Seeking balance: decision support needs of women without cancer and a deleterious BRCA1 or BRCA2 mutation.
Recommendations for women with a deleterious BRCA1 or BRCA2 gene mutation include complex medical approaches related to cancer risk reduction and detection. Current science has not yet fully elucidated decision support needs that women face when living with medical consequences associated with known hereditary cancer risk. The purpose of this study was to describe health communication and decision support needs in healthy women with BRCA1/2 gene mutations. The original researchers completed an interpretive secondary qualitative data analysis of 23 phenomenological narratives collected between 2008 and 2010. The Ottawa Decision Support and Patient Centered Communication frameworks guided the study design and analysis. Women described a pattern wherein breast and ovarian cancer risk, health related recommendations and decisions, and personal values were prioritized over time based on life contexts. Knowing versus acting on cancer risk was not a static process but an ongoing balancing act of considering current and future personal and medical values, further compounded by the complexity of recommendations. Women shared stories of anticipatory, physical and psychosocial consequences of the decision making experience. The findings have potential to generate future research questions and guide intervention development. Importantly, findings indicate a need for ongoing, long-term, support from genetics professionals and decision support interventions, which challenges the current practice paradigm.


How herbivores track variable environments: Response to variability of phytotoxins.
The concentration of toxins in plants can vary with plant phenology and environmental factors. Changes in toxicity may or may not be associated with changes in plant flavor. These factors may make it difficult for herbivores to avoid toxic plants. We conducted three experiments concerning animals' ability to detect toxins. In experiment 1, we examined whether animals familiar with a tastable toxin on food would adjust intake when toxin concentrations changed. Lambs were initially offered oats with either a low, medium, or high concentration of lithium chloride (LiCl; a salty-tasting toxin). Later, when all lambs were offered oats with the medium concentration of LiCl, lambs that were conditioned with the low LiCl concentration decreased intake while lambs conditioned with the high LiCl concentration increased intake. In experiment 2, we examined flavor aversions formed when animals sampled food with two flavor levels prior to illness. Lambs initially ate the same amount of barley with a low and with a high concentration of either sodium saccharin (a sweet flavor) or aluminum sulfate (a bitter flavor). Lambs then received a mild dose of LiCl. Later, when lambs were offered a choice between barley with either a low or high flavor concentration, lambs preferred the barley with the low flavor concentration. Experiment 3 examined how variable toxicity affected intake when the flavor remained constant. Lambs were initially offered oregano-flavored barley and then received a dose of LiCl. Lambs received either a medium dose, a high dose, or a dose that varied randomly among low, medium, or high amounts of LiCl. Lambs in the medium dose group ate more oregano-flavored barley at the end of the trial than did lambs in either of the other groups.


Atom probe tomography of reactor pressure vessel steels: an analysis of data integrity.
In this work, the importance of optimising experimental conditions for the analysis of reactor pressure vessel (RPV) steels using atom probe tomography is explored. The quality of the resultant atom probe data is assessed in terms of detection efficiency, noise levels and mass resolution. It is demonstrated that artefacts can exist even when experimental conditions have been optimised. In particular, it is shown that surface diffusion of some minority species, including P and Si, to major poles prior to field evaporation can be an issue. The effects were most noticeable during laser pulsing. The impact of surface migration on the characterisation of dislocations and grain boundaries is assessed. The importance of selecting appropriate regions of the reconstructed data for subsequent re-analysis is emphasised.


Scalable Fabrication of Kevlar/Ti3C2Tx MXene Intelligent Wearable Fabrics with Multiple Sensory Capabilities.
Fiber-based wearable electronics are highly desirable for wearable devices that are expected to be lightweight, easily prepared, durable, flexible, washable, and conformable. However, developing fiber-based fabric electronics to simulate human perceptual systems or even transcend the sensory capabilities of natural creatures is still a pivotal challenge. Herein, we present a Kevlar/MXene (KM) intelligent wearable fabric with multiple sensory capabilities using an ingenious strategy of continuous wet-spinning. The KM fibers can be washed, knitted, sewed, and fabricated into smart KM fabric sensory systems. An intelligent KM sensory mask is prepared to monitor human breathing in time to detect respiratory problems with high accuracy and portability. It provides an important reference for judging diseases and achieving remote diagnosis. Additionally, a smart temperature-responsive sensory glove is developed to help people make proper behavioral prejudgments and prevent potential injuries by sensing surrounding hazards beforehand. Moreover, this sensory system allows soft robotics to make a rough identification about the basic properties of unknown liquid molecules. Overall, by the virtue of the ultrafast responsiveness (90 ms), resilience (110 ms), and ultrasensitive capability in pressure responding, this KM sensory system offers a gentle approach for wireless detection in information encryption, transmission, and preservation by touching the sensory system with variable pressing time on the basis of the International Morse code principles, establishing a competitive and promising candidate for next generation wearable flexible fabric electronics.


[Standards of examination, anesthesia and postoperative care of surgical patients with concomitant cardiovascular diseases].
The authors present the standards for postoperative care of patients with concomitant cardiovascular diseases used at Medical Center No. 122 in St. Petersburg. Special attention is paid to detailed assessment of cardiac function, continuity of the pre-, intra-, and postoperative cardio- and vasotropic therapy, and adequacy of anesthesiological protection as the main guarantee of an uneventful postoperative course. The authors consider it important that preoperative examinations include echocardiography and daily ECG monitoring; preoperative treatment is to include antibiotic prevention of infective endocarditis and heparin prevention of pulmonary artery embolism in the risk group patients. Alternative methods for intraoperative hemodynamic monitoring are pulmonary artery catheterization and integral rheography with the real-time data processing. The importance of regional anesthesia and the hazards of hypercorrection of the globular volume are emphasized.


Microsurgical endarterectomy under barbiturate protection: a prospective study.
Carotid endarterectomy has the potential to improve on the natural history of untreated carotid artery disease with respect to subsequent infarction in symptomatic patients with causative angiographic lesions. This benefit of a reduced risk of stroke can be realized only if the perioperative morbidity and mortality rates are kept low. An approach to symptomatic carotid artery bifurcation disease is outlined, with a defined protocol of microsurgical endarterectomy utilizing barbiturate protection during the period of potential focal temporary cerebral ischemia. This protocol includes preoperative antiplatelet therapy, barbiturate anesthesia, the avoidance of an internal shunt, the use of the operating microscope, and strict control of postoperative hypertension. A series of 200 consecutive endarterectomies performed within this protocol in 180 patients and the resultant combined permanent morbidity and mortality rate of 1.5% are reported.


Attitudes of registered physiotherapists in Israel toward people identifying as lesbian, gay, and bisexual: a cross-sectional survey.
This study aimed to explore the attitudes of registered physiotherapists (PTs) in Israel toward people identifying as lesbian, gay, or bisexual (LGB) and to identify background characteristics associated with their attitudes toward LGB individuals. This nationwide study in Israel employed an observational design. Participants completed an anonymous online questionnaire which included demographic characteristics (e.g., age, sex, gender, sexual orientation, religious affiliation, and religiousness) and questions regarding sources of knowledge about LGB individuals, and type of acquaintance with an LGB individual. In addition to two self-assessment questions regarding levels of homophobia (active engagement against LGB individuals) and heterosexism (holding negative opinions regarding LGB individuals) answered on a five point Likert scale (1 - not at all homophobic/ heterosexist, 5- very homophobic/ heterosexist) and the Hebrew version of the Attitudes Toward Homosexuality Scale (ATHS). Participants were recruited through professional organizations, social media, and word of mouth. The data of 383 registered PTs practicing in Israel were analyzed. The median score regarding level of homophobia and heterosexism was one ("not at all"). ATHS scores ranged between 32 and 110 (out of 110), with a median score of 106 and 41% scoring below the median. Multivariant logistic regression indicated that identifying as men, heterosexual orientation, and religiousness were significantly associated with less positive attitudes toward LGB individuals. Only 2% of the participants reported having been introduced to issues regarding the LGB community during their professional physiotherapy education. Registered PTs in Israel demonstrated favorable attitudes toward LGB individuals, as reflected both by ATHS scores and levels of self-reported homophobia and heterosexism. Based on the current results regarding sources of knowledge, updating the physiotherapy curriculum to include information regarding sexual orientation and health of the LGB community is suggested.


Throughput Analysis of Buffer-Aided Decode-and-Forward Wireless Relaying with RF Energy Harvesting.
In this paper, we investigated a buffer-aided decode-and-forward (DF) wireless relaying system over fading channels, where the source and relay harvest radio-frequency (RF) energy from a power station for data transmissions. We derived exact expressions for end-to-end throughput considering half-duplex (HD) and full-duplex (FD) relaying schemes. The numerical results illustrate the throughput and energy efficiencies of the relaying schemes under different self-interference (SI) cancellation levels and relay deployment locations. It was demonstrated that throughput-optimal relaying is not necessarily energy efficiency-optimal. The results provide guidance on optimal relaying network deployment and operation under different performance criteria.


Patients' knowledge of diabetes foot complications and self-management practices in Ghana: A phenomenological study.
The prevalence of diabetes is increasing in low and middle-income countries (LMICs) and over two-thirds of these are not diagnosed. Consequently, diabetes complications usually exist at the time of diagnosis. Foot ulcers is a leading cause of disability and mortality among diabetes patients. To assess the knowledge and experiences of adult patients with Diabetes on diabetes complications and self-management practices with emphasis on foot care. This applied phenomenological study design. Twenty patients attending Diabetes clinics were purposively sampled from two hospitals in Ghana. Face-to-face semi-structured interviews were conducted to evaluate patient's understanding of diabetes and self-management practices. The interviews were audio-taped, transcribed, and analysed to generate themes using the constant comparison method. Three-quarters of the participants in the study correctly defined diabetes as high blood glucose levels, but few knew the risk factors and complications of diabetes. Stroke and Hypertension were the most popular complications known, whiles diabetes foot complications were the least known. Almost all participants showed awareness of dietary self-management practices, but few had limited knowledge in foot care practices. Diabetes education in LMICs should promote self-management practices, especially foot care and clear dietary guidelines. There is also opportunity to invest in specialist diabetes training for healthcare providers and increase community-based care for people living with diabetes in Ghana.


A framework to explore micronutrient deficiency in maternal and child health in Malawi, Southern Africa.
Global food insecurity is associated with micronutrient deficiencies and it has been suggested that 4.5 billion people world-wide are affected by deficiencies in iron, vitamin A and iodine. Zinc has also been identified to be of increasing concern. The most vulnerable are young children and women of childbearing age. A pilot study has been carried out in Southern Malawi, to attempt to link the geochemical and agricultural basis of micronutrient supply through spatial variability to maternal health and associated cultural and social aspects of nutrition. The aim is to establish the opportunity for concerted action to deliver step change improvements in the nutrition of developing countries. Field work undertaken in August 2007 and July/August 2008 involved the collection of blood, soil and crop samples, and questionnaires from ~100 pregnant women. Complex permissions and authorisation protocols were identified and found to be as much part of the cultural and social context of the work as the complexity of the interdisciplinary project. These issues are catalogued and discussed. A preliminary spatial evaluation is presented linking soil quality and food production to nutritional health. It also considers behavioural and cultural attitudes of women and children in two regions of southern Malawi, (the Shire Valley and Shire Highlands plateau). Differences in agricultural practice and widely varying soil quality (e.g. pH organic matter, C/N and metal content) were observed for both regions and full chemical analysis of soil and food is underway. Early assessment of blood data suggests major differences in health and nutritional status between the two regions. Differences in food availability and type and observations of life style are being evaluated through questionnaire analysis. The particular emphasis of the study is on the interdisciplinary opportunities and the barriers to progress in development support in subsistence communities. Engaging at the community level and the balance of expectations from both study subjects and research team highlight the merit of careful and detailed planning and project delivery.


The circle of security parenting and parental conflict: a single case study.
The Circle of Security Parenting (COS-P) is an early attachment based intervention that can be used with groups, dyads, and individuals. Created in the USA and now used in many countries, COS-P is a visually based approach that demonstrates its central principles through videos of parent/child interactions. The core purpose of the COS-P is to provide an opportunity for caregivers to reflect on their child's needs and on the challenges each parent faces in meeting those needs. Even though there is a wide range of clinical settings in which child/parent attachment is an important component of assessment there is limited empirical data on when and how attachment based interventions are appropriate for specific clinical profiles and contexts. The aim of this paper is to present a clinical application of COS-P in order to explore and reflect on some specific therapeutic tasks where it works and on some clinical indicators and contexts appropriate for its application. A single case study of a father, "M." (43 years old) in conflict for the custody of his 5 years old daughter is reported. The Adult Attachment Projective Picture System (AAP), the Parenting Stress Index, the Strengths and Difficulties Questionnaire, and the Parental Alliance Measure, were administered pre- and post-intervention. The clinical significance analysis method revealed that numerous changes occurred in the father. The AAP showed improvements in the level of agency of self. M. made gains in his capacity to use internal resources and to increase his agency of self. M. was classified as recovered in his perception of the child's functioning and as improved in his parenting stress and parenting alliance with the mother. Considerations on specific contexts and clinical indicators for the application of COS-P are proposed.


Generation of cytotoxic T lymphocytes in vitro. V. Response of normal and immune spleen cells to subcellular alloantigens.
Subcellular particulate membrane fragments prepared from murine lymphoid or tumor cells were used as a cell-free antigen source in order to stimulate the generation of cytolytic thymus-derived effector cells (CTL) in vitro. When cultivated with normal spleen cells as a source of responding lymphocytes, particulate antigen preparations induced only low CTL activities; in contrast, virtually normal responses were observed when immune spleens were used as a source of responding cells. In both cases, results were compared to those responses obtained with intact irradiated (1000 rads) normal spleen cells as stimulating antigen. The effector cells generated with particulate antigen preparations (obtained either by hypotonic shock or by sonication) were shown to be T cells and were characterized with regard to the kinetics of their response and their dose-activity relationship. It was also shown that the responses observed were specific, both at the level of initiation and at the effector level. The results obtained suggest that there exists a fundamental difference between normal and alloimmune spleen cells in their ability to respond in vitro to stimulation by subcellular antigen preparations.


Molecular Examination of Ion-Pair Competition in Alkaline Aluminate Solutions Using In Situ Liquid SIMS.
Understanding the structure and composition of aluminate complexes in extremely alkaline systems such as Bayer liquors has received enormous attention due to their fundamental and industrial importance. However, obtaining direct molecular information of the underlying ion-ion interactions using traditional approaches such as NMR spectroscopy or Raman spectroscopy is challenging due to the weakness of these interactions and/or their complex overlapping spectral signatures. Here, we exploit in situ liquid secondary-ion mass spectrometry (SIMS) as a new approach and show how it enables new insights. In contrast with traditional techniques, using SIMS we succeeded in acquiring information on dominant ion clusters in these alkaline systems. In Na+/K+ mixed alkaline aluminate solutions, we clearly observe preferential formation of Na+-anion clusters over K+-anion clusters. Evaluation of these clusters by density functional theory (DFT) calculations shows that these structures are stable and that their relative bond energies are consistent with their observed SIMS signal intensity differences. This demonstrates a key advantage of in situ liquid SIMS for overcoming ambiguities obscuring important information in these systems on constituent molecular clusters defined by relatively weak ion-pair competition and ion-solvent interactions.


Test Problems for Large-Scale Multiobjective and Many-Objective Optimization.
The interests in multiobjective and many-objective optimization have been rapidly increasing in the evolutionary computation community. However, most studies on multiobjective and many-objective optimization are limited to small-scale problems, despite the fact that many real-world multiobjective and many-objective optimization problems may involve a large number of decision variables. As has been evident in the history of evolutionary optimization, the development of evolutionary algorithms (EAs) for solving a particular type of optimization problems has undergone a co-evolution with the development of test problems. To promote the research on large-scale multiobjective and many-objective optimization, we propose a set of generic test problems based on design principles widely used in the literature of multiobjective and many-objective optimization. In order for the test problems to be able to reflect challenges in real-world applications, we consider mixed separability between decision variables and nonuniform correlation between decision variables and objective functions. To assess the proposed test problems, six representative evolutionary multiobjective and many-objective EAs are tested on the proposed test problems. Our empirical results indicate that although the compared algorithms exhibit slightly different capabilities in dealing with the challenges in the test problems, none of them are able to efficiently solve these optimization problems, calling for the need for developing new EAs dedicated to large-scale multiobjective and many-objective optimization.


The Forsyth County Cervical Cancer Prevention Project--II. Compliance with screening follow-up of abnormal cervical smears.
The Forsyth County Cervical Cancer Prevention Project was a community-wide cancer education program to address the problem of cervical cancer incidence and mortality among minority women in Forsyth County, North Carolina. This paper reports program results with regard to increasing compliance with follow-up for abnormal cervical smears. An analysis of trends prior to and after implementation of the educational program was conducted in one private and two public health primary care clinics to provide an assessment of impact of the project in improving compliance with follow-up among black women. A similar analysis also was conducted for white women. The results of medical record reviews of follow-up procedures for 878 abnormal cervical smears suggested a modest program effect among black women. The percentage of black women who returned for follow-up and treatment of an abnormal cervical smear significantly increased during the time the program was in effect. The trend analysis further indicated that the decline did not begin prior to the intervention period and was maintained throughout the duration of the intervention. No significant change in the percentage who returned for follow-up was found for white women.


Towards universal access to skilled birth attendance: the process of transforming the role of traditional birth attendants in Rural China.
Institution-based childbirth, with the ultimate goal of universal access to skilled birth attendance (SBA), has been selected as a key strategy to reduce the maternal mortality rate in many developing countries. However, the question of how to engage traditional birth attendants (TBAs) in the advocacy campaign for SBA poses a number of challenges. This paper aims to demonstrate how TBAs in rural regions of China have been integrated into the health system under a policy of institutional delivery. Research was conducted through literature and document reviews and individual in-depth interviews with stakeholders of the safe motherhood program in rural Guangxi Zhuang Autonomous Region, China. A total of 33 individual interviews were conducted with regional and local politicians, policy makers, health managers, health providers, civil society members, village cadres for women affairs, former TBAs, village maternal health workers, mothers and their mother-in-laws. Since 1998, TBA's traditional role of providing in-home care during childbirth has been restructured and their social role has been strengthened in rural Guangxi. TBAs were redesigned to function as the linkage between women and the health system. A new policy in 1999 shifted the role of TBAs to village maternal health workers whose responsibilities were mainly to promote perinatal care and institution-based delivery of pregnant women. This successful transformation involved engaging with government and other actors, training TBAs for their new role, and providing incentives and sanctions for human resources management. The China experience of transforming the role of TBAs in Guangxi rural area is an example of successfully engaging TBAs in promoting institution-based childbirth.


Protective effect of ginsenoside metabolite compound K against diabetic nephropathy by inhibiting NLRP3 inflammasome activation and NF-κB/p38 signaling pathway in high-fat diet/streptozotocin-induced diabetic mice.
Though the antidiabetic effect of ginsenoside compound K (CK) has been well studied, the effect of CK on diabetic nephropathy (DN) is not clear. Whether CK would have a protective effect against DN and it could exert the protective effect by inhibiting the oxidative stress, NLRP3 inflammasome and NF-κB/p38 signaling pathway were investigated in this study. Here, the HFD (high fat diet)/STZ (streptozotocin)-induced DN mice model was established to assess the CK effect in vivo. Parallel experiments uncovering the molecular mechanism by which CK prevents from DN was performed in rat glomerular mesangial cell line HBZY-1 exposed to high glucose. CK (10, 20, 40 mg/kg/day) were intragastrically administered for 8 weeks, the general status, biochemical parameters, renal pathological changes and oxidative stress-parameters were observed, and the NLRP3 inflammasome and NF-κB/p38 signaling pathway were evaluated. The results showed that the elevated fasting blood glucose, serum creatinine, blood urea nitrogen and 24-hour urine protein of the DN mice were significantly decreased, and the proliferation of glomerular mesangial matrix was alleviated by CK. In addition, the generation of ROS in the kidney was significantly decreased, and the expression of Nox1 and Nox4 proteins were down-regulated. Further, the expression of NLRP3 inflammasome components (NLRP3, ASC and Caspase-1) and the inflammatory cytokines IL-1β and IL-18 were also significantly down-regulated in vivo and in vitro. The phosphorylation of renal p38 MAPK was also inhibited by CK. MCC950 (an inhibitor of NLRP3 inflammasome) and VX-765 (a Caspase-1 Inhibitor) showed significant interaction with CK on the decrease of IL-1β concentration in HBZY-1 cells. In conclusion, our study provided evidence that the protective effect of CK on diabetes-induced renal injury is associated with down-regulating the expression of NADHP oxidase, and inhibition of ROS-mediated activation of NLRP3 inflammasome and NF-κB/p38 signaling pathway, suggesting its therapeutic implication for renal inflammation.


The Effects of Bradykinin B1 Receptor Antagonism on the Myocardial and Vascular Consequences of Hypertension in SHR Rats.
It is known that non-steroidal anti-inflammatory drugs increase cardiovascular (CV) morbidity and mortality. In this study, we examined whether a novel anti-inflammatory drug, bradykinin B1 receptor antagonist (FGY-1153) treatment could influence the development of hypertensive organ damages in spontaneously hypertensive rats (SHR). SHRs were treated with low (FGY-120) or high dose FGY-1153 (FGY-400) and with placebo (Control) for 26 weeks. Wistar-Kyoto rats were used as aged-matched, normotensive controls (WKY). Body weight, food consumption and blood pressure were measured regularly. Echocardiography was performed at the beginning and at the end of the study. Light and electron microscopic analysis of heart and great vessels were performed, and the extent of fibrotic areas was measured. The phosphorylation state of prosurvival Akt-1/glycogen synthase kinase (GSK)-3β pathway and the activation of signaling factors playing part in the fibrotic processes - mitogen activated protein kinases (MAPKs), and TGF-β/Smad2 - were monitored using Western-blot. Body weight and food consumption as well as the elevated blood pressure in SHRs was not influenced by FGY-1153 treatment. However, both doses of FGY-1153 treatment decreased left ventricular (LV) hypertrophy and diastolic dysfunction in hypertensive animals. Moreover systolic LV function was also preserved in FGY-120 group. Increased intima-media thickness and interstitial fibrosis were not significantly diminished in great vessels. FGY-1153 treatment inhibited the expression of TGFβ and the phosphorylation of SMAD2 in the heart. Our results suggest that the tested novel anti-inflammatory compound has no deleterious effect on CV system, moreover it exerts moderate protective effect against the development of hypertensive cardiopathy.


[Expression and bioinformatics analysis of long-chain non-coding RNA PVT1 in tumors].
Objective: To study the expression and mechanism of long-chain non-coding RNA PVT1 in tumor by bioinformatics analysis and experimental verification, and to provide new ideas for the study of the pathogenesis of tumors. Methods: The expression of PVT1 in 14 common tumors was downloaded from starBase v2.0 public database, which also was verified by PVT1 RNA-in situ hybridization.The upstream transcription factors, the downstream target microRNA(miRNA) for PVT1 and the target genes for the target miRNAs were predicted and analyzed by using bioinformatics based on the database of UCSC Genome Browser, HMDD v2.0, miRTar Base, JASPAR databases. Results: StarBase database analysis and RNA in situ hybridization showed that PVT1 was highly expressed in kidney clear cell carcinoma and colon and rectal adenocarcinoma. PVT1 was regulated by the upstream transcription factors CREB1, Atf1, SP1, KLF5, STAT3, while it could control the expression of the downstream target miR-16. bcl-2, VEGFA, CCNE1, CCND1 and SHOC2 showed an interaction with the transcription factor of PVT1, which formed a feedback regulatory pathway. Conclusions: PVT1 is highly expressed in kidney clear cell carcinoma and colon and rectal adenocarcinoma.The predictive analysis of bioinformatics demonstrates that transcription factor/PVT1/miR-16/target gene signal axon may be an important molecular mechanism, which provide a valuable clue for further functional mechanism research of long-chain non-coding RNA.


The behavioural response of mice lacking NK₁ receptors to guanfacine resembles its clinical profile in treatment of ADHD.
Mice with functional ablation of substance P-preferring neurokinin-1 receptors (NK1R-/- mice) display behavioural abnormalities resembling those in attention deficit hyperactivity disorder (ADHD). Here, we investigated whether the ADHD treatment, guanfacine, alleviated the hyperactivity and impulsivity/inattention displayed by NK1R-/- mice in the light/dark exploration box (LDEB) and 5-choice serial reaction-time task (5-CSRTT), respectively. Following reports of co-morbid anxiety in ADHD, we also investigated effects of guanfacine on anxiety-like behaviour displayed by NK1R-/- and wild-type (WT) mice in the elevated plus maze (EPM). Mice were treated with guanfacine (0.1, 0.3 or 1.0 mg·kg(-1), i.p.), vehicle or no injection and tested in the 5-CSRTT or the LDEB. Only the lowest dose of guanfacine was used in the EPM assays. In the 5-CSRTT, a low dose of guanfacine (0.1 mg·kg(-1)) increased attention in NK1R-/- mice, but not in WT mice. This dose did not affect the total number of trials completed, latencies to respond or locomotor activity in the LDEB. Impulsivity was decreased by the high dose (1.0 mg·kg(-1)) of guanfacine, but this was evident in both genotypes and is likely to be secondary to a generalized blunting of behaviour. Although the NK1R-/- mice displayed marked anxiety-like behaviour, guanfacine did not affect the behaviour of either genotype in the EPM. This evidence that guanfacine improves attention at a dose that did not affect arousal or emotionality supports our proposal that NK1R-/- mice express an attention deficit resembling that of ADHD patients.


Molecular cloning, expression, and characterization of E2F transcription factor 4 from Antheraea pernyi.
The E2F transcription factor family is distributed widely in eukaryotes and has been well studied among mammals. In the present study, the E2F transcription factor 4 (E2F4) gene was isolated from fat bodies of Antheraea pernyi and sequenced. E2F4 comprised a 795 bp open reading frame encoding a deduced amino acid sequence of 264 amino acid residues. The recombinant protein was expressed in Escherichia coli (Transetta DE3), and anti-E2F4 antibodies were prepared. The deduced amino acid sequence displayed significant homology to an E2F4-like protein from Bombyx mori L. Quantitative real-time polymerase chain reaction analysis revealed that E2F4 expression was highest in the integument, followed by the fat body, silk glands, and haemocytes. The expression of E2F4 was upregulated in larvae challenged by bacterial (Escherichia coli, Micrococcus luteus), viral (nuclear polyhedrosis virus), and fungal (Beauveria bassiana) pathogens. These observations indicated that E2F4 is an inducible protein in the immune response of A. pernyi and probably in other insects.


Roles of neuropilins in neuronal development, angiogenesis, and cancers.
Neuropilin-1 (NRP1) and neuropilin-2 (NRP2) are transmembrane glycoproteins that have been characterized as receptors for both semaphorins for neuronal guidance and vascular endothelial growth factor (VEGF) for angiogenesis. Biologic properties of NRPs have been linked to their unique domain structures. However, molecular interaction among NRPs, VEGF, and VEGF receptors is still not clear. Although several types of cancer cells can express NRPs, the role of NRPs in tumor pathogenesis is largely unknown. Thus, future investigations should include determining the effects and mechanisms of NRPs on proliferation, apoptosis, and migration of neuronal , endothelial, and cancer cells. Study of protein-protein interaction, signal transduction pathways, and NRP-mediated gene expression is particularly important to understand NRPs functions, which may have significant clinical applications in the treatment of neurological disorders, cardiovascular diseases, and certain cancers.


Preoperative grading of presumptive low-grade astrocytomas on MR imaging: diagnostic value of minimum apparent diffusion coefficient.
Histopathologic grade of glial tumors is inversely correlated with the minimum apparent diffusion coefficient (ADC). We assessed the diagnostic values of minimum ADC for preoperative grading of supratentorial astrocytomas that were diagnosed as low-grade astrocytomas on conventional MR imaging. Among 118 patients with astrocytomas (WHO grades II-IV), 16 who showed typical MR imaging findings of low-grade supratentorial astrocytomas on conventional MR imaging were included. All 16 patients underwent preoperative MR imaging and diffusion-weighted imaging. The minimum ADC value of each tumor was determined from several regions of interest in the tumor on ADC maps. To assess the relationship between the minimum ADC and tumor grade, we performed the Mann-Whitney U test. A receiver operating characteristic (ROC) analysis was used to determine the cutoff value of the minimum ADC that had the best combination of sensitivity and specificity for distinguishing low- and high-grade astrocytomas. Eight of the 16 patients (50%) were confirmed as having high-grade astrocytomas (WHO grades III and IV), and the other 8 patients were confirmed as having low-grade astrocytomas (WHO grade II). The median minimum ADC of the high-grade astrocytoma (1.035 x 10(-3) mm(2) . sec(-1)) group was significantly lower than that of the low-grade astrocytoma group (1.19 x 10(-3) mm(2) . sec(-1)) (P = .021). According to the ROC analysis, the cutoff value of 1.055 x 10(-3) mm(2) . sec(-1) for the minimum ADC generated the best combination of sensitivity (87.5%) and specificity (79%) (P = .021). Measuring minimum ADC can provide valuable diagnostic information for the preoperative grading of presumptive low-grade supratentorial astrocytomas.


Origin and molecular evolution of the determinant of methicillin resistance in staphylococci.
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most important multidrug-resistant pathogens around the world. MRSA is generated when methicillin-susceptible S. aureus (MSSA) exogenously acquires a methicillin resistance gene, mecA, carried by a mobile genetic element, staphylococcal cassette chromosome mec (SCCmec), which is speculated to be transmissible across staphylococcal species. However, the origin/reservoir of the mecA gene has remained unclear. Finding the origin/reservoir of the mecA gene is important for understanding the evolution of MRSA. Moreover, it may contribute to more effective control measures for MRSA. Here we report on one of the animal-related Staphylococcus species, S. fleurettii, as the highly probable origin of the mecA gene. The mecA gene of S. fleurettii was found on the chromosome linked with the essential genes for the growth of staphylococci and was not associated with SCCmec. The mecA locus of the S. fleurettii chromosome has a sequence practically identical to that of the mecA-containing region (∼12 kbp long) of SCCmec. Furthermore, by analyzing the corresponding gene loci (over 20 kbp in size) of S. sciuri and S. vitulinus, which evolved from a common ancestor with that of S. fleurettii, the speciation-related mecA gene homologues were identified, indicating that mecA of S. fleurettii descended from its ancestor and was not recently acquired. It is speculated that SCCmec came into form by adopting the S. fleurettii mecA gene and its surrounding chromosomal region. Our finding suggests that SCCmec was generated in Staphylococcus cells living in animals by acquiring the intrinsic mecA region of S. fleurettii, which is a commensal bacterium of animals.


SPINK1 promotes cell growth and metastasis of lung adenocarcinoma and acts as a novel prognostic biomarker.
Serine protease inhibitor Kazal type 1 (SPINK1) plays a role in protecting the pancreas against premature activation of trypsinogen and is involved in cancer progression. SPINK1 promoted LAC cells growth, migration, and invasion. Mechanistically, we found that SPINK1 promoted LAC cells migration and invasion via up-regulating matrix metalloproteinase 12 (MMP12). We observed that SPINK1 expression was only up-regulated in lung adenocarcinoma (LAC) tissues, and was an independent prognostic factor for poor survival. Our results indicate that SPINK1 might be a potential biomarker for LAC that promotes progression by MMP12. [BMB Reports 2018; 51(12): 648-653].


Ca2+-dependent binding of cytosolic components to insulin-secretory granules results in Ca2+-dependent protein phosphorylation.
1. Incubation of a rat islet cell tumour homogenate with [gamma-32P]ATP resulted in the Ca2+-dependent phosphorylation of 100000-, 57000-, 29000-, 26000- and 14000-Mr proteins. The Ca2+ concentration required was in the low-microM range. 2. Isolated insulin granules did not exhibit Ca2+-dependent protein phosphorylation, whereas a soluble protein fraction showed the Ca2+-dependent phosphorylation of a 57000-Mr protein. Combination of insulin granules with the soluble protein fraction resulted in the additional Ca2+-dependent phosphorylations of 100000-, 29000- and 10000-Mr proteins. The latter phosphorylations were not enhanced by exogenous calmodulin, but nevertheless were inhibited by trifluoperazine. Removal of endogenous calmodulin from the soluble protein fraction before incubation with insulin granules did not abolish the Ca2+-dependent phosphorylations of the 100000-, 29000- and 10000-Mr proteins but rendered the Ca2+-dependent phosphorylation of the 57000-Mr soluble protein dependent on exogenous calmodulin. 3. The components of the soluble protein fraction responsible for the interaction with insulin granules bound to intact granules in a Ca2+-dependent manner. 4. After phosphorylation, the 29000-Mr protein remained attached to granules, whereas the 100000- and 10000-Mr proteins dissociated from granules. 5. These Ca2+-dependent phenomena may be of regulatory importance in the secretory mechanism.


Reactive Carbonyl Species Activate Caspase-3-Like Protease to Initiate Programmed Cell Death in Plants.
Reactive oxygen species (ROS)-triggered programmed cell death (PCD) is a typical plant response to biotic and abiotic stressors. We have recently shown that lipid peroxide-derived reactive carbonyl species (RCS), downstream products of ROS, mediate oxidative signal to initiate PCD. Here we investigated the mechanism by which RCS initiate PCD. Tobacco Bright Yellow-2 cultured cells were treated with acrolein, one of the most potent RCS. Acrolein at 0.2 mM caused PCD in 5 h (i.e. lethal), but at 0.1 mM it did not (sublethal). Specifically, these two doses caused critically different effects on the cells. Both lethal and sublethal doses of acrolein exhausted the cellular glutathione pool in 30 min, while the lethal dose only caused a significant ascorbate decrease and ROS increase in 1-2 h. Prior to such redox changes, we found that acrolein caused significant increases in the activities of caspase-1-like protease (C1LP) and caspase-3-like protease (C3LP), the proteases which trigger PCD. The lethal dose of acrolein increased the C3LP activity 2-fold more than did the sublethal dose. In contrast, C1LP activity increments caused by the two doses were not different. Acrolein and 4-hydroxy-(E)-2-nonenal, another RCS, activated both proteases in a cell-free extract from untreated cells. H2O2 at 1 mM added to the cells increased C1LP and C3LP activities and caused PCD, and the RCS scavenger carnosine suppressed their activation and PCD. However, H2O2 did not activate the proteases in a cell-free extract. Thus the activation of caspase-like proteases, particularly C3LP, by RCS is an initial biochemical event in oxidative signal-stimulated PCD in plants.


Drug development against sleeping sickness: old wine in new bottles?
Atoxyl, the first medicinal drug against human African trypanosomiasis (HAT), also known as sleeping sickness, was applied more than 100 years ago. Ever since, the search for more effective, more specific and less toxic drugs continued, leading to a set of compounds currently in use against this devastating disease. Unfortunately, none of these medicines fulfill modern pharmaceutical requirements and may be considered as therapeutic ultima ratio due to the many, often severe side effects. Starting with a historic overview on drug development against HAT, we present a selection of trypanosome specific pathways and enzymes considered as highly potent druggable targets. In addition, we describe cellular mechanisms the parasite uses for differentiation and cell density regulation and present our considerations how interference with these steps, elementary for life cycle progression and infection, may lead to new aspects of drug development. Finally we refer to our recent work about CNS infection that offers novel insights in how trypanosomes hide in an immune privileged area to establish a chronic state of the disease, thereby considering new ways for drug application. Depressingly, HAT specific drug development has failed over the last 30 years to produce better suited medicine. However, unraveling of parasite-specific pathways and cellular behavior together with the ability to produce high resolution structures of essential parasite proteins by X-ray crystallography, leads us to the optimistic view that development of an ultimate drug to eradicate sleeping sickness from the globe might just be around the corner.


The role of T lymphocytes and monocytes in the regulation of human erythropoietic peripheral blood burst forming units.
To clarify the role of T lymphocytes or monocytes in the regulation of human peripheral blood erythroid burst forming unit proliferation, equal numbers of purified T cells, B cells or monocytes were cultured in vitro with null cells in the plasma clot system. BFUE proliferation was directly proportional to the T cell concentration and inversely proportional to monocyte concentration in culture. The effect of B cells was variable and dependent on the extent of T cell contamination. Addition of a highly specific anti-human thymocyte IgG preparation (ATG) to null cells, T cells + null cells or B cells + null cells significantly reduced or eliminated BFUE proliferation. A burst promoting activity (BPA) was found in the supernatants of T cell enriched mixed lymphocyte cultures and could oppose the inhibition of BFUE proliferation by ATG. A burst inhibitory activity was found in the supernatants of monocyte enriched cultures. These studies provide further evidence that BFUE proliferation is determined by opposing actions of stimulator T cells and inhibitor monocytes and/or their soluble products.


MUTAGENIC EFFECTS OF HYDROXYLAMINE IN VIVO.
Hydroxylamine can induce any one of the four types of transition mutations in bacteriophage S13 if the mutagen is added directly to agar plates seeded with phage and bacterial indicators. The phage can also be mutated by treating the host cell with hydroxylamine before infecting it with phage. These effects of hydroxylamine in vivo contrast with the mutagenic effect in vitro, which seems to be exclusively on cytosine.


Neuroleptics in the short-term treatment of anorexia nervosa. A double-blind placebo-controlled study with sulpiride.
There is a remarkable lack of controlled investigations about the usefulness of psychotropic drugs in anorexia nervosa despite the popular use of neuroleptics in these patients. Inspired by a previous study using pimozide, a double-blind placebo-controlled cross-over study with sulpiride was carried out in 18 female anorexia nervosa inpatients. No direct effect of sulpiride has been established with regard to behavioural and attitudinal characteristics as measured by behaviour observation scales as well as by two self-report questionnaires (Eating Attitudes Test, Body Attitudes Test). Regarding daily weight gain, sulpiride was on the whole superior to placebo, especially in the first treatment period of three weeks. In the cross-over analysis, however, this effect did not reach statistical significance.


Ten years of highly active antiretroviral therapy for HIV infection.
Over the past 10 years, the management of HIV infection has been transformed by an increased number of effective antiretrovirals (ARVs), with more convenient dosing and improved tolerability. Optimal management of HIV infection includes at least three effective ARVs; from at least two different drug classes. Current strategies and drugs can effectively control HIV and significantly reduce morbidity and mortality. However, no cure is yet possible. Appropriate use of ARVs leads to suppression of virological replication (to below the limit of detection using commercial assays to measure HIV in plasma) and an increase in CD4(+) T cells with few adverse effects. Greater than 95% adherence to drug therapy is required for effective viral suppression and immunological improvement. Monotherapy, two-drug combinations, sequential ARVs, drug "cycling", and treatment interruptions are ineffective management strategies and lead to earlier disease progression and emergence of drug resistance. Drug-drug interactions are common and caution is required when prescribing ARVs that inhibit or induce the cytochrome P450 pathway.


Hybrid multiobjective evolutionary design for artificial neural networks.
Evolutionary algorithms are a class of stochastic search methods that attempts to emulate the biological process of evolution, incorporating concepts of selection, reproduction, and mutation. In recent years, there has been an increase in the use of evolutionary approaches in the training of artificial neural networks (ANNs). While evolutionary techniques for neural networks have shown to provide superior performance over conventional training approaches, the simultaneous optimization of network performance and architecture will almost always result in a slow training process due to the added algorithmic complexity. In this paper, we present a geometrical measure based on the singular value decomposition (SVD) to estimate the necessary number of neurons to be used in training a single-hidden-layer feedforward neural network (SLFN). In addition, we develop a new hybrid multiobjective evolutionary approach that includes the features of a variable length representation that allow for easy adaptation of neural networks structures, an architectural recombination procedure based on the geometrical measure that adapts the number of necessary hidden neurons and facilitates the exchange of neuronal information between candidate designs, and a microhybrid genetic algorithm ( microHGA) with an adaptive local search intensity scheme for local fine-tuning. In addition, the performances of well-known algorithms as well as the effectiveness and contributions of the proposed approach are analyzed and validated through a variety of data set types.


Homoeologous chromosomes of Xenopus laevis are highly conserved after whole-genome duplication.
It has been suggested that whole-genome duplication (WGD) occurred twice during the evolutionary process of vertebrates around 450 and 500 million years ago, which contributed to an increase in the genomic and phenotypic complexities of vertebrates. However, little is still known about the evolutionary process of homoeologous chromosomes after WGD because many duplicate genes have been lost. Therefore, Xenopus laevis (2n=36) and Xenopus (Silurana) tropicalis (2n=20) are good animal models for studying the process of genomic and chromosomal reorganization after WGD because X. laevis is an allotetraploid species that resulted from WGD after the interspecific hybridization of diploid species closely related to X. tropicalis. We constructed a comparative cytogenetic map of X. laevis using 60 complimentary DNA clones that covered the entire chromosomal regions of 10 pairs of X. tropicalis chromosomes. We consequently identified all nine homoeologous chromosome groups of X. laevis. Hybridization signals on two pairs of X. laevis homoeologous chromosomes were detected for 50 of 60 (83%) genes, and the genetic linkage is highly conserved between X. tropicalis and X. laevis chromosomes except for one fusion and one inversion and also between X. laevis homoeologous chromosomes except for two inversions. These results indicate that the loss of duplicated genes and inter- and/or intrachromosomal rearrangements occurred much less frequently in this lineage, suggesting that these events were not essential for diploidization of the allotetraploid genome in X. laevis after WGD.


[Cardiac perforation by a gastric ulcer: an unusual cause of death, after an esophageal and gastric resection of an epidermoid esophageal carcinoma].
We report here the case of a 55 year old female that underwent surgery for a well differentiated squamous cell carcinoma of the esophagus (middle third). Four months after surgery, she complains of neck pain, for which she is prescribed non steroidal antiinflammatory drugs (NSAID). A CT-scan and a Barium swallow are then normal. After three weeks of treatment, the patient is admitted on emergency to the Intensive Care Unit for a resuscitation hematemesis and atrial fibrillation with a fast ventricular response. The symptoms are stabilized after the transfusion of a few packed red blood cells. A few hours later, however, a massive hematemesis recurs and the patient dies despite intense resuscitation measures. Autopsy reveals three gastric ulcers, one of which had perforated through the cardiac left ventricular wall.


[On the chemotherapy of Ewing's sarcoma (author's transl)].
Because of the high incidence of pulmonary and skeletal metastases after only local treatment adjuvant systemic chemotherapy is mandatory in Ewing's sarcoma. The drugs most often used thereby are Actinomycin D, Cyclophosphamid, Anthracyclines and Vincristine. In polychemotherapeutic trials two year disease-free survival rates of 80% and more have been accomplished. The rate of local tumour control after radiotherapy is enhanced by chemotherapy but untoward reactions of bone and soft tissue are also. The extent of radiation portals and time indispensable dose of radiation therefore have to be reviewed again. But in view of debilitating side effects of radio-chemotherapy surgical procedures have to be considered individually.


Systematic Chemoenzymatic Synthesis of O-Sulfated Sialyl Lewis x Antigens.
O-Sulfated sialyl Lewis x antigens play important roles in nature. However, due to their structural complexity, they are not readily accessible by either chemical or enzymatic synthetic processes. Taking advantage of a bacterial sialyltransferase mutant that can catalyze the transfer of different sialic acid forms from the corresponding sugar nucleotide donors to Lewis x antigens which are fucosylated glycans as well as an efficient one-pot multienzyme (OPME) sialylation system, O-sulfated sialyl Lewis x antigens containing different sialic acid forms and O-sulfation at different locations were systematically synthesized by chemoenzymatic methods.


Antibacterial activity of turmeric oil: a byproduct from curcumin manufacture.
Curcumin, the yellow color pigment of turmeric, is produced industrially from turmeric oleoresin. The mother liquor after isolation of curcumin from oleoresin contains approximately 40% oil. The oil was extracted from the mother liquor using hexane at 60 degrees C, and the hexane extract was separated into three fractions using silica gel column chromatography. These fractions were tested for antibacterial activity by pour plate method against Bacillus cereus, Bacillus coagulans, Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Fraction II eluted with 5% ethyl acetate in hexane was found to be most active fraction. The turmeric oil, fraction I, and fraction II were analyzed by GC and GC-MS. ar-Turmerone, turmerone, and curlone were found to be the major compounds present in these fractions along with other oxygenated compounds.


Postnatal regulation of hypothalamic neuropeptide expression by leptin: implications for energy balance and body weight regulation.
Leptin is produced mainly by adipose tissue and has been shown to regulate feeding, energy balance and neuroendocrine function. Regulation of energy homeostasis by leptin is thought to be mediated by hypothalamic neuropeptides, at least in adult rodents. The neonatal period is a critical stage of development during which mammals have to optimize caloric intake to support growth and development, as well as maintain body temperature. It is likely that leptin is involved in the transition from preweaning to adult metabolism. To test this hypothesis, we compared the effect of leptin treatment on body weight and adiposity between neonatal and adult mice. We also determined whether well known hypothalamic neuropeptide targets, e.g. neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related peptide (AGRP) and cocaine and amphetamine-regulated transcript (CART) were regulated in a pattern consistent with their presumed roles as mediators of leptin action. Once daily intraperitoneal leptin injection for 7 days did not alter body weight, fat content or expression of hypothalamic neuropeptide mRNAs in 10-day-old mice. In contrast, leptin decreased body weight and adiposity, increased CART and suppressed NPY and AGRP mRNA expression in adult mice. These results are consistent with previous studies showing that the timing of leptin's anorectic action develops after weaning. Furthermore, the association between leptin's ability to influence body weight in adult mice but not in neonates, and the regulation of hypothalamic neuropeptide mRNA expression, is consistent with the view that these peptides mediate leptin's effects on energy balance.


Cellular microenvironment influences the ability of mammary epithelia to undergo cell cycle.
The use of cell culture models is a principal and fundamental technology used in understanding how mammalian cells work. However, for some cell types such as mammary epithelia, the lines selected for extended culture are often transformed or have chromosomal abnormalities, while primary cultures have such a curtailed lifespan that their use is restricted. For example, mammary luminal epithelial cells (MECs) are used to study mechanisms of breast cancer, but the proliferation of primary cell cultures is highly limited. Here we describe the establishment of a new culture system to allow extended analysis of cultures of primary mouse MECs. In 2D monolayer culture, primary MECs showed a burst of proliferation 2-3 days post isolation, after which cell cycle decreased substantially. Addition of mammary epithelial growth factors, such as Epidermal Growth Factor, Fibroblast Growth Factor-2, Hepatocyte Growth Factor, and Receptor Activator for Nuclear Factor κB Ligand, or extracellular matrix proteins did not maintain their proliferation potential, neither did replating the cells to increase the mitogenic response. However, culturing MECs directly after tissue extraction in a 3D microenvironment consisting of basement membrane proteins, extended the time in culture in which the cells could proliferate. Our data reveal that the cellular microenvironment has profound effects on the proliferative properties of the mammary epithelia and is dominant over growth factors. Moreover, manipulating the cellular environment using this novel method can maintain the proliferative potential of primary MECs, thus enabling cell cycle to be studied as an endpoint after gene transfer or gene deletion experiments.


Partitioning Phenotypic Variance Due to Parent-of-Origin Effects Using Genomic Relatedness Matrices.
We propose a new method, G-REMLadp, to estimate the phenotypic variance explained by parent-of-origin effects (POEs) across the genome. Our method uses restricted maximum likelihood analysis of genome-wide genetic relatedness matrices based on individuals' phased genotypes. Genome-wide SNP data from parent child duos or trios is required to obtain relatedness matrices indexing the parental origin of offspring alleles, as well as offspring phenotype data to partition the trait variation into variance components. To calibrate the power of G-REMLadp to detect non-null POEs when they are present, we provide an analytic approximation derived from Haseman-Elston regression. We also used simulated data to quantify the power and Type I Error rates of G-REMLadp, as well as the sensitivity of its variance component estimates to violations of underlying assumptions. We subsequently applied G-REMLadp to 36 phenotypes in a sample of individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We found that the method does not seem to be inherently biased in estimating variance due to POEs, and that substantial correlation between parental genotypes is necessary to generate biased estimates. Our empirical results, power calculations and simulations indicate that sample sizes over 10000 unrelated parent-offspring duos will be necessary to detect POEs explaining < 10% of the variance with moderate power. We conclude that POEs tagged by our genetic relationship matrices are unlikely to explain large proportions of the phenotypic variance (i.e. > 15%) for the 36 traits that we have examined.


[Alphavirus reproduction in cultures of transplantable human lymphoblastoid cells during persistent infections].
The results of virological investigations of alphavirus persistence in human B-cell lines Raji and L-101 are presented. The formation of persisting infection was shown to depend both on the cell line and on the virus type. Productive persistent infection of Raji cells with Venezuelan equine encephalitis virus was followed for 11 months. The presence of the virus was confirmed by electron microscopic and immunofluorescent examinations. Infectious virus production varied from 0.001 to dozens PFU/cell, and the content of viable cells from 100,000 to 300,000 in 1 ml of the culture fluid. Virus infectivity in the culture medium varied within the range of 5-7 lg PFU/ml. Human lymphoblastoid cells Raji persistently infected with Venezuelan equine encephalitis virus were examined cytologically, karyologically, and electron microscopically. The long-term presence of the virus resulted in profound alterations in the cell population. Morphology of the cells and processes of division were changed, the mitotic index decreased, the rate of 3H-thymidine incorporation into cellular DNA increased. The mechanisms of persistence are discussed.


Histone H1- and other protein- and amino acid-hydroperoxides can give rise to free radicals which oxidize DNA.
Exposure of amino acids, peptides and proteins to radicals, in the presence of oxygen, gives high yields of hydroperoxides. These materials are readily decomposed by transition metal ions to give further radicals. We hypothesized that hydroperoxide formation on nuclear proteins, and subsequent decomposition of these hydroperoxides to radicals, might result in oxidative damage to associated DNA. We demonstrate here that exposure of histone H1 and model compounds to gamma-radiation in the presence of oxygen gives hydroperoxides in a dose-dependent manner. These hydroperoxides decompose to oxygen- and carbon-centred radicals (detected by electron paramagnetic resonance spectroscopy) on exposure to Cu(+) and other transition metal ions. These hydroperoxide-derived radicals react readily with pyrimidine DNA bases and nucleosides to give adduct species (i.e. protein-DNA base cross-links). Product analysis has demonstrated that radicals from histone H1-hydroperoxides, and other protein and amino acid hydroperoxides, can also oxidize both free 2'-deoxyguanosine and intact calf thymus DNA to give the mutagenic oxidized base 7, 8-dihydro-8-oxo-2'-deoxyguanosine (8-hydroxy-2'-deoxyguanosine, 8-oxodG). The yield of 7,8-dihydro-8-oxo-2'-deoxyguanosine is proportional to the initial protein-hydroperoxide concentration, and corresponds (for histone H1-hydroperoxide, 280 microM) to approx. 1. 4% conversion for free 2'-deoxyguanosine (200 microM), and 0.14% for 2'-deoxyguanosine in DNA (70 microgram/ml). Evidence has also been obtained with DNA for reaction at cytosine and thymine, but not adenine; the lack of damage to the latter may result from damage transfer to 2'-deoxyguanosine residues. These studies demonstrate that initial radical-induced damage to nuclear proteins can give rise to subsequent DNA damage; the latter includes both DNA-protein cross-links and formation of oxidized DNA bases.


Fast odour dynamics are encoded in the olfactory system and guide behaviour.
Odours are transported in turbulent plumes, which result in rapid concentration fluctuations1,2 that contain rich information about the olfactory scenery, such as the composition and location of an odour source2-4. However, it is unclear whether the mammalian olfactory system can use the underlying temporal structure to extract information about the environment. Here we show that ten-millisecond odour pulse patterns produce distinct responses in olfactory receptor neurons. In operant conditioning experiments, mice discriminated temporal correlations of rapidly fluctuating odours at frequencies of up to 40 Hz. In imaging and electrophysiological recordings, such correlation information could be readily extracted from the activity of mitral and tufted cells-the output neurons of the olfactory bulb. Furthermore, temporal correlation of odour concentrations5 reliably predicted whether odorants emerged from the same or different sources in naturalistic environments with complex airflow. Experiments in which mice were trained on such tasks and probed using synthetic correlated stimuli at different frequencies suggest that mice can use the temporal structure of odours to extract information about space. Thus, the mammalian olfactory system has access to unexpectedly fast temporal features in odour stimuli. This endows animals with the capacity to overcome key behavioural challenges such as odour source separation5, figure-ground segregation6 and odour localization7 by extracting information about space from temporal odour dynamics.


Does probability of occurrence relate to population dynamics?
Hutchinson defined species' realized niche as the set of environmental conditions in which populations can persist in the presence of competitors. In terms of demography, the realized niche corresponds to the environments where the intrinsic growth rate (r) of populations is positive. Observed species occurrences should reflect the realized niche when additional processes like dispersal and local extinction lags do not have overwhelming effects. Despite the foundational nature of these ideas, quantitative assessments of the relationship between range-wide demographic performance and occurrence probability have not been made. This assessment is needed both to improve our conceptual understanding of species' niches and ranges and to develop reliable mechanistic models of species geographic distributions that incorporate demography and species interactions. The objective of this study is to analyse how demographic parameters (intrinsic growth rate r and carrying capacity K) and population density (N) relate to occurrence probability (Pocc ). We hypothesized that these relationships vary with species' competitive ability. Demographic parameters, density, and occurrence probability were estimated for 108 tree species from four temperate forest inventory surveys (Québec, Western US, France and Switzerland). We used published information of shade tolerance as indicators of light competition strategy, assuming that high tolerance denotes high competitive capacity in stable forest environments. Interestingly, relationships between demographic parameters and occurrence probability did not vary substantially across degrees of shade tolerance and regions. Although they were influenced by the uncertainty in the estimation of the demographic parameters, we found that r was generally negatively correlated with Pocc , while N, and for most regions K, was generally positively correlated with Pocc . Thus, in temperate forest trees the regions of highest occurrence probability are those with high densities but slow intrinsic population growth rates. The uncertain relationships between demography and occurrence probability suggests caution when linking species distribution and demographic models.


Racial/Ethnic Differences in Bone Mineral Density for Osteoporosis.
We primarily aim to review differences in bone mineral density (BMD) for osteoporosis among different racial/ethnic groups and to highlight the magnitude of racial/ethnic differences in obesity and diabetes. We also explore the factors contributing to the BMD differences among various subgroups. In addition, we investigate the existing disparities in research, educational initiatives, screening practices, and treatment options for osteoporosis and discuss these findings' clinical and public health implications. Racial/ethnic differences in BMD for osteoporosis exist in the USA and other countries. There are disparities regarding osteoporosis screening and treatment. Understanding the factors contributing to these differences can help develop targeted interventions and policies to reduce their impact. Clinicians should consider the racial/ethnic differences in BMD when making treatment decisions and providing preventive care. Future research could contribute to developing effective strategies for preventing osteoporosis among different racial/ethnic groups. This review offered a comprehensive examination of differences in BMD across various racial and ethnic groups, elucidating the influence of genetic, lifestyle, and cultural factors on these differences. This review also highlighted the disparities in osteoporosis screening, treatment options, research on medical effectiveness, and educational outreach tailored to each subgroup. Recognizing the importance of addressing these inequalities, we present this review to advocate for targeted interventions to reduce disparities in osteoporosis and improve bone health for all populations.


Quality of life and myelomeningocele: an ethical and evidence-based analysis of the Groningen Protocol.
In 2005, a group of pediatricians at the University Medical Center in Groningen, The Netherlands, published the Groningen Protocol (GP) for Euthanasia in Newborns. This protocol is a set of guidelines devised in 2001 to clarify and facilitate the assessment of clinically stable neonates deemed to be in unbearable suffering for whom the prognosis is felt to be hopeless. At the time of publication, the GP had been in use for 7 years, and 22 patients, all with diagnosed myelomeningocele (MMC), had met the selection criteria for euthanasia by lethal injection. MMC is the most common neurological congenital anomaly, affecting approximately 300,000 newborns yearly worldwide. Neurosurgeons have a unique perspective on this disease and therefore an important voice, given the significant role they have in caring for these patients at all stages of their lives. This paper reviews the principal ethical arguments presented to date in the literature regarding the GP. It also provides an evidence-based critique of the GP in light of quality-of-life studies addressing adults with MMC, and ascertains whether or not the GP meets the criteria for an evidence-based guideline.


Plasmodium falciparum-infected erythrocytes and beta-hematin induce partial maturation of human dendritic cells and increase their migratory ability in response to lymphoid chemokines.
Acute and chronic Plasmodium falciparum infections alter the immune competence of the host possibly through changes in dendritic cell (DC) functionality. DCs are the most potent activators of T cells, and migration is integral to their function. Mature DCs express lymphoid chemokine receptors (CCRs), expression of which enables them to migrate to the lymph nodes, where they encounter naïve T cells. The present study aimed to investigate the impact of the synthetic analog to malaria parasite pigment hemozoin, i.e., β-hematin, or infected erythrocytes (iRBCs) on the activation status of human monocyte-derived DCs and on their expression of CCRs. Human monocyte-derived DCs partially matured upon incubation with β-hematin as indicated by an increased expression of CD80 and CD83. Both β-hematin and iRBCs provoked the release of proinflammatory and anti-inflammatory cytokines, such as interleukin-6 (IL-6), IL-10, and tumor necrosis factor alpha, but not IL-12, and induced upregulation of the lymphoid chemokine receptor CXCR4, which was coupled to an increased migration to lymphoid ligands. Taken together, these results suggest that the partial and transient maturation of human myeloid DCs upon stimulation with malaria parasite-derived products and the increased IL-10 but lack of IL-12 secretion may lead to suboptimal activation of T cells. This may in turn lead to impaired adaptive immune responses and therefore insufficient clearance of the parasites.


Effects of nitric oxide on the vestibular functional recovery after unilateral labyrinthectomy.
The effects of nitric oxide on the vestibular function recovery following unilateral labyrinthectomy were studied. Male Sprague-Dawley rats treated with N-omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, were subjected to destruction of the unilateral vestibular apparatus and spontaneous nystagmus was observed. To explore the role of nitric oxide on the potassium current, the whole cell patch clamp technique was applied on isolated medial vestibular nuclear neurons. The frequency of spontaneous nystagmus that appeared in L-NAME-treated rats was higher and maintained longer than in control animals. Potassium currents in the isolated medial vestibular nucleus were inhibited by nitric oxide liberating agents, sodium nitroprusside and S-nitroso-N-acetylpenicillamine. After blockade of calcium dependent potassium currents by high EGTA (11 mM)-containing pipette solution, sodium nitroprusside did not inhibit the outward potassium currents. 8-Bromoguanosine 3,5-cyclic monophosphate, a membrane-permeable cGMP analogue, produced similar effects to inhibit the outward potassium currents as sodium nitroprusside. These results suggest that nitric oxide production after unilateral labyrinthectomy would help to facilitate vestibular compensation by inhibiting calcium-dependent potassium currents through increasing intracellular cyclic GMP, thereby increasing excitability in ipsilateral vestibular nuclear neurons.


Pathologic measures of quality compare favorably in patients undergoing robot-assisted radical cystectomy to open cystectomy cohorts: a National Cancer Database analysis.
This study aims to assess the impact of facility characteristics on measures of surgical quality (positive surgical margin rates and lymph-node yield) in patients undergoing robot-assisted (RARC) versus open (ORC) radical cystectomy using the National Cancer Database. Patients who received RC between the years of 2010-2013 were stratified according to surgery type (ORC vs. RARC), and corresponding patient and facility-level variables (facility type and volume) were assessed. Logistic regression models for procedure type, positive surgical margins (PSMs), and LN dissection (LND) rates were estimated. Radical cystectomies (ORC = 13,236, RARC = 3687) were performed more often in academic centers (58.3%) compared to community centers (31.6%). As facility volume increased, centers performed more LNDs during ORCs (p = 0.03) and the number of nodes retrieved increased in both ORC and RARC (ORC p < 0.001; RARC p < 0.0001). Increased facility volume also resulted in significantly fewer PSMs within the RARC cohort (p = 0.01). Comparison of ORC and RARC within each facility type cohort identified improved pathological metrics for RARC with fewer PSMs (p = 0.001) as well as increased LNDs (p < 0.0001) and median number of LNs retrieved (p < 0.0001), which suggests that RARC may facilitate comparative outcomes in community centers and academic centers. Overall, higher facility volume and robot-assisted surgery resulted in more favorable pathologic metrics compared to lower facility volume and ORC.


Mid-Infrared Mapping of Four-Layer Graphene Polytypes Using Near-Field Microscopy.
The mid-infrared (MIR) spectral region attracts attention for accurate chemical analysis using photonic devices. Few-layer graphene (FLG) polytypes are promising platforms, due to their broad absorption in this range and gate-tunable optical properties. Among these polytypes, the noncentrosymmetric ABCB/ACAB structure is particularly interesting, due to its intrinsic bandgap (8.8 meV) and internal polarization. In this study, we utilize scattering-scanning near-field microscopy to measure the optical response of all three tetralayer graphene polytypes in the 8.5-11.5 μm range. We employ a finite dipole model to compare these results to the calculated optical conductivity for each polytype obtained from a tight-binding model. Our findings reveal a significant discrepancy in the MIR optical conductivity response of graphene between the different polytypes than what the tight-binding model suggests. This observation implies an increased potential for utilizing the distinct tetralayer polytypes in photonic devices operating within the MIR range for chemical sensing and infrared imaging.


Multifinger prehension: an overview.
The authors review the available experimental evidence on what people do when they grasp an object with several digits and then manipulate it. The article includes three parts, each addressing a specific aspect of multifinger prehension. In the first part, the authors discuss manipulation forces (i.e., the resultant force and moment of force exerted on the object) and the digits' contribution to such forces' production. The second part deals with internal forces defined as forces that cancel each other and do not disturb object equilibrium. The authors discuss the role of the internal forces in maintaining the object stability, with respect to such issues as slip prevention, tilt prevention, and resistance to perturbations. The third part is devoted to the motor control of prehension. It covers such topics as prehension synergies, chain effects, the principle of superposition, interfinger connection matrices and reconstruction of neural commands, mechanical advantage of the fingers, and the simultaneous digit adjustment to several mutually reinforcing or conflicting demands.


Idiopathic aneurysm of the dorsalis pedis artery.
Aneurysms of pedal arteries occur very rarely, but they can be identified and localized by arteriogram. The author describes a case in which the aneurysm was excised after proximal and distal ligation of the artery. Although the patient was diabetic, the postoperative course was uneventful and the results of the surgery were satisfactory.


How to make good children's nurses: children's view.
A consultation was held to seek children's views on how to make better children's nurses to influence a new curriculum. In one-to-one sessions, ten hospitalised children were asked to complete body outlines of 'good' and 'not so good' nurses. Based on this the children were asked about how good children's nurses could be made. They agreed that although children's nurses are special people with some innate characteristics, they also needed education to make them good at nursing children. The children were able to identify three areas of learning that could help to make a good children's nurse. The researchers categorised these as: attitudinal and professional persona; Cognitive and psychomotor learning; experiential learning. The consultation highlighted methodological issues in consulting children about curriculum development, as well as drawing our attention to how children are represented in the children's nursing curriculum. Child nurse lecturers should work in collaboration with clinical colleagues and, more importantly, children to develop teaching and learning in children's nursing.


Development and validation of a stress response measure: the Daily Stress Response Scale (DSRS).
To date, there is a lack of measures for capturing a broad spectrum of psychophysiological stress reactions that can be administered on a daily basis and in different contexts. A need for such a measure is especially salient in settings where stress processes can unfold momentarily and substantially fluctuate daily. Therefore, the main aim of the current study was to develop and validate the Daily Stress Response Scale (DSRS), an instrument capturing a broad spectrum of psychophysiological stress reactions that can be administered in real time and in different contexts. The study was conducted in the early stages of the COVID-19 pandemic in Europe. Participants were 7228 (81% female) Polish university students. The data were collected anonymously through self-completion questionnaires. The DSRS was subject to confirmatory factor analyses (CFA). The DSRS is a 30-item, easy-to-use stress response measure with excellent psychometric properties. Based on CFA results, the scale consists of two subscales, psychological and physiological stress response, which form associations with related external criteria. The DSRS is a reliable and valid measure of psychological and physiological stress reactions that can be used to assess the stress response to daily stressors, including those of an acute nature, such as a crisis, trauma, or surgery.


Early nephrology referral reduces the economic costs among patients who start renal replacement therapy: a prospective cohort study in Korea.
The nature of cost-saving effects of early referral to a nephrologist in patients with chronic kidney disease (CKD) is not fully evaluated. We evaluated the health care costs before and after dialysis according to the referral time. A total of 879 patients who were newly diagnosed as having end-stage renal disease from August 2008 to June 2011 were prospectively enrolled. The early referral (ER) group was defined as patients who were referred to a nephrologist more than a year before dialysis and had visited a nephrology clinic 2 or more times. Patients whose referral time was less than a year were considered the late referral (LR) group. Information about medical costs was acquired from the claim data of the Korea Health Insurance Review and Assessment Service. The total medical costs during the first 12 months after the initiation of dialysis were not different between the 526 ER patients and the 353 LR patients. However, the costs of the ER patients during the first month were significantly lower than those of the LR patients (ER vs. LR: 3029 ± 2219 vs. 3438 ± 2821 US dollars [USD], P = 0.025). The total 12-month health care costs before the initiation of dialysis were significantly lower in the ER group (ER vs. LR: 6206 ± 5873 vs. 8610 ± 7820 USD, P<0.001). In the multivariate analysis, ER significantly lowered the health care costs during the 12 months before (2534.0 ± 436.2 USD, P<0.001) and the first month (428.5 ± 172.3 USD, P = 0.013) after the initiation of dialysis. The ER of patients with CKD to a nephrologist is associated with decreased medical costs during the pretreatment period of renal replacement therapy and the early period of dialysis initiation.


Leucine and isoleucine activate skeletal muscle branched-chain alpha-keto acid dehydrogenase in vivo.
The response of rat skeletal muscle branched-chain alpha-keto acid dehydrogenase to administration of branched-chain amino acids in vivo was determined using a soluble preparation of the enzyme. After detergent extraction of the complex in the presence of kinase and phosphatase inhibitors, initial in vivo activity was typically 1 nmol X min-1 X g muscle-1, with 0.1 mM alpha-[1-14C]ketoisocaproate as substrate. Total activity of the dephosphorylated complex, measured after preincubation with 15 mM Mg2+, typically reached a maximum of 29 nmol X min-1 X g-1. Thus in overnight-fasted rats the complex was 2-3% active. Initial activity increased three- to fivefold after leucine or isoleucine (at higher concentrations) but not valine administration in vivo. After intravenous leucine injection (0.25 mmol/kg) initial muscle enzyme activity increased rapidly and subsequently decreased, paralleling plasma leucine concentrations, while plasma valine and isoleucine decreased. In conclusion, muscle branched-chain alpha-keto acid dehydrogenase complex is rapidly activated when circulating leucine is increased to concentrations that may occur after meals. During hyperleucinemia accelerated valine and isoleucine degradation by muscle may account for the observed "antagonism" among the branched-chain amino acids.


Continued indinavir versus switching to indinavir/ritonavir in HIV-infected patients with suppressed viral load.
To compare continued indinavir (IDV) 8-hourly (q8h) with switching to indinavir/ritonavir (IDV/RTV) 12-hourly (q12h) in HIV-positive patients having suppressed viral load with IDV q8h plus two nucleoside reverse transcriptase inhibitors (NRTI). Multicentre, international, randomized, open-label study enrolling HIV-1 infected patients on IDV 800 mg q8h plus two NRTI with CD4 cell counts > or = 100 x 106/l and plasma HIV RNA < 500 copies/ml for > or = 3 months. Patients were randomized to continue on the same regimen or to switch to IDV plus liquid RTV (IDV/RTV 800 mg/100 mg q12h). Primary endpoint was the proportion of patients remaining < 500 copies/ml at 48 weeks. A total of 323 patients (IDV/RTV, 162; IDV, 161) were evaluable. At 48 weeks, the proportions of patients with plasma HIV RNA < 500 copies/ml were 93%, 88% and 58% in the IDV/RTV arm versus 92% (P = 1), 86% (P = 0.87) and 74% (P = 0.003) in the IDV arm using on-treatment (OT) and intent-to-treat (ITT) [switches included (ITT, S = I) and switches = failure (ITT, S = F)] analyses respectively. Mean increase in CD4 cell count was 88 x 106/cells/l (IDV/RTV arm) and 60 x 106 cells/l (IDV arm) (P = 0.08). More patients discontinued study medication due to adverse events in the IDV/RTV arm than in the IDV arm (P < 0.001). Equivalence of continuing IDV q8h versus switching to IDV/RTV (liquid) q12h in suppressed stable patients was demonstrated by OT and ITT S = I analyses. However, the IDV q8h arm performed better when discontinuations were classified as failures. IDV/RTV q12h can be convenient and equally effective for patients able to tolerate it.


Design, Synthesis and Biological Evaluation of Betulinic Acid Derivatives as New Antitumor Agents for Leukemia.
Chronic myeloid leukemia (CML) is currently treated with imatinib, a Bcr-Abl inhibitor. However, resistance to this drug usually develops over time. Triptolide, a diterpenoid triepoxide, has been shown active against CML cells resistant to imatinib, acting mainly on the level of Bcr-Abl transcription inhibition. Here, we used the triterpene betulinic acid, a known proteasome inhibitor with potential antileukemic activity, as a scaffold for the generation of analogues with predicted triptolide biological activity. Betulinic acid derivatives were designed based on the structure-activity relationship of triptolide and evaluated for their cytotoxic effects in CML cells, lymphocytes and human keratinocytes (HaCaT), as well as against the proteasome complex. The main modification performed on betulinic acid was fluorination at C-28 and epoxidation, both of which are responsible for enhancing activity of triptolide. A total of 10 compounds were obtained: 6 previously described and 4 novel compounds. The cytotoxic activity over a CML cell line (K562) was assessed using flow cytometry and compared to lymphocytes and HaCaT. The results show that betulinic acid was the most cytotoxic compound against CML cells, showing a good selectivity index for cancer over normal cells. The most important trend for the activity in betulinic acid derivatives is the presence of a free hydroxyl group at C-3 and a carboxyl group at C-28. Results also indicated that the epoxide is important for enhancing the activity, while modification at C-28 worsens the activity. Proteasome inhibition assays suggest that proteasome is the main target for betulinic acid and its derivatives.


[Resources of Chinese materia medica in shennonjia].
There are 2023 species of Chinese materia medica in Shennonjia, belonging to 300 families and 974 genera, of which 1800 (including subspecies) are plants, 213 animals and 10 minerals. Protection, exploitation and utilization of these resources have been discussed.


Differential responses of stress genes to low dose-rate gamma irradiation.
In the past, most mechanistic studies of ionizing radiation response have employed very large doses, then extrapolated the results down to doses relevant to human exposure. It is becoming increasingly apparent, however, that this does not give an accurate or complete picture of the effects of most environmental exposures, which tend to be of low dose and protracted over time. We have initiated direct studies of low dose exposures, and using the relatively responsive ML-1 cell line, have shown that changes in gene expression can be triggered by doses of gamma-rays of 10 cGy and less in human cells. We have now extended these studies to investigate the effects on gene induction of reducing the rate of irradiation. In the ML-1 human myeloid leukemia cell line, we have found that reducing the dose rate over three orders of magnitude results in some protection against the induction of apoptosis, but still causes linear induction of the p53-regulated genes CDKN1A, GADD45A, and MDM2 between 2 and 50 cGy. Reducing the rate of exposure reduces the magnitude of induction of CDKN1A and GADD45A, but not the magnitude or duration of cell cycle delay. In contrast, MDM2 is induced to the same extent regardless of the rate of dose delivery. Microarray analysis has identified additional low dose-rate-inducible genes, and indicates the existence of two general classes of low dose-rate responders in ML-1. One group of genes is induced in a dose rate-dependent fashion, similar to GADD45A and CDKN1A. Functional annotation of this gene cluster indicates a preponderance of genes with known roles in apoptosis regulation. Similarly, a group of genes with dose rate-independent induction, such as seen for MDM2, was also identified. The majority of genes in this group are involved in cell cycle regulation. This apparent differential regulation of stress signaling pathways and outcomes in response to protracted radiation exposure has implications for carcinogenesis and risk assessment, and could not have been predicted from classical high dose studies.


Impact of traffic variability on geographic accessibility to 24/7 emergency healthcare for the urban poor: A GIS study in Dhaka, Bangladesh.
Ensuring access to healthcare in emergency health situations is a persistent concern for health system planners. Emergency services, including critical care units for severe burns and coronary events, are amongst those for which travel time is the most crucial, potentially making a difference between life and death. Although it is generally assumed that access to healthcare is not an issue in densely populated urban areas due to short distances, we prove otherwise by applying improved methods of assessing accessibility to emergency services by the urban poor that take traffic variability into account. Combining unique data on emergency health service locations, traffic flow variability and informal settlements boundaries, we generated time-cost based service areas to assess the extent to which emergency health services are reachable by urban slum dwellers when realistic traffic conditions and their variability in time are considered. Variability in traffic congestion is found to have significant impact on the measurement of timely access to, and availability of, healthcare services for slum populations. While under moderate traffic conditions all slums in Dhaka City are within 60-minutes travel time from an emergency service, in congested traffic conditions only 63% of the city's slum population is within 60-minutes reach of most emergency services, and only 32% are within 60-minutes reach of a Burn Unit. Moreover, under congested traffic conditions only 12% of slums in Dhaka City Corporation comply with Bangladesh's policy guidelines that call for access to 1 health service per 50,000 population for most emergency service types, and not a single slum achieved this target for Burn Units. Emergency Obstetric Care (EmOC) and First Aid & Casualty services provide the best coverage, with nearly 100% of the slum population having timely access within 60-minutes in any traffic condition. Ignoring variability in traffic conditions results in a 3-fold overestimation of geographic coverage and masks intra-urban inequities in accessibility to emergency care, by overestimating geographic accessibility in peripheral areas and underestimating the same for central city areas. The evidence provided can help policy makers and urban planners improve health service delivery for the urban poor. We recommend that taking traffic conditions be taken into account in future GIS-based analysis and planning for healthcare service accessibility in urban areas.


Factor V Leiden is not common in patients diagnosed with primary pulmonary hypertension.
Substantial evidence suggests that thrombosis contributes to the pathogenesis of primary pulmonary hypertension (PPH). An abnormal factor V (factor V Leiden) may contribute to thrombosis in the pulmonary microcirculation of PPH patients. A point mutation in which adenine is substituted for guanine at nucleotide 1691 (1691A) alters factor V so that it resists cleavage by activated protein C. Heterozygosity for the 1691A mutation is more common (2-8%) in Caucasian Europeans and Americans than in Africans (1%) and Asians (<1%). The aim of the study was to examine the prevalence of the mutation that codes for factor V Leiden in individuals with PPH. We identified 42 Caucasians diagnosed with PPH. We extracted deoxyribonucleic acid (DNA) from whole blood and assayed DNA samples for the point mutation (1691 A) that codes for factor V Leiden. One out of 42 (2.4%; 95% confidence interval=0.1-12.6) Caucasians diagnosed with PPH was heterozygous for the normal 1691G and mutant 1691A allele. All 10 individuals with familial PPH were homozygous for the normal 1691G allele. The prevalence of heterozygosity for the 1691A allele and the normal 1691G allele does not differ from that observed in reference (control) populations. The low prevalence of the 1691A mutation among individuals diagnosed with primary pulmonary hypertension provides evidence that factor V Leiden does not contribute to the pathogenesis of the disease in most patients.


The long-term fluctuation of the visual field in stable glaucoma.
To determine, in stable glaucoma, the characteristics of the between-examination variability of the visual field recorded with the Humphrey Field Analyser (HFA; Humphrey Systems, Dublin, CA) using the homogeneous, LF(Ho), and heterogeneous, LF(He), components of the long-term fluctuation (LF), thereby providing a technique for separating progressive loss from fluctuation in sensitivity. The LF components were calculated using a two-factor analysis of variance (ANOVA) with replications and were determined between each pair of three successive HFA program 30-2 fields for each patient from two groups, each containing 30 patients with primary open-angle glaucoma. The interval between examinations for the first group was 6 to 9 months and for the second group was 3 weeks. The group mean values for LF(Ho) ranged from 1.50 to 2.19 dB and for LF(He) from 1.70 to 2.05 dB. The average difference between examinations was within +/-0.35 dB for each component, and the 95% limits of agreement for the two groups, respectively, were +/- 2.31 and +/- 2.39 dB for the LF(Ho) and +/- 2.36 and +/- 2.09 dB for the LF(He). The estimate of the 90% confidence limit for the LF(Ho) was 3.30 dB and for the LF(He), 3.60 dB. Little relationship was present between the LF components and the modulus differences in mean deviation (MD), the corrected pattern SD (CPSD), or the mean MD, mean short-term fluctuation, and mean CPSD, of the two fields. Estimation of the LF components and of the corresponding confidence limits yields an expression of the normal between-examination variability of two consecutive fields that can be used as a reliability index. A value outside the confidence limits indicates the necessity for a confirmatory follow-up field.


[Treatment of infantile hydrocephalus with isosorbide dinitrate (author's transl)].
Eighteen of infantile hydrocephalus have been treated with isosorbide dinitrate. Pharmacology of this compound is considered. It appears that completely dinitrated isosorbide is the major metabolite. Isosorbide may be effective in a variable proportion of various types of infantile hydrocephalus. Results of isosorbide dinitrate therapy in children with "communicating" and "noncommunicating" hydrocephalus are reported. Treatment was monitored by simple measurements, and it's toxicity proved to be scanty.


Virtual hysteroscopy: a new non invasive approach for the assessment of uterine cavity.
Endometrial pathology is frequent in premenopausal women and the diagnostic hysteroscopy is considered the gold standard for assessing endometrial cavity and congenital uterine anomalies. However it is an invasive and uncomfortable procedure. Saline contrast hysterosalgingography and hysterosalpingo-contrast sonography allow detailed assessment of the uterine cavity. We propose a virtual hysteroscopy from three-dimensional saline and three-dimensional hysterosalpingo-contrast sonography scan data to generate a virtual reality as a new noninvasive procedure for assessing the uterine cavity in uterine congenital anomaly and endometrial pathology cases as well.


Differential adaptation to multi-stressed conditions of wine fermentation revealed by variations in yeast regulatory networks.
Variation of gene expression can lead to phenotypic variation and have therefore been assumed to contribute the diversity of wine yeast (Saccharomyces cerevisiae) properties. However, the molecular bases of this variation of gene expression are unknown. We addressed these questions by carrying out an integrated genetical-genomic study in fermentation conditions. We report here quantitative trait loci (QTL) mapping based on expression profiling in a segregating population generated by a cross between a derivative of the popular wine strain EC1118 and the laboratory strain S288c. Most of the fermentation traits studied appeared to be under multi-allelic control. We mapped five phenotypic QTLs and 1465 expression QTLs. Several expression QTLs overlapped in hotspots. Among the linkages unraveled here, several were associated with metabolic processes essential for wine fermentation such as glucose sensing or nitrogen and vitamin metabolism. Variations affecting the regulation of drug detoxification and export (TPO1, PDR12 or QDR2) were linked to variation in four genes encoding transcription factors (PDR8, WAR1, YRR1 and HAP1). We demonstrated that the allelic variation of WAR1 and TPO1 affected sorbic and octanoic acid resistance, respectively. Moreover, analysis of the transcription factors phylogeny suggests they evolved with a specific adaptation of the strains to wine fermentation conditions. Unexpectedly, we found that the variation of fermentation rates was associated with a partial disomy of chromosome 16. This disomy resulted from the well known 8-16 translocation. This large data set made it possible to decipher the effects of genetic variation on gene expression during fermentation and certain wine fermentation properties. Our findings shed a new light on the adaptation mechanisms required by yeast to cope with the multiple stresses generated by wine fermentation. In this context, the detoxification and export systems appear to be of particular importance, probably due to nitrogen starvation. Furthermore, we show that the well characterized 8-16 translocation located in SSU1, which is associated with sulfite resistance, can lead to a partial chromosomic amplification in the progeny of strains that carry it, greatly improving fermentation kinetics. This amplification has been detected among other wine yeasts.