Nestin+ progenitor cells isolated from adult human sweat gland stroma promote reepithelialisation and may stimulate angiogenesis in wounded human skin ex vivo.
The combination of an aging population and an increasing prevalence of diseases associated with impaired-wound healing, including obesity, peripheral vascular disease and diabetes, is likely to result in a dramatic increase in the incidence and prevalence of chronic skin wounds. Indeed, systemic reviews are now not only trying to establish both the prevalence and the often under-estimated socio-economic costs of chronic skin wounds, but most importantly are addressing the impact that chronic wounds have on quality of life. Given the clear need for novel approaches to the management of chronic skin ulceration, ideally developed and tested in the human system in a manner that can be rapidly translated into clinical practice, we examined the effects of multipotent primary human nestin+ progenitor cells on human wound healing in an ex vivo model. Human sweat gland-derived nestin+ cells demonstrated the capacity to significantly promote two key wound healing parameters, i.e., both reepithelialisation and angiogenesis in experimentally wounded, organ-cultured human skin. The current data further support the use of full-thickness human skin wound-healing models ex vivo to pre-clinically test wound healing-promoting candidate agents. Whilst larger studies are required to substantiate a firm "proof-of-concept," our preliminary studies encourage further efforts to systemically determine the potential of cell-based regenerative medicine strategies in general, and the use of skin appendage-associated human nestin+ cells in particular, as novel treatment strategies for chronic skin ulceration.


The impact and outcomes of establishing an integrated interdisciplinary surgical team to care for the diabetic foot.
This study aimed to quantify the impact of an integrated diabetic foot surgical service on outcomes and changes in surgical volume and focus. We abstracted registry data from 48 consecutive months at a single institution, evaluating all patients with diabetic foot complications requiring surgery or vascular intervention, and compared outcomes in the 24 months before and after integrating podiatric surgery with vascular surgical limb-salvage service. The service performed 2923 operations; 790 (27.0%) were related to treatment of diabetic foot complications in 374 patients. Of these, 502 were classified as non-vascular diabetic foot surgery and 288 were vascular interventions. Urgent surgery was significantly reduced after team implementation (77.7% vs 48.5%, p < 0.0001; OR = 3.7, 95% CI: 2.4-5.5). The high/low amputation ratio decreased from 0.35 to 0.27 due to an increase in low-level (midfoot) amputations (8.2% vs 26.1%, p < 0.0001; OR = 4.0, 95% CI: 2.0-83.3). A 45.7% reduction in below-knee amputations was realized with a stable above-knee/below-knee amputation ratio (0.73-0.81). One-third of patients required vascular intervention. Vascular reconstructions increased 44.1% following institution of the team. Initial revascularization was endovascular in 70.6% of patients. Repeat endovascular intervention or conversion to open bypass was required in 37.1% of these patients, almost double the reintervention rate of those receiving open bypass first (18.9%). Interdisciplinary diabetic foot surgery teams may significantly impact surgery type, with greater focus on proactive and preventive, rather than reactive and ablative, procedures. Although endovascular limb-sparing procedures have become increasingly applicable, open bypass remains critical to success.


[Interventional radiology in bone metastases].
Interventional radiology takes a large place in the treatment of bone metastases by numerous techniques, percutaneous or endovascular. Vertebroplasty appears actually as the most important technique for stabilisation of spine metastases as it induces satisfactory stabilisation of the vertebra and offer clear improvement of the quality of life. Due to the success of this technique cementoplasty of other bones, mainly pelvic girdle, largely develop. The heath due to the polymerisation of the cement induce carcinolytic effect but this effect is not as important as that can be created with radiofrequency destruction. This last technique appears actually as the most important development to destroy definitively some bone metastases and replace progressively alcoholic destruction of such lesions. Angiographic techniques appear more confidential but endovascular embolization is very useful to diminish the risk of surgical treatment of hyper vascular metastases. Chemoembolization is actually developped to associate the relief of pain induced by endovascular embolization and the carcinolytic effect obtained by local endovascular chemotherapy. All these techniques should develop largely during the next years and their efficacy and safety should improve largely by treating earlier the metastasis.


Acceptability of cervical cancer screening in rural Mozambique.
In Zambézia province, Mozambique, cervical cancer (CC) screening was introduced to rural communities in 2010. Our study sought to determine whether women would accept screening via pelvic examination and visual inspection with acetic acid (VIA) at two clinical sites near the onset of a new CC screening program. A cross-sectional descriptive study of 101 women was undertaken in two rural communities in north-central Mozambique. We assessed a woman's willingness to be screened, knowledge about CC symptoms and treatment, and her recommendations for best methods to deliver information to other women. After the interview, we offered CC screening. Fully 86% of women accepted VIA screening when it was offered, but uptake was 100% at one clinic and only 68% at another. The cause of CC was thought to be associated with promiscuous activity (49%) and curses placed on the woman (42%). All women in one rural Mozambique clinic and two-thirds at a second clinic underwent CC screening. Knowledge about CC screening was significantly associated with uptake, suggesting educational campaigns need to be undertaken. However, educators need to be cautious about linking screening with high-risk behaviors, as women who understood the link trended toward refusing screening.


Analyzing the symmetrical arrangement of structural repeats in proteins with CE-Symm.
Many proteins fold into highly regular and repetitive three dimensional structures. The analysis of structural patterns and repeated elements is fundamental to understand protein function and evolution. We present recent improvements to the CE-Symm tool for systematically detecting and analyzing the internal symmetry and structural repeats in proteins. In addition to the accurate detection of internal symmetry, the tool is now capable of i) reporting the type of symmetry, ii) identifying the smallest repeating unit, iii) describing the arrangement of repeats with transformation operations and symmetry axes, and iv) comparing the similarity of all the internal repeats at the residue level. CE-Symm 2.0 helps the user investigate proteins with a robust and intuitive sequence-to-structure analysis, with many applications in protein classification, functional annotation and evolutionary studies. We describe the algorithmic extensions of the method and demonstrate its applications to the study of interesting cases of protein evolution.


First Report of Powdery Mildew Caused by Podosphaera euphorbiae-hirtae on Euphorbia tithymaloides in California.
Euphorbia tithymaloides (Euphorbiaceae; known as 'Jacob's ladder,' 'Devil's Backbone') is a perennial, succulent spurge, grown primarily as a border plant in ornamental landscapes. In June 2011 and February 2012, the California Department of Food and Agriculture Plant Pest Diagnostics Lab, Sacramento, CA, received an unusual powdery mildew sample on greenhouse-grown E. tithymaloides from a Ventura County, CA nursery. Disease incidence at the nursery was 100%. White mycelial patches were present on the stems and on both sides of the leaves. Over time, heavily infected branches defoliated and brownish, roughened, scabby lesions developed on the stems. Hyphae were thin-walled, up to 8 μm wide and developed nipple-shaped appressoria. Ellipsoid-ovoid conidia measured 21.0 to 32.5 × 13 to 18 μm (avg. 26.4 × 13.9 μm, n = 20) and formed in chains. The rDNA internal transcribed spacer (ITS) region was amplified with primers PFITS-F and PF5.8-R (4). The 387-bp sequence (GenBank JX006103) was 99% similar (346/347 bp) to Podosphaera euphorbia-hirtae (AB040306) from Acalypha australis (Euphorbiaceae) (3). Based on ITS similarity and culture morphology, the fungus was identified as P. euphorbiae-hirtae U. Braun & Somani (1,3). Pathogenicity was confirmed through inoculation by gently pressing diseased leaves from the nursery onto the youngest leaves of three plants each of E. tithymaloides cultivars 'Nano' and 'Variegated.' Leaves of an equal number of control plants were pressed with healthy leaves. Plants were incubated in a dew chamber for 48 h after which they were transferred to a 22°C growth chamber with a 12-h photoperiod. The experiment was repeated once. White powdery mildew colonies formed after 7 days on 'Variegated' and 13 days on 'Nano'. Conidia measured 27.5 to 35.0 × 11 to 15 μm (avg. 30.5 × 12.6 μm, n = 30) which was within the range of P. euphorbia-hirtae. No symptoms developed on the control plants. P. euphorbiae-hirtae has been reported in Asia and the UK on E. tithymaloides and in Asia on A. australis (2). An asexual Oidium stage on Euphorbiaceae in Asia, Africa, Australia, Florida, Puerto Rico, Cuba, and the U.S. Virgin Islands may correspond to P. euphorbiae-hirtae (2). To our knowledge, this is the first report of P. euphorbiae-hirtae in California. Following the 2011 and 2012 detections, all E. tithymaloides plants in the Ventura County, CA nursery were destroyed. A regulatory trace back survey found that the plants were shipped from a Florida supplier, which was also shown to have an outbreak of P. euphorbiae-hirtae. The original source of the Florida E. tithymaloides plants was a 2010 shipment from Costa Rica. The host range of P. euphorbiae-hirtae is restricted to three landscape species in the Euphorbiaceae. References: (1) U. Braun. Beih. Nova Hedwigia 89:143, 1987. (2) D. F. Farr and A. Y. Rossman. Fungal Databases, Systematic Mycology and Microbiology Laboratory, ARS, USDA. Retrieved from http://nt.ars-grin.gov/fungaldatabases/index.cfm May 1, 2012. (3) T. Hirata. et al. Can. J. Bot. 78:1521, 2000. (4) R. Singh et al. Plant Dis. 93:1348, 2009.


Student Learning Dispositions: Multidimensional Profiles Highlight Important Differences among Undergraduate STEM Honors Thesis Writers.
Various personal dimensions of students-particularly motivation, self-efficacy beliefs, and epistemic beliefs-can change in response to teaching, affect student learning, and be conceptualized as learning dispositions. We propose that these learning dispositions serve as learning outcomes in their own right; that patterns of interrelationships among these specific learning dispositions are likely; and that differing constellations (or learning disposition profiles) may have meaningful implications for instructional practices. In this observational study, we examine changes in these learning dispositions in the context of six courses at four institutions designed to scaffold undergraduate thesis writing and promote students' scientific reasoning in writing in science, technology, engineering, and mathematics. We explore the utility of cluster analysis for generating meaningful learning disposition profiles and building a more sophisticated understanding of students as complex, multidimensional learners. For example, while students' self-efficacy beliefs about writing and science increased across capstone writing courses on average, there was considerable variability at the level of individual students. When responses on all of the personal dimensions were analyzed jointly using cluster analysis, several distinct and meaningful learning disposition profiles emerged. We explore these profiles in this work and discuss the implications of this framework for describing developmental trajectories of students' scientific identities.


Global spatial risk assessment of sharks under the footprint of fisheries.
Effective ocean management and the conservation of highly migratory species depend on resolving the overlap between animal movements and distributions, and fishing effort. However, this information is lacking at a global scale. Here we show, using a big-data approach that combines satellite-tracked movements of pelagic sharks and global fishing fleets, that 24% of the mean monthly space used by sharks falls under the footprint of pelagic longline fisheries. Space-use hotspots of commercially valuable sharks and of internationally protected species had the highest overlap with longlines (up to 76% and 64%, respectively), and were also associated with significant increases in fishing effort. We conclude that pelagic sharks have limited spatial refuge from current levels of fishing effort in marine areas beyond national jurisdictions (the high seas). Our results demonstrate an urgent need for conservation and management measures at high-seas hotspots of shark space use, and highlight the potential of simultaneous satellite surveillance of megafauna and fishers as a tool for near-real-time, dynamic management.


Chronic kidney disease (CKD) in disadvantaged populations.
Twelve March 2015 will mark the 10th anniversary of World Kidney Day (WKD), an initiative of the International Society of Nephrology and the International Federation of Kidney Foundations. Since its inception in 2006, WKD has become the most successful effort ever mounted to raise awareness among decision-makers and the general public about the importance of kidney disease. Each year WKD reminds us that kidney disease is common, harmful and treatable. The focus of WKD 2015 is on chronic kidney disease (CKD) in disadvantaged populations. This article reviews the key links between poverty and CKD and the consequent implications for the prevention of kidney disease and the care of kidney patients in these populations.


Frontline nilotinib treatment in Turkish patients with Philadelphia chromosome-positive chronic Myeloid Leukemia in chronic phase: updated results with 2 years of follow-up.
This report presents final results (24 months of follow-up) from the first prospective, national study of frontline nilotinib in chronic myeloid leukemia (CML) patients in Turkey. Patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase (CML-CP; N = 112) received nilotinib 300 mg twice daily. The primary endpoint, which was the cumulative rate of major molecular response (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [BCR-ABL1IS]) by 12 months, was previously reported (66.1% [80% CI, 59.7%-72.0%]). ClinicalTrials.gov identifier NCT01274351 Results: By 24 months, 83.0% of patients achieved MMR, and 50.9% achieved MR4.5 (BCR-ABL1IS ≤0.0032%). Safety results at 24 months were consistent with those at 12 months. No additional deaths or disease progressions to accelerated phase/blast crisis were observed between 12 and 24 months. Treatment with nilotinib 300 mg twice daily for 2 years provided high MMR with a good safety/tolerability profile in newly diagnosed CML-CP patients in Turkey. Assessment of MMR across time points showed increasing rates through 18 months, after which as lower rate of increase was observed. The safety profile of nilotinib 300 mg twice daily with 24 months of follow-up was similar to that observed at 12 months, and no new safety concerns were identified. These efficacy and safety findings are consistent with the results from the 12-month analysis of this study and from previous nilotinib studies. These findings support nilotinib as an option for frontline treatment of CML-CP. Frontline nilotinib treatment provided sustained efficacy, with good tolerability, over 24 months in newly diagnosed CML-CP patients.


Ghrelin increases memory consolidation through hippocampal mechanisms dependent on glutamate release and NR2B-subunits of the NMDA receptor.
Ghrelin (Ghr) is a peptide that participates in the modulation of several biological processes. Ghr administration into the hippocampus improves learning and memory in different memory tests. However, the possible mechanisms underlying this effect on memory have not yet been clarified. The purpose of the present work is to add new insights about the mechanisms by which Ghr modulates long-term memory consolidation in the hippocampus. We examined Ghr effects upon processes related to increased synaptic efficacy as presynaptic glutamate release and changes in the expression of the NR2B-subunits containing n-methyl-d-aspartate receptors (NMDAR), which are critical for LTP induction. We also attempted to determine the temporal window in which Ghr administration induces memory facilitation and if the described effects depend on GHS-R1a stimulation. The present research demonstrated that Ghr increased glutamate release from hippocampal synaptosomes; intra-hippocampal Ghr administration increased NR2B-subunits expression in CA1 and DG subareas and also reversed the deleterious effects of the NR2B-subunit-specific antagonist, Ro 25-6981, upon memory consolidation and LTP generation in the hippocampus. These effects are likely to be the consequence of GHS-R1a activation. According to the results above mentioned and previous findings, we can hypothesize some of the mechanisms by which Ghr modulates memory consolidation. At presynaptic level, Ghr stimulates glutamate release, probably by enhancing [Ca(2+)]i. At postsynaptic level, the glutamate released activates NMDAR while Ghr also mediates effects directly activating its specific receptors and increases NR2B-subunit expression.


Plane-wave theory of a Michelson laser coupler with a dielectric slab beam splitter.
The plane-wave theory for the transmittance and absorbtance of a perfectly aligned Michelson coupler with a dielectric slab beam splitter is presented. It is shown that the transmittance and absorbtance vary sinusoidally and in quadrature. As a result of this quadrature relationship, the maximum transmittance occurs at a setting of the translatable coupler mirror at which the absorbtance is not at an extremum, and so the curve of output power as a function of coupler setting is asymmetrical with respect to the setting yielding maximum transmittance. Experimental measurements of the output power of a far-infrared HCN laser as a function of the coupler setting confirm this asymmetry, which seems to have been overlooked or ignored in previous studies.


Risk of brain tumours in relation to estimated RF dose from mobile phones: results from five Interphone countries.
The objective of this study was to examine the associations of brain tumours with radio frequency (RF) fields from mobile phones. Patients with brain tumour from the Australian, Canadian, French, Israeli and New Zealand components of the Interphone Study, whose tumours were localised by neuroradiologists, were analysed. Controls were matched on age, sex and region and allocated the 'tumour location' of their matched case. Analyses included 553 glioma and 676 meningioma cases and 1762 and 1911 controls, respectively. RF dose was estimated as total cumulative specific energy (TCSE; J/kg) absorbed at the tumour's estimated centre taking into account multiple RF exposure determinants. ORs with ever having been a regular mobile phone user were 0.93 (95% CI 0.73 to 1.18) for glioma and 0.80 (95% CI 0.66 to 0.96) for meningioma. ORs for glioma were below 1 in the first four quintiles of TCSE but above 1 in the highest quintile, 1.35 (95% CI 0.96 to 1.90). The OR increased with increasing TCSE 7+ years before diagnosis (p-trend 0.01; OR 1.91, 95% CI 1.05 to 3.47 in the highest quintile). A complementary analysis in which 44 glioma and 135 meningioma cases in the most exposed area of the brain were compared with gliomas and meningiomas located elsewhere in the brain showed increased ORs for tumours in the most exposed part of the brain in those with 10+ years of mobile phone use (OR 2.80, 95% CI 1.13 to 6.94 for glioma). Patterns for meningioma were similar, but ORs were lower, many below 1.0. There were suggestions of an increased risk of glioma in long-term mobile phone users with high RF exposure and of similar, but apparently much smaller, increases in meningioma risk. The uncertainty of these results requires that they be replicated before a causal interpretation can be made.


Long-living photonic dipole oscillations in photonic crystals.
We investigate the occurrence of photonic dipole oscillations (PDOs) in one-dimensional photonic crystals containing nonlinear composites. Because of the modulation of the graded pump electric fields, optical pulses undergo oscillations inside the curved band structure, analogous to the dipole oscillations in ultracold gases. The implementation of numerical simulations shows that our proposed scheme can produce stable and long-living PDOs. The physical origin is explored to give a clear physical picture. Finally, the tunability of PDOs is discussed.


Novel ACE2 protein interactions relevant to COVID-19 predicted by evolutionary rate correlations.
Angiotensin-converting enzyme 2 (ACE2) is the cell receptor that the coronavirus SARS-CoV-2 binds to and uses to enter and infect human cells. COVID-19, the pandemic disease caused by the coronavirus, involves diverse pathologies beyond those of a respiratory disease, including micro-thrombosis (micro-clotting), cytokine storms, and inflammatory responses affecting many organ systems. Longer-term chronic illness can persist for many months, often well after the pathogen is no longer detected. A better understanding of the proteins that ACE2 interacts with can reveal information relevant to these disease manifestations and possible avenues for treatment. We have undertaken an approach to predict candidate ACE2 interacting proteins which uses evolutionary inference to identify a set of mammalian proteins that "coevolve" with ACE2. The approach, called evolutionary rate correlation (ERC), detects proteins that show highly correlated evolutionary rates during mammalian evolution. Such proteins are candidates for biological interactions with the ACE2 receptor. The approach has uncovered a number of key ACE2 protein interactions of potential relevance to COVID-19 pathologies. Some proteins have previously been reported to be associated with severe COVID-19, but are not currently known to interact with ACE2, while additional predicted novel ACE2 interactors are of potential relevance to the disease. Using reciprocal rankings of protein ERCs, we have identified strongly interconnected ACE2 associated protein networks relevant to COVID-19 pathologies. ACE2 has clear connections to coagulation pathway proteins, such as Coagulation Factor V and fibrinogen components FGA, FGB, and FGG, the latter possibly mediated through ACE2 connections to Clusterin (which clears misfolded extracellular proteins) and GPR141 (whose functions are relatively unknown). ACE2 also connects to proteins involved in cytokine signaling and immune response (e.g. XCR1, IFNAR2 and TLR8), and to Androgen Receptor (AR). The ERC prescreening approach has elucidated possible functions for relatively uncharacterized proteins and possible new functions for well-characterized ones. Suggestions are made for the validation of ERC-predicted ACE2 protein interactions. We propose that ACE2 has novel protein interactions that are disrupted during SARS-CoV-2 infection, contributing to the spectrum of COVID-19 pathologies.


A high-speed vertical optical trap for the mechanical testing of living cells at piconewton forces.
Although atomic force microscopy is often the method of choice to probe the mechanical response of (sub)micrometer sized biomaterials, the lowest force that can be reliably controlled is limited to ≈0.1 nN. For soft biological samples, like cells, such forces can already lead to a strain large enough to enter the non-elastic deformation regime. To be able to investigate the response of single cells at lower forces we developed a vertical optical trap. The force can be controlled down to single piconewtons and most of the advantages of atomic force microscopy are maintained, such as the symmetrical application of forces at a wide range of loading rates. Typical consequences of moving the focus in the vertical direction, like the interferometric effect between the bead and the coverslip and a shift of focus, were quantified and found to have negligible effects on our measurements. With a fast responding force feedback loop we can achieve deformation rates as high as 50 μm/s, which allow the investigation of the elastic and viscous components of very soft samples. The potential of the vertical optical trap is demonstrated by measuring the linearity of the response of single cells at very low forces and a high bandwidth of deformation rates.


Workplace determinants of social capital: cross-sectional and longitudinal evidence from a Finnish cohort study.
To examine which contextual features of the workplace are associated with social capital. This is a cohort study of 43,167 employees in 3090 Finnish public sector workplaces who responded to a survey of individual workplace social capital in 2000-02 (response rate 68%). We used ecometrics approach to estimate social capital of work units. Features of the workplace were work unit's demographic and employment patterns and size, obtained from employers' administrative records. We used multilevel-multinomial logistic regression models to examine cross-sectionally whether these features were associated with social capital between individuals and work units. Fixed effects models were used for longitudinal analyses in a subsample of 12,108 individuals to examine the effects of changes in workplace characteristics on changes in social capital between 2000 and 2004. After adjustment for individual characteristics, an increase in work unit size reduced the odds of high levels of individual workplace social capital (odds ratio 0.94, 95% confidence interval 0.91-0.98 per 30-person-year increase). A 20% increase in the proportion of manual and male employees reduced the odds of high levels of social capital by 8% and 23%, respectively. A 30% increase in temporary employees and a 20% increase in employee turnover were associated with 11% (95% confidence interval 1.04-1.17) and 24% (95% confidence interval 1.18-1.30) higher odds of having high levels of social capital respectively). Results from fixed effects models within individuals, adjusted for time-varying covariates, and from social capital of the work units yielded consistent results. These findings suggest that workplace social capital is contextually patterned. Workplace demographic and employment patterns as well as the size of the work unit are important in understanding variations in workplace social capital between individuals and workplaces.


Stepwise evolution and convergent recombination underlie the global dissemination of carbapenemase-producing Escherichia coli.
Carbapenem-resistant Enterobacteriaceae are considered by WHO as "critical" priority pathogens for which novel antibiotics are urgently needed. The dissemination of carbapenemase-producing Escherichia coli (CP-Ec) in the community is a major public health concern. However, the global molecular epidemiology of CP-Ec isolates remains largely unknown as well as factors contributing to the acquisition of carbapenemase genes. We first analyzed the whole-genome sequence and the evolution of the E. coli sequence type (ST) 410 and its disseminated clade expressing the carbapenemase OXA-181. We reconstructed the phylogeny of 19 E. coli ST enriched in CP-Ec and corresponding to a total of 2026 non-redundant isolates. Using the EpiCs software, we determined the significance of the association between specific mutations and the acquisition of a carbapenemase gene and the most probable order of events. The impact of the identified mutations was assessed experimentally by genetic manipulations and phenotypic testing. In 13 of the studied STs, acquisition of carbapenemase genes occurred in multidrug-resistant lineages characterized by a combination of mutations in ftsI encoding the penicillin-binding protein 3 and in the porin genes ompC and ompF. Mutated ftsI genes and a specific ompC allele related to that from ST38 inducing reduced susceptibility to diverse β-lactams spread across the species by recombination. We showed that these mutations precede in most cases the acquisition of a carbapenemase gene. The ompC allele from ST38 might have contributed to the selection of CP-Ec disseminated lineages within this ST. On the other hand, in the pandemic ST131 lineage, CP-Ec were not associated with mutations in ompC or ftsI and show no signs of dissemination. Lineages of CP-Ec have started to disseminate globally. However, their selection is a multistep process involving mutations, recombination, acquisition of antibiotic resistance genes, and selection by β-lactams from diverse families. This process did not yet occur in the high-risk lineage ST131.


Ocular findings in cerebral palsy patients undergoing orthopedic surgery.
To investigate the prevalence and clinical features of ocular abnormalities in patients with cerebral palsy (CP) and the association with gross motor function. A complete ophthalmologic examination was performed in 88 consecutive patients with CP before and during orthopedic surgery in a tertiary hospital from July 2008 to March 2010. The prevalence and clinical features of ocular abnormalities and the association with gross motor function state were investigated. Seventy-eight patients (89%) had ocular abnormalities. Refractive errors were found in 53 patients (60%). Strabismus including exotropia (50%), esotropia (9%), and hypertropia (9.1%) was found in 52 patients (59%). Posterior segment abnormalities were found in 19 patients (22%), cornea and lens abnormalities in 8 patients (9%), and epiblepharon in 5 patients (6%). Among 57 patients whose visual acuity could be measured, best-corrected visual acuity of the better eye was ≤ 20/40 in 18 patients (32%) and ≤ 20/200 in 3 patients (5%). Objective vision-impairing ocular abnormalities and vertical strabismus were significantly associated with poor gross motor function before orthopedic surgery. Ocular abnormalities were present in the majority of CP patients and patients with poor gross motor function were more likely to be afflicted with vision-impairing ocular abnormalities. Ophthalmologic evaluation is deemed necessary in CP patients, especially in those with poor motor function.


Rationale and Design of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma Subtypes Project.
Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design. We pooled individual-level data from 20 case-control studies (17471 NHL cases, 23096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control. The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes. The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology.


A regulatory effect of INMAP on centromere proteins: antisense INMAP induces CENP-B variation and centromeric halo.
CENP-B is a highly conserved protein that facilitates the assembly of specific centromere structures both in interphase nuclei and on mitotic chromosomes. INMAP is a conserved protein that localizes at nucleus in interphase cells and at mitotic apparatus in mitotic cells. Our previous results showed that INMAP over-expression leads to spindle defects, mitotic arrest and formation of polycentrosomal and multinuclear cells, indicating that INMAP may modulate the function of (a) key protein(s) in mitotic apparatus. In this study, we demonstrate that INMAP interacts with CENP-B and promotes cleavage of the N-terminal DNA binding domain from CENP-B. The cleaved CENP-B cannot associate with centromeres and thus lose its centromere-related functions. Consistent with these results, CENP-B in INMAP knockdown cells becomes more diffused around kinetochores. Although INMAP knockdown cells do not exhibit gross defects in mitotic spindle formation, these cells go through mitosis, especially prophase and metaphase, with different relative timing, indicating subtle abnormality. These results identify INMAP as a model regulator of CENP-B and support the notion that INMAP regulates mitosis through modulating CENP-B-mediated centromere organization.


Accelerated wound healing and anti-inflammatory effects of physically cross linked polyvinyl alcohol-chitosan hydrogel containing honey bee venom in diabetic rats.
Diabetes is one of the leading causes of impaired wound healing. The objective of this study was to develop a bee venom-loaded wound dressing with an enhanced healing and anti-inflammatory effects to be examined in diabetic rats. Different preparations of polyvinyl alcohol (PVA), chitosan (Chit) hydrogel matrix-based wound dressing containing bee venom (BV) were developed using freeze-thawing method. The mechanical properties such as gel fraction, swelling ratio, tensile strength, percentage of elongation and surface pH were determined. The pharmacological activities including wound healing and anti-inflammatory effects in addition to primary skin irritation and microbial penetration tests were evaluated. Moreover, hydroxyproline, glutathione and IL-6 levels were measured in the wound tissues of diabetic rats. The bee venom-loaded wound dressing composed of 10 % PVA, 0.6 % Chit and 4 % BV was more swellable, flexible and elastic than other formulations. Pharmacologically, the bee venom-loaded wound dressing that has the same previous composition showed accelerated healing of wounds made in diabetic rats compared to the control. Moreover, this bee venom-loaded wound dressing exhibited anti-inflammatory effect that is comparable to that of diclofenac gel, the standard anti-inflammatory drug. Simultaneously, wound tissues covered with this preparation displayed higher hydroxyproline and glutathione levels and lower IL-6 levels compared to control. Thus, the bee venom-loaded hydrogel composed of 10 % PVA, 0.6 % Chit and 4 % BV is a promising wound dressing with excellent forming and enhanced wound healing as well as anti-inflammatory activities.


A sex-specific metabolite identified in a marine invertebrate utilizing phosphorus-31 nuclear magnetic resonance.
Hormone level differences are generally accepted as the primary cause for sexual dimorphism in animal and human development. Levels of low molecular weight metabolites also differ between men and women in circulating amino acids, lipids and carbohydrates and within brain tissue. While investigating the metabolism of blue crab tissues using Phosphorus-31 Nuclear Magnetic Resonance, we discovered that only the male blue crab (Callinectes sapidus) contained a phosphorus compound with a chemical shift well separated from the expected phosphate compounds. Spectra obtained from male gills were readily differentiated from female gill spectra. Analysis from six years of data from male and female crabs documented that the sex-specificity of this metabolite was normal for this species. Microscopic analysis of male and female gills found no differences in their gill anatomy or the presence of parasites or bacteria that might produce this phosphorus compound. Analysis of a rare gynandromorph blue crab (laterally, half male and half female) proved that this sex-specificity was an intrinsic biochemical process and was not caused by any variations in the diet or habitat of male versus female crabs. The existence of a sex-specific metabolite is a previously unrecognized, but potentially significant biochemical phenomenon. An entire enzyme system has been synthesized and activated only in one sex. Unless blue crabs are a unique species, sex-specific metabolites are likely to be present in other animals. Would the presence or absence of a sex-specific metabolite affect an animal's development, anatomy and biochemistry?


Interleukin-8 induces lymphocyte chemotaxis into the pleural space. Role of pleural macrophages.
The pleural space is a potential compartment between the lung and chest wall that becomes filled with fluid and inflammatory cells in a number of respiratory diseases. In an attempt to understand one aspect of the inflammatory process in the pleural space, we compared the responses in three different diseases (congestive heart failure [CHF], tuberculosis [TB], and cancer). Large concentrations of interleukin-8 (IL-8) were detected in cancer and TB effusions, but not in CHF. Surprisingly, the concentration of IL-8 correlated best with lymphocyte recruitment and not with neutrophil recruitment. Pleural fluid from cancer and TB patients was chemotactic for lymphocytes, and this activity was partly blocked by an anti-IL-8 antibody in cancer and completely blocked in TB. To determine whether there was the potential for a chemotactic gradient into the pleural space, pleural effusion cells were analyzed for the expression of IL-8. Cells in the effusions of cancer patients expressed IL-8, whereas IL-8 could not be detected from the cells of TB and CHF effusions. To explore the possible role of pleural macrophages in the regulation of IL-8, pleural effusion cells were treated with culture supernatants from stimulated pleural macrophages. Stimulated pleural macrophages were able to induce expression of messenger RNA (mRNA) for IL-8 and IL-8 protein production, and this activity was abrogated by blocking tumor necrosis factor-alpha. These findings suggest that soluble IL-8 is an important factor for the recruitment of lymphocytes into the pleural space, and that this cytokine is produced by both pleural structural and cancer cells after their activation by macrophage-derived, cytokine-mediated signals.


[Prevalence of oral mucosal alterations in Brazilian adolescents held in two juvenile re-education centers].
The purpose of the present study was to verify the prevalence of oral mucosal alterations in Brazilian adolescents institutionalized. A total of 231 adolescents, all male were examined. The criteria used for clinical diagnostic of the lesions were the former proposed by SB 2000 (Brazil). The total oral mucosal lesions prevalence was 27.70% (64 lesions). The total prevalence of buccal mucosal lesions were 27.70% (64 lesions) in 24,24% of the adolescents. The most frequent one was plaque. It was found 293 mucosal alterations. 78.35% of the adolescents examined presented at least one alteration. The melanin pigmentation was the most common alteration. The data collected had been analyzed statistically through Kruskall Wallis non-parametric test and associations through Qui-Square test, considering significant level of 5%. Statistical significant difference was identified concerning between basic lesions and/or mucosal alterations and race (p=0,002) and skin colours and average number of the mucosal alteration (p=0,000) and the present of the melanin pigmentation and leukoedema and race (p=0,000 and p=0,002). There wasn't any statistically significant difference between average number of the mucosal lesions and race (p=0,618).


There Is No Place Like Home: Imitation and the Politics of Recognition in Bolivian Obstetric Care.
This article examines how efforts to "culturally adapt" birthing spaces in a rural Bolivian hospital are generating debates among doctors about what constitutes proper obstetric care. Working at the intersection of national and transnational projects, NGOs in Bolivia have remade the birthing rooms of some public health institutions to look more like a home, with the goal of making indigenous women feel more comfortable and encouraging them to come to the clinic to give birth. Yet narratives of transformation also obscure ongoing conditions of racial and gendered inequality in health services. I demonstrate how doctors' use of culturally adapted technologies enacts shifting affective relations-warm, cold, gentle, harsh-that draws on preoccupations with indigenous culture as a threat to maternal and infant life. In tracing practices of care, I argue that culturally adapted birthing in many ways extends historically rooted practices of doing biomedical work on indigenous bodies.


Fluoride Exposure Effects and Dental Fluorosis in Children in Mexico City.
BACKGROUND The objective of the present study was to determine the prevalence and severity of dental fluorosis and to evaluate exposure to fluoridated products in students in the southwest part of the Federal District (Mexico City). MATERIAL AND METHODS Students between 10 and 12 years of age who were born and raised in the study zone were evaluated. The level of dental fluorosis was determined using the modified Dean index (DI) using criteria recommended by the World Health Organization (WHO). A bivariate analysis was performed with the χ2 test, and odds ratios (OR) and 95% confidence intervals (CI) are presented. Logistic regression was performed to evaluate the association between dental fluorosis and the independent variables. RESULTS A total of 239 students were evaluated. Their mean age was 11±0.82 years, and there were 122 (51%) males. Overall, dental fluorosis was found in 59% of participants; 29.3% had very mild fluorosis, 20.9% had mild fluorosis, 6.7% had moderate fluorosis, and 2.1% had severe fluorosis. The mean fluorosis score was 0.887±0.956. In the final logistic regression model, dental fluorosis was significantly associated with frequency of brushing (OR: 0.444; 95% CI: 0.297-0.666) and with the absence of parental supervision (OR: 0.636; 95% CI: 0.525-0.771). CONCLUSIONS The association found with frequency of brushing and lack of parental supervision may be contributing to the prevalence and severity of dental fluorosis.


Results From Shanghai's (China) 2016 Report Card on Physical Activity for Children and Youth.
Internationally comparable evidence is important to advocate for young people's physical activity. The aim of this article is to present the inaugural Shanghai (China) Report Card on Physical Activity for Children and Youth. Since no national data are available, the working group developed the survey questionnaire and carried out the school surveys for students (n = 71,404), parents (n = 70,346), and school administrators and teachers (n = 1398). The grades of 9 report card indicators were assigned in accordance with the survey results against a defined benchmark: A is 81% to 100%; B is 61% to 80%; C is 41% to 60%, D is 21% to 40%; F is 0% to 20%. The 9 indicators were graded as follows: Overall Physical Activity Levels (F), Organized Sport Participation (F), Active Play (D-), Active Transportation (C-), Sedentary Behavior (F), Family and Peers (B), School (B+), Community and the Built Environment (D+), and Government (D). Levels of physical activity and sedentary behavior were low and below the respective recommended guidelines. Interventions and policies at the community level should be encouraged to promote physical activity and reduce sedentary behavior. Future national surveys should be encouraged to strengthen Shanghai's Report Card on Physical Activity for Children and Youth.


Mineralogy of a mudstone at Yellowknife Bay, Gale crater, Mars.
Sedimentary rocks at Yellowknife Bay (Gale crater) on Mars include mudstone sampled by the Curiosity rover. The samples, John Klein and Cumberland, contain detrital basaltic minerals, calcium sulfates, iron oxide or hydroxides, iron sulfides, amorphous material, and trioctahedral smectites. The John Klein smectite has basal spacing of ~10 angstroms, indicating little interlayer hydration. The Cumberland smectite has basal spacing at both ~13.2 and ~10 angstroms. The larger spacing suggests a partially chloritized interlayer or interlayer magnesium or calcium facilitating H2O retention. Basaltic minerals in the mudstone are similar to those in nearby eolian deposits. However, the mudstone has far less Fe-forsterite, possibly lost with formation of smectite plus magnetite. Late Noachian/Early Hesperian or younger age indicates that clay mineral formation on Mars extended beyond Noachian time.


The risk of morbidity and mortality following recurrent malaria in Papua, Indonesia: a retrospective cohort study.
An acute episode of malaria can be followed by multiple recurrent episodes either due to re-infection, recrudescence of a partially treated parasite or, in the case of Plasmodium vivax or P. ovale, relapse from the dormant liver stage of the parasite. The aim of this study was to quantify the impact of recurrent malaria episodes on morbidity and mortality in Papua, Indonesia. We undertook a retrospective analysis of routinely collected data from malaria patients attending the primary referral hospital in Papua, Indonesia, between April 2004 and December 2013. Multi-state modelling was used to estimate the effect of recurring malaria episodes on re-presentation and admission to hospital and death. The risks of early (≤ 14 days) and late (15 to 365 days) hospital admission and death were estimated separately in our study to distinguish between the direct and indirect effects of malaria recurrence on adverse outcomes. A total of 68,361 patients were included in the analysis, of whom 37,168 (54.4%) presented initially with P. falciparum, 22,209 (32.5%) with P. vivax, and 8984 (13.1%) with other species. During 12 months of follow-up after each of the first four malaria episodes, 10,868 (15.9%) patients were admitted to hospital and 897 (1.3%) died. The risk of re-presenting to the hospital with malaria increased from 34.7% (95% CI 34.4%, 35.1%) at first episode to 58.6% (57.5%, 59.6%) following the third episode of malaria. After adjusting for co-factors, infection with P. vivax was a significant risk factor for re-presentation (hazard ratio (HR) = 1.48 (95% CI 1.44, 1.51)) and late admission to hospital (HR = 1.17 (1.11, 1.22)). Patients infected with P. falciparum had a greater overall rate of mortality within 14 days (HR = 1.54 (1.25, 1.92)), but after multiple episodes of malaria, there was a trend towards a higher rate of early death in patients infected with P. vivax compared to P. falciparum (HR = 1.91 (0.73, 4.97)). Compared to patients initially infected with P. falciparum, those infected with P. vivax had significantly more re-presentations to hospital with malaria, and this contributed to a high risk of inpatient admission and death. These findings highlight the importance of radical cure of P. vivax to eliminate the dormant liver stages that trigger relapses.


Hepatitis C in Black Individuals in the US: A Review.
In the US, the prevalence of hepatitis C virus (HCV) is 1.8% among people who are Black and 0.8% among people who are not Black. Mortality rates due to HCV are 5.01/100 000 among people who are Black and 2.98/100 000 among people who are White. While people of all races and ethnicities experienced increased rates of incident HCV between 2015 and 2021, Black individuals experienced the largest percentage increase of 0.3 to 1.4/100 000 (367%) compared with 1.8 to 2.7/100 000 among American Indian/Alaska Native (50%), 0.3 to 0.9/100 000 among Hispanic (200%), and 0.9 to 1.6/100 000 among White (78%) populations. Among 47 687 persons diagnosed with HCV in 2019-2020, including 37 877 (79%) covered by Medicaid (7666 Black and 24 374 White individuals), 23.5% of Black people and 23.7% of White people with Medicaid insurance initiated HCV treatment. Strategies to increase HCV screening include electronic health record prompts for universal HCV screening, which increased screening tests from 2052/month to 4169/month in an outpatient setting. Awareness of HCV status can be increased through point-of-care testing in community-based settings, which was associated with increased likelihood of receiving HCV test results compared with referral for testing off-site (69% on-site vs 19% off-site, P < .001). Access to HCV care can be facilitated by patient navigation, in which an individual is assigned to work with a patient to help them access care and treatments; this was associated with greater likelihood of HCV care access (odds ratio, 3.7 [95% CI, 2.9-4.8]) and treatment initiation within 6 months (odds ratio, 3.2 [95% CI, 2.3-4.2]) in a public health system providing health care to individuals regardless of their insurance status or ability to pay compared with usual care. Eliminating Medicaid's HCV treatment restrictions, including removal of a requirement for advanced fibrosis or a specialist prescriber, was associated with increased treatment rates from 2.4 persons per month to 72.3 persons per month in a retrospective study of 10 336 adults with HCV with no significant difference by race (526/1388 [37.8%] for Black vs 2706/8277 [32.6%] for White patients; adjusted odds ratio, 1.02 [95% CI, 0.8-1.3]). In the US, the prevalence of HCV is higher in people who are Black than in people who are not Black. Point-of-care HCV tests, patient navigation, electronic health record prompts, and unrestricted access to HCV treatment in community-based settings have potential to increase diagnosis and treatment of HCV and improve outcomes in people who are Black.


Research considerations for more effective groundwater monitoring.
Since numerous pathogens occur in feces, water is monitored for fecal contamination using indicator organisms rather than individual pathogens. Although this approach is supported by health effects data in recreational waters, it is questionable when used for drinking water. Most outbreaks in groundwater occur in systems that have not violated the US EPA's maximum contaminant limit (MCL) for total coliforms within 12 months before the outbreak. Additionally, environmentally stable viruses and parasites are often detected in drinking water samples with no detectable indicators. Recent detections of Escherichia coli O157:H7 and Campylobacter jejuni in groundwaters in the apparent absence of indicators also cast some doubt on the worth of indicators for fecal bacterial pathogens. Individual pathogen monitoring is now technically achievable but currently unreasonable due to the number of possible pathogens and the costs involved. Several alternatives to pathogen monitoring could significantly reduce the frequency at which pathogens occur in waters testing negative for indicators: (i) increasing sample volumes for indicators, (ii) increasing monitoring frequency, (iii) using a suite of indicators, (iv) using a more conservative polymerase chain reaction (PCR) method, (v) sampling when fecal contamination is most likely present or (vi) any combination of these options.


Identification of Steroidogenic Components Derived From Gardenia jasminoides Ellis Potentially Useful for Treating Postmenopausal Syndrome.
Estrogen-stimulating principles have been demonstrated to relieve postmenopausal syndrome effectively. Gardenia jasminoides Ellis (GJE) is an herbal medicine possessing multiple pharmacological effects on human health with low toxicity. However, the therapeutic effects of GJE on the management of postmenopausal syndrome and its mechanism of action have not been fully elucidated. In this study, network pharmacology-based approaches were employed to examine steroidogenesis under the influence of GJE. In addition, the possibility of toxicity of GJE was ruled out and four probable active compounds were predicted. In parallel, a chromatographic fraction of GJE with estrogen-stimulating effect was identified and nine major compounds were isolated from this active fraction. Among the nine compounds, four of them were identified by network pharmacology, validating the use of network pharmacology to predict active compounds. Then the phenotypic approaches were utilized to verify that rutin, chlorogenic acid (CGA) and geniposidic acid (GA) exerted an estrogen-stimulating effect on ovarian granulosa cells. Furthermore, the results of target-based approaches indicated that rutin, CGA, and GA could up-regulate the FSHR-aromatase pathway in ovarian granulosa cells. The stimulation of estrogen production by rat ovarian granulosa cells under the influence of the three compounds underwent a decline when the follicle-stimulating hormone receptor (FSHR) was blocked by antibodies against the receptor, indicating the involvement of FSHR in the estradiol-stimulating activity of the three compounds. The effects of the three compounds on estrogen biosynthesis- related gene expression level were further confirmed by Western blot assay. Importantly, the MTT results showed that exposure of breast cancer cells to the three compounds resulted in reduction of cell viability, demonstrating the cytotoxicity of the three compounds. Collectively, rutin, chlorogenic acid and geniposidic acid may contribute to the therapeutic potential of GJE for the treatment of postmenopausal syndrome.


The Strengths Assessment Inventory-Youth Version: An evaluation of the psychometric properties with male and female justice-involved youth.
Strengths constitute an important element of developmental assessments. It is consistent with evidence-based practice to use assessment tools that adequately measure a given construct and are appropriate for use with their targeted population. The Strengths Assessment Inventory-Youth Version (SAI-Y; Rawana & Brownlee, 2010)-a self-report measure of personal strengths, self-concept, and emotional functioning-was administered to 230 male and female adolescent offenders. Confirmatory factor analyses revealed that the SAI-Y's factor structure demonstrated an acceptable fit overall, while some factors fit the data well, and fewer factors displayed a questionable fit. A majority of scale scores were found to exhibit good reliability for both sexes, with three empirical scale scores demonstrating poor reliability. In addition, scores on the SAI-Y also achieved satisfactory convergent and divergent validity. Total strength scores were significantly correlated in the expected direction with most theoretically related measures of emotional and behavioral functioning (e.g., self-esteem, treatment readiness, antisocial attitudes). Lastly, moderate gender effects and small ethnicity differences in response patterns were found. This was the first validation study of the SAI-Y with a justice-involved sample and the results suggest it is an appropriate measure for use with both male and female justice-involved young persons in detention and in the community. (PsycINFO Database Record


Evaluation of inhaler technique and achievement and maintenance of mastery of budesonide/formoterol Spiromax® compared with budesonide/formoterol Turbuhaler® in adult patients with asthma: the Easy Low Instruction Over Time (ELIOT) study.
Incorrect inhaler technique is a common cause of poor asthma control. This two-phase pragmatic study evaluated inhaler technique mastery and maintenance of mastery with DuoResp® (budesonide-formoterol [BF]) Spiromax® compared with Symbicort® (BF) Turbuhaler® in patients with asthma who were receiving inhaled corticosteroids/long-acting β2-agonists. In the initial cross-sectional phase, patients were randomized to a 6-step training protocol with empty Spiromax and Turbuhaler devices. Patients initially demonstrating ≥1 error with their current device, and then achieving mastery with both Spiromax and Turbuhaler (absence of healthcare professional [HCP]-observed errors), were eligible for the longitudinal phase. In the longitudinal phase, patients were randomized to BF Spiromax or BF Turbuhaler. Co-primary endpoints were the proportions of patients achieving device mastery after three training steps and maintaining device mastery (defined as the absence of HCP-observed errors after 12 weeks of use). Secondary endpoints included device preference, handling error frequency, asthma control, and safety. Exploratory endpoints included assessment of device mastery by an independent external expert reviewing video recordings of a subset of patients. Four hundred ninety-three patients participated in the cross-sectional phase, and 395 patients in the longitudinal phase. In the cross-sectional phase, more patients achieved device mastery after three training steps with Spiromax (94%) versus Turbuhaler (87%) (odds ratio [OR] 3.77 [95% confidence interval (CI) 2.05-6.95], p < 0.001). Longitudinal phase data indicated that the odds of maintaining inhaler mastery at 12 weeks were not statistically significantly different (OR 1.26 [95% CI 0.80-1.98], p = 0.316). Asthma control improved in both groups with no significant difference between groups (OR 0.11 [95% CI -0.09-0.30]). An exploratory analysis indicated that the odds of maintaining independent expert-verified device mastery were significantly higher for patients using Spiromax versus Turbuhaler (OR 2.11 [95% CI 1.25-3.54]). In the cross-sectional phase, a significantly greater proportion of patients using Spiromax versus Turbuhaler achieved device mastery; in the longitudinal phase, the proportion of patients maintaining device mastery with Spiromax versus Turbuhaler was similar. An exploratory independent expert-verified analysis found Spiromax was associated with higher levels of device mastery after 12 weeks. Asthma control was improved by treatment with both BF Spiromax and BF Turbuhaler. EudraCT 2013-004630-14 (registration date 23 January 2014); NCT02570425 .


Paranoia and belief updating during a crisis.
The 2019 coronavirus (COVID-19) pandemic has made the world seem unpredictable. During such crises we can experience concerns that others might be against us, culminating perhaps in paranoid conspiracy theories. Here, we investigate paranoia and belief updating in an online sample (N=1,010) in the United States of America (U.S.A). We demonstrate the pandemic increased individuals' self-rated paranoia and rendered their task-based belief updating more erratic. Local lockdown and reopening policies, as well as culture more broadly, markedly influenced participants' belief-updating: an early and sustained lockdown rendered people's belief updating less capricious. Masks are clearly an effective public health measure against COVID-19. However, state-mandated mask wearing increased paranoia and induced more erratic behaviour. Remarkably, this was most evident in those states where adherence to mask wearing rules was poor but where rule following is typically more common. This paranoia may explain the lack of compliance with this simple and effective countermeasure. Computational analyses of participant behaviour suggested that people with higher paranoia expected the task to be more unstable, but at the same time predicted more rewards. In a follow-up study we found people who were more paranoid endorsed conspiracies about mask-wearing and potential vaccines - again, mask attitude and conspiratorial beliefs were associated with erratic task behaviour and changed priors. Future public health responses to the pandemic might leverage these observations, mollifying paranoia and increasing adherence by tempering people's expectations of other's behaviour, and the environment more broadly, and reinforcing compliance.


Persistent activity and the single-cell frequency-current curve in a cortical network model.
Neurophysiological experiments indicate that working memory of an object is maintained by the persistent activity of cells in the prefrontal cortex and infero-temporal cortex of the monkey. This paper considers a cortical network model in which this persistent activity appears due to recurrent synaptic interactions. The conditions under which the magnitude of spontaneous and persistent activity are close to one another (as is found empirically) are investigated using a simplified mean-field description in which firing rates in these states are given by the intersections of a straight line with the f-I curve of a single pyramidal cell. The present analysis relates a network phenomenon - persistent activity in a 'working memory' state - to single-cell data which are accessible to experiment. It predicts that, in networks of the cerebral cortex in which persistent activity phenomena are observed, average synaptic inputs in both spontaneous and persistent activity should bring the cells close to firing threshold. Cells should be slightly sub-threshold in spontaneous activity, and slightly supra-threshold in persistent activity. The results are shown to be robust to the inclusion of inhomogeneities that produce wide distributions of firing rates, in both spontaneous and working memory states.


Anteroposterior patterning in the zebrafish, Danio rerio: an explant assay reveals inductive and suppressive cell interactions.
We report the first extended culture system for analysing zebrafish (Danio rerio) embryogenesis with which we demonstrate neural induction and anteroposterior patterning. Explants from the animal pole region of blastula embryos ('animal caps') survived for at least two days and increased in cell number. Mesodermal and neural-specific genes were not expressed in cultured animal caps, although low levels of the dorsoanterior marker otx2 were seen. In contrast, we observed strong expression of gta3, a ventral marker and cyt1, a novel type I cytokeratin expressed in the outer enveloping layer. Isolated 'embryonic shield', that corresponds to the amphibian organizer and amniote node, went on to express the mesodermal genes gsc and ntl, otx2, the anterior neural marker pax6, and posterior neural markers eng3 and krx20. The expression of these genes defined a precise anteroposterior axis in shield explants. When conjugated to animal caps, the shield frequently induced expression of anterior neural markers. More posterior markers were rarely induced, suggesting that anterior and posterior neural induction are separable events. Mesodermal genes were also seldom activated in animal caps by the shield, demonstrating that neural induction did not require co-induction of mesoderm in the caps. Strikingly, ventral marginal zone explants suppressed the low levels of otx2 in animal caps, indicating that ventral tissues may play an active role in axial patterning. These data suggest that anteroposterior patterning in the zebrafish is a multi-step process.


Chiral metamaterials: retrieval of the effective parameters with and without substrate.
After the prediction that strong enough optical activity may result in negative refraction and negative reflection, more and more artificial chiral metamaterials were designed and fabricated at difference frequency ranges from microwaves to optical waves. Therefore, a simple and robust method to retrieve the effective constitutive parameters for chiral metamaterials is urgently needed. Here, we analyze the wave propagation in chiral metamaterials and follow the regular retrieval procedure for ordinary metamaterials and apply it in chiral metamaterial slabs. Then based on the transfer matrix technique, the parameter retrieval is extended to treat samples with not only the substrate but also the top layers. After the parameter retrieval procedure, we take two examples to check our method and study how the substrate influences on the thin chiral metamaterials slabs. We find that the substrate may cause the homogeneous slab to be inhomogeneous, i.e. the reflections in forward and backward directions are different. However, the chiral metamaterial where the resonance element is embedded far away from the substrate is insensitive to the substrate.


Behavioural responses of anxiety in aversive and non-aversive conditions between young and aged Sprague-Dawley rats.
Measures of anxiety in behavioural tests remain largely unclear even decades after their establishment. Differences in the severity of anxiety measured by anxiety tests is an important issue that must be addressed. To test the hypothesis that the addition of light as an aversive stimulus will elicit a difference in behaviour between aged and young animals, we compared the responses of aged and young animals in the home cage emergence test (HCET) and elevated plus maze (EPM), in high aversive bright light and low aversive dim light conditions. In the HCET, our results demonstrated that young animals escaped with shorter latency and greater frequency than aged animals in both bright and dim light conditions, indicating that young animals display greater exploratory tendencies than aged animals. In the EPM, bright light conditions induced anxiogenic effects in both age groups. Interestingly, two-way ANOVA showed a significant interaction effect of age and light on the number of entries into the open arms of the EPM as well as frequency of escape in the HCET. These results show that the addition of light as an aversive stimulus in the EPM and HCET produced different responses in aged versus young animals in each test. In conclusion, significant interactions between age and light affected aged and young animals differently in the HCET and EPM, indicating that the two tests measure different aspects of anxiety.


Identification of FGFR4 as a potential therapeutic target for advanced-stage, high-grade serous ovarian cancer.
To evaluate the prognostic value of fibroblast growth factor receptor 4 (FGFR4) protein expression in patients with advanced-stage, high-grade serous ovarian cancer, delineate the functional role of FGFR4 in ovarian cancer progression, and evaluate the feasibility of targeting FGFR4 in serous ovarian cancer treatment. Immunolocalization of FGFR4 was conducted on 183 ovarian tumor samples. The collected FGFR4 expression data were correlated with overall survival using Kaplan-Meier and Cox regression analyses. The effects of FGFR4 silencing on ovarian cancer cell growth, survival, invasiveness, apoptosis, and FGF1-mediated signaling pathway activation were evaluated by transfecting cells with FGFR4-specific siRNAs. An orthotopic mouse model was used to evaluate the effect of injection of FGFR4-specific siRNAs and FGFR4 trap protein encapsulated in nanoliposomes on ovarian tumor growth in vivo. Overexpression of FGFR4 protein was significantly associated with decreased overall survival durations. FGFR4 silencing significantly decreased the proliferation, survival, and invasiveness and increased apoptosis of ovarian cancer cells. Also, downregulation of FGFR4 significantly abrogated the mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and WNT signaling pathways, which are activated by FGF1. Targeting FGFR4 with the FGFR4-specific siRNAs and FGFR4 trap protein significantly decreased ovarian tumor growth in vivo. FGFR4 is a prognostic marker for advanced-stage, high-grade serous ovarian carcinoma. Silencing FGFR4 and inhibiting ligand-receptor binding significantly decrease ovarian tumor growth both in vitro and in vivo, suggesting that targeting ovarian cancer cells with high levels of FGFR4 protein expression is a new therapeutic modality for this disease and will improve survival of it.


Cap and trade schemes on waste management: a case study of the landfill allowance trading scheme (LATS) in England.
The Landfill Allowance Trading Scheme (LATS) is one of the main instruments used in England to enforce the landfill diversion targets established in the Directive 1999/31/EC of the European Parliament and of the Council of 26 April 1999 on the landfill of waste (Landfill Directive). Through the LATS, biodegradable municipal waste (BMW) allowances for landfilling are allocated to each local authority, otherwise known as waste disposal authorities (WDAs). The quantity of landfill allowances received is expected to decrease continuously from 2005/06 to 2019/20 so as to meet the objectives of the Landfill Directive. To achieve their commitments, WDAs can exchange, buy, sell or transfer allowances among each other, or may re-profile their own allocation through banking and/or borrowing. Despite the goals for the first seven years - which included two target years (2005/06 and 2009/10) - being widely achieved (the average allocation of allowances per WDA was 22.9% higher than those finally used), market activity among WDAs was high and prices were not very stable. Results in terms of waste reduction and recycling levels have been satisfactory. The reduction of BMW landfilled (in percentage) was higher during the first seven years of the LATS period (2005/06-2011/12) (around 7% annually) than during the previous period (2001/02-2004/05) (4.2% annually). Since 2008, the significance of the LATS diminished because of an increase in the rate of the UK Landfill Tax. The LATS was suppressed after the 2012/13 target year, before what it was initially scheduled. The purpose of this paper is to describe the particularities of the LATS, analyse its performance as a waste management policy, make a comparison with the Landfill Tax, discuss its main features as regards efficiency, effectiveness and the application of the "polluter pays" principle and finally discuss if the effect of the increase in the Landfill Tax is what made the LATS ultimately unnecessary.


Episomal transgene expression in pluripotent stem cells.
Herpes simplex type 1 (HSV-1) amplicon vectors possess a number of features that make them excellent vectors for the delivery of transgenes into stem cells. HSV-1 amplicon vectors are capable of efficiently transducing both dividing and nondividing cells and since the virus is quite large, 152 kb, it is of sufficient size to allow for incorporation of entire genomic DNA loci with native promoters. HSV-1 amplicon vectors can also be used to incorporate and deliver to cells a variety of sequences that allow extrachromosomal retention. These elements offer advantages over integrating vectors as they avoid transgene silencing and insertional mutagenesis. The construction of amplicon vectors carrying extrachromosomal retention elements, their packaging into HSV-1 viral particles, and the use of HSV-1 amplicons for stem cell transduction will be described.


RPA activates the XPF-ERCC1 endonuclease to initiate processing of DNA interstrand crosslinks.
During replication-coupled DNA interstrand crosslink (ICL) repair, the XPF-ERCC1 endonuclease is required for the incisions that release, or "unhook", ICLs, but the mechanism of ICL unhooking remains largely unknown. Incisions are triggered when the nascent leading strand of a replication fork strikes the ICL Here, we report that while purified XPF-ERCC1 incises simple ICL-containing model replication fork structures, the presence of a nascent leading strand, modelling the effects of replication arrest, inhibits this activity. Strikingly, the addition of the single-stranded DNA (ssDNA)-binding replication protein A (RPA) selectively restores XPF-ERCC1 endonuclease activity on this structure. The 5'-3' exonuclease SNM1A can load from the XPF-ERCC1-RPA-induced incisions and digest past the crosslink to quantitatively complete the unhooking reaction. We postulate that these collaborative activities of XPF-ERCC1, RPA and SNM1A might explain how ICL unhooking is achieved in vivo.


Re-recruiting postpartum women living with HIV into a follow-up study in Cape Town, South Africa.
Recruitment and retention present major challenges to longitudinal research in maternal and child health, yet there are few insights into optimal strategies that can be employed in low-resource settings. Following prior participation in a longitudinal study following women living with HIV through pregnancy and breastfeeding in Cape Town, women were re-contacted at least 18 months after the last study contact and were invited to attend an additional follow-up visit. We describe lessons learnt and offer recommendations for a multiphase recruitment approach. Using telephone calls, home visits, clinic tracing and Facebook/WhatsApp messages, we located 387 of the 463 eligible women and successfully enrolled 353 (91% of those contacted). Phone calls were the most successful strategy, yielding 67% of enrolments. Over half of the women had changed their contact information since participation in the previous study. We recommend that researchers collect multiple contact details and use several recruitment strategies in parallel from the start of a study. Participants in longitudinal studies may require frequent contact to update contact information, particularly in settings where mobility is common.


Double Autosomal/Gonosomal Mosaic Trisomy 47,XXX/47,XX,+14 in a Newborn with Multiple Congenital Anomalies.
Chromosomal trisomies are the most frequent major chromosomal anomalies in humans and can be present in a mosaic or a non-mosaic constitution. We report the first case of a newborn girl presenting with multiple congenital anomalies and a double mosaic trisomy involving chromosome 14 and the X chromosome detected by array CGH. Karyotype analysis revealed a double mosaic with 2 independent abnormal cell lines and the absence of 46,XX and 48,XXX,+14 cell lineages. The patient showed most of the clinical characteristics of mosaic trisomy 14. Analysis of autosomal DNA markers in the proband's blood sample did not support the presence of chimerism. Further analysis of chromosome X DNA markers suggests that the extra X chromosome most probably arose as a consequence of nondisjunction in meiosis II in the maternal lineage.


Occupationally related respiratory symptoms in trout-processing workers.
All eight production workers from a small trout-processing factory were studied because of respiratory or rhinitis symptoms when working next to the automatic gutting machine. Seven of the eight had positive histamine provocation tests. Four patients had elevated total IgE levels while one had a slightly elevated eosinophil count. All workers had either weakly or moderately positive RAST against contaminated water from the outlet drain of the gutting machine. This water contained 1 microgram endotoxin/ml. We concluded that five of the workers had probably developed occupationally related asthma from inhalation of contaminated aerosol from the gutting machine. Inhalation of endotoxin from gram-negative bacteria may be the cause of this disorder. An alternative explanation is a Type I allergy caused by fish or bacterial protein with or without a simultaneous effect of endotoxin.


Co-Transcriptomes of Initial Interactions In Vitro between Streptococcus Pneumoniae and Human Pleural Mesothelial Cells.
Streptococcus pneumoniae (Spn) is a major causative organism of empyema, an inflammatory condition occurring in the pleural sac. In this study, we used human and Spn cDNA microarrays to characterize the transcriptional responses occurring during initial contact between Spn and a human pleural mesothelial cell line (PMC) in vitro. Using stringent filtering criteria, 42 and 23 Spn genes were up-and down-regulated respectively. In particular, genes encoding factors potentially involved in metabolic processes and Spn adherence to eukaryotic cells were up-regulated e.g. glnQ, glnA, aliA, psaB, lytB and nox. After Spn initial contact, 870 human genes were differentially regulated and the largest numbers of significant gene expression changes were found in canonical pathways for eukaryotic initiation factor 2 signaling (60 genes out of 171), oxidative phosphorylation (32/103), mitochondrial dysfunction (37/164), eIF4 and p70S6K signaling (28/142), mTOR signaling (27/182), NRF2-mediated oxidative stress response (20/177), epithelial adherens junction remodeling (11/66) and ubiquitination (22/254). The cellular response appeared to be directed towards host cell survival and defense. Spn did not activate NF-kB or phosphorylate p38 MAPK or induce cytokine production from PMC. Moreover, Spn infection of TNF-α pre-stimulated PMC inhibited production of IL-6 and IL-8 secretion by >50% (p<0.01). In summary, this descriptive study provides datasets and a platform for examining further the molecular mechanisms underlying the pathogenesis of empyema.


Couplet periodic breathing response to high carbon dioxide and low oxygen.
A breathing pattern is described which is characterized by a grouping of two breaths followed by a prolonged apnea and which may involve a mechanism different from at least one type of Cheyne-Stokes breathing. The pattern can be eliminated by breathing 9 percent O(2) or 10 percent CO(2). However, the pattern frequently persists during breathing of high oxygen.


Poor awareness of preventing aspirin-induced gastrointestinal injury with combined protective medications.
To investigate prescribing pattern in low-dose aspirin users and physician awareness of preventing aspirin-induced gastrointestinal (GI) injury with combined protective medications. A retrospective drug utilization study was conducted in the 2nd Affiliated Hospital, School of Medicine, Zhejiang University. The hospital has 2300 beds and 2.5 million outpatient visits annually. Data mining was performed on all aspirin prescriptions for outpatients and emergency patients admitted in 2011. Concomitant use of proton-pump inhibitors (PPIs), histamine 2-receptor antagonists (H2RA) and mucoprotective drugs (MPs) were analyzed. A defined daily dose (DDD) methodology was applied to each MP. A further investigation was performed in aspirin users on combination use of GI injurious medicines [non-steoid anti-inflammatory drugs (NSAIDs), corticosteroids and clopidogrel and warfarin] or intestinal protective drugs (misoprostol, rebamipide, teprenone and gefarnate). Data of major bleeding episodes were derived from medical records and adverse drug reaction monitoring records. The annual incidence of major GI bleeding due to low-dose aspirin was estimated for outpatients. Prescriptions for aspirin users receiving PPIs, H2RA and MPs (n = 1039) accounted for only 3.46% of total aspirin prescriptions (n = 30 015). The ratios of coadministration of aspirin/PPI, aspirin/H2RA, aspirin/MP and aspirin/PPI/MP to the total aspirin prescriptions were 2.82%, 0.12%, 0.40% and 0.12%, respectively. No statistically significant difference was observed in age between patients not receiving any GI protective medications and patients receiving PPIs, H2RA or MPs. The combined medication of aspirin and PPI was used more frequently than that of aspirin and MPs (2.82% vs 0.40%, P < 0.05) and aspirin/H2RA (2.82% vs 0.12%, P < 0.05). The values of DDDs of MPs in descending order were as follows: gefarnate, hydrotalcite > teprenone > sucralfate oral suspension > L-glutamine and sodium gualenate granules > rebamipide > sucralfate chewable tablets. The ratio of MP plus aspirin prescriptions to the total MP prescriptions was as follows: rebamipide (0.47%), teprenone (0.91%), L-glutamine and sodium gualenate granules (0.92%), gefarnate (0.31%), hydrotalcite (1.00%) and sucralfate oral suspension (0.13%). Percentages of prescriptions containing aspirin and intestinal protective drugs among the total aspirin prescriptions were: rebamipide (0.010%), PPI/rebamipide (0.027%), teprenone (0.11%), PPI/teprenone (0.037%), gefarnate (0.017%), and PPI/gefarnate (0.013%). No prescriptions were found containing coadministration of aspirin and other NSAIDs. Among the 3196 prescriptions containing aspirin/clopidogrel, 3088 (96.6%) prescriptions did not contain any GI protective medicines. Of the 389 prescriptions containing aspirin/corticosteroids, 236 (60.7%) contained no GI protective medicines. None of the prescriptions using aspirin/warfarin (n = 22) contained GI protective medicines. Thirty-five patients were admitted to this hospital in 2011 because of acute hemorrhage of upper digestive tract induced by low-dose aspirin. The annual incidence rates of major GI bleeding were estimated at 0.25% for outpatients taking aspirin and 0.5% for outpatients taking aspirin/warfarin, respectively. The prescribing pattern of low-dose aspirin revealed a poor awareness of preventing GI injury with combined protective medications. Actions should be taken to address this issue.


Casimir-force-driven ratchets.
We explore the nonlinear dynamics of two parallel periodically patterned metal surfaces that are coupled by the zero-point fluctuations of the electromagnetic field between them. The resulting Casimir force generates for asymmetric patterns with a time periodically driven surface-to-surface distance a ratchet effect, allowing for directed lateral motion of the surfaces in sizable parameter ranges. It is crucial to take into account inertia effects and hence chaotic dynamics which are described by Langevin dynamics. Multiple velocity reversals occur as a function of driving, mean surface distance, and effective damping. These transport properties are shown to be stable against weak ambient noise.


Effects of stressors and immune activating agents on peripheral and central cytokines in mouse strains that differ in stressor responsivity.
The impact of inflammatory immune activation on behavioral and physiological processes varies with antecedent stressor experiences. We assessed whether immune activation would differentially influence such outcomes as a function of stressor reactivity related to genetic differences. To this end, we assessed the influence of a social stressor (exposure to a dominant mouse) in combination with an acute immune challenge on behavior and on peripheral and central cytokines in stressor-reactive BALB/cByJ mice and the less reactive C57BL/6ByJ strain. As C57BL/6ByJ and BALB/cByJ mice are highly T helper type-1 (Th1) and Th2 responsive, respectively, the stressor effects were assessed in response to different challenges, namely the viral analogue poly I:C and the bacterial endotoxin lipopolysaccharide (LPS). The stressor enhanced the effects of LPS on sickness behaviors and plasma corticosterone particularly in BALB/cByJ mice, whereas the effects of poly I:C, which primarily affects Th1 processes, were not augmented by the stressor. As well, the stressor increased circulating cytokines in LPS treated C57BL/6ByJ mice, whereas the effects of poly I:C were diminished. Finally, like circulating cytokines, mRNA expression of pro-inflammatory cytokines within the prefrontal cortex and hippocampus varied with the mouse strain and with the stressor experience, and with the specific cytokine considered. Together, the experiments indicated that the impact of stressors vary with the nature of the immune challenge to which animals had been exposed. Moreover, given the diversity of the stressor effects on central and peripheral processes, it seems likely that the cytokine changes, HPA activity and sickness operate through independent mechanisms.


Dosimetric evaluation of Acuros XB dose calculation algorithm with measurements in predicting doses beyond different air gap thickness for smaller and larger field sizes.
In this study, dose prediction accuracy of Acuros XB (AXB) dose calculation algorithm beyond air gap thickness (range 2, 4, and 6 cm) in simple inhomogeneous phantoms was investigated. The evaluation of AXB was performed by comparing the doses calculated by AXB with the doses calculated by Anisotropic Analytical Algorithm (AAA) and the measured data for different field sizes (3 × 3, 5 × 5, and 10 × 10 cm(2)) of a 6 MV photon beam. The dose computation was performed within Eclipse treatment planning system, and measurements were acquired with a cylindrical ionization chamber. Central axis depth dose comparisons were done in solid-water material region up to 5 cm distance from air/solid-water interface. The results of AXB had better agreement with measurements at all measured points than that of AAA. The discrepancies between AXB and measured data were seen from - 3.81% to + 0.9%, whereas the AAA differences with measurement from - 3.1% to - 10.9%. The combination of the smallest test field size and the largest air gap produced the highest range (1-5 cm distance from air/solid-water interface) in dose difference (AAA: -4.0% to - 10.6% and AXB: -3.8% to + 0.6%). The AAA computational time was about 8 times faster than that of AXB. In conclusion, AXB is more appropriate to use for dose predictions, especially when low-density heterogeneities are involved.


Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors.
Fenfluramine exhibits antiepileptic properties and thus diminishes epileptiform discharges in experimental animal models of Dravet syndrome. Fenfluramine is metabolized into norfenfluramine in vivo, which shows greater affinity and agonist activity at serotonin 5HT2 receptors (5HT2R) than fenfluramine. In this study, we found that fenfluramine and norfenfluramine disrupted the regulatory association of the sigma 1 receptor (σ1R) with NR1 subunits of glutamate N-methyl-D-aspartate receptors (NMDAR), an effect that was also produced by σ1R antagonists such as S1RA and prevented by σ1R agonists such as PPCC. The antagonists removed σ1R bound to NMDAR NR1 subunits enabling calcium-regulated calmodulin (CaM) to bind to those subunits. As a result, CaM may inhibit calcium permeation through NMDARs. The serotoninergic activity of fenfluramine at 5HT2AR, and likely also at 5HT2CR, collaborated with its activity at σ1Rs to prevent the convulsive syndrome promoted by NMDAR overactivation. Notably, fenfluramine enhanced the inhibitory coupling of G protein-coupled receptors such as 5HT1AR and cannabinoid type 1 receptor with NMDARs, thus allowing the more effective restrain of NMDAR activity. Thus, fenfluramine circumvents the negative side effects of direct NMDAR antagonists and may improve the quality of life of subjects affected by such proconvulsant dysfunctions.


Functional Impact and Evolution of a Novel Human Polymorphic Inversion That Disrupts a Gene and Creates a Fusion Transcript.
Despite many years of study into inversions, very little is known about their functional consequences, especially in humans. A common hypothesis is that the selective value of inversions stems in part from their effects on nearby genes, although evidence of this in natural populations is almost nonexistent. Here we present a global analysis of a new 415-kb polymorphic inversion that is among the longest ones found in humans and is the first with clear position effects. This inversion is located in chromosome 19 and has been generated by non-homologous end joining between blocks of transposable elements with low identity. PCR genotyping in 541 individuals from eight different human populations allowed the detection of tag SNPs and inversion genotyping in multiple populations worldwide, showing that the inverted allele is mainly found in East Asia with an average frequency of 4.7%. Interestingly, one of the breakpoints disrupts the transcription factor gene ZNF257, causing a significant reduction in the total expression level of this gene in lymphoblastoid cell lines. RNA-Seq analysis of the effects of this expression change in standard homozygotes and inversion heterozygotes revealed distinct expression patterns that were validated by quantitative RT-PCR. Moreover, we have found a new fusion transcript that is generated exclusively from inverted chromosomes around one of the breakpoints. Finally, by the analysis of the associated nucleotide variation, we have estimated that the inversion was generated ~40,000-50,000 years ago and, while a neutral evolution cannot be ruled out, its current frequencies are more consistent with those expected for a deleterious variant, although no significant association with phenotypic traits has been found so far.


Association of Metformin Use With End-Stage Renal Disease in Patients With Type 2 Diabetes Mellitus: A Nationwide Cohort Study Under the Pay-for-Performance Program.
Animal studies have demonstrated that metformin exerts a renoprotective effect. Human studies of patients with diabetes mellitus (DM) regarding the association of metformin use with end-stage renal disease (ESRD) are lacking. Patients with type 2 DM and without a history of kidney disease who were enrolled under the pay-for-performance program of the National Health Insurance in Taiwan were identified. Those who received ≥90 cumulative defined daily doses of metformin within 1 year were selected (metformin users) and compared with a 1:1 propensity score-matched metformin nonuser cohort. Primary and secondary outcomes were development of ESRD and chronic kidney disease (CKD), respectively. Independent predictors were investigated using Cox regression analysis. A total of 24 158 pairs of metformin users and nonusers were enrolled, with an incidence of ESRD of 1908 and 1723 and CKD of 1095 and 1056 cases per 100 000 person-years, respectively. Metformin use was independently associated with increased risks of ESRD (adjusted hazard ratio, 1.22; 95% confidence interval, 1.12-1.32) and CKD (adjusted hazard ratio, 1.25; 95% confidence interval, 1.12-1.40) in a dose-response relationship. Patients with hypertension plus nonuse of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers potentiated kidney damage by metformin. In patients with DM, use of metformin may increase the risk of ESRD and CKD. Health care professionals should be alert and closely monitor renal function when prescribing metformin.


Present perspectives on the automated classification of the G-protein coupled receptors (GPCRs) at the protein sequence level.
The G-protein coupled receptors--or GPCRs--comprise simultaneously one of the largest and one of the most multi-functional protein families known to modern-day molecular bioscience. From a drug discovery and pharmaceutical industry perspective, the GPCRs constitute one of the most commercially and economically important groups of proteins known. The GPCRs undertake numerous vital metabolic functions and interact with a hugely diverse range of small and large ligands. Many different methodologies have been developed to efficiently and accurately classify the GPCRs. These range from motif-based techniques to machine learning as well as a variety of alignment-free techniques based on the physiochemical properties of sequences. We review here the available methodologies for the classification of GPCRs. Part of this work focuses on how we have tried to build the intrinsically hierarchical nature of sequence relations, implicit within the family, into an adaptive approach to classification. Importantly, we also allude to some of the key innate problems in developing an effective approach to classifying the GPCRs: the lack of sequence similarity between the six classes that comprise the GPCR family and the low sequence similarity to other family members evinced by many newly revealed members of the family.


Impact of atopy on risk of glioma: a Mendelian randomisation study.
An inverse relationship between allergies with glioma risk has been reported in several but not all epidemiological observational studies. We performed an analysis of genetic variants associated with atopy to assess the relationship with glioma risk using Mendelian randomisation (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. Two-sample MR was undertaken using genome-wide association study data. We used single nucleotide polymorphisms (SNPs) associated with atopic dermatitis, asthma and hay fever, IgE levels, and self-reported allergy as instrumental variables. We calculated MR estimates for the odds ratio (OR) for each risk factor with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighting (IVW), maximum likelihood estimation (MLE), weighted median estimate (WME) and mode-based estimate (MBE) methods. Violation of MR assumptions due to directional pleiotropy were sought using MR-Egger regression and HEIDI-outlier analysis. Under IVW, MLE, WME and MBE methods, associations between glioma risk with asthma and hay fever, self-reported allergy and IgE levels were non-significant. An inverse relationship between atopic dermatitis and glioma risk was found by IVW (OR 0.96, 95% confidence interval (CI) 0.93-1.00, P = 0.041) and MLE (OR 0.96, 95% CI 0.94-0.99, P = 0.003), but not by WME (OR 0.96, 95% CI 0.91-1.01, P = 0.114) or MBE (OR 0.97, 95% CI 0.92-1.02, P = 0.194). Our investigation does not provide strong evidence for relationship between atopy and the risk of developing glioma, but findings do not preclude a small effect in relation to atopic dermatitis. Our analysis also serves to illustrate the value of using several MR methods to derive robust conclusions.


Eating patterns are associated with cognitive function in the elderly at risk of metabolic syndrome from rural areas.
The Mediterranean diet (MedDiet) represents a promising approach in the prevention of cognitive decline, but the evidence for such beneficial effect, especially among elderly populations in non-Mediterranean regions, is at present inconsistent. This study investigated the relationship between adherence to MedDiet and cognitive function (CF), along with selected sociodemographic (SD) and clinical indices, in Polish elderly people > 60 years of age, with high risk of metabolic syndrome (MS), living in rural area. Complete SD and lifestyle information was collected. The dietary outcome was recorded as a MedDiet score with the frequencies of consumption of the main food groups in the a MedDiet pyramid. Parameters identifying MS and body weight status were determined, and 11 psychological test results were examined in four domains: visual memory, executive function, attention, and global cognition. The lower MedDiet score was more often connected with living without children and with CF impairment. The MedDiet score was linked with global cognition; frequency of consumption of vegetable, fish, olive and rapeseed oil with visual memory, attention, executive function respectively. The consumption of full-fat dairy products and red meat and meat products was negatively related to executive and global CF. Also, insufficient physical activity, low educational status, female gender, living without children, and the existence of MS were factors of risk of CF impairment. Greater adherence to MedDiet and frequency of consumption of some foods were associated with better scores in several CF tests in elderly individuals with high risk of MS living in a rural community. However, lifestyle, clinical, and SD factors should also be considered.


Are non-brain stem-dead cardiac donors acceptable donors?
The deleterious effects of brainstem death (BSD) on donor cardiac function and endothelial integrity have been documented previously. Domino cardiac donation (heart of a heart-lung recipient transplanted into another recipient) is a way to avoid the effects of brainstem death and may confer both short- and long-term benefits to allograft recipients. This study evaluates short- and long-term outcome in heart recipients of BSD donors (cadaveric) as compared with domino hearts explanted from patients who underwent heart-lung transplantation. Patients having undergone cardiac transplantation between April 1989 and August 2001 at Papworth Hospital were included (n = 571). Domino donor hearts were used in 81 (14%) of these cases. The pre-operative transpulmonary gradient was not significantly different between the two groups (p = 0.7). There was no significant difference in 30-day mortality (4.9% for domino vs 8.6% for BSD, p = 0.38) or in actuarial survival (p = 0.72). Ischemic time was significantly longer in the BSD group (p < 0.001). Acute rejection and infection episodes were not significantly different (p = 0.24 vs: 0.08). Relative to the BSD group, the risk (95% confidence interval) of acute rejection in the domino group was 0.89 (0.73 to 1.08). Similarly, the relative risk of infection was 0.78 (0.59 to 1.03). The 5-year actuarial survival rates (95% confidence interval) were 78% (69% to 87%) and 69% (65% to 73%) in the domino and BSD groups respectively. Angiography data at 2 years were available in 50 (62%) and 254 (52%) patients in the domino and BSD groups, respectively. The rates for 2-year freedom from cardiac allograft vasculopathy (CAV) were 96% (91% to 100%) and 93% (90% to 96%), respectively. Despite the lack of endothelial cell activation after brainstem death and a shorter ischemic time, the performance of domino donor hearts was similar to that of BSD donor hearts. This may indicate a similar pathology (i.e., endothelial cell activation) in the domino donors.


A novel metal-free method for the selenocyanation of aromatic ketones to afford α-carbonyl selenocyanates.
A new method has been developed for the selenocyanation of aromatic ketones. This reaction avoids the need to use pre-prepared α-halo ketones, providing rapid access to α-carbonyl selenocyanates. We also investigated the mechanism for this reaction and found that it proceeds via sequential radical iodination and nucleophilic substitution reactions.