Automatic upper airway segmentation in static and dynamic MRI via anatomy-guided convolutional neural networks.
Upper airway segmentation on MR images is a prerequisite step for quantitatively studying the anatomical structure and function of the upper airway and surrounding tissues. However, the complex variability of intensity and shape of anatomical structures and different modes of image acquisition commonly used in this application makes automatic upper airway segmentation challenging. In this paper, we develop and test a comprehensive deep learning-based segmentation system for use on MR images to address this problem. In our study, both static and dynamic MRI data sets are utilized, including 58 axial static 3D MRI studies, 22 mid-retropalatal dynamic 2D MRI studies, 21 mid-retroglossal dynamic 2D MRI studies, 36 mid-sagittal dynamic 2D MRI studies, and 23 isotropic dynamic 3D MRI studies, involving a total of 160 subjects and over 20 000 MRI slices. Samples of static and 2D dynamic MRI data sets were randomly divided into training, validation, and test sets by an approximate ratio of 5:2:3. Considering that the variability of annotation data among 3D dynamic MRIs was greater than for other MRI data sets, we increased the ratio of training data for these data to improve the robustness of the model. We designed a unified framework consisting of the following procedures. For static MRI, a generalized region-of-interest (GROI) strategy is applied to localize the partitions of nasal cavity and other portions of upper airway in axial data sets as two separate subobjects. Subsequently, the two subobjects are segmented by two separate 2D U-Nets. The two segmentation results are combined as the whole upper airway structure. The GROI strategy is also applied to other MRI modes. To minimize false-positive and false-negative rates in the segmentation results, we employed a novel loss function based explicitly on these rates to train the segmentation networks. An inter-reader study is conducted to test the performance of our system in comparison to human variability in ground truth (GT) segmentation of these challenging structures. The proposed approach yielded mean Dice coefficients of 0.84±0.03, 0.89±0.13, 0.84±0.07, and 0.86±0.05 for static 3D MRI, mid-retropalatal/mid-retroglossal 2D dynamic MRI, mid-sagittal 2D dynamic MRI, and isotropic dynamic 3D MRI, respectively. The quantitative results show excellent agreement with manual delineation results. The inter-reader study results demonstrate that the segmentation performance of our approach is statistically indistinguishable from manual segmentations considering the inter-reader variability in GT. The proposed method can be utilized for routine upper airway segmentation from static and dynamic MR images with high accuracy and efficiency. The proposed approach has the potential to be employed in other dynamic MRI-related applications, such as lung or heart segmentation.


Research Note: Three-dimensional microstructural basis for chicken eggshell translucency.
Eggshell translucency, an externally observable feature, can influence consumer purchase intentions. The eggshell quality often deteriorates in aging laying hens, leading to increased eggshell translucency. Eggs exchange water vapor through the pores. It is commonly believed that the moisture remaining in the mastoid space contributes to translucent egg formation. However, the precise mechanisms underlying eggshell translucency require further structural investigations. This study aimed to explore the 3-dimensional microstructure of eggshells using micro-computed tomography (micro-CT) to provide insights into the microstructural basis of eggshell translucency. The results revealed that the ratio of pore volume to mastoid space volume was significantly higher in the high-translucency (TH) group than that in the low-translucency (TL) group (P < 0.01); however, the ratio of mastoid space to eggshell volume showed no significant difference. Additionally, measurements of the individual pore morphological features showed that the roundness of the pores in the TH group was significantly higher than that in the TL group, whereas the flatness of the pores in the TH group was significantly lower (P = 0.01). Eggshell porosity directly reflects the water vapor exchange capacity of eggshells, with the TL group exhibiting significantly higher eggshell porosity compared to the TH group (P = 0.02). In conclusion, based on observations of the 3-dimensional microstructure of eggshells, this study elucidated how the volume and morphological characteristics of pores influence the water vapor exchange capacity of eggshells, resulting in eggshell translucency.


Descriptive analysis of pharmacy services provided after community pharmacy screening.
Background Community pharmacies are promising locations for opportunistic screening due to pharmacist accessibility and ability to perform various health and medication management services. Little is known as to the provision of pharmacy services following screening initiatives. Objective To describe provision of pharmacy services for participants following a community pharmacy stroke screening initiative. Setting The Program for the Identification of "Actionable Atrial" Fibrillation Pharmacy initiative took place in 30 pharmacies in Alberta and Ontario, Canada. 1149 participants ≥ 65 were screened for atrial fibrillation, type 2 diabetes, and hypertension. Method Retrospective, secondary analysis of data using participant case-report forms, pharmacy data, and pharmacy claims to describe pharmacy services received by participants post-screening. Main Outcome Measure Number and types of remunerated pharmacy services received by participants post-screening. Results A total of 535/1149 (46.6%) participants screened at their regular pharmacy were included in this analysis. Of these, 165 (30.8%) participants received 229 pharmacy services within 3 months post-screening, including 146 medication reviews, 57 influenza vaccinations, and 21 pharmaceutical opinions. A median (interquartile range, IQR) of 6 (2-11) pharmacy services were delivered, and median (IQR) reimbursement was $187.50 ($67.50-$342.50). Conclusions Approximately one-third of participants received a pharmacy service within 3 months post-screening. Relatively large numbers of annual and follow-up medication reviews were delivered despite low eligibility for annual-only reviews and despite many missed opportunities for pharmacy service provision in at-risk patients. In-pharmacy screening may facilitate provision of some services, namely medication reviews, by providing opportunities to identify patients at-risk.


Impact of maternal fuels and nutritional state on fetal growth.
Several maternal plasma fuel abnormalities have been described in gestational diabetes mellitus (GDM), and all may contribute to the development of fetal macrosomia, generally because of the surfeit of calories they provide. Elevated maternal plasma glucose and amino acid concentrations represent key disturbances, because they are also well-known fetal pancreatic beta-cell secretagogues. Fetal hyperinsulinemia contributes to macrosomia in a special way by selectively accelerating fuel utilization and storage in insulin-sensitive fetal tissues. Maternal obesity intensifies the insulin resistance already present in late pregnancy and probably exaggerates the metabolic abnormalities attending GDM that impact on fetal growth and development. However, the means by which maternal obesity per se promotes the development of heavy babies in nondiabetic pregnancies remains poorly defined. Significant correlations exist between newborn birth weight and the levels of maternal plasma glucose, amino acids, free fatty acids, and triglycerides in diabetic pregnancies. However, the relative influence of each disturbance on fetal birth weight remains controversial and requires more detailed investigation.


Systemic and local inflammation in patients with unstable atherosclerotic plaques.
The response to injury in the vasculature and the heart is inflammation. Atherosclerosis is often the result of injury followed by inflammation and atherosclerosis. Vascular and myocardial infections from various pathogens, including viruses, bacteria, chlamydia, and other infections result in vascular inflammation and almost certainly play a role in the development of atherosclerosis and acute coronary heart disease syndromes in at least some patients. Current evidence favors prior exposure to multiple pathogens as most likely playing a role in initiating inflammation and contributing to atherosclerosis. Genetic predisposition is almost certainly an important factor in the development of inflammation, impaired endothelial vascular repair, vascular infection, thrombosis, and atherosclerosis. The aging process itself is most likely associated with altered vascular and myocardial defense mechanisms predisposing to inflammation. The oxidation of cholesterol and low-density lipoprotein (LDL) leads to the production of oxidized radicals that promote vascular inflammation. Interventional injury, including angioplasty and stenting, causes endothelial inflammation, thrombosis, and fibroproliferation. Systemic evidence of inflammation identifies patients at high risk of future coronary events, including those who appear to be healthy initially as well as those with stable and unstable coronary heart disease syndromes. Increases in serum C-reactive protein (CRP) identify individuals at risk for future vascular events, including unstable angina, acute myocardial infarction, acute cerebrovascular accident, and sudden death. Similarly, systemic elevations in serum troponin 1, serum amyloid-like protein, fibrinogen, and interleukins-1, 2, 6, 8, and 18 identify patients with unstable angina and non-Q-wave myocardial infarction at increased risk for future coronary events. The presence of vascular inflammation may be detected by identifying temperature heterogeneity within plaques that demonstrate inflammation. In the future, the local evaluation of atherosclerotic plaques to detect the presence of inflammation coupled to measurements of systemic markers of inflammation, such as C-reactive protein, may help identify patients at increased risk and allow both local and systemic therapies that reduce their risk and prevent the development of acute coronary syndromes in at least some patients.


Curved block copolymer nanodiscs: structure transformations in cylindrical nanopores using the nonsolvent-assisted template wetting method.
In this work, we study the structure transformations of cylinder-forming polystyrene-block-polydimethylsiloxane (PS31k-b-PDMS14.5k) confined in cylindrical nanopores. PS-b-PDMS nanotubes, nanospheres, and curved nanodiscs are ingeniously prepared by a facile template wetting strategy using anodic aluminum oxide (AAO) templates. Quantitative analyses of the structure transformations from nanospheres to curved nanodiscs are also conducted, showing that the lengths of the curved nanodiscs can be controlled by adjusting the annealing temperature and time. Furthermore, the PDMS domains of the nanostructures can be selectively etched using HF solutions, generating porous PS nanostructures. This work not only offers versatile routes to prepare block copolymer nanostructures with controlled shapes but also provides a deeper understanding of the structure transformation of block copolymers in confined geometries.


Text messaging for maternal and infant retention in prevention of mother-to-child HIV transmission services: A pragmatic stepped-wedge cluster-randomized trial in Kenya.
Timely diagnosis of infant HIV infection is essential for antiretroviral therapy (ART) initiation. In a randomized controlled trial, we found the Texting Improves Testing (TextIT) intervention (a theory-based text messaging system) to be efficacious for improving infant HIV testing rates and maternal retention in prevention of mother-to-child HIV transmission (PMTCT) programs. Using an implementation science approach, we aimed to evaluate real-world effectiveness of the intervention. In a pragmatic, cluster-randomized, stepped-wedge trial with 2 time periods of observation, we randomly allocated 10 clinics to begin implementing the intervention immediately and 10 clinics to begin implementing 6 months later. To approximate real-world conditions, inclusion criteria were broad. Women at clinics implementing the intervention received up to 14 text messages during pregnancy and after delivery and had the option to respond to text messages, call, or send inquiry text messages to a designated clinic phone. The primary outcomes were infant HIV testing and maternal retention in care during the first 8 weeks after delivery. We used modified Poisson regression with robust variance estimation to estimate the relative risk and 95% confidence intervals (CIs). Generalized estimating equations were applied on individual-level data to account for clustering by site. Between February 2015 and December 2016, 4,681 women were assessed for study participation, and 2,515 were included. Participant characteristics at enrollment did not differ by study arm. Overall median age was 27 years (interquartile range [IQR] 23-30), median gestational age was 30 weeks (IQR 28-34), 99% were receiving ART, and 87% who enrolled during intervention phases owned a phone. Of 2,326 infants analyzed, 1,466 of 1,613 (90.9%) in the intervention group and 609 of 713 (85.4%) in the control group met the primary outcome of HIV virologic testing performed before 8 weeks after birth (adjusted relative risk [aRR] 1.03; 95% CI 0.97-1.10; P = 0.3). Of 2,472 women analyzed, 1,548 of 1,725 (90%) in the intervention group and 571 of 747 (76%) in the control group met the primary outcome of retention in care during the first 8 weeks after delivery (aRR 1.12; 95% CI 0.97-1.30; P = 0.1). This study had two main limitations. Staff at all facilities were aware of ongoing observation, which may have contributed to increased rates of infant HIV testing and maternal retention in care at both intervention and control facilities, and programmatic initiatives to improve maternal and infant retention in care were ongoing at all facilities at the time of this study, which likely limited the ability to demonstrate effectiveness of the trial intervention. In this study, a larger proportion of infants in the intervention group received HIV testing compared with the control group, but the difference was small and not statistically significant. There was also a nonsignificant increase in maternal postpartum retention in the intervention periods. Despite the lack of a significant effect of the intervention, key lessons emerged, both for strengthening PMTCT and for implementation research in general. Perhaps most important, improving the implementation of usual care may have been sufficient to substantially improve infant HIV testing rates. ClinicalTrials.gov Trial Number NCT02350140.


Macroeconomics of Natural Disasters: Strengths and Weaknesses of Meta-Analysis Versus Review of Literature.
We use the case of the macroeconomic impact of natural disasters to analyze strengths and weaknesses of meta-analysis in an emerging research field. Macroeconomists have published on this issue since 2002 (we identified 60 studies to date). The results of the studies are contradictory and therefore the need to synthesize the available research is evident. Meta-analysis is a useful method in this field. An important aim of our article is to show how one can use the identified methodological characteristics to better understand the robustness and importance of new findings. To provide a comparative perspective, we contrast our meta-analysis and its findings with the major influential research synthesis in the field: the IPCC's 2012 special report Managing the Risks of Extreme Events and Disasters to Advance Climate Change Adaptation. We show that the IPCC could have been more confident about the negative economic impact of disasters and more transparent on inclusion and qualification of studies, if it had been complemented by a meta-analysis. Our meta-analysis shows that, controlling for modeling strategies and data set, the impact of disasters is significantly negative. The evidence is strongest for direct costs studies where we see no difference between our larger sample and the studies included in the IPCC report. Direct cost studies and indirect cost studies differ significantly, both in terms of the confidence that can be attached to a negative impact of natural disasters and in terms of the sources of heterogeneity of the findings reported in the primary studies.


Autonomous and controlled motivation for interpersonal therapy for depression: Between-therapists and within-therapist effects.
Differences between therapists in the average outcomes their patients achieve are well documented, and researchers have begun to try to explain such differences (Baldwin & Imel, 2013). Guided by Self-Determination Theory (Deci & Ryan, 2000), we examined the effects on outcome of differences between therapists in their patients' average levels of autonomous and controlled motivation for treatment, as well as the effects of differences among the patients within each therapist's caseload. Between and within-therapist differences in the SDT construct of perceived relational support were explored as predictors of patients' motivation. Nineteen therapists treated 63 patients in an outpatient clinic providing manualized interpersonal therapy (IPT) for depression. Patients completed the BDI-II at pretreatment, posttreatment, and each treatment session. The Impact Message Inventory was administered at the third session and scored for perceived therapist friendliness, a core element of relational support. We created between-therapists (therapist-level) scores by averaging over the patients in each therapist's caseload; within-therapist (patient-level) scores were computed by centering within each therapist's caseload. As expected, better outcome was predicted by higher levels of therapist-level and patient-level autonomous motivation and by lower levels of therapist-level and patient-level controlled motivation. In turn, autonomous motivation was predicted by therapist-level and patient-level relational support (friendliness). Controlled motivation was predicted solely by patient self-critical perfectionism. The results extend past work by demonstrating that both between-therapists and within-therapist differences in motivation predict outcome. As well, the results suggest that therapists should monitor their interpersonal impact so as to provide relational support. (PsycINFO Database Record


Stargazin modulates AMPA receptor gating and trafficking by distinct domains.
AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors mediate fast excitatory synaptic transmission in the brain. These ion channels rapidly deactivate and desensitize, which determine the time course of synaptic transmission. Here, we find that the AMPA receptor interacting protein, stargazin, not only mediates AMPA receptor trafficking but also shapes synaptic responses by slowing channel deactivation and desensitization. The cytoplasmic tail of stargazin determines receptor trafficking, whereas the ectodomain controls channel properties. Stargazin alters AMPA receptor kinetics by increasing the rate of channel opening. Disrupting the interaction of stargazin ectodomain with hippocampal AMPA receptors alters the amplitude and shape of synaptic responses, establishing a crucial function for stargazin in controlling the efficacy of synaptic transmission in the brain.


In silico prediction of substrate properties for ABC-multidrug transporters.
Overexpression of ABC (ATP-binding cassette)-type drug efflux pumps, such as ABCB1, ABCC1 and ABCG2 in cancer cells confers multi-drug resistance (MDR) and represents a major cause of treatment failures in cancer therapy. Furthermore, there is increasing evidence for the important contribution of ABC-transporters to bioavailability, distribution, elimination and blood-brain barrier permeation of drug candidates. This review presents an overview on the different computational methods and models pursued to predict ABC-transporter substrate properties of drug-like compounds. They range from linear discriminant analysis to pharmacophore modelling and machine learning algorithms. Many of these models show a satisfying performance within the study-specific, defined chemical space but general applicability for the whole drug-like chemical space still needs to be proven. First attempts aiming towards selectivity profiling for ligands of the two polyspecific transporters ABCB1 and ABCG2 is also discussed. This might pave the way for a pharmacological profiling of compound series with special focus on their ADMET (absorption, distribution, metabolism, excretion and toxicity) properties.


Diagnosis of variants of hyperphenylalaninemia by determination of pterins in urine.
Assessment of urinary pterins is proposed as a rapid method for recognition of the variants of hyperphenylalaninemia. This is achieved by means of oxidation of pterins by iodine in acidic and alkaline solutions and then by high performance liquid chromatography on a cation-exchange column with fluorimetric detection. In biopterin-synthetase deficiency, only neopterin accumulated; in dihydropteridine-reductase (DHPR) deficiency and in phenylketonuria, high levels of pterins are found, but BH4 levels, absent in the former and high in the latter, allow a differential diagnosis. Phenylalanine loads in the controls also lead to increased elimination of pterins, but with a pattern different from that found in phenylketonuria. This method can be used before dietary treatment and thus can be proposed for all newly detected hyperphenylalaninemic babies.


Network-Centric Interventions to Contain the Syphilis Epidemic in San Francisco.
The number of reported early syphilis cases in San Francisco has increased steadily since 2005. It is not yet clear what factors are responsible for such an increase. A recent analysis of the sexual contact network of men who have sex with men with syphilis in San Francisco has discovered a large connected component, members of which have a significantly higher chance of syphilis and HIV compared to non-member individuals. This study investigates whether it is possible to exploit the existence of the largest connected component to design new notification strategies that can potentially contribute to reducing the number of cases. We develop a model capable of incorporating multiple types of notification strategies and compare the corresponding incidence of syphilis. Through extensive simulations, we show that notifying the community of the infection state of few central nodes appears to be the most effective approach, balancing the cost of notification and the reduction of syphilis incidence. Additionally, among the different measures of centrality, the eigenvector centrality reveals to be the best to reduce the incidence in the long term as long as the number of missing links (non-disclosed contacts) is not very large.


Defect physics of intrinsic point defects in BiPO4 photocatalysts: a hybrid functional study.
In this work, the intrinsic point defect properties of bulk BiPO4 under different growth conditions are intensively investigated and explored using first-principles hybrid functional calculations. It is found that Bi vacancies and O vacancies are the primary native defects in BiPO4. Under O-poor conditions, BiPO4 acts as an intrinsic insulator because the O vacancy defects (donor) and the Bi vacancy defects (acceptor) compensate for each other. Under Bi-poor conditions, good p-type conductivity is observed in BiPO4, which affirms the observed p-type conductivity behavior in experiments. Bi vacancies in BiPO4 are very shallow, which make it an excellent acceptor and are mostly responsible for the p-type character. In addition, it is found that the primary Bi vacancy defects of BiPO4 hardly affect its electronic structure and optical absorption spectrum regardless of the charge states. In contrast, the neutral O vacancy defects in BiPO4 introduce an impurity energy level near the VBM and induce a new optical absorption peak at around 370 nm. Furthermore, the O vacancies should be favorable for enhancing the production and separation efficiencies of the photo-generated electrons and holes in BiPO4. While Bi vacancies easily provide p-type carriers, simultaneously, they could become the active sites for the photocatalytic reactions because of their dominant -3 charge state. Therefore, understanding the defect physics in BiPO4 photocatalysts is believed to be beneficial for more research in developing BiPO4 or BiPO4-based photocatalysts.


Sequencing and assembly of the Egyptian buffalo genome.
Water buffalo (Bubalus bubalis) is an important source of meat and milk in countries with relatively warm weather. Compared to the cattle genome, a little has been done to reveal its genome structure and genomic traits. This is due to the complications stemming from the large genome size, the complexity of the genome, and the high repetitive content. In this paper, we introduce a high-quality draft assembly of the Egyptian water buffalo genome. The Egyptian breed is used as a dual purpose animal (milk/meat). It is distinguished by its adaptability to the local environment, quality of feed changes, as well as its high resistance to diseases. The genome assembly of the Egyptian water buffalo has been achieved using a reference-based assembly workflow. Our workflow significantly reduced the computational complexity of the assembly process, and improved the assembly quality by integrating different public resources. We also compared our assembly to the currently available draft assemblies of water buffalo breeds. A total of 21,128 genes were identified in the produced assembly. A list of milk virgin-related genes; milk pregnancy-related genes; milk lactation-related genes; milk involution-related genes; and milk mastitis-related genes were identified in the assembly. Our results will significantly contribute to a better understanding of the genetics of the Egyptian water buffalo which will eventually support the ongoing breeding efforts and facilitate the future discovery of genes responsible for complex processes of dairy, meat production and disease resistance among other significant traits.


Electroreception in marine fishes: chondrichthyans.
Electroreception in marine fishes occurs across a variety of taxa and is best understood in the chondrichthyans (sharks, skates, rays, and chimaeras). Here, we present an up-to-date review of what is known about the biology of passive electroreception and we consider how electroreceptive fishes might respond to electric and magnetic stimuli in a changing marine environment. We briefly describe the history and discovery of electroreception in marine Chondrichthyes, the current understanding of the passive mode, the morphological adaptations of receptors across phylogeny and habitat, the physiological function of the peripheral and central nervous system components, and the behaviours mediated by electroreception. Additionally, whole genome sequencing, genetic screening and molecular studies promise to yield new insights into the evolution, distribution, and function of electroreceptors across different environments. This review complements that of electroreception in freshwater fishes in this special issue, which provides a comprehensive state of knowledge regarding the evolution of electroreception. We conclude that despite our improved understanding of passive electroreception, several outstanding gaps remain which limits our full comprehension of this sensory modality. Of particular concern is how electroreceptive fishes will respond and adapt to a marine environment that is being increasingly altered by anthropogenic electric and magnetic fields.


Outcomes of hip fracture treatment with intravenous morphine and with other analgesics: postoperative analgesic medical expense, severity of pain and hospitalisation-a retrospective study.
This study compares the postoperative medical costs and outcomes of hip fracture patients treated with intravenous (IV) versus other analgesics (weak opioids, NSAIDs or acetaminophen). We performed a retrospective study at a tertiary hospital in Thailand, examining 1,531 patients who underwent hip fracture surgery between 2009 and 2020. We analyzed data on analgesic usage, costs, pain scores, and adverse effects. In the study of 1531 patients, 63% of patients received as-needed analgesics, and 37% received preemptive prescriptions. In both groups, IV morphine was the predominant choice. The mean cost for the IV group was marginally higher than the other analgesics group ($2277 vs $2174). The other analgesics group had a significantly higher consumption of acetaminophen and selective NSAIDs (p = 0.004). Pain scores were similar across both groups, but the IV group had a significantly higher incidence of gastrointestinal side effects (24% vs 10.5%, p < 0.01). The choice of IV or other analgesics in treating hip fractures affects analgesic usage, side effects, medical costs, and patient outcomes. Further studies across different regions are recommended.


Orthodontists' preferences regarding the difference of bracket bonding height between the maxillary incisors.
The vertical position of orthodontic brackets in maxillary incisors may influence the incisal step between the anterior teeth and thereby interfere with the smile esthetics. Even so, esthetic standards have been modified over time and consistently required technical adjustments. This study analyzed orthodontists' preferences regarding the difference of bracket bonding height between the maxillary central incisors (MCI) and maxillary lateral incisors (MLI), and further determined whether the orthodontist sex, age and time of specialization have association to their choices. This study collected data through an electronic form. Study participants analyzed a clinical case in which they indicated their preference for bracket bonding height. The placement height options ranged from 3.0 mm to 5.5 mm from the incisal edge, with 0.5-mm intervals, or at the clinical crown center (CCC). The difference in the bonding height between the MCI and MLI was analyzed, considering the formation of incisal steps between these teeth. Participants indicated that the difference in bracket bonding height between the MCI and MLI should be as follows: 0 mm (3.9%); 0.5 mm (78.3%); 1 mm (7.6%); 1.5 mm (0.2%); and CCC (9.9%). There was no statistically significant correlation between the choice for bracket bonding height and sex, age and time since specialization. Most participating orthodontists choose the 0.5-mm difference in bracket placement height between the MCI and MLI. The variables sex, age and time since specialization did not influence this choice.


Implementation of control strategies for sterile insect techniques.
In this paper, we propose a sex-structured entomological model that serves as a basis for design of control strategies relying on releases of sterile male mosquitoes (Aedes spp) and aiming at elimination of the wild vector population in some target locality. We consider different types of releases (constant and periodic impulsive), providing sufficient conditions to reach elimination. However, the main part of the paper is focused on the study of the periodic impulsive control in different situations. When the size of wild mosquito population cannot be assessed in real time, we propose the so-called open-loop control strategy that relies on periodic impulsive releases of sterile males with constant release size. Under this control mode, global convergence towards the mosquito-free equilibrium is proved on the grounds of sufficient condition that relates the size and frequency of releases. If periodic assessments (either synchronized with the releases or more sparse) of the wild population size are available in real time, we propose the so-called closed-loop control strategy, under which the release size is adjusted in accordance with the wild population size estimate. Finally, we propose a mixed control strategy that combines open-loop and closed-loop strategies. This control mode renders the best result, in terms of overall time needed to reach elimination and the number of releases to be effectively carried out during the whole release campaign, while requiring for a reasonable amount of released sterile insects.


Biofabrication and characterization of silver nanoparticles using aqueous extract of seaweed Enteromorpha compressa and its biomedical properties.
Green synthesis of nanoparticles using seaweeds are fascinating high research attention nowadays and also gaining center of attention in biomedical applications. In this work, we have synthesized biocompatible and functionalized silver nanoparticles using an aqueous extract of seaweed Enteromorpha compressa as a reducing as well as stabilizing agent and their efficient antimicrobial and anticancer activity are reported here. The UV-vis spectra of AgNPs showed the characteristics SPR absorption band at 421 nm. The chemical interaction and crystalline nature of the AgNPs were evaluated by FT-IR and XRD studies. The XRD result of AgNPs shows typical Ag reflection peaks at 38.1°, 44.2°, 64.4° and 77.1° corresponding to (111), (200), (220) and (311) Bragg's planes. The surface morphology and composition of the samples were observed by HRTEM, EDS and SAED pattern analyses. Spherical shaped Ag nano structures were observed in the size ranges between 4 and 24 nm with clear lattice fringes in the HRTEM image. This report reveals that seaweed mediated synthesis of AgNPs and sustained delivery of Ag ions to the bacterial and fungal surface have been reducing their growth rate which was evaluated by well diffusion assay. The synthesized AgNPs showed favorable cytotoxicity against Ehlrich Ascites Carcinoma (EAC) cells with IC50 value was recorded at 95.35 μg mL-1. This study showed cost effective silver nanoparticles synthesis with excellent biocompatibility and thus could potentially be utilized in biomedical and pharmaceutical applications.


Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study.
The contribution of various risk factors to the burden of stroke worldwide is unknown, particularly in countries of low and middle income. We aimed to establish the association of known and emerging risk factors with stroke and its primary subtypes, assess the contribution of these risk factors to the burden of stroke, and explore the differences between risk factors for stroke and myocardial infarction. We undertook a standardised case-control study in 22 countries worldwide between March 1, 2007, and April 23, 2010. Cases were patients with acute first stroke (within 5 days of symptoms onset and 72 h of hospital admission). Controls had no history of stroke, and were matched with cases for age and sex. All participants completed a structured questionnaire and a physical examination, and most provided blood and urine samples. We calculated odds ratios (ORs) and population-attributable risks (PARs) for the association of all stroke, ischaemic stroke, and intracerebral haemorrhagic stroke with selected risk factors. In the first 3000 cases (n=2337, 78%, with ischaemic stroke; n=663, 22%, with intracerebral haemorrhagic stroke) and 3000 controls, significant risk factors for all stroke were: history of hypertension (OR 2.64, 99% CI 2.26-3.08; PAR 34.6%, 99% CI 30.4-39.1); current smoking (2.09, 1.75-2.51; 18.9%, 15.3-23.1); waist-to-hip ratio (1.65, 1.36-1.99 for highest vs lowest tertile; 26.5%, 18.8-36.0); diet risk score (1.35, 1.11-1.64 for highest vs lowest tertile; 18.8%, 11.2-29.7); regular physical activity (0.69, 0.53-0.90; 28.5%, 14.5-48.5); diabetes mellitus (1.36, 1.10-1.68; 5.0%, 2.6-9.5); alcohol intake (1.51, 1.18-1.92 for more than 30 drinks per month or binge drinking; 3.8%, 0.9-14.4); psychosocial stress (1.30, 1.06-1.60; 4.6%, 2.1-9.6) and depression (1.35, 1.10-1.66; 5.2%, 2.7-9.8); cardiac causes (2.38, 1.77-3.20; 6.7%, 4.8-9.1); and ratio of apolipoproteins B to A1 (1.89, 1.49-2.40 for highest vs lowest tertile; 24.9%, 15.7-37.1). Collectively, these risk factors accounted for 88.1% (99% CI 82.3-92.2) of the PAR for all stroke. When an alternate definition of hypertension was used (history of hypertension or blood pressure >160/90 mm Hg), the combined PAR was 90.3% (85.3-93.7) for all stroke. These risk factors were all significant for ischaemic stroke, whereas hypertension, smoking, waist-to-hip ratio, diet, and alcohol intake were significant risk factors for intracerebral haemorrhagic stroke. Our findings suggest that ten risk factors are associated with 90% of the risk of stroke. Targeted interventions that reduce blood pressure and smoking, and promote physical activity and a healthy diet, could substantially reduce the burden of stroke. Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Pfizer Cardiovascular Award, Merck, AstraZeneca, and Boehringer Ingelheim.


Health social workers' assessments as part of a specialized pain rehabilitation: a clinical data-mining study.
This study examines how health social workers (HSWs) assess the rehabilitation needs of patients with long-term pain. Data were extracted from 66 patient assessments through a retrieval form based on the International Classification of Functioning, Disability, and Health. The assessments included information about relations, work, and recreation. Stress management, problem solving, self-care, participation in community life, and providing personal care were missing in parts of or all assessments. Differences in assessments suggest that information was registered based on traditional gender roles and age. Therefore, HSWs need standardized assessment tools to ensure that assessments are relevant for all patients with long-term pain irrespective of gender or age.


PKM2 Promotes Breast Cancer Progression by Regulating Epithelial Mesenchymal Transition.
Breast cancer is the leading cause of females characterized by high invasive potential. It is necessary to explore the underlying mechanism of breast cancer metastases and to find specific therapeutic targets. PKM2 is considered a new biomarker of cancer with upregulated expression in tumor tissue. PKM2 participates in the cancer-specific Warburg effect to regulate fast glucose intake consumption. Besides, PKM2 also contributes to cancer progression, especially tumor metastasis. In this study, we showed that PKM2 is upregulated in breast cancer tissues and the upregulating of PKM2 in breast cancer correlates with poor prognosis. PKM2 can regulate tumor progression by promoting tumor cell viability and mobility. Furthermore, overexpression of PKM2 can promote EMT to encourage tumor metastasis. These findings indicate PKM2 is a potentially useful diagnostic biomarker and therapeutic target in breast cancer.


[Variability in the clinical presentation of the Brown-McLean syndrome].
We report two aphakic patients with Brown-McLean syndrome. One patient was affected by Marfan syndrome, after having undergone lens subluxation surgery and aphakia 23 years previously. The other patient was aphakic due to cataract surgery with complications three years before. Our cases demonstrate that this syndrome can show a variety of clinical characteristics, but peripheral corneal edema is always present. A full understanding of the clinical signs of presentation is of great importance in order to detect this syndrome.


Association between co-morbidities and labour force participation amongst persons with back problems.
There are few studies that have looked at the occurrence of co-morbid conditions amongst patients with back problems. This study assesses the association between of a range of co-morbidities and the labour force participation rates of 45- to 64-year-old Australians with back problems. Logistic regression models were applied to the 2003 Survey of Disability, Ageing and Carers (SDAC) data to look at the relationship between chronic back problems, labour force participation and comorbidities. For some conditions, there is a significant increase in the chance of an individual being out of the labour force, relative to those with back problems alone. For example, an individual with back problems and heart disease is more than 10 times more likely to be out of the labour force than those with back problems alone (OR=10.90, 95% CI=2.91-40.79, P=.0004). Amongst conditions that have a significant impact on labour force participation rates, back problems and multiple co-morbidities are significantly more likely to cause persons with these conditions to be out of the labour force than those with back problems alone or those with no chronic health condition. It is important to consider which co-morbidities an individual has when assessing the impact of back problems on labour force participation, as co-morbid conditions vary in their association with labour force participation.


The extracellular K+ concentration dependence of outward currents through Kir2.1 channels is regulated by extracellular Na+ and Ca2+.
It has been known for more than three decades that outward Kir currents (I(K1)) increase with increasing extracellular K(+) concentration ([K(+)](o)). Although this increase in I(K1) can have significant impacts under pathophysiological cardiac conditions, where [K(+)](o) can be as high as 18 mm and thus predispose the heart to re-entrant ventricular arrhythmias, the underlying mechanism has remained unclear. Here, we show that the steep [K(+)](o) dependence of Kir2.1-mediated outward I(K1) was due to [K(+)](o)-dependent inhibition of outward I(K1) by extracellular Na(+) and Ca(2+). This could be accounted for by Na(+)/Ca(2+) inhibition of I(K1) through screening of local negative surface charges. Consistent with this, extracellular Na(+) and Ca(2+) reduced the outward single-channel current and did not increase open-state noise or decrease the mean open time. In addition, neutralizing negative surface charges with a carboxylate esterifying agent inhibited outward I(K1) in a similar [K(+)](o)-dependent manner as Na(+)/Ca(2+). Site-directed mutagenesis studies identified Asp(114) and Glu(153) as the source of surface charges. Reducing K(+) activation and surface electrostatic effects in an R148Y mutant mimicked the action of extracellular Na(+) and Ca(2+), suggesting that in addition to exerting a surface electrostatic effect, Na(+) and Ca(2+) might inhibit outward I(K1) by inhibiting K(+) activation. This study identified interactions of K(+) with Na(+) and Ca(2+) that are important for the [K(+)](o) dependence of Kir2.1-mediated outward I(K1).


Multidisciplinary home-based rehabilitation in inoperable lung cancer: a randomised controlled trial.
Lung cancer is associated with poor health-related quality of life (HRQoL) and high symptom burden. This trial aimed to assess the efficacy of home-based rehabilitation versus usual care in inoperable lung cancer. A parallel-group, assessor-blinded, allocation-concealed, randomised controlled trial. Eligible participants were allocated (1:1) to usual care (UC) plus 8 weeks of aerobic and resistance exercise with behaviour change strategies and symptom support (intervention group (IG)) or UC alone. Assessments occurred at baseline, 9 weeks and 6 months. The primary outcome, change in between-group 6 min walk distance (6MWD), was analysed using intention-to-treat (ITT). Subsequent analyses involved modified ITT (mITT) and included participants with at least one follow-up outcome measure. Secondary outcomes included HRQoL and symptoms. Ninety-two participants were recruited. Characteristics of participants (UC=47, IG=45): mean (SD) age 64 (12) years; men 55%; disease stage n (%) III=35 (38) and IV=48 (52); radical treatment 46%. There were no significant between-group differences for the 6MWD (n=92) at 9 weeks (p=0.308) or 6 months (p=0.979). The mITT analyses of 6MWD between-group differences were again non-significant (mean difference (95% CI): 9 weeks: -25.4 m (-64.0 to 13.3), p=0.198 and 6 months: 41.3 m (-26.7 to 109.4), p=0.232). Significant 6-month differences, favouring the IG, were found for HRQoL (Functional Assessment of Cancer Therapy-Lung: 13.0 (3.9 to 22.1), p=0.005) and symptom severity (MD Anderson Symptom Inventory-Lung Cancer: -2.2 (-3.6 to -0.9), p=0.001). Home-based rehabilitation did not improve functional exercise capacity but there were improvements in patient-reported exploratory secondary outcomes measures observed at 6 months. Australian New Zealand Clinical Trials Registry (ACTRN12614001268639).


[Adrenal gland morphological alterations in the acquired immunodeficiency syndrome].
In the acquired immunodeficiency syndrome (AIDS), the adrenal glands are subject to opportunistic infections, neoplasm or direct cytopathic effect by HIV. It is know that the incidence and type of adrenal involvement vary according to the patient's place of origin. In this paper we evaluate adrenal involvement in fourteen patients that died from AIDS in the University Hospital of Uberaba, Brazil. The group studied was comprised of thirteen males and thirteen whites. The age was 29.9 +/- 7.8 years, and the body mass index was 19.0 +/- 4.1 kg/m2. Adrenal specimens obtained from autopsies were analyzed by light microscopy. Inflammation was found in 100% of the cases and the etiologic agent(s) was (were) identified in eight (58.1%) patients. Cytomegalovirus was identified in seven cases, Cryptococcus sp and Herpes simplex in two and Histoplasma sp in one case, these pathologic findings were similar to literature. We also found parenchymal calcification and adrenal central vein phlebitis in one case each. Injury was found in some cases without identified infections agent. This fact could be due to the direct cytopathic effect by HIV, or due to toxicity of drug therapy used during treatment of AIDS and opportunistic infections.


A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson's disease.
Parkinson's disease (PD) is a common neurodegenerative disorder of unknown etiology. There is no cure or proven strategy for slowing the progression of the disease. Although there are signs of pathology in many brain regions, the core symptoms of PD are attributable to the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. A potential clue to the vulnerability of these neurons is an increasing reliance with age upon L-type Ca(2+) channels with a pore-forming Cav1.3 subunit to support autonomous activity. This reliance could pose a sustained stress on mitochondrial ATP generating oxidative phosphorylation, accelerating cellular aging and death. Systemic administration of isradipine, a dihydropyridine blocker of these channels, forces dopaminergic neurons in rodents to revert to a juvenile, L-type Ca(2+) channel independent mechanism to generate autonomous activity. This "rejuvenation" confers protection against toxins that produce experimental Parkinsonism, pointing to a potential neuroprotective strategy for PD. Their decades-long track record of safe use in the treatment of hypertension makes dihydropyridines particularly attractive as a therapeutic tool in PD.


Long-term reduction of hippocampal brain-derived neurotrophic factor activity after fetal-neonatal iron deficiency in adult rats.
Fetal-neonatal iron deficiency acutely alters hippocampal biochemistry, neural morphology, and electrophysiology accompanied by a downregulation of brain-derived neurotrophic factor (BDNF). These changes provide a cellular and molecular basis for observed short-term learning and memory impairments. However, the etiology of residual, long-term hippocampal neurotransmission abnormalities and learning impairments after treatment remain unclear. Because BDNF modulates learning and memory, we assessed its expression in 65-d-old formerly iron deficient (FID) male rats that had been iron deficient during the fetal-neonatal period and treated with iron since postnatal day 7. BDNF-III and -IV mRNAs and BDNF protein expression remained down-regulated in FID rats when compared with the always iron-sufficient rats. Expressions of BDNF activity-dependent downstream targets (3-hydroxy-3-methylglutaryl CoA reductase and immediate early genes c-fos, early growth response gene 1 and 2) were reduced in FID rats. In turn, hippocampal expressions of direct targets of early-growth response genes, including hypoxia-inducible factor 1, dual-specificity phosphatase 4, IGF 2, and myelin basic protein were also diminished in FID rats. Collectively, fetal-neonatal iron deficiency lowers hippocampal BDNF expression and function beyond the period of iron deficiency. These findings may underlie the persistence of learning deficits seen after fetal-neonatal iron deficiency.


Expression of mannose binding lectin in HIV-1-infected brain: implications for HIV-related neuronal damage and neuroAIDS.
Mannose binding lectin (MBL) activates complement pathway that leads to pathogen opsonization and phagocytosis. MBL deficiency is linked to HIV transmission and disease progression. We sought to determine the role of MBL in HIV encephalitis (HIVE) by evaluating its presence and distribution in the HIV-1-infected brain and by assessing its association with monocyte chemoattractant protein-1 (MCP-1) expression. This retrospective study utilized archived post-mortem brain tissues obtained from 35 individuals enrolled in a longitudinal study as part of the California NeuroAIDS Tissue Network. MBL, MCP-1 and brain cell markers in post-mortem brain tissues with or without HIVE were evaluated using immunocytochemistry, immunofluorescence, confocal microscopy, and western blots. MBL was expressed in neurons, astrocytes, microglia, and oligodendrocytes of the frontal cortex of the HIV-1-infected brain. Overall, there were 30% to 40% more MBL-positive brain cells in HIVE vs non-HIVE cases (P = 0.01, paired t-test). Specifically, there was an increased MBL expression in the neuronal axons of HIVE cases. Also, western blots showed 3- to 4-fold higher levels of 78 kD MBL trimers in HIVE vs non-HIVE cases. This MBL-HIVE link was further confirmed by MBL associated higher MCP-1 expression in HIVE vs non-HIVE cases. HIV negative healthy individuals and normal or the gp120 transgenic mice did not show any differential MBL expression. Increased MBL expression in the major brain cell types, specifically in the neuronal axons of HIVE brain, and MBL associated higher MCP-1 expression in HIVE suggest that MBL could cause neuroinflammation and neuronal injury through MBL complement activation pathway.


CRISPR/Cas9-mediated knockout of a prolyl-4-hydroxylase subfamily in Nicotiana benthamiana using DsRed2 for plant selection.
The properties of host plants used for molecular farming can be modified by CRISPR/Cas9 genome editing to improve the quality and yield of recombinant proteins. However, it is often necessary to target multiple genes simultaneously, particularly when using host plants with large and complex genomes. This is the case for Nicotiana benthamiana, an allotetraploid relative of tobacco frequently used for transient protein expression. A multiplex genome editing system incorporating the DsRed2 fluorescent marker for the identification and selection of transgenic plants was established. As proof of principle, NbP4H4 was targeted encoding a prolyl-4-hydroxylase involved in protein O-linked glycosylation. Using preselected gRNAs with efficiencies confirmed by transient expression, transgenic plant lines with knockout mutations in all four NbP4H4 genes were obtained. Leaf fluorescence was then used to screen for the absence of the SpCas9 transgene in T1 plants, and transgene-free lines with homozygous or biallelic mutations were identified. The analysis of plant-produced recombinant IgA1 as a reporter protein revealed changes in the number of peptides containing hydroxyproline residues and pentoses in the knockout plants. The selection of efficient gRNAs combined with the DsRed2 marker reduces the effort needed to generate N. benthamiana mutants and simplifies the screening processes to obtain transgene-free progeny.


Multidrug resistance after inappropriate tuberculosis treatment: a meta-analysis.
We conducted a systematic review and meta-analysis to assess the evidence for the postulation that inappropriate tuberculosis (TB) regimens are a risk for development of multidrug-resistant (MDR)-TB. MEDLINE, EMBASE and other databases were searched for relevant articles in January 2011. Cohort studies including TB patients who received treatment were selected and data on treatment regimen, drug susceptibility testing results and genotyping results before treatment and at failure or relapse were abstracted from the articles. Four studies were included in the systematic review and two were included in the meta-analysis. In these two studies the risk of developing MDR-TB in patients who failed treatment and used an inappropriate treatment regimen was increased 27-fold (RR 26.7, 95% CI 5.0-141.7) when compared with individuals who received an appropriate treatment regimen. This review provides evidence that supports the general opinion that the development of MDR-TB can be caused by inadequate treatment, given the drug susceptibility pattern of the Mycobacterium tuberculosis bacilli. It should be noted that only two studies provided data for the meta-analysis. The information can be used to advocate for adequate treatment for patients based on drug resistance profiles.


Combined coinhibitory and costimulatory modulation with anti-BTLA and CTLA4Ig facilitates tolerance in murine islet allografts.
Complex interactions between positive and negative cosignaling receptors ultimately determine the fate of the immune response. The recently identified coinhibitory receptor, B and T lymphocyte attenuator (BTLA), contributes to regulation of autoimmune and potentially alloimmune responses. We investigated the role of BTLA in a fully major histocompatibility complex-mismatched mouse islet transplant model. We report that anti-BTLA mAb (6F7) alone does not accelerate graft rejection. Rather, while CTLA4Ig alone improved allograft survival, the addition of anti-BTLA mAb to CTLA4Ig led to indefinite (>100 days) allograft survival. Immediately after treatment with anti-BTLA mAb and CTLA4Ig, islet allografts showed intact islets and insulin production despite a host cellular response, with local accumulation of Foxp3+ cells. We clearly demonstrate that combined therapy with anti-BTLA mAb and CTLA4Ig mice induced donor-specific tolerance, since mice accepted a second donor-specific islet graft without further treatment and rejected third party grafts. CTLA4Ig and anti-BTLA mAb limited the initial in vivo proliferation of CFSE-labeled allogeneic lymphocytes, and anti-BTLA mAb enhanced the proportion of PD-1 expressing T cells while depleting pathogenic BTLA+ lymphocytes. We conclude that targeting the BTLA pathway in conjunction with CTLA4Ig costimulatory blockade may be a useful strategy for promoting immunological tolerance in murine islet allografts.


Endothelial cell-specific-molecule-1 (endocan) levels in women with premature ovarian insufficiency: a prospective comparative study.
There is an increased risk of cardiovascular disease in women with premature ovarian insufficiency (POI). A relationship between cardiovascular disease and endocan levels has been shown. Endocan is a marker that is prominent in many diseases caused by endothelial dysfunction and can be measured in the blood. POI is also associated with endothelial dysfunction. The causes of POI include chromosomal and genetic defects, autoimmune processes, chemotherapy, radiation, infections and surgery, but many are unidentified (idiopathic). This study aimed to evaluate serum endocan levels in women with idiopathic POI. The blood for analysis was obtained at the early follicular phase of the menstrual cycle and endocan levels were measured using a commercially available enzyme-linked immunosorbent assay kit. There were 38 patients with idiopathic POI in the study group and 39 healthy subjects in the control group. The median ages of the women were not significantly different between the groups 34 [7] years vs. 34 [7] years, respectively (p = .862). The median endocan level was not different in the POI and control group 769 [727] vs. 1077 [403] pg/mL, respectively (p = .603). Endocan is not associated with the cardiovascular diseases risk linked with endothelial dysfunction in idiopathic POI. Clinical trial number: NCT03932877 (Clinicaltrials.gov)IMPACT STATEMENTWhat is already known on this subject? There is an increased risk of cardiovascular disease in premature ovarian insufficiency (POI) due to the decreased level of oestrogen, which is linked with endothelial dysfunction.What do the results of this study add? This study showed that endocan is not associated with the cardiovascular disease risk linked with endothelial dysfunction in idiopathic POI.What are the implications of these findings for clinical practice and/or further research? A marker to be used to predict the risk of cardiovascular disease in patients with POI could facilitate in improving the quality of life of these patients. Moreover, advantageous and easy-to-measure markers are needed in larger sample studies to better understand the cardiovascular diseases risk in POI.


Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle.
Tumor necrosis factor-α (TNF-α) is an inflammatory cytokine that plays a central role in obesity-induced insulin resistance. It also controls cellular lipid metabolism, but the underlining mechanism is poorly understood. We report in this study that phosphoinositide 3-kinase enhancer A (PIKE-A) is a novel effector of TNF-α to facilitate its metabolic modulation in the skeletal muscle. Depletion of PIKE-A in C2C12 myotubes diminished the inhibitory activities of TNF-α on mitochondrial respiration and lipid oxidation, whereas PIKE-A overexpression exacerbated these cellular responses. We also found that TNF-α promoted the interaction between PIKE-A and AMP-activated protein kinase (AMPK) to suppress its kinase activity in vitro and in vivo. As a result, animals with PIKE ablation in the skeletal muscle per se display an upregulation of AMPK phosphorylation and a higher preference to use lipid as the energy production substrate under high-fat diet feeding, which mitigates the development of diet-induced hyperlipidemia, ectopic lipid accumulation, and muscle insulin resistance. Hence, our data reveal PIKE-A as a new signaling factor that is important for TNF-α-initiated metabolic changes in skeletal muscle.


Fibromyalgia interventions, obstacles and prospects: narrative review.
This review aims to increase awareness and improve understanding, diagnosis, and management of fibromyalgia - a complex, distressing health challenge that significantly impacts people's lives due to its variable nature and lack of clear diagnostic markers. Healthcare professionals must assist those with this condition and improve their general quality of life. Further, they can do a lot to improve the lives of people with Fibromyalgia by resolving diagnostic hurdles, promoting collaboration, supporting patient advocacy, advancing medical technology, and adopting novel approaches.


Elastic turbulence in a curvilinear channel flow.
We report detailed quantitative studies of elastic turbulence in a curvilinear channel flow in a dilute polymer solution of high molecular weight polyacrylamide in a high viscosity water-sugar solvent. Detailed studies of the average and rms velocity and velocity gradients profiles reveal the emergence of a boundary layer associated with the nonuniform distribution of the elastic stresses across the channel. The characteristic boundary width is independent of the Weissenberg number Wi and proportional to the channel width, which is consistent with the findings our early investigations of the boundary layer in elastic turbulence in different flow geometries. The nonuniform distribution of the elastic stresses across the channel and appearance of the characteristic spatial scales of the order of the boundary layer width of both velocity and velocity gradient in the correlation functions of the velocity and velocity gradient fields in a bulk flow may suggest that excessive elastic stresses, concentrated in the boundary layer, are ejected into the bulk flow similar to jets observed in passive scalar mixing in elastic turbulence observed recently. Finally, the experimental results show that one of the main predictions of the theory of elastic turbulence, namely, the saturation of the normalized rms velocity gradient in the bulk flow of elastic turbulence contradicts the experimental observations both qualitatively and quantitatively in spite of the fact that the theory explains well the observed sharp power-law decay of the velocity power spectrum. The experimental findings call for further development of theory of elastic turbulence in a bounded container, similar to what was done for a passive scalar problem.


Removing Biases from Molecular Representations via Information Maximization.
High-throughput drug screening -- using cell imaging or gene expression measurements as readouts of drug effect -- is a critical tool in biotechnology to assess and understand the relationship between the chemical structure and biological activity of a drug. Since large-scale screens have to be divided into multiple experiments, a key difficulty is dealing with batch effects, which can introduce systematic errors and non-biological associations in the data. We propose InfoCORE, an Information maximization approach for COnfounder REmoval, to effectively deal with batch effects and obtain refined molecular representations. InfoCORE establishes a variational lower bound on the conditional mutual information of the latent representations given a batch identifier. It adaptively reweighs samples to equalize their implied batch distribution. Extensive experiments on drug screening data reveal InfoCORE's superior performance in a multitude of tasks including molecular property prediction and molecule-phenotype retrieval. Additionally, we show results for how InfoCORE offers a versatile framework and resolves general distribution shifts and issues of data fairness by minimizing correlation with spurious features or removing sensitive attributes. The code is available at https://github.com/uhlerlab/InfoCORE.


Genomic content of Bordetella pertussis clinical isolates circulating in areas of intensive children vaccination.
The objective of the study was to analyse the evolution of Bordetella pertussis population and the influence of herd immunity in different areas of the world where newborns and infants are highly vaccinated. The analysis was performed using DNA microarray on 15 isolates, PCR on 111 isolates as well as GS-FLX sequencing technology on 3 isolates and the B. pertussis reference strain, Tohama I. Our analyses demonstrate that the current circulating isolates are continuing to lose genetic material as compared to isolates circulating during the pre-vaccine era whatever the area of the world considered. The lost genetic material does not seem to be important for virulence. Our study confirms that the use of whole cell vaccines has led to the control of isolates that were similar to vaccine strains. GS-FLX sequencing technology shows that current isolates did not acquire any additional material when compared with vaccine strains or with isolates of the pre-vaccine era and that the sequenced strain Tohama I is not representative of the isolates. Furthermore, this technology allowed us to observe that the number of Insertion Sequence elements contained in the genome of the isolates is temporally increasing or varying between isolates. B. pertussis adaptation to humans is still in progress by losing genetic material via Insertion Sequence elements. Furthermore, recent isolates did not acquire any additional material when compared with vaccine strains or with isolates of the pre-vaccine era. Herd immunity, following intensive vaccination of infants and children with whole cell vaccines, has controlled isolates similar to the vaccine strains without modifying significantly the virulence of the isolates. With the replacement of whole cell vaccines by subunit vaccines, containing only few bacterial antigens targeting the virulence of the bacterium, one could hypothesize the circulation of isolates expressing less or modified vaccine antigens.


Genetic exchanges are more frequent in bacteria encoding capsules.
Capsules allow bacteria to colonize novel environments, to withstand numerous stresses, and to resist antibiotics. Yet, even though genetic exchanges with other cells should be adaptive under such circumstances, it has been suggested that capsules lower the rates of homologous recombination and horizontal gene transfer. We analysed over one hundred pan-genomes and thousands of bacterial genomes for the evidence of an association between genetic exchanges (or lack thereof) and the presence of a capsule system. We found that bacteria encoding capsules have larger pan-genomes, higher rates of horizontal gene transfer, and higher rates of homologous recombination in their core genomes. Accordingly, genomes encoding capsules have more plasmids, conjugative elements, transposases, prophages, and integrons. Furthermore, capsular loci are frequent in plasmids, and can be found in prophages. These results are valid for Bacteria, independently of their ability to be naturally transformable. Since we have shown previously that capsules are commonly present in nosocomial pathogens, we analysed their co-occurrence with antibiotic resistance genes. Genomes encoding capsules have more antibiotic resistance genes, especially those encoding efflux pumps, and they constitute the majority of the most worrisome nosocomial bacteria. We conclude that bacteria with capsule systems are more genetically diverse and have fast-evolving gene repertoires, which may further contribute to their success in colonizing novel niches such as humans under antibiotic therapy.


Possible pathogenic mechanism of propofol infusion syndrome involves coenzyme q.
Propofol is a short-acting intravenous anesthetic agent. In rare conditions, a life-threatening complication known as propofol infusion syndrome can occur. The pathophysiologic mechanism is still unknown. Some studies suggested that propofol acts as uncoupling agent, others suggested that it inhibits complex I or complex IV, or causes increased oxidation of cytochrome c and cytochrome aa3, or inhibits mitochondrial fatty acid metabolism. Although the exact site of interaction is not known, most hypotheses point to the direction of the mitochondria. Eight rats were ventilated and sedated with propofol up to 20 h. Sequential biopsy specimens were taken from liver and skeletal muscle and used for determination of respiratory chain activities and propofol concentration. Activities were also measured in skeletal muscle from a patient who died of propofol infusion syndrome. In rats, authors detected a decrease in complex II+III activity starting at low tissue concentration of propofol (20 to 25 µM), further declining at higher concentrations. Before starting anesthesia, the complex II+III/citrate synthase activity ratio in liver was 0.46 (0.25) and in skeletal muscle 0.23 (0.05) (mean [SD]). After 20 h of anesthesia, the ratios declined to 0.17 (0.03) and 0.12 (0.02), respectively. When measured individually, the activities of complexes II and III remained normal. Skeletal muscle from one patient taken in the acute phase of propofol infusion syndrome also shows a selective decrease in complex II+III activity (z-score: -2.96). Propofol impedes the electron flow through the respiratory chain and coenzyme Q is the main site of interaction with propofol.


Anaerolineaceae and Methanosaeta turned to be the dominant microorganisms in alkanes-dependent methanogenic culture after long-term of incubation.
The methanogenic alkanes-degrading enrichment culture which had been incubated for over 1,300 days amended with n-alkanes (C15-C20) was investigated through clone libraries of bacteria, archaea and assA, mcrA functional genes. These enrichment cultures were obtained from oily sludge after an initial incubation of the oily sludge without any carbon source and then an enrichment transfer with n-alkanes (C15-C20) for acclimation. Activation of alkanes, methane precursor generation and methanogenic pathways are considered as three pivotal stages for the continuous methanogenesis from degradation of alkanes. The presence of functional genes encoding the alkylsuccinate synthase α-subunit indicated that fumarate addition is most likely the one of initial activation step for degradation of n-alkanes. Degradation intermediates of n-alkanes were octadecanoate, hexadecanoate, butyrate, isobutyrate, acetate and propionate, which could provide the appropriate substrates for acetate formation. Both methyl coenzyme M reductase gene and 16S rRNA gene analysis showed that microorganisms of Methanoseata were the most dominant methanogens, capable of using acetate as the electron donor to produce methane. Bacterial clone libraries showed organisms of Anaerolineaceae (within the phylum of Chloroflexi) were predominant (45.5%), indicating syntrophically cooperation with Methanosaeta archaea was likely involved in the process of methanogenic degradation of alkanes. Alkanes may initially be activated via fumarate addition and degraded to fatty acids, then converted to acetate, which was further converted to methane and carbon dioxide by methanogens.


Antibodies against Entamoeba histolytica in human milk and serum in Kenya.
A modified enzyme-linked immunosorbent assay (ELISA) technique has been developed for the detection of secretory immunoglobulin A (SIgA) antibodies against Entamoeba histolytica. By substituting phosphate-buffered saline-Triton for phosphate-buffered saline-Tween as the antibody incubating buffer, unspecific absorption of SIgA was avoided. As revealed by chessboard titrations, the optimal amount of antigen for coating was higher in SIgA than in IgG ELISA. A purified antigen from the membrane pellet fraction of E. histolytica gave equally good reactivity with SIgA and IgG antibodies and was used throughout. A total of 283 milk and 232 serum samples from three areas in Kenya were tested. The samples were collected in maternity hospitals on one of days 1 to 3 after parturition. All milk samples were tested for total SIgA. In one of the study areas (Machakos), the mean level of SIgA was significantly lower than in the other two areas (Mombasa and Nairobi). Eighty-seven of the milk samples (31%) were reactive in the test. The rate of positives was higher in Mombasa, where the SIgA levels were highest. Since both the frequency and the level of serum antibodies were similar in the three study areas, it is likely that the higher milk reactivity in Mombasa was mainly due to the higher SIgA concentrations observed. Antibodies were detected in 32 (14%) of the sera, mostly in low or moderate titers. Surprisingly few mothers had detectable antibodies in both milk and serum. In fact, the majority of positives were reactive in either milk or serum, with a predominance of milk positives. The background for this is probably complex, containing components such as differences in immunoglobulin concentrations in the samples, diversities in local and systemic antigenic stimulation responses, and level of immunological memory.


Microbial Translocation Does Not Drive Immune Activation in Ugandan Children Infected With HIV.
Immune activation is associated with morbidity and mortality during human immunodeficiency virus (HIV) infection, despite receipt of antiretroviral therapy (ART). We investigated whether microbial translocation drives immune activation in HIV-infected Ugandan children. Nineteen markers of immune activation and inflammation were measured over 96 weeks in HIV-infected Ugandan children in the CHAPAS-3 Trial and HIV-uninfected age-matched controls. Microbial translocation was assessed using molecular techniques, including next-generation sequencing. Of 249 children included, 142 were infected with HIV; of these, 120 were ART naive, with a median age of 2.8 years (interquartile range [IQR], 1.7-4.0 years) and a median baseline CD4+ T-cell percentage of 20% (IQR, 14%-24%), and 22 were ART experienced, with a median age of 6.5 years (IQR, 5.9-9.2 years) and a median baseline CD4+ T-cell percentage of 35% (IQR, 31%-39%). The control group comprised 107 children without HIV infection. The median increase in the CD4+ T-cell percentage was 17 percentage points (IQR, 12-22 percentage points) at week 96 among ART-naive children, and the viral load was <100 copies/mL in 76% of ART-naive children and 91% of ART-experienced children. Immune activation decreased with ART use. Children could be divided on the basis of immune activation markers into the following 3 clusters: in cluster 1, the majority of children were HIV uninfected; cluster 2 comprised a mix of HIV-uninfected children and HIV-infected ART-naive or ART-experienced children; and in cluster 3, the majority were ART naive. Immune activation was low in cluster 1, decreased in cluster 3, and persisted in cluster 2. Blood microbial DNA levels were negative or very low across groups, with no difference between clusters except for Enterobacteriaceae organisms (the level was higher in cluster 1; P < .0001). Immune activation decreased with ART use, with marker clustering indicating different activation patterns according to HIV and ART status. Levels of bacterial DNA in blood were low regardless of HIV status, ART status, and immune activation status. Microbial translocation did not drive immune activation in this setting. ISRCTN69078957.


Reduction of paracetamol metabolism after hepatic resection.
Paracetamol is often used as an analgesic following hepatic resection. During liver resection, vascular clamping is carried out to reduce blood loss. Previous studies have described transient postoperative rises in serum aminotransferase levels and decreases in prothrombin time and factor V levels. We have examined paracetamol metabolism after liver resection. A prospective observational study was performed. All patients undergoing liver resection were included. Propacetamol was given every 6 h. Blood samples for plasma paracetamol concentrations were collected before, 1 h after the end of the first injection (T1), just before the second injection (6 h: T6), and just before the fifth injection (24 h: T24). 37 patients were recruited. 13 had hepatic vascular exclusion (HVE group), 13 had portal triad clamping (PTC group) and 11 had abdominal surgery with no liver resection (NLR group: control group). At T6, the plasma paracetamol concentration in the HVE group was significantly higher than in the NLR groups; at T24, this concentration was significantly higher in the HVE group than in the NLR and PTC groups, and was higher in the PTC group than in the NLR group. Prothrombin time and factor V was significantly lower in the HVE group than in the PTC group on the first postoperative day. This study showed a reduction of paracetamol metabolism in the liver resection group with significantly increased paracetamol levels. However, the maximum mean plasma concentration reached was not clinically or toxicologically significant. For these reasons, we cannot suggest that paracetamol should or should not be avoided in patients undergoing liver resection.


Three synchronous multiorgan primary cancers. All stage I.
A patient who has three separate, synchronous, early (stage I) primary cancers of the right lung, right breast, and stomach and whose disease is simultaneously diagnosed and successfully treated sequentially within a single hospital admission is unique. While multiple primary malignant neoplasms are not uncommon, to our knowledge, there has been no report of triple stage I synchronous carcinomas in separate major organ systems. Age, immunodeficiency, somatotype, hereditary tendencies, hormonal and environmental factors, and previous therapy have been incriminated as etiologic factors. Accurate tissue diagnosis and tumor staging are mandatory. In patients with diagnosed cancer, pulmonary lesions should never be presumed metastatic. Individual tumors should be treated independently of other concomitant lesions, and each treatment approach should be curative in nature. Patients with proven multiple malignant neoplasms carry a higher risk of developing other primary neoplasms.


Kidney disease and pregnancy.
The course of 41 pregnancies was studied in 25 patients with renal disease. Histological classification of the disease in each patient was made by renal biopsy. The analysis suggests that the course of pregnancy in women with coexistent renal disease correlates with the underlying renal lesion and probably with the glomerular filtration rate and blood pressure. In patients with heavy proteinuria there is increased oedema formation, making the nephrotic syndrome a frequent complication.


Clinically led performance management in secondary healthcare: evaluating the attitudes of medical and non-clinical managers.
Improving the quality and activity of clinicians' practice improves patient care. Performance-related human resource management (HRM) is an established approach to improving individual practice but with limited use among clinicians. A framework for performance-related HRM was developed from successful practice in non-healthcare organisations centred on distributive leadership and locally provided, validated and interpreted performance measurement. This study evaluated the response of medical and non-clinical managers to its implementation into a large secondary healthcare organisation. A semistructured qualitative questionnaire was developed from themes identified during framework implementation and included attitudes to previous approaches to measuring doctors' performance, and the structure and response to implementation of the performance-related HRM framework. Responses were analysed through a process of data summarising and categorising. A total of 29, from an invited cohort of 31, medical and non-clinical managers from departmental to executive level were interviewed. Three themes were identified: (1) previous systems of managing clinical performance were considered to be ineffective due to insufficient empowerment of medical managers and poor quality of available performance data; (2) the implemented framework was considered to address these needs and was positively received by medical and non-clinical managers; (3) introduction of performance-related HRM required the involvement of the whole organisation to executive level and inclusion within organisational strategy, structure and training. This study suggests that a performance-related HRM framework may facilitate the management of clinical performance in secondary healthcare, but is dependent on the design and methods of application used. Such approaches contrast with those currently proposed for clinicians in secondary healthcare in the UK and suggest that alternative strategies should be considered.


Mitochondrial Genome Fragmentation Unites the Parasitic Lice of Eutherian Mammals.
Organelle genome fragmentation has been found in a wide range of eukaryotic lineages; however, its use in phylogenetic reconstruction has not been demonstrated. We explored the use of mitochondrial (mt) genome fragmentation in resolving the controversial suborder-level phylogeny of parasitic lice (order Phthiraptera). There are approximately 5000 species of parasitic lice in four suborders (Amblycera, Ischnocera, Rhynchophthirina, and Anoplura), which infest mammals and birds. The phylogenetic relationships among these suborders are unresolved despite decades of studies. We sequenced the mt genomes of eight species of parasitic lice and compared them with 17 other species of parasitic lice sequenced previously. We found that the typical single-chromosome mt genome is retained in the lice of birds but fragmented into many minichromosomes in the lice of eutherian mammals. The shared derived feature of mt genome fragmentation unites the eutherian mammal lice of Ischnocera (family Trichodectidae) with Anoplura and Rhynchophthirina to the exclusion of the bird lice of Ischnocera (family Philopteridae). The novel clade, namely Mitodivisia, is also supported by phylogenetic analysis of mt genome and cox1 gene sequences. Our results demonstrate, for the first time, that organelle genome fragmentation is informative for resolving controversial high-level phylogenies.


The MM2QM tool for combining docking, molecular dynamics, molecular mechanics, and quantum mechanics.
The use of the MM2QM tool in a combined docking + molecular dynamics (MD) + molecular mechanics (MM) + quantum mechanical (QM) binding affinity prediction study is presented, and the tool itself is discussed. The system of interest is Mycobacterium tuberculosis (MTB) pantothenate synthetase in complexes with three highly similar sulfonamide inhibitors, for which crystal structures are available. Starting from the structure of MTB pantothenate synthetase in the "open" conformation and following the combined docking + MD + MM + QM procedure, we were able to capture the closing of the enzyme binding pocket and to reproduce the position of the ligands with an average root mean square deviation of 1.6 Å. Protein-ligand interaction energies were reproduced with an average error lower than 10%. The discussion on the MD part and a protein flexibility importance is carried out. The presented approach may be useful especially for finding analog inhibitors or improving drug candidates.


TIF-Seq2 disentangles overlapping isoforms in complex human transcriptomes.
Eukaryotic transcriptomes are complex, involving thousands of overlapping transcripts. The interleaved nature of the transcriptomes limits our ability to identify regulatory regions, and in some cases can lead to misinterpretation of gene expression. To improve the understanding of the overlapping transcriptomes, we have developed an optimized method, TIF-Seq2, able to sequence simultaneously the 5' and 3' ends of individual RNA molecules at single-nucleotide resolution. We investigated the transcriptome of a well characterized human cell line (K562) and identified thousands of unannotated transcript isoforms. By focusing on transcripts which are challenging to be investigated with RNA-Seq, we accurately defined boundaries of lowly expressed unannotated and read-through transcripts putatively encoding fusion genes. We validated our results by targeted long-read sequencing and standard RNA-Seq for chronic myeloid leukaemia patient samples. Taking the advantage of TIF-Seq2, we explored transcription regulation among overlapping units and investigated their crosstalk. We show that most overlapping upstream transcripts use poly(A) sites within the first 2 kb of the downstream transcription units. Our work shows that, by paring the 5' and 3' end of each RNA, TIF-Seq2 can improve the annotation of complex genomes, facilitate accurate assignment of promoters to genes and easily identify transcriptionally fused genes.


Isolation and characterization of two individual glycoprotein components from human milk-fat-globule membranes.
Two individual glycoprotein components from human milk-fat-globule membranes (MFGM) has been purified by selectively extracting the membrane glycoproteins followed by lectin affinity chromatography and gel filtration on Sephadex G-200 in the presence of protein-disaggregating agents. The purified glycoprotein components, termed 'epithelial-membrane glycoprotein' (EMGP-155 and EMGP-39) have estimated molecular weights of 155 000 and 39 000 respectively, and yield a single band under reducing conditions on sodium dodecyl sulphate/polyacrylamide gel. EMGP-155 and EMGP-39 contain 21.0% and 7.0% carbohydrate by weight, with fucose (13.5%, 12.4%), mannose (3.7%, 6.2%), galactose (28.5%, 22.6%), N-acetylglucosamine (17.8%, 7.4%) and sialic acid (36.4%, 51.4%) of the carbohydrate moiety respectively. For both the glycoprotein components, aspartic and glutamic acid and serine are the major amino acid residues.


[Range of the transmissivity of the genetic transfer factors pAP38, pAP39, pAP41 and pAP42].
A study was made of the transmissivity range of the genetic transfer factors pAP38, pAP39, pAP41 and pAP42 identified in E. coli. It was demonstrated that these factors are not capable of transfer to the cells of P. putida, P. fluorescens, R. leguminosarum, A. lipoferum, A. tumefaciens. Factor pAP42 is mobilized to transfer to P. putida and R. leguminosarum with the aid of plasmid RP4. It is assumed that in the course of mobilization, the cointegrative structures are formed between plasmids pAP42 and RP4.


Functional and molecular characterization of the human neutral solute channel aquaporin-9.
In metabolically active cells, the coordinated transport of water and solutes is important for maintaining osmotic homeostasis. We recently identified a broad selective-neutral solute channel, AQP9, from rat liver that allows the passage of a wide variety of water and neutral solutes (H. Tsukaguchi, C. Shayakul, U. V. Berger, B. Mackenzie, S. Devidas, W. B. Guggino, A. N. van Hoek, and M. A. Hediger. J. Biol. Chem. 273: 24737-24743, 1998). A human homolog (hAQP9) with 76% amino acid sequence identity to rat AQP9 (rAQP9) was described, but its permeability was found to be restricted to water and urea (K. Ishibashi, M. Kuwahara, Y. Gu, Y. Tanaka, F. Marumo, and S. Sasaki. Biochem. Biophys. Res. Commun. 244: 268-274, 1998). Here we report a reevaluation of the functional characteristics of hAQP9, its tissue distribution, the structure of its gene, and its chromosomal localization. When expressed in Xenopus oocytes, hAQP9 allowed passage of a wide variety of noncharged solutes, including carbamides, polyols, purines, and pyrimidines in a phloretin- and mercurial-sensitive manner. These functional characteristics are similar to those of rAQP9. Based on Northern blot analysis, both rat and human AQP9 are abundantly expressed in liver, whereas, in contrast to rAQP9, hAQP9 is also expressed in peripheral leukocytes and in tissues that accumulate leukocytes, such as lung, spleen, and bone marrow. The human AQP9 gene is composed of 6 exons and 5 introns distributed over approximately approximately 25 kb. The gene organization is strikingly similar to that reported for human AQP3 and AQP7, suggesting their evolution from a common ancestral gene. The promoter region contains putative tonicity and glucocorticoid-responsive elements, suggesting that AQP9 may be regulated by osmolality and catabolism. Fluorescence in situ hybridization assigned its locus to chromosome 15 q22.1-22.2. Our data show that hAQP9 serves as a promiscuous solute channel expressed in both liver and peripheral leukocytes, where it is ideally suited to transport of metabolites and/or nutrients into and out of these cells


Accumulation of eosinophils in intestine-draining mesenteric lymph nodes occurs after Trichuris muris infection.
Eosinophils have recently been demonstrated capable of localizing to lymph nodes that drain mucosal surfaces, in particular during T helper 2 (Th2) responses. Resistance of mice to infection with the gastrointestinal nematode Trichuris muris depends critically on mounting of a Th2 response and represents a useful model system to investigate Th2 responses. Following infection of resistant BALB/c mice with T. muris, we observed accumulation of eosinophils in intestine-draining mesenteric lymph nodes (MLNs). The accumulation of MLN eosinophils was initiated during the second week of infection and peaked during worm expulsion. In contrast, we detected a comparably late and modest increase in eosinophil numbers in the MLNs of infected susceptible AKR mice. MLN eosinophils localized preferentially to the medullary region of the lymph node, displayed an activated phenotype and contributed to the interleukin-4 (IL-4) response in the MLN. Despite this, mice genetically deficient in eosinophils efficiently generated IL-4-expressing CD4(+) T cells, produced Th2 cytokines and mediated worm expulsion during primary T. muris infection. Thus, IL-4-expressing eosinophils accumulate in MLNs of T. muris-infected BALB/c mice but are dispensable for worm expulsion and generation of Th2 responses, suggesting a distinct or subtle role of MLN eosinophils in the immune response to T. muris infection.


Subplasmalemmal endoplasmic reticulum controls K(Ca) channel activity upon stimulation with a moderate histamine concentration in a human umbilical vein endothelial cell line.
This study was designed to elucidate the role of the subplasmalemmal endoplasmic reticulum (sER) in autacoid-induced stimulation of Ca(2+)-dependent K(+) channels in the umbilical vein endothelial cell-derived cell line EA.hy926. Cells were transfected with the Ca(2+) probe cameleon targeted to the ER for visualization of the ER network. A patch pipette was then placed close to or far (> 5 microm away) from the sER, single channel recordings (patch clamp technique) were monitored simultaneously with measurements of either ER Ca(2+) concentration (using the Ca(2+) probe Cam4-ER) or cytosolic free Ca(2+) concentration ([Ca(2+)](i); using fura-2) using a deconvolution imaging device. A voltage-dependent, large conductance Ca(2+)-dependent K(+) channel (BK(Ca); single channel conductance (gamma), 250 pS) was found. At membrane potentials of +40 and -40 mV, the EC(50) for Ca(2+) was 2.7 and 49.7 microM, respectively. In the vicinity of the sER, the BK(Ca) channel activity induced by 10 microM histamine was 32 times higher (open probability (P(o)) = 0.083 +/- 0.026) than in areas away from the sER (P(o) = 0.0026 +/- 0.002). However, at supramaximal histamine stimulation (100 microM), BK(Ca) channel activation was similar in patches in the vicinity of or away from the sER (P(o) = 0.18 +/- 0.09 and 0.25 +/- 0.07, respectively). In contrast to BK(Ca) channel activity, ER Ca(2+) depletion (Cam4-ER) and elevation of [Ca(2+)](i) in response to 10 and 100 microM histamine were not influenced by the pipette position. We conclude that in endothelial cells, the activation of BK(Ca) channels in response to moderate histamine concentration essentially depends on the proximity of the sER domains to the mouth of this K(+) channel. These findings further support our concept of the subplasmalemmal Ca(2+) control unit (SCCU) and add the local activation of Ca(2+)-activated K(+)-channels to the function of the SCCU.


Volumetric cerebral perfusion imaging in healthy adults: regional distribution, laterality, and repeatability of pulsed continuous arterial spin labeling (PCASL).
The regional distribution, laterality, and reliability of volumetric pulsed continuous arterial spin labeling (PCASL) measurements of cerebral blood flow (CBF) in cortical, subcortical, and cerebellar regions were determined in 10 normal volunteers studied on two occasions separated by 3 to 7 days. Regional CBF, normalized for global perfusion, was highly reliable when measured on separate days. Several regions showed significant lateral asymmetry; notably, in frontal regions CBF was greater in the right than left hemisphere, whereas left was greater than right in posterior regions. There was considerable regional variability across the brain, whereby the posterior cingulate and central and posterior precuneus cortices had the highest perfusion and the globus pallidus the lowest gray matter perfusion. The latter may be due to iron-induced T1 shortening affecting labeled spins and computed CBF signal. High CBF in the posterior cingulate and posterior and central precuneus cortices in this task-free acquisition suggests high activity in these principal nodes of the "default mode network."


Sesamolin inhibits lipid peroxidation in rat liver and kidney.
Although the sesame lignans, sesaminol and sesamolinol, have been shown to possess antioxidative activity, less is known about the metabolism and antioxidative properties of sesamolin, a major constituent of sesame oil. To determine the ability of sesamolin to act as an antioxidant in vivo, we fed rats a diet containing 1% sesamolin for 2 wk and studied its metabolism and its effects on oxidative stress. About 75% of the ingested sesamolin was excreted unmetabolized in feces, but it was not detected in urine. Sesamolin and its metabolites, sesamol and sesamolinol, were excreted primarily as sulfates and glucuronides. The amount of sesamolin and its metabolites was lower in the plasma than in the liver or kidneys. When we compared rats fed a diet containing 1% sesamolin for 14 d with those fed a control diet, we found that liver weight was significantly greater in the former group. Lipid peroxidation activity, measured as 2-thiobarbituric acid reactive substances, was significantly lower in the kidneys and liver of the sesamolin-fed rats than in the controls. In addition, the amount of 8-hydroxy-2'-deoxyguanosine excreted in the urine was significantly lower in the sesamolin-fed rats. These results suggest that sesamolin and its metabolites may contribute to the antioxidative properties of sesame seeds and oil and support our hypothesis that sesame lignans reduce susceptibility to oxidative stress.


Antimicrobial and antioxidant activities and chemical characterization of essential oils of Thymusvulgaris, Rosmarinus officinalis, and Origanum majorana from northeastern México.
There have been no reports of antifungal activity and composition of extracts from Thymus vulgaris, Rosmarinus officinalis or Origanum majorana from northeastern México. Antifungal activity of these oils against Trichophyton rubrum, Trichophyton tonsurans, Trichophyton mentagrophytes, Microsporum gypseum, Microsporum canis and Epidermophyton floccosum was measured by diffusion assay. Additionally, antibacterial and antioxidant activities were evaluated. Antibacterial activity against Staphylococcus aureus and Streptococcus pyogenes was examined by microdilution. Antioxidant activity was assessed by 2,2-difenil-1-picrilhidracil reduction test. The plant oils were characterized by both GC/MS and GC/FID. Oils of T. vulgaris and O. majorana showed growth inhibition activity against dermatophytes, especially T. vulgaris oil, which completely inhibited growth of all tested dermatophytes. The oils also showed bioactivity against bacteria, with minimum inhibitory concentration (MIC) values between 62.5 and 500 μg/mL. The antioxidant activity of the oils was low, with effective concentration (EC50) values <250μg/mL. The major components in the oils were as follows: T. vulgaris, o-cymene, μ-terpinene, thymol and carvacrol; R. officinalis, terpinen-4-ol and 1,8-cineole; O. majorana, terpinen-4-ol and thymol.


Observing countertransference in brief dynamic psychotherapy.
Six cases treated with Brief Dynamic Psychotherapy were studied. Initial countertransferential reactions were identified, and expectations were determined concerning the evolution of the patient-therapist relationship. The existence of a basic pattern of emotional response to the patient in the therapist throughout the treatment was observed, and the authors propose to denominate it countertransferential focus. Three clinical vignettes are reported.


Phylogeny of nodulation and nitrogen-fixation genes in Bradyrhizobium: supporting evidence for the theory of monophyletic origin, and spread and maintenance by both horizontal and vertical transfer.
Bacteria belonging to the genus Bradyrhizobium are capable of establishing symbiotic relationships with a broad range of plants belonging to the three subfamilies of the family Leguminosae (=Fabaceae), with the formation of specialized structures on the roots called nodules, where fixation of atmospheric nitrogen takes place. Symbiosis is under the control of finely tuned expression of common and host-specific nodulation genes and also of genes related to the assembly and activity of the nitrogenase, which, in Bradyrhizobium strains investigated so far, are clustered in a symbiotic island. Information about the diversity of these genes is essential to improve our current poor understanding of their origin, spread and maintenance and, in this study, we provide information on 40 Bradyrhizobium strains, mostly of tropical origin. For the nodulation trait, common (nodA), Bradyrhizobium-specific (nodY/K) and host-specific (nodZ) nodulation genes were studied, whereas for fixation ability, the diversity of nifH was investigated. In general, clustering of strains in all nod and nifH trees was similar and the Bradyrhizobium group could be clearly separated from other rhizobial genera. However, the congruence of nod and nif genes with ribosomal and housekeeping genes was low. nodA and nodY/K were not detected in three strains by amplification or hybridization with probes using Bradyrhizobium japonicum and Bradyrhizobium elkanii type strains, indicating the high diversity of these genes or that strains other than photosynthetic Bradyrhizobium must have alternative mechanisms to initiate the process of nodulation. For a large group of strains, the high diversity of nod genes (with an emphasis on nodZ), the low relationship between nod genes and the host legume, and some evidence of horizontal gene transfer might indicate strategies to increase host range. On the other hand, in a group of five symbionts of Acacia mearnsii, the high congruence between nod and ribosomal/housekeeping genes, in addition to shorter nodY/K sequences and the absence of nodZ, highlights a co-evolution process. Additionally, in a group of B. japonicum strains that were symbionts of soybean, vertical transfer seemed to represent the main genetic event. In conclusion, clustering of nodA and nifH gives additional support to the theory of monophyletic origin of the symbiotic genes in Bradyrhizobium and, in addition to the analysis of nodY/K and nodZ, indicates spread and maintenance of nod and nif genes through both vertical and horizontal transmission, apparently with the dominance of one or other of these events in some groups of strains.