Enhanced expression of contractile endothelin ET(B) receptors in rat coronary artery after organ culture.
Endothelin-1 is a potent vasoconstrictor mediating its effects via two receptor subtypes, the endothelin type A (ET(A)) preferentially situated on smooth muscle cells, mediating vasoconstriction and endothelin type B (ET(B)) mainly located on endothelial cells, mediating vasodilatation. In cardiovascular disease and in organ culture in vitro, endothelin ET(B) receptors are up-regulated on smooth muscle cells. The objectives of the present study were to characterise the endothelin receptor-induced vasoconstriction and quantify the endothelin receptor mRNA levels and immunoreactivity in fresh and cultured rat coronary arteries. We demonstrate that endothelin-1 induces strong and equal concentration-dependent contractions in fresh and cultured segments from the left anterior descending coronary artery. Sarafotoxin 6c, an endothelin ET(B) receptor agonist, had negligible effect in fresh arteries but produced significant vasoconstriction after organ culture. The endothelin ET(B) receptor mRNA level and the receptor protein immunoreactivity were increased, whereas the level of endothelin ET(A) receptor mRNA was down-regulated but not its receptor protein immunoreactivity after organ culture. Pharmacological inhibition of endothelium-derived dilatory mediators did not influence endothelin ET(A) or ET(B) receptor-mediated vasoconstriction in fresh segments. In cultured arteries, inhibition of endothelial vasodilators potentiated the effect of sarafotoxin 6c. In conclusion, endothelin ET(B) receptor stimulation in cultured coronary arteries elicits vasoconstriction. This is likely not related to endothelial dysfunction with putative loss of its vasodilator components, but rather explained by the up-regulation of contractile endothelin ET(B) receptors on smooth muscle cells.


The development of iconicity in children's co-speech gesture and homesign.
Gesture can illustrate objects and events in the world by iconically reproducing elements of those objects and events. Children do not begin to express ideas iconically, however, until after they have begun to use conventional forms. In this paper, we investigate how children's use of iconic resources in gesture relates to the developing structure of their communicative systems. Using longitudinal video corpora, we compare the emergence of manual iconicity in hearing children who are learning a spoken language (co-speech gesture) to the emergence of manual iconicity in a deaf child who is creating a manual system of communication (homesign). We focus on one particular element of iconic gesture - the shape of the hand (handshape). We ask how handshape is used as an iconic resource in 1-5-year-olds, and how it relates to the semantic content of children's communicative acts. We find that patterns of handshape development are broadly similar between co-speech gesture and homesign, suggesting that the building blocks underlying children's ability to iconically map manual forms to meaning are shared across different communicative systems: those where gesture is produced alongside speech, and those where gesture is the primary mode of communication.


Vitamin B6 modulates transcriptional activation by multiple members of the steroid hormone receptor superfamily.
Recent studies have shown that vitamin B6 modulates transcriptional activation by the human glucocorticoid receptor in HeLa S3 cells. We have now examined the possibility that vitamin B6 might similarly influence transcriptional activation by the glucocorticoid receptor in other cell types, as well as gene expression mediated by other members of the steroid hormone receptor superfamily. We show that elevated vitamin B6 concentrations suppress by 40-65% the level of transcription mediated through the endogenous murine L cell glucocorticoid receptor, as well as the human receptor transfected into E8.2 and T47D cells. In contrast, glucocorticoid receptor-mediated transcription was enhanced 60-110% in mild vitamin deficiency. The level of hormone-independent constitutive gene expression was not affected by these same alterations in vitamin B6 concentration. These studies indicated that the transcriptional modulatory effects of the vitamin were neither restricted to specific cell types nor limited to the human form of the glucocorticoid receptor. We next determined if hormone-induced transcription by several other steroid receptors (androgen, progesterone, and estrogen receptors) was analogously affected by alterations in vitamin B6 concentration. Analysis of gene expression mediated through the mouse mammary tumor virus promoter revealed that transcriptional activation of both the androgen and progesterone receptors was reduced by 35-40% under conditions of elevated vitamin B6 and enhanced by 60-90% in deficiency, again under conditions where constitutive expression was unaffected. Using a different promoter, the estrogen-regulated vitellogenin promoter, we found that transcriptional activation of the estrogen receptor was similarly affected. Estrogen-induced gene expression was reduced by 30% under conditions of elevated intracellular vitamin B6 and enhanced by 85% in vitamin deficiency. Thus, vitamin B6 modulates transcriptional activation by multiple classes of steroid hormone receptors. The similarities in vitamin B6 effects on transcription mediated through different promoters, the mouse mammary tumor virus and vitellogenin promoters, suggest that this vitamin may modulate the expression of a diverse array of hormonally responsive genes. These observations together support the hypothesis that vitamin B6 represents a physiological modulator of steroid hormone action.


Multicolor lasers using birefringent filters: experimental demonstration with Cr:Nd:GSGG and Cr:LiSAF.
In this study, we numerically and experimentally investigate application of birefringent filters (BRFs) as frequency selective elements in multicolor lasers. A BRF plate made out of crystalline quartz with an arbitrarily oriented optical axis has been explored. Simulation results have shown that compared to regular BRFs where the optical axis lies in the plane of the plates surface, a BRF with an optical axis pointing out of its surface enables design flexibility in filter parameters, providing access to a wider set of free spectral range and bandwidth values. As a result, multicolor operation could be obtained in many wavelength pairs using a single BRF plate. In the experiments a 3-mm thick quartz BRF with an optical axis 45° to the surface plane has been used. With Cr:Nd:GSGG as a laser medium two-color and three-color cw laser operation has been demonstrated in 11 and 3 different transition combinations, respectively. Moreover, two-color laser operation has been demonstrated in 10 different wavelength pairs in Cr:LiSAF. To our knowledge, this study is the first detailed investigation and experimental demonstration of BRFs with tilted optical axis for multicolor operation of solid-state lasers. Compared to other methods, BRFs enable a rich selection of transition pairs and also the ratio of the power in each line could be regulated by fine adjustment of the rotation angle. Implementation of tilted-axis BRFs should boost development of efficient and low-cost multicolor lasers in other gain media as well.


Properties of the Driving Behavior Survey among individuals with motor vehicle accident-related posttraumatic stress disorder.
Data suggest anxious drivers may engage in problematic behaviors that place themselves and others at increased risk of negative traffic events. Three domains of problematic behavior--exaggerated safety/caution, performance deficits, and hostile/aggressive behaviors--previously were identified during development of the Driving Behavior Survey (DBS), a novel measure of anxiety-related behavior. Extending this research, the current study examined the psychometric properties of DBS scores among individuals with posttraumatic stress disorder (PTSD) subsequent to motor vehicle trauma (N=40). Internal consistencies and 12-week test-retest reliabilities for DBS scales ranged from good to excellent. Comparison of scores to normative student data indicated dose-response relationships for safety/caution and performance deficit subscales, with increased frequency of anxious behavior occurring within the PTSD sample. Associations with standard clinical measures provide additional evidence for anxiety-related driving behavior as a unique marker of functional impairment, distinct from both avoidance and disorder-specific symptoms.


Selection of different surgical methods for uterine fibroids: Protocol for a retrospective clinical study.
Uterine fibroids is a common benign tumor disease of the female reproductive system. The main methods of current clinical treatment of uterine fibroids are conservative treatment and surgical treatment. With the rise of the concept of minimally invasive surgery in gynecology, laparoscopic myomectomy, and vaginal myomectomy have been widely used. This study plans to retrospectively analyze 150 patients with uterine fibroids. They will be divided into laparoscopic myomectomy, vaginal myomectomy group, and open hysteromyoma resection group. This study will compare the intraoperative blood loss, operation time, postoperative exhaust time, postoperative hospital stay and postoperative complications of different surgical methods. This study will compare the clinical efficacy of these 3 common surgical methods through retrospective medical record analysis, and provide more reliable evidence-based medical evidence for clinical treatment choices.


Diagnosis, progression patterns and prognostication in mastocytosis.
Mastocytosis is a heterogeneous group of disorders defined by abnormal growth and accumulation of clonal mast cells. CM is the predominant variant in childhood, whereas the majority of adult patients present with systemic mastocytosis. In over 80% of the latter patients, the KIT mutation D816V is detectable. Whereas childhood mastocytosis often resolves spontaneously before adolescence and has a good prognosis, in most adult patients mastocytosis is a persistent systemic disorder. The course and prognosis in these patients are variable; in indolent variants, the clinical course remains stable over years or even decades. In advanced mastocytosis, the prognosis is less favorable despite novel drugs counteracting growth of neoplastic mast cells. Although WHO criteria are clearly separating prognostic subsets of mastocytosis, little is known about specific prognostic factors predicting the outcome in individual patients. In this article, we review current concepts in mastocytosis, including prognostic parameters for indolent and advanced systemic mastocytosis.


[Principles of age-related changes in the surgical approach to the antrum].
The present authors maintain that the surgical approach to the antrum via the mastoid bone as a method of treating chronic purulent otitis media is very promising because it saves bone conduction structures of the middle ear. In order to provide accurate and safe dissection of the antrum, the authors measured the angle between the external auditory meatus and the horizontal skull plane. As they have previously demonstrated, this angle is correlated with the antrum displacement upwards or downwards. On the basis of over 500 observations, the authors have concluded that the angle increases on the average from 13 degrees to 25 degrees at the age of 5 to 40 years and then decreases, reaching 18 degrees by the age of 70 years. The authors recommend to measure the surgical angle for all types of antrotomic intervention, using contrast X-ray ++ of the auditory meatus in the normal anterior projection of the skull.


Differential mRNA expression of the human DNA methyltransferases (DNMTs) 1, 3a and 3b during the G(0)/G(1) to S phase transition in normal and tumor cells.
DNA methylation is essential for mammalian development, X-chromosome inactivation, and imprinting yet aberrant methylation patterns are one of the most common features of transformed cells. One of the proposed causes for these defects in the methylation machinery is overexpression of one or more of the three known catalytically active DNA methyltransferases (DNMTs) 1, 3a and 3b, yet there are clearly examples in which overexpression is minimal or non-existent but global methylation anomalies persist. An alternative mechanism which could give rise to global methylation errors is the improper expression of one or more of the DNMTs during the cell cycle. To begin to study the latter possibility we examined the expression of the mRNAs for DNMT1, 3a and 3b during the cell cycle of normal and transformed cells. We found that DNMT1 and 3b levels were significantly downregulated in G(0)/G(1)while DNMT3a mRNA levels were less sensitive to cell cycle alterations and were maintained at a slightly higher level in tumor lines compared to normal cell strains. Enzymatic activity assays revealed a similar decrease in the overall methylation capacity of the cells during G(0)/G(1)arrest and again revealed that a tumor cell line maintained a higher methylation capacity during arrest than a normal cell strain. These results reveal a new level of control exerted over the cellular DNA methylation machinery, the loss of which provides an alternative mechanism for the genesis of the aberrant methylation patterns observed in tumor cells.


Spectral Regularization Algorithms for Learning Large Incomplete Matrices.
We use convex relaxation techniques to provide a sequence of regularized low-rank solutions for large-scale matrix completion problems. Using the nuclear norm as a regularizer, we provide a simple and very efficient convex algorithm for minimizing the reconstruction error subject to a bound on the nuclear norm. Our algorithm Soft-Impute iteratively replaces the missing elements with those obtained from a soft-thresholded SVD. With warm starts this allows us to efficiently compute an entire regularization path of solutions on a grid of values of the regularization parameter. The computationally intensive part of our algorithm is in computing a low-rank SVD of a dense matrix. Exploiting the problem structure, we show that the task can be performed with a complexity linear in the matrix dimensions. Our semidefinite-programming algorithm is readily scalable to large matrices: for example it can obtain a rank-80 approximation of a 10(6) × 10(6) incomplete matrix with 10(5) observed entries in 2.5 hours, and can fit a rank 40 approximation to the full Netflix training set in 6.6 hours. Our methods show very good performance both in training and test error when compared to other competitive state-of-the art techniques.


Recurrent herpes simplex after corneal transplantation in rats.
To ascertain the effect of trauma from surgery and rejection on the incidence and timing of recurrent herpes simplex virus (HSV) disease after corneal transplantation. To locate virus antigen and identify cells of the immune system infiltrating corneas with recurrent disease. PVG rats were inoculated on the cornea with HSV-1 McKrae. Recurrent disease was induced either by ultraviolet (UV)-irradiation of the cornea or by corneal transplantation. After corneal transplantation, animals shedding virus in the tear film were killed on days 1 to 4 of shedding. Eyes were fixed, embedded, sectioned, and stained for virus antigens, infiltrating cells, major histocompatibility complex class II, and adhesion molecule molecule expression. In the first 15 days after corneal transplantation, 8 of 91 rats shed virus, and between days 16 and 30, an additional 3 of 60 rats shed virus (12% of total rats, comparable to the percent that shed after UV irradiation). Shedding sometimes was accompanied by punctate epithelial lesions in the recipient cornea and stromal opacity. The rejection process itself did not induce or exacerbate recurrent disease. In all corneas examined from eyes that shed virus, antigen was found in several locations at the graft-host junction, sometimes in the absence of clinical signs of disease, and frequently it extended through the stroma to the endothelium. Granulocytes were the main infiltrating cell in areas of virus antigen. Corneal transplantation trauma is a stimulus to recurrent disease of similar potency to UV irradiation. The graft-host junction is an area in which virus spreads easily and can reach the endothelium readily. In humans, the incidence of recurrent disease at this location may be greater than has been recognized.


Cost-Effectiveness of Apixaban versus Other Direct Oral Anticoagulants and Warfarin in the Prevention of Thromboembolic Complications Among Finnish Patients with Non-Valvular Atrial Fibrillation.
Direct oral anticoagulant (DOAC) use for the prevention of thromboembolic complications in patients with non-valvular atrial fibrillation (AF) has increased steadily in Finland. DOACs have been shown to be cost-effective in comparison to warfarin, but published evidence of relative cost-effectiveness between DOACs is still scarce and mostly based on indirect comparisons of clinical trial evidence. The aim of this study was to compare the cost-effectiveness of apixaban to dabigatran, rivaroxaban and warfarin in a Finnish setting using real-life evidence where available. A lifetime Markov simulation model used previously in a published Finnish assessment comparing apixaban and warfarin was modified and updated with the relative effectiveness and safety data available from the real-world NAXOS-study and representative Finnish input data for patient characteristics, event risks, mortality, resource use, costs, and quality of life. Apixaban's cost-effectiveness was assessed from health care payer perspective (using 3% per year discount rate) based on incremental cost-effectiveness ratio (ICER, cost per quality-adjusted life year [QALY] gained), probability of cost-effectiveness (at willingness-to-pay [WTP] of 35,000 euros/QALY), and net monetary benefit (NMB). Apixaban increased the average modelled quality-adjusted life-expectancy and reduced the average total health care costs of AF patients when compared to warfarin (+0.14 QALYs, -3691 euros), dabigatran (+0.11 QALYs, -404 euros), and rivaroxaban (+0.03 QALYs, -43 euros). The resulting NMB of apixaban versus warfarin, dabigatran and rivaroxaban was 8723, 4168, and 1129 euros, respectively. The respective probabilities of apixaban being cost-effective against each comparator were 100%, 92.7%, and 64.0%. In this modelling study, apixaban dominated other anticoagulants in the Finnish real-life setting.


Eliot Freidson: progression and constraints in the biography of an intellectual.
Eliot Freidson (1923-2005) is considered one of the founders of the sociology of medicine. Both his critics and admirers in the sociological and medical fields recognize his work as an international benchmark. This paper analyzes Freidson's intellectual biography without concentrating on his ideas or their transformation over the course of time. The emphasis is on the personal constraints that marked his intellectual career within a broader context, with the many different opportunities and choices. It establishes the intersection between the singular trajectory of an intellectual, and the structures, processes and events in which he was immersed and which he changed by his actions.


Improvements in Indigenous mortality in the Northern Territory over four decades.
To provide the first report of long-term mortality trends over recent decades for an Indigenous Australian population. Very little information is available about improvements over time, or lack thereof, in the health status of Indigenous Australians. Internally consistent time series of deaths and population data were produced for the Indigenous population of the Northern Territory (NT) for 1966--2001. Time trends for Indigenous mortality rates and differentials between NT Indigenous and total Australian rates were examined for 1967--2000. NT Indigenous mortality declined in all age groups and both sexes. The decline was greatest in age group 0-4 (85%). In those aged five years and over, NT Indigenous mortality declined by 30% in females and 19% in males. However, these declines did not keep pace with the relative decline for the total Australian population, so that mortality rate ratios (NT Indigenous to total Australian) increased for all age groups except 0-4 years. NT Indigenous mortality declined for communicable, maternal, perinatal and nutritional conditions by 62%, and for injury by 33%, but did not decline for non-communicable diseases. Indigenous mortality has improved in the NT in recent decades, but the relative gap between Indigenous and other Australians has increased. Reductions in NT Indigenous mortality reported here may provide some reassurance that improvement in Indigenous health is possible and has occurred, but even greater effort will be required to accelerate the pace of improvement.


Characterization of metabolic phenotypes and distinctive genes in mice with low-weight gain.
Being overweight exacerbates various metabolic diseases, necessitating the identification of target molecules for obesity control. In the current study, we investigated common physiological features related to metabolism in mice with low weight gain: (1) G protein-coupled receptor, family C, group 5, member B-knockout; (2) gastric inhibitory polypeptide receptor-knockout; and (3) Iroquois-related homeobox 3-knockout. Moreover, we explored genes involved in metabolism by analyzing differentially expressed genes (DEGs) between low-weight gain mice and the respective wild-type control mice. The common characteristics of the low-weight gain mice were low inguinal white adipose tissue (iWAT) and liver weight despite similar food intake along with lower blood leptin levels and high energy expenditure. The DEGs of iWAT, epididymal (gonadal) WAT, brown adipose tissue, muscle, liver, hypothalamus, and hippocampus common to these low-weight gain mice were designated as candidate genes associated with metabolism. One such gene tetraspanin 7 (Tspan7) from the iWAT was validated using knockout and overexpressing mouse models. Mice with low Tspan7 expression gained more weight, while those with high Tspan7 expression gained less weight, confirming the involvement of the Tspan7 gene in weight regulation. Collectively, these findings suggest that the candidate gene list generated in this study contains potential target molecules for obesity regulation. Further validation and additional data from low-weight gain mice will aid in understanding the molecular mechanisms associated with obesity.


Diverging functions among calreticulin isoforms in higher plants.
The ER chaperone calreticulin plays vital roles in numerous cellular processes, including Ca2+-homeostasis, apoptosis, and cell adhesion, in animal cells. Although calreticulin has been systematically characterized in animal cells, the focus has been on one of the isoforms. However, recent advances in the plant calreticulin field have revealed functional divergence of calreticulin isoforms. While two of the plant isoforms appear to work within a general ER chaperone framework, the third isoform is associated with folding of receptors for brassinosteroids and bacterial peptides. Hence, the discovery of functional specialization of plant calreticulins opens up new vistas for calreticulins also in the animal field.


Application of error level analysis in image spam classification using deep learning model.
Image spam is a type of spam that contains text information inserted in an image file. Traditional classification systems based on feature engineering require manual extraction of certain quantitative and qualitative image features for classification. However, these systems are often not robust to adversarial attacks. In contrast, classification pipelines that use convolutional neural network (CNN) models automatically extract features from images. This approach has been shown to achieve high accuracies even on challenge datasets that are designed to defeat the purpose of classification. We propose a method for improving the performance of CNN models for image spam classification. Our method uses the concept of error level analysis (ELA) as a pre-processing step. ELA is a technique for detecting image tampering by analyzing the error levels of the image pixels. We show that ELA can be used to improve the accuracy of CNN models for image spam classification, even on challenge datasets. Our results demonstrate that the application of ELA as a pre-processing technique in our proposed model can significantly improve the results of the classification tasks on image spam datasets.


A controlled evaluation of a brief parenting psychoeducation intervention in Burundi.
Conduct problems and emotional distress have been identified as key problems among children and adolescents in post-war Burundi. This pilot study aims to evaluate the impact of a brief parenting psychoeducation intervention on children's mental health. This study employs a controlled pre and post evaluation design. The two-session psychoeducation intervention was offered to groups of parents of children (mean age 12.3 years, 60.8 % female) who had been screened for elevated psychosocial distress. Children in the intervention group (n = 58) were compared to a waitlist control group (n = 62). Outcome indicators included child-reported levels of aggression (using the Aggression Questionnaire), depression symptoms (using the Depression Self Rating Scale) and perceived family social support. The intervention had a beneficial effect on reducing conduct problems compared to the control condition (Cohen d = 0.60), especially among boys, while not showing impact on depression symptoms or family social support. Parents evaluated the intervention positively, with increased awareness of positive parenting strategies and appropriate disciplinary techniques reported as the most common learning points. A brief parenting psychoeducation intervention conducted by lay community counselors is a promising public health strategy in dealing with widespread conduct problems in boys living in violence-affected settings and not so for social and emotional indicators and for girls. An efficacy study is warranted to confirm these preliminary findings.


Prevalence of Helicobacter pylori antibodies in endoscopy personnel and non-medical volunteers of Karachi.
Prevalence of Helicobacter pylori (Hp) is high in developing countries. As endoscopy personnel are at greater risk of exposure to gastric secretions, they are apparently at higher risk of acquiring this infection. The aim of this study was to determine prevalence of Hp antibodies in endoscopy staff and compare it with non-medical volunteers and assess any additional risk of occupational exposure to Hp in the former group. Thirty-three subjects working in endoscopy suites of different hospitals of Karachi and 33 non-medical volunteers were investigated for the prevalence of Hp antibodies by using a commercially available rapid qualitative test (FlexPack HP; Abbott). The two groups were comparable in mean age, sex and social class. Twenty-six of 33 (79%) of the endoscopy personnel and 19/33 (58%) of the non-medical volunteers were positive for Hp serology (p = 0.06 R.R 1.37). Among the endoscopy personnel 13/14 (93%) of endoscopy assistants were positive and this subgroup had a significantly higher prevalence of Hp antibodies as compared to the control group (p = 0.019). No correlation could be found between the positive serology and symptoms of dyspepsia.


Quantitation of natural killer cell function and risk of metastatic poorly differentiated head and neck cancer.
Previous laboratory studies have suggested that natural immunity is a primordial defense mechanism against blood-borne metastatic cancer, its function being most effective against dedifferentiated, low-major-histocompatibility-complex-class-I-antigen-expressing tumors. In this clinical study, 263 previously untreated patients with squamous cell carcinoma of the upper aerodigestive tract were evaluated for natural killer (NK) cell cytotoxicity mediated by peripheral blood lymphocytes against K562 target cells. All patients were evaluated before treatment, underwent subsequent attempts at curative therapy in which they were initially rendered disease-free, and then followed longitudinally for clinical outcome. Using a Cox proportional hazards model, quantitated NK cell cytotoxicity was inversely related to subsequent death with disease (p = 0.05), regional metastases (p = 0.008) and distant metastases (p = 0.03). No relationship between NK cell function and local recurrence could be identified (p = 0.81). Patients were further stratified by degree of differentiation of their respective primary cancer. The prognostic implication provided as to risk of death with disease and progressive metastatic growth was confined to the population with moderate-to-poorly differentiated cancers. Conversely, its function was nonpredictive in patients with well-differentiated cancers; the latter cancers were observed to express higher levels of major histocompatibility complex-class I framework antigens. Results of this clinical study are consistent with previous laboratory investigations and suggest that, within humans, the NK cell functions in metastatic sites against more primitive cancers. Such findings may have implications in designing therapeutic strategies.


Intrinsic capacity and its associations with incident dependence and mortality in 10/66 Dementia Research Group studies in Latin America, India, and China: A population-based cohort study.
The World Health Organization (WHO) has reframed health and healthcare for older people around achieving the goal of healthy ageing. The recent WHO Integrated Care for Older People (ICOPE) guidelines focus on maintaining intrinsic capacity, i.e., addressing declines in neuromusculoskeletal, vitality, sensory, cognitive, psychological, and continence domains, aiming to prevent or delay the onset of dependence. The target group with 1 or more declines in intrinsic capacity (DICs) is broad, and implementation may be challenging in less-resourced settings. We aimed to inform planning by assessing intrinsic capacity prevalence, by characterising the target group, and by validating the general approach-testing hypotheses that DIC was consistently associated with higher risks of incident dependence and death. We conducted population-based cohort studies (baseline, 2003-2007) in urban sites in Cuba, Dominican Republic, Puerto Rico, and Venezuela, and rural and urban sites in Peru, Mexico, India, and China. Door-knocking identified eligible participants, aged 65 years and over and normally resident in each geographically defined catchment area. Sociodemographic, behaviour and lifestyle, health, and healthcare utilisation and cost questionnaires, and physical assessments were administered to all participants, with incident dependence and mortality ascertained 3 to 5 years later (2008-2010). In 12 sites in 8 countries, 17,031 participants were surveyed at baseline. Overall mean age was 74.2 years, range of means by site 71.3-76.3 years; 62.4% were female, range 53.4%-67.3%. At baseline, only 30% retained full capacity across all domains. The proportion retaining capacity fell sharply with increasing age, and declines affecting multiple domains were more common. Poverty, morbidity (particularly dementia, depression, and stroke), and disability were concentrated among those with DIC, although only 10% were frail, and a further 9% had needs for care. Hypertension and lifestyle risk factors for chronic disease, and healthcare utilisation and costs, were more evenly distributed in the population. In total, 15,901 participants were included in the mortality cohort (2,602 deaths/53,911 person-years of follow-up), and 12,939 participants in the dependence cohort (1,896 incident cases/38,320 person-years). One or more DICs strongly and independently predicted incident dependence (pooled adjusted subhazard ratio 1.91, 95% CI 1.69-2.17) and death (pooled adjusted hazard ratio 1.66, 95% CI 1.49-1.85). Relative risks were higher for those who were frail, but were also substantially elevated for the much larger sub-groups yet to become frail. Mortality was mainly concentrated in the frail and dependent sub-groups. The main limitations were potential for DIC exposure misclassification and attrition bias. In this study we observed a high prevalence of DICs, particularly in older age groups. Those affected had substantially increased risks of dependence and death. Most needs for care arose in those with DIC yet to become frail. Our findings provide some support for the strategy of optimising intrinsic capacity in pursuit of healthy ageing. Implementation at scale requires community-based screening and assessment, and a stepped-care intervention approach, with redefined roles for community healthcare workers and efforts to engage, train, and support them in these tasks. ICOPE might be usefully integrated into community programmes for detecting and case managing chronic diseases including hypertension and diabetes.


Regulation of valve endothelial cell vasculogenic network architectures with ROCK and Rac inhibitors.
The age- and disease-dependent presence of microvessels within heart valves is an understudied characteristic of these tissues. Neovascularization involves endothelial cell (EC) migration and cytoskeletal reorientation, which are heavily regulated by the Rho family of GTPases. Given that valve ECs demonstrate unique mesenchymal transdifferentiation and cytoskeletal mechanoresponsiveness, compared to vascular ECs, this study quantified the effect of inhibiting two members of the Rho family on vasculogenic network formation by valve ECs. A tubule-like structure vasculogenesis assay (assessing lacunarity, junction density, and vessel density) was performed with porcine aortic valve ECs treated with small molecule inhibitors of Rho-associated serine-threonine protein kinase (ROCK), Y-27632, or the Rac1 inhibitor, NSC-23766. Actin coordination, cell number, and cell migration were assessed through immunocytochemistry, MTT assay, and scratch wound healing assay. ROCK inhibition reduced network lacunarity and interrupted proper cell-cell adhesion and actin coordination. Rac1 inhibition increased lacunarity and delayed actin-mediated network formation. ROCK inhibition alone significantly inhibited migration, whereas both ROCK and Rac1 inhibition significantly reduced cell number over time compared to controls. Compared to a vascular EC line, the valve ECs generated a network with larger total vessel length, but a less smooth appearance. Both ROCK and Rac1 inhibition interfered with key processes in vascular network formation by valve ECs. This is the first report of manipulation of valve EC vasculogenic organization in response to small molecule inhibitors. Further study is warranted to comprehend this facet of valvular cell biology and pathology and how it differs from vascular biology.


Vaginal Cytomegalovirus Shedding Before and After Initiation of Antiretroviral Therapy in Rakai, Uganda.
Vaginal shedding of cytomegalovirus (CMV) DNA was determined longitudinally among 96 women coinfected with human immunodeficiency virus (HIV), herpes simplex virus 2, and CMV starting antiretroviral therapy (ART) during a placebo-controlled trial of HSV-2 suppression with acyclovir in Rakai, Uganda. Vaginal CMV was detected in 75 of 96 women (78.0%) and 379 of 1080 individual visits (35.1%). ART status, higher HIV RNA viral load before ART initiation, and younger age were significantly associated with increased frequency of CMV shedding (P < .01). Compared to pre-ART, CMV shedding peaked from month 2 to month 4 after ART initiation, suggesting possible immune reconstitution inflammatory syndrome. Further studies need to determine the clinical significance of asymptomatic CMV shedding.


Preserving professional credibility: grounded theory study of medical trainees' requests for clinical support.
To develop a conceptual framework of the influences on medical trainees' decisions regarding requests for clinical support from a supervisor. Phase 1: members of teaching teams in internal and emergency medicine were observed during regular clinical activities (216 hours) and subsequently completed brief interviews. Phase 2: 36 in depth interviews were conducted using videotaped vignettes to probe tacit influences on decisions to request support. Data collection and analysis used grounded theory methods. Three teaching hospitals in an urban setting in Canada. 124 members of teaching teams on general internal medicine wards and in the emergency department, comprising 31 attending physicians, 57 junior and senior residents, 28 medical students, and eight nurses. Purposeful sampling to saturation was conducted. Trainees' decisions about whether or not to seek clinical support were influenced by three issues: the clinical question (clinical importance, scope of practice), supervisor factors (availability, approachability), and trainee factors (skill, desire for independence, evaluation). Trainees perceived that requesting frequent/inappropriate support threatened their credibility and used rhetorical strategies to preserve credibility. These strategies included building a case for the importance of requests, saving requests for opportune moments, making a plan before requesting support, and targeting requests to specific team members. Trainees consider not only clinical implications but also professional credibility when requesting support from clinical supervisors. Exposing the complexity of this process provides the opportunity to make changes to training programmes to promote timely supervision and provides a framework for further exploration of the impact of clinical training on quality of care of patients.


A laboratory ice machine as a cold oligotrophic artificial microbial niche for biodiscovery.
Microorganisms are ubiquitously distributed in nature and usually appear as biofilms attached to a variety of surfaces. Here, we report the development of a thick biofilm in the drain pipe of several standard laboratory ice machines, and we describe and characterise, through culture-dependent and -independent techniques, the composition of this oligotrophic microbial community. By using culturomics, 25 different microbial strains were isolated and taxonomically identified. The 16S rRNA high-throughput sequencing analysis revealed that Bacteroidota and Proteobacteria were the most abundant bacterial phyla in the sample, followed by Acidobacteriota and Planctomycetota, while ITS high-throughput sequencing uncovered the fungal community was clearly dominated by the presence of a yet-unidentified genus from the Didymellaceae family. Alpha and beta diversity comparisons of the ice machine microbial community against that of other similar cold oligotrophic and/or artificial environments revealed a low similarity between samples, highlighting the ice machine could be considered a cold and oligotrophic niche with a unique selective pressure for colonisation of particular microorganisms. The recovery and analysis of high-quality metagenome-assembled genomes (MAGs) yielded a strikingly high rate of new species. The functional profiling of the metagenome sequences uncovered the presence of proteins involved in extracellular polymeric substance (EPS) and fimbriae biosynthesis and also allowed us to detect the key proteins involved in the cold adaptation mechanisms and oligotrophic metabolic pathways. The metabolic functions in the recovered MAGs confirmed that all MAGs have the genes involved in psychrophilic protein biosynthesis. In addition, the highest number of genes for EPS biosynthesis was presented in MAGs associated with the genus Sphingomonas, which was also recovered by culture-based method. Further, the MAGs with the highest potential gene number for oligotrophic protein production were closely affiliated with the genera Chryseoglobus and Mycobacterium. Our results reveal the surprising potential of a cold oligotrophic microecosystem within a machine as a source of new microbial taxa and provide the scientific community with clues about which microorganisms are able to colonise this ecological niche and what physiological mechanisms they develop. These results pave the way to understand how and why certain microorganisms can colonise similar anthropogenic environments.


Antiretroviral treatment attrition in Swaziland: a population-based study.
Swaziland has the highest prevalence of human immunodeficiency virus (HIV) in the world. Attrition (loss to follow-up and mortality) in people living with HIV/AIDS (PLWHA) already on treatment is a major challenge, undermining achievements of the antiretroviral treatment (ART) programme in Swaziland. The contributing factors to attrition in the Swazi context are unclear. This study aims to (1) estimate attrition from the ART programme 12 months after ART initiation in Swaziland, and (2) determine the predictors of attrition in PLWHA treated with ART in Swaziland. A retrospective cohort study using national baseline data was conducted. A competing-risk Cox proportional hazard regression was used to determine the predictors of attrition. We estimated 10·3% (95% confidence interval 10·1-10·6) attrition in 16 423 participants that initiated ART in 2012. Attrition was significantly associated with sex, age, district, treatment supporter at initiation, co-infection of HIV and TB, functional status, WHO clinical stage, and ownership of facility. Our study can form a base of policies, plans, and service delivery strategies for preventing and controlling attrition in Swaziland.


Plantar pressures in the tennis serve.
In-shoe loading patterns were examined in each foot (back and front) separately during two types of tennis serve [first (or flat) and second (or twist) serve] and two service stance styles [foot-up (back foot is moved forward next to front foot for push-off) and foot-back (feet remain at the same relative level)]. Ten competitive tennis players completed five trials for each type of serve and service stance style in random order. Plantar pressure distribution was recorded using Pedar insoles divided into nine areas for analysis. Mean and peak pressures (+15.2%, P < 0.01 and +12.8%, P < 0.05) as well as maximal forces (+20.2%, P < 0.01) were higher under the lateral forefoot of the front foot in first than in second serves, while mean forces were higher (+17.2%, P < 0.05) under the lesser toes. Relative load was higher on the lateral forefoot (+20.4%, P < 0.05) but lower (-32.5%, P < 0.05) on the medial heel of the front foot with foot-up compared with foot-back stance. Using a foot-up stance, loading of the back foot was higher (+31.8%, P < 0.01) under the lateral mid-foot but lower (-29.9%, P < 0.01) under the medial forefoot. The type of serve and the stance style adopted have a significant effect on foot loading. Such findings might help improve mechanical efficiency of the serve.


[Virulence factors of Helicobacter pylori: what are they?].
The pathogenic properties of Helicobacter pylori are due to the ability of this bacterium to survive in the acidic gastric juice, to freely move and multiply within the mucus, to colonize the gastric mucosa and persist as an extracellular bacterium for decades despite the strong immune local and cellular responses they trigger. Every H. pylori isolate expresses properties that permit them colonization and persistence. In contrast, isolates may or not be expressing properties that potentially contribute to the genesis of tissue lesions due to the direct action of deleterious bacterial products or to the induction and/or modulation of the inflammatory response associated with the expression of specific antigens. Those are designated as pathogenic factors and might be useful to discriminate isolates.


Hepatic and renal functions in growing male rats after bisphenol A and octylphenol exposure.
This study aimed to determine the effects of 13-week bisphenol A (BPA) and octylphenol (OP) exposure on the liver, kidney, and spleen of growing male rats. A total of 29 male Wistar rats aged 4-5 weeks were divided into five groups. The treatment groups were given low-dose (125 mg/kg bw/day) or high-dose (250 mg/kg bw/day) BPA or OP. These compounds were dissolved in corn oil and given via oral route for 13 weeks. Rats in the control group received corn oil for 13 weeks, as well. After 13 weeks of treatment, blood samples were analyzed for biochemical parameters. Tissue samples from the liver, kidney, and spleen were histopathologically and histomorphometrically examined. Liver tissue specimens were also stained by immunohistochemically; the number of apoptotic cells was counted, and the apoptotic indices were calculated. There were significant differences between the control and treatment groups with respect to the following parameters: body weight, relative left kidney weight, and total protein, glucose, and alkaline phosphatase levels. Edema and parenchymal degeneration in the liver and tubular degeneration in the kidney were more frequent in the treatment groups. The control and treatment groups were comparable with respect to the frequency of histopathological lesions in the spleen. Glomerular histomorphometry revealed no significant differences between the control and treatment groups. No significant differences existed between the control and treatment groups with respect to the number of apoptotic cells and apoptotic indices. Subchronic exposure to BPA and OP induced functional and structural changes in the liver, kidney, and spleen of growing male rats.


Wnt/β-Catenin and Hippo Pathway Deregulation in Mammary Tumors of Humans, Dogs, and Cats.
Mammary cancer is a common neoplasm in women, dogs, and cats that still represents a therapeutic challenge. Wnt/β-catenin and Hippo pathways are involved in tumor progression, cell differentiation, and metastasis. The aim of this study was to evaluate mRNA and protein expression of molecules involved in these pathways in human (HBC), canine (CMT), and feline mammary tumors (FMT). Real-time quantitative polymerase chain reaction (qPCR) for β-catenin, CCND1, YAP, TAZ, CTGF, and ANKRD1, western blotting for YAP, TAZ, and β-catenin, and immunohistochemistry for estrogen receptor (ER), progesterone receptor (PR), ERBB2, β-catenin, and YAP/TAZ were performed on mammary tumor tissues. The protein expression of active β-catenin was higher in tumors than in healthy tissues in all 3 species. The mRNA expression of the downstream gene CCND1 was increased in HBC ER+ and CMTs compared to healthy tissues. Membranous and cytoplasmic protein expression of β-catenin were strongly negatively correlated in all 3 species. Tumors showed an increased protein expression of YAP/TAZ when compared to healthy tissues. Notably, YAP/TAZ expression was higher in triple negative breast cancers when compared to HBC ER+ and in FMTs when compared to CMTs. The mRNA expression of β-catenin, YAP, TAZ, CTGF, and ANKRD1 was not different between tumors and healthy mammary gland in the 3 species. This study demonstrates deregulation of Wnt/β-catenin and Hippo pathways in mammary tumors, which was more evident at the protein rather than the mRNA level. Wnt/β-catenin and Hippo pathways seem to be involved in mammary carcinogenesis and therefore represent interesting therapeutic targets that should be further investigated.


Pregnancy, childbirth and neonatal outcomes of women with rare inherited coagulation disorders.
We aimed to describe the characteristics and the pregnancy outcomes of women with rare inherited coagulation factor disorders managed at a tertiary obstetric-haematology unit in the United Kingdom. A retrospective service evaluation was conducted using routinely collected medical records. Descriptive analyses were applied to investigate pregnancy, childbirth and neonatal management and outcomes. Overall, 20 patients with rare inherited coagulation disorders were included who birthed 30 live infants from 29 pregnancies. Regarding maternal bleeding outcomes, 3% experienced antepartum haemorrhage, 38% of pregnancies experienced primary post-partum haemorrhage, and none experienced secondary post-partum haemorrhage. Five (17%) neonates had cranial ultrasound scans for imaging to investigate for a neonatal haemorrhage, which were all normal. Although women with rare inherited coagulation disorders may be more susceptible to complications in pregnancy, within this cohort there was no evidence that the condition led to increased morbidity or mortality when best practices were observed.


VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis.
Endocytosis plays a crucial role in receptor signalling. VEGFR2 (also known as KDR) and its ligand VEGFA are fundamental in neovascularisation. However, our understanding of the role of endocytosis in VEGFR2 signalling remains limited. Despite the existence of diverse internalisation routes, the only known endocytic pathway for VEGFR2 is the clathrin-mediated pathway. Here, we show that this pathway is the predominant internalisation route for VEGFR2 only in the absence of ligand. Intriguingly, VEGFA induces a new internalisation itinerary for VEGFR2, the pathway of macropinocytosis, which becomes the prevalent endocytic route for the receptor in the presence of ligand, whereas the contribution of the clathrin-mediated route becomes minor. Macropinocytic internalisation of VEGFR2, which mechanistically is mediated through the small GTPase CDC42, takes place through macropinosomes generated at ruffling areas of the membrane. Interestingly, macropinocytosis plays a crucial role in VEGFA-induced signalling, endothelial cell functions in vitro and angiogenesis in vivo, whereas clathrin-mediated endocytosis is not essential for VEGFA signalling. These findings expand our knowledge on the endocytic pathways of VEGFR2 and suggest that VEGFA-driven internalisation of VEGFR2 through macropinocytosis is essential for endothelial cell signalling and angiogenesis.


Complementarity of assembly-first and mapping-first approaches for alternative splicing annotation and differential analysis from RNAseq data.
Genome-wide analyses estimate that more than 90% of multi exonic human genes produce at least two transcripts through alternative splicing (AS). Various bioinformatics methods are available to analyze AS from RNAseq data. Most methods start by mapping the reads to an annotated reference genome, but some start by a de novo assembly of the reads. In this paper, we present a systematic comparison of a mapping-first approach (FARLINE) and an assembly-first approach (KISSPLICE). We applied these methods to two independent RNAseq datasets and found that the predictions of the two pipelines overlapped (70% of exon skipping events were common), but with noticeable differences. The assembly-first approach allowed to find more novel variants, including novel unannotated exons and splice sites. It also predicted AS in recently duplicated genes. The mapping-first approach allowed to find more lowly expressed splicing variants, and splice variants overlapping repeats. This work demonstrates that annotating AS with a single approach leads to missing out a large number of candidates, many of which are differentially regulated across conditions and can be validated experimentally. We therefore advocate for the combined use of both mapping-first and assembly-first approaches for the annotation and differential analysis of AS from RNAseq datasets.


Dose-response effects of resistance training on physical function in frail older Chinese adults: A randomized controlled trial.
Effective exercise for the frail elderly has been found to contribute to healthy aging; the corresponding relationship between intensity and volume of exercise and health effects remains unclear. The present study aimed to investigate the dose-response effects of resistance training on muscle strength and physical fitness in frail older adults. In this randomized controlled trial, participants were randomized into seven groups: moderate-volume low-intensity, moderate-volume moderate-intensity, moderate-volume high-intensity, high-volume low-intensity, high-volume moderate-intensity, high-volume high-intensity and routine care, receiving 12 weeks of resistance training of different intensities and volumes of exercise. The outcomes were muscle strength (assessed by ergonomics force gauges) and physical fitness function (assessed by the 6-min walking test [6MWT], the 30-s sit-to-stand test [30sSTST] and the 8-foot up-and-go test [8-FUGT]) before and at 6 and 12 weeks of intervention. A total of 161 participants completed the exercise intervention. There were no significant differences in age, sex, height, body weight and body mass index among the seven groups. The exercise volume of resistance training showed linear relationships with muscle strength of the lower limbs, 30sSTST and 6MWT results and a non-linear relationship with 8-FUGT. Resistance training intensity was found to have a linear relationship with muscle strength of the lower limbs and 6MWT and non-linear relationships with 30sSTST and 8-FUGT. The mixed linear model analysis revealed that the lower limb muscle strength differed significantly before and during the intervention (W = 8571.5, Padj < 0.001), before and after the intervention (W = 6968, Padj = 0.001) and during and after the intervention (W = 2834.5, Padj < 0.001); that the 6MWT performance differed during and after the intervention (W = 3184, Padj < 0.001); and that the 30sSTST was different between before and during the intervention (W = 2350.5, Padj = 0.012) and between during and after the intervention (W = 2290.5, Padj = 0.045). Resistance training was found to be associated with muscle strength and physical fitness in frail older adults in a dose-dependent manner. High-intensity resistance training could be more effective for improving the muscle strength of frail older adults, and the improvement of 6MWT performance was even higher. High-volume resistance training significantly improved muscle strength, with even greater improvement in the 30sSTST and 6MWT performances. Both the intensity and volume of exercise were found to greatly value physical function in frail older adults. Low-moderate-intensity resistance training and low-moderate-volume resistance training also had some advantages in terms of safety, efficacy and acceptance in elderly with frailty.


New Perspectives on Pheochromocytoma and Paraganglioma: Toward a Molecular Classification.
A molecular biology-based taxonomy has been proposed for pheochromocytoma and paraganglioma (PPGL). Data from the Cancer Genome Atlas revealed clinically relevant prognostic and predictive biomarkers and stratified PPGLs into three main clusters. Each subgroup has a distinct molecular-biochemical-imaging signature. Concurrently, new methods for biochemical analysis, functional imaging, and medical therapies have also become available. The research community now strives to match the cluster biomarkers with the best intervention. The concept of precision medicine has been long awaited and holds great promise for improved care. Here, we review the current and future PPGL classifications, with a focus on hereditary syndromes. We discuss the current strengths and shortcomings of precision medicine and suggest a condensed manual for diagnosis and treatment of both adult and pediatric patients with PPGL. Finally, we consider the future direction of this field, with a particular focus on how advanced molecular characterization of PPGL can improve a patient's outcome, including cures and, ultimately, disease prevention.


Application of a multiwalled carbon nanotube-chitosan composite as an electrode in the electrosorption process for water purification.
In this study, a multiwalled carbon nanotubes-chitosan (CNTs-CS) composite electrode was fabricated to enable water purification by electrosorption. The CNTs-CS composite electrode was shown to possess excellent capacitive behaviors and good pore accessibility by electrochemical impedance spectroscopy, galvanostatic charge-discharge, and cyclic voltammetry measurements in 1 M H2SO4 electrolyte. Moreover, the CNTs-CS composite electrode showed promising performance for capacitive water desalination. At an electric potential of 1.2 V, the electrosorption capacity and electrosorption rate of NaCl ions on the CNTs-CS composite electrode were determined to be 10.7 mg g(-1) and 0.051 min(-1), respectively, which were considerably higher than those of conventional activated electrodes. The improved electrosorption performance could be ascribed to the existence of mesopores. Additionally, the feasibility of electrosorptive removal of aniline from an aqueous solution has been demonstrated. Upon polarization at 0.6 V, the CNTs-CS composite electrode had a larger electrosorption capacity of 26.4 mg g(-1) and a higher electrosorption rate of 0.006 min(-1) for aniline compared with the open circuit condition. The enhanced adsorption resulted from the improved affinity between aniline and the electrode under electrochemical assistance involving a nonfaradic process. Consequently, the CNT-CS composite electrode, exhibiting typical double-layer capacitor behavior and a sufficient potential range, can be a potential electrode material for application in the electrosorption process.


[Case-control studies in psychiatry: causality, design and warnings].
This present paper is mainly methodological and has been written with the aim of helping researchers in psychiatry to produce results with higher quality and help readers to have adequate assessment values of others. Brief reflection is made on the most important conditions that must be fulfilled to prove a causality hypothesis, regardless of the investigation design used. However, the main purpose of the text is to examine and illustrate how these conditions work under a case-control study environment. Besides outlining the basic aspects concerning design and analysis, areas extremely illustrated with examples of case and controls in psychiatry found in the literature, a number of suggestions to avoid pitfalls that can invalidate research efforts developed using case-control methodology is offered.


[Predictive factors of local recurrence of in situ intraductal carcinoma. Apropos of 217 cases].
The authors have reviewed 217 cases of pure intraductal carcinomas with a mean follow-up of 98 months (with 2 deaths out of 31 recurrences from which 35% into adenocarcinomas). The data concerning the diagnosis, the tumor size, the pathological type, the surgical treatment, more of less associated to radiation therapy are detailed. The aim of this work was to give a more reliable way or approaching the recurrence rate (31/217) to be able to apply a more conservative treatment to these cases. The lymph node dissection and removal seams to be useless in the in situ carcinomas. Concerning the tumor size, the local tumors can be treated by conservative surgical procedures and do not get any benefit from radiotherapy. The opposite is true concerning more largely invasive tumor. Concerning the histology, the non-comedocarcinomatous tumors get less benefit from radiotherapy than the comedocarcinomatous type. The study of the tumor limits and the reliquats seem to be useful. The treatment chosen and applied remains the major prognostic element in the probability of recurrence.


A "Wii" bit of fun: the effects of adding Nintendo Wii(®) Bowling to a standard exercise regimen for residents of long-term care with upper extremity dysfunction.
The aims of this randomized, single-blind crossover trial were to investigate the effect of adding a simulated bowling video game via the Nintendo Wii(®) gaming system to the standard exercise regimen of cognitively intact residents of long-term care (LTC) with upper extremity dysfunction and to identify individual characteristics that might predict improvement. Residents (n=34) were recruited through two LTC facilities in southwestern Ontario and were randomized into a standard exercise (SG) or standard exercise plus Wii bowling (Wii) arm. After 4 weeks of intervention, the groups were crossed over to the opposite arm. Outcomes included measures of pain intensity and bothersomeness, physical activity enjoyment, and a six-item measure of functional capacity designed specifically for residents of LTC. Results suggest that subjects improved on all outcomes from pre- to postintervention but that only enjoyment of activity showed a significant difference between the SG and Wii groups. Effect sizes (Cohen's d) ranged from small (0.30 for bothersomeness) to large (1.77 for functional capacity). Responders, defined as those subjects who reported any degree of improvement following the Wii intervention, were less likely to complain of stiffness or shoulder symptoms and were more likely to complain of hand symptoms than non-responders. Limitations in interpretation and recommendations for future research are presented.


Converging diencephalic and hippocampal supports for episodic memory.
To understand the neural basis of episodic memory it is necessary to appreciate the significance of the fornix. This pathway creates a direct link between those temporal lobe and medial diencephalic sites responsible for anterograde amnesia. A collaboration with Andrew Mayes made it possible to recruit and scan 38 patients with colloid cysts in the third ventricle, a condition associated with variable fornix damage. Complete fornix loss was seen in three patients, who suffered chronic long-term memory problems. Volumetric analyses involving all 38 patients then revealed a highly consistent relationship between mammillary body volume and the recall of episodic memory. That relationship was not seen for working memory or tests of recognition memory. Three different methods all supported a dissociation between recollective-based recognition (impaired) and familiarity-based recognition (spared). This dissociation helped to show how the mammillary body-anterior thalamic nuclei axis, as well as the hippocampus, is vital for episodic memory yet is not required for familiarity-based recognition. These findings set the scene for a reformulation of temporal lobe and diencephalic amnesia. In this revised model, these two regions converge on overlapping cortical areas, including retrosplenial cortex. The united actions of the hippocampal formation and the anterior thalamic nuclei on these cortical areas enable episodic memory encoding and consolidation, impacting on subsequent recall.


Monitoring of outdoor natural gamma absorbed dose rate in air in Hyderabad, Telangana, India.
The Indian Environmental Radiation Monitoring Network continuously monitors the outdoor natural gamma absorbed dose rate in air at different locations throughout India by employing Geiger-Mueller (GM) detector-based field-installed environmental radiation monitors (ERMs). Hyderabad, Telangana, India is known to have high natural background radiation levels due to the presence of high concentrations of primordial radionuclides in its granitic rocks. There are a total of 59 ERMs installed at various locations across Hyderabad. Long-term monitoring data of these locations are presented in this paper. The mean values of outdoor natural gamma absorbed dose rate in air at the monitoring locations were found to vary in the range of 104-258 nGy.h-1 with a mean of 193 ± 40 nGy.h-1. The mean annual effective dose due to outdoor natural gamma radiation was estimated to be 0.24 ± 0.05 mSv.y-1. Analysis of the long-term seasonal variation of outdoor natural gamma absorbed dose rate in air showed that the same was lowest during monsoons.


Serum-induced changes in the physiology of mammalian retinal glial cells: role of lysophosphatidic acid.
1. With a breakdown of the vascular-CNS barrier, serum enters the nervous system. Although this is a frequent pathophysiological event, knowledge of the effects of serum on the function of the nervous system is limited. In this study, we examined the effects of serum on the activity of ion channels in Müller cells: the principal glia of the retina. 2. Freshly dissociated Müller cells from the bovine and human retina were studied with the perforated-patch configuration of the patch clamp technique. In other experiments, electroretinograms (ERGs) were recorded from isolated rat retinas. 3. Perforated-patch recordings revealed that serum induced a calcium-permeable, non-specific cation (NSC) current. Approximately 40 s after induction of this current, an outwardly rectifying K+ current was also detected. Sensitivity to charybdotoxin and margatoxin indicated that this K+ current was due to the activation of Kv1.3 channels. This increase in the Kv1.3 current was dependent on extracellular calcium. 4. The NSC and Kv1.3 currents were activated by serum in 100% and 95% of the sampled Müller cells, respectively. Also, in a minority (21%) of the cells, the inwardly rectifying K+ current was inhibited slightly. These changes in ion channel activity were associated with depolarization of the Müller cells. 5. We hypothesized that activation of NSC channels would reduce the siphoning of K+ via the Müller cells. Consistent with this idea, ERGs from isolated retinas showed serum-induced reductions in the slow PIII component, which is generated by Müller cells responding to light-evoked changes in the extracellular K+ concentration. 6. Lysophosphatidic acid (LPA), a component of serum, had effects on Müller cells that were qualitatively similar to those induced by serum. 7. Our observations demonstrate that exposure to serum alters the activity of multiple types of ion channels in Müller glial cells of the mammalian retina. When there is a breakdown of the blood-retina barrier, LPA may be one of the serum-derived molecules which regulates the physiology of Müller cells.


Pilot study of topical delivery of mono-L-aspartyl chlorin e6 (NPe6): implication of topical NPe6-photodynamic therapy.
Photodynamic therapy (PDT) is an evolving cancer treatment with promising results in treating malignant tumors by photoactivation of a photosensitizer with a specific wavelength. The second generation photosensitizer mono-L-aspartyl chlorin e6 (NPe6) was reported to have significant efficacy in killing cancer cells in vitro and in vivo. Though topical application might yield a higher local concentration and less systemic side effect, no data concerning topical absorption of NPe6 is available even though the drug has already been used in clinical trial for several years. To evaluate the possibility of topical delivery of NPe6 via an animal model, escalated concentrations of NPe6 were applied to BALB/c mouse skin for a different time periods after barrier disruption with tape stripping. Since NPe6 fluorescence intensity and drug concentration in tissue was well correlated, we evaluated drug penetration depth with frozen sections of treated and non-treated skin under a fluorescence microscope. An on-line fluorescence imaging system was used to monitor the NPe6 fluorescence kinetics in the skin. The fluorescence microscope confirmed successful topical delivery of NPe6 in mouse skin with or even without barrier disruption. Orange to red NPe6 fluorescence appeared at the epidermis, dermis, and even the muscular layer when using 10 mg/ml NPe6 application. The fluorescence intensity peaked at 1 h and revealed a dose-dependent response pattern. NPe6 treated versus non-treated skin showed a statistically significant difference by Student's t-test (P<0.05). The results described here suggest that topical delivery of NPe6 is possible. It showed fast and deep penetration into mouse skin. This implies that NPe6 might be useful as a topical photosensitizer for PDT in treating skin cancers.


Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors.
Differentiation is a complex set of events that can be blocked by rearrangements of regulatory genes producing fusion proteins with altered properties. In the case of myxoid liposarcoma (MLS) tumors, the causative abnormality is a fusion between the CHOP transcription factor and the FUS or EWS genes. CHOP belongs to and is a negative regulator of the large CAAT/enhancer binding protein family whose alpha, beta, and delta members are master genes of adipogenesis. Recent clinical data indicate a peculiar sensitivity of these tumors to the natural marine compound trabectedin. One hypothesis is that the activity of trabectedin is related to the inactivation of the FUS-CHOP oncogene. We find that trabectedin causes detachment of the FUS-CHOP chimera from targeted promoters. Reverse transcription-PCR and chromatin immunoprecipitation analysis in a MLS line and surgical specimens of MLS patients in vivo show activation of the CAAT/enhancer binding protein-mediated transcriptional program that leads to morphologic changes of terminal adipogenesis. The activity is observed in cells with type 1 but not type 8 fusions. Hence, the drug induces maturation of MLS lipoblasts in vivo by targeting the FUS-CHOP-mediated transcriptional block. These data provide a rationale for the specific activity of trabectedin and open the perspective of combinatorial treatments with drugs acting on lipogenic pathways.


Androgen and psychosexual development: core gender identity, sexual orientation and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia (CAH).
We assessed core gender identity, sexual orientation, and recalled childhood gender role behavior in 16 women and 9 men with CAH and in 15 unaffected female and 10 unaffected male relatives, all between the ages of 18 and 44 years. Women with congenital adrenal hyperplasia (CAH) recalled significantly more male-typical play behavior as children than did unaffected women, whereas men with and without CAH did not differ. Women with CAH also reported significantly less satisfaction with the female sex of assignment and less heterosexual interest than did unaffected women. Again, men with CAH did not differ significantly from unaffected men in these respects. Our results for women with CAH are consistent with numerous prior reports indicating that girls with CAH show increased male-typical play behavior. They also support the hypotheses that these women show reduced heterosexual interest and reduced satisfaction with the female sex of assignment. Our results for males are consistent with most prior reports that boys with CAH do not show a general alteration in childhood play behavior. In addition, they provide initial evidence that core gender identity and sexual orientation are unaffected in men with CAH. Finally, among women with CAH, we found that recalled male-typical play in childhood correlated with reduced satisfaction with the female gender and reduced heterosexual interest in adulthood. Although prospective studies are needed, these results suggest that those girls with CAH who show the greatest alterations in childhood play behavior may be the most likely to develop a bisexual or homosexual orientation as adults and to be dissatisfied with the female sex of assignment.


Lipid abnormalities in foreign-born and US-born patients in a medical group.
With an increasing foreign-born population in the United States, cardiovascular risk reduction through effective lipid treatment strategy is precluded by limited lipid profile information. This study compares the patterns of lipid abnormalities of foreign-born and US-born patients treated by a single medical group. We conducted a medical record review of 53,361 US-born and 6430 foreign-born patients in 2010. Compared with US-born, a higher proportion of foreign-born patients are younger than 40 years (26% vs 14%), receive Medicaid (24% vs 8%), and are less likely to be obese (26% vs 43%). More foreign-born patients have diabetes (25% vs 22%), are poor (4.7% vs 3.6%), and not on lipid-lowering drugs (63% vs 56%). Place of birth is not associated with total cholesterol levels. Adjusted for social and demographic characteristics, however, foreign-born are more likely than US-born to have elevated low-density lipoprotein cholesterol (adjusted difference, 2.1; 95% CI, 0.6-3.7), depressed high-density lipoprotein cholesterol (adjusted difference, 6.1; 95% CI, 4.4-7.8), and elevated triglycerides (adjusted difference, 2.4; 95% CI, 0.8-4.1). Foreign-born patients, on lipid-lowering medications, are more likely to still have elevated levels of low-density lipoprotein cholesterol (adjusted difference, 3.5; 95% CI, 1.4-5.6). Despite having a similar distribution of total cholesterol as their US-born counterparts, the other lipid fractions among foreign-born patients are more likely to be pathologic. Therefore, dyslipidemia screening tests need to include the lipid subfractions. The higher prevalence of dyslipidemias, both among foreign-born patients with and without lipid-lowering medications, challenges medical groups to intensify effective lipid treatment strategies.


Socioeconomic Disparities and Gender Inequalities in Dementia: a Community-Dwelling Population Study from a Middle-Income Country.
The proportion of the world's older adults and of its dementia cases is increasing in low and middle-income countries. This is particularly true in Colombia. There, the number of individuals with dementia may increase five-fold by 2050. Yet research is lacking on dementia in such settings. This work estimates the prevalence of dementia in a community-dwelling population in Colombia. It also assesses how gender-based differences in cardiovascular conditions and socioeconomic disparities affect dementia. This work analyzes data on 2000 respondents at least 60 years of age in the Health, Well-Being, And Aging (SABE) study in Bogota. Respondents with dementia are those who have cognitive impairment and at least two limitations in instrumental activities of daily living. The SABE study finds 8.4% of respondents have dementia. Age, cardiovascular risks, and socioeconomic disparities contributed to higher odds of dementia. The contributors to dementia can differ for men and women. For example, socioeconomic disparities were a larger contributor to dementia for women than men. The findings support the cognitive reserve hypothesis on dementia. This holds that pre-existing cognitive processes and compensatory mechanisms influence dementia. Women in Latin America are more likely to suffer from socioeconomic disparities that limit their cognitive reserve. This research points to several policy implications that can help offset these disparities and reduce the prevalence of dementia.


Alcohol consumption as a risk factor for non-recovery from common mental disorder: results from the longitudinal follow-up of the National Psychiatric Morbidity Survey.
Alcohol is commonly considered to be associated with persistence of common mental disorder (CMD; anxiety/depression). However no community-based longitudinal studies have investigated the direction of causality. We examined the association between alcohol consumption and recovery from CMD using data on 706 community-based subjects with CMD who were followed for 18 months. Alcohol consumption at baseline was defined as hazardous drinking [Alcohol Use Disorders Identification Test (AUDIT) 8], binge drinking (defined as six or more units of alcohol on one occasion, approximately two to three pints of commercially sold beer) and dependence. When compared with a non-binge-drinking group, non-recovery at follow-up was associated with binge drinking on at least a monthly basis at baseline, although the confidence interval (CI) included unity [adjusted odds ratio (OR) 1.47, 95% CI 0.89-2.45]. There was also weak evidence that alcohol dependence was associated with non-recovery (adjusted OR 1.37, 95% CI 0.67-2.81). There was little evidence to support hazardous drinking as a risk factor for non-recovery (adjusted OR 1.12, 95% CI 0.67-1.88). Binge drinking may be a potential risk factor for non-recovery from CMD, although the possibility of no effect cannot be excluded. Larger studies are required to refute or confirm this finding.


A toolbox of machine learning software to support microbiome analysis.
The human microbiome has become an area of intense research due to its potential impact on human health. However, the analysis and interpretation of this data have proven to be challenging due to its complexity and high dimensionality. Machine learning (ML) algorithms can process vast amounts of data to uncover informative patterns and relationships within the data, even with limited prior knowledge. Therefore, there has been a rapid growth in the development of software specifically designed for the analysis and interpretation of microbiome data using ML techniques. These software incorporate a wide range of ML algorithms for clustering, classification, regression, or feature selection, to identify microbial patterns and relationships within the data and generate predictive models. This rapid development with a constant need for new developments and integration of new features require efforts into compile, catalog and classify these tools to create infrastructures and services with easy, transparent, and trustable standards. Here we review the state-of-the-art for ML tools applied in human microbiome studies, performed as part of the COST Action ML4Microbiome activities. This scoping review focuses on ML based software and framework resources currently available for the analysis of microbiome data in humans. The aim is to support microbiologists and biomedical scientists to go deeper into specialized resources that integrate ML techniques and facilitate future benchmarking to create standards for the analysis of microbiome data. The software resources are organized based on the type of analysis they were developed for and the ML techniques they implement. A description of each software with examples of usage is provided including comments about pitfalls and lacks in the usage of software based on ML methods in relation to microbiome data that need to be considered by developers and users. This review represents an extensive compilation to date, offering valuable insights and guidance for researchers interested in leveraging ML approaches for microbiome analysis.


Gestational age and cognitive ability in early childhood: a population-based cohort study.
Recent studies suggest that children born at late preterm (34-36 weeks gestation) and early term (37-38 weeks) may have poorer developmental outcomes than children born at full term (39-41 weeks). We examined how gestational age is related to cognitive ability in early childhood using the U.K. Millennium Cohort Study. Cognitive development was assessed using Bracken School Readiness Assessment at age 3 years, British Ability Scales II at ages 3, 5 and 7 years and Progress in Mathematics at age 7 years. Sample size varied according to outcome between 12,163 and 14,027. Each gestational age group was compared with the full-term group using differences in z-scores and risk ratios for scoring more than -1 SD below the mean. Children born at <32 weeks gestation scored lower (P < 0.05) than the full-term group on all scales with unadjusted z-score differences ranging between -0.8 to -0.2 SD. In all groups, there was an increased risk (P < 0.05) of scoring less than -1 SD below the mean compared with the full-term group for some of the tests: those born at < 32 weeks had a 40-140% increased risk in seven tests, those born at 32-33 weeks had a 60-80% increased risk in three tests, those born at 34-36 weeks had a 30-40% increased risk in three tests, and those born at 37-38 weeks had a 20% increased risk in two tests. Cognitive ability is related to the entire range of gestational age, including children born at 34-36 and 37-38 weeks gestation.


Hormonal and cell density regulation of hepatic gamma-glutamylcysteine synthetase gene expression.
We previously reported that the activity of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis, is under both hormonal and cell density regulation in cultured rat hepatocytes. Specifically, the addition of insulin or hydrocortisone to culture media or the lowering of the initial plating cell density increased cell GSH by increasing the activity of GCS. In the present study, we examined the molecular mechanism of these effects. To determine whether the increase in GCS activity is associated with an increase in GCS heavy subunit (GCS-HS) mRNA expression, the steady state mRNA levels of GCS-HS were examined with the use of Northern blots. After 24-hr treatment of high density (0.6 x 10(5) cells/cm2) cultured rat hepatocytes with insulin (1 micrograms/ml) or hydrocortisone (50 nM), the steady state GCS-HS mRNA level increased by approximately 1-2 fold. When the plating density was decreased to 0.1 x 10(5) cells/cm2, the steady state GCS-HS mRNA level also increased by 1-2 fold 24 hr later. An increase in the steady state GCS-HS mRNA level was found within 4 hr of either hormonal treatment or cell density manipulation. The increase in steady state GCS-HS mRNA level resulted from increased gene transcription, as the transcriptional rates of GCS-HS after hormonal or cell density manipulation were increased by 2-3-fold, whereas the rates of GCS-HS mRNA degradation remained unchanged. Western blotting confirmed the increase in GCS-HS protein level after hormone treatment or lowering of plating cell density. When examined in vivo, the steady state GCS-HS mRNA level decreased by 50% in a rat in which diabetes had been induced with streptozotocin for 1 week; this was prevented with insulin replacement. In summary, GCS-HS gene expression is under both hormonal and cell density regulation.


Mapping of anion binding sites on cytochrome c by differential chemical modification of lysine residues.
The carbonate binding site on horse cytochrome c was mapped by comparing the yields of carboxydinitrophenyl-cytochromes c, each with a single carboxydinitrophenyl-substituted lysine residue per molecule, when the modification reaction was carried out in the presence and absence of carbonate. The site is located on the "left surface" of the protein and consists of lysine residues 72 and/or 73 as well as 86 and/or 87 (Carbonate Site). Although one of the binding sites for phosphate on cytochrome c (Phosphat Site I) is located near the carbonate site, the sites are distinctly different since carbonate does not displace bound phosphate, as monitored by 31P NMR. Furthermore, citrate interacts with Phosphate Site I with high affinity, whereas chloride, acetate, borate, and cacodylate have a much lower affinity for this site, if they bind to it at all. The affinity of phosphate for Phosphate Site I (KD = 2 X 10(-4) M) is at least 1 order of magnitude higher than it is for other sites of interaction.


Downregulation of SAV1 plays a role in pathogenesis of high-grade clear cell renal cell carcinoma.
Clinical outcome of patients with high-grade ccRCC (clear cell renal cell carcinoma) remains still poor despite recent advances in treatment strategies. Molecular mechanism of pathogenesis in developing high-grade ccRCC must be clarified. In the present study, we found that SAV1 was significantly downregulated with copy number loss in high-grade ccRCCs. Therefore, we investigated the SAV1 function on cell proliferation and apoptosis in vitro. Furthermore, we attempted to clarify the downstream signaling which is regulated by SAV1. We performed array CGH and gene expression analysis of 8 RCC cell lines (786-O, 769-P, KMRC-1, KMRC-2, KMRC-3, KMRC-20, TUHR4TKB, and Caki-2), and expression level of mRNA was confirmed by quantitative RT-PCR (qRT-PCR) analysis. We next re-expressed SAV1 in 786-O cells, and analyzed its colony-forming activity. Then, we transfected siRNAs of SAV1 into the kidney epithelial cell line HK2 and renal proximal tubule epithelial cells (RPTECs), and analyzed their proliferation and apoptosis. Furthermore, the activity of YAP1, which is a downstream molecule of SAV1, was evaluated by western blot analysis, reporter assay and immunohistochemical analysis. We found that SAV1, a component of the Hippo pathway, is frequently downregulated in high-grade ccRCC. SAV1 is located on chromosome 14q22.1, where copy number loss had been observed in 7 of 12 high-grade ccRCCs in our previous study, suggesting that gene copy number loss is responsible for the downregulation of SAV1. Colony-forming activity by 786-O cells, which show homozygous loss of SAV1, was significantly reduced when SAV1 was re-introduced exogenously. Knockdown of SAV1 promoted proliferation of HK2 and RPTEC. Although the phosphorylation level of YAP1 was low in 786-O cells, it was elevated in SAV1-transduced 786-O cells. Furthermore, the transcriptional activity of the YAP1 and TEAD3 complex was inhibited in SAV1-transduced 786-O cells. Immunohistochemistry frequently demonstrated nuclear localization of YAP1 in ccRCC cases with SAV1 downregulation, and it was preferentially detected in high-grade ccRCC. Taken together, downregulation of SAV1 and the consequent YAP1 activation are involved in the pathogenesis of high-grade ccRCC. It is an attractive hypothesis that Hippo signaling could be candidates for new therapeutic target.


Physiotherapy and physical functioning post-stroke: exercise habits and functioning 4 years later? Long-term follow-up after a 1-year long-term intervention period: a randomized controlled trial.
Physical activity is mandatory if patients are to remain healthy and independent after stroke. Maintenance of motor function, tone, grip strength, balance, mobility, gait, independence in personal and instrumental activities of daily living, health-related quality-of-life and an active lifestyle 4 years post-stroke. A prospective randomized controlled trial. Four years post-stroke, 37 of the 75 participating persons were eligible for follow-up; 19 (54.3%) from the intensive exercise group and 18 (45%) from the regular exercise group. Both groups were performing equally well with no significant differences in total scores on the BI (p = 0.3), MAS (p = 0.4), BBS (p = 0.1), TUG (p = 0.08), 6MWT (p = 0.1), bilateral grip strength (affected hand, p = 0.8; non-affected hand, p = 0.9) nor in the items of NHP (p > 0.005). Independence in performing the IADL was 40%, while 60% had help from relatives or community-based services. This longitudinal study shows that persons with stroke in two groups with different exercise regimes during the first year after stroke did not differ in long-term outcomes. Both groups maintained function and had a relatively active life style 4 years after the acute incident. The results underline the importance of follow-up testing and encouragement to exercise, to motivate and sustain physical activity patterns, to maintain physical function, not only in the acute but also in the chronic phase of stroke.


Tenascin in human neoplasia.
Tenascin (TN), a recently characterized extracellular matrix protein, largely confined to the process with the development of embryo in areas of epithelial-mesenchymal interactions, developing neural tissues, bone and cartilage where there are morphogenetic movements and tissue patterning, has a highly restricted expression in adult tissues. The function(s) and molecular mechanisms of enhanced expression of TN in neoplastic lesions, however, remain unclear. Tissue specimens of human neoplasia obtained from 1050 cases of biopsy or surgery and their representative fetal and normal adult tissues were evaluated for immunoreactivity of TN using seven different clones of monoclonal antibodies in a three stage streptavidin biotin immunoperoxidase method. The normal epithelial lined structures such as the mucous membrane and skin had a thin delicate immunoreactive band just beneath the basement membrane at the epithelial mesenchymal interface. Hyperplastic or dysplastic lesions of the epithelium, such as leukoplakia of the oral mucosa, senile keratosis and intraepithelial carcinoma of skin showed an enhanced expression of TN extending down into the connective tissue where the degree of enhanced expression correlated with increasing hyperplasia or dysplasia. The squamous cell carcinoma and adenocarcinoma of different organs, both at the primary site and in lymph node metastasis, showed a widespread stromal immunoreactivity and the expression was affected by infiltration of inflammatory cells, fibrous tissue reaction and tumor cell differentiation. There was heterogeneity in the expression of TN in benign epithelial neoplasms, squamous cell carcinoma and adenocarcinoma which varied in different areas of the same tumor specimen ranging from no reaction to intensely reactive areas. The undifferentiated carcinomas often had low expression in the stroma. The non-epithelial or mesenchymal tumors such as chondrogenic, osteogenic, myogenic, neurogenic, vascular and other miscellaneous neoplasms also had an enhanced expression of TN. When the immunoreactivity of seven different monoclonal antibodies to detect TN were compared, the pattern of expression of TN with different monoclonal antibody in majority of the cases were identical and equivocal, but there were slight differences in the intensity of staining. Using a single monoclonal antibody nearly 94% of the cases of human neoplasia showed an enhanced immunoreaction for TN. In conclusion, the results of the present study when combined with our previous in vitro study (Shrestha et al, Eur J Cancer Oral Oncol, in press) suggest that the enhanced expression of TN in vivo in a wide variety of neoplastic lesions of both epithelial and non-epithelial in origin may affect tumor growth, differentiation, vascularity, cellular adhesion, invasion and metastasis.


High Glucose Enhances Neurotoxicity and Inflammatory Cytokine Secretion by Stimulated Human Astrocytes.
Chronic neuroinflammation caused by activation of microglia and astrocytes in the brain contributes to neuronal loss and disease progression in Alzheimer's disease (AD). Recent research has identified type 2 diabetes mellitus (T2DM) as a risk factor for AD. High blood glucose (hyperglycemia) and the phenomenon of insulin resistance are being considered as the major factors contributing to an increased risk of AD. However, the mechanisms involved in this interaction remain unclear. High glucose has been shown to increase release of pro-inflammatory mediators from various immune cells, including microglia. Since astrocytes are the most abundant glial cell type in the brain, we investigated the effects of elevated glucose concentrations (5.5-30.5 mM) on selected functions of cultured human astrocytes in the presence of inflammatory stimuli. Experiments were conducted using primary human astrocytes and U-118 MG astrocytoma cells. High glucose (30.5 mM) increased mRNA expression of interleukin (IL)-6 and secretion of both IL-6 and IL-8 by astrocytes. This astrocytic inflammatory response to high glucose did not appear to be mediated by augmented p38 or p44/42 mitogen activated protein kinase (MAPK) signaling pathways. In addition, high glucose increased the susceptibility of undifferentiated human SH-SY5Y neuronal cells and retinoic-acid differentiated SH-SY5Y cells to injury by hydrogen peroxide (H2O2) and fibrillar amyloid beta-42 protein (Aβ42), respectively. Our data indicate that hyperglycemia in T2DM may be one of the factors contributing to the observed increased risk of AD by exacerbating astrocyte-mediated neuroinflammation and neuronal injury caused by disease-associated agents.


Training in pediatric hepatology across Europe: a survey of the National Societies Network (2016-2019) of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition.
The widely recognized burden of liver diseases makes training in pediatric hepatology (PH) imperative. The aim of this survey, which was part of a global survey on training in pediatric gastroenterology, hepatology and nutrition (PGHN) across Europe, was to assess the PH and liver transplantation (LT) infrastructure, staff and training programs in PGHN training centers. Standardized questionnaires were collected from training centers via the presidents/representatives of the National Societies Network of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) from June 2016 to December 2019. A total of 100 PGHN training centers participated in the survey (14/100 were national referral centers in PH and/or LT). Dedicated PH clinics were available in 75%, but LT clinics in only 11%. Dedicated beds for PGHN inpatients were available in 47/95 (49%) centers. Full-time or part-time specialists for PH care were available in 31/45 (69%) and 11/36 (31%) centers, respectively. Liver biopsies (LB) were performed in 93% of centers by: a PGHN specialist (35%); an interventional radiologist (26%); a pediatric surgeon (4%); or a combination of them (35%). Dividing the annual number of LBs in the centers performing LBs by the number of trainees gave a median (range) of 10 (1-125) per trainee. Transient elastography was available in 60/92 (65%) of centers. The survey highlighted the differences and shortcomings in PH training across Europe. ESPGHAN should take initiatives together with National Societies to ensure the acquisition of PH knowledge and skills according to the ESPGHAN curriculum.An infographic is available for this article at: http://www.annalsgastro.gr/files/journals/1/earlyview/2022/Infographic-Hepatology-training-paper.pdf.


Management of bipolar disorder during pregnancy and the postpartum period.
Bipolar disorder affects 0.5%-1.5% of individuals in the United States. The typical age at onset is late adolescence or early adulthood, placing women at risk for episodes throughout their reproductive years. General guidelines for the treatment of bipolar disorder are available from the American Psychiatric Association, but additional issues arise when these guidelines are applied in the treatment of peripartum women. The authors summarize knowledge regarding the management of bipolar disorder during pregnancy and the postpartum period, with a focus on managing mania, hypomania, and the psychotic components of the illness. An expert panel reviewed articles that address the management of bipolar disorder and the consequences of the use of mood stabilizers during pregnancy, and a consensus document was generated. The treatment of bipolar disorder in pregnant women involves significant challenges. Some mood stabilizers, e.g., sodium valproate and carbamazepine, are human teratogens. On the other hand, the teratogenicity associated with lithium may have been overestimated in the past. Since treatment can be managed most effectively if pregnancy is planned, clinicians should discuss the issue of pregnancy and its management with every bipolar disorder patient who has childbearing potential, regardless of future reproductive plans. Additional research should address the risks of disturbed sleep to pregnant and postpartum women with bipolar disorder, as well as structural and behavioral consequences to offspring when mood stabilizers are used during pregnancy. Longitudinal and cohort studies can promote these efforts. Given the rate of bipolar disorder in the general population, research efforts will need to be broad based and include multiple collaborating centers.


Is there a relation between clinical disease activity and acute phase response in Behcet's disease?
The aim of this study was to evaluate a possible relation between clinical disease activity determined by a scale validated and most widely used acute phase response parameters in patients with Behcet's Disease (BD). One hundred patients with BD were included in this study. The demographic properties including age, sex, and disease durations were recorded. BD Current Activity Form (BDCAF), which scores the history of clinical features that have been present during the four weeks prior to the day of assessment, was used for the evaluation of disease activity. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were evaluated as acute phase response. The independent samples t test and Pearson's correlation test were performed for the statistical analysis. There were 60 male and 40 female patients with an age range of 19-51 years. The disease durations of the patients were between 12 and 240 months. In the comparison of the laboratory parameters of the patients with or without the components of BDCAF, we found significantly higher levels of ESR and CRP in patients with erythema and arthralgia-arthritis versus without these involvements. There were significant positive correlations between ESR-CRP levels and patient's perception of disease activity (P = 0.012 and P < 0.05, respectively), clinician's overall perception of disease activity (P < 0.005), and total BDCAF score (P = 0.008 and P < 0.000, respectively). In conclusion, the presence of a newly-developed erythema nodosum, superficial thrombophlebitis, or joint involvement may be associated with higher levels of ESR and CRP. Also, correlations between these indices and general disease activity scores may contribute the overall disease activity perception in BD.


Stabilization of the spectrin-like domains of nesprin-1α by the evolutionarily conserved "adaptive" domain.
Nesprins are located at the outer and inner membranes of the nuclear envelope and help link the cytoskeleton to the nucleoskeleton. Nesprin-1α, located at the inner nuclear membrane, binds to A-type lamins and emerin and has homology to spectrin-repeat proteins. However, the mechanical and thermodynamic properties of the spectrin-like repeats (SLRs) of nesprin-1α and the potential structural contributions of the unique central domain were untested. In other spectrin superfamily proteins, tandem spectrin-repeat domains undergo cooperatively coupled folding and unfolding. We hypothesized that the large central domain, which interrupts SLRs and is conserved in other nesprin isoforms, might confer unique structural properties. To test this model we measured the thermal unfolding of nesprin-1α fragments using circular dichroism and dynamic light scattering. The SLRs in nesprin-1α were found to have structural and thermodynamic properties typical of spectrins. The central domain had relatively little secondary structure as an isolated fragment, but significantly stabilized larger SLR-containing molecules by increasing their overall helicity, thermal stability and cooperativity of folding. We suggest this domain, now termed the 'adaptive' domain (AD), also strengthens dimerization and inhibits unfolding. Further engineering of the isolated AD, and AD-containing nesprin molecules, may yield new information about the higher-order association of cooperative protein motifs.