: I group (14 patients) - patients after reconstructive surgery with the use a fibula autograft without the inclusion of a musculocutaneous «islet»; II group (26 patients) - patients after reconstructive surgery with the use a fibula autograft with the inclusion of a musculocutaneous «islet». To correct the prosthetic bed soft tissues, all patients underwent vestibuloplasty with the use of a free dermal autograft. To study microcirculation in tissues, the laser Doppler flowmetry (LDF) method was used. Microcirculation status was assessed by microcirculation index characterizing the level of tissue blood flow; parameter «σ,» which determines the oscillability of the flow of red blood cells and by coefficient of variation, characterizing vasomotor activity of microvessels. According to the Wavelet analysis of LDF-grams the blood flow bypass was determined. An oxygenation study was carried out in the tissues of the plastically restored jaw by optical tissue oximetry, the results of which determined the oxygenation index and the specific oxygen consumption index. According to LDF data after vestibuloplasty, it was found that in I group, the microcirculation in soft tissues of the plastically reconstructed jaw restored in 21 days, and in II group in 2 months, which persisted at 6 months. In I group, the level of oxygenation and specific oxygen consumption normalized in 21 days, and in II group in 2 months, which persisted at 6 months. Based on the results of this functional study, it was found that before vestibuloplasty microcirculation and oxygenation indices in II group patients were lower than those in I group patients. After vestibuloplasty with the use of a free dermal autograft, microcirculation indices in II group patients restored in 2 months, while in I group patients those indices restored in 21 days.


Modifications in the phagocytosis of human neutrophils induced by vinblastine and cytochalasin B: the effects of lithium.
The effects of lithium on the microtubular and microfilament systems of neutrophil granulocytes is described. The phagocytic capacity of human neutrophils was reduced or inhibited by using vinblastine or cytochalasin B. Lithium at concentrations ranging from 0.5 to 2.0 mEq/l proved to be capable of antagonising the action of vinblastine, whereas the action of cytochalasin B was found to be unaffected by lithium. Based on the antagonising effect of lithium on vinblastine-induced inhibition of phagocytosis, it is suggested that lithium acts--at therapeutically achievable levels--on the microtubular system of neutrophils, possibly through modulation of cyclic AMP levels.


Hydroxytyrosol produced by engineered Escherichia coli strains activates Nrf2/HO-1 pathway: An in vitro and in vivo study.
This study explores the biological effects of hydroxytyrosol (HT), produced by the metabolic engineering of Escherichia coli, in a series of in vitro and in vivo experiments. In particular, a metabolically engineered Escherichia coli strain capable of producing HT was constructed and utilized. HEK293 and HeLa cells were exposed to purified HT to determine non-toxic doses that can offer protection against oxidative stress (activation of Nrf2/HO-1 signaling pathway). Male CD-1 mice were orally supplemented with HT to evaluate (1) renal and hepatic toxicity, (2) endogenous system antioxidant response, and (3) activation of Nrf2/HO-1 system in the liver. HT protected cells from oxidative stress through the activation of Nrf2 regulatory network. Activation of Nrf2 signaling pathway was also observed in the hepatic tissue of the mice. HT supplementation was safe and produced differential effects on mice's endogenous antioxidant defense system. HT biosynthesized from genetically modified Escherichia coli strains is an alternative method to produce high-quality HT that exerts favorable effects in the regulation of the organism's response to oxidative stress. Nonetheless, further investigation of the multifactorial action of HT on the antioxidant network regulation is needed.


Working Towards Holistic Scar Assessment and Improved Shared Decision-Making in Global Burn Care.
Cutaneous burn scars impact various aspects of life. Scar treatment is mainly evaluated on scar characteristics. Consensus is needed on which other outcomes to capture, ensuring they are relevant to patients, clinicians and researchers. The aim of this study was to identify, discuss and analyze outcomes related to cutaneous burn scarring, incorporating the voice of patients and views of healthcare professionals. For this, a Delphi process consisting of two survey rounds and a consensus meeting was initiated. Burn scar-related outcomes were identified from an existing comprehensive list of 100 outcomes by an international panel of patients, healthcare professionals and researchers. Fifty-nine outcomes were identified from the Delphi process as related to scarring (≥60% votes). Outcomes less impactful in relation to scar outcomes included psychosocial issues, sense of normality, understanding of treatment, costs and systemic issues. To represent a holistic assessment of outcomes related to cutaneous burn scarring, this Delphi process established a battery of outcomes currently included in scar quality assessment tools, and an expanded set of less frequently considered outcomes. Future work in this area must include the patient voice from developing countries. This is essential to identify globally applicable outcomes related to scarring.


Design of a flexible component gathering algorithm for converting cell-based models to graph representations for use in evolutionary search.
The ability of science to produce experimental data has outpaced the ability to effectively visualize and integrate the data into a conceptual framework that can further higher order understanding. Multidimensional and shape-based observational data of regenerative biology presents a particularly daunting challenge in this regard. Large amounts of data are available in regenerative biology, but little progress has been made in understanding how organisms such as planaria robustly achieve and maintain body form. An example of this kind of data can be found in a new repository (PlanformDB) that encodes descriptions of planaria experiments and morphological outcomes using a graph formalism. We are developing a model discovery framework that uses a cell-based modeling platform combined with evolutionary search to automatically search for and identify plausible mechanisms for the biological behavior described in PlanformDB. To automate the evolutionary search we developed a way to compare the output of the modeling platform to the morphological descriptions stored in PlanformDB. We used a flexible connected component algorithm to create a graph representation of the virtual worm from the robust, cell-based simulation data. These graphs can then be validated and compared with target data from PlanformDB using the well-known graph-edit distance calculation, which provides a quantitative metric of similarity between graphs. The graph edit distance calculation was integrated into a fitness function that was able to guide automated searches for unbiased models of planarian regeneration. We present a cell-based model of planarian that can regenerate anatomical regions following bisection of the organism, and show that the automated model discovery framework is capable of searching for and finding models of planarian regeneration that match experimental data stored in PlanformDB. The work presented here, including our algorithm for converting cell-based models into graphs for comparison with data stored in an external data repository, has made feasible the automated development, training, and validation of computational models using morphology-based data. This work is part of an ongoing project to automate the search process, which will greatly expand our ability to identify, consider, and test biological mechanisms in the field of regenerative biology.


Biomechanical evaluation of the origin of the long head of the biceps tendon.
Lesions of the superior glenoid labrum extending anterior and posterior (SLAP) have recently been recognized as important sources of shoulder pain and dysfunction. Among the 4 described types of SLAP lesions, the type II SLAP involves detachment of the superior labrum from the bony glenoid and destabilization of the origin of the long head of the biceps tendon (LHBT). The purpose of this cadaveric biomechanical study was to evaluate the relative contribution regarding linear stiffness and displacement under load of the 2 origins of the LHBT: the superior glenoid labrum and the supraglenoid tubercle (the biceps anchor). Cadaveric biomechanical study. Seven pairs of fresh-frozen cadaveric shoulders were dissected free of all soft tissue except for the glenoid labrum and LHBT. Tension from 0 to 55 N was applied to the LHBT while keeping the tendon perpendicular to the face of the glenoid. Each specimen was tested for linear stiffness and biceps tendon displacement in the intact state, after releasing 1 of the LHBT origins, and after releasing the remaining origin. The average stiffness of the LHBT origin was 103 N/mm. Sectioning the anchor alone resulted in a 52% reduction in linear stiffness, whereas only detaching the superior glenoid labrum from the 10 o'clock to the 2 o'clock position resulted in a 15% reduction in linear stiffness. Maximum displacement of the biceps tendon origin in the intact state at the 55 N load averaged 0.99 mm. With a minimum load applied, displacement changed less than 1 mm unless both origins were released. The results indicate that the biceps anchor is the primary restraint of the LHBT and that the superior labrum is a secondary restraint in regard to linear stiffness. However, disruption of both restraints is required to produce the laxity typically seen in a type II SLAP lesion.


Proline excretion and indirect suppression in Escherichia coli and Salmonella typhimurium.
The last step in proline biosynthesis in Escherichia coli K-12, Salmonella typhimurium LT7, and a number of other enterobacterial isolates is regulated so that no proline is excreted, even if excess Delta(1)-pyrroline-5-carboxylate, the immediate precursor of proline, is added to a culture. In proline auxotrophs blocked at an early step in proline biosynthesis (proA or proB), reversion to prototrophy is often due to a mutation in the arginine pathway which diverts N-acetyl glutamate gamma-semialdehyde to proline synthesis, thus bypassing the proA or proB block. In such double mutants (proAB, argD), the last step in proline synthesis appears to be unregulated, since proline is excreted. Feedback inhibition and repression of the arginine pathway overcomes indirect suppression (restoring the Pro(-) phenotype), but proline regulation is not restored; double mutants still excrete proline when fed Delta(1)-pyrroline-5-carboxylate exogeneously. A new class of proline analogue-resistant mutant, due to mutation at argD, is also described.


Potassium channels in Necturus proximal tubule.
Potassium channels from the apical and basolateral membranes of Necturus proximal tubule were studied using the patch-clamp technique. The conductance of the basolateral channel was dependent on the pipette K+ concentration (apparent Km, 65.5 mM K+; maximum channel conductance, 49.8 pS). The permeability ratio (PK+/PNa+) was approximately 10:1. The fractional open time increased with hyperpolarization, whereas mean open times did not change. Ba2+ (0.1 mM pipette concentration) blocked the channel and reduced the mean open time. The apical K+ channel was activated with depolarization and had a slope conductance of 60 pS in the inside-out configuration (100 mM KCl in the pipette and 2.5 mM KCl in the bath). The K+-Na+ selectivity ratio was 32:1. These different channel types will allow independent control of the apical and basolateral membrane K+ conductances.


Successful treatment of mast cell activation syndrome with sunitinib.
Mast cell (MC) activation syndrome (MCAS) is a recently recognized, likely prevalent collection of heterogeneous illnesses of inappropriate MC activation with little to no MC neoplasia likely driven by heterogeneous patterns of constitutively activating mutations in MC regulatory elements including various tyrosine kinases (TKs, dominantly KIT). MCAS typically presents as chronic multisystem polymorbidity of generally inflammatory ± allergic theme. As with indolent systemic mastocytosis (SM), treatment of MCAS focuses more against MC mediators than MC neoplasia, but some cases prove refractory even to the TK inhibitor (TKI) imatinib reported useful both in uncommon SM cases not bearing SM's usual imatinib-resistant KIT-D816V mutation and in some cases of MCAS (which rarely bears KIT-D816V). Most allergy is principally a MC activation phenomenon and sunitinib is a multitargeted TKI shown helpful in controlling a murine model of oral allergy syndrome. We present the first report of use of sunitinib in life-threatening MCAS refractory to multiple agents including imatinib achieving immediate, complete, sustained, non-toxic remission suggesting a new option for treatment of aggressive MC disease.


A novel pharmacological approach of musculoskeletal losses associated with simulated microgravity.
Exposure to microgravity (weightlessness) is known to cause rapid bone and muscle losses. We have used the hind limb-suspended (HLS) rat model to simulate microgravity-induced musculoskeletal losses in order to assess resulting hormonal changes and to develop a novel pharmacological countermeasure. Previously, we demonstrated significant decreases in circulatory hormonal levels [serum thyroxin, 1,25(OH)2 vitamin D (p<0.05), and serum testosterone (p<0.001)] in HLS rats. Both thyroxin and 1,25(OH)2 vitamin D levels returned to normal soon after removal from HLS, while testosterone levels matched normal levels only after a further 3-4 weeks. However, even by day 42, bone mineral density (BMD) remained significantly lower, although serum hormones were back to normal. Because serum testosterone levels become undetectable in HLS rats, we hypothesized that the replacement of testosterone during HLS could prevent musculoskeletal losses. Based on these data, an intervention study was carried out to assess the efficacy of testosterone and synthetic anabolic steroid, nandrolone decanoate (ND), in prevention of weightlessness-induced musculoskeletal losses. HLS rats (control) had a significant reduction of muscle volume (42.9 -/+ 3.0, versus 56 -/+ 1.8 in ground control rats; p<0.01). Both testosterone and ND treatments prevented this muscle loss (51.5 -/+ 2 cm(3) and 51.6 -/+ 1.2, respectively; a 63% improvement, p<0.05). Similarly, BMD of the placebo-treated HLS rats was significantly lower than that of ground control rats (0.416 -/+ 0.011 versus 0.354 -/+0.014, p<0.05), and testosterone and ND prevented this bone loss (0.404 -/+ 0.013 versus. 0.409 -/+ 0.011, respectively). These data suggest that both testosterone and ND therapy can minimize the musculoskeletal losses associated with exposure to simulated weightlessness. Experiments using the combination of bisphosphonate and testosterone demonstrated complete protection of both muscle and bone in these HLS rats. Therefore, considering that: 1) testosterone is anabolic to osteoblasts and muscle cells and also decreases the rate of bone turnover, 2) serum testosterone levels are markedly suppressed in simulated weightlessness, and 3) testosterone replacement therapy prevented musculoskeletal losses in HLS rats, we propose that the musculoskeletal losses observed in this animal model (i.e., simulated microgravity) are related to their testosterone deficiency. Since serum sex hormones levels are markedly reduced in this model of simulated microgravity, androgen replacement with a bisphosphonate seems to be a rational counter.


Validity of internal expression of the major histocompatibility complex class I in the diagnosis of inflammatory myopathies.
The inflammatory myopathies (IMs) are a group of disorders characterised by weakness and inflammation of the skeletal muscles. Muscle biopsy is the most crucial test to confirm the clinical diagnosis, but also the most common cause of misdiagnosis. There are currently no markers specific or sensitive enough to distinguish IMs from other diseases with similar clinical and morphological features, and an international multidisciplinary effort is under way to develop new classification criteria for IMs. Standards for Reporting of Diagnostic Accuracy recommendations to validate a diagnostic test based on the quantification of internal major histocompatibility complex class I (MHC-I) positive fibres were adopted. MHC-I immunostained specimens from 64 patients were scored by two independent blinded investigators, and the percentage of positive fibres was determined. Agreement between investigators was evaluated with the k-weighted statistic. The receiver operating characteristic curve, area under the curve, sensitivity, specificity, and positive and negative predictive values of each percentage range of positive fibres versus the diagnosis of IM were calculated. The main difference between IM and non-inflammatory samples was the number of internal MHC-I positive fibres. The k-weighted value was 0.89 for a percentage of MHC-I positive fibres above 50%; the positive predictive value was 100%, and the negative predictive value was 94%. This is the first study on the validity of a quantitative analysis of internal MHC-I positive fibres for an IM diagnosis performed according to Standards for Reporting of Diagnostic Accuracy recommendations. The interobserver agreement was almost perfect, thus making the method reproducible. Applying an MHC-I cut-off above 50% is an optimal marker for polymyositis (PM) and dermatomyositis (DM) diagnosis.


Self-association is required for occupation of adjacent binding sites in Pseudomonas aeruginosa type III secretion system promoters.
ExsA is a member of the AraC/XylS family of transcriptional regulators and is required for expression of the Pseudomonas aeruginosa type III secretion system (T3SS). All P. aeruginosa T3SS promoters contain two adjacent binding sites for monomeric ExsA. The amino-terminal domain of ExsA (NTD) is thought to mediate interactions between the ExsA monomers bound to each site. Threading the NTD onto the AraC backbone revealed an α-helix that likely serves as the primary determinant for dimerization. In this study, we performed alanine scanning mutagenesis of the ExsA α-helix (residues 136 to 152) to identify determinants required for self-association. Residues L137, C139, L140, K141, and L148 exhibited self-association defects and were required for maximal activation by ExsA. Disruption of self-association resulted in decreased binding to T3SS promoters, particularly loss of binding by the second ExsA monomer. Removing the NTD or increasing the space between the ExsA-binding sites restored the ability of the second ExsA monomer to bind the PexsC promoter. This finding indicated that, in the absence of self-association, the NTD prevents binding by a second monomer. Similar findings were seen with the PexoT promoter; however, binding of the second ExsA monomer in the absence of self-association also required the presence of a high-affinity site 2. Based on these data, ExsA self-association is necessary to overcome inhibition by the NTD and to compensate for low-affinity binding sites, thereby allowing for full occupation and activation of ExsA-dependent promoters. Therefore, ExsA self-association is indispensable and provides an attractive target for antivirulence therapies.


Concomitant aortic valve replacement and surgical angioplasty of left main coronary ostium.
The association of calcific aortic valve disease and isolated coronary ostial stenosis is rare. A 80-year-old woman was found to have severe aortic stenosis with critical narrowing of the ostium of the left main coronary artery. She was successfully managed by simultaneous aortic valve replacement and patch angioplasty of the left main coronary artery, using a patch of autologous pericardium fixed in glutaraldehyde. Angiographic control at 1 month coupled with intravascular echographic imaging showed adequate relief of the ostial stenosis and patency of the left main trunk.


Efficacy of Different Powers of Low-Level Red Light in Children for Myopia Control.
To compare the efficacy and safety of low-level red light (LRL) in controlling myopia progression at 3 different powers: 0.37 mW, 0.60 mW, and 1.20 mW. Single-center, single-masked, randomized controlled trial. Two hundred children aged 6-15 with myopia of -0.50 diopter (D) or more and astigmatism of -2.50 D or less were enrolled from April to May 2022. Follow-up ended in December 2022. Participants were assigned randomly to 3 intervention groups and 1 control group (1:1:1:1). All participants wore single-vision spectacles. Moreover, the intervention group randomly received LRL at 3 different powers twice daily for 3 minutes per session, with a minimum 4-hour interval. Changes in spherical equivalent (SE), axial length (AL), and subfoveal choroidal thickness (SFCT) were measured. After 6 months, SE progression was significantly lower in the 0.37-mW group (0.01 D; 95% confidence interval [CI], -0.12 to 0.15), 0.60-mW group (-0.05 D; 95% CI, -0.18 to 0.07), and 1.20-mW group (0.16 D; 95% CI, 0.03 to 0.30) compared to the control group (-0.22 D; 95% CI, -0.50 to 0.30; adjusted P < 0.001 for all). AL changes in the 0.37-mW group (0.04 mm; 95% CI, -0.01 to 0.08), 0.60-mW group (0.00 mm; 95% CI, -0.05 to 0.05), and 1.20-mW group (-0.04 mm; 95% CI, -0.08 to 0.01) were significantly smaller than the control group (0.27 mm; 95% CI, 0.22 to 0.33; adjusted P < 0.001 for all). Similarly, increases in SFCT were significantly greater in the 0.37-mW group (22.63 μm; 95% CI, 12.13 to 33.34 μm), 0.60-mW group (36.17 μm; 95% CI, 24.37 to 48.25 μm), and 1.20-mW group (42.59 μm; 95% CI, 23.43 to 66.24 μm) than the control group (-5.07 μm; 95% CI, -10.32 to -0.13 μm; adjusted P < 0.001 for all). No adverse events were observed. LRL effectively controlled myopia progression at 0.37 mW, 0.60 mW, and 1.20 mW. Further research is required. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Indoor air quality in schools of a highly polluted south Mediterranean area.
This study aimed at surveying lower secondary schools in southern Italy, in a highly polluted area. A community close to an industrial area and three villages in rural areas was investigated. Indoor temperature, relative humidity (RH), gaseous pollutants (CO2 and NO2 ), selected biological pollutants in indoor dust, and the indoor/outdoor mass concentration and elemental composition of PM2.5 were ascertained. Temperature and RH were within, or close to, the comfort range, while CO2 frequently exceeded the threshold of 1000 ppm, indicating inadequate air exchange rate. In all the classrooms, median NO2 levels were above the WHO threshold value. Dermatophagoides p. allergen concentration was below the sensitizing threshold, while high endotoxin levels were detected in the classrooms, suggesting schools may produce significant risks of endotoxin exposure. Concentration and solubility of PM2.5 elements were used to identify the sources of indoor particles. Indoor concentration of most elements was higher than outdoors. Resuspension was responsible for the indoor increase in soil components. For elements from industrial emission (Cd, Co, Ni, Pb, Sb, Tl, V), the indoor concentration depended on penetration from the outside. For these elements, differences in rural vs industrial concentrations were found, suggesting industrial sources may influence indoor air quality nearby schools.


Genetic variation within the TRPM5 locus associates with prediabetic phenotypes in subjects at increased risk for type 2 diabetes.
The functional knockout of the calcium-sensitive, nonselective cation channel TRPM5 alters glucose-induced insulin secretion and glucose tolerance. We hypothesized that genetic variation in the TRPM5 gene may contribute to prediabetic phenotypes, including pancreatic β-cell dysfunction. We genotyped 1798 white subjects at increased type 2 diabetes mellitus risk for 9 TRPM5 single nucleotide polymorphisms (namely, rs2301696, rs800344, rs800345, rs800347, rs800348, rs2074234, rs2301698, rs886277, and rs2301699) and also performed correlational analyses with metabolic traits. An oral glucose tolerance test (OGTT) was conducted on all subjects, and a subset (n = 525) additionally underwent a hyperinsulinemic-euglycemic clamp. The 9 chosen single nucleotide polymorphisms cover 100% of the common genetic variation (minor allele frequency ≥0.05) within the TRPM5 locus (D' = 1.0; r² ≥ 0.8). Rs800344, rs800345, and rs2301699 were significantly associated with area under the curve (AUC) glucose during the OGTT in the additive and dominant models after adjustment for sex, age, and body mass index (all Ps ≤ .0025). Furthermore, rs800344 was significantly associated with 2-hour glucose in the dominant model (P = .0009). After stratification for sex, rs2301699 was significantly associated with the ratio of AUC insulin 0 to 30 minutes to AUC glucose 0 to 30 minutes in women (P = .0097), but not in men (P = .3), in the dominant model. Female minor allele carriers of rs2301699 showed significantly lower glucagon-like peptide-1 levels at 30 minutes during the OGTT compared with major allele homozygotes (P = .0124), whereas in male subjects, no significant differences were found (P = .3). In our German population, the common TRPM5 variants are likely to be associated with prediabetic phenotypes; and this may in turn contribute to the development of type 2 diabetes mellitus.


Interaction between alpha and beta adrenergic receptors and cholinergic receptors in isolated perfused rat heart: effects on cAMP-protein kinase and phosphorylase.
The ability of acetylcholine to antagonize catecholamine-induced activation of myocardial cyclic AMP dependent protein kinase and glycogen phosphorylase activity was assessed using isolated perfused rat hearts. Perfused hearts were treated with either saline, epinephrine, epinephrine plus phentolamine or isoproterenol. After 1 minute of infusion of the indicated drug a second infusion containing acetylcholine was started. After an additional minute hearts were frozen and analyzed for cyclic nucleotide content and enzyme activity. In the presence of the alpha receptor blocking agent, phentolamine, epinephrine is a more effective activator of protein kinase than in its absence. Under these conditions the antagonistic action of acetylcholine on protein kinase activation is more pronounced. In the presence of epinephrine plus phentolamine or in the presence of isoproterenol the antagonistic action of acetylcholine on phosphorylase activity can be accounted for by a reduction in cyclic AMP-protein kinase. This same action of acetylcholine on epinephrine-stimulated phosphorylase in the aabsence of phentolamine, however, cannot be totally accounted for by a reduction in cyclic AMP content or in protein kinase activity.


[Structural variation in the human genome contributes to variation of traits].
The human genome contains a large number of single nucleotide polymorphisms (SNPs) that contribute to normal variation of human traits. Many SNPs have also been shown to affect the development and predisposition of disease. Comparisons of genomes have recently shown that also large DNA segments can vary in structure and number of copies between individuals. A large number of duplications, deletions and inversions has been detected, ranging in size from a few thousand to several millions base pairs. Here we describe the structural variations detected in the human genome, their impact on normal phenotypic variation in the population, and how differences in genome structure may contribute to development of disease. This article is based on studies of literature retrieved through a non-systematic search of PubMed. Many structural variations in the genome overlap with genes. Duplications and deletions may change the copy number of genes, and inversions may disrupt gene structure. Some of the affected genes contribute to phenotypic variation between healthy individuals, while others can predispose to disease or contribute to disease development. Diseases caused by such structural variations constitute a major health problem in the population.


Human cultured epidermis accelerates wound healing regardless of its viability in a diabetic mouse model.
Allogeneic cultured epidermis (allo-CE) is a cultured keratinocyte sheet manufactured from donor cells and promotes wound healing when used in deep dermal burns, donor sites, and chronic ulcers and serves as a wound dressing. Allo-CE is usually cryopreserved to be ready to use. However, the cryopreservation procedure will damage the cell viability, and the influence of Allo-CE, according to its viability or wound healing process, has not been evaluated sufficiently. In this study, we aimed to prove the influence of keratinocyte viability contained in allo-CEs on wound healing. We prepared CEs with Green's method using keratinocytes obtained from a polydactyly patient and then prepared four kinds of CEs with different cell viabilities [fresh, cryopreserved, frozen, and FT (freeze and thaw)]. The cell viabilities of fresh, cryopreserved, frozen, and FT CEs were 95.7%, 59.9%, 16.7%, and 0.0%, respectively. The four CEs had homogeneous characteristics, except for small gaps found in the FT sheet by transmission electron microscopy observation. The four CEs were applied on the full-thickness skin defect of diabetic mice (BKS.Cg-Dock 7m +/+ Leprdb/Jcl), and the wound area and neoepithelium length were evaluated on days 4, 7, and 14. As a result, FT CEs without viable cells similarly promoted epithelialization on days 4 and 7 (p<0.05) and accelerated wound closure on day 7 (p<0.01) as fresh CEs compared with the control group. In conclusion, the promoting effect of allo-CE on wound healing does not depend on cell viability. Lyophilized CEs may be a suitable wound dressing with a long storage period at room temperature.


The vestibular implant: A probe in orbit around the human balance system.
The primary goal of the vestibular implant is to restore the vestibular function in patients with a disabling bilateral vestibular loss for whom there is currently no available treatment. The prototype developed by our team is a hybrid system consisting of a modified cochlear implant incorporating additional vestibular electrodes. Therefore, in addition of delivering sound information it is also capable of delivering motion information to the central nervous system using electrical stimulation. To date, thirteen patients have been implanted with such vestibular implant prototypes. For ethical reasons, only deaf ears were implanted and all patients experienced a clinical benefit from the hearing rehabilitation. The recent demonstration of partial restoration of the vestibulo-ocular and the vestibulo-collic reflexes in implanted patients suggests that gaze stabilization and postural control, fundamental functions of the balance system, can be artificially restored using a vestibular implant. This allows us to glimpse a useful clinical application in a near future. In parallel, we show how the vestibular implant provides a unique opportunity to explore the integration of the vestibular sensory input into the multisensory, multimodal balance system in humans, since it is able to selectively stimulate the vestibular system.


Amantadine-resistant influenza A (H3N2) viruses in Iran.
Adamantanes have been used for the prophylaxis and treatment of Influenza A virus (IAV) infections worldwide. However, they have limited use because of increasing number of resistant viruses during recent years. In investigating the frequency of amantadine-resistant IAVs (H3N2) circulating in Iran in 2005-2008, we found that M2 sequences of recently circulating viruses that were amantadine-resistant contained a Ser31Asn mutation. Thus, adamantanes should not be used for treatment or prophylaxis of recent IAVs (H3N2) infections. In future, their potential use will depend on the resistance of circulating viruses.


Cutaneous fixed drug eruption to fluconazole.
Fixed drug eruption (FDE) is an uncommon medication-induced cutaneous reaction. A case of fluconazole-induced FDE is described. A 64-year-old woman presented with eight ovoid hyperpigmented patches on the arms, palm and lower leg that had recurred multiple times at the identical sites at seemingly random intervals over the prior six months. The clinicopathologic diagnosis strongly favored FDE, though the culprit medication remained elusive. Further evaluation and oral rechallenge confirmed the diagnosis of FDE to fluconazole. The patient had not related the eruption to this medication due to the short courses of therapy and prior use without incident. FDE to fluconazole has only been rarely reported in the literature. The presentation and evaluation of FDE is reviewed.


Response-reinforcer relationships and improved learning in autistic children.
In order to affect more rapid response acquisition for autistic children, researchers have recently begun to investigate the functional relationships of reinforcers to other components of the operant conditioning paradigm. Previous research suggested that functional relationships between target behaviors and reinforcers might be especially effective. For example, locating a reward inside a container might be a more efficient way to teach a child to open the container than by handling the child a reward for opening an empty container. The present experiment assessed, within a multiple baseline design, the possibility of improving autistic children's learning by changing arbitrary response-reinforcer relationships (while holding target behaviors and reinforcers constant) so that the target behaviors became functional (i.e., a direct part of the response chain required for the child to procure the reinforcer). The results showed that: (1) arranging functional response-reinforcer relationships produced immediate improvement in the children's learning, and resulted in rapid acquisition of criterion level responding; and (2) high levels of correct responding initially produced by functional response-reinforcer relationships were continued even when previously ineffective arbitrary response-reinforcer conditions were reinstated. The results are discussed in terms of understanding and improving autistic children's learning.


[Continuous determination of Cu, Cr, Co, Ni, Pb, Cd of geo-chemical exploration samples by HG-AAS].
The method of analysis to the determination of Cu, Cr, Co, Ni, Pb, Cd in the phase analysis of geo-chemical exploration samples by the HG-AAS has been introduced. In recent years, the workers of geo-chemical exploration are more interested in technology of phase analysis with the development of search for mineral in geology. In phase analysis, contents of the same element with different phase are largely differ so that it brings difficulties for extracting, preparation and determination of the solution. In addition, the exist of many-common elements, especially Ca, Mg, Mn, Fe, are very easy to bring effects. But the contents of Cu, Cr, Co, Ni, Pb, Cd in the analysis solution of water-extractable phase and ion phase, are low and difficult to determination. During the extracting of the phase, to carry out parallel samples analysis, one sample will prepare eight solution at least and large work. So it is necessary to search for a simple and quickly liable method of analysis. On determination, using phosphoric acid as matrix modifier, it not only eliminated the effect of matrix, but also improved the precision of all kinds of elements.


Health Professions Digital Education on Antibiotic Management: Systematic Review and Meta-Analysis by the Digital Health Education Collaboration.
Inappropriate antibiotic prescription is one of the key contributors to antibiotic resistance, which is managed with a range of interventions including education. We aimed to summarize evidence on the effectiveness of digital education of antibiotic management compared to traditional education for improving health care professionals' knowledge, skills, attitudes, and clinical practice. Seven electronic databases and two trial registries were searched for randomized controlled trials (RCTs) and cluster RCTs published between January 1, 1990, and September 20, 2018. There were no language restrictions. We also searched the International Clinical Trials Registry Platform Search Portal and metaRegister of Controlled Trials to identify unpublished trials and checked the reference lists of included studies and relevant systematic reviews for study eligibility. We followed Cochrane methods to select studies, extract data, and appraise and synthesize eligible studies. We used random-effect models for the pooled analysis and assessed statistical heterogeneity by visual inspection of a forest plot and calculation of the I2 statistic. Six cluster RCTs and two RCTs with 655 primary care practices, 1392 primary care physicians, and 485,632 patients were included. The interventions included personal digital assistants; short text messages; online digital education including emails and websites; and online blended education, which used a combination of online digital education and traditional education materials. The control groups received traditional education. Six studies assessed postintervention change in clinical practice. The majority of the studies (4/6) reported greater reduction in antibiotic prescription or dispensing rate with digital education than with traditional education. Two studies showed significant differences in postintervention knowledge scores in favor of mobile education over traditional education (standardized mean difference=1.09, 95% CI 0.90-1.28; I2=0%; large effect size; 491 participants [2 studies]). The findings for health care professionals' attitudes and patient-related outcomes were mixed or inconclusive. Three studies found digital education to be more cost-effective than traditional education. None of the included studies reported on skills, satisfaction, or potential adverse effects. Findings from studies deploying mobile or online modalities of digital education on antibiotic management were complementary and found to be more cost-effective than traditional education in improving clinical practice and postintervention knowledge, particularly in postregistration settings. There is a lack of evidence on the effectiveness of other digital education modalities such as virtual reality or serious games. Future studies should also include health care professionals working in settings other than primary care and low- and middle-income countries. PROSPERO CRD42018109742; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=109742.


A nicotine delivery device without the nicotine? Tobacco industry development of low nicotine cigarettes.
Defining harm reduction and regulating potentially reduced exposure products (PREPs), including low nicotine products, are key issues in tobacco control policy. The US Congress has been considering legislation authorising the Food and Drug Administration (FDA) to regulate tobacco products. To investigate tobacco industry perceptions, interests, motivations, and knowledge regarding the marketability of low nicotine tobacco products. Qualitative analysis of internal tobacco industry documents identified in the Legacy Tobacco Documents Library between February 2002 and June 2004. Search terms included low-, no-, reduced-nicotine; denicotinization; low-, reduced- alkaloids; Next; de-nic; and key names of people, organisations, projects, and their common abbreviations and acronyms. The tobacco industry has made repeated efforts to develop low nicotine cigarettes. Reasons for doing so include consumer appeal and economic importance in a highly competitive cigarette market for "healthier" products. The industry considered the development of a new "denic" market segment a critical challenge. The tobacco industry exploits consumer misunderstanding of the health effects of nicotine in development and marketing efforts. The industry has risked the development of a less addictive product to expand the market reach of tobacco products based on perceived health benefits and appeal to quitters.


Flaxseed Reduces Cancer Risk by Altering Bioenergetic Pathways in Liver: Connecting SAM Biosynthesis to Cellular Energy.
This article illustrates how dietary flaxseed can be used to reduce cancer risk, specifically by attenuating obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). We utilize a targeted metabolomics dataset in combination with a reanalysis of past work to investigate the "metabo-bioenergetic" adaptations that occur in White Leghorn laying hens while consuming dietary flaxseed. Recently, we revealed how the anti-vitamin B6 effects of flaxseed augment one-carbon metabolism in a manner that accelerates S-adenosylmethionine (SAM) biosynthesis. Researchers recently showed that accelerated SAM biosynthesis activates the cell's master energy sensor, AMP-activated protein kinase (AMPK). Our paper provides evidence that flaxseed upregulates mitochondrial fatty acid oxidation and glycolysis in liver, concomitant with the attenuation of lipogenesis and polyamine biosynthesis. Defatted flaxseed likely functions as a metformin homologue by upregulating hepatic glucose uptake and pyruvate flux through the pyruvate dehydrogenase complex (PDC) in laying hens. In contrast, whole flaxseed appears to attenuate liver steatosis and body mass by modifying mitochondrial fatty acid oxidation and lipogenesis. Several acylcarnitine moieties indicate Randle cycle adaptations that protect mitochondria from metabolic overload when hens consume flaxseed. We also discuss a paradoxical finding whereby flaxseed induces the highest glycated hemoglobin percentage (HbA1c%) ever recorded in birds, and we suspect that hyperglycemia is not the cause. In conclusion, flaxseed modifies bioenergetic pathways to attenuate the risk of obesity, type 2 diabetes, and NAFLD, possibly downstream of SAM biosynthesis. These findings, if reproducible in humans, can be used to lower cancer risk within the general population.


Locking versus nonlocking construct in an osteoporotic, segmental fibula defect model.
Early studies on the treatment of osteoporotic distal fibular fractures suggest that poor bone quality can compromise fixation and, therefore, clinical outcome. Multiple prior biomechanical studies evaluated length-stable fracture models with destructive load-to-failure protocols, which may not represent a clinically relevant failure mode. The current authors compared a lateral locked construct with 2 distinct nonlocked constructs in an osteoporotic, segmental fibula defect model. Eighteen adult cadaveric ankles were randomized to a one-third tubular plate with nonlocking screws, a precontoured fibular plate with nonlocking screws, or the same pre-contoured plate with locking screws. Each was nondestructively loaded with an external rotation of 2.5 Nm for 10,000 cycles. The primary outcome was the change in construct stiffness. Secondary outcomes included maximal rotational displacement and change in insertion torques. Average increase in stiffness of the one-third tubular plate was 0.35 Nm/degree (P<.001), which was significantly greater than that in the nonlocking and locking precontoured plates (0.15 and 0.17 Nm/degree, respectively; P=.69). All 3 constructs externally rotated to 11.7°±4.6°, 8.6°±3.6°, and 10.9°±4.7°, respectively (P=.50). Average loss of insertion torque in the 4 proximal positions was 32.7%±19%, 41.3%±20.2%, 57.8%±19%, and 64.9%±29.2% (P>.05). Average loss in the 4 distal positions for nonlocking constructs (71.6%±21%, 70.4%±26.4%, 93.1%±11%, and 83.3%±35.4%) was significantly different from that for the locking construct (15%±21.4%, 11.7%±24%, 9.2%±9.2%, and 20.8%±23.3%) (P<.05). No evidence in the current study supports the use of a locking plate for osteoporotic specimens.


Verbal fluency in Alzheimer's disease and mild cognitive impairment in individuals with low educational level and its relationship with reading and writing habits.
Verbal fluency (VF) has contributed to building cognitive maps as well as differentiating healthy populations from those with dementia. To compare the performance of healthy controls and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) in two semantic VF tasks (animals/clothes) and a phonemic VF task (letter P). Also, to analyze the relationship between the frequency of reading and writing habits (FRWH) and VF in individuals with low educational level. Sixty-seven older adults aged 60-80 years and with 2-8 years of schooling were divided into three groups: controls (n=25), older adults with MCI (n=24), and older adults with AD (n=18). We analyzed the type, mean size, and number of clusters, switches, intersections, and returns. A post-hoc single-factor ANOVA analysis was conducted to verify differences between groups. Total words in the phonemic VF and the animal category discriminated the three groups. Regarding the animal category, AD patients performed worse than controls in the total number of words, taxonomic clusters, returns, and number of words remembered. We found a moderate correlation between FRWH and total number of words in the phonemic fluency. Semantic (animate) and phonemic (total words) VF differentiated controls and clinical groups from each other - the phonemic component was more related to FRWH than the semantic one. The phonemic VF seems to be more related to cognitive reserve. VF tasks, considering total words and cluster analyses, are a valuable tool to test healthy and cognitively impaired older adults who have a low educational level.


Epidemiology of clinical benign prostatic hyperplasia.
Clinical benign prostatic hyperplasia (BPH) is one of the most common diseases in ageing men and the most common cause of lower urinary tract symptoms (LUTS). The prevalence of BPH increases after the age of 40 years, with a prevalence of 8%-60% at age 90 years. Some data have suggested that there is decreased risk among the Asians compared to the western white population. Genetics, diet and life style may play a role here. Recent reports suggest the strong relationship of clinical BPH with metabolic syndrome and erectile dysfunction, as well as the possible role of inflammation as a cause of the prostatic hyperplasia. Lifestyle changes including exercise and diet are important strategies in controlling this common ailment.


Sinusotomy with Intraoperative Mitomycin C Administration in Selected Eyes with Advanced Glaucomatous Damage.
Purpose: The surgical outcome of sinusotomy with intra-operative mitomycin C administration (0.04%, 3 minutes) in a total of 17 selected glaucoma eyes from 14 patients with advanced glaucomatous damage was examined. Selection criteria were (1) an eye with visual field defect threatening the central fixation, while the central visual acuity of the contralateral eye was already impaired; and/or (2) an aphakic or pseudophakic eye with advanced glaucomatous damage in a patient of advanced age.Materials and Methods: Patient's age, preoperative mean deviation (Humphrey 30-2 program) and intraocular pressure (IOP) averaged 63.5 +/- 11.1 (mean +/- standard deviation) years, -18.6 +/- 6.7 (mean +/- standard deviation) dB, and 20.7 +/- 4.1 (mean +/- standard deviation) mmHg, respectively.Results: No postoperative hypotony (< 5 mmHg) or deterioration of visual acuity equal to or more than 2 lines of Ishihara Visual Acuity Chart were encountered and the mean postoperative IOP ranged between 11 and 13 mmHg up to 18 months postoperatively with less medication than preoperatively. The success was defined as IOP </= 15 mmHg without oral carbonic anhydrase inhibitors and with less medication than preoperatively. The life-table method analysis according to the above criteria yielded a success probability of 70.6 +/- 11.1 (mean +/- standard deviation) % (standard error) at 18 months postoperatively.


Constraining the formation and transport of lunar impact glasses using the ages and chemical compositions of Chang'e-5 glass beads.
Impact glasses found in lunar soils provide a possible window into the impact history of the inner solar system. However, their use for precise reconstruction of this history is limited by an incomplete understanding of the physical mechanisms responsible for their origin and distribution and possible relationships to local and regional geology. Here, we report U-Pb isotopic dates and chemical compositions of impact glasses from the Chang'e-5 soil and quantitative models of impact melt formation and ejection that account for the compositions of these glasses. The predominantly local provenance indicated by their compositions, which constrains transport distances to <~150 kilometers, and the age-frequency distribution are consistent with formation mainly in impact craters 1 to 5 kilometers in diameter. Based on geological mapping and impact cratering theory, we tentatively identify specific craters on the basaltic unit sampled by Chang'e-5 that may have produced these glasses and compare their ages with the impact record of the asteroid belt.


Localization of isoketal adducts in vivo using a single-chain antibody.
Isoketals are highly reactive gamma-ketoaldehydes formed by the oxidation of arachidonic acid that rapidly adduct to proteins. To investigate the formation of isoketal adducts in vivo, we isolated and characterized a single-chain antibody from a phage displayed recombinant ScFv library that bound a model peptide adducted with synthetic 15-E2-isoketal. Recognition of isoketal adduct by this anti-isoketal adduct single-chain antibody was essentially independent of the amino acid sequence of adducted peptides or proteins. The antibody did not cross-react with 4-hydroxynonenal or 4-oxononanal adducts or with 15-F2t-isoprostane (8-iso-prostaglandin F2alpha). We investigated the formation of isoketal adducts in a well-established model of oxidative injury, hyperoxia. Exposure to >98% oxygen for 7 h dramatically increased both the number of immunoreactive airway epithelial cells and the intensity of immunoreactivity compared with animals exposed to normal room air (21% oxygen). We conclude that isoketal adducts form in epithelial cells as a result of high oxygen exposure and that this single-chain antibody provides a valuable tool to localize the formation of isoketal adducts in tissues in vivo.


Genetic modification of respiratory capacity in potato.
Mitochondrial respiration was altered in transgenic potato (Solanum tuberosum) lines by overexpression of the alternative oxidase Aox1 gene. Overexpressing lines showed higher levels of Aox1 mRNA, increased levels of alternative oxidase protein(s), and an unusual higher molecular weight polypeptide, which may be a normal processing/modification intermediate. Evidence suggests that the alternative oxidase protein is further processed/modified beyond removal of the transit peptide. Addition of pyruvate to mitochondria oxidizing succinate or NADH increased the alternative pathway capacity but did not eliminate the difference in the capacity between these two substrates. Induction of alternative pathway capacity by aging of tubers appeared to be more dependent on increased levels of alternative oxidase protein than changes in its oxidation state. In leaf and tuber mitochondria, overexpressing lines possessed higher alternative pathway capacity than the control line, which suggests that changing the alternative oxidase protein level by genetic engineering can effectively change alternative pathway capacity.


Formation Flight of Multiple UAVs via Onboard Sensor Information Sharing.
To monitor large areas or simultaneously measure multiple points, multiple unmanned aerial vehicles (UAVs) must be flown in formation. To perform such flights, sensor information generated by each UAV should be shared via communications. Although a variety of studies have focused on the algorithms for formation flight, these studies have mainly demonstrated the performance of formation flight using numerical simulations or ground robots, which do not reflect the dynamic characteristics of UAVs. In this study, an onboard sensor information sharing system and formation flight algorithms for multiple UAVs are proposed. The communication delays of radiofrequency (RF) telemetry are analyzed to enable the implementation of the onboard sensor information sharing system. Using the sensor information sharing, the formation guidance law for multiple UAVs, which includes both a circular and close formation, is designed. The hardware system, which includes avionics and an airframe, is constructed for the proposed multi-UAV platform. A numerical simulation is performed to demonstrate the performance of the formation flight guidance and control system for multiple UAVs. Finally, a flight test is conducted to verify the proposed algorithm for the multi-UAV system.


Targeting pathophysiological rhythms: prednisone chronotherapy shows sustained efficacy in rheumatoid arthritis.
This 9-month open-label extension of the Circadian Administration of Prednisone in Rheumatoid Arthritis Study (CAPRA 1) investigated the long-term safety and efficacy of prednisone chronotherapy with a novel modified-release (MR) prednisone for up to 12 months. Of 288 patients with rheumatoid arthritis originally randomised to MR or immediate-release (IR) prednisone, 249 continued with prednisone chronotherapy (2-10 mg/day) in the 9-month open-label extension. Duration of morning stiffness of the joints (MS), disease activity scores (DAS28), American College of Rheumatology (ACR20) responses and plasma levels of interleukin 6 (IL-6) were assessed. Safety was analysed from adverse event reports and laboratory investigations. During the 3-month double-blind phase, patients in the MR group achieved a reduction in MS of 33.1% while no change was observed in the IR group. After 6 months of treatment, MS was reduced in the IR/MR group by 54% and in the MR/MR group by 56%. MS reduction after 12 months was 45% (IR/MR group) and 55% (MR/MR group). Plasma levels of IL-6 declined on MR treatment. DAS28 was reduced from 5.8 to 4.8 (MR/MR group) and 4.9 (IR/MR group), respectively. 37% of the 219 patients who completed the 12-month study achieved improvement according to the ACR20 criteria. Adverse events did not differ from the known profile of low-dose prednisone. Prednisone chronotherapy with the MR tablet was safe and well tolerated and provided a sustained improvement which resulted in a better benefit to risk ratio of low-dose glucocorticoid treatment for at least 12 months.


Fragmentation impairs the microclimate buffering effect of tropical forests.
Tropical forest species are among the most sensitive to changing climatic conditions, and the forest they inhabit helps to buffer their microclimate from the variable climatic conditions outside the forest. However, habitat fragmentation and edge effects exposes vegetation to outside microclimatic conditions, thereby reducing the ability of the forest to buffer climatic variation. In this paper, we ask what proportion of forest in a fragmented ecosystem is impacted by altered microclimate conditions driven by edge effects, and extrapolate these results to the whole Atlantic Forest biome, one of the most disturbed biodiversity hotspots. To address these questions, we collected above and below ground temperature for a full year using temperature sensors placed in forest fragments of different sizes, and at different distances from the forest edge. In the Atlantic forests of Brazil, we found that the buffering effect of forests reduced maximum outside temperatures by one third or more at ground level within a forest, with the buffering effect being stronger below-ground than one metre above-ground. The temperature buffering effect of forests was, however, reduced near forest edges with the edge effect extending up to 20 m inside the forest. The heavily fragmented nature of the Brazilian Atlantic forest means that 12% of the remaining biome experiences altered microclimate conditions. Our results add further information about the extent of edge effects in the Atlantic Forest, and we suggest that maintaining a low perimeter-to-area ratio may be a judicious method for minimizing the amount of forest area that experiences altered microclimatic conditions in this ecosystem.


[Familial bullous disease of the lungs as a cause of spontaneous pneumothorax].
Problems of surgical treatment of familial spontaneous pneumothorax, which is a manifestation of a hereditary form of bullous disease of the lungs, are discussed. Study of 2 families showed that the disease is inherited according to the autosome-dominant type with incomplete penetrance and/or variation expressivity. Operation was performed on 5 of 9 patients. Bullectomy and pleurodesis by means of parietal pleurectomy were conducted. Follow-up for periods of 1 to 27 years showed surgical treatment to be effective.


Bacteriology of aspiration pneumonia in children.
Aspiration pneumonia in adults has been shown to involve anaerobes about 90% of the time. Studies of the bacteriology of aspiration pneumonia in children done in the past have either failed to exclude the oral and upper respiratory tract flora or have not utilized proper anaerobic culture techniques or both. In the present study. 74 institutionalized children with aspiration pneumonia were studied by percutaneous transtracheal aspiration. Their average age was 8 years. Fifty-two patients had pneumonitis, 12, necrotizing pneumonia, and 10, lung abscess. Only one patient (with lung abscess) had a complicating empyema. There was an average of five bacteria isolated per specimen--2.8 anaerobes and 2.2 nonanaerobes. The predominant anaerobic isolates were Gram-positive cocci, Bacteroides melaninogenicus, and fuso-bacteria; there were ten patients who yielded members of the Bacteroides fragilis group. The predominant nonanaerobes were alpha-hemolytic streptococci, Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. Thus, aspiration pneumonia in children, as in adults, commonly involves anaerobic bacteria. When aspiration occurs in a medical institution, nosocomial pathogens which are aerobic or facultative will also often be involved, in both children and adults.


Effects of parathyroid hormone on puppies during development of Ca and vitamin D deficiency.
The acute effects of parathyroid extract (PTE) were studied repeatedly in young dogs (prelabeled with 45Ca and [3H]tetracycline) during the development of calcium (Ca) and vitamin D deficiency. Blood Ca and radioactivity changes were monitored sequentially after subcutaneous PTE, injected seven times over 63 days. In control dogs, all sequential responses to acute PTE challenges were constant in both magnitude of increase and time at which maximum response occurred over the entire experiment. Under chronic Ca and D deficiency, plasma 25-hydroxyvitamin D in experimental dogs decreased continuously to very low levels at 63 days, whereas 1,25-dihydroxyvitamin D initially increased to a maximum at 32 days and thereafter decreased. In response to an acute challenge of PTE, dogs on the deficient diet for 3 and 10 days showed a greater response of blood Ca and 45Ca than the controls but subsequently showed a smaller response than controls after 49 and 63 days on the deficient diet. Compared with control dogs, the time of maximal response of blood Ca and 45Ca to PTE occurred much earlier in dogs that were on the deficient diet for 35-63 days. The blood [3H]tetracycline response (index of bone resorption) to exogenous PTE in the deficient dogs, however, was constant and similar to that of the control dogs during the entire period. The data suggest that the bone resorption response to PTE was normal in Ca- and D-deficient puppies with hypocalcemia.(ABSTRACT TRUNCATED AT 250 WORDS)


Bioassay of some Egyptian isolates of Bacillus thuringiensis against Culex pipiens (Diptera: Culicidae).
Some Egyptian isolates of Bacillus thuringiensis (BT) were grown on economic media contain 4% of fodder yeast in tap water and incubated under shaking conditions for four days. The biological activities of these isolates against Culex pipiens (Diptera: Culicidae) were carried out to determine their effectiveness against field and laboratory strains of 3rd larval instar. All isolates of BT were more pathogenic to laboratory strain. causing up to 84% larval mortality. The insecticidal activities of these isolates were extended to the pupal stage causing a significant effect on pupal mortality in both strains tested. A pronounced effect on adult emergence was noticed with remarkable adult malformations especially in the case of the isolate No. 2. The reproductivety of females was affected significantly by all isolates applied.


[Health care, needs and barriers in seeking medical care for global health and sexual and reproductive health, among students from Félix Houphouët-Boigny University, Abidjan, Côte d'Ivoire].
In Ivory Coast, little is known about health needs and health access barriers among young people. The aim of this study was to describe health provision, health needs and barriers when seeking medical care, with an emphasis on sexual and reproductive health, and the acceptability of a medical examination for students attending their first year at the Houphouët-Boigny University, Abidjan, Ivory Coast. We conducted a representative cross-sectional study among second year students who were selected by two-stage equiprobable random sampling. In-depth interviews were conducted among students and the university health center staff. Five hundred and forty three students (322 men and 221 women) answered a questionnaire (participation rate 98.4%). Among women who ever had sex, 38.4% (95%CI [30.5%-47.0%]) had unmet contraception needs and 31.2% [23.7%-40.0%] had experienced an unwanted pregnancy. Fear about impaired fertility was the leading reason for non-use of hormonal contraception, the method of choice among most students. The main health problems among students, by order of frequency were malaria (54.3%), respiratory infection (44.6%), constipation (28.0%) and psychological problems (25.9%). High cost perception of services offered, despite their gratuity, were the main barriers against access to the university health center, indicating a lack of communication about this structure and its services. The majority of students favored the establishment of a medical examination during the first year at the university. Establishing a medical examination would improve health center visibility. The following services could be offered: (i) HIV, chlamydia and gonorrhea screening, (ii) hepatitis B virus screening and vaccination, (iii) provision and information about contraceptive methods, (iv) presentation of the university health center services. Dedicated spaces where students could have access to information about health-related topics (e.g. sexuality, nutrition, depression) could complete the university's healthcare offer.


Flavonolignan 2,3-dehydrosilydianin activates Nrf2 and upregulates NAD(P)H:quinone oxidoreductase 1 in Hepa1c1c7 cells.
Silybum marianum (milk thistle) is a medicinal plant used for the treatment of various liver disorders. This study examined whether the main flavonolignans from S. marianum (i.e. silybin, silychristin, silydianin) and their 2,3-dehydro derivatives (i.e. 2,3-dehydrosilybin, 2,3-dehydrosilychristin, 2,3-dehydrosilydianin) activate the Nrf2 pathway, which regulates the expression of genes encoding many cytoprotective enzymes, including NAD(P)H:quinone oxidoreductase 1 (NQO1). After 48h of exposure, 2,3-dehydrosilydianin at concentrations of 25μM and higher significantly elevated the activity of NQO1 in murine hepatoma Hepa1c1c7 cells. In contrast, other tested compounds at non-cytotoxic concentrations had a mild or negligible effect on the NQO1 activity. Using a luciferase reporter assay, 2,3-dehydrosilydianin was found to significantly activate transcription via the antioxidant response element in stably transfected human AREc32 reporter cells. Moreover, 2,3-dehydrosilydianin caused the accumulation of Nrf2 and significantly induced the expression of the Nqo1 gene at both the mRNA and protein levels in Hepa1c1c7 cells. We found that 2,3-dehydrosilydianin also increased to some extent the expression of other Nrf2 target genes, namely of the heme oxygenase-1 gene (Hmox1) and the glutamate-cysteine ligase modifier subunit gene (Gclm). We conclude that 2,3-dehydrosilydianin activates Nrf2 and induces Nrf2-mediated gene expression in Hepa1c1c7 cells.


Does the leakage radiation profile mirror the intensity profile of surface plasmon polaritons?
Although the leakage radiation (LR) image intensity is considered to be in proportion to the surface plasmon polariton (SPP) intensity at the metal-air interface, it has not been proven experimentally, to the best of our knowledge. Here we investigate the relationship between the measured LR intensity profile of SPP interference fringes, which are produced by two SPP launching gratings, and the simulated SPP intensity. The experimental modulation depths agree well with the simulation result of the in-plane electric field component of SPPs, which demonstrates that the image intensity in LR microscopy provides the intensity profile of the in-plane component.


Seed Mass and the Evolution of Early-Seedling Etiolation.
The influence of seed mass on the evolution of seedling-foraging strategies for light acquisition under deep shade was assessed in a comparative study of etiolation behavior. This was done across 50 Australian species varying in seed reserve mass by eight orders of magnitude during the first week after germination. Proportional increase in hypocotyl length in shade compared to light was similar across the range of seed reserve mass. Etiolation did not lead to increase in hypocotyl length per wet mass, in other words, etiolated hypocotyls were not thinner. However, hypocotyl length per dry mass did increase, more so in smaller-seeded species. Thus, part of the hypocotyl elongation was because of increased water content, which would increase vulnerability to loss of turgor. There was also reallocation of dry matter from root to hypocotyl, again more so in smaller-seeded species, which would decrease anchorage strength and increase vulnerability to soil drying. Results were very similar when considered as correlated evolutionary divergences, compared to the cross-species patterns. The higher-risk etiolation behavior of smaller-seeded species can be understood through their having little to lose. Because they hold less reserve resource uncommitted and attempt a faster initial growth rate, their chances of sustained longevity in shade below the compensation point are very low.


Nicotinamide Antagonizes Lipopolysaccharide-Induced Hypoxic Cell Signals in Human Macrophages.
Mechanisms to control the immune response are important to pathogen evasion and host defense. Gram-negative bacteria are common pathogens that can activate host immune responses through their outer membrane component, LPS. Macrophage activation by LPS induces cell signals that promote hypoxic metabolism, phagocytosis, Ag presentation, and inflammation. Nicotinamide (NAM) is a vitamin B3 derivative and precursor in the formation of NAD, which is a required cofactor in cellular function. In this study, treatment of human monocyte-derived macrophages with NAM promoted posttranslational modifications that antagonized LPS-induced cell signals. Specifically, NAM inhibited AKT and FOXO1 phosphorylation, decreased p65/RelA acetylation, and promoted p65/RelA and hypoxia-inducible transcription factor-1α (HIF-1α) ubiquitination. NAM also increased prolyl hydroxylase domain 2 (PHD2) production, inhibited HIF-1α transcription, and promoted the formation of the proteasome, resulting in reduced HIF-1α stabilization, decreased glycolysis and phagocytosis, and reductions in NOX2 activity and the production of lactate dehydrogenase A. These NAM responses were associated with increased intracellular NAD levels formed through the salvage pathway. NAM and its metabolites may therefore decrease the inflammatory response of macrophages and protect the host against excessive inflammation but potentially increase injury through reduced pathogen clearance. Continued study of NAM cell signals in vitro and in vivo may provide insight into infection-associated host pathologies and interventions.


Comparative genomic analysis of genogroup 1 and genogroup 2 rotaviruses circulating in seven US cities, 2014-2016.
For over a decade, the New Vaccine Surveillance Network (NVSN) has conducted active rotavirus (RVA) strain surveillance in the USA. The evolution of RVA in the post-vaccine introduction era and the possible effects of vaccine pressure on contemporary circulating strains in the USA are still under investigation. Here, we report the whole-gene characterization (eleven ORFs) for 157 RVA strains collected at seven NVSN sites during the 2014 through 2016 seasons. The sequenced strains included 52 G1P[8], 47 G12P[8], 18 G9P[8], 24 G2P[4], 5 G3P[6], as well as 7 vaccine strains, a single mixed strain (G9G12P[8]), and 3 less common strains. The majority of the single and mixed strains possessed a Wa-like backbone with consensus genotype constellation of G1/G3/G9/G12-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1, while the G2P[4], G3P[6], and G2P[8] strains displayed a DS-1-like genetic backbone with consensus constellation of G2/G3-P[4]/P[6]/P[8]-I2-R2-C2-M2-A2-N2-T2-E2-H2. Two intergenogroup reassortant G1P[8] strains were detected that appear to be progenies of reassortment events between Wa-like G1P[8] and DS-1-like G2P[4] strains. Two Rotarix® vaccine (RV1) and two RV5 derived (vd) reassortant strains were detected. Phylogenetic and similarity matrices analysis revealed 2-11 sub-genotypic allelic clusters among the genes of Wa- and DS-1-like strains. Most study strains clustered into previously defined alleles. Amino acid (AA) substitutions occurring in the neutralization epitopes of the VP7 and VP4 proteins characterized in this study were mostly neutral in nature, suggesting that these RVA proteins were possibly under strong negative or purifying selection in order to maintain competent and actual functionality, but fourteen radical (AA changes that occur between groups) AA substitutions were noted that may allow RVA strains to gain a selective advantage through immune escape. The tracking of RVA strains at the sub-genotypic allele constellation level will enhance our understanding of RVA evolution under vaccine pressure, help identify possible mechanisms of immune escape, and provide valuable information for formulation of future RVA vaccines.


Second-hand smoke increases bronchial hyperreactivity and eosinophilia in a murine model of allergic aspergillosis.
Involuntary inhalation of tobacco smoke has been shown to aggravate the allergic response. Antibodies to fungal antigens such as Aspergillus fumigatus (Af) cause an allergic lung disease in humans. This study was carried out to determine the effect of environmental tobacco smoke (ETS) on a murine model of allergic bronchopulmonary aspergillosis (ABPA). BALB/c mice were exposed to aged and diluted sidestream cigarette smoke to simulate 'second-hand smoke'. The concentration was consistent with that achieved in enclosed public areas or households where multiple people smoke. During exposure, mice were sensitized to Af antigen intranasally. Mice that were sensitized to Af antigen and exposed to ETS developed significantly greater airway hyperreactivity than did mice similarly sensitized to Af but housed in ambient air. The effective concentration of aerosolized acetylcholine needed to double pulmonary flow resistance was significantly lower in Af + ETS mice compared to the Af + AIR mice. Immunological data that supports this exacerbation of airway hyperresponsiveness being mediated by an enhanced type 1 hypersensitivity response include: eosinophilia in peripheral blood and lung sections. All Af sensitized mice produced elevated levels of IL4, IL5 and IL10 but no IFN-gamma indicating a polarized Th2 response. Thus, ETS can cause exacerbation of asthma in ABPA as demonstrated by functional airway hyperresponsiveness and elevated levels of blood eosinophilia.


Response of growth performance and cecum microbial community to cyclic heat stress in broilers.
Heat stress (HS) can affect growth performance through alterations in specific gut microbiota, which greatly threatens poultry production. How HS affects the mechanisms of microbial changes in the poultry cecum and the complex interactions between cecal microbial changes and growth performance have not yet been well evaluated. This study was conducted to examine the changes in growth performance and cecal microbiotal community in cyclic heat stress (CHS)-treated broilers. A total of 200 twenty-eight-day-old female Arbor Acres (AA) broilers were equally allotted into neutral ambient temperature group (TN group, 24 ± 1°C, 24 h/day) and CHS group (33 ± 1°C, 8 h/day) with five replicates of 10 broilers each, respectively. Growth performance, cecum microbial diversity, flora composition, and community structure were analyzed on days 35 and 42. The decreased average daily feed intake (ADFI), average daily gain (ADG), and the increased feed/gain ratio (F:G) were observed in heat-stressed broilers on days 35 and 42. The alpha and beta diversity index had no significant changes at the two experimental periods (P > 0.05). At the genus level, CHS significantly increased the relative abundance of Enterococcus at 42 days (P < 0.05). Based on the analysis of linear effect size feature selection, CHS made an enriched Reyranella and a reduced Romboutsia and Ruminiclostridium at 35 days of age (P < 0.05). CHS made an enriched Weissella and Enterococcus at 42 days of age (P < 0.05). The present study revealed that CHS reduces broiler growth performance and alters the microbial community of the cecum microbiota and the abundance of species. These findings are of critical importance to alleviate the negative effects of CHS on broiler chickens' growth performance by maintaining gut microbial balance.