Plasmodium vivax in vitro continuous culture: the spoke in the wheel.
Understanding the life cycle of Plasmodium vivax is fundamental for developing strategies aimed at controlling and eliminating this parasitic species. Although advances in omic sciences and high-throughput techniques in recent years have enabled the identification and characterization of proteins which might be participating in P. vivax invasion of target cells, exclusive parasite tropism for invading reticulocytes has become the main obstacle in maintaining a continuous culture for this species. Such advance that would help in defining each parasite protein's function in the complex process of P. vivax invasion, in addition to evaluating new therapeutic agents, is still a dream. Advances related to maintenance, culture medium supplements and the use of different sources of reticulocytes and parasites (strains and isolates) have been made regarding the development of an in vitro culture for P. vivax; however, only some cultures having few replication cycles have been obtained to date, meaning that this parasite's maintenance goes beyond the technical components involved. Although it is still not yet clear which molecular mechanisms P. vivax prefers for invading young CD71+ reticulocytes [early maturation stages (I-II-III)], changes related to membrane proteins remodelling of such cells could form part of the explanation. The most relevant aspects regarding P. vivax in vitro culture and host cell characteristics have been analysed in this review to explain possible reasons why the species' continuous in vitro culture is so difficult to standardize. Some alternatives for P. vivax in vitro culture have also been described.


MAPKAP kinase 2 blocks tristetraprolin-directed mRNA decay by inhibiting CAF1 deadenylase recruitment.
Tristetraprolin (TTP) directs its target AU-rich element (ARE)-containing mRNAs for degradation by promoting removal of the poly(A) tail. The p38 MAPK pathway regulates mRNA stability via the downstream kinase MAPK-activated protein kinase 2 (MAPKAP kinase 2 or MK2), which phosphorylates and prevents the mRNA-destabilizing function of TTP. We show that deadenylation of endogenous ARE-containing tumor necrosis factor mRNA is inhibited by p38 MAPK. To investigate whether phosphorylation of TTP by MK2 regulates TTP-directed deadenylation of ARE-containing mRNAs, we used a cell-free assay that reconstitutes the mechanism in vitro. We find that phosphorylation of Ser-52 and Ser-178 of TTP by MK2 results in inhibition of TTP-directed deadenylation of ARE-containing RNA. The use of 14-3-3 protein antagonists showed that regulation of TTP-directed deadenylation by MK2 is independent of 14-3-3 binding to TTP. To investigate the mechanism whereby TTP promotes deadenylation, it was necessary to identify the deadenylases involved. The carbon catabolite repressor protein (CCR)4.CCR4-associated factor (CAF)1 complex was identified as the major source of deadenylase activity in HeLa cells responsible for TTP-directed deadenylation. CAF1a and CAF1b were found to interact with TTP in an RNA-independent fashion. We find that MK2 phosphorylation reduces the ability of TTP to promote deadenylation by inhibiting the recruitment of CAF1 deadenylase in a mechanism that does not involve sequestration of TTP by 14-3-3. Cyclooxygenase-2 mRNA stability is increased in CAF1-depleted cells in which it is no longer p38 MAPK/MK2-regulated.


Can the use of road safety measures on national roads in Norway be interpreted as an informal application of the ALARP principle?
The ALARP principle, stating that risks should be reduced to a level "As Low As Reasonably Practicable", is widely known and discussed in risk management. The principle is flexible, as the interpretation of the key concepts of reasonable and practicable can be adapted to different contexts. This paper discusses whether the use of road safety measures on national roads in Norway can be interpreted as an informal application of the ALARP-principle. According to official guidelines, priority setting for major road investments should be based on cost-benefit analysis. Most road safety measures are low-cost projects that have traditionally not been subject to cost-benefit analysis. A use of these measures regarded as reasonable in the ALARP sense may include considerations of cost, efficiency and fair distribution. Data on 328 road safety measures implemented around 2000 is used to evaluate factors influencing their use. It is argued that the use of these measures is consistent with an informal application of the ALARP-principle.


Time to change your mind? Modelling transient properties of cortex formation highlights the importance of evolving cell division strategies.
The successful development of the mammalian cerebral neocortex is linked to numerous cognitive functions such as language, voluntary movement, and episodic memory. Neocortex development occurs when neural progenitor cells divide and produce neurons. Critically, although the progenitor cells are able to self-renew they do not reproduce themselves endlessly. Hence, to fully understand the development of the neocortex we are faced with the challenge of understanding temporal changes in cell division strategy. Our approach to modelling neuronal production uses non-autonomous ordinary differential equations and allows us to use a ternary coordinate system in order to define a strategy space, through which we can visualise evolving cell division strategies. Using this strategy space, we fit the known data and use approximate Bayesian computation to predict the founding progenitor population sizes, currently unavailable in the experimental literature. Counter-intuitively, we show that humans can generate a larger number of neurons than a macaque's even when starting with a smaller number of progenitor cells. Accompanying the article is a self-contained piece of software, which provides the reader with immediate simulated results that will aid their intuition. The software can be found at www.dpag.ox.ac.uk/team/noemi-picco.


Evolution of the gyrB gene and the molecular phylogeny of Enterobacteriaceae: a model molecule for molecular systematic studies.
Phylogenetic trees showing the evolutionary relatedness of Enterobacteriaceae based upon gyrB and 16S rRNA genes were compared. Congruence among trees of these molecules indicates that the genomes of these species are not completely mosaic and that molecular systematic studies can be carried out. Phylogenetic trees based on gyrB sequences appeared to be more reliable at determining relationships among Serratia species than trees based on 16S rRNA gene sequences. gyrB sequences from Serratia species formed a monophyletic group validated by significant bootstrap values. Serratia fonticola had the most deeply branching gyrB sequence in the Serratia monophyletic group, which was consistent with its atypical phenotypic characteristics. Klebsiella and Enterobacter genera seemed to be polyphyletic, but the branching patterns of gyrB and 16S rRNA gene trees were not congruent. Enterobacter aerogenes was grouped with Klebsiella pneumoniae on the gyrB phylogenetic tree, which supports that this species could be transferred to the Klebsiella genus. Unfortunately, 16S rRNA and gyrB phylogenetic trees gave conflicting evolutionary relationships for Citrobacter freundii because of its unusual gyrB evolutionary process. gyrB lateral gene transfer was suspected for Hafnia alvei. Saturation of gyrB genes was observed by the pairwise comparison of Proteus spp., Providencia alcalifaciens and Morganella morganii sequences. Depending on their level of variability, 16S rRNA gene sequences were useful for describing phylogenetic relationships between distantly related Enterobacteriaceae, whereas gyrB sequence comparison was useful for inferring intra- and some intergeneric relationships.


Enhanced telomere rejuvenation in pluripotent cells reprogrammed via nuclear transfer relative to induced pluripotent stem cells.
Although somatic cell nuclear transfer (SCNT) and induction of pluripotency (to form iPSCs) are both recognized reprogramming methods, there has been relatively little comparative analysis of the resulting pluripotent cells. Here, we examine the capacity of these two reprogramming approaches to rejuvenate telomeres using late-generation telomerase-deficient (Terc(-/-)) mice that exhibit telomere dysfunction and premature aging. We found that embryonic stem cells established from Terc(-/-) SCNT embryos (Terc(-/-) ntESCs) have greater differentiation potential and self-renewal capacity than Terc(-/-) iPSCs. Remarkably, SCNT results in extensive telomere lengthening in cloned embryos and improved telomere capping function in the established Terc(-/-) ntESCs. In addition, mitochondrial function is severely impaired in Terc(-/-) iPSCs and their differentiated derivatives but significantly improved in Terc(-/-) ntESCs. Thus, our results suggest that SCNT-mediated reprogramming mitigates telomere dysfunction and mitochondrial defects to a greater extent than iPSC-based reprogramming. Understanding the basis of this differential could help optimize reprogramming strategies.


Artificial oxygen carriers rescue placental hypoxia and improve fetal development in the rat pre-eclampsia model.
Pre-eclampsia affects approximately 5% of all pregnant women and remains a major cause of maternal and fetal morbidity and mortality. The hypertension associated with pre-eclampsia develops during pregnancy and remits after delivery, suggesting that the placenta is the most likely origin of this disease. The pathophysiology involves insufficient trophoblast invasion, resulting in incomplete narrow placental spiral artery remodeling. Placental insufficiency, which limits the maternal-fetal exchange of gas and nutrients, leads to fetal intrauterine growth restriction. In this study, in our attempt to develop a new therapy for pre-eclampsia, we directly rescued placental and fetal hypoxia with nano-scale size artificial oxygen carriers (hemoglobin vesicles). The present study is the first to demonstrate that artificial oxygen carriers successfully treat placental hypoxia, decrease maternal plasma levels of anti-angiogenic proteins and ameliorate fetal growth restriction in the pre-eclampsia rat model.


Rapid reversal of stress induced loss of synapses in CA3 of rat hippocampus following water maze training.
The impact was examined of exposing rats to two life experiences of a very different nature (stress and learning) on synaptic structures in hippocampal area CA3. Rats were subjected to either (i) chronic restraint stress for 21 days, and/or (ii) spatial training in a Morris water maze. At the behavioural level, restraint stress induced an impairment of acquisition of the spatial response. Moreover, restraint stress and water maze training had contrasting impacts on CA3 synaptic morphometry. Chronic stress induced a loss of simple asymmetric synapses [those with an unperforated postsynaptic density (PSD)], whilst water maze learning reversed this effect, promoting a rapid recovery of stress-induced synaptic loss within 2-3 days following stress. In addition, in unstressed animals a correlation was found between learning efficiency and the density of synapses with an unperforated PSD: the better the performance in the water maze, the lower the synaptic density. Water maze training increased the number of perforated synapses (those with a segmented PSD) in CA3, both in stressed and, more notably, in unstressed rats. The distinct effects of stress and learning on CA3 synapses reported here provide a neuroanatomical basis for the reported divergent effects of these experiences on hippocampal synaptic activity, i.e. stress as a suppressor and learning as a promoter of synaptic plasticity.


Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.
NIDDM occurs commonly among women with polycystic ovary syndrome (PCOS). The prevalence and natural history of its precursor, impaired glucose tolerance (IGT), is less well known. The objective of this study was to characterize the prevalence and incidence of glucose intolerance in a large cohort of women with well-characterized PCOS. A total of 122 women with clinical and hormonal evidence of PCOS were recruited from the Medicine, Endocrinology, Gynecology, and Pediatrics Clinics at the University of Chicago. All women had a standard oral glucose tolerance test (OGTT) with measurement of glucose and insulin levels. A subset of 25 women were subsequently restudied with the aim of characterizing the natural history of glucose tolerance in PCOS. Glucose tolerance was abnormal in 55 (45%) of the 122 women: 43 (35%) had IGT and 12 (10%) had NIDDM at the time of initial study. The women with NIDDM differed from those with normal glucose tolerance in that they had a 2.6-fold higher prevalence of first-degree relatives with NIDDM (83 vs. 31%, P < 0.01 by chi 2) and were significantly more obese (BMI 41.0 +/- 2.4 vs. 33.4 +/- 1.1 kg/m2, P < 0.01). For the entire cohort of 122 women, there was a significant correlation between fasting and 2-h glucose concentrations (r = 0.76, P < 0.0001); among the subset with IGT, the fasting glucose concentration was poorly predictive of the 2-h level (r = 0.25, NS). After a mean follow-up of 2.4 +/- 0.3 years (range 0.5-6.3), 25 women had a second OGTT. The glucose concentration at 2 h during the second glucose tolerance test was significantly higher than the 2-h concentration during the first study (161 +/- 9 vs. 139 +/- 6 mg/dl, P < 0.02). The prevalence of IGT and NIDDM in women with PCOS is substantially higher than expected when compared with age- and weight-matched populations of women without PCOS. The conversion from IGT to NIDDM is accelerated in PCOS. The fasting glucose concentration does not reliably predict the glucose concentration at 2 h after an oral glucose challenge, particularly among those with IGT, the subgroup at highest risk for subsequent development of NIDDM. We conclude that women with PCOS should periodically have an OGTT and must be closely monitored for deterioration in glucose tolerance.


COVID-19 and UK family carers: policy implications.
Informal (unpaid) carers are an integral part of all societies and the health and social care systems in the UK depend on them. Despite the valuable contributions and key worker status of informal carers, their lived experiences, wellbeing, and needs have been neglected during the COVID-19 pandemic. In this Health Policy, we bring together a broad range of clinicians, researchers, and people with lived experience as informal carers to share their thoughts on the impact of the COVID-19 pandemic on UK carers, many of whom have felt abandoned as services closed. We focus on the carers of children and young people and adults and older adults with mental health diagnoses, and carers of people with intellectual disability or neurodevelopmental conditions across different care settings over the lifespan. We provide policy recommendations with the aim of improving outcomes for all carers.


A mouse model of sitosterolemia: absence of Abcg8/sterolin-2 results in failure to secrete biliary cholesterol.
Mutations in either of two genes comprising the STSL locus, ATP-binding cassette (ABC)-transporters ABCG5 (encoding sterolin-1) and ABCG8 (encoding sterolin-2), result in sitosterolemia, a rare autosomal recessive disorder of sterol trafficking characterized by increased plasma plant sterol levels. Based upon the genetics of sitosterolemia, ABCG5/sterolin-1 and ABCG8/sterolin-2 are hypothesized to function as obligate heterodimers. No phenotypic difference has yet been described in humans with complete defects in either ABCG5 or ABCG8. These proteins, based upon the defects in humans, are responsible for regulating dietary sterol entry and biliary sterol secretion. In order to mimic the human disease, we created, by a targeted disruption, a mouse model of sitosterolemia resulting in Abcg8/sterolin-2 deficiency alone. Homozygous knockout mice are viable and exhibit sitosterolemia. Mice deficient in Abcg8 have significantly increased plasma and tissue plant sterol levels (sitosterol and campesterol) consistent with sitosterolemia. Interestingly, Abcg5/sterolin-1 was expressed in both liver and intestine in Abcg8/sterolin-2 deficient mice and continued to show an apical expression. Remarkably, Abcg8 deficient mice had an impaired ability to secrete cholesterol into bile, but still maintained the ability to secrete sitosterol. We also report an intermediate phenotype in the heterozygous Abcg8+/- mice that are not sitosterolemic, but have a decreased level of biliary sterol secretion relative to wild-type mice. These data indicate that Abcg8/sterolin-2 is necessary for biliary sterol secretion and that loss of Abcg8/sterolin-2 has a more profound effect upon biliary cholesterol secretion than sitosterol. Since biliary sitosterol secretion is preserved, although not elevated in the sitosterolemic mice, this observation suggests that mechanisms other than by Abcg8/sterolin-2 may be responsible for its secretion into bile.


Pre-concentration by liquid intake by paper (P-CLIP): a new technique for large volumes and digital microfluidics.
Microfluidic platforms are an attractive option for incorporating complex fluid handling into low-cost and rapid diagnostic tests. A persistent challenge for microfluidics, however, is the mismatch in the "world-to-chip" interface - it is challenging to detect analytes present at low concentrations in systems that can only handle small volumes of sample. Here we describe a new technique termed pre-concentration by liquid intake by paper (P-CLIP) that addresses this mismatch, allowing digital microfluidics to interface with volumes on the order of hundreds of microliters. In P-CLIP, a virtual microchannel is generated to pass a large volume through the device; analytes captured on magnetic particles can be isolated and then resuspended into smaller volumes for further processing and analysis. We characterize this method and demonstrate its utility with an immunoassay for Plasmodium falciparum lactate dehydrogenase, a malaria biomarker, and propose that the P-CLIP strategy may be useful for a wide range of applications that are currently limited by low-abundance analytes.


Exploiting biomaterial approaches to manufacture an artificial trabecular meshwork: A progress report.
Glaucoma is the second leading cause of irreversible blindness worldwide. Glaucoma is a progressive optic neuropathy in which permanent loss of peripheral vision results from neurodegeneration in the optic nerve head. The trabecular meshwork is responsible for regulating intraocular pressure, which to date, is the only modifiable risk factor associated with the development of glaucoma. Lowering intraocular pressure reduces glaucoma progression and current surgical approaches for glaucoma attempt to reduce outflow resistance through the trabecular meshwork. Many surgical approaches use minimally invasive glaucoma surgeries (MIGS) to control glaucoma. In this progress report, biomaterials currently employed to treat glaucoma, such as MIGS, and the issues associated with them are described. The report also discusses innovative biofabrication approaches that aim to revolutionise glaucoma treatment through tissue engineering and regenerative medicine (TERM). At present, there are very few applications targeted towards TM engineering in vivo, with a great proportion of these biomaterial structures being developed for in vitro model use. This is a consequence of the many anatomical and physiological attributes that must be considered when designing a TERM device for microscopic tissues, such as the trabecular meshwork. Ongoing advancements in TERM research from multi-disciplinary teams should lead to the development of a state-of-the-art device to restore trabecular meshwork function and provide a bio-engineering solution to improve patient outcomes.


[Splanchnic vein aneurysms: a report of 13 cases].
Splanchnic vein aneurysms are a rare and poorly known entity. From a review of 13 cases and reports from the literature, we have defined the imaging features and modalities for their diagnosis and management. Retrospective study of 13 patients (7 females, 6 males, mean age of 53.5 years) who presented between 1993 and 2005 with splanchnic vein aneurysms. All patient charts were reviewed to collect and analyze epidemiological data, underlying etiologies, imaging work-up for diagnosis and management. Aneurysms were defined as fusiform or saccular enlargement of the portal venous vein or its branches, superior mesenteric vein and splenic vein. A total of 16 splanchnic vein aneurysms were identified. Four patients had portal venous hypertension. The imaging work-up was variable and included mainly non-invasive modalities (US: 8 patients; CTA: 8 patients and MRA: 9 patients) and conventional angiography in 2 patients. Eight aneurysms involved the portal vein (50%), 5 the splenic vein (31.3%), and 3 the superior mesenteric vein (18.7%). None of the patients underwent surgical or endovascular management. Imaging follow-up was performed in 12 patients, with no interval change over time with up to 10 years follow-up. In our series, the portal vein was most frequently involved. Diagnosis was exclusively based on imaging and management was limited to follow-up.


Nifedipine as a uterine relaxant for external cephalic version: a randomized controlled trial.
To estimate the effectiveness of nifedipine as a uterine relaxant during external cephalic version to correct breech presentation. In this randomized, double-blind, placebo-controlled trial, women with a singleton fetus in breech presentation and a gestational age of 36 weeks or more were eligible for enrollment. Participating women received two doses of either nifedipine 10 mg or placebo, 30 and 15 minutes before the external cephalic version attempt. The primary outcome was a cephalic-presenting fetus immediately after the procedure. Secondary outcome measures were cephalic presentation at delivery, mode of delivery, and adverse events. A sample size of 292 was calculated to provide 80% power to detect a 17% improvement of the external cephalic version success rate, assuming a placebo group rate of 40% and alpha of .05. Outcome data for 310 of 320 randomly assigned participants revealed no significant difference in external cephalic version success rates between treatment (42%) and control group (37%) (relative risk 1.1, 95%; 95% confidence interval 0.85-1.5). The cesarean delivery rate was 51% in the treatment group and 46% in the control group (relative risk 1.1, 95% confidence interval 0.88-1.4). Nifedipine did not significantly improve the success of external cephalic version. Future use of nifedipine to improve the outcome of external cephalic version should be limited to large clinical trials.


Attitudes to spiritual care among nursing staff in a Swedish oncology clinic.
To identify factors which may influence attitudes to spiritual care, test the relevance of these identified influencing factors in a Swedish nursing context, and replicate a part of a previous study by Strang et al. (Journal of Clinical Nursing 2002;11:48-57) dealing with attitudes to spiritual care in a holistic perspective. A questionnaire was handed out to all nursing staff at a Swedish oncology clinic (n=93) excluding the radiation therapy ward. Data were obtained from 68 nurses or nursing auxiliaries. (i) Literature review of international research reports concerning spiritual care in a nursing context. (ii) Construction of a questionnaire comprising 17 questions with given alternatives based on the previous literature study. (iii) Operationalization of the concept 'attitudes to spiritual care' into some more easily measurable questions through identification in earlier research reports of conceivable indicators of attitudes to spiritual care. (iv) Construction of a suggestion for a definition of the concept 'spiritual care' from the results of Strang et al. (2002) to be used in the questionnaire. (v) Statistical analysis of the data from the questionnaire and a comparison with previous studies. The replicating part of the study are mainly in accordance with Strang et al. (2002) and lead to the conclusions that holistic care (i) is desirable, (ii) should include spiritual needs of the patients and (iii) is not yet realized in Swedish health care. The identified influencing factors are relevant in a Swedish nursing context. The factors influencing the largest number of indicators of attitudes to spiritual care are 'non-organized religiousness' and 'degree of comfort while providing spiritual care'. Other influencing factors are: 'belief in God', 'belief in life after death', 'organized religiousness', 'profession', and 'the perceived degree of education in spiritual care'. Knowledge of attitudes towards spiritual care among nursing staff and factors influencing these attitudes will improve the possibilities of meeting the spiritual needs of patients.


Pterostilbene protects vascular endothelial cells against oxidized low-density lipoprotein-induced apoptosis in vitro and in vivo.
Vascular endothelial cell (VEC) apoptosis is the main event occurring during the development of atherosclerosis. Pterostilbene (PT), a natural dimethylated analog of resveratrol, has been the subject of intense research in cancer and inflammation. However, the protective effects of PT against oxidized low-density lipoprotein (oxLDL)-induced apoptosis in VECs have not been clarified. We investigated the anti-apoptotic effects of PT in vitro and in vivo in mice. PT at 0.1-5 μM possessed antioxidant properties comparable to that of trolox in a cell-free system. Exposure of human umbilical vein VECs (HUVECs) to oxLDL (200 μg/ml) induced cell shrinkage, chromatin condensation, nuclear fragmentation, and cell apoptosis, but PT protected against such injuries. In addition, PT injection strongly decreased the number of TUNEL-positive cells in the endothelium of atherosclerotic plaque from apoE(-/-) mice. OxLDL increased reactive oxygen species (ROS) levels, NF-κB activation, p53 accumulation, apoptotic protein levels and caspases-9 and -3 activities and decreased mitochondrial membrane potential (MMP) and cytochrome c release in HUVECs. These alterations were attenuated by pretreatment with PT. PT inhibited the expression of lectin-like oxLDL receptor-1 (LOX-1) expression in vitro and in vivo. Cotreatment with PT and siRNA of LOX-1 synergistically reduced oxLDL-induced apoptosis in HUVECs. Overexpression of LOX-1 attenuated the protection by PT and suppressed the effects of PT on oxLDL-induced oxidative stress. PT may protect HUVECs against oxLDL-induced apoptosis by downregulating LOX-1-mediated activation through a pathway involving oxidative stress, p53, mitochondria, cytochrome c and caspase protease. PT might be a potential natural anti-apoptotic agent for the treatment of atherosclerosis.


Workplace learning and career progression: qualitative perspectives of UK dietitians.
Post-graduate education and continuous professional development (CPD) within dietetics lack clearly defined pathways. The current literature primarily focuses on new graduate perceptions of workplace learning (WPL). The present study raises issues of how CPD is sustained throughout a National Health Service (NHS) career, how informal learning might be made more visible and whether the workplace withholds learning opportunities. Qualified dietitians participated in focus groups (n = 32) and a nominal group technique (n = 24). Data from audio recordings were transcribed and triangulated. Thematic analysis took an interpretative approach. One size for WPL for dietetics and, likely, other allied health professionals (AHPs) did not meet the learning needs of everyone. The informal implicit learning affordances often went unrecognised. A greater emphasis on teaching, picking up on the strong preference for discussion with others voiced in the present study, may improve recognition of all WPL opportunities. Better scaffolding or guided support of entry level dietitians may ease the transition from study to workplace and challenge any perception of 'clipped wings'. Where development and career progression proves difficult for experienced dietitians, mentoring or stepping outside the NHS may revitalise by providing new communities of practice. WPL cannot be understood as a unitary concept. Dietitians engage with WPL differently across their careers. Future visions of WPL, especially explicit post-graduate career and education frameworks, must accommodate these differences to retain the highest calibre dietitians. The implications of a period of learning 'maintenance' rather than CPD among experienced dietitians offers a topic for further research, particularly as the workforce ages.


Carotid arteriography impacts carotid stenosis management.
Recent literature advocates carotid endarterectomy on duplex alone. The authors hypothesized that carotid angiography adds information that alters clinical management in a substantial number of patients compared to the use of carotid duplex examination alone. The records of 182 consecutive patients who underwent carotid artery duplex and subsequent carotid/cerebral angiography for suspected carotid artery stenosis between January 1998 and April 1999 were reviewed retrospectively. Carotid artery duplex examinations were stratified based on stenosis: < or =39%, 40% to 59%, 60% to 79% (moderate), 80% to 99% (severe), 100%. Carotid stenosis on angiograms was determined by NASCET criteria. New information found at angiography included vertebral, subclavian, or arch atherosclerosis, intracranial pathosis, or a change in duplex stenosis category to a degree of stenosis not requiring surgery. Clinical importance was attributed to angiograms that altered the patients' management plan. Angiography provided additional information in 53% (97/182) of patients. Vertebral disease was found in 25.1%, subclavian disease in 16.4%, intracranial disease in 15.3%, aortic arch disease in 3.3%. Patient treatment was altered in 30% (55/182). Angiographic findings downgraded the stenosis to medical therapy in 20.9% (38/182). The surgical plan was influenced in 5.5% (10/182). Nine intracranial aneurysms were discovered. Carotid angiography was essential for vascular bypass surgery planning in 3.3% (6/182). Angioplasty was performed in 2.2% (4/182). The accurate determination of stenosis is critical in determining optimal treatment of patients with carotid artery stenosis. Routine carotid angiography remains valuable in the clinical treatment of these patients.


Comparison of the constant flow and occlusion methods for assessment of bronchoconstriction in guinea-pigs.
Assessments of total respiratory compliance (C) and conductance (G) with the constant inspiratory flow and the occlusion methods were compared in the basal state and during histamine or serotonin induced bronchoconstriction in 22 normal, anaesthetized, paralysed, mechanically ventilated guinea-pigs. In the basal state, no significant difference was found between the C and G values measured by both methods. During drug-induced bronchoconstriction, small but significant differences were observed between the respiratory parameters measured by the two methods, and expressed as the percentage ratio (R) to the corresponding basal values (respectively RCCF and RCOC, and RGCF and RGOC). This discrepancy, which was independent of the drug and of the dose, was probably attributable to a modification of the visco elastic properties of the lung due to either the mechanical ventilation or the infused drug. Nevertheless, this study demonstrates that both methods can be considered as equivalent for bronchoconstriction assessment because very strong correlations were found between RCCF and RCOC (r = 0.96, p less than 0.001) and between RGCF and RGOC (r = 0.97, p less than 0.001), and because the slopes of the linear relationships were not significantly different from unity in both cases.


Microheterogeneity and coevolution: an examination of rDNA sequence characteristics in Neoparamoeba pemaquidensis and its prokinetoplastid endosymbiont.
Neoparamoeba pemaquidensis, the etiological agent of amoebic gill disease, has shown surprising sequence variability among different copies of the 18S ribosomal RNA gene within an isolate. This intra-genomic microheterogeneity was confirmed and extended to an analysis of the internal transcribed spacer (ITS) region. High levels of intra-genomic nucleotide diversity (Pi=0.0201-0.0313) were found among sequenced ITS regions from individual host amoeba isolates. In contrast, the ITS region of its endosymbiont revealed significantly lower levels of intra-genomic nucleotide diversity (Pi=0.0028-0.0056) compared with the host N. pemaquidensis. Phylogenetic and ParaFit coevolution analyses involving N. pemaquidensis isolates and their respective endosymbionts confirmed a significant coevolutionary relationship between the two protists. The observation of non-shared microheterogeneity and coevolution emphasizes the complexity of the interactions between N. pemaquidensis and its obligate endosymbiont.


A biocompatibility study of new nanofibrous scaffolds for nervous system regeneration.
The development of therapeutic approaches for spinal cord injury (SCI) is still a challenging goal to achieve. The pathophysiological features of chronic SCI are glial scar and cavity formation: an effective therapy will require contribution of different disciplines such as materials science, cell biology, drug delivery and nanotechnology. One of the biggest challenges in SCI regeneration is to create an artificial scaffold that could mimic the extracellular matrix (ECM) and support nervous system regeneration. Electrospun constructs and hydrogels based on self-assembling peptides (SAPs) have been recently preferred. In this work SAPs and polymers were assembled by using a coaxial electrospinning setup. We tested the biocompatibility of two types of coaxially electrospun microchannels: the first one made by a core of poly(ε-caprolactone) and poly(d,l-lactide-co-glycolide) (PCL-PLGA) and a shell of an emulsion of PCL-PLGA and a functionalized self-assembling peptide Ac-FAQ and the second one made by a core of Ac-FAQ and a shell of PCL-PLGA. Moreover, we tested an annealed scaffold by PCL-PLGA microchannel heat-treatment. The properties of coaxial scaffolds were analyzed using scanning electron microscopy (SEM), Fourier transform spectroscopy (FTIR), contact angle measurements and differential scanning calorimetry (DSC). In vitro cytotoxicity was assessed via viability and differentiation assays with neural stem cells (NSCs); whereas in vivo inflammatory response was evaluated following scaffold implantation in rodent spinal cords. Emulsification of the outer shell turned out to be the best choice in terms of cell viability and tissue response: thus suggesting the potential of using functionalized SAPs in coaxial electrospinning for applications in regenerative medicine.


Boys are not exempt: Sexual exploitation of adolescents in sub-Saharan Africa.
Research on youth sexual exploitation in Africa has largely neglected the experiences of exploited boys. To date, much of the research in sub-Saharan Africa continues to consider boys mainly as exploiters but not as exploited. Using the only publicly available population-based surveys from the National Survey of Adolescents, conducted in four sub-Saharan African countries - Burkina Faso, Ghana, Malawi, and Uganda-we assessed factors associated with transactional sexual behaviour among never-married adolescent boys and girls. We also examined whether boys' reported sexual exploitation was linked to similar risky sexual behaviours as has been noted among girls in sub-Saharan Africa. Results from our analyses indicated that even though adolescent girls have a somewhat higher likelihood of reporting sexual abuse and exploitation, the odds of trading sex were significantly elevated for previously traumatized boys (that is those with a history of sexual and physical abuse) but not for their female counterparts. Just like adolescent girls, transactional sexual behaviour was associated with the risk of having concurrent multiple sexual partners for boys. These findings support the reality of boys' sexual exploitation within the African context, and further highlight the importance of including males in general and boys in particular in population-based studies on sexual health, risk, and protective factors in the sub-Saharan African region. Understanding the factors linked to sexual exploitation for both boys and girls will help in developing policies and programs that could improve the overall sexual and reproductive health outcomes among adolescents and youth in sub-Saharan Africa.


Fortifying a meal with oyster mushroom powder beneficially affects postprandial glucagon-like peptide-1, non-esterified free fatty acids and hunger sensation in adults with impaired glucose tolerance: a double-blind randomized controlled crossover trial.
Impaired glucose tolerance (IGT) is a pathophysiological condition characterized by insulin resistance with known metabolic consequences such as postprandial hyperglycemia and hypertriglyceridemia. We hypothesized that fortifying a meal with mushrooms rich in β-glucans may diminish glucose and triglyceride responses by improving postprandial gastrointestinal hormone release. In a randomized controlled crossover study, 22 subjects with IGT ingested a meal either enriched with 20 g powder (8.1 g β-glucans) of oven-dried Pleurotus ostreatus (enriched meal, EN) or without enrichment (control meal, CON). Blood was collected before and repeatedly within 4 h after the meal to determine AUC of glucose (primary outcome), insulin, triglycerides, non-esterified free fatty acids (NEFAs), glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP) and ghrelin. Appetite sensations (hunger, satiety, fullness, and desire to eat) were assessed before and after meal consumption by visual analog scales. Postprandial glucose, insulin, triglycerides, GIP and ghrelin concentrations as well as the corresponding AUCs did not differ between EN and CON. NEFAs-AUC was 14% lower (P = 0.026) and GLP-1-AUC 17% higher (P = 0.001) after EN compared to CON. Appetite ratings did not differ between treatments, except for hunger (AUC 22% lower after EN vs. CON; P = 0.031). The observed immediate postprandial metabolic changes indicate that an easily manageable fortification of a single meal with powder from dried oyster mushrooms as β-glucan source may improve postprandial metabolism. If the effect is preserved long term, this measure can diminish the risk for further development of overweight/obesity and type 2 diabetes in subjects with IGT. German Clinical Trial Register on 09/08/2018; trial-ID: DRKS00015244.


Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort.
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3'-5' exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi-Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in ∼8370 patients with SLE and ∼7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P=0.0008, OR=1.73, 95% CI=1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P=2.99E-13, OR=5.2, 95% CI=3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.


The role of femoral venous pressure and femoral venous oxygen saturation in the setting of intra-abdominal hypertension: a pig model.
Femoral venous access is frequently used in critically ill patients. Because raised intra-abdominal pressure (IAP) is also frequently found in this group of patients, we examined the impact of IAP and positive end-expiratory pressure (PEEP) on femoral venous pressure (FVP) and femoral venous oxygen saturation (Sfvo2) in an animal model. Thirteen adult pigs received standardized anesthesia and ventilation. Randomized levels of IAP (3 [baseline], 18, and 26 mmHg) were applied, with levels of PEEP (5, 8, 12, and 15 cmH2O) applied randomly at each IAP level. We measured bladder pressure (IAP), superior vena cava pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, FVP, mixed venous oxygen saturation (Svo2), and Sfvo2. We found that FVP correlated well with IAP (FVP = 4.1 + [0.12 × PEEP] + [1.00 × IAP]; R = 0.89, P < 0.001) with a moderate bias and precision of 5.0 and 3.8 mmHg, respectively. Because the level of agreement did not meet the recommendations of the World Society of Abdominal Compartment Syndrome, FVP cannot currently be recommended to measure IAP, and further clinical trials are warranted. However, a raised FVP should prompt the measurement of the bladder pressure. Femoral venous oxygen saturation did correlate neither with Svo2 nor with abdominal perfusion pressure. Therefore, Sfvo2 is of no clinical use in the setting of raised IAP.


Biochanin A Ameliorates Arsenic-Induced Hepato- and Hematotoxicity in Rats.
Biochanin A (BCA) is a natural organic compound of the phytoestrogenic isoflavone class that has antioxidant and metal chelator properties in the presence of transition metal ions, however, its efficacy in animal models is still obscure. Therefore, the objective of this study was to investigate the protective effects of BCA against arsenic-induced hepatic injury and hematotoxicity in rats. The results suggest that arsenic intoxicated rats showed significantly higher levels of plasma hepatic markers than normal control rats. Furthermore, an increase in lipid peroxidation with depletion of reduced glutathione (GSH) and activities of superoxide dismutase (SOD) and catalase (CAT) occurred in the livers of rats exposed to arsenic. Administration of BCA (20 mg/kg·bw/day) and selenium (3 mg/kg·bw/day) resulted in a significant reversal of hepatic and oxidative stress markers in arsenic-intoxicated rats. A low dose of BCA (10 mg/kg·bw/day) did not show any preventive effect, while a high dose of BCA (40 mg/kg·bw/day) partially prevented all hepatotoxicity events. These biochemical perturbations were supported by histopathological observations of the liver. Our results suggest that administration of BCA (20 mg/kg·bw/day) attenuated the arsenic hepatotoxicity, a property that could contribute to the therapeutic approaches for chronic liver diseases.


Increased frequency of genital human papillomavirus infection in human immunodeficiency virus-seropositive Taiwanese women.
Human papillomavirus (HPV) infection is associated with increased incidence and severity of HPV-related cervical dysplasia and cervical cancer in women with human immunodeficiency virus (HIV) infection. This study examined the incidence of genital HPV infection in HIV-infected Taiwanese women and its relationship with cervical neoplasia. This hospital-based, case-control study enrolled 31 consecutive HIV-seropositive women and 124 age-matched women who were free from HIV infection. Polymerase chain reaction (PCR) was used to distinguish high-risk (types 16, 18, 31, 33, 52 and 58) and low-risk HPV (types 6 and 11). The occurrence of genital HPV infection was compared between women with and without HIV infection. In addition, CD4 lymphocyte counts were determined by flow cytometry and Papanicolaou test was done in women with HIV infection. HPV and Papanicolaou test were done soon after the diagnosis of HIV infection. HIV seropositive women had a significantly greater high-risk HPV infection rate (48.4%; 15/31) than women without HIV infection (20.2%; 25/124; odds ratio, 3.71; p = 0.001). However, the prevalence of cervical intraepithelial neoplasia was similar between women with and without HIV infection. The CD4 lymphocyte counts in HIV-seropositive women were similar between those with and without genital HPV infection. The risk of genital HPV infection was significantly increased in HIV-infected women. Due to the association between high-risk HPV infection and the development of cervical dysplasia and cervical cancer, regular follow-up of Papanicolaou test is necessary in these women.


Anticipation and management of junctional ectopic tachycardia in postoperative cardiac surgery: Single center experience with high incidence.
Junctional ectopic tachycardia (JET) often occurs in the early postoperative period following surgery for congenital heart diseases and may lead to hemodynamic compromise. Its exact etiology is unknown, however, longer cardiopulmonary bypass (CPB) time, aortic cross clamp (ACC) time, catecholamines, and hypomagnesemia are known risk factors. JET is associated with increased postoperative morbidity and mortality. A prospective cohort study of 194 consecutive children who underwent open heart surgery on CPB over 1 year period, patients was divided into three groups; JET, non-JET arrhythmia, and no arrhythmia groups. Information on patient's demographics (sex, age, and body weight), type of surgical interventions, duration of CPB and ACC, the use of inotropic support, duration of intensive care unit (ICU) stay, and response to different therapeutic methods were collected. JET was documented in 53 patients (27%) most commonly following tetralogy of Fallot (TOF) repair and was associated with longer CPB and ACC times (118 and 77 min, respectively) as compared to non-JET arrhythmia (93.9 and 55.3 min, respectively) and no arrhythmia groups (94.9 and 54.8 min, respectively). Patients with JET required more inotropic support and longer ICU stay as compared to other groups. Amiodarone was safe and effective in treatment of JET. Atrial electrocardiogram (ECG) and Lewis lead ECG were helpful tools in JET diagnosis. The mortality was 11.5% in JET patients. Incidence of JET was 27% possibly due to the large number of Fallot repair and Senning operation. Longer CPB and ACC times are risk factors for JET.


Immature epithelial Na+ channel expression is one of the pathogenetic mechanisms leading to human neonatal respiratory distress syndrome.
Noninfective acute respiratory disease develops in approximately 1% of all newborn infants and results in their admission to a critical care unit. Transient tachypnea of the newborn occurs as a result of a delay in the clearance of fetal lung liquid; however, respiratory distress syndrome, typically thought to be exclusively a problem of relative surfactant deficiency, is now suspected to be characterized by an even greater air space fluid burden from the inability to absorb fetal lung liquid. In vivo experiments have demonstrated that the lung epithelium secretes Cl and fluid throughout gestation and develops the ability to actively reabsorb Na+ only during late gestation. At birth, the mature lung switches from active Cl- (fluid) secretion to active Na+ (fluid) absorption in response to circulating catecholamines. Changes in oxygen tension augment the Na(+)-transporting capacity of the epithelium and increase gene expression for the epithelial Na+ channel (ENaC). The inability of the immature fetal lung to switch from fluid secretion to fluid absorption results, at least in large part, from an immaturity in the expression of ENaC, which can be upregulated by glucocorticosteroids. Both pharmacological blockade of the lung's epithelial Na+ channel and genetic knockout experiments using mice deficient in the ENaC pore-forming subunit have demonstrated the critical physiological importance of lung Na+ transport at birth. When Na+ transport is ineffective, newborn animals develop respiratory distress and hypoxemia, retain their fetal lung liquid and, in the case of the ENaC knockout mice, die. Bioelectrical studies of human infants' nasal epithelia demonstrate that both transient tachypnea of the newborn and respiratory distress syndrome have defective amiloride-sensitive Na+ transport. These results suggest that neonatal respiratory distress syndrome has, in addition to a relative deficiency in surfactant, defective Na+ transport, which plays a mechanistic role in the development of the disease.


Characterization of a hyperthermophilic P-type ATPase from Methanococcus jannaschii expressed in yeast.
We report on the biochemical and structural properties of a putative P-type H(+)-ATPase, MJ1226p, from the anaerobic hyperthermophilic Archaea Methanococcus jannaschii. An efficient heterologous expression system was developed in Saccharomyces cerevisiae and a four-step purification protocol, using n-dodecyl beta-d-maltoside, led to a homogeneous detergent-solubilized protein fraction with a yield of over 2 mg of protein per liter of culture. The three-dimensional structure of the purified detergent-solubilized protein obtained at 2.4 nm resolution by electron microscopy showed a dimeric organization in which the size and the shape of each monomer was compatible with the reported structures of P-type ATPases. The purified MJ1226p ATPase was inactive at 40 degrees C and was active at elevated temperature reaching high specific activity, up to 180 micromol of P(i) x min(-1) x mg(-1) at 95 degrees C. Maximum ATPase activity was observed at pH 4.2 and required up to 200 mm monovalent salts. The ATPase activity was stable for several days upon storage at 65 degrees C and was highly resistant to urea and guanidine hydrochloride. The protein formed catalytic phosphoenzyme intermediates from MgATP or P(i), a functional characteristic specific of P-type ATPases. The highly purified, homogeneous, stable, and active MJ1226p ATPase provides a new model for further structure-function studies of P-type ATPases.


Open access in primary care: results of a North Carolina pilot project.
Appointment delays impede access to primary health care. By reducing appointment delays, open access (OA) scheduling may improve access to and the quality of primary health care. The objective of this pilot study was to assess the potential impact of OA on practice and patient outcomes by using pilot-study data from 4 North Carolina primary care practices. We conducted an interrupted time-series pilot study of 4 North Carolina primary care practices (2 family medicine and 2 pediatric practices) participating in a quality-improvement (QI) collaborative from May 2001 to May 2002. The year-long collaborative comprised 25 practices and consisted of three 2-day meetings led by expert faculty, monthly data feedback, and monthly conference calls. Our main outcome measures were appointment delays, appointment no-shows, patient satisfaction, continuity of care, and staff satisfaction during the 12-month study period. Providers in all 4 practices successfully implemented OA. On average, providers reduced their delay to the third available preventive care appointment from 36 to 4 days. No-show rates declined (first quarter [Q1] rate: 16%; fourth quarter [Q4] rate: 11%; no-show reduction: 5% [95% confidence interval: 1%, 10%]), and overall patient satisfaction improved (Q1: 45% rated overall visit quality as excellent; Q4: 61% rated overall visit quality as excellent; change in satisfaction: 16% [95% confidence interval: 0.2%, 30%]). Continuity of care followed a similar pattern of improvement, but the change was not statistically significant. Staff satisfaction neither improved nor declined. This pilot study suggests that primary care practices can implement OA successfully by using QI-collaborative methods. These results provide preliminary evidence that OA may improve practice and patient outcomes in primary care. These analyses should be repeated in larger groups of practices with longer follow-up.


Transcriptomic Signatures of Ageing Vary in Solitary and Social Forms of an Orchid Bee.
Eusocial insect queens are remarkable in their ability to maximize both fecundity and longevity, thus escaping the typical trade-off between these two traits. Several mechanisms have been proposed to underlie the remolding of the trade-off, such as reshaping of the juvenile hormone (JH) pathway, or caste-specific susceptibility to oxidative stress. However, it remains a challenge to disentangle the molecular mechanisms underlying the remolding of the trade-off in eusocial insects from caste-specific physiological attributes that have subsequently arisen. The socially polymorphic orchid bee Euglossa viridissima represents an excellent model to address the role of sociality per se in longevity as it allows direct comparisons of solitary and social individuals within a common genetic background. We investigated gene expression and JH levels in young and old bees from both solitary and social nests. We found 902 genes to be differentially expressed with age in solitary females, including genes involved in oxidative stress, versus only 100 genes in social dominant females, and 13 genes in subordinate females. A weighted gene coexpression network analysis further highlights pathways related to ageing in this species, including the target of rapamycin pathway. Eleven genes involved in translation, apoptosis, and DNA repair show concurrent age-related expression changes in solitary but not in social females, representing potential differences based on social status. JH titers did not vary with age or social status. Our results represent an important step in understanding the proximate mechanisms underlying the remodeling of the fecundity/longevity trade-off that accompanies the evolutionary transition from solitary life to eusociality.


A comparison of the efficacy of piperacillin-tazobactam and cefoperazone-sulbactam therapies in the empirical treatment of patients with febrile neutropenia.
Empirical antibiotic therapy in neutropenic patients presenting with fever plays a significant role in reducing mortality related to infection. Empirical therapies with broad-spectrum intravenous bactericidal, anti-pseudomonal antibiotics are accepted treatments for febrile neutropenic patients. The aim of this study was to compare the efficacy of piperacillin-tazobactam (PIP-TAZO) and cefoperozone-sulbactam (CS) therapies in adult patients with haematological malignancies presenting with neutropenic fever in a prospective study design. Patients with haematological malignancies (leukaemia, lymphoma, multiple myeloma, and myelodysplastic syndrome) were recruited from June 2010-May 2013. Participants were over 18 years old, with an absolute neutrophil count (ANC) of less than 500/mm³ following chemotherapy or expected to have an ANC less than 500/mm³ in the first 48 h post-chemotherapy, and with an oral body temperature ≥ 38.3°C at a single measurement or 38.0°C after 1-h monitoring. Patients were randomised to the two treatment groups. The initial empirical therapy comprised PIP-TAZO (4.5 g/6 h/day, IV) and CS (2 g/8 h/day, IV). The overall success rate was 61% with CS and 49% with PIP-TAZO (p =0.247). Factors affecting the treatment success included a neutrophil count <100/mm3, being in the relapse/refractory stage of malignancy, and the presence of a microbiologically documented infection (p <0.05). PIP-TAZO and CS monotherapies are equally effective and safe for the empirical treatment of febrile neutropenic patients.


RegulatorTrail: a web service for the identification of key transcriptional regulators.
Transcriptional regulators such as transcription factors and chromatin modifiers play a central role in most biological processes. Alterations in their activities have been observed in many diseases, e.g. cancer. Hence, it is of utmost importance to evaluate and assess the effects of transcriptional regulators on natural and pathogenic processes. Here, we present RegulatorTrail, a web service that provides rich functionality for the identification and prioritization of key transcriptional regulators that have a strong impact on, e.g. pathological processes. RegulatorTrail offers eight methods that use regulator binding information in combination with transcriptomic or epigenomic data to infer the most influential regulators. Our web service not only provides an intuitive web interface, but also a well-documented RESTful API that allows for a straightforward integration into third-party workflows. The presented case studies highlight the capabilities of our web service and demonstrate its potential for the identification of influential regulators: we successfully identified regulators that might explain the increased malignancy in metastatic melanoma compared to primary tumors, as well as important regulators in macrophages. RegulatorTrail is freely accessible at: https://regulatortrail.bioinf.uni-sb.de/.


Results on the Spin-Dependent Scattering of Weakly Interacting Massive Particles on Nucleons from the Run 3 Data of the LUX Experiment.
We present experimental constraints on the spin-dependent WIMP (weakly interacting massive particle)-nucleon elastic cross sections from LUX data acquired in 2013. LUX is a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility (Lead, South Dakota), which is designed to observe the recoil signature of galactic WIMPs scattering from xenon nuclei. A profile likelihood ratio analysis of 1.4×10^{4} kg day of fiducial exposure allows 90% C.L. upper limits to be set on the WIMP-neutron (WIMP-proton) cross section of σ_{n}=9.4×10^{-41} cm^{2} (σ_{p}=2.9×10^{-39} cm^{2}) at 33 GeV/c^{2}. The spin-dependent WIMP-neutron limit is the most sensitive constraint to date.


Direct comparison of selective endothelin A and non-selective endothelin A/B receptor blockade in chronic heart failure.
To investigate the potential differential effects of selective endothelin (ET) A and dual ET-A/B receptor blockade in patients with chronic heart failure. Nine patients with chronic heart failure (New York Heart Association class II-III) each received intravenous infusions of BQ-123 alone (selective ET-A blockade) and combined BQ-123 and BQ-788 (dual ET-A/B blockade) in a randomised, placebo controlled, three way crossover study. Selective ET-A blockade increased cardiac output (maximum mean (SEM) 33 (12)%, p < 0.001) and reduced mean arterial pressure (maximum -13 (4)%, p < 0.001) and systemic vascular resistance (maximum -26 (8)%, p < 0.001), without changing heart rate (p = 0.38). Dual ET-A/B blockade significantly reduced the changes in all these haemodynamic variables compared with selective ET-A blockade (p < 0.05). Selective ET-A blockade reduced pulmonary artery pressure (maximum 25 (7)%, p = 0.01) and pulmonary vascular resistance (maximum 72 (39)%, p < 0.001). However, there was no difference between these effects and those seen with dual ET-A/B blockade. Unlike selective ET-A blockade, dual ET-A/B blockade increased plasma ET-1 concentrations (by 47 (4)% with low dose and 61 (8)% with high dose, both p < 0.05). While there appeared to be similar reductions in pulmonary pressures with selective ET-A and dual ET-A/B blockade, selective ET-A blockade caused greater systemic vasodilatation and did not affect ET-1 clearance. In conclusion, there are significant haemodynamic differences between selective ET-A and dual ET-A/B blockade, which may determine responses in individual patients.


Does music training facilitate the mnemonic effect of song? An exploration of musicians and nonmusicians with and without Alzheimer's dementia.
The efficacy of using sung words as a mnemonic device for verbal memory has been documented in persons with probable Alzheimer's dementia (AD), but it is not yet known whether this effect is related to music training. Given that music training can enhance cognitive functioning, we explored the effects of music training and modality (sung vs. spoken) on verbal memory in persons with and without AD. We used a mixed factorial design to compare learning (5 trials), delayed recall (30-min and, 24-hour), and recognition of sung versus spoken information in 22 healthy elderly (15 musicians), and 11 people with AD (5 musicians). Musicians with AD showed better total learning (over 5 trials) of sung information than nonmusicians with AD. There were no significant differences in delayed recall and recognition accuracy (of either modality) between musicians with and without AD, suggesting that music training may facilitate memory function in AD. Analysis of individual performances showed that two of the five musicians with AD were able to recall some information on delayed recall, whereas the nonmusicians with AD recalled no information on delay. The only significant finding in regard to modality (sung vs. spoken) was that total learning was significantly worse for sung than spoken information for nonmusicians with AD. This may be due to the need to recode information presented in song into spoken recall, which may be more cognitively demanding for this group. This is the first study to demonstrate that music training modulates memory of sung and spoken information in AD. The mechanism underlying these results is unclear, but may be due to music training, higher cognitive abilities, or both. Our findings highlight the need for further research into the potentially protective effect of music training on cognitive abilities in our aging population.


In vitro and in vivo uptake study of Escherichia coli Nissle 1917 bacterial ghosts: cell-based delivery system to target ocular surface diseases.
For the successful topical administration of drugs or vaccines to treat ocular surface diseases, efficient and well-tolerated delivery systems/carriers for conjunctival delivery are crucial in the development of new treatment strategies. The present study investigated the efficiency of internalization of bacterial ghosts (BGs) produced from probiotic Escherichia coli Nissle 1917 (EcN) by human conjunctival epithelial (HCjE) cell line, the EcN BGs cytotoxicity for HCjE cells, and in vivo uptake of EcN BGs by conjunctival guinea pig epithelial cells. The uptake of EcN BGs by HCjE cells was analyzed by laser scanning microscopy and flow cytometry. Immunohistochemistry was used to localize the EcN BGs in the guinea pig conjunctival tissue. Cytotoxicity of EcN BGs on HCjE cells was evaluated by measurement of LDH. Laser scanning microscopy and flow cytometry revealed that EcN BGs internalization by HCjE cells was time- and dose dependent. No cytotoxic effect on HCjE cells was observed after EcN BGs inoculation for 30 and 120 minutes, as well as 24 hours. In addition, the uptake of EcN BGs was detected in the conjunctival cells after in vivo administration of EcN BGs into the eye of the guinea pig. The findings that EcN BGs are nontoxic and effectively internalized in vitro by human and in vivo by guinea pig conjunctival cells comprise an important contribution to the future use of BGs as a system for conjunctival delivery of drugs and vaccines, either to treat or prevent ocular surface diseases.


A highly divergent archaeo-eukaryotic primase from the Thermococcus nautilus plasmid, pTN2.
We report the characterization of a DNA primase/polymerase protein (PolpTN2) encoded by the pTN2 plasmid from Thermococcus nautilus. Sequence analysis revealed that this protein corresponds to a fusion between an N-terminal domain homologous to the small catalytic subunit PriS of heterodimeric archaeal and eukaryotic primases (AEP) and a C-terminal domain related to their large regulatory subunit PriL. This unique domain configuration is not found in other virus- and plasmid-encoded primases in which PriS-like domains are typically fused to different types of helicases. PolpTN2 exhibited primase, polymerase and nucleotidyl transferase activities and specifically incorporates dNTPs, to the exclusion of rNTPs. PolpTN2 could efficiently prime DNA synthesis by the T. nautilus PolB DNA polymerase, suggesting that it is used in vivo as a primase for pTN2 plasmid replication. The N-terminal PriS-like domain of PolpTN2 exhibited all activities of the full-length enzyme but was much less efficient in priming cellular DNA polymerases. Surprisingly, the N-terminal domain possesses reverse transcriptase activity. We speculate that this activity could reflect an ancestral function of AEP proteins in the transition from the RNA to the DNA world.


The relationship between the Bayley Scales of Infant Development and preschool gross motor and cognitive performance.
Early identification of disabilities enables early intervention by occupational therapists and other health professionals. Because the number of children who can be seen in therapy is limited, it is important to be able to identify those infants most likely to have deficits at a later age. Therefore, it is necessary to study and understand the relationship between infants' scores on early developmental assessments and later developmental outcomes. The purpose of this study was to determine the extent to which scores on the Bayley Scales of Infant Development (BSID) during the first 2 years of life are related to motor and cognitive performance at 4 1/2 years for a sample of children identified at birth as biologically high risk. This retrospective study involved 70 children who were evaluated at corrected ages of 4 months, 1 year, 2 years, and 4 1/2 years. The 4-month BSID Mental and Motor Scale scores did not relate significantly to later cognitive motor performance. In contrast, the 12-month BSID Mental Scale scores related significantly to preschool scores on both the motor and cognitive measures. However, the 24-month BSID Mental Scale scores related significantly only to scores on the preschool cognitive measures. Though significant, these correlation coefficients had small magnitudes. Thus, therapists should be cautious about using BSID testing at 4 months, 1 year, and 2 years when attempting to predict later preschool performance.


Success Rate and Complications of Sharp Recanalization for Treatment of Central Venous Occlusions.
To evaluate success and safety of needle (sharp) recanalization as a method to re-establish access in patients with chronic central venous occlusions. Thirty-nine consecutive patients who underwent this procedure were retrospectively reviewed to establish success rate and associated complications. In all cases, a 21- or 22-gauge needle was used to restore connection between two chronically occluded segments after conventional wire and catheter techniques had failed. The needle was guided toward a target placed through a separate access by fluoroscopic guidance. When successful, the procedure was completed by placing a catheter, ballooning the segment, and/or stenting. The procedure was successful in 37 of the 39 patients (95%). The vast majority of the treated lesions were in the SVC and/or right innominate vein. Occlusions ranged in length between 10 and 110 mm, and the average length of occluded venous segment was 40 mm in the treated group. There were four minor (SIR classification B) complications involving pain management after the procedure. There were two major (SIR classification D) complications both of which involved hemorrhage into the pericardium treated with covered stents (5.1%). Sharp recanalization is a viable procedure for patients who have exhausted standard wire and catheter techniques. The operator performing this procedure should be familiar with potential complications so that they can be addressed urgently if needed.


Role of the Gastrointestinal Tract Microbiome in the Pathophysiology of Diabetes Mellitus.
The incidence of diabetes mellitus is rapidly increasing throughout the world. Although the exact cause of the disease is not fully clear, perhaps, genetics, ethnic origin, obesity, age, and lifestyle are considered as few of many contributory factors for the disease pathogenesis. In recent years, the disease progression is particularly linked with functional and taxonomic alterations in the gastrointestinal tract microbiome. A change in microbial diversity, referred as microbial dysbiosis, alters the gut fermentation profile and intestinal wall integrity and causes metabolic endotoxemia, low-grade inflammation, autoimmunity, and other affiliated metabolic disorders. This article aims to summarize the role of the gut microbiome in the pathogenesis of diabetes. Additionally, we summarize gut microbial dysbiosis in preclinical and clinical diabetes cases reported in literature in the recent years.


Elastography in hepatology.
A common characteristic of all chronic liver diseases is the occurrence and progression of fibrosis toward cirrhosis. Consequently, liver fibrosis assessment plays an important role in hepatology. Besides its importance for prognosis, determining the level of fibrosis reveals the natural history of the disease and the risk factors associated with its progression, to guide the antifibrotic action of different treatments. Currently, in clinical practice, there are three available methods for the evaluation of liver fibrosis: liver biopsy, which is still considered to be the 'gold standard'; serological markers of fibrosis and their mathematical combination - suggested in recent years to be an alternative to liver biopsy - and, more recently, transient elastography (TE). TE is a new, simple and noninvasive method used to measure liver stiffness. This technique is based on the progressing speed of an elastic shear wave within the liver. Currently, there are only a few studies that have evaluated TE effectiveness in chronic liver diseases, mostly in patients infected with the hepatitis C virus. Further studies are needed in patients with chronic liver disease, to assess the effectiveness of the fibrosis treatment.


Sexual dysfunction among women with diabetes mellitus in a diabetic center in Amol.
Sexual disorders among diabetic men have been proved in different studies but sexual dysfunction of diabetic women has received attention only recently. Neuropathy, vascular impairment, and psychological complaints have been implicated in the pathogenesis of decreased libido, low arousability, decreased vaginal lubrication, orgasmic dysfunction, and dyspareunia among diabetic women. The aim of this research was to study the prevalence of sexual dysfunction in different areas among diabetic women. A cross-sectional study was conducted on 500 women who were recruited from a diabetes center, based on questionnaires completed by them. Data regarding demographic features, physical complications, and sexual disorders were obtained. Medical records of patients were used to obtain body mass index (BMI) and details of complications. Mean age of participants, duration of diabetes, and BMI was 48.8 ± 0.4, 8.9 ± 0.32 years, and 28.9 ± 0.23, respectively. Prevalence of sexual dysfunction was 32.3%. Low sexual desire was seen in 81.8%, disorders of arousal in 78.3%, of orgasm in 47.5%, and 35.1% had disorder in resolution area. There was no significant relationship between some factors such as age, duration of diabetes, BMI, and frequency of sexual dysfunction. Frequency of diabetic complications demonstrated a significant effect on the prevalence of sexual dysfunction. Sexual problems are frequent among diabetic women and deserve more attention in clinical practice and researches.


Perp is a mediator of p53-dependent apoptosis in diverse cell types.
The induction of apoptosis by the p53 protein is critical for its activity as a tumor suppressor. Although it is clear that p53 induces apoptosis at least in part by direct transcriptional activation of target genes, the set of p53 target genes that mediate p53 function in apoptosis in vivo remains to be well defined. The Perp (p53 apoptosis effector related to PMP-22) gene is highly expressed in cells undergoing p53-dependent apoptosis as compared to cells undergoing p53-dependent G1 arrest. Perp is a direct p53 target, and its overexpression is sufficient to induce cell death in fibroblasts, implicating it as an important component of p53 apoptotic function. Here, through the generation of Perp-deficient mice, we analyze the role of Perp in the p53 apoptosis pathway in multiple primary cell types by comparing the cell death responses of Perp null cells to those of wild-type and p53 null cells. These experiments demonstrate the involvement of Perp in p53-mediated cell death in thymocytes and neurons but not in E1A-expressing MEFs, indicating a cell type-specific role for Perp in the p53 cell death pathway. In addition, we show that Perp is not required for proliferation-associated functions of p53. Thus, Perp selectively mediates the p53 apoptotic response, and the requirement for Perp is dictated by cellular context.


Curriculum reform: a narrated journey.
Curriculum reform poses significant challenges for medical schools across the globe. Understanding the medical educator's personal and lived experience of curriculum change is paramount. This paper illustrates the use of narrative inquiry as a means of exploring the author's own evolving professional identity as a medical educator engaged in planning and leading curriculum reform and in understanding the meanings she and other medical educators attribute to their roles as agents of change in a medical school. In 2002 it was decided to radically reform a school of medicine's (SoM) traditional 6-year medical degree course (converting it to a 5-year, integrated, case-based programme). This followed a decade of adverse external reports by the national accreditation agency. The 2001 accreditation report was the most significant catalyst for change, and drew attention to the School's need for a 'collective will' to introduce a series of specific curriculum reforms. To support this reform, a new curriculum working group (NCWG) supported by a dedicated medical education unit (MEU) was established. In late 2002 the author joined the School as the director of that unit. This paper draws on a 3-year study which captured the stories of the curriculum planning project between 2002 and 2005, as well as stories of curriculum reform from past deans of the same medical school dating back to 1965. Narrative inquiry is used as a means of probing the author's own lived experience as coordinator of the new curriculum project and the experiences of key members of the NCWG, including the dean, and of former deans from the same medical school over its 40-year history. Through a living, telling and retelling of the story of curriculum change, narrative inquiry has a role to play in both elucidating the individual lived experience of curriculum change and shaping the evolving professional identity of the medical educator as an agent of change.


Effects of fungal statins on high-glucose-induced mouse mesangial cell hypocontractility may involve filamentous actin, t-complex polypeptide 1 subunit beta, and glucose regulated protein 78.
Glomerular hyperfiltration is associated with mesangial cell hypocontractility. How 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) influence mesangial cell contraction is unclear. We investigated the effect of statins on mesangial cell hypocontractility and identified candidate proteins and filamentous/globular (F/G)-actin involved in this process. A high-glucose-induced mouse mesangial cell hypocontractility model was treated with fungal statins, simvastatin (Sim), lovastatin (Lov), and pravastatin (Pra). The optimum statin dose was determined by an 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay and then applied to a cell model. A 2-dimensional gel/matrix-assisted laser desorption/ionization time-of-flight mass spectrometer analysis was used to evaluate protein expression cells incubated in the presence of a normal level of glucose (N), a high level of glucose (H), and a high level of glucose plus Sim (H + S). Candidate proteins were analyzed. Finally, the ratio of F/G actin in groups N, H, and H+S was evaluated. The MTT assay showed that Sim and Lov exerted dose- and time-related inhibition of proliferation of mesangial cells at N, but Pra had no effect. The optimum doses selected for Sim was 1 microM and for Lov was 3 microM, which were 1 increment before significant proliferation inhibition. Both doses reversed cell hypocontractility significantly, but Sim was chosen for further proteomic and F/G actin analyses. Proteomic analysis of groups N, H, and H + S showed that 18 proteins were involved in hypocontractility. These proteins were grouped and analyzed based on their known functions. Two selected proteins, TCP-1beta and GRP78, that were upregulated and downregulated, respectively, were confirmed by Western blot and immunohistochemistry. In regard to the F/G actin, group H had a significantly lower ratio than that of group N, and group H + S returned to a level similar to that of group N. In conclusion, Sim and Lov both seem to reverse mesangial cell hypocontractility. The process of Sim reversal of mesangial cell hypocontractility may involve F-actin, TCP-1beta, and GRP78.


Do larger people have more naevi? Naevus frequency versus naevus density.
It is unclear which of the number or the density of naevi on the skin is the more appropriate measure of risk of melanoma. Furthermore, the relationship between the number of naevi and their density in an individual has not been explored. Thus, for example, it is unknown if larger people tend to have more naevi by virtue of having a larger skin area, or if the density of naevi is similar in people of different body sizes. In this study, we explored the relationship between the number and the density of naevi in a sample of adolescents. A sample survey of naevi in 472 grade 9 secondary school students (aged 14-15 years) was conducted in Tasmania, Australia during 1992, and a subset of these individuals was followed up in 1997. Counts of naevi of various sizes were taken on the arm, leg, and back. Naevus density was estimated by using an algorithm to estimate body surface area from the height and weight of an individual. More general relationships of the naevus counts to height and weight were also explored. Finally, we considered whether the relationship between naevus density and the anthropometric variables could be confounded by exposure to ultraviolet radiation. The mean number of naevi was very similar in the two samples. Naevus density was slightly lower in the 1997 sample, mainly because of increasing body size in the cohort. The numbers of naevi were only weakly related to height and weight in males, and there was essentially no relationship in females. Regression analysis showed significant relationships of weight to the back naevus counts in males in 1992 and 1997, and to the arm naevus count in males in 1997; otherwise, none of the regression coefficients for height and weight were statistically significant. This picture did not change following adjustment for potentially confounding variables indicating time spent outdoors or in the sun. Furthermore, there was no evidence that time spent in the sun was related to the body mass index. It appears that the number and density of naevi in an individual are unrelated. Accordingly, with the present state of knowledge concerning the risk of melanoma, both the number and density of naevi should be considered as equally valid in future studies as markers of the risk of melanoma, and in studies on the natural history of naevi. If the disease mechanism is systemic, and not related to particular naevi, naevus density might form the better marker of risk. However, if the disease mechanism is related to effects on particular naevi, then the risk would vary in proportion to the number of naevi.


The Synergistic Effect of Nanocrystals Combined With Ultrasound in the Generation of Reactive Oxygen Species for Biomedical Applications.
Reactive oxygen species (ROS) effects on living cells and tissues is multifaceted and their level or dose can considerably affect cell proliferation and viability. It is therefore necessary understand their role also designing ways able to regulate their amount inside cells, i.e., using engineered nanomaterials with either antioxidant properties or, for cancer therapy applications, capable to induce oxidative stress and cell death, through tunable ROS production. In this paper, we report on the use of single-crystalline zinc oxide (ZnO) round-shaped nanoparticles, yet ZnO nanocrystals (NCs) functionalized with amino-propyl groups (ZnO-NH2 NCs), combined with pulsed ultrasound (US). We show the synergistic effects produced by NC-assisted US which are able to produce different amount of ROS, as a result of inertial cavitation under the pulsed US exposure. Using Passive Cavitation Detection (PCD) and Electron Paramagnetic Resonance (EPR) spectroscopy, we systematically study which are the key parameters, monitoring, and influencing the amount of generated ROS measuring their concentration in water media and comparing all the results with pure water batches. We thus propose a ROS generation mechanism based on the selective application of US to the ZnO nanocrystals in water solutions. Ultrasound B-mode imaging is also applied, proving in respect to pure water, the enhanced ecographic signal generation of the aqueous solution containing ZnO-NH2 NCs when exposed to pulsed ultrasound. Furthermore, to evaluate the applicability of ZnO-NH2 NCs in the biomedical field, the ROS generation is studied by interposing different tissue mimicking materials, like phantoms and ex vivo tissues, between the US transducer and the sample well. As a whole, we clearly proof the enhanced capability to produce ROS and to control their amount when using ZnO-NH2 NCs in combination with pulsed ultrasound anticipating their applicability in the fields of biology and health care.


Murine embryonic stem cell-derived pyramidal neurons integrate into the cerebral cortex and appropriately project axons to subcortical targets.
Although embryonic stem (ES) cells have been induced to differentiate into diverse neuronal cell types, the production of cortical projection neurons with the correct morphology and axonal connectivity has not been demonstrated. Here, we show that in vitro patterning is critical for generating neural precursor cells (ES-NPCs) competent to form cortical pyramidal neurons. During the first week of neural induction, these ES-NPCs begin to express genes that are specific for forebrain progenitors; an additional week of differentiation produces mature neurons with many features of cortical pyramidal neurons. After transplantation into the murine cerebral cortex, these specified ES-NPCs manifest the correct dendritic and axonal connectivity for their areal location. ES-NPCs transplanted into the deep layers of the motor cortex differentiate into layer 5 pyramidal neurons and extend axons to distant subcortical targets such as the pons and as far caudal as the pyramidal decussation and descending spinal tract and, importantly, do not extend axons to inappropriate targets such as the superior colliculus (SC). ES-NPCs transplanted into the visual cortex extend axons to the dorsal aspect of the SC and pons but avoid ventral SC and the pyramidal tract, whereas cells transplanted deep into the somatosensory cortex project axons to the ventral SC, avoiding the dorsal SC. Thus, these data establish that ES-derived cortical projection neurons can integrate into anatomically relevant circuits.


Prevalence of chronic airflow limitation in Kashmir, North India: results from the BOLD study.
Data on spirometrically defined chronic airflow limitation (CAL) are scarce in developing countries. To estimate the prevalence of spirometrically defined CAL in Kashmir, North India. Using Burden of Obstructive Lung Disease survey methods, we administered questionnaires to randomly selected adults aged ⩾40 years. Post-bronchodilator spirometry was performed to estimate the prevalence of CAL and its relation to potential risk factors. Of 1100 participants initially recruited, 953 (86.9%) responded and 757 completed acceptable spirometry and questionnaires. The prevalence of a forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio less than the lower limit of normal was 17.3% (4.5) in males and 14.8% (2.1) in females. Risk factors for CAL included higher age, cooking with wood and lower educational status. The prevalence of current smoking was 61% in males and 22% in females; most smoked hookahs. CAL was found equally in non-smoking males and females, and was independently associated with the use of the hookah, family history of respiratory disease and poor education. A self-reported doctor's diagnosis of chronic obstructive pulmonary disease was reported in 8.4/1000 (0.9% of females and 0.8% of males). Spirometrically confirmed CAL is highly prevalent in Indian Kashmir, and seems to be related to the high prevalence of smoking, predominantly in the form of hookah smoking.


Hypoxia triggers meiotic fate acquisition in maize.
Evidence from confocal microscopic reconstruction of maize anther development in fertile, mac1 (excess germ cells), and msca1 (no germ cells) flowers indicates that the male germ line is multiclonal and uses the MAC1 protein to organize the somatic niche. Furthermore, we identified redox status as a determinant of germ cell fate, defining a mechanism distinct from the animal germ cell lineage. Decreasing oxygen or H(2)O(2) increases germ cell numbers, stimulates superficial germ cell formation, and rescues germinal differentiation in msca1 flowers. Conversely, oxidizing environments inhibit germ cell specification and cause ectopic differentiation in deeper tissues. We propose that hypoxia, arising naturally within growing anther tissue, acts as a positional cue to set germ cell fate.


Looking through a keyhole at the tobacco industry. The Brown and Williamson documents.
To introduce a series of papers discussing previously undocumented tobacco industry activities regarding strategies to avoid products liability litigation, understand nicotine addiction, and manipulate both internal and external scientific research on the effects of both active and passive smoking. Documents from Brown and Williamson Tobacco Corporation (B&W), the British American Tobacco Company (BAT), and other tobacco interests provided by an anonymous source, obtained from Congress, and received from the private papers of a former BAT officer. All available materials, including confidential reports regarding research and internal memoranda exchanged between tobacco industry lawyers. These documents provide our first look at the inner workings of the tobacco industry during the crucial period in which the scientific case that smoking is addictive and kills smokers solidified. The documents show a sophisticated legal and public relations strategy to avoid liability for the diseases induced by tobacco use. The documents show that lawyers steered scientists away from particular research avenues, which is inconsistent with the company's purported disbelief in the causation and addiction claims; if the company had been genuinely unconvinced by the causation and addiction hypotheses, then it should have had no concern that new research would provide ammunition for the enemy. Quite the contrary, the documents show that B&W and BAT recognized more than 30 years ago that nicotine is addictive and that tobacco smoke is "biologically active" (eg, carcinogenic).


Antitumor activity of a hydrogel loaded with lipophilic bismuth nanoparticles on cervical, prostate, and colon human cancer cells.
The objective of this study was to analyze the antitumor activity of a hydrogel loaded with lipophilic bismuth nanoparticles on human cervical, prostate, and colon cancer cell lines. The effect of lipophilic bismuth nanoparticles on the viability of cancer cell lines (HeLa, DU145, and HCT-116) and non-cancer lung fibroblasts (HLF; LL 47[MaDo]) was determined with the MTT cell viability assay and compared with known antineoplastic drugs. The biocompatibility at an organismal level was verified in a murine model by histological examination. A lipophilic bismuth nanoparticle hydrogel at 50 µM time-dependently inhibited the growth of the three cancer cell lines, in a time-dependent way. A 1-hour exposure to 250 µM lipophilic bismuth nanoparticle hydrogel, inhibited the growth of the three cancer cell lines. The in-vitro efficacy of lipophilic bismuth nanoparticle was similar to the one of docetaxel and cisplatin, but without inhibiting the growth of non-cancer control cells. Histology confirmed the biocompatibility of lipophilic bismuth nanoparticles as there were no signs of cytotoxicity or tissue damage in any of the evaluated organs (kidney, liver, brain, cerebellum, heart, and jejunum). In conclusion, a lipophilic bismuth nanoparticle hydrogel is an innovative, low-cost alternative for the topical treatment of cervicouterine, prostate, and colon human cancers.


Detection of unexpected tones with short and long durations.
The detectability of short and long unexpected tones masked by a continuous wideband noise was assessed using a probe-signal method. This method leads the listener to expect a target frequency by presenting the signal most often at that frequency, and only occasionally at other unexpected probe frequencies. The probe-signal contour (percent correct as a function of probe frequency) was considerably broader with 5-ms than with 295-ms signals. However, auditory filter shapes measured using the notched-noise technique were very similar for those two signal durations, indicating that the results obtained in the probe-signal conditions do not simply reflect peripheral frequency selectivity. Further supporting this interpretation, probe tones having the same frequency but a different duration from the target were poorly detected. It is proposed that the subject listens through a time-frequency window whose location and shape in the time-frequency plane is determined by the duration and frequency of the target.


A new family of genes and pseudogenes potentially expressing testis- and brain-specific leucine zipper proteins in man and mouse.
We have characterized a new mouse gene highly transcribed in the testis, and a derived intronless gene expressed in the embryo. The latter gene is present in Mus musculus domesticus and in Mus musculus castaneus but is absent in Mus spretus. The sequencing of different clones from a testis cDNA library reveals a complex transcriptional regulation for the intron-containing gene. The use of several promoters, alternative splicing and trans-splicing, and of two different polyadenylation sites account for the diversity. The different cDNAs encode proteins with features of basic helix-loop-helix leucine zipper (bHLH-ZIP) DNA-binding factors with homology to a new brain-specific factor. The presence of multiple CK2 and PKC phosphorylation sites suggests that their activity may be regulated by phosphorylation. In man, a pseudogene, apparently derived from the same transcript as in mouse and showing 90% homology in the coding region, is present within an intron of another gene. Interestingly, although the human pseudogene is highly mutated in human, in the mouse it has only four nucleotide changes compared with the cDNA of origin, and is still capable of encoding a protein.


Successful aging and the epidemiology of HIV.
By 2015, it is estimated that nearly half of those living with HIV in the US will be 50 years of age and older. This dramatic change in the demographics of this clinical population represents unique challenges for patients, health care providers, and society-at-large. Fortunately, because of highly active antiretroviral therapy (HAART) and healthy lifestyle choices, it is now possible for many infected with HIV to age successfully with this disease; however, this depends upon one's definition of successful aging. It is proposed that successful aging is composed of eight factors: length of life, biological health, cognitive efficiency, mental health, social competence, productivity, personal control, and life satisfaction. Unfortunately, HIV and medication side effects can compromise these factors, thus diminishing one's capacity to age successfully with this disease. This article explores how HIV, medication side effects from HAART, and lifestyle choices can compromise the factors necessary to age successfully. Implications for practice and research are posited.


Barriers to HIV/AIDS knowledge and prevention among deaf and hard of hearing people.
This study investigated knowledge about HIV/AIDS and barriers to HIV/AIDS education and prevention among deaf and hard of hearing people. Focus groups and individual interviews were used to elicit information from various groups of people with a hearing loss in different regions of New York State. Themes elicited in the interviews suggested that deaf sign language users are less knowledgeable about HIV/AIDS than oral deaf and hard of hearing participants, and that deaf adolescents have more knowledge than deaf adults. These findings likely reflect differences in levels of education and English proficiency. In addition, participants living in urban areas and in sizeable deaf communities are more exposed to information about HIV/AIDS than other participants. All participants reported difficulties in communication with medical providers, limiting their access to health information and proper medical care. Recommendations for the design and dissemination of educational materials and greater access to services for deaf and hard of hearing people are provided.


Effects of Isometric Handgrip Training in Patients With Peripheral Artery Disease: A Randomized Controlled Trial.
Background Meta-analyses have shown that isometric handgrip training (IHT) can reduce brachial systolic and diastolic blood pressure (BP) by >6/4 mm Hg, respectively. However, whether IHT promotes these effects among patients with peripheral artery disease, who exhibit severe impairment in cardiovascular function, is currently unknown. This study aimed to evaluate the effects of IHT on the cardiovascular function of patients with peripheral artery disease. Methods and Results A randomized controlled trial with peripheral artery disease patients assigned to either the IHT or control group was conducted. The IHT group performed 3 sessions per week, for 8 weeks, of unilateral handgrip exercises, consisting of 4 sets of isometric contractions for 2 minutes at 30% of maximum voluntary contraction and a 4-minute interval between sets. The control group received a compression ball in order to minimize the placebo effects, representing sham training. The primary outcome was brachial BP. The secondary outcomes were central BP, arterial stiffness parameters, cardiac autonomic modulation, and vascular function. The IHT program reduced diastolic BP (75 [10] mm Hg preintervention versus 72 [11] mm Hg postintervention), with no change in the control group (74 [11] mm Hg preintervention versus 74 [11] mm Hg postintervention), with this between-group difference being significant (P=0.04). Flow-mediated dilation improved in the IHT group (6.0% [5.7] preintervention versus 9.7% [5.5] postintervention), with no change in the control group (7.6% [5.5] preintervention versus 7.4% [5.1] postintervention), with this between-group difference being significant (P=0.04). There was no change in other measured variables over the intervention period. Conclusions IHT reduced brachial diastolic BP and improved local vascular function in patients with peripheral artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02742220.


Wattpad as a resource for literary studies. Quantitative and qualitative examples of the importance of digital social reading and readers' comments in the margins.
The end of deep reading is a commonplace in public debates, whenever societies talk about youth, books, and the digital age. In contrast to this, we show for the first time and in detail, how intensively young readers write and comment literary texts at an unprecedented scale. We present several analyses of how fiction is transmitted through the social reading platform Wattpad, one of the largest platforms for user-generated stories, including novels, fanfiction, humour, classics, and poetry. By mixed quantitative and qualitative methods and scalable reading we scrutinise texts and comments on Wattpad, what themes are preferred in 13 languages, what role does genre play for readers behaviour, and what kind of emotional engagement is prevalent when young readers share stories. Our results point out the rise of a global reading culture in youth reading besides national preferences for certain topics and genres, patterns of reading engagement, aesthetic values and social interaction. When reading Teen Fiction social-bonding (affective interaction) is prevalent, when reading Classics social-cognitive interaction (collective intelligence) is prevalent. An educational outcome suggests that readers who engage in Teen Fiction learn to read Classics and to judge books not only in direct emotional response to character's behaviour, but focusing more on contextualised interpretation of the text.