Awareness and Perceptions of Emergency Contraceptive Pills Among Women in Kinshasa, Democratic Republic of the Congo.
Despite the commitment of the Democratic Republic of the Congo (DRC) to expand the family planning method mix and increase access to services, awareness of emergency contraception is low among women, and the method remains underused and poorly integrated in family planning programming. Data from 15 focus group discussions conducted in 2016 among women aged 15-35 were used to examine awareness and perceptions of, and attitudes toward, emergency contraceptives. After facilitators explained emergency contraceptive pills' mechanism of action and other characteristics, participants were asked about the potential benefits and risks of making the method more widely available. Transcripts were analyzed using an iterative approach. Women reported employing a wide range of postcoital contraceptive behaviors, albeit often using inappropriate products, and generally agreed that emergency contraceptive pills seemed to be a potentially effective solution to their family planning needs. Perceived benefits and limitations of the method were almost always framed in reference to other, better-known contraceptives, and women expressed strong preferences for pharmacy-based provision that aligned with their usual behaviors for obtaining contraceptives. Participants were reluctant to see the method available for free. Emergency contraceptive pills have the potential to address gaps in the family planning method mix in the DRC. Assessing whether women have incomplete or erroneous information about family planning methods can provide better understanding of women's contraceptive choices in low-income countries.


Social Firms as a means of vocational recovery for people with mental illness: a UK survey.
Employment is associated with better quality of life and wellbeing in people with mental illness. Unemployment is associated with greater levels of psychological illness and is viewed as a core part of the social exclusion faced by people with mental illness. Social Firms offer paid employment to people with mental illness but are under-investigated in the UK. The aims of this phase of the Social Firms A Route to Recovery (SoFARR) project were to describe the availability and spread of Social Firms across the UK, to outline the range of opportunities Social Firms offer people with severe mental illness and to understand the extent to which they are employed within these firms. A UK national survey of Social Firms, other social enterprises and supported businesses was completed to understand the extent to which they provide paid employment for the mentally ill. A study-specific questionnaire was developed. It covered two broad areas asking employers about the nature of the Social Firm itself and about the employees with mental illness working there. We obtained returns from 76 Social Firms and social enterprises / supported businesses employing 692 people with mental illness. Forty per cent of Social Firms were in the south of England, 24% in the North and the Midlands, 18% in Scotland and 18% in Wales. Other social enterprises/supported businesses were similarly distributed. Trading activities were confined mainly to manufacturing, service industry, recycling, horticulture and catering. The number of employees with mental illness working in Social Firms and other social enterprises/supported businesses was small (median of 3 and 6.5 respectively). Over 50% employed people with schizophrenia or bipolar disorder, though the greatest proportion of employees with mental illness had depression or anxiety. Over two thirds of Social Firms liaised with mental health services and over a quarter received funding from the NHS or a mental health charity. Most workers with mental illness in Social Firms had been employed for over 2 years. Social Firms have significant potential to be a viable addition to Individual Placement and Support (IPS), supporting recovery orientated services for people with the full range of mental disorders. They are currently an underdeveloped sector in the UK.


The use of Virtual Reality for needle-related procedural pain and distress in children and adolescents in a paediatric oncology unit.
It is essential to minimize pain and distress during painful procedures in children. This study examined the effect of using non-immersive Virtual Reality (VR) during a needle-related procedure on reported pain or distress of children and adolescents in a paediatric oncology unit and surveyed their response to the use of VR-equipment during the procedure. Twenty-one children and adolescents were included in an intervention group with non-immersive VR and another 21 children and adolescents in a control group where they underwent either venous punctures or subcutaneous venous port devices. Self-reported pain and distress, heart rate and observational pain scores were collected before, during and after the procedures. Semi-structured qualitative interviews were conducted in conjunction with the completed intervention. Self-reported and observed pain and distress scores were low and few significant differences of quantitative data between the groups were found. Two themes emerged in the analysis of the interviews; the VR game should correspond to the child and the medical procedure and children enjoyed the VR game and found that it did distract them during the procedure. The interviews showed that non-immersive VR is a positive experience for children undergoing a minor procedure such as venous puncture or a subcutaneous venous port access.


The effects of allium sativum on immunity within the scope of COVID-19 infection.
The severity of coronavirus disease 2019 (COVID-19) infection is quite variable and the manifestations varies from asymptomatic disease to severe acute respiratory infection. Fever, dry cough, dyspnea, myalgia, fatigue, loss of appetite, olfactory and gustatory dysfunctions are the most prevalent general symptoms. Decreased immune system cells such as suppressed regulatory T cells, cytotoxic and helper T cells, natural killer cells, monocytes/macrophages and increased proinflammatory cytokines are the characteristic features. Compounds derived from Allium sativum (garlic) have the potential to decrease the expression of proinflammatory cytokines and to reverse the immunological abnormalities to more acceptable levels. Allium sativum is suggested as a beneficial preventive measure before being infected with SARS-CoV-2 virus. Allium sativum is a functional food well-known for its immunomodulatory, antimicrobial, antiinflammatory, antimutagenic, antitumor properties. Its antiviral efficiency was also demonstrated. Some constituents of this plant were found to be active against protozoan parasites. Within this context, it appears to reverse most immune system dysfunctions observed in patients with COVID-19 infection. The relations among immune system parameters, leptin, leptin receptor, adenosin mono phosphate-activated protein kinase, peroxisome proliferator activated receptor-gamma have also been interpreted. Leptin's role in boosting proinflammatory cytokines and in appetite decreasing suggest the possible beneficial effect of decreasing the concentration of this proinflammatory adipose tissue hormone in relieving some symptoms detected during COVID-19 infection. In conclusion, Allium sativum may be an acceptable preventive measure against COVID-19 infection to boost immune system cells and to repress the production and secretion of proinflammatory cytokines as well as an adipose tissue derived hormone leptin having the proinflammatory nature.


A clinicopathological study of collagen sponge as a dural graft in neurosurgery.
There is frequently a need for dural grafts to cover defects resulting from retraction, shrinkage, or excision following neurosurgical procedures. Several materials have been evaluated both experimentally and clinically, and then discarded. Collagen, in its various forms, continues to be an area of intense interest. In this study the authors examined the suitability of collagen sponge to effect dural repair. In a 5-year clinical study 102 collagen sponge implants were examined macroscopically and histologically. Graft encapsulation, neomembrane formation, delayed hemorrhage, and foreign body reactions were not found. The porous nature of the collagen sponge encouraged fibroblastic ingrowth and dural repair. Meningocerebral adhesions were present in 11 patients, all of whom had required significant cortical resection or had pia-arachnoid disruption during the initial surgery. Inflammatory cells were seen only in response to infection. Postoperative cerebrospinal fluid leaks developed in only three of 67 patients who underwent an intradural posterior fossa procedure. In a prospective arm of the study involving 459 patients, the wound infection rate using collagen sponge was 6.1%, which compared favorably (p = 0.67) with the 5.7% rate in a similar group of 637 patients in whom collagen sponge had not been used.


Synthetic head and neck and phantom images for determining deformable image registration accuracy in magnetic resonance imaging.
Magnetic resonance imaging (MRI) provides noninvasive evaluation of patient's anatomy without using ionizing radiation. Due to this and the high soft-tissue contrast, MRI use has increased and has potential for use in longitudinal studies where changes in patients' anatomy or tumors at different time points are compared. Deformable image registration can be useful for these studies. Here, we describe two datasets that can be used to evaluate the registration accuracy of systems for MR images, as it cannot be assumed to be the same as that measured on CT images. Two sets of images were created to test registration accuracy. (a) A porcine phantom was created by placing ten 0.35-mm gold markers into porcine meat. The porcine phantom was immobilized in a plastic container with movable dividers. T1-weighted, T2-weighted, and CT images were acquired with the porcine phantom compressed in four different ways. The markers were not visible on the MR images, due to the selected voxel size, so they did not interfere with the measured registration accuracy, while the markers were visible on the CT images and were used to identify the known deformation between positions. (b) Synthetic images were created using 28 head and neck squamous cell carcinoma patients who had MR scans pre-, mid-, and postradiotherapy treatment. An inter- and intrapatient variation model was created using these patient scans. Four synthetic pretreatment images were created using the interpatient model, and four synthetic post-treatment images were created for each of the pretreatment images using the intrapatient model. The T1-weighted, T2-weighted, and CT scans of the porcine phantom in the four positions are provided. Four T1-weighted synthetic pretreatment images each with four synthetic post-treatment images, and four T2-weighted synthetic pretreatment images each with four synthetic post-treatment images are provided. Additionally, the applied deformation vector fields to generate the synthetic post-treatment images are provided. The data are available on TCIA under the collection MRI-DIR. The proposed database provides two sets of images (one acquired and one computer generated) for use in evaluating deformable image registration accuracy. T1- and T2-weighted images are available for each technique as the different image contrast in the two types of images may impact the registration accuracy.


Public Health Insurance Expansion for Immigrant Children and Interstate Migration of Low-Income Immigrants.
Federal policy changes in 2002 and 2009 led some states to expand public health insurance coverage to non-US-born children and pregnant women who are lawful permanent residents during their first 5 years of residency in the United States. In other states, there were concerns that insurance expansion could attract immigrants to relocate to gain free health insurance coverage. To examine whether expansion of public health insurance to non-US-born, lawful permanent resident children and pregnant women during their first 5 years of residency is associated with increased interstate migration among these groups. This difference-in-differences analysis included data on 208 060 immigrants from the American Community Survey from 2000 through 2016, with analysis including all 50 states and the District of Columbia. The study sample included 2 treatment groups that became eligible under the expanded coverage: lawful permanent resident adults with at least 1 non-US-born child younger than 18 years (n = 36 438) and lawful permanent resident women of reproductive age (n = 87 418). Control groups that remained ineligible under the expanded coverage included lawful permanent resident adults without non-US-born children (n = 171 622), lawful permanent resident single men (n = 56 142), and lawful permanent resident postreproductive women (n = 15 129). A difference-in-differences design compared migration rates between eligible and ineligible immigrant groups before and after insurance coverage expansions. Data analysis was performed from November 3, 2018, to May 31, 2019. Public health insurance coverage for immigrant women and children who were lawful permanent residents within 5 years of residency. Migration to a health expansion state from any other state and from a neighboring state. Of 208 060 immigrants (47% women in the weighted sample; mean [SD] age, 32.97 [12.94] years; 63% Hispanic), the mean (SD) annual move rate across the entire sample was 3% (17%). Expansion of public health insurance to non-US-born children or pregnant women within their first 5 years of residency was not associated with interstate movement for health care benefits. Coverage expansion for non-US-born children of lawful permanent residents was not associated with a change in the rate of in-migration higher than 1.78 percentage points or lower than -1.28 percentage points. The corresponding estimate for coverage expansion of lawful permanent resident pregnant women was a change higher than 1.38 percentage points and lower than -1.20 percentage points. The results suggest that states considering expanding health care benefits coverage to recently arrived immigrant children and pregnant women may be unlikely to experience in-migration of these persons from other states, which has important implications for understanding short- and long-term program costs.


Robot-Assisted Radical Cystectomy with Total Intracorporeal Urinary Diversion: Comparative Analysis with Extracorporeal Urinary Diversion.
To compare the perioperative outcomes, postoperative complications, and early oncologic outcomes of intracorporeal urinary diversion (ICUD) with those of extracorporeal urinary diversion (ECUD) following robot-assisted radical cystectomy (RARC) performed by a single surgeon at a tertiary referral hospital. We reviewed a prospectively maintained, institutional review board-approved database of 70 patients treated with RARC and pelvic lymph node (LN) dissection for bladder cancer performed from 2007 through 2014. Data were collected for 64 patients who underwent either ICUD or ECUD. Thirty-eight patients underwent ECUD, and the remaining 26 underwent ICUD. Urinary diversion was performed extracorporeally in the first 37 cases and performed intracorporeally thereafter. There were no significant differences in patient characteristics between the ECUD and ICUD groups. Mean total operative time was 468 minutes for ECUD and 581 minutes for ICUD (P < .05). Mean estimated blood loss was 265 and 148 mL, respectively (P < .05). Minor and total complication rates for patients with the ECUD were higher than in patients with the ICUD (minor: 47.4% vs. 15.4%; total: 57.9% vs. 30.8%; P < .05). All patients showed negative surgical margin, while 21% in the ECUD group and 26.9% in the ICUD group had pathologic stage T3 or T4 (P > .05). The mean LN yield was 23.2 and 31.8, respectively (P < .05). From our experience, the results show that ICUD after RARC can be successful, with the benefits of decreased blood loss and lower transfusion and complication rates than ECUD. A larger series and long-term follow-up data will be necessary to support our results.


Frequent nut consumption and decreased risk of cholecystectomy in women.
Gallstone disease is a major source of morbidity in the developed countries. Nuts are rich in several compounds that may protect against gallstone disease. The association between nut intake and cholecystectomy was examined in a large cohort of women. We prospectively studied nut (peanuts, other nuts, and peanut butter) consumption in relation to the risk of cholecystectomy in a cohort of 80,718 women from the Nurses' Health Study who were 30-55 y old in 1980 and had no history of gallstone disease. As part of the Nurses' Health Study, the women reported on questionnaires mailed to them every 2 y both their consumption of nuts and whether they had undergone cholecystectomy. The women were followed through 2000. During 1,393,256 person-years of follow-up from 1980 to 2000, we documented 7831 cholecystectomies. After adjustment for age and other known or suspected risk factors, women who consumed > or =5 units of nuts (1 unit = 1 oz or 28.6 g nuts)/wk (frequent consumption) had a significantly lower risk of cholecystectomy (relative risk: 0.75; 95% CI: 0.66, 0.85; P for trend < 0.0001) than did women who never ate nuts or who ate <1 unit/mo (rare consumption). Further adjustment for fat consumption (saturated fat, trans fat, polyunsaturated fat, and monounsaturated fat) did not materially alter the relation. In analyses examining consumption of peanuts and other nuts separately, both were associated with a lower risk of cholecystectomy. In women, frequent nut consumption is associated with a reduced risk of cholecystectomy.


Novel dual-function CellDetect® staining technology: wedding morphology and tinctorial discrimination to detect cervical neoplasia.
A persistent goal of oncologic histochemistry is to microscopically identify neoplasia tinctorially. Consequently, the newly developed CellDetect® staining technology, that appears to exhibit this property, warrants clinical evaluation. The objective of this study was to compare the diagnostic results using CellDetect® to the outcomes of standard microscopic examination based on hematoxylin and eosin (H&E) staining for the recognition of different squamous epithelial phenotypes of the uterine cervix. Pairs of adjacent sections were made from 60 cervical biopsy cases that were diagnosed originally as either normal or neoplastic (CIN, SCC). One section of the pair was stained for H&E; the second section, with CellDetect®. Based on the examination of these pairs by two experienced pathologists, we investigated the following issues:(1) diagnostic agreement between the pathologists on each pair; (2) agreement between H&E and CellDetect® for each pair (3) tinctorial characteristics in micro-regions (n = 130) evaluated as either normal, reactive or neoplastic. Qualitatively, CellDetect®-stained preparations displayed cyto-morphological detail comparable to H&E images. Tinctorially, non-neoplastic cells appeared green/blue when stained withCellDetect®, contrasting with cytologically neoplastic foci, where cells of every grade were red/magenta in color. Due to these tinctorial characteristics, even small foci of neoplasia could be readily distinguished that were inconspicuous on H&E at low magnification. In some instances, this prompted re-examination of the H&E and revision of the diagnosis. Quantitatively, we found that despite diagnostic variation between pathologists, in about 3% of the cases, each pathologist made the same diagnosis regardless of whether CellDetect® or H&E was used, i.e. there was 100% self-agreement for each pathologist between stains. Particularly noteworthy was the finding of a 0% false negative rate, coupled with a 10-15% false positive rate. Regarding specificity, the performance in reactive squamous processes was similar to that observed for morphologically normal squamous epithelium. In this first order assessment of clinical applicability, CellDetect® staining technology was at least comparable to results using H&E, and perhaps surperior. CellDetect® provided a uniquely useful tinctorial clue for the detection of neoplasia, which exhibited an impressive 0% false negative rate. A more extensive, blinded study is needed to confirm these promising findings.


Solid-state solubility influences encapsulation and release of hydrophobic drugs from PLGA/PLA nanoparticles.
Biodegradable nanoparticles formulated from poly(D,L-lactide-co-glycolide) (PLGA) and polylactide (PLA) polymers are being extensively investigated for various drug delivery applications. In this study, we hypothesize that the solid-state solubility of hydrophobic drugs in polymers could influence their encapsulation and release from nanoparticles. Dexamethasone and flutamide were used as model hydrophobic drugs. A simple, semiquantitative method based on drug-polymer phase separation was developed to determine the solid-state drug-polymer solubility. Nanoparticles using PLGA/PLA polymers were formulated using an emulsion-solvent evaporation technique, and were characterized for size, drug loading, and in vitro release. X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC) were used to determine the physical state of the encapsulated drug. Results demonstrated that the solid-state drug-polymer solubility depends on the polymer composition, molecular weight, and end-functional groups (ester or carboxyl) in polymer chains. Higher solid-state drug-polymer solubility resulted in higher drug encapsulation in nanoparticles, but followed an inverse correlation with the percent cumulative drug released. The XRD and DSC analyses demonstrated that the drug encapsulated in nanoparticles was present in the form of a molecular dispersion (dissolved state) in the polymer, whereas in microparticles, the drug was present in both molecular dispersion and crystalline forms. In conclusion, the solid-state drug-polymer solubility affects the nanoparticle characteristics, and thus could be used as an important preformulation parameter.


Msps/XMAP215 interacts with the centrosomal protein D-TACC to regulate microtubule behaviour.
The XMAP215/ch-TOG/Msps family of microtubule-associated proteins (MAPs) promote microtubule growth in vitro and are concentrated at centrosomes in vivo. We show here that Msps (mini-spindles protein) interacts with the centrosomal protein D-TACC, and that this interaction strongly influences microtubule behaviour in Drosophila embryos. If D-TACC levels are reduced, Msps does not concentrate at the centrosomes efficiently and the centrosomal microtubules appear to be destabilized. If D-TACC levels are increased, both D-TACC and Msps accumulate around the centrosomes/spindle poles, and the centrosomal microtubules appear to be stabilized. We show that the interaction between D-TACC and Msps is evolutionarily conserved. We propose that D-TACC and Msps normally cooperate to stabilize centrosomal microtubules by binding to their minus ends and binding to their plus ends as they grow out from the centrosome.


Trajectories of change in cognitive function in people with chronic obstructive pulmonary disease.
To describe changes in cognitive function, as measured by the trail making test; to identify distinct patterns of change in cognitive function; and to examine predictors of change in cognitive function in people with severe chronic obstructive pulmonary disease. How cognitive function changes in people with chronic obstructive pulmonary disease and what factors influence those changes over time is not well known, despite the fact that it declines rapidly in this population and significantly impacts functional decline in healthy older adults. A secondary analysis and longitudinal study with a follow-up period of 3 years. A data set from the National Emphysema Treatment Trial provided participant data. Patients with severe chronic obstructive pulmonary disease (n = 307) were recruited at a clinical site. Several demographic and clinical measures were assessed at baseline. Trail making test scores were measured at baseline, 1, 2 and 3 years. Cognitive function was stable for 3 years in people with chronic obstructive pulmonary disease. However, four distinct patterns of change in cognitive function were identified. Age, education, 6-min walk distance and cognitive impairment scores at baseline on the trail making test Part B were significant predictors of worsening cognitive function and below-average cognitive function over 3 years. These findings suggest that increasing exercise capacity improves cognitive function and delays deterioration of cognitive function in people with COPD. Understanding the trajectories of change in cognitive function and predictors of change in cognitive function over 3 years may enable health care providers to identify patients at greatest risk of developing mental deterioration and those who might benefit from interventions to improve cognitive function. Health care providers should periodically assess and frequently screen people with COPD for cognitive function.


New TNM classification (AJCC eighth edition) of bone and soft tissue sarcomas: JCOG Bone and Soft Tissue Tumor Study Group.
The Cancer Staging Manual of the American Joint Committee on Cancer (AJCC) has recently been revised and updated to its eighth edition. This review focuses on the new staging system of bone and soft tissue sarcomas and outlines the revision points and caveats in the latest edition. The major changes in the eighth edition of the AJCC staging for bone and soft tissue sarcomas are the following four points. (i) Tumors are described separately according to the primary sites. For bone sarcoma, three tumor locations are described: (a) appendicular skeleton, trunk, skull and facial bones; (b) spine and (c) pelvis. Meanwhile, four tumor locations are described for soft tissue sarcoma: (1) trunk and extremity; (2) retroperitoneum; (3) head and neck and (4) visceral sites. (ii) Histologic grading system in bone sarcoma is changed to three-grade classifications. (iii) For soft tissue sarcoma, AnyTN1M0 tumor in the trunk and extremity is classified as stage IV, whereas for the retroperitoneal tumor, anyTN1M0 remains as stage IIIB. (iv) For soft tissue sarcomas in the trunk, extremity and retroperitoneum, tumor size was classified into four categories: (a) ≤5 cm; (b) >5 cm and ≤10 cm; (c) >10 cm and ≤15 cm and (d) >15 cm. In addition, the notation about the depth of the tumor (superficial or deep from the superficial fascia) has been eliminated.


Mixed-effects Poisson regression analysis of adverse event reports: the relationship between antidepressants and suicide.
A new statistical methodology is developed for the analysis of spontaneous adverse event (AE) reports from post-marketing drug surveillance data. The method involves both empirical Bayes (EB) and fully Bayes estimation of rate multipliers for each drug within a class of drugs, for a particular AE, based on a mixed-effects Poisson regression model. Both parametric and semiparametric models for the random-effect distribution are examined. The method is applied to data from Food and Drug Administration (FDA)'s Adverse Event Reporting System (AERS) on the relationship between antidepressants and suicide. We obtain point estimates and 95 per cent confidence (posterior) intervals for the rate multiplier for each drug (e.g. antidepressants), which can be used to determine whether a particular drug has an increased risk of association with a particular AE (e.g. suicide). Confidence (posterior) intervals that do not include 1.0 provide evidence for either significant protective or harmful associations of the drug and the adverse effect. We also examine EB, parametric Bayes, and semiparametric Bayes estimators of the rate multipliers and associated confidence (posterior) intervals. Results of our analysis of the FDA AERS data revealed that newer antidepressants are associated with lower rates of suicide adverse event reports compared with older antidepressants. We recommend improvements to the existing AERS system, which are likely to improve its public health value as an early warning system.


'Loss of self': a psychosocial study of the quality of life of adults with diabetic foot ulceration.
At present, recognition of the importance of psychosocial factors in the care of individuals with diabetes is still in its infancy. Understanding of the specific psychosocial factors relating to diabetic foot ulceration is embryonic. The study reported in this paper begins to raise awareness of psychosocial quality of life issues for patients living with diabetic foot ulceration, as narrated by the patients themselves. Findings revealed a range of restrictions on daily life that profoundly affected the individual's sense of self. These findings have implications for patients' adherence to treatment. Implications of these findings for health promotion are also reported.


The case of CAUSE: neurobiological mechanisms for grounding an abstract concept.
How can we understand causal relationships and how can we understand words such as 'cause'? Some theorists assume that the underlying abstract concept is given to us, and that perceptual correlation provides the relevant hints towards inferring causation from perceived real-life events. A different approach emphasizes the role of actions and their typical consequences for the emergence of the concept of causation and the application of the related term. A model of causation is proposed that highlights the family resemblance between causal actions and postulates that symbols are necessary for binding together the different partially shared semantic features of subsets of causal actions and their goals. Linguistic symbols are proposed to play a key role in binding the different subsets of semantic features of the abstract concept. The model is spelt out at the neuromechanistic level of distributed cortical circuits and the cognitive functions they carry. The model is discussed in light of behavioural and neuroscience evidence, and questions for future research are highlighted. In sum, taking causation as a concrete example, I argue that abstract concepts and words can be learnt and grounded in real-life interaction, and that the neurobiological mechanisms realizing such abstract semantic grounding are within our grasp.This article is part of the theme issue 'Varieties of abstract concepts: development, use and representation in the brain'.


Early life trauma, depression and the glucocorticoid receptor gene--an epigenetic perspective.
Hopes to identify genetic susceptibility loci accounting for the heritability seen in unipolar depression have not been fully realized. Family history remains the 'gold standard' for both risk stratification and prognosis in complex phenotypes such as depression. Meanwhile, the physiological mechanisms underlying life-event triggers for depression remain opaque. Epigenetics, comprising heritable changes in gene expression other than alterations of the nucleotide sequence, may offer a way to deepen our understanding of the aetiology and pathophysiology of unipolar depression and optimize treatments. A heuristic target for exploring the relevance of epigenetic changes in unipolar depression is the hypothalamic-pituitary-adrenal (HPA) axis. The glucocorticoid receptor (GR) gene (NR3C1) has been found to be susceptible to epigenetic modification, specifically DNA methylation, in the context of environmental stress such as early life trauma, which is an established risk for depression later in life. In this paper we discuss the progress that has been made by studies that have investigated the relationship between depression, early trauma, the HPA axis and the NR3C1 gene. Difficulties with the design of these studies are also explored. Future efforts will need to comprehensively address epigenetic natural histories at the population, tissue, cell and gene levels. The complex interactions between the epigenome, genome and environment, as well as ongoing nosological difficulties, also pose significant challenges. The work that has been done so far is nevertheless encouraging and suggests potential mechanistic and biomarker roles for differential DNA methylation patterns in NR3C1 as well as novel therapeutic targets.


Counseling about sudden unexpected death in epilepsy (SUDEP): A global survey of neurologists' opinions.
To investigate the opinions and attitudes of neurologists on the counseling about sudden unexpected death in epilepsy (SUDEP) worldwide. Practicing neurologists from around the world were invited to participate in an online survey. On February 18th, 2021, we emailed an invitation including a questionnaire (using Google-forms) to the lead neurologists from 50 countries. The survey anonymously collected the demographic data of the participants and answers to the questions about their opinions and attitudes toward counseling about SUDEP. In total, 1123 neurologists from 27 countries participated; 41.5% of the respondents reported they discuss the risk of SUDEP with patients and their care-givers only rarely. Specific subgroups of patients who should especially be told about this condition were considered to be those with poor antiseizure medication (ASM) adherence, frequent tonic-clonic seizures, or with drug-resistant epilepsy. The propensity to tell all patients with epilepsy (PWE) about SUDEP was higher among those with epilepsy fellowship. Having an epilepsy fellowship and working in an academic setting were factors associated with a comfortable discussion about SUDEP. There were significant differences between the world regions. Neurologists often do not discuss SUDEP with patients and their care-givers. While the results of this study may not be representative of practitioners in each country, it seems that there is a severe dissociation between the clinical significance of SUDEP and the amount of attention that is devoted to this matter in daily practice by many neurologists around the world.


Network observability transitions.
In the modeling, monitoring, and control of complex networks, a fundamental problem concerns the comprehensive determination of the state of the system from limited measurements. Using power grids as example networks, we show that this problem leads to a new type of percolation transition, here termed a network observability transition, which we solve analytically for the configuration model. We also demonstrate a dual role of the network's community structure, which both facilitates optimal measurement placement and renders the networks substantially more sensitive to "observability attacks." Aside from their immediate implications for the development of smart grids, these results provide insights into decentralized biological, social, and technological networks.


Diagnostic errors and flaws in clinical reasoning: mechanisms and prevention in practice.
Diagnostic errors account for more than 8% of adverse events in medicine and up to 30% of malpractice claims. Mechanisms of errors may be related to the working environment but cognitive issues are involved in about 75% of the cases, either alone or in association with system failures. The majority of cognitive errors are not related to knowledge deficiency but to flaws in data collection, data integration, and data verification that may lead to premature diagnostic closure. This paper reviews some aspects of the literature on cognitive psychology that help us to understand reasoning processes and knowledge organisation and summarises biases related to clinical reasoning. It reviews the strategies described to prevent cognitive diagnostic errors. Many approaches propose awareness and reflective practice during daily activities, but the improvement of the quality of training at the pre-graduate, postgraduate and continuous levels, by using evidence-based education, should also be considered. Several conditions must be fulfilled to increase the understanding, the prevention, and the correction of diagnostic errors related to clinical reasoning: physicians must be willing to understand their own reasoning and decision processes; training efforts should be provided during the whole continuum of a clinician's career; and the involvement of medical schools, teaching hospitals, and medical societies in medical education research should be increased to improve evidence about error prevention.


Antitumor effects of L-BLP25 antigen-specific tumor immunotherapy in a novel human MUC1 transgenic lung cancer mouse model.
L-BLP25 antigen-specific cancer immunotherapeutic agent is currently in phase III clinical trials for non-small cell lung cancer. Using a novel human MUC1 transgenic (hMUC1.Tg) lung cancer mouse model, we evaluated effects of L-BLP25 combined with low-dose cyclophosphamide (CPA) pretreatment on Th1/Th2 cytokine production and antitumor activity. A chemically-induced lung tumor model was developed in hMUC1.Tg C57BL/6 mice by administering 10 weekly 0.75-mg/g doses of the chemical carcinogen urethane by intraperitoneal injection. Serum cytokines associated with Th1/Th2 polarization and inflammation were measured by multiplex cytokine assay during tumorigenesis. Antitumor activity of L-BLP25 (10 μg) with CPA (100 mg/kg) pretreatment was evaluated following either one or two eight-week cycles of treatment by preparing lung whole mounts and counting tumor foci, and assessing IFN-γ production by ELISpot assay. During the carcinogenesis phase, no detectable Th1- or Th2-associated cytokine responses were observed, but levels of pro-inflammatory cytokines were increased with distinctive kinetics. A single cycle of L-BLP25 consisting of eight weekly doses was ineffective, whereas adding a second cycle given during tumor progression showed a significant reduction in the incidence of tumor foci. Administering two cycles of L-BLP25 induced Th1 cytokines IL-12, IL-2 and IFNγ at 24 h after the last dose, while Th2 and inflammatory cytokines were elevated to a lesser extent. Urethane-induced lung tumors in hMUC1.Tg mice can be used as a model to assess the efficacy of the MUC1 antigen-specific cancer immunotherapeutic agent L-BLP25. The results indicate that the antitumor response to L-BLP25 requires at least two cycles and pre-treatment with CPA. In addition, monitoring pro-inflammatory serum cytokines may be useful as a biomarker of L-BLP25 response. Taken together, the preclinical lung tumor model can be utilized for determining effective combinations of L-BLP25 with chemotherapy and/or other immunotherapies.


Standard virtual biological parts: a repository of modular modeling components for synthetic biology.
Fabrication of synthetic biological systems is greatly enhanced by incorporating engineering design principles and techniques such as computer-aided design. To this end, the ongoing standardization of biological parts presents an opportunity to develop libraries of standard virtual parts in the form of mathematical models that can be combined to inform system design. We present an online Repository, populated with a collection of standardized models that can readily be recombined to model different biological systems using the inherent modularity support of the CellML 1.1 model exchange format. The applicability of this approach is demonstrated by modeling gold-medal winning iGEM machines. The Repository is available online as part of http://models.cellml.org. We hope to stimulate the worldwide community to reuse and extend the models therein, and contribute to the Repository of Standard Virtual Parts thus founded. Systems Model architecture information for the Systems Model described here, along with an additional example and a tutorial, is also available as Supplementary information. The example Systems Model from this manuscript can be found at http://models.cellml.org/workspace/bugbuster. The Template models used in the example can be found at http://models.cellml.org/workspace/SVP_Templates200906.


Chromogenic oxazines for cyanide detection.
[reaction: see text] We have designed two heterocyclic compounds for the colorimetric detection of cyanide. The skeleton of both molecules fuses a benzooxazine ring to an indoline fragment and can be assembled efficiently in three synthetic steps starting from commercial precursors. The two compounds differ in the nature of the substituent on the carbon atom at the junction of the fused heterocycles, which can be either a methyl or a phenyl group. In the presence of cyanide, both molecules are converted quantitatively into cyanoamines with the concomitant appearance of an intense band in the visible region of the absorption spectrum. The developing absorption is a result of the opening of the benzooxazine ring with the formation of a 4-nitrophenylazophenolate chromophore. Nuclear magnetic resonance spectroscopy and X-ray crystallographic analyses demonstrate that the covalent attachment of a cyanide anion to the indoline fragment is responsible for these transformations. The chromogenic process is particularly fast for the methyl-substituted oxazine and can be exploited to detect micromolar concentrations of cyanide in water. Furthermore, the colorimetric response of this compound to cyanide does not suffer the interference of the halide anions, which instead are known to complicate the detection of cyanide in conventional sensing protocols. Thus, our mechanism and compounds for the colorimetric identification of cyanide can lead to the development of practical strategies for the convenient determination of this toxic anion in aqueous environments.


Science and Orthodox Christianity: An Overview.
This essay offers an overview of the history of the relations between science and Eastern Christianity based on Greek-language sources. The civilizations concerned are the Byzantine Empire, the Christian Orthodox communities of the Ottoman Empire, and modern Greece, as a case study of a national state. Beginning with the Greek Church Fathers, the essay investigates the ideas of theologians and scholars on nature. Neoplatonism, the theological debates of Iconoclasm and Hesychasm, the proposed union of the Eastern and Western Churches, and the complex relations with the Hellenic past all had notable impacts on the conception of science held by the Byzantine Orthodox. From the sixteenth through the eighteenth centuries, the Christian Orthodox world did not actively participate in the making of the new science that was developing in modern Europe. It had to deal with the assimilation of scientific ideas produced by Western Christianity, and its main concern was the "legitimacy" of knowledge that did not originate directly from its own spiritual tradition. Finally, with regard to the Greek state, beyond the specific points of contact between the sciences and Orthodox Christianity—pertaining, for example, to materialism, evolution, and the calendar—the essay presents the constant background engagement with religion visible in most public pronouncements of scientists and intellectuals.


Sedentary behavior, physical activity and cardiorespiratory fitness on leukocyte telomere length.
Background: Emerging work is starting to investigate the cumulative effects of moderate-to-vigorous physical activity (MVPA), sedentary behavior and cardiorespiratory fitness on health. The objective of this study was to examine the cumulative and independent associations of MVPA, sedentary behavior and cardiorespiratory fitness on leukocyte telomere length (LTL). Methods: Data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES) were used (N = 1868 adults 20+ years); analyzed in 2016. Sedentary behavior and MVPA were subjectively assessed with cardiorespiratory fitness determined from a submaximal treadmill-based test; participants were classified as above or below the median values for each of these three parameters. A blood sample was obtained from each participant to assess LTL via quantitative polymerase chain reaction, with participants grouped into LTL tertiles. Results: Participants who engaged in higher MVPA, sat less and had higher cardiorespiratory fitness had an increased odds (ranging from 85% to 105%) of being in LTL tertile 3 (vs. 1). In an extended adjusted multinomial logistic regression model, only MVPA was positively associated with LTL (odds ration [OR] = 1.37; 95% CI: 0.99-1.90; P = 0.05). Conclusion: All three behavior characteristics, but particularly MVPA, may be important in preserving LTLs.


Designing nanoconjugates to effectively target pancreatic cancer cells in vitro and in vivo.
Pancreatic cancer is the fourth leading cause of cancer related deaths in America. Monoclonal antibodies are a viable treatment option for inhibiting cancer growth. Tumor specific drug delivery could be achieved utilizing these monoclonal antibodies as targeting agents. This type of designer therapeutic is evolving and with the use of gold nanoparticles it is a promising approach to selectively deliver chemotherapeutics to malignant cells. Gold nanoparticles (GNPs) are showing extreme promise in current medicinal research. GNPs have been shown to non-invasively kill tumor cells by hyperthermia using radiofrequency. They have also been implemented as early detection agents due to their unique X-ray contrast properties; success was revealed with clear delineation of blood capillaries in a preclinical model by CT (computer tomography). The fundamental parameters for intelligent design of nanoconjugates are on the forefront. The goal of this study is to define the necessary design parameters to successfully target pancreatic cancer cells. The nanoconjugates described in this study were characterized with various physico-chemical techniques. We demonstrate that the number of cetuximab molecules (targeting agent) on a GNP, the hydrodynamic size of the nanoconjugates, available reactive surface area and the ability of the nanoconjugates to sequester EGFR (epidermal growth factor receptor), all play critical roles in effectively targeting tumor cells in vitro and in vivo in an orthotopic model of pancreatic cancer. Our results suggest the specific targeting of tumor cells depends on a number of crucial components 1) targeting agent to nanoparticle ratio 2) availability of reactive surface area on the nanoparticle 3) ability of the nanoconjugate to bind the target and 4) hydrodynamic diameter of the nanoconjugate. We believe this study will help define the design parameters for formulating better strategies for specifically targeting tumors with nanoparticle conjugates.


Consideration of stiffness of wall layers is decisive for patient-specific analysis of carotid artery with atheroma.
The paper deals with the impact of chosen geometric and material factors on maximal stresses in carotid atherosclerotic plaque calculated using patient-specific finite element models. These stresses are believed to be decisive for the plaque vulnerability but all applied models suffer from inaccuracy of input data, especially when obtained in vivo only. One hundred computational models based on ex vivo MRI are used to investigate the impact of wall thickness, MRI slice thickness, lipid core and fibrous tissue stiffness, and media anisotropy on the calculated peak plaque and peak cap stresses. The investigated factors are taken as continuous in the range based on published experimental results, only the impact of anisotropy is evaluated by comparison with a corresponding isotropic model. Design of Experiment concept is applied to assess the statistical significance of these investigated factors representing uncertainties in the input data of the model. The results show that consideration of realistic properties of arterial wall in the model is decisive for the stress evaluation; assignment of properties of fibrous tissue even to media and adventitia layers as done in some studies may induce up to eightfold overestimation of peak stress. The impact of MRI slice thickness may play a key role when local thin fibrous cap is present. Anisotropy of media layer is insignificant, and the stiffness of fibrous tissue and lipid core may become significant in some combinations.


Abnormal Uterine Bleeding- evaluation by Endometrial Aspiration.
Endometrial evaluation is generally indicated in cases presenting with abnormal uterine bleeding (AUB), especially in women more than 35 years of age. AUB encompasses a variety of presentation, for example, heavy menstrual bleeding, frequent bleeding, irregular vaginal bleeding, postcoital and postmenopausal bleeding to name a few. Many methods are used for the evaluation of such cases, with most common being sonography and endometrial biopsy with very few cases requiring more invasive approach like hysteroscopy. Endometrial aspiration is a simple and safe office procedure used for this purpose. We retrospectively analyzed cases of AUB where endometrial aspiration with Pipette (Medgyn) was done in outpatient department between January 2015 and April 2016. Case records (both paper and electronic) were used to retrieve data. One hundred and fifteen cases were included in the study after applying inclusion and exclusion criteria. Most cases were between 46 and 50 years of age followed by 41-45 years. No cases were below 25 or more than 65 years of age. Heavy menstrual bleeding was the most common presentation of AUB. Adequate samples were obtained in 86% of cases while 13.9% of cases' sample was inadequate for opinion, many of which were later underwent hysteroscopy and/or dilatation and curettage (D and C) in operation theater; atrophic endometrium was the most common cause for inadequate sample. Uterine malignancy was diagnosed in three cases. Endometrial aspiration has been compared with traditional D and C as well as postoperative histopathology in various studies with good results. Many such studies are done in India as well as in western countries confirming good correlation with histopathology and adequate tissue sample for the pathologist to give a confident diagnosis. No complication or side effect was noted with the use of this device. Endometrial aspiration is a simple, safe, and effective method to sample endometrium in cases of AUB avoiding risk of anesthesia and is less time-consuming. Many similar devices are also available in the market and need to be popularized in all parts of the country.


Spatial morphological and molecular differences within solid tumors may contribute to the failure of vascular disruptive agent treatments.
Treatment of solid tumors with vascular disrupting agent OXi4503 results in over 90% tumor destruction. However, a thin rim of viable cells persists in the tumor periphery following treatment, contributing to subsequent recurrence. This study investigates inherent differences in the microenvironment of the tumor periphery that contribute to treatment resistance. Using a murine colorectal liver metastases model, spatial morphological and molecular differences within the periphery and the center of the tumor that may account for differences in resistance to OXi4503 treatment were investigated. H&E staining and immunostaining were used to examine vessel maturity and stability, hypoxia and HIF1α levels, accumulation of immune cells, expression of proangiogenic factors/receptors (VEGF, TGF-β, b-FGF, and AT1R) and expression of EMT markers (ZEB1, vimentin, E-cadherin and β-catenin) in the periphery and center of established tumors. The effects of OXi4503 on tumor vessels and cell kinetics were also investigated. Significant differences were found between tumor periphery and central regions, including association of the periphery with mature vessels, higher accumulation of immune cells, increased growth factor expression, minimal levels of hypoxia and increased evidence of EMT. OXi4503 treatment resulted in collapse of vessels in the tumor center; however vasculature in the periphery remained patent. Similarly, tumor apoptosis and proliferation were differentially modulated between centre and periphery after treatment. The molecular and morphological differences between tumor periphery and center may account for the observed differential resistance to OXi4503 treatment and could provide targets for drug development to totally eliminate metastases.


Effectiveness of border screening for detecting influenza in arriving airline travelers.
We measured symptom and influenza prevalence, and the effectiveness of symptom and temperature screening for identifying influenza, in arriving international airline travelers. This cross-sectional study collected data from travelers to Christchurch International Airport, New Zealand, in winter 2008, via a health questionnaire, temperature testing, and respiratory sampling. Forms were returned by 15 976 (68%) travelers. Of these, 17% reported at least 1 influenza symptom, with runny or blocked nose (10%) and cough (8%) most common. Respiratory specimens were obtained from 3769 travelers. Estimated prevalence of influenza was 1.1% (4% among symptomatic, 0.2% among asymptomatic). The sensitivity of screening criteria ranged from 84% for "any symptom" to 3% for a fever of 37.8 °C or greater. The positive predictive value was low for all criteria. Border screening using self-reported symptoms and temperature testing has limitations for preventing pandemic influenza from entering a country. Using "any symptom" or cough would lead to many uninfected people being investigated, yet some infected people would remain undetected. If more specific criteria such as fever were used, most infected people would enter the country despite screening.


Dynamics and adaptive benefits of modular protein evolution.
During protein evolution, novel domain arrangements are continuously formed. Rearrangements are important for the creation of molecular biodiversity and for functional molecular changes which underlie developmental shifts in the bauplan of organisms. Here we review the mechanisms by which new arrangements arise and the potential benefits of rearrangements. We concentrate on how new domains emerge and why they rapidly spread across genomes, gaining higher copy numbers than older, more established domains. This spread is most likely a consequence of their high adaptive potential but is unlikely to make up on its own for the drastic loss of domains, which is observed across different taxa. We show that a significant portion of the recently emerged domains, especially those in multidomain families, are highly disordered and speculate about the significance of these findings for the evolvability of novel genetic material.


Adenoviral-mediated delivery of the herpes simplex virus thymidine kinase gene selectively sensitizes human ovarian carcinoma cells to ganciclovir.
One strategy used for gene therapy of cancer is molecular chemotherapy. This approach is based on selective expression of an encoded toxin in cancer cells to achieve their eradication. One potential advantage of this strategy derives from a phenomenon, termed the bystander effect, whereby only a fraction of cells needs to be transduced to eradicate a tumor population. Despite the theoretical advantages of this phenomenon, it has only been described in a few cellular targets. Therefore, we undertook strategies to develop a molecular chemotherapy approach for ovarian carcinoma utilizing the herpes simplex virus thymidine kinase (HSV-TK) gene. Initially, we established that human ovarian carcinoma cell lines could be transduced at high efficiency with adenoviral vectors encoding reporter genes. We next determined that the human ovarian cell line SKOV3 could exhibit bystander killing by stably transducing it to express HSV-TK and performing cell mixing experiments with varying percentages of HSV-TK-expressing and HSV-TK-nonexpressing cells. Based on these findings, we constructed a recombinant adenovirus encoding HSV-TK and utilized it to induce human ovarian carcinoma cell lines to the sensitizing effects of ganciclovir. In addition, primary cultures of ovarian carcinoma cells were found to be highly transducible with recombinant adenoviral vectors and could be induced to the sensitizing effects of ganciclovir after induction of HSV-TK expression by the adenoviral vector. These studies indicate that molecular chemotherapy using a recombinant adenoviral vector expressing HSV-TK may provide a rational strategy for human ovarian carcinoma.


The Influence of Body Mass and Height on Equine Hoof Conformation and Symmetry.
Despite the likelihood that a horse's mass influences hoof morphology, empirical evidence is lacking. A clearer understanding of factors influencing hoof shape could enable prevention, or better treatment, of foot-based disorders; common causes of equine lameness. The study's aim was to investigate the relationship between horse body size, in terms of mass and height, and fore hoof dimensions. A further aim was to determine changes in the occurrence of hoof asymmetry as body size increases. Height, mass, and fore hoof dimensions; coronet band width (CBW); hoof base width (HBW); dorsal hoof wall angle (DHWA); and hoof spread (HS) of 63 riding school horses were measured within two weeks of routine shoeing. Regression analysis demonstrated positive relationships between body mass and both CBW and HBW in left and right hooves, indicating basic hoof dimensions increased as body mass increased. No relationship between horse height and hoof variables was found, suggesting mass is more influential on hoof morphology. Left and right DHWL were moderately correlated; however, paired t-test results identified a greater right than left DHWA. As left DHWA increased, left HS decreased, indicating development of a more upright hoof geometry. Both left and right HS increased as corresponding HBW increased. Both hooves tended toward a more upright conformation as horse height and body mass increased. However, asymmetries observed suggest a splayed left hoof compared to a "boxy" right hoof. Such morphological adjustments may indicate variation in horn tubule orientation in response to greater structural loading; an important consideration for hoof practitioners.


Inhibition of hepatitis C virus infection in cell culture by small interfering RNAs.
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and hepatocellular carcinoma, yet fully efficacious treatments are missing. In this study, we investigated RNA interference (RNAi), a specific gene silencing process mediated by small interfering RNA (siRNA) duplexes, as an antiviral strategy against HCV. Synthetic siRNAs were designed to target conserved sequences of the HCV 5' nontranslated region (NTR) located in a functional, stem-loop structured domain of the HCV internal ribosome entry site (IRES), which is crucial for initiation of polyprotein translation. Several siRNAs dramatically reduced or even abrogated the replication of selectable subgenomic HCV replicons upon cotransfection of human hepatoma cells with viral target and siRNAs, or upon transfection of cells supporting autonomous replication of HCV replicon with siRNAs. Importantly, three siRNAs also proved capable of strongly inhibiting virus production in cell culture. One siRNA, targeting a sequence that is highly conserved across all genotypes and forms a critical pseudoknot structure involved in translation, was identified as the most promising therapeutic candidate. These results indicate that the HCV life cycle can be efficiently blocked by using properly-designed siRNAs that target functionally important, highly conserved sequences of the HCV IRES. This finding offers a novel approach towards developing IRES-based antiviral treatment for chronic HCV infections.


Turnover and accumulation of genetic diversity across large time-scale cycles of isolation and connection of populations.
Major climatic and geological events but also population history (secondary contacts) have generated cycles of population isolation and connection of long and short periods. Recent empirical and theoretical studies suggest that fast evolutionary processes might be triggered by such events, as commonly illustrated in ecology by the adaptive radiation of cichlid fishes (isolation and reconnection of lakes and watersheds) and in epidemiology by the fast adaptation of the influenza virus (isolation and reconnection in hosts). We test whether cyclic population isolation and connection provide the raw material (standing genetic variation) for species evolution and diversification. Our analytical results demonstrate that population isolation and connection can provide, to populations, a high excess of genetic diversity compared with what is expected at equilibrium. This excess is either cyclic (high allele turnover) or cumulates with time depending on the duration of the isolation and the connection periods and the mutation rate. We show that diversification rates of animal clades are associated with specific periods of climatic cycles in the Quaternary. We finally discuss the importance of our results for macroevolutionary patterns and for the inference of population history from genomic data.


Resurrecting Van Leeuwenhoek's rotifers: a reappraisal of the role of disaccharides in anhydrobiosis.
In 1702, Van Leeuwenhoek was the first to describe the phenomenon of anhydrobiosis in a species of bdelloid rotifer, Philodina roseola. It is the purpose of this review to examine what has been learned since then about the extreme desiccation tolerance in rotifers and how this compares with our understanding of anhydrobiosis in other organisms. Remarkably, much of what is known today about the requirements for successful anhydrobiosis, and the degree of biostability conferred by the dry state, was already determined in principle by the time of Spallanzani in the late 18th century. Most modern research on anhydrobiosis has emphasized the importance of the non-reducing disaccharides trehalose and sucrose, one or other sugar being present at high concentrations during desiccation of anhydrobiotic nematodes, brine shrimp cysts, bakers' yeast, resurrection plants and plant seeds. These sugars are proposed to act as water replacement molecules, and as thermodynamic and kinetic stabilizers of biomolecules and membranes. In apparent contradiction of the prevailing models, recent experiments from our laboratory show that bdelloid rotifers undergo anhydrobiosis without producing trehalose or any analogous molecule. This has prompted us to critically re-examine the association of disaccharides with anhydrobiosis in the literature. Surprisingly, current hypotheses are based almost entirely on in vitro data: there is very limited information which is more than simply correlative in the literature on living systems. In many species, disaccharide accumulation occurs at approximately the same time as desiccation tolerance is acquired. However, several studies indicate that these sugars are not sufficient for anhydrobiosis; furthermore, there is no conclusive evidence, through mutagenesis or functional knockout experiments, for example, that sugars are necessary for anhydrobiosis. Indeed, some plant seeds and micro-organisms, like the rotifer, exhibit excellent desiccation tolerance in the absence of high intracellular sugar concentrations. Accordingly, it seems appropriate to call for a re-evaluation of our understanding of anhydrobiosis and to embark on new experimental programmes to determine the key molecular mechanisms involved.


Antimicrobial susceptibilities of Corynebacterium species and other non-spore-forming gram-positive bacilli to 18 antimicrobial agents.
The susceptibilities of 265 strains of Corynebacterium species and other non-spore-forming gram-positive bacilli to 18 antimicrobial agents were tested. Most strains were susceptible to vancomycin, doxycycline, and fusidic acid. Corynebacterium jeikeium and Corynebacterium urealyticum were the most resistant organisms tested. Resistance to beta-lactams, clindamycin, erythromycin, azythromycin, ciprofloxacin and gentamicin was common among strains of Corynebacterium xerosis and Corynebacterium minutissimum. Ampicillin resistance among Listeria monocytogenes was more prevalent than previously reported. Optochin, fosfomycin, and nitrofurantoin showed very little activity against most organisms tested, but the use of nitrofurantoin as a selective agent in culture medium may prevent the recovery of some isolates. Except for the unvarying activity of vancomycin against Corynebacterium species, the antimicrobial susceptibilities of the latter to other antibiotics are usually unpredictable, such that susceptibility tests are necessary for selecting the best antimicrobial treatment.


Hazard proximities of childhood cancers in Great Britain from 1953-80.
Firstly, to examine relationships between the birth and death addresses of children dying from leukaemia and cancer in Great Britain, and the sites of potential environmental hazards; and secondly to measure relative case densities close to, and at increasing distances from, different hazard types. Home address postcodes (PCs) and their map coordinates were identified at birth and at death in children who died from leukaemia or cancer. Potentially hazardous industrial addresses and PCs were listed from business and other directories, and map coordinates obtained from the Central Postcode Directory or else located directly on Ordnance Survey (OS) maps. Railway lines and motorways were digitised from OS maps. Numbers of deaths (and births) at successive radial distances from these hazards were counted and compared with expected numbers. The latter were based on a count of all PCs at similar distances. Relative case density ratios at successive distances from the hazards were obtained from observed and expected numbers, aggregated over similar sites. This was repeated for different hazard types and results were tested for evidence of systematic centrifugal case density gradients. All 22,458 children dying from leukaemia or cancer aged 0-15 years, in England, Wales, and Scotland, between 1953 and 1980. Relative excesses of leukaemias and of solid cancers were found near the following: (1) oil refineries, major oil storage installations, railside oil distribution terminals and factories making bitumen products; (2) motor car factories, coach builders, and car body repairers; (3) major users of petroleum products including manufacturers of solvents, paint sprayers, fibreglass fabricators, paint and varnish makers, plastics and detergent manufacturers, and galvanisers; (4) users of kilns and furnaces including steelworks, power stations, galvanisers, cement makers, brickworks, crematoria and aluminium, zinc, and iron/steel foundries; (5) airfields, railways, motorways and harbours. The findings for leukaemias and for solid cancers were indistinguishable. The hazard proximities of birth addresses were stronger than for death addresses. For children who had moved house between birth and death, the proximity effect was limited to the birth addresses. Childhood cancers are geographically associated with two main types of industrial atmospheric effluent namely: (1) petroleum derived volatiles and (2) kiln and furnace smoke and gases, and effluents from internal combustion engines.


Management of status epilepticus.
Status epilepticus is an increasingly recognized public health problem in the United States. Status epilepticus is associated with a high mortality rate that is largely contingent on the duration of the condition before initial treatment, the etiology of the condition, and the age of the patient. Treatment is evolving as new medications become available. Three new preparations--fosphenytoin, rectal diazepam, and parenteral valproate--have implications for the management of status epilepticus. However, randomized controlled trials show that benzodiazepines (in particular, diazepam and lorazepam) should be the initial drug therapy in patients with status epilepticus. Despite the paucity of clinical trials comparing medication regimens for acute seizures, there is broad consensus that immediate diagnosis and treatment are necessary to reduce the morbidity and mortality of this condition. Moreover, investigators have reported that status epilepticus often is not considered in patients with altered consciousness in the intensive care setting. In patients with persistent alteration of consciousness for which there is no clear etiology, physicians should be more quickly prepared to obtain electroencephalography to identify status epilepticus. Physicians should rely on a standardized protocol for management of status epilepticus to improve care for this neurologic emergency.


Aggression and anxiety in adolescent AAS-treated hamsters: A role for 5HT3 receptors.
Previously, we have shown that anabolic androgenic steroid (AAS) exposure throughout adolescence stimulates offensive aggression while also reducing anxious behaviors during the exposure period. Interestingly, AAS exposure through development correlates with alterations to the serotonin system in regions known to contain 5HT3 receptors that influence the control of both aggression and anxiety. Despite these effects, little is known about whether these separate developmental AAS-induced behavioral alterations occur as a function of a common neuroanatomical locus. To begin to address this question, we localized 5HT3 receptors in regions that have been implicated in aggression and anxiety. To examine the impact these receptors may have on AAS alterations to behavior, we microinjected the 5HT3 agonist mCPBG directly into a region know for its influence over aggressive behavior, the lateral division of the anterior hypothalamus, and recorded alterations to anxious behaviors using the elevated plus maze. AAS exposure primarily reduced the presence of 5HT3 receptors in aggression/anxiety regions. Accordingly, mCPBG blocked the anxiolytic effects of adolescent AAS exposure. These data suggest that the 5HT3 receptor plays a critical role in the circuit modulating developmental AAS-induced changes to both aggressive and anxious behaviors, and further implicates the lateral division of the anterior hypothalamus as an important center for the negative behavioral effects of developmental AAS-exposure.


Assessment of subendocardial structure and function.
The combination of high energy expenditure and the borderline adequacy of perfusion make the subendocardium uniquely vulnerable to injury. Selective subendocardial involvement is usually a marker of subclinical disease. Technical advances in new noninvasive imaging modalities, especially in spatial resolution, now permit qualitative and quantitative assessment of subendocardial structure, function, and perfusion. Many newer techniques have the potential to provide superior prognostic information to current standard assessment methods. This review describes the contemporary capabilities of multiple imaging modalities for assessment of the subendocardium, and seeks to guide the clinician regarding the information and technical deficiencies of each modality.


Structure of the toxic core of α-synuclein from invisible crystals.
The protein α-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term NACore, appears to be responsible for amyloid formation and cytotoxicity of human α-synuclein. Here we describe crystals of NACore that have dimensions smaller than the wavelength of visible light and thus are invisible by optical microscopy. As the crystals are thousands of times too small for structure determination by synchrotron X-ray diffraction, we use micro-electron diffraction to determine the structure at atomic resolution. The 1.4 Å resolution structure demonstrates that this method can determine previously unknown protein structures and here yields, to our knowledge, the highest resolution achieved by any cryo-electron microscopy method to date. The structure exhibits protofibrils built of pairs of face-to-face β-sheets. X-ray fibre diffraction patterns show the similarity of NACore to toxic fibrils of full-length α-synuclein. The NACore structure, together with that of a second segment, inspires a model for most of the ordered portion of the toxic, full-length α-synuclein fibril, presenting opportunities for the design of inhibitors of α-synuclein fibrils.


Pesticides and cancer.
Epidemiologic evidence on the relationship between chemical pesticides and cancer is reviewed. In animal studies, many pesticides are carcinogenic, (e.g., organochlorines, creosote, and sulfallate) while others (notably, the organochlorines DDT, chlordane, and lindane) are tumor promoters. Some contaminants in commercial pesticide formulations also may pose a carcinogenic risk. In humans, arsenic compounds and insecticides used occupationally have been classified as carcinogens by the International Agency for Research on Cancer. Human data, however, are limited by the small number of studies that evaluate individual pesticides. Epidemiologic studies, although sometimes contradictory, have linked phenoxy acid herbicides or contaminants in them with soft tissue sarcoma (STS) and malignant lymphoma; organochlorine insecticides are linked with STS, non-Hodgkin's lymphoma (NHL), leukemia, and, less consistently, with cancers of the lung and breast; organophosphorous compounds are linked with NHL and leukemia; and triazine herbicides with ovarian cancer. Few, if any, of these associations can be considered established and causal. Hence, further epidemiologic studies are needed with detailed exposure assessment for individual pesticides, taking into consideration work practices, use of protective equipment, and other measures to reduce risk.


A genome-wide linkage scan in a Dutch family identifies a premature ovarian failure susceptibility locus.
Premature ovarian failure (POF) is characterized by elevated gonadotrophins and amenorrhea before the age of 40 years and occurs approximately in 1% of women. POF etiology is highly heterogeneous with a wide spectrum of etiological pathogenic mechanisms including genetic causes. These mostly involve numerical, structural or monogenic defects on the X-chromosome. Mutations in a small number of autosomal genes (such as FOXL2 and NOBOX) have been identified as a cause of POF. However, in most cases, the disease underlying mechanisms are largely unknown. We performed a genome-wide linkage analysis in a relatively large Dutch family with seven patients suffering from POF, showing a dominant pattern of inheritance. A genome-wide analysis, using 50K single nucleotide polymorphism arrays, was combined with conventional parametric linkage analysis. We identified three genomic regions on chromosomes 5, 14 and 18 yielding suggestive linkage (multipoint LOD score of 2.4 for each region). After inclusion of one elder unaffected family member, only the region on chromosome 5 remains as a putative POF locus. In addition, we investigated a second family (three living patients over three generations) for the regions on chromosome 5, 14 and 18. Haplotype analysis supported only the locus on chromosome 5q14.1-q15. We performed the first genome-wide linkage search in familial POF and identified a region on chromosome 5q14.1-q15, which may harbor a novel POF susceptibility gene.


Cardiothoracic surgery resident education: update on resident recruitment and job placement.
Applications to cardiothoracic surgery training programs have steadily declined. The application cycle for 2004 marked the first time the number of applicants was lower than the positions offered. This survey reflects on this trend in applications and the perspectives of current and graduating residents. In June 2004, the Thoracic Surgery Residents Association, in conjunction with CTSNet, surveyed residents completing accredited cardiothoracic training or additional subspecialization. Participation was anonymous and voluntary. Of the 140 graduates, 88 responded. Most were male (92%) and married (72%). Their average age was 35.7 years, and 56% had children. The mean educational debt was less than $50,000. Of the 88 respondents, 69 (78%) had plans to seek jobs whereas 15 (17%) sought additional training. Among job-seeking residents, 12% received no offers. Also, 59% of graduates initially sought a position in academics and 41% in private practice. Nearly one quarter (23%) reported that they would not choose a career in cardiothoracic surgery again, and more than half (52%) would not strongly recommend cardiothoracic surgery to potential trainees. Almost all (90%) of the graduates believed that the number of cardiothoracic training spots should be decreased, and 92% believed that a reduction in training positions should be achieved by closing marginal training programs. Additionally, 91% believed reimbursement for cardiothoracic surgery was inadequate, and 88% thought low reimbursement resulted in restricted patient access and decreased quality of care. Cardiothoracic training programs are having difficulty in both applicant recruitment and in suitable job placement. This frustration in the job search coupled with reimbursement and lifestyle issues most likely contributes to the general dissatisfaction conveyed by the graduates. If these trends continue, the field will be faced with a crisis of unfilled residency programs and unemployed graduates.


Association of sleep, screen time and physical activity with overweight and obesity in Mexico.
Approximately 70% of adults in Mexico are overweight or obese. Unhealthy lifestyle behaviors are also prevalent. We examined the association of three lifestyle behaviors with body mass index (BMI) categories in adults from Mexico. We used publicly available data from the ENSANUT 2016 survey (n = 6419). BMI was used to categorize participants. Differences in sleep duration, suffering from symptoms of insomnia, TV watching time, time in front of any screen, vigorous physical activity (yes vs no), moderate physical activity (> 30 min/day-yes vs. no) and walking (> 60 min/day-yes vs. no) were compared across BMI groups using adjusted linear and logistic regression analyses. Thirty-nine percent of participants were overweight and 37% obese. Time in front of TV, in front of any screen, sleep duration and physical activity were significantly associated with overweight and obesity. Compared to normal weight participants, participants in the obese II category spend on average 0.60 h/day (95% CI 0.36-0.84, p = 0.001) and participants in the obese III category 0.54 h/day (95% CI 0.19-0.89, p < 0.001) more in front of any screen; participants in the obese II category reported 0.55 h/day less sleep (95% CI - 0.67 to - 0.43, p < 0.001); participants in the obese III category were less likely to engage in vigorous activity (OR = 0.60, 95% CI 0.43-0.84, p ≤ 0.003), or walking (OR = 0.65, 95% CI 0.49-0.88, p = 0.005). Screen time, sleeping hours, and physical activity were associated with overweight and obesity. However, these associations were not consistent across all BMI categories. Assuming established causal connections, overweight individuals and individuals with obesity would benefit from reduced screen time and engaging in moderate/vigorous physical activity. Level III: observational case-control analytic study.


Exhaustion of CD4+ T-cells mediated by the Kynurenine Pathway in Melanoma.
Kynurenine pathway (KP) activation by the enzymatic activity of indoleamine 2,3-dioxygenase1 (IDO1) and kynurenine (KYN) production represents an attractive target for reducing tumour progression and improving anti-tumour immunity in multiple cancers. However, immunomodulatory properties of other KP metabolites such as 3-hydroxy kynurenine (3-HK) and kynurenic acid (KYNA) are poorly understood. The association of the kynurenine metabolic pathway with T-cell status in the tumour microenvironment were characterized, using gene expression data of 368 cutaneous skin melanoma (SKCM) patients from the TCGA cohort. Based on the identified correlations, we characterized the production of KYN, 3-HK, and KYNA in vitro using melanoma-derived cell lines and primary CD4+ CD25- T-cells. Activation of the CD4+ T-cells produced IFNγ, which yielded increased levels of KYN and KYNA. Concurrently, kynurenine 3-monooxygenase (KMO) expression and proliferation of CD4+ T-cells were reduced, whereas exhaustion markers such as PD-L1, AHR, FOXP3, and CTLA4 were increased. Additionally, an analysis of the correlation network reconstructed using TCGA-SKCM emphasized KMO and KYNU with high variability among BRAF wild-type compared with V600E, which underscored their role in distinct CD4+ T-cell behavior in tumour immunity. Our results suggest that, in addition to IDO1, there is an alternative immune regulatory mechanism associated with the lower KMO expression and the higher KYNA production, which contributes to dysfunctional effector CD4+ T-cell response.


HIV eradication: combinatorial approaches to activate latent viruses.
The concept of eradication of the Human Immune Deficiency Virus (HIV) from infected patients has gained much attention in the last few years. While combination Anti-Retroviral Therapy (c-ART) has been extremely effective in suppressing viral replication, it is not curative. This is due to the presence of a reservoir of latent HIV infected cells, which persist in the presence of c-ART. Recently, pharmaceutical approaches have focused on the development of molecules able to induce HIV-1 replication from latently infected cells in order to render them susceptible to viral cytopathic effects and host immune responses. Alternative pathways and transcription complexes function to regulate the activity of the HIV promoter and might serve as molecular targets for compounds to activate latent HIV. A combined therapy coupling various depressors and activators will likely be the most effective in promoting HIV replication while avoiding pleiotropic effects at the cellular level. Moreover, in light of differences among HIV subtypes and variability in integration sites, the combination of multiple agents targeting multiple pathways will increase likelihood of therapeutic effectiveness and prevent mutational escape. This review provides an overview of the mechanisms that can be targeted to induce HIV activation focusing on potential combinatorial approaches.


Renal tumours in a Tsc1+/- mouse model show epigenetic suppression of organic cation transporters Slc22a1, Slc22a2 and Slc22a3, and do not respond to metformin.
Metformin, a substrate of several poly-specific organic cation transporters, is a widely used biguanide for the treatment of type II diabetes. Recent studies suggest that metformin attenuates mTORC1 signalling by the activation of 5' adenosine monophosphate-activated protein kinase (AMPK) in the presence or absence of a functional hamartin/tuberin (TSC1/TSC2) complex. Metformin has also been reported to inhibit mTORC1 independent of AMPK through p53-dependent regulated in development and DNA damage responses 1 (REDD1) or by inhibiting Rag GTPases. These observations suggest that metformin could have therapeutic potential for tuberous sclerosis, an inherited disorder characterised by the aberrant activation of mTORC1 and the development of tumours in many organs, including the kidneys. In this study, we investigated the effect of metformin on renal lesions in a Tsc1(+/-) mouse model of tuberous sclerosis. Continuous treatment of metformin for 9 months at doses of up to 600 mg/kg/day had no significant effect on renal lesions in nine treated mice compared to 10 controls. Metformin treatment appeared to attenuate mTORC1 signalling in Tsc1(+/-) kidney tissues but not in renal tumours. Surprisingly, the expression of the organic cation transporters Slc22a1, Slc22a2 and Slc22a3 essential for the cellular uptake of metformin was highly suppressed in renal tumours. Treatment of cultured cells derived from a Tsc1-associated renal tumour with 5-aza-2-deoxycytidine or trichostatin A greatly increased the expression of these genes. These data suggest that the epigenetic suppression of the organic cation transporters in Tsc-associated mouse renal tumours may contribute to the lack of response to metformin treatment.


Comparative study of class 1 integron and Vibrio cholerae superintegron integrase activities.
Superintegrons (SIs) and multiresistant integrons (MRIs) have two main structural differences: (i) the SI platform is sedentary, while the MRI platform is commonly associated with mobile DNA elements and (ii) the recombination sites (attC) of SI gene cassette clusters are highly homogeneous, while those of MRI cassette arrays are highly variable in length and sequence. In order to determine if the latter difference was correlated with a dissimilarity in the recombination activities, we conducted a comparative study of the integron integrases of the class 1 MRI (IntI1) and the Vibrio cholerae SI (VchIntIA). We developed two assays that allowed us to independently measure the frequencies of cassette deletion and integration at the cognate attI sites. We demonstrated that the range of attC sites efficiently recombined by VchIntIA is narrower than the range of attC sites efficiently recombined by IntI1. Introduction of mutations into the V. cholerae repeats (VCRs), the attC sites of the V. cholerae SI cassettes, allowed us to map positions that affected the VchIntIA and IntI1 activities to different extents. Using a cointegration assay, we established that in E. coli, attI1-x-VCR recombination catalyzed by IntI1 was 2,600-fold more efficient than attIVch-x-VCR recombination catalyzed by VchIntIA. We performed the same experiments in V. cholerae and established that the attIVch-x-VCR recombination catalyzed by VchIntIA was 2,000-fold greater than the recombination measured in E. coli. Taken together, our results indicate that in the V. cholerae SI, the substrate recognition and recombination reactions mediated by VchIntIA might differ from the class 1 MRI paradigm.


Prediction and final temporal errors are used for trial-to-trial motor corrections.
Many daily life situations (e.g. dodging an approaching object or hitting a moving target) require people to correct planning of future movements based on previous temporal errors. However, the actual temporal error can be difficult to perceive: imagine a baseball batter that swings and misses a fastball. Here we show that in such situations people can use an internal error signal to make corrections in the next trial. This signal is based on the discrepancy between the actual and the planned action onset time: the prediction error. In this study, we used three interception tasks: reaching movements, saccadic eye movements and a button press that released a cursor moving ballistically for a fixed time. We found that action onset depended on the previous temporal error in the arm movement experiment only and not in the saccadic and button press experiments. However, this dependency was modulated by the movement time: faster arm movements depended less on the previous actual temporal error. An analysis using a Kalman filter confirmed that people used the prediction error rather than the previous temporal error for trial-by-trial corrections in fast arm movements, saccades and button press.


Characterization of newly identified DnaA and DnaB proteins from Acetobacter.
Although chromosomal replication is an essential feature of the bacterial life cycle, the replication mechanism and involved molecular players have never been properly characterized in the Acetobacter genera. Thanks to whole-genome sequencing, the unknown replication proteins from Acetobacter pasteurianus and Acetobacter orleanensis, DnaA-like and DnaB-like, could be identified. Despite the low nucleotide or amino acid similarity to the respective orthologs from Escherichia coli, their involvement during replication regulation was corroborated by artificial microRNA. In the Acetobacter genome, a novel replication origin, oriAo, was detected with three 9-nucleotide-long DnaA boxes to which DnaA-like proteins bind actively. Bacterial two-hybrid systems and co-immunoprecipitation confirmed the homologous and heterologous interactions between DnaA-like and DnaB-like proteins with their E. coli orthologs. This communication is due to the conserved tryptophan at position 6 for E. coli or 25 for Acetobacter that unables DnaA-like proteins to form oligomeric protein structures after its substitution. Altogether, these results provide novel insights into the genome replication mechanism in Acetobacter.


Muscular dystrophy begins early in embryonic development deriving from stem cell loss and disrupted skeletal muscle formation.
Examination of embryonic myogenesis of two distinct, but functionally related, skeletal muscle dystrophy mutants (mdx and cav-3(-/-)) establishes for the first time that key elements of the pathology of Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy type 1C (LGMD-1c) originate in the disruption of the embryonic cardiac and skeletal muscle patterning processes. Disruption of myogenesis occurs earlier in mdx mutants, which lack a functional form of dystrophin, than in cav-3(-/-) mutants, which lack the Cav3 gene that encodes the protein caveolin-3; this finding is consistent with the milder phenotype of LGMD-1c, a condition caused by mutations in Cav3, and the earlier [embryonic day (E)9.5] expression of dystrophin. Myogenesis is severely disrupted in mdx embryos, which display developmental delays; myotube morphology and displacement defects; and aberrant stem cell behaviour. In addition, the caveolin-3 protein is elevated in mdx embryos. Both cav-3(-/-) and mdx mutants (from E15.5 and E11.5, respectively) exhibit hyperproliferation and apoptosis of Myf5-positive embryonic myoblasts; attrition of Pax7-positive myoblasts in situ; and depletion of total Pax7 protein in late gestation. Furthermore, both cav-3(-/-) and mdx mutants have cardiac defects. In cav-3(-/-) mutants, there is a more restricted phenotype comprising hypaxial muscle defects, an excess of malformed hypertrophic myotubes, a twofold increase in myonuclei, and reduced fast myosin heavy chain (FMyHC) content. Several mdx mutant embryo pathologies, including myotube hypotrophy, reduced myotube numbers and increased FMyHC, have reciprocity with cav-3(-/-) mutants. In double mutant (mdxcav-3(+/-)) embryos that are deficient in dystrophin (mdx) and heterozygous for caveolin-3 (cav-3(+/-)), whereby caveolin-3 is reduced to 50% of wild-type (WT) levels, these phenotypes are severely exacerbated: intercostal muscle fibre density is reduced by 71%, and Pax7-positive cells are depleted entirely from the lower limbs and severely attenuated elsewhere; these data suggest a compensatory rather than a contributory role for the elevated caveolin-3 levels that are found in mdx embryos. These data establish a key role for dystrophin in early muscle formation and demonstrate that caveolin-3 and dystrophin are essential for correct fibre-type specification and emergent stem cell function. These data plug a significant gap in the natural history of muscular dystrophy and will be invaluable in establishing an earlier diagnosis for DMD/LGMD and in designing earlier treatment protocols, leading to better clinical outcome for these patients.


An international study to increase concordance in Ki67 scoring.
Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from eight countries calibrated to a specific Ki67 scoring method and then scored 50 centrally MIB-1 stained tissue microarray cases. Simple instructions prescribed scoring pattern and staining thresholds for determination of the percentage of stained tumor cells. To calibrate, laboratories scored 18 'training' and 'test' web-based images. Software tracked object selection and scoring. Success for the calibration was prespecified as Root Mean Square Error of scores compared with reference <0.6 and Maximum Absolute Deviation from reference <1.0 (log2-transformed data). Prespecified success criteria for tissue microarray scoring required intraclass correlation significantly >0.70 but aiming for observed intraclass correlation ≥0.90. Laboratory performance showed non-significant but promising trends of improvement through the calibration exercise (mean Root Mean Square Error decreased from 0.6 to 0.4, Maximum Absolute Deviation from 1.6 to 0.9; paired t-test: P=0.07 for Root Mean Square Error, 0.06 for Maximum Absolute Deviation). For tissue microarray scoring, the intraclass correlation estimate was 0.94 (95% credible interval: 0.90-0.97), markedly and significantly >0.70, the prespecified minimum target for success. Some discrepancies persisted, including around clinically relevant cutoffs. After calibrating to a common scoring method via a web-based tool, laboratories can achieve high inter-laboratory reproducibility in Ki67 scoring on centrally stained tissue microarray slides. Although these data are potentially encouraging, suggesting that it may be possible to standardize scoring of Ki67 among pathology laboratories, clinically important discrepancies persist. Before this biomarker could be recommended for clinical use, future research will need to extend this approach to biopsies and whole sections, account for staining variability, and link to outcomes.


Effects of Hairy Nanoparticles on Polymer Crystallization Kinetics.
We previously showed that nanoparticles (NPs) could be ordered into structures by using the growth rate of polymer crystals as the control variable. In particular, for slow enough spherulitic growth fronts, the NPs grafted with amorphous polymer chains are selectively moved into the interlamellar, interfibrillar, and interspherulitic zones of a lamellar morphology, specifically going from interlamellar to interspherulitic with progressively decreasing crystal growth rates. Here, we examine the effect of NP polymer grafting density on crystallization kinetics. We find that while crystal nucleation is practically unaffected by the presence of the NPs, spherulitic growth, final crystallinity, and melting point values decrease uniformly as the volume fraction of the crystallizable polymer, poly(ethylene oxide) or PEO, ϕPEO, decreases. A surprising aspect here is that these results are apparently unaffected by variations in the relative amounts of the amorphous polymer graft and silica NPs at constant ϕ, implying that chemical details of the amorphous defect apparently only play a secondary role. We therefore propose that the grafted NPs in this size range only provide geometrical confinement effects which serve to set the crystal growth rates and melting point depressions without causing any changes to crystallization mechanisms.


Spatial variation in coral reef fish and benthic communities in the central Saudi Arabian Red Sea.
Local-scale ecological information is critical as a sound basis for spatial management and conservation and as support for ongoing research in relatively unstudied areas. We conducted visual surveys of fish and benthic communities on nine reefs (3-24 km from shore) in the Thuwal area of the central Saudi Arabian Red Sea. Fish biomass increased with increasing distance from shore, but was generally low compared to reefs experiencing minimal human influence around the world. All reefs had a herbivore-dominated trophic structure and few top predators, such as sharks, jacks, or large groupers. Coral cover was considerably lower on inshore reefs, likely due to a 2010 bleaching event. Community analyses showed inshore reefs to be characterized by turf algae, slower-growing corals, lower herbivore diversity, and highly abundant turf-farming damselfishes. Offshore reefs had more planktivorous fishes, a more diverse herbivore assemblage, and faster-growing corals. All reefs appear to be impacted by overfishing, and inshore reefs seem more vulnerable to thermal bleaching. The study provides a description of the spatial variation in biomass and community structure in the central Saudi Arabian Red Sea and provides a basis for spatial prioritization and subsequent marine protected area design in Thuwal.


The effects of the combination of egg and fiber on appetite, glycemic response and food intake in normal weight adults - a randomized, controlled, crossover trial.
This study evaluated appetite and glycemic effects of egg-based breakfasts, containing high and moderate protein (30 g protein and 20 g protein +7 g fiber, respectively) compared to a low-protein cereal breakfast (10 g protein) examined in healthy adults (N = 48; age 24 ± 1 yr; BMI 23 ± 1 kg/m(2); mean ± SE). Meals provided 390 kcal/serving and equal fat content. Food intake was measured at an ad libitum lunch meal and blood glucose response was measured. Visual analog scales (VAS) were used to assess hunger, satisfaction, fullness, and prospective food intake. The egg-based breakfast meal with high protein produced greater overall satiety (p < 0.0001), and both high protein and moderate protein with fiber egg-based breakfasts reduced postprandial glycemic response (p < 0.005) and food intake (p < 0.05) at subsequent meal (by 135 kcal and 69 kcal; effect sizes 0.44 and 0.23, respectively) compared to a cereal-based breakfast with low protein and fiber.


[Gene therapy for breast cancer].
Breast cancer is sensitive to chemotherapy and endocrine therapy, but the prognosis of advanced or relapsed breast cancer is unsatisfactory. Gene therapy is promising as another useful therapeutic approach for advanced breast cancer. Strategies of gene therapy for breast cancer in ongoing clinical protocols can be divided into four: (1) suppression of oncogenes or transduction of tumor suppressors; (2) enhancement of immunological response to cancer cells; (3) transduction of suicide genes; and (4) protection of bone marrow using drug resistance genes. We have started a clinical study of gene therapy for breast cancer using multidrug resistance gene (MDR1), in which advanced or relapsed breast cancer patients received high dose chemotherapy and autologous peripheral blood stem cell transplantation (PBSCT) with MDR1-transduced hemopoietic cells, and then were treated with docetaxel. Two patients have been treated so far, and in vivo enrichment of MDR1-transduced cells with docetaxel treatment after PBSCT was seen in both cases. Both patients are in complete remission and have no apparent adverse effect from MDR1 gene transduction.