GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2.
The principal inhibitory neurotransmitter GABA (gamma-aminobutyric acid) exerts its effects through two ligand-gated channels, GABA(A) and GABA(C) receptors, and a third receptor, GABA(B) , which acts through G proteins to regulate potassium and calcium channels. Cells heterologously expressing the cloned DNA encoding the GABA(B)R1 protein exhibit high-affinity antagonist-binding sites, but they produce little of the functional activity expected from studies of endogenous GABA(B) receptors in the brain. Here we describe a new member of the GABA(B) polypeptide family, GABA(B)R2, that shows sequence homology to GABA(B)R1. Neither GABA(B)R1 nor GABA(B)R2, when expressed individually, activates GIRK-type potassium channels; however, the combination of GABA(B)R1 and GABA(B)R2 confers robust stimulation of channel activity. Both genes are co-expressed in individual neurons, and both proteins co-localize in transfected cells. Moreover, immunoprecipitation experiments indicate that the two polypeptides associate with each other, probably as heterodimers. Several G-protein-coupled receptors (GPCRs) exist as high-molecular-weight species, consistent with the formation of dimers by these receptors, but the relevance of these species for the functioning of GPCRs has not been established. We have now shown that co-expression of two GPCR structures, GABA(B)R1 and GABA(B)R2, belonging to the same subfamily is essential for signal transduction by GABA(B) receptors.


Role of reactive oxygen species in the anticancer activity of botanicals: Comparing sensitivity profiles.
Numerous botanicals have been shown to exhibit in vitro and in vivo anticancer activity, some of which is the result of the induction of reactive oxygen species (ROS) in cancer cells with a high ROS content. The present study compared sensitivities to a series of botanicals among cancer cell lines, using an XTT viability test, in order to create a specific cancer-herb profile. Of the 27 botanicals screened, 10 exhibited a cytotoxic effect, 7 of which were ROS-mediated. The sensitivity profiles of the ROS-inducing botanicals in 10 cancer cell lines were similar, unlike 3 cytotoxic ROS-independent botanicals that displayed divergent botanical-specific profiles. The correlation between sensitivity profiles of ROS-inducing botanicals suggests a common mechanism of action, in contrast to the varied mechanism of ROS-independent botanicals. This implies that the investigation of the anticancer activity of botanicals should start with the examination of ROS-mediated activity. Further investigation of ROS sensitivity among various tumor types is required in order to guide research into developing evidence-based guidelines in the use of botanicals for cancer treatment.


LGI1 mutations in autosomal dominant partial epilepsy with auditory features.
S: Mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features (ADPEAF), a form of familial temporal lobe epilepsy with auditory ictal manifestations. The authors aimed to determine what proportion of ADPEAF families carries a mutation, to estimate the penetrance of identified mutations, and to identify clinical features that distinguish families with and without mutations. The authors sequenced LGI1 in 10 newly described ADPEAF families and analyzed clinical features in these families and others with mutations reported previously. Three of the families had missense mutations in LGI1 (C42R, I298T, and A110D). Penetrance was 54% in eight families with LGI1 mutations the authors have identified so far (five reported previously and three reported here). Excluding the original linkage family, the authors have found mutations in 50% (7/14) of tested families. Families with and without mutations had similar clinical features, but those with mutations contained significantly more subjects with auditory symptoms and significantly fewer with autonomic symptoms. In families with mutations, the most common auditory symptom type was simple, unformed sounds (e.g., buzzing and ringing). In two of the newly identified families with mutations, some subjects with mutations had idiopathic generalized epilepsies. LGI1 mutations are a common cause of autosomal dominant partial epilepsy with auditory features. Current data do not reveal a clinical feature that clearly predicts which families with autosomal dominant partial epilepsy with auditory features have a mutation. Some families with LGI1 mutations contain individuals with idiopathic generalized epilepsies. This could result from either an effect of LGI1 on risk for generalized epilepsy or an effect of co-occurring idiopathic generalized epilepsy-specific genes in these families.


Reperitonealization and invagination of the lesser curvature of the stomach following proximal gastric vagotomy.
Lesser curve necrosis usually presents as free perforation. A case of large gastric ulcer occurring very shortly after proximal gastric vagotomy (PGV) for a duodenal ulcer that was almost certainly due to ischemic necrosis of the lesser curve is presented here. Reperitonealization and invagination of the lesser curve is recommended following PGV so that, if necrosis occurs, it will take place within the stomach and not into the free peritoneal cavity. This maneuver may also avoid possible vagal reinnervation and the formation of dense adhesions between the stomach and liver.


Novel insights into the function of Arabidopsis R2R3-MYB transcription factors regulating aliphatic glucosinolate biosynthesis.
Arabidopsis transcription factors, MYB28, MYB29 and MYB76, positively regulate aliphatic glucosinolate (AGSL) biosynthesis. Mutual transcriptional regulation among these MYB genes makes it difficult to elucidate their individual function simply by analyzing knock-out mutants or ectopically overexpressing lines of these genes. In this study, we constructed transgenic lines expressing each MYB gene driven by its own promoter in the myb28myb29 background, where the expression of the endogenous MYB28, MYB29 and MYB76 was repressed with no AGSL accumulation. In leaves, transgenic MYB28 expression activated AGSL biosynthetic genes and restored accumulation of AGSLs with short side chains. Transgenic MYB29 expression activated the same biosynthetic pathway, but induction of the genes involved in side chain elongation was weaker than that by MYB28, resulting in a weaker recovery of AGSLs. Neither MYB28 nor MYB29 recovered long-chain AGSL accumulation. MYB76 was considered to require both MYB28 and MYB29 for its normal level of expression in leaves, and could not activate AGSL biosynthesis on its own. Interestingly, the accumulation in seeds of long- and short-chain AGSLs was restored by transgenic expression of MYB28 and MYB76, respectively. A sulfur stress experiment indicated that MYB28 expression was induced by sulfur deficiency, while the expression levels of MYB29 and MYB76 were positively correlated with sulfur concentration. This study illustrated how the individual MYBs work in regulating AGSL biosynthesis when expressed alone under normal transcriptional regulation.


Dietary patterns and risk of ovarian cancer in the California Teachers Study cohort.
Previous studies have examined the association between individual foods or nutrients, but not overall diet, and ovarian cancer risk. To account for the clustering of foods in the diet, we investigated the association between dietary patterns and risk of ovarian cancer in the prospective California Teachers Study cohort. Of 97,292 eligible women who completed the baseline dietary assessment in 1995-1996, 311 women developed epithelial ovarian cancer on or before December 31, 2004. Based on principal components analysis, 5 major dietary patterns were identified and termed plant-based, high-protein/high-fat, high-carbohydrate, ethnic, and salad-and-wine. Multivariable Cox proportional hazards regression analysis was used to estimate associations between these dietary patterns and risk of incident ovarian cancer. Most of the dietary patterns were not significantly associated with ovarian cancer risk. However, women who followed a plant-based diet had higher risk; comparing those in the top quintile of plant-based food intake with those in the lowest quintile, the relative risk of ovarian cancer was 1.65 (95% confidence interval = 1.07-2.54; P(trend) = 0.03). Associations with the 5 dietary patterns did not vary by known ovarian cancer risk factors or other behavioral or sociodemographic characteristics. Overall, our results show no convincing associations between dietary patterns and ovarian cancer risk.


[H+-K+-exchange and formation of H2 in E. coli mutants with defects in the H+-ATPase complex and potassium transport].
It was shown that 2H(+)-K(+)-exchange through H(+)-K(+)-pump composed of H(+)-ATPase complex F0F1 and Trk-system of potassium accumulation, H(+)-K(+)-exchange through H(+)-K(+)-antiport, composed of H(+)-channel F0 and of system with Trk-defect, and H2-production in E. coli grown in anaerobic conditions, change in mutants with defects of F0F1 and potassium transport. In unc-mutant of E. coli AN 936 with defects of c-subunit F0 (M(r) 8,4 kDa) H(+)-K(+)-exchange and H2-production disappeared. Mutants of E. coli TK 509 (2240) with defect of Trk-system not able to perform 2H(+)-K(+)-exchange, performed, however H(+)-K(+)-exchange and H2-production which can be blocked of N, N'-dicyclohexylcarbodiimide (DCCD). In mutant of E. coli Tk 509 (2242) with defects of KdpA-protein of Kdp-system of potassium accumulation, Trk A and Trk D proteins of corresponding systems of potassium accumulation, the H(+)-K(+)-exchange disappeared, while H(+)-formation and H2-production, blocked by DCCD, external osmotic pressure and absence of potassium in the medium, persisted. It is assumed that 2H(+)-K(+)-exchange, H(+)-K(+)-exchange and H2-production are connected, and the membrane-bound format-hydrogenlyase oxidizing format to H2 and CO2, directly take part in interaction with F0F1 and Trk, as well as F0 and defective Trk-system in formation of supercomplexs. It is assumed that the format-hydrogen-lyase can interact with F0F1 without the Trk-system.


Insulin infusion test of gastric acid secretion.
In view of the disadvantages of the standard insulin test for completeness of vagotomy a continuous insulin infusion test has been developed. Twenty-six tests were carried out on 12 healthy male volunteers. A dose of 0.04 unit of soluble insulin/kg/hr was found to produce the highest acid secretion with the least severity of symptoms of hypoglycaemia. The pattern of response was a plateau of acid secretion and of hypoglycaemia, and repeated studies in six subjects showed that the results were reproducible. Evaluation of this test after vagotomy and comparison with the standard insulin test are now required.


Core-doped Ceramic Nd:YAG Laser.
We report on a diode end-pumped composite core-doped ceramic Nd:YAG laser. The ceramic Nd:YAG rod consists of a centrally doped region of 1.5 mm in diameter in a 3 mm rod. An output power of 144 W was achieved with an absorbed pump power of 226 W corresponding to an opt.-opt. efficiency of 64% by longitudinal pumping with fiber-coupled laser diodes.


Serum Biomarkers Associated with Clinical Outcomes Fail to Predict Brain Metastases in Patients with Stage IV Non-Small Cell Lung Cancers.
Lung cancers account for the majority of brain metastases which pose major therapeutic challenges. Biomarkers prognosticating for the development of brain metastases in patients with non-small cell lung cancers (NSCLC) may improve personalized care. Six serum proteomic biomarkers were previously investigated at Memorial Sloan Kettering but their associations with brain metastases were unknown. Serum NSE, CYFRA 21-1, ProGRP, SCC-Ag, TIMP1, and HE4 by ELISA-based proteomic assays were prospectively collected from consecutive patients with stage IV NSCLC. Pre-treatment serum biomarker levels as well as age, histology, and epidermal growth factor receptor (EGFR) mutation status were evaluated for association with the baseline presence of brain metastases using logistic regression and multivariable analysis. For patients without brain metastases at baseline, the cumulative incidence of subsequent brain metastases were compared according to baseline biomarkers and clinical factors using Gray's test. A total of 118 patients were enrolled, 31 (26%; 95% CI 0.19-0.35) had brain metastases at baseline and a further 26 (22%; 95% CI 0.15-0.30) developed brain metastases subsequently. Pre-treatment serum biomarker levels were available in 104 patients. There was no significant association between the six serum biomarkers and the baseline presence or subsequent development of brain metastases. Age younger than 65 years was the only clinical factor significantly associated with brain metastasis at baseline (OR 3.00; 95% CI 1.22-7.34, P = 0.02) by multivariable analysis. A trend toward increased cumulative incidence of subsequent brain metastases was observed in patients with EGFR mutation (p = 0.2), but this was not statistically significant possibly due to small sample size. Serum NSE, CYFRA 21-1, Pro-GRP, SCC-Ag, TIMP1, and HE4 are not significantly associated with brain metastases. Our methods taking into account follow-up time may be applied to independent datasets to identify a patient cohort with a higher biologic propensity for developing brain metastases. Such information may be useful for the study of agents targeting the development of brain metastases.


Predictors of Morbidity and Cleavage Plane in Surgical Resection of Pure Convexity Meningiomas Using Cerebrospinal Fluid Sensitive Image Subtraction Magnetic Resonance Imaging.
Meningiomas are the most common primary intracranial tumors. Since the adhesions in the plane of dissection are of interest in surgical planning, we suggest that digital image subtraction of FLAIR data from the T2 sequence of MRI may represent better the CSF spaces in the brain-tumor interface and may be a predictor of the intraoperative cleavage plane. From 2006 to 2016, 83 convexity meningiomas were resected in the Department of Neurosurgery of the University Hospital Complex of Vigo, an analysis of preoperative MRI was performed to assess peritumoral edema (PTE), tumor volume, among others; a digital subtraction of T2-FLAIR sequences was performed and analyzed in relationship to the cleavage plane described in the intraoperative report and postoperative neurological deficits. Simpson grade 1 resection was achieved in 85.54%, the overall 5-year PFS was 93.75%. Our rate of permanent new neurological deficit was 4.82% and the overall complication rate of 14.46%. The grade of PTE was proportional to tumor volume, 20 ± 2.8, 30 ± 5.3, and 34 ± 4.3 cm3 for grades 1, 2, and 3, respectively, positive cleft sign on image subtraction was predictive of good intraoperative cleavage plane and low grade cleavage plane (P = 0.04), and was a protective factor for postoperative neurological deficit (P = 0.02). Positive cleft sign in T2-FLAIR digital subtraction image is an independent predictor of good intraoperative cleavage plane, PTE is an independent predictor of the bad cleavage plane. Negative cleft sign in the image subtraction and a bad intraoperative cleavage plane are predictors of postoperative neurological deficit.


SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland.
The pituitary gland adapts the proportion of each of its endocrine cell types to meet differing hormonal demands throughout life. There is circumstantial evidence that multipotent adult progenitor cells contribute to this plasticity, but these cells have not been identified. Here, we describe a small (<0.05%) population of progenitor cells in the adult pituitary gland. We show that these cells express SOX2, a marker of several early embryonic progenitor and stem cell types, and form "pituispheres" in culture, which can grow, form secondary spheres, and differentiate to all of the pituitary endocrine cell types, as well as folliculostellate cells. Differentiation of cells in the pituispheres was associated with the expression of nestin, SOX9, and S100. Cells expressing SOX2 and E-cadherin are found throughout Rathke's pouch (RP) in embryos but persist in the adult gland, mostly in a narrow zone lining the pituitary cleft, but also are scattered throughout the pituitary. However, unlike in embryonic RP, most of these SOX2(+) cells in the adult gland also express SOX9 and S100. We suggest that this SOX2(+)/SOX9(+) population represents transit-amplifying cells, whereas the SOX2(+)/SOX9(-) cells we identify are multipotent progenitor/stem cells persisting in the adult pituitary.


Exophiala werneckii endophthalmitis following cartaract surgery in an immunocompetent individual.
A case of infectious endophthalmitis caused by the saprophyte Exophiala werneckii is reported. This has not been recognized as a pathogen for ocular infections previously. The infection followed uncomplicated cataract surgery involving phacoemulsification and IOL implant. Clinical presentation was that of an indolent endophthalmitis with relatively acute onset. Pars plana vitrectomy, fungal stains, and culture established the diagnosis. Initial management consisted of empirical intravitreal injection of vancomycin, ceftazidime, and amphotericin B. Treatment was supplemented with a 3-week course of systemic fluconazole and topical therapy with natamycin, atropine, ciprofloxacin, and diclofenac. The visual acuity returned to 20/20-2 with no recurrence of infection. The source of the infection could not be determined. Fungal endophthalmitis has to be considered as a rare, though important, complication following ophthalmic surgery. Specific fungal stains and cultures are helpful for establishing the diagnosis early in the course of disease. E werneckii should be considered in the differential diagnosis of fungal endophthalmitis.


3.0-T functional brain imaging: a 5-year experience.
The aim of this paper is to illustrate the technical, methodological and diagnostic features of functional imaging (comprising spectroscopy, diffusion, perfusion and cortical activation techniques) and its principal neuroradiological applications on the basis of the experience gained by the authors in the 5 years since the installation of a high-field magnetic resonance (MR) magnet. These MR techniques are particularly effective at 3.0 Tesla (T) owing to their high signal, resolution and sensitivity, reduced scanning times and overall improved diagnostic ability. In particular, the high-field strength enhances spectroscopic analysis due to a greater signal-to-noise ratio (SNR) and improved spectral, space and time resolution, resulting in the ability to obtain high-resolution spectroscopic studies not only of the more common metabolites, but also--and especially--of those which, due to their smaller concentrations, are difficult to detect using 1.5-T systems. All of these advantages can be obtained with reduced acquisition times. In diffusion studies, the high-field strength results in greater SNR, because 3.0-T magnets enable increased spatial resolution, which enhances accuracy. They also allow exploration in greater detail of more complex phenomena (such as diffusion tensor and tractography), which are not clearly depicted on 1.5-T systems. The most common perfusion study (with intravenous injection of a contrast agent) benefits from the greater SNR and higher magnetic susceptibility by achieving dramatically improved signal changes, and thus greater reliability, using smaller doses of contrast agent. Functional MR imaging (fMRI) is without doubt the modality in which high-field strength has had the greatest impact. Images acquired with the blood-oxygen-level-dependent (BOLD) technique benefit from the greater SNR afforded by 3.0-T magnets and from their stronger magnetic susceptibility effects, providing higher signal and spatial resolution. This enhances reliability of the localisation of brain functions, making it possible to map additional areas, even in the millimetre and submillimetre scale. The data presented and results obtained to date show that 3.0-T morphofunctional imaging can become the standard for high-resolution investigation of brain disease.


Methane Oxidation Coupled to Selenate Reduction in a Membrane Bioreactor under Oxygen-Limiting Conditions.
Microbial methane oxidation coupled to a selenate reduction process has been proposed as a promising solution to treat contaminated water, yet the underlying microbial mechanisms are still unclear. In this study, a novel methane-based membrane bioreactor system integrating hollow fiber membranes for efficient gas delivery and ultrafiltration membranes for biomass retention was established to successfully enrich abundant suspended cultures able to perform methane-dependent selenate reduction under oxygen-limiting conditions. The microbial metabolic mechanisms were then systematically investigated through a combination of short-term batch tests, DNA-based stable isotope probing (SIP) microcosm incubation, and high-throughput sequencing analyses of 16S rRNA gene and functional genes (pmoA and narG). We confirmed that the methane-supported selenate reduction process was accomplished by a microbial consortia consisting of type-II aerobic methanotrophs and several heterotrophic selenate reducers. The mass balance and validation tests on possible intermediates suggested that methane was partially oxidized into acetate under oxygen-limiting conditions, which was consumed as a carbon source for selenate-reducing bacteria. High-throughput 16S rRNA gene sequencing, DNA-SIP incubation with 13CH4, and subsequent functional gene (pmoA and narG) sequencing results collectively proved that Methylocystis actively executed partial methane oxidation and Acidovorax and Denitratisoma were dominant selenate-reducing bacteria, thus forming a syntrophic partnership to drive selenate reduction. The findings not only advance our understanding of methane oxidation coupled to selenate reduction under oxygen-limiting conditions but also offer useful information on developing methane-based biotechnology for bioremediation of selenate-contaminated water.


Analysis of Predictors of Breast Cancer Screening among Japanese Women using Nationally Representative Survey Data, 2001-2013.
Predictors of participation in breast cancer screening in recent years or the trend of participation rate by predictors over the years has not been investigated in Japan. In this study, we investigated predictors for participation in breast cancer screening and analyzed the trend of participation rate depending on the predictors using nationally representative survey data in Japan. The data of "Comprehensive Survey of Living Conditions" in Japan from 2001 to 2013 were used. Participation in breast cancer screening was used as an outcome. Next, as explanatory variables, we used age group, marital status, living arrangements, educational level, household income, employment status, smoking status, regular outpatient visit status, and self-rated health status. Then, the participation rate for breast cancer screening was calculated for each of the factors over the years. In addition, multivariate logistic regression analysis was conducted to analyze the association between each factor and the participation rate using data from 2010 and 2013. We found that non-married women, women with lower educational level, women with low household income, self-employed or unemployed women, smokers, and women with low self-rated health status were significantly less likely to participate in breast cancer screening. Conversely, the participation rate increased for all predictor groups from 2001 to 2013, and the increase in the participation rate for never-married women was particularly evident compared with the other marital statuses. However, significant differences in the participation rate for breast cancer screening existed depending on marital status, household income, employment status, and smoking status throughout the analyzed years. Our findings suggest that further recommendations for breast cancer screening are particularly needed among women of low socioeconomic status and those who are self-employed or unemployed to increase the participation rate in Japan.


Trehalose suppresses antibody aggregation during the culture of Chinese hamster ovary cells.
The aggregation of therapeutic antibodies during the manufacturing process is problematic because of the potential risks posed by the aggregates, such as an unexpected immune response. One of the hallmark effects of trehalose, a disaccharide consisting of two alpha-glucose units, is as a chemical chaperone with anti-aggregation activity. In this study, Chinese hamster ovary (CHO) cell line producing a diabody-type bispecific antibody were cultured in medium containing trehalose and the aggregation of the secreted proteins during the culture process was analyzed. An analysis of the various forms of the antibody (monomeric, dimeric, and large aggregates) showed that trehalose decreased the relative content of large aggregates by two thirds. The aggregation kinetics indicated that trehalose directly inhibited the polymerization and aggregation steps in a nucleation-dependent aggregation mechanism. Moreover, both specific and volumetric antibody production were increased in CHO cells cultured in trehalose-containing medium. Thus, the addition of trehalose to recombinant CHO cell cultures would offer a practical strategy for quality improvement in the production of therapeutic antibodies.


The effect of ionic strength and phosphate ions on the construction of redox polyelectrolyte-enzyme self-assemblies.
Layer by layer assembly of polyelectrolytes with proteins is a convenient tool for the development of functional biomaterials. Most of the studies presented in the literature are based on the electrostatic interaction between components of opposite charges, limiting the assembly possibilities. However, this process can be tuned by modifying the environment where the main constituents are dissolved. In this work, the electron transfer behavior between an electroactive polyelectrolyte (polyallylamine derivatized with an osmium complex) and a redox enzyme (glucose oxidase) is studied by assembling them in the presence of phosphate ions at different ionic strengths. Our results show that the environment from which the assembly is constructed has a significant effect on the electrochemical response. Notably, the polyelectrolyte dissolved in the presence of phosphate at high ionic strength presents a globular structure which is preserved after adsorption with substantial effects on the buildup of the multilayer system, improving the electron transfer process through the film.


Tax thresholds yield multiple optimal cooperation levels in the spatial public goods game.
Income redistribution, which involves transferring income from certain individuals to others, plays a crucial role in human societies. Previous research has indicated that tax-based redistribution can promote cooperation by enhancing incentives for cooperators. In such a tax system, all individuals, irrespective of their income levels, contribute to the tax system, and the tax revenue is subsequently redistributed to everyone. In this study, we relax this assumption by introducing a tax threshold, signifying that only individuals with incomes exceeding the threshold will be subject to taxation. In particular, we employ the spatial public goods game to investigate the influence of tax rates-the percentage of income allocated to tax-and tax thresholds, which determine the income level at which individuals become taxable, on the evolution of cooperation. Our extensive numerical simulations disclose that tax thresholds produce complex outcomes for the evolution of cooperation, depending on tax rates. Notably, at low tax rates (i.e., below 0.41), as the tax threshold increases, discontinuous phase transitions in cooperation performance suggest the presence of multiple intervals of effective tax thresholds that promote peak cooperation levels. Nevertheless, irrespective of the chosen tax rate, once the tax threshold surpasses a critical threshold, the redistribution mechanism fails, causing the collapse of cooperation. Evolutionary snapshots show that self-organized redistribution forms an intermediary layer on the peripheries of cooperative clusters, effectively shielding cooperators from potential defectors. Quantitative analyses shed light on how self-organized redistribution narrows the income gap between cooperators and defectors through precise identification of tax-exempt entities, thereby amplifying the cooperative advantage. Collectively, these findings enhance our comprehension of how income redistribution influences cooperation, highlighting the pivotal role of tax thresholds.


A systematic review and meta-analysis of left atrial strain in hypertrophic cardiomyopathy and its prognostic utility.
Despite advances in noninvasive imaging modalities to identify atrial fibrillation (AF) risk in Hypertrophic Cardiomyopathy (HCM), there is a paucity of evidence concerning the impact of low Left Atrial strain (LAS) on AF and major adverse cardiac events (MACE) incidence in these patients. This study investigated the diagnostic and prognostic significance of LAS in predicting AF and MACE in HCM. Findings revealed lower LA reservoir (MD: -11.79, 95% CI -14.83, -8.74; p<0.00001), booster (MD: -4.10, 95% CI -6.29, -1.91; p=0.0002), and conduit (MD: -7.52, 95% CI -9.39, -5.65; p<0.00001) strains in HCM patients versus healthy controls, and also indicated a significant association between low LA reservoir/conduit/booster strain and the development of new AF as well as MACE prevalence in HCM patients. The results from this study suggest the valuable role of LA strain in HCM and its utility in predicting the development of new AF and cardiac events in HCM patients.


Effect of Dietary Fiber Enrichment and Different Cooking Methods on Quality of Chicken Nuggets.
The effect of dietary fiber enrichment (wheat bran) and cooking methods (oven, steam and microwave) on functional and physico-chemical properties of raw nuggets formulation as well as nutritional, color and textural properties of chicken nuggets were analyzed in this study. Among different cooking methods used for nuggets preparation, steam cooked nuggets had significantly (p<0.05) higher water holding capacity (56.65%), cooking yield (97.16%) and total dietary fiber content (4.32%) in comparison to oven and microwave cooked nuggets. The effect of cooking methods and wheat bran incorporation was also noticed on textural properties of the nuggets. Hardness, firmness and toughness values of oven and steam cooked nuggets were significantly (p<0.05) higher than microwave cooked nuggets. Among nuggets prepared by different cooking methods, cohesiveness of microwave cooked nuggets was found to be significantly (p<0.05) highest, whereas, oven cooked nuggets had significantly (p<0.05) highest gumminess and chewiness values. Steam cooked nuggets were found to be better among all nuggets due to their higher cooking yield and dietary fiber content.


Evidence-Based Assessments for Transdiagnostic Eating Disorder Symptoms: Guidelines for Current Use and Future Directions.
Eating disorders are severe and often chronic mental illnesses that are associated with high impairment and mortality rates. Recent estimates suggest that eating disorder prevalence rates are on the rise, indicating an increased need for accurate assessment and detection. The current review provides an overview of transdiagnostic eating disorder assessments, including interview, self-report, health and primary care screeners, and technology-based and objective assessments. We focused on assessments that are transdiagnostic in nature and exhibit high impact in the field. We provide recommendations for how these assessments should be used in research and clinical settings. We also discuss considerations that are crucial for assessment, including the use of a categorical versus dimensional diagnostic framework, assessment of eating disorders in related fields (i.e., anxiety and depression), and measurement-based care for eating disorders. Finally, we provide suggestions for future research, including the need for more research on short transdiagnostic screeners for use in health care settings, standardized assessments for ecological momentary assessment, development of state-based assessment of eating disorder symptoms, and consideration of assessment across multiple timescales.


The influence of surface area, porous structure, and surface state on the supercapacitor performance of titanium oxynitride: implications for a nanostructuring strategy.
A recent surge of interest in metal (oxy)nitride materials for energy storage devices has given rise to the rapid development of various nanostructuring strategies for these materials. In supercapacitor applications, early transition metal (oxy)nitrides have been extensively explored, among which titanium oxynitride stands out due to its great potential for charge storage. Despite recent advances in supercapacitors based on titanium oxynitride, many underlying factors governing their capacitive performance remain elusive. In this work, nanostructured titanium oxynitride is prepared by firing an organic-inorganic hybrid precursor under a hot ammonia atmosphere, and the influence of its physical characteristics on the supercapacitor performance is investigated. New insights into the effects of surface area, porous structure, and surface state of titanium oxynitride on the supercapacitor performance are revealed through which a comprehensive understanding about the capacitive behavior of titanium oxynitride is provided. In addition, the implications of these insights for a nanostructuring strategy striving for higher capacitance and improved stability are discussed.


Financing gaps for Pakistan's contraceptive prevalence goals: Analyses using the Guttmacher adding-it-up methodology.
The objective of the paper is to identify levels of and gaps in family planning financing in Pakistan and to assess whether current funding is sufficient to meet national and FP2030 goals to increase contraceptive use to 60% by 2030. We estimate the cost of family planning services nationally and by province based on the Essential Services Package and WHO/UNFPA cost by applying the existing Guttmacher global Adding-It-Up methodology. Additional data are also analyzed to assess trends in expenditures on family planning between 2017 and 2021. The estimated cost of family planning services provided in Pakistan in 2017 was US$81 million, equivalent to US$0.38 per capita. The estimated gap in costs to provide contraceptive services to the additional 8.6 million women with unmet need for modern contraception was US$93 million. While we found evidence of an upward trend in overall government expenditure on family planning services over the period 2017-21, the pace of increase was slow and uneven across regions. The evidence highlights the persistent inadequacy of financing for contraceptive services especially if Pakistan intends to achieve its ambitious national and FP2030 goal of increasing contraceptive prevalence to 60% by 2030. A doubling of current funding for contraceptive services is required in Pakistan. Additional financing needs to be directed towards the poorest women with unmet need to avoid unintended pregnancies and to improve equity in reproductive health outcomes.


Brain-gut interactions increase peripheral nociceptive signaling in mice with postinfectious irritable bowel syndrome.
To investigate the peripheral sensory effects of repeated stress in patients with postinfectious irritable bowel syndrome (IBS), we tested whether stress following self-limiting bacterial colitis increases colonic dorsal root ganglia (DRG) nociceptive signaling. C57BL/6 mice were infected with Citrobacter rodentium. Stress was induced using a 9-day water avoidance paradigm (days 21-30 after infection). Colonic DRG neuronal excitability was measured using perforated patch clamp techniques, in vitro multi-unit afferent recordings, and measurements of visceromotor reflexes. Combined stress and prior infection increased corticosterone and epinephrine levels, compared with infected animals, but did not alter the resolution of colonic inflammation. These changes were associated with increased neuronal excitability and parallel changes in multi-unit afferent recordings and visceromotor reflex thresholds. Protease activity was increased at day 30 following infection with C rodentium. Protease inhibitors markedly reduced the effects of colonic supernatants on neuronal excitability from C rodentium but not stressed animals. Colonic DRG neurons expressed messenger RNAs for the β(2) adrenergic and glucocorticoid receptors; incubation with stress mediators recapitulated the effects on neuronal excitability observed with chronic stress alone. PAR2 activation with concentrations of the activating peptide SLIGRL that had no effect on neuronal excitability in controls caused marked increases in excitability when applied to neurons from chronically stressed animals. Stress, combined with prior acute colitis, results in exaggerated peripheral nociceptive signaling. Proteases and stress mediators can signal directly to colonic DRG neurons; further analysis of these pathways could provide new targets for treatment of patients with postinfectious IBS.


The DISC1 promoter: characterization and regulation by FOXP2.
Disrupted in schizophrenia 1 (DISC1) is a leading candidate susceptibility gene for schizophrenia, bipolar disorder and recurrent major depression, which has been implicated in other psychiatric illnesses of neurodevelopmental origin, including autism. DISC1 was initially identified at the breakpoint of a balanced chromosomal translocation, t(1;11) (q42.1;14.3), in a family with a high incidence of psychiatric illness. Carriers of the translocation show a 50% reduction in DISC1 protein levels, suggesting altered DISC1 expression as a pathogenic mechanism in psychiatric illness. Altered DISC1 expression in the post-mortem brains of individuals with psychiatric illness and the frequent implication of non-coding regions of the gene by association analysis further support this assertion. Here, we provide the first characterization of the DISC1 promoter region. Using dual luciferase assays, we demonstrate that a region -300 to -177 bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, while a region -982 to -301 bp relative to the TSS confers a repressive effect. We further demonstrate inhibition of DISC1 promoter activity and protein expression by forkhead-box P2 (FOXP2), a transcription factor implicated in speech and language function. This inhibition is diminished by two distinct FOXP2 point mutations, R553H and R328X, which were previously found in families affected by developmental verbal dyspraxia. Our work identifies an intriguing mechanistic link between neurodevelopmental disorders that have traditionally been viewed as diagnostically distinct but which do share varying degrees of phenotypic overlap.


Structural requirements for inverse agonism and neutral antagonism of indole-, benzimidazole-, and thienopyrrole-derived histamine H4 receptor ligands.
The human histamine H(4) receptor (hH(4)R), coexpressed with Galpha(i2) and Gbeta(1)gamma(2) in Sf9 insect cells, is highly constitutively active, and thioperamide [THIO; N-cyclohexyl-4-(imidazol-4-yl)-1-piperidinecarbothioamide] is one of the most efficacious hH(4)R inverse agonists. High constitutive hH(4)R activity may have pathophysiological implications in which case inverse agonists may behave differently than neutral antagonists. To learn more about the structural requirements for hH(4)R inverse agonism, we investigated 25 compounds (indole, benzimidazole, and thienopyrrole derivatives) structurally related to the standard antagonist JNJ-7777120 [1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine]. We characterized the compounds in radioligand binding assays by using [(3)H]histamine ([(3)H]HA) and in steady-state GTPase assays in the presence (antagonist mode) and absence (inverse agonist mode) of the agonist HA, yielding the following results: 1) Twenty-two compounds were inverse agonists (efficacy: 15-62% of the THIO effect), and only three compounds (12%) showed neutral antagonism. Thus, inverse agonism is far more common than neutral antagonism. 2) The inverse agonistic efficacy of the R5-monosubstituted indole-derived compounds increased with the volume of R5. R5 may interact with Trp(6.48) of the rotamer toggle switch and stabilize the inactive receptor conformation. 3) A subset of compounds showed large differences between the K(i) value from [(3)H]HA competition binding and the EC(50) value from steady-state GTPase assays, whereas the K(b) values were closer to the K(i) values. Thus, the two-state model should be extended to a model comprising a constitutively active hH(4)R state, which can be discriminated by inverse agonists from a structurally distinct HA-stabilized active state.


Asymmetric evolutionary responses to sex-specific selection in a hermaphrodite.
Sex allocation theory predicts that simultaneous hermaphrodites evolve to an evolutionary stable resource allocation, whereby any increase in investment to male reproduction leads to a disproportionate cost on female reproduction and vice versa. However, empirical evidence for sexual trade-offs in hermaphroditic animals is still limited. Here, we tested how male and female reproductive traits evolved under conditions of reduced selection on either male or female reproduction for 40 generations in a hermaphroditic snail. This selection favors a reinvestment of resources from the sex function under relaxed selection toward the other function. We found no such evolutionary response. Instead, juvenile survival and male reproductive success significantly decreased in lines where selection on the male function (i.e., sexual selection) was relaxed, while relaxing selection on the female function had no effect. Our results suggest that most polymorphisms under selection in these lines were not sex-antagonistic. Rather, they were deleterious mutations affecting juvenile survival (thus reducing both male and female fitness) with strong pleiotropic effects on male success in a sexual selection context. These mutations accumulated when sexual selection was relaxed, which supports the idea that sexual selection in hermaphrodites contributes to purge the mutation load from the genome as in separate-sex organisms.


Review of occupational health nurse data from recent national sample surveys of registered nurses-part I.
The U.S. Department of Health and Human Services obtains information about U.S. registered nurses through the periodic National Sample Survey of Registered Nurses (NSSRN). Occupational health nurses comprise less than 1% of the U.S. nursing population and published NSSRN reports usually include only estimates of the total occupational health nurse population and minimal information about occupational health nurses' characteristics. The objectives of this study were to develop a knowledge base of occupational health nurses' characteristics; examine characteristics that may influence entry and retention in occupational health nursing practice; and explore indications of demand for occupational health nurses. Descriptive and inferential statistics were used in a secondary analysis of data from recent (1992 to 2004) NSSRN. The findings are reported in two parts. This article, Part I, provides descriptive data about occupational health nurses based on responses to the 1992 through 2004 NSSRN questionnaires. Part II will provide findings from analysis of 2004 responses indicative of occupational health nurses' entry, retention, and demand characteristics.


Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma.
Primary aldosteronism is the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D have been described in aldosterone-producing adenomas (APAs). Our aim was to investigate the prevalence of somatic mutations in these genes in unselected patients with APA (n=474), collected through the European Network for the Study of Adrenal Tumors. Correlations with clinical and biochemical parameters were first analyzed in a subset of 199 patients from a single center and then replicated in 2 additional centers. Somatic heterozygous KCNJ5 mutations were present in 38% (180/474) of APAs, whereas ATP1A1 mutations were found in 5.3% (25/474) and ATP2B3 mutations in 1.7% (8/474) of APAs. Previously reported somatic CACNA1D mutations as well as 10 novel CACNA1D mutations were identified in 44 of 474 (9.3%) APAs. There was no difference in the cellular composition of APAs or in CYP11B2, CYP11B1, KCNJ5, CACNA1D, or ATP1A1 gene expression in APAs across genotypes. Patients with KCNJ5 mutations were more frequently female, diagnosed younger, and with higher minimal plasma potassium concentrations compared with CACNA1D mutation carriers or noncarriers. CACNA1D mutations were associated with smaller adenomas. These associations were largely dependent on the population structure of the different centers. In conclusion, recurrent somatic mutations were identified in 54% of APAs. Young women with APAs are more likely to be KCNJ5 mutation carriers; identification of specific characteristics or surrogate biomarkers of mutation status may lead to targeted treatment options.


Induction and reversal of cardiac phenotype of human hypertrophic cardiomyopathy mutation cardiac troponin T-Q92 in switch on-switch off bigenic mice.
The aim of this study was to establish reversibility of cardiac phenotypes in hypertrophic cardiomyopathy (HCM) by generating bigenic mice in which expression of the mutant transgene could be turned on and off as needed. Advances in molecular therapeutics could ultimately lead to therapies aimed at correcting the causal mutations. However, whether cardiac phenotypes, once established, are permanent, or could be reversed, if expression of the mutant protein is turned off, is unknown. We generated ligand-inducible bigenic mice, turned on and off expression of cardiac troponin T-Q92 (cTnT-Q92), responsible for human HCM, and characterized molecular, histologic, and functional phenotypes. We established six lines and in dose-titration studies showed that treatment with 1,000 mug/kg of mifepristone consistently switched on cTnT-Q92 expression in the heart. Short-term (16 days) induced expression enhanced myocardial systolic function without changing myocardial cyclic adenosine monophosphate levels. Levels of PTEN, a regulator of cardiac function, phospho-protein kinase C-Zetalambda-Thr538 and phosphor-protein kinase D-Ser744-748 were reduced, whereas messenger ribonucleic acid (mRNA) levels of NPPA, NPPB, and sarcoplasmic reticulum calcium adenine triphosphatase 2 (ATP2A2) (hypertrophic markers) and procollagen COL1A1, COL1A2, and COL3A1 were unchanged. Long-term (70 days) induced expression increased COL1A1 and COL1A3 mRNAs levels and collagen volume fraction and reduced levels of NPPA and NPPB. Switching off expression of the cTnT-Q92 reversed functional, molecular, and histologic phenotypes completely. The initial phenotype induced by cTnT-Q92 is enhanced myocardial systolic function followed by changes in signaling kinases and interstitial fibrosis. Established phenotypes in HCM reverse upon turning off expression of the mutant protein. These findings provoke pursuing specific therapies directed at correcting the underlying the genetic defect in HCM.


Patient costs of diabetes mellitus care in public health care facilities in Kenya.
To estimate the direct and indirect costs of diabetes mellitus care at five public health facilities in Kenya. We conducted a cross-sectional study in two counties where diabetes patients aged 18 years and above were interviewed. Data on care-seeking costs were obtained from 163 patients seeking diabetes care at five public facilities using the cost-of-illness approach. Medicines and user charges were classified as direct health care costs while expenses on transport, food, and accommodation were classified as direct non-health care costs. Productivity losses due to diabetes were classified as indirect costs. We computed annual direct and indirect costs borne by these patients. More than half (57.7%) of sampled patients had hypertension comorbidity. Overall, the mean annual direct patient cost was KES 53 907 (95% CI, 43 625.4-64 188.6) (US$ 528.5 [95% CI, 427.7-629.3]). Medicines accounted for 52.4%, transport 22.6%, user charges 17.5%, and food 7.5% of total direct costs. Overall mean annual indirect cost was KES 23 174 (95% CI, 20 910-25 438.8) (US$ 227.2 [95% CI, 205-249.4]). Patients reporting hypertension comorbidity incurred higher costs compared with diabetes-only patients. The incidence of catastrophic costs was 63.1% (95% CI, 55.7-70.7) and increased to 75.4% (95% CI, 68.3-82.1) when transport costs were included. There are substantial direct and indirect costs borne by diabetic patients in seeking care from public facilities in Kenya. High incidence of catastrophic costs suggests diabetes services are unaffordable to majority of diabetic patients and illustrate the urgent need to improve financial risk protection to ensure access to care.


[Manifestations, diagnosis and treatment of non-tuberculous mycobacterial infections in non-immunodepressed patients].
Non-tuberculous mycobacteria (NTM) can be the etiologic agents of chronic pulmonary disease, lymphadenitis, skin and soft-tissue infection and disseminated disease in non-immunocompromised patients. The recognition of disease needs repeated isolation of the NTM from bronchopulmonary secretions or from tissue biopsies, and its identification by specific laboratory methods. A wide spectrum of clinical presentations and severity of disease can be found, from spontaneous healing to progressive and destructive lung disease, and death, according to predisposing conditions and mycobacterial species. The choice of surgical and drug treatment will depend on identification of specific pathogen and clinical evaluation.


Patient-centered quality indicators for pulmonary resection.
Quality of care is increasingly scrutinized. However, no standard quality measures exist for surgical care of patients undergoing pulmonary resection. Our thoracic surgical team developed a set of patient-centered quality of care measures specific to patients undergoing pulmonary resection. Measures were chosen that demonstrated evidence-based preoperative assessment, adequate mediastinal staging, and interventions to prevent and expeditiously treat postoperative morbidity. Medical records of all patients undergoing pulmonary resection in 2005 were analyzed. In all, 606 patients (men:women = 330:276) underwent 628 pulmonary resections. Median age was 65.8 years (range, 2 to 93). Operative mortality was 2.1%. Pulmonary function testing within 1 year before surgery was documented in 74.2%. Electrocardiogram within 90 days before surgery was documented in 81.6% of patients 50 years and older. Smoking history was documented in all patients, and smoking cessation consultation was offered to 85.7% of current smokers. Deep venous thrombosis prophylaxis was implemented in 99.7%. Mediastinal staging was documented in 94.0% of patients undergoing lung cancer resection (n = 333). Postoperatively, 92.4% of patients used incentive spirometry. Atrial fibrillation treatment occurred within 45 minutes of onset in 70.5%. Postoperative analog pain scores were above 6 in only 7.4% of assessments; treatment and reassessment occurred within 2 hours in 81.0%. Follow-up planning was documented at hospital discharge in 100%. No National Quality Forum "never events" occurred. Patient-centered and clinically relevant quality measures can be developed and evaluated in general thoracic surgery. This panel of quality indicators highlights and guide areas for potential improvement in the care of patients undergoing pulmonary resection.


Nanofibrous Aerogel Bulk Assembled by Cross-Linked SiC/SiOx Core-Shell Nanofibers with Multifunctionality and Temperature-Invariant Hyperelasticity.
Nanofibrous aerogels constructed solely by ceramic components with temperature-invariant hyperelasticity could have broad technological implications in extreme environments. However, creating such materials has proven to be extremely challenging. Despite the results from laboratory, those aerogels are, unfortunately, still plagued with issues that would retard their further application: inferior structural integrity, failure at large compressive deformation, high production cost, and inability to withstand rigorous working conditions. To tackle these challenges, we report a facile strategy combining the chemical vapor deposition process and layer-by-layer self-assembly to construct hyperelastic SiC nanofibrous aerogels with three-dimensional porous architecture and improved structural integrity. The resultant aerogels outperform their natural counterparts and most state-of-the-art ceramic nanofibrous aerogels in their capability to quickly recover from large compressive deformation (50% strain), function in a wide range of temperatures, from -196 °C to 1100 °C in air, maintain high particle matter removal efficiency of >99.96%, and rapidly absorb various organic solvents and oils with high capacity and robust recoverability. Nanofibrous aerogels constructed by such a versatile method could provide fresh insights into the exploration of multifunctional nanofibrous aerogels for a variety of applications in extreme environments.


Genetic similarity of island populations of tent caterpillars during successive outbreaks.
Cyclic or fluctuating populations experience regular periods of low population density. Genetic bottlenecks during these periods could give rise to temporal or spatial genetic differentiation of populations. High levels of movement among increasing populations, however, could ameliorate any differences and could also synchronize the dynamics of geographically separated populations. We use microsatellite markers to investigate the genetic differentiation of four island and one mainland population of western tent caterpillars, Malacosoma californicum pluviale, in two periods of peak or pre-peak density separated by 8 years. Populations showed high levels of genetic variation and little genetic differentiation either temporally between peaks or spatially among sites. Mitochondrial haplotypes were also shared between one island population and one mainland population in the two years studied. An isolation-by-distance analysis showed the FST values of the two geographically closest populations to have the highest level of differentiation in both years. We conclude that high levels of dispersal among populations maintain both synchrony of population dynamics and override potential genetic differentiation that might occur during population troughs. As far we are aware, this is the first time that genetic similarity between temporally separated population outbreaks in insects has been investigated. A review of genetic data for both vertebrate and invertebrate species of cyclic animals shows that a lack of spatial genetic differentiation is typical, and may result from high levels of dispersal associated with fluctuating dynamics.


Hospitalized Patients' Knowledge of Care: a Systematic Review.
Patients' comprehension of their medical conditions is fundamental to patient-centered care. Hospitalizations present opportunities to educate patients but also challenges to patient comprehension given the complexity and rapid pace of clinical care. We conducted a systematic review of the literature to characterize the current state of inpatients' knowledge of their hospitalization, assess the methods used to determine patient comprehension, and appraise the effects of interventions on improving knowledge. We searched MEDLINE, EMBASE, and the Cochrane Library for articles published from January 1, 1995 through December 11, 2017. Eligible studies included patients under inpatient or observation status on internal medicine, family medicine, or neurology services. We extracted study characteristics (author, year, country, study design, sample size, patient characteristics, methods, intervention, primary endpoints, results) in a standardized fashion. The quality of observational studies was assessed using the NIH Quality Assessment Tool for Observation Cohort and Cross-Sectional Studies and the quality of interventional studies was assessed using adapted EPOC criteria from the Cochrane Collaboration. Twenty-eight studies met the criteria for inclusion, including 17 observational studies and 11 interventional studies. Patient knowledge of all aspects of their hospitalization was poor and patients often overestimated their knowledge. Older patients and those with lower education levels were more likely to have poorer knowledge. Intervention methods varied, but generally showed improvements in patient knowledge. Few interventional studies assessed the effect on health behaviors or outcomes and those that did were often underpowered. Clinicians should be aware that comprehension is often poor among hospitalized patients, especially in those with lower education and advanced age. Our results are limited by overall poor quality of interventional studies. Future research should use objective, standardized measures of patient comprehension and interventions should be multifaceted in approach, focusing on knowledge improvement while also addressing other factors influencing outcomes.


Availability, healthiness, and price of packaged and unpackaged foods in India: A cross-sectional study.
Background: Vulnerable populations are the most prone to diet-related disease. The availability, healthiness, and price of foods have established associations with diet-related disease in communities. However, data describing this in India are sparse, particularly in urban slums and rural areas. Aim: To quantify and compare availability, healthiness, and price of packaged and unpackaged foods and beverages in India, and to identify opportunities to improve diets and health of vulnerable populations. Methods: Nutrition data and price were collected on foods and beverages available at 44 stores in urban, urban slum, and rural areas in four states in India between May and August 2018. Healthiness was assessed using the Australasian Health Star Rating system and product retail prices were examined. Comparisons in the findings were made across state, community area type, and adherence to current and draft Indian food labeling regulations. Results: Packaged foods and beverages (n = 1443, 89%) were more prevalent than unpackaged (n = 172, 11%). Unpackaged products were healthier than packaged (mean Health Star Rating = 3.5 vs 2.0; p < 0.001) and lower in price (median price per 100 g/ml: 13.42 Indian rupees vs 25.70 Indian rupees; p < 0.001), a pattern observed across most community area types and states. 96% of packaged products were compliant with current Indian labeling regulations but only 23% were compliant with proposed labeling regulations. Conclusions: Unpackaged products were on average much healthier and lower in price than packaged foods and beverages. Food policies that support greater availability, accessibility and consumption of unpackaged foods, while limiting consumption of packaged foods, have enormous potential for sustaining the health of the Indian population.


The Gly56Arg mutation in NR2E3 accounts for 1-2% of autosomal dominant retinitis pigmentosa.
Mutations in the orphan nuclear receptor gene NR2E3 have been found to cause both recessive and dominant retinopathies. The purpose of this study was to determine the prevalence of the recently described Gly56Arg mutation in a well characterized cohort of families with autosomal dominant retinitis pigmentosa (adRP). A cohort of 215 families with adRP which have already been screened for mutations in 13 of the other known adRP genes was used to determine the frequency of the Gly56Arg mutation. The 92 families without a disease-causing mutation in a known gene were tested for the presence of the Gly56Arg mutation using direct DNA sequencing. An additional set of 100 normal controls (200 chromosomes) was also screened by DNA sequencing. The Gly56Arg mutation was found in three of the 92 adRP families studied and was not found in unaffected control samples. The Gly56Arg mutation in NR2E3 accounts for approximately 1%-2% of adRP, making it one of the more common single mutations in adRP.


Does breast composition influence late adverse effects in breast radiotherapy?
Large breast size is associated with increased risk of late adverse effects after surgery and radiotherapy for early breast cancer. It is hypothesised that effects of radiotherapy on adipose tissue are responsible for some of the effects seen. In this study, the association of breast composition with late effects was investigated along with other breast features such as fibroglandular tissue distribution, seroma and scar. The patient dataset comprised of 18 cases with changes in breast appearance at 2 years follow-up post-radiotherapy and 36 controls with no changes, from patients entered into the FAST-Pilot and UK FAST trials at The Royal Marsden. Breast composition, fibroglandular tissue distribution, seroma and scar were assessed on planning CT scan images and compared using univariate analysis. The association of all features with late-adverse effect was tested using logistic regression (adjusting for confounding factors) and matched analysis was performed using conditional logistic regression. In univariate analyses, no statistically significant differences were found between cases and controls in terms of breast features studied. A statistically significant association (p < 0.05) between amount of seroma and change in photographic breast appearance was found in unmatched and matched logistic regression analyses with odds ratio (95% CI) of 3.44 (1.28-9.21) and 2.57 (1.05-6.25), respectively. A significant association was found between seroma and late-adverse effects after radiotherapy although no significant associations were noted with breast composition in this study. Therefore, the cause for large breast size as a risk factor for late effects after surgery and optimally planned radiotherapy remains unresolved.


[Association between tumor necrosis factor-beta polymorphisms and coronary heart disease in a Chinese population].
To investigate the association between tumor necrosis factor-beta (TNF-beta) gene polymorphisms and coronary heart disease (CHD). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequence specific primer-PCR (PCR-SSP) were used for the detection of TNF-beta genotype in 210 patients with CHD and 186 healthy controls. The serum TNF-beta levels were measured by enzyme-linked immunosorbent assay (ELISA). The frequencies of CC, CA and AA genotypes of C804A in patients and controls were 25.7% and 37.1%, 49.5% and 45.7%, 24.8% and 17.2%, respectively; there were statistically significant differences in the distributions of the genotypes (P<0.05) and the allele frequencies (P<0.05) between the two groups; the risk of suffering from CHD in those of AA and CA genotypes was 1.704 times that in those of CC genotype (OR=1.704, 95%CI: 1.109-2.617). However, there was no significant difference in the distribution of the genotype of G252A between the patients and controls, though significant difference was seen between the subgroups of the CHD group. The serum TNF-beta and high sensitive C-reactive protein (hsCRP) levels of the patients were significantly higher than those of the controls (P<0.05); however, there were no significant differences in regard to different TNF-beta genotypes among the patients and controls respectively. The single nucleotide polymorphism (SNP) at position 804 in the exon 3 of TNF-beta gene is associated with CHD and the allele A may be a risk factor for CHD in Chinese. The polymorphism of G252A may not play an important role in the pathogenesis of CHD.


Evaluating the Effectiveness of NoteAid in a Community Hospital Setting: Randomized Trial of Electronic Health Record Note Comprehension Interventions With Patients.
Interventions to define medical jargon have been shown to improve electronic health record (EHR) note comprehension among crowdsourced participants on Amazon Mechanical Turk (AMT). However, AMT participants may not be representative of the general population or patients who are most at-risk for low health literacy. In this work, we assessed the efficacy of an intervention (NoteAid) for EHR note comprehension among participants in a community hospital setting. Participants were recruited from Lowell General Hospital (LGH), a community hospital in Massachusetts, to take the ComprehENotes test, a web-based test of EHR note comprehension. Participants were randomly assigned to control (n=85) or intervention (n=89) groups to take the test without or with NoteAid, respectively. For comparison, we used a sample of 200 participants recruited from AMT to take the ComprehENotes test (100 in the control group and 100 in the intervention group). A total of 174 participants were recruited from LGH, and 200 participants were recruited from AMT. Participants in both intervention groups (community hospital and AMT) scored significantly higher than participants in the control groups (P<.001). The average score for the community hospital participants was significantly lower than the average score for the AMT participants (P<.001), consistent with the lower education levels in the community hospital sample. Education level had a significant effect on scores for the community hospital participants (P<.001). Use of NoteAid was associated with significantly improved EHR note comprehension in both community hospital and AMT samples. Our results demonstrate the generalizability of ComprehENotes as a test of EHR note comprehension and the effectiveness of NoteAid for improving EHR note comprehension.


Requirements of class II-mediated B cell differentiation for class II cross-linking and cyclic AMP.
Cells of the mouse B cell clone, CH12.LX, receive Ag-dependent differentiative signals through their surface membrane class II molecules. The present study was performed to determine the role of class II cross-linking and cAMP in the successful delivery of these signals. Delivery of differentiative signals by anti-Ek mAb was increased by further cross-linking with a secondary anti-isotype antibody. Intact or (Fab')2, but not Fab forms of anti-Ek successfully delivered the Ag-dependent differentiative signal. Inability of monovalent Fab fragments to deliver the signal could not be attributed to an inability to adequately bind Ek molecules. The requirement for cAMP for class II-mediated signaling was also examined, because previous studies have implicated elevated cAMP levels as necessary for class II signaling. Both Ag-dependent, Ek-mediated differentiation and the Ek-mediated inhibition of Ag-independent LPS-induced differentiation were inhibited by the adenyl cyclase inhibitor 2'5'ddA, although elevation of cAMP was not in itself sufficient to deliver the differentiative signal. Inhibition of LPS-induced differentiation could be mediated by mAb binding to either Ek, Abk, or Abb on CH12.LX or an Ab-bearing transfectant, CH12.ABB1. This inhibition was abrogated by 2'5'ddA in the case of Ek or Abb, both of which deliver Ag-dependent differentiative signals to CH12.LX cells. In the case of Abk, which does not deliver such signals to CH12.LX, 2'5'ddA did not abrogate anti-Abk-mediated inhibition of the LPS response. The effects of 2'5'ddA were reversed by the cAMP analog, dibutyryl cAMP, and Ag-dependent-induced differentiation of CH12.LX or CH12.ABB1 was accompanied by an increase in cAMP levels.


The role of evidence in humanitarian assessment: the Seed System Security Assessment and the Emergency Market Mapping and Analysis.
This paper reviews advances in the development and use of two evidence-based assessment toolkits: the Seed System Security Assessment (SSSA) and the Emergency Market Mapping and Analysis (EMMA). Both were created in the past five years and have been employed in a range of acute and chronic stress contexts across Africa, Asia, and parts of the Americas, in periods of civil strife, displacement, and drought, as well as following earthquakes, flooding, and political instability. The aims of this paper are threefold: to review advances with regard to each tool; to compare how each toolkit gathers and uses evidence, while considering possibilities for greater complementarity; and to reflect on the nature of 'evidence' used to guide humanitarian response in sudden-onset and chronic crisis situations. A comparison highlights the importance of triangulation and informed analysis for drawing conclusions from imperfect evidence, understanding the limitations of each assessment methodology, and confronting tacit assumptions.


Computer simulations of nematic drops: coupling between drop shape and nematic order.
We perform Monte Carlo computer simulations of nematic drops in equilibrium with their vapor using a Gay-Berne interaction between the rod-like molecules. To generate the drops, we initially perform NPT simulations close to the nematic-vapor coexistence region, allow the system to equilibrate and subsequently induce a sudden volume expansion, followed with NVT simulations. The resultant drops coexist with their vapor and are generally not spherical but elongated, have the rod-like particles tangentially aligned at the surface and an overall nematic orientation along the main axis of the drop. We find that the drop eccentricity increases with increasing molecular elongation, κ. For small κ the nematic texture in the drop is bipolar with two surface defects, or boojums, maximizing their distance along this same axis. For sufficiently high κ, the shape of the drop becomes singular in the vicinity of the defects, and there is a crossover to an almost homogeneous texture; this reflects a transition from a spheroidal to a spindle-like drop.


[Hemoglobin S haplotypes: their epidemiologic, anthropologic and clinical importance].
The link between beta s-gene haplotypes and sickle cell anemia has permitted a better understanding of the biological manifestations of this disease. The use of better laboratory methods can help rule out other hereditary factors that can camouflage the real hemoglobin genotype. The clinical heterogeneity of sickle cell disease, which is characterized by the presence of S hemoglobin, can be explained in terms of fetal hemoglobin (HbF) levels, ratio of G gamma chains to A gamma chains, 2,3-diphosphoglycerate levels, linked mutations, beta s haplotypes, coexistence of alpha-thalassemia, and environmental factors. The inheritance of Sen and Arab/Indian beta-gene cluster polymorphisms is associated with a milder clinical course, whereas the Central African Republic (CAR) or Bantu, Cameroon, and Benin haplotypes are linked with severe sickle cell disease. The CAR haplotype carries the worst prognosis of all (less than 12% HbF levels and adult-type G gamma:A gamma ratio). Once characterized, these DNA polymorphisms also assume great importance as anthropologic and genetic markers. In America, beta s haplotypes are contributing to a better understanding of Black American roots and their African ancestry. There is ample evidence of genetic variability not only between different Black populations in America, but also within the same country, as is the case in Costa Rica.


Predicting two-dimensional semiconducting boron carbides.
Carbon and boron can mix to form numerous two-dimensional (2D) compounds with strong covalent bonds, yet very few possess a bandgap for functional applications. Motivated by the structural similarity between graphene and recently synthesized borophene, we propose a new family of semiconducting boron carbide monolayers composed of B4C3 pyramids and carbon hexagons, denoted as (B4C3)m(C6)n (m, n are integers) by means of the global minimum search method augmented with first-principles calculations. These monolayers are isoelectronic to graphene yet exhibit increased bandgaps with decreasing n/m, due to the enhanced localization of boron multicenter bonding states as a consequence of the electronic transfer from boron to carbon. In particular, the B4C3 monolayer is even more stable than the previously synthesized BC3 monolayer and has a direct bandgap of 2.73 eV, with the promise for applications in optical catalysis and optoelectronics. These results are likely to inform the on-going effort on the design of semiconducting 2D materials based on other light elements.


Subdural electrodes versus stereoelectroencephalography for pediatric epileptogenic zone localization: a retrospective cohort study.
The objective of this study was to compare the relative safety and effectiveness of invasive monitoring with subdural electrodes (SDEs) and stereoelectroencephalography (sEEG) in pediatric patients with drug-resistant epilepsy. A retrospective cohort study was performed in 176 patients who underwent invasive monitoring evaluations at UPMC Children's Hospital of Pittsburgh between January 2000 and September 2021. To examine differences between SDE and sEEG groups, independent-samples t-tests for continuous variables and Pearson chi-square tests for categorical variables were performed. A p value < 0.1 was considered statistically significant. There were 134 patients (76%) in the SDE group and 42 (24%) in the sEEG group. There was a difference in the proportion with complications (17.9% in the SDE group vs 7.1% in the sEEG group, p = 0.09) and resection (75.4% SDE vs 21.4% sEEG, p < 0.01) between SDE and sEEG patients. However, there was no observable difference in the rates of postresection seizure freedom at 1-year clinical follow-up (60.2% SDE vs 75.0% sEEG, p = 0.55). These findings reveal a difference in rates of surgical complications and resection between SDEs and sEEG. Larger prospective, multi-institutional pediatric comparative effectiveness studies may further explore these associations.


Expression of beta 1 integrins in IgA nephropathy.
To compare the expression of beta 1 integrins in renal biopsies from patients with IgA nephropathy with that found in normal human kidney. Thirty renal biopsies from patients with IgA disease plus six control specimens were stained with monoclonal antibodies directed against the alpha 1, alpha 2, alpha 3, alpha 4, alpha 5, alpha 6, alpha v, and beta 1 integrin chains using the alkaline phosphatase anti-alkaline phosphatase (APAAP) technique. The intensity of integrin expression was graded semiquantitatively by a pathologist unaware of the antibody used. Glomerular crescents stained strongly for alpha 3, alpha v, and beta 1, but integrin expression was greatly reduced or absent in fibrotic glomeruli. There were no alterations in the intensity of mesangial cell staining for any of the integrins tested. There was accentuated staining for the alpha 2, alpha 5, alpha v, and beta 1 chains in areas of interstitial scarring plus alpha 2, alpha 3, alpha v, and beta 1 on damaged tubules. Inflammatory cells expressed alpha 4, alpha 5, and beta 1. In IgA nephropathy the interstitium is the main site of altered beta 1 integrin expression. Glomerular crescents also express several beta 1 integrins, but we found no differences in the intensity of integrin expression on mesangial cells. Altered beta 1 integrin expression may play a role in tubulointerstitial scarring in IgA disease. Thus modulation of integrin expression might attenuate this process.


Advanced In Silico Approaches for Drug Discovery: Mining Information from Multiple Biological and Chemical Data Through mtk- QSBER and pt-QSPR Strategies.
The last decade has been seeing an increase of public-private partnerships in drug discovery, mostly driven by factors such as the decline in productivity, the high costs, time, and resources needed, along with the requirements of regulatory agencies. In this context, traditional computer-aided drug discovery techniques have been playing an important role, enabling the identification of new molecular entities at early stages. However, recent advances in chemoinformatics and systems pharmacology, alongside with a growing body of high quality, publicly accessible medicinal chemistry data, have led to the emergence of novel in silico approaches. These novel approaches are able to integrate a vast amount of multiple chemical and biological data into a single modeling equation. The present review analyzes two main kinds of such cutting-edge in silico approaches. In the first subsection, we discuss the updates on multitasking models for quantitative structure-biological effect relationships (mtk- QSBER), whose applications have been significantly increasing in the past years. In the second subsection, we provide detailed information regarding a novel approach that combines perturbation theory with quantitative structure-property relationships modeling tools (pt- QSPR). Finally, and most importantly, we show that the joint use of mtk-QSBER and pt- QSPR modeling tools are apt to guide drug discovery through its multiple stages: from in vitro assays to preclinical studies and clinical trials.


Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia.
The cytolytic function of natural killer (NK) cells is induced by the engagement of a series of activating receptors and coreceptors some of which have recently been identified and collectively termed natural cytotoxicity receptors (NCRs). Here, we analyzed the cytolytic function of NK cells obtained from patients with acute myeloid leukemia (AML). In sharp contrast with healthy donors, in most (16 of 18) patients with AML the majority of NK cells displayed low NCR surface density (NCR(dull)). This phenotype correlated with a weak cytolytic activity against autologous leukemic cells that could not be reversed by the monoclonal antibody-mediated disruption of HLA class I/killer immunoglobulinlike receptor interaction. The remaining 2 patients were characterized by NK cells having an NCR(bright) phenotype. Surprisingly, although displaying NCR-mediated cytolytic activity, these NCR(bright) NK cells were unable to kill autologous leukemic blasts. Importantly, the leukemic blasts from these 2 patients were also resistant to lysis mediated by normal NCR(bright) allogeneic NK cells. Our study suggests that in most instances the inability of NK cells to kill autologous leukemic blasts is consequent to low NCR surface expression. In few cases, however, this failure appears to involve a mechanism of tumor escape based on down-regulation of ligands relevant for NCR-mediated target cell recognition.


Pharmacokinetics of a modified, compounded theophylline product in dogs.
Theophylline is a commonly used bronchodilator drug for treatment of chronic canine bronchitis, but no formulations validated in dogs are currently available. An oral, modified and compounded theophylline product (MCT), which could fulfil this need, is available through a USP-compliant, veterinary compounding pharmacy; however, its pharmacokinetic properties are unknown. The aim of this study was to determine the pharmacokinetics of MCT. Plasma drug concentrations were measured in seven healthy, fed dogs after single doses of intravenous aminophylline (8.6 mg/kg theophylline equivalent) and oral MCT (10 mg/kg). Systemic bioavailability of the MCT was 96.2 ± 32.9%. MCT times to maximum concentration, mean absorption time and terminal half-life were 8.85 ± 3.63, 6.95 ± 3.42, and 8.67 ± 1.62 hr, respectively. Based on simulations of 10 mg/kg and 12-hr dosing, steady-state plasma theophylline concentrations are expected to exceed the minimum therapeutic concentration for 71.7 ± 35.6% of the dosing interval. Overall, the MCT product investigated showed similar pharmacokinetic characteristics compared to previously validated extended-release theophylline products. An oral dose of 10 mg/kg q 12 hr is likely an appropriate dosage to begin therapy; however, therapeutic drug monitoring may be warranted because of inter-individual variation.


Metformin inhibits androgen-induced IGF-IR up-regulation in prostate cancer cells by disrupting membrane-initiated androgen signaling.
We have previously demonstrated that, in prostate cancer cells, androgens up-regulate IGF-I receptor (IGF-IR) by inducing cAMP-response element-binding protein (CREB) activation and CREB-dependent IGF-IR gene transcription through androgen receptor (AR)-dependent membrane-initiated effects. This IGF-IR up-regulation is not blocked by classical antiandrogens and sensitizes cells to IGF-I-induced biological effects. Metformin exerts complex antitumoral functions in various models and may inhibit CREB activation in hepatocytes. We, therefore, evaluated whether metformin may affect androgen-dependent IGF-IR up-regulation. In the AR(+) LNCaP prostate cancer cells, we found that metformin inhibits androgen-induced CRE activity and IGF-IR gene transcription. CRE activity requires the formation of a CREB-CREB binding protein-CREB regulated transcription coactivator 2 (CRTC2) complex, which follows Ser133-CREB phosphorylation. Metformin inhibited Ser133-CREB phosphorylation and induced nuclear exclusion of CREB cofactor CRTC2, thus dissociating the CREB-CREB binding protein-CRTC2 complex and blocking its transcriptional activity. Similarly to metformin action, CRTC2 silencing inhibited IGF-IR promoter activity. Moreover, metformin blocked membrane-initiated signals of AR to the mammalian target of rapamycin/p70S6Kinase pathway by inhibiting AR phosphorylation and its association with c-Src. AMPK signals were also involved to some extent. By inhibiting androgen-dependent IGF-IR up-regulation, metformin reduced IGF-I-mediated proliferation of LNCaP cells. These results indicate that, in prostate cancer cells, metformin inhibits IGF-I-mediated biological effects by disrupting membrane-initiated AR action responsible for IGF-IR up-regulation and suggest that metformin could represent a useful adjunct to the classical antiandrogen therapy.


Mechanisms underlying imiquimod-induced regression of basal cell carcinoma in vivo.
Imiquimod is a local immune response modifier that has demonstrated potent antiviral and antitumor activity. It enhances innate and acquired immune responses via endogenous cytokine production and has proven efficacious in clearing superficial basal cell carcinoma (sBCC). To evaluate the mechanisms by which topical imiquimod treatment leads to sBCC clearance in vivo. A pilot, open-label, nonrandomized study. Zurich, Switzerland. Six persons 18 years or older who had nonrecurrent primary tumors that had not undergone previous biopsy or treatment but were suitable for treatment by surgical excision. The tumors were located on the scalp, extremities, or trunk; had a minimum diameter of 1 cm and a maximum diameter of 2 cm; and were clinically and histologically consistent with sBCC. Daily application of 5% imiquimod cream 5 times per week for a maximum of 6 weeks. When the tumor began to show signs of erosion, it was surgically excised. Parameters reflecting tumor apoptotic status (Bcl-2), expression of death receptors (Fas and Fas ligand [FasL]), intercellular adhesion molecule (ICAM) 1, immunosuppressive microenvironment (interleukin 10), and antigen presentation machinery (transporter associated with antigen presentation [TAP] 1) before and after imiquimod treatment were evaluated. The changes in the interferon gamma messenger RNA (mRNA) levels relative to CD4 and CD8 mRNA were assessed using quantitative polymerase chain reaction. Tumor cells became more susceptible to apoptosis through decreased Bcl-2 expression after treatment with 5% imiquimod cream. Inflammatory infiltrate developed rapidly (within 3 to 5 days after treatment initiation) and was associated with the enhanced expression of ICAM-1. This early response tended to be a mixed cellular response of macrophages and lymphocytes. Interferon gamma was produced by CD4 and CD8 T cells. Imiquimod treatment induced a massive increase in macrophage peritumoral and intratumoral infiltration. Interleukin 10 was produced by infiltrating cells but was not produced by tumor cells. Tumor expression of TAP-1 and Fas/FasL appeared to be unaffected in the first 5 days of treatment.


Factors influencing occurrence of colibacillosis in calves.
This investigation describes some of the husbandry factors influencing the occurrence of colibacillosis in calves. Diarrhoea and mortality were usually associated with an increase in the proportion of "pathogenic" to total E coli to about 50 per cent in the faeces although there were occasions when the proportion of "pathogenic" E coli increased but no disease occurred. These increases often followed changes of diet which appeared to be more important than environmental conditions. The use of uncontaminated houses to break the cycle of infection appeared to have the greatest influence on the disease pattern.


[Biopercular syndrome caused by unilateral ischemia. Report of one case].
Biopercular syndrome is a labio-facio-pharyngeal-laryngeal-gloso-masticatory diplegia, with automatic dissociation of movements. Ischemia is the most common etiology when it occurs bilaterally in the opercular area, but it has been also described in patients with bilateral subcortical lesions. There are few cases described with unilateral lesions. We report a 76-year-old woman who developed a biopercular syndrome caused by unilateral ischemic lesion of the right middle cerebral artery confirmed by magnetic resonance imaging and cerebral SPECT.


Scanning Micro-Mirror with an Electrostatic Spring for Compensation of Hard-Spring Nonlinearity.
A scanning micro-mirror operated at the mechanical resonant frequency often suffer nonlinearity of the torsion-bar spring. The torsion-bar spring becomes harder than the linear spring with the increase of the rotation angle (hard-spring effect). The hard-spring effect of the torsion-bar spring generates several problems, such as hysteresis, frequency shift, and instability by oscillation jump. In this paper, a scanning micro-mirror with an electrostatic-comb spring is studied for compensation of the hard-spring effect of the torsion-bar spring. The hard-spring effect of the torsion-bar spring is compensated with the equivalent soft-spring effect of the electrostatic-comb spring. The oscillation curve becomes symmetric at the resonant frequency although the resonant frequency increases. Theoretical analysis is given for roughly explaining the compensation. A 0.5 mm square scanning micro-mirror having two kinds of combs, i.e., an actuator comb and a compensation comb, is fabricated from a silicon-on-insulator wafer for testing the compensation of the hard-spring in a vacuum and in atmospheric air. The bending of the oscillation curve is compensated by applying a DC voltage to the electrostatic-comb spring in vacuum and atmosphere. The compensation is attributed by theoretical approach to the soft-spring effect of the electrostatic-comb spring.


Water disinfection by ozonation has advantages over UV irradiation in a brackish water recirculation aquaculture system for Pacific white shrimp (Litopenaeus vannamei).
By keeping tropical shrimp, like Litopenaeus vannamei, in recirculating aquaculture systems (RAS), valuable food for human consumption can be produced sustainable. L. vannamei tolerates low salinities, and therefore, the systems can operate under brackish water conditions. The stabilization of the microbial community in RAS might be difficult under high organic loads, and therefore, water treatment measures like UV irradiation or ozone application are commonly used for bacterial reduction. To investigate the impact of these measures, the effects of UV irradiation and ozone application were studied in small-scale brackish water RAS with a salinity of 15‰ stocked with L. vannamei. UV reactors with 7 and 9 W were used, and by ozonizers with a power of 5-50 mg/hr, the redox potential in the water was adjusted to 350 mV. Ozone had a stabilizing effect on the microbial composition in the water and on biofilms of tank surfaces and shrimp carapaces, prevented an increase of nitrite and accelerated the degradation of nitrate in the water. UV irradiation led to changes in the microbial composition and was less effective in optimizing the chemical water quality. Thus, the use of ozone could be recommended for water treatment in brackish water RAS for shrimp.


Magnetic rotations of uric acid crystals and uratic crystals by static magnetic fields of up to 500 mT.
In recent years, the disease concerning ureteral calculus is increasing possibly due to the changing lifestyles. For example, it is well known that the urinary calculi have a large impact to gout. As eating habitual diseases, gout and the hyper-uricemia are related to the formation of urinary calculus. In the previous studies, therapeutic agents were developed to enhance the uric acid excretion. From the viewpoint of side effects induction by the chemical agents, we are motivated to explore an alternative method to control the formation of ureteral crystals stimulator by physical stimulations. Therefore in the present study, we focused on the behaviors of uric acid crystals under magnetic fields of several hundreds of mT (Tesla). The uric acid crystals were re-crystallized from a suspension of uric acid powder, and the micro-crystals were prepared to be floating in the solution. We generated horizontal magnetic fields of maximum 500 mT by an electromagnet which contained a CCD microscope. A permanent magnet with magnetic fields of 200∼400 mT was also utilized. During the magnetic fields were applied to the uric acid crystals, we observed that the uric acid crystals were oriented by the magnetic fields down to 200 mT at the room temperature. It was speculated that the dimagnetic anisotropy in the uric acid crystals exhibited the rotational responses. The results indicate the possible remote control of the uric acid crystals in living body by the magnetic fields of 200 mT to 500 mT.


The Antimicrobial Activities of Silver Nanoparticles Synthesized from Medicinal Mushrooms.
Crude polysaccharide extracts derived from Agaricus bisporus (A), A. brasiliensis (B), and Phellinus linteus (P) were used for the synthesis of silver nanoparticles (AgNPs, labeled AAgNP, BAgNP, PAgNP, respectively). UV and FT-IR spectra, size distribution, and zeta potential of the respective particles were recorded, and TEM and SEM-EDS characterization was done. UV-Vis spectroscopy showed maximum absorbance at 415 nm for A, at 400 nm for P, and at 420 nm for B. SEM-EDS analysis showed BAgNP to consist of almost 90% of silver, while silver content in AAgNP and PAgNP was much lower, 46.5 and 52.3%, respectively. Individual extracts as well as the Ag-NPs were tested against a panel of clinically isolated and ATCC derived pathogens. In almost all cases minimum inhibitory concentration (MIC) was significantly lower than those of antibiotics, suggesting up to 100 times more effectivity. BAgNP, PAgNP, and AAgNP appeared very active against Pseudomonas aeruginosa ATCC 27853 (MIC: 0.19, 0.19, 0.97 μg/mL, respectively). The same nanoparticles were also very effective toward Candida albicans ATCC 10231 (MIC: 0.39, 0.78, 0.97 μg/mL, respectively). Our study indicates that the bactericidal effect of PAgNP, AAgNP, BAgNP on E. coli 25922 ATCC (MBC: 1.56, 0.97, 6.25 μg/mL, respectively) is significantly more pronounced than that of amoxicillin. A pure solution of colloidal silver nanoparticles showed significantly weaker microbiostatic/microbiocidal potential than all tested mushroom extracts' AgNPs, as well as amoxicillin. Silver nanoparticles made with extracts of A, B, and P seem welcome as an addition to the inventory of antimicrobial compounds used in clinical medicine against bacterial and yeast infection.


Dynamic analysis of the mesenchymal-epithelial transition of blood-brain barrier forming glia in Drosophila.
During development, many epithelia are formed by a mesenchymal-epithelial transition (MET). Here, we examine the major stages and underlying mechanisms of MET during blood-brain barrier formation in Drosophila We show that contact with the basal lamina is essential for the growth of the barrier-forming subperineurial glia (SPG). Septate junctions (SJs), which provide insulation of the paracellular space, are not required for MET, but are necessary for the establishment of polarized SPG membrane compartments. In vivo time-lapse imaging reveals that the Moody GPCR signaling pathway regulates SPG cell growth and shape, with different levels of signaling causing distinct phenotypes. Timely, well-coordinated SPG growth is essential for the uniform insertion of SJs and thus the insulating function of the barrier. To our knowledge, this is the first dynamic in vivo analysis of all stages in the formation of a secondary epithelium, and of the key role trimeric G protein signaling plays in this important morphogenetic process.


Molecular staging of prostate cancer in the year 2007.
Numerous attempts towards improving patient management by molecular staging have been fruitless so far. No single molecular parameter is routinely analyzed in prostate cancer tissue. This may be partly due to genuine properties of prostate cancer that may make this tumor a difficult target. Furthermore, inherent logistical problems result in a shortage of prostate cancer tissue for research purposes. For the future, it can be hoped that the availability of more powerful molecular techniques in combination with better tissue archives will allow more rapid progress. Powerful DNA array and proteomics methods allow the systematic analysis of virtually all genes of a cancer on the DNA, RNA, and protein level. Although such approaches are sometimes labeled as "fishing expeditions," it cannot be totally disregarded that the simultaneous analysis of all genes has a high likelihood of identifying significant new information. In future, one of the major scientific challenges will be the validation of several potential biomarkers in large enough and clinically well-characterized patient cohorts. In particular, studies on needle core biopsies and hormone refractory cancers are imperatively needed for investigating the natural history of the disease or to discover potential predictive markers for radiation therapy and new therapeutic target genes to answer the clinically most important questions for optimal clinical decision making in prostate cancer patients: which patients will not require local therapy? If local therapy is needed, what is the treatment of choice? What medications should be given if metastases are present?


Hysterosalpingography using a flat panel unit: evaluation and optimization of ovarian radiation dose.
The aim of the present study was the evaluation and optimization of radiation dose to the ovaries (D) in hysterosalpingography (HSG). The study included a phantom study and a clinical one. In the phantom study, we evaluated imaging results for different geometrical setups and irradiation conditions. In the clinical study, 34 women were assigned into three different fluoroscopy modes and D was estimated with direct cervical TLD measurements. In the phantom study, we used a source-to-image-distance (SID) of 110 cm and a field diagonal of 48 cm, and thus decreased air KERMA rate (KR) by 19% and 70%, respectively, for beam filtration: 4 mm Al and 0.9 mm Cu (Low dose). The least radiation exposure was accomplished by using the 3.75 pps fluoroscopy mode in conjunction with beam filtration: Low dose. In the clinical study, D normalized to 50 s of fluoroscopy time with a 3.75 pps fluoroscopy mode reached a value of 0.45 ± 0.04 mGy. Observers' evaluation of diagnostic image quality did not significantly differ for the three different modes of acquisition that were compared. Digital spot radiographs could be omitted in modern flat panel systems during HSG. Fluoroscopy image acquisitions in a modern flat panel unit at 3.75 pps and a beam filtration of 4 mm Al and 0.9 mm Cu demonstrate acceptable image quality with an average D equal to 0.45 mGy. This value is lower compared to the studied literature. For these reasons, the proposed method may be recommended for routine HSG examination in order to limit radiation exposure to the ovaries.


Circular RNA ITCH suppresses proliferation and promotes apoptosis in human epithelial ovarian cancer cells by sponging miR-10a-α.
To explore the effect of Circular RNA Itchy E3 ubiquitin protein ligase (Circ-ITCH) on regulating epithelial ovarian cancer (EOC) cells proliferation and apoptosis, as well as its potential target microRNAs (miR) in vitro. Circ-ITCH mimic, blank mimic, Circ-ITCH inhibitor and blank inhibitor plasmids were transfected into SKOV3 cells. Rescue experiments were carried out by transfecting blank mimic, miR-10a mimic, Circ-ITCH mimic and miR-10a mimic/Circ-ITCH mimic plasmids into SKOV3 cells. Quantitative polymerase chain reaction (qPCR) was performed to detect RNA expression. Cells proliferation was determined by Cell Counting Kit-8 (CCK-8) assay, and cells apoptosis rate was detected using Annexin V (AV) / propidium iodide (PI) assay. Circ-ITCH expression was decreased in Human EOC cell lines SKOV3, A-2780, OVCAR-3 and HO-8910 compared with human normal ovarian epithelial cell line IOSE80, and the most significant reduction of Circ-ITCH expression was presented in SKOV3 cells. Cells proliferation was suppressed by Circ-ITCH mimic transfection and promoted by Circ-ITCH inhibitor transfection in SKOV3 cells. Cells apoptosis was enhanced by Circ-ITCH mimic transfection and inhibited by Circ-ITCH inhibitor transfection in SKOV3 cells. In addition, Circ-ITCH adversely regulated miR-10a expression in SKOV3 cells but not miR-4251 or miR-6505. Rescue experiments were subsequently performed, which exhibited that Circ-ITCH adversely regulated miR-10a expression, whereas miR-10a did not affect Circ-ITCH expression. And most importantly, miR-10a mimic attenuated the effect of Circ-ITCH on reducing proliferation and promoting apoptosis in SKOV3 cells. Circ-ITCH suppresses cells proliferation and promotes cells apoptosis via sponging miR-10a in EOC cells.