Limbic grey matter changes in early Parkinson's disease.
The purpose of this study was to investigate local and network-related changes of limbic grey matter in early Parkinson's disease (PD) and their inter-relation with non-motor symptom severity. We applied voxel-based morphometric methods in 538 T1 MRI images retrieved from the Parkinson's Progression Markers Initiative website. Grey matter densities and cross-sectional estimates of age-related grey matter change were compared between subjects with early PD (n = 366) and age-matched healthy controls (n = 172) within a regression model, and associations of grey matter density with symptoms were investigated. Structural brain networks were obtained using covariance analysis seeded in regions showing grey matter abnormalities in PD subject group. Patients displayed focally reduced grey matter density in the right amygdala, which was present from the earliest stages of the disease without further advance in mild-moderate disease stages. Right amygdala grey matter density showed negative correlation with autonomic dysfunction and positive with cognitive performance in patients, but no significant interrelations were found with anxiety scores. Patients with PD also demonstrated right amygdala structural disconnection with less structural connectivity of the right amygdala with the cerebellum and thalamus but increased covariance with bilateral temporal cortices compared with controls. Age-related grey matter change was also increased in PD preferentially in the limbic system. In conclusion, detailed brain morphometry in a large group of early PD highlights predominant limbic grey matter deficits with stronger age associations compared with controls and associated altered structural connectivity pattern. This provides in vivo evidence for early limbic grey matter pathology and structural network changes that may reflect extranigral disease spread in PD. Hum Brain Mapp 38:3566-3578, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.


Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.
The functional interaction of BAFF and APRIL with TNF receptor superfamily members BAFFR, TACI and BCMA is crucial for development and maintenance of humoral immunity in mice and humans. Using a candidate gene approach, we identified homozygous and heterozygous mutations in TNFRSF13B, encoding TACI, in 13 individuals with common variable immunodeficiency. Homozygosity with respect to mutations causing the amino acid substitutions S144X and C104R abrogated APRIL binding and resulted in loss of TACI function, as evidenced by impaired proliferative response to IgM-APRIL costimulation and defective class switch recombination induced by IL-10 and APRIL or BAFF. Family members heterozygous with respect to the C104R mutation and individuals with sporadic common variable immunodeficiency who were heterozygous with respect to the amino acid substitutions A181E, S194X and R202H had humoral immunodeficiency. Although signs of autoimmunity and lymphoproliferation are evident, the human phenotype differs from that of the Tnfrsf13b-/- mouse model.


Effects of Postexercise Sauna Bathing on Recovery of Swim Performance.
Despite indications of positive effects of sauna (SAU) interventions, effects on performance recovery are unknown. The aim of the current study was to investigate acute effects of SAU bathing after an intensive training session on recovery of swim performance. In total, 20 competitive swimmers and triathletes (3 female and 17 male) with a minimum of 2 y of competition experience (national level or higher) participated in the study. Athletes completed an intensive training session followed by either a SAU bathing intervention or a placebo (PLAC) condition in a randomized order. SAU consisted of 3 × 8 min of SAU bathing at 80-85°C, whereas during PLAC, athletes applied a deidentified, pH-balanced massage oil while passively resting in a seated position. Prior to training, swimmers conducted a 4 × 50-m all-out swim test that was repeated on the following morning. Furthermore, subjective ratings of fatigue and recovery were measured. Swimmers performed significantly worse after SAU (4 × 50-m pre-post difference: +1.69 s) than after PLAC (-0.66 s; P = .02), with the most pronounced decrease in the first 50 m (P = .04; +2.7%). Overall performance of 15 athletes deteriorated (+2.6 s). The subjective feeling of stress was significantly higher after SAU than after PLAC (P = .03). Based on published findings, the smallest substantial change in swimming performance is an increase in time of more than 1.2 s; thus, the observed reductions appear relevant for competitive swimmers. According to the current results, coaches and athletes should be careful with postexercise SAU if high-intensity training and/or competitions are scheduled on the following day.


Laboratory production of infectious stocks of rabbit oral papillomavirus.
Several small, raised lesions from the underside of the tongue of domestic rabbits were isolated, and an extract prepared and tested for the presence of rabbit oral papillomavirus (ROPV). Two weeks after inoculation of this extract into the underside of rabbit tongues, multiple small discrete, grey-white nodules were observed that reached a maximum size of 2 mm in diameter by 5 weeks. These lesions showed typical ROPV pathology, and nuclei stained positive for papillomavirus (PV) group-specific antigen (GSA) by immunocytochemistry. Tissue fragments from rabbit tongues were incubated with a suspension of ROPV and placed subrenally into athymic mice. After 60 days, cysts were removed, sections cut for histology, and a virus stock prepared. GSA staining and in situ hybridization demonstrated that the xenografts were morphologically transformed with areas showing strong nuclear staining for viral capsid antigen and ROPV DNA. Extracts prepared from the pooled xenografts contained infectious ROPV as demonstrated by inoculation into the undersurface of tongues of nonimmune New Zealand White rabbits. The results demonstrated that stocks of infectious ROPV can be prepared in the athymic mouse xenograft system for use in studies on the experimental transmission of a mucosal-targeting animal papillomavirus.


Influence of local demography on asymptotic and transient dynamics of a yellow-bellied marmot metapopulation.
Despite recent advances in biodemography and metapopulation ecology, we still have limited understanding of how local demographic parameters influence short- and long-term metapopulation dynamics. We used long-term data from 17 local populations, along with the recently developed methods of matrix metapopulation modeling and transient sensitivity analysis, to investigate the influence of local demography on long-term (asymptotic) versus short-term (transient) dynamics of a yellow-bellied marmot metapopulation in Colorado. Both long- and short-term dynamics depended primarily on a few colony sites and were highly sensitive to changes in demography at these sites, particularly in survival of reproductive adult females. Interestingly, the relative importance of sites differed between long- and short-term dynamics; the spatial structure and local population sizes, while insignificant for asymptotic dynamics, were influential on transient dynamics. However, considering the spatial structure was uninformative about the relative influence of local demography on metapopulation dynamics. The vital rates that were the most influential on local dynamics were also the most influential on both long- and short-term metapopulation dynamics. Our results show that an explicit consideration of local demography is essential for a complete understanding of the dynamics and persistence of spatially structured populations.


Nuclear envelope attachment of telomeres limits TERRA and telomeric rearrangements in quiescent fission yeast cells.
Telomere anchoring to nuclear envelope (NE) is a key feature of nuclear genome architecture. Peripheral localization of telomeres is important for chromatin silencing, telomere replication and for the control of inappropriate recombination. Here, we report that fission yeast quiescent cells harbor predominantly a single telomeric cluster anchored to the NE. Telomere cluster association to the NE relies on Rap1-Bqt4 interaction, which is impacted by the length of telomeric sequences. In quiescent cells, reducing telomere length or deleting bqt4, both result in an increase in transcription of the telomeric repeat-containing RNA (TERRA). In the absence of Bqt4, telomere shortening leads to deep increase in TERRA level and the concomitant formation of subtelomeric rearrangements (STEEx) that accumulate massively in quiescent cells. Taken together, our data demonstrate that Rap1-Bqt4-dependent telomere association to NE preserves telomere integrity in post-mitotic cells, preventing telomeric transcription and recombination. This defines the nuclear periphery as an area where recombination is restricted, creating a safe zone for telomeres of post-mitotic cells.


Transitions during effective treatment for cocaine-abusing homeless persons: establishing abstinence, lapse, and relapse, and reestablishing abstinence.
Data are reported on drug use among cocaine-dependent homeless persons who participated in a clinical trial that compared day treatment only (DT, n = 69) with day treatment plus abstinent-contingent housing and work (DT+, n = 72). Drug use was measured with multiple weekly urine toxicologies. Compared with DT participants, more DT+ participants established abstinence, maintained abstinence for longer durations, were marginally significantly more likely to lapse, and significantly less likely to relapse. Of all participants who established abstinence and then relapsed, DT+ participants relapsed later and were more likely to reestablish abstinence. These analyses yield information on the processes involved in the manner in which drug use changes as a result of abstinent-contingent housing and work.


Gabapentin enacarbil for the treatment of restless legs syndrome (RLS).
Gabapentin enacarbil is a new treatment for restless legs syndrome (RLS). It is a prodrug of the anticonvulsant gabapentin. However, unlike gabapentin, gabapentin enacarbil does not demonstrate saturable absorption. This allows for once-daily dosing and less variability in serum levels. This review focuses on therapies used to treat RLS, both historical and recent. Data from available trials are summarized, with a particular focus on the efficacy and safety of gabapentin enacarbil. Potential advantages and disadvantages of this therapy in comparison with other RLS treatment modalities are discussed. Placebo-controlled trials of gabapentin enacarbil demonstrate considerable efficacy in the treatment of RLS. However, head-to-head trials comparing gabapentin enacarbil with other medications used in the treatment of RLS, including gabapentin, are lacking. Potential advantages with gabapentin enacarbil related to its pharmacokinetic profile are thus difficult to ascertain. Efficacy of gabapentin enacarbil appears comparable with that of the dopamine agonists, long considered the therapy of choice in patients with RLS. Given the lack of direct-comparison trials, and the significant cost differential of gabapentin enacarbil versus established therapies, the drug is likely to be used for patients who have failed other medication trials, or those who experience prolonged symptoms and prefer once-daily dosing.


Nonlinear parameter estimation by weighted linear associative memory with nonzero interception.
The method of linear associative memory (LAM) has recently been applied in nonlinear parameter estimation. In the method of LAM, a model response, nonlinear with respect to the parameters, is approximated linearly by a matrix, which maps inversely from a response vector to a parameter vector. This matrix is determined from a set of initial training parameter vectors and their response vectors according to a given cost function, and can be updated recursively and adaptively with a pair of newly generated parameter-response vector. The advantage of LAM is that it can yield good estimation of the true parameter from a given observed response even if the initial training parameter vectors are far from the true values. In a previous paper, we have significantly improved the LAM method by introducing a weighted linear associative memory (WLAM) approach for nonlinear parameter estimation. In the WLAM approach, the contribution of each pair of parameter-response vector to the cost function is weighted in a way such that if a response vector is closer to the observed one then its pair plays more important role in the cost function. However, in both LAM and WLAM, the linear association is introduced with zero interceptions, which would not give an exact association even if the model function is linear and so will affect the efficiency of the estimations. In this paper, we construct a theory which introduces a linear association memory with a nonzero interception (WLAMB). The results of our estimation tests on two quite different models, Van der Pol equation and somatic shunt cable model, suggest that WLAMB can still significantly improve on WLAM.


Factors associated with hypertension prevalence, unawareness and treatment among Costa Rican elderly.
Reliable information on the prevalence of hypertension is crucial in the development of health policies for prevention, control, and early diagnosis of this condition. This study describes the prevalence of hypertension among Costa Rican elderly, and identifies co-factors associated with its prevalence, unawareness and treatment. The prevalence of hypertension is estimated for the Costa Rican elderly. Measurement error is assessed, and factors associated with high blood pressure are explored. Data for this study came from a nationally representative sample of about 2,800 individuals from CRELES (Costa Rica: Longevity and Healthy Aging Study). Two blood pressure measures were collected using digital monitors. Self reports of previous diagnosis, and medications taken were also recorded as part of the study. No evidence of information bias was found among interviewers, or over time. Hypertension prevalence in elderly Costa Ricans was found to be 65% (Males = 60%, Females = 69%). Twenty-five percent of the studied population did not report previous diagnoses of hypertension, but according to our measurement they had high blood pressure. The proportion of unaware men is higher than the proportion of unaware women (32% vs. 20%). The main factors associated with hypertension are: age, being overweight or obese, and family history of hypertension. For men, current smokers are 3 times more likely to be unaware of their condition than non smokers. Both men and women are less likely to be unaware of their condition if they have a family history of hypertension. Those women who are obese, diabetic, have suffered heart disease or stroke, or have been home visited by community health workers are less likely to be unaware of their hypertension. The odds of being treated are higher in educated individuals, those with a family history of hypertension, elderly with diabetes or those who have had heart disease. Sex differences in terms of hypertension prevalence, unawareness, and treatment in elderly people have been found. Despite national programs for hypertension detection and education, unawareness of hypertension remains high, particularly among elderly men. Modifiable factors identified to be associated with prevalence such as obesity and alcohol intake could be used in educational programs aimed at the detection and treatment of those individuals who have the condition.


Benign prostatic hyperplasia: correlations between receptor density and binding affinity of alpha(1)-adrenoceptors and several clinical parameters.
The aim of the study was to determine whether relations do exist between the concentration and activity of alpha(1)-adrenoceptors, both inside the prostatic adenoma and the periurethral zone corresponding to the bladder neck, and clinical and biological parameters such as symptoms, evaluated by the American Urological Association (AUA) score, age, weight of the prostate, PSA, and the flow rate. Twenty patients with symptomatic benign prostatic hyperplasia were selected for an open prostatectomy. One gram of tissue was dissected from inside the adenoma and 1 g from the periurethral zone corresponding to the bladder neck. The alpha(1)-adrenoceptors were evaluated for the apparent dissociation constant (K(d)) and the maximal number of binding sites (B(max)). A correlation seems to exist between receptor density inside the adenoma and the bladder neck and an inverse correlation between receptor density and the AUA total symptoms score. Finally, a highly significant difference was found in patients with an AUA score of <15 or >15. No relationship was found between receptor binding affinity and the considered clinical parameters.


Advancement of human leukocyte antigen-partially matched related hematopoietic stem cell transplantation.
Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the most effective options for hematological malignancies, and human leukocyte antigen-partially matched related donors (PMRDs) are a valuable option for HSCT. Several protocols (with or without ex vivo T-cell depletion (TCD)) have been established worldwide. TCD including CD34(+) positive selection and CD3/CD19 depletion has successfully overcome the human leukocyte antigen disparity. However, TCD is associated with prolonged immune deficiencies, increased risks of infectious complications, and high transplantation-related mortality. PMRD HSCTwithout ex vivo TCD is well developed, and numerous patients have benefitted from it. Here, we review the literature on PMRD HSCT.


Burnout and the provision of psychosocial care amongst Australian cancer nurses.
To assess the prevalence of burnout amongst Australian cancer nurses as well as investigate the systemic and individual factors associated with burnout, including training and supervision for nurses in psychosocial care. Burnout amongst cancer nurses can have serious consequences for the individual nurse, the hospital and patients. Psychosocial care has been demonstrated in many studies to reduce distress in cancer patients; however, previous studies have suggested that providing psychosocial care can be stressful if nurses feel they lack appropriate training. Psychosocial skill training and supervision may be a way of improving job satisfaction and reducing burnout amongst nurses. Two hundred and thirty cancer nurses were recruited between November 2010 and April 2011 and completed an online questionnaire. Burnout levels within this population were found to be below nursing norms. Adequacy of training and supervision, frequency of supervision and percentage of role spent managing psychosocial care were found to be associated with burnout. Workload, Control, Reward and Community were independent predictors of burnout, and nurses with a greater mismatch in these areas identified as having High levels of burnout. Strategies to reduce burnout include providing cancer nurses with a varied and sustainable workload, awarding financial and social recognition of efforts and encouraging nurses to develop a sense of control over their work. Providing regular training and supervision in psychosocial care that is perceived to be adequate may also assist in reducing burnout.


Life extension research: health, illness, and death.
Scientists, bioethicists, and policy makers are currently engaged in a contentious debate about the scientific prospects and morality of efforts to increase human longevity. Some demographers and geneticists suggest that there is little reason to think that it will be possible to significantly extend the human lifespan. Other biodemographers and geneticists argue that there might well be increases in both life expectancy and lifespan. Bioethicists and policy makers are currently addressing many of the ethical, social, and economic issues raised by life extension research. However, the emphasis on philosophical argument supporting or condemning efforts to increase human longevity means that much less attention is currently being given to the factors that might play a role in generating interest in efforts to increase human longevity. This analysis considers three factors that might play a role in heightening public interest in efforts to develop biomedical technologies capable of retarding or reversing aging processes. While discussions of life extension research can seem quite futuristic and impractical, there are some powerful existential factors that might well generate considerable public support for life extension strategies if effective biomedical interventions emerge. Rather than providing philosophical justifications supporting or condemning efforts to increase human longevity, this essay seeks to promote a better understanding of the factors generating contemporary interest in prolonging life and postponing death.


Extraordinary Redox Activities in Ladder-Type Conjugated Molecules Enabled by B ← N Coordination-Promoted Delocalization and Hyperconjugation.
The introduction of B ← N coordinate bond-isoelectronic to C-C single bond-into π-systems represents a promising strategy to impart exotic redox and electrochromic properties into conjugated organic molecules and macromolecules. To achieve both reductive and oxidative activities using this strategy, a cruciform ladder-type molecular constitution was designed to accommodate oxidation-active, reduction-active, and B ← N coordination units into a compact structure. Two such compounds (BN-F and BN-Ph) were synthesized via highly efficient N-directed borylation. These molecules demonstrated well-separated, two reductive and two oxidative electron-transfer processes, corresponding to five distinct yet stable oxidation states, including a rarely observed boron-containing radical cation. Spectroelectrochemical measurements revealed unique optical characteristics for each of these reduced/oxidized species, demonstrating multicolor electrochromism with excellent recyclability. Distinct color changes were observed between each redox state with clear isosbestic points on the absorption spectra. The underlying redox mechanism was elucidated by a combination of computational and experimental investigations. Single-crystal X-ray diffraction analysis on the neutral state, the oxidized radical cation, and the reduced dianion of BN-Ph revealed structural transformations into two distinct quinonoid constitutions during the oxidation and reduction processes, respectively. B ← N coordination played an important role in rendering the robust and reversible multistage redox properties, by extending the charge and spin delocalization, by modulating the π-electron density, and by a newly established hyperconjugation mechanism.


Health care utilisation under the 30-Baht Scheme among the urban poor in Mitrapap slum, Khon Kaen, Thailand: a cross-sectional study.
In 2001, the Government of Thailand introduced a universal coverage scheme with the aim of ensuring equitable health care access for even the poorest citizens. For a flat user fee of 30 Baht per consultation, or for free for those falling into exemption categories, every scheme participant may access registered health services. The exemption categories include children under 12 years of age, senior citizens aged 60 years and over, the very poor, and volunteer health workers. The functioning of these exemption mechanisms and the effect of the scheme on health service utilisation among the poor is controversial. This cross-sectional study investigated the prevalence of 30-Baht Scheme registration and subsequent self-reported health service utilisation among an urban poor population in the Teparuk community within the Mitrapap slum in Khon Kaen city, northeastern Thailand. Furthermore, the effectiveness of the exemption mechanisms in reaching the very poor and the elderly was examined. Factors for users' choice of health facilities were identified. Overall, the proportion of the Teparuk community enrolled with the 30-Baht Scheme was high at 86%, with over one quarter of these exempted from paying the consultation fee. User fee exemption was significantly more frequent among households with an above-poverty-line income (64.7%) compared to those below the poverty line (35.3%), chi2 (df) = 5.251 (1); p-value = 0.018. In addition, one third of respondents over 60 years of age were found to be still paying user fees. Self-reported use of registered medical facilities in case of illness was stated to be predominantly due to the service being available through the scheme, with service quality not a chief consideration. Overall consumer satisfaction was high, especially among those not required to pay the 30 Baht user fee. Whilst the 30-Baht Scheme seems to cover most of the poor population of Mitrapap slum in Khon Kaen, the user fee exemption mechanism only works partially with regard to reaching the poorest and exempting senior citizens. Service utilisation and satisfaction are highest amongst those who are fee-exempt. Service quality was not an important factor influencing choice of health facility. Ways should be sought to improve the effectiveness of the current exemption mechanisms.


A model integration approach linking signalling and gene-regulatory logic with kinetic metabolic models.
Systems biology has to increasingly cope with large- and multi-scale biological systems. Many successful in silico representations and simulations of various cellular modules proved mathematical modelling to be an important tool in gaining a solid understanding of biological phenomena. However, models spanning different functional layers (e.g. metabolism, signalling and gene regulation) are still scarce. Consequently, model integration methods capable of fusing different types of biological networks and various model formalisms become a key methodology to increase the scope of cellular processes covered by mathematical models. Here we propose a new integration approach to couple logical models of signalling or/and gene-regulatory networks with kinetic models of metabolic processes. The procedure ends up with an integrated dynamic model of both layers relying on differential equations. The feasibility of the approach is shown in an illustrative case study integrating a kinetic model of central metabolic pathways in hepatocytes with a Boolean logical network depicting the hormonally induced signal transduction and gene regulation events involved. In silico simulations demonstrate the integrated model to qualitatively describe the physiological switch-like behaviour of hepatocytes in response to nutritionally regulated changes in extracellular glucagon and insulin levels. A simulated failure mode scenario addressing insulin resistance furthermore illustrates the pharmacological potential of a model covering interactions between signalling, gene regulation and metabolism.


The taxonomy of telemedicine.
The purpose of this article is to present a taxonomy for telemedicine. The field has markedly grown, with an increasing number of applications, a variety of technologies, and newly introduced terminology. A taxonomy would serve to bring conceptual clarity to this burgeoning set of alternatives to in-person healthcare delivery. The article starts with a brief discussion of the importance of taxonomy as an information management strategy to improve knowledge sharing, facilitate research and policy initiatives, and provide some guidance for the orderly development of telemedicine. We provide a conceptual context for the proliferation of related concepts, such as telehealth, e-health, and m-health, as well as a classification of the content of these concepts. Our main concern is to develop an explicit taxonomy of telemedicine and to demonstrate how it can be used to provide definitive information about the true effects of telemedicine in terms of cost, quality, and access. Taxonomy development and refinement is an iterative process. If this initial attempt at classification proves useful, subject matter experts could enhance the development and proliferation of telemedicine by testing, revising, and verifying this taxonomy.


Iron stores and serum transferrin receptor levels during recombinant human erythropoietin treatment of anemia in rheumatoid arthritis.
Ten rheumatoid arthritis (RA) patients with anemia of chronic disorders (ACD) were treated with recombinant human erythropoietin (r-Hu-Epo) using a dose of 250 U/kg s.c. 3 times a week for 6 weeks, in order to evaluate its effects on the anemia, iron stores, and serum-soluble transferrin receptor (sTfR) levels. All patients showed a rise in hemoglobin (Hb). Median Hb increased from 5.9 (5.5-7.0) at baseline to 6.7 (5.8-7.8) at 3 weeks and to 7.2 (5.9-8.5) mmol/l at 6 weeks during treatment. Ferritin levels decreased significantly during the 6 weeks, and five patients were iron deficient after 6 weeks of treatment. TfR levels increased significantly at 3 and 6 weeks during treatment. These preliminary findings may indicate that r-Hu-Epo is effective in improving ACD in RA. The sTfR rise may be explained by an increase in erythroid precursor cell mass or increased TfR expression and a decrease in tissue iron stores, although direct effects of Epo on TfR regulation cannot be excluded. Large double-blind studies with r-Hu-Epo in patients with RA and ACD are warranted.


AMP-activated protein kinase regulates E3 ligases in rodent heart.
The degradation of proteins by the ubiquitin proteasome system (UPS) is required for the maintenance of cellular homeostasis in the heart. An important regulator of metabolic homeostasis is AMP-activated protein kinase (AMPK). AMPK activation inhibits protein synthesis and activates autophagy, but whether AMPK plays a role in regulating protein breakdown through the UPS in the heart is not known. To determine whether AMPK enhances UPS-mediated protein degradation by directly regulating the ubiquitin ligases Atrogin-1 and muscle RING finger protein 1 (MuRF1) in the heart. Nutrient deprivation and pharmacological or genetic activation of AMPK increased mRNA expression and protein levels of Atrogin-1 and MuRF1 and consequently enhanced protein degradation in neonatal cardiomyocytes. Inhibition of AMPK abrogated these effects. Using gene reporter and chromatin immunoprecipitation assays, we found that AMPK regulates MuRF1 expression by acting through the myocyte enhancer factor 2 (MEF2). We further validated these findings in vivo using MEF2-LacZ reporter mice. Furthermore, we demonstrated in adult cardiomyocytes that MuRF1 is necessary for AMPK-mediated proteolysis through the UPS in the heart. Consequently, MuRF1 knockout mice were protected from severe cardiac dysfunction during fasting. AMPK regulates the transcription of Atrogin-1 and MuRF1 and enhances UPS-mediated protein degradation in heart. Specifically, AMPK regulates MuRF1 through the transcription factor MEF2. The absence of MuRF1 in the heart preserves cardiac function during fasting. The results strengthen the hypothesis that AMPK serves as a modulator of intracellular protein degradation in the heart.


Evaluation of the genotoxicity of cell phone radiofrequency radiation in male and female rats and mice following subchronic exposure.
The National Toxicology Program tested two common radiofrequency radiation (RFR) modulations emitted by cellular telephones in a 2-year rodent cancer bioassay that included interim assessments of additional animals for genotoxicity endpoints. Male and female Hsd:Sprague Dawley SD rats and B6C3F1/N mice were exposed from Gestation day 5 or Postnatal day 35, respectively, to code division multiple access (CDMA) or global system for mobile modulations over 18 hr/day, at 10-min intervals, in reverberation chambers at specific absorption rates of 1.5, 3, or 6 W/kg (rats, 900 MHz) or 2.5, 5, or 10 W/kg (mice, 1,900 MHz). After 19 (rats) or 14 (mice) weeks of exposure, animals were examined for evidence of RFR-associated genotoxicity using two different measures. Using the alkaline (pH > 13) comet assay, DNA damage was assessed in cells from three brain regions, liver cells, and peripheral blood leukocytes; using the micronucleus assay, chromosomal damage was assessed in immature and mature peripheral blood erythrocytes. Results of the comet assay showed significant increases in DNA damage in the frontal cortex of male mice (both modulations), leukocytes of female mice (CDMA only), and hippocampus of male rats (CDMA only). Increases in DNA damage judged to be equivocal were observed in several other tissues of rats and mice. No significant increases in micronucleated red blood cells were observed in rats or mice. In conclusion, these results suggest that exposure to RFR is associated with an increase in DNA damage. Environ. Mol. Mutagen. 61:276-290, 2020. © 2019 Wiley Periodicals, Inc.


Increased Risk of Acute Coronary Syndrome in Patients With Diverticular Disease: A Nationwide Population-Based Study.
Diverticular disease and acute coronary syndrome (ACS) are common disorders that share several risk factors. Few researchers have evaluated the association between diverticular disease and ACS. We aimed to assess the risk of ACS in patients with diverticular disease. A nationwide retrospective cohort study was conducted by analyzing data from the National Health Insurance Research Database in Taiwan. All patients aged ≥20 years with a diagnosis of diverticular disease from January 1, 2000, to December 31, 2011, were included in this study. For comparison, patients without diverticular disease were randomly selected and matched with the study cohort at a 4:1 ratio according to age, sex, and the year of the diagnosis of diverticular disease. Patients with incomplete age or sex information and a history of cardiovascular diseases were excluded from the study. All patients were followed until an ACS event, withdrawal from the insurance program, or December 31, 2011. In this study, 52,681 patients with diverticular disease and 210,724 patients without diverticular disease were included. Men accounted for 56.1% of patients and 57.8% of patients were ≥50 years old. The overall incidence density of ACS in patients with diverticular disease (45.5 per 10,000 person-years) was significantly higher than in those without diverticular disease (30.3 per 10,000 person-years), with an adjusted hazard ratio (HR) of 1.23 (95% confidence interval [CI], 1.14-1.32) after adjustment for age, sex, and comorbidities. The cumulative incidence of ACS in patients with diverticular disease was significantly higher than that in the control cohort (log-rank test, P < 0.001). The adjusted HRs for the development of ACS were 1.25 (95% CI, 1.15-1.37) and 1.19 (95% CI, 1.07-1.32) in patients with diverticulitis and diverticulosis, respectively. The adjusted HRs of ACS in patients with diverticular disease additionally increased from 1.97 (95% CI, 1.73-2.23) in patients with 1 comorbidity to 5.51 (95% CI, 3.88-7.84) in those with ≥5 comorbidities. This large population-based retrospective study revealed an association between diverticular disease and ACS. Further research is warranted to determine the exact mechanism of the link between these diseases.


A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency.
Primary Ovarian Insufficiency (POI) affects ~1% of women under forty. Exome sequencing of two Finnish sisters with non-syndromic POI revealed a homozygous mutation in FANCM, leading to a truncated protein (p.Gln1701*). FANCM is a DNA-damage response gene whose heterozygous mutations predispose to breast cancer. Compared to the mother's cells, the patients' lymphocytes displayed higher levels of basal and mitomycin C (MMC)-induced chromosomal abnormalities. Their lymphoblasts were hypersensitive to MMC and MMC-induced monoubiquitination of FANCD2 was impaired. Genetic complementation of patient's cells with wild-type FANCM improved their resistance to MMC re-establishing FANCD2 monoubiquitination. FANCM was more strongly expressed in human fetal germ cells than in somatic cells. FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. This mutation may provoke meiotic defects leading to a depleted follicular stock, as in Fancm-/- mice. Our findings document the first Mendelian phenotype due to a biallelic FANCM mutation.


Effect of chronic alcohol feeding on physiological and molecular parameters of renal thiamin transport.
The renal thiamin reabsorption process plays an important role in regulating thiamin body homeostasis and involves both thiamin transporters-1 and -2 (THTR1 and THTR2). Chronic alcohol use is associated with thiamin deficiency. Although a variety of factors contribute to the development of this deficiency, effects of chronic alcohol use on renal thiamin transport have not been thoroughly examined. We addressed this issue by examining the effect of chronic alcohol feeding of rats with liquid diet on physiological and molecular parameters of renal thiamin transport. Chronic alcohol feeding caused a significant inhibition in carrier-mediated thiamin transport across the renal brush-border membrane and was evident as early as 2 wk after initiation of alcohol feeding. Similarly, thiamin transport across the renal basolateral membrane was significantly inhibited by chronic alcohol feeding. The inhibition in renal thiamin transport was associated with a marked decrease in the level of expression of THTR1 and -2 proteins, mRNAs, and heterogeneous nuclear RNAs. Chronic alcohol feeding also caused a significant reduction in the level of expression of thiamin pyrophosphokinase but not that of the mitochondrial thiamin pyrophosphate transporter. These studies show that chronic alcohol feeding inhibits the entry and exit of thiamin in the polarized renal epithelial cells and that the effect is, at least in part, mediated at the transcriptional level. These findings also suggest that chronic alcohol feeding interferes with the normal homeostasis of thiamin in renal epithelial cells.


A mobile secretory vesicle cluster involved in mass transport from the Golgi to the plant cell exterior.
Secretory proteins and extracellular glycans are transported to the extracellular space during cell growth. These materials are carried in secretory vesicles generated at the trans-Golgi network (TGN). Analysis of the mammalian post-Golgi secretory pathway demonstrated the movement of separated secretory vesicles in the cell. Using secretory carrier membrane protein 2 (SCAMP2) as a marker for secretory vesicles and tobacco (Nicotiana tabacum) BY-2 cell as a model cell, we characterized the transport machinery in plant cells. A combination of analyses, including electron microscopy of quick-frozen cells and four-dimensional analysis of cells expressing fluorescent-tagged SCAMP2, enabled the identification of a clustered structure of secretory vesicles generated from TGN that moves in the cell and eventually fuses with plasma membrane. This structure was termed the secretory vesicle cluster (SVC). The SVC was also found in Arabidopsis thaliana and rice (Oryza sativa) cells and moved to the cell plate in dividing tobacco cells. Thus, the SVC is a motile structure involved in mass transport from the Golgi to the plasma membrane and cell plate in plant cells.


Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome.
Metabolic syndrome is a growing health problem worldwide. It is therefore imperative to develop new strategies to treat this pathology. In the past years, the manipulation of NAD(+) metabolism has emerged as a plausible strategy to ameliorate metabolic syndrome. In particular, an increase in cellular NAD(+) levels has beneficial effects, likely because of the activation of sirtuins. Previously, we reported that CD38 is the primary NAD(+)ase in mammals. Moreover, CD38 knockout mice have higher NAD(+) levels and are protected against obesity and metabolic syndrome. Here, we show that CD38 regulates global protein acetylation through changes in NAD(+) levels and sirtuin activity. In addition, we characterize two CD38 inhibitors: quercetin and apigenin. We show that pharmacological inhibition of CD38 results in higher intracellular NAD(+) levels and that treatment of cell cultures with apigenin decreases global acetylation as well as the acetylation of p53 and RelA-p65. Finally, apigenin administration to obese mice increases NAD(+) levels, decreases global protein acetylation, and improves several aspects of glucose and lipid homeostasis. Our results show that CD38 is a novel pharmacological target to treat metabolic diseases via NAD(+)-dependent pathways.


Examining clinical leadership in Kenyan public hospitals through the distributed leadership lens.
Clinical leadership is recognized as a crucial element in health system strengthening and health policy globally yet it has received relatively little attention in low and middle income countries (LMICs). Moreover, analyses of clinical leadership tend to focus on senior-level individual leaders, overlooking a wider constellation of middle-level leaders delivering health care in practice in a way affected by their health care context. Using the theoretical lens of 'distributed leadership', this article examines how middle-level leadership is practised and affected by context in Kenyan county hospitals, providing insights relevant to health care in other LMICs. The article is based on empirical qualitative case studies of clinical departmental leadership in two Kenyan public hospitals, drawing on data gathered through ethnographic observation, interviews and focus groups. We inductively and iteratively coded, analysed and theorized our findings. We found the distributed leadership lens useful for the purpose of analysing middle-level leadership in Kenyan hospitals, although clinical departmental leadership was understood locally in more individualized terms. Our distributed lens revealed medical and nursing leadership occurring in parallel and how only doctors in leadership roles were able to directly influence behaviour among their medical colleagues, using inter-personal skills, power and professional expertize. Finally, we found that Kenyan hospital contexts were characterized by cultures, norms and structures that constrained the way leadership was practiced. We make a theoretical contribution by demonstrating the utility of using distributed leadership as a lens for analysing leadership in LIMC health care contexts, revealing how context, power and inter-professional relationships moderate individual leaders' ability to bring about change. Our findings, have important implications for how leadership is conceptualized and the way leadership development and training are provided in LMICs health systems.


Needle autopsy to establish the cause of death in HIV-infected hospitalized adults in Uganda: a comparison to complete autopsy.
Minimal invasive but accurate methods to establish the cause of death in HIV-infected patients are needed. We studied the agreement in cause of death between blind and ultrasound-guided needle autopsy and complete autopsy in HIV-infected patients in Uganda. We subsequently performed a blind and ultrasound-guided needle autopsy followed by a complete autopsy in HIV-infected adults who died during hospitalization. Two teams of pathologists reviewed the tissue from either the needle autopsies or the complete autopsy and formulated the major diagnoses, that is, diseases directly contributing to death. The primary outcome was concordance in major diagnosis between needle and complete autopsies. We performed 96 blind needle and complete autopsies and 95 ultrasound-guided needle autopsies. Concordance in major diagnosis between blind needle and complete autopsy was 50%. For the main major diagnosis, tuberculosis (TB) concordance was higher (71%; P < 0.01). Blind needle autopsy identified at least 1 major diagnosis in 60% of patients; and in 46%, there was complete concordance for all major diagnoses. The main reason for discordance was sampling error of the lesion. Concordance with the addition of ultrasound guidance was 52% for all major diagnoses and 79% for TB. Major diagnoses were mainly identified in tissue cores from the liver (76%) and the spleen (82%). Blind needle autopsy identified half of the major diagnosis. The addition of ultrasound guidance did not significantly improve the performance of needle autopsy. Needle autopsy is a valuable method to confirm causes of death in HIV-infected patients, especially for highly prevalent diseases like TB.


Congruent strategies for carbohydrate sequencing. 3. OSCAR: an algorithm for assigning oligosaccharide topology from MSn data.
This is the third in a sequence of reports devoted to the development of congruent strategies for carbohydrate sequencing. Two previous reports outlined the strategies for observing structural detail from MSn data and introduced tools that compile, search, and compare fragment spectra in a bottom-up approach to oligosaccharide sequencing. In this third report, we introduce the operational details of an algorithm that we define as the Oligosaccharide Subtree Constraint Algorithm (OSCAR). This algorithm assimilates analyst-selected MSn ion fragmentation pathways into oligosaccharide topology (branching and linkage) using what may be considered a top-down sequencing strategy. Guided by a series of logical constraints, this de novo algorithm provides molecular topology without presumed biosynthetic constraints or external comparisons. In this introductory study, OSCAR is applied to a series of permethylated oligomers and isomeric glycans, and topologies are assigned in a few hundredths of a second.


Nitric oxide sustains long-term skeletal muscle regeneration by regulating fate of satellite cells via signaling pathways requiring Vangl2 and cyclic GMP.
Satellite cells are myogenic precursors that proliferate, activate, and differentiate on muscle injury to sustain the regenerative capacity of adult skeletal muscle; in this process, they self-renew through the return to quiescence of the cycling progeny. This mechanism, while efficient in physiological conditions does not prevent exhaustion of satellite cells in pathologies such as muscular dystrophy where numerous rounds of damage occur. Here, we describe a key role of nitric oxide, an important signaling molecule in adult skeletal muscle, on satellite cells maintenance, studied ex vivo on isolated myofibers and in vivo using the α-sarcoglycan null mouse model of dystrophy and a cardiotoxin-induced model of repetitive damage. Nitric oxide stimulated satellite cells proliferation in a pathway dependent on cGMP generation. Furthermore, it increased the number of Pax7(+)/Myf5(-) cells in a cGMP-independent pathway requiring enhanced expression of Vangl2, a member of the planar cell polarity pathway involved in the Wnt noncanonical pathway. The enhanced self-renewal ability of satellite cells induced by nitric oxide is sufficient to delay the reduction of the satellite cell pool during repetitive acute and chronic damages, favoring muscle regeneration; in the α-sarcoglycan null dystrophic mouse, it also slowed disease progression persistently. These results identify nitric oxide as a key messenger in satellite cells maintenance, expand the significance of the Vangl2-dependent Wnt noncanonical pathway in myogenesis, and indicate novel strategies to optimize nitric oxide-based therapies for muscular dystrophy.


The relationship between anticipated response and subsequent experience of cancer treatment-related side effects: A meta-analysis comparing effects before and after treatment exposure.
To review the evidence for a systematic relationship between cancer patients' pre-treatment expectations (anticipated side effects) and subsequent experience of treatment-related side effects, and to compare this relationship in patients with no prior treatment experience (cognitive expectations) and with some prior treatment experience (conditioned response). A total of 12,952 citations were identified through a comprehensive search of the literature published on or before November 2016 and screened against inclusion criteria. Studies were eligible if they included participants undergoing curative treatment for cancer, measured a treatment side effect, examined the relationship between anticipation and experience of side effects, and reported quantitative data. Thirty-one studies were included in the review and meta-analysis (total N = 5069). The side effects examined were nausea (anticipatory and post-treatment), vomiting, fatigue, pain, problems with concentration, and skin reactions. Meta-analyses indicated positive associations between anticipation and subsequent experience for all included side effects in patients with no prior treatment exposure (r = 0.153-0.431). Stronger associations were found for all included side effects in patients with previous treatment experience (r = 0.211-0.476), except for fatigue (r = 0.266) and pain (r = 0.235). No significant differences were found when overall effect sizes for patients with and without prior treatment exposure were compared for each side effect, except for anticipatory nausea (p = 0.012). These results may have implications for future interventions that target patients' expectations of cancer treatment-related side effects. Future research could explore patient reports of messages received about likely treatment effects both before and during treatment.


Sympatry and allopatry in two desert ant sister species: how do Cataglyphis bicolor and C. savignyi coexist?
Two extremely morphologically similar sister species of desert ants, Cataglyphis bicolor and C. savignyi, exhibit broadly overlapping distributional ranges within Tunisia. In order to analyse the microhabitats of C. bicolor and C. savignyi within the sympatric and allopatric areas of both ant species, the plant species located at 113 different nest sites of the two ant species were determined. In the sympatric area, the two species exhibit a clear-cut nest site segregation. This is not the case in the allopatric areas. Hence the two species differentiate their microhabitat only when they are sympatric. The plant species associated mainly with the nest sites of C. bicolor indicate that this species prefers a type of vegetation that needs irrigation. This is in contrast to the nest sites of C. savignyi, which are usually found around plants that characterize typical dry steppe areas. As the ants' foraging paths recorded in the sympatric area reveal, C. bicolor performs significantly shorter foraging runs with respect to both length and time, and covers a much smaller foraging range than C. savignyi does. This result reflects the fact that the microhabitat occupied by the colonies of C. bicolor is richer in food abundance. When direct interspecific interactions were investigated by placing a bait midway between two heterospecific nests, C. bicolor foragers dominated over those of C. savignyi. The same dominance of C. bicolor over C. savignyi occurred in laboratory experiments. These results suggest that the dominant species drives the subordinate one out of the high quality microhabitats, and that the subordinate species is forced to survive in the less lucrative habitats. In conclusion, coexistence seems to be maintained by the asymmetric competitive relationship between the two species and the fact that the subordinate species has the ability to endure in the less favourable microhabitat.


The masterclass of the european school of oncology: the 'key educational event' of the school.
The European School of Oncology (ESO) Clinical Masterclass is a one-week, full-immersion course, where students and teachers intensively interact with each other. This educational event is designed for medical or clinical oncologists who are defining and orientating their professional careers. Since 2002 nine Masterclasses have been organised in different European cities in which more than 500 oncologists have participated. In this paper, we are presenting data derived from the analysis of the questionnaire distributed to all participants.


The vasomotor centre and its afferent pathways.
1. Experiments were carried out on two groups of anaesthetized greyhounds. The response of the first group to infusions of angiotensin II into a vertebral artery for 5 min and to bilateral occlusion of the common carotid arteries for 2 min was studied before and after bilateral ablation of the areas postrema. The response of the second group to infusions of angiotensin and to carotid occlusion was studied before and after mid-collicular transection of the midbrain. 2. Bilateral ablation of the areas postrema abolished the response to angiotensin infused into a vertebral artery at the dose used but did not significantly alter the response to carotid occlusion. Transection of the midbrain did not abolish the response to either procedure. 3. It is concluded that the structures involved in the cardiovascular response to carotid occlusion are anatomically distinct from the area postrema and that neither response requires the integrity of connections above the pons. 4. An attempt has been made to construct a schematic diagram of the vasomotor centre.


The impact of cessation media messages on cessation-related outcomes: results from a national experiment of smokers.
Examine effects of exposure to two types of cessation advertisements on changes in cessation-related outcomes. Experimental data from a nationally representative, longitudinal sample of smokers, collected in three waves over 4 weeks. National. Subjects. Three thousand and two adult U.S. smokers aged 18+ completed baseline and follow-up interviews at 2 and 4 weeks, from December 2010 to February 2011. Six randomly assigned conditions consisting of repeated exposure to cessation advertisements: why-to-quit advertisements featuring emotional, personal testimonies (1: WTQ-T) or graphic images (2: WTQ-G); how-to-quit advertisements (3: HTQ), a combination of both (4: WTQ-T + HTQ; 5: WTQ-G + HTQ), and no-ad condition (6: control). Cessation-related beliefs, attitudes, intentions, and quitting behavior. Multivariable ordinary least squares and logistic regressions testing whether exposure to antitobacco television advertisements were associated with changes in tobacco-related outcomes. Exposure to WTQ-T or WTQ-G advertisements, both alone and combined with HTQ advertisements, elicited positive change in beliefs, attitudes, and intentions as compared to controls. Smokers in three of four WTQ conditions were substantially more likely to have quit smoking at 4 weeks than controls (odds ratios range from 5.9 to 10.1, p < .05 or better). No effects were found for the HTQ-only condition. Exposure to WTQ advertisements markedly increases the odds that a smoker will quit in the study period, suggesting positive movement toward successful, long-term cessation. HTQ advertisements did not enhance advertising effectiveness and may not be suitable as a primary message strategy.


Serum osteoprotegerin (OPG) levels are associated with disease progression and response to androgen ablation in patients with prostate cancer.
Osteoprotegerin (OPG) is a tumour and/or bone derived factor that may protect tumour cells from apoptosis. In this study, we have measured serum OPG levels in untreated prostate cancer patients with advanced prostate cancer compared to patients with organ confined disease and in treated patients receiving androgen ablation. Serum OPG levels were measured by ELISA in samples collected from 104 patients with either newly diagnosed (n = 59) or advanced prostate cancer treated by androgen ablation (n = 45) and compared with levels in serum from patients with benign prostatic hyperplasia (BPH) (n = 10) and young healthy men (n = 10). Untreated patients with locally advanced disease had significantly higher OPG levels than those with organ confined disease. Patients with advanced disease responding to androgen ablation (serum PSA < 1 ng/ml) had serum OPG levels that were significantly lower than those with clinically progressing disease (PSA > 10 ng/ml). OPG levels in the latter were not significantly different from levels in patients with early signs of biochemical progression (PSA >1 but <10 ng/ml). OPG is a potential new marker, which is elevated in the serum of patients with advanced prostate cancer and may be an indicator of early disease progression.


Detection of human cytomegalovirus antigenaemia: a rapid diagnostic technique for predicting cytomegalovirus infection/pneumonitis in lung and heart transplant recipients.
New rapid diagnostic techniques offer the opportunity of early diagnosis of human cytomegalovirus (CMV) infection in immunocompromised patients at risk of developing CMV disease. The use of human CMV antigenaemia as a predictor of clinical CMV infection and disease in lung and heart transplant recipients was studied prospectively. Twenty three heart and nine lung transplant recipients who survived 40 days were observed by standard CMV surveillance with serological testing, culture, and by sequential testing for CMV antigenaemia. CMV antigenaemia testing is a rapid and quantifiable technique in which a viral lower matrix protein is detected in cytospin preparations of peripheral blood polymorphonuclear leucocytes (PMNLs) by immunofluorescent staining. Eleven patients developed CMV infection and five developed CMV disease (four pneumonitis, one duodenitis). These clinical events occurred at a median of 65 days following transplantation. CMV antigenaemia occurred in 17 patients at a median of 35 days following transplantation. Detection of CMV antigenaemia had a sensitivity of 100%, a specificity of 93.7%, and a positive predictive value of 94.1% for CMV related illness. CMV antigenaemia was positive at a significant interval before the clinical event. High levels of CMV antigenaemia (> 50 CMV antigen positive cells/2 x 10(5) PMNLs) occurred in 11 patients and five of these developed disease. CMV antigenaemia of > 50 CMV antigen positive cells/2 x 10(5) PMNLs had a positive predictive value of 45.5% for disease but a negative predictive value of 100%. Patients with disease had higher levels of antigenaemia than those without disease. CMV antigenaemia is a rapid diagnostic technique which can identify patients likely to develop CMV disease, potentially allowing early treatment.


Tissue-engineered follicles produce live, fertile offspring.
Oocytes grown in vitro are of low quality and yield few live births, thus limiting the ability to store or bank the ova of women wishing to preserve their fertility. We applied tissue engineering principles to the culture of immature mouse follicles by designing an alginate hydrogel matrix to maintain the oocyte's 3- dimensional (3D) architecture and cell-cell interactions in vitro. A 3D culture mimics the in vivo follicle environment, and hydrogel-encapsulated follicles develop mature oocytes within the capacity for fertilization similar to that of oocytes matured in vivo. Embryos derived from cultured oocytes fertilized in vitro and transferred to pseudopregnant female mice were viable, and both male and female offspring were fertile. Our results demonstrate that alginate hydrogel-based 3D in vitro culture of follicles permits normal growth and development of follicles and oocytes. This system creates new opportunities for discovery in follicle biology and establishes a core technology for human egg banks for preservation of fertility.


A uniaxial load frame for in situ neutron studies of stress-induced changes in cementitious materials and related systems.
For in situ neutron scattering experiments on cementitious materials, it is of great interest to have access to a robust device which can induce uniaxial load on a given solid sample. Challenges involve selection of materials making up the apparatus that are both weak neutron scatterers and yet adequately strong to induce loads of up to a few kilonewtons on the sample. Here, the design and experimental commissioning of a novel load frame is provided with the intended use as a neutron scattering sample environment enabling time-dependent stress-induced changes to be probed in an engineering material under compression. The frame is a scaled down version of a creep apparatus, which is typically used in the laboratory to measure deformation due to creep in concrete. Components were optimized to enable 22 MPa of compressive stress to be exerted on a 1 cm diameter cement cylinder. To minimize secondary scattering signals from the load frame, careful selection of the metal components was needed. Furthermore, due to the need to maximize the wide angular detector coverage and signal to noise for neutron total scattering measurements, the frame was designed specifically to minimize the size and required number of support posts while matching sample dimensions to the available neutron beam size.


Reflex sympathetic changes in aortic diastolic pressure-diameter relationship.
In anesthetized vagotomized cats with the chest opened and artificially ventilated, aortic blood pressure (AP) and external diameter (AD; ultrasound technique) were measured in the proximal third of the descending thoracic aorta. Slow sinusoidal oscillations (0.2-0.3 Hz in aortic volume were produced by a piston pump connected to a femoral artery. Diastolic pressure-diameter relationship (PDR) curves were obtained during control conditions and during stimulation of either the cut central end of the left inferior cardiac nerve (ICN) or the decentralized thoracic sympathetic chain (SC). In six cats with both carotid arteries occluded ICN stimulation reflexly shifted the PDR curves to lower diameters for any given pressure (mean deltaAD 3.2% at control AP). A smaller response to ICN stimulation was obtained in five cats with one patent carotid artery (mean deltaAD 2.3% at control AP). Stimulation of sympathetic efferents to the aorta (SC) caused similar responses in five animals (mean deltaAD 3.4% at control AP). This reflex control of the thoracic aorta may be involved in cardioaortic coupling and may influence the sensitivity of aortic mechanoreceptors.


Dynamic properties influence the perception of facial expressions.
Two experiments were conducted to investigate the role played by dynamic information in identifying facial expressions of emotion. Dynamic expression sequences were created by generating and displaying morph sequences which changed the face from neutral to a peak expression in different numbers of intervening intermediate stages, to create fast (6 frames), medium (26 frames), and slow (101 frames) sequences. In experiment 1, participants were asked to describe what the person shown in each sequence was feeling. Sadness was more accurately identified when slow sequences were shown. Happiness, and to some extent surprise, was better from faster sequences, while anger was most accurately detected from the sequences of medium pace. In experiment 2 we used an intensity-rating task and static images as well as dynamic ones to examine whether effects were due to total time of the displays or to the speed of sequence. Accuracies of expression judgments were derived from the rated intensities and the results were similar to those of experiment 1 for angry and sad expressions (surprised and happy were close to ceiling). Moreover, the effect of display time was found only for dynamic expressions and not for static ones, suggesting that it was speed, not time, which was responsible for these effects. These results suggest that representations of basic expressions of emotion encode information about dynamic as well as static properties.


Drilling predation on serpulid polychaetes (Ditrupa arietina) from the pliocene of the Cope Basin, Murcia Region, Southeastern Spain.
We report quantitative analyses of drilling predation on the free-living, tube-dwelling serpulid polychaete Ditrupa arietina from the Cope Cabo marine succession (Pliocene, Spain). Tubes of D. arietina are abundant in the sampled units: 9 bulk samples from 5 horizons yielded ~5925 specimens of D. arietina. Except for fragmentation, tubes were well preserved. Complete specimens ranged from 3.1 to 13.4 mm in length and displayed allometric growth patterns, with larger specimens being relatively slimmer. Drilled Ditrupa tubes were observed in all samples. Drillholes, identified as Oichnus paraboloides, were characterized by circular to elliptical outline (drillhole eccentricity increased with its diameter), parabolic vertical profile, outer diameter larger than inner diameter, penetration of one tube wall only, narrow range of drill-hole sizes, and non-random (anterior) distribution of drillholes. A total of 233 drilled specimens were identified, with drilling frequencies varying across horizons from 2.7% to 21% (3.9% for pooled data). Many tube fragments were broken across a drillhole suggesting that the reported frequencies are conservative and that biologically-facilitated (drill-hole induced) fragmentation hampers fossil preservation of complete serpulid tubes. No failed or repaired holes were observed. Multiple complete drillholes were present (3.9%). Drilled specimens were significantly smaller than undrilled specimens and tube length and drill-hole diameter were weakly correlated. The results suggest that drillholes were produced by a size-selective, site-stereotypic predatory organism of unknown affinity. The qualitative and quantitative patterns reported here are mostly consistent with previous reports on recent and fossil Ditrupa and reveal parallels with drilling patterns documented for scaphopod mollusks, a group that is ecologically and morphologically similar to Ditrupa. Consistent with previous studies, the results suggest that free-dwelling serpulid polychaetes are preyed upon by drilling predators and may provide a viable source of data on biotic interactions in the fossil record.


Exosomes: Basic Biology and Technological Advancements Suggesting Their Potential as Ischemic Heart Disease Therapeutics.
Exosomes are small nano-sized vesicles that deliver biologically active RNA molecules and proteins to recipient cells through binding, fusion or endocytosis. There is emerging evidence that endogenous exosomes released by cardiovascular cells and progenitor cells impact cell survival and proliferation, thus regulating angiogenesis, cardiac protection and repair. These cardioprotective and regenerative traits have the potential to translate in to novel therapeutic options for post-ischaemic cardiac regeneration, thus potentially delaying the progression to ischaemic heart failure. Cellular stressors influence exosomes' secretion and the molecular composition of the exosome cargo, thus impacting on the above processes. Evidences are emerging that loading of proteins and RNAs in the exosomes cargos can be manipulated. Similarly, manipulation of exosomes surface proteins' expression to target exosomes to specific cells and tissues is doable. In addition, nature-inspired synthetic exosomes can be assembled to deliver specific clues to the recipient cells, including proliferative and differentiation stimuli, or shed paracrine signals enabling to reconstructing the heart homeostatic micro-environment. This review will describe exosome biogenesis and emerging evidence of exosome-mediated regenerative cell-to-cell communications and will conclude discussing possibilities of using exosomes to treat ischemic heart disease.


Infiltrating history into the public health curriculum.
The insertion of history into the medical school curriculum has been discussed over a long period of time. But the role of history in the public health curriculum has not been the subject of much discussion, despite the changes in UK public health training and the advent of multidisciplinary public health. This article reviews the history of inserting history into the curriculum in a leading public health postgraduate institution. It discusses the strategies used to secure acceptance for history; the positioning of history within the curriculum both as a core and a special subject; and the different curriculum content and learning approaches which have been used over time. It reviews recent developments in distance learning and the launch of a history Massive Open On line Course. It concludes that no one approach can be recommended for inserting history and that flexibility, persistence, alliances and the willingness to adapt to local circumstances are important. Students themselves are now more receptive to historical approaches and can appreciate the value of a discipline which teaches critical skills of analysis and assessment of evidence. It remains to be discussed how the discipline and such approaches can be transferred into wider professional public health training and at the undergraduate level.


Effects of the 5-HT1A partial agonists gepirone, ipsapirone and buspirone on local cerebral glucose utilization in the conscious rat.
The azospirones gepirone (10 mg/kg), ipsapirone (10 mg/kg) and buspirone (10 mg/kg) were examined for their effect on regional cerebral glucose utilization in conscious rats using quantitative 2-deoxy-glucose autoradiography. All three 5-HT1A partial agonists reduced glucose utilization in the hippocampus and dentate gyrus by 20-25% and increased glucose utilization by 38-65% in the lateral habenular nucleus; an important relay between striatal/limbic areas and the mid-brain raphe nuclei. The findings emphasize the potential importance of the hippocampus as a site of action for 5-HT1A receptor active drugs in vivo and also suggest that functional activity in the striatal/limbic-habenular-raphe pathway may be influenced by gepirone, ipsapirone and buspirone.


Chronic intestinal failure after Crohn disease: when to perform transplantation.
Because of the severity of disease and additional surgery, Crohn disease (CD) may result in intestinal failure (IF) and dependency on home parenteral nutrition (HPN). Defining the indication and timing for intestinal transplantation (ITx) is challenging. To determine the limitations of conventional surgery and to facilitate the decision making for transplantation. Data were collected prospectively and obtained by retrospective review of medical records from all patients with CD who were assessed for ITx in Oxford, United Kingdom, and Berlin, Germany, from October 10, 2003, through July 31, 2013. Patients were considered suitable for ITx if a diagnosis of irreversible IF was established and life-threatening complications under HPN were unresolvable. Twenty patients with CD and IF, established on HPN, were evaluated for ITx. The mean (SD) age at CD onset was 17.8 (9.8) years. On first diagnosis, most patients had a stricturing CD. By the time of referral, most had a combination of stricturing and fistulizing disease. New scoring system: a modification of the American Gastroenterology Association guidelines for ITx. Modifications are related to CD-specific issues that potentially lead to a poorer outcome and are based on the findings of the study to determine the expected benefit from ITx. A scoring system that would alert the physician to the severity of the patient's CD and trigger early referral for ITx. This system may translate into better long-term outcomes for patients with CD. In addition, the Karnofsky performance status score was used to compare pretransplantation and posttransplantation outcomes. Ten patients underwent ITx, 4 were on the waiting list, and 4 were unavailable for follow-up. One patient was taken off the waiting list because of severe deterioration. One patient underwent conventional stricturoplasty and did not need transplantation. Among the transplant recipients, 17 (85%) had a stoma or enterocutaneous fistula, and the mean (SD) residual bowel length was 71.5 (38) cm. A total of 80% of transplant recipients had life-threatening catheter infections, and 13 (65%) had a significant decrease in the estimated glomerular filtration rate. At a mean (SD) follow-up of 27.6 (36.1) months for transplant recipients, the patient and graft survival is 80%, and their Karnofsky performance status score increased by a mean of 18.6%. Intestinal transplantation is a suitable treatment option for patients with CD and IF. It should be considered before any additional attempts at conventional surgery, which may cause eligible patients to miss this opportunity through perioperative complications. The suggested scoring system enables the physician to identify patients who may benefit from transplantation before HPN-associated secondary organ failure.


Divergent selection and drift shape the genomes of two avian sister species spanning a saline-freshwater ecotone.
The role of species divergence due to ecologically based divergent selection-or ecological speciation-in generating and maintaining biodiversity is a central question in evolutionary biology. Comparison of the genomes of phylogenetically related taxa spanning a selective habitat gradient enables discovery of divergent signatures of selection and thereby provides valuable insight into the role of divergent ecological selection in speciation. Tidal marsh ecosystems provide tractable opportunities for studying organisms' adaptations to selective pressures that underlie ecological divergence. Sharp environmental gradients across the saline-freshwater ecotone within tidal marshes present extreme adaptive challenges to terrestrial vertebrates. Here, we sequence 20 whole genomes of two avian sister species endemic to tidal marshes-the saltmarsh sparrow (Ammospiza caudacutus) and Nelson's sparrow (A. nelsoni)-to evaluate the influence of selective and demographic processes in shaping genome-wide patterns of divergence. Genome-wide divergence between these two recently diverged sister species was notably high (genome-wide F ST = 0.32). Against a background of high genome-wide divergence, regions of elevated divergence were widespread throughout the genome, as opposed to focused within islands of differentiation. These patterns may be the result of genetic drift resulting from past tidal march colonization events in conjunction with divergent selection to different environments. We identified several candidate genes that exhibited elevated divergence between saltmarsh and Nelson's sparrows, including genes linked to osmotic regulation, circadian rhythm, and plumage melanism-all putative candidates linked to adaptation to tidal marsh environments. These findings provide new insights into the roles of divergent selection and genetic drift in generating and maintaining biodiversity.


The role of CpG islands hypomethylation and abnormal expression of neuronal protein synuclein-gamma (SNCG) in ovarian cancer.
The synucleins are a family of small cytoplasmic proteins that are expressed predominantly in neurons. Recently, their expression has been found also in many human cancers. To understand the molecular mechanisms underlying the abnormal expression of SNCG in malignant ovarian tumors, in this study, we examined the methylation status of a CpG island located in exon 1 of SNCG gene in a panel of ovarian malignant tumors to determine if DNA methylation is related to clinical and histological tumor characteristics. SNCG mRNA expression in tumor samples was assessed by RT-PCR. Methylation status of SNCG gene was studied using methylation specific PCR (MSP). Study group included 43 ovarian carcinoma samples (40 primary and 3 metastatic). The expression of SNCG mRNA was detectable in 33 of 43 ovarian cancer cases (76.7%). There were no significant differences in the mRNA expression between serous or nonserous tumors. The presence of SNCG mRNA in tumor samples was not correlated with age and menopausal status of patients, also no correlation was found with clinical stage or histological grading of malignant tumors. In 29 of 43 (67.4%) cases of tumors unmethylated product of MSP amplification was present. In a group of SNCG mRNA-positive tumors there were 75.7% (25 of 33) cases with demethylated or hypomethylated exon 1 of SNCG. The differences between the groups were statistically significant (chi2 =4.46; p=0.034). Demethylation of SNCG was not related to clinical tumor stage (p>0.05), but it was strongly associated with tumor grading (chi2=6.66; p=0.035). Aberrant methylation of SNCG was more often seen in tumors of women after menopause (78.2% vs 55%). In postmenopausal women 18 of 33 (62.1%) tumor samples synuclein-gamma mRNA expression was found, however the differences were not statistically significant. No correlations between SNCG hypomethylation and patient age, clinical stage and tumor grading were found. In 9 of 43 samples (21%) both products of amplification with methylated or unmethylated primer sets were found. In all of these cases SNCG mRNA was present. SNCG mRNA is expressed in a substantial proportion of malignant ovarian tumors and demethylation is an important event in abnormal synuclein-gamma expression in most of these cases.


TRAIL dependent fratricidal killing of gp120 primed hepatocytes by HCV core expressing hepatocytes.
The mechanism by which HIV and HCV cooperatively accelerate hepatocyte damage is not clearly understood; however, each virus affects the TRAIL: TRAIL-receptor system. We, therefore, questioned whether the independent effects of HCV and HIV combine to synergistically result in TRAIL dependent hepatocyte killing. We describe that Huh7 hepatocytes treated with HIV gp120 results in both increase TRAIL-R2 expression and an acquired sensitivity to TRAIL mediated killing. Moreover HCV infection and HCV core expression alone in Huh7 cells upregulates TRAIL. Co-incubation of HIV gp120 primed hepatocytes with HCV core expressing hepatocytes results in the selective death of the HIV gp120 primed hepatocytes that is selectively blocked by TRAIL-R2-Fc fusion protein. Liver biopsies from HIV mono-infected patients have increased TRAIL-R2; biopsies from HCV infected patients have increased TRAIL, while co-infected liver biopsies have increased PARP cleavage within hepatocytes indicating enhanced apoptosis. These findings suggest a pathogenic model to understand why HIV/HCV co-infection accelerates liver injury.


Probing RbBr solvation in freestanding sub-2 nm water clusters.
Concentration dependent solvation of RbBr in freestanding sub-2 nm water clusters was studied using core level photoelectron spectroscopy with synchrotron radiation. Spectral features recorded from dilute to saturated clusters indicate that either solvent shared or contact ion pairs are present in increasing amount when the concentration exceeds 2 mol kg-1. For comparison, spectra from anhydrous RbBr clusters are also presented.


Apparent deficiency of mucosal vascular collagen type IV associated with angiodysplasia of the colon.
To investigate the presence and distribution of vascular collagen type IV in colonic tissue in cases of angiodysplasia and age and sex matched controls. Sections of colon from seven cases of colonic angiodysplasia and eight age and sex matched controls were examined for the presence of collagen type IV in vessels of the mucosa and submucosa. Immunohistochemical staining was performed on paraffin wax embedded sections, and the degree of vascular staining for each marker compared between mucosa and submucosa and between cases and controls. Staining for endothelial markers P-selection and factor VIII was used to control for non-specific differences in immunostaining. In both the angiodysplastic tissues and approximately half the control tissues, staining for collagen type IV was considerably weaker in vessels in the mucosa than in the submucosa. In angiodysplasia, ectatic vessels in the mucosa appeared to contain less collagen type IV than similarly sized vessels in the submucosa, and perforating vessels appeared in many cases to lose staining at the level of the muscularis mucosae. No differences were found in staining intensity for the control endothelial markers between cases and controls. The apparent relative deficiency of collagen type IV in the mucosal vessels in angiodysplasia may be related to their susceptibility to ectasia and haemorrhage. The finding of a similar deficiency in half of the control cases may reflect a population at risk of this relatively common condition.


Internet-Communication Disorder: It's a Matter of Social Aspects, Coping, and Internet-Use Expectancies.
Online communication applications such as Facebook, WhatsApp, and Twitter are some of the most frequently used Internet applications. There is a growing amount of individuals suffering diminished control over their use of online communication applications which leads to diverse negative consequences in offline life. This could be referred to as Internet-communication disorder (ICD). The current study investigates the role of individual characteristics (e.g., psychopathological symptoms, feelings of loneliness) and specific cognitions. In a sample of 485 participants a structural equation model was tested to investigate predictors and mediators which may predict an excessive use. The results emphasize that a higher level of social loneliness and less perceived social support enhance the risk of a pathological use. The effects of psychopathological symptoms (depression and social anxiety) as well as individual characteristics (self-esteem, self-efficacy, and stress vulnerability) on ICD symptoms are mediated by Internet-use expectancies and dysfunctional coping mechanisms. The results illustrate mediation effects which are in line with the theoretical model by Brand et al. (2016). As suggested in the model social aspects seem to be key predictors of ICD symptoms. Further research should investigate convergent and divergent factors of other types of specific Internet-use disorders.


Statistically optimal analysis of state-discretized trajectory data from multiple thermodynamic states.
We propose a discrete transition-based reweighting analysis method (dTRAM) for analyzing configuration-space-discretized simulation trajectories produced at different thermodynamic states (temperatures, Hamiltonians, etc.) dTRAM provides maximum-likelihood estimates of stationary quantities (probabilities, free energies, expectation values) at any thermodynamic state. In contrast to the weighted histogram analysis method (WHAM), dTRAM does not require data to be sampled from global equilibrium, and can thus produce superior estimates for enhanced sampling data such as parallel/simulated tempering, replica exchange, umbrella sampling, or metadynamics. In addition, dTRAM provides optimal estimates of Markov state models (MSMs) from the discretized state-space trajectories at all thermodynamic states. Under suitable conditions, these MSMs can be used to calculate kinetic quantities (e.g., rates, timescales). In the limit of a single thermodynamic state, dTRAM estimates a maximum likelihood reversible MSM, while in the limit of uncorrelated sampling data, dTRAM is identical to WHAM. dTRAM is thus a generalization to both estimators.


Fabrication of acrylic resin copings for CeraOne provisional restorations.
A technique is described for fabricating autopolymerizing acrylic resin copings for CeraOne provisional restorations. This method has the advantage of providing a chemical bond rather than only a bond between the mechanical coping and the relined provisional crown, as is the case when using the provisional components supplied by the manufacturer. The technique describes provisionalization at the time of stage II surgery. This type of coping can also be used after a period of soft tissue healing when a healing abutment is employed. The benefits of the procedure include increased patient satisfaction and reduced chair time for repairs.


The 5' Untranslated Region of the EFG1 Transcript Promotes Its Translation To Regulate Hyphal Morphogenesis in Candida albicans.
Extensive 5' untranslated regions (UTR) are a hallmark of transcripts determining hyphal morphogenesis in Candida albicans The major transcripts of the EFG1 gene, which are responsible for cellular morphogenesis and metabolism, contain a 5' UTR of up to 1,170 nucleotides (nt). Deletion analyses of the 5' UTR revealed a 218-nt sequence that is required for production of the Efg1 protein and its functions in filamentation, without lowering the level and integrity of the EFG1 transcript. Polysomal analyses revealed that the 218-nt 5' UTR sequence is required for efficient translation of the Efg1 protein. Replacement of the EFG1 open reading frame (ORF) by the heterologous reporter gene CaCBGluc confirmed the positive regulatory importance of the identified 5' UTR sequence. In contrast to other reported transcripts containing extensive 5' UTR sequences, these results indicate the positive translational function of the 5' UTR sequence in the EFG1 transcript, which is observed in the context of the native EFG1 promoter. It is proposed that the 5' UTR recruits regulatory factors, possibly during emergence of the native transcript, which aid in translation of the EFG1 transcript.IMPORTANCE Many of the virulence traits that make Candida albicans an important human fungal pathogen are regulated on a transcriptional level. Here, we report an important regulatory contribution of translation, which is exerted by the extensive 5' untranslated regulatory sequence (5' UTR) of the transcript for the protein Efg1, which determines growth, metabolism, and filamentation in the fungus. The presence of the 5' UTR is required for efficient translation of Efg1, to promote filamentation. Because transcripts for many relevant regulators contain extensive 5' UTR sequences, it appears that the virulence of C. albicans depends on the combination of transcriptional and translational regulatory mechanisms.


Inhibition of serine/threonine protein phosphatases promotes opening of voltage-activated L-type Ca2+ channels in insulin-secreting cells.
The biological activity of many proteins, including voltage-sensitive ion channels, is controlled by their state of phosphorylation. Ca2+ influx through voltage-activated L-type Ca2+ channels serves as the major stimulatory signal in insulin-secreting cells. We have now investigated the extent to which Ca2+ handling in clonal insulin-secreting RiNm5F cells was affected by okadaic acid, an inhibitor of various serine/threonine protein phosphatases. Whole-cell patch-clamp experiments showed that okadaic acid generated an increase in membrane current, suggesting that it promotes Ca2+ influx through L-type voltage-gated Ca2+ channels probably by modifying their phosphorylation state. Okadaic acid was found to provoke a transient rise in the cytoplasmic free Ca2+ concentration ([Ca2+]i) but had no further effect on the K(+)-induced increase. The Ca2+ transient induced by okadaic acid was dependent on the presence of extracellular Ca2+ and was abolished by D600, a blocker of voltage-activated L-type Ca2+ channels. Concomitant with the rise in [Ca2+]i, okadaic acid induced insulin secretion, a phenomenon that was also dependent on extracellular Ca2+. It is proposed that hyperphosphorylation of voltage-activated L-type Ca2+ channels in insulin-secreting cells lowers the threshold potential for their activation.


The choice of prior distribution for a covariance matrix in multivariate meta-analysis: a simulation study.
Bayesian meta-analysis is an increasingly important component of clinical research, with multivariate meta-analysis a promising tool for studies with multiple endpoints. Model assumptions, including the choice of priors, are crucial aspects of multivariate Bayesian meta-analysis (MBMA) models. In a given model, two different prior distributions can lead to different inferences about a particular parameter. A simulation study was performed in which the impact of families of prior distributions for the covariance matrix of a multivariate normal random effects MBMA model was analyzed. Inferences about effect sizes were not particularly sensitive to prior choice, but the related covariance estimates were. A few families of prior distributions with small relative biases, tight mean squared errors, and close to nominal coverage for the effect size estimates were identified. Our results demonstrate the need for sensitivity analysis and suggest some guidelines for choosing prior distributions in this class of problems. The MBMA models proposed here are illustrated in a small meta-analysis example from the periodontal field and a medium meta-analysis from the study of stroke. Copyright © 2015 John Wiley & Sons, Ltd.


Tinnitus features according to caffeine consumption.
Consumption of high amounts of caffeine has been historically associated with tinnitus worsening. However, recent studies demonstrated that this seems not to be true, and caffeine may even improve tinnitus distress. To analyze tinnitus features according to caffeine consumption levels. Case-control study. Tinnitus patients were compared with patients without tinnitus concerning caffeine consumption. Tinnitus characteristics were correlated to the amount of caffeine consumption among the tinnitus patients. One hundred and forty two patients with and 140 patients without tinnitus were enrolled. Patients without tinnitus consumed more caffeine than patients with tinnitus (300mL/day versus 100mL/day, P=0.0001). Among the patients with tinnitus, no differences concerning age, gender, tinnitus laterality, periodicity, quality, type of onset, tinnitus matching, hearing loss, THI scores and VAS (volume) according to the amount of caffeine consumed have been found. Concerning VAS (distress), the subgroup that consumed less than 150mL of caffeine daily had greater scores (6 versus 5, P=0.048). Data from this study are on line with more recent studies that were not able to demonstrate any kind of association between high consume of caffeine and tinnitus distress. Moreover, this study was not able to point any possible tinnitus subtype affected by high amounts of caffeine consumption. The higher VAS distress score in the low caffeine consumption subgroup may represent a protective effect of caffeine, which is also on line with other studies. High amounts of caffeine consumption is not associated with tinnitus and with no tinnitus subgroup, according to tinnitus characteristics. An eventual protective effect of caffeine should be evaluated in further prospective studies.


Development and feasibility testing of a smart phone based attentive eating intervention.
Attentive eating means eating devoid of distraction and increasing awareness and memory for food being consumed. Encouraging individuals to eat more attentively could help reduce calorie intake, as a strong evidence base suggests that memory and awareness of food being consumed substantially influence energy intake. The development and feasibility testing of a smartphone based attentive eating intervention is reported. Informed by models of behavioral change, a smartphone application was developed. Feasibility was tested in twelve overweight and obese volunteers, sampled from university staff. Participants used the application during a four week trial and semi-structured interviews were conducted to assess acceptability and to identify barriers to usage. We also recorded adherence by downloading application usage data from participants' phones at the end of the trial. Adherence data indicated that participants used the application regularly. Participants also felt the application was easy to use and lost weight during the trial. Thematic analysis indicated that participants felt that the application raised their awareness of what they were eating. Analysis also indicated barriers to using a smartphone application to change dietary behavior. An attentive eating based intervention using smartphone technology is feasible and testing of its effectiveness for dietary change and weight loss is warranted.


Transplants in myelodysplastic syndromes.
Myelodysplastic syndromes are one of the most common hematological disorders in the elderly. Therefore, an increase in the prevalence of de novo but also of secondary forms after prior chemotherapy or radiotherapy, respectively, is anticipated within the next years. Allogeneic stem cell transplantation is considered the only potentially curable therapy, but many patients are not eligible because of age or comorbidities. Reduced-intensity conditioning regimens have improved early tolerability of the procedure, although late effects remain a challenge in the care of these patients. However, hypomethylating agents have become available as alternative therapeutic approaches with a moderate toxicity profile.


Psychometric validation of the PROQOL-HIV questionnaire, a new health-related quality of life instrument-specific to HIV disease.
This study reports the psychometric validation of a new HIV/AIDS-specific health-related quality of life (HRQL) questionnaire, the Patient Reported Outcomes Quality of Life-HIV. The instrument was developed simultaneously across Europe, North and South America, Africa, Asia, and Australia to assess multidimensional quality of life impairments in the era of highly active antiretroviral therapy. A cross-sectional study was performed in 8 countries. The pilot 70-item questionnaire was co-administered with the HIV symptoms index, the EQ-5D and Medical Outcomes Study-HIV questionnaires. Demographic and biomedical data were collected. After item analysis and reduction, convergent discriminant concurrent validity and known-group validity were examined. Internal consistency and reliability scores were assessed using Cronbach alpha and intraclass correlation. The final sample of 791 patients was composed of 64% males (median age: 41 years, HIV diagnosis = 5 years), 13.8% were treatment naive. Item reduction yielded a 43-item form surveying 8 dimensions and 1 global health item that showed good convergent and discriminant validity and reliability (98% scaling success; Cronbach alphas 0.77-0.89). Correlations with EQ-5D and Medical Outcomes Study-HIV complied with concurrent validity expectations; likewise, correlations against the number of self-reported symptoms and depression showed good support for criterion validity. A test-retest study on French patients (n = 34) showed temporal stability (intraclass correlation coefficient = 0.86). Significant and meaningful differences of HRQL scores between countries were found. The Patient Reported Outcomes Quality of Life-HIV questionnaire is a valid and reliable instrument for assessing HRQL specific to HIV disease in different cultures and healthcare systems.


The sequence and structure of the meadow grasshopper (Chorthippus parallelus) mitochondrial srRNA, ND2, COI, COII ATPase8 and 9 tRNA genes.
The nucleotide sequence of the mitochondrial ND2, COI, COII, ATPase8, srRNA and nine tRNA genes have been sequenced from two individual of the meadow grasshopper Chorthippus parallelus. Comparisons are made to other insects for which the same regions are completely sequenced. Percentage A + T is found to be relatively low in C. parallelus though consistent with that of the other Orthopteran, Locusta migratoria. The relative number of substitutions observed in the different protein-coding genes was analysed between pairs of insect species sharing different levels of relatedness. A clear change in this rate was observed between the within-genus and between-genera comparisons. This change is interpreted in terms of the functional constraints acting on these four different genes. The patterns seem to result from an early saturation of COI and COII genes with synonymous substitutions, and a tolerance of ND2 and ATPase8 function to high levels of amino acid replacements. This analysis highlights a need for further sequence studies and comparisons between taxa of different levels of divergence in order to understand the patterns of mtDNA evolution on which many evolutionary investigations are based.


Effect of lipopolysaccharide on inflammation and insulin action in human muscle.
Accumulating evidence from animal studies suggest that chronic elevation of circulating intestinal-generated lipopolysaccharide (LPS) (i.e., metabolic endotoxemia) could play a role in the pathogenesis of insulin resistance. However, the effect of LPS in human muscle is unclear. Moreover, it is unknown whether blockade/down regulation of toll-like receptor (TLR)4 can prevent the effect of LPS on insulin action and glucose metabolism in human muscle cells. In the present study we compared plasma LPS concentration in insulin resistant [obese non-diabetic and obese type 2 diabetic (T2DM)] subjects versus lean individuals. In addition, we employed a primary human skeletal muscle cell culture system to investigate the effect of LPS on glucose metabolism and whether these effects are mediated via TLR4. Obese non-diabetic and T2DM subjects had significantly elevated plasma LPS and LPS binding protein (LBP) concentrations. Plasma LPS (r = -0.46, P = 0.005) and LBP (r = -0.49, P = 0.005) concentrations negatively correlated with muscle insulin sensitivity (M). In human myotubes, LPS increased JNK phosphorylation and MCP-1 and IL-6 gene expression. This inflammatory response led to reduced insulin-stimulated IRS-1, Akt and AS160 phosphorylation and impaired glucose transport. Both pharmacologic blockade of TLR4 with TAK-242, and TLR4 gene silencing, suppressed the inflammatory response and insulin resistance caused by LPS in human muscle cells. Taken together, these findings suggest that elevations in plasma LPS concentration found in obese and T2DM subjects could play a role in the pathogenesis of insulin resistance and that antagonists of TLR4 may improve insulin action in these individuals.