New insecticides for management of tomato yellow leaf curl, a virus vectored by the silverleaf whitefly, Bemisia tabaci.
Greenhouse studies using a randomized complete block design were carried out to evaluate the effect of six insecticides on transmission of Tomato yellow leaf curl virus (TYLCV) by the silverleaf whitefly, Bemisia tabaci biotype B Gennadius (Hemiptera: Aleyrodidae) to tomato, Lycopersicon esculentum (Miller) (Solanales: Solanaceae), seedlings that were inoculated with whiteflies from a TYLCV colony in cages 3, 7, or 14 d after treatment with insecticide. The purpose was to reveal differences in residual efficacy of four materials that are nearing registration for use on tomato-cyazypyr, flupyradifurone, pyrafluquinazon, and sulfoxaflor-and to compare them with two established insecticides, pymetrozine and a zeta-cypermethrin/bifenthrin combination. Differences in efficacy were expected because these six materials represent five distinct modes of action and both contact and systemic materials. Percentage of tomato seedlings expressing virus symptoms tended to be lowest in seedlings treated with flupyradifurone. The zeta-cypermethrin/bifenthrin insecticide demonstrated comparable efficacy to flupyradifurone in some trials at 3 and 7 d after treatment inoculations, but not the 14 d after treatment inoculation. Pyrafluquinazon was not statistically different from cyazypyr or sulfoxaflor in percentage of plants with virus symptoms in any trial. Percentage virus in the cyazypyr and sulfoxaflor treatments was not statistically different in the 3 and 7 d after treatment inoculations. Among seedlings treated with insecticide, percentage with virus symptoms tended to be highest in the seedlings treated with pymetrozine.


Radiofrequency exposure in Greek indoor environments.
This is the first measurement campaign that takes place in Greece in order to assess the exposure levels in different microenvironments (offices, bedrooms, living rooms, schools). Due to the exponential growth in the use of wireless network devices, the aim of this work was to perform indoor measurements with the use of personal dosimeters. The measurement period was 3 d in each of the 40 different locations that were selected, both in the urban and suburban area of Thessaloniki, the second largest city of Greece. The measurements took place from 23 July 2010 to 19 January 2012. After processing the obtained data with the robust regression on order statistics (ROS) method, various statistical exposure quantities were calculated. Compared to similar measurement campaigns across Europe, a larger proportion of measurement data above the detection limit for specific frequency bands (at most 56% for the DCS Rx frequency band) was found. Furthermore, mean exposure levels in the mobile downlink frequency bands were higher than those in other studies (GSM Rx: 0.259 V m, DCS Rx: 0.131 V m, UMTS Rx: 0.12 V m), yet many times below the ICNIRP guidelines. On the other hand, maximum exposures were found to be of the same magnitude (GSM Rx: 0.38 V m, DCS Rx: 0.3 V m, UMTS Rx: 0.28 V m). These measurement results indicate that signals from mobile base stations are dominant in workplaces and schools, whereas wireless phones and computer networks play the leading role in home environments. While the former reach their maximum values during daytime, the latter have an observable increase in the evening after work hours.


The carriage of interleukin-1B-31*C allele plus Staphylococcus aureus and Haemophilus influenzae increases the risk of recurrent tonsillitis in a Mexican population.
The aim of the present study was to estimate the relative contribution of immunogenetic and microbiological factors in the development of recurrent tonsillitis in a Mexican population. Patients (n = 138) with recurrent tonsillitis and an indication of tonsillectomy (mean age: 6.05 years ± 3.00; median age: 5 years, female: 58; age range: 1-15 years) and 195 non-related controls older than 18 years and a medical history free of recurrent tonsillitis were included. To evaluate the microbial contribution, tonsil swab samples from both groups and extracted tonsil samples from cases were cultured. Biofilm production of isolated bacteria was measured. To assess the immunogenetic component, DNA from peripheral blood was genotyped for the TNFA-308G/A single-nucleotide polymorphism (SNP) and for the IL1B -31C/T SNP. Normal microbiota, but no pathogens or potential pathogens, were identified from all control sample cultures. The most frequent pathogenic species detected in tonsils from cases were Staphylococcus aureus (48.6%, 67/138) and Haemophilus influenzae (31.9%, 44/138), which were found more frequently in patient samples than in samples from healthy volunteers (P < 0.0001). Importantly, 41/54 (75.9%) S. aureus isolates were biofilm producers (18 weak and 23 strong), whereas 17/25 (68%) H. influenzae isolates were biofilm producers (10 weak, and 7 strong biofilm producers). Patients with at least one copy of the IL1B-31*C allele had a higher risk of recurrent tonsillitis (OR = 4.03; 95% CI = 1.27-14.27; P = 0.013). TNFA-308 G/A alleles were not preferentially distributed among the groups. When considering the presence of IL1B-31*C plus S. aureus, IL1B-31*C plus S. aureus biofilm producer, IL1B-31*C plus H. influenzae or IL1B-31*C plus H. influenzae biofilm producer, the OR tended to infinite. Thus, the presence of IL1B-31*C allele plus the presence of S. aureus and/or H. influenzae could be related to the development of tonsillitis in this particular Mexican population.


Imaging of Corneal Neovascularization: Optical Coherence Tomography Angiography and Fluorescence Angiography.
The purpose of this study was to compare optical coherence tomography angiography (OCTA) and indocyanine green angiography (ICGA) for the assessment of corneal neovascularization (CoNV). Patients with CoNV extending at least 3 mm into the cornea were included. All patients underwent corneal imaging at the same visit. Images were recorded using the AngioVue OCTA system (Optovue, Inc.) with the long corneal adaptor module (CAM-L). ICGA images were recorded with fluorescent filters using the Heidelberg system (HRA2 Scanning Laser Ophthalmoscope; Heidelberg Engineering). Images were graded for quality by two independent observers. Vessel parameters: area, number, diameter, branch and end points, and tortuosity, were compared between devices. Bland-Altman plots were used to assess differences between parameters. Fifteen patients with CoNV predominantly associated with microbial keratitis were included. Mean subjective image quality score was better for ICGA (3.3 ± 0.9) than for OCTA (2.1 ± 1.2, P = 0.002), with almost perfect interobserver agreement for ICGA images (κ = 0.83) and substantial agreement for OCTA images (κ = 0.69). Agreement of grading of all investigated vessel parameters between ICGA and OCT images was slight to moderate, with significant differences found for vessel diameter (-8.98 μm, P = 0.01, 95% limits of agreement [LOA]: -15.89 to -2.07), number of branch (25.93, P = 0.09, 95% LOA: -4.31 to 56.17), and terminal points (49, P = 0.05, 95% LOA: 0.78 to 97.22). Compared with ICGA, current OCTA systems are less precise in capturing small vessels in CoNV complexes, and validation studies are needed for OCTA segmentation software. OCTA, however, complements ICGA by providing evidence of red blood cell flow, which together with depth information, may be helpful when planning treatment of CoNV.


Responses to autobiographical memories involving being a victim or perpetrator of betrayal in people with OCD and community controls.
Mental contamination in people with OCD has been linked to the perceived impact of being betrayed and betraying others. In this study, participants with OCD (N = 56) and community controls (N = 37) were randomised to an induction involving eliciting autobiographical memories of either being betrayed by someone they trusted or betraying someone that trusted them. The OCD group experienced greater increases in state mental contamination and anxiety than the control group, but no differences were observed between groups in urges to wash or drink. Both betrayal conditions elicited similar levels of mental contamination and anxiety. The results of this study suggest that people with OCD experience similar increases in mental contamination and anxiety not only when recalling memories of being a victim of betrayal but also when recalling being a perpetrator. People with OCD are therefore more sensitive to betrayal experiences than community controls. Clinical implications and implications for future research are discussed.


A simplified method for administration of intra-arterial nicardipine for vasospasm with cervical catheter infusion.
Cerebral vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage. Nicardipine has previously been used to treat vasospasm through superselective intracranial microcatheter injections. To evaluate a simple method of treatment of vasospasm with slow infusion of nicardipine from a cervical catheter. Twenty-seven patients with symptomatic vasospasm were treated over 4 years with cervical catheter infusions. Nicardipine was infused at 20 mg/h for 30 to 60 minutes. Angioplasty was used in severe cases at the operator's discretion. Outcome at discharge and follow-up was evaluated with Glasgow Outcome Scale. Twenty-seven patients (17 women, 12 men) received intra-arterial therapy for vasospasm. Vasospasm treatment was done at a mean post-hemorrhage date of 7.2 days (range, 4-15 days). They underwent 48 sessions of treatment (mean, 1.8 per patient) in 72 separate arterial territories. Twelve patients underwent multiple treatments. The mean dose used per session was 19.2 mg (range, 5-50 mg). Four patients underwent angioplasty for severe vasospasm. Twenty-two patients (81.5%) had clinical improvement after the infusion. Angiographic improvement was seen in 86.1% of the vessels analyzed, which had moderate or severe spasm before infusion. Overall, 17 patients (62.9%) had good outcome (Glasgow Outcome Scale score, 4 and 5) at discharge, 11 had poor outcome, and 1 patient died. Follow-up was available in 19 patients, and 18 were doing well (Glasgow Outcome Scale score, 4 and 5). Intra-arterial nicardipine is an effective and safe treatment for cerebral vasospasm. In most patients, infusion can be performed from the cervical catheter, with microcatheter infusion and angioplasty reserved for the more severe and resistant cases.


Safety and immunogenicity of a recombinant live attenuated tetravalent dengue vaccine (DENVax) in flavivirus-naive healthy adults in Colombia: a randomised, placebo-controlled, phase 1 study.
Dengue virus is the most serious mosquito-borne viral threat to public health and no vaccines or antiviral therapies are approved for dengue fever. The tetravalent DENVax vaccine contains a molecularly characterised live attenuated dengue serotype-2 virus (DENVax-2) and three recombinant vaccine viruses expressing the prM and E structural genes for serotypes 1, 3, and 4 in the DENVax-2 genetic backbone. We aimed to assess the safety and immunogenicity of tetravalent DENVax formulations. We undertook a randomised, double-blind, phase 1, dose-escalation trial between Oct 11, 2011, and Nov 9, 2011, in the Rionegro, Antioquia, Colombia. The first cohort of participants (aged 18-45 years) were randomly assigned centrally, via block randomisation, to receive a low-dose formulation of DENvax, or placebo, by either subcutaneous or intradermal administration. After a safety assessment, participants were randomly assigned to receive a high-dose DENVax formulation, or placebo, by subcutaneous or intradermal administration. Group assignment was not masked from study pharmacists, but allocation was concealed from participants, nurses, and investigators. Primary endpoints were frequency and severity of injection-site and systemic reactions within 28 days of each vaccination. Secondary endpoints were the immunogenicity of DENVax against all four dengue virus serotypes, and the viraemia due to each of the four vaccine components after immunisation. Analysis was by intention to treat for safety and per protocol for immunogenicity. Because of the small sample size, no detailed comparison of adverse event rates were warranted. The trial is registered with ClinicalTrials.gov, number NCT01224639. We randomly assigned 96 patients to one of the four study groups: 40 participants (42%) received low-dose vaccine and eight participants (8%) received placebo in the low-dose groups; 39 participants (41%) received high-dose vaccine, with nine (9%) participants assigned to receive placebo. Both formulations were well tolerated with mostly mild and transient local or systemic reactions. No clinically meaningful differences were recorded in the overall incidence of local and systemic adverse events between patients in the vaccine and placebo groups; 68 (86%) of 79 participants in the vaccine groups had solicited systemic adverse events compared with 13 (76%) of 17 of those in the placebo groups. By contrast, 67 participants (85%) in the vaccine group had local solicited reactions compared with five (29%) participants in the placebo group. Immunisation with either high-dose or low-dose DENVax formulations induced neutralising antibody responses to all four dengue virus serotypes; 30 days after the second dose, 47 (62%) of 76 participants given vaccine seroconverted to all four serotypes and 73 (96%) participants seroconverted to three or more dengue viruses. Infectious DENVax viruses were detected in only ten (25%) of 40 participants in the low-dose group and 13 (33%) of 39 participants in the high-dose group. Our findings emphasise the acceptable tolerability and immunogenicity of the tetravalent DENVax formulations in healthy, flavivirus-naive adults. Further clinical testing of DENVax in different age groups and in dengue-endemic areas is warranted. Takeda Vaccines.


Atrial Function and Its Role in the Non-invasive Evaluation of Diastolic Function in Congenital Heart Disease.
Diastolic dysfunction has correlated with adverse outcomes in various forms of unrepaired and repaired or palliated congenital heart disease (CHD). The non-invasive assessment of diastolic function in pediatric and adult patients with CHD remains challenging. Atrial size has a pivotal role in the evaluation of diastolic function; however, a growing body of evidence supports the additional role of atrial function as a more sensitive parameter of ventricular diastolic dysfunction. While the importance of atrial function is becoming clearer in adult acquired heart disease, it remains ambiguous in those with CHD. In this review we set the stage with the current understanding of diastolic function assessment in CHD, followed by insight into atrial form and function including its non-invasive assessment, and conclude with the current knowledge of atrial function in CHD. A general pattern of decrease in reservoir and conduit function with compensatory increase followed by decompensatory decrease in contractile function seems to be the common pathway of atrial dysfunction in most forms of CHD.


Responses to opposed directions of motion: continuum or independent mechanisms?
Opponency between opposite directions of motion is a characteristic of many models of movement detection and is commonly invoked in explanations of the motion after-effect. If detection of opposite directions is mediated by a single mechanism, then a single, smooth psychometric function for the discrimination of global direction in random-dot kinematograms should be found as a function of the percent of directional coherence of dots in the display, ranging from 100% coherence leftwards through 0% coherence to 100% coherence rightwards. Moreover, after rightward motion adaptation, a single psychometric function should still be observed if adaptation affects the perceptual system prior to opponent interactions. If, however, leftward and rightward detectors operate independently, then the slopes of the leftward and rightward halves of the function may differ, particularly after unidirectional adaptation. We measured the probability of a "rightward" direction response for nine values of motion coherence for five observers with and without prior rightward motion adaptation. Although a smooth psychometric function was found without motion adaptation, after adaptation, the rightward half of the psychometric function was flattened whereas the leftward half remained unchanged. Such results indicate that movement direction analysers operate in a non-opponent manner.


[Repair of extensive gluteal-sacral defect with posterior femoral cutaneous neurovascular island flap].
To explore the clinical value of repairing extensive gluteal-sacral defects with the posterior femoral cutaneous neurovascular island flap. From July 2002 to May 2005, the posterior femoral cutaneous neurovascular flap was applied to repairing extensive gluteal-sacral defects in 6 patients (3 males, 3 females; aged 31-59 years). Three patients had a skin defect in the gluteal-sacral region caused by squamous cell carcinoma, 1 patient had the defect in the same region caused by malignant fibrohistiocytoma, and 2 patients had the defect caused by bedsores of grade III . The area of defects ranged from 15 cm X 8 cm to 16 cm X 10 cm. The flaps ranged in area from 15 cm x 8 cm to 18 cm x 10 cm. In all the 6 patients had their flaps survived well and the wounds gained the primary healing. The follow-up for 2. 5-12 months revealed that, flaps were satisfactory in their appearance, texture, and sensory functions. The repair of extensive gluteal-sacral defects with the posterior femoral cutaneous neurovascular island flap has advantages of the unchanged anatomic structures, reliable blood supply, easy dissection for extensive defects, good sensory recovery, and sacrificing no major vessels; therefore, this kind of repair is an optimal approach to repairing extensive gluteal-sacral defects.


Multistage neoplastic transformation of Syrian hamster embryo cells cultured at pH 6.70.
We have reported that the frequency of induction of the morphologically transformed phenotype in early passage Syrian hamster embryo cells is increased in carcinogen-treated cultures when the cells are cultured in media of pH 6.70, instead of the traditionally used pH 7.35. The purpose of the studies reported here was to determine the neoplastic potential of cells derived from colonies of morphologically normal, altered, and transformed phenotypes from untreated and carcinogen-treated cultures generated under low pH conditions. Results from these studies indicate that cells derived from morphologically transformed colonies generated at pH 6.70 following benzo[a]pyrene or 3-methylcholanthrene treatment became established as immortal cell lines with a frequency of 30 and 14%, respectively. In contrast, cells derived from morphologically transformed colonies in untreated cultures and morphologically normal colonies from carcinogen-treated cultures establish as immortal cell lines at a frequency of 3% or less. Acquisition of aneuploidy was associated with immortalization in most cell lines. Ninety-two % of the immortal lines eventually progressed to the neoplastic phenotype upon subsequent cell culture, as assessed by cell injection into newborn hamsters. Approximately 75% of the neoplastic cell lines exhibited anchorage-independent growth in agarose. A comparison of these results to those generated at pH 7.35 by other investigators indicates that pH 6.70 culture of SHE cells is primarily enhancing early stages of the transformation process, i.e., induction of morphological transformation, while the frequency of progression from the morphologically transformed phenotype to neoplasia appears similar between the two pH values. These results support earlier indications that pH 6.70 culture of SHE cell is a useful model system for the study of multistage carcinogenesis.


Cell Blebbing in Confined Microfluidic Environments.
Migrating cells can extend their leading edge by forming myosin-driven blebs and F-actin-driven pseudopods. When coerced to migrate in resistive environments, Dictyostelium cells switch from using predominately pseudopods to blebs. Bleb formation has been shown to be chemotactic and can be influenced by the direction of the chemotactic gradient. In this study, we determine the blebbing responses of developed cells of Dictyostelium discoideum to cAMP gradients of varying steepness produced in microfluidic channels with different confining heights, ranging between 1.7 μm and 3.8 μm. We show that microfluidic confinement height, gradient steepness, buffer osmolarity and Myosin II activity are important factors in determining whether cells migrate with blebs or with pseudopods. Dictyostelium cells were observed migrating within the confines of microfluidic gradient channels. When the cAMP gradient steepness is increased from 0.7 nM/μm to 20 nM/μm, cells switch from moving with a mixture of blebs and pseudopods to moving only using blebs when chemotaxing in channels with confinement heights less than 2.4 μm. Furthermore, the size of the blebs increases with gradient steepness and correlates with increases in myosin-II localization at the cell cortex. Reduction of intracellular pressure by high osmolarity buffer or inhibition of myosin-II by blebbistatin leads to a decrease in bleb formation and bleb size. Together, our data reveal that the protrusion type formed by migrating cells can be influenced by the channel height and the steepness of the cAMP gradient, and suggests that a combination of confinement-induced myosin-II localization and cAMP-regulated cortical contraction leads to increased intracellular fluid pressure and bleb formation.


Persistent intestinal metaplasia after endoscopic eradication therapy of neoplastic Barrett's esophagus increases the risk of dysplasia recurrence: meta-analysis.
Endoscopic eradication therapy (EET) is the main treatment for dysplastic Barrett's esophagus and intramucosal adenocarcinoma. Although the goal of EET is to achieve complete remission of intestinal metaplasia (CRIM), treatment might achieve complete remission of dysplasia (CR-D) only, without achieving CRIM. Persistent intestinal metaplasia after eradication of dysplasia might carry a higher risk for progression into advanced neoplasia. We performed a systematic review and meta-analysis after searching multiple databases to identify studies that evaluated dysplasia recurrence risk after successful eradication of neoplasia with EET. We calculated the pooled cumulative incidence of dysplasia and advanced neoplasia recurrence after CRIM and CR-D only and then compared the two using risk ratios. Forty studies were included (4410 patients with total follow-up of 12,976 patient-years). A total of 4061 achieved CRIM and 349 achieved CR-D only. The cumulative incidence of CR-D only was 14% (95% confidence interval [CI], 10%-19%). The pooled cumulative incidence of any dysplasia recurrence after achieving CRIM was 5% (95% CI, 3%-7%) and 12% (95% CI, 4%-23%) after achieving CR-D only. Comparing dysplasia detection after achieving CR-D only with CRIM, there was a significantly higher risk for detection after CR-D (risk ratio [RR], 2.8; 95% CI, 1.7-4.6). The pooled cumulative incidence rate of high-grade dysplasia (HGD)/esophageal adenocarcinoma (EAC) recurrence was 3% (95% CI, 2%-4%) after achieving CRIM and 6% (95% CI, 0%-16%) after achieving CR-D only. Comparing HGD/EAC recurrence after achieving CR-D only with CRIM, there was a significantly higher risk for recurrence after CR-D (RR, 3.6; 95% CI, 1.45-9). When excluding patients who underwent ablation for non-dysplastic Barrett's esophagus only, these differences persisted with dysplasia recurrence after achieving CR-D only compared with CRIM showing a significantly higher risk for recurrence after CR-D (RR, 2.9; 95% CI, 1.66-5). CRIM was associated with a lower risk of dysplasia and advanced neoplasia recurrence compared with CR-D only. Achieving CRIM should remain the goal of EET in dysplastic Barrett's esophagus.


A Divalent Pentastable Redox-Switchable Donor-Acceptor Rotaxane.
Donor-acceptor materials with small HOMO-LUMO gaps are important in molecular electronics, but are often difficult to synthesise. A simple and efficient way to position tetrathiafulvalene (TTF) as the donor and naphthalene diamide (NDI) as the acceptor in close proximity to each other in a divalent crown/ammonium pseudo[2]rotaxane is presented. The divalent design provides high chelate cooperativity and much stronger binding compared with a monovalent analogue. The pseudo[2]rotaxane was then doubly interlocked by stoppering it in a catalyst-free 1,3-dipolar cycloaddition. UV/Vis and cyclic voltammetry experiments with the resulting [2]rotaxane revealed the optoelectronic properties of an intramolecular charge transfer with a small HOMO-LUMO energy gap. Redox-switching experiments showed the rotaxane to be pentastable. DFT calculations provided insights into the electronic structures of the five redox states.


p97/VCP- and Lys48-linked polyubiquitination form a new signaling pathway in DNA damage response.
RNF8/RNF168-dependent Lys63-linked polyubiquitination at sites of DNA double-strand breaks (DSBs) was originally regarded as the sole ubiquitin-signaling pathway involved in the DNA damage response (DDR). However, ubiquitin-dependent p97/VCP segregase activity and RNF8-dependent Lys48-linked polyubiquitin chains at DSB sites have recently been identified as components of an additional and parallel ubiquitin-signaling DDR pathway. This newly identified pathway is essential to spatiotemporal protein turnover and regulates both main branches of DSB repair, homologous recombination and nonhomologous end joining. In this report, the function of the RNF8/Lys48 polyubiquitin chains/p97 pathway is discussed in the context of DSB repair and p97 chromatin-related functions.


A major developmental transition in early Xenopus embryos: II. Control of the onset of transcription.
We have shown in the accompanying paper that a developmental transition occurs at the midblastula stage (cleavage 12) in Xenopus embryos, and that this midblastula transition (MBT) is apparently initiated when the ratio of nucleus to cytoplasm reaches a critical value. One manifestation of this transition is the onset of transcription. We show here that a plasmid containing a cloned gene coding for a yeast leucine tRNA comes under developmental control when injected into cleaving eggs. In pre-MBT eggs this plasmid is transiently transcribed and then becomes inactive; however, it becomes transcriptionally active again at the MBT. This pre-MBT suppression of transcription can be reversed by addition of competing DNA. The amount of DNA needed to induce premature transcription is equal to the amount of nuclear DNA present after 12 cleavages (24 ng), suggesting that the MBT is triggered by the DNA through titration of suppressor components present in the egg.


Marriage or dissolution? Union transitions among poor cohabiting women.
The objective of this paper is to identify the incentives and barriers to marriage among cohabiting women, especially disadvantaged mothers who are targets of welfare reform. We use the newly released cohabitation data from the National Longitudinal Survey of Youth (1979-2000), which tracks the partners of cohabiting women across survey waves. Our results support several conclusions. First, cohabiting unions are short-lived--about one-half end within one year, and over 90% end by the fifth year. Unlike most previous research, our results show that most cohabiting unions end by dissolution of the relationship rather than by marriage. Second, transitions to marriage are especially unlikely among poor women; less than one-third marry within five years. Cohabitation among poor women is more likely than that among nonpoor women to be a long-term alternative or substitute for traditional marriage. Third, our multinomial analysis of transitions from cohabitation into marriage or dissolution highlights the salience of economically disadvantaged family backgrounds, cohabitation and fertility histories, women's economic resources, and partner characteristics. These results are interpreted in a policy environment that increasingly views marriage as an economic panacea for low-income women and their children.


Differential resource selection within shared habitat types across spatial scales in sympatric toads.
Differential habitat selection is a central component in the evolution of species, but it has been quantified rarely for sympatric species in relation to the multiple impacts of resources at the spatial scales at which animals operate. Our main goal was to quantify the selection of terrestrial summer habitats in a natural floodplain in Italy by two sympatric amphibians (Bufo bufo spinosus and B. viridis) as a function of habitat type, prey density, and temperature. We applied a Bayesian resource selection model at three spatial scales: (1) home range placement within the floodplain, (2) space use within 95% home ranges, and (3) space use within 50% core areas. Using these data we explored whether processes acting at large scales lead to space use patterns at small scales and whether the two species use the same habitat types in a way that would facilitate coexistence. Habitat selection was determined by habitat type, prey density, and temperature at all spatial scales, resulting in slightly higher prey density and significantly lower temperature within than outside home ranges. We conclude that amphibians perceive the distribution of habitat types as well as gradients in prey density and temperature at all spatial scales. The effects of habitat type dominated home range placement while prey density and temperature most strongly affected space use within home ranges. Our results suggest that home range placement relies on broad habitat features that indicate resource availability at small spatial scales. At the smallest spatial scale, the selection of prey and refugia is most probably facilitated due to the accumulation of environmental information as animals may sample the entire area. Both species largely preferred the same habitat types, but used them differently in relation to resources across the three spatial scales. For example, while one species used the same habitat type for foraging, the other used it for resting or both resting and foraging. Niche differentiation through differential resource selection within shared habitat types at all spatial scales may therefore facilitate the coexistence of the two species in terrestrial summer habitats.


Clusterin Seals the Ocular Surface Barrier in Mouse Dry Eye.
Dry eye is a common disorder caused by inadequate hydration of the ocular surface that results in disruption of barrier function. The homeostatic protein clusterin (CLU) is prominent at fluid-tissue interfaces throughout the body. CLU levels are reduced at the ocular surface in human inflammatory disorders that manifest as severe dry eye, as well as in a preclinical mouse model for desiccating stress that mimics dry eye. Using this mouse model, we show here that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to the galectin LGALS3, a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. These findings define a fundamentally new mechanism for ocular surface protection and suggest CLU as a biotherapeutic for dry eye.


Frailty: implications for clinical practice and public health.
Frailty is an emerging global health burden, with major implications for clinical practice and public health. The prevalence of frailty is expected to rise alongside rapid growth in the ageing population. The course of frailty is characterised by a decline in functioning across multiple physiological systems, accompanied by an increased vulnerability to stressors. Having frailty places a person at increased risk of adverse outcomes, including falls, hospitalisation, and mortality. Studies have shown a clear pattern of increased health-care costs and use associated with frailty. All older adults are at risk of developing frailty, although risk levels are substantially higher among those with comorbidities, low socioeconomic position, poor diet, and sedentary lifestyles. Lifestyle and clinical risk factors are potentially modifiable by specific interventions and preventive actions. The concept of frailty is increasingly being used in primary, acute, and specialist care. However, despite efforts over the past three decades, agreement on a standard instrument to identify frailty has not yet been achieved. In this Series paper, we provide an overview of the global impact and burden of frailty, the usefulness of the frailty concept in clinical practice, potential targets for frailty prevention, and directions that need to be explored in the future.


Simple analytical model of bias dependence of the photocurrent of metal-semiconductor-metal photodetectors.
The current-voltage (I-V) characteristics of metal-semiconductor-metal (MSM) photodetectors under various light intensities are examined. The current shows an initial increase followed by saturation and a subsequent sharp increase as bias increases. We propose a theoretical model for bias dependence in all regions of operation except for breakdown, based on drift collection of carriers in the depleted regions under the contacts and diffusion and recombination in the undepleted region. This is based on the solution of the diffusion equation in the undepleted area between the two contacts of the MSM structure. The solution is subject to boundary conditions on excess minority carriers at the cathode end and continuity of current at the anode end. The latter is written in terms of a parameter, denoted as effective diffusion length, which describes the collection efficiency of carriers at the anode. The closed-form solution thus derived corroborates with physical expectations in several limiting cases. To compare theory with experiment, we propose methods to extract parameters that are used to normalize the I-V curves and calculate depletion widths under different light intensities, from current- and capacitance-voltage measurements. A close match between experimental and theoretical results is observed, and possible breakdown mechanisms are discussed.


Effect of an 8-weeks aerobic training program in elderly on oxidative stress and HSP72 expression in leukocytes during antioxidant supplementation.
To investigate the effect of aerobic training in the context of antioxidant supplementation on systemic oxidative stress and leukocytes heat shock protein (Hsp)72 expression in the elderly. Sixteen septuagenarians (8 males and 8 females, mean age 74.6) were supplemented with Vitamin C and E (respectively 500 and 100mg per day) and randomly assigned either to sedentary (AS) or individualized aerobically trained (AT) group for 8 weeks. Plasma Vitamin C and E concentrations and aerobic fitness, as well as resting and post graded exercise (GXT) Hsp72 expression in leukocytes, plasma levels of thiobarbituric acid reactive substances (TBARS) and advanced oxidation protein product (AOPP) were measured pre and post training / supplementation. At the end of the intervention, the two groups showed a significant increase in resting plasma vitamin C and E (approximately 50 and 20% increase respectively) and a significant decrease in both resting and post GXT plasma TBARS and AOPP (approximately 25 and 20% decrease respectively). These changes were of similar magnitude in the two groups. The reduced oxidative stress was concomitant with a 15% decreased expression of Hsp72 in monocytes and granulocytes in both groups. This study provides evidence that in elderly, increased concentration of antioxidant vitamins C and E is associated with a reduction in oxidative stress and leukocytes Hsp72. In this context, 8 weeks of aerobic training has no impact on oxidative stress or leukocytes Hsp72 expression in elderly people.


Role for ETS domain transcription factors Pea3/Erm in mouse lung development.
During the development of the mouse lung, the expression of a number of genes, including those encoding growth factors and components of their downstream signaling pathways, is enriched in the epithelium and/or mesenchyme of the distal buds. In this location, they regulate processes such as cell proliferation, branching morphogenesis, and the differentiation of specialized cell types. Here, we report that the expression of Pea3 and Erm (or Etv5, Ets variant gene 5), which encode Pea3 subfamily ETS domain transcription factors, is initially restricted to the distal buds of the developing mouse lung. Erm is transcribed exclusively in the epithelium, while Pea3 is expressed in both epithelium and mesenchyme. Erm/Pea3 are downstream of FGF signaling from the mesenchyme, but their responses toward different FGFs are not the same. The functions of the two proteins were investigated by transgenic expression of a repressor form of Erm specifically in the embryonic lung epithelium. When examined at E18.5, the distal epithelium of transgenic lungs is composed predominantly of immature type II cells, while no mature type I cells are observed. In contrast, the differentiation of proximal epithelial cells, including ciliated cells and Clara cells, appears to be unaffected. A model is proposed for the role of Pea3/Erm during the dynamic process of lung bud outgrowth and proximal-distal differentiation, in response to FGF signaling. Our results provide the first functional evidence that Pea3 subfamily members play a role in epithelial-mesenchymal interactions during lung organogenesis.


The crisis in antibiotic resistance.
The synthesis of large numbers of antibiotics over the past three decades has caused complacency about the threat of bacterial resistance. Bacteria have become resistant to antimicrobial agents as a result of chromosomal changes or the exchange of the exchange of genetic material via plasmids and transposons. Streptococcus pneumoniae, Streptococcus pyogenes, and staphylococci, organisms that cause respiratory and cutaneous infections, and members of the Enterobacteriaceae and Pseudomonas families, organisms that cause diarrhea, urinary infection, and sepsis, are now resistant to virtually all of the older antibiotics. The extensive use of antibiotics in the community and hospitals has fueled this crisis. Mechanisms such as antibiotic control programs, better hygiene, and synthesis of agents with improved antimicrobial activity need to be adopted in order to limit bacterial resistance.


Extreme Overvalued Beliefs.
An extreme overvalued belief is shared by others in a person's cultural, religious, or subcultural group. The belief is often relished, amplified, and defended by the possessor of the belief and should be differentiated from a delusion or obsession. Over time, the belief grows more dominant, more refined, and more resistant to challenge. The individual has an intense emotional commitment to the belief and may carry out violent behavior in its service. Study participants (n = 109 forensic psychiatrists) were asked to select among three definitions (i.e., obsession, delusion, and extreme overvalued belief) as the motive for the criminal behavior seen in 12 randomized fictional vignettes. Strong interrater agreement (kappa = 0.91 [95% CI 0.83-0.98]) was seen for vignettes representing extreme overvalued belief. Vignettes representing delusion and obsession also had strong reliability (kappa = 0.99 for delusion and 0.98 for obsession). This preliminary report suggests that forensic psychiatrists, given proper definitions, possess a substantial ability to identify delusion, obsession, and extreme overvalued belief. The rich historical foundation of extreme overvalued belief and this small survey study highlight the benefit of inclusion of "extreme overvalued belief" in future glossaries of the Diagnostic and Statistical Manual.


Transcriptional and translational control of C/EBPs: the case for "deep" genetics to understand physiological function.
The complexity of organisms is not simply determined by the number of their genes, but to a large extent by how gene expression is controlled. In addition to transcriptional regulation, this involves several layers of post-transcriptional control, such as translational repression, microRNA-mediated mRNA degradation and translational inhibition, alternative splicing, and the regulated generation of functionally distinct gene products from a single mRNA through alternative use of translation initiation sites. Much progress has been made in describing the molecular basis for these gene regulatory mechanisms. However, it is now a major challenge to translate this knowledge into deeper understanding of the physiological processes, both normal and pathological, that they govern. Using the C/EBP family of transcription factors as an example, the present review describes recent genetic experiments addressing this general problem and discusses how the physiological importance of newly discovered regulatory mechanisms might be determined.


Layer- and cell-type-specific differences in neural activity in mouse barrel cortex during a whisker detection task.
To address the question which neocortical layers and cell types are important for the perception of a sensory stimulus, we performed multielectrode recordings in the barrel cortex of head-fixed mice performing a single-whisker go/no-go detection task with vibrotactile stimuli of differing intensities. We found that behavioral detection probability decreased gradually over the course of each session, which was well explained by a signal detection theory-based model that posits stable psychometric sensitivity and a variable decision criterion updated after each reinforcement, reflecting decreasing motivation. Analysis of multiunit activity demonstrated highest neurometric sensitivity in layer 4, which was achieved within only 30 ms after stimulus onset. At the level of single neurons, we observed substantial heterogeneity of neurometric sensitivity within and across layers, ranging from nonresponsiveness to approaching or even exceeding psychometric sensitivity. In all cortical layers, putative inhibitory interneurons on average proffered higher neurometric sensitivity than putative excitatory neurons. In infragranular layers, neurons increasing firing rate in response to stimulation featured higher sensitivities than neurons decreasing firing rate. Offline machine-learning-based analysis of videos of behavioral sessions showed that mice performed better when not moving, which at the neuronal level, was reflected by increased stimulus-evoked firing rates.


Lone atrial fibrillation: electrophysiology, risk factors, catheter ablation and other non-pharmacologic treatments.
Atrial fibrillation occurring in the absence of cardiovascular disease in individuals younger than 60 years is known as lone atrial fibrillation. Nearly 1-12% of atrial fibrillation is considered to be lone atrial fibrillation. As our understanding of atrial fibrillation grows, we wonder as to whether there is such as thing as "lone" atrial fibrillation? We know that male sex, obesity, obstructive sleep apnea, alcohol consumption and endurance sports increase the risk of developing lone atrial fibrillation. Family history of atrial fibrillation increases the risk strongly and there are several recognized mutations that are causative of lone atrial fibrillation. Common triggers for origin of atrial fibrillation are the pulmonary veins. The atrial substrate provides the reentry circuits for perpetuating the arrhythmia. The autonomic nervous system is a key modulator and allows the continuation of the atrial fibrillation. Catheter ablation has been very effective in the treatment of this condition. The ablation procedure involves isolation of the pulmonary veins, antrum, complex fractionated electrograms and other sites. Alternatively surgical techniques can be used to isolate the pulmonary veins and surgical techniques have evolved to minimally invasive procedures and these are as effective as catheter ablation. Early intervention improves the left atrial remodeling and may lead to fewer recurrences.


MOC-PS(SM) CME article: patient safety in the office-based setting.
After studying this article, the participant should be able to: 1. Discern the importance of the physician's office administrative structure. 2. Recognize the necessity of a system for quality assessment. 3. Assess which procedures are safe in the office-based setting. 4. Know the basic steps for properly evaluating patients for office-based plastic surgery. This article reviews the literature on office-based patient safety issues. It places special emphasis on the statements and advisories published by the American Society of Plastic Surgeons' Convened Task Force on Patient Safety in the Office-Based Setting. The article divides patient safety in the health care delivery system into four broad categories. First, patient safety starts with emphasis at the administrative level. The physician or independent governing body must develop a system of quality assessment that functions to minimize preventable errors and report outcomes and errors. Second, the clinical aspects of patient safety require that the physician evaluate whether the procedure(s) and the patient are proper for the office setting. Third, this article gives special attention to liposuction, the most frequently performed office-based plastic surgery procedure. Finally, the article reviews the management of postoperative pain, nausea, and vomiting. Patient safety must be every physician's highest priority, as reflected in the Hippocratic Oath: primum non nocere ("first, do no harm").


Mathematic model analysis of Gaussian beam propagation through an arbitrary thickness random phase screen.
In order to research the statistical properties of Gaussian beam propagation through an arbitrary thickness random phase screen for adaptive optics and laser communication application in the laboratory, we establish mathematic models of statistical quantities, which are based on the Rytov method and the thin phase screen model, involved in the propagation process. And the analytic results are developed for an arbitrary thickness phase screen based on the Kolmogorov power spectrum. The comparison between the arbitrary thickness phase screen and the thin phase screen shows that it is more suitable for our results to describe the generalized case, especially the scintillation index.


Calorimetric measurements on Li4C60 and Na4C60.
We show specific heat data for Na4C60 and Li4C60 in the range 0.4-350 K for samples characterized by Raman spectroscopy and X-ray diffraction. At high temperatures, the two different polymer structures have very similar specific heats both in absolute values and in general trend. The specific heat data are compared with data for undoped polymeric and pristine C60. At high temperatures, a difference in specific heat between the intercalated and undoped C60 polymers of 100 J K(-1) mol(-1) is observed, in agreement with the Dulong-Petit law. At low temperatures, the specific heat data for Li4C60 and Na4C60 are modified by the stiffening of vibrational and librational molecular motion induced by the polymer bonds. The covalent twin bonds in Li4C60 affect these motions to a somewhat higher degree than the single intermolecular bonds in Na4C60. Below 1 K, the specific heats of both materials become linear in temperature, as expected from the effective dimensionality of the structure. The contribution to the total specific heat from the inserted metal ions can be well described by Einstein functions with TE = 386 K for Li4C60 and TE = 120 K for Na4C60, but for both materials we also observe a Schottky-type contribution corresponding to a first approximation to a two-level system with ΔE = 9.3 meV for Li4C60 and 3.1 meV for Na4C60, probably associated with jumps between closely spaced energy levels inside "octahedral-type" ionic sites. Static magnetic fields up to 9 T had very small effects on the specific heat below 10 K.


Fermented wheat germ extract induced cell death and enhanced cytotoxicity of Cisplatin and 5-Fluorouracil on human hepatocellular carcinoma cells.
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Due to the difficulties of early diagnosis, curative treatments are not available for most patients. Palliative treatments such as chemotherapy are often associated with low response rate, strong adverse effects and limited clinical benefits for patients. The alternative approaches such as fermented wheat germ extract (FWGE) with anti-tumor efficacy may provide improvements in the clinical outcome of current therapy for HCC. This study aimed to clarify antitumor efficacy of FWGE and the combination drug effect of FWGE with chemotherapeutic agents, cisplatin and 5-fluorouracil (5-Fu) in human HCC cells, HepG2, Hep3B, and HepJ5. The present study indicated that FWGE exhibited potential to suppress HepG2, Hep3B, and HepJ5 cells, with the half maximal inhibitory concentrations (IC50) of FWGE were 0.494, 0.371 and 1.524 mg/mL, respectively. FWGE also induced Poly (Adenosine diphosphate ribose) polymerase (PARP) associated cell death in Hep3B cells. Moreover, the FWGE treatment further enhanced the cytotoxicity of cisplatin in all tested HCC cells, and cytotoxicity of 5-Fu in a synergistic manner in HepJ5 cells. Collectively, the results identified the anti-tumor efficacy of FWGE in HCC cells and suggested that FWGE can be used as a supplement to effectively improve the tumor suppression efficiency of cisplatin and 5-Fu in HCC cells.


Early and late renal adverse effects after potentially nephrotoxic treatment for childhood cancer.
Great improvements in diagnostics and treatment for malignant disease in childhood have led to a major increase in survival. However, childhood cancer survivors (CCS) are at great risk for developing adverse effects caused by multimodal treatment for their malignancy. Nephrotoxicity is one of these known (acute) side effects of several treatments, including cisplatin, carboplatin, ifosfamide, radiotherapy and nephrectomy, and can cause glomerular filtration rate impairment, proteinuria, tubulopathy and hypertension. However, evidence about the long-term effects of these treatments on renal function remains inconclusive. To reduce the number of (long-term) nephrotoxic events in CCS, it is important to know the risk of, and risk factors for, early and late renal adverse effects, so that ultimately treatment and screening protocols can be adjusted. To evaluate existing evidence on the effects of potentially nephrotoxic treatment modalities on the prevalence of and associated risk factors for renal dysfunction in survivors treated for childhood cancer with a median or mean survival of at least one year after cessation of treatment, where possible in comparison with healthy controls or CCS treated without potentially nephrotoxic treatment. We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2011), MEDLINE/PubMed (from 1945 to December 2011) and EMBASE/Ovid (from 1980 to December 2011). With the exception of case reports, case series and studies including fewer than 20 participants, we included studies with all study designs that reported on renal function (one year or longer after cessation of treatment) in children and adults who were treated for a paediatric malignancy (aged 18 years or younger at diagnosis) with cisplatin, carboplatin, ifosfamide, radiation including the kidney region and/or a nephrectomy. Two review authors independently performed study selection, risk of bias assessment and data extraction using standardised data collection forms. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. The search strategy identified 5504 studies, of which 5138 were excluded on the basis of title and/or abstract. The full-text screening of the remaining 366 articles resulted in the inclusion of 57 studies investigating the prevalence of and sometimes also risk factors for early and late renal adverse effects of treatment for childhood cancer. The 57 studies included at least 13,338 participants of interest for this study, of whom at least 6516 underwent renal function testing. The prevalence of renal adverse effects ranged from 0% to 84%. This variation may be due to diversity in included malignancies, prescribed treatments, reported outcome measurements and the methodological quality of available evidence.Chronic kidney disease/renal insufficiency (as defined by the authors of the original studies) was reported in 10 of 57 studies. The prevalence of chronic kidney disease ranged between 0.5% and 70.4% in the 10 studies and between 0.5% and 18.8% in the six studies that specifically investigated Wilms' tumour survivors treated with a unilateral nephrectomy.A decreased (estimated) glomerular filtration rate was present in 0% to 50% of all assessed survivors (32/57 studies). Total body irradiation; concomitant treatment with aminoglycosides, vancomycin, amphotericin B or cyclosporin A; older age at treatment and longer interval from therapy to follow-up were significant risk factors reported in multivariate analyses. Proteinuria was present in 0% to 84% of all survivors (17/57 studies). No study performed multivariate analysis to assess risk factors for proteinuria.Hypophosphataemia was assessed in seven studies. Reported prevalences ranged between 0% and 47.6%, but four of seven studies found a prevalence of 0%. No studies assessed risk factors for hypophosphataemia using multivariate analysis. The prevalence of impairment of tubular phosphate reabsorption was mostly higher (range 0% to 62.5%; 11/57 studies). Higher cumulative ifosfamide dose, concomitant cisplatin treatment, nephrectomy and longer follow-up duration were significant risk factors for impaired tubular phosphate reabsorption in multivariate analyses.Treatment with cisplatin and carboplatin was associated with a significantly lower serum magnesium level in multivariate analysis, and the prevalence of hypomagnesaemia ranged between 0% and 37.5% in the eight studies investigating serum magnesium.Hypertension was investigated in 24 of the 57 studies. Reported prevalences ranged from 0% to 18.2%. A higher body mass index was the only significant risk factor noted in more than one multivariate analysis. Other reported factors that significantly increased the risk of hypertension were use of total body irradiation, abdominal irradiation, acute kidney injury, unrelated or autologous stem cell donor type, growth hormone therapy and older age at screening. Previous infection with hepatitis C significantly decreased the risk of hypertension.Because of the profound heterogeneity of the studies, it was not possible to perform any meta-analysis. The prevalence of renal adverse events after treatment with cisplatin, carboplatin, ifosfamide, radiation therapy involving the kidney region and/or nephrectomy ranged from 0% to 84%. With currently available evidence, it was not possible to draw any conclusions with regard to prevalence of and risk factors for renal adverse effects. Future studies should focus on adequate study design and reporting and should deploy multivariate risk factor analysis to correct for possible confounding. Until more evidence becomes available, CCS should be enrolled into long-term follow-up programmes to monitor their renal function and blood pressure.


Seagrass ecosystem response to long-term high CO2 in a Mediterranean volcanic vent.
We examined the long-term effect of naturally acidified water on a Cymodocea nodosa meadow growing at a shallow volcanic CO2 vent in Vulcano Island (Italy). Seagrass and adjacent unvegetated habitats growing at a low pH station (pH = 7.65 ± 0.02) were compared with corresponding habitats at a control station (pH = 8.01 ± 0.01). Density and biomass showed a clear decreasing trend at the low pH station and the below- to above-ground biomass ratio was more than 10 times lower compared to the control. C content and δ(13)C of leaves and epiphytes were significantly lower at the low pH station. Photosynthetic activity of C. nodosa was stimulated by low pH as seen by the significant increase in Chla content of leaves, maximum electron transport rate and compensation irradiance. Seagrass community metabolism was intense at the low pH station, with significantly higher net community production, respiration and gross primary production than the control community, whereas metabolism of the unvegetated community did not differ between stations. Productivity was promoted by the low pH, but this was not translated into biomass, probably due to nutrient limitation, grazing or poor environmental conditions. The results indicate that seagrass response in naturally acidified conditions is dependable upon species and geochemical characteristics of the site and highlight the need for a better understanding of complex interactions in these environments.


The Inhibition of Heat Shock Protein 90 Facilitates the Degradation of Poly-Alanine Expanded Poly (A) Binding Protein Nuclear 1 via the Carboxyl Terminus of Heat Shock Protein 70-Interacting Protein.
Since the identification of poly-alanine expanded poly(A) binding protein nuclear 1 (PABPN1) as the genetic cause of oculopharyngeal muscular dystrophy (OPMD), considerable progress has been made in our understanding of the pathogenesis of the disease. However, the molecular mechanisms that regulate the onset and progression of the disease remain unclear. In this study, we show that PABPN1 interacts with and is stabilized by heat shock protein 90 (HSP90). Treatment with the HSP90 inhibitor 17-AAG disrupted the interaction of mutant PABPN1 with HSP90 and reduced the formation of intranuclear inclusions (INIs). Furthermore, mutant PABPN1 was preferentially degraded in the presence of 17-AAG compared with wild-type PABPN1 in vitro and in vivo. The effect of 17-AAG was mediated through an increase in the interaction of PABPN1 with the carboxyl terminus of heat shock protein 70-interacting protein (CHIP). The overexpression of CHIP suppressed the aggregation of mutant PABPN1 in transfected cells. Our results demonstrate that the HSP90 molecular chaperone system plays a crucial role in the selective elimination of abnormal PABPN1 proteins and also suggest a potential therapeutic application of the HSP90 inhibitor 17-AAG for the treatment of OPMD.


[Insomnia and increased use of sleep medication among seniors: problems and alternative treatment].
To investigate the problem of insomnia and increased used of sleep medication among seniors and to look at an alternative form of treatment (cognitive-behavioural therapy [CBT]) that has been adapted specifically for this population. MEDLINE and PsycINFO were searched from 1990 to 2005 using the key words insomnia, elderly (older adults), hypnotics (sleep medication), and cognitive behavior therapy. When discussing the efficacy of treatment, sources quoted offer level I evidence. Studies on the deleterious effects of hypnotics primarily offer level II evidence, so their findings must be interpreted with caution (some studies present conflicting results). Insomnia in elderly people is associated with marked distress or deterioration in social or physical functioning. Hypnotics can be dangerous for elderly people because they raise the risk of adverse effects on cognitive function and the risk of drug-drug interactions. Treatment should be based on CBT alone or on a combination of CBT and appropriate pharmaceutical therapy. Cognitive-behavioural therapy adapted specifically to the problem of insomnia in seniors is one of the recommended options. The gains often include a notable decrease in use of sleep medication and in the emotional distress associated with insomnia.


The role of BoFLC2 in cauliflower (Brassica oleracea var. botrytis L.) reproductive development.
In agricultural species that are sexually propagated or whose marketable organ is a reproductive structure, management of the flowering process is critical. Inflorescence development in cauliflower is particularly complex, presenting unique challenges for those seeking to predict and manage flowering time. In this study, an integrated physiological and molecular approach was used to clarify the environmental control of cauliflower reproductive development at the molecular level. A functional allele of BoFLC2 was identified for the first time in an annual brassica, along with an allele disrupted by a frameshift mutation (boflc2). In a segregating F₂ population derived from a cross between late-flowering (BoFLC2) and early-flowering (boflc2) lines, this gene behaved in a dosage-dependent manner and accounted for up to 65% of flowering time variation. Transcription of BoFLC genes was reduced by vernalization, with the floral integrator BoFT responding inversely. Overall expression of BoFT was significantly higher in early-flowering boflc2 lines, supporting the idea that BoFLC2 plays a key role in maintaining the vegetative state. A homologue of Arabidopsis VIN3 was isolated for the first time in a brassica crop species and was up-regulated by two days of vernalization, in contrast to findings in Arabidopsis where prolonged exposure to cold was required to elicit up-regulation. The correlations observed between gene expression and flowering time in controlled-environment experiments were validated with gene expression analyses of cauliflowers grown outdoors under 'natural' vernalizing conditions, indicating potential for transcript levels of flowering genes to form the basis of predictive assays for curd initiation and flowering time.


Integrating Hi-C links with assembly graphs for chromosome-scale assembly.
Long-read sequencing and novel long-range assays have revolutionized de novo genome assembly by automating the reconstruction of reference-quality genomes. In particular, Hi-C sequencing is becoming an economical method for generating chromosome-scale scaffolds. Despite its increasing popularity, there are limited open-source tools available. Errors, particularly inversions and fusions across chromosomes, remain higher than alternate scaffolding technologies. We present a novel open-source Hi-C scaffolder that does not require an a priori estimate of chromosome number and minimizes errors by scaffolding with the assistance of an assembly graph. We demonstrate higher accuracy than the state-of-the-art methods across a variety of Hi-C library preparations and input assembly sizes. The Python and C++ code for our method is openly available at https://github.com/machinegun/SALSA.


Sex differences in rank attainment and research activities among academic psychiatrists.
Data from a survey distributed to all full-time faculty in academic departments of psychiatry were used to examine possible sex differences in research activities and rank attainment among psychiatrists. A total of 1923 psychiatrists responded, 1564 men (81.3%) and 359 women (18.7%). Continuous dependent variables were analyzed by using analyses of covariance with the year graduated from medical school as a covariate. For categorical dependent variables, the sample was divided into four 10-year cohorts based on the year graduated from medical school, and differences between men and women were analyzed with chi 2 tests. Over the entire sample, men were more likely than women to have had research training, to have ever been principal investigators on peer-reviewed grants, to mentor research trainees, to be currently involved in research activities, and to meet defined criteria as a "researcher." Many gender differences remained significant after controlling for seniority and research training. In every cohort, the men had attained higher academic rank than the women. In general, differences in research activity and productivity were most marked in the youngest cohort. To ensure a rich talent pool for psychiatric research, efforts must be made to recruit and support researchers from among the increased number of women in psychiatry.


Carbonate based ionic liquid synthesis (CBILS®): thermodynamic analysis.
Within the last decade the Carbonate Based Ionic liquid Synthesis (CBILS®) has developed towards a widely applicable, greener and halogen free process for the industrial production of ionic liquids. A large number of diverse starting materials have been screened experimentally, to explore the structural limits of the core reaction step, which is the quaternization of nitrogen, phosphor or sulfur based nucleophiles with carbonic acid dialkyl or diaryl esters to the corresponding quaternary alkyl- or arylcarbonates. In order to overcome the large experimental effort of empirical screening, a practical method based on quantum-chemical calculation has been developed for an assessment of feasibility of chemical reactions. This method has been successfully tested with 16 typical CBILS® reactions by calculation of their thermodynamic functions. Thermodynamic equilibrium constants as a measure for the practical yield of the CBILS® reactions at 298 K and 393 K have been determined for both the gaseous state and the liquid state. The method has been evaluated by comparison of the theoretical results with experimental data and it can be considered as the powerful tool to reduce "trial and failure" for the industrial application of the CBILS® process.


An integrated approach reveals regulatory controls on bacterial translation elongation.
Ribosomes elongate at a nonuniform rate during translation. Theoretical models and experiments disagree on the in vivo determinants of elongation rate and the mechanism by which elongation rate affects protein levels. To resolve this conflict, we measured transcriptome-wide ribosome occupancy under multiple conditions and used it to formulate a whole-cell model of translation in E. coli. Our model predicts that elongation rates at most codons during nutrient-rich growth are not limited by the intracellular concentrations of aminoacyl-tRNAs. However, elongation pausing during starvation for single amino acids is highly sensitive to the kinetics of tRNA aminoacylation. We further show that translation abortion upon pausing accounts for the observed ribosome occupancy along mRNAs during starvation. Abortion reduces global protein synthesis, but it enhances the translation of a subset of mRNAs. These results suggest a regulatory role for aminoacylation and abortion during stress, and our study provides an experimentally constrained framework for modeling translation.


Malignant Mesothelioma Diagnosed by Bronchoscopic Biopsy.
Malignant mesothelioma is a rare malignant neoplasm that arises from mesothelial surfaces of the pleural cavity, peritoneal cavity, tunica vaginalis, or pericardium. Typically, pleural fluid cytology or closed pleural biopsy, surgical intervention (video thoracoscopic biopsy or open thoracotomy) is conducted to obtain pleural tissue specimens. However, endobronchial lesions are rarely seen and cases diagnosed from bronchoscopic biopsy are also rarely reported. We reported the case of a 77-year-old male who was diagnosed as malignant mesothelioma on bronchoscopic biopsy from obstructing masses of the endobronchial lesion.


Regulation of Adaptive NK Cells and CD8 T Cells by HLA-C Correlates with Allogeneic Hematopoietic Cell Transplantation and with Cytomegalovirus Reactivation.
Mass cytometry was used to investigate the effect of CMV reactivation on lymphocyte reconstitution in hematopoietic cell transplant patients. For eight transplant recipients (four CMV negative and four CMV positive), we studied PBMCs obtained 6 mo after unrelated donor hematopoietic cell transplantation (HCT). Forty cell-surface markers, distinguishing all major leukocyte populations in PBMC, were analyzed with mass cytometry. This group included 34 NK cell markers. Compared with healthy controls, transplant recipients had higher HLA-C expression on CD56(-)CD16(+) NK cells, B cells, CD33(bright) myeloid cells, and CD4CD8 T cells. The increase in HLA-C expression was greater for CMV-positive HCT recipients than for CMV negative recipients. Present in CMV-positive HCT recipients, but not in CMV-negative HCT recipients or controls, is a population of killer cell Ig-like receptor (KIR)-expressing CD8 T cells not previously described. These CD8 T cells coexpress CD56, CD57, and NKG2C. The HCT recipients also have a population of CD57(+)NKG2A(+) NK cells that preferentially express KIR2DL1. An inverse correlation was observed between the frequencies of CD57(+)NKG2C(+) NK cells and CD57(+)NKG2A(+) NK cells. Although CD57(+)NKG2A(+) NK cells are less abundant in CMV-positive recipients, their phenotype is of a more activated cell than the CD57(+)NKG2A(+) NK cells of controls and CMV-negative HCT recipients. These data demonstrate that HCT and CMV reactivation are associated with an increased expression of HLA-C. This could influence NK cell education during lymphocyte reconstitution. The increased inhibitory KIR expression by proliferating CMV-specific CD8 T cells suggests regulatory interactions between HLA-C and KIR might promote Graft-versus-Leukemia effects following transplantation.


Inhibition of tiller bud outgrowth in the tin mutant of wheat is associated with precocious internode development.
Tillering (branching) is a major yield component and, therefore, a target for improving the yield of crops. However, tillering is regulated by complex interactions of endogenous and environmental signals, and the knowledge required to achieve optimal tiller number through genetic and agronomic means is still lacking. Regulatory mechanisms may be revealed through physiological and molecular characterization of naturally occurring and induced tillering mutants in the major crops. Here we characterize a reduced tillering (tin, for tiller inhibition) mutant of wheat (Triticum aestivum). The reduced tillering in tin is due to early cessation of tiller bud outgrowth during the transition of the shoot apex from the vegetative to the reproductive stage. There was no observed difference in the development of the main stem shoot apex between tin and the wild type. However, tin initiated internode development earlier and, unlike the wild type, the basal internodes in tin were solid rather than hollow. We hypothesize that tin represents a novel type of reduced tillering mutant associated with precocious internode elongation that diverts sucrose (Suc) away from developing tillers. Consistent with this hypothesis, we have observed upregulation of a gene induced by Suc starvation, downregulation of a Suc-inducible gene, and a reduced Suc content in dormant tin buds. The increased expression of the wheat Dormancy-associated (DRM1-like) and Teosinte Branched1 (TB1-like) genes and the reduced expression of cell cycle genes also indicate bud dormancy in tin. These results highlight the significance of Suc in shoot branching and the possibility of optimizing tillering by manipulating the timing of internode elongation.


SysBioMed report: advancing systems biology for medical applications.
The following report selects and summarises some of the conclusions and recommendations generated throughout a series of workshops and discussions that have lead to the publication of the Science Policy Briefing (SPB) Nr. 35, published by the European Science Foundation. (Large parts of the present text are directly based on the ESF SPB. Detailed recommendations with regard to specific application areas are not given here but can be found in the SPB. Issues related to mathematical modelling, including training and the need for an infrastructure supporting modelling are discussed in greater detail in the present text.)The numerous reports and publications about the advances within the rapidly growing field of systems biology have led to a plethora of alternative definitions for key concepts. Here, with 'mathematical modelling' the authors refer to the modelling and simulation of subcellular, cellular and macro-scale phenomena, using primarily methods from dynamical systems theory. The aim of such models is encoding and testing hypotheses about mechanisms underlying the functioning of cells. Typical examples are models for molecular networks, where the behaviour of cells is expressed in terms of quantitative changes in the levels of transcripts and gene products. Bioinformatics provides essential complementary tools, including procedures for pattern recognition, machine learning, statistical modelling (testing for differences, searching for associations and correlations) and secondary data extracted from databases.Dynamical systems theory is the natural language to investigate complex biological systems demonstrating nonlinear spatio-temporal behaviour. However, the generation of experimental data suitable to parameterise, calibrate and validate such models is often time consuming and expensive or not even possible with the technology available today. In our report, we use the term 'computational model' when mathematical models are complemented with information generated from bioinformatics resources. Hence, 'the model' is, in reality, an integrated collection of data and models from various (possibly heterogeneous) sources. The present report focuses on a selection of topics, which were identified as appropriate case studies for medical systems biology, and adopts a particular perspective which the authors consider important. We strongly believe that mathematical modelling represents a natural language with which to integrate data at various levels and, in doing so, to provide insight into complex diseases: 1. Modelling necessitates the statement of explicit hypotheses, a process which often enhances comprehension of the biological system and can uncover critical points where understanding is lacking. 2. Simulations can reveal hidden patterns and/or counter-intuitive mechanisms in complex systems. 3. Theoretical thinking and mathematical modelling constitute powerful tools to integrate and make sense of the biological and clinical information being generated and, more importantly, to generate new hypotheses that can then be tested in the laboratory.Medical Systems Biology projects carried out recently across Europe have revealed a need for action: 4. While the need for mathematical modelling and interdisciplinary collaborations is becoming widely recognised in the biological sciences, with substantial implications for the training and research funding mechanisms within this area, the medical sciences have yet to follow this lead. 5. To achieve major breakthroughs in Medical Systems Biology, existing academic funding schemes for large-scale projects need to be reconsidered. 6. The hesitant stance of the pharmaceutical industry towards major investment in systems biology research has to be addressed. 7. Leading medical journals should be encouraged to promote mathematical modelling.


Analysis of the solution structure of human interleukin-4 determined by heteronuclear three-dimensional nuclear magnetic resonance techniques.
Human interleukin-4 (IL-4) is a member of the family of haemopoietic cytokines that modulate cell proliferation and differentiation within the immune system. It has a four-helix-bundle structure, and possesses a high degree of mobility in certain regions, notably in the two long loops running the length of the bundle in its up-up-down-down topology. Information from a variety of three-dimensional heteronuclear NMR experiments, including chemical shifts, coupling constants and NOE data, is analysed in terms of the solution structure of IL-4. In addition, structure calculations with and without specific restraints such as hydrogen bond location or torsion angle restrictions are compared in the light of the dynamic behaviour of the polypeptide chain. Particular emphasis is placed on defining the lengths and positions of secondary structure elements, and on the likely structural preferences within the less well ordered loop regions. The overall topology of IL-4 is compared with those defined in recent structure determinations of related proteins. This analysis is combined with recent mutagenesis data to propose a possible mode of interaction of IL-4 with its receptor.


Hemin treatment protects neonatal rats from sevoflurane-induced neurotoxicity via the phosphoinositide 3-kinase/Akt pathway.
Anaesthesia-related neurotoxicity in the developing brain is a controversial issue that has recently attracted much attention. Hemin plays a protective role in hypoxic and ischemic brain damage; however, its effects on sevoflurane-induced neurotoxicity remain unclear. Our aim was to investigate the mechanisms of sevoflurane neurotoxicity and potential neuroprotective roles of hemin upon sevoflurane exposure. Hippocampi were harvested 18 h after sevoflurane exposure. Haem oxygenase 1 (HMOX1), superoxide dismutase 2 (SOD2), discs large MAGUK scaffold protein 4 (DLG4), phosphorylated Akt, Akt, cleaved caspase 3, and neuroglobin were detected by western blotting. A water maze test was used to assess learning and memory ability in P30 rats. Sevoflurane inhalation increased cleaved caspase 3 levels. Hemin treatment enhanced the antioxidant defence response, protecting rats from oxidative stress injury. Hemin plays its neuroprotective role via phosphoinositide 3-kinase (PI3K)/Akt signalling. A single inhalation of sevoflurane did not affect DLG4 expression, while hemin treatment did. Platform crossing increased in rats treated with hemin as well, which may be related to increased DLG4. Neuroglobin expression was not affected, suggesting that it may act upstream of PI3K/Akt signalling. Our study demonstrates that hemin plays a protective role in anaesthesia-induced neurotoxicity by both inhibiting apoptosis via the PI3K/Akt pathway and increasing the expression of antioxidant enzymes, reducing oxidative damage. The results provide mechanistic insight into the effects of sevoflurane anaesthesia on the developing brain and suggest that hemin could help avoid these effects.


Spinal epidural lipomatosis in a pediatric patient with a malignant brain tumor: illustrative case.
Spinal epidural lipomatosis (SEL) in pediatric patients with concomitant malignant brain neoplasms is rare and can present with rapid deterioration in neurological function. A 4-year-old boy with SEL became paraplegic 4 months after completion of chemoradiation for his previously resected, intracranial atypical teratoid rhabdoid tumor. The patient presented with rapid deterioration in lower extremity sensory and motor function, which, given his oncological history, was concerning for disease progression. Of note, 8 months prior, the patient was started on corticosteroid therapy for respiratory dysfunction. Magnetic resonance imaging revealed significant progression of lumbosacral SEL requiring surgical decompression with subsequent neurological improvement. When evaluating pediatric patients with primary or metastatic brain tumors with new or worsening myelopathy and motor or sensory deficits, it is important to consider SEL.


Attenuating persistent sodium current-induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress.
Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the atria. Similar to humans, increased persistent Na+ current leads to the development of an atrial myopathy and spontaneous and long-lasting episodes of AF in mice. How increased persistent Na+ current causes both structural and electrophysiological remodeling in the atria is unknown. We crossbred mice expressing human F1759A-NaV1.5 channels with mice expressing human mitochondrial catalase (mCAT). Increased expression of mCAT attenuated mitochondrial and cellular reactive oxygen species (ROS) and the structural remodeling that was induced by persistent F1759A-Na+ current. Despite the heterogeneously prolonged atrial action potential, which was unaffected by the reduction in ROS, the incidences of spontaneous AF, pacing-induced after-depolarizations, and AF were substantially reduced. Expression of mCAT markedly reduced persistent Na+ current-induced ryanodine receptor oxidation and dysfunction. In summary, increased persistent Na+ current in atrial cardiomyocytes, which is observed in patients with AF, induced atrial enlargement, fibrosis, mitochondrial dysmorphology, early after-depolarizations, and AF, all of which can be attenuated by resolving mitochondrial oxidative stress.


Bioinformatics of antimicrobial resistance in the age of molecular epidemiology.
Antimicrobial resistance is a global health challenge and has an evolutionary trajectory ranging from proto-resistance in the environment to untreatable clinical pathogens. Resistance is not static, as pathogenic strains can move among patient populations and individual resistance genes can move among pathogens. Effective treatment of resistant infections, antimicrobial stewardship, and new drug discovery increasingly rely upon genotype information, powered by decreasing costs of DNA sequencing. These new approaches will require advances in microbial informatics, particularly in development of reference databases of molecular determinants such as our Comprehensive Antibiotic Resistance Database and clinical metadata, new algorithms for prediction of resistome and resistance phenotype from genotype, and new protocols for global collection and sharing of high-throughput molecular epidemiology data.


Can policy affect initiation of addictive substance use? Evidence from opioid prescribing.
Drug control policy can have unintended consequences by pushing existing users to alternative, possibly more dangerous substances. Policies that target only new users may therefore be especially promising. Using commercial insurance claims data, we provide the first evidence on a set of new policies intended to reduce opioid initiation in the form of limits on initial prescription length. We also provide the first evidence on the impact of must-access prescription drug monitoring programs (MA-PDMPs), laws that do not target new users, on initial opioid use. Although initial limit policies reduce the average length of initial prescriptions, they do so primarily by raising the frequency of short prescriptions, resulting in increases in opioids dispensed to new users. In contrast, we find that MA-PDMPs reduce opioids dispensed to new users, even though they do not explicitly set out to do so. Neither policy significantly affects extreme use such as doctor shopping among new patients, because such behavior is very rare.


Globesity: the root causes of the obesity epidemic in the USA and now worldwide.
The epidemic of obesity is a well-known phenomenon affecting the world population. This pandemic has occurred since the 1980's with increasing frequency, despite multiple attempts and recommendations to mitigate the prevalence of obesity and its co-morbidities. The causes of obesity have been recognized and are largely related to a genetic predisposition and an environmental susceptibility to gain weight due to increased energy intake and reduced energy expenditures. Furthermore, various structural environmental changes that have occurred since the 1980's have created an obesogenic environment with abundance of high-caloric density, low-quality food and under activity. All of this leads to increased body weight gain and a global public health problem--not only a distinct patient's disease that generally fails to respond to diets and/or increased activity. The structural environmental changes resulted from the unintended consequences of laws that created unregulated marketing and advertisements, food subsidies to a "food industrial complex" which manufactures obesogenic foods that foster addiction to its foodstuffs. Additionally, the economic policies implemented over the last 3 to 4 decades have produced a stagnation of income and wages for the preponderance of the population with major wealth disparities between the majority of people versus the top of the socioeconomic group. The current economic realities have resulted in altered family dynamics, eating habits, and food availability compared to previous generations. The root causes of the epidemic of obesity are governmental policies and the food industry which make obesity difficult to escape in the US and now worldwide.


Dimerization partners determine the activity of the Twist bHLH protein during Drosophila mesoderm development.
The basic helix-loop-helix transcription factor Twist regulates a series of distinct cell fate decisions within the Drosophila mesodermal lineage. These twist functions are reflected in its dynamic pattern of expression, which is characterized by initial uniform expression during mesoderm induction, followed by modulated expression at high and low levels in each mesodermal segment, and finally restricted expression in adult muscle progenitors. We show two distinct partner-dependent functions for Twist that are crucial for cell fate choice. We find that Twist can form homodimers and heterodimers with the Drosophila E protein homologue, Daughterless, in vitro. Using tethered dimers to assess directly the function of these two particular dimers in vivo, we show that Twist homodimers specify mesoderm and the subsequent allocation of mesodermal cells to the somatic muscle fate. Misexpression of Twist-tethered homodimers in the ectoderm or mesoderm leads to ectopic somatic muscle formation overriding other developmental cell fates. In addition, expression of tethered Twist homodimers in embryos null for twist can rescue mesoderm induction as well as somatic muscle development. Loss of function analyses, misexpression and dosage experiments, and biochemical studies indicate that heterodimers of Twist and Daughterless repress genes required for somatic myogenesis. We propose that these two opposing roles explain how modulated Twist levels promote the allocation of cells to the somatic muscle fate during the subdivision of the mesoderm. Moreover, this work provides a paradigm for understanding how the same protein controls a sequence of events within a single lineage.


[What happens to children and adolescents with mental disorders? Findings from long-term outcome research].
Research on the long-term outcome of mental disorders originating in childhood and adolescence is an important part of developmental psychopathology. After a brief sketch of relevant terms of outcome research, the first part of this review reports findings based on heterotypic cohort studies. The major second part of this review presents findings based on long-term outcome studies dealing with homotypic diagnostic groups. In particular, the review focuses on the course and prognosis of ADHD, anxiety disorders, depression, conduct disorders, eating disorders, autism spectrum disorders, schizophrenia, and selective mutism. Findings mainly support the vulnerability hypothesis regarding mental disorders with early manifestation in childhood and adolescence as frequent precursors of mental disorders in adulthood. The discussion focuses on the impact of early manifesting disorders in the frame of general mental morbidity and of the effect of interventions, which is not yet sufficiently discernible.


"But He's a Star Football Player!": How Social Status Influences Mock Jurors' Perceptions in a Sexual Assault Case.
There have been several recent, high-profile cases in the media that have shed light on the perceived leniency in sentencing defendants in sexual assault cases. In a number of these cases, the defendant was well known within their community (e.g., Brock Turner; People v. Turner) or nationally (e.g., Ghomeshi; R v. Ghomeshi). The purpose of this study was to examine how the social status of the defendant (low vs. high), victim social status (low vs. high), victim gender (male vs. female), and the reason the victim was unconscious during the assault (consuming alcohol vs. consuming cold medicine) influenced mock jurors' decisions in a sexual assault case. Mock jurors (N = 489) read a mock trial transcript depicting an alleged sexual assault. Mock jurors were asked to render a dichotomous verdict, continuous guilt rating, and rate their perceptions of the victim and defendant. There was no influence of the variables on mock jurors' dichotomous verdicts; however, social status influenced guilt ratings. There also was a combined influence of the defendant's social status and the reason the victim was unconscious such that when the defendant was described as low status, and the victim was unconscious due to alcohol consumption, the defendant received higher guilt ratings compared with when the victim was unconscious due to cold medicine. Moreover, the victim was perceived as having more control over the situation when the defendant was the star quarterback (i.e., high status), the victim was female, and she was unconscious due to alcohol consumption compared with cold medicine. These results suggest that victims may be blamed based on their perceived social status and other factors that may have influenced their control over the sexual assault, such as alcohol consumption.


Structural evolution of iron forming iron oxide in a deep eutectic-solvothermal reaction.
Deep eutectic solvents (DES) and their hydrated mixtures are used for solvothermal routes towards greener functional nanomaterials. Here we present the first static structural and in situ studies of the formation of iron oxide (hematite) nanoparticles in a DES of choline chloride : urea where xurea = 0.67 (aka. reline) as an exemplar solvothermal reaction, and observe the effects of water on the reaction. The initial speciation of Fe3+ in DES solutions was measured using extended X-ray absorption fine structure (EXAFS), while the atomistic structure of the mixture was resolved from neutron and X-ray diffraction and empirical potential structure refinement (EPSR) modelling. The reaction was monitored using in situ small-angle neutron scattering (SANS), to determine mesoscale changes, and EXAFS, to determine local rearrangements of order around iron ions. It is shown that iron salts form an octahedral [Fe(L)3(Cl)3] complex where (L) represents various O-containing ligands. Solubilised Fe3+ induced subtle structural rearrangements in the DES due to abstraction of chloride into complexes and distortion of H-bonding around complexes. EXAFS suggests the complex forms [-O-Fe-O-] oligomers by reaction with the products of thermal hydrolysis of urea, and is thus pseudo-zero-order in iron. In the hydrated DES, the reaction, nucleation and growth proceeds rapidly, whereas in the pure DES, the reaction initially proceeds quickly, but suddenly slows after 5000 s. In situ SANS and static small-angle X-ray scattering (SAXS) experiments reveal that nanoparticles spontaneously nucleate after 5000 s of reaction time in the pure DES before slow growth. Contrast effects observed in SANS measurements suggest that hydrated DES preferentially form 1D particle morphologies because of choline selectively capping surface crystal facets to direct growth along certain axes, whereas capping is restricted by the solvent structure in the pure DES.


Scoring system to identify men at high risk of stroke: a strategy for general practice.
The major risk factors for stroke are well described and there is good evidence that the risks associated with hypertension and cigarette smoking are reversible by appropriate interventions. However, if disease prevention measures are to be efficient, it is important that a system which can identify individuals at high risk of stroke be available for use in general practice. A study was therefore undertaken to design an effective and practical system for detecting men aged 40 to 59 years at high risk of stroke in primary care. Stroke incidence and risk factor data were examined in a cohort of 7735 men aged 40 to 59 years who had taken part in the British regional heart study. Analysis was performed using data from initial entry into the study and then from five and 11.5 years of follow up. Subjects were randomly selected from the age-sex register of one general practice in each of 24 different towns throughout the United Kingdom, representing the full range of cardiovascular mortality rates. A simple scoring system derived from logistic regression using age, systolic blood pressure, current cigarette consumption, and evidence of anginal chest pain was able to detect more than 80% of all strokes occurring within five years in the top fifth of the score distribution. The inclusion of other risk factors for stroke did not increase the score's predictive ability. The combination of smoking and hypertension, while much less sensitive than the scoring system, was a better indicator of risk than any single risk factor, all of whose predictive values were poor. Based on readily measured variables, this scoring system could be used in general practice to identify men at high risk of stroke who would benefit from further intervention. Effective identification of high risk individuals requires assessment of the combined effects of multiple risk factors.


Doctors who kill themselves: a study of the methods used for suicide.
Medical practitioners have a relatively high rate of suicide. Death entry data for doctors who died by suicide or undetermined cause between 1979 and 1995 in England and Wales were used to compare methods used for suicide by doctors with those used by the general population. Methods used were analysed according to gender, occupational status and speciality, to assess the extent to which access to dangerous means influences the pattern of suicide. Self-poisoning with drugs was more common in the doctors than in general population suicides (57% vs. 26.6%; OR=3.65, 95% CI 2.85-4. 68), including in retired doctors. Barbiturates were the most frequent drugs used. Half of the anaesthetists who died used anaesthetic agents. Self-cutting was also more frequently used as a method of suicide. The finding that the greater proportion of suicide deaths in doctors were by self-poisoning may reflect the fact that doctors have ready access to drugs, and have knowledge of which drugs and doses are likely to cause death. The specific finding that a large proportion of suicides in anaesthetists involved anaesthetic agents supports this explanation. Availability of method may be a factor contributing to the relatively high suicide rate of doctors. This fact might influence clinical management of doctors who are known to be depressed or suicidal.


Amish microcephaly: Long-term survival and biochemical characterization.
Amish microcephaly (MCPHA, OMIM #607196) is a metabolic disorder that has been previously characterized by severe infantile lethal congenital microcephaly and alpha-ketoglutaric aciduria. All reported patients have been from the Pennsylvania Amish community and homozygous for a p.Gly177Ala mutation in SLC25A19. We present a further male patient with MCPHA born to distantly consanguineous parents in Ontario, Canada with Amish ancestors. Microcephaly was evident at 21 weeks gestation on ultrasound. At birth, the facial appearance and brain MRI scan were characteristic of MCPHA, with the additional features of partial agenesis of the corpus callosum and a closed spinal dysraphic state. Urine levels of alpha-ketoglutaric acid were normal at birth and during metabolic crisis, but were markedly elevated during a time of metabolic stability. A severe lactic acidosis was present during metabolic crises and responded to treatment with a high fat diet. At age 7 years, the child is healthy but has severe microcephaly and profound developmental delay. SLC25A19 has been described as a mitochondria inner membrane transporter for both deoxynucleotides and thiamine pyrophosphate (TPP). The biochemical phenotype of MCPHA may be attributable to decreased activity of the three mitochondrial enzymes that require TPP as a cofactor: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched chain amino acid dehydrogenase. We confirm that alpha-ketoglutaric aciduria is not a constant finding in MCPHA and suggest that a persistent lactic acidemia may be more common. The diagnosis should be considered in patients with severe congenital microcephaly, especially in association with lissencephaly, dysgenesis of the corpus callosum, or a spinal dysraphic state.


Assessing dietary intake in children and adolescents: Considerations and recommendations for obesity research.
Abstract Dietary intake and food habits are important contributors to the obesity epidemic. They are highly modifiable components of energy balance and are usually targeted in both obesity prevention and treatment programs. However, measurement of total diet creates challenges and can convey a large burden in terms of cost, technical expertise, impact on respondents and time. It is not surprising therefore that comprehensive reports of dietary intake in children are uncommon and, when reported, have limitations. The aim of this paper is to guide researchers and practitioners in selecting the most appropriate dietary assessment method for situations involving children and adolescents. This paper presents a summary of the issues to consider when choosing a method, a description of some of the more commonly used dietary assessment methods for young people and a series of case-studies to illustrate the range of circumstances faced when measuring dietary intake. We recommend that researchers consider the specific components of dietary intake addressed in their research and practice, and whether diet should be reported comprehensively or as targeted components. Other considerations include age, cognitive ability, weight status, physical activity level, respondent burden, and reliability and validity in the context of program goals and research questions. A checklist for selecting the appropriate dietary methodology is provided. This guide aims to facilitate the reporting of dietary intake and food habits in the context of obesity using valid and reliable measures, thus contributing to the evidence-base for nutrition policies and programs relating to obesity.