Mutagens in contaminated soil: a review.
The intentional and accidental discharges of toxic pollutants into the lithosphere results in soil contamination. In some cases (e.g., wood preserving wastes, coal-tar, airborne combustion by-products), the contaminated soil constitutes a genotoxic hazard. This work is a comprehensive review of published information on soil mutagenicity. In total, 1312 assessments of genotoxic activity from 118 works were examined. The majority of the assessments (37.6%) employed the Salmonella mutagenicity test with strains TA98 and/or TA100. An additional 37.6% of the assessments employed a variety of plant species (e.g., Tradescantia clone 4430, Vicia faba, Zea mays, Allium cepa) to assess mutagenic activity. The compiled data on Salmonella mutagenicity indicates significant differences (p<0.0001) in mean potency (revertents per gram dry weight) between industrial, urban, and rural/agricultural sites. Additional analyses showed significant empirical relationships between S9-activated TA98 mutagenicity and soil polycyclic aromatic hydrocarbon (PAH) concentration (r2=0.19 to 0.25, p<0.0001), and between direct-acting TA98 mutagenicity and soil dinitropyrene (DNP) concentration (r2=0.87, p<0.0001). The plant assay data revealed excellent response ranges and significant differences between heavily contaminated, industrial, rural/agricultural, and reference sites, for the anaphase aberration in Allium cepa (direct soil contact) and the waxy locus mutation assay in Zea mays (direct soil contact). The Tradescantia assays appeared to be less responsive, particularly for exposures to aqueous soil leachates. Additional data analyses showed empirical relationships between anaphase aberrations in Allium, or mutations in Arabidopsis, and the 137Cs contamination of soils. Induction of micronuclei in Tradescantia is significantly related to the soil concentration of several metals (e.g., Sb, Cu, Cr, As, Pb, Cd, Ni, Zn). Review of published remediation exercises showed effective removal of genotoxic petrochemical wastes within one year. Remediation of more refractory genotoxic material (e.g., explosives, creosote) frequently showed increases in mutagenic hazard that remained for extended periods. Despite substantial contamination and mutagenic hazards, the risk of adverse effect (e.g., mutation, cancer) in humans or terrestrial biota is difficult to quantify.


Applicability of tandem affinity purification MudPIT to pathway proteomics in yeast.
A combined multidimensional chromatography-mass spectrometry approach known as "MudPIT" enables rapid identification of proteins that interact with a tagged bait while bypassing some of the problems associated with analysis of polypeptides excised from SDS-polyacrylamide gels. However, the reproducibility, success rate, and applicability of MudPIT to the rapid characterization of dozens of proteins have not been reported. We show here that MudPIT reproducibly identified bona fide partners for budding yeast Gcn5p. Additionally, we successfully applied MudPIT to rapidly screen through a collection of tagged polypeptides to identify new protein interactions. Twenty-five proteins involved in transcription and progression through mitosis were modified with a new tandem affinity purification (TAP) tag. TAP-MudPIT analysis of 22 yeast strains that expressed these tagged proteins uncovered known or likely interacting partners for 21 of the baits, a figure that compares favorably with traditional approaches. The proteins identified here comprised 102 previously known and 279 potential physical interactions. Even for the intensively studied Swi2p/Snf2p, the catalytic subunit of the Swi/Snf chromatin remodeling complex, our analysis uncovered a new interacting protein, Rtt102p. Reciprocal tagging and TAP-MudPIT analysis of Rtt102p revealed subunits of both the Swi/Snf and RSC complexes, identifying Rtt102p as a common interactor with, and possible integral component of, these chromatin remodeling machines. Our experience indicates it is feasible for an investigator working with a single ion trap instrument in a conventional molecular/cellular biology laboratory to carry out proteomic characterization of a pathway, organelle, or process (i.e. "pathway proteomics") by systematic application of TAP-MudPIT.


Review: an urgent need for research on factors impacting adherence to and retention in care among HIV-positive youth and adolescents from key populations.
The 50% increase in HIV-related deaths in youth and adolescents (aged 10-24) from 2005 to 2012 highlights the need to improve HIV treatment and care in this population, including treatment adherence and retention. Youth and adolescents from key populations or young key populations (YKP) in particular are highly stigmatized and may face additional barrier(s) in adhering to HIV treatment and services. We reviewed the current knowledge on treatment adherence and retention in HIV care among YKP to identify gaps in the literature and suggest future directions to improve HIV care for YKP. We conducted a comprehensive literature search for YKP and their adherence to antiretroviral therapy (ART) and retention in HIV care on PsycInfo (Ovid), PubMed and Google Scholar using combinations of the keywords HIV/AIDS, ART, adolescents, young adults, adherence (or compliance), retention, men who have sex with men, transgender, injection drug users, people who inject drugs and prisoners. We included empirical studies on key populations defined by WHO; included the terms youth and adolescents and/or aged between 10 and 24; examined adherence to or retention in HIV care; and published in English-language journals. All articles were coded using NVivo. The systematic search yielded 10 articles on YKP and 16 articles on behaviourally infected youth and adolescents from 1999 to 2014. We found no studies reporting on youth and adolescents identified as sex workers, transgender people and prisoners. From existing literature, adherence to ART was reported to be influenced by age, access to healthcare, the burden of multiple vulnerabilities, policy involving risk behaviours and mental health. A combination of two or more of these factors negatively impacted adherence to ART among YKP. Collectively, these studies demonstrated that future programmes need to be tailored specifically to YKP to ensure adherence. There is an urgent need for more systematic research in YKP. Current limited evidence suggests that healthcare delivery should be tailored to the unique needs of YKP. Thus, research on YKP could be used to inform future interventions to improve access to treatment and management of co-morbidities related to HIV, to ease the transition from paediatric to adult care and to increase uptake of secondary prevention methods.


Surgical Simulation Training Reduces Intraoperative Cataract Surgery Complications Among Residents.
This retrospective consecutive case series examined whether training on a surgical simulator reduces intraoperative complication rates among novice ophthalmology residents learning cataract surgery. Beginning July 2014, training on the Eyesi simulator became mandatory for novice postgraduate year 3 ophthalmology residents before live cataract surgery at our institution. Complication rates of the 11 simulator-trained residents (study group) were compared with their immediate 11 simulator-naive predecessors (comparison group). Only straightforward cataract cases (according to standardized preoperative criteria) where postgraduate year 3 residents served as the primary surgeon were included. Complication data were obtained from Morbidity and Mortality records and compared using Fisher exact test. A survey was administered to the residents to gauge the perceived utility of simulation training. The simulator-trained group (n = 501 cataract cases) and the simulator-naive comparison group (n = 454 cases) were analyzed. The complication rate in the simulator group was 2.4% compared with 5.1% in the comparison group (P = 0.037, Fisher exact test). Both the mean posterior capsule tear rate and vitreous prolapse rate in the simulator group were 2.2% compared with 4.8% in the comparison group (P = 0.032, Fisher exact test). The survey had a response rate of 100% (11/11), and 91% (10/11) of respondents felt that the training was "extremely worthwhile" and should be mandatory. The addition of surgical simulation training was associated with a significantly reduced rate of complications, including posterior capsule tears and vitreous prolapse, among novice postgraduate year 3 residents. There is a perceived utility among residents to incorporate virtual simulation into surgical training.


The juggling act: Do student nurses who care for dependants need an adapted course? An applied policy research study.
In line with many countries worldwide, the Department of Health mandate to Health Education England seeks to promote the diversity of applicants by widening participation in nurse education. A number of studies have explored the experience of non-traditional students undertaking nursing courses. This study aimed to explore and understand the experiences of student nurses undertaking their nurse education whilst caring for dependant family. The study used an applied qualitative research approached based on methods developed for applied social policy research. The study was undertaken in an institution of higher education in the North East of England. The study population consisted of a convenience sample of 14 respondents, 13 female and 1 male. Ten respondents lived with partners and 3 had disabled dependants within the family. The age range of dependent children ranged from 3months to 19years. Data was collected through focus groups and telephone interviews using a semi-structured interview schedule. Framework analysis was used to analyse the data. Three superordinate themes were identified, Altruism and Commitment, Maturity and Family and Social Mobility, that best encapsulate the characteristics that enable this group to function well and complete their nurse education. Analysis identified a highly motivated group of students who's individual accounts showed that their lives, whilst in nurse education, were a constant series of compromises and 'juggling' between the demands of the course and the demands of their families. This group of students do not need an adapted course, but instead wish for a realistic nursing course where expectations are managed in an honest way. Basic common sense and good management of nursing courses will help ensure that this motivated group of people achieve their goals with minimum hardship or difficulties.


[3H-cortisol binding with hormone-sensitive and hormone-resistant thymocytes].
A study was made of 3H-cortisol binding with total, hormone-sensitive and hormone-resistant populations of adrenalectomized rat thymocytes before and after their division using BCA and percoll gradients. Subpopulations of small and large thymocytes obtained by using percoll were hormone resistant and hormone sensitive, respectively. The method of thymocyte division on percoll gradient was effective for a study of thymocyte interaction with glucocorticoids. The data obtained showed that there were differences in the index of cortisol binding with subpopulations of rat thymocytes.


Pseudopapillary tumor of the pancreas. An algorithmic approach.
Solid-cystic pseudopapillary tumor of the pancreas is a rare tumor, but has favorable prognosis even in the presence of distant metastases. It is often associated with diagnostic and therapeutic challenges. Described are two cases of solid-cystic pseudopapillary tumor of the pancreas managed in our hospital between January 2000 and January 2010. One female and one male with mean age of 42 years (range: 33 to 51 years). Data collected were: presenting symptoms, signs, imaging and management. Literature review was obtained from computer generated MEDLINE and Google Scholar search for solid-cystic pseudopapillary tumor of the pancreas between 1980 and 2010. Articles relevant to the scope of this paper were selected. The incidence of solid-cystic pseudopapillary tumors of the pancreas in our institution is 2 cases in 10 years; i.e., 0.2 cases/year. Clinical presentation include; palpable abdominal mass, vague abdominal discomfort, increasing abdominal girth, significant weight loss, nausea and vomiting in both patients. The mean diameter of the tumors was 7.0 cm (range: 5.9 to 8.0 cm). Pancreaticoduodenectomy was performed on both patients. None received adjuvant therapy and no cancer recurrence was detected on follow-up. Solid-cystic pseudopapillary tumor of the pancreas is a rare tumor with a favorable prognosis even with distant metastases; therefore, attempts must be made to differentiate it from other pancreatic neoplasms. Clinical and radiological studies alone are insufficient to establish the diagnosis of a pancreatic mass and tissue biopsy should be sought. Surgery is generally curative and should be pursued independent of size and distant metastases.


Cleaved and missed sites for trypsin, lys-C, and lys-N can be predicted with high confidence on the basis of sequence context.
Trypsin, Lys-C, and Lys-N are the most broadly used enzymes in proteomics. Here, on the basis of large-scale peptide mass spectrometry (MS) data sets, an approach is described to confidently identify missed cleavage sites in either phosphorylated or unmodified substrates for these three proteases, or any protease, on the basis of side chain species present within 15 residues of the cleavage-specificity residue. Previously known effects of proline, negatively charged side chains, and phospho-modified residues have been quantified, and additional side chain effects were noted. By applying a set of quantitative side chain rules established for each of the three proteases, scissile and nonscissile sites could be established, on the basis of protein sequence alone, with near certainty for Lys-C, and with a high degree of confidence for trypsin or Lys-N. These rules were applicable to orthogonal peptide data sets, including the two largest in the PeptideAtlas database. The approach described here facilitates the comprehensive modeling of substrate recognition in proteolysis.


What are the barriers and challenges faced by adolescents when searching for sexual health information on the internet? Implications for policy and practice from a qualitative study.
As sexual health information is increasingly presented digitally, and adolescents are increasingly seeking sexual health information on the internet, it is important to explore the challenges presented by this developing source of information provision. This study examined the key barriers and challenges faced by young people when accessing and using sexual health information online. A novel qualitative approach was used which combined paired interviews with real-time online activities. A purposive sample of 49 young people aged between 16 and 19 years and diverse in terms of gender, sexuality, religion and socio-demographic background were recruited from areas across Scotland. Data analysis comprised framework analysis of conversational data (including pair interactions), descriptive analysis of observational data, and data integration. This study highlighted practical and socio-cultural barriers to engagement with online sexual health content. Key practical barriers included difficulty filtering overabundant content; limited awareness of specific, relevant, trusted online sources; difficulties in finding locally relevant information about services; and difficulties in navigating large organisations' websites. Key socio-cultural barriers included fear of being observed; wariness about engaging with visual and auditory content; concern about unintentionally accessing sexually explicit content; and reticence to access sexual health information on social networking platforms or through smartphone applications. These practical and socio-cultural barriers restricted access to information and influenced searching practices. This study provides insights into some of the key barriers faced by young people in accessing and engaging with sexual health information and support online. Reducing such challenges is essential. We highlight the need for sexual health information providers and intervention developers to produce online information that is accurate and accessible; to increase awareness of and promote reliable, accessible sources; and to be sensitive to young people's concerns about 'being seen' accessing sexual health information regarding audio-visual content and platform choice.


[DNA content in the nuclei of breast cancer cells and their metastases to the regional lymph nodes analyzed by impulse cytophotometry].
The data are reaorted on the distribution of the DNA content in cell nuclei of normal human mammary gland, in benign processes, cancer and its metastases in regional lymphnodes by the method of impulse cytophotometry. In benign processes the distribution of DNA in epithelial cells was not shown to differ from the control, however, in some cases there is an increased proliferative activity of the epithelium. Cytophotometrical structure of human breast cancer in general traits reflects the pattern of DNA distribution in them. A tumor consisting of monomorphous elements more frequently shows one type of tumor cells with a different degree of their proliferative activity. The presence of large number of anaplastic cells would correspond to the peaks of anaeploid and polyploid cells on DNA-histograms. A correlation between the DNA content in epithelial cell nuclei of the primary tumor and its metastases in regional lymph nodes was found to remain in the uniform cytologic picture.


No increased risk of Alzheimer's disease among people with immune-mediated inflammatory diseases: findings from a longitudinal cohort study of U.S. older adults.
Immune-mediated inflammatory diseases (IMID) are characterized by systemic inflammation affecting the joints and bodily organs. Studies examining the association between individual IMIDs and the risk of Alzheimer's disease (AD) have yielded inconsistent findings. This study examines AD risk across a group of IMIDs in a large population-based sample of older adults. Data on a national sample of US adults over age 50 was drawn from the Health and Retirement Study (HRS) and linked Medicare claims from 2006 to 2014. IMIDs include rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and related conditions. We identified IMIDs from 2006 to 2009 Medicare claims using International Classification of Diseases (ICD9-CM) codes. The date of incident AD was derived from Chronic Conditions Warehouse (CCW) identifiers. We examined the risk of AD from 2009 to 2014 using Cox proportional hazards models, both unadjusted and adjusted for age, gender, education, race, and the genetic risk factor APOE-e4. One hundred seventy-one (6.02%) of the 2842 total HRS respondents with Medicare coverage and genetic data were classified with IMIDs. Over the subsequent 6 years, 9.36% of IMID patients developed AD compared to 8.57% of controls (unadjusted hazard ratio (HR): 1.09, 95% CI .66-1.81, p = 0.74). Adjusted HR 1.27 (95% CI 0.76-2.12, p = 0.35). Age (HR for 10-year increment 3.56, p < .001), less than high school education (HR 1.70, p = .007), and APOE-e4 (HR 2.61, p < .001 for one or two copies), were also statistically significant predictors of AD. HRS respondents with common IMIDs do not have increased risk of Alzheimer's disease over a 6-year period.


European consensus on patient contact shielding.
Patient contact shielding has been in use for many years in radiology departments in order to reduce the effects and risks of ionising radiation on certain organs. New technologies in projection imaging and CT scanning such as digital receptors and automatic exposure control systems have reduced doses and improved image consistency. These changes and a greater understanding of both the benefits and the risks from the use of shielding have led to a review of shielding use in radiology. A number of professional bodies have already issued guidance in this regard. This paper represents the current consensus view of the main bodies involved in radiation safety and imaging in Europe: European Federation of Organisations for Medical Physics, European Federation of Radiographer Societies, European Society of Radiology, European Society of Paediatric Radiology, EuroSafe Imaging, European Radiation Dosimetry Group (EURADOS), and European Academy of DentoMaxilloFacial Radiology (EADMFR). It is based on the expert recommendations of the Gonad and Patient Shielding (GAPS) Group formed with the purpose of developing consensus in this area. The recommendations are intended to be clear and easy to use. They are intended as guidance, and they are developed using a multidisciplinary team approach. It is recognised that regulations, custom and practice vary widely on the use of patient shielding in Europe and it is hoped that these recommendations will inform a change management program that will benefit patients and staff.


Non-neoplastic disorders of the parotid gland.
The parotid glands are subject to many pathological disorders other than neoplastic diseases. This large group of disorders is classified for the parotid glands into infectious, metabolic and endocrine, traumatic, congenital, and acquired cystic diseases. The other major salivary glands also can be affected by many of these conditions. In recent years more and more patients have been examined and treated who have had diseases classified according to our concepts. Surgical procedures are now commonly recommended for these groups of patients not only for diagnosis but for treatment as well. The microscopic examination of permanently prepared, stained excised tissues still remains the final diagnostic procedure in most patients in spite of more recently developed diagnostic techniques. Further, the well trained surgeon of today is in a position to assure the patient that permanent injury to the facial nerve trunk or to its branches is only a remote possibility. Lastly, our medical and surgical experiences are discussed in the following groups of patients: those with acute suppurative sialadenitis, those with acute abscess, those with chronic obstructive and non-obstructive sialadenitis, those with traumatic lesions, those with congenital lesions, and those with acquired cystic lesions.


Detection of anti-sperm antibodies in serum, seminal plasma and cervical mucus by the immunobead test.
Anti-sperm antibodies in serum and seminal plasma were detected by means of an indirect immunobead test (IBT). Immunobeads with separate specificites for each immunoglobulin class (IBT-IgG, IBT-IgM, and IBT-IgA) were used. Semen parameters were controlled in all sperm donors and Biggers-Whitten-Whittingham (BWW) medium supplemented with human serum albumin (HSA) was used to increase sperm motility. This technique was tested with high titre anti-human sperm sera induced in rabbits. Sperm tails showed a good response by IBT. We included in this study 178 men and 35 women evaluated for infertility and the sera were also tested by the Tray Agglutination Test (TAT). Although the presence of semen markers such as agglutination or trembling of spermatozoa is meaningful even by itself, the percentage of anti-sperm antibodies was increased in the patients with markers, both using IBT (21.4%) and using TAT (35.7%). At high titres of specific immunoglobulins (rabbit antisera and vasectomized men), the correlation between IBT and TAT techniques was better than in sera with very low titres, in which more positive TAT's were detected.


The serotonin transporter gene length polymorphism (5-HTTLPR) and life events: no evidence for an interaction effect on neuroticism and anxious depressive symptoms.
The finding of a significant gene by environment interaction effect on depression of the serotonin transporter length polymorphism (5-HTTLPR) and the Number of experienced Life Events (NLE) was not replicated in two large meta-analyses (Munafo et al., 2009; Risch et al., 2009). These meta-analyses have been criticized on the grounds that large studies that get most weight in meta-analyses have the poorest measurement quality of life events and, as a consequence, do not find an effect. Another issue is the time frame across which the NLE are measured. Proximal life events appear to be better predictors of depression than more distal events. We present the results of analyses of the 5-HTTLPR × NLE effect on anxious depression and neuroticism scores in a sample of 1,155 twins and their parents and siblings from 438 families. The interaction effect was tested separately for NLE experienced across the life span and NLE experienced in the past year. There was a significant main effect of NLE on anxious depression and neuroticism, especially when these were experienced in the past year. No interaction with 5-HTTLPR was found for NLE either experienced across the life span or across the past year. Our results support the two recent meta-analyses. Given recent insights from genome wide association studies, it seems more useful to focus on the joint effect of several genes, that are, for example, part of the same biological pathway, in interaction with the environment, than on one candidate gene.


Antimicrobial Prescriptions for Dogs in the Capital of Spain.
Objective: To characterize antimicrobial prescription patterns for dogs in veterinary practices in Spain using the city of Madrid as a model. Design: Retrospective survey. Settings: Dogs attending veterinary practices in the city of Madrid in 2017 were enrolled. Subjects: Three hundred dogs from 30 veterinary practices randomly selected from a set of 388 practices grouped by zip code. The inclusion criterion for dogs was treatment with antibiotics within a few days of the data collection day. Results: For the 300 dogs enrolled, 374 treatments with antimicrobials were recorded, 62.8% (235/374) were veterinary medicinal products and 37.2% (139/374) human medicinal products. The main route of administration was oral (209/374; 55.9%) followed by parenteral (100/374; 26.7%) and topical (65/374; 17.4%). Sixty-five dogs (21.7%) received a perioperative antimicrobial treatment, mainly associated with female obstetrical surgery (19/65; 29%), while 78.3% (235/300) received a pharmaceutical treatment mainly for skin (72/235; 30.6%), respiratory (47/235; 20%), or digestive (41/235; 17.4%) diseases. The most frequently used antimicrobials were beta-lactams for oral (119/209) and parenteral (79/100) administration, especially the combination amoxicillin with clavulanic acid (83/209; oral), amoxicillin alone (42/100; parenteral), and aminoglycosides (32/65) for topical use. Diagnostic confirmation with culture was carried out on only 13 out of 235 dogs receiving therapeutic treatment and nine underwent an antimicrobial susceptibility test. In addition, cytology was performed in 15 dogs. Conclusions: The pattern of antimicrobial prescriptions for dogs in our study was quite similar to that previously described in several European countries, and encompassed the same two highly interconnected key features: major use of amoxicillin with clavulanic acid and a very low level of antimicrobial susceptibility testing before prescription. Consequently, we recommend that the measures for rationalizing antimicrobial prescription for dogs in Spain should follow those implemented in other countries, especially confirming the diagnosis and promoting the use of hygiene measures by owners.


Accessibility of DNA-epoxycellulose to sequence-specific DNA-binding proteins.
Phage lambda DNA was covalently coupled to epoxy-activated cellulose to form a stable DNA-cellulose matrix for affinity chromatography of sequence-specific DNA-binding proteins. The accessibility of three specific six-base sequences, GGATCC (BamHI), GAATTC (EcoRI) and AAGCTT (HindIII) was studied quantitatively and qualitatively by restriction analysis followed by labelling of their recessed ends. All sites are randomly accessible. The site accessibility is variable, BamHI greater than HindIII greater than EcoRI, and within the range 20-100% depending on base composition and internal structure of the sequence. DNA-epoxycellulose, because of its high efficiency of coupling, capacity, stability and accessibility, can be of great help in the isolation and characterization of sequence-specific DNA-binding proteins.


Symmetry characteristics of the genetic code.
The symmetric pattern of codon degeneracies is discussed by using empirical arguments processed within a group-theoretic framework. It is reasoned that the genetic code is a relation rather than a mapping, and the symmetry of a relation defined on the codons is investigated. The principal results are (i) a new extraction of the basic symmetry inherent in the standard genetic code; (ii) the unification of the symmetry of ambiguous codon assignments with that of the standard genetic code; and (iii) the primacy of the concept of a biological context as that device which degenerates the code relation to a mapping.


Mobile intracardiac calcinosis: a new risk of thromboembolism in patients with haemodialysed end stage renal disease.
Cardiac calcinosis is a common complication of end stage renal disease. A newly observed risk of thromboembolism is reported in four patients with mobile cardiac calcinosis, treated with long term dialysis. Rapidly growing mobile calcification was confirmed by echocardiography. Each patient had an imbalance in serum calcium x inorganic phosphate (Ca x P product >/= 50); this imbalance could not be treated due to the sudden death of the patient or the need for surgical resection to prevent recurrent cerebral thromboembolism. Histological examination revealed intracardiac calcinosis in three cases, and each case showed haemodialysis hypoparathyroidism (intact PTH < 160 pg/ml). Thromboembolism in such cases is rare, however it indicates a need for cautious echocardiographic monitoring in end stage renal disease in patients with an uncontrolled Ca x P product.


Altered Inhibitory Control Mechanism of Internet Addiction: An Electroencephalogram Study of Brain Oscillations and Connectivity.
The development of the Internet has changed people's lives and has resulted in a new type of addictive behavior. In the past decade, Internet game addiction has been identified as a mental illness. Considering internet game addiction as the only cause of mental illness is limited in its view, as internet games, social platforms and other internet multimedia are also widely used. Thus, other internet-related behaviors, that maybe addictive, should also be included. Previous neuroimaging studies have reported a role of alteration in brain's inhibitory control mechanism in addiction. However, the results are still diverse with inconsistent findings. In this study, we used an Internet-related stop signal task with EEG signals recorded to study the relationship between internet addiction through brain oscillations and functional connectivity. We also compared the differences in the brain connectivity between addicted and non-addicted participants using phase lag index. We found that the brain connectivity in participants addicted to the internet is significantly greater than that of nonaddicted users.Clinical Relevance- In this study, we assessed brain functional networks of participants with Internet Gaming Disorder and internet addiction.


Ecust004 Suppresses Breast Cancer Cell Growth, Invasion, and Migration via EMT Regulation.
Erianin is a small chemical compound extracted from Dendrobium chrysotoxum and has excellent antineoplastic effects against a variety of cancers. Combretastatin A-4 (CA4) is the most effective member of natural phenolic stilbene compounds isolated from the African willow tree Combretum caffrum. Ecust004 (Chemical Formula: C18H21NO7S) is a drug candidate optimized from structure-activity relationship studies of the sulfamate derivatives of Erianin and CA4, which has better bioavailability and pharmacokinetic profiles than Erianin and CA4. To investigate the antitumor activity of Ecust004 in different types of breast cancer cells, MDA-MB-231 and MCF7 cells were treated with Ecust004. MTT and CCK8 were used to determine the effects of Ecust004 on cell proliferation. Wound-healing and Transwell assays were used to evaluate the migration and invasion level of cells treated with Ecust004. The expression of genes and proteins associated with epithelial-mesenchymal transition was detected by RT-PCR and Western blotting. In vivo studies further clarified the functional effects of Ecust004. Ecust004 treatment decreased the growth and proliferation of MDA-MB-231 and MCF7 cells at a lower dosage than Erianin. In addition, compared to Erianin and CA4, Ecust004 can better inhibit the invasion and migration of MDA-MB-231 and MCF7 cells. Accordingly, the expression of genes associated with epithelial-mesenchymal transition, such as E-cadherin and vinculin, was increased. Finally, compared with Erianin and CA4, Ecust004 exhibited a better anti-tumor activity in vivo. Ecust004 inhibits the proliferation, invasion, and migration of breast cancer cells, and therefore represents a potential agent for development as an antitumor drug.


Nitrosamine-induced cancer: selective repair and conformational differences between O6-methylguanine residues in different positions in and around codon 12 of rat H-ras.
Mammary and skin tumors induced in rodents by N-methyl-N-nitrosourea treatment have a G:C to A:T transition mutation in codon 12 of H-ras, probably resulting from alkylation of O6 of guanine by the carcinogen. This codon contains two guanines (5'-GGA-3'), but mutations are observed only in the central base pair of this codon. The same selectivity for mutations of -GGA-sequences has also been observed in Escherichia coli. It is known that the central G in the sequence GGA is a preferred site for alkylation, but the magnitude of chemical selectivity is insufficient to provide a complete explanation for the biological observation which is still unexplained. We have measured accurate rates of repair by the E. coli and gene O6-alkylguanine-DNA-alkyltransferase of an O6-methylguanine in various positions in chemically synthesized 15-base pair DNA duplexes having the H-ras sequence. The rate of repair varied 25-fold, depending on the sequence flanking the methylguanine. An O6-methylguanine in position 2 of codon 12 was the least well repaired. The combination of this slow repair and sequence selectivity in alkylation appears to be the explanation for the selective mutation of this position. Using an antibody to probe the accessibility of the O6-methyldeoxyguanosine, it was shown that the rate of repair is a reflection of the conformation of the sequence containing the alkylated base, because the avidity constants between antibody and O6-methylguanine were also dependent on the sequence flanking the methylguanine, with the most rapidly repaired O6-methylguanines being those most easily bound by the antibody.


A pharmacokinetic binding model for bevacizumab and VEGF165 in colorectal cancer patients.
To characterize the population pharmacokinetics of bevacizumab, its binding properties to VEGF165 and the effect of demographic data and VEGF-A polymorphisms on the interplay between bevacizumab serum pharmacokinetics and VEGF165 serum concentrations in patients with colorectal cancer stage IV. Bevacizumab and VEGF165 data were collected from 19 adult patients with metastatic colorectal cancer enrolled in an observational clinical study. Bevacizumab was administered with one of the following combinations: 5-FU/Leucovorin/Irinotecan, 5-FU/Leucovorin/Oxaliplatin, Capecitabine/Irinotecan at doses ranging from 5 to 10 mg/kg every 2 or 3 weeks. Data analysis was performed using nonlinear mixed-effects modeling implemented in NONMEM 7.3. A target-mediated drug disposition model adequately described bevacizumab concentration changes over time and its binding characteristics to VEGF165. The estimated clearance of bevacizumab was 0.18 L/day, the free VEGF165 levels at baseline were 212 ng/L, and the elimination rate constant of free VEGF165 was 0.401 day(-1). Body weight was allometrically included in all PK parameters. The final model adequately described the pre- and post-dose concentrations of total bevacizumab and free VEGF165 in patients with colorectal cancer. Model parameters were consistent with those previously reported for patients with solid tumors. Correlations between the binding affinity of bevacizumab and the VEGF-2578C/A and VEGF-634G/C polymorphisms were noticed.


[Neutrophils mediate T lymphocyte function in septic mice via the CD80/cytotoxic T lymphocyte antigen-4 signaling pathway].
To investigate the effect of neutrophils on T lymphocyte function in septic mice and the role of CD80/cytotoxic T lymphocyte antigen-4 (CTLA-4) signaling pathway in this modulated effects. (1) In vivo experiment: 6-8 weeks old male C57BL/6 mice were divided into sham operation group (Sham group, n = 20), Sham+CTLA-4 antibody treatment group (Sham+aCTLA-4 group, n = 20), cecum ligation and perforation (CLP) induced sepsis model group (CLP group, n = 30) and CLP+CTLA-4 antibody treatment group (CLP+aCTLA-4 group, n = 30) according to the random number table. CLP was used to reproduce mouse sepsis model. The mice in the Sham group were treated identically but their cecums were neither punctured nor ligated. In CTLA-4 antibody treatment groups, 50 μg CTLA-4 antibody was injected intraperitoneally 6 hours and 24 hours after the operation. Forty-eight hours after operation, 6 mice in Sham group and Sham+aCTLA-4 group, 14 mice in CLP group and CLP+aCTLA-4 group were randomly selected to detect the expression of CD69 in spleen. At the same time, spleen, bone marrow and peripheral blood were collected, and the expression of CD80 on neutrophils was detected by flow cytometry. The expression of CTLA-4 on the surface of T lymphocytes in spleen was detected by immunofluorescence and flow cytometry. The remaining mice in each group were used to observe the 96-hour survival after operation. (2) In vitro experiment 1: neutrophils were extracted from bone marrow of healthy mice and stimulated with LPS (1 mg/L) for 4, 8 and 12 hours respectively. The control group was added with the same amount of phosphate buffer saline (PBS) at each time point, and the expression of CD80 was detected at each time point. (3) In vitro experiment 2: splenic T lymphocytes of healthy mice were extracted and divided into PBS control group, LPS group (final concentration of LPS 1 mg/L), neutrophil group and neutrophil+LPS group. In the latter two groups, the co-culture model of neutrophils and T lymphocytes was established, and then the corresponding treatment was given to detect the expression of CTLA-4 on the surface of T lymphocytes. With the above four groups as controls, CTLA-4 antibody treatment groups (final concentration of CTLA-4 antibody 50 mg/L) were set up respectively. After 48 hours, the level of interleukin-2 (IL-2) in the cell supernatant was detected by enzyme linked immunosorbent assay (ELISA). (1) Results of in vivo experiment: compared with Sham group, the expression of CD80 on neutrophils in spleen, bone marrow and peripheral blood was significantly up-regulated, while the expression of CTLA-4 on the surface of T lymphocytes was significantly increased [(9.98±0.84)% vs. (3.48±0.64)%, P < 0.05]. It suggested that neutrophils may affect T lymphocytes function through CD80/CTLA-4 pathway in sepsis. Compared with CLP group, CTLA-4 antibody could significantly improve the 96-hour cumulative survival rate of CLP mice (56.25% vs. 18.75%, P < 0.05), and increase the expression of CD69 on the surface of T lymphocytes. It suggested that CTLA-4 antibodies might increase T lymphocytes activation in sepsis and improve survival. (2) Results of in vitro experiment: with the prolongation of LPS stimulation, the expression of CD80 on neutrophils gradually increased in time-dependent manner as compared with PBS control group [4 hours: (6.35±0.40)% vs. (3.41±0.40)%, 8 hours: (8.57±0.64)% vs. (3.09±0.27)%, 12 hours: (19.83±1.06)% vs. (5.16±0.36)%, all P < 0.05]. Compared with PBS control group, the expression of CTLA-4 on CD4+/CD8+ T lymphocytes was not significantly affected by LPS stimulation alone, but CTLA-4 was increased after co-culture with neutrophils [CD4+: (4.92±0.30)% vs. (3.33±0.25)%, CD8+: (4.26±0.21)% vs. (2.53±0.66)%, both P < 0.05], and the increased trend of CTLA-4 was more obvious after co-culture with LPS-stimulated neutrophils [CD4+: (6.34±0.50)% vs. (3.33±0.25)%, CD8+: (6.21±0.41)% vs. (2.53±0.66)%, both P < 0.05]. In the PBS control group and LPS group, CTLA-4 antibody had no significant effect on IL-2 secretion of T lymphocytes. Compared with PBS control group, co-culture with neutrophils could inhibit the secretion of IL-2 by T lymphocytes (ng/L: 1 938.00±68.45 vs. 2 547.00±218.00, P < 0.05), and the inhibitory effect of neutrophils stimulated by LPS was more obvious (ng/L: 1 073.00±34.39 vs. 2 547.00±218.00, P < 0.05). CTLA-4 antibodies could partially restore IL-2 secretion. In conclusion, after promoting the expression of CTLA-4 on the surface of T lymphocytes, neutrophils might mediate the inhibition of T lymphocytes function by reducing the production of IL-2. Neutrophils mediate T lymphocytes dysfunction in sepsis, and the CD80/CTLA-4 pathway plays an important role. The CTLA-4 antibody improves survival and T lymphocytes function in sepsis mice, which may be a new method of immunotherapy for sepsis.


Granulocyte colony-stimulating factor and an RARalpha specific agonist, VTP195183, synergize to enhance the mobilization of hematopoietic progenitor cells.
Failure to mobilize adequate numbers of hematopoietic stem and progenitor cells (HSPC) is an important clinical problem. Since bone marrow (BM) neutrophils play a central role in HSPC mobilization, we hypothesized that granulocyte colony-stimulating factor (G-CSF)-mediated mobilization would be enhanced by further expanding the size of the BM granulocyte pool. We tested the potential of the retinoic acid receptor alpha (RARalpha) specific agonist VTP195183, and the pan-RAR agonist all-trans retinoic acid (ATRA), to enhance G-CSF-mediated mobilization of HSPC, in two mouse strains. Pretreatment of mice with VTP195183 significantly increased the number of leukocytes, colony-forming cells, and early engrafting hematopoietic stem cells (HSC) mobilized in the blood in response to G-CSF. In contrast, ATRA had only a marginal effect on G-CSF-induced mobilization. HSPC mobilization synergy between VTP195183 and G-CSF occurred only when mice were preconditioned with VTP195183 prior to G-CSF. This preconditioning was shown to increase the numbers of granulocyte/macrophage progenitors in the BM. Treatment with VTP195183 and G-CSF was accompanied by enhanced levels of active neutrophil proteases in the BM extracellular fluid compared to G-CSF treatment alone. VTP195183 treatment increases the numbers of immature granulocyte progenitors in BM and subsequently synergizes to enhance G-CSF-mediated mobilization of HSPC. These data demonstrate a novel approach to improve G-CSF-induced mobilization by accelerating granulocyte maturation in the BM. These findings are currently being tested in a clinical trial of VTP195183 plus G-CSF for mobilization of HSPC in human patients.


Supervised learning and the finite-temperature string method for computing committor functions and reaction rates.
A central object in the computational studies of rare events is the committor function. Though costly to compute, the committor function encodes complete mechanistic information of the processes involving rare events, including reaction rates and transition-state ensembles. Under the framework of transition path theory, Rotskoff et al. [Proceedings of the 2nd Mathematical and Scientific Machine Learning Conference, Proceedings of Machine Learning Research (PLMR, 2022), Vol. 145, pp. 757-780] proposes an algorithm where a feedback loop couples a neural network that models the committor function with importance sampling, mainly umbrella sampling, which collects data needed for adaptive training. In this work, we show additional modifications are needed to improve the accuracy of the algorithm. The first modification adds elements of supervised learning, which allows the neural network to improve its prediction by fitting to sample-mean estimates of committor values obtained from short molecular dynamics trajectories. The second modification replaces the committor-based umbrella sampling with the finite-temperature string (FTS) method, which enables homogeneous sampling in regions where transition pathways are located. We test our modifications on low-dimensional systems with non-convex potential energy where reference solutions can be found via analytical or finite element methods, and show how combining supervised learning and the FTS method yields accurate computation of committor functions and reaction rates. We also provide an error analysis for algorithms that use the FTS method, using which reaction rates can be accurately estimated during training with a small number of samples. The methods are then applied to a molecular system in which no reference solution is known, where accurate computations of committor functions and reaction rates can still be obtained.


Progeny counter mechanism in malaria parasites is linked to extracellular resources.
Malaria is caused by the rapid proliferation of Plasmodium parasites in patients and disease severity correlates with the number of infected red blood cells in circulation. Parasite multiplication within red blood cells is called schizogony and occurs through an atypical multinucleated cell division mode. The mechanisms regulating the number of daughter cells produced by a single progenitor are poorly understood. We investigated underlying regulatory principles by quantifying nuclear multiplication dynamics in Plasmodium falciparum and knowlesi using super-resolution time-lapse microscopy. This confirmed that the number of daughter cells was consistent with a model in which a counter mechanism regulates multiplication yet incompatible with a timer mechanism. P. falciparum cell volume at the start of nuclear division correlated with the final number of daughter cells. As schizogony progressed, the nucleocytoplasmic volume ratio, which has been found to be constant in all eukaryotes characterized so far, increased significantly, possibly to accommodate the exponentially multiplying nuclei. Depleting nutrients by dilution of culture medium caused parasites to produce fewer merozoites and reduced proliferation but did not affect cell volume or total nuclear volume at the end of schizogony. Our findings suggest that the counter mechanism implicated in malaria parasite proliferation integrates extracellular resource status to modify progeny number during blood stage infection.


Regulation of the rat BB1 RNA during normal rat lung development.
BB1 was recently cloned from the WI-38 human fetal lung cell line. Human BB1 (hBB1) is expressed by multiple tissues, including lung. Because inhibition of BB1 translation using antisense oligodeoxynucleotides resulted in prevention of G1 traversal in cultured cells, we hypothesized that BB1 gene expression would be regulated during lung development with greater expression during periods of active lung growth. To gain insight into the expression of BB1 during lung development, a rat BB1 (rBB1) homologue was cloned and used in Northern hybridization analyses and in situ hybridization histochemistry (ISHH). Northern hybridization analyses of fetal and postnatal rat lung demonstrate that rBB1 RNA abundance is relatively low on fetal days E17 through E19, with a small peak of expression occurring on fetal day E20, then increases at birth with peak expression in adult lung. ISHH correlates with the Northern hybridization data and reveals rBB1 RNA expression throughout lung from E17 to E21 in both epithelium and mesenchyme. In postnatal lung, more intense expression of BB1 was observed than in fetal lung, localizing BB1 transcripts to proximal and distal airways and mesenchymal cells surrounding airways. Proliferating cell nuclear antigen (PCNA) was identified in lung sections adjacent to those used for ISHH and it was found that BB1 expression was present in PCNA-positive cells; however, BB1 expression was not limited to PCNA-positive cells in either the fetal or postnatal periods. This was most apparent in adult (60-day) rat lung where essentially no PCNA-positive cells were detected, but intense BB1 expression was detected in airway epithelium and surrounding mesenchyme. These studies demonstrate developmental regulation of BB1 during lung development. The findings are consistent with BB1 action in cell growth-related processes of fetal and early postnatal lung; however, the distribution of BB1 expression in relation to PCNA localization suggests that BB1 participates in cellular functions in addition to cell proliferation.


A DFT perspective on organometallic lanthanide chemistry.
Computational studies of the coordination chemistry and bonding of lanthanides have grown in recent decades as the need for understanding the distinct physical, optical, and magnetic properties of these compounds increased. Density functional theory (DFT) methods offer a favorable balance of computational cost and accuracy in lanthanide chemistry and have helped to advance the discovery of novel oxidation states and electronic configurations. This Frontier article examines the scope and limitations of DFT in interpreting structural and spectroscopic data of low-valent lanthanide complexes, elucidating periodic trends, and predicting their properties and reactivity, presented through selected examples.


Impacts of Environmental Heterogeneity on Moss Diversity and Distribution of Didymodon (Pottiaceae) in Tibet, China.
Tibet makes up the majority of the Qinghai-Tibet Plateau, often referred to as the roof of the world. Its complex landforms, physiognomy, and climate create a special heterogeneous environment for mosses. Each moss species inhabits its own habitat and ecological niche. This, in combination with its sensitivity to environmental change, makes moss species distribution a useful indicator of vegetation alteration and climate change. This study aimed to characterize the diversity and distribution of Didymodon (Pottiaceae) in Tibet, and model the potential distribution of its species. A total of 221 sample plots, each with a size of 10 × 10 m and located at different altitudes, were investigated across all vegetation types. Of these, the 181 plots in which Didymodon species were found were used to conduct analyses and modeling. Three noteworthy results were obtained. First, a total of 22 species of Didymodon were identified. Among these, Didymodon rigidulus var. subulatus had not previously been recorded in China, and Didymodon constrictus var. constrictus was the dominant species. Second, analysis of the relationships between species distributions and environmental factors using canonical correspondence analysis revealed that vegetation cover and altitude were the main factors affecting the distribution of Didymodon in Tibet. Third, based on the environmental factors of bioclimate, topography and vegetation, the distribution of Didymodon was predicted throughout Tibet at a spatial resolution of 1 km, using the presence-only MaxEnt model. Climatic variables were the key factors in the model. We conclude that the environment plays a significant role in moss diversity and distribution. Based on our research findings, we recommend that future studies should focus on the impacts of climate change on the distribution and conservation of Didymodon.


[Delivery of oral health in andalusian health service on the de-escalation of SARS-CoV-2].
The pandemic declared by SARS-CoV-2 has meant a crisis in the health system that forced the urgent implementation of preventive public health measures. The respiratory transmission virus remains stable on surfaces, being able to spread by air in respiratory droplets or in procedures that generate aerosols. Dental activity is one of the professional sectors with the highest exposure index, both due to the generation of aerosols in most interventions, as well as the impossibility of maintaining a safe distance between patients and professionals. The postponement of scheduled and non-urgent healthcare activities in dental offices is one of the measures implemented to reduce the risk that it posed for the health and well-being of citizens. This report addresses the recommendations and measures to be taken into account to minimize risks in the Oral Health Units of the Andalusian Public Health System, to address the oral pathology of the population assigned in the scenario of improvement of the pandemic and its partial lack of confinement.


Outcome of children identified as anemic by routine screening in an inner-city clinic.
Children found to be anemic on routine screening by HemoCue, a rapid and relatively inexpensive method of screening for hemoglobin (Hb), are often prescribed iron as a diagnostic tool and potential treatment for presumed iron deficiency anemia (IDA). We questioned this approach given the declining prevalence of IDA and the concomitant relative increase in other causes of anemia. To evaluate the practice of Hb screening for IDA by determining the prevalence of anemia by HemoCue; the proportion of anemic patients treated with iron and followed up; the frequency of repeated Hb testing, additional iron studies, and iron prescriptions; and the 6-month outcomes of treated and untreated anemia. Retrospective cohort study. Of 1358 children aged 9 to 36 months who underwent screening, 343 (25%) had anemia, defined as a Hb level of less than 110 g/L. Outpatient medical records of 334 of the anemic children revealed that 239 (72%) were prescribed iron while 95 (28%) were not prescribed iron at the first visit for anemia. Anemia follow-up rates were low for the prescribed and not prescribed groups: 7% vs 5% returned within 1 month, while 37% vs 42% did not return within 6 months for follow-up. Of the children who were prescribed iron, 107 (71%) of 150 responded to treatment or anemia resolved within 6 months compared with 27 (68%) of 40 not prescribed iron. Children underwent repeated blood testing for measurement of Hb and complete blood cell count, but underwent few iron-specific studies. Routine screening for IDA by HemoCue followed by a therapeutic trial of iron was problematic because of a high rate of anemia in this predominantly African American population, low follow-up rates, and a high spontaneous resolution rate. Prospective studies are needed to evaluate other screening methods to differentiate IDA from other forms of anemia and to improve compliance and outcome in inner-city children.


Primary care electronic medication record discrepancies in patients starting treatment at a hospital-based ambulatory care pharmacy and impact on prevalence of potential drug-drug interactions.
Our objective was to evaluate the prevalence of discrepancies between primary care electronic medication records (EMR) and patient reported medication (PRM) in ambulatory patients starting a hospital dispensing treatment (HDT) at a hospital-based ambulatory care pharmacy (HACPh). Our secondary aims were to analyse factors associated with the presence of discrepancies and their impact on the prevalence of potential drug-drug interactions (DDIs) with the HDT. Retrospective study including 230 patients starting a HDT at the HACPh. Pharmacists interviewed patients and PRM was compared with EMR. Discrepancies were classified as omissions (medication in the PRM not present in the EMR) and commissions (medication active in the EMR that the patients were not taking). Potential DDIs with the HDT were screened, and univariate and multivariate analyses were performed to detect factors associated with the presence of discrepancies. We identified 221 discrepancies in 116 (50.4%) patients. Being visited by three or more medical specialties (OR 1.93, 95% CI 1.11 to 3.37) and attending private healthcare (OR 4.36, 95% CI 1.14 to 16.72) in the 12 months before the study inclusion were the factors independently associated with the presence of discrepancies. Among patients with commissions (n=91), 15.4% had a potential DDI between the HDT and one medication from the EMR that they were not taking at that moment. Among patients with omissions (n=45), 11.1% had a potential DDI between the HDT and a medication in the PRM not present in the EMR. About 40% of patients had one or more medications in the EMR which they were not taking and one fifth used medications that were not listed in the EMR. EMR should not be used as the only source of information when screening for DDIs, especially in patients followed by different medical specialties or combining private and public healthcare.


Pangenome-based genome inference allows efficient and accurate genotyping across a wide spectrum of variant classes.
Typical genotyping workflows map reads to a reference genome before identifying genetic variants. Generating such alignments introduces reference biases and comes with substantial computational burden. Furthermore, short-read lengths limit the ability to characterize repetitive genomic regions, which are particularly challenging for fast k-mer-based genotypers. In the present study, we propose a new algorithm, PanGenie, that leverages a haplotype-resolved pangenome reference together with k-mer counts from short-read sequencing data to genotype a wide spectrum of genetic variation-a process we refer to as genome inference. Compared with mapping-based approaches, PanGenie is more than 4 times faster at 30-fold coverage and achieves better genotype concordances for almost all variant types and coverages tested. Improvements are especially pronounced for large insertions (≥50 bp) and variants in repetitive regions, enabling the inclusion of these classes of variants in genome-wide association studies. PanGenie efficiently leverages the increasing amount of haplotype-resolved assemblies to unravel the functional impact of previously inaccessible variants while being faster compared with alignment-based workflows.


Comprehensive Genomic Profiling of a Rare Thyroid Follicular Dendritic Cell Sarcoma.
We previously reported an extremely rare case of follicular dendritic cell sarcoma (FDCS) presented as a thyroid mass. Given the rarity of this disease, there are no personalized and molecularly targeted treatment options due to the lack of knowledge in the genomic makeup of the tumor. A 44-year-old white woman was diagnosed with an extranodal FDCS in thyroid. The patient underwent a total thyroidectomy, central compartment dissection, parathyroid re-implantation, and adjuvant radiation therapy. Tumor DNA sequencing of 236 genes by FoundationOne panel found truncating mutations in PTEN and missense mutations in RET and TP53. However, patient-matched germline DNA was not sequenced which is critical for identification of true somatic mutations. Furthermore, the FoundationOne panel doesn't measure genomic rearrangements which have been shown to be abundant in sarcomas and are associated with sarcoma tumorigenesis and progression. In the current study, we carried out comprehensive genomic sequencing of the tumor, adjacent normal tissues, and patient-matched blood, in an effort to understand the genomic makeup of this rare extranodal FDCS and to identify potential therapeutic targets. Eighty-one somatic point mutations were identified in tumor but not in adjacent normal tissues or blood. A clonal truncating mutation in the CLTCL1 gene, which stabilizes the mitotic spindle, was likely a driver mutation of tumorigenesis and could explain the extensive copy number aberrations (CNAs) and genomic rearrangements in the tumor including a chr15/chr17 local chromothripsis resulted in 6 expressed fusion genes. The fusion gene HDGFRP3→SHC4 led to a 200-fold increase in the expression of oncogene SHC4 which is a potential target of the commercial drug Dasatinib. Missense mutations in ATM and splice-site mutation in VEGFR1 were also detected in addition to the TP53 missense mutation reported by FoundationOne.


Psychological counselling in problematic diabetes: does it help?
In past decades clinicians have increasingly recognized the importance of psychological support for people with diabetes and their families, and many have recommended integrating psychological counselling into routine diabetes care. It is therefore important to consider whether psychological interventions in diabetes are effective in improving clinical outcomes. This review was limited to the literature reporting on the treatment of five common psychological problems known to complicate diabetes management: depression, eating disorders, anxiety/stress, self-destructive behaviour and interpersonal/family conflicts. A literature search was undertaken using MedLine and PsychInfo, including studies published in English peer-reviewed journals between 1990 and 2001, reporting on the effects of psychological interventions in the areas mentioned. Case studies were excluded from the review. In line with earlier reviews, relatively little empirical research was found to substantiate the effect of psychological counselling in complicated diabetes. Most studies are uncontrolled, and involve small samples. In total only 11 randomized controlled trials were identified. Results indicate that cognitive behaviour therapy (CBT) is effective in the treatment of depression in Type 2 diabetes patients, both in reducing depressive symptoms and HbA1c. Favourable effects have been observed in pilot studies applying CBT in the field of stress management, eating disorders and self-destructive behaviour, but future research should substantiate these preliminary findings. Behaviour family therapy proved beneficial in terms of resolving family conflicts, but did not impact glycaemic control. Evidence to support the effect of psychological treatment in problematic diabetes is still scarce, due to limited research in this area. Suggestions are made to further develop psychotherapeutic research in diabetes care. We conclude that future research should gain from a behavioural medicine approach to diabetes, with close collaboration between diabetologists and psychologists.


Associations of dietary and sedentary behaviours of pregnant women with their children's birth weight: findings from the CHAT trial in Australia.
To examine the associations of pregnant women's dietary and sedentary behaviours with their children's birth weight. Secondary data analysis was conducted using data from a randomised controlled trial, Communicating Healthy Beginnings Advice by Telephone, conducted in Australia. Information on mothers' socio-demographics, dietary and sedentary behaviours during pregnancy was collected by telephone survey at the third trimester. Birth weight data were extracted from the child's health record book. Multinomial logistic regression models were built to examine the associations of pregnant women's dietary and sedentary behaviours with children's birth weight. Participating families. Pregnant women and their children. A total of 1132 mother-child dyads were included in the analysis. The majority of infants (87 %, n 989) were of normal birth weight (2500 g to <4000 g), 4 % (n 50) had low birth weight (<2500 g) and 8 % (n 93) had macrosomia (≥4000 g). Mothers who ate processed meat during pregnancy were more likely to have macrosomia (adjusted risk ratio (ARR) 1·80, 95 % CI (1·12, 2·89)). The risk of macrosomia decreased as the number of dietary recommendations met by mothers increased (ARR 0·84, 95 % CI (0·71, 0·99)). Children's birth weight was not associated with mothers' sedentary time. Children's low birth weight was not associated with mothers' dietary and sedentary behaviours during pregnancy. Maternal consumption of processed meat during pregnancy was associated with an increased risk of macrosomia. Increasing number of dietary recommendations met by mothers was associated with a lower risk of macrosomia. The findings suggested encouraging pregnancy women to meet dietary recommendation will benefit children's birth weight.


[Diagnostic and therapeutic aspects of pneumonias after cardiosurgical operations associated with artificial ventilation].
Artificial ventilation (AV)-associated pneumonias are the most common infectious complication in cardiosurgery. This prospective comparative study covered 50 patients with AV-associated pneumonias occurring after surgery under extracorporeal circulation (EC). All the patients received the routine perioperative antibiotic prevention regimen (cefuroxime or ceftriaxone). According to the initial therapy, the patients with evolving pneumonia, the patients were divided into 2 groups: 1) those were given cefuroxime (maxipim); 2) those receiving a combination of maxipim or clarithromycin (clacid). The analysis has indicated that if pneumonia develops after surgery under EC, then this most frequently occurs in the first 5 postoperative days, i.e. early AV-associated pneumonias are prevalent. In cases of concurrent pneumonia, the duration of EC, the length of stay in an intensive care unit, and the total period of hospi- talization considerably increase. For cardiosurgical patients, the laboratory guide for establishing the diagnosis of AV-associated pneumonia is the elevated blood cell levels of more than 15 x 10(9)/l, unlike those of more than 10 x 10(9)/l proposed for most patients. The etiology of AV-associated pneumonia is shown to vary with the timing of complication occurrence. There is evidence for the involvement of intracellular microorganisms (Chlamydia, Mycoplasma) in the development of early AV-associated pneumonias in at least every 10 patients. The advantages of a study of bronchoalveolar lavage samples over that of endotracheal aspirates for the etiological diagnosis of pneumonias were revealed. The advisability of prescribing a combination of a beta-lactam antibiotic (third- or fourth-generation cephalosporin) and a macrolide (clarythromycin) in early AV-associated pneumonias is warranted. The objective criterion for the adequacy of this combination is positive changes in the marker of severe bacterial infections (procalcitonin). An algorithm is offered for antibacterial therapy for AV-associated pneumonias developing after cardiosurgical operations, which considers the performed antibiotic prevention and the timing of pneumonia development.


Quantifying the effect of seed orientation in postplanning dosimetry of low-dose-rate prostate brachytherapy.
Radioactive seed orientations are usually ignored in clinical brachytherapy dosimetry for prostate implants. Associated with the anisotropic dose distribution of seeds, these orientations could cause dose differences between the planning configurations and the clinical postplanning dosimetry. This study will quantify the impact of seed orientation on the dosimetry. 3D seed positions and θ and φ polar angles were obtained using five independent fluoroscopic images for 287 patients. Five dose calculation methods are compared: TG43-1D (1), TG43-2D parallel to implant axis (2) and with orientations (3), Monte Carlo (MC) simulations parallel (4), and MC simulations with orientations (5). GEANT4 v4.9.6 MC simulations were made in 1 mm(3) voxelized geometries based on the DICOM-RT information. Materials were assigned using thresholds based on the HU number, as recommended in TG186 reports. Seed voxels are overridden with prostatic materials and the layered mass geometry [Enger et al., Phys. Med. Biol. 57(19), 6269-6277 (2012)] allows subsequent placement of the source geometry. 500 million histories were used per patient. 3D dose and DVHs for each structure were calculated. The various seed orientations do not result in statistically significant differences on the dose metrics for the clinical target volume (CTV) or the urethra, based on the Student t-test p-value. Difference as low as -0.238% and 0.059% has been seen on the CTV D90, respectively, for the MC and the TG43. The difference between parallel and oriented calculations for the organs at risk (OARs) can differ by 2% on average. Based on the results from this study, seed orientations have no significant impact of CTV and urethra dose metrics but can affect OARs that are external to the CTV.


Aphidicolin-induced FRA3B breakpoints cluster in two distinct regions.
The common fragile site at chromosomal band 3p14.2 (FRA3B) is the most sensitive single site in the human genome to induced chromosomal lesions. This fragile site may predispose chromosome 3p to breakage that is commonly observed in lung, renal, and many other cancers. We previously used aphidicolin induction of FRA3B expression in a chromosome 3-only somatic cell hybrid to generate a series of hybrids with breakpoints in the 3p14.2 region. These breakpoints were localized to two distinct clusters, separated by 200 kb, that lie on either side of a region of frequent breakage within FRA3B as observed by FISH analysis. Seven proximal aphidicolin-induced breakpoints were localized at or near the end of a THE element. The THE-1 element is flanked by LINE and Alu repetitive elements. The eight distal aphidicolin-induced breakpoints clustered in a region capable of forming multiple hairpin-like structures. Thus repetitive elements and hairpin-like structures may be responsible for chromosome fragility in this region.


Autophagy gene polymorphism is associated with susceptibility to leprosy by affecting inflammatory cytokines.
Autophagy and inflammation closely interact with each other, and together, they play critical roles in bacterial infection. Leprosy is caused by the infection of Mycobacterium leprae (M. leprae). The objective of the study was to investigate the association between polymorphisms in IRGM, an autophagy gene, and susceptibility to leprosy, and identify possible functions of the polymorphism in the infection of M. leprae. Two polymorphisms in IRGM, rs4958842 and rs13361189, were tested in 412 leprosy cases and 432 healthy controls. Levels of inflammatory cytokines including interleukin 1 beta, IL-4, IL-6, and interferon gamma (INF-γ) were measured after the infection of M. leprae in the peripheral blood mononuclear cell (PBMC) of subjects with different genotypes of rs13361189. Data showed that prevalence of rs13361189TC and CC genotypes were significantly higher in leprosy patients than in healthy controls (odds ratio (OR) = 1.49, 95 % confidence interval (CI) 1.09-2.04, P = 0.012; OR = 2.58, 95 % CI 1.65-4.05, P < 0.001; respectively). Furthermore, the frequency of rs13361189CC genotype was increased in patients with complications than those without complications (P = 0.011). When analyzing the effect of rs13361189 polymorphism on M. leprae infection, we identified that M. leprae-infected PBMC with rs13361189CC genotype expressed significantly elevated levels of INF-γ and IL-4 than those with TT genotype. Our results suggested autophagy gene polymorphism was associated with the increased risk of leprosy by affecting inflammatory cytokines.


Inflammation and Immune Activation in Antiretroviral-Treated Human Immunodeficiency Virus Type 1-Infected African Infants and Rotavirus Vaccine Responses.
Biomarkers of inflammation and immune activation were correlated with rotavirus vaccine responses in 68 human immunodeficiency virus type 1 (HIV-1)–infected (and 116 HIV-exposed but uninfected (HEU) African infants receiving pentavalent rotavirus vaccine (RV5) in a clinical trial. Prevaccination, HIV-1+ infants had significantly higher concentrations of interferon γ (IFNγ), interleukin1β, interleukin 2, interleukin 6, interleukin 10 (IL-10), and soluble CD14 compared with HEU infants. Postvaccination concentrations of neutralizing antibodies to RV5 were negatively correlated with prevaccination concentrations of IL-10 (RV5 surface proteins G1 and P1) and IFNγ (G1) in the HIV-1+ infants, whereas antirotavirus immunoglobulin A (IgA) levels were not. Heightened inflammation and immune activation in HIV-1+ infants did not alter IgA responses associated with protection from rotavirus disease.


Systematic review of the effects of pomegranate (Punica granatum) on osteoarthritis.
Background: Considering limitations of the established osteoarthritis (OA) medications, attention to adjuvant and complementary treatments has increased in OA individuals. Recent investigations have reported advantages of pomegranate in OA and indicate that pomegranate can be a therapeutic option; nevertheless, no systematic review exists regarding OA and pomegranate. Therefore, we systematically studied accessible researches regarding pomegranate and OA in human, animal, and in vitro models and likely mechanistic pathways. Methods: Present systematic review study was recorded on the international prospective register of systematic reviews database. Electronic databases (Scopus, PubMed, Embase, WOS, ProQuest) and search engine Google Scholar were searched until February 2021. Search alerts were turned on to recognize papers published following the primary search. Two investigators independently searched using MESH and non-MESH words in title, abstract, and keywords. Inclusion criteria were related clinical, animal, and in vitro studies published in any language as a full text. Exclusion criteria were reviews, book chapters, conference abstracts, and articles regarding pomegranate in health problems other than OA. Hand searching was used to check the references or citations of eligible papers and grey literature (theses etc.) to find potential researches. Results: Twenty-three articles were included in our systematic review. Human, animal, and in vitro researches demonstrated favorable properties of pomegranate in improving clinical features and reducing inflammatory, oxidative stress, and apoptosis markers in OA. Conclusion: Present paper provides convincing evidence about the efficacy of pomegranate in OA and gives a justification for the importance of additional clinical studies.


One hundred years of population ecology: Successes, failures and the road ahead.
Population ecology is the most mature of the three subdisciplines of ecology partly because it has a solid mathematical foundation and partly because it can address the primary questions of distribution and abundance with experimental protocols. Yet there is much left to do to integrate our population knowledge into community and ecosystem ecology to help address the global issues of food security and the conservation of biodiversity. Many different approaches are now being developed to bring about this integration and much more research will be necessary to decide which if any will be most useful in achieving our goals of explaining the changes we see in the distribution and abundance of animals and plants. Food web ecology would appear to be the best approach at present because it uses the detailed information of the population ecology of particular species in combination with data on consumer-resource interactions to apply to the applied problems of biodiversity conservation, food security, pest management and disease prevention. If we can use our understanding of population ecology to address the practical problems of our time in a creative way, we will benefit both the human population and the Earth's biodiversity. Much remains to be done.


Enhanced biological phosphate removal by granular sludge in a sequencing batch reactor.
A laboratory-scale sequencing batch reactor was started-up with flocculated biomass and operated primarily for enhanced biological phosphate removal. Ten weeks after the start-up, gradual formation of granular sludge was observed. The compact biomass structure allowed halving the settling time, the initial reactor volume, and doubling the influent COD concentration. Continued operation confirmed the possibility of maintaining a stable granular biomass with a sludge volume index less than 40 ml g-1, while securing a removal efficiency of 95% for carbon, 99.6% for phosphate, and 71% for nitrogen. Microscopic observations revealed a morphological diversity.


Survey of current pre-discharge home visiting practices of occupational therapists.
Discharge planning frequently involves occupational therapy pre-discharge home visiting as one component of intervention. Pre-discharge home visits aim to maximise a person's functional performance within the context of their home and community environment, bridging the transition between hospital and home. The aim of this study was to describe the pre-discharge home visiting practices of occupational therapy departments. This descriptive study used a postal survey which was sent to occupational therapists in 215 public and privately funded hospitals in New South Wales, Australia. The survey enquired about the number of pre-discharge home visits completed per month, who went on visits and time spent on visits. Descriptive statistics were used in analyses. Surveys were returned by occupational therapists from 53 departments, representing a response rate of 25%. Respondents estimated that they conducted approximately 13 pre-discharge home visits per month (range: 1-60). Visits were estimated to take an average of 1 hour and 20 minutes (excluding travel time). Approximately one-quarter of respondents felt that there was pressure to reduce the number of pre-discharge home visits conducted. Using their local hospital records, nine hospital departments estimated that the number of home visits completed per month had reduced by 50% compared with the number of home visits five years previously. Findings suggest a wide variation in current pre-discharge home visiting practice. There is a need for well-designed clinical trials that investigate the effectiveness of these costly and time-consuming visits on functional performance.


[Interaction of connective tissue structural glycoprotein with proteoglycans and glycosaminoglycans].
It was shown that structural glycoprotein (SGP) of connective tissue isolated from be cattle heart valves and nasal septum cartilage formed water-soluble complexes with protein-chondroitin-4-sulphate and different heparin fractions. SGP formed no mentioned complexes with hyaluronic acid. Probably this plays an important role in the formation of collagen and elastin fibers.


Computer analysis of reflex control and organization: respiratory sinus arrhythmia.
Respiratory sinus arrhythmia in waking man is described by differential equations which relate thorax circumference acceleration to instantaneous heart rate. Consequent experiments show that the arrhythmia is initiated by stretch receptors within the thorax rather than by hemodynamic or central factors, and that it is due mainly to superimposed biphasic inspiratory heart rate transients of about 15 seconds' duration. Analysis of respiration heart rate reflex provides a new quantitative physiological tool.


U.S. Food and Drug Administration approval summary: Erlotinib for the first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations.
On May 14, 2013, the U.S. Food and Drug Administration approved erlotinib (Tarceva, Astellas Pharma Inc., Northbrook, IL, http://www.us.astellas.com/) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. This indication for erlotinib was approved concurrently with the cobas EGFR Mutation Test (Roche Molecular Systems, Inc., Basel, Switzerland, http://www.molecular.roche.com), a companion diagnostic test for patient selection. The approval was based on clinically important improvements in progression-free survival (PFS) and objective response rate (ORR) and an acceptable toxicity profile demonstrated in a multicenter, open label trial enrolling 174 patients with metastatic NSCLC whose tumors had EGFR mutations as determined by a laboratory-developed test. Patients were randomized (1:1) to receive erlotinib (150 mg/day) or platinum-based doublet chemotherapy. The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival (OS) and ORR. Superior PFS (hazard ratio [HR] 0.34; 95% confidence interval [CI]: 0.23, 0.49; p < .001) and ORR (65% vs. 16%) were observed in the erlotinib arm. Median PFS was 10.4 months and 5.2 months in the erlotinib and chemotherapy arms, respectively. There was no difference in OS (HR 0.93; 95% CI: 0.64, 1.35) with median OS of 22.9 months and 19.5 months in the erlotinib and chemotherapy arms, respectively. The most frequent (≥30%) adverse reactions in the erlotinib-treated patients were rash, diarrhea, asthenia, cough, dyspnea, and decreased appetite. The most frequent (≥5%) grade 3 and 4 adverse reactions were rash and diarrhea.


Abdominal surgery in the older Crohn's population.
The surgical literature perceives that the elderly cohort of Crohn's patients may have increased risk with surgery. A retrospective review and prospective database analysis of all patients with histologically proven Crohn' s disease who had a laparotomy at a single Sydney teaching hospital were performed. The last laparotomy of each patient was included in the analysis for morbidity and mortality to assess whether an older cohort was at an increased risk. A total of 156 patients had 298 laparotomies for histopathologically proven Crohn's disease. The frequency distribution of age at last laparotomy was bimodal, and the statistically determined cut-off age between younger and older cohorts was 55 years. Thirty-three patients were older than 55 years. There was no difference in duration of symptoms before first diagnosis (older, 17 months vs younger, 25 months), previous number of Crohn's operations (42.4 vs 39.8%), or duration of known Crohn's disease. Isolated large bowel disease was more common in the elderly cohort (42.4 vs 18.7%, chi2 = 8.09, P < 0.01). Small bowel and ileocaecal resections were more common in the younger cohort (72.4 vs 51.6%, chi2 = 5.19, P < 0.025). There was one death in each cohort (overall mortality 1.3%) and anastomotic leak rates (defined as the number of leaks per number of patients with anastomoses), were 4.3% (older) vs 5.3% (younger) despite frank sepsis present in 21.2% of all subjects at the time of surgery. The older group had more cardiac (18.2 vs 0.8%, P < 0.001) and respiratory complications (18.2 vs 2.4%; P = 0.0003) and a longer mean but not median postoperative hospital admission. In conclusion, clinical features and presentation are similar in the older and younger Crohn's patients having a laparotomy. However, in the older patient there is a greater likelihood of large bowel disease, ileocaecal resection is done less commonly, there is a higher risk of minor cardiopulmonary postoperative complications, but with similar mortality and anastomotic leak rates to the younger patient.


Lacrimal Drainage Obstruction and Gastroesophageal Reflux Disease: A Nationwide Longitudinal Cohort Study.
This study aimed to evaluate the association between gastroesophageal reflux disease (GERD) and development of lacrimal drainage obstruction (LDO). It has been hypothesized that GERD may contribute toward the development of LDO. This was a retrospective study of Koreans aged 40 to 79 years registered in the Korean National Health Screening Cohort from 2002 to 2013. Incident cases of LDO were identified according to the Korean Classification of Disease. We compared hazard ratios (HRs) for LDO between 22,570 patients with GERD and 112,850 patients without GERD by 1:5 propensity score-matched analysis. A total of 135,420 patients, representing 1,237,909 person-years, were evaluated. LDO developed in 1998 (8.9%) patients with GERD and 8565 (7.6%) patients without GERD (P<0.001). The incidence of LDO per 1000 person-years in patients with GERD was 9.7 and 8.3 in those without GERD; the age-adjusted and sex-adjusted HR was 1.17 (95% confidence interval, 1.11-1.23). This association between GERD and LDO was more pronounced among younger individuals (HR, 1.20 for patients 40 to 59-y old; HR, 1.12 for patients 60 to 79-y old) and among men (HR, 1.20 for men; HR, 1.14 for women). Patients with GERD had a higher risk of LDO than those without GERD, irrespective of history of proton-pump inhibitor use. In the sensitivity analysis, GERD patients with esophagitis had a higher risk of LDO than those without esophagitis. Our findings suggest that GERD is associated with an increased risk of subsequent LDO and that this effect is more pronounced among adults aged 40 to 59-years old and men.


[Presentation of a clinical case of systemic juvenile rheumatoid arthritis].
A case of a 6-year-old male child was studied. Initially, he presented large-joint arthritis of the right knee and heel, with clinical data of systemic inflammation, such as fever, increase in sedimentation rate and leucocytosis, during more than six weeks of evolution. A wrong initial diagnosis of septic arthritis was made, but the lack of response to antibiotics and surgical drainage of the knee led to a trial with prednisone, which induced clinical remission. The patient remained hospitalized for 24 days and underwent surgical drainage, knee arthroscopy, two bone gammagrams, nuclear magnetic resonance, and antibiotics, as well as considerable stress and uncertainty for him and his family. Thus, it is very important to make an early diagnosis of juvenile rheumatoid arthritis and avoid complications. Recent literature was examined with special emphasis on opportune clinical diagnosis, as well as on therapeutic innovations, which have been able to modify the course of the disease and improve the quality of life of these patients. Pediatricians and general practitioners should take into account this diagnosis when seeing a patient with arthritis, especially when the signs point towards a systemic disease affecting two or more joints.


Annexin V-CLIO: a nanoparticle for detecting apoptosis by MRI.
Annexin V, which recognizes the phosphatidylserine of apoptotic cells, was conjugated to crosslinked iron oxide (CLIO) nanoparticles, a functionalized superparamagnetic preparation developed for target-specific magnetic resonance imaging (MRI). The resulting nanoparticle had an average of 2.7 annexin V proteins linked per CLIO nanoparticle through disulfide bonds. Using camptothecin to induce apoptosis, a mixture of Jurkat T cells (69% healthy and 31% apoptotic) was incubated with annexin V-CLIO and was applied to magnetic columns. The result was an almost complete removal of the apoptotic cells (> 99%). In a phantom MRI experiment, untreated control cells (12% apoptotic cells, 88% healthy cells) and camptothecin-treated cells (65% apoptotic cells, 35% healthy cells) were incubated with either annexin V-CLIO (1.0, 0.5, and 0.1 microgram Fe/mL) or with unlabeled CLIO. A significant signal decrease of camptothecin-treated cells relative to untreated cells was observed even at the lowest concentration tested. Unmodified CLIO failed to cause a significant signal change of apoptotic cells. Hence, annexin V-CLIO allowed the identification of cell suspensions containing apoptotic cells by MRI even at very low concentrations of magnetic substrate. Conjugation of annexin V to CLIO affords a strategy for the development of a MRI imaging probe for detecting apoptosis.


On-line chloride removal from ion chromatography for trace-level analyses of phosphite and other anions by coupled ion chromatography-inductively coupled plasma mass spectrometry.
Ion chromatography (IC) combined with inductively coupled plasma mass spectrometry (ICPMS) is an ideal tool for measuring low concentrations of anionic species such as phosphite; however, the high concentration of chloride and other anions in natural solutions may negatively impact chromatographic separation and data quality. We developed an on-line mechanism of removing chloride from a sample within an ion chromatograph, using an additional valve and a separation column that transfers chloride to waste while phosphite and most other anions are retained. We installed this system in a coupled IC/ICPMS system (ICS6000 and Element 2 in medium-resolution mode) and determined linearity and detection limits. In addition, we measured phosphorus species by NMR for comparison as an alternative method for phosphite determination. Chloride was fully removed from the samples while phosphite was retained and could be analysed by IC/ICPMS. Concentrations could be measured down to 0.003 μmol/L and possibly less with good linearity over the explored range (up to 1.615 μmol/L; r2 = 0.999). In contrast, the detection limit by NMR was 6.46 μmol/L. The on-line removal mechanism works well for simplifying sample matrices. It removes the need for costly pre-analytical sample treatment with OnGuard columns. We confirm that IC/ICPMS is the most powerful technique for quantifying phosphite in natural solutions. The new chloride-removal method may also be applicable to analyses of other anions.


Effects of PPARgamma ligands and C/EBPbeta enhancer on expression of extracellular-superoxide dismutase.
Extracellular-superoxide dismutase (EC-SOD) is the major SOD isozyme in the blood vessel walls and may be important for antioxidant capability of the vascular walls. Expression of EC-SOD is known to be regulated by numerous substances such as cytokines and vasoactive factors. Recently, we found that the plasma EC-SOD levels in type 2 diabetic patients were significantly and inversely related to indices of insulin resistance, whereas they were strongly and positively related to adiponectin. Administration of pioglitazone significantly increased the plasma level of EC-SOD and adiponectin. Transcription factors such as CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptors (PPARs) are known to regulate genes associated with insulin resistance. The aim of this study was to assess the contribution of these transcription factors on the EC-SOD level. We found that a C/EBPbeta enhancer, prolactin, significantly induced the EC-SOD mRNA and protein levels in cultured fibroblast cell lines, but PPARgamma ligands, pioglitazone and other thiazolidinedione agents did not. Deletion analysis of the EC-SOD promoter-luciferase construct showed that an important element responsible for prolactin is located between -242 and -178 in the promoter region of the EC-SOD gene in which a known C/EBPbeta-binding site is located. Increasing the EC-SOD expression by treatment with ligands of transcription factors might be one approach to ameliorate the pathological conditions of insulin resistance.


Myonuclear domain size and myosin isoform expression in muscle fibres from mammals representing a 100,000-fold difference in body size.
This comparative study of myonuclear domain (MND) size in mammalian species representing a 100,000-fold difference in body mass, ranging from 25 g to 2500 kg, was undertaken to improve our understanding of myonuclear organization in skeletal muscle fibres. Myonuclear domain size was calculated from three-dimensional reconstructions in a total of 235 single muscle fibre segments at a fixed sarcomere length. Irrespective of species, the largest MND size was observed in muscle fibres expressing fast myosin heavy chain (MyHC) isoforms, but in the two smallest mammalian species studied (mouse and rat), MND size was not larger in the fast-twitch fibres expressing the IIA MyHC isofom than in the slow-twitch type I fibres. In the larger mammals, the type I fibres always had the smallest average MND size, but contrary to mouse and rat muscles, type IIA fibres had lower mitochondrial enzyme activities than type I fibres. Myonuclear domain size was highly dependent on body mass in the two muscle fibre types expressed in all species, i.e. types I and IIA. Myonuclear domain size increased in muscle fibres expressing both the beta/slow (type I; r = 0.84, P < 0.001) and the fast IIA MyHC isoform (r = 0.90; P < 0.001). Thus, MND size scales with body size and is highly dependent on muscle fibre type, independent of species. However, myosin isoform expression is not the sole protein determining MND size, and other protein systems, such as mitochondrial proteins, may be equally or more important determinants of MND size.


Near-edge x-ray absorption and natural circular dichroism spectra of L-alanine: a theoretical study based on the complex polarization propagator approach.
The complex polarization propagator method [J. Chem. Phys. 123, 194103 (2005)] has been employed in conjunction with density functional theory and gauge-including atomic orbitals in order to determine the near-edge x-ray absorption and natural circular dichroism spectra of L-alanine in its neutral and zwitterionic forms. Results are presented for the K-edges of carbon, nitrogen, and oxygen. In contrast to traditional methods, the proposed approach enables a direct determination of the spectra at an arbitrary frequency instead of focusing on the rotatory strengths for individual electronic transitions. The propagator includes a complete set of nonredundant electron-transfer operators and allows for full core-hole relaxation. The theoretical spectrum at the nitrogen K-edge of the zwitterion compares well with the experimental spectrum.


Geographical structuring of genetic diversity across the whole distribution range of Narcissus longispathus, a habitat-specialist, Mediterranean narrow endemic.
High mountain ranges of the Mediterranean Basin harbour a large number of narrowly endemic plants. In this study an investigation is made of the levels and partitioning of genetic diversity in Narcissus longispathus, a narrow endemic of south-eastern Spanish mountains characterized by a naturally fragmented distribution due to extreme specialization on a rare habitat type. By using dense sampling of populations across the species' whole geographical range, genetic structuring at different geographical scales is also examined. Using horizontal starch-gel electrophoresis, allozyme variability was screened at 19 loci for a total of 858 individuals from 27 populations. The data were analysed by means of standard statistical approaches in order to estimate gene diversity and the genetic structure of the populations. Narcissus longispathus displayed high levels of genetic diversity and extensive diversification among populations. At the species level, the percentage of polymorphic loci was 68 %, with average values of 2.1, 0.11 and 0.14 for the number of alleles per locus, observed heterozygosity and expected heterozygosity, respectively. Southern and more isolated populations tended to have less genetic variability than northern and less-isolated populations. A strong spatial patterning of genetic diversity was found at the various spatial scales. Gene flow/drift equilibrium occurred over distances <4 km. Beyond that distance divergence was relatively more influenced by drift. The populations studied seem to derive from three panmictic units or 'gene pools', with levels of admixture being greatest in the central and south-eastern portions of the species' range. In addition to documenting a case of high genetic diversity in a narrow endemic plant with naturally fragmented populations, the results emphasize the need for dense population sampling and examination of different geographical scales for understanding population genetic structure in habitat specialists restricted to ecological islands.


Binaural response organization within a frequency-band representation of the inferior colliculus: implications for sound localization.
The auditory system of the mustache bat (Pteronotus parnellii) contains a disproportionately large representation of a narrow frequency band, corresponding to the dominant, 60 kHz component of its echolocation signal. In the inferior colliculus (IC), the 60 kHz representation comprises an architectonically distinct region called the dorsoposterior division (DPD), which is accessible for detailed physiological study. We examined the topographic distribution of binaural responses within this one frequency-band representation of the inferior colliculus. We describe two primary results. First, neurons with different binaural response properties are spatially segregated into one of four binaural response-specific regions of the DPD: a large region of monaural (EO) responses; two regions containing neurons excited by sound from both ears (EE); and a region containing neurons excited by one ear and inhibited by the other (EI). Regions dominated by 60 kHz EI responses are also found in the lateral extremity of the IC, probably within the external nucleus. These results demonstrate functionally defined subdivisions in a single frequency-band representation of the IC. Moreover, they suggest that brain stem auditory projections to the DPD and/or intrinsic connections within the DPD are highly organized. Second, within the EI region of the DPD, there is a systematic shift in the sensitivity of EI multiunit responses to interaural intensity disparities (IIDs). Dorsally, EI neurons are suppressed only by relatively loud ipsilateral sounds, and there is a systematic decrease in the relative ipsilateral intensity required for suppression at more ventral recording sites. This result demonstrates that neurons sensitive to a sound localization cue are systematically organized within a frequency-band representation of the inferior colliculus. It has implications for the manner in which the location of a sound source is encoded within the primary auditory pathway.