The predictive value of renal vascular resistance for late renal allograft loss.
The renal artery resistance index (RI), assessed by Doppler ultrasonography, was recently identified as a new risk marker for late renal allograft loss. This finding requires confirmation since RI in that study was not measured at predetermined time points and ultrasonography is operator-dependent. We investigated the predictive value of renal vascular resistance (RVR), a less operator-dependent method as assessed by mean arterial pressure divided by renal blood flow, for the prediction of recipient mortality and death-censored graft loss. RVR was compared to commonly used risk markers such as creatinine clearance (CrCl), serum creatinine (SCreat) and proteinuria (UProt) in 793 first-time cadaveric renal transplant recipients at predetermined time points after transplantation using receiver operating characteristics (ROC) and Cox survival analyses. The present study showed that RVR is a prominent risk marker for recipient mortality and death-censored graft loss. However, the predictive value of RVR for recipient mortality owed mainly to the impact of mean arterial blood pressure. In contrast, RVR constituted more than the sum of its components for death-censored graft loss, but showed less predictive value than SCreat in univariate analysis. As the assessment of RVR is expensive and time-consuming, we believe that RVR holds no clinical merit for the follow-up of renal transplant recipients.


Outcome and characteristics of invasive fungal infections in critically ill burn patients: A multicenter retrospective study.
Characteristics and outcome of invasive fungal infection (IFI) in critically ill burn patients have been poorly explored. We report the factors associated with 90-day mortality in a multicentre retrospective European study. All burn patients with confirmed IFI admitted between 1 January 2010 to 31 December 2015 in 10 centres in France and Belgium were included. Ninety-four patients were enrolled with 110 cases of IFIs: 79 (71.8%) were yeasts IFI and 31 (28.2%) filamentous IFI. Incidence was 1% among admitted patients. The 90-day mortality was 37.2% for all IFIs combined, 52% for filamentous infection and 31.9% for yeast infection. Patients with more than one IFI had a higher 90-day mortality than patients with only one episode (61.5% vs 33.5% (P = .006)). In multivariate analysis, higher Simplified Acute Physiology Score II (OR = 1.05 (95% CI: 1.02-1.09) P = .003), bacterial co-infection (OR = 3.85 (95% CI: 1.23-12.01), P = .014) and use of skin allografts at the time of IFI diagnosis (OR = 3.87 (95% CI: 1.31-11.42), P = .021) were associated with 90-day mortality. Although rare, invasive fungal infections remain associated with poor outcome in burn patients. Bacterial co-infection and presence of allograft were potentially modifiable factors independently associated with outcome.


Interactions between Neisseria meningitidis and the complement system.
Meningococcal infection remains a worldwide health problem, and understanding the mechanisms by which Neisseria meningitidis evades host innate and acquired immunity is crucial. The complement system is vital for protecting individuals against N. meningitidis. However, this pathogen has evolved several mechanisms to avoid killing by human complement. Bacterial structures such as polysaccharide capsule and those which mimic or bind host molecules function to prevent complement-mediated lysis and phagocytosis. This review provides an update on the recent findings on the diverse mechanisms by which N. meningitidis avoids complement-mediated killing, and how polymorphisms in genes encoding human complement proteins affect susceptibility to this important human pathogen.


Clinical significance of transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant depression: synthesis of recent data.
Transcranial magnetic stimulation (TMS) is a novel treatment for patients with major depressive disorder. Although clearly safer and better tolerated than many other pharmacotherapeutic options or electroconvulsive therapy, questions have persisted about the magnitude of the efficacy of TMS in patients with pharmacoresistant depression, and the clinical significance of these outcomes. Previous studies have explored whether specific patient characteristics are associated with a greater likelihood of clinical benefit. In the largest such analysis conducted to date, the authors confirmed previous observations that the lower the number of prior failed antidepressant treatments, the better the clinical outcome of treatment with TMS. This relationship between prior treatment resistance and subsequent treatment outcome is consistent with previous evidence from antidepressant studies. The authors examined the clinical significance of the treatment effects seen with TMS in pharmacoresistant major depression in their recently completed studies by comparing these outcomes with the results reported in several large, comprehensive published reference datasets of antidepressant medications studied in both treatment-responsive and treatment-resistant patient populations. The efficacy of TMS demonstrated in randomized controlled trials was comparable to that of pharmaceutical antidepressants studied in similarly designed registration trials and to the adjunctive use of atypical antipsychotic medications in controlled trials of antidepressant non-responders. These data may be helpful in treatment-planning decisions when using TMS in clinical practice.


Receptivity to cigarette and tobacco control messages and adolescent smoking initiation.
Tobacco industry cigarette advertising is associated with increased adolescent smoking, while counter tobacco advertising is associated with reduced smoking. As these campaigns compete for influence, there is a need to understand their inter-relationship on youth smoking. This study reports data from a national population of families (n=1036) with an oldest child aged 10-13 years, identified by random digit dialling. Parent and child dyads completed baseline questionnaires in 2003. Adolescents were resurveyed in 2007-2008 (response rate 74%). Adjusted logistic regression explores associations between receptivity to cigarette and tobacco control advertising and adolescent smoking initiation. In 2007-2008, 57.9% of adolescents reported a favourite tobacco control advertisement and 43.3% reported being receptive to cigarette advertisements. Thirty per cent reported receptivity to cigarette and tobacco control advertisements. Among those receptive to cigarette advertising, having a favourite anti-smoking advertisement had a borderline significant association with a 30% lower smoking rate. Anti-industry tobacco control messages were three times more likely to be favourites of those who were receptive to cigarette advertising than other tobacco control advertising. Receptivity to tobacco control advertising appeared to ameliorate the promotion of initiation from cigarette advertising. Anti-industry advertising appears to be the most effective counter for tobacco control and should be considered for wider use. A larger longitudinal study is needed to confirm these findings.


Infant feeding practice and associated factors of HIV positive mothers attending prevention of mother to child transmission and antiretroviral therapy clinics in Gondar Town health institutions, Northwest Ethiopia.
It has been estimated that 430,000 children under 15 years of age were newly infected with HIV in 2008, and more than 71% are living in sub-Saharan Africa. In the absence of intervention to prevent mother-to-child transmission, 30-45% of infants born to HIV-positive mothers in developing countries become infected during pregnancy, delivery and breastfeeding. The aim of this study was to assess infant feeding practice and associated factors of HIV positive mothers attending prevention of mother to child transmission and antiretroviral therapy clinics of Northwest Ethiopia. Institution based cross sectional study was conducted from January to May 2011 among all HIV positive mothers with less than two years old child attending prevention of mother to child transmission and antiretroviral therapy clinics in Gondar Town health institutions. A structured pre-tested questionnaire using interview technique was used for data collection. The data was entered and analyzed using SPSS version 16 statistical package. A total of 209 HIV positive mothers were included in the study. Of these, 187 (89.5%) had followed the recommended way of infant feeding practice while significant percentage (10.5%) had practiced mixed breast feeding. In multivariate analysis, disclosure of HIV status with their spouse, insufficient breast milk and occupational status were found to be independently associated (p-value of < 0.05) with recommended infant feeding practice. Lack of resource, stigma of HIV/AIDS, and husband opposition were also obtained as factors that influenced choice of infant feeding options by respondents. Higher proportion of respondents used the recommended way of infant feeding practice by WHO as well as by Ethiopian Ministry of Health. However, mixed feeding in the first 6 months of age, an undesirable practice in infant feeding, were reported in this study. Infant feeding education that is aligned to national policy should be strengthened in primary health care, particularly in situations where prevention of mother to child transmission of HIV is prioritized.


Metagenomic biomarker discovery and explanation.
This study describes and validates a new method for metagenomic biomarker discovery by way of class comparison, tests of biological consistency and effect size estimation. This addresses the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities, which is a central problem to the study of metagenomics. We extensively validate our method on several microbiomes and a convenient online interface for the method is provided at http://huttenhower.sph.harvard.edu/lefse/.


Value and impact of necropsy in paediatric cardiology.
To assess the current value of necropsy in paediatric cardiology and cardiothoracic surgery and determine its potential impact on clinical practice. Descriptive study of all paediatric cardiac deaths occurring over four years in a tertiary referral centre. Data were obtained from reviewing the hospital files, available necropsy records and specimens, and audit reports. Paediatric patients with congenital or acquired heart disease, who died of a cardiac cause between January 1992 and July 1995. Inclusion criteria were that the diagnosis of heart disease was made before death, and that patients were managed thereafter medically and/or surgically at the referral centre. The value of necropsy was assessed according to its contribution in establishing the cause of death (confirmed, clarified, precise cause of death uncertain) and the anatomy (simple confirmation or additional information provided). For cases not submitted to necropsy the clinical information relating to the cause of death was assessed and the case assigned as cause of death firm, uncertain, or unknown. One hundred and six deaths were identified (61 males, age at death: one day to 20 years). Seventy occurred early (a month or less) after surgery and were graded as postoperative deaths. The rest were considered to be either medical or late surgical deaths. Necropsy was performed in 59 (55.6%). The precise cause of death was confirmed in 33 (55.9%), clarified in 22 (37.3%), and remained uncertain in four (7.8%). Additional information regarding the anatomy was found in eight (13.6%) cases. In five cases (8.5%) the necropsy detected findings which, if known before death, would probably have improved outcome. For the patients dying without a necropsy, the cause of death remained uncertain in 10 (21.3%) and unknown in seven (14.9%). In 36% of cases, therefore, a firm cause of death that might have been provided by a necropsy was missing. In paediatric cardiology necropsy continues to provide clinically relevant information at a high level. It remains vital for ensuring quality of medical care, in instigating improvements in future management, and increasing understanding of congenital heart disease. The procedure should therefore be sought actively in all cases.


Suicide in older people without psychiatric disorder.
To determine the psychological characteristics and nature of life problems, including physical illness, in people 60 years and over dying through suicide in the absence of psychiatric disorder. Psychological autopsy interviews with relatives and friends for 23 people aged 60 years or over who had died through suicide and did not have a psychiatric disorder at the time of death. Three (13%) of the sample had significant psychiatric symptoms, one had a diagnosis of personality disorder, and ten (43.5%) had significantly abnormal personality traits. Physical illness and recent bereavement were the commonest life problems associated with suicide. Five (21.7%) of the sample were suffering from severe physical illness at the time of death. Sub-syndromal psychiatric disorder may be less important than personality factors, physical illness, and recent bereavement as important contributory factors to suicide in older people not suffering from psychiatric illness at the time of death.


Lysine triggers apoptosis through a NADPH oxidase-dependent mechanism in human renal tubular cells.
Progressive chronic kidney disease (CKD) is common in lysinuric protein intolerance (LPI), a primary inherited aminoaciduria characterized by massive Lysine excretion in urine. However, by which mechanisms Lysine may cause kidney damage to tubule cells is still not understood. This study determined whether Lysine overloading of human proximal tubular cells (HK-2) in culture enhances apoptotic cell loss and its associated mechanisms. Overloading HK-2 with Lysine levels reproducing those observed in urine of patients affected by LPI (10 mM) increased apoptosis (+30%; p < 0.01 vs.C), as well as Bax and Apaf-1 expressions (+30-50% p < 0.05), while downregulated Bcl-2 (-40% p < 0.05). Apoptosis induced by high Lysine was no longer observed after addition of caspase-9 and caspase-3 inhibitors while caspase-8 inhibitor had no protective effect. High Lysine induced elevations in ROS generation and NADPH oxidase subunits mRNAs (p22 (phox) +106 ± 23%, p67 (phox) +108 ± 22% and gp91 (phox) +75 ± 4% p < 0.05-0.01). In addition, the NADPH oxidase inhibitor DPI prevented both ROS production and apoptosis. Treating HK-2 with antioxidants, such as Cysteine and its analog, N-acetyl-L-cysteine (NAC), rescued the HK-2 from apoptosis induced by Lysine. In summary, our data show that high Lysine in vitro increases the permissiveness of proximal tubule kidney cells to apoptosis by triggering a pathway involving NADPH oxidase signaling. This event may represent a key cellular effect in the increasing the susceptibility of human tubular cells to apoptosis when the tubules cope with a high Lysine load. This effect is instrumental to renal damage and disease progression in patients with LPI.


Pornography, sexual socialization, and satisfaction among young men.
In spite of a growing presence of pornography in contemporary life, little is known about its potential effects on young people's sexual socialization and sexual satisfaction. In this article, we present a theoretical model of the effects of sexually explicit materials (SEM) mediated by sexual scripting and moderated by the type of SEM used. An on-line survey dataset that included 650 young Croatian men aged 18-25 years was used to explore empirically the model. Descriptive findings pointed to significant differences between mainstream and paraphilic SEM users in frequency of SEM use at the age of 14, current SEM use, frequency of masturbation, sexual boredom, acceptance of sex myths, and sexual compulsiveness. In testing the model, a novel instrument was used, the Sexual Scripts Overlap Scale, designed to measure the influence of SEM on sexual socialization. Structural equation analyses suggested that negative effects of early exposure to SEM on young men's sexual satisfaction, albeit small, could be stronger than positive effects. Both positive and negative effects-the latter being expressed through suppression of intimacy-were observed only among users of paraphilic SEM. No effect of early exposure to SEM was found among the mainstream SEM users. To counterbalance moral panic but also glamorization of pornography, sex education programs should incorporate contents that would increase media literacy and assist young people in critical interpretation of pornographic imagery.


Eutherians experienced elevated evolutionary rates in the immediate aftermath of the Cretaceous-Palaeogene mass extinction.
The effect of the Cretaceous-Palaeogene (K-Pg) mass extinction on the evolution of many groups, including placental mammals, has been hotly debated. The fossil record suggests a sudden adaptive radiation of placentals immediately after the event, but several recent quantitative analyses have reconstructed no significant increase in either clade origination rates or rates of character evolution in the Palaeocene. Here we use stochastic methods to date a recent phylogenetic analysis of Cretaceous and Palaeocene mammals and show that Placentalia likely originated in the Late Cretaceous, but that most intraordinal diversification occurred during the earliest Palaeocene. This analysis reconstructs fewer than 10 placental mammal lineages crossing the K-Pg boundary. Moreover, we show that rates of morphological evolution in the 5 Myr interval immediately after the K-Pg mass extinction are three times higher than background rates during the Cretaceous. These results suggest that the K-Pg mass extinction had a marked impact on placental mammal diversification, supporting the view that an evolutionary radiation occurred as placental lineages invaded new ecological niches during the Early Palaeocene.


Synergistic antitumor effect of melatonin with several chemotherapeutic drugs on human Ewing sarcoma cancer cells: potentiation of the extrinsic apoptotic pathway.
Ewing sarcoma, the second most frequent bone cancer type, affects mainly adolescents, who have a survival of 50% 5 yr after diagnosis. Current treatments include a combination of surgery, radiotherapy and chemotherapy, which present potential serious side effects. Melatonin, a natural molecule without relevant side effects, has been previously shown to induce cytotoxicity in SK-N-MC cells, a Ewing sarcoma cell line. Here, we found that there is a synergy in the antitumor effect when melatonin (50 mum-1 mm) is combined with vincristine at the concentration of 5-10 nm or with ifosfamide at the range of 100 mum-1 mm. This synergism is due to the potentiation of cell death, particularly to the potentiation of apoptosis, i.e., mainly the extrinsic apoptotic pathway. There is a significant increase in the activation of caspase-3, -8, -9 and Bid when melatonin is combined with vincristine or ifosfamide compared to the individual treatments. Finally, there is also a potentiation of the early free radical production, likely dependent on the extrinsic apoptosis pathway activation, when the drugs are combined with melatonin. Other proteins which are related to this pathway including mitogen-activated protein kinase or protein kinase B/Akt are not involved in apoptosis induced by these agents separately or when combined. The results shown here together with the facts that: (i) no relevant side effects have been reported for melatonin and (ii) melatonin has a cytoprotective effect on noncancer cells, opens the door for a new approach in the treatment of the Ewing sarcoma family of tumors.


Variation in the functional power of human sweat glands.
A method has been worked out for the measurement of the volume of sweat produced by individual glands. A special paper, impregnated with iodine, absorbs water in a uniform way and shows the area of wetting by a sharply defined blue dot. Indirect calibrations showed that 1 cm.(3) of water would form a spot of 700 cm.(2) area, and that this relation of volume to area was a constant one over a wide range. The actual volumes encountered in prints of the sweat glands were from 5 x 10(-9) to 4 x 10(-6) cm.(3). The relative activity of glands at any instant of time can be expressed by the statistical distribution of log diameter of the dots on the print. This distribution, which might at first sight seem rather artificial, has the advantage of being unaffected by a proportionate change in the output of water from each gland. Thus it is independent of the duration of contact between print paper and skin, and of changes in the average flow from the field as a whole. It is sensitive only to changes in the activity of glands relative to each other. The methods of printing and statistical analysis were used to study the relative activity of glands in a field of 22 mm. diameter. Glands of the forearm and back were studied both under direct stimulation with mecholyl and under the reflex stimulation of environmental heat, similar results being obtained with the two kinds of stimuli. Glands of the abdomen and leg, stimulated with mecholyl, were studied in one experiment. Detailed comparison of the dots in consecutive prints showed that the large dots remained large and the small dots continued to be small. These persistent differences in the outflow of water from adjacent glands were interpreted as being due to differences in the functional power of the glands. Repeated prints of the glands during a period of 75 minutes, in which the sweat flow was declining, showed that the relative activity of the glands remained constant. This meant that the set of glands, although differing greatly in power, varied together as a functional unit. Different regions of the body show not only the variation of glandular power within each small area, but also marked differences in the average power of glands belonging to the different regions. Glands of the back, for instance, show a much greater outflow than glands of the forearm when stimulated equally with a local injection of mecholyl. Equal rates of outflow, therefore, do not mean equal states of functional activity, unless the regions being compared are of equal functional power.


Estimating meme fitness in adaptive memetic algorithms for combinatorial problems.
Among the most promising and active research areas in heuristic optimisation is the field of adaptive memetic algorithms (AMAs). These gain much of their reported robustness by adapting the probability with which each of a set of local improvement operators is applied, according to an estimate of their current value to the search process. This paper addresses the issue of how the current value should be estimated. Assuming the estimate occurs over several applications of a meme, we consider whether the extreme or mean improvements should be used, and whether this aggregation should be global, or local to some part of the solution space. To investigate these issues, we use the well-established COMA framework that coevolves the specification of a population of memes (representing different local search algorithms) alongside a population of candidate solutions to the problem at hand. Two very different memetic algorithms are considered: the first using adaptive operator pursuit to adjust the probabilities of applying a fixed set of memes, and a second which applies genetic operators to dynamically adapt and create memes and their functional definitions. For the latter, especially on combinatorial problems, credit assignment mechanisms based on historical records, or on notions of landscape locality, will have limited application, and it is necessary to estimate the value of a meme via some form of sampling. The results on a set of binary encoded combinatorial problems show that both methods are very effective, and that for some problems it is necessary to use thousands of variables in order to tease apart the differences between different reward schemes. However, for both memetic algorithms, a significant pattern emerges that reward based on mean improvement is better than that based on extreme improvement. This contradicts recent findings from adapting the parameters of operators involved in global evolutionary search. The results also show that local reward schemes outperform global reward schemes in combinatorial spaces, unlike in continuous spaces. An analysis of evolving meme behaviour is used to explain these findings.


Common mechanisms regulating dark noise and quantum bump amplification in Drosophila photoreceptors.
Absolute visual thresholds are limited by "dark noise," which in Drosophila photoreceptors is dominated by brief (∼10 ms), small (∼2 pA) inward current events, occurring at ∼2/s, believed to reflect spontaneous G protein activations. These dark events were increased in rate and amplitude by a point mutation in myosin III (NINAC), which disrupts its interaction with the scaffolding protein, INAD. This phenotype mimics that previously described in null mutants of ninaC (no inactivation no afterpotential; encoding myosin III) and an associated protein, retinophilin (rtp). Dark noise was similarly increased in heterozygote mutants of diacylglycerol kinase (rdgA/+). Dark noise in ninaC, rtp, and rdgA/+ mutants was greatly suppressed by mutations of the Gq α-subunit (Gαq) and the major light-sensitive channel (trp) but not rhodopsin. ninaC, rtp, and rdgA/+ mutations also all facilitated residual light responses in Gαq and PLC hypomorphs. Raising cytosolic Ca(2+) in the submicromolar range increased dark noise, facilitated activation of transient receptor potential (TRP) channels by exogenous agonist, and again facilitated light responses in Gαq hypomorphs. Our results indicate that RTP, NINAC, INAD, and diacylglycerol kinase, together with a Ca(2+)-dependent threshold, share common roles in suppressing dark noise and regulating quantum bump generation; consequently, most spontaneous G protein activations fail to generate dark events under normal conditions. By contrast, quantum bump generation is reliable but delayed until sufficient G proteins and PLC are activated to overcome threshold, thereby ensuring generation of full-size bumps with high quantum efficiency.


Linking planetary boundaries and ecosystem accounting, with an illustration for the Colombian Orinoco river basin.
Economic development has increased pressures on natural resources during the last decades. The concept of planetary boundaries has been developed to propose limits on human activities based on earth processes and ecological thresholds. However, this concept was not developed to downscale planetary boundaries to sub-global level. The absence of boundaries at sub-global levels constrains the use of the concept in environmental governance and natural resource management, because decisions are typically taken at these levels. Decisions at the national level are currently supported, among others, by statistical frameworks in particular the System of National Accounts. However, statistical frameworks were not developed to compile environmental information, hindering environmental decision making. Our study examines if and how ecosystem accounting can be used in combination with the concept of planetary boundaries in guiding human activities at the level of a river basin. We assess the applicability of both frameworks for natural resource management in the Orinoco river basin, based on adaptive management components. Our analysis indicates that differences in the purpose of analysis, information provided, and methods constrain the potential integration of both frameworks. Nevertheless, the way both frameworks conceptualize the social system and the interactions between social and ecological systems can facilitate translating planetary boundaries into indicators considered in ecosystem accounting. The information recorded in national ecosystem accounts can support establishing ecological thresholds and, more fundamentally, to relate ecological thresholds to human impacts on ecosystem condition. Capitalizing on these synergies requires further exchange of experiences between the communities working on ecosystem accounting and planetary boundaries.


Do Recent Advances in Diagnostic and Therapeutic Procedures Negate the Benefit of Postmastectomy Radiotherapy in N1 Patients With a Low Risk of Locoregional Recurrence?
Recent advances in breast cancer management might make the use of postmastectomy radiotherapy (PMRT) redundant in the treatment of pT1/T2N1 patients. We investigated the impact of PMRT on disease-free survival (DFS) in these patients who have a low risk of locoregional recurrence (LRR) after contemporary multidisciplinary management.Between 1998 and 2011, 1123 patients underwent upfront surgery for pathologically diagnosed pT1/T2N1 breast cancer, at a single institution. A retrospective review was performed on 692 patients who had a mastectomy with axillary lymph node (LN) clearance. Most patients received adjuvant systemic chemotherapy and/or endocrine therapy. PMRT was administered to 17.8% of the patients. The median follow-up time was 98 months.The entire cohort was divided into 2 groups, the early-era (1998-2003) and late-era (2004-2011) cohorts. Grouping was based on the use of modern therapies since 2004 including sentinel LN (SLN) biopsy, anthracycline/taxane-based chemotherapy, and aromatase inhibitors. Late-era patients had a significantly lower 5-year LRR compared with early-era patients (3.2% vs 10.3%, respectively; P < 0.001). In late-era patients, although PMRT did not significantly reduce the 5-year LRR rate (1% vs 3.8%, respectively), it did improve the 5-year DFS rate (96.1% vs 87.5%, respectively). After controlling for all clinicopathological variables, PMRT was independently associated with improved DFS. In subgroup analysis, depending on the presence of micro- or macrometastasis in the axillary nodes, the benefit of PMRT was most apparent in patients with macrometastasis (hazard ratio, 0.19). In the late-era cohort with no PMRT, the 3-year distant metastasis risk increased according to LN tumor burden (0%, 5.2%, and 9.8% in micrometastasis, SLN macrometastasis, and non-SLN macrometastasis, respectively).Advanced surgical and systemic therapies might not negate the benefit of PMRT in recently diagnosed pN1 patients who have a very low risk for LRR. Our data indicate that the overall recurrence risk combined with the LRR should be considered for an indication of PMRT, and raises the question of whether the receipt of PMRT would improve outcome in patients with micrometastasis.


Telomere length as a predictor of emotional processing in the brain.
Shorter telomere length (TL) has been associated with the development of mood disorders as well as abnormalities in brain morphology. However, so far, no studies have considered the role TL may have on brain function during tasks relevant to mood disorders. In this study, we examine the relationship between TL and functional brain activation and connectivity, while participants (n = 112) perform a functional magnetic resonance imaging (fMRI) facial affect recognition task. Additionally, because variation in TL has a substantial genetic component we calculated polygenic risk scores for TL to test if they predict face-related functional brain activation. First, our results showed that TL was positively associated with increased activation in the amygdala and cuneus, as well as increased connectivity from posterior regions of the face network to the ventral prefrontal cortex. Second, polygenic risk scores for TL show a positive association with medial prefrontal cortex activation. The data support the view that TL and genetic loading for shorter telomeres, influence the function of brain regions known to be involved in emotional processing.


[Estimating the Prevalence and Incidence Rate of Autism Spectrum Disorder (ASD): Interprovincial Comparisons].
Objective The prevalence of diagnosed autism spectrum disorders (ASD) has risen steadily over time. There is therefore a need for the monitoring of treated ASD for timely policy making. The objective of this study is to report and compare over a 10-year period the prevalence and incidence rate of diagnosed ASD in four Canadian provinces. Methods This study utilized data from the provinces of Manitoba, Ontario, Quebec and Nova Scotia with access to linked administrative database sources used in the Canadian Chronic Diseases Surveillance Systems to assess the prevalence and incidence rate of a physician diagnosis of ASD. Estimates were produced using health datasets for outpatient and inpatient care (Med-Echo in Quebec, the Canadian Institute of Health Information Discharge Abstract Database in the three other provinces, plus the Ontario Mental Health Reporting System). Dates of service, diagnosis, and physician specialty were extracted. The target population consisted of all residents aged 24 and under eligible for healthcare coverage under provincial law between 1999 and 2012. To be considered as having ASD, an individual had to have at least one physician claim or hospital discharge abstract indicating one of the following: ICD-9 codes 299.0 to 299.9 or their ICD-10 equivalents, F84.0 to F84.9. The estimates were presented in yearly brackets between 1999-2000 and 2011-2012 by sex and age groups. The main analyses focused on those aged 17 years or less, with the 18 to 24 years group added to show the subsequent progression of the disorder. Results Our findings show that the annual prevalence of ASD rose steadily between 1999 and 2012 in all provinces and for all age groups although this increase varied across Canadian provinces. There were higher annual prevalence estimates in Ontario (4.8 per 1,000) and Nova Scotia (4.2 per 1,000) compared to Quebec (3.0 per 1,000) and Manitoba (2.5 per 1,000), among persons aged 17 years and younger in 2011. As compared to 1999, Quebec and Ontario reported a fivefold and fourfold increase in 2010-2012, the highest among provinces. The prevalence was four times higher in boys than in girls. By age group, the highest prevalence was observed in those aged between 1 to 4 and 5 to 9 years depending on the province. ASD was generally diagnosed before age 10. Incident cases were more frequently diagnosed by pediatricians followed by either psychiatrists or general practitioners depending on the province. Conclusion Our research confirms that ASD has risen steadily in terms of prevalence and incidence rate and that it varies considerably across provinces. It also demonstrates that health administrative databases can be used as registers for ASD. Information derived from these databases could support and monitor development of improved coordination and shared care to meet the continuous and changing needs of patients and families over time. Implication for future research include exploring the etiology of ASD in more recent cohorts as well as investigating the association between variations in health service availability and the prevalence of ASD.


Experiences and perceptions of residential and home care services among older lesbian women and gay men in Australia.
The needs of older lesbian and gay people regarding access and use of aged-care services remain underresearched. This paper reports the findings of 33 qualitative interviews with older lesbian women and gay men about their perceptions and experiences of residential aged-care and home-based aged-care services in Australia. The focus of this paper is their preparedness for using aged-care services. The results highlight that participants had a number of concerns related to accessing residential-care services in particular, including perceptions of a lack of inclusivity and concerns of potential for discrimination and hostility, loss of access to community and partners, decreased autonomy and concerns relating to quality of care and the potential for elder abuse. Participants noted a number of strategies they employed in avoiding residential-care services, including the use of home-care services, renovating the home for increased mobility, moving to locations with greater access to outside home-care services, a preference for lesbian/gay-specific housing and residential-care options if available, and the option of voluntary euthanasia to ensure dignity and autonomy. Participants, on the whole, were hopeful that they would never require the use of residential-care services, with some believing that having current good health or the support of friends could prevent this from happening. The findings suggest that older lesbian and gay people have a variety of concerns with aged-care and may need additional support and education to improve their perceptions and experiences of services, whether these are needed presently or in the future.


Population genetics of the roan antelope (Hippotragus equinus) with suggestions for conservation.
The roan antelope (Hippotragus equinus) is the second largest African antelope, distributed throughout the continent in sub-Saharan savannah habitat. Mitochondrial DNA (mtDNA) control region sequencing (401 bp, n = 137) and microsatellite genotyping (eight loci, n = 137) were used to quantify the genetic variability within and among 18 populations of this species. The within-population diversity was low to moderate with an average mtDNA nucleotide diversity of 1.9% and average expected heterozygosity with the microsatellites of 46%, but significant differences were found among populations with both the mtDNA and microsatellite data. Different levels of genetic resolution were found using the two marker sets, but both lent strong support for the separation of West African populations (samples from Benin, Senegal and Ghana) from the remainder of the populations studied across the African continent. Mismatch distribution analyses revealed possible past refugia for roan in the west and east of Africa. The West African populations could be recognized together as an evolutionarily significant unit (ESU), referable to the subspecies H. e. koba. Samples from the rest of the continent constituted a geographically more diverse assemblage with genetic associations not strictly corresponding to the other recognized subspecies.


Plasma noradrenaline concentrations in experimental renovascular hypertension in the rat.
1. Plasma noradrenaline concentrations and dopamine beta-hydroxylase activity have been measured at various stages in the development of hypertension in the one-kidney Goldblatt rat (unilateral renal arterial constriction and contralateral nephrectomy). 2. Although plasma noradrenaline concentrations were significantly elevated from control values at 7, 14 and 28 days, plasma dopamine beta-hydroxylase activity was not significantly different from control values except at 24 h. 3. These findings suggest that peripheral sympathetic activity is increased in the one-kidney Goldblatt model of experimental hypertension but that plasma dopamine beta-hydroxylase activity is poor index of this increase. 4. Both the rise in blood pressure and the rise in plasma noradrenaline concentrations were prevented by pretreatment with intracisternal 6-hydroxydopamine, suggesting that the increased sympathetic activity is at least in part centrally mediated.


Low level laser therapy (Classes I, II and III) for treating osteoarthritis.
Osteoarthritis (OA) affects a large proportion of the population. Low Level Laser Therapy (LLLT) is a light source that generates extremely pure light, of a single wavelength. The effect is not thermal, but rather related to photochemical reactions in the cells. LLLT was introduced as an alternative non-invasive treatment for OA about 10 years ago, but its effectiveness is still controversial. To assess the effectiveness of LLLT in the treatment of OA. We searched MEDLINE, EMBASE, the Cochrane Musculoskeletal registry, the registry of the Rehabilitation and Related Therapies field and the Cochrane Controlled Trials Register up to December 31, 2002. Following an a priori protocol, only controlled clinical trials of LLLT for the treatment of patients with a clinical diagnosis of OA were eligible. Abstracts were excluded unless further data could be obtained from the authors. Two reviewers independently selected trials and abstracted data using predetermined forms. Heterogeneity was tested with Cochran's Q test. A fixed effects model was used throughout for continuous variables, except where heterogeneity existed, in which case, a random effects model was used. Results were analyzed as weighted mean differences (WMD) with 95% confidence intervals (CI), where the difference between the treated and control groups was weighted by the inverse of the variance. Standardized mean differences (SMD) were calculated by dividing the difference between treated and control by the baseline variance. SMD were used when different scales were used to measure the same concept (e.g. pain). Dichotomous outcomes were analyzed with odds ratios. Five trials were included, with 112 patients randomized to laser, 85 patients to placebo laser. Treatment duration ranged from 4 to 10 weeks. Pain was assessed by four trials. The pooled estimate (random effects) of three trials showed no statistically different effect on pain measured using a scale (SMD: -0.2, 95% CI: -1.0, +0.6), but there was statistically significant heterogeneity (p>0,05). Two of the trials showed no effect and one demonstrated very beneficial effects with laser. In another trial, with no scale-based pain outcome, significantly more patients reported pain relief (yes/no) with laser with an odds ratio of 0.05, (95% CI: 0.0 to 1.56). Other outcomes of joint tenderness, joint mobility and strength were not significant. For OA, the results are conflicting in different studies and may depend on the method of application and other features of the LLLT application. Clinicians and researchers should consistently report the characteristics of the LLLT device and the application techniques used. New trials on LLLT should make use of standardized, validated outcomes. Despite some positive findings, this meta-analysis lacked data on how LLLT effectiveness is affected by four important factors: wavelength, treatment duration of LLLT, dosage and site of application over nerves instead of joints. There is clearly a need to investigate the effects of these factors on LLLT effectiveness for OA in randomized controlled clinical trials.


Transcript profiling of the Pseudomonas aeruginosa genomic islands PAGI-2 and pKLC102.
The phylogenetically ancient genomic islands of the abundant PAGI-2/pKLC102 family are prone to horizontal gene transfer amongst proteobacteria, and account for most genomic diversity in Pseudomonas aeruginosa. The mRNA expression levels of the sequenced PAGI-2 and pKLC102 islands were determined in P. aeruginosa clone C strains C and SG17M during exponential and stationary growth in Luria broth or Vogel-Bonner mineral medium. Of the 111 ORFs of PAGI-2, only one gene was significantly expressed at a level of more than 0.0001% of total RNA. The individual mRNA transcripts of the 103 pKLC102 ORFs, however, were present in the range of 0.001% to more than 1% in the bacterial RNA population, and amounted altogether to more than 10% of cellular RNA. Homologous genes were strongly transcribed from pKLC102, but not at all from PAGI-2 under the tested conditions. Thus PAGI-2, which was stably captured by its host chromosome, was transcriptionally silent, whereas the mRNA transcripts derived from the mobile and episomally replicating pKLC102 were constitutively more abundant in the cell than the mRNA pool transcribed from the core genome.


The effect of acute sleep deprivation on visual evoked potentials in professional drivers.
Previous studies have demonstrated that as little as 18 hours of sleep deprivation can cause deleterious effects on performance. It has also been suggested that sleep deprivation can cause a "tunnel-vision" effect, in which attention is restricted to the center of the visual field. The current study aimed to replicate these behavioral effects and to examine the electrophysiological underpinnings of these changes. Repeated-measures experimental study. University laboratory. Nineteen professional drivers (1 woman; mean age = 45.3 +/- 9.1 years). Two experimental sessions were performed; one following 27 hours of sleep deprivation and the other following a normal night of sleep, with control for circadian effects. A tunnel-vision task (central versus peripheral visual discrimination) and a standard checkerboard-viewing task were performed while 32-channel EEG was recorded. For the tunnel-vision task, sleep deprivation resulted in an overall slowing of reaction times and increased errors of omission for both peripheral and foveal stimuli (P < 0.05). These changes were related to reduced P300 amplitude (indexing cognitive processing) but not measures of early visual processing. No evidence was found for an interaction effect between sleep deprivation and visual-field position, either in terms of behavior or electrophysiological responses. Slower processing of the sustained parvocellular visual pathway was demonstrated. These findings suggest that performance deficits on visual tasks during sleep deprivation are due to higher cognitive processes rather than early visual processing. Sleep deprivation may differentially impair processing of more-detailed visual information. Features of the study design (eg, visual angle, duration of sleep deprivation) may influence whether peripheral visual-field neglect occurs.


Eighty-three per cent of elite athletes return to preinjury sport after anterior cruciate ligament reconstruction: a systematic review with meta-analysis of return to sport rates, graft rupture rates and performance outcomes.
The primary objective was to calculate the rate of return to sport (RTS) following anterior cruciate ligament (ACL) reconstruction in elite athletes. Secondary objectives were to estimate the time taken to RTS, calculate rates of ACL graft rupture, evaluate postsurgical athletic performance and identify determinants of RTS. Pooled RTS and graft rupture rates were calculated using random effects proportion meta-analysis. Time to RTS, performance data and determinants of RTS were synthesised descriptively. MEDLINE, EMBASE, AMED, CINAHL, AMI, PEDro, SPORTDiscus and The Cochrane Library were searched from inception to 19 January 2016. Hand searching of 10 sports medicine journals and reference checking were also performed. Studies were included if they reported the ratio of elite athletes who returned to their preinjury level of sport following ACL reconstruction. Twenty-four studies were included. The pooled RTS rate was 83% (95% CI 77% to 88%). The mean time to RTS ranged from 6 to 13 months. The pooled graft rupture rate was 5.2% (95% CI 2.8% to 8.3%). Six out of nine studies that included a noninjured control group found no significant deterioration in athletic performance following ACL reconstruction. Indicators of greater athletic skill or value to the team were associated with RTS. Eighty-three per cent of elite athletes returned to sport following ACL reconstruction, while 5.2% sustained a graft rupture. Most athletes who returned to sport performed comparably with matched, uninjured controls. This information may assist in guiding expectations of athletes and clinicians following ACL reconstruction.


Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association.
Hypertriglyceridemia (triglycerides 200-499 mg/dL) is relatively common in the United States, whereas more severe triglyceride elevations (very high triglycerides, ≥500 mg/dL) are far less frequently observed. Both are becoming increasingly prevalent in the United States and elsewhere, likely driven in large part by growing rates of obesity and diabetes mellitus. In a 2002 American Heart Association scientific statement, the omega-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were recommended (at a dose of 2-4 g/d) for reducing triglycerides in patients with elevated triglycerides. Since 2002, prescription agents containing EPA+DHA or EPA alone have been approved by the US Food and Drug Administration for treating very high triglycerides; these agents are also widely used for hypertriglyceridemia. The purpose of this advisory is to summarize the lipid and lipoprotein effects resulting from pharmacological doses of n-3 FAs (>3 g/d total EPA+DHA) on the basis of new scientific data and availability of n-3 FA agents. In treatment of very high triglycerides with 4 g/d, EPA+DHA agents reduce triglycerides by ≥30% with concurrent increases in low-density lipoprotein cholesterol, whereas EPA-only did not raise low-density lipoprotein cholesterol in very high triglycerides. When used to treat hypertriglyceridemia, n-3 FAs with EPA+DHA or with EPA-only appear roughly comparable for triglyceride lowering and do not increase low-density lipoprotein cholesterol when used as monotherapy or in combination with a statin. In the largest trials of 4 g/d prescription n-3 FA, non-high-density lipoprotein cholesterol and apolipoprotein B were modestly decreased, indicating reductions in total atherogenic lipoproteins. The use of n-3 FA (4 g/d) for improving atherosclerotic cardiovascular disease risk in patients with hypertriglyceridemia is supported by a 25% reduction in major adverse cardiovascular events in REDUCE-IT (Reduction of Cardiovascular Events With EPA Intervention Trial), a randomized placebo-controlled trial of EPA-only in high-risk patients treated with a statin. The results of a trial of 4 g/d prescription EPA+DHA in hypertriglyceridemia are anticipated in 2020. We conclude that prescription n-3 FAs (EPA+DHA or EPA-only) at a dose of 4 g/d (>3 g/d total EPA+DHA) are an effective and safe option for reducing triglycerides as monotherapy or as an adjunct to other lipid-lowering agents.


Evaluation of performance reference compounds (PRCs) to monitor emerging polar contaminants by polar organic chemical integrative samplers (POCIS) in rivers.
In this work, a method combining polar organic chemical integrative samplers (POCIS) and ultraperformance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) was assessed for the determination of two corrosion inhibitors (benzotriazole and methylbenzotriazole), seven pesticides (atrazine, diuron, isoproturon, linuron, metolachlor, penconazole, terbuthylazine), and four pharmaceuticals (carbamazepine, diclofenac, metformin, sulfamethoxazole) in river water. As a first step, two POCIS sorbents, hydrophilic-lipophilic balance (HLB) and Strata X-CW, were compared. The comparison of the uptake profiles of the studied compounds showed that the HLB sorbent provides better uptake (higher sampled amount and better linearity) than Strata X-CW except for the basic compound metformin. Since the sampling rate (R s) of POCIS depends on environmental factors, seven compounds were evaluated as potential performance reference compounds (PRCs) through kinetic experiments. Deisopropylatrazine-d5 (DIA-d5) and, as far as we know, for the first time 4-methylbenzotriazole-d3 showed suitable desorption. The efficiency of both compounds to correct for the effect of water velocity was shown using a channel system in which POCIS were exposed to 2 and 50 cm s(-1). Finally, POCIS were deployed upstream and downstream of agricultural wine-growing and tree-growing areas in the Lienne River and the Uvrier Canal (Switzerland). The impact of the studied areas on both streams could be demonstrated.


Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline.
What are the benefits and harms of thyroid hormones for adults with subclinical hypothyroidism (SCH)? This guideline was triggered by a recent systematic review of randomised controlled trials, which could alter practice. Current guidelines tend to recommend thyroid hormones for adults with thyroid stimulating hormone (TSH) levels >10 mIU/L and for people with lower TSH values who are young, symptomatic, or have specific indications for prescribing. The guideline panel issues a strong recommendation against thyroid hormones in adults with SCH (elevated TSH levels and normal free T4 (thyroxine) levels). It does not apply to women who are trying to become pregnant or patients with TSH >20 mIU/L. It may not apply to patients with severe symptoms or young adults (such as those ≤30 years old). A guideline panel including patients, clinicians, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines using the GRADE approach. The systematic review included 21 trials with 2192 participants. For adults with SCH, thyroid hormones consistently demonstrate no clinically relevant benefits for quality of life or thyroid related symptoms, including depressive symptoms, fatigue, and body mass index (moderate to high quality evidence). Thyroid hormones may have little or no effect on cardiovascular events or mortality (low quality evidence), but harms were measured in only one trial with few events at two years' follow-up. The panel concluded that almost all adults with SCH would not benefit from treatment with thyroid hormones. Other factors in the strong recommendation include the burden of lifelong management and uncertainty on potential harms. Instead, clinicians should monitor the progression or resolution of the thyroid dysfunction in these adults. Recommendations are made actionable for clinicians and their patients through visual overviews. These provide the relative and absolute benefits and harms of thyroid hormones in multilayered evidence summaries and decision aids available in MAGIC (https://app.magicapp.org/) to support shared decisions and adaptation of this guideline.


Surface science.
During the past 15 years, surfaces have been increasingly studied on the atomic scale. As a result, their atomic structure and composition and the dynamics of gas-surface interactions are much better understood. Modern surface science is beginning to have an impact on many technologies. Techniques are readily available to study solid-vacuum and solid-gas interfaces. Studies of solid-liquid and solid-solid interfaces are difficult and appear to be challenging frontier areas of research. Surface science is at the heart of most research and development problems in energy conversion and storage.


Intracellular pH regulation by Mycobacterium smegmatis and Mycobacterium bovis BCG.
Mycobacteria are likely to encounter acidic pH in the environments they inhabit; however intracellular pH homeostasis has not been investigated in these bacteria. In this study, Mycobacterium smegmatis and Mycobacterium bovis [Bacille Calmette--Guérin (BCG)] were used as examples of fast- and slow-growing mycobacteria, respectively, to study biochemical and physiological responses to acidic pH. M. smegmatis and M. bovis BCG were able to grow at pH values of 4.5 and 5.0, respectively, suggesting the ability to regulate internal pH. Both species of mycobacteria maintained their internal pH between pH 6.1 and 7.2 when exposed to decreasing external pH and the maximum Delta pH observed was approximately 2.1 to 2.3 units for both bacteria. The Delta pH of M. smegmatis at external pH 5.0 was dissipated by protonophores (e.g. carbonyl cyanide m-chlorophenylhydrazone), ionophores (e.g. monensin and nigericin) and N,N'-dicyclohexylcarbodiimide (DCCD), an inhibitor of the proton-translocating F(1)F(0)-ATPase. These results demonstrate that permeability of the cytoplasmic membrane to protons and proton extrusion by the F(1)F(0)-ATPase plays a key role in maintaining internal pH near neutral. Correlations between measured internal pH and cell viability indicated that the lethal internal pH for both strains of mycobacteria was less than pH 6.0. Compounds that decreased internal pH caused a rapid decrease in cell survival at acidic pH, but not at neutral pH. These data indicate that both strains of mycobacteria exhibit intracellular pH homeostasis and this was crucial for the survival of these bacteria at acidic pH values.


Preparation of "dummy" l-phenylalanine molecularly imprinted microspheres by using ionic liquid as a template and functional monomer.
In this study, dummy imprinting technology was employed for the preparation of l-phenylalanine-imprinted microspheres. Ionic liquids were utilized as both a "dummy" template and functional monomer, and 4-vinylpyridine and ethylene glycol dimethacrylate were used as the assistant monomer and cross-linker, respectively, for preparing a surface-imprinted polymer on poly(divinylbenzene) microspheres. By the results obtained by theoretical investigation, the interaction between the template and monomer complex was improved as compared with that between the template and the traditional l-phenylalanine-imprinted polymer. The batch experiments indicated that the imprinting factor reached 2.5. Scatchard analysis demonstrated that the obtained "dummy" molecularly imprinted microspheres exhibited an affinity of 77.4 M·10-4 , significantly higher that of a traditional polymer directly prepared by l-phenylalanine, which is in agreement with theoretical results. Competitive adsorption experiments also showed that the molecularly imprinted polymer with the dummy template effectively isolated l-phenylalanine from l-histidine and l-tryptophan with separation factors of 5.68 and 2.68, respectively. All these results demonstrated that the polymerizable ionic liquid as the dummy template could enhance the affinity and selectivity of molecularly imprinted polymer, thereby promoting the development of imprinting technology for biomolecules.


Visualizing helicases unwinding DNA at the single molecule level.
DNA helicases are motor proteins that catalyze the unwinding of double-stranded DNA into single-stranded DNA using the free energy from ATP hydrolysis. Single molecule approaches enable us to address detailed mechanistic questions about how such enzymes move processively along DNA. Here, an optical method has been developed to follow the unwinding of multiple DNA molecules simultaneously in real time. This was achieved by measuring the accumulation of fluorescent single-stranded DNA-binding protein on the single-stranded DNA product of the helicase, using total internal reflection fluorescence microscopy. By immobilizing either the DNA or helicase, localized increase in fluorescence provides information about the rate of unwinding and the processivity of individual enzymes. In addition, it reveals details of the unwinding process, such as pauses and bursts of activity. The generic and versatile nature of the assay makes it applicable to a variety of DNA helicases and DNA templates. The method is an important addition to the single-molecule toolbox available for studying DNA processing enzymes.


Differential regulation of the Hippo pathway by adherens junctions and apical-basal cell polarity modules.
Adherens junctions (AJs) and cell polarity complexes are key players in the establishment and maintenance of apical-basal cell polarity. Loss of AJs or basolateral polarity components promotes tumor formation and metastasis. Recent studies in vertebrate models show that loss of AJs or loss of the basolateral component Scribble (Scrib) cause deregulation of the Hippo tumor suppressor pathway and hyperactivation of its downstream effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). However, whether AJs and Scrib act through the same or independent mechanisms to regulate Hippo pathway activity is not known. Here, we dissect how disruption of AJs or loss of basolateral components affect the activity of the Drosophila YAP homolog Yorkie (Yki) during imaginal disc development. Surprisingly, disruption of AJs and loss of basolateral proteins produced very different effects on Yki activity. Yki activity was cell-autonomously decreased but non-cell-autonomously elevated in tissues where the AJ components E-cadherin (E-cad) or α-catenin (α-cat) were knocked down. In contrast, scrib knockdown caused a predominantly cell-autonomous activation of Yki. Moreover, disruption of AJs or basolateral proteins had different effects on cell polarity and tissue size. Simultaneous knockdown of α-cat and scrib induced both cell-autonomous and non-cell-autonomous Yki activity. In mammalian cells, knockdown of E-cad or α-cat caused nuclear accumulation and activation of YAP without overt effects on Scrib localization and vice versa. Therefore, our results indicate the existence of multiple, genetically separable inputs from AJs and cell polarity complexes into Yki/YAP regulation.


Design, synthesis and characterisation of new chimeric ruthenium(II)-gold(I) complexes as improved cytotoxic agents.
Two heterobimetallic complexes, i.e. [RuCl2(p-cymene)(μ-dppm)AuC] (1) and [RuCl2(p-cymene)(μ-dppm)Au(S-thiazoline)] (3), based on known cytotoxic [Ru(p-cymene)Cl2(PR3)] and [AuX(PR3)] (X = Cl, SR) molecular scaffolds, with the diphosphane linker 1,1-bis(diphenylphosphino)methane, dppm, were conveniently prepared and characterised. Remarkably, the new compounds manifested a more favourable in vitro pharmacological profile toward cancer cells than individual ruthenium and gold species being either more cytotoxic or more selective. The interactions of the studied compounds with (pBR322) DNA and their inhibitory effects on cathepsin B were also assessed. In addition, their reactivity toward suitable models of protein targets was explored and clear evidence gained for disruption of the bimetallic motif and for protein binding of monometallic fragments. Overall, the data reported here strongly support the concept of multifunctional heterometallic compounds as "improved" candidate agents for cancer treatment. The mechanistic and pharmacological implications of the present findings are discussed.


Hashimoto's thyroiditis: TGAb, TPOAb, TRAb and recovery from hypothyroidism.
Hashimoto described four patients with goiter. The histology of the goiter was characterized by diffuse lymphocytic infiltration, fibrosis and epithelial cell destruction. Thyroglobulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb) have been used to diagnose Hashimoto's thyroiditis. Patients with positive TGAb and/or TPOAb have been assumed to have Hashimoto's thyroiditis. Approximately 10% of those with positive TGAb and/or TPOAb have hypothyroidism. There are two types of autoimmune thyroiditis: goitrous Hashimoto's thyroiditis and atrophic thyroiditis. The latter patients have blocking antibody (thyroid-stimulating hormone [TSH]-stimulation blocking antibody [TSBAb]). TSBAb is a TSH-receptor antibody (TRAb). TSBAb causes thyroid atrophy and hypothyroidism. TGAb and/or TPOAb do not necessarily cause hypothyroidism. Hypothyroid patients with Hashimoto's thyroiditis usually receive life-long l-thyroxine therapy. However, spontaneous recovery from hypothyroidism has been reported. Patients who had Hashimoto's hypothyroidism and then Graves' hyperthyroidism (and vice versa), have also been reported. Hashimoto's hypothyroidism and Graves' hyperthyroidism could be the opposite spectrums of one disease.


Maltoma of the thyroid in a man with Hashimoto's thyroiditis.
We report the case of a 42-yr-old man with primary thyroid lymphoma arising from mucosa-associated lymphoid tissue (MALT-lymphoma, maltoma). The patient underwent a hemithyroidectomy for a growing mass in the right lobe of the thyroid while being treated with 1-thyroxine for Hashimoto's thyroiditis. The clinical diagnosis of Hashimoto's disease was confirmed by aspiration biopsy of the mass during the course of L-thyroxine treatment. Postoperatively, histology showed atypical lymphoproliferative infiltrates suspicious of low-grade non-Hodgkin's lymphoma of mucosa-associated lymphoid tissue-type, coexisting with a reactive process typical of chronic lymphocytic thyroiditis. Immunophenotyping showed a mixed B- and T-lymphocyte population, which was nondiagnostic. However, Southern blot analysis revealed a clonal rearrangement of the Ig heavy chain gene. This case demonstrates that cytology or histology may not distinguish between reactive or low-grade lymphomatous thyroid processes. The use of molecular technique was essential to prove clonality and the presence of lymphoma.


Cardiac lysosomal derangements in mouse heart after long-term exposure to nonmetabolizable sugars.
Hearts of late fetal mice were maintained in organ culture in the presence of 30-100 mM sucrose or mannitol. Activities of several lysosomal enzymes (cathepsin D, beta-acetylglucosaminidase, acid phosphatase) were increased by up to 30% after 18-24 hours and by up to 50% after 48-72 hours, as compared to enzyme activities in litter-matched hearts maintained in control medium or medium supplemented with equimolar urea. Simultaneously, the ratio of nonsedimentable to sedimentable enzyme activity was significantly increased, suggesting increased lysosomal fragility. Light and electron microsopic examination of the hearts revealed marked vacuolization in myocytic, interstitial, and endothelial cells. The vacuoles were limited by single membranes, often contained particulate or amorphous cellular debris resulting from autophagocytosis, and in cytochemical preparations frequently exhibited an electron-dense reaction product indicative of acid phosphatase activity. Hydrocortisone failed to prevent the marked lysosomal activation induced by the sugars. In conclusion, prolonged exposure to nonmetabolizable sugars induces severe lysosomal derangements with prominent autophagy, in fetal mouse heart maintained in organ culture.


Vitamin D status in Crohn's disease: association with nutrition and disease activity.
Forty patients with Crohn's disease were divided into undernourished (18) and well nourished (22) groups depending on whether their midarm circumference was below or above 90% of the ideal standard. Plasma 25-(OH)D3 and the dihydroxylated metabolites, 24,25-(OH)2D3 and 1,25-(OH)2D3 were measured in the summer. Results were related to clinical and biochemical parameters and also compared with results from patients with ulcerative colitis and healthy subjects who served as controls. Plasma 25-(OH)D3 was reduced in the undernourished Crohn's group compared with the well nourished Crohn's group, who did not differ from the controls. Over 50% of the undernourished Crohn's group had evidence of secondary hyperparathyroidism and raised alkaline phosphatase concentrations, although concentrations of 1,25-(OH)2D3 were normal. The low 25-(OH)D3 concentrations related to disease activity. It is suggested that undernourished Crohn's patients who have high levels of disease activity are at risk of vitamin D deficiency, and attempts should be made to improve their vitamin D nutrition.


Induction of oxazolone-mediated features of atopic dermatitis in NOD-scid IL2Rγ(null) mice engrafted with human peripheral blood mononuclear cells.
Animal models mimicking human diseases have been used extensively to study the pathogenesis of autoimmune diseases and the efficacy of potential therapeutics. They are, however, limited with regard to their similarity to the human disease and cannot be used if the antagonist and its cognate receptor require high similarity in structure or binding. Here, we examine the induction of oxazolone-mediated features of atopic dermatitis (AD) in NOD-scid IL2Rγ(null) mice engrafted with human peripheral blood mononuclear cells (PBMC). The mice developed the same symptoms as immunocompetent BALB/c mice. Histological alterations induced by oxazolone were characterized by keratosis, epithelial hyperplasia and influx of inflammatory cells into the dermis and epidermis. The cellular infiltrate was identified as human leukocytes, with T cells being the major constituent. In addition, oxazolone increased human serum IgE levels. The response, however, required the engraftment of PBMC derived from patients suffering from AD, which suggests that this model reflects the immunological status of the donor. Taken together, the model described here has the potential to evaluate the efficacy of therapeutics targeting human lymphocytes in vivo and, in addition, might be developed further to elucidate molecular mechanisms inducing and sustaining flares of the disease.


Diversity and evolution of the primate skin microbiome.
Skin microbes play a role in human body odour, health and disease. Compared with gut microbes, we know little about the changes in the composition of skin microbes in response to evolutionary changes in hosts, or more recent behavioural and cultural changes in humans. No studies have used sequence-based approaches to consider the skin microbe communities of gorillas and chimpanzees, for example. Comparison of the microbial associates of non-human primates with those of humans offers unique insights into both the ancient and modern features of our skin-associated microbes. Here we describe the microbes found on the skin of humans, chimpanzees, gorillas, rhesus macaques and baboons. We focus on the bacterial and archaeal residents in the axilla using high-throughput sequencing of the 16S rRNA gene. We find that human skin microbial communities are unique relative to those of other primates, in terms of both their diversity and their composition. These differences appear to reflect both ancient shifts during millions of years of primate evolution and more recent changes due to modern hygiene.


Severe transient hypoglycemia causes reversible change in the apparent diffusion coefficient of water.
The aim of this study was to determine the effects of temporary severe hypoglycemia on the apparent diffusion coefficient (ADC) acquired by diffusion-weighted MRI of brain water with the use of serial multislice ADC mapping in rats. Severe hypoglycemia reduces the extracellular space volume, as does ischemia. Demonstrating a reduction of ADC with hypoglycemia should increase our understanding of the mechanisms underlying ADC changes in ischemia and other conditions. Fasted rats were given regular insulin (15 IU/kg IP). Rats were subjected to 15 minutes (n = 5) and 50 minutes (n = 5) of temporary severe hypoglycemia, causing a transiently isoelectric electroencephalogram (EEG). ADC mapping was performed every 30 seconds beginning at the onset of isoelectricity for 8.5 minutes. ADC maps were also obtained later during the isoelectric EEG period and 10, 20, 30, and 40 minutes after glucose infusion. Control images were obtained from a separate group of animals suffering cardiac arrest (n = 5). Abnormal ADC values were not observed before the onset of cerebral isoelectricity, except for isolated areas in the cortex and periventricular regions. Cortical ADC values globally declined at the onset of EEG isoelectricity. The ADC decline spread to subcortical regions within a few minutes. During the isoelectric period, significant declines of ADC values (27% to 45%) occurred in the entire brain. Glucose infusion normalized most of the ADC changes, even after a 50-minute period of isoelectricity. ADC mapping during hypoglycemia clearly demonstrates changes likely related to energy depletion. Most of these ADC declines were reversible. Hypoglycemia is a condition known to be associated with shrinkage of the extracellular space. These observations support the hypothesis that ADC reductions observed in ischemia are also related to shifts of water from the extracellular to the intracellular compartment.


The 8p11 myeloproliferative syndrome: review of literature and an illustrative case report.
The 8p11 myeloproliferative syndrome (EMS), also called stem cell leukemia/lymphoma (SCLL), is a relatively rare condition characterized in its typical form by the occurrence, either simultaneously or sequentially, of a bcr/abl-negative myeloproliferative disorder and a lymphoma, usually a precursor T lymphoblastic lymphoma. The disease most often terminates in acute myeloid leukemia which is resistant to conventional chemotherapy. The defining cytogenetic abnormality, a translocation at the 8p11 locus, always involves the fibroblast growth factor 1 (FGFR1) gene. To date, eight partner genes have been identified in association with FGFR1 rearrangements. The most frequent FGFR1 translocation partner is the zinc finger gene ZNF198 located at 13q11. The t(8;13)(p11;q11) disrupts intron 8 of the FGFR1 gene and fuses proline-rich and zinc finger domains of the ZNF198 gene with the cytoplasmic tyrosine kinase domain of FGFR1. Oligomerization of the fusion protein occurs, with subsequent activation of downstream signal transduction pathways, culminating in neoplastic cell transformation. This review describes the historical development of the EMS/SCLL and outlines its cytogenetic abnormalities and molecular mechanisms with an illustrative case.


The insertion of fluorescent proteins in a variable region of respiratory syncytial virus L polymerase results in fluorescent and functional enzymes but with reduced activities.
The respiratory syncytial virus (RSV) Large protein L is the catalytic subunit of the RNA-dependent RNA polymerase complex. Currently, no structural information is available for RSV L. Sequence alignments of L protein from human and bovine strains of RSV revealed the existence of two variable regions, VR1 and VR2. Following comparison with morbillivirus and rhabdovirus L genes, VR2, which is located between domains V and VI, was chosen as an insertion site for sequences encoding the epitope tag HA or the fluorescent proteins eGFP and mCherry. Recombinant tagged-L proteins co-localized with RSV N and P proteins in transfected cells. These recombinant polymerases were shown to be functional using a viral minigenome system assay, their activities being reduced by ~70% compared to the unmodified L polymerase. We have also shown by site-directed mutagenesis that the GDNQ motif (residues 810-813 for the Long strain of HRSV) is essential for L activity.


Collective physician perspectives on non-oral medication approaches for the management of clinically relevant unresolved issues in Parkinson's disease: Consensus from an international survey and discussion program.
Navigate PD was an educational program established to supplement existing guidelines and provide recommendations on the management of Parkinson's disease (PD) refractory to oral/transdermal therapies. It involved 103 experts from 13 countries overseen by an International Steering Committee (ISC) of 13 movement disorder specialists. The ISC identified 71 clinical questions important for device-aided management of PD. Fifty-six experts responded to a web-based survey, rating 15 questions as 'critically important;' these were refined to 10 questions by the ISC to be addressed through available evidence and expert opinion. Draft guidance was presented at international/national meetings and revised based on feedback. Key take-home points are: • Patients requiring levodopa >5 times daily who have severe, troublesome 'off' periods (>1-2 h/day) despite optimal oral/transdermal levodopa or non-levodopa-based therapies should be referred for specialist assessment even if disease duration is <4 years. • Cognitive decline related to non-motor fluctuations is an indication for device-aided therapies. If cognitive impairment is mild, use deep brain stimulation (DBS) with caution. For patients who have cognitive impairment or dementia, intrajejunal levodopa infusion is considered as both therapeutic and palliative in some countries. Falls are linked to cognitive decline and are likely to become more frequent with device-aided therapies. • Insufficient control of motor complications (or drug-resistant tremor in the case of DBS) are indications for device-aided therapies. Levodopa-carbidopa intestinal gel infusions or subcutaneous apomorphine pump may be considered for patients aged >70 years who have mild or moderate cognitive impairment, severe depression or other contraindications to DBS.


The effect of long-term low-dose diphosphonate treatment on rat bone.
Weaning, male rats were given ethane-1-hydroxy 1,1-diphosphonate (EHDP) or dichloromethylene diphosphonate (Cl2MDP) 0.5 mgP/kg/day for 140 days. Samples prepared after sacrifice were: (1) thin ground (30 micrometers) transverse tibial sections, (2) methacrylate-embedded 5 micrometers sections of the proximal tibial metaphysis, and (3) ultrathin calcified metaphyseal sections for electron microscopy. Cl2MDP reduced the diaphyseal medullary cavity, and EHDP increased the osteoid width. Both drugs increased endosteal bone apposition (possible secondarily to the impaired resorption) and, perhaps as a result, periosteal apposition was increased. Consequently, diaphyseal bone area was unchanged. Metaphyseal bone area was increased and osteoclast numbers reduced, in contrast to the increased osteoclast numbers reported previously in animal experiments with diphosphonates. Acid phosphatase activity within osteoclasts was markedly reduced with EDHP and unchanged with Cl2MDP. The ultrastructural changes in osteoclasts, i.e., a deficiency of ruffled borders, reduced numbers of cytoplasmic vacuoles and the presence of crystals between bone and the osteoclastic plasmalemma, were more marked with EHDP than Cl2MDP.


Design and rationale for the Patient and Provider Assessment of Lipid Management (PALM) registry.
Despite improvements in diagnosis and treatment, the prevalence of hyperlipidemia among adults in the United States remains high. Data are limited on treatment patterns and patient perceptions of cardiovascular disease risk since the release of new lipid guidelines. The objectives of the PALM registry are to assess contemporary patterns of lipid-lowering therapy use among adults receiving care in a nationally representative cohort of community clinics, determine consistency of treatment with varying lipid guidelines, identify factors affecting use of lipid-lowering therapy including patient-reported statin intolerance, and assess patient and provider knowledge of cardiovascular risk reduction goals. The PALM registry will enroll 7,500 patients likely to be considered for lipid-lowering therapy from 175 cardiology, primary care, and endocrinology practices across the United States. In this cross-sectional, observational registry, a novel tablet-based platform will be used to collect patient-reported knowledge, attitudes, and beliefs regarding cardiovascular risk reduction and lipid management. Chart abstraction and core laboratory lipid levels will describe current lipid management. Provider surveys will assess perception of current lipid-lowering goals and barriers to optimal cardiovascular risk reduction. The PALM registry will allow for better understanding of current practice patterns, patient experiences, and patient and provider attitudes toward cholesterol management for cardiovascular disease risk reduction. These data can be used to better understand gaps in care and design targeted interventions to improve uptake of lipid-lowering therapies for cardiovascular risk reduction.


Closed reduction of forearm refractures with flexible intramedullary nails in situ.
Refractures of the forearm after flexible intramedullary nailing are rare. An alternative to nail replacement is closed reduction with the nails in situ. We successfully performed this maneuver on a thirteen-year-old boy. However, no data on the stability of previously bent nails are available. The purpose of the present study was to assess the mechanical stability of titanium and stainless steel flexible intramedullary nails after one cycle of reversed bending. In an in vitro study, ten titanium and eighteen stainless steel 3.0-mm flexible intramedullary nails were subjected to an increasing lateral bending force until the point of first plastic deformation. As an analogy to the clinical case, they were then bent to an angle of 21 degrees and were manually reduced back to their original straight position and the experiment was repeated. The forces needed to achieve first plastic deformation and modified spring constants (force/deflection) were calculated and were compared between the native and previously bent nails. The average force required for permanent deformation of the previously bent nails was reduced by 37% for both titanium and stainless steel nails (from 21 to 13.2 N for titanium nails [p < 0.01] and from 25 to 15.7 N for stainless steel nails [p < 0.001]). The average modified spring constant decreased by 15.1% (from 0.814 to 0.691 N/ degrees ) for titanium nails (p < 0.001) and by 12.2% (from 0.991 to 0.870 N/ degrees ) for stainless steel nails (p < 0.001). Overall, steel nails were stiffer and stronger than titanium nails were. There was no macroscopic evidence of metal fracture or fatigue after one cycle of reversed bending to 21 degrees. Closed reduction of a forearm refracture with flexible intramedullary nails in situ is a safe, noninvasive, and effective alternative to nail replacement. However, mechanical stability of the nails is significantly reduced after the procedure. Therefore, the patient should be instructed to avoid any excessive forces to the forearm until fracture union has been documented radiographically, and casting for a limited time may be appropriate.


Community appeal: Explanation without information.
Formal or categorical explanation involves the use of a label to explain a property of an object or group of objects. In four experiments, we provide evidence that label entrenchment, the degree to which a label is accepted and used by members of the community, influences the judged quality of a categorical explanation whether or not the explanation offers substantive information about the explanandum. Experiment 1 shows that explanations using unentrenched labels are seen as less comprehensive and less natural, independent of the causal information they provide. Experiment 2 shows that these intuitions persist when the community has no additional, relevant featural information, so the label amounts to a mere name for the explanandum. Experiment 3 finds a similar effect when the unentrenched label is not widely used, but is defined by a group of experts and the recipient of the explanation is herself an expert familiar with the topic. The effect also obtains for categories that lack a coherent causal structure. Experiment 4 further demonstrates the domain generality of the entrenchment effect and provides evidence against several interpretations of the results. A majority of participants in Experiments 3 and 4 could not report the impact of entrenchment on their judgments. We argue that this reliance on community cues arose because the community often has useful information to provide about categories. The common use of labels as conduits for this communal knowledge results in reliance on community cues even when they are uninformative. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Evolving techniques for gene fusion detection in soft tissue tumours.
Chromosomal rearrangements resulting in the fusion of coding parts from two genes or in the exchange of regulatory sequences are present in approximately 20% of all human neoplasms. More than 1000 such gene fusions have now been described, with close to 100 of them in soft tissue tumours. Although little is still known about the functional outcome of many of these gene fusions, it is well established that most of them have a major impact on tumorigenesis. Furthermore, the strong association between type of gene fusion and morphological subtype makes them highly useful diagnostic markers. Until recently, the vast majority of gene fusions were identified through molecular cytogenetic characterization of rearrangements detected at chromosome banding analysis, followed by use of the reverse transcriptase-polymerase chain reaction (RT-PCR) and Sanger sequencing. With the advent of next-generation sequencing (NGS) technologies, notably of whole transcriptomes or all poly-A(+) mRNA molecules, the possibility of detecting new gene fusions has increased dramatically. Already, a large number of novel gene fusions have been identified through NGS approaches and it can be predicted that these technologies soon will become standard diagnostic clinical tools.


Gene correction of a duchenne muscular dystrophy mutation by meganuclease-enhanced exon knock-in.
Duchenne muscular dystrophy (DMD) is a severe inherited, muscle-wasting disorder caused by mutations in the DMD gene. Gene therapy development for DMD has concentrated on vector-based DMD minigene transfer, cell-based gene therapy using genetically modified adult muscle stem cells or healthy wild-type donor cells, and antisense oligonucleotide-induced exon-skipping therapy to restore the reading frame of the mutated DMD gene. This study is an investigation into DMD gene targeting-mediated correction of deletions in human patient myoblasts using a target-specific meganuclease (MN) and a homologous recombination repair matrix. The MN was designed to cleave within DMD intron 44, upstream of a deletion hotspot, and integration-competent lentiviral vectors expressing the nuclease (LVcMN) were generated. MN western blotting and deep gene sequencing for LVcMN-induced non-homologous end-joining InDels (microdeletions or microinsertions) confirmed efficient MN expression and activity in transduced DMD myoblasts. A homologous repair matrix carrying exons 45-52 (RM45-52) was designed and packaged into integration-deficient lentiviral vectors (IDLVs; LVdRM45-52). After cotransduction of DMD myoblasts harboring a deletion of exons 45 to 52 with LVcMN and LVdRM45-52 vectors, targeted knock-in of the RM45-52 region in the correct location in DMD intron 44, and expression of full-length, correctly spliced wild-type dystrophin mRNA containing exons 45-52 were observed. This work demonstrates that genome surgery on human DMD gene mutations can be achieved by MN-induced locus-specific genome cleavage and homologous recombination knock-in of deleted exons. The feasibility of human DMD gene repair in patient myoblasts has exciting therapeutic potential.


Experimental and Computational Observations of Immunogenic Cobalt Porphyrin Lipid Bilayers: Nanodomain-Enhanced Antigen Association.
Cobalt porphyrin phospholipid (CoPoP) can incorporate within bilayers to enable non-covalent surface-display of antigens on liposomes by mixing with proteins bearing a polyhistidine tag (his-tag); however, the mechanisms for how this occurs are poorly understood. These were investigated using the his-tagged model antigen Pfs25, a protein antigen candidate for malaria transmission-blocking vaccines. Pfs25 was found to associate with the small molecule aquocobalamin, a form of vitamin B12 and a cobalt-containing corrin macrocycle, but without particle formation, enabling comparative assessment. Relative to CoPoP liposomes, binding and serum stability studies indicated a weaker association of Pfs25 to aquocobalamin or cobalt nitrilotriacetic acid (Co-NTA) liposomes, which have cobalt displayed in the aqueous phase on lipid headgroups. Antigen internalization by macrophages was enhanced with Pfs25 bound to CoPoP liposomes. Immunization in mice with Pfs25 bound to CoPoP liposomes elicited antibodies that recognized ookinetes and showed transmission-reducing activity. To explore the physical mechanisms involved, we employed molecular dynamics (MD) simulations of bilayers containing phospholipid, cholesterol, as well as either CoPoP or NTA-functionalized lipids. The results show that the CoPoP-containing bilayer creates nanodomains that allow access for a limited but sufficient amount of water molecules that could be replaced by his-tags due to their favorable free energy properties allowing for stabilization. The position of the metal center within the NTA liposomes was much more exposed to the aqueous environment, which could explain its limited capacity for stabilizing Pfs25. This study illustrates the impact of CoPoP-induced antigen particleization in enhancing vaccine efficacy, and provides molecular insights into the CoPoP bilayer properties that enable this.


Induction of nuclear protein-1 by thyroid hormone enhances platelet-derived growth factor A mediated angiogenesis in liver cancer.
Background & Aims: Hepatocellular carcinoma (HCC) is among the leading causes of cancer deaths worldwide. Many studies indicate that disruption of cellular thyroid hormone signaling promotes HCC progression. However, the mechanisms underlying the regulation of genes downstream of thyroid hormone actions in HCC have remained elusive. In the current study, we identified NUPR1 (nuclear protein-1), a stress-induced protein that overexpresses in various neoplasia, is upregulated by triiodothyronine/thyroid hormone receptor (T3/TR) signaling and aimed to elucidate its role in angiogenesis in cancer progression. Methods: Quantitative reverse transcription-PCR, luciferase promoter and chromatin immunoprecipitation assays were performed to identify the NUPR1 regulatory mechanism by T3/TR. In vitro and In vivo vascular formations were performed to detect the angiogenic function of NUPR1. Human angiogenesis arrays were performed to identify the downstream angiogenic pathway. The sorafenib resistant ability of TR/NUPR1 was further examined in vitro and in vivo. Clinical relevance of TR, NUPR1 and platelet-derived growth factor A (PDGFA) were investigate in HCC samples using qRT-PCR and western blot. Results: Our experiments disclosed positive regulation of NUPR1 expression by T3/TR through direct binding to the -2066 to -1910 region of the NUPR1 promoter. Elevated NUPR1 and TR expression link to poor survival in clinical HCC specimens. An analysis of clinicopathological parameters showed that expression of NUPR1 is associated with vascular invasion and pathology stage. Functional studies revealed that NUPR1 induced endothelial cell angiogenesis in vitro and in vivo. Using a human angiogenesis array, we identified PDGFA as a target of NUPR1 in the downstream angiogenic pathway. NUPR1 induced transcription of PDGFA through direct binding to the corresponding promoter region, and inhibition of the PDGFA signaling pathway impaired angiogenesis in human umbilical vein endothelial cells (HUVECs). Notably, the angiogenic effects of NUPR1/PDGFA were mediated by the MEK/ERK signaling pathway. TR/NUPR1 expression increased cell viability and resistance to sorafenib treatment. Moreover NUPR1 expression was positively correlated with TRα, TRβ, and PDGFA expression. Conclusions: We propose that the T3/TR/NUPR1/PDGFA/MEK/ERK axis has a vital role in hepatocarcinogenesis and suggest NUPR1 as a potential therapeutic target in HCC.


Advancing the science of health professions education through a shared understanding of terminology: a content analysis of terms for "faculty".
Health professions educators risk misunderstandings where terms and concepts are not clearly defined, hampering the field's progress. This risk is especially pronounced with ambiguity in describing roles. This study explores the variety of terms used by researchers and educators to describe "faculty", with the aim to facilitate definitional clarity, and create a shared terminology and approach to describing this term. The authors analyzed journal article abstracts to identify the specific words and phrases used to describe individuals or groups of people referred to as faculty. To identify abstracts, PubMed articles indexed with the Medical Subject Heading "faculty" published between 2007 and 2017 were retrieved. Authors iteratively extracted data and used content analysis to identify patterns and themes. A total of 5,436 citations were retrieved, of which 3,354 were deemed eligible. Based on a sample of 594 abstracts (17.7%), we found 279 unique terms. The most commonly used terms accounted for approximately one-third of the sample and included faculty or faculty member/s (n = 252; 26.4%); teacher/s (n = 59; 6.2%) and medical educator/s (n = 26; 2.7%) were also well represented. Content analysis highlighted that the different descriptors authors used referred to four role types: healthcare (e.g., doctor, physician), education (e.g., educator, teacher), academia (e.g., professor), and/or relationship to the learner (e.g., mentor). Faculty are described using a wide variety of terms, which can be linked to four role descriptions. The authors propose a template for researchers and educators who want to refer to faculty in their papers. This is important to advance the field and increase readers' assessment of transferability.


Cardiovascular implications of COVID-19 versus influenza infection: a review.
Due to the overlapping clinical features of coronavirus disease 2019 (COVID-19) and influenza, parallels are often drawn between the two diseases. Patients with pre-existing cardiovascular diseases (CVD) are at a higher risk for severe manifestations of both illnesses. Considering the high transmission rate of COVID-19 and with the seasonal influenza approaching in late 2020, the dual epidemics of COVID-19 and influenza pose serious cardiovascular implications. This review highlights the similarities and differences between influenza and COVID-19 and the potential risks associated with coincident pandemics. COVID-19 has a higher mortality compared to influenza with case fatality rate almost 15 times more than that of influenza. Additionally, a significantly increased risk of adverse outcomes has been noted in patients with CVD, with ~ 15 to 70% of COVID-19 related deaths having an underlying CVD. The critical care need have ranged from 5 to 79% of patients hospitalized due to COVID-19, a proportion substantially higher than with influenza. Similarly, the frequency of vascular thrombosis including deep venous thrombosis and pulmonary embolism is markedly higher in COVID-19 patients compared with influenza in which vascular complications are rarely seen. Unexpectedly, while peak influenza season is associated with increased cardiovascular hospitalizations, a decrease of ~ 50% in cardiovascular hospitalizations has been observed since the first diagnosed case of COVID-19, owing in part to deferred care. In the coming months, increasing efforts towards evaluating new interventions will be vital to curb COVID-19, especially as peak influenza season approaches. Currently, not enough data exist regarding co-infection of COVID-19 with influenza or how it would progress clinically, though it may cause a significant burden on an already struggling health care system. Until an effective COVID-19 vaccination is available, high coverage of influenza vaccination should be of utmost priority.


Hydrogen-bonded metallo-supramolecular polymers based on ruthenium or iron complexes for the selective extraction of single-walled carbon nanotubes.
The chemical functionalization of nano-carbon materials such as single-walled carbon nanotubes (SWNTs) and graphene by metal complexes has attracted much attention due to the multitude of potential applications in efficient energy-conversion and -storage devices. The solubilization and single-chirality separation of SWNTs by surface modifications is a useful approach to manipulate SWNTs in the liquid phase. In this study, several Ru and Fe complexes containing two terminal quadruple hydrogen-bonded (H-bonded) ureidopyrimidinedione (UPy) groups were synthesized (Ru-1, Ru-UPy, and Fe-UPy) to form H-bonded supramolecular polymers by self-association. In order to control the solubility of these complexes in nonpolar solvents, Ru-UPy and Fe-UPy were endowed with long alkyl side chain groups in the coordinated 2,6-bis(benzimidazol-2-yl)pyridine ligand, while Ru-1 and Ru-2 do not contain such long alkyl chain groups. AFM measurements revealed that Ru-1, Ru-UPy, and Fe-UPy form a fiber-like network morphology on HOPG surfaces, arising from the H-bonded aggregation. However, only Ru-UPy and Fe-UPy are able to solubilize SWNTs effectively upon simple sonication in chlorobenzene. After the solubilization of a CoMoCAT® SWNT in chlorobenzene using Ru-UPy or Fe-UPy, UV-Vis-NIR spectra showed sharp peaks at 996 and 1150 nm, which were attributed to (6, 5) and (7, 6)-SWNTs. The Raman spectra of the solubilized SWNTs revealed peaks that were attributed to the radial breathing mode (RBM), which suggests an enrichment of semiconducting SWNTs, i.e., Ru-UPy and Fe-UPy are able to selectively solubilize semiconducting SWNTs. Cyclic voltammograms of films of SWNTs covered with Ru-UPy or Fe-UPy on ITO electrodes showed a well-defined adsorbed Ru(ii/iii) or Fe(ii/iii) wave. Upon addition of acid, the redox response from the adsorbed H-bonded Ru-UPy and Fe-UPy disappeared and only SWNTs were left on the ITO electrode. Moreover, the Ru-UPy/SWNT and Fe-UPy/SWNT hybrids exhibited non-linear I-V characteristics.


Analysis of the Aspergillus fumigatus proteome reveals metabolic changes and the activation of the pseurotin A biosynthesis gene cluster in response to hypoxia.
The mold Aspergillus fumigatus is the most important airborne fungal pathogen. Adaptation to hypoxia represents an important virulence attribute for A. fumigatus. Therefore, we aimed at obtaining a comprehensive overview about this process on the proteome level. To ensure highly reproducible growth conditions, an oxygen-controlled, glucose-limited chemostat cultivation was established. Two-dimensional gel electrophoresis analysis of mycelial and mitochondrial proteins as well as two-dimensional Blue Native/SDS-gel separation of mitochondrial membrane proteins led to the identification of 117 proteins with an altered abundance under hypoxic in comparison to normoxic conditions. Hypoxia induced an increased activity of glycolysis, the TCA-cycle, respiration, and amino acid metabolism. Consistently, the cellular contents in heme, iron, copper, and zinc increased. Furthermore, hypoxia induced biosynthesis of the secondary metabolite pseurotin A as demonstrated at proteomic, transcriptional, and metabolite levels. The observed and so far not reported stimulation of the biosynthesis of a secondary metabolite by oxygen depletion may also affect the survival of A. fumigatus in hypoxic niches of the human host. Among the proteins so far not implicated in hypoxia adaptation, an NO-detoxifying flavohemoprotein was one of the most highly up-regulated proteins which indicates a link between hypoxia and the generation of nitrosative stress in A. fumigatus.