Knowledge, Attitude, and Practice of Mothers regarding Oral Hygiene of Primary School children in Chennai, Tamil Nadu, India.
Children depend on their parents and caretakers for maintenance of their oral health. Parents play a major role in both preventive and treatment regime in these children. This study was conducted with the aim of evaluating the influence of parental education on knowledge, attitude, and practice of mothers regarding oral health of primary schoolchildren in Chennai. A 15-item self-administered questionnaire was used among 465 parents of preschool children in Chennai, of which 432 mothers returned the filled questionnaire. The data collected were subjected to statistical analysis using frequency of responses and chi-square test (p < 0.01). Data were analyzed using statistical package. Of the 432 mothers who participated in the study, 150 (35%) have studied up to school level and 282 (65%) have completed diploma/degree. The knowledge of mothers regarding the knowledge of importance of oral health for general health is appreciable, but the awareness of proper brushing habit, treatment of caries, and importance of dental visits is less in mothers who have school education when compared with graduate mothers. Mothers who are graduates are more aware of the importance of oral health in children, treatment of dental caries, and brushing technique than mothers with school education. Hence, it is essential that government and health care providers impart oral health knowledge to mothers, as they are the role-models for their children.How to cite this article: Gurunathan D, Moses J, Arunachalam SK. Knowledge, Attitude, and Practice of Mothers regarding Oral Hygiene of Primary School children in Chennai, Tamil Nadu, India. Int J Clin Pediatr Dent 2018;11(4):338-343.


The time course and characterization of myocardial hemorrhage after coronary reperfusion in the anesthetized dog.
We quantitated hemorrhage associated with reperfusion after varying periods of myocardial ischemia and examined the flow characteristics that accompany reperfusion hemorrhage. Anesthetized dogs were reperfused after 2, 6 or 24 hours of circumflex occlusion. A control group underwent coronary occlusion without reperfusion. Radioactive microspheres were injected before and 5 minutes and 24 hours after reperfusion. The papillary muscles were analyzed for hemoglobin content, flow during myocardial ischemia and flow early and 24 hours after reperfusion. Myocardial creatine kinase activity was assayed to determine the severity of myocardial necrosis in the papillary muscles. Hemorrhage into the posterior papillary muscle was dependent upon the duration of coronary artery occlusion. Posterior papillary hemoglobin averaged 14 mg/g in the 2-hour group, 28 mg/g in the 6-hour group and 36 mg/g in the group reperfused 24 hours after occlusion, compared with 8.7 mg/g in the control group. Myocardial hemorrhage was associated with severe depression in myocardial CK and marked depression in flow to the ischemic area (i.e., collateral flow) during the occlusion. Early reflow averaged 112 ml/min/100 g in the 2-hour group, 61 ml/min/100 g in the 6-hour group and only 5.8 ml/min/100 g in the 24-hour group. Therefore, myocardial hemorrhage induced by reperfusion of the acutely ischemic myocardium is associated with severe ischemia during occlusion and severe myocardial necrosis, but does not depend upon the magnitude of early reflow. Myocardial hemorrhage may occur even though initial reflow values are markedly decreased.


The novel cyclin-dependent kinase inhibitor flavopiridol downregulates Bcl-2 and induces growth arrest and apoptosis in chronic B-cell leukemia lines.
Flavopiridol is a novel, potent inhibitor of cyclin-dependent kinases (CDK). This synthetic flavone has been reported to exhibit antitumor activity in murine and human tumor cell lines in vitro and in vivo and is currently undergoing clinical phase I evaluation. In the present study, 1 Epstein-Barr virus (EBV)-transformed B-prolymphocytic cell line (JVM-2), 1 EBV-transformed B-CLL cell line (I83CLL), and 1 non-EBV transformed B-CLL cell line (WSU-CLL) were used as targets. Treatment of the cells with flavopiridol (100 nmol/L to 400 nmol/L) led to a marked dose- and time-dependent inhibition of cell growth and survival as determined using trypan blue exclusion. Morphologic analysis showed characteristic apoptotic changes such as chromatin condensation and fragmentation, membrane blebbing, and formation of apoptotic bodies. Furthermore, quantitative assessment of apoptosis-associated DNA strand breaks by in situ TdT labeling showed that a significant number of flavopiridol-treated cells underwent apoptosis. These cellular effects were associated with a significant decrease in bcl-2 expression as observed by Northern and Western blotting. The results showed that flavopiridol downregulates bcl-2 mRNA and bcl-2 protein expression within 24 hours. Genistein and quercetin, two flavonoids that do not inhibit CDKs, did not affect bcl-2 expression. These data suggest an additional mechanism of action of this new flavone which might be useful as an agent in the treatment of chronic lymphoid malignancies.


[The development of dental robot implantation technology].
With the advancement of technology, intelligent technology has achieved unprecedented progress and breakthroughs in various fields. Dental implant robots represent a significant leap in the field of dental medical technology. This article aims to review the development of dental robot implantation technology both domestically and internationally, to compare the similarities and differences between existing dental implant methods and robotic implantation, to analyze the characteristics and current applications of robotic implantation technology, and to provide a forward-looking perspective. This review summarized 63 literatures and compared 1 176 implants, dental robot implantation demonstrates significant advantages in terms of precision, efficiency, and minimally invasive procedures. It effectively addresses issues such as implant position deviation, limited surgical visibility, and restricted operating space associated with traditional implantation methods. With widespread adoption in the future, it may reduce the overall technological expenses, and optimize its advantages and potential benefits.


When has the cause analysis reached the root?
Until a few years ago, the triennial JCAHO survey only peripherally involved the risk manager. With the advent of the sentinel event policy, this will certainly change regardless of whether the organization chooses to self-report. It is anticipated that the risk manager will be involved with the triennial survey particularly with regards to the PI standards. The mechanisms used by the organization to manage sentinel events will be scored within these standards and will be examined as part of the survey whether or not an event has occurred. The goal of ensuring that errors are managed in a manner that corrects the most fundamental contributing causes lies within the role of the risk manager.


Non-ionizing radiation with nanosecond pulsed electric fields as a cancer treatment: in vitro studies.
Cancer continues to be a major risk to the health and well being among populations around the world. A new method using ion-ionizing radiation with nanosecond pulsed electric fields (nsPEFs) provides a novel means to treat cancer at local sites. NsPEFs promote cell death in several cell types and here we investigated mechanisms for cell death induction. In murine B16f10 melanoma, murine E4 squamous carcinoma, murine Hep1-6 and human HepG2 hepatocellular carcinoma, nsPEFs induced cell death in 90-95% of cells. Cell death coincides with decreases in the mitochondria membrane potential, increases in YO-PRO-1 uptake and active caspases in the presence or absence of cytochrome c release. The results indicate that nsPEFs induced cell death by multiple apoptosis mechanisms that involve mitochondrial responses, but not necessarily through cytochrome c release. Further, these in vitro studies suggest a potential to induce cell death that bypasses cancer mechanisms that evade apoptosis.


Adolescents' Self Perceptions: Connecting Psychosocial Competencies to the Sexual Self-Concept.
Adolescence is a crucial period for the development of the sexual self-concept. While existing research shows that adolescents' sexual self-concept varies, few studies have examined its relation with psychosocial competencies such as the general self-concept, interpersonal skills, and self-control capacities. The objective of this study was to examine the association between dimensions of the sexual self-concept (sexual self- and body esteem, self-efficacy, and anxiety) and psychosocial competencies among Canadian adolescents. Self-reported data from 1584 adolescents aged between 14 and 18 years (49.7% girls) were analyzed using path analysis. Results show that adolescents whose general self-concept was characterized by more internally consistent self-beliefs and greater self-worth, and who perceived their interpersonal skills as more developed, displayed higher sexual self- and body esteem, higher sexual self-efficacy, and lower sexual anxiety. Self-control capacities were positively correlated with sexual body-esteem and negatively correlated with sexual anxiety. These associations were, however, minimal and, when significant, exhibited a counterintuitive relationship with the sexual self-concept in the path model. Age, gender and sexual experience did not moderate these associations. Findings from the study highlight the need to pursue research on the interface between sexuality and psychosocial functioning to increase current understanding of adolescent development.


Prospective comparison of amoxicillin-clavulanic acid and cefaclor in treatment of uncomplicated urinary tract infections.
Patients with acute, uncomplicated urinary tract infections were treated with either amoxicillin-clavulanic acid (A-C) in fixed combination or cefaclor for 10 days in a prospective randomized comparison. The A-C group included 29 women and 1 man (mean age, 25.5 years), and the cefaclor group included 35 women and 1 man (mean age, 24.9 years). The cure rates were 26 (87%) of 30 with A-C and 26 (72%) of 36 with cefaclor (P greater than 0.20). There was one failure in each group, each caused by an isolate resistant to ampicillin. There were one relapse and two reinfections in the A-C group, compared with seven relapses and two reinfections in the cefaclor group. Side effects, including patients started on antibiotics but whose cultures did not confirm urinary tract infections, were diarrhea in 7 (16%) and rash in 1 (2%) of 44 A-C patients, compared with diarrhea in 1 (2%) and yeast vaginitis in 3 (6%) of 48 cefaclor patients. Although the A-C group had a greater proportion of antibody-coated bacterium-positive infections (22 versus 18 with cefaclor), there was a lower recurrence rate with fewer relapses in patients treated with A-C.


Personalised 3D Printed Medicines: Optimising Material Properties for Successful Passive Diffusion Loading of Filaments for Fused Deposition Modelling of Solid Dosage Forms.
Although not readily accessible yet to many community and hospital pharmacists, fuse deposition modelling (FDM) is a 3D printing technique that can be used to create a 3D pharmaceutical dosage form by employing drug loaded filaments extruded via a nozzle, melted and deposited layer by layer. FDM requires printable filaments, which are commonly manufactured by hot melt extrusion, and identifying a suitable extrudable drug-excipient mixture can sometimes be challenging. We propose here the use of passive diffusion as an accessible loading method for filaments that can be printed using FDM technology to allow for the fabrication of oral personalised medicines in clinical settings. Utilising Hansen Solubility Parameters (HSP) and the concept of HSP distances (Ra) between drug, solvent, and filament, we have developed a facile pre-screening tool for the selection of the optimal combination that can provide a high drug loading (a high solvent-drug Ra, >10, and an intermediate solvent-filament Ra value, ~10). We have identified that other parameters such as surface roughness and stiffness also play a key role in enhancing passive diffusion of the drug into the filaments. A predictive model for drug loading was developed based on Support Vector Machine (SVM) regression and indicated a strong correlation between both Ra and filament stiffness and the diffusion capacity of a model BCS Class II drug, nifedipine (NFD), into the filaments. A drug loading, close to 3% w/w, was achieved. 3D printed tablets prepared using a PVA-derived filament (Hydrosupport, 3D Fuel) showed promising characteristics in terms of dissolution (with a sustained release over 24 h) and predicted chemical stability (>3 years at 25 °C/60% relative humidity), similar to commercially available NFD oral dosage forms. We believe FDM coupled with passive diffusion could be implemented easily in clinical settings for the manufacture of tailored personalised medicines, which can be stored over long periods of time (similar to industrially manufactured solid dosage forms).


Long-Term Deficits in Behavior Performances Caused by Low- and High-Linear Energy Transfer Radiation.
Efforts to protect astronauts from harmful galactic cosmic radiation (GCR) require a better understanding of the effects of GCR on human health. In particular, little is known about the lasting effects of GCR on the central nervous system (CNS), which may lead to behavior performance deficits. Previous studies have shown that high-linear energy transfer (LET) radiation in rodents leads to short-term declines in a variety of behavior tests. However, the lasting impact of low-, medium- and high-LET radiation on behavior are not fully defined. Therefore, in this study C57BL/6 male mice were irradiated with 100 or 250 cGy of γ rays (LET ∼0.3 KeV/μm), 10 or 100 cGy of 1H at 1,000 MeV/n (LET ∼0.2 KeV/μm), 28Si at 300 MeV/n (LET ∼69 KeV/μm) or 56Fe at 600 MeV/n (LET of ∼180 KeV/μm), and behavior metrics were collected at 5 and 9 months postirradiation to analyze differences among radiation qualities and doses. A significant dose effect was observed on recognition memory and activity levels measured 9 months postirradiation, regardless of radiation source. In contrast, we observed that each ion species had a distinct effect on anxiety, motor coordination and spatial memory at extended time points. Although 28Si and 56Fe are both regarded as high-LET particles, they were shown to have different detrimental effects on behavior. In summary, our findings suggest that GCR not only affects the CNS in the short term, but also has lasting damaging effects on the CNS that can cause sustained declines in behavior performance.


Supplementation with antioxidants and folinic acid for children with Down's syndrome: randomised controlled trial.
To assess whether supplementation with antioxidants, folinic acid, or both improves the psychomotor and language development of children with Down's syndrome. Randomised controlled trial with two by two factorial design. Children living in the Midlands, Greater London, and the south west of England. 156 infants aged under 7 months with trisomy 21. Daily oral supplementation with antioxidants (selenium 10 mug, zinc 5 mg, vitamin A 0.9 mg, vitamin E 100 mg, and vitamin C 50 mg), folinic acid (0.1 mg), antioxidants and folinic acid combined, or placebo. Griffiths developmental quotient and an adapted MacArthur communicative development inventory 18 months after starting supplementation; biochemical markers in blood and urine at age 12 months. Children randomised to antioxidant supplements attained similar developmental outcomes to those without antioxidants (mean Griffiths developmental quotient 57.3 v 56.1; adjusted mean difference 1.2 points, 95% confidence interval -2.2 to 4.6). Comparison of children randomised to folinic acid supplements or no folinic acid also showed no significant differences in Griffiths developmental quotient (mean 57.6 v 55.9; adjusted mean difference 1.7, -1.7 to 5.1). No between group differences were seen in the mean numbers of words said or signed: for antioxidants versus none the ratio of means was 0.85 (95% confidence interval 0.6 to 1.2), and for folinic acid versus none it was 1.24 (0.87 to 1.77). No significant differences were found between any of the groups in the biochemical outcomes measured. Adjustment for potential confounders did not appreciably change the results. This study provides no evidence to support the use of antioxidant or folinic acid supplements in children with Down's syndrome. Clinical trials NCT00378456.


Evidence-based appraisal of the role of SJTs in selection.
A recent opinion article in Clinical Medicine promoted a new preference-based algorithm to allocate training places for the UK Foundation Programme Office (UKFPO). This replaced the previous process, which ranked candidates based on medical school academic achievement (the educational performance measure; EPM) and the score on a situational judgement test (SJT). Although not without risks, we believe that the new system has positive potential. In presenting their case, Sam et al summarised evidence relating to the UKFPO in an unbalanced way, leading to what we believe are erroneous inferences, particularly with regard to differential attainment. Here, we provide an example of how the general evidence base and conceptual understanding of the validity of SJTs for medical selection is poorly understood. We highlight important research findings that were not cited by Sam et al and provide what we believe is a more balanced and accurate interpretation of the evidence base relating the UKFPO SJT, and SJTs used in medical selection in general. We do this with particular reference to the validity of such tools in this context, as well as their potential impact on under-represented groups in medicine, compared with other selection assessments.


Re-experiencing old memories via hippocampus: a PET study of autobiographical memory.
The time-scale of medial temporal lobe (MTL) involvement in storage and retrieval of episodic memory is keenly debated. To test competitive theories of long-term memory consolidation, the present work aimed at characterizing which cerebral regions are involved during retrieval of recent and remote strictly episodic autobiographical memory. Using positron emission tomography (PET), we examined mental retrieval of recent (0-1 year) and remote (5-10 years) autobiographical memories, controlling for the nature of the autobiographical memories (i.e., specificity, state of consciousness, vividness of mental visual imagery, emotion) retrieved during scanning by behavioral measures assessed at debriefing for each event recalled. Cognitive results showed that specificity and emotion did not change with time interval although both autonoetic consciousness and mental image quality were significantly higher for recent memories, suggesting an underlying shift in the phenomenal experience of remembering with the passage of time. The SPM analysis revealed common activations during the recollection of recent and remote memories that involved a widespread but mainly left-sided cerebral network, consistent with previous studies. Subtraction analysis demonstrated that the retrieval of recent (relative to remote) autobiographical memories principally activated the left dorsolateral prefrontal cortex whereas the retrieval of remote (relative to recent) autobiographical memories activated the inferior parietal cortex bilaterally. ROIs analysis revealed more hippocampal activity for remote memories than for recent ones and a preferentially right-sided involvement of the hippocampal responses whatever the remoteness of autobiographical memories. New insights based on higher hippocampal response to the remoteness of episodic autobiographical memories challenge the standard model and are less discrepant with the multiple trace theory.


Cocoa has more phenolic phytochemicals and a higher antioxidant capacity than teas and red wine.
Black tea, green tea, red wine, and cocoa are high in phenolic phytochemicals, among which theaflavin, epigallocatechin gallate, resveratrol, and procyanidin, respectively, have been extensively investigated due to their possible role as chemopreventive agents based on their antioxidant capacities. The present study compared the phenolic and flavonoid contents and total antioxidant capacities of cocoa, black tea, green tea, and red wine. Cocoa contained much higher levels of total phenolics (611 mg of gallic acid equivalents, GAE) and flavonoids (564 mg of epicatechin equivalents, ECE) per serving than black tea (124 mg of GAE and 34 mg of ECE, respectively), green tea (165 mg of GAE and 47 mg of ECE), and red wine (340 mg of GAE and 163 mg of ECE). Total antioxidant activities were measured using the 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assays and are expressed as vitamin C equivalent antioxidant capacities (VCEACs). Cocoa exhibited the highest antioxidant activity among the samples in ABTS and DPPH assays, with VCEACs of 1128 and 836 mg/serving, respectively. The relative total antioxidant capacities of the samples in both assays were as follows in decreasing order: cocoa > red wine > green tea > black tea. The total antioxidant capacities from ABTS and DPPH assays were highly correlated with phenolic content (r2 = 0.981 and 0.967, respectively) and flavonoid content (r2 = 0.949 and 0.915). These results suggest that cocoa is more beneficial to health than teas and red wine in terms of its higher antioxidant capacity.


Psychological wellbeing facilitates accurate HIV risk appraisal in gay and bisexual men.
Background Accurate HIV risk appraisal is key to effective HIV prevention. This study focuses on the role of psychological wellbeing in determining perceived HIV risk in a sample of gay and bisexual (GBM) in the UK. Overall, 191 HIV-negative GBM completed a cross-sectional survey, in which they provided demographic information and completed measures of engagement in actual sexual risk behaviours, diagnosis with a sexually transmissible infection in the past 12 months, frequency of HIV testing, use of post-exposure prophylaxis (PEP), perceived HIV risk, lesbian, gay, bisexual and transgender (LGBT) identity, sexual identity openness and psychological wellbeing. Results showed that there was a correlation between engagement in actual HIV risk behaviours and perceived HIV risk, suggesting relatively accurate HIV risk appraisal in the participant sample. LGBT identity and sexual identity openness were associated with increased psychological wellbeing. Structural equation modelling showed that psychological wellbeing has an effect on perceived HIV risk through the mediator of LGBT identity. It appears that a state of psychological wellbeing facilitates the construction of a strong and robust LGBT identity, which can be displayed to others, and that a strong LGBT identity in turn facilitates accurate HIV risk appraisal in GBM. In order to achieve our target of zero new HIV infections by 2030, it will be essential to focus on enhancing psychological wellbeing in people at risk of HIV.


Mid-trimester maternal serum markers in predicting adverse pregnancy outcome.
In a prospective study, we investigated the association between mid-trimester maternal serum AFP (ms-AFP), maternal serum hCG (ms-hCG) levels and adverse pregnancy outcome in a South-Western Greek population. 126 healthy Greek women with spontaneous pregnancies were investigated for ms-AFP and ms-hCG levels between the 13th and 24th weeks of gestation and followed for adverse pregnancy outcome. Abnormal outcomes were considered as ms-AFP levels or ms-hCG levels > 2.0 multiples of the median value for gestation (MoM). Statistical analysis was performed by Pearson's chi-square test. Elevated ms-AFP levels were detected in a total of 25 out of the 126 women studied (19.84%). Elevated ms-hCG levels were detected in a total of ten of the 126 women studied (7.93%). Elevated ms-AFP and ms-hCG levels were detected in a total of four of the 126 women studied (3.17%). Multiparameter testing of placental function in the mid-trimester (uterine artery Doppler, placental morphology, ms-AFP and ms-hCG screening) may allow us to identify women with increased risk of developing severe placental insufficiency and pregnancy complications.


Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2-093, and BIA 2-024.
Carbamazepine (CBZ) has been extensively used in the treatment of epilepsy, as well as in the treatment of neuropathic pain and affective disorders. However, the mechanisms of action of this drug are not completely elucidated and are still a matter of debate. Since CBZ is not very effective in some epileptic patients and may cause several adverse effects, several antiepileptic drugs have been developed by structural variation of CBZ, such as oxcarbazepine (OXC), which is used in the treatment of epilepsy since 1990. (S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz [b,f]azepine-5-carboxamide (BIA 2-093) and 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f] azepine-5-carboxamide (BIA 2-024), which were recently developed by BIAL, are new putative antiepileptic drugs, with some improved properties. In this review, we will focus on the mechanisms of action of CBZ and its derivatives, OXC, BIA 2-093 and BIA 2-024. The available data indicate that the anticonvulsant efficacy of these AEDs is mainly due to the inhibition of sodium channel activity.


Glucose-dependent insulinotropic polypeptide augments glucagon responses to hypoglycemia in type 1 diabetes.
Glucose-dependent insulinotropic polypeptide (GIP) is glucagonotropic, and glucagon-like peptide-1 (GLP-1) is glucagonostatic. We studied the effects of GIP and GLP-1 on glucagon responses to insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Ten male subjects with T1DM (C-peptide negative, age [mean ± SEM] 26 ± 1 years, BMI 24 ± 0.5 kg/m(2), HbA1c 7.3 ± 0.2%) were studied in a randomized, double-blinded, crossover study, with 2-h intravenous administration of saline, GIP, or GLP-1. The first hour, plasma glucose was lowered by insulin infusion, and the second hour constituted a "recovery phase." During the recovery phase, GIP infusions elicited larger glucagon responses (164 ± 50 [GIP] vs. 23 ± 25 [GLP-1] vs. 17 ± 46 [saline] min ⋅ pmol/L, P < 0.03) and endogenous glucose production was higher with GIP and lower with GLP-1 compared with saline (P < 0.02). On the GIP days, significantly less exogenous glucose was needed to keep plasma glucose above 2 mmol/L (155 ± 36 [GIP] vs. 232 ± 40 [GLP-1] vs. 212 ± 56 [saline] mg ⋅ kg(-1), P < 0.05). Levels of insulin, cortisol, growth hormone, and noradrenaline, as well as hypoglycemic symptoms and cognitive function, were similar on all days. Our results suggest that during hypoglycemia in patients with T1DM, exogenous GIP increases glucagon responses during the recovery phase after hypoglycemia and reduces the need for glucose administration.


[Safety patient in medication use and administration].
We face two realities of great importance in health today: first patient safety as a basic and essential component of quality of care, and secondly the complexity of drug management. Ensure appropriate use and administration medication is essential to guarantee patient safety and necessary condition to ensure optimal levels of quality of clinical practice. We made an analysis of both realities to see what are the implications to health professionals in this area.


An examination of concepts in vocational rehabilitation that could not be linked to the ICF based on an analysis of secondary data.
In the last few years the International Classification of Functioning, Disability and Health (ICF) has become a widely known and useful reference classification in vocational rehabilitation. It would be equally important to know which aspects of work-related health information cannot be assigned to distinct ICF categories. The objective of this study is to examine the concepts derived from three studies conducted within the ICF Core Set for vocational rehabilitation project, which could not be linked to distinct ICF codes in order to complement the current understanding of functioning in vocational rehabilitation. Secondary data analysis of the concepts from the systematic literature review, expert survey and patient focus group study of the ICF Core Set for vocational rehabilitation project that were marked as nd = not definable, nc = not covered or pf = personal factor. Nd-concepts were assigned to the biopsychosocial model of the ICF; additional ICF categories were formulated where needed. Nc-concepts were grouped into common themes not covered by the ICF. Pf-categories were linked to a proposed personal factors classification. 1093 nd-concepts were matched to overarching terms in the ICF, and "other specified"-categories were detailed. 1924 pf-concepts were linked to 31 second level categories of a proposed personal factors classification. 441 nc-concepts were grouped into six themes including the concept of well-being and attributes related to processes and time. With concepts that emerged from the secondary analysis of data gathered during the vocational rehabilitation ICF Core Set project, we have enriched the ICF model with constructs specific to vocational rehabilitation. However, additional research is needed to further explore personal factors specific to vocational rehabilitation. The influence of themes complementary to the ICF such as well-being and quality of life on return-to-work should be further investigated.


Kaposi's sarcoma and its relationship to cytomegalovirus (CMNV). III. CMV DNA and CMV early antigens in Kaposi's sarcoma.
DNA-DNA reassociation kinetics, anti-complement immunofluorescence (ACIF) and ACIF-blocking tests were used to search for cytomegalovirus (CMV) gene products in Kaposi's sarcoma (DS) biopsies and early cell cultures deriving from them. Three of eight tumor biopsies were positive for CMV DNA; two of them at 0.35 genome/cell and one at one copy 25% genome/cell. CMV-related antigens, mainly localized in the nucleus, were found in cryostat sections of seven of 31 tumor biopsies and four of 12 KS cell lines at early passage level. It appears that the antigen is present in a high number of tumor cells, like the Epstein-Barr virus nuclear antigen (EBNA) in EBV-transformed cells. Inevitably, the increasing data concerning the oncogenic potential of CMV lead on to consideration of the increasing evidence of its association with Kaposi's sarcoma, a multiple hemorrhagic sarcoma with an epidemiologic distribution in Africa similar to that of Burkitt's lymphoma.


Constitutive desensitization: a new paradigm for g protein-coupled receptor regulation.
GPCRs are a large family of cell-surface proteins that regulate many important biochemical pathways and physiological responses. The isolation and characterization of GPCRs represent one of the more remarkable success stories that occurred during the revolution in biology of the last quarter century. Of the many discoveries that originated in the laboratory of Robert Lefkowitz at Duke University concerning GPCR regulation, none is more fundamental than the elucidation of the families of GRKs and arrestin proteins that terminate GPCR signaling. In this essay, we will discuss how advances in microscopy and biology have made the visualization of GPCR, GRK, and arrestin activity possible in single cells. Additionally, we will discuss how imaging studies using arrestins and a naturally occurring mutant of the vasopressin receptor led to the recognition of a novel phenotypic receptor behavior, in which the receptor desensitizes in the absence of agonist. We have termed this process constitutive desensitization, and this unexpected receptor property suggests that it may be possible to develop novel classes of signal-inhibiting drugs distinct from conventional antagonists.


Current methods in the molecular typing of Mycobacterium tuberculosis and other mycobacteria.
In the epidemiology of tuberculosis (TB) and nontuberculous mycobacterial (NTM) diseases, as in all infectious diseases, the key issue is to define the source of infection and to disclose its routes of transmission and dissemination in the environment. For this to be accomplished, the ability of discerning and tracking individual Mycobacterium strains is of critical importance. Molecular typing methods have greatly improved our understanding of the biology of mycobacteria and provide powerful tools to combat the diseases caused by these pathogens. The utility of various typing methods depends on the Mycobacterium species under investigation as well as on the research question. For tuberculosis, different methods have different roles in phylogenetic analyses and person-to-person transmission studies. In NTM diseases, most investigations involve the search for environmental sources or phylogenetic relationships. Here, too, the type of setting determines which methodology is most suitable. Within this review, we summarize currently available molecular methods for strain typing of M. tuberculosis and some NTM species, most commonly associated with human disease. For the various methods, technical practicalities as well as discriminatory power and accomplishments are reviewed.


Simultaneous perfect phase matching for second and third harmonic generations in ZnS/YF(3) photonic crystal for visible emissions.
Theoretically designed and experimentally realized simultaneous perfect phase matching of second and third harmonic generations were demonstrated in a one-dimensional ZnS/YF(3) photonic crystal (PC) structure. Dramatic enhancement of second harmonic generation (SHG) and third harmonic generation (THG) in forward and backward directions near the photonic band edge were observed. This enhancement came from a combination of large ZnS nonlinear susceptibility coefficients, high density of optical modes and perfect phase matching of the fundamental and the harmonic waves near the photonic band edge due to modification of the dispersion curve by the PC structure. Total SHG and THG conversion efficiency over 4% is measured in only six micrometers length of photonic crystal. Theoretical calculations show good agreement with experimental measurements.


Raccoon dog model shows preservation of bone during prolonged catabolism and reduced physical activity.
The raccoon dog (Nyctereutes procyonoides) is a promising animal model capable of preventing disuse-induced osteoporosis. Previous data suggest that this species resembles bears in the preservation of bone mass and biomechanical properties during prolonged passivity and catabolism. This longitudinal study examined the osteological properties of tibiae in farm-bred raccoon dogs that were either fed or fasted (n=6 per group) for a 10 week period. Peripheral quantitative computed tomography was utilized and plasma markers of bone turnover measured before fasting and at 9 weeks followed by mechanical testing (three-point bending), micro-computed tomography and Fourier transform infrared imaging at 10 weeks. Passive wintering with prolonged catabolism (body mass loss 32%) had no significant effects on bone mineralization, porosity or strength. The concentration of C-terminal telopeptide of type I collagen, indicative of bone resorption, increased in the plasma of the fasted raccoon dogs, while the bone formation markers were unchanged. The levels of 25-hydroxyvitamin D were reduced in the fasted animals. Based on these data, the preservation of bone in wintering raccoon dogs shares characteristics with that of bears with no apparent decrease in the formation of bone but increased resorption. To conclude, raccoon dogs were able to minimize bone loss during a 10 week period of catabolism and passivity.


Evidence for Bulk Ripplocations in Layered Solids.
Plastically anisotropic/layered solids are ubiquitous in nature and understanding how they deform is crucial in geology, nuclear engineering, microelectronics, among other fields. Recently, a new defect termed a ripplocation-best described as an atomic scale ripple-was proposed to explain deformation in two-dimensional solids. Herein, we leverage atomistic simulations of graphite to extend the ripplocation idea to bulk layered solids, and confirm that it is essentially a buckling phenomenon. In contrast to dislocations, bulk ripplocations have no Burgers vector and no polarity. In graphite, ripplocations are attracted to other ripplocations, both within the same, and on adjacent layers, the latter resulting in kink boundaries. Furthermore, we present transmission electron microscopy evidence consistent with the existence of bulk ripplocations in Ti3SiC2. Ripplocations are a topological imperative, as they allow atomic layers to glide relative to each other without breaking the in-plane bonds. A more complete understanding of their mechanics and behavior is critically important, and could profoundly influence our current understanding of how graphite, layered silicates, the MAX phases, and many other plastically anisotropic/layered solids, deform and accommodate strain.


Empirical evaluation of age groups and age-subgroup analyses in pediatric randomized trials and pediatric meta-analyses.
An important step toward improvement of the conduct of pediatric clinical research is the standardization of the ages of children to be included in pediatric trials and the optimal age-subgroups to be analyzed. We set out to evaluate empirically the age ranges of children, and age-subgroup analyses thereof, reported in recent pediatric randomized clinical trials (RCTs) and meta-analyses. First, we screened 24 RCTs published in Pediatrics during the first 6 months of 2011; second, we screened 188 pediatric RCTs published in 2007 in the Cochrane Central Register of Controlled Trials; third, we screened 48 pediatric meta-analyses published in the Cochrane Database of Systematic Reviews in 2011. We extracted information on age ranges and age-subgroups considered and age-subgroup differences reported. The age range of children in RCTs published in Pediatrics varied from 0.1 to 17.5 years (median age: 5; interquartile range: 1.8-10.2) and only 25% of those presented age-subgroup analyses. Large variability was also detected for age ranges in 188 RCTs from the Cochrane Central Register of Controlled Trials, and only 28 of those analyzed age-subgroups. Moreover, only 11 of 48 meta-analyses had age-subgroup analyses, and in 6 of those, only different studies were included. Furthermore, most of these observed differences were not beyond chance. We observed large variability in the age ranges and age-subgroups of children included in recent pediatric trials and meta-analyses. Despite the limited available data, some age-subgroup differences were noted. The rationale for the selection of particular age-subgroups deserves further study.


Experiences of loneliness: a study protocol for a systematic review and thematic synthesis of qualitative literature.
Loneliness is a highly prevalent, harmful, and aversive experience which is fundamentally subjective: social isolation alone cannot account for loneliness, and people can experience loneliness even with ample social connections. A number of studies have qualitatively explored experiences of loneliness; however, the research lacks a comprehensive overview of these experiences. We present a protocol for a study that will, for the first time, systematically review and synthesise the qualitative literature on experiences of loneliness in people of all ages from the general, non-clinical population. The aim is to offer a fine-grained look at experiences of loneliness across the lifespan. We will search multiple electronic databases from their inception onwards: PsycINFO, MEDLINE, Scopus, Child Development & Adolescent Studies, Sociological Abstracts, International Bibliography of the Social Sciences, CINAHL, and the Education Resource Information Center. Sources of grey literature will also be searched. We will include empirical studies published in English including any qualitative study design (e.g. interview, focus group). Studies should focus on individuals from non-clinical populations of any age who describe experiences of loneliness. All citations, abstracts, and full-text articles will be screened by one author with a second author ensuring consistency regarding inclusion. Potential conflicts will be resolved through discussion. Thematic synthesis will be used to synthesise this literature, and study quality will be assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Qualitative Research. The planned review will be reported according to the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) statement. The growing body of research on loneliness predictors, outcomes, and interventions must be grounded in an understanding of the lived experience of loneliness. This systematic review and thematic synthesis will clarify how loneliness is subjectively experienced across the lifespan in the general population. This will allow for a more holistic understanding of the lived experience of loneliness which can inform clinicians, researchers, and policymakers working in this important area. PROSPERO CRD42020178105 .


Simultaneous determination of arginine, citrulline, and asymmetric dimethylarginine in plasma by reverse-phase high-performance liquid chromatography.
Arginine, citrulline and asymmetric dimethylarginine (ADMA) are three molecules in the nitric oxide (NO) pathway which provide useful information about vascular endothelial function. ADMA accumulates with patients with chronic kidney disease (CKD) and inhibits NO synthesis. We describe the modification of a previously established method for the measurement of amino acids analysis for simultaneous detection of arginine, citrulline, and ADMA in plasma and to validate its performance in patients with CKD. Arginine, citrulline, and ADMA were simultaneously separated by reverse-phase high-performance liquid chromatography by precolumn derivatization with O-phthalaldehyde using the modified method. It was then applied for analysis in thirty patients with CKD and thirty healthy controls so as to cover the entire measuring range, i.e., normal and uremic range. The method showed a good performance in terms of linearity, precision, and recovery. The detection limit of the assay for ADMA was found to be 0.05 μmol/L at a signal-to-noise ratio of 3:1. The average within run coefficient of variation for ADMA using this method was 4.7% in the normal range and 1.9% in the uremic range, while the average between-day precision in the normal and uremic range was 6.5% and 5.2%, respectively. Patients with CKD were found to have higher concentration of ADMA compared to controls. This method can be useful in assessing the baseline cardiovascular risk in an individual as well as in the follow-up of the patients who are receiving L-arginine, and thus, assess the response to treatment by simultaneous measurement of arginine and ADMA.


The function annotations of ST3GAL4 in human LAMP1 and Lassa virus GP-C interaction from the perspective of systems virology.
Lassa virus (LASV) is a single-stranded RNA virus that has plagued the Sub-Saharan part of Africa, precisely Nigeria where various pathogenic strains with varied genomic isoforms have been identified. The human lysosomal-associated membrane protein 1 (LAMP1) is alternately required for the micropinocytosis of LASV. Therefore, it is of interest to understand the mechanism of action of the host LAMP1 with LASV protein during infection. The role of ST3 beta-galactoside alpha-2, 3-sialyltransferase 4 (ST3GAL4) in the interaction between LASV (glycoprotein) GP-C and the human LAMP1 is relevant in this context. Deposited curated protein sequences of both LAMP1 and LASV GP-C were retrieved for the study. The ST3GAL4 associated data was constructed and analysed from weighted network analysis to infer the function annotations and molecular mediators that characterize the LASV infection. The gene network shows that glycoprotein sialylation, sialyltransferase enzymatic activities and glycosphingolipid biosynthesis are linked with the ST3GAL4 function. However, the physical interaction of FAM 213A, CD8B molecule and proprotein convertase subtilisin/kexin type 1 inhibitor (PCSK1N) with ST3GAL4 is intriguing in this perspective. There are 11 glycosylated asparagine sequons of the human LAMP1 but only nine were assigned a sialylated glycan cap to mediate the LASV GP-C and LAMP1 interaction having exceeded a recommended glycosylation threshold of 0.5. Therefore, the sialylated glycans of the human LAMP1 are a total of nine and these sialylated glycans mediate the molecular recognition between LASV and LAMP1. This study therefore, predicts that there is a cellular interchange between N-linked glycosylation properties of the human LAMP1 and LASV glycoprotein, and sialylation functions of ST3GAL4 in LASV infectivity. Further studies and the clinical trial of this predictive model on the sialylated glycans of LAMP1 will facilitate the understanding of the LASV micropinocytosis process in host cells.


Clinical and diagnostic value of the combination of lymphocyte count and creatine kinase in the detection of coronavirus 2019.
The present study aimed to investigate the diagnostic efficiency of the absolute number of lymphocytes (LYM) and creatine kinase (CK) levels in the diagnosis of coronavirus disease 2019 (COVID-19). For this, the clinical data from 84 patients with COVID-19 admitted to Tianjin Haihe Hospital (Tianjin, China) between January and February 2020 were collected. The patients were divided into the following groups: The common COVID-19 group (n=61) and severe COVID-19 group (n=23). In addition, 30 healthy subjects were included as a control group. The results demonstrated that the percentage of neutrophils (NEU%) was significantly increased, while the absolute number of white blood cells, LYM and the percentage of lymphocytes (LYM%) were significantly decreased in patients with COVID-19. Furthermore, in the severe group, the absolute number of red blood cells in female patients, the NEU%, the neutrophil-to-lymphocyte ratio (NLR) and the serum levels of interleukin-6 and C-reactive protein (CRP) were markedly elevated, while those of LYM and LYM% were significantly decreased (all P<0.05). In addition, in the receiver operating characteristics curve analysis for the combination of LYM + CK, the area under the curve values were 0.96 and 1.00, with a sensitivity of 95.08 and 100%, specificity of 86.67 and 100% and cut-off values of 0.42 and 0.50 for the common and severe COVID-19 group, respectively. The results indicated that the diagnostic efficiency of LYM + CK was higher than that of each single factor. Finally, a moderate correlation of lactate dehydrogenase with CRP and NLR (r=0.492 and 0.433, respectively; both P<0.05) was obtained. Overall, the results of the present study indicated that the values of LYM and CK were associated with the progression of COVID-19, suggesting that the combination of both factors may be of clinical diagnostic value for COVID-19.


RFX proteins, a novel family of DNA binding proteins conserved in the eukaryotic kingdom.
Until recently, the RFX family of DNA binding proteins consisted exclusively of four mammalian members (RFX1-RFX4) characterized by a novel highly conserved DNA binding domain. Strong conservation of this DNA binding domain precluded a precise definition of the motif required for DNA binding. In addition, the biological systems in which these RFX proteins are implicated remained obscure. The recent identification of four new RFX genes has now shed light on the evolutionary conservation of the RFX family, contributed greatly to a detailed characterization of the RFX DNA binding motif, and provided clear evidence for the function of some of the RFX proteins. RFX proteins have been conserved throughout evolution in a wide variety of species, including Saccharomyces cerevisiae, Schizosaccharomyces pombe, Caenorhabditis elegans, mouse and man. The characteristic RFX DNA binding motif has been recruited into otherwise very divergent regulatory factors functioning in a diverse spectrum of unrelated systems, including regulation of the mitotic cell cycle in fission yeast, the control of the immune response in mammals, and infection by human hepatitis B virus.


Developmental changes in synaptic membrane order: a comparison of regions in the rat brain.
Developmental changes in synaptic membrane order were followed in 5 regions of the rat brain, the cortex (Cx), cerebellum (Cb), brainstem (BS), lateral subcortex (LSCx) and midline subcortex (MSCx). Membrane order was assessed by the fluorescence polarization technique, using 1,6-diphenyl-1,3,5-hexatriene (DPH) as the probe. The results illustrate that the developmental increase in membrane order proceeds from caudal to rostral brain regions. Thus, at the earliest time point examined (day 3) steady-state anisotropy (rs) in the BS was significantly higher than in the Cx and reached adult values by day 14 while the Cx values were still significantly less than the adult value even at day 30. The thermotropic behavior of the membranes was investigated over the range of 20-37 degrees C. The Arrhenius slopes among the Cx, BS, LSCx and MSCx were similar across all ages studied, suggesting that the developmental increase in order primarily results from a change in entropy. In contrast, the Arrhenius slopes for the Cb increase greater than 100% during development, suggesting that a change in enthalpy is important for the increase in membrane order. Multilamellar liposomes prepared from membrane lipid extracts generally showed the same developmental changes in order as the intact membranes. These data indicate that the increase in membrane order results from a marked change in bulk lipid composition rather than a secondary lipid matrix change (e.g. in membrane asymmetry) and/or from the developmental increase in the protein/lipid ratio.


"A Lightbulb Moment": Using the Theory of Planned Behavior to Explore the Challenges and Opportunities for Early Engagement of Australian Men Who Use Violence in Their Relationships.
Intimate partner violence (IPV) is a common complex social and public health problem. Interventions for IPV male perpetrators are an essential component of an early and effective response. Yet little is known about how to engage men in interventions for help-seeking. Using the theory of planned behavior (TPB), we explored men's perceptions of seeking help for an unhealthy relationship and how they could be supported to recognize their behavior and undertake change at an early stage. We recruited 23 men who were currently attending a men's behavior change program in Australia to take part in focus groups. These were recorded, transcribed, and thematically analyzed. The TPB concepts of behavioral beliefs, perceived control, and subjective norms were found throughout the data. Behavioral beliefs covered four subthemes: self-awareness, self-reflection and agency, the influence of others to change, and needing the right message in the right place. Perceived control was connected to these men's understandings of what it means to be a man. Subjective norms were rarely raised, but there was some indication that men's perceptions of societal norms about men as violent influenced a perceived lack of agency to change behavior. Our findings highlight the complexity of, and challenges in, engaging men who may use violence before they reach crisis point and justice intervenes. Despite this, participating men could find acceptable an appropriately developed and easy-to-access intervention that enhances recognition of behaviors and provides links to supports. Health professionals or researchers developing early interventions targeting these men need to take the engagement challenges into account.


Emerging tick-borne pathogens in the Nordic countries: A clinical and laboratory follow-up study of high-risk tick-bitten individuals.
Despite the presence of several microorganisms, other than Borrelia burgdorferi sensu lato (Bbsl) and TBE virus, in Ixodes ricinus ticks from the Nordic countries, data is lacking on their pathogenic potential in humans. In this study, we wanted to investigate the aetiology and clinical manifestations of tick-transmitted infections in individuals seeking medical care following a tick-bite. The sampling frame was participants of a large-scale, prospective, multi-centre, follow-up study of tick-bitten volunteers recruited in Sweden, Finland and Norway in the years 2007-2015. Participants who sought medical care during the three-month follow-up period and from whom blood samples were collected during this healthcare visit (n = 92) were tested, using PCR, for exposure to spotted fever group (SFG) Rickettsia spp., Anaplasma phagocytophilum and Babesia spp. Moreover, 86 of these individuals had two serum samples, collected three months apart, tested serologically for six tick-borne microorganisms. The selected organisms - Bbsl, SFG rickettsiae, Anaplasma phagocytophilum, TBE virus, Babesia microti and Bartonella henselae - have all been detected in field-collected ticks from the Nordic countries. Medical records were reviewed and questionnaires were completed to determine clinical manifestations. We found Lyme borreliosis to be the most common tick-transmitted infection as seen in 46 (54%) of the 86 participants with available medical records. Among the 86 participants with paired sera, serological or molecular evidence of recent exposure to other microorganisms than Bbsl could be demonstrated in eight (9%). Five participants (6%) exhibited serological evidence of recent concomitant exposure to more than one tick-borne microorganism. Clinical presentations were mild with one exception (TBE). In conclusion, our data suggest a low risk of infection with tick-borne microorganisms, other than Bbsl, in immunocompetent tick-bitten persons from the examined regions, a low occurrence of co-infection and mostly mild or no overt clinical signs of infection in immunocompetent persons exposed to the studied agents.


Differential regulation and properties of angiopoietin-like proteins 3 and 4.
Angiopoietin-like protein 3 and 4 (Angptl3 and Angptl4) are two members of the angiopoietin-like family of proteins. These two closely related proteins have been reported to similarly affect lipid metabolism through their capacity to inhibit lipoprotein lipase. We undertook a series of studies to compare the structure, function, and regulation of Angptl3 and Angptl4. Previously, we reported that Angptl4 exists as variable-sized oligomers that contain intermolecular disulfide bonds. We now have evidence that although there are no intermolecular disulfide bonds evident in Angptl3, higher molecular weight forms do exist. In addition, Angptl4 exhibits a widespread distribution of tissue expression, while Angptl3 is exclusively expressed in the liver. Treatments with various ligands of nuclear receptors reveal that Angptl3 is a target gene of liver X receptor, while Angptl4 expression is activated by ligands of all peroxisome proliferator-activated receptors. Expression of Angptl4 in adipose tissue and liver is induced by fasting, while Angptl3 expression is not appreciably affected by nutritional status. We suggest that the differential regulation of Angptl3 and Angptl4 by sites of expression, nutritional status, and ligands of nuclear receptors may confer unique roles of each in lipoprotein metabolism.


Diurnal variations in scrotal temperature of normal men and patients with varicocele before and after treatment.
Scrotal temperature was monitored using a portable data recorder for periods of 24 h in six normal volunteers and 48 infertile patients with unilateral varicocele while subjects pursued their regular daily activities. Temperatures during sleep (TS) were generally higher than daytime values (TD), probably as a consequence of thermal insulation in bed. These diurnal variations were found to be less pronounced in the infertile patients than in volunteers (TS - TD = 0.29 degrees C +/- 0.06 degrees C vs 0.88 degrees C +/- 0.12 degrees C; P < 0.01). Moreover, scrotal temperatures at night of patients and volunteers were indistinguishable statistically, but were different during daytime hours. After successful ligation or embolization of the spermatic-vein in 16 patients, no change in scrotal temperature was observed. Although sperm counts were higher after treatment, this difference was not significant (67.4 +/- 17.2 x 10(6) vs 105.8 +/- 25.5 x 10(6); P > 0.05). The data support the view that varicocele-related damage to the testis results from a lack of adequate cooling, and that treatment does not normalize the temperature pattern.


Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.
The impact of in vivo T-cell depletion on transplantation outcomes in patients transplanted with reduced-intensity conditioning (RIC) remains controversial. This study assessed the outcome of 1250 adult patients with de novo AML in first CR (CR1) given PBSC from HLA-identical siblings after chemotherapy-based RIC. A total of 554 patients did not receive any form of in vivo T-cell depletion (control group), whereas antithymocyte globulin (ATG) and alemtuzumab were given in 444 and 252 patients, respectively. The incidences of grade II-IV acute GVHD were 21.4, 17.6 and 10.2% in control, ATG and alemtuzumab patients, respectively (P<0.001). In multivariate analysis, the use of ATG and the use of alemtuzumab were each associated with a lower risk of chronic GVHD (P<0.001 each), but a similar risk of relapse, and of nonrelapse mortality, and similar leukemia-free survival and OS. Further, among patients given BU-based RIC, the use of <6 mg/kg ATG did not increase the risk of relapse (hazard ratio, HR=1.1), whereas there was a suggestion for higher relapse risk in patients given 6 mg/kg ATG (HR=1.4, P=0.08). In summary, these data suggest that a certain amount of in vivo T-cell depletion can be safely used in the conditioning of AML patients in CR1 given PBSC after chemotherapy-based RIC.


Platelet function during and after thrombolytic therapy for acute myocardial infarction with reteplase, alteplase, or streptokinase.
Changes in platelet aggregation (PA) and platelet surface receptor expression induced by thrombolytic therapy for acute myocardial infarction may influence the rate of initial reperfusion and early reocclusion. In the RAPID-1 (Reteplase Angiographic Phase II International Dose-finding study), RAPID-2 (Reteplase vs Alteplase Patency Investigation During myocardial infarction), INJECT (INternational Joint Efficacy Comparison of Thrombolytics), and GUSTO-3 (Global Use of Strategies To Open occluded coronary arteries) trials, 126 patients were enrolled in a single center. Patients were treated with either conventional alteplase (100 mg/180 min; n=15), accelerated alteplase (100 mg/90 min; n=21), reteplase 10+10-U double bolus (n=50), reteplase 10+5-U double bolus (n=15), reteplase 15-U single bolus (n=15), or streptokinase (1.5 MU/60 min; n=10). PA (after stimulation with ADP), P-selectin expression and fibrinogen binding to glycoprotein (GP) IIb/IIIa (determined by flow cytometry with and without stimulation with ADP), and levels of soluble P-selectin, prothrombin fragments F1 and F2, thrombin-antithrombin complexes (TAT), and antithrombin III (ATIII) were determined. PA decreased significantly at 1 and 2 hours in patients treated by 10+10-U reteplase or by streptokinase. Fibrinogen binding to platelet GP IIb/IIIa followed a similar pattern. Significant thrombin generation and significantly elevated thrombin levels during thrombolysis were reflected by increased F1 and F2 fragments and TAT levels in all treatment groups. ATIII levels decreased significantly during thrombolytic therapy. A decrease in PA in patients treated by reteplase or streptokinase compared with alteplase could be observed in the early phase. Double bolus (10+10 U) reteplase and streptokinase resulted in lower PA at 1 and 2 hours than therapy with accelerated alteplase. Total fibrinogen and fibrinogen binding to GP IIb/IIIa tended to be lower during the first 2 hours after reteplase than after accelerated alteplase.


Severe fatigue after treatment for childhood cancer.
Treatment strategies for childhood cancer are improving, resulting in higher survival rates. However, the consequences of childhood cancer do not end with the successful completion of cancer treatment. Most patients will develop late effects after cessation of treatment. Severe fatigue is seen as a common and debilitating late effect in cancer survivors. Although most research on fatigue has been performed in patients after adult-onset cancer, our review focuses on fatigue after childhood cancer. To estimate the prevalence of severe fatigue after treatment for childhood cancer. Secondary objectives are to describe the course of severe fatigue following cancer treatment and to examine risk factors for fatigue, or factors associated with it. We searched the Cochrane Central Register of Controlled Trials (the Cochrane Library 2019; issue 8 March 2019), MEDLINE/PubMed (from 1945 to 8 March 2019), Embase/Ovid (from 1947 to 8 March 2019), reference lists of included articles and several conference proceedings from 2011 to 2018. Observational studies, randomised controlled trials and controlled clinical trials reporting on fatigue in participants after treatment for childhood cancer. Case series and case reports were not eligible for inclusion. Two review authors independently extracted data and assessed risks of bias. If the publication did not present the prevalence of severe fatigue, we contacted study authors for additional information. We included 30 studies (18,682 participants in total). Eighteen studies contributed to the main objective and 22 studies contributed to the secondary objectives. We found substantial differences between studies in cancer diagnosis, cancer treatment, age of participants, questionnaires used to assess fatigue, and sample size. All included studies scored at least one 'Risk of bias' item as unclear or high risk. We identified both clinical and statistical heterogeneity and therefore could not pool results, so we present them descriptively. Eighteen studies (describing 14,573 survivors) reported the prevalence of severe fatigue, which ranged from 0% to 61.7%. In a subgroup of three studies including children aged up to 18 years at fatigue assessment (268 survivors), prevalence rates ranged from 6.7% to 12.5%. In comparison, in a subgroup of 12 studies including participants aged 16 and over (13,952 survivors), prevalence rates ranged from 4.4% to 61.7%. The prevalence of severe fatigue in a subgroup of survivors of haematological cancer was presented in seven studies and ranged from 1.8% to 35.9% (1907 survivors). Prevalence of severe fatigue in brain cancer survivors was presented in two studies (252 survivors) and was 14.6% and 21.1% respectively. One study presented a prevalence for bone cancer survivors of 0.0% (17 survivors). Four studies provided prevalence rates of severe fatigue in control groups of siblings or population-based controls, which ranged from 3.1% to 10.3%. In these four studies, survivors were more often fatigued than controls, but this difference was statistically significant in only two studies. Studies assessing risk and associated factors for fatigue were heterogeneous, and definitions of the factors under study were often inconsistent, with results therefore presented descriptively. They found that depression might be associated with fatigue. In contrast, age at diagnosis and education level did not seem to be associated with fatigue. We were unable to calculate any overall risk estimate for any of the reported risks and associated factors, because we could not conduct meta-analysis. One study provided information about the course of fatigue over time, and found that over the course of 2.7 years, 32 of the 102 participants (31.4%) reported persistent severe fatigue. It is unclear how many childhood cancer survivors suffer from severe fatigue. This review encountered several difficulties. We found statistical and clinical heterogeneity and great variation in the reporting of possible risk and associated factors. The evidence in this review is therefore weak, and the exact prevalence of severe fatigue after treatment for childhood cancer remains to be determined. This is also the case for the course of severe fatigue following treatment and the strength of the relationship between fatigue and associated and risk factors. Despite these limitations, our review does provide a comprehensive overview of the existing literature about severe fatigue after treatment for childhood cancer.


cDNA cloning and expression analysis of gustavus gene in the oriental river prawn Macrobrachium nipponense.
The gustavus gene is required for localizing pole plasm and specifying germ cells. Research on gustavus gene expression will advance our understanding of the biological function of gustavus in animals. A cDNA encoding gustavus protein was identified and termed MnGus in the oriental river prawn Macrobrachium nipponense. Bioinformatic analyses showed that this gene encoded a protein of 262 amino acids and the protein belongs to the Spsb1 family. Real-time quantitative PCR analyses revealed that the expression level of MnGus in prawn embryos was slightly higher at the cleavage stage than at the blastula stage, and reached the maximum level during the zoea stage of embryos. The minimum level of MnGus expression occurred during the perinucleolus stage in the ovary, while the maximum was at the oil globule stage, and then the level of MnGus expression gradually decreased with the advancement of ovarian development. The expression level of MnGus in muscle was much higher than that in other tissues in mature prawn. The gustavus cDNA sequence was firstly cloned from the oriental river prawn and the pattern of gene expression was described during oocyte maturation, embryonic development, and in other tissues. The differential expression patterns of MnGus in the embryo, ovary and other somatic tissues suggest that the gustavus gene performs multiple physiological functions in the oriental river prawn.


The impact of COVID-19 on hip and knee arthroplasty surgical volume in China.
The reduction of hip and knee arthroplasty surgical volume has been reported in many countries during the COVID-19 pandemic. In China, there is no national joint registry system and the impact of COVID-19 towards surgical volume remains unclear. The aim of this study was to investigate the hip and knee arthroplasty surgical volume in China during the pandemic and evaluate its change trends. Annual sale numbers of prostheses used in total knee arthroplasty (TKA), total hip arthroplasty (THA), and femoral head replacement (FHR) from 2011 to 2021 was collected from providers registered in National Medical Products Administration (NMPA). Annual surgical volume of TKA, THA, FHR, unicompartmental knee arthroplasty (UKA), and revision of hip/knee arthroplasty (RJA) was collected from member hospitals of Beijing Joint Society (BJS). We used linear regression to estimate the loss of surgical volume. Annual surgical volume obtained from Britain and Australian joint registries were used to make comparison. In China, the surgical volume of THA/FHR, TKA, and UKA in 2020 all decreased compared to the predicted value, with a reduction of 82,525 cases (13.46%), 165,178 cases (33.50%), and 151 cases (0.65%), respectively. All the three procedures showed significant recovery in 2021. The surgical volumes of THA/FHR and UKA were 68,813 and 9402 cases higher than predicted levels, respectively, while TKA volume remained slightly below the predicted level. The regional statistics in Beijing showed similar change mode. In 2020, the surgical volume of THA/FHR, TKA, FHR, and UKA all decreased compared to the predicted value, with a reduction of 5031 cases (43.37%), 5290 cases (40.69%), 620 cases (29.18%), and 925 cases (39.11%), respectively. In 2021, with the exception of FHR, the number of these procedures increased compared to 2020, but remained below the predicted value. Compared with the data from Britain and Australia, China experienced less reduction and faster recovery in the proportions of elderly people (> 65 years old) who undergo hip and knee arthroplasty during the COVID-19 pandemic. During the COVID-19 pandemic, although hip and knee arthroplasty surgical volume in China showed a similar "restoration-recovery" change pattern with other countries, China took fewer losses in this field.


CD-tagging-MS2: detecting allelic expression of endogenous mRNAs and their protein products in single cells.
Discriminating between the mRNA and protein outputs of each of the alleles of an endogenous gene in intact cells, is a difficult task. To examine endogenous transcripts originating from a specific allele, we applied Central Dogma tagging (CD-tagging), which is based on a tag insertion into an endogenous gene by creation of a new exon. Previously, CD-tagging was used to tag endogenous proteins. Here we developed a CD-tagging-MS2 approach in which two tags were inserted in tandem; a fluorescent protein tag in conjunction with the mRNA MS2 tag used for tagging mRNAs in cells. A cell clone library of CD-tagged-MS2 genes was generated, and protein and mRNA distributions were examined and characterized in single cells. Taking advantage of having one allele tagged, we demonstrate how the transcriptional activity of all alleles, tagged and untagged, can be identified using single molecule RNA fluorescence in situ hybridization (smFISH). Allele-specific mRNA expression and localization were quantified under normal and stress conditions. The latter generate cytoplasmic stress granules (SGs) that can store mRNAs, and the distribution of the mRNAs within and outside of the SGs was measured. Altogether, CD-tagging-MS2 is a robust and inexpensive approach for direct simultaneous detection of an endogenous mRNA and its translated protein product in the same cell.


Mutation in resting cells: the role of endogenous DNA damage.
In E coli, new spontaneous mutations can arise in bacteria that are non-dividing and in which there is little or no DNA synthesis. These mutations are almost invariably those that enable the cell to resume growth, a phenomenon that has been termed directed or adaptive mutation. Evidence is accumulating from studies with DNA repair deficient strains that damage produced by endogenous mutagens may be an important source of such mutations. A DNA lesion that can miscode can explain the apparent adaptive behaviour since if a "mutant" RNA transcript confers sufficient advantage that the cell is triggered into a cycling state, the ensuing round of DNA replication will be likely to fix the mutation by means of a DNA miscoding event. The most important lesion in this respect appears to be 8-oxoG, which can pair equally well with adenine or cytosine and so give rise to G to T transversions. It is responsible for almost half the G to T transversions arising in non-growing repair proficient bacteria. Alkylations contribute to the production of both transitions and transversions but only those at A:T base pairs are important in repair proficient bacteria. There is also a report of a lesion susceptible to UvrA,B,C dependent excision repair, but whether it is important in bacteria possessing excision repair has not been addressed. Data on mammalian cells are almost non-existent, but there is evidence that point mutations can occur in vivo in postmitotic neurons. The underlying assumption that there is little or no DNA synthesis in non-dividing bacteria has been challenged by recent data suggesting that there may be extensive cryptic DNA turnover.


Position and momentum mapping of vibrations in graphene nanostructures.
Propagating atomic vibrational waves-phonons-determine important thermal, mechanical, optoelectronic and transport characteristics of materials. Thus a knowledge of phonon dispersion (that is, the dependence of vibrational energy on momentum) is a key part of our understanding and optimization of a material's behaviour. However, the phonon dispersion of a free-standing monolayer of a two-dimensional material such as graphene, and its local variations, have remained elusive for the past decade because of the experimental limitations of vibrational spectroscopy. Even though electron energy loss spectroscopy (EELS) in transmission has recently been shown to probe local vibrational charge responses1-4, such studies are still limited by momentum space integration due to the focused beam geometry; they are also restricted to polar materials such as boron nitride or oxides1-4, in which huge signals induced by strong dipole moments are present. On the other hand, measurements on graphene performed by inelastic X-ray (neutron) scattering spectroscopy5-7 or EELS in reflection8,9 do not have any spatial resolution and require large microcrystals. Here we provide a new pathway to determine phonon dispersions down to the scale of an individual free-standing graphene monolayer by mapping the distinct vibrational modes for a large momentum transfer. The measured scattering intensities are accurately reproduced and interpreted with density functional perturbation theory10. Additionally, a nanometre-scale mapping of selected momentum-resolved vibrational modes using graphene nanoribbon structures has enabled us to spatially disentangle bulk, edge and surface vibrations. Our results are a proof-of-principle demonstration of the feasibility of studying local vibrational modes in two-dimensional monolayer materials at the nanometre scale.


Potential energy landscapes identify the information-theoretic nature of the epigenome.
Epigenetics is the study of biochemical modifications carrying information independent of DNA sequence, which are heritable through cell division. In 1940, Waddington coined the term "epigenetic landscape" as a metaphor for pluripotency and differentiation, but methylation landscapes have not yet been rigorously computed. Using principles from statistical physics and information theory, we derive epigenetic energy landscapes from whole-genome bisulfite sequencing (WGBS) data that enable us to quantify methylation stochasticity genome-wide using Shannon's entropy, associating it with chromatin structure. Moreover, we consider the Jensen-Shannon distance between sample-specific energy landscapes as a measure of epigenetic dissimilarity and demonstrate its effectiveness for discerning epigenetic differences. By viewing methylation maintenance as a communications system, we introduce methylation channels and show that higher-order chromatin organization can be predicted from their informational properties. Our results provide a fundamental understanding of the information-theoretic nature of the epigenome that leads to a powerful approach for studying its role in disease and aging.


Insulin-like growth factor-I and complications of prematurity: a focus on bronchopulmonary dysplasia.
At least four premature newborn complications have been reported to be associated with low serum insulin-like growth factor-I (IGF-I) levels: bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis and brain damage. Local IGF-I concentrations have only been reported for bronchopulmonary dysplasia and these findings show that lung IGF-I levels are clearly increased (epithelial lining fluid levels), emphasizing the fact that IGF-I is differently regulated in the general circulation or at local level. The present review discusses the meaning of the association between serum IGF-I amounts and development of complications in premature newborns. Finally, some methodological indications are reported regarding the IGF-I assay procedures. It is important to establish what are the possible relationships between blood levels and those of different compartments involved in the diseases.


[Risk factors in the elderly. A study of 143 patients].
Growing old is a process of natural diminish with decrease of biological answer to extrinsic and intrinsic factors and a bigger risk of presenting cardiovascular and metabolic processes. The aim of this study has been to analyse the incidence of cardiovascular factors in an aged population from Almería. The group is by 172 patients (29 gave up); average global age 72.6 +/- 6.1 (85 women and 58 men). In all cases history and a whole clinic exam have been undertaken; general analytical study (glucose, creatinine, hepatic function cholesterol, HDL-c, LDL-c, trigliceride fibrinogen, microalbuminuria, etc.); blood pressure. T Students, varianza analysis, Kolmogorov-Smirnov test. With regard to overweight, this was bigger in women (32.1 +/- 4.8 Kg/m2) in relation to men (27.9 +/- 4 Kg/m2). The most frequent risk factor has been hypertension (50.3%) followed by over weight-obesity (46.8%) and hypercholesterolemia (45.4%), only 11.2% did not present any risk factor; shile three factors appeared in 29.5%. Hypertension patients have more risk factors (increase of cholesterol and triglicerids, obesity, diabetes) than normotensive old patients; also diabetic patients have a bigger cardiovascular and lipid risk than non diabetic patients. The ingestion of estatinas or fibrates improves the lipid profile of old patients. In summarizing, conventional therapy can improve the cardiologic and metabolic situation, decreasing so the morbidity and mortality of old patients.


Levofloxacin-Induced Acute Immune-Mediated Thrombocytopenia of Rapid-Onset.
Drug-induced immune thrombocytopenia (D-ITP) typically occurs after the patient has been receiving the implicated drug for at least 1 week, due to newly forming drug-dependent antibodies ("typical-onset" D-ITP). A "rapid-onset" form of D-ITP can occur when previous sensitization has occurred, where antibodies have thus already been formed, and a precipitous platelet count fall occurs upon reexposure. Typical-onset D-ITP has been reported after levofloxacin, but the rapid-onset form with a well-documented previous exposure has not been described. We report a 76-year-old male treated with levofloxacin for acute exacerbation of chronic obstructive pulmonary disease. After a single 750 mg oral dose of levofloxacin, his platelet count fell from 187 to 5 × 109/L (nadir) over 4 days. Other causes of thrombocytopenia were ruled out. He had received a previous course of levofloxacin 6 months earlier. Discontinuation of levofloxacin and treatment with intravenous immunoglobulin and dexamethasone resulted in platelet count recovery. Levofloxacin-dependent antibodies were not detectable, consistent with the known low sensitivity of laboratory tests for drug-dependent antibodies, presumably indicating antibodies against levofloxacin metabolites, as is indirectly supported by the abrupt but relatively slow platelet count decline observed. This case illustrates a rapid-onset presentation of levofloxacin-induced D-ITP in the setting of previous drug exposure.


Progressive multi-organ expression of immunoglobulin G4-related disease: A case report.
A 63-year-old Caucasian man presented with a cholestatic syndrome, renal failure and arthralgias. A laboratory examination revealed high immunoglobulin G (IgG) and IgG4 levels (5.95 g/L; normal range: 0.08-1.4 g/L), pointing to a diagnosis of systemic IgG4-related disease, with definite radiological evidence of biliary and pancreatic expression, and plausible renal, articular, salivary and lacrimal glands involvement. Due to the rarity of the condition, there are currently no random control trials to point to the optimal therapeutic approach. The patient has been on steroid therapy with the subsequent introduction of azathioprine, with a complete resolution of all symptoms, a rapid reduction to normalization of all blood tests, and a complete regression of the radiological picture. Our experience underlines the complexity of IgG4-related disease and its variable and sometimes progressive presentation, while pointing out the need for a careful and complete assessment for possible multi-organ involvement.


Nitrogen, Phosphorus, and Sulfur Co-Doped Hollow Carbon Shell as Superior Metal-Free Catalyst for Selective Oxidation of Aromatic Alkanes.
Metal-free heteroatom-doped carbocatalysts with a high surface area are desirable for catalytic reactions. In this study, we found an efficient strategy to prepare nitrogen, phosphorus, and sulfur co-doped hollow carbon shells (denote as NPS-HCS) with a surface area of 1020 m(2) g(-1). Using a poly(cyclotriphosphazene-co-4,4'-sulfonyldiphenol) (PZS) shell as carbon source and N, P, S-doping source, and the ZIF-67 core as structural template as well as extra N-doping source, NPS-HCS were obtained with a high surface area and superhydrophilicity. All these features render the prepared NPS-HCS a superior metal-free carbocatalyst for the selective oxidation of aromatic alkanes in aqueous solution. This study provides a reliable and facile route to prepare doped carbocatalysts with enhanced catalytic properties.


The smell of lung disease: a review of the current status of electronic nose technology.
There is a need for timely, accurate diagnosis, and personalised management in lung diseases. Exhaled breath reflects inflammatory and metabolic processes in the human body, especially in the lungs. The analysis of exhaled breath using electronic nose (eNose) technology has gained increasing attention in the past years. This technique has great potential to be used in clinical practice as a real-time non-invasive diagnostic tool, and for monitoring disease course and therapeutic effects. To date, multiple eNoses have been developed and evaluated in clinical studies across a wide spectrum of lung diseases, mainly for diagnostic purposes. Heterogeneity in study design, analysis techniques, and differences between eNose devices currently hamper generalization and comparison of study results. Moreover, many pilot studies have been performed, while validation and implementation studies are scarce. These studies are needed before implementation in clinical practice can be realised. This review summarises the technical aspects of available eNose devices and the available evidence for clinical application of eNose technology in different lung diseases. Furthermore, recommendations for future research to pave the way for clinical implementation of eNose technology are provided.


Plasminogen activator inhibitor (PAI)-1 overexpression in retinal microvessels of PAI-1 transgenic mice.
Previous studies have suggested that disturbances in plasminogen activator inhibitor (PAI)-1 may be relevant to the development of diabetic microvascular complications. To determine whether overexpression of PAI-1 in cells of retinal microvasculature would result in a disease similar to that observed in diabetes, ocular tissue from transgenic mice that overexpress human PAI-1 were examined. Transgenic mice were administered ZnSO4 (25 mM) in their water for up to 49 weeks to activate the metallothionein promoter and stimulate human PAI-1. Colloidal gold immunocytochemistry was used to quantify the human PAI-1 antigen at 7, 20, 34, and 49 weeks of ZnSO4 administration. Cross sections of retinal microvessels were examined by electron microscopy for changes in basement membrane (BM) thickness. Retinal digest preparations were examined by light microscopy for possible microangiopathy, including changes in endothelial cell-to-pericyte ratios. Human PAI-1 immunoreactivity was detected throughout the retinal capillaries of transgenic mice receiving zinc and increased significantly (P < 0.001) after 20 to 49 weeks of ZnSO4 administration compared with age-matched transgenic control mice. At 20 and 49 weeks, retinal capillaries of transgenic mice that received zinc showed significantly thickened BMs compared with control animals (P < 0.001). Moreover, wholemounts of the retinal vasculature from PAI-1 transgenic mice demonstrated an increased endothelial cell-to-pericyte ratio. PAI-1 overexpression in retinal microvasculature leads to retinal disease similar to that observed in diabetic retinopathy.


[Socio-demographic factors associated with three sedentary behaviors in Brazilian workers].
This study focused on the association between socio-demographic characteristics and three sedentary behaviors among industrial workers in Brazil. Data were analyzed on 47,477 workers from 24 Brazilian states, collected by questionnaires from 2006 to 2008. Individual and simultaneous presence of ≥ 4 hours of TV time per day, commuting by car or motorcycle, and sitting most of the time at work were investigated, as well as associations between these behaviors and gender, age, schooling, and family income. Simple and multiple binary logistic regression were used. Older workers and those with more schooling and higher income had increased odds of presenting two or all of the three target behaviors. Associations between gender and sedentary behaviors depend on the specific behavior. Such information can be useful for planning interventions to reduce sedentary behavior, with better targeting and more effectiveness in reaching different population subgroups.


Differential electrophysiological actions of endothelin-1 on Cl- and K+ currents in myocytes isolated from aorta, basilar and pulmonary artery.
The electrophysiological effects of endothelin (ET)-1 were compared in myocytes isolated from rat small pulmonary artery, basilar artery and aorta. ET-1 evoked depolarization in all three smooth muscle cell types. Depolarizing oscillations in membrane current also were observed in pulmonary and aortic myocytes. In voltage-clamp experiments ET-1 induced a gradual inhibition of the Ca(++)-independent outward current (IK) in pulmonary and aortic myocytes, whereas in basilar myocytes ET-1 inhibited the Ca(++)-activated K+ current (IK(Ca)). ET-1 also evoked a transient enhancement of IK(Ca) and oscillations in inward current in aortic and pulmonary myocytes. The inward currents were inhibited by caffeine, which suggests Ca(++)-dependent activation. Ion-exchange experiments indicated that in pulmonary myocytes oscillatory currents were caused solely by the movement of Cl-, whereas in aortic myocytes they were the consequence of both Ca(++)-activated Cl-(ICl(Ca)) and non-selective cation currents (INS). No inward current was evoked in basilar myocytes in response to ET-1 or photorelease of Ca++, which suggests that these cells do not possess ICl(Ca). Experiments with ET receptor ligands indicated that in basilar myocytes ETA receptor stimulation is responsible for IK(Ca) inhibition, whereas in aortic and pulmonary myocytes ETB and ETA receptor stimulation mediates inhibition of IK and activation of ICl(Ca), INS and IK(Ca), respectively. In the future, it may be possible to exploit these differential effects of ET-1 pharmacologically to assist development of tissue-specific modulators for the treatment of vascular disease.


Exploring the intracellular pharmacokinetics of the 5-fluorouracil nucleotides during capecitabine treatment.
Three intracellularly formed metabolites are responsible for the antineoplastic effect of capecitabine: 5-fluorouridine 5'-triphosphate (FUTP), 5-fluoro-2'-deoxyuridine 5'-triphosphate (FdUTP), and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). The objective of this study was to explore the pharmacokinetics of these intracellular metabolites during capecitabine treatment. Serial plasma and peripheral blood mononuclear cell (PBMC) samples were collected from 13 patients treated with capecitabine 1000 mg QD (group A) and eight patients receiving capecitabine 850 mg m(-2) BID for fourteen days, every three weeks (group B). Samples were collected on day 1 and, for four patients of group B, also on day 14. The capecitabine and 5-fluorouracil (5-FU) plasma concentrations and intracellular metabolite concentrations were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using non-compartmental analysis. Only FUTP could be measured in the PBMC samples. The FdUTP and FdUMP concentrations were below the detection limits (LOD). No significant correlation was found between the plasma 5-FU and intracellular FUTP exposure. The FUTP concentration-time profiles demonstrated considerable inter-individual variation and accumulation of the metabolite in PBMCs. FUTP levels ranged between <LOD and 1.0 μM on day 1, and from 0.64 to 14 μM on day 14. The area under the FUTP concentration-time curve was significantly increased on day 14 of the treatment compared to day 1 (mean ± SD: 28 ± 19 μM h vs. 2.0 ± 1.9 μM h). To our knowledge, this is the first time that intracellular FUTP concentrations were measured in patients treated with capecitabine. During 14 days of treatment with capecitabine twice daily, intracellular accumulation of FUTP occurs.


Increase of nesting habitat suitability for green turtles in a warming Mediterranean Sea.
Climate change is reshaping global ecosystems at an unprecedented rate, with major impacts on biodiversity. Therefore, understanding how organisms can withstand change is key to identify priority conservation objectives. Marine ectotherms are being extremely impacted because their biology and phenology are directly related to temperature. Among these species, sea turtles are particularly problematic because they roam over both marine and terrestrial habitats throughout their life cycles. Focusing on green turtles (Chelonia mydas) in the Mediterranean Sea, we investigated the future potential changes of nesting grounds through time, assuming that marine turtles would shift their nesting locations. We modeled the current distribution of nesting grounds including both terrestrial and marine variables, and we projected the potential nesting distribution across the Mediterranean basin under alternative future greenhouse gas emission scenario (2000-2100). Our models show an increase in nesting probability in the western Mediterranean Sea, irrespective of the climate scenario we consider. Contrary to what is found in most global change studies, the worse the climate change scenario, the more suitable areas for green turtles will potentially increase. The most important predictors were anthropogenic variables, which negatively affect nesting probability, and sea surface temperature, positively linked to nesting probability, up to a maximum of 24-25 °C. The importance of the western Mediterranean beaches as potential nesting areas for sea turtles in the near future clearly call for a proactive conservation and management effort, focusing on monitoring actions (to document the potential range expansion) and threat detection.


X-ray Pulsar in the Crab Nebula.
X-ray pulsations have been observed in the Crab Nebula at a frequency closely matching the radio and optical pulsations. About 5 percent of the total x-ray power of the nebula appears in the pulsed component. The x-ray pulsations have the form of a main pulse and an interpulse separated by about 12 milliseconds.


KDM6A/UTX promotes spermatogenic gene expression across generations and is not required for male fertility.
Paternal chromatin undergoes extensive structural and epigenetic changes during mammalian spermatogenesis, producing sperm with an epigenome optimized for the transition to embryogenesis. Lysine demethylase 6a (KDM6A, also called UTX) promotes gene activation in part via demethylation of H3K27me3, a developmentally important repressive modification abundant throughout the epigenome of spermatogenic cells and sperm. We previously demonstrated increased cancer risk in genetically wild type mice derived from a paternal germ line lacking Kdm6a (Kdm6a cKO), indicating a role for KDM6A in regulating heritable epigenetic states. However, the regulatory function of KDM6A during spermatogenesis is not known. Here, we show that Kdm6a is transiently expressed in spermatogenesis, with RNA and protein expression largely limited to late spermatogonia and early meiotic prophase. Kdm6a cKO males do not have defects in fertility or the overall progression of spermatogenesis. However, hundreds of genes are deregulated upon loss of Kdm6a in spermatogenic cells, with a strong bias towards downregulation coinciding with the time when Kdm6a is expressed. Misregulated genes encode factors involved in chromatin organization and regulation of repetitive elements, and a subset of these genes was persistently deregulated in the male germ line across two generations of offspring of Kdm6a cKO males. Genome-wide epigenetic profiling revealed broadening of H3K27me3 peaks in differentiating spermatogonia of Kdm6a cKO mice, suggesting that KDM6A demarcates H3K27me3 domains in the male germ line. Our findings highlight KDM6A as a transcriptional activator in the mammalian male germ line that is dispensable for spermatogenesis but important for safeguarding gene regulatory state intergenerationally.


[Ovarian fibroma. Report of two cases; familial incidence?].
Twenty three percent of the total gynecological neoplasms are ovarian tumors. Four percent of these, are ovarian fibromas. One third of patients with ovarian tumors are asymptomatic and half have no palpable masses. In contrast to what radiologic examination can offer in diagnosing ovarian fibromas, pathological analyses renders an accurate and final diagnostic. World-wide literature shows a prevalence of ovarian fibromas in members of the same family. We present two cases of sisters with similar clinical histories of bilateral calcified ovarian fibromas. Radiologic findings showed pelvic tumors in both patients. After exploratory laparotomy, the tumors were analyzed pathologically and identified as calcified ovarian fibromas.


A photoactivatable small-molecule inhibitor for light-controlled spatiotemporal regulation of Rho kinase in live embryos.
To uncover the molecular mechanisms of embryonic development, the ideal loss-of-function strategy would be capable of targeting specific regions of the living embryo with both temporal and spatial precision. To this end, we have developed a novel pharmacological agent that can be light activated to achieve spatiotemporally limited inhibition of Rho kinase activity in vivo. A new photolabile caging group, 6-nitropiperonyloxymethyl (NPOM), was installed on a small-molecule inhibitor of Rho kinase, Rockout, to generate a 'caged Rockout' derivative. Complementary biochemical, cellular, molecular and morphogenetic assays in both mammalian cell culture and Xenopus laevis embryos validate that the inhibitory activity of the caged compound is dependent on exposure to light. Conveniently, this unique reagent retains many of the practical advantages of conventional small-molecule inhibitors, including delivery by simple diffusion in the growth medium and concentration-dependent tuneability, but can be locally activated by decaging with standard instrumentation. Application of this novel tool to the spatially heterogeneous problem of embryonic left-right asymmetry revealed a differential requirement for Rho signaling on the left and right sides of the primitive gut tube, yielding new insight into the molecular mechanisms that generate asymmetric organ morphology. As many aromatic/heterocyclic small-molecule inhibitors are amenable to installation of this caging group, our results indicate that photocaging pharmacological inhibitors might be a generalizable technique for engendering convenient loss-of-function reagents with great potential for wide application in developmental biology.


Food poisoning outbreaks associated with manufactured foods in England and Wales: 1980-1989.
In the ten-year period, 1980-89, 294 reported outbreaks of food poisoning were associated with eating pre-cooked sliced meats, meat products and other manufactured foods in England and Wales, including 65 outbreaks in which the product was imported. Salmonellas were the most commonly reported agent, causing 132 (45%) of the outbreaks; other bacteria caused a further 51 (17%) outbreaks. The remainder were due to viruses (five outbreaks), scombrotoxin (60 outbreaks), or were of unknown cause (46 outbreaks). The number of outbreaks associated with manufactured foods accounted for only a small proportion (less than 5%) of food poisoning outbreaks reported to CDSC during this period and needs to be set against the huge amounts of manufactured foods consumed. However, because of the quantities made and the widespread distribution of particular products, such outbreaks may affect many individuals who are geographically widespread.