Blockade of fatty acid signalling inhibits lipopolysaccharide-induced macrophage recruitment and progression of apical periodontitis.
To examine the role of palmitic acid in lipopolysaccharide (LPS)-stimulated chemotaxis of macrophages and the potential contribution of saturated fatty acid in signalling during the pathogenesis of apical periodontitis. J774, a mouse macrophage cell line, was used in the experiments. After treatment with LPS, proteolytic maturation of sterol regulatory element-binding protein-1c (SREBP-1c) and expression of fatty acid synthase (FASN) were examined by Western analysis. Levels of palmitic acid were measured by reverse phase-high performance liquid chromatography-mass spectrometry. Knockdown of SREBP-1c and FASN was accomplished by small interfering RNA technology. Secretion of CC-chemokine ligand 2 (CCL2) and cellular chemotaxis were assessed by enzyme-linked immunosorbent assay and transwell migration assay, respectively. Sulfo-N-succinimidyl oleate (SSO) treatment was used to inhibit fatty acid signalling in vitro and also in a rat model of apical periodontitis. All data were first subjected to Levene's test. In vitro data were then analysed using ANOVA followed by Tukey's multiple comparison test. Data from animal experiments were analysed by independent t-tests. The significant level was set at 0.05. LPS stimulated proteolytic maturation of SREBP-1c and FASN expression in macrophages and significantly enhanced palmitic acid synthesis (P < 0.05). Knockdown of SREBP-1c attenuated LPS-enhanced FASN expression. Knockdown of FASN significantly suppressed LPS-enhanced palmitic acid synthesis (P < 0.05). LPS and exogenous palmitic acid significantly enhanced CCL2 secretion and macrophage chemotaxis (all P < 0.05). Inhibition of FASN expression significantly alleviated LPS-augmented CCL2 secretion (P < 0.05). SSO significantly suppressed CCL2 secretion and macrophage chemotaxis augmented by LPS and palmitic acid (all P < 0.05). In a rat model of induced apical periodontitis, SSO treatment significantly attenuated progression of apical periodontitis and macrophage recruitment (all P < 0.05). LPS/SREBP-1c/FASN/palmitic acid signalling contributed to tissue destruction caused by bacterial infection. Modulation of lipid metabolism and signalling may be helpful for the management of apical periodontitis.


Pulmonary bacterial defense. Effect of the burn wound on transfer of alveolar macrophage activation in rats by parabiosis.
The alveolar macrophage was studied in parabiotic rats using an inbred strain. Parabiotic pairs were sutured together at five weeks of age. Rats were subjected to a full thickness cutaneous burn of 20 per cent of the body surface area at seven weeks of age, and alveolar macrophages were washed from the lungs at six days post burn. The number of alveolar macrophages, their per cent of activation, and their ability to phagocytize and kill P aeruginosa in vitro were significantly increased at six days post burn in the burned controls and in both the burned and unburned members of the parabiotic pairs. No change in the alveolar macrophages was found in either unburned parabiotic pairs or in those which were sham-burned. These results indicate that a humoral or cellular agent produced either within the cutaneous burn wound or elsewhere as a response to the injury, traverses the parabiotic cross circulation to stimulate the alveolar macrophages.


Association of Screening and Brief Intervention With Substance Use in Massachusetts Middle and High Schools.
Screening and brief intervention (SBI) programs in schools have the potential to provide substance use prevention messages to large numbers of adolescents. This study evaluated the association between exposure to a school-based SBI program and reductions in substance use among youths after enactment of a law that required Massachusetts schools to provide SBI to all students. To estimate the association between exposure to a school-based SBI program and changes in substance use among youths. In this mixed-method quality improvement study using an effectiveness-implementation hybrid design, stakeholder interviews were conducted to describe the operations, timing, and impressions of SBI implementation at 14 intervention schools in Massachusetts. Repeated cross-sectional surveys of youths in intervention and comparison groups were administered between December 19, 2017, and May 22, 2019, to assess substance use and associated measures of perceived risk, knowledge, and adult support before and approximately 3 months after SBI implementation among exposed groups. A difference-in-differences framework was used to estimate substance use outcomes associated with SBI exposure among students in middle school (grades 7 and 8) and high school (grades 9 and 10) using adjusted overlap-weighted generalized models to account for covariate imbalance between exposed and unexposed school grades. In addition, 14 school staff members were interviewed about implementation. Exposure vs nonexposure to a school-based SBI program. Frequency of alcohol, cannabis, and e-cigarette use (measured in days) and any binge drinking in the past 3 months. Between December 2017 and May 2019, 8771 survey responses were collected from 4587 students in grades 7 through 10 who were attending one of 23 participating school districts. The median (IQR) age was 13 (13-14) years (range, 12-17 years); 2226 students self-identified as female (48.5%), 2206 (48.1%) as male, and 155 (3.4%) as transgender or preferred not to answer. Overall, 163 students (3.6%) identified their race as Asian, 146 (3.2%) as Black or African American, 2952 (64.4%) as White, and 910 (19.8%) as mixed or other race (including American Indian or Alaska Native and Native Hawaiian or Pacific Islander); 416 students (9.1%) preferred not to answer or were missing data on race. A total of 625 students (13.6%) identified their ethnicity as Hispanic and 3962 (86.4%) as non-Hispanic. Cannabis use increased over time in both the SBI group (middle school: marginal estimated probability, 0.73 [95% CI, 0.21-2.51] at baseline vs 2.01 [95% CI, 0.60-6.70] at follow-up; high school: marginal estimated probability, 2.86 [95% CI, 0.56-14.56] at baseline vs 3.10 [95% CI, 0.57-16.96] at follow-up) and the control group (middle school: marginal estimated probability, 0.24 [95% CI, 0.05-1.03] at baseline vs 3.38 [95% CI, 0.81-14.18] at follow-up; high school: marginal estimated probability, 1.30 [95% CI, 0.27-6.29] at baseline vs 1.72 [95% CI, 0.34-8.66] at follow-up). e-cigarette use also increased over time in both the SBI group (middle school: marginal estimated probability, 0.81 [95% CI, 0.22-3.01] at baseline vs 1.94 [95% CI, 0.53-7.02] at follow-up; high school: marginal estimated probability, 3.82 [95% CI, 0.72-20.42] at baseline vs 3.51 [95% CI, 0.55-22.59] at follow-up) and the control group (middle school: marginal estimated probability, 0.51 [95% CI, 0.12-2.30] at baseline vs 3.40 [95% CI, 0.72-16.08] at follow-up; high school: marginal estimated probability, 2.29 [95% CI, 0.41-12.65] at baseline vs 3.53 [95% CI, 0.62-20.16] at follow-up). Exposure to SBI was associated with a significantly smaller increase in the rate of cannabis use among middle school students (adjusted rate ratio [aRR], 0.19; 95% CI, 0.04-0.86) and significantly smaller increases in the rates of cannabis and e-cigarette use among all female students (cannabis use: aRR, 0.17 [95% CI, 0.03-0.96]; e-cigarette use: aRR, 0.16 [95% CI, 0.03-0.82]) compared with nonexposure. No other significant differences were observed among students in grades 7 and 8, and no differences were found in any comparison between groups in grades 9 and 10. In this quality improvement study, exposure to a school-based SBI program was associated with a significantly smaller increase in the rate of cannabis use among middle school students and significantly smaller increases in the rates of cannabis and e-cigarette use among all female students. These findings suggest that implementation of SBI programs in schools may help to reduce substance use among middle school and female students, and further study of these programs is warranted.


Intraspecific and interspecific extracellular metabolites remodel biofilms formed by thermophilic spoilage bacteria.
Thermophilic spoilage bacteria and their biofilms formed during milk powder processing posed threats to safety and quality of dairy products. This research aims to understand more about the bacterial behaviours and their social models in biofilms. Interactional effects from both extracellular metabolites and co-culture on biofilms formation of the contaminating thermophilic bacteria were determined. The results showed that strong biofilm formers always had high AI-2 activities, including Geobacillus stearothermophilus gs1, Bacillus licheniformis bl1 and Thermoactinomyces vulgaris tv1. Metabolites from themself or other species altered their biofilm biomass detected by crystal violet staining. Dual-species cultures observed by confocal laser scanning microscope indicated either synergistic or inhibitory effects between B. circulans bc1 and G. stearothermophilus gs1, as well as B. licheniformis bl1 and G. stearothermophilus gs1. Fourier transform infrared spectrometry results revealed the significant diversities in polysaccharides of the biofilm matrix. Cell communication played an important role on biofilm formation in the complex microbial community. Intraspecific and interspecific extracellular metabolites influenced collective bacterial behaviours under mixed circumstances. This research provided evidences on cell communication and biofilm formation of thermophilic bacteria in dairy industry.


Ibuprofen as risk-factor for complications of acute anterior sinusitis in children.
Non-steroidal anti-inflammatory drugs (NSAIDs) are known to inhibit chemotaxis, oxidative burst and phagocytosis, bacterial killing in granulocytes as well as inhibiting neutrophil aggregation or degranulation, thereby interfering with the function of lymphocytes. On the other hand, ibuprofen is widely prescribed in pediatrics for its powerful analgesic and antipyretic effects. To our knowledge, no previous publication outlines the relationship between Ibuprofen therapy and an increased risk of intracranial and/or orbital complications of acute fronto-ethmoidal sinusitis in childhood. To look for a relationship between ibuprofen and occurrence of intra-cranial and/or orbital complications of acute fronto-ethmoidal sinusitis in pediatrics. The medical charts of patients younger than 18 years admitted into the E.N.T. departments of 4 academic care centers during 2 consecutive years for fronto ethmoidal sinusitis were reviewed retrospectively. The history of ibuprofen intake, the occurrence of complication (orbital or intracranial) as well as the usual demographic data were noted. A statistical analysis was performed in order to ascertain whether a relationship between taking NSAIDs and the onset of an intracranial and/or orbital complication exists. Intake of ibuprofen appeared to be a risk-factor of intracranial complications or associated orbital and intracranial complications of acute fronto-ethmoidal sinusitis in children. Neither gender nor age nor initial pain intensity were statistically related to the onset of complications. This retrospective multicenter cohort study appears to suggest that ibuprofen increases the risk of orbital and/or intracranial complications of acute fronto-ethmoidal sinusitis in childhood. Therefore, we recommend not prescribing ibuprofen if one suspects an acute sinusitis in a child or adolescent.


Development of a stable oral pediatric solution of hydrochlorothiazide by the combined use of cyclodextrins and hydrophilic polymers.
Hydrochlorothiazide (HCT) is widely used in pediatrics for hypertension management. Due to the lack of pediatric commercial forms, community or hospital pharmacies generally prepare HCT extemporaneous pediatric suspensions by dispersing in water a portion of a crushed tablet or the drug powder; however, any dose or stability control is usually done on these preparations. Obtaining stable HCT solutions is very challenging, due to its low water-solubility and pH-dependent degradation. The aim of this work was to develop a stable 2 mg/mL-HCT oral pediatric solution without using co-solvents. Combined use of cyclodextrins (CD) and hydrophilic polymers was exploited to improve poor HCT solubility and stability. HPβCD and SBEβCD were selected, considering their safe toxicological profiles, while PVP resulted the best among the tested polymers. Low PVP concentrations (0.2-1.0%) improved the solubilizing efficiency of both CDs, allowing to reach the prefixed HCT concentration. Different CD-PVP concentrations were used to prepare several 2 mg/mL-HCT solutions in pH 5.5 buffer. The best stability was shown by solutions containing the highest SBEβCD concentration (25 mM), which allowed a 3-months stability at 4 °C. In vivo studies on rats showed that such formulation allowed a more pronounced and more reproducible diuretic effect than the corresponding HCT suspension.


Isolation, structural characterization, biological activity, and application of Glycyrrhiza polysaccharides: Systematic review.
Glycyrrhiza, one of the most widely used Chinese herbal medicines, is a perennial plant with good medicinal value. Polysaccharides as one of the main bioactive components of Glycyrrhiza, mainly composed of arabinose, glucose, galactose, rhamnose, mannose, xylose, and galacturonic acid in different proportions and types of glycosidic bonds. Glycyrrhiza polysaccharides (GP) have many biological activities, such as anti-oxidation, immune regulation, anti-tumor, apoptosis, anti-microbial, anti-inflammatory and regulation of intestinal flora. In this paper, relevant articles on the isolations, structural characterizations, and biological activities of GP published in the last 15 years (2006-2020) were referred to for a systematic review of the species. A total of 947 articles were searched from the database including NCBI, Science Direct, Web of Science, and How Net, and 109 of them were cited on the summarization of the past scientific researches of the polysaccharides of Glycyrrhiza genus. We hope that this work may provide new insights for further study and development of Glycyrrhiza.


Antiseizure Drug Levels in Children Aged 2-12 Years Presenting With Breakthrough Seizures: A Single Center Cross-sectional Study.
To study the antiseizure drug levels and associated factors in children with breakthrough seizures. This cross-sectional study conducted at a public hospital from November, 2017 to April, 2019, included 145 children with epilepsy aged 2 to 12 years presenting with breakthrough seizure. Antiseizure drug levels were measured, and the levels were categorized as within, below, and above the reference range. Children with epilepsy receiving sodium valproate, phenytoin and carbamazepine were 111 (73%), 31 (20.4%) and 10 (6.6%), respectively, of which 7 were receiving multiple antiseizure drugs. Drug levels below the reference range were found in 64 (44.1%), within the reference range in 70 (48.3%), and the above reference range in 11 (7.6%) children. Nearly half the children with breakthrough seizures had sub-therapeutic levels, especially those on phenytoin therapy. Drug levels in below therapeutic range were not associated with occurrence of breakthrough seizures.


Synthesis and biological activity of new bisbenzofuran-imidazolium salts.
A series of novel bisbenzofuran-imidazolium salts were designed and prepared. The in vitro antitumor activity of these derivatives was evaluated against a panel of human tumor cell lines (A549, HL-60, MCF-7, SMMC-7721 and SW480). Results demonstrated that 2-methyl-benzimidazole ring and substitution of the imidazolyl-3-position with a 4-methoxyphenacyl or 2-naphthylacyl substituent were important for promoting cytotoxic activity. Notably, compound 23 was found to be the most potent compound with IC50 values of 0.64-1.47 μM against five human tumor cell lines, and exhibited higher selectivity to MCF-7 and SW-480 cell lines with IC50 values 15.3-fold and 9.1-fold lower than DDP.


[Seating, postural support, safety and satisfaction of users of wheelchairs in a CABA Rehabilitation Institute. Descriptive study].
In the world, 75 million people require a wheelchair (W/C) but only between 5% and 15% of them have one. The WHO defines a W/C as adequate if it meets the needs of the user and their environment, offers appropriate seating and postural support and if it is safe and durable. The primary objective is to describe the seating, postural support and safety of W/Cs users who attend the I.Re.P kinesiology service. The secondary objective is to learn about their satisfaction with their W/Cs and related services. The subjects were W/C users who attend the I.Re.P. kinesiology service. The W/Cs were evaluated following the WHO guidelines, and the satisfaction using the QUEST 2.0 questionnaire. Within 30 patients, 21 were men aged around 48.17 years. Only 1 subject had all the correct measures of safety, seating and posture adjustment. 6 had all the correct measures for an adequate seating and 5 had all the safety measures. Regarding satisfaction, high scores have been found with respect to W/C and low scores with respect to related services. All in all, the total satisfaction got mostly medium and high scores. Only 1 subject out of the 30 evaluated complied with all the seating, postural adjustment and safety requirements necessary to consider an adequate W/C. Most subjects reported being more satisfied with their W/C than with the related services.


A retrospective study on infant bed-sharing in a clinical practice population.
In 2005 the American Academy of Pediatrics published new recommendations on infant sleep environment which advised against infants bed-sharing. A retrospective study was done to determine the prevalence of infant bed-sharing and its associations in a clinical practice. Demographic data were collected from 2,405 infants from a large family practice residency program, which included OB care, in Missouri between March 2002 and February 2008. Data were extracted from electronic medical records at the first four well-child visits: 1 month, 2-3 months, 4-5 months, and 6-8 months of age. Data analysis was performed using SPSS statistical software package, version 12.0 and 15.0 (SPSS, Inc, Chicago, Ill). At the first, second, third, and fourth well-child visit 19, 18, 12, and 11% of infants bed-shared with an adult. Bed-sharing was associated with an infant missing one or more well-child visits (first and third visits only), breastfeeding (first and second well-child visits only), and low SES. Stratified analysis by residence showed that over the 6-year study the decrease in the rate of bed-sharing, in the urban and non-urban areas, was statistically significant (P = 0.005, 0.04, respectively). Infants born 2006-2007 had a decreased rate of bed-sharing compared to infants born 2002-2005 (0.22, 0.30, respectively, P = 0.00). In light of the high rate of bed-sharing recorded at the first well-child visit, the researchers recommend an increased emphasis on safe sleeping education during the third trimester of pregnancy.


Adoption of AI in response to COVID-19-a configurational perspective.
Although the importance of artificial intelligence (AI) has often been highlighted in strategic agility and decision outcomes, whether it helps firms strengthen their competitiveness and the means firms use to achieve such competitiveness are still under-researched. Our research thus joins the recent discussion on digitalization trends and strategic responses to COVID-19 to better understand how firms strengthen their competitiveness during such challenging times. Namely, this study incorporates the strategic responses to COVID-19 into the technology-organization-environment (TOE) framework by investigating the impacts of different configurations of TOE contexts and strategic responses on a firm's competitive advantage. We used fuzzy-set qualitative comparative analysis to investigate how TOE contexts and strategic responses integrate into configurations and impact a firm's competiveness. By applying a configurational approach with data from 514 exporting firms in China, we find a strong indication of the equifinality of different strategies, indicating that multiple strategic paths can be used to respond to crises. The adoption of AI, while important, is not sufficient to enhance a firm's competitiveness. Our results stress the significance of data quality, organizational resources and capabilities, and digital business model innovation for AI adoption. We also identify successful strategic paths of AI adoption aversion and ambidextrous strategies. The findings have practical implications for firms seeking effective strategies to respond to future crises and sustain their competitive advantages.


Unveiling annual growth chronologies from inter-nodal branch elongations in a fruticose lichen in southern Europe.
Techniques for retrospective analysis of size dynamics at annual resolution remain poorly developed in lichens in general, and fruticose lichens in particular. Only a few attempts in very high latitudes suggested that growth might be studied as a chronosequence of inter-nodal branch elongations. Here we evaluated, for the first time, this hypothesis in a dry Mediterranean environment using the lichen Cladonia rangiformis as a case study. Mixed models supported a strong positive relationship between humidity measured as precipitation/PET and inter-nodal branch elongations. Importantly, model selection suggested that (i) the number of intermodal elongations were a major determinant of stem elongation, and (ii) a second-order temporal autocorrelation denoted legacies of environmental influences at least over the next 2 y. The strong growth-humidity relationship, along with the potential legacies observed, support the idea that inter-nodal branch elongations could be used to reconstruct growth chronologies at annual resolution in drylands. This finding highlights the high vulnerability of these organisms to rising aridity, and opens a new venue for climate reconstruction and other potential applications in Ecology and Earth Science disciplines.


Surface adsorption of metallic species onto microplastics with long-term exposure to the natural marine environment.
Microplastics are ubiquitous in most biomes and environments, representing one of the most pressing global environmental challenges. This study investigated the ability of pre-production microplastic pellets to accumulate metals from the marine environment. An accidental ocean discharge of poly(propylene) pellets occurred via a wastewater treatment centre at the coastal city of Warrnambool, Victoria - Australia. These pellets were collected routinely from Shelly Beach, adjacent to the ocean discharge site over a period of 16-months following the spill. This collection formed a unique time-series that accurately represented the degree to which metal ions in the coastal marine environment accumulate on plastic debris. Elemental analysis indicated an increase in concentration over time of rare earth elements and a selection of other metals supporting the hypothesis that microplastics selectively adsorb metals from the environment. A subset of the poly(propylene) pellets contained a surfactant coating which significantly increased the adsorption capacity. The surface properties in relation to adsorption were further explored with surface imaging and these results are also discussed. This study shows how microplastics act as nucleation points and carriers of trace metal ions in marine environments.


Bortezomib and dexamethasone for multiple myeloma: higher AST and LDH levels associated with a worse prognosis on overall survival.
Bortezomib offers a novel approach to the treatment of multiple myeloma producing rapid control. The aim of this study was to investigate the outcomes of bortezomib and dexamethasone-treated patients with multiple myeloma. We conducted a retrospective study of 44 consecutively-treated multiple myeloma patients with bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11 of a 21-day cycle or 1.3 mg/m(2) intravenously 1, 8, 15, and 22 of every 35-day cycle) and dexamethasone. The median time to progression, progression free survival time, and overall survival time in the treatment groups was 14.9, 14.9, and 38.3 months, respectively. The present study also suggests the possibility that the prognosis of patients with high levels of AST and LDH might be worse. Our results indicate that the treatment of multiple myeloma with bortezomib and dexamethasone is feasible.


Vaginal misoprostol for cervical priming before hysteroscopy in perimenopausal and postmenopausal women.
To evaluate the effectiveness and possible adverse effects of vaginal misoprostol for cervical priming before hysteroscopy in perimenopausal and postmenopausal women. A total of 105 women scheduled for hysteroscopy were randomly assigned to 2 groups. The study group (n=51) received 400 microg of vaginal misoprostol at least 12 h before the procedure and the control group (n=54) received no cervical priming agent. The primary outcome measure was the number of women who required cervical dilation. Secondary outcomes were cervical width (the largest size of Hegar dilator inserted without resistance) as well as complications and adverse effects. In the misoprostol group 27 women (52.9%) required cervical dilation vs. 53 (98.1%) in the control group (P<0.0001). The largest size of Hegar dilator inserted without resistance was 7.6+/-1.4 mm in the misoprostol group vs. 5.0+/-1.1 mm in the control group (P<0.0001). A similar effect of misoprostol on cervical dilation was also found in the subgroup of treated postmenopausal women. Only 2 women (3.9%) experienced mild lower abdominal pain after misoprostol application. Vaginal misoprostol applied before hysteroscopy reduced cervical resistance and the need for cervical dilation in perimenopausal and postmenopausal women, with only mild adverse effects.


Optimum needle length for DPT inoculation of Indian infants.
Correct placement of the injected DPT vaccine into the deep muscular layers decreases the local reactions, including the sterile abscess formation. However, recommendations on size of the needle to be used and the angle of injection are not easily available, are not uniform and are based on case reports. The only study based on scientific data of ultrasonographic measurement of fat layer and muscle layer thickness of thigh of only 24 infants of 4 months age covers only American children. (Hick et al, Pediatrics 1989; 84: 136-37). In the present study, we have produced similar data on 215 Indian children belonging to all those age groups in which DPT vaccinations are given. Mean thickness of skin + fat layer in the middle one-third of the anterolateral aspect of thigh was 1.03 +/- 0.23 cm, 1.04 +/- 0.21 cm, 0.95 +/- 0.19 cm and 1.06 +/- 0.27 cm in the age groups of 6-12 weeks (Groups I), 13-18 weeks (Group II), 19-24 weeks (Groups III) and 18 +/- 1 month (Group IV) respectively. These age groups correspond to the timings of first 3 primary doses and the first booster dose of the DPT vaccine in our immunization clinic. Mean thickness of all the soft tissues together at the same site were 1.87 +/- 0.35, 2.17 +/- 0.38, 2.07 +/- 0.39 and 2.07 +/- 0.26 cm respectively for the groups I to IV.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical Outcomes of Alveolar Ridge Augmentation with In Situ Autogenous Block Bone: A Retrospective Review.
To present clinical outcomes of alveolar ridge augmentation using in situ autogenous block bone and to compare the outcomes with previous studies. The medical records of patients with a severe horizontal bone defect in a partially edentulous alveolar ridge (width < 3.5 mm), who received bone augmentation using in situ autogenous block bone, were retrospectively reviewed. After a 6-month or longer healing period, the augmentation effect was examined before implant placement. Cone beam computed tomography (CBCT) was performed before and after surgeries. The alveolar width of the bone grafts was measured on the CBCT images. A total of 16 patients (22 grafts) were included. Graft exposure was seen in three grafts, which were classified as failed cases. The augmentation volume at implant placement in the failed cases was significantly lower than that of the successful cases. There were no significant differences in augmentation between anterior maxillary and mandibular implant sites. Autogenous bone grafting using in situ block bone is an effective and reliable approach for horizontal bone augmentation in the mandible and anterior maxilla that eliminates second donor site morbidity. Complete release of the buccal flap and tension-free suture is the key to avoiding wound dehiscence and ensuring the effectiveness of bone augmentation.


HIV-exposed infants with EBV infection have a reduced persistence of the immune response to the HBV vaccine.
In sub-Saharan African countries Epstein Barr virus (EBV) infection occurs in early childhood. We aim to investigate the factors associated with EBV acquisition and the impact of EBV infection on the humoral response to HBV vaccination in infants born from HIV-positive, antiretroviral-treated mothers in Malawi. A total of 149 HIV-exposed infants were included in this longitudinal study. EBV anti-VCA IgG were measured using an ELISA assay. The EBV seroconversion was correlated with the maternal viro-immunological conditions, with infant growth and immunological vulnerability, and with the humoral response to the HBV vaccine. No infant was EBV-positive at 6 months (n. 52 tested). More than a third of infants (49/115 or 42.6 %) on study beyond 6 months seroconverted at 12 months. At 24 months, out of 66 tested infants, only 13 remained EBV-uninfected, while 53 (80.3 %) acquired EBV infection, rising the total proportion of EBV seroconversion to 88.7 % (102/115 infants). EBV seroconversion was significantly associated with a low maternal educational status but had no impact on infant growth or vulnerability to infections. Reduced HBsAb levels and accelerated waning of antibodies were associated with early EBV seroconversion. We found a heterogeneous timing of acquisition of EBV with the majority of infants born from HIV + mothers acquiring infection after 6 months. Anti-HBs levels were lower and appeared to wane faster in infants acquiring EBV infection.


Arterial supply of forearm bones and its importance for the operative treatment of fractures.
The operative exposure of a fracture in an osteosynthesis causes disturbances in the blood supply, which often leads to a prolonged process of healing or even to healing problems, a fracture non-union, which is frequently located at the forearm. In order to damage the supplying vessels as little as possible, the position, direction and penetration of the arteries of radius and ulna are demonstrated and systematised in this study. Near the elbow arteries, coming from large adjoining vessels, penetrate the area of the capsular insertion. The nutrient arteries enter both bones in the second proximal quarter of diaphysis, at the radius from anterior to medial, at the ulna from anterior to anteroradial. Small vessels, which penetrate closely proximal to the articular surface in order to supply the distal forearm bones, come from an anastomosis between the radial, the interosseous and the ulnar arteries. In this study access vessels, choice and position of implants will be discussed.


Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non-Muscle-Invasive Bladder Cancer.
Improved risk stratification and predictive biomarkers of treatment response are needed for non-muscle-invasive bladder cancer (NMIBC). Here we assessed the clinical utility of targeted RNA and DNA molecular profiling in NMIBC. Gene expression in NMIBC samples was profiled by NanoString nCounter, an RNA quantification platform, from two independent cohorts (n = 28, n = 50); targeted panel sequencing was performed in a subgroup (n = 50). Gene signatures were externally validated using two RNA sequencing datasets of NMIBC tumors (n = 438, n = 73). Established molecular subtype classifiers and novel gene expression signatures were assessed for associations with clinicopathologic characteristics, somatic tumor mutations, and treatment outcomes. Molecular subtypes distinguished between low-grade Ta tumors with FGFR3 mutations and overexpression (UROMOL-class 1) and tumors with more aggressive clinicopathologic characteristics (UROMOL-classes 2 and 3), which were significantly enriched with TERT promoter mutations. However, UROMOL subclasses were not associated with recurrence after bacillus Calmette-Guérin (BCG) immunotherapy in two independent cohorts. In contrast, a novel expression signature of an inflamed tumor microenvironment (TME) was associated with improved recurrence-free survival after BCG. Expression of immune checkpoint genes (PD-L1/PD-1/CTLA-4) was associated with an inflamed TME, but not with higher recurrence rates after BCG. FGFR3 mutations and overexpression were both associated with low immune signatures. Assessment of the immune TME, rather than molecular subtypes, is a promising predictive biomarker of BCG response. Modulating the TME in an immunologically "cold" tumor warrants further investigation. Integrated transcriptomic and exome sequencing should improve treatment selection in NMIBC.


NK cell-derived extracellular granzyme B drives epithelial ulceration during HSV-2 genital infection.
Genital herpes is characterized by recurrent episodes of epithelial blistering. The mechanisms causing this pathology are ill defined. Using a mouse model of vaginal herpes simplex virus 2 (HSV-2) infection, we show that interleukin-18 (IL-18) acts upon natural killer (NK) cells to promote accumulation of the serine protease granzyme B in the vagina, coinciding with vaginal epithelial ulceration. Genetic loss of granzyme B or therapeutic inhibition by a specific protease inhibitor reduces disease and restores epithelial integrity without altering viral control. Distinct effects of granzyme B and perforin deficiency on pathology indicates that granzyme B acts independent of its classic cytotoxic role. IL-18 and granzyme B are markedly elevated in human herpetic ulcers compared with non-herpetic ulcers, suggesting engagement of these pathways in HSV-infected patients. Our study reveals a role for granzyme B in destructing mucosal epithelium during HSV-2 infection, identifying a therapeutic target to augment treatment of genital herpes.


Apparent decrease in population clearance of theophylline: implications for dosage.
Having observed in recent years that the theophylline dose requirements needed to attain peak serum concentrations of 10 to 20 micrograms/ml infrequently reached previously described mean values, we hypothesized that a downward shift in the range of dose requirements had occurred among patients with asthma. We examined dosage requirements needed to attain peak serum concentrations of 10 to 20 micrograms/ml in all patients with chronic asthma treated with theophylline by the Pediatric Allergy and Pulmonary Clinic at the University of Iowa from 1990 to 1994 (n = 300) and at the Pediatric Pulmonary Clinic at the University of Florida from 1992 to 1995 (n = 93). We then compared these doses to previous dose requirements from 1978 to 1983 determined in the same manner. Despite similar mean peak serum concentrations during both time periods (14 micrograms/ml), mean theophylline dosage requirements during the period of this study were approximately 25% lower among all age groups than those previously observed (p < 0.001). There were no significant differences in mean dosage requirements between the Iowa and Florida patients in any age group examined. Theophylline dose requirements needed to attain serum concentrations of 10 to 20 micrograms/ml have decreased significantly from those on which current dosing recommendations are based. This suggests a decrease in mean clearance of the population.


pH Responsive Carboxymethyl Chitosan/Poly(amidoamine) Molecular Gate Membrane for CO2/N2 Separation.
Efficient carbon dioxide separation is an emerging field of interest in the era of energy scarcity and environmental calamity. The present study focuses on the versatile aspects of carboxymethyl chitosan and dendrimer in terms of CO2 separation. A comprehensive study has been accomplished to inspect the physicochemical properties of the prepared membrane. The mixed gas (CO2/N2) separation performances have been measured varying the temperature (60-110 °C) and sweep/feedwater flow ratio (0.33-3). The blend membrane containing 10 weight (wt.)% dendrimer presented highest CO2 permeance of ∼100 GPU and CO2/N2 selectivity ∼149 on maintenance of sweep/feedwater flow ratio 2.33 and 1.67, respectively, at an operating temperature of 90 °C. The remarkable performance displayed by the membrane has been explained with reference to the dendrimer molecular gate mechanism and the salting out effect offered by carboxymethyl chitosan matrix.


[Prevention and aging--topics for medical training and continuing education? Analysis of current and future situations].
Due to the current demographic changes, prevention, health promotion, and aging are key topics for future healthcare delivery systems. Interviews with physicians and analyses of the medical training and continuing education show substantial deficits within these areas. The restructuring of the medical training in Germany, together with the introduction of a new boardcertification ordinance, offers the opportunity to strengthen these topics.


Transition metals mediate enzymatic inactivation caused by favism-inducing agents.
Enzymatic activity of purified or membrane-bound acetylcholine esterase was lost when incubated aerobically in the presence of both favism-inducing agent (isouramil or divicine) and copper ions. The requirement for oxygen could be substituted by hydrogen peroxide. Chelating agents provided total protection to the proteins. The suggested mechanism of enzymatic inactivation is analogous to that suggested earlier for the effects of superoxide and ascorbate, and involves the site-specific formation of hydroxyl radicals in the metal-mediated Haber-Weiss reaction. These findings may be relevant to the understanding of the pathogenesis of favism.


The novel tetrahydropyrimidine derivative as inhibitor of SARS CoV-2: synthesis, modeling and molecular docking analysis.
N-(1,3-Benzothiazol-2-yl)-N-(1,4,5,6-tetrahydro-1H-pyrimidine-2-yl) amine was synthesized and characterized by elemental analysis, FT-IR, NMR and X-ray single crystal diffraction. The compound structure belongs to the triclinic system with the P-1 space group with unit cell parameters a = 11.9290(4), b = 13.2547(4) and c = 15.3904(5) Å. Hirhsfeld surface analysis is performed to revealintermolecular interactions with these interactions. The molecular structure, vibrational spectroscopic data and HOMOs and LUMOs analyses were calculated by using the DFT/B3LYP method with the 6-311 + G(d,p)) basis set. Some of pharmacokinetic parameters and drug-likeness properties of the compound were also performed. Besides these, the present work is a searching to test N-(1,3-benzothiazol-2-yl)-N-(1,4,5,6-tetrahydro-1H-pyrimidine-2-yl) amine as an inhibitor for the SARS-CoV-2. For this aim, the molecular docking analysis of the synthesized compound was applied along with Favipiravir. Besides the docking results, ADMET properties of the compound were also calculated.Communicated by Ramaswamy H. Sarma.


Women's empowerment is associated with maternal nutrition and low birth weight: evidence from Bangladesh Demographic Health Survey.
The burden of maternal undernutrition and low birth weight (LBW) incurs enormous economic costs due to their adverse consequences. Women's empowerment is believed to be one of the key factors for attaining maternal and child health and nutritional goals. Our objective was to investigate the association of women's empowerment with maternal undernutrition and LBW. We used nationally representative data from the Bangladesh Demographic Health Survey for 2011 and 2014. We analysed 27357 women and 9234 mother-child pairs. A women's empowerment index (WEI) was constructed using principal component analysis with five groups of indicators: a) education, b) access to socio-familial decision making, c) economic contribution and access to economic decision making, d) attitudes towards domestic violence and e) mobility. We estimated odds ratios as the measure of association between the WEI and the outcome measures using generalized estimating equations to account for the cluster level correlation. The overall prevalence of maternal undernutrition was 20% and LBW was 18%. The WEI was significantly associated with both maternal undernutrition and LBW with a dose-response relationship. The adjusted odds of having a LBW baby was 32% [AOR (95% CI): 0.68 (0.57, 0.82)] lower in the highest quartile of the WEI relative to the lowest quartile. Household wealth significantly modified the effect of the WEI on maternal nutrition; in the highest wealth quintile, the odds of maternal undernutrition was 54% [AOR (95% CI): 0.46 (0.33, 0.64)] lower while in the lowest wealth quintile the odds of undernutrition was only 18% [AOR (95% CI): 0.82 (0.67, 1.00)] lower comparing the highest WEI quartile with the lowest WEI quartile. However, the absolute differences in prevalence of undernutrition between the highest and lowest WEI quartiles were similar across wealth quintiles (6-8%). This study used a comprehensive measure of women's empowerment and provides strong evidence that low levels of women's empowerment are associated with maternal undernutrition as well as with delivering LBW babies in Bangladesh. Therefore, policies to increase empowerment of women would contribute to improved public health.


Alternatives to psychiatric hospitalization for children.
The impetus for the dramatic increase in the number of treatment alternatives for children has come from changes in the theoretical conceptualization of treatment, social and political pressures, and financial considerations. This article reviews the literature on alternatives to hospitalization, appraising the available data on the effectiveness of psychiatric hospitalization and its alternatives and considers future research needs and the development of services in this area.


Comparison of the aflatoxin B1-8,9-epoxide conjugating activities of two bacterially expressed alpha class glutathione S-transferase isozymes from mouse and rat.
The complementary DNAs of rat glutathione S-transferase (GST, EC 22.214.171.124) Yc1 and of mouse Yc were expressed from a prokaryotic expression vector in E. coli. The purified proteins were analyzed for their activity toward aflatoxin B1-8,9-epoxide (AFBO), the reactive intermediate of the fungal mycotoxin aflatoxin B1 (AFB). The mouse Yc isozyme had about 50-fold higher conjugating activity toward AFBO than the rat Yc1 isozyme (144 nmol/mg/min versus 3.3 nmol/mg/min). The rat Yc1 isozyme had specific activities toward 1-chloro-2,4-dinitrobenzene, cumene hydroperoxide and ethacrynic acid of 10.7, 0.98 and 0.92 mumol/mg/min, respectively, whereas the mouse Yc isozyme had specific activities of 5.7, 2.1 and 0.1 mumol/mg/min for these substrates, respectively. These data provide further support for the hypothesis that the constitutive presence of the alpha class GST Yc isozyme in mouse liver protects mice from the hepatocarcinogenic effects of aflatoxin B1.


Toxic epidermal necrolysis related to Cisplatin and pemetrexed for metastatic non-small cell lung cancer.
Toxic epidermal necrolysis (TEN) is an uncommon but life-threatening adverse drug reaction. Pemetrexed is a multitargeted antifolate. It was first used in combination with cisplatin as a front-line treatment for malignant pleural mesothelioma. The same combination is nowadays approved in the first-line setting for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). We report the case of a 50-year-old man treated for metastatic NSCLC. Within 5 days after administration of the second cycle of cisplatin and pemetrexed, he developed large blisters, which secondarily became hemorrhagic, and mucosal lesions. The characteristic clinical appearance, the histopathological findings, and the clinical course were decisive for the diagnosis of TEN. Treatment with systemic steroids and intravenous antibiotics as well as topical wound treatment led to resolution and improvement of his general condition. To the best of our knowledge, this is the third case of TEN due to pemetrexed in a patient with NSCLC. Clinicians should be aware of TEN as a rare but potentially fatal disorder requiring hospitalization and multidisciplinary management.


The Acquisition of Clause Chaining in Nungon.
The clause chain is an under-investigated complex sentence type, found in hundreds of languages. In a clause chain, as many as 20 or more 'medial' clauses with under-specified verbal predicates combine with a single 'final' clause with fully-specified verbal predicate. Clause chains are of interest for three main reasons: (a) the special syntactic relationship between clauses, which is neither textbook subordination nor coordination; (b) the potential extreme length of a single chain; and (c) switch-reference marking in clause chains of some languages could require speakers to plan at least one clause ahead as they speak. Research on child production of complex sentences has largely overlooked clause chains. Longitudinal data for three children aged 1;1 to 3;3 acquiring the Papuan language Nungon show that Nungon-speaking children begin producing clause chains around the age of 2;4, with a marked increase in rate of use around age 2;11. Chain length is limited to two clauses until age 3;1. Different-subject marking in medial clauses is used by all three children early, but is first attested in one-clause, 'root medial' contexts, rather than in chains. Bayesian statistical models confirm the strong tendency for children to use root medials in expressions of desires and commands. Children's production of three types of complex sentences-clause chains, subordinated final clauses, and coordinated final clauses-is shown to be subject to the same type of developmental constraint; but once development reaches an adequate level for increased complex sentence production, children acquiring Nungon produce many more clause chains than complex sentences involving subordinated or coordinated final clauses.


Electrolytic manganese residue-based cement for manganese ore pit backfilling: Performance and mechanism.
Slag backfilling with electrolytic manganese residue (EMR) is an economical and environmentally-friendly method. However, high ammonium-nitrogen and manganese ions in EMRs limit this practice. In this study, a method of highly efficient simultaneous stabilization/solidification of ultrafine EMR by making EMR-based cementitious material (named EMR-P) was proposed and tested via single-factor and response surface optimization experiments. Results show that the stabilization efficiency of NH4+ and Mn2+ were above 95%, and the unconfined compressive strength of the EMR-P was 18.85 MPa (megapascal = N/mm2). The mechanistic study concluded that the soluble manganese sulfate and ammonium sulfate in EMR were converted into the insoluble precipitates of manganite (MnOOH), gypsum (CaSO4), MnNH4PO4·H2O, and struvite (MgNH4PO4∙6 H2O), leading to the stabilization of NH4+ and Mn2+ in the EMR-P. Leaching tests of EMR-P indicated that NH4+, Mn2+, and others heavy metals in the leachate were within the permitted level of the GB/T8978-1996. The novelty of this study includes the addition of phosphate and magnesium ions to precipitate ammonium-nitrogen and the combination between calcium ions (from CaHPO4∙2 H2O) and sulfate (from the EMR) to form calcium sulfate to improve the stability and unconfined compressive strength of cementitious materials (EMR-P).


Resonant inelastic x-ray scattering data for Ruddlesden-Popper and reduced Ruddlesden-Popper nickelates.
Ruddlesden-Popper and reduced Ruddlesden-Popper nickelates are intriguing candidates for mimicking the properties of high-temperature superconducting cuprates. The degree of similarity between these nickelates and cuprates has been the subject of considerable debate. Resonant inelastic x-ray scattering (RIXS) has played an important role in exploring their electronic and magnetic excitations, but these efforts have been stymied by inconsistencies between different samples and the lack of publicly available data for detailed comparison. To address this issue, we present open RIXS data on La4Ni3O10 and La4Ni3O8.


Nitric oxide as a regulator of neuronal motility and regeneration in the locust embryo.
Nitric oxide (NO) is known as a gaseous messenger in the nervous system. It plays a role in synaptic plasticity, but also in development and regeneration of nervous systems. We have studied the function of NO and its signaling cascade via cyclic GMP in the locust embryo. Its developing nervous system is well suited for pharmacological manipulations in tissue culture. The components of this signaling pathway are localized by histochemical and immunofluorescence techniques. We have analyzed cellular mechanisms of NO action in three examples: 1. in the peripheral nervous system during antennal pioneer axon outgrowth, 2. in the enteric nervous system during migration of neurons forming the midgut nerve plexus, and 3. in the central nervous system during axonal regeneration of serotonergic neurons after axotomy. In each case, internally released NO or NO-induced cGMP synthesis act as permissive signals for the developmental process. Carbon monoxide (CO), as a second gaseous messenger, modulates enteric neuron migration antagonistic to NO.


Efficacy of the spiral flow generating extended tube during paediatric CCTA.
To compare the computed tomography (CT) number for paediatric cardiac computed tomography angiography (CCTA) and visualisation score of the three-dimensional (3D) images using the conventional T-shaped extended tube (T-tube) and spiral flow-generating extended tube (spiral-tube) connected between the contrast injector and cannula. In total, 108 patients suspected to have congenital heart disease (CHD) were considered for inclusion. We utilised the T-tube for intravenous contrast and spiral-tube in 54 patients each. Observers individually inspected randomized volume rendering images of the internal thoracic artery, each acquired from the with or without spiral-tube groups, using a four-point scale. We compared the mean CT number of the ascending aorta (AAO) and pulmonary artery (PA), contrast noise ratio (CNR), CT number for the AAO and PA enhancement ratio, and the visualisation scores between the groups. There were no significant differences in patient characteristics between the with or without spiral-tube groups (p > 0.05). The mean CT number ±standard deviation for the AAO and PA, and the CNR without or with spiral-tube groups were 441.2 ± 89.2 and 489.8 ± 86.1 HU for the AAO, 436.3 ± 100.6 and 475.3 ± 85.2 HU for the PA, and 9.5 ± 2.2 and 10.8 ± 2.4 for the CNR, respectively (p < 0.05). In the spiral-tube group, the CT number, CNR, and visualisations score of the 3D images were significantly higher for the AAO and PA than those in the T-tube group (p < 0.05). The spiral-tube proved to be beneficial in improving the CT number for the AAO and PA, CNR, and visualisation score compared with the conventional T-tube during paediatric CCTA. The spiral-tube may allow the visualisation of smaller blood vessels than those visualised by the conventional T-tube for paediatric patients in CCTA.


New Insights into Gastrointestinal Involvement in Late-Onset Pompe Disease: Lessons Learned from Bench and Bedside.
There are new emerging phenotypes in Pompe disease, and studies on smooth muscle pathology are limited. Gastrointestinal (GI) manifestations are poorly understood and underreported in Pompe disease. To understand the extent and the effects of enzyme replacement therapy (ERT; alglucosidase alfa) in Pompe disease, we studied the histopathology (entire GI tract) in Pompe mice (GAAKO 6neo/6neo). To determine the disease burden in patients with late-onset Pompe disease (LOPD), we used Patient-Reported Outcomes Measurements Information System (PROMIS)-GI symptom scales and a GI-focused medical history. Pompe mice showed early, extensive, and progressive glycogen accumulation throughout the GI tract. Long-term ERT (6 months) was more effective to clear the glycogen accumulation than short-term ERT (5 weeks). GI manifestations were highly prevalent and severe, presented early in life, and were not fully amenable to ERT in patients with LOPD (n = 58; age range: 18-79 years, median age: 51.55 years; 35 females; 53 on ERT). GI manifestations cause a significant disease burden on adults with LOPD, and should be evaluated during routine clinical visits, using quantitative tools (PROMIS-GI measures). The study also highlights the need for next generation therapies for Pompe disease that target the smooth muscles.


Antiepileptic drugs with mood stabilizing properties and their relation with psychotropic drug use in institutionalized epilepsy patients with intellectual disability.
A large number of patients with epilepsy and intellectual disability take medication, amongst which antiepileptic and psychotropic drugs, often simultaneously. Certain antiepileptic drugs have mood-stabilizing properties, e.g. carbamazepine, valproic acid and lamotrigine. The aim of this study was to investigate whether the use of these mood-stabilizers is associated with a different use of psychotropic drugs in a population of institutionalized epilepsy patients with intellectual disability. We performed a retrospective, cohort study of adults with intellectual disability and epilepsy at the long-stay department of an epilepsy centre in The Netherlands. 246 residents were included. In patients using lamotrigine we found a statistically significant lower use of antidepressants. We also found significant less prescriptions of anxiolytics in patients using AEDs with mood-stabilizing properties (carbamazepine, valproic acid and lamotrigine). When considering the effect of gender, we found that male patients took significantly more antipsychotics. Most important, we found an inverse relation between the drug load of carbamazepine and/or valproic acid and/or lamotrigine and the use of psychotropic drugs. In a population of institutionalized epilepsy patients with intellectual disability, higher drug loads of mood-stabilizing antiepileptic drugs correspond with less use of psychotropic drugs.


Prevalence of genetically confirmed skeletal muscle channelopathies in the era of next generation sequencing.
We provide an up-to-date and accurate minimum point prevalence of genetically defined skeletal muscle channelopathies which is important for understanding the population impact, planning for treatment needs and future clinical trials. Skeletal muscle channelopathies include myotonia congenita (MC), sodium channel myotonia (SCM), paramyotonia congenita (PMC), hyperkalemic periodic paralysis (hyperPP), hypokalemic periodic paralysis (hypoPP) and Andersen- Tawil Syndrome (ATS). Patients referred to the UK national referral centre for skeletal muscle channelopathies and living in UK were included to calculate the minimum point prevalence using the latest data from the Office for National Statistics population estimate. We calculated a minimum point prevalence of all skeletal muscle channelopathies of 1.99/100 000 (95% CI 1.981-1.999). The minimum point prevalence of MC due to CLCN1 variants is 1.13/100 000 (95% CI 1.123-1.137), SCN4A variants which encode for PMC and SCM is 0.35/100 000 (95% CI 0.346 - 0.354) and for periodic paralysis (HyperPP and HypoPP) 0.41/100 000 (95% CI 0.406-0.414). The minimum point prevalence for ATS is 0.1/100 000 (95% CI 0.098-0.102). There has been an overall increase in point prevalence in skeletal muscle channelopathies compared to previous reports, with the biggest increase found to be in MC. This can be attributed to next generation sequencing and advances in clinical, electrophysiological and genetic characterisation of skeletal muscle channelopathies.


Chondrotoxicity of quinolones in vivo and in vitro.
Chondrotoxicity is a rare toxicological finding which is observed in dogs after administration of quinolone antibacterials. To study this effect chondrocytes from articular cartilage of dogs were isolated, and incubated with quinolone derivatives. The effects on cell viability, mitochondrial dehydrogenase, and proteoglycan synthesis were determined. These results were compared with in vivo findings in dogs treated with these quinolones. It was concluded that inhibition of mitochondrial dehydrogenase activity and of proteoglycan synthesis are major reasons for cartilage damage. Therefore this in vitro model is capable of identifying strongly arthropathogenic quinolones without the need of performing animal studies.


Molecularly imprinted polymer specific to creatinine complex with copper(II) ions for voltammetric determination of creatinine.
Synthesis of creatinine-imprinted polymer is challenging because of its insolubility in aprotic solvents, traditionally utilized for synthesizing molecularly imprinted polymer (MIP). Moreover, creatinine is not electroactive at conventional electrodes, and thus, introducing an electrochemical sensing platform for its determination is a difficult target. This study addressed the above-cited issues to introduce a novel creatinine voltammetric sensor with high selectivity and sensitivity. Creatinine-copper complex was found to be soluble in acetonitrile and was utilized as a template for the MIP synthesis. Methacrylic acid, ethylene glycol dimethacrylate, and azobisisobutyronitrile were used as functional monomers, cross-linker, and initiator, respectively. The MIP holding creatinine sites were used to modify the carbon paste electrode. Since creatinine did not exhibit a significant voltammetric signal, an indirect sensing technique was employed. This was based on using Cu(II) ion as an electrochemical probe. The MIP-modified electrode signal for copper ion was significantly improved in the presence of creatinine. However, the introduction of creatinine in the Cu(II) solution did not affect the NIP-modified electrode response to copper ion. The proposed sensor indicated a linear current response in the range 1 × 10-7-1 × 10-5 mol L-1 with a detection limit of 5.9 × 10-8 mol L-1 (S/N = 3). Moreover, this method presents excellent performance in real sample analysis, with values of favorable creatinine recovery in plasma. The system exhibits acceptable precision (RSD = 4.04) and favorable selectivity toward creatinine.


A multimodal study regarding neural correlates of the subjective well-being in healthy individuals.
Although happiness or subjective well-being (SWB) has drawn much attention from researchers, the precise neural structural correlates of SWB are generally unknown. In the present study, we aimed to investigate the associations between gray matter (GM) volumes, white matter (WM) microstructures, and SWB in healthy individuals, mainly young adults using multimodal T1 and diffusion tensor imaging studies. We enrolled 70 healthy individuals using magnetic resonance imaging. We measured their SWB using the Concise Measure of Subjective Well-Being. Voxel-wise statistical analysis of GM volumes was performed using voxel-based morphometry, while fractional anisotropy (FA) values were analyzed using tract-based spatial statistics. In healthy individuals, higher levels of SWB were significantly correlated with increased GM volumes of the anterior insula and decreased FA values in clusters of the body of the corpus callosum, precuneus WM, and fornix cres/stria terminalis. A correlational analysis revealed that GM volumes and FA values in these significant regions were significantly correlated with severity of psychological symptoms such as depression, anxiety, and quality of life. Our findings indicate that GM volumes and WM microstructures in these regions may contribute to SWB, and could be the neural basis for psychological symptom severity as well as quality of life in healthy individuals.


On the mechanism of hyperacidification in lemon. Comparison of the vacuolar H(+)-ATPase activities of fruits and epicotyls.
Lemon fruit vacuoles acidify their lumens to pH 2.5, 3 pH units lower than typical plant vacuoles. To study the mechanism of hyperacidification, the kinetics of ATP-driven proton pumping by tonoplast vesicles from lemon fruits and epicotyls were compared. Fruit vacuolar membranes. H+ pumping by epicotyl membranes was chloride-dependent, stimulated by sulfate, and inhibited by the classical vacuolar ATPase (V-ATPase) inhibitors nitrate, bafilomycin, N-ethylmaleimide, and N,N'-dicyclohexylcarbodiimide. In addition, the epicotyl H+ pumping activity was inactivated by oxidation was reversed by dithiothreitol. Cold inactivation of the epicotyl V-ATPase by nitrate ( > or = 100 mM) was correlated with the release of V1 complexes from the membrane. In contrast, H+ pumping by the fruit tonoplast-enriched membranes was chloride-independent, largely insensitive to the V-ATPase inhibitors, and resistant to oxidation. Unlike the epicotyl inhibitors, and resistant to oxidation. Unlike the epicotyl H(+)-ATPase, the fruit H(+)-ATPase activity was partially inhibited by 200 microM vanadate. Cold inactivation treatment failed to inhibit H+ pumping activity of the fruit membranes, even though immunoblasts showed that V1 complexes were released from the membrane. However, cold inactivation doubled the percent inhibition by 200 microM vanadate from 30% to 60%. These results suggest the presence of two H(+)-ATPases in the fruit preparation: a V-ATPase and an unidentified vanadate-sensitive H(+)-ATPase. Attempts to separate the two activities in their native membranes on linear sucrose density density gradients were unsuccessful. However, following detergent-solubilization and centrifugation on a glycerol density gradient, the two ATPase activities were resolved: a nitrate-sensitive V-type ATPase that is also partially inhibited by 200 microM vanadate, and an apparently novel vanadate-sensitive ATPase that is also partially inhibited by nitrate.


NIDCD's 5-year strategic plan seeks innovations in assistive device technologies.
The National Institute on Deafness and Other Communication Disorders (NIDCD) recently announced the release of its five-year strategic plan, with scientific priorities that include basic research, model systems, innovative technologies, individualized treatment approaches, scientific data sharing, and translation of research into clinical tools [1].


Levels of Physical Activity and Sedentary Behavior During and After Hospitalization: A Systematic Review.
To systematically review and synthesize the evidence on physical activity and sedentary behavior during and after hospitalization. Electronic databases and reference lists of relevant articles were searched from 2000 to April 2020. Studies which continuously monitored physical activity and/or sedentary behavior in hospitalized adults across 2 settings (ie, without a break in measurement between settings). Monitoring could occur from an acute to a subacute or rehabilitation hospital setting, an acute setting to home, or from a subacute or rehabilitation setting to home. Data extraction and methodological quality assessments were independently performed by 2 reviewers using standardized checklists. A total of 15 of the 5579 studies identified were included. The studies were composed of heterogenous patient populations. All studies monitored patients with either an accelerometer and/or pedometer and reported a variety of measures, including steps per day, sedentary time, and activity counts. The majority of studies (12 of 15) showed that patients engaged in 1.3 to 5.9 times more physical activity and up to 67% less daily sedentary behavior at home after discharge from acute or subacute settings. Patients engaged in more physical activity and less sedentary behavior at home compared to both the acute and subacute hospital settings. This may reflect the natural course of recovery or the effect of setting on activity levels. Enabling early discharge home through the implementation of home-hospitalization models may result in increased patient physical activity and reduced sedentary behavior. Further experimental studies are required investigating the effect of home-based models of care on physical activity and sedentary behavior.


[Influence of thyroid hormones on monoamine oxidase activity in newborn rats].
In young Rats made hypothyroid from birth, the activity of monoamine oxidase at 20 days is smaller than controls in brain, heart and kidney. In Rats made hyperthyroid by injections of thyroxine, the activity is lower in brain kidney and liver and is 3.8 times higher in the heart.


Genetic evidence of ribosomal antisuppressors in Podospora anserina.
Antisuppressors were screened for with the help of informational suppressors in Podospores anserina. Four mutations in the AS1 locus and two in the AS2 locus were isolated, using allele non specific suppressors supposed to be ribosomal ambiguity mutations. Four mutations in the AS3 locus and 45 in the AS4 locus were obtained, using a nonsense (t-RNA like) suppressor. All antisuppressors are partially dominant. Most mutations in the AS4 locus are lethal. The four mutants at the AS3 locus and 6 out of the 8 viable mutants at the AS4 locus are cold sensitive. Phenotypic properties and action spectra of the antisuppressors suggest that they are restrictive ribosomal mutations.


Comparative Effectiveness of Digital Breast Tomosynthesis and Mammography in Older Women.
Digital breast tomosynthesis (DBT) has become a prevalent mode of breast cancer screening in recent years. Although older women are commonly screened for breast cancer, little is known about screening outcomes using DBT among older women. To assess proximal screening outcomes with DBT compared to traditional two-dimensional(2-D) mammography among women 67-74 and women 75 and older. Cohort study. Medicare fee-for-service beneficiaries aged 67 years and older with no history of prior cancer who received a screening mammogram in 2015. Use of subsequent imaging (ultrasound and diagnostic mammography) as an indication of recall, breast cancer detection, and characteristics of breast cancer at the time of diagnosis. Analyses used weighted logistic regression to adjust for potential confounders. Our study included 26,406 women aged 67-74 and 17,001 women 75 and older who were screened for breast cancer. Among women 75 and older, the rate of subsequent imaging among women screened with DBT did not differ significantly from 2-D mammography (91.8 versus 97.0 per 1,000 screening mammograms, p=0.37). In this age group, DBT was associated with 2.1 additional cancers detected per 1,000 screening mammograms compared to 2D (11.5 versus 9.4, p=0.003), though these additional cancers were almost exclusively in situ and stage I invasive cancers. For women 67-74 years old, DBT was associated with a higher rate of subsequent imaging than 2-D mammography (113.9 versus 100.3, p=0.004) and a higher rate of stage I invasive cancer detection (4.7 versus 3.7, p=0.002), but not other stages. Breast cancer screening with DBT was not associated with lower rates of subsequent imaging among older women. Most additional cancers detected with DBT were early stage. Whether detecting these additional early-stage cancers among older women improves health outcomes remains uncertain.


Classification of benign and malignant breast masses based on shape and texture features in sonography images.
The purpose of this research was evaluating novel shape and texture feature' efficiency in classification of benign and malignant breast masses in sonography images. First, mass regions were extracted from the region of interest (ROI) sub-image by implementing a new hybrid segmentation approach based on level set algorithms. Then two left and right side areas of the masses are elicited. After that, six features (Eccentricity_feature, Solidity_feature, DeferenceArea_Hull_Rectangular, DeferenceArea_Mass_Rectangular, Cross-correlation-left and Cross-correlation-right) based on shape, texture and region characteristics of the masses were extracted for further classification. Finally a support vector machine (SVM) classifier was utilized to classify breast masses. The leave-one-case-out protocol was utilized on a database of eighty pathologically-proven breast sonographic images of patients (forty-seven benign cases and thirty-three malignant cases) to evaluate our method. The classification results showed an overall accuracy of 95.00%, sensitivity of 90.91%, specificity of 97.87%, positive predictive value of 96.77%, negative predictive value of 93.88%, and Matthew's correlation coefficient of 89.71%. The experimental results declare that our proposed method is actually a beneficial tool for the diagnosis of the breast cancer and can provide a second opinion for a physician's decision or can be used for the medicine training especially when coupled with other modalities.


PFASUM: a substitution matrix from Pfam structural alignments.
Detecting homologous protein sequences and computing multiple sequence alignments (MSA) are fundamental tasks in molecular bioinformatics. These tasks usually require a substitution matrix for modeling evolutionary substitution events derived from a set of aligned sequences. Over the last years, the known sequence space increased drastically and several publications demonstrated that this can lead to significantly better performing matrices. Interestingly, matrices based on dated sequence datasets are still the de facto standard for both tasks even though their data basis may limit their capabilities. We address these aspects by presenting a new substitution matrix series called PFASUM. These matrices are derived from Pfam seed MSAs using a novel algorithm and thus build upon expert ground truth data covering a large and diverse sequence space. We show results for two use cases: First, we tested the homology search performance of PFASUM matrices on up-to-date ASTRAL databases with varying sequence similarity. Our study shows that the usage of PFASUM matrices can lead to significantly better homology search results when compared to conventional matrices. PFASUM matrices with comparable relative entropies to the commonly used substitution matrices BLOSUM50, BLOSUM62, PAM250, VTML160 and VTML200 outperformed their corresponding counterparts in 93% of all test cases. A general assessment also comparing matrices with different relative entropies showed that PFASUM matrices delivered the best homology search performance in the test set. Second, our results demonstrate that the usage of PFASUM matrices for MSA construction improves their quality when compared to conventional matrices. On up-to-date MSA benchmarks, at least 60% of all MSAs were reconstructed in an equal or higher quality when using MUSCLE with PFASUM31, PFASUM43 and PFASUM60 matrices instead of conventional matrices. This rate even increases to at least 76% for MSAs containing similar sequences. We present the novel PFASUM substitution matrices derived from manually curated MSA ground truth data covering the currently known sequence space. Our results imply that PFASUM matrices improve homology search performance as well as MSA quality in many cases when compared to conventional substitution matrices. Hence, we encourage the usage of PFASUM matrices and especially PFASUM60 for these specific tasks.


Fibroblast growth factor 23 as a biomarker of right ventricular dysfunction in pulmonary hypertension.
Fibroblast growth factor 23 (FGF-23) has been associated with left ventricular hypertrophy (LVH) and heart failure. However, its role in right ventricular (RV) remodeling and RV failure is unknown. This study analyzed the utility of FGF-23 as a biomarker of RV function in patients with pulmonary hypertension (PH). In this observational study, FGF-23 was measured in the plasma of patients with PH (n = 627), dilated cardiomyopathy (DCM, n = 59), or LVH with severe aortic stenosis (n = 35). Participants without LV or RV abnormalities served as controls (n = 36). Median FGF-23 plasma levels were higher in PH patients than in healthy controls (p < 0.001). There were no significant differences between PH, DCM, and LVH patients. Analysis across tertiles of FGF-23 levels in PH patients revealed an association between higher FGF-23 levels and higher levels of NT-proBNP and worse renal function. Furthermore, patients in the high-FGF-23 tertile had a higher pulmonary vascular resistance (PVR), mean pulmonary artery pressure, and right atrial pressure and a lower cardiac index (CI) than patients in the low tertile (p < 0.001 for all comparisons). Higher FGF-23 levels were associated with higher RV end-diastolic diameter and lower tricuspid annular plane systolic excursions (TAPSE) and TAPSE/PASP. Receiver operating characteristic analysis revealed FGF-23 as a good predictor of RV maladaptation, defined as TAPSE < 17 mm and CI < 2.5 L/min/m2. Association of FGF-23 with parameters of RV function was independent of the glomerular filtration rate in regression analysis. FGF-23 may serve as a biomarker for maladaptive RV remodeling in patients with PH.


The effects of maternal smoking exposure during pregnancy on postnatal outcomes: A cross sectional study.
The purpose of this article was to evaluate the effect of maternal smoking exposure during pregnancy on postnatal outcomes. This prospective study enrolled 278 pregnant women in the third trimester, who were asked to complete a questionnaire which included inquires about the nature and extent of smoking exposure during their pregnancy. In addition to the questionnaire, each study subject provided urine sample for the measurement of cotinine. Using data generated from this inquiry, we analyzed the association between maternal smoking exposure and birth outcomes. From the 278 enrollees in this study, a minority of subjects (7.2%) smoked, while 40.6% of the study subjects were exposed to environmental tobacco smoke during pregnancy. There was significantly higher birth weight (3205.2 ± 373.1 vs 3089.7 ± 363.0 vs 2959.0 ± 403.7 g, p = 0.004), larger chest size (33.1 ± 1.7 cm vs 32.7 ± 1.5 cm vs 32.0 ± 1.7 cm, p = 0.009), higher bilirubin on postnatal day 3 (8.9 ± 1.6 vs 8.6 ± 1.5 vs 7.8 ± 1.4 mg/dL, p = 0.015), but lower maternal urinary cotinine level (83.7 ± 132.4 vs 153.2 ± 96.0 vs 800.5 ± 1027.8 μg/g creatinine, p < 0.001) in smoking-free status than in passive or active smoking status. Significant risks of birth weight < 2500 g (AOR 3.93 (95% CI 1.61-9.59), p = 0.003) and maternal urinary cotinine ≥ 143 μg/g creatinine (AOR 3.38 (95% CI 2.02-5.66), p < 0.001) were observed as smoking exposure increased. There was significantly higher birth weight (p = 0.048), larger chest size (p = 0.045), and higher bilirubin level on postnatal day 3 (p < 0.001) in the group with cotinine <143 μg/g creatinine than in the group with cotinine ≥ 143 μg/g creatinine. Our results demonstrated that maternal smoking exposure during pregnancy is associated with low birth weight and small chest circumference. Although the incidence of active smoking in Taiwanese pregnant women is low, most of them are exposed to passive smoking environment. Further studies are required to evaluate useful interventions to enhance a smoking-free environment during pregnancy.


Decoding cognition in real-time.
How can we study unobservable cognitive processes that cannot be measured directly? This has been an enduring challenge for cognitive scientists. In this essay we discuss advances in neurotechnology that could allow cognitive processes to be decoded in real-time and the implications that this may have for cognitive science and the treatment of neuropsychiatric disease.


Publicly Funded Oral Chronic Hepatitis B Treatment Patterns in Ontario over 16 Years: An Ecologic Study.
Reimbursement for the use of hepatitis B virus (HBV) treatments has not been previously reported for public payers. To describe the number of users and total cost of HBV treatments over the last 16 years among residents of Ontario, Canada, who were covered by the public drug program. We conducted a repeated cross-sectional study for HBV treatments reimbursed by the public drug program in Ontario from January 1, 2000, to December 31, 2015. We projected total spending to 2020 based on current utilization trends. HBV drug users per year increased 30-fold, from 132 users in 2000 to 4,035 users in 2015. Total spending on HBV treatments increased 150-fold, from $136,368 annually in 2000 to $21.0 million in 2015. The spending on HBV agents is projected to increase by 65%, with an estimated drug cost of $34.6 million by 2020. Although not reimbursed as first-line therapy, tenofovir disoproxil fumarate has become the most commonly reimbursed HBV treatment and was associated with an increase in HBV treatment use and total spending. Results of this study found that rapid growth of HBV treatments led to a sustained increase in spending for public payers in Ontario. This study was funded by grants from the Ontario Ministry of Health and Long-Term Care (MOHLTC) and Ontario Strategy for Patient-Orientated Research (SPOR) Support Unit, which is supported by the Canadian Institutes of Health Research and the Province of Ontario. This study was also supported by the Institute for Clinical Evaluative Sciences (ICES), a non-profit research institute sponsored by the Ontario MOHLTC. The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Parts of this material are based on data and information compiled and provided by the Canadian Institute for Health Information (CIHI). However, the analyses, conclusions, opinions and statements expressed herein are those of the authors and not necessarily those of CIHI. Mamdani has received honoraria from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Bayer. Janssen has received research support, consulting, and/or speaking fees from Gilead, Roche, Merck, AbbVie, Bristol-Myers Squibb, Arbutus, Janssen, and MedImmune. No other authors have any conflicts of interest to declare.


Prostaglandins: mechanisms of action and regulation of production in bone.
Prostaglandins (PGs), particularly PGE2, are produced by bone and have powerful effects on bone metabolism. PGs have an initial, transient, direct inhibitory effect on osteoclast function. However, the major long-term effect in bone organ culture is to stimulate bone resorption by increasing the replication and differentiation of new osteoclasts. PGs also stimulate osteoclast formation in cell culture systems. Stimulation of osteoclastic bone resorption may be important in mediating bone loss in response to mechanical forces and inflammation. PGs have a biphasic effect on bone formation. At relatively low concentrations or in the presence of glucocorticoids, the replication and differentiation of osteoblasts is stimulated and bone formation is increased. This increase is associated with an increase in production of insulin-like growth factor-I (IGF-I). However, at high concentrations or in the presence of IGF-I, PGE2 inhibits collagen synthesis. In osteoblastic cell lines this inhibition can be shown to occur at the level of transcription of the collagen gene. The stimulatory effect on bone formation has been demonstrated when PGs are administered exogenously, but it is not clear how endogenous PG production affects bone formation in physiological or pathologic circumstances. The production of PGs in bone is highly regulated. The major source appears to be cells of the osteoblast lineage. A major site of regulation is at the level of the enzyme PG endoperoxide synthase (cyclooxygenase or PGH synthase). PGE2 production and PGH synthase mRNA are increased by PTH and interleukin-1 and decreased by estrogen. Glucocorticoids probably act by a different mechanism, decreasing either arachidonic acid or PGH synthase activity.(ABSTRACT TRUNCATED AT 250 WORDS)


Distribution of genetic diversity among disjunct populations of the rare forest understory herb, Trillium reliquum.
We assessed genetic diversity and its distribution in the rare southeastern US forest understory species, Trillium reliquum. In all, 21 loci were polymorphic (PS=95.5%) and the mean number of alleles per polymorphic locus was 3.05. However, genetic diversity was relatively low (Hes=0.120) considering the level of polymorphism observed for this outcrossing species. A relatively high portion of the genetic diversity (29.7%) was distributed among populations. There was no relationship between population size and genetic diversity, and we did not detect significant inbreeding. These results are best explained by the apparent self-incompatibility of this species, its longevity and clonal reproduction. To address questions regarding the history of T. reliquum's rarity, we compared results for T. reliquum with that of its more common and partially sympatric congener, T. cuneatum. Despite shared life history traits and history of land use, we observed significant genetic differences between the two species. Although T. cuneatum contains slightly lower polymorphism (Ps=85%), we detected significantly higher genetic diversity (Hes=0.217); most of its genetic diversity is contained within its populations (GST=0.092). Our results suggest that not only is there little gene flow among extant T. reliquum populations, but that rarity and population isolation in this species is of ancient origins, rather than due to more recent anthropogenic fragmentation following European colonization. The Chattahoochee River was identified as a major barrier to gene exchange.


Exploring the "N-Terminal Anchor" Binding Interface of the T3SS Chaperone-Translocator Complexes from P. aeruginosa.
The type III secretion system is a large multiprotein complex that many Gram-negative bacteria use for infection. A crucial part of the complex is its translocon pore formed by two proteins: the major and minor translocators. The pore completes a proteinaceous channel from the bacterial cytosol through the host cell membrane and allows the direct injection of bacterial toxins. Effective pore formation is predicated by the translocator proteins binding to a small chaperone within the bacterial cytoplasm. Given the vital role of the chaperone-translocator interaction, we investigated the specificity of the "N-terminal anchor" binding interface present in both translocator-chaperone complexes from Pseudomonas aeruginosa. Isothermal calorimetry (ITC), alanine scanning, and the selection of a motif-based peptide library using ribosome display were used to characterize the major (PopB) and minor (PopD) translocator interactions with their chaperone PcrH. We show that 10 mer PopB51-60 and PopD47-56 peptides bind to PcrH with a KD of 148 ± 18 and 91 ± 9 μM, respectively. Moreover, mutation to alanine of each of the consensus residues (xxVxLxxPxx) of the PopB peptide severely affected or completely abrogated binding to PcrH. When the directed peptide library (X-X-hydrophobic-X-L-X-X-P-X-X) was panned against PcrH, there was no obvious convergence at the varied residues. The PopB/PopD wild-type (WT) sequences were also not prevalent. However, a consensus peptide was shown to bind to PcrH with micromolar affinity. Thus, selected sequences were binding with similar affinities to WT PopB/PopD peptides. These results demonstrate that only the conserved "xxLxxP" motif drives binding at this interface.


Neurobehavioral assessment predicts differential outcome between VLBW and ELBW preterm infants.
To evaluate the impact of birth weight on development of very low birth weight (VLBW) infants using the Neurobehavioral Assessment of the Preterm Infant (NAPI) before hospital discharge, and to show the relation to follow-up outcomes at 12, 18 and 30 months of age. In total, 113 preterm infants were assessed with the NAPI at 36 weeks postmenstrual age. Later, neurodevelopment was examined using the Bayley Infant Neurodevelopmental Screener (BINS) at 12 months and the Bayley Scales of Infant Development, at 18 and 30 months. The cohort was divided into two groups, based on birth weight, extremely low birth weight (ELBW) (<1000 g) and VLBW (1000 to 1500 g). ELBW infants showed significantly lower NAPI scores compared with VLBW infants at 36 weeks. The predischarge NAPI scores correlated with the 12, 18 and 30 months scores when the ELBW infants continue to have lower performance than the VLBW infants. In all, 14 infants developed cerebral palsy. These infants had significantly lower NAPI, BINS and Bayley scores compared with all other preterm infants. NAPI before discharge provides clinically meaningful information related to later neurodevelopmental outcome.


Role of the conserved tryptophan 82 of Lactobacillus casei thymidylate synthase.
Thymidylate synthase (TS; EC 22.214.171.124) catalyzes the reductive methylation of 2'-deoxyuridine-5'-monophosphate (dUMP) by 5,10-methylene-5,6,7,8-tetrahydrofolate (CH2H4folate) to produce 2'-deoxythymidine-5'-monophosphate (dTMP) and 7,8-dihydrofolate (H2folate). Major advances in the understanding of the mechanism of TS have been made by studying site-specific mutants of the enzyme. Trp82 is completely conserved in all of the 20 TS sequences known. It forms part of the CH2H4folate binding pocket, is reported to be a component of a catalytically important H-bond network, and is suspected to be the source of an unusual absorbance change at 330 nm when TS forms a ternary complex with 5-fluoro-dTMP and CH2H4folate. We therefore prepared and characterized a set of 12 mutants at position 82 of Lactobacillus casei TS. Eight Trp82 mutants were active enough for us to determine their kinetic constants for dTMP production, while four were inactive. The active mutants had higher Km values for dUMP (2- to 10-fold) and CH2H4folate (2- to 27-fold), and lower kcat values (12- to 250-fold) than wild-type TS. The most active mutants were those containing the aromatic side chains Phe and His at position 82. All of the Trp82 mutants catalyzed the debromination of 5-bromo-dUMP with kinetic parameters similar to those of wild-type TS, and all formed ternary complexes with 5-fluoro-dUMP and CH2H4folate. The absence of Trp82 did not prevent the absorbance change at 330 nm on ternary complex formation. Trp82, a completely conserved residue that was shown by X-ray crystallography to interact directly with CH2H4folate and indirectly with dUMP, does not appear to be essential for binding or catalysis. We do, however, find a preference for an aromatic side chain at position 82. Trp82 does not contribute to the unique spectral change at 330 nm that accompanies TS ternary complex formation.


Fecal detection of Mycobacterium avium paratuberculosis using the IS900 DNA sequence in Crohn's disease and ulcerative colitis patients and healthy subjects.
Despite the increasing evidence of MAP/DNA isolation in Crohn's disease (CD), its potential pathogenetic role remains unclear. To further clarify the possible relationship between MAP and CD, we investigated the presence of IS900 DNA fragment in feces from Crohn's disease and ulcerative colitis (UC) patients and from healthy controls (HC). Stool samples were collected from 31 CD, 20 UC, and 23 HC and stored at -20°C in 200-mg aliquots. DNA was extracted. MAP presence was detected with a specific PCR amplifying a 409-bp fragment from IS900. The specificity of PCR for IS900 was confirmed sequencing three positive products. Statistical analysis was performed using the Chi-square test. Twenty-one of 31 CD (68%), 13 of 20 UC (65%) and 11 of 23 HC (48%) were MAP-positive (CD vs. HC: p = ns; UC vs. HC: p = ns). With the limits of a small sample size, the IS900-positive percentage in CD and UC was higher than HC, although the difference was not statistically significant. The possibility to track the MAP presence in human feces represents a new approach to the "MAP hypothesis". Detection of MAP DNA in feces is very common, reaching very high prevalence both in CD and in UC and even in HC. Our findings seem consistent with a high prevalence of MAP asymptomatic infection among the general population and so the possible involvement of MAP in CD pathogenesis could be linked to a specific immune defective response.


AURORA: A Unified fRamework fOR Anomaly detection on multivariate time series.
The ability to accurately and consistently discover anomalies in time series is important in many applications. Fields such as finance (fraud detection), information security (intrusion detection), healthcare, and others all benefit from anomaly detection. Intuitively, anomalies in time series are time points or sequences of time points that deviate from normal behavior characterized by periodic oscillations and long-term trends. For example, the typical activity on e-commerce websites exhibits weekly periodicity and grows steadily before holidays. Similarly, domestic usage of electricity exhibits daily and weekly oscillations combined with long-term season-dependent trends. How can we accurately detect anomalies in such domains while simultaneously learning a model for normal behavior? We propose a robust offline unsupervised framework for anomaly detection in seasonal multivariate time series, called AURORA. A key innovation in our framework is a general background behavior model that unifies periodicity and long-term trends. To this end, we leverage a Ramanujan periodic dictionary and a spline-based dictionary to capture both seasonal and trend patterns. We conduct experiments on both synthetic and real-world datasets and demonstrate the effectiveness of our method. AURORA has significant advantages over existing models for anomaly detection, including high accuracy (AUC of up to 0.98), interpretability of recovered normal behavior ( 100 % accuracy in period detection), and the ability to detect both point and contextual anomalies. In addition, AURORA is orders of magnitude faster than baselines.


Group therapy for survivors of childhood sexual abuse who have chronic mental illness.
Medication and supportive services are usually the approaches used to treat women with chronic mental illness (CMI). The goal of this study was to evaluate the outcomes of group therapy for women with CMI in comparison with those for women without CMI, all of whom experienced childhood sexual abuse. The sample ( N=121) consisted of women, all of whom were sexually abused as children. The results indicated that abused women with CMI had improved self-esteem and decreased symptom scores at the same rate as abused women without CMI. It was suggested that nurses can play an essential role in their practice with this population.


Pheomelanin and eumelanin in human skin determined by high-performance liquid chromatography and its relation to in vivo reflectance measurements.
Clinical experience has shown that red haired, fair-skinned people have an increased frequency of skin cancer and in addition a relatively high content of pheomelanin and low content of eumelanin in their skin. Of these, eumelanin is presumed photoprotective, and pheomelanin phototoxic. Thus, a fast, easy, and non-invasive method for determining skin content of eumelanin and pheomelanin was sought. Skin reflectance measurements using a UV-Optimize apparatus were performed before taking suction blisters of the same skin area. Each skin sample was freeze dried and submitted to alkaline hydrogen peroxide degradation. Two eumelanin degradation compounds:Pyrrole-2,3-dicarboxylic acid (PDCA) and pyrrole-2,3,5-tricarboxylic acid (PTCA), and two pheomelanin degradation compounds: Thiazole-4,5-dicarboxylic acid (TDCA) and 1,3-thiazole-2,4,5-tricarboxylic acid (TTCA) were determined in a single chromatographic analysis. Each degradation compound was correlated to reflectance measurements of red (660 nm), green (555 nm), and blue (488 nm) light and additionally correlated to the pigmentation % and redness % given by UV-Optimize. Neither of the investigated parameters were significantly correlated to either PDCA or TTCA. Contrarily, a highly significant correlation was found for the eumelanin marker, PTCA (r2=0.79, P<0.0001). The pheomelanin marker, TDCA, was likewise found to be significantly correlated (r2=0.43, P<0.0001). Based on the coefficients of determination it was concluded that in vivo spectrophotometric reflectance measurements of human skin were highly useful for determining the eumelanin content of skin and to classify the pheomelanin content of skin non-invasively. This may be used individually and in population-based studies.


In vitro activity of ceftazidime (GR 20263) and other beta-lactam antibiotics against Haemophilus influenzae.
Minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) were determined for ceftazidime (GR 20263 - pentahydrate), RO 13-9904, cefoperazone, cefotaxime, lamoxactam, cefamandole and ampicillin using clinical isolates of beta-lactamase-producing and beta-lactamase-negative Haemophilus influenzae. RO 13-9904 and cefotaxime were the most active, followed by ceftazidime, lamoxactam and cefoperazone. Ceftazidime displayed high stability against the beta-lactamase-producing strains with a low MBC:MIC ratio.


Vulnerabilities and cultural change: drug use among Puerto Rican adolescents in the United States.
The investigations examined drug usage-based and culture-based differences in young Puerto Ricans living in New York (100 nonusers and 192 drug users), Americans living in New York (100 nonusers and 99 drug users), and Puerto Ricans living in Puerto Rico (100 nonusers and 98 drug users). The Associative Group Analysis method was used to measure cultural change in three dimensions: dominant perceptions, priorities, and evaluations. The findings show that the Puerto Rican drug user and nonuser groups in New York differed significantly in their paths of acculturation. The nonusers were shown to progress successfully in learning American meanings and adopting American perspectives and cultural norms. The drug users were attracted to dominant American priorities (e.g., wealth and freedom) but showed little progress in adopting deeper American cultural meanings necessary for effective coping.


Collective variable-based enhanced sampling and machine learning.
Collective variable-based enhanced sampling methods have been widely used to study thermodynamic properties of complex systems. Efficiency and accuracy of these enhanced sampling methods are affected by two factors: constructing appropriate collective variables for enhanced sampling and generating accurate free energy surfaces. Recently, many machine learning techniques have been developed to improve the quality of collective variables and the accuracy of free energy surfaces. Although machine learning has achieved great successes in improving enhanced sampling methods, there are still many challenges and open questions. In this perspective, we shall review recent developments on integrating machine learning techniques and collective variable-based enhanced sampling approaches. We also discuss challenges and future research directions including generating kinetic information, exploring high-dimensional free energy surfaces, and efficiently sampling all-atom configurations.


Kininase-independent potentiation of endothelium-dependent relaxations to kinins by converting enzyme inhibitor perindoprilat.
The present study examined whether or not the resistance to degradation of bradykinin analogs affects the kinin-potentiating action of the inhibitor of converting enzyme, perindoprilat. Hydrolysis of Hyp3,Tyr(Me)8 -bradykinin by ACE present in isolated canine coronary arteries was assessed by determination of peptide metabolites using electrospray mass spectrometry, and compared to that of bradykinin. Contractions and relaxations of isolated rings of coronary arteries, with and without endothelium, were recorded as changes in isometric force. After a 30 min incubation, most of the bradykinin was degraded by the arteries, while less than 10 % of Hyp3,Tyr(Me)8 -bradykinin was hydrolysed. In organ chambers, Hyp3,Tyr(Me)8 -bradykinin like bradykinin caused relaxations of isolated canine coronary arteries with endothelium that could be attributed to both NO and endothelium-derived hyperpolarizing factor (EDHF). Perindoprilat caused a comparable leftward shift in the concentration-relaxation curves for bradykinin and Hyp3,Tyr(Me)8 -bradykinin. Impairment of the degradation of bradykinin is not an essential mechanism by which perindoprilat potentiates the actions of kinins.