Maspin expression is characteristic for cisplatin-sensitive ovarian cancer cells and for ovarian cancer cases of longer survival rates.
High cytoplasmic expression of maspin was described in ovarian cancers of shorter survival rates. Until now, no relationship has been described between expression of maspin and sensitivity to cisplatin in ovarian cancers. This study aimed at examining the relationship between expression of maspin, detected by immunohistochemistry and clinical response to cisplatin in ovarian cancer cases as well as the in vitro sensitivity to cisplatin of 11 ovarian cancer cell lines. The analyzes were performed on 73 samples of ovarian cancer and on A2780P, A2780RCIS, CAOV-3, EFO 21, EFO 27, ES-2, Mdah 2774, OAW 42, OVCAR-3, PA-1, and SKOV-3 ovarian cancer cells. Cytoplasmic maspin expression in studied cells significantly correlated with cisplatin sensitivity. A significantly shorter overall survival and progression-free survival was associated with lower cytoplasmic maspin expression at first-look laparotomies and nuclear maspin expression and secondary cytoreductions. Higher nuclear maspin at first-look laparotomies expression was specific for cases of complete response. In the study, the elevated expression of maspin was shown to be typical for cisplatin-sensitive ovarian cancers.


Psychosocial aspects in cardiac rehabilitation: From theory to practice. A position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation of the European Society of Cardiology.
A large body of empirical research shows that psychosocial risk factors (PSRFs) such as low socio-economic status, social isolation, stress, type-D personality, depression and anxiety increase the risk of incident coronary heart disease (CHD) and also contribute to poorer health-related quality of life (HRQoL) and prognosis in patients with established CHD. PSRFs may also act as barriers to lifestyle changes and treatment adherence and may moderate the effects of cardiac rehabilitation (CR). Furthermore, there appears to be a bidirectional interaction between PSRFs and the cardiovascular system. Stress, anxiety and depression affect the cardiovascular system through immune, neuroendocrine and behavioural pathways. In turn, CHD and its associated treatments may lead to distress in patients, including anxiety and depression. In clinical practice, PSRFs can be assessed with single-item screening questions, standardised questionnaires, or structured clinical interviews. Psychotherapy and medication can be considered to alleviate any PSRF-related symptoms and to enhance HRQoL, but the evidence for a definite beneficial effect on cardiac endpoints is inconclusive. A multimodal behavioural intervention, integrating counselling for PSRFs and coping with illness should be included within comprehensive CR. Patients with clinically significant symptoms of distress should be referred for psychological counselling or psychologically focused interventions and/or psychopharmacological treatment. To conclude, the success of CR may critically depend on the interdependence of the body and mind and this interaction needs to be reflected through the assessment and management of PSRFs in line with robust scientific evidence, by trained staff, integrated within the core CR team.


Proteomics: a strategy to understand the novel targets in protein misfolding and cancer therapy.
Proteins carry out important functions as they fold themselves. Protein misfolding occurs during different biochemical processes and may lead to the development of diseases such as cancer, which is characterized by genetic instability. The cancer microenvironment exposes malignant cells to a variety of stressful conditions that may further promote protein misfolding. Tumor development and progression often arises from mutations that interfere with the appropriate function of tumor-suppressor proteins and oncogenes. These may be due to alteration of catalytic activity of the protein, loss of binding sites for effector proteins or alterations of the native folded protein conformation. Src family kinases, p53, mTOR and C-terminus of HSC70 interacting protein (CHIPs) are some examples associated with protein misfolding and tumorigenesis. Molecular chaperones, such as heat-shock protein (HSP)70 and HSP90, assist protein folding and recognize target misfolded proteins for degradation. It is likely that this misfolding in cancer is linked by common principles, and may, therefore, present an exciting possibility to identify common targets for therapeutic intervention. Here we aim to review a number of examples that show how alterations in the folding of tumor-suppressor proteins or oncogenes lead to tumorigenesis. The possibility of targeting the targets to repair or degrade protein misfolding in cancer therapy is discussed.


Nudge, nudge or shove, shove-the right way for nudges to increase the supply of donated cadaver organs.
Richard Thaler and Cass Sunstein (2008) contend that mandated choice is the most practical nudge for increasing organ donation. We argue that they are wrong, and their mistake results from failing to appreciate how perceptions of meaning can influence people's responses to nudges. We favor a policy of default to donation that is subject to immediate family veto power, includes options for people to opt out (and be educated on how to do so), and emphasizes the role of organ procurement organizations and in-house transplant donation coordinators creating better environments for increasing the supply of organs and tissues obtained from cadavers. This policy will provide better opportunities for offering nudges in contexts where in-house coordinators work with families. We conclude by arguing that nudges can be introduced ethically and effectively into these contexts only if nudge designers collaborate with in-house coordinators and stakeholders.


Type 2 diabetes mellitus: phylogenetic motifs for predicting protein functional sites.
Diabetes mellitus, commonly referred to as diabetes, is a medical condition associated with abnormally high levels of glucose (or sugar) in the blood. Keeping this view, we demonstrate the phylogenetic motifs (PMs) identification in type 2 diabetes mellitus very likely corresponding to protein functional sites. In this article, we have identified PMs for all the candidate genes for type 2 diabetes mellitus. Glycine 310 remains conserved for glucokinase and potassium channel KCNJ11. Isoleucine 137 was conserved for insulin receptor and regulatory subunit of a phosphorylating enzyme. Whereas residues valine, leucine, methionine were highly conserved for insulin receptor. Occurrence of proline was very high for calpain 10 gene and glucose transporter.


Hsp20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2.
Heat shock proteins (Hsps) are well appreciated as intrinsic protectors of cardiomyocytes against numerous stresses. Recent studies have indicated that Hsp20 (HspB6), a small heat shock protein, was increased in blood from cardiomyopathic hamsters. However, the exact source of the increased circulating Hsp20 and its potential role remain obscure. In this study, we observed that the circulating Hsp20 was increased in a transgenic mouse model with cardiac-specific overexpression of Hsp20, compared with wild-type mice, suggesting its origin from cardiomyocytes. Consistently, culture media harvested from Hsp20-overexpressing cardiomyocytes by Ad.Hsp20 infection contained an increased amount of Hsp20, compared to control media. Furthermore, we identified that Hsp20 was secreted through exosomes, independent of the endoplasmic reticulum-Golgi pathway. To investigate whether extracellular Hsp20 promotes angiogenesis, we treated human umbilical vein endothelial cells (HUVECs) with recombinant human Hsp20 protein, and observed that Hsp20 dose-dependently promoted HUVEC proliferation, migration and tube formation. Moreover, a protein binding assay and immunostaining revealed an interaction between Hsp20 and VEGFR2. Accordingly, stimulatory effects of Hsp20 on HUVECs were blocked by a VEGFR2 neutralizing antibody and CBO-P11 (a VEGFR inhibitor). These in vitro data are consistent with the in vivo findings that capillary density was significantly enhanced in Hsp20-overexpressing hearts, compared to non-transgenic hearts. Collectively, our findings demonstrate that Hsp20 serves as a novel cardiokine in regulating myocardial angiogenesis through activation of the VEGFR signaling cascade.


An initiative in mentoring to promote residents' and faculty members' careers.
Internal medicine trainees and faculty recognize the value of effective mentoring to help meet the personal and professional needs of residents. However, the paradigm of the mentor-trainee relationship is seriously threatened by increased clinical, research, and administrative demands on both faculty and housestaff. Moreover, the current criteria for promotion in most teaching hospitals emphasize scholarship, rather than citizenship, so activities such as mentoring devolve to a lower priority. In 2000, the Department of Medicine at Brigham and Women's/Faulkner Hospital initiated a program to improve the effectiveness of housestaff mentoring and recognize faculty contributions to resident career development. The authors report the feedback received from a survey of the 2002-03 medical housestaff (74% response rate) and describe their experiences with the initiation of this program. Over 90% of the housestaff respondents thought it important that the Department assigns an individual faculty mentor. In practice, time-consuming professional responsibilities made meetings difficult, but most pairs supplemented their interactions with e-mail. Discussions primarily focused on career advice and support. Housestaff thought mentors were helpful and available when needed. The department has established new metrics for recognizing faculty mentoring and now publicly rewards mentoring excellence. Of note, unassigned mentoring has increased since the initiation of this program. The authors conclude that the formal mentoring program has ensured that all trainees are provided with a mentor, which has facilitated faculty-housestaff interactions and increased recognition of faculty contributions to mentoring.


Origin and evolution of HIV-1 in breast milk determined by single-genome amplification and sequencing.
HIV transmission via breastfeeding accounts for a considerable proportion of infant HIV acquisition. However, the origin and evolution of the virus population in breast milk, the likely reservoir of transmitted virus variants, are not well characterized. In this study, HIV envelope (env) genes were sequenced from virus variants amplified by single-genome amplification from plasmas and milk of 12 chronically HIV-infected, lactating Malawian women. Maximum likelihood trees and statistical tests of compartmentalization revealed interspersion of plasma and milk HIV env sequences in the majority of subjects, indicating limited or no compartmentalization of milk virus variants. However, phylogenetic tree analysis further revealed monotypic virus variants that were significantly more frequent in milk (median proportion of identical viruses, 29.5%; range, 0 to 61%) than in plasma (median proportion of identical viruses, 0%; range, 0 to 26%) (P = 0.002), suggesting local virus replication in the breast milk compartment. Moreover, clonally amplified virus env genes in milk produced functional virus Envs that were all CCR5 tropic. Milk and plasma virus Envs had similar predicted phenotypes and neutralization sensitivities to broadly neutralizing antibodies in both transmitting and nontransmitting mothers. Finally, phylogenetic comparison of longitudinal milk and plasma virus env sequences revealed synchronous virus evolution and new clonal amplification of evolved virus env genes in milk. The limited compartmentalization and the clonal amplification of evolving, functional viruses in milk indicate continual seeding of the mammary gland by blood virus variants, followed by transient local replication of these variants in the breast milk compartment.


Cranial ultrasound for the diagnosis of giant cell arteritis. A retrospective cohort study.
Establishing a diagnosis of giant cell arteritis, or indeed ruling it out, may be difficult. We describe an evaluation of temporal artery colour duplex ultrasound as first line investigation in patients with suspected giant cell arteritis. A retrospective cohort study of all patients undergoing colour duplex ultrasound for suspected giant cell arteritis between January 2005 and January 2014 was undertaken at a teaching hospital. A minimum clinical follow-up of three months was required. Patients were classified on the basis of ultrasound reports, using described features such as a halo sign or arterial wall thickening and clinical diagnosis of giant cell arteritis after at least 3 months follow-up, determined by the treating physician. The relationship of colour duplex ultrasound to a final clinical diagnosis of giant cell arteritis was analysed. A total of 87 patients underwent colour duplex ultrasound: 36 (41%) had clinically confirmed giant cell arteritis at 3-month follow-up. The positive predictive value of colour duplex ultrasound for a clinical diagnosis at 3 months was 97% (95% confidence interval (CI) 93 to 99%) and negative predictive value 88% (95% CI 76 to 95%). Sensitivity was 81% (95% CI 64 to 92%) and specificity 98% (95% CI 90 to 100%). A high positive and negative predictive value of arteritis on colour duplex ultrasound indicates that temporal artery biopsy may be unnecessary in suspected giant cell arteritis, particularly where clinical suspicion of giant cell arteritis is high or low.


Cost-Effectiveness Analysis in Telehealth: A Comparison between Home Telemonitoring, Nurse Telephone Support, and Usual Care in Chronic Heart Failure Management.
To assess the cost effectiveness of home telemonitoring (HTM) and nurse telephone support (NTS) compared with usual care (UC) in the management of patients with chronic heart failure, from a third-party payer's perspective. We developed a Markov model with a 20-year time horizon to analyze the cost effectiveness using the original study (Trans-European Network-Home-Care Management System) and various data sources. A probabilistic sensitivity analysis was performed to assess the decision uncertainty in our model. In the original scenario (which concerned the cost inputs at the time of the original study), HTM and NTS interventions yielded a difference in quality-adjusted life-years (QALYs) gained compared with UC: 2.93 and 3.07, respectively, versus 1.91. An incremental net monetary benefit analysis showed €7,697 and €13,589 in HTM and NTS versus UC at a willingness-to-pay (WTP) threshold of €20,000, and €69,100 and €83,100 at a WTP threshold of €80,000, respectively. The incremental cost-effectiveness ratios were €12,479 for HTM versus UC and €8,270 for NTS versus UC. The current scenario (including telenurse cost inputs in NTS) yielded results that were slightly different from those for the original scenario, when comparing all New York Heart Association (NYHA) classes of severity. NTS dominated HTM, compared with UC, in all NYHA classes except NYHA IV. This modeling study demonstrated that HTM and NTS are viable solutions to support patients with chronic heart failure. NTS is cost-effective in comparison with UC at a WTP of €9000/QALY or higher. Like NTS, HTM improves the survival of patients in all NYHA classes and is cost-effective in comparison with UC at a WTP of €14,000/QALY or higher.


Determination of trace heavy metals in harvested rainwater used for drinking in Hebron (south West Bank, Palestine) by ICP-MS.
Rainwater samples harvested for drinking from the west part of Hebron (south of West Bank in Palestine), the largest city in the West Bank, were analyzed for the content of different trace heavy metals (Cr, Mn, Co, Ni, Cu, Zn, Mo, Ag, Cd, Bi, and Pb) by inductively coupled plasma mass spectrometry (ICP-MS). This study was conducted to determine the water quality of harvested rainwater used for drinking of south West Bank (case study, Hebron area). A total of 44 water samples were collected in November 2012 from 44 house cisterns used to collect rainwater from the roofs of houses. The samples were analyzed for their pH, temperature, electrical conductivity, total dissolved solids, and different heavy metal contents. The pH of all water samples was within the US Environmental Protection Agency limits (6.5-8.5), while some water samples were found to exceed the allowed WHO limit for total dissolved solids (TDSs) in drinking water. Results showed that concentrations of the heavy metals vary significantly between the 44 samples. Results also showed that the concentration of five heavy metals (Cr, Mn, Ni, Ag, and Pb) is higher than the WHO limits for these heavy metals in drinking water. Overall, our findings revealed that harvested rainwater used for drinking of this part of south West Bank is contaminated with heavy metals that might affect human health.


Characterizing dual wavelength polarimetry through the eye for monitoring glucose.
Diabetes is an insidious disease that afflicts millions of people worldwide and typically requires the person with the disease to monitor their blood sugar level via finger or forearm sticks multiple times daily. Therefore, the ability to noninvasively measure glucose would be a significant advancement for the diabetic community. The use of optically polarized light passed through the anterior chamber of the eye is one proposed noninvasive approach for glucose monitoring. However, the birefringence of the cornea and the difficulty in coupling the light across the eye have been major drawbacks toward realizing this approach. A dual wavelength optical polarimetric approach has been proposed as a means to potentially overcome the birefringence noise but has never been fully characterized. Therefore, in this paper an optical model has been developed along with experiments performed on New Zealand White rabbit eyes for characterizing the light path and corneal birefringence at two different wavelengths as they are passed through the anterior chamber of the eye. The results show that, without index matching, it is possible to couple the light in and out of the eye but only across a very limited range otherwise the light does not come back out of the eye. It was also shown that there is potential to use a dual wavelength approach to accommodate the birefringence noise of the cornea in the presence of eye motion. These results will be used to help guide the final design of the polarimetric system for use in noninvasive monitoring of glucose in vivo.


Cognitive behavioral therapy for eating disorders.
Cognitive behavioral therapy (CBT) is the leading evidence-based treatment for bulimia nervosa. A new "enhanced" version of the treatment appears to be more potent and has the added advantage of being suitable for all eating disorders, including anorexia nervosa and eating disorder not otherwise specified. This article reviews the evidence supporting CBT in the treatment of eating disorders and provides an account of the "transdiagnostic" theory that underpins the enhanced form of the treatment. It ends with an outline of the treatment's main strategies and procedures.


Identifying minimally acceptable interpretive performance criteria for screening mammography.
To develop criteria to identify thresholds for minimally acceptable physician performance in interpreting screening mammography studies and to profile the impact that implementing these criteria may have on the practice of radiology in the United States. In an institutional review board-approved, HIPAA-compliant study, an Angoff approach was used in two phases to set criteria for identifying minimally acceptable interpretive performance at screening mammography as measured by sensitivity, specificity, recall rate, positive predictive value (PPV) of recall (PPV(1)) and of biopsy recommendation (PPV(2)), and cancer detection rate. Performance measures were considered separately. In phase I, a group of 10 expert radiologists considered a hypothetical pool of 100 interpreting physicians and conveyed their cut points of minimally acceptable performance. The experts were informed that a physician's performance falling outside the cut points would result in a recommendation to consider additional training. During each round of scoring, all expert radiologists' cut points were summarized into a mean, median, mode, and range; these were presented back to the group. In phase II, normative data on performance were shown to illustrate the potential impact cut points would have on radiology practice. Rescoring was done until consensus among experts was achieved. Simulation methods were used to estimate the potential impact of performance that improved to acceptable levels if effective additional training was provided. Final cut points to identify low performance were as follows: sensitivity less than 75%, specificity less than 88% or greater than 95%, recall rate less than 5% or greater than 12%, PPV(1) less than 3% or greater than 8%, PPV(2) less than 20% or greater than 40%, and cancer detection rate less than 2.5 per 1000 interpretations. The selected cut points for performance measures would likely result in 18%-28% of interpreting physicians being considered for additional training on the basis of sensitivity and cancer detection rate, while the cut points for specificity, recall, and PPV(1) and PPV(2) would likely affect 34%-49% of practicing interpreters. If underperforming physicians moved into the acceptable range, detection of an additional 14 cancers per 100000 women screened and a reduction in the number of false-positive examinations by 880 per 100000 women screened would be expected. This study identified minimally acceptable performance levels for interpreters of screening mammography studies. Interpreting physicians whose performance falls outside the identified cut points should be reviewed in the context of their specific practice settings and be considered for additional training.


Developing and testing of a screening tool to predict people without IgE-mediated allergy: a quantitative analysis of the predictive value of a screening tool.
Consultations in primary care for allergies are common. It can be difficult to differentiate between IgE-mediated (atopic) symptoms - which respond to allergen-specific interventions - and those that are non-atopic, without performing objective tests that are largely unavailable in UK general practice. To develop and test a screening tool that can accurately discriminate between atopic and non-atopic individuals. A validation study that took place in 2012 in adult volunteers aged >16 years in Scotland. A questionnaire screening tool was developed using questions from a large cohort study and through consultation with experts. Participants answered the questions and had skin prick tests for four aeroallergens (house dust mite, cat, dog, and mixed grasses). Participants were classified as atopic if any average wheal diameter was ≥3 mm bigger than the negative control. Sensitivity, specificity, and positive and negative predictive values of individual and combinations of questions were calculated. In all, 143 participants completed the questionnaire and underwent skin prick testing. Of these, 81 (56.6%) were atopic. Negative predictive values for the individual questions ranged from 48.2% (55 not atopic out of 114 negative answers) to 72.0% (18/25). An optimum combination of four questions was identified, in which a negative answer to all four questions was reported by 24 participants, 21 (87.5%) of whom were not atopic. The authors have identified a set of questions that correctly predict negative skin prick tests to common aeroallergens 88% of the time. These may be useful to exclude patients who do not warrant further investigation and who can reliably be advised that allergen avoidance is neither necessary nor helpful.


Registration Accuracy of CT/MRI Fusion for Localisation of Deep Brain Stimulation Electrode Position: An Imaging Study and Systematic Review.
Postoperative imaging is essential for verifying electrode location in patients undergoing deep brain stimulation (DBS). MRI offers better visualisation of brain targets, but concerns about adverse events have limited its use. Preoperative stereotactic MRI fused with a postoperative stereotactic CT, demonstrating the electrode position, is now widely used. The aims of this study were to: (1) evaluate the accuracy of image registration using Neuroinspire, and (2) undertake a systematic review of the literature on CT/MRI fusion techniques to ascertain the accuracy of other software packages. Twenty patients who underwent bilateral subthalamic nucleus DBS for Parkinson's disease were selected. The postoperative CT was registered and fused with the preoperative MRI using Neuroinspire. The position of each electrode tip was determined in stereotactic coordinates both in the (unfused) postoperative CT and the fused CT/MRI. The difference in tip position was used to evaluate the registration accuracy. The mean error ± SD of CT/MRI fusion using Neuroinspire was 0.25 ± 0.15, 0.33 ± 0.26 and 0.46 ± 0.55 mm in lateral, anteroposterior and vertical axes. A systematic review suggested that CT/MRI registration with Neuroinspire is more accurate than that achieved with other tested CT/MRI fusion algorithms. CT/MRI fusion for localisation of electrode placement offers an accurate, reliable and safe modality for assessing electrode location.


Influence of abdominal aortic curvature and resting versus exercise conditions on velocity fields in the normal abdominal aortic bifurcation.
Local hemodynamics are considered an important atherogenetic factor in the abdominal aortic bifurcation. This study addresses the quantitative flow fields in a pulsatile flow model of a normal abdominal aortic bifurcation when encountering realistic upstream anatomy, realistic inlet flow conditions and different physiologic flow conditions (rest vs. exercise). Two-dimensional laser Doppler anemometry measurements gave axial as well as radial velocities. The localization and magnitude of peak velocities, retrograde flow and secondary velocity patterns were found to be determined to a great extent by the curvature of the abdominal aorta, the triphasic flow wave form and the inlet velocity profile. Significant changes were also seen when simulating different physiologic flow conditions. Thus retrograde velocities were present at both the flow divider and the lateral vessel wall for the rest condition but not for the exercise flow conditions, and the location of low and retrograde velocities during diastole were as much determined by abdominal aortic curvature as by the bifurcation for nearly all flow conditions and locations. In conclusion, the anatomy and hemodynamics in the abdominal aorta cannot be neglected when studying the hemodynamics in the abdominal aortic bifurcation.


Device-measured light-intensity physical activity and mortality: A meta-analysis.
The association of light-intensity physical activity (LPA) with mortality is poorly understood. This meta-analysis of cohort studies aimed to examine the dose-response relationships between daily device-measured LPA and mortality in adults aged 18 or older and to explore whether the associations were independent of moderate-to-vigorous physical activity (MVPA). Searches for prospective cohort studies providing effect estimates of daily LPA (exposure) on all-cause mortality (outcome) were systematically undertaken in electronic databases up to April 30, 2019. Subgroup analyses and meta-regression analyses with random-effects models were performed to quantify the dose-response relationships between daily LPA and mortality. Sensitivity analyses were also conducted to assess the stability of the results. A total of 11 studies were included in the meta-analysis. Analyses contained 49 239 individuals (mean age 60.7, SD = 13.6) who were followed up for a mean 6.2 years (2.3-14.2 years), during which 3669 (7.5%) died. In comparison with the reference group (<3 h/d), the pooled HRs (and 95% CIs) of mortality were 0.71 (0.62-0.82), 0.68 (0.59-0.79), 0.56 (0.44-0.71) for groups 3 to <5 h/d, 5 to <7 h/d, and more than 7 hours a day LPA, respectively. Meta-regression models indicated that there was a log-cubic dose-response relationship between daily LPA and mortality in adults and older people, independent of MVPA. Time spent in daily LPA was associated with reduced risks of mortality in adults and older people. These data support the inclusion of LPA in the future physical activity guidelines.


Associations of elements of the Golgi apparatus with microtubules.
The intracellular spatial relationships between elements of the Golgi apparatus (GA) and microtubules in interphase cells have been explored by double immunofluorescence microscopy. By using cultured cells infected with the temperature-sensitive Orsay-45 mutant of vesicular stomatitis virus and a temperature shift-down protocol, we visualized functional elements of the GA by immunolabeling of the G protein of the virus that was arrested in the GA during its intracellular passage to the plasma membrane 13 min after the temperature shift-down. Complete disassembly of the cytoplasmic microtubules by nocodazole at the nonpermissive temperature before the temperature shift led to the dispersal of the GA elements, from their normal compact perinuclear configuration close to the microtubule-organizing center (MTOC) into the cell periphery. Washout of the nocodazole that led to the reassembly of the microtubules from the MTOC also led to the recompaction of the GA elements to their normal configuration. During this recompaction process, GA elements were seen in close lateral apposition to microtubules. In cells treated with nocodazole followed by taxol, an MTOC developed, but most of the microtubules were free of the MTOC and were assembled into bundles in the cell periphery. Under these circumstances, the GA elements that had been dispersed into the cell periphery by the nocodazole treatment remained dispersed despite the presence of an MTOC. In cells treated directly with taxol, free microtubules were seen in the cytoplasm in widely different, bundled configurations from one cell to another, but, in each case, elements of the GA appeared to be associated with one of the two end regions of the microtubule bundles, and to be uncorrelated with the locations of the vimentin intermediate filaments in these cells. These results are interpreted to suggest two types of associations of elements of the GA with microtubules: one lateral, and the other (more stable) end-on. The end-on association is suggested to involve the minus-end regions of microtubules, and it is proposed that this accounts for the GA-MTOC association in normal cells.


Regulators of macrophage activation.
Macrophages are ubiquitous phagocytes that can constitute up to 15% of the cellular content of tissues. These heterogeneous cells of the innate immune system perform important functions during health and disease. Equipped with receptors for the T helper cell cytokines INF-γ and IL-4, macrophages undergo specific activation programs during Th1 or Th2 immune responses. These activation profiles, termed classical (M1) or alternative (M2) activation respectively, are further tuned by the presence and recognition of microbial-associated molecular patterns, other cytokines, lipids, and even adhesion to the substratum. The activation of macrophages also relies on the maturation background of the cells, elicitation of complicated intracellular signalling cascades, and the crosstalk between the different signalling elements. Of interest, not all genes participating in the activation-related signalling cascades are equally important for the elicitation of functional profiles and a regulator gene hierarchy is emerging for the different types of activation. In this issue of the European Journal of Immunology, two papers add to our understanding of how cellular kinases and phosphatases, related to the PI3K pathway, regulate M1 or M2 activation programmes in macrophages.


Reliability of Interaural Time Difference-Based Localization Training in Elderly Individuals with Speech-in-Noise Perception Disorder.
Previous studies have shown that interaural-time-difference (ITD) training can improve localization ability. Surprisingly little is, however, known about localization training vis-à-vis speech perception in noise based on interaural time difference in the envelope (ITD ENV). We sought to investigate the reliability of an ITD ENV-based training program in speech-in-noise perception among elderly individuals with normal hearing and speech-in-noise disorder. The present interventional study was performed during 2016. Sixteen elderly men between 55 and 65 years of age with the clinical diagnosis of normal hearing up to 2000 Hz and speech-in-noise perception disorder participated in this study. The training localization program was based on changes in ITD ENV. In order to evaluate the reliability of the training program, we performed speech-in-noise tests before the training program, immediately afterward, and then at 2 months' follow-up. The reliability of the training program was analyzed using the Friedman test and the SPSS software. Significant statistical differences were shown in the mean scores of speech-in-noise perception between the 3 time points (P=0.001). The results also indicated no difference in the mean scores of speech-in-noise perception between the 2 time points of immediately after the training program and 2 months' follow-up (P=0.212). The present study showed the reliability of an ITD ENV-based localization training in elderly individuals with speech-in-noise perception disorder.


Recruitment of inhibitory neuronal pathways regulating dopaminergic activity for the control of cocaine seeking.
Drug seeking is associated with the ventral tegmental area (VTA) dopaminergic (DA) activity. Previously, we have shown that brief optogenetic inhibition of VTA DA neurons with 1 s pulses delivered every 9 s attenuates cocaine seeking under extinction conditions in rats without producing overt signs of dysphoria or locomotor sedation. Whether recruitment of neuronal pathways inhibiting VTA neuronal activity would suppress drug seeking remains unknown. Here, we asked if optogenetic stimulation of the lateral habenula (LHb) efferents in the rostromedial tegmental nucleus (RMTg) as well as RMTg efferents in VTA would reduce drug seeking. To investigate this, we measured how recruitment of elements of this inhibitory pathway affects cocaine seeking in male rats under extinction conditions. The effectiveness of brief optogenetic manipulations was confirmed electrophysiologically at the level of electrical activity of VTA DA neurons. Real-time conditioned place aversion (RT-CPA) and open field tests were performed to control for potential dysphoric/sedating effects of brief optogenetic stimulation of LHb-RMTg-VTA circuitry. Optogenetic stimulation of either RMTg or LHb inhibited VTA DAergic neuron firing, whereas similar stimulation of RMTg efferents in VTA or LHb efferents in RMTg reduced cocaine seeking under extinction conditions. Moreover, stimulation of LHb-RMTg efferents produced an effect that was maintained 24 h later, during cocaine seeking test without stimulation. This effect was specific, as brief optogenetic stimulation did not affect locomotor activity and was not aversive. Our results indicate that defined inhibitory pathways can be recruited to inhibit cocaine seeking, providing potential new targets for non-pharmacological treatment of drug craving.


11C-Methionine PET of Myocardial Inflammation in a Rat Model of Experimental Autoimmune Myocarditis.
Myocarditis represents a major cause of dilated cardiomyopathy and sudden cardiac death in younger adults. Currently, definitive diagnosis of myocarditis requires endomyocardial biopsy, which is highly invasive and has the drawback of variable sensitivity due to inherent sampling error. Therefore, reliable noninvasive methods to detect and monitor cardiac inflammation are clinically relevant. In this study, we explored the potential of radiolabeled methionine to assess myocardial inflammatory activity in a rat model of experimental autoimmune myocarditis (EAM). Autoimmune myocarditis was induced by immunizing Lewis rats twice with porcine cardiac myosin and Freund complete adjuvant. Control animals were treated with adjuvant alone. Dual-tracer autoradiography was performed to assess 14C-methionine uptake and to compare the distributions of 14C-methionine versus 18F-FDG. Hematoxylin and eosin staining and anti-CD68 macrophage staining were performed for histologic analysis. Additionally, cardiac 11C-methionine PET was performed to evaluate the feasibility of in vivo imaging. 18F-FDG PET was also conducted to compare the in vivo uptake of 11C-methionine and 18F-FDG. Multiple focal cardiac inflammatory lesions were histologically identified in myosin-immunized rats, whereas no cardiac lesions were observed in the controls. Autoradiographic images clearly showed a high-density accumulation of 14C-methionine in inflammatory lesions of EAM rats, whereas no significant uptake was observed in the control animals. 14C-methionine uptake was significantly higher in inflammatory lesions than in remote noninflammatory areas and control rat hearts. The distribution of 14C-methionine correlated well with that of 18F-FDG and with macrophage density. The contrast between inflammatory and noninflammatory areas was higher for 18F-FDG than for 14C-methionine (3.45 ± 0.68 vs. 2.07 ± 0.21, respectively; P < 0.05). In the PET imaging study, the regional 11C-methionine uptake (percentage injected dose per cubic centimeter) observed in EAM rats was significantly higher than the values obtained for control animals (0.64 ± 0.09 vs. 0.28 ± 0.02, respectively; P < 0.001). A good positive correlation between 11C-methionine and 18F-FDG uptake was found. In a rat model of autoimmune myocarditis, we demonstrated the colocalization of radiolabeled methionine accumulation with 18F-FDG uptake in histologically proven inflammatory lesions. These data suggest that 11C-methionine might represent a promising candidate for the noninvasive detection and monitoring of myocarditis.


Integration of non-oral bacteria into in vitro oral biofilms.
Biofilms are polymicrobial communities that grow on surfaces in nature. Oral bacteria can spontaneously form biofilms on the surface of teeth, which may compromise the health of the teeth, or their surrounding (periodontal) tissues. While the oral bacteria exhibit high tropism for their specialized ecological niche, it is not clear if bacteria that are not part of the normal oral microbiota can efficiently colonize and grow within oral biofilms. By using an in vitro "supragingival" biofilm model of 6 oral species, this study aimed to investigate if 3 individual bacterial species that are not part of the normal oral microbiota (Eschericia coli, Staphylococcus aureus, Enterococcus faecails) and one not previously tested oral species (Aggregatibacter actinomycetemcomitans) can be incorporated into this established supragingival biofilm model. Staphylococcus aureus and A. actinomycetemcomitans were able to grow efficiently in the biofilm, without disrupting the growth of the remaining species. They localized in sparse small aggregates within the biofilm mass. Enterococcus faecalis and E. coli were both able to populate the biofilm at high numbers, and suppressed the growth of A. oris and S. mutants. Enterococcus faecalis was arranged in a chain-like conformation, whereas E. coli was densely and evenly spread throughout the biofilm mass. In conclusion, it is possible for selected species that are not part of the normal oral microbiota to be introduced into an oral biofilm, under the given experimental micro-environmental conditions. Moreover, the equilibrated incorporation of A. actinomycetemcomitans and S. aureus in this oral biofilm model could be a useful tool in the study of aggressive periodontitis and peri-implantitis, in which these organisms are involved, respectively.


Disrupted functional brain connectivity networks in children with attention-deficit/hyperactivity disorder: evidence from resting-state functional near-infrared spectroscopy.
Significance: Attention-deficit/hyperactivity disorder (ADHD) is the most common psychological disease in childhood. Currently, widely used neuroimaging techniques require complete body confinement and motionlessness and thus are extremely hard for brain scanning of ADHD children. Aim: We present resting-state functional near-infrared spectroscopy (fNIRS) as an imaging technique to record spontaneous brain activity in children with ADHD. Approach: The brain functional connectivity was calculated, and the graph theoretical analysis was further applied to investigate alterations in the global and regional properties of the brain network in the patients. In addition, the relationship between brain network features and core symptoms was examined. Results: ADHD patients exhibited significant decreases in both functional connectivity and global network efficiency. Meanwhile, the nodal efficiency in children with ADHD was also found to be altered, e.g., increase in the visual and dorsal attention networks and decrease in somatomotor and default mode networks, compared to the healthy controls. More importantly, the disrupted functional connectivity and nodal efficiency significantly correlated with dimensional ADHD scores. Conclusions: We clearly demonstrate the feasibility and potential of fNIRS-based connectome technique in ADHD or other neurological diseases in the future.


Microbial genome sequencing and pathogenesis.
The year 1997 saw the publication of the complete nucleotide sequence of Helicobacter pylori and Escherichia coli. It is conceivable that the complete nucleotide sequence for all the major human bacterial pathogens will be available by the end of the century. Database alignments have been used to ascribe the putative functions of open reading frames in the sequenced isolates and to define the differences between bacterial species at the nucleotide level. The most striking finding from all genome projects has been the high proportion of open reading frames that have no known function. Experimental data demonstrating the utility of the genome sequencing projects are only just beginning to emerge.


Young children who commit crime: epidemiology, developmental origins, risk factors, early interventions, and policy implications.
An early onset of delinquency prior to age 13 years increases the risk of later serious, violent, and chronic offending by a factor of 2-3. Also child delinquents, compared to juveniles who start offending at a later age, tend to have longer delinquent careers. This article summarizes the report of the Office of Juvenile Justice and Delinquency Prevention's Study Group on Very Young Offenders, chaired by Rolf Loeber and David P. Farrington. The Study Group, consisting of 16 scholars and 23 coauthors, worked for 2 years on preparing a report, undertaking extensive secondary data analyses, and writing chapters in different speciality areas. The report consists of a state of the art review of the developmental background of child delinquents. The report also summarizes risk and protective factors in the individual, family, peer group, school, and neighborhood that affect that development. Lastly, the report renews relevant preventive and remedial interventions in the juvenile justice system, families, peer groups, schools. and neighborhoods, and makes a case for improvement in the integration of services for child delinquents. Policy recommendations are presented to improve methods of dealing with child delinquents by juvenile justice, child welfare, and mental health agencies.


Intraspecific competition in ant-lion (Macroleon quinquemaculatus) larvae in the field.
The number of larvae of the pit-digging ant-lion Macroleon quinquemaculatus at a food-poor site in Tanzania increased between May and October 1983 and then remained at high density until the following rainy season in March. Food availability was low and small larvae were most likely to suffer food shortage. Hunger level varied within and between instars: hunger was greatest after moults and only third-instar larvae weighing more than 100 mg were well fed. A simple model showed that exploitation competition was asymmetric and most likely to affect small larvae, by removing small prey. Exploitation was estimated to reduce food intake by 30-60%. Within-site differences in growth rate and size were associated with differences in larval density. Small larvae were much more likely to move than large larvae; the latter tended to occupy the periphery of the habitat. The reduction in food intake experienced by small larvae was a consequence of interference competition, which was the main factor operating at this site.


Corneal topography-guided penetrating keratoplasty and suture adjustment: new approach for astigmatism control.
To describe a new keratoplasty procedure using intraoperative topography to reduce postoperative astigmatism. One hundred sixty-five eyes of 150 consecutive patients were enrolled in this prospective study. The most common diagnosis was keratoconus (78.8%). As many as 5.5% had post-laser in situ keratomileusis ectasia. Keratoplasty was performed with the Hanna Corneal Trephine System. A 24-bite running suture was placed, using a specially developed marker. Suture adjustment was performed with the aid of an intraoperative topographer (Keratron Scout; OPTIKON 2000, Rome, Italy). The aim of the adjustment was to obtain an astigmatism < or =2.0 D on the operating table. In case of >3.0 D of astigmatism at 1 month after surgery, suture adjustment was performed using the same intraoperative topographer. At 12 months postoperatevely (suture in), data from 108 (64%) eyes were available. The mean refractive astigmatism was 3.53 D, and the mean topographical astigmatism was 4.7 D. At 18 months (suture out), data from 32 eyes (19.4%) were available, and at 24 months, data from 29 eyes (13.3%) were available. The mean refractive astigmatism was 3.39 D at 18 months and 3.47 D at 24 months. The mean topographic astigmatism was 2.30 D at 18 months and 1.76 D at 24 months. Mean best spectacle-corrected visual acuity (BSCVA) was 0.51 at 3 months, 0.63 at 12 months (suture in), 0.67 at 18 months (suture out), and 0.78 at 24 months postoperatively. The combination of intraoperative topography and a 24-bite single running suture resulted in a stable astigmatism throughout the follow-up period, even after suture removal. BSCVA reached a 20/40 level as early as 3 months postoperatively and continued to rise after suture removal. The stability of astigmatism and BSCVA shortened the postoperative visual rehabilitation time and provided a high quality of vision early in the postoperative period.


Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults.
Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% had amyloid-β (Aβ) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aβ plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrP(C)) was seen in highly exposed subjects. The down-regulation of the PrP(C) is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrP(C) and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders.


Prolonged mechanical ventilation with air induces apoptosis and causes failure of alveolar septation and angiogenesis in lungs of newborn mice.
Defective lung septation and angiogenesis, quintessential features of neonatal chronic lung disease (CLD), typically result from lengthy exposure of developing lungs to mechanical ventilation (MV) and hyperoxia. Previous studies showed fewer alveoli and microvessels, with reduced VEGF and increased transforming growth factor-beta (TGFbeta) signaling, and excess, scattered elastin in lungs of premature infants and lambs with CLD vs. normal controls. MV of newborn mice with 40% O(2) for 24 h yielded similar lung structural abnormalities linked to impaired VEGF signaling, dysregulated elastin production, and increased apoptosis. These studies could not determine the relative importance of cyclic stretch vs. hyperoxia in causing these lung growth abnormalities. We therefore studied the impact of MV for 24 h with air on alveolar septation (quantitative lung histology), angiogenesis [CD31 quantitative-immunohistochemistry (IHC), immunoblots], apoptosis [TdT-mediated dUTP nick end labeling (TUNEL), active caspase-3 assays], VEGF signaling [VEGF-A, VEGF receptor 1 (VEGF-R1), VEGF-R2 immunoblots], TGFbeta activation [phosphorylated Smad2 (pSmad2) quantitative-IHC], and elastin production (tropoelastin immunoblots, quantitative image analysis of Hart's stained sections) in lungs of 6-day-old mice. Compared with unventilated controls, MV caused a 3-fold increase in alveolar area, approximately 50% reduction in alveolar number and endothelial surface area, >5-fold increase in apoptosis, >50% decrease in lung VEGF-R2 protein, 4-fold increase of pSmad2 protein, and >50% increase in lung elastin, which was distributed throughout alveolar walls rather than at septal tips. This study is the first to show that prolonged MV of developing lungs, without associated hyperoxia, can inhibit alveolar septation and angiogenesis and increase apoptosis and lung elastin, findings that could reflect stretch-induced changes in VEGF and TGFbeta signaling, as reported in CLD.


Conserving the stage: climate change and the geophysical underpinnings of species diversity.
Conservationists have proposed methods for adapting to climate change that assume species distributions are primarily explained by climate variables. The key idea is to use the understanding of species-climate relationships to map corridors and to identify regions of faunal stability or high species turnover. An alternative approach is to adopt an evolutionary timescale and ask ultimately what factors control total diversity, so that over the long run the major drivers of total species richness can be protected. Within a single climatic region, the temperate area encompassing all of the Northeastern U.S. and Maritime Canada, we hypothesized that geologic factors may take precedence over climate in explaining diversity patterns. If geophysical diversity does drive regional diversity, then conserving geophysical settings may offer an approach to conservation that protects diversity under both current and future climates. Here we tested how well geology predicts the species diversity of 14 US states and three Canadian provinces, using a comprehensive new spatial dataset. Results of linear regressions of species diversity on all possible combinations of 23 geophysical and climatic variables indicated that four geophysical factors; the number of geological classes, latitude, elevation range and the amount of calcareous bedrock, predicted species diversity with certainty (adj. R(2) = 0.94). To confirm the species-geology relationships we ran an independent test using 18,700 location points for 885 rare species and found that 40% of the species were restricted to a single geology. Moreover, each geology class supported 5-95 endemic species and chi-square tests confirmed that calcareous bedrock and extreme elevations had significantly more rare species than expected by chance (P<0.0001), strongly corroborating the regression model. Our results suggest that protecting geophysical settings will conserve the stage for current and future biodiversity and may be a robust alternative to species-level predictions.


Does quantifying epicardial and intrathoracic fat with noncontrast computed tomography improve risk stratification beyond calcium scoring alone?
Noncontrast cardiac computed tomography allows calculation of coronary artery calcium score (CACS) and measurement of epicardial adipose tissue (EATv) and intrathoracic fat (ITFv) volumes. It is unclear whether fat volume information contributes to risk stratification. Cardiac computed tomography was performed in 760 consecutive patients with acute chest pain admitted thorough the emergency department. None had prior coronary artery disease. CACS was calculated using the Agatston method. EATv and ITFv were semiautomatically calculated. Median patient follow-up was 3.3 years. Mean patient age was 54.4±13.7 years and Framingham risk score 8.2±8.2. The 45 patients (5.9%) with major acute cardiac events (MACE) were older (64.8±13.9 versus 53.7±13.4 years), more frequently male (60% versus 40%), and had a higher median Framingham risk score (16 versus 4) and CACS (268 versus 0) versus those without events (all P<0.01). The MACE group had a higher median of EATv (154 versus 116 mL) and ITFv (330 versus 223 mL), and a higher prevalence of EATv >125 mL (67% versus 44%) and ITFv >250 mL (64% versus 42%) (all P<0.01). CACS, EATv, and ITFv were all independently associated with MACE. CACS was associated with MACE after adjustment for fat volumes (P<0.0001), whereas EATv and ITFv improved the risk model only in patients with CACS >400. CACS and fat volumes are independently associated with MACE in acute chest pain patients and beyond that provided by clinical information alone. Although fat volumes may add prognostic value in patients with CACS >400, CACS is most strongly correlated with outcome.


PREVALENCE, ANTIBIOTIC AND PULSED-FIELD GEL ELECTROPHORESIS PATTERNS OF STAPHYLOCOCCUS AUREUS SMALL-COLONY VARIANTS IN CYSTIC FIBROSIS PATIENTS.
Staphylococcus aureus is the most common pathogen isolated from respiratory tract samples in cystic fibrosis (CF) cases. Rate of infection with S. aureus small-colony variants (SCVs) also is increasing in CF patients. In this study, we aimed to determine the prevalence, antibiotic susceptibility and genotypic property of S. aureus SCVs in respiratory tract samples of CF patients admitted to Istanbul Faculty of Medicine Hospital, Turkey. Among 305 respiratory tract samples from 84 CF patients, normal S. aureus isolates were present in 71% of the CF patients and S. aureus SCVs in 21%. The highest antibiotic resistance was against penicillin (82%) followed by clarithromycin (21%) in S. aureus SCVs, while resistance to levofloxacin was low (2%) in normal S. aureus isolates but was 16% in S. aureus SCVs. No mecA and mecC were detected. The S. aureus strains constituted 24 different genotypes based on pulsed field gel-electrophoresis assay. The possible existence of S. aureus SCVs that are more resistant to antibiotis than normal S. aureus should be taken into considerstion when treating CF patients for this pernicious bacterial infection.


Congenital myasthenic syndrome caused by mutations in DPAGT.
Congenital myasthenic syndromes with prominent limb girdle involvement are an important differential diagnosis for congenital myopathies because of the therapeutic considerations. We present a case where accurate diagnosis was delayed for many years. Fluctuations of weakness were misinterpreted as effects of alternative treatments. Weakness was generalised, most prominently in the arms. Fatigability was more prominent in less affected muscles revealed by a positive Simpson test. Stimulation single fibre electromyography confirmed the suspected neuromuscular transmission defect. The marked response to pyridostigmine and cognitive impairment pointed to a myasthenic syndrome due to impaired glycosylation. Two mutations in trans were found in DPAGT1, the gene coding for dolichyl-phosphate N-acetylglucosaminephosphotransferase, one novel, the other previously reported in a rare form of congenital disorder of glycosylation. Gene expression studies revealed that both mutations reduce DPAGT1 expression. Phenotypic features not previously described for DPAGT1 CMS included restricted ocular abduction and long finger flexor contractures.


Holy basil (Ocimum sanctum Linn.) leaf extract enhances specific cognitive parameters in healthy adult volunteers: A placebo controlled study.
Ocimum sanctum (OS), known as Holy basil, has been documented to possess neuroprotective, cognition-enhancing and stress relieving effects in animal models. However there is paucity of clinical studies to document these effects. Effect of OS on parameters related to cognition and stress in humans was evaluated with administration of 300 milligram capsules of ethanolic leaf extracts of Ocimum sanctum (EtOS) or placebo per day, over 30 days. Intra-group comparison of Sternberg and Stroop test showed improvement in both the placebo and EtOS groups, however, the improvement stabilized after day 15 in the placebo group. Intergroup comparison revealed a significant improvement of the following cognitive parameters in the EtOS as compared to the placebo: reaction time (RT) and error rate (ER) of Sternberg test, RT of neutral task of Stroop, RT and ER of interference task of Stroop. The intra-group comparison of P300 latency, salivary cortisol, and State-Trait Anxiety Inventory showed improvement over time in the EtOS group alone, though the inter-group difference was significant in the P300 latency alone. There were no changes in heart rate (HR), AHR, or galvanic skin response (GSR) or AGSR. Ocimum sanctum leaf extract seems to have potential cognition-enhancing properties in humans.


Combined Treatment of Heteronemin and Tetrac Induces Antiproliferation in Oral Cancer Cells.
Heteronemin, a marine sesterterpenoid-type natural product, possesses an antiproliferative effect in cancer cells. In addition, heteronemin has been shown to inhibit p53 expression. Our laboratory has demonstrated that the thyroid hormone deaminated analogue, tetrac, activates p53 and induces antiproliferation in colorectal cancer. However, such drug mechanisms are still to be studied in oral cancer cells. We investigated the antiproliferative effects by Cell Counting Kit-8 and flow cytometry. The signal transduction pathway was measured by Western blotting analyses. Quantitative PCR was used to evaluate gene expression regulated by heteronemin, 3,3',5,5'-tetraiodothyroacetic acid (tetrac), or their combined treatment in oral cancer cells. Heteronemin inhibited not only expression of proliferative genes and Homo Sapiens Thrombospondin 1 (THBS-1) but also cell proliferation in both OEC-M1 and SCC-25 cells. Remarkably, heteronemin increased TGF-β1 expression in SCC-25 cells. Tetrac suppressed expression of THBS-1 but not p53 expression in both cancer cell lines. Furthermore, the synergistic effect of tetrac and heteronemin inhibited ERK1/2 activation and heteronemin also blocked STAT3 signaling. Combined treatment increased p53 protein and p53 activation accumulation although heteronemin inhibited p53 expression in both cancer cell lines. The combined treatment induced antiproliferation synergistically more than a single agent. Both heteronemin and tetrac inhibited ERK1/2 activation and increased p53 phosphorylation. They also inhibited THBS-1 expression. Moreover, tetrac suppressed TGF-β expression combined with heteronemin to further enhance antiproliferation and anti-metastasis in oral cancer cells.


Graphene oxide modulates dendritic cell ability to promote T cell activation and cytokine production.
An important aspect of immunotherapy is the ability of dendritic cells (DCs) to prime T cell immunity, an approach that has yielded promising results in some early phase clinical trials. However, novel approaches are required to improve DC therapeutic efficacy by enhancing their uptake of, and activation by, disease relevant antigens. The carbon nano-material graphene oxide (GO) may provide a unique way to deliver antigen to innate immune cells and modify their ability to initiate effective adaptive immune responses. We have assessed whether GO of various lateral sizes affects DC activation and function in vitro and in vivo, including their ability to take up, process and present the well-defined model antigen ovalbumin (OVA). We have found that GO flakes are internalised by DCs, while having minimal effect on their viability, activation phenotype or cytokine production. Although adsorption of OVA protein to either small or large GO flakes promoted its uptake into DCs, large GO interfered with OVA processing. In terms of modulation of DC function, delivery of OVA via small GO flakes significantly enhanced DC ability to induce proliferation of OVA-specific CD4+ T cells, promoting granzyme B secretion in vitro. On the other hand, delivery of OVA via large GO flakes augmented DC ability to induce proliferation of OVA-specific CD8+ T cells, and their production of IFN-γ and granzyme B. Together, these data demonstrate the capacity of GO of different lateral dimensions to act as a promising delivery platform for DC modulation of distinct facets of the adaptive immune response, information that could be exploited for future development of targeted immunotherapies.


Early bilateral sensory deprivation blocks the development of coincident discharge in rat barrel cortex.
Several theories have proposed a functional role for synchronous neuronal firing in generating the neural code of a sensory perception. Synchronous neural activity develops during a critical postnatal period of cortical maturation, and severely reducing neural activity in a sensory pathway during this period could interfere with the development of coincident discharge among cortical neurons. Loss of such synchrony could provide a fundamental mechanism for the degradation of acuity shown in behavioral studies. We tested the hypothesis that synchronous discharge of barrel cortex neurons would fail to develop after sensory deprivation produced by bilateral whisker trimming from birth to postnatal day 60. By studying the correlated discharge of cortical neuron pairs, we found evidence for strong correlated firing in control animals, and this synchrony was almost absent among pairs of cortical barrel neurons in deprived animals. The degree of synchrony impairment was different in subregions of rat barrel cortex. The model that best fits the data is that cortical neurons receiving direct inputs from the primary sensory (lemniscal) pathway show the greatest decrement in synchrony following sensory deprivation, while neurons with diverse inputs from other areas of thalamus and cortex are relatively less affected in this dimension of cortical function.


Distinct Ecological Niche of Anal, Oral, and Cervical Mucosal Microbiomes in Adolescent Women.
Human body sites represent ecological niches for microorganisms, each providing variations in microbial exposure, nutrient availability, microbial competition, and host immunological responses. In this study, we investigated the oral, anal, and cervical microbiomes from the same 20 sexually active adolescent females, using culture-independent, next-generation sequencing. DNA from each sample was amplified for the bacterial 16S rRNA gene and sequenced on an Illumina platform using paired-end reads. Across the three anatomical niches, we found significant differences in bacterial community composition and diversity. Overall anal samples were dominated with Prevotella and Bacteriodes, oral samples with Streptococcus and Prevotella, and cervical samples with Lactobacillus. The microbiomes of a few cervical samples clustered with anal samples in weighted principal coordinate analyses, due in part to a higher proportion of Prevotella in those samples. Additionally, cervical samples had the lowest alpha diversity. Our results demonstrate the occurrence of distinct microbial communities across body sites within the same individual.


Alternative generation of CNS neural stem cells and PNS derivatives from neural crest-derived peripheral stem cells.
Neural crest-derived stem cells (NCSCs) from the embryonic peripheral nervous system (PNS) can be reprogrammed in neurosphere (NS) culture to rNCSCs that produce central nervous system (CNS) progeny, including myelinating oligodendrocytes. Using global gene expression analysis we now demonstrate that rNCSCs completely lose their previous PNS characteristics and acquire the identity of neural stem cells derived from embryonic spinal cord. Reprogramming proceeds rapidly and results in a homogenous population of Olig2-, Sox3-, and Lex-positive CNS stem cells. Low-level expression of pluripotency inducing genes Oct4, Nanog, and Klf4 argues against a transient pluripotent state during reprogramming. The acquisition of CNS properties is prevented in the presence of BMP4 (BMP NCSCs) as shown by marker gene expression and the potential to produce PNS neurons and glia. In addition, genes characteristic for mesenchymal and perivascular progenitors are expressed, which suggests that BMP NCSCs are directed toward a pericyte progenitor/mesenchymal stem cell (MSC) fate. Adult NCSCs from mouse palate, an easily accessible source of adult NCSCs, display strikingly similar properties. They do not generate cells with CNS characteristics but lose the neural crest markers Sox10 and p75 and produce MSC-like cells. These findings show that embryonic NCSCs acquire a full CNS identity in NS culture. In contrast, MSC-like cells are generated from BMP NCSCs and pNCSCs, which reveals that postmigratory NCSCs are a source for MSC-like cells up to the adult stage.


Dendritic cells infected with Mycobacterium bovis bacillus Calmette Guerin activate CD8(+) T cells with specificity for a novel mycobacterial epitope.
Although CD4(+) T cells are essential for protective immunity against Mycobacterium tuberculosis infection, recent reports indicate that CD8(+) T cells may also play a critical role in the control of this infection. However, the epitope specificity and the mechanisms of activation of mycobacteria-reactive CD8(+) T cells are poorly characterized. In order to study the CD8(+) T cell responses to the model mycobacterial antigen, MPT64, we used recombinant vaccinia virus expressing MPT64 (VVWR-64) and a panel of MPT64-derived peptides to establish that the peptide MPT64(190-198) contains an H-2D(b)-restricted CD8(+) T cell epitope. A cytotoxic T lymphocyte response to this peptide could be demonstrated in M. bovis bacillus Calmette Guerin (BCG)-infected mice following repeated in vitro stimulation. When bone marrow-derived dendritic cells (DC) were infected with BCG, the expression of MHC class I molecules by DC was up-regulated in parallel with MHC class II and B7-2, whereas CD1d expression level was not modified. Moreover, BCG-infected DC activated MPT64(190-198)-specific CD8(+) T cells to secrete IFN-gamma, although with a lower efficacy than VVWR-64-infected DC. The production of IFN-gamma by MPT64(190-198)-specific CD8(+) T cells was inhibited by antibodies to MHC class I, but not to CD1d. These data suggest that mycobacteria-specific CD8(+) T cells are primed during infection. Therefore, anti-mycobacterial vaccine strategies targeting the activation of specific CD8(+) T cells by DC may have improved protective efficacy.


Agreement and Correlation between Arterial and Central Venous Blood Gas Following Coronary Artery Bypass Graft Surgery.
Arterial blood sampling, used to assess patients in acute conditions, may result in complications such as thrombosis and embolism. However, it can be replaced by venous blood sampling, but there is a dearth of information on this. To assess the correlation and agreement between the arterial and central venous blood gases analyses in patients undergoing elective Coronary Artery Bypass Graft (CABG) surgery. In this cross-sectional study, 100 ICU patients undergoing elective CABG surgery were recruited. 2 mm arterial and a 2 mm venous blood samples were obtained from each patient's arterial and central venous lines, respectively. To predict Arterial Blood Gas (ABG) values based on central Venous Blood Gas (VBG) values, the linear regression analysis was used and for evaluating their agreement Bland-Altman method was used. In total of 200 samples were obtained. The mean and Standard Deviation (SD) of age was 58.9±9.1 years and 51% of the participants were female. There was a strong correlation between ABG and central VBG values regarding pH, partial Pressure of Carbon Dioxide (PCO2), Bicarbonate (HCO3) and Base Excess (BE) (r= 0.73, r=0.74, r=0.67 and r=0.71, respectively; p<0.001); however, the correlation between the arterial and venous Partial Pressure of Oxygen (PO2) and Oxygen Saturation (SO2) was moderate (r=0.29, p=0.005 and r=0.27, p=0.006, respectively). The Bland-Altman analysis showed an excellent agreement between all the variables (p<0.001). Central VBG analysis cannot replace ABG analysis in measuring exact PO2 status, necessitating arterial sampling in some matters, but with respect to the accuracy of pulse oximetry measurements in determining the exact PO2 status, for the rest of the indices a central VBG rather than an ABG can be utilised for determining patient's acid-base status. Particularly in patients who are hospitalised for a long time and have a central venous catheter in place like patients who have undergone CABG, thus reducing the risk and need for invasive arterial sampling.


Laparoscopic pyeloplasty with simultaneous pyelolithotomy using a flexible ureteroscope.
Laparoscopic pyeloplasty is rapidly becoming the gold standard in the repair of adults with uretero-pelvic junction obstruction. Renal calculi are a recognized complication of uretero-pelvic junction obstruction and their presence has often been used to justify percutaneous nephrolithotomy and endopyelotomy as primary treatment. Stones developing secondary to uretero-pelvic junction obstruction have been removed through simultaneous laparoscopic pyeloplasty and pyelolithotomy, but with rigid laparoscopic instruments access is limited to the renal pelvis. As exemplified within this report, endourologic techniques such as flexible ureteroscopy can be combined with laparoscopic pyeloplasty to deal with complex stone disease and to provide optimal treatment of the patient with a uretero-pelvic junction obstruction.


Low Fidelity Trainer for Fiberoptic Scope Use in the Emergency Department.
The low fidelity trainer for fiberoptic scope is designed to train emergency medicine (EM) residents PGY I-IV, and medical students interested in EM. Fiberoptic intubation is a skill that Emergency Medicine (EM) providers should be familiar with, though it is a rarely encountered procedure in the clinical setting. Approximately 1% of endotracheal intubations are performed using fiberoptic intubation.1,2 The success rate of first attempt fiberoptic intubation is about 50%. When fiberoptic intubation is used as a rescue device it has been shown to be about 70 % successful.1 Despite being an important skill for emergency physicians to have, fiberoptic intubation competency is not required during emergency medicine residency1 and resident physicians have limited exposure to learning this life-saving skill.Given that fiberoptic intubation is a rarely performed procedure in the clinical setting, the most practical way for EM learners to gain proficiency would be through simulation. The use of fiberoptic trainers in anesthesiologist resident training has shown improvement in first pass success and overall skills with using the fiberoptic scope.3-6 Simulation has also been shown to improve resident procedural knowledge and skills in many other fields.7-11 Simulation offers training with seldom performed procedures, and there is evidence that simulation does improve patient outcomes and reduce errors.2,12-14 In order to help EM learners gain confidence and increase their comfort in using the fiberoptic scope, we developed a low fidelity training model that allows the learner to practice fiberoptic intubation. By the end of this training session, learners will be able to 1) list indications, contraindication, and complications in performing fiberoptic intubations, 2) know how to use and maneuver a fiberoptic scope, and 3) be able to successfully intubate the trainer model. The training model consists of a large 55-gallon tote with polyvinyl chloride (PVC) pipes enclosed in the tote. The pipes were arranged in various manners: several pipes simulated the oropharynx and trachea, and others were arranged into a series of mazes, to require the learner to manipulate the scope through the maze to reach the end. The multiple stations within the model provided ample opportunity for the learner to acquire confidence with the fiberoptic scope and the movements required to maneuver the scope into position. The model was used in our weekly Emergency Medicine conference during a low fidelity simulation day. The residents were split into groups consisting of 5-6 learners. The residents and medical students were given a brief 5-minute lecture on fiberoptic intubation, which reviewed indications for fiberoptic intubation, and a demonstration on how to operate the fiberoptic scope. Following the briefing, each group had approximately 25-30 minutes to practice using the simulated fiberoptic scope model. Each learner in the group was then encouraged to practice navigating the other mazes at their own discretion. Residents and medical students were given a survey before and after using the fiberoptic training model to assess their knowledge and confidence in performing the procedure. The use of the fiberoptic trainer was successful in helping learners to become more familiar with the fiberoptic scope and learn the skills to maneuver the scope successfully through the trainer. Each resident performed a survey prior to and after the fiberoptic instruction and training. They were asked to rate their confidence in identifying airway landmarks, perform the procedure without supervision, and identify correct supplies needed for procedure. All areas increased in confidence except in identifying correct supplies for PGY-II (-0.1), and PGY-III (-0.4). The greatest increase was amongst PGY-I residents in confidence identifying airway landmarks, with an increase of 4.2. As with any simulation model, this model does not perfectly recreate human anatomy. For example, in our model there were no simulated secretions or blood. The actual appearance of the anatomy will be very different from that which was used in our model, which may lead to an unsuccessful intubation attempt. The scenarios in which we were using the trainer was a low stress environment, unlike the usual emergency setting. Despite this, there was an increase in learner confidence in using a fiberoptic scope to manage emergency airways. It also offered a unique experience and gave the learners an opportunity to learn how to manipulate the fiberoptic scope that a traditional high fidelity model may not offer. Future comparisons could be made between a low fidelity simulation and high fidelity simulation device, and the addition of simulated secretions could help increase learning and confidence in fiberoptic intubations. Difficult airway management, Fiberoptic intubation, fiberoptic use in emergency department.


Health inequalities, risky behaviours and protective factors in adolescents: an analysis of secondary survey data from the UK.
Adolescents are at risk of developing detrimental health behaviours that will affect their adult health. The aim was to estimate prevalence of health risk behaviours (HRB), comparing young people (12-18 years old) in Wiltshire (UK) who are vulnerable (looked after children, special education needs and disabilities, young carers and military dependents) to those who are not vulnerable and assess whether these behaviours are associated with protective factors (e.g. friendship groups). Secondary analysis of cross-sectional survey data (n = 4129). In total, 900 vulnerable young people were compared with 3229 non-vulnerable young people. Differences between the two groups were assessed using Chi-squared tests, and associations with possible protective factors were assessed using logistic regression (adjusting for confounding factors). Vulnerable young people have a higher prevalence of smoking tobacco (15% vs 9%, P < 0.001), using cannabis (7% vs 5%, P = 0.03) and self-harming (16% vs 9%, P < 0.001) monthly or more compared with the rest of the Wiltshire adolescent population. Whilst vulnerable young people have many shared protective factors with non-vulnerable young people, there are also differences between the two groups. There are shared protective factors across HRB that can build on the resilience of a young person, impacting their current and future health. Therefore, we should focus our attention on developing protective factors that promote health and well-being, not solely delivering specialist interventions targeted at specific risks. Further consideration should be given to identifying and promoting protective factors specifically for vulnerable people as they have higher levels of HRB and experience protective factors differently.


Autosomal Dominant Hypocalcemia Type 1 (ADH1) Associated With Myoclonus and Intracerebral Calcifications.
Autosomal dominant hypocalcemia type 1 (ADH1) is a disorder of extracellular calcium homeostasis caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR). More than 35% of ADH1 patients have intracerebral calcifications predominantly affecting the basal ganglia. The clinical consequences of such calcifications remain to be fully characterized, although the majority of patients with these calcifications are considered to be asymptomatic. We report a 20-year-old female proband with a severe form of ADH1 associated with recurrent hypocalcemic and hypercalcemic episodes, persistent childhood hyperphosphatemia, and a low calcium/phosphate ratio. From the age of 18 years, she had experienced recurrent myoclonic jerks affecting the upper limbs that were not associated with epileptic seizures, extra-pyramidal features, cognitive impairment, or alterations in serum calcium concentrations. Computed tomography (CT) scans revealed calcifications of the globus pallidus regions of the basal ganglia bilaterally, and also the frontal lobes at the gray-white matter junction, and posterior horn choroid plexuses. The patient's myoclonus resolved following treatment with levetiracetam. CASR mutational analysis identified a reported germline gain-of-function heterozygous missense mutation, c.2363T>G; p.(Phe788Cys), which affects an evolutionarily conserved phenylalanine residue located in transmembrane domain helix 5 of the CaSR protein. Analysis of the cryo-electron microscopy CaSR structure predicted the wild-type Phe788 residue to form interactions with neighboring phenylalanine residues, which likely maintain the CaSR in an inactive state. The p.(Phe788Cys) mutation was predicted to disrupt these interactions, thereby leading to CaSR activation. These findings reveal myoclonus as a novel finding in an ADH1 patient with intracerebral calcifications.


Phase-specific bioactivity and altered Ostwald ripening pathways of calcium carbonate polymorphs in simulated body fluid.
Calcium carbonate is an abundant biomineral, and already archeological records demonstrate its bioactivity and applicability for osseo-integrative implants. Its solubility, which is generally higher than those of calcium phosphates, depends on its polymorph turning calcium carbonate into a promising biomaterial with tunable bioresorption rate. However, the phase-dependent bioactivity of calcium carbonate, i.e., its osteoconductivity, is still insufficiently characterized. In this study, we address this issue by monitoring the behavior of the four most important calcium carbonate phases, i.e., calcite, aragonite, vaterite, and amorphous calcium carbonate, in simulated body fluid solution at 37 °C. Our results demonstrate that the thermodynamically stable calcite phase is essentially inert. In contrast, the metastable phases aragonite and vaterite are bioactive, thus promoting the formation of calcium phosphate. Amorphous calcium carbonate (ACC) shows prominent bioactivity accompanied by pronounced redissolution processes. Mg-stabilized ACC was additionally tested since its increased stability eases formulation and handling in future applications. It is highly bioactive and, moreover, the additional release of Mg promotes cell viability. Overall, our results demonstrate that bioactivity of calcium carbonate is phase-dependent, allowing tailored response and bioactivity of future calcareous biomaterials. Our results also reveal that phosphate ions strongly interfere with Ostwald-Lussac step ripening of calcium carbonate, kinetically stabilizing metastable polymorphs such as vaterite and aragonite; this is a distinctive feature of the calcium carbonate mineral system which clearly has to be considered in future applications of calcium carbonate as a bioceramic.


The bedside evaluation: ritual and reason.
The bedside evaluation, consisting of the history and physical examination, was once the primary means of diagnosis and clinical monitoring. The recent explosion of imaging and laboratory testing has inverted the diagnostic paradigm. Physicians often bypass the bedside evaluation for immediate testing and therefore encounter an image of the patient before seeing the patient in the flesh. In addition to risking delayed or missed diagnosis of readily recognizable disease, physicians who forgo or circumvent the bedside evaluation risk the loss of an important ritual that can enhance the physician-patient relationship. Patients expect that some form of bedside evaluation will take place when they visit a physician. When physicians complete this evaluation in an expert manner, it can have a salutary effect. If done poorly or not at all, in contrast, it can undermine the physician-patient relationship. Studies suggest that the context, locale, and quality of the bedside evaluation are associated with neurobiological changes in the patient. Recognizing the importance of the bedside evaluation as a healing ritual and a powerful diagnostic tool when paired with judicious use of technology could be a stimulus for the recovery of an ebbing skill set among physicians.


Children's differentiation between beliefs about matters of fact and matters of opinion.
Two experiments investigated children's implicit and explicit differentiation between beliefs about matters of fact and matters of opinion. In Experiment 1, 8- to 9-year-olds' (n = 88) explicit understanding of the subjectivity of opinions was found to be limited, but their conformity to others' judgments on a matter of opinion was considerably lower than their conformity to others' views regarding an ambiguous fact. In Experiment 2, children aged 6, 8, or 10 years (n = 81) were asked to make judgments either about ambiguous matters of fact or about matters of opinion and then heard an opposing judgment from an expert. All age groups conformed to the opposing judgments on factual matters more than they did to the experts' views on matters of opinion. However, only the oldest children explicitly recognized that opinions are subjective and cannot be "wrong." Implications of these results for models of children's reasoning about epistemic states are discussed.


Key viral immune genes and pathways identify elite athletes with URS.
Habitual intense exercise may increase the incidence of upper respiratory symptoms (URS) in elite athletes. This study investigated whether immune gene expression could identify gene markers that discriminate athletes with a higher prevalence of URS. This cross-sectional analysis of elite Australian athletes from various sports investigated whether athletes retrospectively reporting URS for two days or more in a month (n=38), had an altered immune gene expression profile compared with asymptomatic athletes (n=33). Peripheral blood samples were collected during Olympic selection events with corresponding URS data collected for the one-month period before sampling. Digital immune gene expression analysis was undertaken using the NanoString PanCancer Immune Profiling panel. Fifty immune genes were differentially expressed between the groups (p<0.05) and approximately 78% of these genes were more highly expressed in athletes reporting URS. Many of these genes were interferon-stimulated genes or genes involved in the Jak/Stat signalling pathway. Only interferon alpha inducible protein 27 (IFI27), an interferon stimulated gene involved in viral response, remained significantly higher in athletes reporting URS (log2 fold-difference=2.49, odds ratio 1.02 per unit increase; p<0.01) post-adjustment and discriminated athletes reporting URS from asymptomatic athletes with 78% accuracy. Expression of IFI27 could differentiate athletes reporting URS from asymptomatic athletes, a gene that is upregulated in the immune response to viral infection. Upregulation of viral signalling pathways provides novel information on the potential aetiology of URS in elite Olympic athletes.


Audit of preventive activities in 16 inner London practices using a validated measure of patient population, the 'active patient' denominator. Healthy Eastenders Project.
Reliable comparison of the results of audit between general practices and over time requires standard definitions of numerators and denominators. This is particularly relevant in areas of high population turnover and practice list inflation. Without simple validation to remove supernumeraries, population coverage and professional activity may be underestimated. This audit study aimed to define a standard denominator, the 'active patient' denominator, to enable comparison of professional activity and population coverage for preventive activities between general practices and over time. It also aimed to document the extent to which computers were used for recording such activities. A random sample of people in the age group 30-64 years was drawn from the computerized general practice registers of the 16 inner London general practices that participated in the 'healthy eastenders project'. A validation procedure excluded those patients who were likely to have died or moved away, or who for administrative reasons were unable to contribute to the numerator; this allowed the creation of the active patient denominator. An audit of preventive activities with numerators drawn from both paper and computerized medical records was carried out and results were presented so that practices could compare their results with those of their peers and over time. Of the original sample of 2331 people, 25% (practice range 13%-37%) were excluded as a result of the validation procedure. A denominator based on the complete, unexpurgated practice register rather than the validated active patient denominator would have reduced the proportion of people with blood pressure recorded within the preceding five years from 77% to 61%, recording of smoking status from 68% to 53% and recording of cervical smears from 80% to 66%. Only 53% of the last recordings, within the preceding five years, of blood pressure and only 54% of those of smoking status were recorded on the practice computer. In contrast, 82% of recorded cervical smears were recorded on computer. The active patient denominator produces a more accurate estimate of population coverage and professional activity, both of which are underestimated by the complete, unexpurgated practice register. A standard definition of the denominator also allows comparisons to be made between practices and over time. As only half of the recordings of some preventive activities were recorded on computer, it is doubtful whether it is advisable to rely on computers for audit where paper records are also maintained.


Energy restriction negates NMDA receptor antagonist efficacy in ischemic stroke.
Preclinical evaluation of drugs for neurological disorders is usually performed on overfed rodents, without consideration of how metabolic state might affect drug efficacy. Using a widely employed mouse model of focal ischemic stroke, we found that that the NMDA receptor antagonist dizocilpine (MK-801) reduces brain damage and improves functional outcome in mice on the usual ad libitum diet, but exhibits little or no therapeutic efficacy in mice maintained on an energy-restricted diet. Thus, NMDA receptor activation plays a central role in the mechanism by which a high dietary energy intake exacerbates ischemic brain injury. These findings suggest that inclusion of subjects with a wide range of energy intakes in clinical trials for stroke may mask a drug benefit in the overfed/obese subpopulation of subjects.


Cognitive Function Changes in Older People. Results of Second Wave of Cognition of Older People, Education, Recreational Activities, NutritIon, Comorbidities, fUnctional Capacity Studies (COPERNICUS).
Cognitive reserve explains why subjects with more years of education, professional achievement, or participation in recreational activities show less cognitive decline with aging. We hypothesize that levels of recreational travel, education, occupation, systemic health, physical performance, and current cognitive activity levels affect the trajectory of cognitive function in older, healthy people in Poland. Healthy, older people (N = 205) were examined and followed-up at 2 years. Participants completed physical and cognitive function assessments: including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and its two subtests Delayed Recall (DR) and Verbal Fluency (VF), and Trail Making Test Part B (TMT B). Factors associated with cognitive functioning were also examined. The MMSE result significantly decreased over 2 years. No significant decrease in other cognitive tests was noted. However, the trajectory of cognitive tests results varied between individual participants. Percentage of variance of change was explained by the following predictors: 21 in MMSE, 24 in MoCA, 8 in DR, 25 in VF, and 24 in TMT B. Age and the presence of varicose veins were significantly linked to negative changes in MMSE and MoCA scores, while working in a professional occupational status associated with a higher score. The subgroup with varicose veins did worse on the Delayed Recall subtest of MoCA. Cognitive reserve could be extended by proxies of reserve that are related to systemic health and travel activity. The latter is a combination of social, physical, and cognitive activity and potentially might serve as an intervention to improve cognitive function in older people. However, due to the limitations of this study, results should be interpreted with caution and needs to be replicated in the further studies.


The impacts of different proxies for financialization on carbon emissions in top-ten emitter countries.
The nexus of financialization and carbon emissions has been widely discussed in the literature. A vast body of literature that estimates the impact of financialization on carbon emissions proxies financialization with either domestic credit or market capitalization. However, these representatives do not fully respond to the complicated nature of financial development. To fill the gaps in the existing literature, nine different proxies for financial development are used in the links with carbon emissions in the framework of EKC theory for the years 1980-2014. This study exposes reliable and robust empirical results due to the use of a number of proxies for financialization and second-generation econometric approaches in the empirical analysis. The quantile regression approach deals with unobserved heterogeneity for each cross-section and estimates different slope parameters at varying quantiles. Because non-normality and heterogeneity are detected in dataset, quantile regression provides more robust and reliable estimates than conventional econometric techniques. Results from quantile regression estimator support mixed effects of financial development on carbon emissions over quantiles; in addition, the impact of financial development on carbon emissions is varying not only for each quantile but also for different proxies of financial development. The EKC hypothesis is validated for the top-ten emitter economies. Interpretations and policy suggestions are further discussed in the present study.


Perception of mercury contamination by Brazilian adolescents in a gold mining community: an ethnographic approach.
This study used ethnographic methods to examine the perception of mercury contamination by adolescents in the mining community of Poconé, Mato Grosso, Brazil. In Phase I, 53 students aged 13 to 16 years in six schools presented theatrical sketches about community health risks to generate key terms for a pile sorting activity in Phase II. Mercury was reported by four of the 15 groups (26%). In Phase II, researchers conducted semi-structured interviews and pile sorts with 31 students to assess adolescent attitudes about mercury and to generate an ethnomedical model of mercury perception. The lack of consensus evident in the model reveals that while students view mercury as an overall threat, many of them do not understand how its presence can harm human health. Few adolescents felt confident about their knowledge (3%) or could accurately explain how it was used (9%), even though many of them had relatives working as miners (55%). Further analysis of pile sort data suggests that mercury may not belong in a 'typical risks' domain. The authors argue that ethnographic methods are a useful tool for public health research, and hope that these findings can contribute to health education interventions in the field.


Spinal Fractures in Patients With Ankylosing Spondylitis: Etiology, Diagnosis, and Management.
In patients with ankylosing spondylitis, the altered biomechanics of the spine increase the incidence of spinal fractures and the risk of subsequent displacement and neurologic injury. Radiographic evaluation is difficult and requires imaging of the entire spine and the use of advanced imaging. Nonsurgical treatment has a high rate of complications and is typically pursued only when surgical intervention would carry unacceptably high perioperative risks. The surgical approach depends on the fracture location and any deformity present. Anterior fixation alone has been associated with high failure rates; therefore, posterior or combined anterior-posterior fixation should be considered. With either nonsurgical or surgical management, complications are frequent and can result in high mortality rates; however, good outcomes can be achieved if an appropriate level of suspicion of fracture is maintained and care is taken to avoid complications related to patient transport, transfer, and positioning.


Prediagnostic circulating levels of sex hormones and survival in esophageal adenocarcinoma.
Sex hormonal differences may contribute to the strong male predominance in esophageal adenocarcinoma (EAC), but whether sex hormone levels influence survival in EAC is unstudied. Our study aimed to assess associations between prediagnostic sex hormone levels and survival in EAC. In a population-based cohort study, 244 male EAC patients from the Janus Serum Bank Cohort in Norway were followed up through 2018. Associations between prediagnostic serum levels of 12 sex hormone measures and disease-specific mortality were assessed using multivariable Cox regression, providing hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, calendar year, body mass index, tobacco smoking, physical activity and surgical resection. Higher levels of sex hormone-binding globulin (SHBG) indicated decreased disease-specific mortality (HR 0.68, 95% CI 0.44-1.07, highest vs lowest tertile). In stratified analyses by surgery, such associations remained in nonoperated patients (HR 0.58, 95% CI 0.35-0.96, highest vs lowest tertile), but not in operated patients. Higher levels of follicle-stimulating hormone (FSH) were associated with increased disease-specific mortality in an exposure-response pattern; HRs for the middle and highest tertiles vs the lowest tertile were 1.35 (95% CI 0.89-2.05) and 1.61 (95% CI 1.06-2.43), respectively. No clear associations were observed with serum levels of dehydroepiandrosterone sulfate, luteinizing hormone, prolactin, testosterone, 17-OH-progesterone, progesterone, estradiol, androstenedione, testosterone:estradiol ratio or free testosterone index. These findings suggest that higher endogenous levels of SHBG and lower levels of FSH may increase the survival in EAC. The other 10 examined sex hormone measures may not influence the survival.