Beta Changes Induced by Acute Hand Loss Model during NMES.
Neuromuscular electrical stimulation (NMES) has been demonstrated to effectively modulate cortical activities by evoking muscle contraction in upper limb and generating joint movements, which showed an excellent performance in motor rehabilitation. However, due to hand loss and cortical function reorganization induced by hand amputation, how neural activities in sensorimotor cortex response to NMES-evoked muscle contraction in the end of an amputation stump is not clear. In this paper, Ischemic nerve block (INB) technique was used to build an acute hand loss model, and 64-channel EEG signals were recorded from 11 healthy subjects to perform a 2×2 factorial design protocol, with the INB state and the current intensity as factors. The changes of NMES-evoked sensorimotor cortical activities were quantified by computing Beta-band event-related desynchronization (Beta ERD) patterns and the time-varying functional connectivity using adaptive directed transfer function (ADTF) before and during INB. The acute hand "loss" resulted in ipsilateral dominance of Beta ERD induced by NMES with two current intensities in the topographic maps, that is, ipsilateral Beta ERD was significantly higher than that the contralateral one (p<0.05). However, before INB, Beta ERD in the contralateral sensorimotor cortex induced by NMES above motor threshold was significantly higher than that in the ipsilateral area (p< 0.01). Meanwhile, whatever before or during INB, clustering coefficients of the ADTF network in sensorimotor cortex showed temporal dynamics during two NMES tasks. During INB, NMES above motor threshold-evoked lower clustering coefficients of the time-varying network in sensorimotor cortex than that before INB (p<0.05). The present results suggest that the loss of the hand proprioception will degrade cortical activities in the contralateral area, and increase cortical activities in the ipsilateral area compensatively responding to NMES. This finding may be particularly important to improve the reconstruction of the proprioception function of hand prosthesis.


DPOFA, a Cl⁻/HCO₃⁻ exchanger antagonist, stimulates fluid absorption across basolateral surface of the retinal pigment epithelium.
Retinal detachment is a disorder of the eye in which sensory retina separates from the retinal pigment epithelium (RPE) due to accumulation of fluid in subretinal space. Pharmacological stimulation of fluid reabsorption from subretinal space to choroid across the RPE has been suggested as a treatment strategy for retinal detachment. DPOFA, (R)-(+)-(5,6-dichloro 2,3,9,9a-tetrahydro 3-oxo-9a-propyl-1H-fluoren-7-yl)oxy]acetic acid, is an abandoned drug capable of inhibiting Cl⁻/HCO₃⁻ exchanger activity. We hypothesized that DPOFA may increase fluid absorption across basolateral surface of the RPE. Reverse transcription polymerase chain reaction (RT-PCR) analysis of mRNA for six different transporters that may act as Cl⁻/HCO₃⁻ exchangers was conducted in bovine and human RPE to confirm that RPE from two species expresses the same repertoire of Cl⁻/HCO₃⁻ exchanger isoforms. The degree of amino acid homology between orthologous human and bovine RPE-specific isoforms was calculated after performing protein alignments. Transport of fluid across bovine RPE-choroid explants mounted in the Ussing chamber was used to assess the ability of DPOFA to modulate fluid absorption across the RPE. Using RT-PCR we showed that three isoforms (SLC4A2, SLC4A3, and SLC26A6) are strongly expressed in human and bovine RPE preparations. Amino acid comparisons conducted for RPE-specific isoforms support the use of bovine RPE-choroid explants as an adequate experimental system for assessing fluid absorption activity for DPOFA. Our data is consistent with the fact that DPOFA stimulates fluid absorption across the RPE in bovine RPE-choroid explants. DPOFA seems to stimulate transport of water across the RPE in bovine RPE-choroid explants. Additional experiments are required to establish dose-dependent effect of DPOFA on fluid absorption in the bovine RPE-choroid experimental system.


Effects of remifentanil/histamine mixtures in rats responding under a choice procedure.
Intravenous drug self-administration remains the 'gold standard' for assessing abuse liability. Failure of a drug to maintain self-administration might indicate the absence of positive reinforcing effects but might also indicate the presence of aversive effects. Sensitivity to aversive and punishing effects of drugs (as well as nondrug stimuli) might collectively determine the likelihood of use, abuse and relapse. Using a choice procedure, this study compared the effects of remifentanil (mu opioid receptor agonist; 0.001-0.01 mg/kg/infusion) and histamine (H1-4 receptor agonist; 0.32-3.2 mg/kg/infusion), alone and in mixtures, to test the hypothesis that remifentanil/histamine mixtures are less reinforcing compared with remifentanil alone and less punishing compared with histamine alone. Male Sprague-Dawley rats (n = 10) chose between an intravenous infusion + a pellet and a pellet alone. Rats were indifferent to saline, chose remifentanil + a pellet over a pellet alone, and chose a pellet alone over histamine + a pellet. The effects of remifentanil/histamine mixtures generally were different from the constituent doses of histamine alone but not from remifentanil alone. A mixture containing 3.2 mg/kg/infusion histamine and either 0.001 or 0.0032 mg/kg/infusion remifentanil was not different from saline but was different from the effects of the constituent dose, insofar as choice increased compared with 3.2 mg/kg/infusion histamine alone and decreased compared with 0.001 or 0.0032 mg/kg/infusion remifentanil alone. Reinforcing doses of remifentanil combined with punishing doses of histamine can yield mixtures that are neither preferred nor avoided, offering 'proof-of-principle' for using drug mixtures to avoid adverse effects of opioid receptor agonists.


Sex and age differences in the association of depression with obstructive coronary artery disease and adverse cardiovascular events.
Young women with coronary heart disease have high rates of depression and a higher risk of adverse events than men of similar age. Whether depression has a higher prognostic value in this group than in men and older women is not known. Our objective was to assess whether depression in young women is associated with higher risk of coronary artery disease (CAD) and adverse outcomes compared with similarly aged men and older women. We examined 3237 patients undergoing coronary angiography for evaluation of CAD and followed them for 2.9 years (median). Depressive symptoms were assessed with the Patient Health Questionnaire (PHQ)-9, and CAD burden was dichotomized based on its presence or absence. After multivariable adjustment for CAD risk factors, depressive symptoms predicted CAD presence in women aged ≤ 55 years (odds ratio=1.07 95% confidence interval [CI] 1.02 to 1.13 per 1 point increase in PHQ-9 score), but not in men aged ≤ 55 years or women aged >55 years. Depressive symptoms also predicted increased risk of death in women aged ≤ 55 years (adjusted hazard ratio=1.07, 95% CI 1.02 to 1.14, per 1 point increase in PHQ-9 score), but not in men aged ≤ 55 years and women aged >55 years, with P=0.02 for the depression-sex interaction and P=0.02 for depression-sex-age interaction. Among patients with suspected or established CAD, depressive symptoms are associated with increased risk of death, particularly in young women. This group may be especially vulnerable to the adverse cardiovascular effects of depression.


Relations between social competence and academic achievement in early adolescence.
Relations between academic performance and 3 aspects of social competence--socially responsible behavior, sociometric status, and self-regulatory processes (goal setting, interpersonal trust, and problem-solving styles)--were studied. Based on a sample of 423 12- and 13-year-old students, correlational findings indicate that each aspect of social competence is related significantly to students' grades. Results from multiple regression analyses suggest that when accounting for students' IQ, sex, ethnicity, school absence, and family structure, socially responsible behavior mediates almost entirely the relations between students' grades and the other 2 aspects of social competence. Socially responsible behavior and peer status appear to be related by way of their joint association with goals to be socially responsible, interpersonal trust, and problem-solving styles. Similarly, relations between socially responsible behavior and the background variables are explained by joint relations with the self-regulatory processes. The social nature of learning and the role of self-regulation in both interpersonal and behavioral aspects of social competence are discussed.


Transcription of prostatic steroid binding protein (PSBP) gene is induced by epithelial-mesenchymal interaction.
The prostate gland develops from the fetal urogenital sinus at the base of the urinary bladder. It finally differentiates into three lobes; ventral, lateral and dorsal lobes of the prostate. In spite of their common developmental origin and similar glandular structure, these lobes show the different biochemical characteristics, for example, in the proteins they secrete. In the present study, we investigate the involvement of the epithelial-mesenchymal interaction in the lobe-specific differentiation of the prostatic epithelium by means of epithelial-mesenchymal recombination experiments. We have used a prostatic steroid-binding protein (PSBP) as a specific differentiation marker for the ventral prostate. PSBP is a tetramer which consists of 2 sub-units, one containing the polypeptides C1 and C3 and the other containing the polypeptides C2 and C3. Northern analysis with a complementary DNA probe encoding C1 peptide (PSBP-C1) revealed that the mRNAs were detected exclusively in the ventral prostate but not in the dorsal prostate or in other organs such as urinary bladder and kidney. In situ hybridization with a complementary (anti-sense) RNA probe demonstrated that the transcripts were found only in the epithelium, not in the mesenchyme of the ventral prostate. In situ hybridization also showed that, in normal development, the mRNAs for PSBP-C1 in the ventral epithelium were first detectable at day 14 after birth, coinciding with the onset of its cytodifferentiation, and that they reached mature levels by day 21. We then carried out tissue-recombination experiments to examine whether the transcription of the PSBP-C1 gene in the epithelium is affected by the surrounding mesenchyme. Fetal urogenital sinuses were subdivided into ventral and dorsal halves. Following collagenase treatment, both halves were separated into their epithelial and mesenchymal compartments. Homotypic (ventral epithelium plus ventral mesenchyme [Ev/Mv] and dorsal epithelium plus dorsal mesenchyme [Ed/Md]) and heterotypic (ventral epithelium plus dorsal mesenchyme [Ev/Md] and dorsal epithelium plus ventral mesenchyme [Ed/Mv]) recombinations were carried out. After 4-5 weeks of growth in male host, the glandular structures characteristic for prostate glands were formed in all explants. However, in situ hybridization revealed the transcripts of the PSBP-C1 gene only in the epithelium associated with the ventral mesenchyme (Ev/Mv and Ed/Mv).(ABSTRACT TRUNCATED AT 400 WORDS)


Vildagliptin increases butyrate-producing bacteria in the gut of diabetic rats.
Emerging evidence supports a key role for the gut microbiota in metabolic diseases, including type 2 diabetes (T2D) and obesity. The dipeptidyl peptidase-4 inhibitor vildagliptin is highly efficacious in treating T2D. However, whether vildagliptin can alter the gut microbiome is still unclear. This study aimed to identify whether vildagliptin modifies the gut microbiota structure during T2D treatment. Diabetic Sprague-Dawley (SD) rats were induced by a high-fat diet and streptozotocin injection (HFD/STZ). Diabetic rats were orally administered a low dose of vildagliptin (LV, 0.01 g/kg/d vildagliptin), high dose of vildagliptin (HV, 0.02 g/kg/d vildagliptin), or normal saline for 12 weeks. Fasting blood glucose, blood glucose after glucose loading, and serum insulin levels were significantly reduced in the LV and HV groups compared with those in the T2D group. The serum GLP-1 level increased more in the vildagliptin-treated group than in the T2D group. Pyrosequencing of the V3-V4 regions of 16S rRNA genes revealed that vildagliptin significantly altered the gut microbiota. The operational taxonomic units (OTUs) and community richness (Chao1) index were significantly reduced in the vildagliptin and diabetic groups compared with those in the control group. At the phylum level, a higher relative abundance of Bacteroidetes, lower abundance of Firmicutes, and reduced ratio of Fimicutes/Bacteroidetes were observed in the vildagliptin-treated group. Moreover, vildagliptin treatment increased butyrate-producing bacteria, including Baceroides and Erysipelotrichaeae, in the diabetic rats. Moreover, Lachnospira abundance was significantly negatively correlated with fasting blood glucose levels. In conclusion, vildagliptin treatment could benefit the communities of the gut microbiota.


Three siblings with self-resolving congenital hyperthyrotropinaemia secondary to thyrotropin receptor blocking antibodies.
Thyrotropin receptor blocking antibodies are a rare cause of hyperthyrotropinaemia and more rarely of congenital hypothyroidism. We report a case of hyperthyrotropinaemia but normal thyroid hormone in the newborn of a mother with hypothyroidism treated with thyroxine. Two older siblings had similar high thyrotropin and normal thyroid function in the newborn period which did not require hormone treatment and resolved spontaneously. Demonstration of thyrotropin receptor antibodies in the child confirmed our diagnosis. Our case was not treated with thyroid replacement hormone and has remained biochemically euthyroid, with thyrotropin levels returning to normal over a period of months.


Strategic planning for instream flow restoration: a case study of potential climate change impacts in the central Columbia River basin.
We provide a case study prioritizing instream flow restoration activities by sub-basin according to the habitat needs of Endangered Species Act (ESA)-listed salmonids relative to climate change in the central Columbia River basin in Washington State (USA). The objective is to employ scenario analysis to inform and improve existing instream flow restoration projects. We assess the sensitivity of late summer (July, August, and September) flows to the following scenario simulations - singly or in combination: climate change, changes in the quantity of water used for irrigation and possible changes to existing water resource policy. Flows for four sub-basins were modeled using the Water Evaluation and Planning system (WEAP) under historical and projected conditions of 2020 and 2040 for each scenario. Results indicate that Yakima will be the most flow-limited sub-basin with average reductions in streamflow of 41% under climate conditions of 2020 and 56% under 2040 conditions; 1.3-2.5 times greater than those of other sub-basins. In addition, irrigation plays a key role in the hydrology of the Yakima sub-basin - with flow reductions ranging from 78% to 90% under severe to extreme (i.e., 20-40%) increases in agricultural water use (2.0-4.4 times the reductions in the other sub-basins). The Yakima and Okanogan sub-basins are the most responsive to simulations of flow-bolstering policy change (providing salmon with first priority water allocation and at biologically relevant flows), as demonstrated by 91-100% target flows attained. The Wenatchee and Methow sub-basins do not exhibit similar responsiveness to simulated policy changes. Considering climate change only, we conclude that flow restoration should be prioritized first in the Yakima and Wenatchee sub-basins, and second in the Okanogan and Methow. Considering both climate change and possible policy changes, we recommend that the Yakima sub-basin receive the highest priority for flow restoration activities to sustain critical instream habitat for ESA-listed salmonids.


How we do it: the double keyhole micro-endoscopic combined complex pituitary adenoma surgery.
Surgical removal of complex pituitary adenomas (PA) is a technically challenging procedure. To ensure safe and efficient surgery, we employ the micro-endoscopic combination technique. In this study, we present our approach to the removal of a complex PA using the micro-endoscopic combination strategy. We describe our surgical setup and workflow in detail. Our experience with this case highlights the effectiveness of the micro-endoscopic combination technique in the management of complicated skull base surgeries with good teamwork and cooperation.


Factors influencing the activity of tiamulin against Histomonas meleagridis in vitro.
In this study, we investigated the activity of tiamulin fumerate against three strains of Histomonas meleagridis in vitro under different conditions. Tiamulin reduced histomonal growth of all three strains at concentrations of 20 ppm and higher. Cultures in phosphate-buffered saline-based medium were more susceptible than cultures in traditional Dwyers medium. When the cultures were inoculated with higher numbers of histomonads, the activity of tiamulin was reduced. Bacteria present in the cultures were resistant against tiamulin.


Extrapyramidal symptoms and tolerability of olanzapine versus haloperidol in the acute treatment of schizophrenia.
A relative lack of extrapyramidal symptoms (EPS, i.e., the syndromes of dystonia, parkinsonism, akathisia, dyskinesia) is one criterion used to determine whether an antipsychotic is "atypical." The extrapyramidal symptom profiles of the novel antipsychotic olanzapine and the conventional antipsychotic haloperidol were compared in a population of 2606 patients from three well-controlled prospective clinical trials. Extrapyramidal symptom data were analyzed for 1796 patients treated with olanzapine (5 to 20 mg/day) and 810 patients treated with haloperidol (5 to 20 mg/day) for up to 6 weeks of therapy. Patients were monitored weekly by three methods of extrapyramidal symptom assessment: (1) detection of extrapyramidal adverse events (signs and symptoms) by casual observation, nonprobing inquiry, and spontaneous report; (2) objective rating scale scores: and (3) use of concomitant anticholinergic medications. Emergence of EPS was assessed by (1) analysis of the incidence of extrapyramidal syndrome categories based on adverse events, (2) the incidence of extrapyramidal syndromes based on categorical analysis of rating scale scores, (3) analysis of mean maximum change in rating scale scores, and (4) categorical analysis of anticholinergic medication use. Outcome of EPS was assessed by (1) analysis of mean change in rating scale scores at endpoint and (2) mean anticholinergic use at endpoint. Olanzapine was statistically significantly (p = .014, p < .001) superior to haloperidol in all four analyses related to emergence of EPS and in the two analyses related to outcome. Furthermore, during acute treatment, statistically significantly fewer patients treated with olanzapine (0.3%) discontinued the study because of any extrapyramidal adverse event than patients treated with haloperidol (2.7%, p < .001). Olanzapine exhibited a statistically significantly lower extrapyramidal symptom profile than the conventional antipsychotic haloperidol at comparably effective antipsychotic doses. The lower extrapyramidal symptom profile with olanzapine was evident despite statistically significantly more frequent use of anticholinergic drugs among haloperidol-treated patients. Fewer olanzapine-treated than haloperidol-treated patients discontinued because of EPS, suggesting that olanzapine should contribute to better compliance with longer term maintenance treatment, with minimal anticholinergic-associated events.


Sex difference in prevalence of depression after stroke.
This study investigated the sex difference in prevalence of depression at 90 days after first-ever stroke. Patients with first-ever stroke (n = 786) were identified from the population-based Brain Attack Surveillance in Corpus Christi project (2011-2016). Poststroke depressive symptoms were assessed by the 8-item Patient Health Questionnaire, and prestroke depression status (history and medication use) was self-reported. Logistic regression was used to examine the association between sex and depression after stroke, and effect modification by prestroke depression status, accounting for missing data. Women were more likely to have a history of and be on medication for depression at the time of stroke than men (p < 0.001). Prevalence of depression at 90 days was 28.2% for men (95% confidence interval [CI], 23.7%-32.8%) and 32.7% for women (95% CI, 27.8%-37.5%). The age-adjusted odds ratio (OR) of depression after stroke comparing women and men was 1.34 (95% CI, 0.97-1.85), and fully attenuated after adjustment for sociodemographic, stroke, and prestroke characteristics. Effect modification by prestroke depression status was present (p = 0.038). Among participants on medication for depression at the time of stroke, women were significantly less likely to have depression at 90 days compared with men (OR, 0.39; 95% CI, 0.16-0.96), whereas significant sex differences were not noted among those with and without a depression history. The sex difference in prevalence of depression at 90 days after first-ever stroke was not significant overall, but varied by prestroke depression status. Interventions to address and prevent poststroke depression are needed, particularly among those with prestroke depression but not undergoing treatment for depression at stroke onset.


Insufficient accuracy and specificity of polyanion precipitation methods for quantifying low-density lipoproteins.
Recently, polyanion precipitation assays for low-density lipoprotein (LDL)-cholesterol have been found to underestimate their analyte in normolipidemic samples (Siekmeier et al., Clin Chim Acta 1988;177:221-30). Therefore, accuracy, specificity, and interference by nonesterified fatty acids have been studied for three precipitants (obtained by heparin, dextran sulfate, or polyvinyl sulfate precipitation). At normal concentrations of LDL, precipitation is incomplete, whereas it is nearly quantitative at high concentrations of LDL. The polyvinyl sulfate reagent markedly responds to variations in the amount of non-LDL protein present in the precipitation mixture. In the dextran sulfate and the polyvinyl sulfate method, but not in the heparin method, the percentages of LDL precipitated notably increase as the concentration of the polyanion compound is decreased. In either assay, very-low-density lipoproteins, but not high-density lipoproteins, are significantly coprecipitated (dextran sulfate 28%, polyvinyl sulfate and heparin 66%) in a concentration-independent fashion. Increased concentrations of nonesterified fatty acids markedly interfere with the dextran sulfate and polyvinyl sulfate assay, but do not much affect results with the heparin reagent.


Large two-photon absorption cross sections of hemiporphyrazines in the excited state: the multiphoton absorption process of hemiporphyrazines with different central metals.
A series of five hemiporphyrazines (Hps) with different coordinating central atoms (H2, GeCl2, InCl, Pt, Pb), and the acyclic derivative 1,3-bis-(6'-amino-4'-butoxy-2'-pyridylimino)-1,3-dihydroisoindoline have been synthesized and their multiphoton absorption properties examined at the second harmonic frequency of the Nd:YAG laser in the nanosecond time regime. Metal-free and platinum Hps display saturation of optical transmittance within incident fluence values of 6 J cm(-2). Comparison with other similar molecular structures like phthalocyanines and related molecules shows that Hps are strong nonlinear absorbers. The experimental curves of nonlinear transmission at 532 nm have been fitted by means of a three-level model with the occurrence of simultaneous two-photon absorption from an excited state. In the sole case of the InCl complex we found that a five-level model is needed because of the participation of triplet states. Contrary to phthalocyanines, naphthalocyanines, and porphyrins, a heavy central atom does not improve the nonlinear absorption properties since a different excited states dynamic is involved. The large nonlinear absorption of Hps combined with the very small absorption in the visible spectral range makes these molecules a very interesting class of molecules for nonlinear optical applications.


Resveratrol attenuates malathion-induced liver damage by reducing oxidative stress.
Malathion is an organophosphate insecticide which disrupts the antioxidant system of the body. Resveratrol is a phytoestrogen and antioxidant of the red grape. This study was designed to evaluate the effects of resveratrol against toxic effects of malathion to the liver of rats. In this study, 48 male rats were randomly assigned to 8 groups: control normal (saline) and malathion control-treated groups (50 mg/kg), resveratrol groups (2, 8, and 20 mg/kg), and malathion + resveratrol-treated groups (2, 8, and 20 mg/kg). Treatments were administered intraperitoneally daily for 14 days. Griess technique was assessed for determined serum nitrite oxide level. Aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase concentrations were determined for liver functional disturbances. In addition, thiobarbituric acid reactive species, antioxidant capacity, the diameter of hepatocytes, and the central hepatic vein (CHV) were investigated. Malathion administration significantly improved liver malondialdehyde (MDA) and nitrite oxide level, the mean diameter of CHV and hepatocyte, and liver enzymes and decreased tissue ferric-reducing ability of plasma (FRAP) level compared to the normal control group (P < 0.01). The resveratrol and resveratrol + malathion treatments at all doses significantly reduced the mean diameter of hepatocyte and CHV, liver enzymes, kidney MDA, and nitrite oxide levels and increased tissue FRAP level compared to the malathion control group (P < 0.01). It seems that resveratrol administration improved liver injury induced by malathion in rats.


Efficient and specific oligo-based depletion of rRNA.
In most organisms, ribosomal RNA (rRNA) contributes to >85% of total RNA. Thus, to obtain useful information from RNA-sequencing (RNA-seq) analyses at reasonable sequencing depth, typically, mature polyadenylated transcripts are enriched or rRNA molecules are depleted. Targeted depletion of rRNA is particularly useful when studying transcripts lacking a poly(A) tail, such as some non-coding RNAs (ncRNAs), most bacterial RNAs and partially degraded or immature transcripts. While several commercially available kits allow effective rRNA depletion, their efficiency relies on a high degree of sequence homology between oligonucleotide probes and the target RNA. This restricts the use of such kits to a limited number of organisms with conserved rRNA sequences. In this study we describe the use of biotinylated oligos and streptavidin-coated paramagnetic beads for the efficient and specific depletion of trypanosomal rRNA. Our approach reduces the levels of the most abundant rRNA transcripts to less than 5% with minimal off-target effects. By adjusting the sequence of the oligonucleotide probes, our approach can be used to deplete rRNAs or other abundant transcripts independent of species. Thus, our protocol provides a useful alternative for rRNA removal where enrichment of polyadenylated transcripts is not an option and commercial kits for rRNA are not available.


The Comparability of Perceived Physical and Mental Health Measures Across Immigrants and Natives in the United States.
The comparative study of perceived physical and mental health in general-and the comparative study of health between the native-born and immigrants, in particular-requires that the groups understand survey questions inquiring about their health in the same way and display similar response patterns. After all, observed differences in perceived health may not reflect true differences but rather cultural bias in the health measures. Research on cross-country measurement equivalence between immigrants and natives on self-reported health measures has received very limited attention to date, resulting in a growing demand for the validation of existing perceived health measures using samples of natives and immigrants and establishing measurement equivalence of health-related assessment tools. This study, therefore, aims to examine measurement equivalence of self-reported physical and mental health indicators between immigrants and natives in the United States. Using pooled data from the 2015-2017 IPUMS Health Surveys, we examine the cross-group measurement equivalence properties of five concepts that are measured by multiple indicators: (1) perceived limitations in activities of daily life; (2) self-reported disability; (3) perceived functional limitations; (4) perceived financial stress; and (5) nonspecific psychological distress. Furthermore, we examine the comparability of these data among respondents of different ethnoracial origins and from different regions of birth, who report few versus many years since migration, their age, gender, and the language used to respond to the interview (e.g., English vs. Spanish). We test for measurement equivalence using multigroup confirmatory factor analysis. The results reveal that health scales are comparable across the examined groups. This finding allows drawing meaningful conclusions about similarities and differences among natives and immigrants on measures of perceived health in these data.


Robust 3-D modeling of vasculature imagery using superellipsoids.
This paper presents methods to model complex vasculature in three-dimensional (3-D) images using cylindroidal superellipsoids, along with robust estimation and detection algorithms for automated image analysis. This model offers an explicit, low-order parameterization, enabling joint estimation of boundary, centerlines, and local pose. It provides a geometric framework for directed vessel traversal, and extraction of topological information like branch point locations and connectivity. M-estimators provide robust region-based statistics that are used to drive the superellipsoid toward a vessel boundary. A robust likelihood ratio test is used to differentiate between noise, artifacts, and other complex unmodeled structures, thereby verifying the model estimate. The proposed methodology behaves well across scale-space, shows a high degree of insensitivity to adjacent structures and implicitly handles branching. When evaluated on synthetic imagery mimicking specific structural complexities in tumor microvasculature, it consistently produces ubvoxel accuracy estimates of centerlines and widths in the presence of closely-adjacent vessels, branch points, and noise. An edit-based validation demonstrated a precision level of 96.6% at a recall level of 95.4%. Overall, it is robust enough for large-scale application.


Confidential reproductive health care for adolescents.
There have been recent legislative efforts in the USA to implement mandated parental involvement for minor adolescents seeking services for contraception and, in some cases, sexually transmitted diseases. Research collecting information from adolescents in family planning clinics shows that the majority report that a parent knows they use the clinic for sexual health services. Similarly, a majority of minor adolescent females expects that they would use family planning clinics for prescription contraception, even if parental involvement were required. About one in five expected she would obtain contraception from a private doctor. A substantial minority, however, would engage in unsafe sex, and this response would be more common among teenagers whose parents did not know they used the clinic. Parental involvement laws for contraception might discourage some teenagers from using other services, such as testing or treatment for sexually transmitted diseases. It is likely that mandated parental involvement laws would do little to decrease levels of teenage sexual activity but would, instead, increase rates of teenage pregnancy and, perhaps, rates of sexually transmitted diseases.


Gold levels produced by treatment with auranofin and sodium aurothiomalate.
Sixty-three patients with rheumatoid arthritis were randomly divided into 3 groups, and treated with either sodium aurothiomalate (Myocrisin), auranofin, or placebo. Gold levels in whole blood, plasma, and haemolysate were measured serially along with clinical and laboratory parameters of efficacy. Auranofin produced a higher ratio of haemolysate to plasma gold than Myocrisin, and it appears that the affinity of the red cell for gold is reduced during therapy with auranofin. Gold levels did not correlate with changes in the pain score, erythrocyte sedimentation rate, and C-reactive protein, nor with the development of toxicity. In the Myocrisin group the haemolysate gold level achieved was dependent on the number of cigarettes smoked. In the auranofin group there was no such correlation, but the haemolysate gold level was higher for smokers than non-smokers. The likely action of gold is discussed.


Mediastinal lymphoma-induced superior vena cava syndrome and chylopericardium in a pregnant lady: A case report.
Mediastinal malignancies are a commonly identified etiology in superior vena cava syndrome (SVCS), and despite the known management of chemotherapy, radiotherapy, or a combination of both, this can prove to be a dilemma during pregnancy. Reported cases of SVCS management during pregnancy are scarce. Chylopericardium is a rare entity with a myriad of causes, the most common of which is a primary idiopathic origin. Initial management depends on the presence or absence of cardiac tamponade. Long-term therapy is a matter of serious debate, with some opting for conservative treatment, and others favoring a more invasive surgical approach. Cases reporting the occurrence of chylopericardium in association with pregnancy are also limited. In this report, we discuss the case of a 28-year-old pregnant woman who had both SVCS and chylopericardium as a result of a mediastinal lymphoma.


Sleep apnea in young abstinent recreational MDMA ("ecstasy") consumers.
Methylenedioxymethamphetamine (MDMA, "ecstasy") is a popular recreational drug of abuse and a selective brain serotonin neurotoxin. Functional consequences of MDMA neurotoxicity have defied ready characterization. Obstructive sleep apnea (OSA) is a common form of sleep-disordered breathing in which brain serotonin dysfunction may play a role. The present study sought to determine whether abstinent recreational MDMA users have an increased prevalence of OSA. We studied 71 medically healthy recreational MDMA users and 62 control subjects using all-night sleep polysomnography in a controlled inpatient research setting. Rates of apneas, hypopneas, and apnea hypopnea indices were compared in the 2 groups, controlling for body mass index, age, race, and gender. Recreational MDMA users who had been drug free for at least 2 weeks had significantly increased rates of obstructive sleep apnea and hypopnea compared with controls. The odds ratio (95% confidence interval) for sleep apnea (mild, moderate, and severe combined) in MDMA users during non-REM sleep was 8.5 (2.4-30.4), which was greater than that associated with obesity [6.9 (1.7-28.2)]. Severity of OSA was significantly related to lifetime MDMA exposure. These findings suggest that prior recreational methylenedioxymethamphetamine use increases the risk for obstructive sleep apnea and lend support to the notion that brain serotonin neuronal dysfunction plays a role in the pathophysiology of sleep apnea.


Differential effect of anionic and cationic drugs on the synaptosome-associated acetylcholinesterase activity of dog brain.
The evoked effects of the negatively charged drugs phenobarbital and barbituric acid, the positively charged imipramine, perphenazine and trifluoperazine, and the neutral primidone, on the synaptosome-associated acetylcholinesterase activity were studied. A marked increase in the enzyme activity was exhibited in the presence of low concentrations (up to 3 mM) of phenobarbital, barbituric acid and primidone. Higher concentrations (up to 10 mM), however, led to a progressive inhibition of the enzyme activity. However, the activity of the enzyme was not affected by imipramine, but it was decreased by perphenazine and trifluoperazine. Arrhenius plots of acetylcholinesterase activity exhibited a break point at 23.4 degrees C for the untreated (control) synaptosomes, which was shifted to around 16 degrees C in the synaptosomes treated with the charged drugs. The allosteric inhibition by F- of acetylcholinesterase was studied in control synaptosomes and in those treated with the charged drugs. Changes in the Hill coefficients in combination with changes in Arrhenius activation energy produced by the charged drugs would be expected if it is assumed that charged drugs 'fluidize' the synaptosomal plasma membranes.


Neural oscillations reveal differences in the process of word learning among school-aged children from lower socioeconomic status backgrounds.
Building a robust vocabulary in grade school is essential for academic success. Children from lower socioeconomic status (SES) households on average perform below their higher SES peers on word learning tasks, negatively impacting their vocabulary; however, significant variability exists within this group. Many children from low SES homes perform as well as, or better than, their higher SES peers on measures of word learning. The current study addresses what processes underlie this variability, by comparing the neural oscillations of 44 better versus worse word learners (ages 8-15 years) from lower SES households as they infer the meaning of unknown words. Better word learners demonstrated increases in theta and beta power as a word was learned, whereas worse word learners exhibited decreases in alpha power. These group differences in neural oscillatory engagement during word learning indicate there may be different strategies employed based on differences in children's skills. Notably, children with greater vocabulary knowledge are more likely to exhibit larger beta increases; a strategy which is associated with better word learning. This sheds new light on the mechanisms that support word learning in children from low SES households.


Frequency and transmission of glutamate receptors GRIK2 and GRIK3 polymorphisms in patients with obsessive compulsive disorder.
Several lines of evidence suggest that obsessive compulsive disorder (OCD) could be the consequence of glutamatergic dysfunction. We performed a case-control study in 156 patients and 141 controls and the transmission disequilibrium test in 124 parent-offspring trios to search for association between OCD and two kainate receptors, GRIK2 and GRIK3. Using three single nucleotide polymorphisms (SNP) in GRIK2 and one in GRIK3, we found no evidence for association in case-control or family-based analyses. Only the GRIK2 SNP I867, recently associated with autism, was less transmitted than expected (p < 0.03), supporting a functional role for this variant. These findings suggest the need for further investigation of the role of GRIK2 in OCD.


Evolutionary history of the sex-peptide (Acp70A) gene region in Drosophila melanogaster.
In Drosophila the products of the seminal fluid stimulate oviposition and suppress remating in the female. Of all the accessory gland peptides (Acp's) involved in these two responses, the sex-peptide (coded by the Acp70A gene) is among the best characterized at the functional level. A 1.2-kb fragment encompassing the Acp70A gene of nine lines from a natural population of D. melanogaster and one allele of D. sechellia was sequenced to study the forces shaping nucleotide variation within and between species. The coding region of D. simulans and D. mauritiana was also sequenced. A Ser to Ala replacement polymorphism at the last position of the signal peptide was detected in D. melanogaster. The Ser and Ala alleles are at intermediate frequencies. The level of nucleotide variation is lower for the derived Ala allele, which is compatible with a recent origin and an increase in frequency due to positive selection. Variation at the 5' flanking region is structured in two major highly differentiated haplotypes, whose distribution does not conform to neutral expectations. Selective and/or historical factors could contribute to the observed overall patterning of nucleotide variation at the Acp70A region.


Role of endoscopic ultrasound in the molecular diagnosis of pancreatic cancer.
Pancreatic ductal adenocarcinoma remains one of the most deadly types of tumor. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a safe, cost-effective, and accurate technique for evaluating and staging pancreatic tumors. However, EUS-FNA may be inconclusive or doubtful in up to 20% of cases. This review underlines the clinical interest of the molecular analysis of samples obtained by EUS-FNA in assessing diagnosis or prognosis of pancreatic cancer, especially in locally advanced tumors. On EUS-FNA materials DNA, mRNA and miRNA can be extracted, amplified, quantified and subjected to methylation assay. Kras mutation assay, improves diagnosis of pancreatic cancer. When facing to clinical and radiological presentations of pseudo-tumorous chronic pancreatitis, wild-type Kras is evocative of benignity. Conversely, in front of a pancreatic mass suspected of malignancy, a mutated Kras is highly evocative of pancreatic adenocarcinoma. This strategy can reduce false-negative diagnoses, avoids the delay of making decisions and reduces loss of surgical resectability. Similar approaches are conducted using analysis of miRNA expression as well as Mucin or markers of invasion (S100P, S100A6, PLAT or PLAU). Beyond the diagnosis approach, the prediction of response to treatment can be also investigated form biomarkers expression within EUS-FNA materials.


Development of a limits of stability protocol for use in transtibial prosthesis users: Learning effects and reliability of outcome variables.
The aims of this study were to empirically quantify reliability and learning effects of a Limits of Stability protocol for transtibial prosthesis users. Outcome variables from center of pressure and center of mass were tested on: 1) multiple test repetitions within a single test occasion; and 2) between multiple test occasions. Trantibial prosthesis users (n=7) and matched controls (n=7) executed five trials of the Limits of Stability protocol on two occasions per day, on two consecutive days. Inter-trial learning effects and reliability of outcomes extracted via center of mass and center of pressure were evaluated utilizing standard biomechanics laboratory equipment. Reliability was good to excellent except the reaction time variable which was poor (Pooled 95%CI of ICC=0.248-0.484). An inter-trial learning effect was present in directional control for prosthesis users when the first trial was included in analysis (center of mass: 95%CI of r=0.065-0.239; center of pressure: 95%CI of r=0.076-0.249). The use of standard biomechanics lab equipment can produce reliable results for the Limits of Stability protocol. Researchers should be aware of low reliability of reaction time variable in the protocol assessed and should execute at least one practice trial prior to that which is used in subsequent analysis.


Coping with changing conditions: alternative strategies for the delivery of maternal and child health and family planning services in Dhaka, Bangladesh.
The door-to-door distribution of contraceptives and information on maternal and child health and family planning (MCH-FP) services, through bimonthly visits to eligible couples by trained fieldworkers, has been instrumental in increasing the contraceptive prevalence rate and immunization coverage in Bangladesh. The doorstep delivery strategy, however, is labour-intensive and costly. More cost-effective service delivery strategies are needed, not only for family planning services but also for a broader package of reproductive and other essential health services. Against this backdrop, operations research was conducted by the Centre for Health and Population Research at the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) from January 1996 to May 1997, in collaboration with government agencies and a leading national nongovernmental organization, with a view to developing and field-testing alternative approaches to the delivery of MCH-FP services in urban areas. Two alternative strategies featuring the withdrawal of home-based distribution and the delivery of basic health care from fixed-site facilities were tested in two areas of Dhaka. The clinic-based service delivery strategy was found to be a feasible alternative to the resource-intensive doorstep system in urban Dhaka. It did not adversely affect programme performance and it allowed the needs of clients to be addressed holistically through a package of essential health and family planning services.


Developing culturally sensitive HIV/AIDS and substance abuse prevention curricula for Native American youth.
In 1990, researchers and health care professionals joined with members of several southwestern Native American communities to form an HIV/AIDS and substance abuse prevention partnership. Culturally sensitive approaches to theory-based interventions were developed into highly replicable, structured, school-based and community-based intervention programs. Process evaluations indicated high levels of program acceptance and fidelity. Outcome evaluations demonstrated significant positive preventive intervention effects among participants. This article reports how NAPPASA school prevention curricula were developed and discusses three critical processes in developing these successful curricula: 1) selection of integrative theory to address the multi-dimensional antecedents of HIV/AIDS and substance abuse among Native Americans, 2) use of ethnographic methodology to obtain intensive input from target groups and community members to ensure cultural and developmental sensitivity in the curriculum, and 3) use of process and outcome evaluations of pilot and field trials to develop an optimal curriculum.


Supraphysiological thermal injury in Dunning AT-1 prostate tumor cells.
To investigate the potential application of thermal therapy in the treatment of prostate cancer, the effects of supraphysiological temperatures (40-70 degrees C) for clinically relevant time periods (approximately 15 minutes) were experimentally studied on attached Dunning AT-1 rat prostate cancer cells using multiple assays. The membrane and reproductive machinery were the targets of injury selected for this study. In order to assess membrane injury, the leakage of calcein was measured dynamically, and the uptake of PI was measured postheating (1-3 hours). Clonogenicity was used as a measure of injury to the reproductive machinery 7 days post-injury after comparable thermal insults. Experimental results from all three assays show a broad trend of increasing injury with an increase in temperature and time of insult. Membrane injury, as measured by the fluorescent dye assays, does not correlate with clonogenic survival for many of the thermal histories investigated. In particular, the calcein assay at temperatures of < or = 40 degrees C led to measurable injury accumulation (dye leakage), which was considered sublethal, as shown by significant survival for comparable insult in the clonogenic assay. Additionally, the PI uptake assay used to measure injury post-thermal insult shows that membrane injury continues to accumulate after thermal insult at temperatures > or = 50 degrees C and may not always correlate with clonogenicity at hyperthermic temperatures such as 45 degrees C. Last, although the clonogenic assay yields the most accurate cell survival data, it is difficult to acquire these data at temperatures > or = 50 degrees C because the thermal transients in the experimental setup are significant as compared to the time scale of the experiment. To improve prediction and understanding of thermal injury in this prostate cancer cell line, a first-order rate process model of injury accumulation (the Arrhenius model) was fit to the experimental results. The activation energy (E) obtained using the Arrhenius model for an injury criterion of 30 percent for all three assays revealed that the mechanism of thermal injury measured is likely different for each of the three assays: clonogenics (526.39 kJ/mole), PI (244.8 kJ/mole), and calcein (81.33 kJ/mole). Moreover, the sensitivity of the rate of injury accumulation (d omega/dt) to temperature was highest for the clonogenic assay, lowest for calcein leakage, and intermediate for PI uptake, indicating the strong influence of E value on d omega/dt. Since the clonogenic assay is linked to the ultimate survival of the cell and accounts for all lethal mechanisms of cellular injury, the E and A values obtained from clonogenic study are the best values to apply to predict thermal injury in cells. For higher temperatures (> or = 50 degrees C) indicative of thermal therapies, the results of PI uptake can be used as a conservative estimate of cell death (underprediction). This is useful until better experimental protocols are available to account for thermal transients at high temperature to assess clonogenic ability. These results provide further insights into the mechanisms of thermal injury in single cell systems and may be useful for designing optimal protocols for clinical thermal therapy.


Diagnostic criteria for persistent postural-perceptual dizziness (PPPD): Consensus document of the committee for the Classification of Vestibular Disorders of the Bárány Society.
This paper presents diagnostic criteria for persistent postural-perceptual dizziness (PPPD) to be included in the International Classification of Vestibular Disorders (ICVD). The term PPPD is new, but the disorder is not. Its diagnostic criteria were derived by expert consensus from an exhaustive review of 30 years of research on phobic postural vertigo, space-motion discomfort, visual vertigo, and chronic subjective dizziness. PPPD manifests with one or more symptoms of dizziness, unsteadiness, or non-spinning vertigo that are present on most days for three months or more and are exacerbated by upright posture, active or passive movement, and exposure to moving or complex visual stimuli. PPPD may be precipitated by conditions that disrupt balance or cause vertigo, unsteadiness, or dizziness, including peripheral or central vestibular disorders, other medical illnesses, or psychological distress. PPPD may be present alone or co-exist with other conditions. Possible subtypes await future identification and validation. The pathophysiologic processes underlying PPPD are not fully known. Emerging research suggests that it may arise from functional changes in postural control mechanisms, multi-sensory information processing, or cortical integration of spatial orientation and threat assessment. Thus, PPPD is classified as a chronic functional vestibular disorder. It is not a structural or psychiatric condition.


Non-Markovian data-driven modeling of single-cell motility.
Trajectories of human breast cancer cells moving on one-dimensional circular tracks are modeled by the non-Markovian version of the Langevin equation that includes an arbitrary memory function. When averaged over cells, the velocity distribution exhibits spurious non-Gaussian behavior, while single cells are characterized by Gaussian velocity distributions. Accordingly, the data are described by a linear memory model which includes different random walk models that were previously used to account for various aspects of cell motility such as migratory persistence, non-Markovian effects, colored noise, and anomalous diffusion. The memory function is extracted from the trajectory data without restrictions or assumptions, thus making our approach truly data driven, and is used for unbiased single-cell comparison. The cell memory displays time-delayed single-exponential negative friction, which clearly distinguishes cell motion from the simple persistent random walk model and suggests a regulatory feedback mechanism that controls cell migration. Based on the extracted memory function we formulate a generalized exactly solvable cell migration model which indicates that negative friction generates cell persistence over long timescales. The nonequilibrium character of cell motion is investigated by mapping the non-Markovian Langevin equation with memory onto a Markovian model that involves a hidden degree of freedom and is equivalent to the underdamped active Ornstein-Uhlenbeck process.


Cyclooxygenase 2 rescues LNCaP prostate cancer cells from sanguinarine-induced apoptosis by a mechanism involving inhibition of nitric oxide synthase activity.
Expression of cyclooxygenase-2 (Cox-2), an inducible enzyme responsible for the production of prostaglandins from arachidonic acid, is elevated in human prostate tumor samples. The aim of this study was to investigate whether expression of Cox-2 is effective against prostate cancer cell apoptosis triggered by sanguinarine, the quaternary benzophenanthridine alkaloid with antineoplastic properties. Sanguinarine effectively induced apoptosis in LNCaP human prostate cancer epithelial cells as assessed by caspase-3 activation assay, Annexin V staining assay, or by visual analysis for the apoptotic morphology changes. Sanguinarine-mediated apoptosis was associated with the increase of nitric oxide (NO) formation in prostate cancer cells as assessed by measurements of nitrites with Sievers nitric oxide analyzer as well as flow cytometry analysis using NO fluorescent sensor. Activation of NO synthase (NOS) activity was crucial for sanguinarine-induced cell death because NOS inhibitor L-NMMA efficiently protected cells from apoptosis. Adenovirus-mediated transfer of Cox-2 into LNCaP cells inhibited sanguinarine-induced apoptosis and prevented an increase in NO production. Surprisingly, NO donors failed to induce apoptosis in LNCaP cells, suggesting that constitutive NO generation is not sufficient for triggering apoptosis in these cells. Besides NO generation, NOS is also capable of producing superoxide radicals. Sanguinarine-induced production of superoxide radicals, and the addition of MnTBAP, a scavenger of superoxide radicals, efficiently inhibited sanguinarine-mediated apoptosis. These results suggest that Cox-2 expression rescues prostate cancer cells from sanguinarine-induced apoptosis by a mechanism involving inhibition of NOS activity, and that coadministration of Cox-2 inhibitors with sanguinarine may be developed as a strategy for the management of prostate cancer.


The genes for small nucleolar RNAs in Trypanosoma brucei are organized in clusters and are transcribed as a polycistronic RNA.
Because the organization of snoRNA genes in vertebrates, plants and yeast is diverse, we investigated the organization of snoRNA genes in a distantly related organism, Trypanosoma brucei. We have characterized the second example of a snoRNA gene cluster that is tandemly repeated in the T.BRUCEI: genome. The genes encoding the box C/D snoRNAs TBR12, TBR6, TBR4 and TBR2 make up the cluster. In a genomic organization unique to trypanosomes, there are at least four clusters of these four snoRNA genes tandemly repeated in the T. BRUCEI: genome. We show for the first time that the genes encoding snoRNAs in both this cluster and the SLA cluster are transcribed in an unusual way as a polycistronic RNA.


Metabolic learning and memory formation by the brain influence systemic metabolic homeostasis.
Metabolic homeostasis is regulated by the brain, but whether this regulation involves learning and memory of metabolic information remains unexplored. Here we use a calorie-based, taste-independent learning/memory paradigm to show that Drosophila form metabolic memories that help in balancing food choice with caloric intake; however, this metabolic learning or memory is lost under chronic high-calorie feeding. We show that loss of individual learning/memory-regulating genes causes a metabolic learning defect, leading to elevated trehalose and lipid levels. Importantly, this function of metabolic learning requires not only the mushroom body but also the hypothalamus-like pars intercerebralis, while NF-κB activation in the pars intercerebralis mimics chronic overnutrition in that it causes metabolic learning impairment and disorders. Finally, we evaluate this concept of metabolic learning/memory in mice, suggesting that the hypothalamus is involved in a form of nutritional learning and memory, which is critical for determining resistance or susceptibility to obesity. In conclusion, our data indicate that the brain, and potentially the hypothalamus, direct metabolic learning and the formation of memories, which contribute to the control of systemic metabolic homeostasis.


Cortisol increases CXCR4 expression but does not affect CD62L and CCR7 levels on specific T cell subsets in humans.
Glucocorticoids are well known to affect T cell migration, leading to a redistribution of the cells from blood to the bone marrow, accompanied by a concurrent suppression of lymph node homing. Despite numerous studies in this context, with most of them employing synthetic glucocorticoids in nonphysiological doses, the mechanisms of this redistribution are not well understood. Here, we investigated in healthy men the impact of cortisol at physiological concentrations on the expression of different migration molecules on eight T cell subpopulations in vivo and in vitro. Hydrocortisone (cortisol, 22 mg) infused during nocturnal rest when endogenous cortisol levels are low, compared with placebo, differentially reduced numbers of T cell subsets, with naive CD4(+) and CD8(+) subsets exhibiting the strongest reduction. Hydrocortisone in vivo and in vitro increased CXCR4 expression, which presumably mediates the recruitment of T cells to the bone marrow. Expression of the lymph node homing receptor CD62L on total CD3(+) and CD8(+) T cells appeared reduced following hydrocortisone infusion. However, this was due to a selective extravasation of CD62L(+) T cell subsets, as hydrocortisone affected neither CD62L expression on a subpopulation level nor CD62L expression in vitro. Corresponding results in the opposite direction were observed after blocking of endogenous cortisol synthesis by metyrapone. CCR7, another lymph node homing receptor, was also unaffected by hydrocortisone in vitro. Thus, cortisol seems to redirect T cells to the bone marrow by upregulating their CXCR4 expression, whereas its inhibiting effect on T cell homing to lymph nodes is apparently regulated independently of the expression of classical homing receptors.


Body height and immune efficacy: testing body stature as a signal of biological quality.
According to the good genes hypothesis and energy allocation theory, human adult body height may reflect biological quality. An important aspect of this quality is immune system functioning (ISF). The aim of this study was to evaluate the relationship between ISF and body height in healthy people. The ISF was determined by several important innate (total complement and lysozyme activity, neutrophil function) and adaptive immune parameters (lymphocytes, IgA and IgG, and response to the flu vaccine). Overall, 96 males and 97 females were subjected to flu vaccination, and of these, 35 males and 34 females were subjected to tetanus. Blood samples were collected before and four weeks after vaccination. Immunomodulatory factors, participant's age, body fat, and free testosterone levels, were controlled. There was no association between body height and all analysed immune parameters for both sexes. That might suggest that in Western society, a women's preference for taller men is not related to 'good genes for immune competence'. We propose the novel Immunity Priority Hypothesis that explains the lack of relationship between adult body stature and ISF. This hypothesis, however, does not contradict the signalling role of a man's body height as a morphological marker of biological quality.


Slowly developing toxic epidermal necrolysis-like reaction associated with pemetrexed and carboplatin.
Most cutaneous adverse drug reactions reported in association with chemotherapy, such as a limited maculopapular rash, are considered mild and do not affect the continuation of the treatment. Toxic epidermal necrolysis (TEN), however, is a life-threatening reaction that needs treatment discontinuation. The present case shows the slow progression from a pemetrexed and carboplatin-associated maculopapular rash to a TEN-like reaction.


Radiofluorination of a highly potent ATM inhibitor as a potential PET imaging agent.
Ataxia telangiectasia mutated (ATM) is a key mediator of the DNA damage response, and several ATM inhibitors (ATMi) are currently undergoing early phase clinical trials for the treatment of cancer. A radiolabelled ATMi to determine drug pharmacokinetics could assist patient selection in a move towards more personalised medicine. The aim of this study was to synthesise and investigate the first 18F-labelled ATM inhibitor [18F]1 for non-invasive imaging of ATM protein and ATMi pharmacokinetics. Radiofluorination of a confirmed selective ATM inhibitor (1) was achieved through substitution of a nitro-precursor with [18F]fluoride. Uptake of [18F]1 was assessed in vitro in H1299 lung cancer cells stably transfected with shRNA to reduce expression of ATM. Blocking studies using several non-radioactive ATM inhibitors assessed binding specificity to ATM. In vivo biodistribution studies were performed in wild-type and ATM-knockout C57BL/6 mice using PET/CT and ex vivo analysis. Uptake of [18F]1 in H1299 tumour xenografts was assessed in BALB/c nu/nu mice. Nitro-precursor 2 was synthesised with an overall yield of 12%. Radiofluorination of 2 achieved radiochemically pure [18F]1 in 80 ± 13 min with a radiochemical yield of 20 ± 13% (decay-corrected) and molar activities up to 79.5 GBq/μmol (n = 11). In vitro, cell-associated activity of [18F]1 increased over 1 h, and retention of [18F]1 dropped to 50% over 2 h. [18F]1 uptake did not correlate with ATM expression, but could be reduced significantly with an excess of known ATM inhibitors, demonstrating specific binding of [18F]1 to ATM. In vivo, fast hepatobiliary clearance was observed with tumour uptake ranging 0.13-0.90%ID/g after 1 h. Here, we report the first radiofluorination of an ATM inhibitor and its in vitro and in vivo biological evaluations, revealing the benefits but also some limitations of 18F-labelled ATM inhibitors.


[Overcoming disease and biography of lumbar disk surgery patients--a typology based on 30 case studies].
A random sample of 30 patients hospitalized for lumbar disc surgery was studied on four specific occasions: before surgery in a biographic interview; during post-operative treatment by behavioural observations; at discharge from hospital and 15 months on average after surgery in further interviews about their ability to cope with the illness and about their social adaptation. Data analysis was carried out according to the method of structural hermeneutics (Oevermann et al. 1979). By contrastive comparison of the cases, a typology of coping behaviour in patients during the out-patient, in-patient, and post-hospitalization phase was developed. 15 patients showed a consistent type of coping behaviour which we have termed "autonomistic". This finds expression at the behavioural level in a patient-doctor struggle who determines treatment. It is motivated by an ambivalence conflict between fear of and desire for dependence and care. Variants of autonomistic coping behaviour and their dependence on biographic influences are presented using 2 case histories. Against this background the problem of adaptivity is discussed.


Menstrual Cycle Variations in Gray Matter Volume, White Matter Volume and Functional Connectivity: Critical Impact on Parietal Lobe.
The role of gonadal hormones in neural plasticity remains unclear. This study aimed to examine the effects of naturally fluctuating hormone levels over the menstrual cycle in healthy females. Gray matter, functional connectivity (FC) and white matter changes over the cycle were assessed by using functional magnetic resonance imaging (fMRI), resting state fMRI, and structural MRIs, respectively, and associated with serum gonadal hormone levels. Moreover, electrocutaneous sensitivity was evaluated in 14 women in four phases of their menstrual cycle (menstrual, follicular, ovulatory, and luteal). Electrocutaneous sensitivity was greater during follicular compared to menstrual phase. Additionally, pain unpleasantness was lower in follicular phase than other phases while pain intensity ratings did not change over the cycle. Significant variations in cycle phase effects on gray matter volume were found in the left inferior parietal lobule (IPL) using voxel-based morphometry. Subsequent Freesurfer analysis revealed greater thickness of left IPL during the menstrual phase when compared to other phases. Also, white matter volume fluctuated across phases in left IPL. Blood estradiol was positively correlated with white matter volume both in left parietal cortex and whole cortex. Seed-driven FC between left IPL and right secondary visual cortex was enhanced during ovulatory phase. A seed placed in right IPL revealed enhanced FC between left and right IPL during the ovulatory phase. Additionally, we found that somatosensory cortical gray matter was thinner during follicular compared to menstrual phase. We discuss these results in the context of likely evolutionary pressures selecting for enhanced perceptual sensitivity across modalities specifically during ovulation.


Snowpack measurements suggest role for multi-year sea ice regions in Arctic atmospheric bromine and chlorine chemistry.
As sources of reactive halogens, snowpacks in sea ice regions control the oxidative capacity of the Arctic atmosphere. However, measurements of snowpack halide concentrations remain sparse, particularly in the high Arctic, limiting our understanding of and ability to parameterize snowpack participation in tropospheric halogen chemistry. To address this gap, we measured concentrations of chloride, bromide, and sodium in snow samples collected during polar spring above remote multi-year sea ice (MYI) and first-year sea ice (FYI) north of Greenland and Alaska, as well as in the central Arctic, and compared these measurements to a larger dataset collected in the Alaskan coastal Arctic by Krnavek et al. (2012). Regardless of sea ice region, these surface snow samples generally featured lower salinities, compared to coastal snow. Surface snow in FYI regions was typically enriched in bromide and chloride compared to seawater, indicating snowpack deposition of bromine and chlorine-containing trace gases and an ability of the snowpack to participate further in bromine and chlorine activation processes. In contrast, surface snow in MYI regions was more often depleted in bromide, indicating it served as a source of bromine-containing trace gases to the atmosphere prior to sampling. Measurements at various snow depths indicate that the deposition of sea salt aerosols and halogen-containing trace gases to the snowpack surface played a larger role in determining surface snow halide concentrations compared to upward brine migration from sea ice. Calculated enrichment factors for bromide and chloride, relative to sodium, in the MYI snow samples suggests that MYI regions, in addition to FYI regions, have the potential to play an active role in Arctic boundary layer bromine and chlorine chemistry. The ability of MYI regions to participate in springtime atmospheric halogen chemistry should be considered in regional modeling of halogen activation and interpretation of satellite-based tropospheric bromine monoxide column measurements.


Dialysate delivery: historical, theoretical, and practical aspect.
Maintenance hemodialysis has progressed from a tentative therapy for a few patients in Seattle to a generally available treatment sustaining 100,000 patients around the world. The technical principles of dialysis are sufficiently understood to permit fabrication of disposable dialyzers in sheet, coil, or hollow-fiber configuration. Dialysate delivery systems can serve either single patients or groups of patients with high efficiency. Reduction in size of single-parent systems by incorporation of dialysate regeneration or miniaturization of components in a suitcase will promote patient mobility.


Epidemiology of tuberculosis in Europe.
The risk of exposure to tuberculosis depends upon the incidence of infectious cases, the duration of their infectiousness, and the number of personal interactions an infectious case accomplishes per unit of time. The risk of infection, given exposure, depends on the density of infectious particles in the ambient air x duration of exposure to that air. The risk of infection has rapidly declined in Europe for decades by 10% or more annually, resulting in a shift of the infected to the oldest generation. Thus, with the passage of time, cohorts are increasingly replaced by successive cohorts with less and less infection. The risk of progression from infection to tuberculosis depends largely on the cellular immune system's capability to prevent tubercle bacilli from multiplication. The three most important risk factors for the progression from subclinical infection to tuberculosis include: human immunodeficiency virus (HIV) infection, recency of infection, and fibrotic residuals from earlier tuberculosis. The number of tuberculosis cases has rapidly decreased during this century, accompanied by an upward shift in the median age of patients. In recent years, tuberculosis among immigrants has gained in significance and is likely to continue to do so, while HIV infection has limited impact on the tuberculosis epidemic in Europe. The risk of dying from tuberculosis is determined by form and site of disease, and patient's and doctor's delay. The number of deaths caused by tuberculosis in Europe is rapidly decreasing.


Patient characteristics and outcomes associated with nitrovasodilator use in the treatment of acute heart failure.
Nitrovasodilators (NVs) are commonly recommended for the treatment of acute heart failure (AHF); however, registries suggest their use is not common. The objectives of this study were to determine patient characteristics associated with NV use and to explore the association between NV use and outcomes [length of stay (LoS) and inpatient mortality] in patients with AHF. A survey of US physicians (n = 426) who treat at least 5 AHF patients per month with NV provided a patient sample (n = 812 treated with NV and n = 322 not-NV) derived from chart review. Factors associated with NV use as well as patient characteristics and outcomes associated with NV use were explored using bivariate analysis, logistic regression, and negative binomial regression as appropriate. NV-treated patients were more likely to be female, have a higher systolic blood pressure, higher B-type natriuretic peptide and troponin, and stay in the intensive care unit while hospitalized, but less likely to be hyponatremic or hospitalized once previously. Overall, average LoS was 5.10 days (SD = 4.52) with 5.21 days (SD = 0.15) for the NV group and 4.94 days (SD = 0.31) for the non-NV group. The overall inpatient mortality rate was 2.1%. Among physicians who frequently use NV to treat AHF patients, there are distinct patient characteristics between NV treated and nontreated patients, suggesting a phenotype-driven approach. However, no differences in LoS or mortality were observed.


A World First in Cancer Data Collection Trial.
An innovative study to collect comprehensive cancer data is underway in the Barwon Southwestern region of Victoria. The Evaluation of Cancer Outcomes (ECO) Trial involves the collection of a nationally developed and agreed set of clinical cancer data items across the region. Cancer is the leading cause of death in Australia and cancer surveillance relies heavily on accurate incidence and mortality data collection. The Victorian Government and Victorian Department of Human Services recently identified a lack of useful data surrounding patients diagnosed with cancer, their treatment, clinical course and outcomes. This article discusses the need for an improved and extended cancer data collection model and highlights the importance of timely population data on processes and outcomes of cancer.


Plasmid-mediated quinolone resistance determinants among enterobacterial isolates from outpatients in Brazil.
The aim of this study was to determine the spread of plasmid-mediated quinolone resistance determinants [qnr-like, aac(6')-Ib-cr and qepA genes] among nalidixic acid-resistant enterobacterial strains isolated from outpatients from Southeast Brazil, their transferability and the genetic structures associated with the qnr genes. The qnrA, qnrB and qnrS genes were screened by a multiplex PCR-based technique from 257 non-repetitive nalidixic acid-resistant enterobacterial isolates collected from January 2000 to May 2005. Conjugation experiments were performed to determine whether the qnr-carrying plasmids were self-transferable. Genetic structures surrounding the qnr genes were analysed by PCR and cloning. The aac(6')-Ib-cr and qepA genes were screened among qnr-positive strains. Six qnrB-like-positive isolates (2.3%) were detected, whereas no qnrA- or qnrS-positive isolates were detected. Three Escherichia coli and two Klebsiella pneumoniae isolates harboured a qnrB2 gene and a single Citrobacter freundii isolate had the qnrB8 gene. One qnrB2-positive isolate also had the extended-spectrum beta-lactamase bla(CTX-M-2) gene. All these isolates also possessed chromosomal substitutions in gyrase- and topoisomerase-encoding genes, explaining their high-level resistance to quinolones. This study constitutes the first epidemiological survey of the three known Qnr determinants among Brazilian isolates and shows their low prevalence in that country, with the qnrB2 gene being mostly identified.


On-farm dynamic management of genetic diversity: the impact of seed diffusions and seed saving practices on a population-variety of bread wheat.
Since the domestication of crop species, humans have derived specific varieties for particular uses and shaped the genetic diversity of these varieties. Here, using an interdisciplinary approach combining ethnobotany and population genetics, we document the within-variety genetic structure of a population-variety of bread wheat (Triticum aestivum L.) in relation to farmers' practices to decipher their contribution to crop species evolution. Using 19 microsatellites markers, we conducted two complementary graph theory-based methods to analyze population structure and gene flow among 19 sub-populations of a single population-variety [Rouge de Bordeaux (RDB)]. The ethnobotany approach allowed us to determine the RDB history including diffusion and reproduction events. We found that the complex genetic structure among the RDB sub-populations is highly consistent with the structure of the seed diffusion and reproduction network drawn based on the ethnobotanical study. This structure highlighted the key role of the farmer-led seed diffusion through founder effects, selection and genetic drift because of human practices. An important result is that the genetic diversity conserved on farm is complementary to that found in the genebank indicating that both systems are required for a more efficient crop diversity conservation.


Analysis of cytochrome P450 CYP119 ligand-dependent conformational dynamics by two-dimensional NMR and X-ray crystallography.
Defining the conformational states of cytochrome P450 active sites is critical for the design of agents that minimize drug-drug interactions, the development of isoform-specific P450 inhibitors, and the engineering of novel oxidative catalysts. We used two-dimensional (1)H,(15)N HSQC chemical shift perturbation mapping of (15)N-labeled Phe residues and x-ray crystallography to examine the ligand-dependent conformational dynamics of CYP119. Active site Phe residues were most affected by the binding of azole inhibitors and fatty acid substrates, in agreement with active site localization of the conformational changes. This was supported by crystallography, which revealed movement of the F-G loop with various azoles. Nevertheless, the NMR chemical shift perturbations caused by azoles and substrates were distinguishable. The absence of significant chemical shift perturbations with several azoles revealed binding of ligands to an open conformation similar to that of the ligand-free state. In contrast, 4-phenylimidazole caused pronounced NMR changes involving Phe-87, Phe-144, and Phe-153 that support the closed conformation found in the crystal structure. The same closed conformation is observed by NMR and crystallography with a para-fluoro substituent on the 4-phenylimidazole, but a para-chloro or bromo substituent engendered a second closed conformation. An open conformation is thus favored in solution with many azole ligands, but para-substituted phenylimidazoles give rise to two closed conformations that depend on the size of the para-substituent. The results suggest that ligands selectively stabilize discrete cytochrome P450 conformational states.


Study of Factors Influencing Dry Eye in Rheumatoid Arthritis.
The present study investigated the relationship between dry eye and the disease activity in patients with rheumatoid arthritis (RA). Patients with RA were divided by the Ocular Surface Disease Index (OSDI) into the symptomatic group (score ≥ 12) and the asymptomatic group (score < 12). By using the Disease Activity Score (DAS-28) questionnaire, they were divided into the active group (score > 2.6) and the stable group (score ≤ 2.6). In the control group, 20 healthy adults with matched sex and age were selected. RA patients and healthy adults were inspected for the tear film break time (TBUT), tear meniscus height (TMH), corneal fluorescein staining (CFS), meibomian scan (MS), meibomian gland secretion score (MSS), and eyelid margin assessment (EMS). The TBUT of the RA group was significantly less than that of the control group, while the CFS, MS, EMS, and MSS were higher. The TBUT of the symptomatic RA group was significantly less than that of the asymptomatic group, and the CFS was higher. In the active RA group, only the CFS was higher than that of the stable group, and there was no significant difference between the two groups for other parameters. Furthermore, there was no significant correlation between the course of RA and the dry eye (P > 0.05). The rheumatoid activity does not necessarily lead to an aggravation of dry eye. Regardless of the duration, RA was not found to exhibit relation with the severity of dry eye. Translational Relevance. RA patients with disease active period cannot be ignored for the existence of dry eye, since patients with dry eye often lack the signs and symptoms.


How behavioural ageing affects infectious disease.
Ageing is associated with profound changes in behaviour that could influence exposure and susceptibility to infectious disease. As well as determining emergent patterns of infection across individuals of different ages, behavioural ageing could interact with, confound, or counteract age-related changes in other traits. Here, we examine how behavioural ageing can manifest and influence patterns of infection in wild animals. We discuss a range of age-related changes that involve interactions between behaviour and components of exposure and susceptibility to infection, including social ageing and immunosenescence, acquisition of novel parasites and pathogens with age, changes in spatial behaviours, and age-related hygiene and sickness behaviours. Overall, most behavioural changes are expected to result in a reduced exposure rate, but there is relatively little evidence for this phenomenon, emerging largely from a rarity of explicit tests of exposure changes over the lifespan. This review offers a framework for understanding how ageing, behaviour, immunity, and infection interact, providing a series of hypotheses and testable predictions to improve our understanding of health in ageing societies.


Expression of interleukin-1 (IL-1) ligands system in the most common endometriosis-associated ovarian cancer subtypes.
Endometrioid carcinoma of the ovary is one of the most types of epithelial ovarian cancer associated to endometrioisis. Endometrioid tumors as well as endometriotic implants are characterized by the presence of epithelial cells, stromal cells, or a combination of booth, that resemble the endometrial cells, suggesting a possible endometrial origin of these tumors. Pro-inflammatory cytokines, including interleukin-1 (IL-1) have been reported to be involved in both endometriosis and ovarian carcinogenesis. The major objective of this study was to determine the level expression of IL-1 ligands system (IL-1alpha, IL-1beta and IL-1RA) in the most common subtypes of ovarian cancer cells compared to endometrial cells. We used primary endometrial cells, endometrial cell line RL-952 and different subtypes of epithelial ovarian cancer cell lines including TOV-112D (endometrioid), TOV-21G (clear cell) and OV-90 (serous). Immunofluorescence and real-time PCR analysis were used respectively for detecting IL-1 ligands at the levels of cell-associated protein and mRNA. Soluble IL-1 ligands were analyzed by ELISA. We demonstrated that IL-1 ligands were expressed by all endometriosis-associated ovarian cancer subtypes and endometrial cells. In contrast to other cancer ovarian cells, endometrioid cells exhibit a specific decrease of cell-associated IL-1RA expression and its soluble secretion. Endometrioid ovarian cancer exhibits an alteration in the expression of IL-1RA, a key protector against tumorogenic effects of IL-1. This alteration evokes the same alteration observed in endometriotic cells in previous studies. This suggests a possible link between the endometrium, the tissue ectopic endometriosis and endometrioid ovarian cancer.


Mapping U.S. government tobacco control leadership: networked for success?
In order to better understand how tobacco control efforts are coordinated across agencies of the Department of Health and Human Services (DHHS), we assessed tobacco control-related communication between tobacco control leaders across DHHS. Cross-sectional surveys were collected from individuals representing 11 DHHS agencies, and social network analyses were used to assess linkages and map agencies' tobacco control communication. Individuals within the Office of the Secretary and Centers for Disease Control and Prevention (CDC) were most central to the network, and those of highest rank were most likely to be central to the network (F = 4.03, p = .024). The Centers for Medicare and Medicaid Services, Food and Drug Administration, Health Resources and Services Administration, and Substance Abuse and Mental Health Services Administration had no or almost no contact with other agencies. There was considerable between-agency contact variability, and the CDC was the most central agency. Tobacco control communication across DHHS agencies was present but extremely variable. This inconsistency may compromise the ability of the DHHS to address tobacco use, a critical public health problem, in a coordinated and efficient fashion. In light of the new leadership at DHHS, this analysis describes a systems approach that can be reimplemented as a means of understanding and improving communication and collaboration to improve public health.


New insights into cochlear sound encoding.
The inner ear uses specialized synapses to indefatigably transmit sound information from hair cells to spiral ganglion neurons at high rates with submillisecond precision. The emerging view is that hair cell synapses achieve their demanding function by employing an unconventional presynaptic molecular composition. Hair cell active zones hold the synaptic ribbon, an electron-dense projection made primarily of RIBEYE, which tethers a halo of synaptic vesicles and is thought to enable a large readily releasable pool of vesicles and to contribute to its rapid replenishment. Another important presynaptic player is otoferlin, coded by a deafness gene, which assumes a multi-faceted role in vesicular exocytosis and, when disrupted, causes auditory synaptopathy. A functional peculiarity of hair cell synapses is the massive heterogeneity in the sizes and shapes of excitatory postsynaptic currents. Currently, there is controversy as to whether this reflects multiquantal release with a variable extent of synchronization or uniquantal release through a dynamic fusion pore. Another important question in the field has been the precise mechanisms of coupling presynaptic Ca (2+) channels and vesicular Ca (2+) sensors. This commentary provides an update on the current understanding of sound encoding in the cochlea with a focus on presynaptic mechanisms.


Factors associated with choice of a low-fat or low-carbohydrate diet during a behavioral weight loss intervention.
Individuals undertaking a weight loss effort have a choice among proven dietary approaches. Factors contributing to choice of either a low-fat/low-calorie diet or a low-carbohydrate diet, two of the most studied and popular dietary approaches, are unknown. The current study used data from participants randomized to the 'choice' arm of a trial examining whether being able to choose a diet regimen yields higher weight loss than being randomly assigned to a diet. At study entry, participants attended a group session during which they were provided tailored feedback indicating which diet was most consistent with their food preferences using the Geiselman Food Preference Questionnaire (FPQ), information about both diets, and example meals for each diet. One week later, they indicated which diet they chose to follow during the 48-week study, with the option of switching diets after 12 weeks. Of 105 choice arm participants, 44 (42%) chose the low-fat/low-calorie diet and 61 (58%) chose the low-carbohydrate diet. In bivariate analyses, diet choice was not associated with age, race, sex, education, BMI, or diabetes (all p > 0.05). Low-carbohydrate diet choice was associated with baseline higher percent fat intake (p = 0.007), lower percent carbohydrate intake (p = 0.02), and food preferences consistent with a low-carbohydrate diet according to FPQ (p < 0.0001). In a multivariable logistic regression model, only FPQ diet preference was associated with diet choice (p = 0.001). Reported reasons for diet choice were generally similar for those choosing either diet; however, concerns about negative health effects of the unselected diet was rated as more influential among participants selecting the low-fat diet. Only three low-carbohydrate and two low-fat diet participants switched diets at 12 weeks. Results suggest that when provided a choice between two popular weight loss dietary approaches, an individual's selection is likely influenced by baseline dietary intake pattern, and especially by his or her dietary preferences. Research is needed to determine if congruency between food preferences and dietary approach is associated with weight loss.


Influence of beta-lactam antibiotics and ciprofloxacin on composition and immunogenicity of Escherichia coli outer membrane.
The effects of subinhibitory concentrations of different beta-lactam antibiotics and one quinolone on the sedimentation of outer membranes (OMs) of Escherichia coli and on the qualitative properties and immunogenicity of OM components were studied. Membranes were prepared by osmotic lysis of plasmolyzed bacteria. OM and cytoplasmic membrane vesicles were separated by sucrose density ultracentrifugation. Two peaks of OM vesicles with different buoyant densities could be isolated; the quantitative contribution of these to the total OM varied, depending upon the growth phase. In early log phase, the OM consisted mainly of lighter material; in late log and stationary phases, the OM consisted mainly of heavier material. Moxalactam, imipenem, and ciprofloxacin inhibited the formation of heavier material in all growth phases. The immunogenicity of OM vesicles was tested in mice by the hemolytic plaque test. The lighter OM material was markedly less immunogenic than the heavier OM material. The vesicles from antibiotic-treated bacteria and those from early-log-phase cells were less immunogenic than vesicles from untreated late-log-phase and stationary-phase bacteria. These changes were found for the immune response against lipopolysaccharides, as well as against OM proteins. Thus, the immunogenicity of OM components seems to be dependent upon the quantitative composition of lighter and heavier compounds, which is strongly influenced by growth phase and treatment with certain antibiotics.


Experimental Studies of Front-of-Package Nutrient Warning Labels on Sugar-Sweetened Beverages and Ultra-Processed Foods: A Scoping Review.
Policies that require front-of-package (FoP) nutrient warnings are becoming increasingly common across the globe as a strategy to discourage excess consumption of sugary drinks and ultra-processed food. However, a better understanding of the pathway through which FoP nutrient warnings work, as well as a review of how outcomes being measured in recent studies map onto this pathway, are needed in order to inform policy on the most effective FoP label design for reducing purchases of ultra-processed foods. This scoping review describes a conceptual model for how FoP nutrient warnings affect consumer behavior, examines which of these outcomes are currently being measured, and summarizes evidence from randomized controlled experiments. Twenty-two studies which experimentally tested nutrient warnings against a control label or other labeling systems were included for full-text review. Our conceptual model includes attention; comprehension, cognitive elaboration, and message acceptance; negative affect and risk perception; behavioral intentions, and behavioral response, along with other elements such as external factors and interpersonal communications. We found that many studies focused on outcomes such as attention, comprehension, and behavioral intentions, but considerable gaps in the evidence remain, particularly for intermediary steps on the pathway to behavioral change, such as negative affect and social interactions. FoP nutrient warnings were visually attended to by consumers, easy to understand, helped consumers identify products high in nutrients of concern, and discouraged them from purchasing these products, although other labeling systems were perceived as containing more information and performed better at helping consumers rank the healthfulness of products. More research is needed to understand whether and how nutrient warnings work in the real world to discourage consumer purchases of sugary drinks and ultra-processed food.


A comparative analysis of stably expressed genes across diverse angiosperms exposes flexibility in underlying promoter architecture.
Promoters regulate both the amplitude and pattern of gene expression-key factors needed for optimization of many synthetic biology applications. Previous work in Arabidopsis found that promoters that contain a TATA-box element tend to be expressed only under specific conditions or in particular tissues, while promoters that lack any known promoter elements, thus designated as Coreless, tend to be expressed more uniformly. To test whether this trend represents a conserved promoter design rule, we identified stably expressed genes across multiple angiosperm species using publicly available RNA-seq data. Comparisons between core promoter architectures and gene expression stability revealed differences in core promoter usage in monocots and eudicots. Furthermore, when tracing the evolution of a given promoter across species, we found that core promoter type was not a strong predictor of expression pattern. Our analysis suggests that core promoter types are correlative rather than causative in promoter expression patterns and highlights the challenges in finding or building constitutive promoters that will work across diverse plant species.


Myocardial infarction in the Wisconsin Longitudinal Study: the interaction among environmental, health, social, behavioural and genetic factors.
This study examined how environmental, health, social, behavioural and genetic factors interact to contribute to myocardial infarction (MI) risk. Survey data collected by Wisconsin Longitudinal Study (WLS), USA, from 1957 to 2011, including 235 environmental, health, social and behavioural factors, and 77 single- nucleotide polymorphisms were analysed for association with MI. To identify associations with MI we utilized recursive partitioning and random forest prior to logistic regression and chi-squared analyses. 6198 WLS participants (2938 men; 3260 women) who (1) had a MI before 72 years and (2) had a MI between 65 and 72 years. In men, stroke (LR OR: 5.01, 95% CI 3.36 to 7.48), high cholesterol (3.29, 2.59 to 4.18), diabetes (3.24, 2.53 to 4.15) and high blood pressure (2.39, 1.92 to 2.96) were significantly associated with MI up to 72 years of age. For those with high cholesterol, the interaction of smoking and lower alcohol consumption increased prevalence from 23% to 41%, with exposure to dangerous working conditions, a factor not previously linked with MI, further increasing prevalence to 50%. Conversely, MI was reported in <2.5% of men with normal cholesterol and no history of diabetes or depression. Only stroke (4.08, 2.17 to 7.65) and diabetes (2.71, 1.81 to 4.04) by 65 remained significantly associated with MI for men after age 65. For women, diabetes (5.62, 4.08 to 7.75), high blood pressure (3.21, 2.34 to 4.39), high cholesterol (2.03, 1.38 to 3.00) and dissatisfaction with their financial situation (4.00, 1.94 to 8.27) were significantly associated with MI up to 72 years of age. Conversely, often engaging in physical activity alone (0.53, 0.32 to 0.89) or with others (0.34, 0.21 to 0.57) was associated with the largest reduction in odds of MI. Being non-diabetic with normal blood pressure and engaging in physical activity often lowered prevalence of MI to 0.2%. Only diabetes by 65 (4.25, 2.50 to 7.24) and being exposed to dangerous work conditions at 54 (2.24, 1.36 to 3.69) remained significantly associated with MI for women after age 65, while still menstruating at 54 (0.46, 0.23 to 0.91) was associated with reduced odds of MI. Together these results indicate important differences in factors associated with MI between the sexes, that combinations of factors greatly influence the likelihood of MI, that MI-associated factors change and associations weaken after 65 years of age in both sexes, and that the limited genotypes assessed were secondary to environmental, health, social and behavioral factors.


Advances in the use of chloroquine and hydroxychloroquine for the treatment of COVID-19.
Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading worldwide. Antiviral therapy is the most important treatment for COVID-19. Among the drugs under investigation, anti-malarials, chloroquine (CQ) and hydroxychloroquine (HCQ), are being repurposed as treatment for COVID-19. CQ/HCQ were shown to prevent receptor recognition by coronaviruses, inhibit endosome acidification, which interferes with membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. A number of in vitro studies revealed inhibitory effects of CQ/HCQ on various coronaviruses, including SARS-CoV-2 although conflicting results exist. Several clinical studies showed that CQ/HCQ alone or in combination with a macrolide may alleviate the clinical symptoms of COVID-19, promote viral conversion, and delay disease progression, with less serious adverse effects. However, recent studies indicated that the use of CQ/HCQ, alone or in combination with a macrolide, did not show any favorable effect on patients with COVID-19. Adverse effects, including prolonged QT interval after taking CQ/HCQ, may develop in COVID-19 patients. Therefore, current data are not sufficient enough to support the use of CQ/HCQ as therapies for COVID-19 and increasing caution should be taken about the application of CQ/HCQ in COVID-19 before conclusive findings are obtained by well-designed, multi-center, randomized, controlled studies.


Intraoperative multi-exposure speckle imaging of cerebral blood flow.
Multiple studies have demonstrated that laser speckle contrast imaging (LSCI) has high potential to be a valuable cerebral blood flow monitoring technique during neurosurgery. However, the quantitative accuracy and sensitivity of LSCI is limited, and highly dependent on the exposure time. An extension to LSCI called multi-exposure speckle imaging (MESI) overcomes these limitations, and was evaluated intraoperatively in patients undergoing brain tumor resection. This clinical study ( n = 8) recorded multiple exposure times from the same cortical tissue area spanning 0.5-20 ms, and evaluated images individually as single-exposure LSCI and jointly using the MESI model. This study demonstrated that the MESI estimates provided the broadest flow sensitivity for sampling the flow magnitude in the human brain, closely followed by the shorter exposure times. Conservation of flow analysis on vascular bifurcations was used to validate physiological accuracy, with highly conserved flow estimates (<10%) from both MESI and 1 ms LSCI ( n = 14 branches). The MESI model had high goodness-of-fit with proper image calibration and acquisition, and was used to monitor blood flow changes after tissue cautery. Results from this study demonstrate that intraoperative MESI can be performed with high quantitative accuracy and sensitivity for cerebral blood flow monitoring.