The impact of funding deadlines on personal workloads, stress and family relationships: a qualitative study of Australian researchers.
To examine the impact of applying for funding on personal workloads, stress and family relationships. Qualitative study of researchers preparing grant proposals. Web-based survey on applying for the annual National Health and Medical Research Council (NHMRC) Project Grant scheme. Australian researchers (n=215). Almost all agreed that preparing their proposals always took top priority over other work (97%) and personal (87%) commitments. Almost all researchers agreed that they became stressed by the workload (93%) and restricted their holidays during the grant writing season (88%). Most researchers agreed that they submitted proposals because chance is involved in being successful (75%), due to performance requirements at their institution (60%) and pressure from their colleagues to submit proposals (53%). Almost all researchers supported changes to the current processes to submit proposals (95%) and peer review (90%). Most researchers (59%) provided extensive comments on the impact of writing proposals on their work life and home life. Six major work life themes were: (1) top priority; (2) career development; (3) stress at work; (4) benefits at work; (5) time spent at work and (6) pressure from colleagues. Six major home life themes were: (1) restricting family holidays; (2) time spent on work at home; (3) impact on children; (4) stress at home; (5) impact on family and friends and (6) impact on partner. Additional impacts on the mental health and well-being of researchers were identified. The process of preparing grant proposals for a single annual deadline is stressful, time consuming and conflicts with family responsibilities. The timing of the funding cycle could be shifted to minimise applicant burden, give Australian researchers more time to work on actual research and to be with their families.


Predictors of marker-informativeness for an outbred F2 design.
Generalization of the polymorphism information content (PIC) index to represent marker informativeness (MI) for a three-generation F2 design requires that two additional sources of non-informativeness be added to the PIC formula: the probability of matings between like-heterozygous F1 individuals, of which one is non-informative; and that of matings between like-heterozygous F1 individuals, which are both fully informative but where line of origin of the same alleles is reciprocal. Given the dense marker-maps currently available for some species, this F2 informativeness parameter constitutes the natural criterion for marker selection in F2 designs, and two computer programs to predict MI from grandparental marker-genotypes were developed for an F2 population originating from two divergent selection lines of outbred mice (F approximately 0.2). A total of 403 markers had been genotyped for the F0 grandparents (n=31), and 14 markers had also been genotyped in the complete pedigree including 559 F2 individuals. One program was based on assumptions of random-mating (RM), while the other (PED) accounted for the pedigreed mating structure. For the 403 markers, the correlation between MI from RM and from PED was 0.95, and the average deviation between the two predictions was 0.005 MI units (MI ranged from 0 to 1). Correlations between predicted and realized MI for the 14 fully genotyped markers were 0.97 for PED and 0.94 for RM, while the corresponding average of deviations between predicted and actual values were 0.01 and 0.04, respectively. Absolute deviations from realized MI never exceeded 0.09 and 0.16 for PED and RM, respectively. Simulated optimization of the mating system to maximize average MI of 28 markers on one chromosome led to improvements in the range of 15-20% average MI (0.07-0.09 MI units). The degree of relative advantage conferred by the F2 generalization of the PIC index over the traditional index was found to be of minor significance.


A multi-centre cohort study of the physical health of 5-year-old children conceived after intracytoplasmic sperm injection, in vitro fertilization and natural conception.
Over a million children have been born from assisted conception worldwide. Newer techniques being introduced appear less and less 'natural', such as intracytoplasmic sperm injection (ICSI), but there is little information on these children beyond the neonatal period. 540 ICSI conceived 5-year-old children from five European countries were comprehensively assessed, along with 538 matched naturally conceived children and 437 children conceived with standard IVF. Of the 540 ICSI children examined, 63 (4.2%) had experienced a major congenital malformation. Compared with naturally conceived children, the odds of a major malformation were 2.77 (95% CI 1.41-5.46) for ICSI children and 1.80 (95% CI 0.85-3.81) for IVF children; these estimates were little affected by adjustment for socio-demographic factors. The higher rate observed in the ICSI group was due partially to an excess of malformations in the (boys') urogenital system. In addition, ICSI and IVF children were more likely than naturally conceived children to have had a significant childhood illness, to have had a surgical operation, to require medical therapy and to be admitted to hospital. A detailed physical examination revealed no further substantial differences between the groups, however. Singleton ICSI and IVF 5-year-olds are more likely to need health care resources than naturally conceived children. Assessment of singleton ICSI and IVF children at 5 years of age was generally reassuring, however, we found that ICSI children presented with more major congenital malformations and both ICSI and IVF children were more likely to need health care resources than naturally conceived children. Ongoing monitoring of these children is therefore required.


Anti-prion activity generated by a novel vaccine formulation.
Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of domestic and wild cervids in North America. To address possible prevention regimens for CWD, we have used a mouse model system and the Rocky Mountain Laboratory (RML) mouse-adapted scrapie prion strain to screen efficacy of potential vaccine candidates. Three peptides derived from the primary amino acid sequence of the prion protein were conjugated to blue carrier protein (BCP) and formulated in an adjuvant containing M. avium subsp. avium. CL57/BL6 mice were vaccinated and boosted with 50 microg of the carrier protein-peptide conjugate formulation; all vaccines produced a humoral immune response as measured by ELISA. Disease challenge with the RML scrapie prion strain revealed anti-prion activity was generated by the vaccine formulations as measured by a delay in clinical disease onset and prolonged survivorship.


The pulmonary surfactant protein C (SP-C) precursor is a type II transmembrane protein.
Human pulmonary-surfactant-associated protein C (SP-C) is an extremely hydrophobic peptide comprising 34-35 amino acids. It is involved in the reduction of surface tension at the air/liquid in the lung. In order to understand the mechanism by which this molecule is generated from its 197-amino-acid-residues-long precursor and secreted into the alveolar space, we analysed the biosynthesis and processing of this precursor in an 'in vitro' system. Our results show that the SP-C precursor is a 21 kDa integral membrane protein. It is anchored in the membrane by a hydrophobic domain that comprises the 20-amino-acid-residues-long hydrophobic core of the mature SP-C peptide. The N-terminus remains in the cytoplasm, which leads to a type II transmembrane orientation of the precursor. Membrane integration occurs in a signal-peptidase-independent manner. The hydrophobic domain acts as both signal sequence and membrane-anchoring domain. We suggest that correct membrane insertion of the SP-C precursor, which is strictly dependent on the hydrophobic-amino-acid sequence represented by the hydrophobic core of the mature SP-C, is itself a prerequisite for further processing and intracellular transport of the mature SP-C.


Increased dopamine after mating impairs olfaction and prevents odor interference with pregnancy.
In rodents, social odor sensing influences female reproductive status by affecting neuroendocrine cascades. The odor of male mouse urine can induce ovulation or block pregnancy within 3 d post coitus. Females avoid the action of such olfactory stimuli after embryonic implantation. The mechanisms underlying these changes are unknown. Here we report that shortly after mating, a surge in dopamine in the mouse main olfactory bulb impairs the perception of social odors contained in male urine. Treatment of females at 6.5 d post coitus with a dopamine D2 receptor antagonist restores social odor sensing and favors disruption of pregnancy by inhibition of prolactin release, when administered in the presence of alien male urine odors. These results show that an active sensory barrier blocks social olfactory cues detrimental to pregnancy, consistent with the main olfactory bulb being a major relay through which social odor modulates reproductive status.


Pharmacological treatment of severe, therapy-resistant asthma in children: what can we learn from where?
There is a lack of high-quality evidence on what treatment should be used in children with properly characterised severe, therapy-resistant asthma. Data have to be largely extrapolated from trials in children with mild asthma, and adults with severe asthma. Therapeutic options can be divided into medications used in lower doses for children with less severe asthma, and those used in other paediatric diseases but not for asthma (for example, methotrexate). In the first category are high-dose inhaled corticosteroids (ICS) (≤ 2,000 μg · day(-1) fluticasone equivalent), oral prednisolone, the anti-immunoglobulin (Ig)E antibody omalizumab, high-dose long-acting β(2)-agonists, low-dose oral theophylline and intramuscular triamcinolone. If peripheral airway inflammation is thought to be a problem, the use of fine-particle ICS or low-dose oral corticosteroids may be considered. More experimental therapies include oral macrolides, cyclosporin, cytotoxic drugs such as methotrexate and azathioprine, gold salts, intravenous infusions of Ig, subcutaneous β(2)-agonist treatment and, in those sensitised to fungi, oral antifungal therapy with itraconazole or voriconazole. Those with recurrent severe exacerbations, particularly in the context of good baseline asthma control, are particularly difficult to treat; baseline control and lung function must be optimised with the lowest possible dose of ICS, and allergen triggers and exposures minimised. The use of high-dose ICS, leukotriene receptor antagonists or both at the time of exacerbations can be considered. There is no evidence regarding which therapeutic option to recommend. Better evidence is required for all these treatment options, underscoring the need for the international and co-ordinated approach which we have previously advocated.


Canadian Helicobacter pylori consensus conference. Canadian Association of Gastroenterology.
These guidelines were created to dispel confusion and provide guidance about how the isolation of Helicobacter pylori infection has led to new opportunities and initiatives to improve patient care. The guidelines are designed for practical application in management decisions, but must remain flexible and amenable to change with new information. Updated versions of the recommendations are anticipated. Although it is now clear that H pylori is a major gastrointestinal pathogen, the extent of the clinical consequences posed by this microorganism has yet to be fully defined.


Scintillation index of flat-topped Gaussian laser beam in strongly turbulent medium.
In a strongly turbulent medium, the scintillation index of flat-topped Gaussian beams is derived and evaluated. In the formulation, unified solution of Rytov method is utilized. Our results correctly reduce to the existing strong turbulence scintillation index of the Gaussian beam, and naturally to spherical and plane wave scintillations. Another checkpoint of our result is the scintillation index of flat-topped Gaussian beams in weak turbulence. Regardless of the order of flatness, scintillations of flat-topped Gaussian beams in strong turbulence are found to be determined mainly by the small-scale effects. For large-sized beams in moderate and strongly turbulent medium, flatter beams exhibit smaller scintillations.


Stealth Engineering for In Vivo Drug Delivery Systems.
In generic terms, a drug delivery substrate (DDS) can be described as a vehicle to transport drug to the point of interest. A DDS that would ideally have the capability to control drug dosage and achieve target specificity, localization, and higher therapeutic efficacy has been pursued as a holy grail in pharmaceutical research. Over the years, diverse classes, structures, and modifications of DDS have been proposed to achieve this aim. One of its major deterrents, however, is rapid elimination of drug by the immune system before intended functionality. Stealth engineering is broadly defined as a method of designing a drug carrier to minimize or delay opsonization until the encapsulated drug is delivered to the intended target. Stealth-engineered DDS has been successful in extending drug circulation lifetime from a few minutes to several days. Currently, this field of research has made much progress since its initiation in 1960s with liposomes to DNA boxes. Activity has also benefited several areas of medicine, where it has been applied in cancer, gene therapy, bone regrowth, and infection treatment. This review covers the progress of some types of DDS that have been published and indexed in major databases (including ScienceDirect, PubMed, and Google Scholar) in the scientific literature.


HIV-1 Transmission Patterns in Men Who Have Sex with Men: Insights from Genetic Source Attribution Analysis.
Near 60% of new HIV infections in the United Kingdom are estimated to occur in men who have sex with men (MSM). Age-disassortative partnerships in MSM have been suggested to spread the HIV epidemics in many Western developed countries and to contribute to ethnic disparities in infection rates. Understanding these mixing patterns in transmission can help to determine which groups are at a greater risk and guide public health interventions. We analyzed combined epidemiological data and viral sequences from MSM diagnosed with HIV at the national level. We applied a phylodynamic source attribution model to infer patterns of transmission between groups of patients. From pair probabilities of transmission between 14,603 MSM patients, we found that potential transmitters of HIV subtype B were on average 8 months older than recipients. We also found a moderate overall assortativity of transmission by ethnic group and a stronger assortativity by region. Our findings suggest that there is only a modest net flow of transmissions from older to young MSM in subtype B epidemics and that young MSM, both for Black or White groups, are more likely to be infected by one another than expected in a sexual network with random mixing.


Identification of the human liver cytochrome P450 enzymes involved in the metabolism of zileuton (ABT-077) and its N-dehydroxylated metabolite, Abbott-66193.
In vitro studies were conducted to identify the hepatic cytochrome P450 (CYP) forms involved in the oxidative metabolism of [14C]zileuton (ABT-077) and its N-dehydroxylated metabolite, [14C]Abbott-66193, by human liver microsomes. The two compounds were metabolized by parallel pathways to form the corresponding ring-hydroxylated and diastereomer sulfoxide metabolites. Results suggested that whereas the metabolism of zileuton and Abbott-66193 were mediated by the same CYP forms, the CYP forms responsible for hydroxylation (CYP1A2 and CYP2C9/10) were distinct from those involved in sulfoxidation (CYP3A > CYP2C9/10). Sulfoxidation (zileuton, Km = 0.82 +/- 0.40 mM, Vmax = 39.1 +/- 21.8 pmol/min/mg; Abbott-66193, Km = 0.23 +/- 0.06 mM, Vmax = 507 +/- 215 pmol/min/mg; mean +/- SD, N=3) was highly correlated with the CYP3A-specific erythromycin N-demethylase activity (r=0794-0.856; p<0.01, N=11) in human microsomes and was inhibited (32-67%) by ketoconazole and troleandomycin. In addition, purified recombinant human CYP3A4/rat NADPH-P450 reductase fusion protein catalyzed only the sulfoxidation of zileuton and Abbott-66193; no hydroxylated metabolites were detected. On the other hand, hydroxylation of the two compounds (zileuton, Km = 0.34 +/- 0.25 mM, Vmax = 17.8 +/- 5.58 pmol/min/mg; Abbott-66193,Km = 0.39 +/- 0.14 mM, Vmax = 1061 +/- 220 pmol/min/mg) was significantly correlated with 7-ethoxyresorufin O-deethylase (CYP1A2; r=0.652-0.762; p<0.01, N=11) and tolbutamide methyl hydroxylase (CYP2C9/10; r=0.863-0.935; p<0.01, N=10) activity in human liver microsome, and was inhibited (26-51%) by well-known CYP1A2 inhibitors (furafylline and alpha-naphthoflavone). Furthermore, microsomes from human B-lymphoblastoid cells expressing CYP1A2 catalyzed only the hydroxylation of zileuton and Abbott-66193; sulfoxide were not formed. Abbott-66193 was a better substrate for CYP2C9/10, when compared with zileuton: 1) the effect of sulfaphenazole on hydroxylation in human liver microsomes was more pronounced for Abbott-66193 than zileuton (56% vs. 9% inhibition); and 2) the rate of Abbott-66193 hydroxylation by purified CYP2C9 was almost 30-fold greater than that of zilueton.


An assessment of food safety needs of restaurants in Owerri, Imo State, Nigeria.
One hundred and forty five head chefs and catering managers of restaurants in Owerri, Nigeria were surveyed to establish their knowledge of food safety hazards and control measures. Face-to-face interviews were conducted and data collected on their knowledge of risk perception, food handling practices, temperature control, foodborne pathogens, and personal hygiene. Ninety-two percent reported that they cleaned and sanitized food equipment and contact surfaces while 37% engaged in cross-contamination practices. Forty-nine percent reported that they would allow a sick person to handle food. Only 70% reported that they always washed their hands while 6% said that they continued cooking after cracking raw eggs. All respondents said that they washed their hands after handling raw meat, chicken or fish. About 35% lacked knowledge of ideal refrigeration temperature while 6% could not adjust refrigerator temperature. Only 40%, 28%, and 21% had knowledge of Salmonella, E. coli, and Hepatitis A, respectively while 8% and 3% had knowledge of Listeria and Vibrio respectively, as pathogens. Open markets and private bore holes supplied most of their foods and water, respectively. Pearson's Correlation Coefficient analysis revealed almost perfect linear relationship between education and knowledge of pathogens (r = 0.999), cooking school attendance and food safety knowledge (r = 0.992), and class of restaurant and food safety knowledge (r = 0.878). The lack of current knowledge of food safety among restaurant staff highlights increased risk associated with fast foods and restaurants in Owerri.


Construction of a combinatorial library of chimeric tumor-specific promoters.
Gene therapy is a fast-developing field of molecular medicine. New, effective, and cancer-specific promoters are in high demand by researchers seeking to treat cancer through expression of therapeutic genes. Here, we created a combinatorial library of tumor-specific chimeric promoter modules for identifying new promoters with desired functions. The library was constructed by randomly combining promoter fragments from eight human genes involved in cell proliferation control. The pool of chimeric promoters was inserted into a lentiviral expression vector upstream of the CopGFP reporter gene, transduced into A431 cells, and enriched for active promoters by cell sorting. The enriched library contained a remarkably high proportion of active and tumor-specific promoters. This approach to generating combinatorial libraries of chimeric promoters may serve as a useful tool for selecting highly specific and effective promoters for cancer research and gene therapy.


Chemical communication in the honey bee scarab pest Oplostomus haroldi: role of (Z)-9-pentacosene.
Oplostomus haroldi Witte belongs to a unique genus of afro-tropical scarabs that have associations with honey bee colonies, from which they derive vital nutrients. Although the attributes of the honey bee nest impose barriers to communication among nest invaders, this beetle still is able to detect conspecific mates for reproduction. Here, we show, through behavioral studies, that cuticular lipids serve as mate discrimination cues in this beetle. We observed five steps during mating: arrestment, alignment, mounting, and copulation, and a post-copulatory stage, lasting ~40-70 % of the total mating duration, that suggested mate guarding. Chemical analysis identified the same nine straight-chain alkanes (C(23)-C(31)), six methyl-branched alkanes (6), and five mono-unsaturated alkenes in the cuticular lipids of both sexes. Methyl alkanes constituted the major component (46 %) of male cuticular lipids, while mono-unsaturated alkenes were most abundant (53 %) in females. (Z)-9-Pentacosene was twice as abundant in females than in males, and ~20 fold more concentrated in beetles than in worker bees. In mating assays, (Z)-9-pentacosene elicited arrestment, alignment, and mounting, but not copulation, by male beetles. These results represent the first evidence of a contact sex pheromone in a scarab beetle. Such contact pheromones may be an essential, cryptic mechanism for arthropods associated with eusocial insects.


Blastic plasmacytoid dendritic cell neoplasm: a clinicopathologic review.
Blastic plasmacytoid dendritic cell neoplasm is a rare entity grouped with the acute myeloid leukemia-related precursor neoplasms in the 2008 World Health Organization classification. It was previously postulated to originate from natural killer cells, T cells, or monocytes but is now believed to arise from the plasmacytoid dendritic cell. The pathogenesis of blastic plasmacytoid dendritic cell neoplasm is not well understood, although the neoplasm demonstrates frequent deletion of tumor suppressor genes, including RB1, CDKN1B, CDKN2A, and TP53. Blastic plasmacytoid dendritic cell neoplasm is a clinically aggressive tumor that often initially presents as cutaneous lesions and subsequently progresses to bone marrow involvement and leukemic dissemination. It is characterized by enhanced expression of CD56, CD4, and CD123, which can be detected by flow cytometry/immunohistochemistry. The differential diagnoses include myeloid sarcoma/acute myeloid leukemia, T-cell lymphoblastic leukemia/lymphoma, NK-cell lymphoma/leukemia, and some mature T-cell lymphomas/leukemias. Patients usually respond to initial chemotherapy but often relapse. Stem cell transplant may improve survival.


Point: active surveillance for favorable risk prostate cancer.
Active surveillance for favorable risk prostate cancer has become increasingly popular in populations where prostate cancer screening is widespread, because of evidence that prostate cancer screening results in the detection of disease that is not clinically significant in many patients (i.e., untreated, would not pose a threat to health). This approach is supported by data showing that patients who fall into the category of clinically insignificant disease can be identified with reasonable accuracy, and that patients who are initially classified as low-risk who reclassified over time as higher-risk and are treated radically are still cured in most cases. Active surveillance means 1) identifying patients who have a low likelihood of disease progression during their lifetime, based on clinical and pathologic features of the disease, and patient age and comorbidity; 2) close monitoring over time; 3) developing reasonable criteria for intervention, which will identify more aggressive disease in a timely fashion and not result in excessive treatment; and 4) meeting the communication challenge to reduce the psychological burden of living with untreated cancer. This article reviews the results of active surveillance, the criteria for patient selection, and the appropriate triggers for intervention.


QuantiFERON®-TB gold in-tube performance for diagnosing active tuberculosis in children and adults in a high burden setting.
To determine whether QuantiFERON®-TB Gold In-Tube (QFT) can contribute to the diagnosis of active tuberculosis (TB) in children in a high-burden setting and to assess the performance of QFT and tuberculin skin test (TST) in a prospective cohort of TB suspect children compared to adults with confirmed TB in Tanzania. Sensitivity and specificity of QFT and TST for diagnosing active TB as well as indeterminate QFT rates and IFN-γ levels were assessed in 211 TB suspect children in a Tanzanian district hospital and contrasted in 90 adults with confirmed pulmonary TB. Sensitivity of QFT and TST in children with confirmed TB was 19% (5/27) and 6% (2/31) respectively. In adults sensitivity of QFT and TST was 84% (73/87) and 85% (63/74). The QFT indeterminate rate in children and adults was 27% and 3%. Median levels of IFN-γ were lower in children than adults, particularly children <2 years and HIV infected. An indeterminate result was associated with age <2 years but not malnutrition or HIV status. Overall childhood mortality was 19% and associated with an indeterminate QFT result at baseline. QFT and TST showed poor performance and a surprisingly low sensitivity in children. In contrast the performance in Tanzanian adults was good and comparable to performance in high-income countries. Indeterminate results in children were associated with young age and increased mortality. Neither test can be recommended for diagnosing active TB in children with immature or impaired immunity in a high-burden setting.


Natural infections of Pintomyia verrucarum and Pintomyia maranonensis by Leishmania (Viannia) peruviana in the Eastern Andes of northern Peru.
The natural infection of sand flies by Leishmania was investigated in Andean areas located between the Central and Eastern Cordilleras of northern Peru where cutaneous leishmaniasis caused by Leishmania (Viannia) peruviana is endemic. Sand flies were captured at five locations along the Utcubamba River in the Department of Amazonas, and morphologically identified under a microscope. Among 422 female sand flies dissected, the most dominant species was Pintomyia verrucarum (320 flies), followed by Pi. maranonensis (83 flies), Pi. robusta (13 flies), and Lutzomyia castanea (6 flies). Genetic analysis of sand flies from these areas together with those from other areas revealed that individuals of Pi. verrucarum were closely related regardless of morphological variation of their spermathecae. On the other hand, individuals of Pi. maranonensis collected in the study area were distant from those of other areas with genetic distances over the intraspecific level but mostly below the interspecific level, suggesting the unique characteristics of sand flies in this area. The natural infection of sand flies by flagellate parasites was detected mainly in the hindgut of each one of Pi. verrucarum and Pi. maranonensis. Both parasite species were identified as L. (V.) peruviana based on cytochrome b and mannose phosphate isomerase gene analyses. In addition, parasite species obtained from the lesion of a patient with cutaneous leishmaniasis in the study area in this period was identified as L. (V.) peruviana. These results strongly suggest that Pi. verrucarum and Pi. maranonensis are responsible for the transmission of L. (V.) peruviana in these areas. This is the first report of the natural infection of Pi. maranonensis by L. (V.) peruviana.


Endoscopic submucosal dissection for duodenal tumors.
Recently, endoscopic submucosal dissection (ESD) for the duodenal tumors has come to be treated in many institutions, but has also showed many problems of feasibility and safety compared with endoscopic mucosal resection (EMR). Although duodenal ESD is expected to be more effective for the prevention of postoperative local recurrence, high incidence rate of duodenal perforation and emergency surgical rescue are big problem. Prophylactic mucosal closure by clipping device, polyglycolic acid sheets shielding, and the laparoscopic and endoscopic cooperative surgery are reported to be effective measures to overwhelm the various problems associated with duodenal ESD. However, duodenal ESD still has quite a bit of room for improvement of the procedure, and currently the indication should be well discussed before treatment in consideration of the expected therapeutic effect and complications.


Marginal adaptation of new bioceramic materials and mineral trioxide aggregate: a scanning electron microscopy study.
This study aimed to compare the marginal adaptation of new bioceramic materials, EndoSequence Root Repair Material (ERRM putty and ERRM paste), to that of mineral trioxide aggregate (MTA) as root-end filling materials. Thirty-six extracted human single-rooted teeth were prepared and obturated with gutta-percha and AH-26 sealer. The roots were resected 3 mm from the apex. Root-end cavities were then prepared with an ultrasonic retrotip. The specimens were divided into three groups (n=12) and filled with MTA, ERRM putty or ERRM paste. Epoxy resin replicas from the resected root-end surfaces and longitudinally sectioned roots were fabricated. The gaps at the material/dentin interface were measured using scanning electron microscope (SEM). Transversal, longitudinal, and overall gap sizes were measured for each specimen. The data were analyzed using the Kruskal-Wallis test. In transversal sections, no significant difference was found between MTA, ERRM putty and ERRM paste (P=0.31). However, in longitudinal sections, larger gaps were evident between ERRM paste and dentinal walls compared to MTA and ERRM putty (P=0.002 and P=0.033, respectively). Considering the overall gap size values, the difference between three tested materials was not statistically significant (P=0.17). Within the limits of this study, the marginal adaptation of ERRM paste and putty was comparable to that of MTA. However, ERRM putty might be more suitable for filling the root-end cavities because of its superior adaptation compared to ERRM paste in longitudinal sections.


Improvement of clinical outcome by early nephrology referral in type II diabetics on hemodialysis.
To evaluate the influence of early nephrology referral on clinical outcome in type II diabetes mellitus patients on maintenance hemodialysis dialysis. This study retrospectively analyzed the type II diabetic patients entering our PD program from February 1988 to June 2001. Patients who were presented to a nephrologist more than 6 months before starting dialysis were defined as early referral (ER). Patients were considered late referral (LR) if they were transferred to the nephrology department within 6 months before initial dialysis. Hundred and fifteen type II diabetic patients receiving HD for at least 3 months were enrolled in this study. Sixteen of the 53 patients (46.1%) were in the ER group and 62 of the 115 (53.9%) were in the LR group. In univariate analysis by Cox proportional hazards mode, the early referral (Exp (Coef) = 0.423, p < 0.01), good glycemic control (Exp (Coef) = 0.16, p < 0.05), and age at dialysis (Exp (Coef) = 1.026, p < 0.05 (had significantly influenced the patient survival. The residual renal function in the ER group, estimated by creatinine clearance (Ccr), significantly exceeded that of the LR group (ER vs. LR: 4.46 +/- 1.56 vs. 2.51 +/- 1.70 mL/min, p < 0.001). The patients with early referral had significantly better survival (p < 0.05). Five-year survival improved significantly in the early referral group compared to the late referral group (ER: 72.4%; LR: 35.2%, p < 0.05). We demonstrate that the time of referral before starting dialysis is a predictor of survival for type II diabetics on HD. Patients with early referral are associated with longer survival. The beneficial effect might be associated with the timely initiation of the chronic HD program. These results suggest that early referral before dialysis is important in determining the long-term prognosis in type II diabetics on HD.


Sod1 deficiency reduces incubation time in mouse models of prion disease.
Prion infections, causing neurodegenerative conditions such as Creutzfeldt-Jakob disease and kuru in humans, scrapie in sheep and BSE in cattle are characterised by prolonged and variable incubation periods that are faithfully reproduced in mouse models. Incubation time is partly determined by genetic factors including polymorphisms in the prion protein gene. Quantitative trait loci studies in mice and human genome-wide association studies have confirmed that multiple genes are involved. Candidate gene approaches have also been used and identified App, Il1-r1 and Sod1 as affecting incubation times. In this study we looked for an association between App, Il1-r1 and Sod1 representative SNPs and prion disease incubation time in the Northport heterogeneous stock of mice inoculated with the Chandler/RML prion strain. No association was seen with App, however, significant associations were seen with Il1-r1 (P = 0.02) and Sod1 (P<0.0001) suggesting that polymorphisms at these loci contribute to the natural variation observed in incubation time. Furthermore, following challenge with Chandler/RML, ME7 and MRC2 prion strains, Sod1 deficient mice showed highly significant reductions in incubation time of 20, 13 and 24%, respectively. No differences were detected in Sod1 expression or activity. Our data confirm the protective role of endogenous Sod1 in prion disease.


Similar cranial trauma prevalence among Neanderthals and Upper Palaeolithic modern humans.
Neanderthals are commonly depicted as leading dangerous lives and permanently struggling for survival. This view largely relies on the high incidences of trauma that have been reported1,2 and have variously been attributed to violent social behaviour3,4, highly mobile hunter-gatherer lifestyles2 or attacks by carnivores5. The described Neanderthal pattern of predominantly cranial injuries is further thought to reflect violent encounters with large prey mammals, resulting from the use of close-range hunting weapons1. These interpretations directly shape our understanding of Neanderthal lifestyles, health and hunting abilities, yet mainly rest on descriptive, case-based evidence. Quantitative, population-level studies of traumatic injuries are rare. Here we reassess the hypothesis of higher cranial trauma prevalence among Neanderthals using a population-level approach-accounting for preservation bias and other contextual data-and an exhaustive fossil database. We show that Neanderthals and early Upper Palaeolithic anatomically modern humans exhibit similar overall incidences of cranial trauma, which are higher for males in both taxa, consistent with patterns shown by later populations of modern humans. Beyond these similarities, we observed species-specific, age-related variation in trauma prevalence, suggesting that there were differences in the timing of injuries during life or that there was a differential mortality risk of trauma survivors in the two groups. Finally, our results highlight the importance of preservation bias in studies of trauma prevalence.


Priority mental, neurological and substance use disorders in rural Kenya: Traditional health practitioners' and primary health care workers' perspectives.
Over 75% of people with mental neurological and substance use disorders (MNSD) live in low and middle-income countries with limited access to specialized care. The World Health Organization's Mental Health Gap Action Program (mhGAP) aims to address the human resource gap but it requires contextualization. We conducted a qualitative study in rural coastal Kenya to explore the local terms, perceived causes and management modalities of priority MNSD listed in the mhGAP, to inform implementation in this setting. We conducted 8 focus group discussions with primary health care providers and traditional health practitioners and used the framework method to conduct thematic analysis. We identified local terms, perceived causes and treatment options for MNSD. We also explored possibilities for collaboration between the traditional health practitioners and primary health care providers. We found local terms for depression, psychoses, epilepsy, disorders due to substance use and self-harm/ suicide but none for dementia. Child and adolescent mental and behavioral problems were not regarded as MNSD but consequences of poor parenting. Self-harm/suicide was recognized in the context of other MNSD. Causes of MNSD were broadly either biological or supernatural. Treatment options were dependent on perceived cause of illness. Most traditional health practitioners were willing to collaborate with primary health care providers mainly through referring cases. Primary health care providers were unwilling to collaborate with traditional health practitioners because they perceived them to contribute to worsening of patients' prognoses. Local terms and management modalities are available for some priority MNSD in this setting. Community level case detection and referral may be hindered by lack of collaboration between traditional health practitioners and primary health care providers. There is need for training on the recognition and management of all priority MNSD.


Stimulated thermal Rayleigh scattering in optical fibers.
Recently, mode instability was observed in optical fiber lasers at high powers, severely limiting power scaling for single-mode outputs. Some progress has been made towards understanding the underlying physics. A thorough understanding of the effect is critical for continued progress of this very important technology area. Mode instability in optical fibers is, in fact, a manifestation of stimulated thermal Rayleigh scattering. In this work, a quasi-closed-form solution for the nonlinear coupling coefficient is found for stimulated thermal Rayleigh scattering in optical fibers. The results help to significantly improve understanding of mode instability.


[Characteristics and prognosis of malignant disease of the breast in women of very low age].
This study aims to describe characteristics of malignant diseases of the breast in women of very low age (thus with breast cancer diagnosed before 35th year of age) and compare those characteristics with the phenotype of "average" breast cancer in Czech female population. 98 women diagnosed with breast cancer before the age of 35 and treated between 2001 and 2010 in private medical center Medicon Praha s.r.o, were enrolled to this retrospective study. The control group of 100 women was constituted by random choice from patients older than 35 years at the time of diagnosis treated in the same time period. Size of the tumors at presentation were similar in both study groups. Tumors in younger group exhibited higher proliferative activity, higher grade and lower count of estrogen receptors. On the contrary, in the group of older women was significantly higher percentage of lobular type of cancer and also the proportion of in situ carcinomas. The number of multifocal tumors, positivity of HER-2/neu and progesterone receptors were all without statistically significant difference. In younger women neoadjuvant chemotherapy has been used more frequently. Prognosis of the disease did not differ in both groups. Tumors diagnosed in women younger than 35 years can be considered more aggressive. However, using adequate treatment makes the prognosis comparable in both age groups.


Transverse grating-assisted narrow-bandwidth acousto-optic tunable filter.
An experimental acousto-optic tunable filter that has a narrow spectral bandwidth (0.2 nm at 1550 nm) and a fast (10-micros) tuning capability with a continuous tuning range of approximately 50 nm is described. The tunable filter consists of an acousto-optic beam deflector with a diffraction grating whose grating vector is transverse to the direction of light propagation.


The complete nucleotide sequence and environmental distribution of the cryptic, conjugative, broad-host-range plasmid pIPO2 isolated from bacteria of the wheat rhizosphere.
Plasmid pIPO2 is a cryptic, conjugative, broad-host-range plasmid isolated from the wheat rhizosphere. It efficiently self-transfers between alpha, beta and gamma Proteobacteria and has a mobilizing/retromobilizing capacity for IncQ plasmids. The complete nucleotide sequence of pIPO2 is presented on the basis of its mini-Tn5::luxABtet-tagged derivative, pIPO2T. The pIPO2 sequence is 39815 bp long and contains at least 43 complete ORFs. Apart from a suite of ORFs with unknown function, all of the genes carried on pIPO2 are predicted to be involved in plasmid replication, maintenance and conjugative transfer. The overall organization of these genes is different from previously described plasmids, but is similar to the genetic organization seen in pSB102, a conjugative plasmid recently isolated from the bacterial community of the alfalfa rhizosphere. The putative conjugative transfer region of pIPO2 covers 23 kb and contains the genes required for DNA processing (Dtr) and mating pair formation (Mpf). The organization of these transfer genes in pIPO2 is highly similar to the genetic organization seen in the environmental plasmid pSB102 and in pXF51 from the plant pathogen Xylella fastidiosa. Plasmids pSB102 and pXF51 have recently been proposed to form a new family of environmental broad-host-range plasmids. Here it is suggested that pIPO2 is a new member of this family. The proposed Mpf system of pIPO2 shares high amino acid sequence similarity with equivalent VirB proteins from the type IV secretion system of Brucella spp. Sequence information was used to design primers specific for the detection of pIPO2. Environmental DNA from a range of diverse habitats was screened by PCR with these primers. Consistently positive signals for the presence of pIPO2 were obtained from a range of soil-related habitats, including the rhizospheres of young wheat plants, of field-grown oats and of grass (all gramineous plants), as well as from the rhizosphere of tomato plants. These data add to the growing evidence that plasmids carry advantageous genes with as yet undefined functions in plant-associated communities.


Age-related eye disease and survival. The Beaver Dam Eye Study.
To investigate the relationship of cataract, age-related maculopathy, glaucoma, and visual impairment to survival in the population-based Beaver Dam Eye Study. In this population-based study, visual acuity was measured with use of standardized protocols. At baseline, stereoscopic color fundus photographs and color slit-lamp and retroillumination photographs were graded in a masked fashion to determine the presence of age-related maculopathy and cataract, respectively. Deaths were ascertained by contacting family members, daily review of obituaries, and use of vital status records. Subjects aged 43 through 84 years who lived in Beaver Dam, Wis, were identified and examined between 1988 and 1990. From the time of the baseline examination until a median of 4 years later, 9.5% (467/4926) of the population had died. After correcting for age and sex, poorer survival was associated with more severe nuclear sclerosis (5-year survival of 88.9% for the most severe compared with 94.1% for the least severe stage) and visual impairment (5-year survival of 87.5% for impaired compared with 91.8% for unimpaired vision). However, after controlling for systemic factors, only more severe nuclear sclerosis in people without diabetes was significantly associated with poorer survival (hazard ratio per level of severity, 1.19; 95% confidence interval, 1.00 to 1.40). These data suggest that after controlling for age and sex, nuclear sclerotic cataract severity, cataract surgery, and visual impairment are risk indicators for poorer survival. Cortical cataract, posterior subcapsular cataract, glaucoma, and age-related maculopathy were unrelated to poorer survival.


Genotoxicity and Hemocompatibility of a Novel Calcium Aluminate-Based Cement.
The aim of this in vitro study was to evaluate the genotoxicity and hemocompatibility of a novel calcium aluminate-based cement, EndoBinder (EB) (Binderware, São Carlos, SP, Brazil) and compare it with Angelus White Mineral Trioxide Aggregate (MTA) (AWMTA) (Angelus, Soluções Odontológicas, Londrina, PR, Brazil). For evaluation of genotoxicity, a comet assay was performed with Chinese hamster ovary (CHO) cells that had been grown for 24 h in Dulbecco's Modified Eagle Medium incubated with each of the cements for 24 h at 37°C. DNA percentage in head and Olive tail moment were analyzed. For assessment of hemocompatibility, erythrocyte lysis quantification, and concentration of plasma fibrinogen were determined in human blood samples placed in contact with each of the materials. One way analysis of variance (ANOVA) followed by post hoc Tukey test and Student t-test were used for data analysis of genotoxicity and hemocompatibility, respectively. Results showed that the genotoxic effects of EB and AWMTA were comparable to that of the negative control, with no statistically significant differences between AWMTA and negative control (P>0.05). Compared to AWMTA, EB showed greater hemolytic potential when placed in direct contact with erythrocytes (P<0.05). Fibrinogen values were low for both materials, with protein concentration being greater in samples exposed to EB than to AWMTA. Both materials presented a higher hemolytic behaviour compared to what is established by international standards. Fibrinogen formation was low for both materials, and DNA damage induction was not observed in a comet assay.


Evaluation of a new silver foam dressing in patients with critically colonised venous leg ulcers.
To evaluate the performance (efficacy and safety) of an absorbent dressing impregnated with silver salts (UrgoCell Silver) in the management of leg ulcers with clinical signs of critical colonisation. This was a prospective multicentre non-comparative phase III clinical trial. Patients were assessed weekly for up to four weeks. Assessment included clinical assessment of critical colonisation (severe spontaneous pain between dressing changes, erythema, oedema, malodour and heavy exudate), wound area tracing and photography. Acceptability was documented by the nursing staff when dressings were changed between two weekly evaluations. Forty-five leg ulcers were included. At baseline the mean number of clinical signs of critical colonisation per ulcer was 3.6 +/- 0.7, which decreased to 1.2 +/- 1.2 at the end of the fourth week of follow-up (an average reduction of 2.3 +/- 1.3, p < 0.001). Oedema, malodour, erythema and spontaneous pain disappeared at the fourth week in 80%, 70%, 69% and 65% of the treated ulcers respectively. Compared with baseline, the mean reduction in ulcer area was 35.0 +/- 58.0% (median 33%, p < 0.001) after the four weeks treatment. Granulation tissue covered a mean 77% of the ulcer surface area at four weeks, compared with 41% at baseline. Only three local events were documented: contact dermatitis, a burning sensation and erythema. The results suggest that the test dressing had a favourable influence on the wound prognosis, and was well tolerated and accepted in the treatment of venous leg ulcers with clinical signs of critical colonisation.


Single-incision laparoscopic surgery: initial urological experience and comparison with natural-orifice transluminal endoscopic surgery.
Laparoscopic approaches have increasingly assumed a central role in the management of benign and malignant surgical diseases. While laparoscopy is less morbid than open surgery, it still requires several incisions, each > or =1-2 cm long. Each incision risks morbidity from bleeding, hernia and/or internal organ damage, and incrementally decreases cosmesis. An alternative to conventional laparoscopy is single-incision laparoscopic surgery (SILS), in which articulating or bent instrumentation with specialized multi-lumen ports is used. These technical innovations obviate the need to externally space trocars for triangulation, thus allowing the creation of a small, solitary portal of entry into the abdomen. Laboratory and early clinical series showed the feasibility as well as safe and successful completion of SILS. Natural-orifice transluminal endoscopic surgery (NOTES) is another exciting development in minimally invasive urology, but existing flexible endoscopes and instruments are limited in providing a platform for this form of advanced surgery, resulting in the slow adoption of NOTES. Future work is needed to improve existing instrumentation, increase clinical experience, assess the benefits of both surgical approaches, and explore other potential applications for these novel techniques.


Bioengineering a pre-vascularized pouch for subsequent islet transplantation using VEGF-loaded polylactide capsules.
The effectiveness of cell transplantation can be improved by optimization of the transplantation site. For some types of cells that form highly oxygen-demanding tissue, e.g., pancreatic islets, a successful engraftment depends on immediate and sufficient blood supply. This critical point can be avoided when cells are transplanted into a bioengineered pre-vascularized cavity which can be formed using a polymer scaffold. In our study, we tested surface-modified poly(lactide-co-caprolactone) (PLCL) capsular scaffolds containing the pro-angiogenic factor VEGF. After each modification step (i.e., amination and heparinization), the surface properties and morphology of scaffolds were characterized by ATR-FTIR and XPS spectroscopy, and by SEM and AFM. All modifications preserved the gross capsule morphology and maintained the open pore structure. Optimized aminolysis conditions decreased the Mw of PLCL only up to 10% while generating a sufficient number of NH2 groups required for the covalent immobilization of heparin. The heparin layer served as a VEGF reservoir with an in vitro VEGF release for at least four weeks. In vivo studies revealed that to obtain highly vascularized PLCL capsules (a) the optimal VEGF dose for the capsule was 50 μg and (b) the implantation time was four weeks when implanted into the greater omentum of Lewis rats; dense fibrous tissue accompanied by vessels completely infiltrated the scaffold and created sparse granulation tissue within the internal cavity of the capsule. The prepared pre-vascularized pouch enabled the islet graft survival and functioning for at least 50 days after islet transplantation. The proposed construct can be used to create a reliable pre-vascularized pouch for cell transplantation.


Short-course versus long-course oral antibiotic treatment for infections treated in outpatient settings: a review of systematic reviews.
To summarize the evidence comparing the effectiveness of short and long courses of oral antibiotics for infections treated in outpatient settings. We identified systematic reviews of randomized controlled trials for children and adults with bacterial infections treated in outpatient settings from Medline, Embase, CINAHL, Cochrane Database of Systematic Reviews and The Database of Review of Effects. Data were extracted on the primary outcome of clinical resolution and secondary outcomes. We identified 30 potential reviews, and included 9. There was no difference in the clinical cure for children treated with short or long course antibiotics for Group A streptococcal tonsillopharyngitis (OR 1.03, 95% CI:0.97, 1.11); community acquired pneumonia (RR 0.99, 95% CI:0.97, 1.01); acute otitis media [<2 years old OR: 1.09 (95% CI:0.76, 1.57); ≥2 years old OR: 0.85 (95% CI:0.60, 1.21)]; or urinary tract infection (RR 1.06, 95% CI:0.64, 1.76). There was no difference in the clinical cure for adults treated with short or long course antibiotics for acute bacterial sinusitis (RR 0.95, 95% CI:0.81, 1.21); uncomplicated cystitis in non-pregnant women (RR 1.10, 95% CI:0.96, 1.25), or elderly women (RR: 0.98, 95% CI:0.62, 1.54); acute pyelonephritis (RR 1.03, 95% CI:0.80, 1.32); or community acquired pneumonia (RR: 0.96, 95% CI:0.74, 1.26). We found inadequate evidence about the effect on antibiotic resistance. This overview of systematic reviews has identified good quality evidence that short course antibiotics are as effective as longer courses for most common infections managed in ambulatory care. The impact on antibiotic resistance and associated treatment failure requires further study.


Effects of a mechanical stimulation of localization of annexin-like proteins in Bryonia dioica internodes.
Mechanical stimulation exerted by rubbing a young internode of Bryonia dioica plants inhibits its growth. Previous cellular and biochemical studies showed that this growth inhibition is associated with Ca(2+) redistribution and profound modifications of plasma membrane characteristics. We extracted and purified Ca(2+)-dependent phospholipid-binding proteins from B. dioica internodes. Two main proteins, p33 and p35, and other minor bands were isolated and identified as annexin-like proteins because of their biochemical properties and their cross-reactions with antibodies against maize (Zea mays L.) annexins. Rabbit antiserum was obtained by injection of B. dioica p35. This antiserum was used for the immunocytolocalization of annexin-like proteins in internode parenchyma cells. It appeared that the distribution of annexin-like proteins was different before and 30 min after the mechanical stimulation. Western analysis of proteins in membrane fractions after separation by free-flow electrophoresis showed that p35 was present in most fractions, whereas p33 appeared mainly in plasmalemma-enriched fractions after the mechanical stimulation. It is hypothesized that a subcellular redistribution of these proteins might be involved in growth inhibition by mechanical stress.


Comparing tailored and untailored text messages for smoking cessation: a randomized controlled trial among adolescent and young adult smokers.
The aim was to compare the effectiveness of untailored text messages for smoking cessation to tailored text messages delivered at a higher frequency. From February 2007 to August 2009, 2030 users of an internet-based smoking cessation program with optional text message support aged 15-25 years were consecutively randomized to versions of the program that offered either tailored or untailored text messages. Thirty-day point abstinence from smoking was measured self-reportedly at 12-months follow-up. Response rates were 36.3% and 38.1% in the tailored and untailored group, respectively. We analyzed the entire study population, as well as those opting for text messages (n = 1619). In intention-to-treat analysis with multiple imputation of missing data, the odds ratio for 30-day point abstinence was 1.28 (95% CI 0.91-2.08) for the tailored compared with untailored messages. When restricting the analysis to those who had chosen to receive text messages, the corresponding odds ratio was 1.45 (95% CI 1.01-2.08). The higher long-term quit rates in the group receiving the tailored text messages compared with untailored text messages in the restricted analysis indicated that tailoring and higher frequency of text messages increases quit rates among young smokers.


Trends in cancer mortality in China: an update.
Cancer deaths of China with the world population nearly a quarter will have a severe impact on global cancer trend and burden. The study aims to provide a comprehensive overview of long-term trends in cancer mortality in China. We used joinpoint analysis to detect changes in trends and generalized additive models to study birth cohort effect of risk factors between 1987 and 2009. Mortality of all cancers declined steadily in urban areas, but not in rural areas. Decreasing mortality from cancers of the stomach, esophagus, nasopharynx, and cervix uteri was observed, while lung and female breast cancer mortality increased. Mortality from leukemia remained relatively stable, and cancer of liver, colorectal, and bladder had different trends between the rural and urban areas. Generational risks peaked in the cohorts born around 1925-1930 and tended to decline in successive cohorts for most cancers except for leukemia, whose relative risks were rising in the very recent cohorts. The observed trends primarily reflect dramatic changes in socioeconomic development and lifestyle in China over the past two decades, and mortality from cancers of lung and female breast still represents a major public health priority for the government.


Knox meets Cox: adapting epidemiological space-time statistics to demographic studies.
Many important questions and theories in demography focus on changes over time, and on how those changes differ over geographic and social space. Space-time analysis has always been important in studying fertility transitions, for example. However demographers have seldom used formal statistical methods to describe and analyze time series of maps. One formal method, used widely in epidemiology, criminology, and public health, is Knox 's space-time interaction test. In this article, we discuss the potential of the Knox test in demographic research and note some possible pitfalls. We demonstrate how to use familiar proportional hazards models to adapt the Knox test for demographic applications. These adaptations allow for nonrepeatable events and for the incorporation of structural variables that change in space and time. We apply the modified test to data on the onset offertility decline in Brazil over 1960-2000 and show how the modified method can produce maps indicating where and when diffusion effects seem strongest, net of covariate effects.


FOXO1 and ETV6 genes may represent novel regulators of splicing factor expression in cellular senescence.
Cellular plasticity is a key facet of cellular homeostasis requiring correct temporal and spatial patterns of alternative splicing. Splicing factors, which orchestrate this process, demonstrate age-related dysregulation of expression; they are emerging as potential influences on aging and longevity. The upstream drivers of these alterations are still unclear but may involve aberrant cellular signaling. We compared the phosphorylation status of proteins in multiple signaling pathways in early and late passage human primary fibroblasts. We then assessed the impact of chemical inhibition or targeted knockdown of direct downstream targets of the ERK and AKT pathways on splicing factor expression, cellular senescence, and proliferation kinetics in senescent primary human fibroblasts. Components of the ERK and AKT signaling pathways demonstrated altered activation during cellular aging. Inhibition of AKT and ERK pathways led to up-regulation of splicing factor expression, reduction in senescent cell load, and partial reversal of multiple cellular senescence phenotypes in a dose-dependent manner. Furthermore, targeted knockdown of the genes encoding the downstream targets FOXO1 or ETV6 was sufficient to mimic these observations. Our results suggest that age-associated dysregulation of splicing factor expression and cellular senescence may derive in part from altered activity of ERK and AKT signaling and may act in part through the ETV6 and FOXO1 transcription factors. Targeting the activity of downstream effectors of ERK and AKT may therefore represent promising targets for future therapeutic intervention.-Latorre, E., Ostler, E. L., Faragher, R. G. A., Harries, L. W. FOXO1 and ETV6 genes may represent novel regulators of splicing factor expression in cellular senescence.


Inactivation of thermogenic UCP1 as a historical contingency in multiple placental mammal clades.
Mitochondrial uncoupling protein 1 (UCP1) is essential for nonshivering thermogenesis in brown adipose tissue and is widely accepted to have played a key thermoregulatory role in small-bodied and neonatal placental mammals that enabled the exploitation of cold environments. We map ucp1 sequences from 133 mammals onto a species tree constructed from a ~51-kb sequence alignment and show that inactivating mutations have occurred in at least 8 of the 18 traditional placental orders, thereby challenging the physiological importance of UCP1 across Placentalia. Selection and timetree analyses further reveal that ucp1 inactivations temporally correspond with strong secondary reductions in metabolic intensity in xenarthrans and pangolins, or in six other lineages coincided with a ~30 million-year episode of global cooling in the Paleogene that promoted sharp increases in body mass and cladogenesis evident in the fossil record. Our findings also demonstrate that members of various lineages (for example, cetaceans, horses, woolly mammoths, Steller's sea cows) evolved extreme cold hardiness in the absence of UCP1-mediated thermogenesis. Finally, we identify ucp1 inactivation as a historical contingency that is linked to the current low species diversity of clades lacking functional UCP1, thus providing the first evidence for species selection related to the presence or absence of a single gene product.


Deep vein thrombosis: update on diagnosis and management.
Diagnosis of deep vein thrombosis (DVT) requires a multifaceted approach that includes clinical assessment, evaluation of pre-test probability, and objective diagnostic testing. Common symptoms and signs of DVT are pain, swelling, erythema and dilated veins in the affected limb. The pre-test probability of DVT can be assessed using a clinical decision rule that stratifies DVT into "unlikely" or "likely". If DVT is "unlikely", refer for D-dimer test. If the D-dimer level is normal, DVT can be excluded; if the D-dimer level is increased, refer for compression ultrasound. If DVT is "likely", refer for compression ultrasound. When DVT is confirmed, anticoagulation is indicated to control symptoms, prevent progression and reduce the risk of post-thrombotic syndrome and pulmonary embolism. Anticoagulation may consist of a parenteral anticoagulant overlapped by warfarin or followed by a direct oral anticoagulant (DOAC) (dabigatran or edoxaban), or of a DOAC (apixaban or rivaroxaban) without initial parenteral therapy. DOACs are the preferred treatment for DVT because they are at least as effective, safer and more convenient than warfarin. DOACs may require dose reduction or avoidance in patients with renal dysfunction, and should be avoided in pregnancy. Recent evidence shows that DVT in patients with cancer may be treated with edoxaban (after discontinuation of 5 days of initial heparin or low molecular weight heparin [LMWH]) or rivaroxaban if patients prefer not to have daily injections of LMWH, but the risk of gastrointestinal bleeding is higher with DOACs than with LMWH in patients with gastrointestinal cancer.


How many well-baby visits are necessary in the first 2 years of life?
Since we could find no scientific basis for the 10 well-baby visits recommended in the first 2 years of life in Ontario, we carried out a randomized trial in 570 healthy, low-risk newborns to determine the efficacy and safety of decreasing the number of scheduled well-baby visits from 10 to 5. Among the 466 babies still in the trial at the end of the study period those in the 10-visit group had had a mean of 7.63 scheduled and 0.26 unscheduled well-baby visits and those in the 5-visit group a mean of 4.77 scheduled and 1.42 unscheduled well-baby visits. Reducing the recommended number of visits did not result in an increased incidence of illness or an increased prevalence of undetected abnormality, and the physical development of the babies in the two groups was almost identical. The mean scores of the two groups in assessments of mental development, maternal-child relations, maternal anxiety and parental satisfaction with health care were close. The results suggest that the recommended number of well-baby visits for healthy, low-risk newborns can be reduced to five for children of multiparas and six for children of primiparas. Any additional well-baby visits should be scheduled according to the needs and experience of the parents.


Identifying knowledge gaps in seagrass research and management: An Australian perspective.
Seagrass species form important marine and estuarine habitats providing valuable ecosystem services and functions. Coastal zones that are increasingly impacted by anthropogenic development have experienced substantial declines in seagrass abundance around the world. Australia, which has some of the world's largest seagrass meadows and is home to over half of the known species, is not immune to these losses. In 1999 a review of seagrass ecosystems knowledge was conducted in Australia and strategic research priorities were developed to provide research direction for future studies and management. Subsequent rapid evolution of seagrass research and scientific methods has led to more than 70% of peer reviewed seagrass literature being produced since that time. A workshop was held as part of the Australian Marine Sciences Association conference in July 2015 in Geelong, Victoria, to update and redefine strategic priorities in seagrass research. Participants identified 40 research questions from 10 research fields (taxonomy and systematics, physiology, population biology, sediment biogeochemistry and microbiology, ecosystem function, faunal habitats, threats, rehabilitation and restoration, mapping and monitoring, management tools) as priorities for future research on Australian seagrasses. Progress in research will rely on advances in areas such as remote sensing, genomic tools, microsensors, computer modeling, and statistical analyses. A more interdisciplinary approach will be needed to facilitate greater understanding of the complex interactions among seagrasses and their environment.


A human (3.3 kb) haptoglobin-CAT transgene is modulated in lungs of transgenic mice by inflammation.
Four independent lines of transgenic mice were produced carrying integrated copies of a chimeric gene composed of 3.3 kb of the human haptoglobin 5' regulatory region fused to the CAT (chloramphenicol acetyl transferase) reporter gene. Although the endogenous mouse haptoglobin (Hp) and human haptoglobin (HP) genes express mainly in liver and lung, expression of the human 3.3-kb HP-CAT transgene was not detected until after induction of inflammation and then only in lungs. The results indicated that the transgene maintained the regulatory DNA elements required for lung specific responsiveness to inflammation in vivo but lacked the DNA sequence required for robust expression in liver. The DNA sequence(s) responsible for the normally high level of HP expression in liver either reside outside the 3.3-kb regulatory region of the HP chimeric gene or this region contains a suppressor sequence affecting tissue specific expression in the liver.


Value of 3 Tesla diffusion-weighted magnetic resonance imaging for assessing liver fibrosis.
Limited data are available regarding the role of magnetic resonance imaging (MRI), particularly the new generation 3 Tesla technology, and especially diffusion-weighted imaging (DWI) in predicting liver fibrosis. The aim of our pilot study was to assess the clinical performance of the apparent diffusion coefficient (ADC) of liver parenchyma for the assessment of liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). 18 patients with biopsy-proven NAFLD underwent DWI with 3 Tesla MRI. DWI was performed with single-shot echo-planar technique at b values of 0-500 and 0-1000 s/mm2. ADC was measured in four locations in the liver and the mean ADC value was used for analysis. Staging of fibrosis was performed according to the METAVIR system. The median age of patients was 52 years (range 23-73). The distribution of patients in different fibrosis stages was: 0 (n=1), 1 (n=7), 2 (n=1), 3 (n=5), 4 (n=4). Fibrosis stage was poorly associated with ADC at b value of 0-500 s/mm2 (r= -0.30, P=0.27). However it was significantly associated with ADC at b value of 0-1000 s/mm2 (r= -0.57, P=0.01). For this b value (0-1000 s/mm2) the area under receiver-operating characteristic curve was 0.93 for fibrosis stage ≥3 and the optimal ADC cut-off value was 1.16 ×10-3 mm2/s. 3 Tesla DWI can possibly predict the presence of advanced fibrosis in patients with NAFLD.


Development and application of a chronic kidney disease-specific health literacy, knowledge and disease awareness assessment tool for patients with chronic kidney disease in Taiwan.
This study aims to develop an assessment tool for health literacy and knowledge specific to chronic kidney disease (CKD) for use in examining the associations between health literacy, disease-specific knowledge and disease awareness among patients with CKD in Taiwan. An assessment tool in Mandarin and Taiwanese was developed based on patient input, panel discussions with experts and a literature review, and checked for validity and reliability in a pilot test. Formal data were collected through population-based sampling with a set quota according to region and hospital accreditation level. Cross-sectional data were collected to confirm the reliability and validity of the assessment tool. Levels of health literacy, disease knowledge, and disease awareness were then reported and analysed. Sample hospitals included 10 medical centres, 18 regional hospitals and 15 local hospitals in Taiwan. Researchers were granted Internal Review Board approval and obtained agreement to collect data in all study settings. Patients at least 20 years old who had been diagnosed with CKD of any stage were eligible to participate. The formal assessment collected 1155 valid questionnaires, yielding an 87.3% response rate. The mean age of participants was 67.48 years (SD=12.87, range 22-98), while 484 (41.95%) were female and 78% were aware they had CKD. The self-devised instrument proved to have excellent reliability and validity. Use of the instrument in the main study showed that CKD-specific health literacy was significantly associated with age (β=-0.33, p<0.00), educational attainment and disease awareness (β=0.13, p<0.00). CKD-specific knowledge was also significantly associated with age (β=-0.18, p<0.00), educational attainment and disease awareness (β=0.19, p<0.00). This CKD-specific health literacy and knowledge assessment tool developed for Mandarin and Taiwanese-speaking patients is reliable and well validated. Patients with CKD who are aware of and understand their disease performed better in the assessment.


Micro-Surface and -Interfacial Tensions Measured Using the Micropipette Technique: Applications in Ultrasound-Microbubbles, Oil-Recovery, Lung-Surfactants, Nanoprecipitation, and Microfluidics.
This review presents a series of measurements of the surface and interfacial tensions we have been able to make using the micropipette technique. These include: equilibrium tensions at the air-water surface and oil-water interface, as well as equilibrium and dynamic adsorption of water-soluble surfactants and water-insoluble and lipids. At its essence, the micropipette technique is one of capillary-action, glass-wetting, and applied pressure. A micropipette, as a parallel or tapered shaft, is mounted horizontally in a microchamber and viewed in an inverted microscope. When filled with air or oil, and inserted into an aqueous-filled chamber, the position of the surface or interface meniscus is controlled by applied micropipette pressure. The position and hence radius of curvature of the meniscus can be moved in a controlled fashion from dimensions associated with the capillary tip (~5⁻10 μm), to back down the micropipette that can taper out to 450 μm. All measurements are therefore actually made at the microscale. Following the Young⁻Laplace equation and geometry of the capillary, the surface or interfacial tension value is simply obtained from the radius of the meniscus in the tapered pipette and the applied pressure to keep it there. Motivated by Franklin's early experiments that demonstrated molecularity and monolayer formation, we also give a brief potted-historical perspective that includes fundamental surfactancy driven by margarine, the first use of a micropipette to circuitously measure bilayer membrane tensions and free energies of formation, and its basis for revolutionising the study and applications of membrane ion-channels in Droplet Interface Bilayers. Finally, we give five examples of where our measurements have had an impact on applications in micro-surfaces and microfluidics, including gas microbubbles for ultrasound contrast; interfacial tensions for micro-oil droplets in oil recovery; surface tensions and tensions-in-the surface for natural and synthetic lung surfactants; interfacial tension in nanoprecipitation; and micro-surface tensions in microfluidics.


HGF is an autocrine growth factor for skeletal muscle satellite cells in vitro.
Muscle satellite cell activation following injury is essential for muscle repair, and hepatocyte growth factor/scatter factor (HGF) was the first growth factor shown to be able to stimulate activation and early division of adult satellite cells in culture and in muscle tissue. In addition, HGF was shown to be present in uninjured and injured skeletal muscle. Experiments in this report demonstrate that cultured satellite cells also synthesize and secrete HGF. Reverse transcription-polymerase chain reaction (RT-PCR) was used to demonstrate the presence of HGF mRNA in cultured adult satellite cells as early as 12 h from the time of plating. Message content was detectable at early times in culture and appeared to increase between 36 and 48 h. HGF protein expression was demonstrated during this time period by immunofluorescence localization; HGF was localized to mononucleated cells and multinucleated myotubes. HGF message was not detectable in muscle-derived fibroblast clones, and fibroblast-like cells in satellite cell cultures were negative for HGF by immunofluorescence analysis. Furthermore, Western blot analysis revealed the presence of HGF in satellite cell culture conditioned medium, associated with the cell surface and inside cells. Finally, the addition of neutralizing HGF antibodies during the proliferation phase in culture (42-90 h) significantly reduced cell proliferation. These experiments indicate that HGF is expressed by cultured satellite cells and that endogenous HGF from satellite cells can act in an autocrine fashion. Because HGF plays a central role in satellite cell activation, it is likely that direct administration of HGF into damaged muscle may represent a potentially useful approach for stimulating muscle repair. This approach may also be useful in enhancing the efficiency of myoblast transplantation in vivo.


Global longitudinal strain, myocardial storage and hypertrophy in Fabry disease.
Detecting early cardiac involvement in Fabry disease (FD) is important because therapy may alter disease progression. Cardiovascular magnetic resonance (CMR) can detect T1 lowering, representing myocardial sphingolipid storage. In many diseases, early mechanical dysfunction may be detected by abnormal global longitudinal strain (GLS). We explored the relationship of early mechanical dysfunction and sphingolipid deposition in FD. An observational study of 221 FD and 77 healthy volunteers (HVs) who underwent CMR (LV volumes, mass, native T1, GLS, late gadolinium enhancement), ECG and blood biomarkers, as part of the prospective multicentre Fabry400 study. All FD had normal LV ejection fraction (EF 73%±8%). Mean indexed LV mass (LVMi) was 89±39 g/m2 in FD and 55.6±10 g/m2 in HV. 102 (46%) FD participants had left ventricular hypertrophy (LVH). There was a negative correlation between GLS and native T1 in FD patients (r=-0.515, p<0.001). In FD patients without LVH (early disease), as native T1 reduced there was impairment in GLS (r=-0.285, p<0.002). In the total FD cohort, ECG abnormalities were associated with a significant impairment in GLS compared with those without ECG abnormalities (abnormal: -16.7±3.5 vs normal: -20.2±2.4, p<0.001). GLS in FD correlates with an increase in LVMi, storage and the presence of ECG abnormalities. In LVH-negative FD (early disease), impairment in GLS is associated with a reduction in native T1, suggesting that mechanical dysfunction occurs before evidence of sphingolipid deposition (low T1). NCT03199001; Results.


Measurement of endothelial permeability to 125I-low density lipoproteins in rabbit arteries by use of en face preparations.
A procedure of en face quantitative autoradiography of the endothelium (Hautchen preparations) was developed to examine regional variations in 125I-low density lipoprotein (125I-LDL) permeability in the arterial wall in vivo. Endothelial preparations from fixed arterial tissue and calibration standards consisting of known concentrations of 125I-albumin were dipped in nuclear emulsion, exposed for 1-3 months, developed, and stained with hematoxylin. Digital image analysis was used to analyze dark-field images of autoradiographs. Background grain densities on cold endothelial preparations were 30-100% higher than on glass, but the variability in grain densities on the two different surfaces was similar. Regression slopes of grain density versus concentration for calibration standards were the same for sections placed on cold tissue or glass. For 1-5-microns-thick calibration standards of the same concentration, the grain density was proportional to the total amount of radioactivity per unit area. The results indicated that errors arising from nonuniformities in preparation thickness were minimal, and permeabilities and intimal concentrations could be determined. Rabbits were killed 10 minutes after injection of 125I-LDL, and endothelial preparations were made. For regions of uniformly low grain density in the rabbit aorta, the 125I-LDL permeability was 1.9 +/- 0.8 x 10(-8) cm/sec, and the effective diffusion coefficient was 5.4 +/- 3.1 x 10(-10) cm2/sec. Errors in the estimated permeability arising from nonuniformities in tissue thickness were the same as the reported experimental variability. Analysis of elevated regions of permeability suggested that 125I-LDL was binding to the extracellular matrix. Approximately 25% of the sites of elevated grain density were associated with mitotic endothelial cells, and such regions had higher permeabilities than sites associated with nonmitotic cells. Around intercostal arteries, sites of highest permeability were distal and lateral to the vessels and occurred where lesions first develop in hypercholesterolemic rabbits.


Chirality sensing of choline derivatives by a triple anion helicate cage through induced circular dichroism.
Chirality sensing of choline derivatives is achieved by a self-assembled, racemic triple anion helicate cage which exhibits induced circular dichroism (ICD) upon encapsulation of a chiral guest. The host-guest interactions were illustrated by NMR, crystal structure, CD and DFT calculations. The absolute configurations and ee values were determined by ICD.


Associations between body-mass index and COVID-19 severity in 6·9 million people in England: a prospective, community-based, cohort study.
Obesity is a major risk factor for adverse outcomes after infection with SARS-CoV-2. We aimed to examine this association, including interactions with demographic and behavioural characteristics, type 2 diabetes, and other health conditions. In this prospective, community-based, cohort study, we used de-identified patient-level data from the QResearch database of general practices in England, UK. We extracted data for patients aged 20 years and older who were registered at a practice eligible for inclusion in the QResearch database between Jan 24, 2020 (date of the first recorded infection in the UK) and April 30, 2020, and with available data on BMI. Data extracted included demographic, clinical, clinical values linked with Public Health England's database of positive SARS-CoV-2 test results, and death certificates from the Office of National Statistics. Outcomes, as a proxy measure of severe COVID-19, were admission to hospital, admission to an intensive care unit (ICU), and death due to COVID-19. We used Cox proportional hazard models to estimate the risk of severe COVID-19, sequentially adjusting for demographic characteristics, behavioural factors, and comorbidities. Among 6 910 695 eligible individuals (mean BMI 26·78 kg/m2 [SD 5·59]), 13 503 (0·20%) were admitted to hospital, 1601 (0·02%) to an ICU, and 5479 (0·08%) died after a positive test for SARS-CoV-2. We found J-shaped associations between BMI and admission to hospital due to COVID-19 (adjusted hazard ratio [HR] per kg/m2 from the nadir at BMI of 23 kg/m2 of 1·05 [95% CI 1·05-1·05]) and death (1·04 [1·04-1·05]), and a linear association across the whole BMI range with ICU admission (1·10 [1·09-1·10]). We found a significant interaction between BMI and age and ethnicity, with higher HR per kg/m2 above BMI 23 kg/m2 for younger people (adjusted HR per kg/m2 above BMI 23 kg/m2 for hospital admission 1·09 [95% CI 1·08-1·10] in 20-39 years age group vs 80-100 years group 1·01 [1·00-1·02]) and Black people than White people (1·07 [1·06-1·08] vs 1·04 [1·04-1·05]). The risk of admission to hospital and ICU due to COVID-19 associated with unit increase in BMI was slightly lower in people with type 2 diabetes, hypertension, and cardiovascular disease than in those without these morbidities. At a BMI of more than 23 kg/m2, we found a linear increase in risk of severe COVID-19 leading to admission to hospital and death, and a linear increase in admission to an ICU across the whole BMI range, which is not attributable to excess risks of related diseases. The relative risk due to increasing BMI is particularly notable people younger than 40 years and of Black ethnicity. NIHR Oxford Biomedical Research Centre.


Western blot analysis of the reactivity between envelope proteins of hepatitis B viruses from Brazilian carriers and antibodies raised against recombinant hepatitis B vaccines.
A Western blot assay was standardized to evaluate the antigenic reactivity of hepatitis B virus (HBV) strains circulating in Brazilian population with antibodies raised against recombinant hepatitis B (HB) vaccines. In this assay, HBV envelope proteins from infected human blood were detected by antibodies from rabbits immunized with either of two recombinant vaccines. These were Engerix B (Smith Kline Beecham, Belgium) containing exclusively S protein particles and TGP-943 (Takeda Chemical Industries, Japan) containing M protein particles. Forty-seven serum samples, presenting HB surface antigen. (HBsAg) reverse passive haemagglutination assay (RPHA) titers ranging from 1:32 to > or =1:4096 after HBV particles concentration, were tested. Twenty-seven samples were from acute hepatitis cases and 20 were from chronic cases (11 from cirrhotic patients and 9 from asymptomatic carriers). Four HBV serotypes, adw2, adw4, ayw2 and ayw3, were identified in these samples. Infectivity of these sera was evaluated by HBV DNA detection by polymerase chain reaction (PCR). HBV DNA was present in 62% of samples from acute cases and in all samples from chronic cases. Despite the differences between serotypes, genotypes, forms of infection, and infectivity of the samples, antibodies against both vaccines reacted with HBV envelope proteins from all but one sample. In one sample from cirrhotic patient, only a small protein of unexpected size reacted with TGP-943 antibodies.


Comparative genomic analysis of isoproturon-mineralizing sphingomonads reveals the isoproturon catabolic mechanism.
The worldwide use of the phenylurea herbicide, isoproturon (IPU), has resulted in considerable concern about its environmental fate. Although many microbial metabolites of IPU are known and IPU-mineralizing bacteria have been isolated, the molecular mechanism of IPU catabolism has not been elucidated yet. In this study, complete genes that encode the conserved IPU catabolic pathway were revealed, based on comparative analysis of the genomes of three IPU-mineralizing sphingomonads and subsequent experimental validation. The complete genes included a novel hydrolase gene ddhA, which is responsible for the cleavage of the urea side chain of the IPU demethylated products; a distinct aniline dioxygenase gene cluster adoQTA1A2BR, which has a broad substrate range; and an inducible catechol meta-cleavage pathway gene cluster adoXEGKLIJC. Furthermore, the initial mono-N-demethylation genes pdmAB were further confirmed to be involved in the successive N-demethylation of the IPU mono-N-demethylated product. These IPU-catabolic genes were organized into four transcription units and distributed on three plasmids. They were flanked by multiple mobile genetic elements and highly conserved among IPU-mineralizing sphingomonads. The elucidation of the molecular mechanism of IPU catabolism will enhance our understanding of the microbial mineralization of IPU and provide insights into the evolutionary scenario of the conserved IPU-catabolic pathway.


Age-based demographic and reproductive assessment of orangespine Naso lituratus and bluespine Naso unicornis unicornfishes.
Bluespine unicornfish Naso unicornis and orangespine unicornfish Naso lituratus were sampled in Pohnpei and Guam, Micronesia, over 13 months to identify reproductive and age-based demographic features necessary for informed management. Age and reproductive information were derived from analysis of sagittal otoliths and gonads. Both species had moderate life spans [maximum ages of 23 (N. unicornis) and 14 years (N. lituratus)] compared with published estimates of conspecifics from other locations (>30 years) and of other Naso species. Length at maturation for N. unicornis was similar between Pohnpei and Guam while females consistently matured at a larger size [c. 30 cm fork length (LF )] than males (c. 27 cm LF ). This sex-specific pattern was reversed in N. lituratus for which estimates of maturation length (females: 15 cm LF ; males: 18 cm LF ) were only obtained from Guam. Developmental patterns in female gonads of both species suggested that initiation of maturation occurs very early. Growth patterns of N. lituratus displayed rapid asymptotic growth compared with N. unicornis and other congeners as well as slight sex-specific patterns of length-at-age. Results highlight the considerable spatial variation that may occur in the population biology of these species across various scales. Additionally, proper management remains complicated without improved knowledge of fishery trends and reproductive behaviour in unicornfishes, species that are prime fishery targets in Micronesia and elsewhere.


Cis-dichlorodiammineplatinum upregulates angiotensin II type 1 receptors through reactive oxygen species generation and enhances VEGF production in bladder cancer.
We previously reported that angiotensin II type 1 receptor (AT1R) antagonists enhanced the cytotoxity of cis-dichlorodiammineplatinum (CDDP) in a bladder cancer xenograft model. To elucidate the synergistic mechanism, we investigated whether reactive oxygen species (ROS) generation induced by CDDP may affect the regulation of AT1R expression. Five invasive human bladder cancer cell lines, T24, UMUC-3, 5637, KU-1, and KU-19-19, were used in the in vitro study. For the in vivo study, T24 cells were used. We also examined AT1R and vascular endothelial growth factor (VEGF) expression in human bladder cancer specimens that had been treated with CDDP-based chemotherapy. The in vitro study showed that AT1R expression was significantly upregulated by CDDP in T24, KU-1, and KU-19-19 cells. On the other hand, AT1R expression was not changed in UMUC-3 and 5637 cells. ROS generation was also significantly upregulated by CDDP in T24, KU-1, and KU-19-19 cells. The upregulation of AT1R expression induced by CDDP was significantly suppressed by scavenging free radicals. Angiotensin II induced VEGF production in CDDP-treated cells; however, the AT1R antagonist significantly inhibited the increase in VEGF. The in vivo study results also showed that CDDP treatment upregulated AT1R expression, resulting in increased VEGF. Clinical specimens from patients who underwent cystectomy after neoadjuvant CDDP-based chemotherapy showed significantly higher AT1R and VEGF expression than corresponding transurethral resection specimens. Our findings indicate that CDDP upregulates AT1R expression though ROS generation and enhances VEGF production. Therefore, AT1R blockade may be an effective strategy for bladder cancer in combination with CDDP-based chemotherapy.


Diffusion-weighted MRI: distinction of skull base chordoma from chondrosarcoma.
Chordoma and chondrosarcoma of the skull base are rare tumors with overlapping presentations and anatomic imaging features but different prognoses. We hypothesized that these tumors might be distinguished by using diffusion-weighted MR imaging. We retrospectively reviewed 19 patients with pathologically confirmed chordoma or chondrosarcoma who underwent both conventional and diffusion-weighted MR imaging. Differences in distributions of ADC were assessed by the Kruskal-Wallis test. Associations between histopathologic diagnosis and conventional MR imaging features (T2 signal intensity, contrast enhancement, and tumor location) were assessed with the Fisher exact test. Chondrosarcoma was associated with the highest mean ADC value (2051 ± 261 × 10(-6) mm(2)/s) and was significantly different from classic chordoma (1474 ± 117 × 10(-6) mm(2)/s) and poorly differentiated chordoma (875 ± 100 × 10(-6) mm(2)/s) (P < .001). Poorly differentiated chordoma was characterized by low T2 signal intensity (P = .001), but other conventional MR imaging features of enhancement and/or lesion location did not reliably distinguish these tumor types. Diffusion-weighted MR imaging may be useful in assessing clival tumors, particularly in differentiating chordoma from chondrosarcoma. A prospective study of a larger cohort will be required to determine the value of ADC in predicting histopathologic diagnosis.


The cardiac muscle duplex as a method to study myocardial heterogeneity.
This paper reviews the development and application of paired muscle preparations, called duplex, for the investigation of mechanisms and consequences of intra-myocardial electro-mechanical heterogeneity. We illustrate the utility of the underlying combined experimental and computational approach for conceptual development and integration of basic science insight with clinically relevant settings, using previously published and new data. Directions for further study are identified.


Electrocatalytic Oxidation of Alcohols, Tripropylamine, and DNA with Ligand-Free Gold Nanoclusters on Nitrided Carbon.
Electrocatalytic properties of ligand-free gold nanoclusters (AuNCs, <2 nm) grown on nitrided carbon supports (denoted as AuNCs@N-C) were evaluated for the oxidation of representative organic molecules including alcohols, an amine, and deoxyguanosine in oligonucleotides. AuNCs@N-C catalysts were incorporated into films of architecture {PDDA/AuNCs@N-C} n by using layer-by-layer assembly with oppositely charged poly(diallyldimethylammonium) (PDDA) on pyrolytic graphite (PG) electrodes. Cyclic voltammetry and electrochemical impedance spectroscopy (EIS) were used to survey the electrocatalytic properties of these AuNCs@N-C films. Ligand-free AuNCs in these films demonstrated excellent electrocatalytic oxidation activity with maximum peak currents and the lowest potentials for oxidizing ethanol, propanol, and tripropylamine (TprA) compared to controls with Au-surface capping agents or to larger sized Au nanocrystals on the nitrided carbon supports. EIS kinetic studies showed that ligand-free AuNCs films have the smallest charge-transfer resistance, largest electrochemically active surface area, and largest apparent standard rate constants, as compared to the control films for all compounds examined. DNA films on AuNCs@N-C were oxidized at deoxyguanosine moieties with good catalytic activity that depended on charge transport within the films.


Risk factors of excessive daytime sleepiness in a prospective population-based cohort.
Although excessive daytime sleepiness is commonly evaluated in clinical and research settings using the Epworth Sleepiness Scale, few studies have assessed the factors associated with its incidence in the general population. We prospectively investigated the predictors of incident and persistent excessive daytime sleepiness in 2,751 subjects (46.1% men, mean age 56.0 ± 9.8 years) from the CoLaus-PsyCoLaus population-based cohort (Lausanne, Switzerland) over 5 years. Participants completed the Epworth Sleepiness Scale and the Pittsburgh Sleep Quality Index, and underwent a full clinical evaluation at baseline and 5 years afterwards. Ambulatory polysomnography was performed at baseline in a sub-sample of 1,404 subjects. Among the 2,438 subjects without excessive daytime sleepiness (Epworth Sleepiness Scale ≤ 10) at baseline, the 5-year incidence of excessive daytime sleepiness was 5.1% (n = 124). Multivariate logistic regression revealed that male sex, depressive symptoms, reported poor sleep quality and moderate to severe obstructive sleep apnea were independent predictors of incident excessive daytime sleepiness, while older age, moderate coffee consumption, periodic leg movement during sleep and hypertension were independent protective factors. Stratified analysis according to sex and age showed some distinctive associations. Among the 313 patients with excessive daytime sleepiness at baseline, 137 (43.8%) had persistent excessive daytime sleepiness 5 years later. Our findings provide new insights into the predictors of incident excessive daytime sleepiness, but interventional studies are needed to understand the impact of treating these risk factors on the incidence of excessive daytime sleepiness.


Molecular crypsis by pathogenic fungi using human factor H. A numerical model.
Molecular mimicry is the formation of specific molecules by microbial pathogens to avoid recognition and attack by the immune system of the host. Several pathogenic Ascomycota and Zygomycota show such a behaviour by utilizing human complement factor H to hide in the blood stream. We call this type of mimicry molecular crypsis. Such a crypsis can reach a point where the immune system can no longer clearly distinguish between self and non-self cells. Thus, a trade-off between attacking disguised pathogens and erroneously attacking host cells has to be made. Based on signalling theory and protein-interaction modelling, we here present a mathematical model of molecular crypsis of pathogenic fungi using the example of Candida albicans. We tackle the question whether perfect crypsis is feasible, which would imply that protection of human cells by complement factors would be useless. The model identifies pathogen abundance relative to host cell abundance as the predominant factor influencing successful or unsuccessful molecular crypsis. If pathogen cells gain a (locally) quantitative advantage over host cells, even autoreactivity may occur. Our new model enables insights into the mechanisms of candidiasis-induced sepsis and complement-associated autoimmune diseases.


Role of oxidative stress and Ca²⁺ signaling on molecular pathways of neuropathic pain in diabetes: focus on TRP channels.
Diabetes mellitus, a debilitating chronic disease, affects ~100 million people. Peripheral neuropathy is one of the most common early complications of diabetes in ~66 % of these patients. Altered Ca(2+) handling and Ca(2+) signaling were detected in a huge variety of preparations isolated from animals with experimentally induced type 1 and 2 diabetes as well as patients suffering from the disease. We reviewed the role of Ca(2+) signaling through cation channels and oxidative stress on diabetic neuropathic pain in sensory neurons. The pathogenesis of diabetic neuropathy involves the polyol pathway, advanced glycation end products, oxidative stress, protein kinase C activation, neurotrophism, and hypoxia. Experimental studies with respect to oxidative stress and Ca(2+) signaling, inhibitor roles of antioxidants in diabetic neuropathic pain are also summarized in the review. We hypothesize that deficits in insulin, triggers alterations of sensory neurone phenotype that are critical for the development of abnormal Ca(2+) homeostasis and oxidative stress and associated mitochondrial dysfunction. The transient receptor potential channels are a large family of proteins with six main subfamilies. The sheer number of different TRPs with distinct functions supports the statement that these channels are involved in a wide range of processes ranging in diabetic neuropathic pain and it seems that the TRPC, TRPM and TRPV groups are mostly responsible from diabetic neuropathic pain. In conclusion, the accumulating evidence implicating Ca(2+) dysregulation and over production of oxidative stress products in diabetic neuropathic pains, along with recent advances in understanding of genetic variations in cation channels such as TRP channels, makes modulation of neuronal Ca(2+) handling an increasingly viable approach for therapeutic interventions against the painful and degenerative aspects of many diabetic neuropathies.


Academic stress from the viewpoint of Iranian adolescents: A qualitative study.
Academic stress is one of the major affecting factors on adolescent health. This study investigates adolescents' view about the sources of academic stress, with which their identification could be used for the reduction of adolescent academic stress. This qualitative study was conducted with Directional Content Analysis methodology. Semi-structured interview methods were used for data collection. Participants were students aged 12-18 years old. Purposeful sampling with Opportunistic Maximum Variation Method was performed in terms of type of schools, socioeconomic classes, and gender of students. A total of 43 interviews and were conducted by two interviewers. A total of 173 codes, 11 subcategories, and 5 categories were extracted as academic stressors. The categories included family factors (32 codes); peers (18 codes); teachers, school supervisors, and educational system (72 codes); homework and test scores (32 codes); and educational assistance classes (19 codes). This study showed that students have different sources of academic stress. Awareness of their source of stress can help parents and teachers to revise their treat about students' function and policymaker to provide better planning and management for students.