Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype.
Aberrant methylation of 5' CpG islands is thought to play an important role in the inactivation of tumor suppressor genes in cancer. In colorectal cancer, a group of tumors is characterized by a hypermethylator phenotype termed CpG island methylator phenotype (CIMP), which includes methylation of such genes as p16 and hMLH1. To study whether CIMP is present in gastric cancer, the methylation status of five newly cloned CpG islands was examined in 56 gastric cancers using bisulfite-PCR. Simultaneous methylation of three loci or more was observed in 23 (41%) of 56 cancers, which suggests that these tumors have the hypermethylator phenotype CIMP. There was a significant concordance between CIMP and the methylation of known genes including p16, and hMLH1; methylation of p16 was detected in 16 (70%) of 23 CIMP+ tumors, 1 (8%) of 12 CIMP intermediate tumors, and 1 (5%) of 21 CIMP- tumors (P<0.0001). Methylation of the hMLH1 gene was detected in three of five tumors that showed microsatellite instability, and all three of the cases were CIMP+. The CIMP phenotype is an early event in gastric cancer, being present in the normal tissue adjacent to cancer in 5 of 56 cases. These results suggest that CIMP may be one of the major pathways that contribute to tumorigenesis in gastric cancers.


Volume of food consumed affects satiety in men.
This study tested the hypothesis that the amount (weight or volume) of food consumed affects the satiating potency of a food, independent of its energy content. Normal-weight young men (n = 20) were tested in a within-subjects design. Subjects were served a milk-based drink or no drink (control), followed 30 min later by a self-selected lunch and > 4 h later by a self-selected dinner. Milk drinks were equal in energy content (2088 kJ, or 499 kcal) and had similar proportions of fat (30.3%), carbohydrate (54.7%), and protein (15%) across three volumes: 300, 450, and 600 mL. Ratings of palatability, sensory properties, and energy content of the drinks and of hunger completed before consumption of the preloads were not significantly different among conditions. The results showed that preload volume affected energy intake at lunch (P < or = 0.009) such that energy intake was less after the 600-mL preload than after the 300-mL preload. This effect was still present when energy intake at dinner was included (P < or = 0.022). At lunch, including energy from the preload, subjects overate relative to the control condition (4323 +/- 322 kJ) after the 300- (5263 +/- 321 kJ) and 450-mL (5011 +/- 300 kJ) preloads but not after the 600-mL (4703 +/- 353 kJ) preload. Thus, the best adjustment for the energy in the preloads was with the largest, least energy-dense drink. Consistent with the effects on intake, the volume of the drinks affected ratings of hunger and fullness. These results indicate that the volume consumed is an important determinant of satiety after milk drinks under these conditions.


Household decision-making on child health care in developing countries: the case of Nepal.
Quantitative studies on health care utilization often overlook the importance of capturing the 'pathway' of household decision-making processes. This paper offers a four-step construct which maps out a hierarchical scale of household decision-making regarding child health care. The construct begins with the perception of illness, moves on to choice of care and provider, and finally ends with health care expenditure. The construct is substantiated by means of a descriptive analysis of nationally representative data from the 1996 round of the Nepal Living Standards Survey. About 10% of the total population reported illness, 69% of whom sought care, and depending upon the provider they chose, spent between 2.5 to 4.3% of their per capita household total annual expenditure on health care. Bivariate analysis detected age and gender biases in the perception of illness, but if a child was reported ill, all subsequent steps were found to be free from such differences. Further analysis, that took into account the changing effects of income and mother's education, indicated that there may be conceptually different household dynamics that underlie boys' and girls' illness perception; this ultimately determines whether or not health care is sought. The authors put forward a hypothesis to be tested by future studies. They argue that gender role significantly affects the perception of illness, but not necessarily the subsequent care-seeking. The relevance of this hypothesis to explaining the typical South Asian characteristic of differential child mortality rates is discussed.


Kinetics and mechanism of jack bean urease inhibition by Hg2+.
Jack bean urease (EC 22.214.171.124) is a metalloenzyme, which catalyzes the hydrolysis of urea to produce ammonia and carbon dioxide. The heavy metal ions are common inhibitors to control the rate of the enzymatic urea hydrolysis, which take the Hg2+ as the representative. Hg2+ affects the enzyme activity causing loss of the biological function of the enzyme, which threatens the survival of many microorganism and plants. However, inhibitory kinetics of urease by the low concentration Hg2+ has not been explored fully. In this study, the inhibitory effect of the low concentration Hg2+ on jack bean urease was investigated in order to elucidate the mechanism of Hg2+ inhibition. According to the kinetic parameters for the enzyme obtained from Lineweaver-Burk plot, it is shown that the Km is equal to 4.6±0.3 mM and Vm is equal to 29.8±1.7 μmol NH3/min mg. The results show that the inhibition of jack bean urease by Hg2+ at low concentration is a reversible reaction. Equilibrium constants have been determined for Hg2+ binding with the enzyme or the enzyme-substrate complexes (Ki =0.012 μM). The results show that the Hg2+ is a noncompetitive inhibitor. In addition, the kinetics of enzyme inhibition by the low concentration Hg2+ has been studied using the kinetic method of the substrate reaction. The results suggest that the enzyme first reversibly and quickly binds Hg2+ and then undergoes a slow reversible course to inactivation. Furthermore, the rate constant of the forward reactions (k+0) is much larger than the rate constant of the reverse reactions (k-0). By combining with the fact that the enzyme activity is almost completely lost at high concentration, the enzyme is completely inactivated when the Hg2+ concentration is high enough. These results suggest that Hg2+ has great impacts on the urease activity and the established inhibition kinetics model is suitable.


Onchocerca volvulus: genetic diversity of parasite isolates from Sudan.
Onchocerciasis in Sudan exists in three distinct foci which exhibit differing clinical presentations. Previous studies have demonstrated that a tandemly repeated Onchocerca sequence family with a unit repeat length of 150 bp (the O-150 family) is a useful marker for deducing relationships among different O. volvulus populations. In the current study, the O-150 repeat families of O. volvulus from Sudan were analyzed and compared to each other and to those of parasites from West Africa. Similar to West African and American O. volvulus, the O-150 families of the Sudanese parasites could be divided into clusters within which little or no intracluster variation was evident, suggesting that the O-150 family in these parasites was subject to the forces of concerted evolution. Statistical analysis of the O-150 families from the different Sudanese parasite isolates, employing a nested algorithm based on an analysis of variance, revealed that O. volvulus endemic to the northern focus at Abu Hamed were significantly different from all other O. volvulus populations examined to date. In contrast, parasites from the southern and eastern foci of Sudan were indistinguishable from those endemic to the West African savanna. The significance of these data are discussed in light of knowledge of the biogeography and biology of transmission of O. volvulus in Africa.


Vitamin D deficiency in patients with congestive heart failure: mechanisms, manifestations, and management.
Recent research suggests that vitamin D may play a role in cardiovascular (CV) health. Although its exact role is still debated and is a matter of controversy, vitamin D deficiency has been linked to increased prevalence of CV risk factors and events. Factors that predispose persons with congestive heart failure (CHF) to hypovitaminosis D include nutritional deficiency, decreased skin production, reduced intestinal absorption, and hepatorenal disease. It is possible that low vitamin D can in turn aggravate CHF. The extent of deficiency can be severe enough to cause hypocalcemia, secondary hyperparathyroidism, osteomalacia, and decreased bone density. No clear data exist showing improvement in CV clinical outcomes with vitamin D replacement. Screening is advocated in most patients, although benefits of replacement are most likely to accrue in those with severe lack or with abnormalities of calcium-parathyroid-bone metabolism. According to current guidelines and research, vitamin D goals of >20 ng/ml in most patients with CHF and >30 ng/ml in those with secondary hyperparathyroidism seem to be appropriate to aim for. Further research is needed to fully unravel the association among CV risk, CHF and hypovitaminosis D, and translate this knowledge into clinically meaningful management recommendations.


[Overweight, obesity and associated factors in first grade schoolchildren in a city of the metropolitan region of São Paulo, Brazil].
This study assessed the prevalence of overweight in public school first graders and the association between overweight and socio-environmental factors in a city in Greater Metropolitan São Paulo, Brazil. Children enrolling in public school first grade in Cajamar in 2005 were assessed. Overweight was defined according to body mass index, by gender and age. Socio-environmental information was obtained using a questionnaire applied to 58.6% of the children's mothers. Poisson regression models were used to evaluate associations between overweight in schoolchildren and socio-environmental variables. Seventeen percent of the children were overweight. Factors associated with overweight were: mother's obesity (PR = 3.54; CI: 2.16-5.80), high consumption of junk food (PR = 2.12; CI: 1.30-3.45), more than 4 hours a day watching TV (PR = 2.08; CI: 1.03-4.20), and daily household per capita availability of vegetal oil (around 3 tablespoons) (PR = 1.52; CI: 1.01-2.31). The family environment has a strong influence on overweight in children entering first grade in public schools. Prevention of childhood overweight should preferably target the parents and other caregivers.


Similar oropharyngeal leak pressures during anaesthesia with i-gel, LMA-ProSeal and LMA-Supreme Laryngeal Masks.
We test the hypothesis that there are differences in performance among three extra-glottic airway devices during spontaneous breathing anaesthesia. One hundred and fifty consecutive patients (ASA Grade 1-2, aged 18-80 yr) were randomly allocated for airway management with the i-gel (Intersurgical Ltd, Wokingham, Berkshire UK), the LMA-ProSeal and the LMA-Supreme (The Laryngeal Mask Company Ltd, Wooburn Green, Bucks, UK). Anaesthesia was with fentanyl/propofol/sevoflurane mixture. A laryngoscope-guided, gastric tube-guided technique was used for insertion. The following primary variables were assessed: ease of insertion, effective airway time, anatomical position, oropharyngeal leak pressure among devices, and change in oropharyngeal leak pressure between 30 and 60 minutes for each device during the spontaneous breathing anaesthesia. Differences detected were that the LMA-Supreme was easier to insert and had a shorter effective airway time than the LMA-Proseal and i-gel. Anatomical position was better for the LMA-Supreme than for the i-gel. Oropharyngeal leak pressures were similar among devices during apnoea and spontaneous ventilation, but much higher than in the first generation classic type of laryngeal masks. There were no changes in oropharyngeal leak pressure for any device during the spontaneous breathing phase. There were no differences in performance for any variable between the LMA-ProSeal and i-gel. The LMA-Supreme is easier and quicker to insert than the LMA-ProSeal and i-gel using a laryngoscope-guided, gastric tube-guided technique and is associated with better anatomical positioning than the i-gel. Oropharyngeal leak pressures are similar among devices.


Foibles, Follies, and Fusion: Assessment of Statistical Label Fusion Techniques for Web-Based Collaborations using Minimal Training.
Labeling or parcellation of structures of interest on magnetic resonance imaging (MRI) is essential in quantifying and characterizing correlation with numerous clinically relevant conditions. The use of statistical methods using automated methods or complete data sets from several different raters have been proposed to simultaneously estimate both rater reliability and true labels. An extension to these statistical based methodologies was proposed that allowed for missing labels, repeated labels and training trials. Herein, we present and demonstrate the viability of these statistical based methodologies using real world data contributed by minimally trained human raters. The consistency of the statistical estimates, the accuracy compared to the individual observations and the variability of both the estimates and the individual observations with respect to the number of labels are discussed. It is demonstrated that the Gaussian based statistical approach using the previously presented extensions successfully performs label fusion in a variety of contexts using data from online (Internet-based) collaborations among minimally trained raters. This first successful demonstration of a statistically based approach using "wild-type" data opens numerous possibilities for very large scale efforts in collaboration. Extension and generalization of these technologies for new application spaces will certainly present fascinating areas for continuing research.


Psychologic stress and blood glucose levels in nondiabetic subjects.
This study analyzed the effect of a standardized psychologic stressor on blood glucose levels in nondiabetic subjects. Subjects participated in a stress and nonstress session, presented in counterbalanced order. At each session, subjects were fed a carbohydrate load and blood glucose responses were measured 0, 30, 60, 90, and 120 min after the load. On nonstress days, subjects relaxed after drinking the load, while on stress days subjects participated in 30 min of competitive tasks immediately after the drink. The stress impaired the subjects' ability to handle the carbohydrate load; whereas on nonstress days, blood glucose levels peaked at 30 min after the load, on stress days the peak blood glucose response was delayed until 60 min after the drink.


Pubic bone age estimation in adult women.
In recent years, numerous physical anthropologists have pointed out the need for regional standards for estimating age in various world populations. While investigating aging methods for East European populations, dramatic changes were noted in the pubic symphyseal morphology and structure of older adult female individuals. These changes were not captured in the typically used pubic symphysis aging methods. This paper defines and tests the need for a new phase, phase VII, that follows the Suchey-Brooks phase VI. In addition, Suchey-Brooks phases V and VI are redefined. Phase definitions, decision-making rules, and comparison graphics for the new method are presented. Balkan (n = 85) and Eastern Tennessee (n = 104) samples, totaling 189 individuals, were used in the analysis. Pearson correlation coefficients between four observers and a control seriation were strong, indicating ease of replicability between investigators. No statistically significant intra-observer error was detected. Summary statistics show that individuals in phase V were on average in the early 50s, while individuals in phase VI were in their mid 50s to mid 60s, and individuals in phase VII were in their mid 70s. Since linear regression models tend to under-age the elderly and over-age the young, transition analysis, using an unrestricted cumulative probit model, was undertaken to evaluate the phases and to produce point estimates for the ages-at-transition for the Balkan sample. The highest posterior density region point estimates with their associated upper and lower bounds can be used for predicting age for unknown forensic cases related to the Balkan sample. Further, the mean ages and standard deviations for phases V-VII for the Tennessee sample are presented for use in American forensic cases.


IL-2 receptor expression and ki-67 flow cytometric analysis in B-chronic lymphocytic-leukemia.
Chronic lymphocytic leukemia (CLL) is typically an indolent lympho-proliferative disorder. Its clinical course is notable for marked heterogeneity, but in a subset of patients, the disease pursues a relatively rapid clinical course. To identify patients that may have aggressive disease, the growth fraction as determined by Ki-67 proliferation marker, DNA and RNA content, and IL-2 receptor expression were determined in 46 patients with CLL by flow cytometry. Our results indicate a significant statistical correlation between Ki-67 positivity and IL-2 expression in B-CLL cells. No correlation between the proliferative activity or RNA content and IL-2 expression was found. Our data indicate that measurement of both IL-2 receptor and Ki-67 expression in B-CLL can identify a subset of patients with a high risk of rapid clinical progression.


Preparation, characterization and in vitro evaluation of solid dispersions containing docetaxel.
Solid dispersions using water-soluble carriers were studied for improving the dissolution of docetaxel, a poorly soluble compound. In order to obtain the most optimized formulation, we prepared many solid dispersions with different carriers, different solvents, or at a series of drug-to-carrier ratios, and compared their dissolution. The accumulative dissolution of docetaxel from poloxamer 188 was more excellent than that from PVP(k30) and glyceryl monostearate, and the dissolution of docetaxel from solid dispersion was markedly higher than that of pure docetaxel; meanwhile the increased dissolution was partly dependent on the ratios of docetaxel and poloxamer 188. The ethanol used to prepare solid dispersion is of more significant effect on the dissolution of docetaxel than that of acetone. The docetaxel/poloxamer 188 system was characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and environmental scanning electron microscope (ESEM). The results of DSC, XRD, and ESEM analyses of docetaxel/poloxamer 188 system showed that there are intermolecular interactions between docetaxel and poloxamer, and the crystallinity of docetaxel disappeared. These results show that solid dispersion is a promising approach of developing docetaxel drug formulates.


Worked examples and tutored problem solving: redundant or synergistic forms of support?
The current research investigates a combination of two instructional approaches, tutored problem solving and worked examples. Tutored problem solving with automated tutors has proven to be an effective instructional method. Worked-out examples have been shown to be an effective complement to untutored problem solving, but it is largely unknown whether they are an effective complement to tutored problem solving. Further, while computer-based learning environments offer the possibility of adaptively transitioning from examples to problems while tailoring to an individual learner, the effectiveness of such machine-adapted example fading is largely unstudied. To address these research questions, one lab and one classroom experiment were conducted. Both studies compared a standard Cognitive Tutor with two example-enhanced Cognitive Tutors, in which the fading of worked-out examples occurred either in a fixed way or adaptively. Results indicate that the adaptive fading of worked-out examples leads to higher transfer performance on delayed posttests than the other two methods.


Developing and fostering a dynamic program for training in veterinary pathology and clinical pathology: veterinary students to post-graduate education.
Recent reports project a deficiency of veterinary pathologists, indicating a need to train highly qualified veterinary pathologists, particularly in academic veterinary medicine. The need to provide high-quality research training for veterinary pathologists has been recognized by the veterinary pathology training program of the Ohio State University (OSU) since its inception. The OSU program incorporates elements of both residency training and graduate education into a unified program. This review illustrates the components and structure of the training program and reflects on future challenges in training veterinary pathologists. Key elements of the OSU program include an experienced faculty, dedicated staff, and high-quality students who have a sense of common mission. The program is supported through cultural and infrastructure support. Financial compensation, limited research funding, and attractive work environments, including work-life balance, will undoubtedly continue to be forces in the marketplace for veterinary pathologists. To remain competitive and to expand the ability to train veterinary pathologists with research skills, programs must support strong faculty members, provide appropriate infrastructure support, and seek active partnerships with private industry to expand program opportunities. Shortages of trained faculty may be partially resolved by regional cooperation to share faculty expertise or through the use of communications technology to bridge distances between programs. To foster continued interest in academic careers, training programs will need to continue to evolve and respond to trainees' needs while maintaining strong allegiances to high-quality pathology training. Work-life balance, collegial environments that foster a culture of respect for veterinary pathology, and continued efforts to reach out to veterinary students to provide opportunities to learn about the diverse careers offered in veterinary pathology will pay long-term dividends for the future of the profession.


Understanding the biogeochemical mechanisms of metal removal from acid mine drainage with a subsurface limestone bed at the Motokura Mine, Japan.
Subsurface limestone beds (SLBs) are used as a passive treatment technique to remove toxic metals from acid mine drainage (AMD). In this study, we investigated the mechanisms and thermodynamics of metal (manganese, copper, zinc, cadmium, and lead) precipitation in the SLB installed at the Motokura Mine. Field surveys in 2017 and 2018 showed that the pH of the SLB influent (initially 5-6) increased to approximately 8 in the drain between 24 and 45 m from the inlet. This increase was caused by limestone dissolution and resulted in the precipitation of hydroxides and/or carbonates of copper, zinc, and lead, as expected from theoretical calculations. Manganese and cadmium were removed within a pH range of approximately 7-8, which was lower than the pH at which they normally precipitate as hydroxides (pH 9-10). X-ray absorption near-edge structure analysis of the sediment indicated that δ-MnO2, which has a high cation-exchange capacity, was the predominant tetravalent manganese compound in the SLB rather than trivalent compound (MnOOH). Biological analysis indicates that microorganism activity of the manganese-oxidizing bacteria in the SLB provided an opportunity for δ-MnO2 formation, after which cadmium was removed by surface complexation with MnO2 (≡ MnOH0 + Cd2+ ⇄ ≡ MnOCd+ + H+). These findings show that biological agents contributed to the precipitation of manganese and cadmium in the SLB, and suggest that their utilization could enhance the removal performance of the SLB.


Chitosan-thiamine pyrophosphate as a novel carrier for siRNA delivery.
A novel siRNA carrier was formulated between chitosan (CS) and thiamine pyrophosphate (TPP). Their ability to deliver siRNA were evaluated in stable and constitutive EGFP-expressing HepG2 cells. CS-TPP was prepared by dissolving CS in TPP solution at a CS:TPP molar ratio of 1.5:1. Complexes of CS-TPP/siRNA were formed at varying weight ratios and characterized using gel electrophoresis. Their morphologies and particle sizes were evaluated, and the transfection efficiency and cytotoxicity of CS-TPP/siRNA complexes were examined in stable and constitutive EGFP-expressing HepG2 cells. Gel electrophoresis results indicated that binding of CS-TPP and siRNA depended on the molecular weight (MW) and weight ratio of CS, and the particle sizes of CS-TPP/siRNA complexes were in nano-size. The CS-TPP-mediated siRNA silencing of the endogenous EGFP gene occurred maximally with 70-73% efficiency. The CS-TPP/siRNA complex with the lowest MW of CS (20 kDa) at a weight ratio of 80 showed the strongest inhibition of gene expression, which was higher than Lipofectamine 2000. Over 90% the average cell viabilities of the complexes were observed by MTT assay. This study suggests that CS-TPP is straightforward to prepare, safe and exhibits significantly improved siRNA delivery potential in vitro.


Hispanic cultural norms for health-seeking behaviors in the face of symptoms.
This study examines factors that contribute to the delayed use of medical care among Hispanics when chronic disease-related symptoms (warning signs) occur. As an adjunct to a larger project funded by the National Cancer Institute, this study accessed a population of primarily Hispanic, mostly male employees at public work sites in two Arizona counties. Through focus groups and a survey of employees, a model describing the factors underlying health care use was tested. Seriousness of symptoms has the most effect on visits to doctor, with more serious symptoms leading to prompter visits. Faith in God and seriousness of symptoms both are related to the search for a doctor one can trust. Also, a cluster of variables describing past bad experiences, practical barriers, and emotional avoidance are related to the desire to get advice or medical help from someone who is close; these influence the search for a trusted doctor, which in turn leads to prompter visits to doctor.


Placenta-derived, cellular messenger RNA expression in the maternal blood of preeclamptic women.
To perform gene expression profiling and real-time quantitative reverse-transcription polymerase chain reaction (PCR) analysis to identify biomarkers of preeclampsia in cellular messenger RNA (mRNA) from maternal blood. We performed a microarray analysis with five maternal blood samples from women with preeclampsia and five matched control subjects. Up-regulated gene expression was further analyzed through reverse-transcription PCR analysis with 28 consecutive blood samples from women affected with preeclampsia and 29 controls. Both pregnancy-specific beta1 glycoprotein and trophoblast glycoprotein were selected based on microarray analysis. Reverse-transcription PCR analysis detected significantly increased mRNA concentrations among women in the preeclampsia group. When stratified according to mild or severe preeclampsia, 19.2-fold and 41.8-fold increases in pregnancy-specific beta1 glycoprotein and 8.3-fold and 10.6-fold increases in trophoblast glycoprotein were observed, respectively. Among women with hemolysis, elevated liver enzymes, and low platelet count syndrome, 51.6-fold and 13.1-fold increases in pregnancy-specific beta1 glycoprotein and trophoblast glycoprotein were observed, respectively. In the preeclampsia group, pregnancy-specific beta1 glycoprotein correlated with severity of proteinuria (P<.001) and systolic blood pressure (P=.01). The mRNA expression of pregnancy-specific beta1 glycoprotein and trophoblast glycoprotein is up-regulated in cells circulating within blood from women with preeclampsia, and pregnancy-specific beta1 glycoprotein expression is positively correlated with the clinical severity of preeclampsia. II.


[Pathogenesis of respiratory insufficiency in patients submitted to bilateral aortofemoral shunting in Leriche's syndrome].
The complementary system is activated in response to development of the reperfusion syndrome in patients subjected to bilateral aortofemoral shunting for Leriche's syndrome. These changes result in the development of respiratory disorders presenting as constriction of the small and medium-sized bronchi, increase of pulmonary shunting of the blood, and manifest hypoxia.


What motivates the sharing of consumer-generated genomic information?
Genomic medicine is an emerging practice that followed the completion of the Human Genome Project and that considers genomic information about an individual in the provision of their clinical care. Large and start-up direct-to-consumer genetic testing companies like Ancestry, 23andMe, Luna DNA, and Nebula Genomics have capitalized on findings from the Human Genome Project by offering genetic health testing services to consumers without a clinical intermediary. Genomic medicine is thus further propelled by unprecedented supply and demand market forces driven by direct-to-consumer genetic testing companies. As government entities like the National Human Genome Research Institute question how genomics can be implemented into routine medical practice to prevent disease and improve the health of all members of a diverse community, we believe that stakeholders must first examine how and scenarios in which stakeholders can become motivated to share or receive genomic information. In this commentary, we discuss consumers three scenarios: satisfying personal curiosity, providing a social good, and receiving a financial return. We examine these motivations based on recent events and current avenues through which have engaged or can engage in genomic data sharing via private, secure (e.g. centralized genomic databases and de-centralized platforms like blockchain) and public, unsecure platforms (e.g. open platforms that are publicly available online). By examining these scenarios, we can likely determine how various stakeholders, such as consumers, might prefer to extract value from genomic information and how privacy preferences among those stakeholders might vary depending on how they seek to use or share genomic information. From there, one can recommend best practices to promote transparency and uphold privacy standards and expectations among stakeholders engaged in genomic medicine.


Noise and edge artifacts in maximum-likelihood reconstructions for emission tomography.
Images produced in emission tomography with the expectation-maximization algorithm have been observed to become more noisy and to have large distortions near edges as iterations proceed and the images converge towards the maximum-likelihood estimate. It is our conclusion that these artifacts are fundamental to reconstructions based on maximum-likelihood estimation as it has been applied usually; they are not due to the use of the expectation-maximization algorithm, which is but one numerical approach for finding the maximum-likelihood estimate. In this paper, we develop a mathematical approach for suppressing both the noise and edge artifacts by modifying the maximum-likelihood approach to include constraints which the estimate must satisfy.


Immunization of HLA-A2+ melanoma patients with MAGE-3 or MelanA peptide-pulsed autologous peripheral blood mononuclear cells plus recombinant human interleukin 12.
Vaccination with dendritic cells (DCs) pulsed with tumor antigen peptides has shown promise in the treatment of melanoma. Interleukin (IL)-12 production by DCs is a key component for their efficacy. Murine studies have shown that IL-12 promotes potent antitumor immunization when coadministered with peptides loaded onto other class I MHC+ cells, thus bypassing the need to use DCs. The easiest cell source to obtain in large quantity from human patients is peripheral blood mononuclear cells (PBMCs). A Phase I clinical trial was thus performed in patients with metastatic melanoma using immunization with autologous PBMCs pulsed with a MAGE-3 or a MelanA peptide, coadministered with various doses of recombinant human (rh)IL-12. Patients receiving low-to-moderate doses of rhIL-12 developed increased specific CD8+ T-cell responses. Of the eight patients showing increased immunity, six had evidence of clinical activity, with one complete, one partial, one minor, and three mixed responses observed. In two patients with mixed responses, growing tumors were found to lack expression of the antigen used to immunize. Thus, vaccination with peptide-pulsed PBMCs plus rhIL-12 induces specific immunity and has clinical activity, without the need to generate DCs. Outgrowth of antigen-negative tumors argues for the future development of polyepitope vaccines.


Spindle assembly checkpoint and its regulators in meiosis.
BACKGROUND Meiosis is a unique form of cell division in which cells divide twice but DNA is duplicated only once. Errors in chromosome segregation during meiosis will result in aneuploidy, followed by loss of the conceptus during pregnancy or birth defects. During mitosis, cells utilize a mechanism called the spindle assembly checkpoint (SAC) to ensure faithful chromosome segregation. A similar mechanism has been uncovered for meiosis in the last decade, especially in the past several years. METHODS For this review, we included data and relevant information obtained through a PubMed database search for all articles published in English from 1991 through 2011 which included the term 'meiosis', 'spindle assembly checkpoint', or 'SAC'. RESULTS There are 91 studies included. Evidence for the existence of SAC functions in meiosis is provided by studies on the SAC proteins mitotic-arrest deficient-1 (Mad1), Mad2, budding uninhibited by benzimidazole-1 (Bub1), Bub3, BubR1 and Mps1; microtubule-kinetochore attachment regulators Ndc80 complex, chromosomal passenger complex, mitotic centromere-associated kinesin (MCAK), kinetochore null 1 (KNL1) and Mis12 complex and spindle stability regulators. CONCLUSIONS SAC and its regulators exist and function in meiosis, and their malfunctions may cause germ cell aneuploidy. However, species and sexual differences exist. Moreover, interaction of SAC components with other regulators is still poorly understood, which needs further study.


Periodic orbit analysis demonstrates genetic constraints, variability, and switching in Drosophila courtship behavior.
We use symbolic dynamics to describe Drosophila courtship communication. We posit that behavior should be defined in terms of irreducible periodic orbits of fundamental acts. This leads to a first operational definition of behavior, which allows for a fine grained quantitative analysis of behavior. We obtain evidence that during Drosophila courtship, individual characteristics of the protagonists are exchanged (predominantly from the male to the female) and that males in the presence of fruitless males perform a behavioral switch from male to female behavior.


Social Robot Navigation Tasks: Combining Machine Learning Techniques and Social Force Model.
Social robot navigation in public spaces, buildings or private houses is a difficult problem that is not well solved due to environmental constraints (buildings, static objects etc.), pedestrians and other mobile vehicles. Moreover, robots have to move in a human-aware manner-that is, robots have to navigate in such a way that people feel safe and comfortable. In this work, we present two navigation tasks, social robot navigation and robot accompaniment, which combine machine learning techniques with the Social Force Model (SFM) allowing human-aware social navigation. The robots in both approaches use data from different sensors to capture the environment knowledge as well as information from pedestrian motion. The two navigation tasks make use of the SFM, which is a general framework in which human motion behaviors can be expressed through a set of functions depending on the pedestrians' relative and absolute positions and velocities. Additionally, in both social navigation tasks, the robot's motion behavior is learned using machine learning techniques: in the first case using supervised deep learning techniques and, in the second case, using Reinforcement Learning (RL). The machine learning techniques are combined with the SFM to create navigation models that behave in a social manner when the robot is navigating in an environment with pedestrians or accompanying a person. The validation of the systems was performed with a large set of simulations and real-life experiments with a new humanoid robot denominated IVO and with an aerial robot. The experiments show that the combination of SFM and machine learning can solve human-aware robot navigation in complex dynamic environments.


Leptin receptor and functional effects of leptin in human endothelial progenitor cells.
Circulating endothelial progenitor cells (EPCs) may be involved in the maintenance of vascular homeostasis and their impairment may be conducive to vascular disease. We studied the role of an adipocyte-derived hormone, leptin, in the regulation of human EPC function. EPCs were grown from human circulating mononuclear cells. The presence of the leptin receptor and the functional effects of leptin in EPCs were investigated. EPCs stained positive for endothelial cell markers (Flk-1 and Tie-2 receptors) and the hematopoietic CD34 marker. The presence of the long form of the leptin receptor in EPCs was confirmed by Western blotting and with immunofluorescence. Leptin, at a physiological concentration of 10 ng/ml, significantly increased tube formation from 2.1+/-2.2 to 12.4+/-4.9 tubes/25 mm2. At a higher concentration of 100 ng/ml of leptin, tube formation was reduced compared to the lower concentration. This higher concentration of leptin also inhibited EPC migration, decreasing it from 0.45+/-0.14 to 0.28+/-0.12 mm/48 h. Leptin did not have any effect on EPC proliferation. In summary, the leptin receptor is present in human EPCs and leptin may affect EPC function, both in physiological and in hyperleptinemic conditions. These findings are relevant to leptin-mediated regulation of vasculogenesis in humans, and the association between hyperleptinemia and obesity with cardiovascular disease.


Why are you hitting yourself? Whole-exome sequencing diagnosis of monogenic autoimmunity.
Inborn errors of immunity may present with autoimmunity and autoinflammation as hallmark clinical manifestations. We aimed to identify the potential monogenic causes of autoimmune disorders in 26 patients from a pediatric reference hospital in Mexico through whole-exome sequencing. We specifically selected patients with a family history of autoimmune diseases, early-onset symptoms, and difficult-to-control autoimmune disorders or autoimmunity associated with infection predisposition. We identified the genetic variants that were compatible with the patients' phenotype in 54% of the patients. Autoimmune diseases are often caused by a combination of genetic factors, but cases that appear at a young age are resistant to treatment or occur in clusters, as well as the presence of autoimmune symptoms alongside infectious diseases should raise suspicion for an underlying inborn error of immunity.


American contact dermatitis society core allergen series.
Evidence for the effectiveness of patch testing and the need for an expanded series that provides experience and evidence-based suggestions for an extended patch testing series are examined in this review. Many of those testing with shorter allergen series are interested in expanding the spectrum of patch testing. The American Contact Dermatitis Society (ACDS) Core Allergen Series Group has arranged a group of suggested allergen groups that can be logically scaled up or down depending on the needs of the patch tester and the community being tested. This is not an "ACDS 80 Standard." We suggest a core group of allergens similar to the TRUE Test (SmartPractice, Phoenix, Ariz) with subsequent trays providing a greater breadth of coverage in a logical fashion, with more likely allergens being higher in the tray. For more extensive testing, specialty trays (ie, cosmetics, metals, plant, etc) are recommended.


Mid-infrared ZBLAN fiber supercontinuum source using picosecond diode-pumping at 2 µm.
We present the first demonstration of mid-IR supercontinuum generation directly pumped with picosecond pulses from a Thulium fiber-amplified gain-switched laser diode at 2 µm. We achieve more than two octaves of bandwidth from 750 - 4000 nm in step-index ZBLAN fiber with Watt-level average power and spectral flatness of less than 1.5 dB over a 1300 nm range in the mid-IR from 2450 - 3750 nm. The system offers high stability, power-scaling capability to the 10 W regime, and demonstrates an attractive route towards relatively inexpensive, versatile and practical sources of high power broadband mid-IR radiation.


Immunohistochemical expression of MYH protein can be used to identify patients with MYH-associated polyposis.
MYH-associated polyposis is a recently described, autosomal-recessive disease characterized by multiple colorectal adenomas and cancer. There are only few immunohistochemical studies of the MYH protein. We investigated the expression pattern of the MYH protein to evaluate whether a immunohistochemical approach could be used in clinical practice to screen patients for germline mutations in the MYH gene. The expression of MYH, MSH2, MLH1, and MSH6 proteins was studied by immunohistochemistry in 20 samples (colorectal adenomas or cancer) from 18 patients with biallelic MYH mutation, in 11 samples from patients with germline adenomatous polyposis coli (APC) mutations, in 20 samples from patients with sporadic colorectal cancers, and in 10 samples from patients with normal colonic mucosa without malignancies. In all cases the mismatch repair proteins were expressed normally. Nuclear and cytoplasmic immunoreactivity for the MYH protein were observed in normal colorectal mucosa, in sporadic colorectal carcinomas, and in adenomas and carcinomas from patients carrying APC germline mutations. Adenomas and carcinomas from patients with MYH biallelic mutation showed a different pattern of expression: a strong granular cytoplasmic staining was observed without any nuclear expression. The same immunophenotype was observed in the surrounding normal mucosa. Patients with biallelic MYH mutations showed disappearance of staining from the nucleus, and segregation of immunoreactivity in the cytoplasm, both in neoplastic and surrounding healthy mucosa. Because this pattern of expression seems to be specific for biallelic mutations, it follows that immunohistochemistry might be used in clinical practice to screen patients at risk for MYH-associated polyposis.


Irinotecan hepatic arterial infusion chemotherapy for hepatic metastases from colorectal cancer: results of a phase I clinical study.
Hepatic arterial infusion chemotherapy is a promising approach in liver metastases from colorectal cancer, but chemical hepatitis, biliary sclerosis, arterial thrombosis and right upper quadrant pain are limiting factors. Irinotecan (CPT-11) is an active drug in colorectal cancer. We planned a short hepatic arterial infusion of CPT-11 to describe the toxicity, to determine the dose-limiting toxicity, and to define the doses of CPT-11 to be recommended for phase II studies. Fourteen patients with a median liver substitution of 30% (10-60%) were enrolled. All patients received hepatic arterial infusion chemotherapy with CPT-11 on an outpatient basis every 3 weeks as a short, 30-min infusion. At 240 mg/m2, 2 of 4 patients experienced grade 4 diarrhea and neutropenia, and 3 of them also reported grade 4 abdominal pain of the right upper quadrant. The maximum tolerated dose was reached at 240 mg/m2. The recommended doses of CPT-11 for phase II studies is 200 mg/m2, given every 3 weeks. CPT-11 presents a low hepatic toxic profile and could be considered a new active drug, suitable for hepatic arterial infusion in liver metastases from colorectal cancer.


Molecular characterization of organic electronic films.
Organic electronics have emerged as a viable competitor to amorphous silicon for the active layer in low-cost electronics. The critical performance of organic electronic materials is closely related to their morphology and molecular packing. Unlike their inorganic counterparts, polymers combine complex repeat unit structure and crystalline disorder. This combination prevents any single technique from being able to uniquely solve the packing arrangement of the molecules. Here, a general methodology for combining multiple, complementary techniques that provide accurate unit cell dimensions and molecular orientation is described. The combination of measurements results in a nearly complete picture of the organic film morphology.


Dimorphic ejaculates and sperm release strategies associated with alternative mating behaviors in the squid.
Sperm competition is a powerful postcopulatory selective force influencing male adaptations associated with increasing fertilization success, and it is usually related to the evolution of different strategies of ejaculate expenditure between individuals. Ejaculates may also be influenced by additional selective pressures associated with sperm competition, such as timing between insemination and fertilization, female reproductive tract morphology, and fertilization environment. Also, males that adopt alternative mating tactics may face distinct sperm competition pressures, which may lead to the evolution of intraspecific diversity in ejaculates. In loliginid squids, males with alternative reproductive tactics (sneakers and consorts) differ not only in mating behavior, but also transfer spermatophores into two distinct sites within the female. Here, we compared structure and functioning of spermatophores between sneakers and consorts in the squid Doryteuthis plei applying microscopy techniques and in vitro experiments. Sneakers and consorts exhibit differences in spermatophore structure that lead to distinct spermatophoric reactions and spermatangium morphologies. Moreover, in sneakers, sperm release lasts longer and their sperm show an aggregative behavior not detected in consorts. Slow sperm release may be a strategy to guarantee longer sperm provision, given the wide interval between sneaker mating and egg release. For consorts, in turn, intense and quick sperm discharge may be advantageous, as timing between mating and egg-laying is relatively short. Within the complex squid mating system, factors such as (i) different fertilization sites and (ii) interval between mating and egg release may also influence sperm competition, and ultimately shape the evolution of divergent ejaculates between dimorphic males.


Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study.
This multicenter, open-label, randomized phase 2 study assessed the efficacy and safety of pomalidomide (POM) with/without low-dose dexamethasone (LoDEX) in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior therapies (including lenalidomide [LEN] and bortezomib [BORT]) and had progressed within 60 days of their last therapy were randomized to POM (4 mg/day on days 1-21 of each 28-day cycle) with/without LoDEX (40 mg/week). The primary end point was progression-free survival (PFS). In total, 221 patients (median 5 prior therapies, range 1-13) received POM+LoDEX (n = 113) or POM (n = 108). With a median follow-up of 14.2 months, median PFS was 4.2 and 2.7 months (hazard ratio = 0.68, P = .003), overall response rates (ORRs) were 33% and 18% (P = .013), median response duration was 8.3 and 10.7 months, and median overall survival (OS) was 16.5 and 13.6 months, respectively. Refractoriness to LEN, or resistance to both LEN and BORT, did not affect outcomes with POM+LoDEX (median PFS 3.8 months for both; ORRs 30% and 31%; and median OS 16 and 13.4 months). Grade 3-4 neutropenia occurred in 41% (POM+LoDEX) and 48% (POM); no grade 3-4 peripheral neuropathy was reported. POM+LoDEX was effective and generally well tolerated and provides an important new treatment option for RRMM patients who have received multiple prior therapies. This trial was registered at www.clinicaltrials.gov as #NCT00833833.


Progress and Future Prospectives in Skin-on-Chip Development with Emphasis on the use of Different Cell Types and Technical Challenges.
Understanding the healthy and diseased state of skin is important in many areas of basic and applied research. Although the field of skin tissue engineering has advanced greatly over the last years, current in vitro skin models still do not mimic the complexity of the human skin. Skin-on-chip and induced pluripotent stem cells (iPSC) might be key technologies to improve in vitro skin models. This review summarizes the state of the art of in vitro skin models with regard to cell sources (primary, cell line, iPSC) and microfluidic devices. It can be concluded that iPSC have the potential to be differentiated into many kinds of immunologically matched cells and skin-on-chip technology might lead to more physiologically relevant skin models due to the controlled environment, possible exchange of immune cells, and an increased barrier function. Therefore the combination of iPSC and skin-on-chip is expected to lead to superior healthy and diseased in vitro skin models.


Mortality and kidney histopathology of chinook salmon Oncorhynchus tshawytscha exposed to virulent and attenuated Renibacterium salmoninarum strains.
An isolate of Renibacterium salmoninarum (strain MT 239) exhibiting reduced virulence in rainbow trout Oncorhynchus mykiss was tested for its ability to cause bacterial kidney disease (BKD) in chinook salmon Oncorhynchus tshawytscha, a salmonid species more susceptible to BKD. Juvenile chinook salmon were exposed to either 33209, the American Type Culture Collection type strain of R. salmoninarum, or to MT 239, by an intraperitoneal injection of 1 x 10(3) or 1 x 10(6) bacteria fish(-1), or by a 24 h immersion in 1 x 10(5) or 1 x 10(7) bacteria ml(-1). For 22 wk fish were held in 12 degrees C water and monitored for mortality. Fish were sampled periodically for histological examination of kidney tissues. In contrast to fish exposed to the high dose of strain 33209 by either injection or immersion, none of the fish exposed to strain MT 239 by either route exhibited gross clinical signs or histopathological changes indicative of BKD. However, the MT 239 strain was detected by the direct fluorescent antibody technique in 4 fish that died up to 11 wk after the injection challenge and in 5 fish that died up to 20 wk after the immersion challenge. Viable MT 239 was isolated in culture from 3 fish that died up to 13 wk after the immersion challenge. Total mortality in groups injected with the high dose of strain MT 239 (12%) was also significantly lower (p < 0.05) than mortality in groups injected with strain 33209 (73 %). These data indicate that the attenuated virulence observed with MT 239 in rainbow trout also occurs in a salmonid species highly susceptible to BKD. The reasons for the attenuated virulence of MT 239 were not determined but may be related to the reduced levels of the putative virulence protein p57 associated with this strain.


Crepuscular flight activity of Culex erraticus (Diptera: Culicidae).
Circadian patterns of flight activity in mosquitoes can influence pathogen transmission by regulating dispersal potential of vectors and contact rates between vectors and reservoir and/or dead-end hosts. We investigated circadian activity patterns of Culex erraticus (Dyar and Knab) at a wetland field site in central Alabama, by aspirating resting adults and questing females in the morning and evening hours, respectively. Mosquitoes were aspirated at regular time intervals to determine the time of day during which peak resting site-seeking and host-seeking activities occurred. Day-to-day variation in activity patterns due to wind, humidity, and temperature was examined using stepwise linear regression. We found a distinct peak in flight activity during the morning hours (2 h before and 2 h after sunrise) for females and males of Culex erraticus, the most commonly encountered species at the site. The exact time of the peak varied from day to day, and was largely a function of temperature. A less distinct peak in activity was observed for questing females in the evening, although flights generally commenced just after sunset and peaked 30-60 min after sunset. A significant amount of day-to-day variation in the number of questing females was attributable to relative humidity. Our study demonstrates predictable patterns of circadian activity for Cx. erraticus, a suspected bridge vector of eastern equine encephalitis virus. Moreover, these patterns are modulated by environmental conditions. This information may be used to develop vector control strategies and make predictions about factors that affect the spread of mosquito-vectored pathogens.


Anomaly in the electronic structure of the Na(x)CoO(2-y) cathode as a source of its step-like discharge curve.
In this paper we would like to show a new approach to an explanation of the nature of the discharge-charge curve of Na/Na(+)/NaxCoO2-y batteries, which can justify the existence of the step-like characteristics. This is still an open problem, which until now had no proper description in the literature. On the basis of comprehensive experimental studies of physicochemical properties of NaxCoO2-y cathode material (XRD, electrical conductivity, thermoelectric power, electronic specific heat) supported by calculations performed using the DFT method with accounting for chemical disorder, it has been shown that the observed step-like character of the discharge curve reflects the variation of the chemical potential of electrons (Fermi level) in the density of states of NaxCoO2-y, which is anomalously perturbed by the presence of the oxygen vacancy defects and sodium ordering. Our studies of structural, electronic and thermal properties of NaxCoO2-y cathode material as a function of concentration of electrochemically intercalated sodium document strong and step-like shift of the position of the Fermi level during introduction of electrons in this process. This effect is coherently supported by the shape of calculated density of states (DOS) of NaxCoO2-y having included oxygen defects and sodium ordering.


Prostaglandin E2 inhibits IL-10 production by bovine CD4+ T cells.
Although prostaglandin E2 (PGE2) is a pro-inflammatory mediator, it also produces some effect which is anti-inflammatory in character. It is suggested that one of the mechanisms responsible for the latter effect is the increased synthesis of IL-10. The aim of this study has been to determine the influence of PGE2 on IL-10 production by bovine CD4+ and CD8+ T cells and NK cells. With this aim, peripheral blood mononuclear cells collected from 12-month-old heifers (n = 10) were treated without or with PGE2 (10(-6) M). Flow cytometric analysis showed that PGE2 caused a reduction in the percentage of IL-10 producing CD4+ T cells (P < 0.001), while leaving the secretion of this cytokine by CD8+ T cells and NK cells unaffected. This seems to indicate that PGE2 in cattle does not produce an anti-inflammatory effect by increasing the synthesis of IL-10; contrary to this, it may aggravate an inflammatory response by inhibiting the secretion of this cytokine by CD4+ T cells.


Glycopeptidolipids, a Double-Edged Sword of the Mycobacterium abscessus Complex.
Mycobacterium abscessus is a rapidly-growing species causing a diverse panel of clinical manifestations, ranging from cutaneous infections to severe respiratory disease. Its unique cell wall, contributing largely to drug resistance and to pathogenicity, comprises a vast panoply of complex lipids, among which the glycopeptidolipids (GPLs) have been the focus of intense research. These lipids fulfill various important functions, from sliding motility or biofilm formation to interaction with host cells and intramacrophage trafficking. Being highly immunogenic, the induction of a strong humoral response is likely to select for rough low-GPL producers. These, in contrast to the smooth high-GPL producers, display aggregative properties, which strongly impacts upon intracellular survival. A propensity to grow as extracellular cords allows these low-GPL producing bacilli to escape the innate immune defenses. Transitioning from high-GPL to low-GPL producers implicates mutations within genes involved in biosynthesis or transport of GPL. This leads to induction of an intense pro-inflammatory response and robust and lethal infections in animal models, explaining the presence of rough isolates in patients with decreased pulmonary functions. Herein, we will discuss how, thanks to the generation of defined GPL mutants and the development of appropriate cellular and animal models to study pathogenesis, GPL contribute to M. abscessus biology and physiopathology.


Correlation bias in U.S. census adjustment.
One form of error that can affect census adjustments is correlation bias, reflecting people who are doubly missing--from the census and from the adjusted counts as well. This article presents a method for estimating the total national number of doubly-missing people and their distribution by race and sex. Application to the 1990 U.S. census adjustment leads to an estimate of 3 million doubly-missing people. Correlation bias is likely to be a serious problem for census adjustment in 2000. The methods of this article are well suited for measuring its magnitude.


Directionlets: anisotropic multidirectional representation with separable filtering.
In spite of the success of the standard wavelet transform (WT) in image processing in recent years, the efficiency of its representation is limited by the spatial isotropy of its basis functions built in the horizontal and vertical directions. One-dimensional (1-D) discontinuities in images (edges and contours) that are very important elements in visual perception, intersect too many wavelet basis functions and lead to a nonsparse representation. To efficiently capture these anisotropic geometrical structures characterized by many more than the horizontal and vertical directions, a more complex multidirectional (M-DIR) and anisotropic transform is required. We present a new lattice-based perfect reconstruction and critically sampled anisotropic M-DIR WT. The transform retains the separable filtering and subsampling and the simplicity of computations and filter design from the standard two-dimensional WT, unlike in the case of some other directional transform constructions (e.g., curvelets, contourlets, or edgelets). The corresponding anisotropic basis unctions (directionlets) have directional vanishing moments along any two directions with rational slopes. Furthermore, we show that this novel transform provides an efficient tool for nonlinear approximation of images, achieving the approximation power O(N(-1.55)), which, while slower than the optimal rate O(N(-2)), is much better than O(N(-1)) achieved with wavelets, but at similar complexity.


Peripheral Nerve Fibers and Their Neurotransmitters in Osteoarthritis Pathology.
The importance of the nociceptive nervous system for maintaining tissue homeostasis has been known for some time, and it has also been suggested that organogenesis and tissue repair are under neuronal control. Changes in peripheral joint innervation are supposed to be partly responsible for degenerative alterations in joint tissues which contribute to development of osteoarthritis. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters, allowing response to peripheral neuronal stimuli. Among them are mesenchymal stem cells, synovial fibroblasts, bone cells and chondrocytes of different origin, which express distinct subtypes of adrenoceptors (AR), receptors for vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP). Some of these cell types synthesize and secrete neuropeptides such as SP, and they are positive for tyrosine-hydroxylase (TH), the rate limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters are involved in the pathology of inflammatory diseases such as rheumatoid arthritis (RA) which manifests mainly in the joints. In addition, they seem to play a role in pathogenesis of priori degenerative joint disorders such as osteoarthritis (OA). Altogether it is evident that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for joint tissue and bone homeostasis. They modulate articular cartilage, subchondral bone and synovial tissue properties in physiological and pathophysiological conditions, in addition to their classical neurological features.


A ruthenium(II) complex as turn-on Cu(II) luminescent sensor based on oxidative cyclization mechanism and its application in vivo.
Copper ions play a vital role in a variety of fundamental physiological processes not only in human beings and plants, but also for extensive insects and microorganisms. In this paper, a novel water-soluble ruthenium(II) complex as a turn-on copper(II) ions luminescent sensor based on o-(phenylazo)aniline was designed and synthesized. The azo group would undergo a specific oxidative cyclization reaction with copper(II) ions and turn into high luminescent benzotriazole, triggering significant luminescent increasements which were linear to the concentrations of copper(II) ions. The sensor distinguished by its high sensitivity (over 80-fold luminescent switch-on response), good selectivity (the changes of the emission intensity in the presence of other metal ions or amino acids were negligible) and low detection limit (4.42 nM) in water. Moreover, the copper(II) luminescent sensor exhibited good photostability under light irradiation. Furthermore, the applicability of the proposed sensor in biological samples assay was also studied and imaged copper(II) ions in living pea aphids successfully.


Developmental stress selectively affects the song control nucleus HVC in the zebra finch.
Songbirds sing complex songs as a result of evolution through sexual selection. The evolution of such sexually selected traits requires genetic control, as well as selection on their expression. Song is controlled by a discrete neural pathway in the brain, and song complexity has been shown to correlate with the volume of specific song control nuclei. As such, the development of these nuclei, in particular the high vocal centre (HVC), is thought to be the mechanism controlling signal expression indicating male quality. We tested the hypothesis that early developmental stress selectively affects adult HVC size, compared with other brain nuclei. We did this by raising cross-fostered zebra finches (Taeniopygia guttata) under stressed and controlled conditions and determining the effect on adult HVC size. Our results confirm the strong influence of environmental conditions, particularly on HVC development, and therefore on the expression of complex songs. The results also show that both environmental and genetic factors affect the development of several brain nuclei, highlighting the developmental plasticity of the songbird brain. In all, these results explain how the complex song repertoires of songbirds can evolve as honest indicators of male quality.


The development of fears from early adolesence to young adulthood: a multivariate study.
Common fears change over development. Genetic and environmental risk factors for fears are partly shared across fears and partly fear-specific. The nature of the changes in common and fear-specific genetic and environmental risk factors over time is unknown. Self-reported fears were obtained at ages 13-14, 16-17 and 19-20 from 2404 twins in the Swedish Twin Study of Child and Adolescent Development. A multivariate longitudinal twin analysis was conducted with Mx. Eighteen individual items formed four fear factors: animal, blood-injury, situational, and social. The best-fit model had no quantitative or qualitative sex effects or shared environmental effects, but included a strong common factor with a stable cross-time structure with highest loadings on situational and lowest loadings on social fears. New common and fear-specific genetic risk factors emerged over development. With increasing age, genetic effects declined in overall importance and became more fear-specific. Cross-time continuity in specific genetic effects was highest for animal and lowest for social fears. Social fears had a 'burst' of specific genetic effects in late adolescence. Individual-specific environmental factors impacted both on the general fear factor and on specific fears. Compared to genetic effects, the impact of the unique environment was more time-specific. Genetic and environmental risk factors for individual fears are partly mediated through a common fear factor and are partly fear-specific in their effect. The developmental pattern of these risk factors is complex and dynamic with new common and specific genetic effects arising in late adolescence and early adulthood.


Genome-wide analysis of factors affecting transcription elongation and DNA repair: a new role for PAF and Ccr4-not in transcription-coupled repair.
RNA polymerases frequently deal with a number of obstacles during transcription elongation that need to be removed for transcription resumption. One important type of hindrance consists of DNA lesions, which are removed by transcription-coupled repair (TC-NER), a specific sub-pathway of nucleotide excision repair. To improve our knowledge of transcription elongation and its coupling to TC-NER, we used the yeast library of non-essential knock-out mutations to screen for genes conferring resistance to the transcription-elongation inhibitor mycophenolic acid and the DNA-damaging agent 4-nitroquinoline-N-oxide. Our data provide evidence that subunits of the SAGA and Ccr4-Not complexes, Mediator, Bre1, Bur2, and Fun12 affect transcription elongation to different extents. Given the dependency of TC-NER on RNA Polymerase II transcription and the fact that the few proteins known to be involved in TC-NER are related to transcription, we performed an in-depth TC-NER analysis of a selection of mutants. We found that mutants of the PAF and Ccr4-Not complexes are impaired in TC-NER. This study provides evidence that PAF and Ccr4-Not are required for efficient TC-NER in yeast, unraveling a novel function for these transcription complexes and opening new perspectives for the understanding of TC-NER and its functional interconnection with transcription elongation.


Assessment of serum microRNA-21 and miRNA-205 as diagnostic markers for stage I and II breast cancer in Indian population.
Current markers (carcinoembryonic antigen [CEA] and carbohydrate antigen 15-3 [CA15-3]) lack sensitivity in diagnosis of breast cancer. The aberrantly expressed circulating miRNAs were shown as diagnostic markers in breast cancer. However, there are very few studies from the Indian population. We studied the diagnostic utility of miRNA-21, miRNA-155 and miRNA-205 compared to CEA and CA15-3 in stage I and II breast cancer patients. Sixty newly diagnosed women with stage I/II breast cancer and 20 healthy controls were recruited. Expression of circulating miRNAs was studied using reverse transcription-polymerase chain reaction, whereas CEA and CA 15-3 were analyzed by enzyme-linked immunosorbent assay. miRNA-21 and miRNA-155 were upregulated, miRNA-205 down-regulated (P < 0.05) and serum CEA and CA15-3 levels increased in breast cancer patients (P < 0.001). Receiver operating characteristic curve analysis showed significant area under curve (AUC) for all markers (0.656 to 0.993; P = 0.015 to <0.001) validating their diagnostic potential. Unlike CEA and CA15-3, miRNAs retained their sensitivity even at higher cut-offs (95% CI of mean). Logistic regression analysis showed significant association between disease and marker positivity for miRNA-21 and miRNA-205 but not for miRNA-155. Combining CA15-3 with miRNAs did not improve their diagnostic performance. However, combining CEA with either miRNA-21 (AUC = 0.742; P < 0.001 versus AUC = 0.656; P = 0.018) or miRNA-205 (AUC = 0.733; P < 0.001 versus AUC = 0.700; P < 0.001) increased its diagnostic performance. Our study shows miRNA-21 and miRNA-205, are useful as diagnostic markers for breast cancer in the Indian population and combination of these miRNAs with CEA but not with CA 15-3 improved their diagnostic performance.


Spatio-temporal control of neural activity in vivo using fluorescence microendoscopy.
Controlling neural activity with high spatio-temporal resolution is desired for studying how neural circuit dynamics control animal behavior. Conventional methods for manipulating neural activity, such as electrical microstimulation or pharmacological blockade, have poor spatial and/or temporal resolution. Algal protein channelrhodopsin-2 (ChR2) enables millisecond-precision control of neural activity. However, a photostimulation method for high spatial resolution mapping in vivo is yet to be established. Here, we report a novel optical/electrical probe, consisting of optical fiber bundles and metal electrodes. Optical fiber bundles were used as a brain-insertable endoscope for image transfer and stimulating light delivery. Light-induced activity from ChR2-expressing neurons was detected with electrodes bundled to the endoscope, enabling verification of light-evoked action potentials. Photostimulation through optical fiber bundles of transgenic mice expressing ChR2 in layer 5 cortical neurons resulted in single-whisker movement, indicating spatially restricted activation of neurons in vivo. The probe system described here and a combination of various photoactive molecules will facilitate studies on the causal link between specific neural activity patterns and behavior.


Active participation in fieldwork level I: fieldwork educator and student perceptions.
ABSTRACT Fieldwork experiences bridge the gap between a student's education and entry-level practice. Academic programs, faculty members, and fieldwork educators are challenged to prepare occupational therapy students for entry-level practice. The Accreditation Council for Occupational Therapy Education (ACOTE) standards advocate for both active participation and guided observation in Level I fieldwork experience ( American Occupational Therapy Association (AOTA), 2007) . Students report their most meaningful learning experiences, which include performance of clinical skills and participation in clinical reasoning. However, many students enrolled in the author's entry-level master's program and the other schools within a regional consortium report their Level I fieldwork experience is primarily observation. This article describes the results of a survey administered to fieldwork educators and occupational therapy students eliciting their perceptions of active participation in Level I fieldwork. Results indicate that perceptions of the groups are dissimilar. Recommendations and implications for increased active participation in Level I fieldwork are discussed.


Human immunodeficiency virus type 1 Pr55gag and Pr160gag-pol expressed from a simian virus 40 late replacement vector are efficiently processed and assembled into viruslike particles.
Human immunodeficiency virus type 1 (HIV-1) gag and pol genes were expressed by using fragments of the BH10 clone of HIV inserted into a simian virus 40 late replacement vector. An initial construct containing the entire coding regions of gag, pol, and vif produced only minute amounts of the gag precursor, Pr55gag. However, high-level expression was obtained when an additional sequence from the env gene (the rev-responsive element) was inserted 3' of vif in the correct orientation, and rev was provided in trans from a second vector. Western immunoblot analysis of transfected cells showed the presence of large amounts of both Pr55gag and Pr160gag-pol as well as all of the expected cleavage products. Electron microscopy of thin sections of transfected cells showed a multitude of viruslike particles. Both immature particles in the process of budding and particles containing the condensed core characteristic of HIV were observed. Analysis of the released viruslike particles showed the presence of active reverse transcriptase. Sucrose gradient analysis of particles produced from [3H]uridine-labeled cells indicated a peak of radioactivity which cosedimented with a peak of p24, suggesting that the particles contained RNA.


A Highly Efficacious PS Gene Editing System Corrects Metabolic and Neurological Complications of Mucopolysaccharidosis Type I.
Our previous study delivered zinc finger nucleases to treat mice with mucopolysaccharidosis type I (MPS I), resulting in a phase I/II clinical trial (ClinicalTrials.gov: NCT02702115). However, in the clinical trial, the efficacy needs to be improved due to the low transgene expression level. To this end, we designed a proprietary system (PS) gene editing approach with CRISPR to insert a promoterless α-l-iduronidase (IDUA) cDNA sequence into the albumin locus of hepatocytes. In this study, adeno-associated virus 8 (AAV8) vectors delivering the PS gene editing system were injected into neonatal and adult MPS I mice. IDUA enzyme activity in the brain significantly increased, while storage levels were normalized. Neurobehavioral tests showed that treated mice had better memory and learning ability. Also, histological analysis showed efficacy reflected by the absence of foam cells in the liver and vacuolation in neuronal cells. No vector-associated toxicity or increased tumorigenesis risk was observed. Moreover, no off-target effects were detected through the unbiased genome-wide unbiased identification of double-stranded breaks enabled by sequencing (GUIDE-seq) analysis. In summary, these results showed the safety and efficacy of the PS in treating MPS I and paved the way for clinical studies. Additionally, as a therapeutic platform, the PS has the potential to treat other lysosomal diseases.


Monoclonal antibodies to the p21 products of the transforming gene of Harvey murine sarcoma virus and of the cellular ras gene family.
We have isolated eight rat lymphocyte-myeloma hybrid cell lines producing monoclonal antibodies that react with the 21,000-dalton transforming protein (p21) encoded by the v-ras gene of Harvey murine sarcoma virus (Ha-MuSV). These antibodies specifically immunoprecipitate both phosphorylated and non-phosphorylated forms of p21 from lysates of cells transformed by Ha-MuSV. All eight react with the products of closely related ras genes expressed in cells transformed by two additional sarcoma viruses (rat sarcoma virus and BALB sarcoma virus) or by a cellular Harvey-ras gene placed under the control of a viral promoter. Three of the antibodies also react strongly with the p21 encoded by the v-ras gene of Kirsten MuSV. These same three antibodies immunoprecipitate the predominant p21 species synthesized normally in a variety of rodent cell lines, including the p21 produced at high levels in 416B murine hemopoietic cells. This suggests that an endogenous gene closely related to Kirsten-ras is expressed in these cells. The monoclonal antibodies have been used to confirm two properties associated with p21; localization at the inner surface of the membrane of Ha-MuSV-transformed cells, assayed by immunofluorescence microscopy, and binding of guanine nucleotides.


Pregnancy outcome after gestational exposure to terfenadine: A multicenter, prospective controlled study.
Terfenadine is a selective, nonsedative, H(1)-blocker antihistamine used for a variety of allergic conditions. The widespread popularity of terfenadine and its use by many women in their reproductive age raises concerns regarding its safety during pregnancy. Presently, no prospective controlled study has addressed its safety during gestation. We sought to determine whether terfenadine use during pregnancy is associated with an increased risk of major malformations, decreased birth weight, perinatal complications, or developmental delays. A multicenter, prospective controlled study was performed. Pregnant women exposed to terfenadine during gestation were matched with control subjects exposed to drugs not known to adversely affect pregnancy outcome. The primary end point was the incidence of major malformations. Secondary outcomes of interest were pregnancy outcome, rates of preterm delivery, birth weight, and developmental milestones. One hundred eighteen women were exposed to terfenadine during pregnancy. Among those exposed during the first trimester (n = 65), rates of major malformations in the terfenadine group did not differ from rates in their matched control subjects (0% vs 2%; relative risk, 0.57; 95% confidence interval, 0.06-5.39; P =.53). The birth weight in the terfenadine-exposed newborns was significantly lower compared with that in their matched control subjects (3335 +/- 582 vs 3499 +/- 617 g; P =.04). However, the rates of birth weight below 2500 g and birth weight below the 10th percentile for gestational age were not different between the groups. Univariate and multiple regression analysis revealed that none of the terfenadine therapy-related factors (daily dose, duration of therapy, and trimester of exposure) had a significant predictive effect on birth weight. Gestational age at delivery, rates of preterm deliveries, and developmental milestones were comparable between the groups. On the basis of the limited sample size of this study, it appears that terfenadine is not associated with a 6-fold or greater increased incidence of major malformations. Terfenadine use during gestation was not associated with increased rates of prematurity or developmental delays. Further studies will be needed to confirm the finding of lower birth weight in newborns exposed to terfenadine.


A Double-Edged Sword: Aneuploidy is a Prevalent Strategy in Fungal Adaptation.
Aneuploidy, a deviation from a balanced genome by either gain or loss of chromosomes, is generally associated with impaired fitness and developmental defects in eukaryotic organisms. While the general physiological impact of aneuploidy remains largely elusive, many phenotypes associated with aneuploidy link to a common theme of stress adaptation. Here, we review previously identified mechanisms and observations related to aneuploidy, focusing on the highly diverse eukaryotes, fungi. Fungi, which have conquered virtually all environments, including several hostile ecological niches, exhibit widespread aneuploidy and employ it as an adaptive strategy under severe stress. Gambling with the balance between genome plasticity and stability has its cost and in fact, most aneuploidies have fitness defects. How can this fitness defect be reconciled with the prevalence of aneuploidy in fungi? It is likely that the fitness cost of the extra chromosomes is outweighed by the advantage they confer under life-threatening stresses. In fact, once the selective pressures are withdrawn, aneuploidy is often lost and replaced by less drastic mutations that possibly incur a lower fitness cost. We discuss representative examples across hostile environments, including medically and industrially relevant cases, to highlight potential adaptive mechanisms in aneuploid yeast.


Intracerebral hemorrhage despite prophylactic administration of vitamin K in infants--two case reports.
The incidence of vitamin K deficiency in infancy has decreased markedly, due to prophylactic administration of vitamin K during the neonatal period. However, vitamin K deficiency bleeding may occur during or after the neonatal period despite prophylactic administration in Japan. Two cases are reported of intracranial hemorrhage associated with coagulopathy in full-term infants who had received prophylactic administration of vitamin K. More reliable methods for prophylactic administration should be established.


Transdermal delivery of carvedilol containing glycyrrhizin and chitosan as permeation enhancers: biochemical, biophysical, microscopic and pharmacodynamic evaluation.
The present study was aimed at unveiling the influence of glycyrrhizin and chitosan on rat epidermis and to correlate these effects with percutaneous permeation characteristics of carvedilol. The permeation of carvedilol across excised rat epidermis was significantly higher (p < 0.05) when glycyrrhizin, chitosan, or glycyrrhizin-chitosan mixture was used as a donor vehicle as compared to propylene glycol:ethanol (7:3) mixture. Epidermis obtained after 12 hr treatment of viable rat skin with a glycyrrhizin-chitosan mixture showed significantly higher (p < 0.05) permeability to carvedilol as compared to that after treatment with glycyrrhizin or chitosan alone. Further, the application of patches containing glycyrrhizin-chitosan mixture resulted in sustained release of carvedilol, which was able to control the hypertension in deoxycorticosterone acetate induced hypertensive rats through 28 hr. Estimation of microconstituents in rat epidermis revealed maximum extraction of cholesterol, sphingosine, and triglycerides after treatment with glycyrrhizin-chitosan mixture. This was manifested in altered lipid and protein-specific thermotropic transitions. Further, increase in intercellular space, disordered lipid structure and corneocyte detachment as observed in SEM and TEM suggests great potential of glycyrrhizin for use as a percutaneous permeation enhancer.


Intrinsic versus extrinsic regional vascular control during hemorrhagic hypotension and shock.
An analysis of both intrinsic (eg, autoregulatory) and extrinsic adrenoreceptor regulation of the vascular smooth muscle within skeletal muscle (SM), cutaneous (C), and mesenteric (M) tissues obtained during local tissue hypotension (LH), hemorrhagic hypotension (HH), and shock (S) is presented. A series of pressure/conductance curves show that the intrinsic regulation of vascular tone remains down to LH values of 40 mm Hg in M to 60 mm Hg in SM and does not occur in C; all three vascular beds respond to HH by exhibiting strong extrinsic vasoconstriction, the elevated tone persists throughout HH in C but lasts only a few minutes in M while SM vasoconstriction may last up to 45 min; and during the terminal phase of S, vascular tone was best maintained in C. In vitro studies suggest that the prehemorrhage alpha 1 adrenoreceptor control is greatest in M and least in SM. During compensatory and early decompensatory HH, alpha 1 receptors are depressed in SM. M vessels show this alpha 1 receptor hyposensitivity only during compensatory HH. All vessels show strong responsiveness to NE during all stages of HH and S, yet M vessels demonstrate a progressive increase in the NE concentrations required to elicit and ED50, suggesting some degree of adrenoreceptor desensitization or down regulation. This is in contrast to the adrenoreceptor hypersensitivity noted in SM during both compensatory and decompensatory stages. C vessels show this pattern in all stages except S. These data verify that each vascular bed has its own unique set of vascular control mechanisms that can act independently during HH and S.


Clinical Utility of Imaging Left Ventricular Assist Devices with 320 Row Multidetector Computed Tomography.
Evaluation of left ventricular devices is becoming increasingly important as the implantation of these devices increases. Cardiac computed tomography angiography (CCTA) has many potential advantages compared with plain radiographs and echocardiography to troubleshoot these devices and potentially help guide therapy. Heart failure (HF) remains a deadly, progressive disease with substantive and increasing morbidity, mortality, cost, and prevalence. Use of left ventricular assist devices (LVAD) as treatment for refractory HF has been steadily rising during the last decade. Seventy-four LVAD recipients who met an indication for CCTA were referred for scanning at our center for a total of 94 studies. All recipients had received a Heart Mate II (Thoratec, Pleasanton, CA) LVAD at a previous time. All patients underwent gated CCTA on a 320 row multidetector scanner (Aquilion ONE, Toshiba Medical Systems, Irvine, California, USA). Images were then reconstructed and analysis was performed using multiple oblique views. All 94 studies had technically good images. In survival analysis, 43 of the 74 LVAD patients had normal CCTA findings while 31 had abnormal CCTA results. The 6, 12, and 18 months survival was 93%, 79%, and 77% in those with normal results and 71%, 61%, and 61%, respectively, in the abnormal CCTA findings. Overall survival was statistically significant in when comparing the two groups (p = 0.003). Cardiac computed tomography angiography may be used as an aid for risk stratification and a potential indicator of short- and long-term prognosis in LVAD patients.


Phylogeny and salt-tolerance of freshwater Nostocales strains: Contribution to their systematics and evolution.
Phylogenetic relationships among heterocytous genera (the Nostocales order) have been profoundly modified since the use of polyphasic approaches that include molecular data. There is nonetheless still ample scope for improving phylogenetic delineations of genera with broad ecological distributions, particularly by integrating specimens from specific or up-to-now poorly sampled habitats. In this context, we studied 36 new isolates belonging to Chrysosporum, Dolichospermum, Anabaena, Anabaenopsis, and Cylindrospermopsis from freshwater ecosystems of Burkina-Faso, Senegal, and Mayotte Island. Studying strains from these habitats is of particular interest as we suspected different range of salt variations during underwent periods of drought in small ponds and lakes. Such salt variation may cause different adaptation to salinity. We then undertook a polyphasic approach, combining molecular phylogenies, morphological analyses, and physiological measurements of tolerance to salinity. Molecular phylogenies of 117 Nostocales sequences showed that the 36 studied strains were distributed in seven lineages: Dolichospermum, Chrysosporum, Cylindrospermopsis/Raphidiopsis, Anabaenopsis, Anabaena sphaerica var tenuis/Sphaerospermopsis, and two independent Anabaena sphaerica lineages. Physiological data were congruent with molecular results supporting the separation into seven lineages. In an evolutionary context, salinity tolerance can be used as an integrative marker to reinforce the delineation of some cyanobacterial lineages. The history of this physiological trait contributes to a better understanding of processes leading to the divergence of cyanobacteria. In this study, most of the cyanobacterial strains isolated from freshwater environments were salt-tolerant, thus suggesting this trait constituted an ancestral trait of the heterocytous cyanobacteria and that it was probably lost two times secondarily and independently in the ancestor of Dolichospermum and of Cylindrospermopsis.


The protein made from a common allele of KIR3DL1 (3DL1*004) is poorly expressed at cell surfaces due to substitution at positions 86 in Ig domain 0 and 182 in Ig domain 1.
KIR3DL1 is an inhibitory HLA-B receptor of human NK and T cells that exhibits genetic and phenotypic polymorphism. KIR3DL1*004, a common allotype, cannot be detected on the surface of PBLs using the KIR3DL1-specific Ab DX9. The nature of this phenotype was investigated through comparison of 3DL1*004 with 3DL1*002, an allele giving high DX9 binding to cell surfaces. Analysis of Jurkat T cell transfectants with 3DL1*004 cDNA showed that 3DL1*004 is poorly expressed at the cell surface, but detectable intracellularly. Analysis of recombinant mutants made between 3DL1*004 and 3DL1*002 showed that polymorphism in Ig domains 0 and 1 (D0 and D1) causes the intracellular retention of 3DL1*004. Reciprocal point mutations were introduced into 3DL1*004 and 3DL1*002 at positions 44 and 86 of the D0 domain, where 3DL1*004 has unique residues, and at position 182 of the D1 domain, where 3DL1*004 resembles 3DL1*005, an allotype giving low DX9-binding phenotype. Leucine 86 in 3DL1*004 is the principal cause of its intracellular retention, with a secondary and additive contribution from serine 182. By contrast, glycine 44, which is naturally present in 3DL1*004, slightly increased cell surface expression when introduced into 3DL1*002. In 3DL1*004, the presence of leucine at position 86 corrupts the WSXPS motif implicated in proper folding of the KIR D0 Ig-like domain. This study demonstrates how a difference between KIR3DL1 allotypes in the D0 domain profoundly affects cell surface expression and function.


Bacterial and fungal communities in boreal forest soil are insensitive to changes in snow cover conditions.
The northern regions are experiencing considerable changes in winter climate leading to more frequent warm periods, rain-on-snow events and reduced snow pack diminishing the insulation properties of snow cover and increasing soil frost and freeze-thaw cycles. In this study, we investigated how the lack of snow cover, formation of ice encasement and snow compaction affect the size, structure and activities of soil bacterial and fungal communities. Contrary to our hypotheses, snow manipulation treatments over one winter had limited influence on microbial community structure, bacterial or fungal copy numbers or enzyme activities. However, microbial community structure and activities shifted seasonally among soils sampled before snow melt, in early and late growing season and seemed driven by substrate availability. Bacterial and fungal communities were dominated by stress-resistant taxa such as the orders Acidobacteriales, Chaetothyriales and Helotiales that are likely adapted to adverse winter conditions. This study indicated that microbial communities in acidic northern boreal forest soil may be insensitive to direct effects of changing snow cover. However, in long term, the detrimental effects of increased ice and frost to plant roots may alter plant derived carbon and nutrient pools to the soil likely leading to stronger microbial responses.


Efficacy of Wen-Dan Decoction in the treatment of patients with coronary heart disease: A protocol for systematic review and meta-analysis.
Coronary heart disease (CHD) is a heart disease caused by myocardial ischemia, hypoxia or necrosis due to stenosis or occlusion of lumen caused by coronary atherosclerosis. It belongs to ischemic cardiomyopathy and is more common in clinic. Previous studies have shown that Wen-Dan Decoction (WDD) is safe and effective, but there is a lack of systematic reviews. The purpose of this study is to systematically study the efficacy of WDD in the treatment of patients with CHD. We will search the following databases: PubMed, EMBASE, Web of Science, Central, Chinese databases China Biomedical Literature, Wanfang Chinese digital periodical and conference database (Wanfang Database), China National Knowledge Infrastructure database, and VIP Chinese Science and Technique Journals Database (VIP) from inception to August 2021. All published randomized controlled trials related to this study will be included. The ongoing or unpublished trials will be searched from National Institutes of Health clinical registry Clinical Trials, International Clinical Trials Registry Platform and the Chinese clinical trial registration platform. Two researchers separately screened the literature and extracted data. The primary outcome is total effective rate. The RevMan V5.3 will be used to evaluate literature and data analysis synthesis. This study will provide a reliable evidence-based basis for the clinical application of WDD in the treatment of patients with CHD. The effectiveness of WDD for CHD will be evaluated. 2021110001.


Stearate-enriched plant sterol esters lower serum LDL cholesterol concentration in normo- and hypercholesterolemic adults.
Studies in our laboratory have previously demonstrated in hamsters a superior cholesterol-lowering ability of plant sterol (PS) esters enriched in stearate compared with linoleate. We therefore conducted a randomized, double-blind, 2-group parallel, placebo-controlled study to test the cholesterol-lowering properties of stearate-enriched PS esters in normo- and hypercholesterolemic adults. Thirty-two adults, 16 per group with equal number of males and females in each group, participated in the 4-wk study. Participants consumed 3 g/d (1 g three times per day with meals) of either PS esters or placebo delivered in capsules. Serum LDL cholesterol concentration significantly decreased 0.42 mmol/L (11%) and the LDL:HDL cholesterol ratio decreased 10% with PS ester supplementation, whereas LDL particle size and lipoprotein subclass particle concentrations (as measured by NMR) were not affected. The percent change in LDL cholesterol was positively correlated with baseline lathosterol concentration (r = 0.729; P = 0.0014), indicating an association between the magnitude of LDL change and the rate of whole-body cholesterol synthesis. Serum campesterol (but not sitosterol) concentration significantly increased in the PS ester group. Serum tocopherol, retinol, and beta-carotene concentrations were not affected by PS ester supplementation. Thus, our findings demonstrate the usefulness of a novel stearate-enriched PS ester compound in decreasing LDL cholesterol in both normo- and hypercholesterolemic adults. The extent to which PS ester fatty acid composition affects intestinal micelle formation and cholesterol absorption in humans requires further study.


A critical review of reviews on the treatment of chronic low back pain.
Systematic literature review. To critically appraise the methodology of systematic reviews of conservative therapies for chronic nonspecific low back pain and to study the relation between the methodologic quality and other characteristics of these reviews. Systematic reviews offer a concise summary of the evidence on treatment effectiveness, but flaws in their methodology can lead to invalid conclusions with serious implications for quality of patient care. Searches of MEDLINE, EMBASE, Psychinfo, and the Cochrane Library were conducted. Titles, abstracts, and articles were reviewed by two blinded authors using three inclusion criteria: 1) chronic nonspecific low back pain, 2) systematic review, and 3) conservative treatment intervention. Data were extracted from each review by three authors. The search strategy retrieved 1102 titles and abstracts; 109 met inclusion criteria. A review of the full text of these articles excluded an additional 73 articles. Data abstraction and methodologic assessment were conducted on 36 articles reviewing 19 discrete interventions. The average quality score was 4.1, ranging from 1 (low) to 7 (high). There was a trend for recent reviews to be of higher quality. Fifty-six percent of the reviews had positive conclusions, but they had lower quality scores compared with those that had negative or uncertain conclusions. There were 27 (73%) qualitative and 10 (27%) quantitative summaries of results. Although the overall quality of systematic reviews was satisfactory, the quality of the individual papers included in the reviews varied considerably. The reviews often provided contradictory evidence on the effectiveness of a wide range of commonly used conservative interventions for chronic nonspecific low back pain. These findings illustrate the pitfalls of systematic reviews where there are a number of low-quality trials and underscore the need for high-quality primary trials that will allow for more conclusive reviews.


Teleseismic search for slow precursors to large earthquakes.
Some large earthquakes display low-frequency seismic anomalies that are best explained by episodes of slow, smooth deformation immediately before their high-frequency origin times. Analysis of the low-frequency spectra of 107 shallow-focus earthquakes revealed 20 events that had slow precursors (95 percent confidence level); 19 were slow earthquakes associated with the ocean ridge-transform system, and 1 was a slow earthquake on an intracontinental transform fault in the East African Rift system. These anomalous earthquakes appear to be compound events, each comprising one or more ordinary (fast) ruptures in the shallow seismogenic zone initiated by a precursory slow event in the adjacent or subjacent lithosphere.


Hypnosis and the treatment of ulcerative colitis and Crohn's disease.
Ulcerative colitis and Crohn's Disease can be cured if they are treated as autoimmune diseases with a special understanding of the personality conflicts in the patient. The author hypothesizes that all autoimmune diseases are characterized by a high normal amount of the aggressive instinctual drives and ambivalence about their realization. Each patient's personality causes the ambivalence to be somaticized into specific autoimmune bodies that aggressively are overproduced and then attack specific tissues. Hypnosis helps in gaining insight, reinforcing interpretations, handling stress, visualizing normal intestinal areas, and controlling of the autoimmune antibodies to the normal level. This paper deals specifically with these 2 diseases.


Effect of magnesium on parathyroid cells: evidence for two sensing receptors or two intracellular pathways?
It currently remains controversial as to the intracellular mechanisms coupled to the inhibition of parathyroid hormone (PTH) secretion that are modulated by extracellular divalent cations. To study mechanisms responsible for regulation of PTH release by cations, we investigated the effect of Mg2+ on cytosolic Ca2+ levels ([Ca2+]i) and PTH secretion in single isolated bovine parathyroid cells. Addition of 9.0 mM Mg2+ evoked a spike of [Ca2+]i in approximately 80% of cells in the presence of extracellular Ca2+. Mg2+ decreased steady-state [Ca2+]i, which represented inhibition of influx of extracellular Ca2+ in 13-78% of cells. The percentage of cells that had a decline in steady-state [Ca2+]i after exposure to Mg2+ was dependent on the extracellular Ca2+ concentration. The effect of Mg2+ on intracellular Ca2+ response was dose dependent. Extracellular Mg2+ inhibited PTH secretion in cells that showed decline in steady-state [Ca2+]i, although cells that showed a spike after addition of Mg2+ secreted more PTH than cells that did not show a spike. The spike of [Ca2+]i and decline in steady-state [Ca2+]i that occur in response to extracellular Mg2+ may be caused independently by two distinct mechanisms that differentially regulate secretion of PTH.