A randomised controlled trial of spinal manipulative therapy in acute low back pain.
To determine whether treatment with spinal manipulative therapy (SMT) administered in addition to standard care is associated with clinically relevant early reductions in pain and analgesic consumption. 104 patients with acute low back pain were randomly assigned to SMT in addition to standard care (n = 52) or standard care alone (n = 52). Standard care consisted of general advice and paracetamol, diclofenac or dihydrocodeine as required. Other analgesic drugs or non-pharmacological treatments were not allowed. Primary outcomes were pain intensity assessed on the 11-point box scale (BS-11) and analgesic use based on diclofenac equivalence doses during days 1-14. An extended follow-up was performed at 6 months. Pain reductions were similar in experimental and control groups, with the lower limit of the 95% CI excluding a relevant benefit of SMT (difference 0.5 on the BS-11, 95% CI -0.2 to 1.2, p = 0.13). Analgesic consumptions were also similar (difference -18 mg diclofenac equivalents, 95% CI -43 mg to 7 mg, p = 0.17), with small initial differences diminishing over time. There were no differences between groups in any of the secondary outcomes and stratified analyses provided no evidence for potential benefits of SMT in specific patient groups. The extended follow-up showed similar patterns. SMT is unlikely to result in relevant early pain reduction in patients with acute low back pain.


Near Axisymmetric Partial Wetting Using Interface-Localized Liquid Dielectrophoresis.
The wetting of solid surfaces can be modified by altering the surface free energy balance between the solid, liquid, and vapor phases. Liquid dielectrophoresis (L-DEP) can produce wetting on normally nonwetting surfaces, without modification of the surface topography or chemistry. L-DEP is a bulk force acting on the dipoles of a dielectric liquid and is not normally considered to be a localized effect acting at the interface between the liquid and a solid or other fluid. However, if this force is induced by a nonuniform electric field across a solid-liquid interface, it can be used to enhance and control the wetting of a dielectric liquid. Recently, it was reported theoretically and experimentally that this approach can cause a droplet of oil to spread along parallel interdigitated electrodes thus forming a stripe of liquid. Here we show that by using spiral-shaped electrodes actuated with four 90° successive phase-shifted signals, a near axisymmetric spreading of droplets can be achieved. Experimental observations show that the induced wetting can achieve film formation, an effect not possible with electrowetting. We show that the spreading is reversible thus enabling a wide range of partial wetting droplet states to be achieved in a controllable manner. Furthermore, we find that the cosine of the contact angle has a quadratic dependence on applied voltage during spreading and deduce a scaling law for the dependence of the strength of the effect on the electrode size.


EF-P dependent pauses integrate proximal and distal signals during translation.
Elongation factor P (EF-P) is required for the efficient synthesis of proteins with stretches of consecutive prolines and other motifs that would otherwise lead to ribosome pausing. However, previous reports also demonstrated that levels of most diprolyl-containing proteins are not altered by the deletion of efp. To define the particular sequences that trigger ribosome stalling at diprolyl (PPX) motifs, we used ribosome profiling to monitor global ribosome occupancy in Escherichia coli strains lacking EF-P. Only 2.8% of PPX motifs caused significant ribosomal pausing in the Δefp strain, with up to a 45-fold increase in ribosome density observed at the pausing site. The unexpectedly low fraction of PPX motifs that produce a pause in translation led us to investigate the possible role of sequences upstream of PPX. Our data indicate that EF-P dependent pauses are strongly affected by sequences upstream of the PPX pattern. We found that residues as far as 3 codons upstream of the ribosomal peptidyl-tRNA site had a dramatic effect on whether or not a particular PPX motif triggered a ribosomal pause, while internal Shine Dalgarno sequences upstream of the motif had no effect on EF-P dependent translation efficiency. Increased ribosome occupancy at particular stall sites did not reliably correlate with a decrease in total protein levels, suggesting that in many cases other factors compensate for the potentially deleterious effects of stalling on protein synthesis. These findings indicate that the ability of a given PPX motif to initiate an EF-P-alleviated stall is strongly influenced by its local context, and that other indirect post-transcriptional effects determine the influence of such stalls on protein levels within the cell.


A Comparison of the Responsiveness of the Postural Assessment Scale for Stroke and the Berg Balance Scale in Patients With Severe Balance Deficits After Stroke.
Previous evidence that the Postural Assessment Scale for Stroke (PASS) and the Berg Balance Scale (BBS) have similar responsiveness is doubtful. Compared with the BBS, the PASS has more items assessing basic balance abilities (such as postural transition during lying and sitting), so it should be more likely to detect changes in patients with severe balance deficits. We aimed to compare the responsiveness of the PASS and the BBS in patients with stroke who have severe balance deficits. The PASS and BBS scores of 49 patients with severe balance deficits at 14 and 30 days after stroke were retrieved. The group-level responsiveness was examined with the standardized response mean (SRM). The individual-level responsiveness was examined by the proportion of patients who achieved clinically significant improvements (ie, their pre-post change scores in the PASS/BBS exceeded the minimal detectable change with 95% confidence of each measure). The responsiveness of the 2 measures was compared using the bootstrap approach. The comparisons of responsiveness showed significant differences between the PASS and the BBS at both the group and individual levels. At the group level, the PASS indicated moderate changes in balance function (SRM = 0.79), but the BBS indicated only small changes (SRM = 0.39). At the individual level, the PASS showed that 42.9% of patients had clinically significant improvements, while the BBS showed that only 6.1% of patients had clinically significant improvements. Compared with the BBS, the PASS was better able to detect balance improvements in patients having severe balance deficits. The PASS is recommended as an outcome measure to detect change in balance in patients with stroke who have severe balance deficits.


Cinnamaldehyde potentially attenuates gestational hyperglycemia in rats through modulation of PPARγ, proinflammatory cytokines and oxidative stress.
Cinnamon has a history of use for medicinal purposes and its major benefits have been linked to cinnamaldehyde. The present study aimed to investigate the hypoglycemic action of cinnamaldehyde against fatty-sucrosed diet/streptozotocin (FSD/STZ)-rat model of gestational diabetes. Female albino rats were divided into three groups. Group I fed with normal diet (ND) while group II and III were fed with FSD for eight weeks (five weeks pre-gestational and three weeks gestational). Rats of group III were administered with a daily oral dose of 20mg/kg cinnamaldehyde one week before mating onward. At the 7th day of gestation, FSD-fed rats were injected intraperitoneally with STZ (25mg/kg b.wt.) to induce gestational diabetes. Pre-mating treatment of cinnamaldehyde controls hyperphagia and glucose intolerance during the gestational period than in diabetic rats. It also reduced levels of fructosamine, total cholesterols, triglycerides, leptin, tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA) and nitric oxide (NO), while it significantly increased levels of high-density lipoprotein (HDL)-cholesterol, adiponectin, liver glycogen, reduced glutathione (GSH) and catalase activity at term pregnancy. In addition, cinnamaldehyde administration up-regulated the mRNA expression of peroxisome proliferated activated receptor-gamma (PPARγ) and also ameliorated the number of viable fetuses, implantation loss sites, fetal glucose and insulin levels. In conclusion, cinnamaldehyde has safe hypoglycemic action on gestational diabetes by potentiating insulin secretion and sensitivity through activating the antioxidant defense system, suppressing pro-inflammatory cytokines production, upregulating PPARγ gene expression and alleviating the reproductive performance.


Tumor suppressive miR-124 targets androgen receptor and inhibits proliferation of prostate cancer cells.
Although prostate cancer (CaP) is the most frequently diagnosed malignant tumor in American men, the mechanisms underlying the development and progression of CaP remain largely unknown. Recent studies have shown that downregulation of the microRNA miR-124 occurs in several types of human cancer, suggesting a tumor suppressive function of miR-124. Until now, however, it has been unclear whether miR-124 is associated with CaP. In the present study, we completed a series of experiments to understand the functional role of miR-124 in CaP. We detected the expression level of miR-124 in clinical CaP tissues, evaluated the influence of miR-124 on the growth of CaP cells and investigated the mechanism underlying the dysregulation of miR-124. We found that (i) miR-124 directly targets the androgen receptor (AR) and subsequently induces an upregulation of p53; (ii) miR-124 is significantly downregulated in malignant prostatic cells compared to benign cells, and DNA methylation causes the reduced expression of miR-124; and (iii) miR-124 can inhibit the growth of CaP cells in vitro and in vivo. Data from this study revealed that loss of miR-124 expression is a common event in CaP, which may contribute to the pathogenesis of CaP. Our studies also suggest that miR-124 is a potential tumor suppressive gene in CaP, and restoration of miR-124 expression may represent a novel strategy for CaP therapy.


Interactions between the intrarenal dopaminergic and the renin-angiotensin systems in the control of systemic arterial pressure.
Systemic arterial hypertension is one of the leading causes of morbidity and mortality in the general population, being a risk factor for many cardiovascular diseases. Although its pathogenesis is complex and still poorly understood, some systems appear to play major roles in its development. This review aims to update the current knowledge on the interaction of the intrarenal renin-angiotensin system (RAS) and dopaminergic system in the development of hypertension, focusing on recent scientific hallmarks in the field. The intrarenal RAS, composed of several peptides and receptors, has a critical role in the regulation of blood pressure (BP) and, consequently, the development of hypertension. The RAS is divided into two main intercommunicating axes: the classical axis, composed of angiotensin-converting enzyme, angiotensin II, and angiotensin type 1 receptor, and the ACE2/angiotensin-(1-7)/Mas axis, which appears to modulate the effects of the classical axis. Dopamine and its receptors are also increasingly showing an important role in the pathogenesis of hypertension, as abnormalities in the intrarenal dopaminergic system impair the regulation of renal sodium transport, regardless of the affected dopamine receptor subtype. There are five dopamine receptors, which are divided into two major subtypes: the D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R) receptors. Mice deficient in any of the five dopamine receptor subtypes have increased BP. Intrarenal RAS and the dopaminergic system have complex interactions. The balance between both systems is essential to regulate the BP homeostasis, as alterations in the control of both can lead to hypertension.


Clinically oriented physiology teaching: strategy for developing critical-thinking skills in undergraduate medical students.
Medicine is an applied science, interpreting evidence and applying it to real life by using clinical reasoning skills and experience. COPT (clinically oriented physiology teaching) was incorporated in physiology instruction aiming to relate the study of physiology to real-life problems, to generate enthusiasm and motivation for learning, and to demonstrate the vocational relevance of physiology among students by integrating clinical experience with teaching. COPT consisted of two elements: 1) critical-thinking questions (CTQ) and 2) clinical case studies. After a few topics were taught, CTQ and case studies were given as an assignment. Answers were discussed in the next class. Two exams, each of which contained CTQ and recall questions, were conducted, one before (exam 1) and one after (exam 2) the implementation of COPT. Analysis of student performance in the examinations revealed that the students did better in exam 2 (P < 0.0001). Feedback from students indicated that this method was useful and challenging.


Proteome- and transcriptome-driven reconstruction of the human myocyte metabolic network and its use for identification of markers for diabetes.
Skeletal myocytes are metabolically active and susceptible to insulin resistance and are thus implicated in type 2 diabetes (T2D). This complex disease involves systemic metabolic changes, and their elucidation at the systems level requires genome-wide data and biological networks. Genome-scale metabolic models (GEMs) provide a network context for the integration of high-throughput data. We generated myocyte-specific RNA-sequencing data and investigated their correlation with proteome data. These data were then used to reconstruct a comprehensive myocyte GEM. Next, we performed a meta-analysis of six studies comparing muscle transcription in T2D versus healthy subjects. Transcriptional changes were mapped on the myocyte GEM, revealing extensive transcriptional regulation in T2D, particularly around pyruvate oxidation, branched-chain amino acid catabolism, and tetrahydrofolate metabolism, connected through the downregulated dihydrolipoamide dehydrogenase. Strikingly, the gene signature underlying this metabolic regulation successfully classifies the disease state of individual samples, suggesting that regulation of these pathways is a ubiquitous feature of myocytes in response to T2D.


Economic and social factors are some of the most common barriers preventing women from accessing maternal and newborn child health (MNCH) and prevention of mother-to-child transmission (PMTCT) services: a literature review.
Support to health programming has increasingly placed an emphasis on health systems strengthening. Integration of prevention of mother-to-child transmission (PMTCT) and maternal and newborn child health (MNCH) services has been one of the areas where there has been a shift from a siloed to a more integrated approach. The scale-up of anti-retroviral therapy has made services increasingly available while also bringing them closer to those in need. However, addressing supply side issues around the availability and quality of care at the health centre level alone cannot guarantee better results without a more explicit focus on access issues. Access to PMTCT care and treatment services is affected by a number of barriers which influence decisions of women to seek care. This paper reviews published qualitative and quantitative studies that look at demand side barriers to PMTCT services and proposes a categorisation of these barriers. It notes that access to PMTCT services as well as eventual uptake and retention in PMTCT care starts with access to MNCH in general. While poverty often prevents women, regardless of HIV status, from accessing MNCH services, women living with HIV who are in need of PMTCT services face an additional set of PMTCT barriers. This review proposes four categories of barriers to accessing PMTCT: social norms and knowledge, socioeconomic status, physiological status and psychological conditions. Social norms and knowledge and socioeconomic status stand out. Transport is the most frequently mentioned socioeconomic barrier. With regard to social norms and knowledge, non-disclosure, stigma and partner relations are the most commonly cited barriers. Some studies also cite physiological barriers. Barriers related to social norms and knowledge, socioeconomic status and physiology can all be affected by the mental and psychological state of the individual to create a psychological barrier to access. Increased coverage and uptake of PMTCT services can be achieved if policy makers and programme managers better understand the barriers that may prevent their potential target population from taking up and adhering to their services. The categorisation presented in this review provides further insight into the type of barriers that may exist .


Anti-platelet effects of olive oil extract: in vitro functional and proteomic studies.
Platelets play a key role in haemostasis and wound healing, contributing to formation of vascular plugs. They are also involved in formation of atherosclerosic plaques. Some traditional diets, like the Mediterranean diet, are associated with a lower risk of cardiovascular disease. Components in these diets may have anti-platelet functions contributing to their health benefits. We studied the effects of alperujo extract, an olive oil production waste product containing the majority of polyphenols found in olive fruits, through measurement of effects on platelet aggregation and activation in isolated human platelets, and through identification of changes in the platelet proteome. Alperujo extract (40 mg/L) significantly decreased in vitro ADP- (p = 0.002) and TRAP- (p = 0.02) induced platelet activation as measured by the flow cytometry using the antibody for p-selectin (CD62p), but it did not affect the conformation of the fibrinogen receptor as measured by flow cytometry using the antibodies for anti-fibrinogen, CD42a and CD42b. Alperujo extract (100 mg/L) inhibited both collagen- and TRAP-induced platelet aggregation by 5% (p < 0.05), and a combination of hydroxytyrosol and 3,4-dihydroxyphenylglycol were, at least partly, responsible for this effect. Proteomic analysis identified nine proteins that were differentially regulated by the alperujo extract upon ADP-induced platelet aggregation. These proteins represent important mechanisms that may underlie the anti-platelet effects of this extract: regulation of platelet structure and aggregation, coagulation and apoptosis, and signalling by integrin αIIb/β3. Alperujo extract may protect against platelet activation, platelet adhesion and possibly have anti-inflammatory properties.


Proteome profile of the endomembrane of developing coleoptiles from switchgrass (Panicum virgatum).
The cost-effective production of biofuels from lignocellulosic material will likely require manipulation of plant biomass, specifically cell walls. The North American native prairie grass Panicum virgatum (switchgrass) is seen as a potential biofuel crop with an array of genetic resources currently being developed. We have characterized the endomembrane proteome of switchgrass coleoptiles to provide additional information to the switchgrass community. In total, we identified 1750 unique proteins from two biological replicates. These data have been deposited in the ProteomeXchange with the identifier PXD001351 (http://proteomecentral.proteomexchange.org/dataset/PXD001351).


The relation of object naming and other visual speech production tasks: a large scale voxel-based morphometric study.
We report a lesion-symptom mapping analysis of visual speech production deficits in a large group (280) of stroke patients at the sub-acute stage (<120 days post-stroke). Performance on object naming was evaluated alongside three other tests of visual speech production, namely sentence production to a picture, sentence reading and nonword reading. A principal component analysis was performed on all these tests' scores and revealed a 'shared' component that loaded across all the visual speech production tasks and a 'unique' component that isolated object naming from the other three tasks. Regions for the shared component were observed in the left fronto-temporal cortices, fusiform gyrus and bilateral visual cortices. Lesions in these regions linked to both poor object naming and impairment in general visual-speech production. On the other hand, the unique naming component was potentially associated with the bilateral anterior temporal poles, hippocampus and cerebellar areas. This is in line with the models proposing that object naming relies on a left-lateralised language dominant system that interacts with a bilateral anterior temporal network. Neuropsychological deficits in object naming can reflect both the increased demands specific to the task and the more general difficulties in language processing.


Laughter's influence on the intimacy of self-disclosure.
If laughter functions to build relationships between individuals, as current theory suggests, laughter should be linked to interpersonal behaviors that have been shown to be critical to relationship development. Given the importance of disclosing behaviors in facilitating the development of intense social bonds, it is possible that the act of laughing may temporarily influence the laugher's willingness to disclose personal information. We tested this hypothesis experimentally by comparing the characteristics of self-disclosing statements produced by those who had previously watched one of three video clips that differed in the extent to which they elicited laughter and positive affect. The results show that disclosure intimacy is significantly higher after laughter than in the control condition, suggesting that this effect may be due, at least in part, to laughter itself and not simply to a change in positive affect. However, the disclosure intimacy effect was only found for observers' ratings of participants' disclosures and was absent in the participants' own ratings. We suggest that laughter increases people's willingness to disclose, but that they may not necessarily be aware that it is doing so.


An outbreak of acute haemorrhagic conjunctivitis in Melaka, Malaysia.
This paper reports a second outbreak of acute haemorrhagic conjunctivitis due to coxsackievirus A24 in peninsular Malaysia. Between June 2002 and early October 2003, 10,327 patients, comprising 3,261 children and 7,066 adults, were treated for acute conjunctivitis in 11 government health clinics in the Melaka Tengah district of the state of Melaka. The figure grossly underestimates the size of the outbreak; as no patients treated in private clinics in the same district were included. Institution and household surveillance showed that the commonest presenting clinical feature of the illness was eye-discharge (91.2%), followed by foreign body sensation (81.8%), pain (78.3%) and subconjunctival haemorrhage (74.4%). The mean duration of illness was 6.5 and five days for patients with and without subconjunctival haemorrhage respectively.


Flickering admissibility: neuroimaging evidence in the U.S. courts.
This article explores the admissibility of neuroimaging evidence in U.S. courts, recognizing various trends in decisions about such evidence.While courts have routinely admitted some neuroimages, such as CT scans and MRI, as proof of trauma and disease, they have been more circumspect about admitting the PET and SPECT scans and fMRI evidence. With the latter technologies, courts have often expressed reservations about what can be inferred from the images. Moreover, courts seem unwilling to find neuroimaging sufficient to prove either insanity or incompetency, but are relatively lenient about admitting neuroimages in death penalty hearings. Some claim that fMRI and "brain fingerprinting" are able to detect deception. Other scholars argue that brain fingerprinting is a dubious concept and that fMRI is not yet sufficiently reliable. Moreover, there are substantial concerns about privacy and the perils of mind reading implicit in such technology. Yet, there is a movement to try to make these new technologies "courtroom ready" in the near future, raising a host of legal, policy, and ethical questions to be answered.


Land-use type and intensity differentially filter traits in above- and below-ground arthropod communities.
Along with the global decline of species richness goes a loss of ecological traits. Associated biotic homogenization of animal communities and narrowing of trait diversity threaten ecosystem functioning and human well-being. High management intensity is regarded as an important ecological filter, eliminating species that lack suitable adaptations. Below-ground arthropods are assumed to be less sensitive to such effects than above-ground arthropods. Here, we compared the impact of management intensity between (grassland vs. forest) and within land-use types (local management intensity) on the trait diversity and composition in below- and above-ground arthropod communities. We used data on 722 arthropod species living above-ground (Auchenorrhyncha and Heteroptera), primarily in soil (Chilopoda and Oribatida) or at the interface (Araneae and Carabidae). Our results show that trait diversity of arthropod communities is not primarily reduced by intense local land use, but is rather affected by differences between land-use types. Communities of Auchenorrhyncha and Chilopoda had significantly lower trait diversity in grassland habitats as compared to forests. Carabidae showed the opposite pattern with higher trait diversity in grasslands. Grasslands had a lower proportion of large Auchenorrhyncha and Carabidae individuals, whereas Chilopoda and Heteroptera individuals were larger in grasslands. Body size decreased with land-use intensity across taxa, but only in grasslands. The proportion of individuals with low mobility declined with land-use intensity in Araneae and Auchenorrhyncha, but increased in Chilopoda and grassland Heteroptera. The proportion of carnivorous individuals increased with land-use intensity in Heteroptera in forests and in Oribatida and Carabidae in grasslands. Our results suggest that gradients in management intensity across land-use types will not generally reduce trait diversity in multiple taxa, but will exert strong trait filtering within individual taxa. The observed patterns for trait filtering in individual taxa are not related to major classifications into above- and below-ground species. Instead, ecologically different taxa resembled each other in their trait diversity and compositional responses to land-use differences. These previously undescribed patterns offer an opportunity to develop management strategies for the conservation of trait diversity across taxonomic groups in permanent grassland and forest habitats.


Steady-state and femtosecond transient absorption spectroscopy of new two-photon absorbing fluorene-containing quinolizinium cation membrane probes.
The synthesis, linear photophysical characterization, and nonlinear optical properties of two new symmetrical fluorene-containing quinolizinium derivatives, 2,8-bis((E)-2-(7-(diphenylamino)-9,9-dihexyl-9H-fluoren-2-yl)vinyl)quinolizinium hexafluorophosphate (1) and 2,8-bis((E)-2-(7-((7-(diphenylamino)-9,9-dihexyl-9H-fluoren-2-yl)ethynyl)-9,9-dihexyl-9H-fluoren-2yl)vinyl)quinolizinium hexafluorophosphate (2), are reported. The nature of the dual-band steady-state fluorescence emission of 1 and 2 was determined, and violation of Kasha's rule along with a strong dependence on solvent polarity were shown. A relatively complex structure of two-photon absorption (2PA) spectra of 1 and 2, with maximum cross sections of ∼400-600 GM, was determined using the open aperture Z-scan method. Different types of fast relaxation processes with characteristic times of 0.3-0.5 ps and 1.5-2 ps were observed in the excited states of the new compounds via femtosecond transient absorption pump-probe spectroscopy. To better understand the photophysical behavior of 1 and 2, a quantum-mechanical study was undertaken using TD-DFT and ZINDO/S methods. Simulated linear absorption spectra were found to be in good agreement with experimental data, while 2PA cross sections were overestimated. Although the new dyes were highly fluorescent in nonpolar solvents, they were essentially nonfluorescent in polar media. Significantly, the quinolizinium dyes exhibited fluorescence turn-on behavior upon binding to bovine serum album (BSA) protein, exhibiting over 4-fold fluorescence enhancement, which was a finding that was leveraged to demonstrate cell membrane fluorescence imaging of HeLa cells.


Gingival condition and tooth-brushing behavior after alcohol consumption.
Various studies have reported the relationship between alcohol consumption and gingival condition. However, they focus on the direct effects of alcohol consumption or alcohol sensitivity on gingival condition, and it is unclear how oral health behaviors relate these relationships. The aims of this study were to assess the inter-relationships between gingival condition, tooth-brushing behavior after drinking alcohol and alcohol sensitivity in university students who drink more than once per week on average. A total of 808 students (541 males, 267 females) that habitually consume alcohol were analyzed. The disease activity of gingival condition was assessed as the percentage of bleeding on probing (%BOP). Additional information regarding alcohol sensitivity and oral health behaviors, including tooth-brushing behavior after drinking, were also collected. Thirteen percent of the current participants reported neglecting tooth-brushing after drinking, and their alcohol consumption was higher than those who did not neglect tooth-brushing. Logistic regression analysis showed that high %BOP (%BOP ≥ 20) was associated with male (OR = 1.53; 95% CI, 1.01-2.33), neglect of tooth-brushing after drinking (OR = 2.60; 95% CI, 1.20-5.61) and debris index (OR = 8.38; 95% CI, 4.24-16.60) in participants with low alcohol sensitivity. In participants with high alcohol sensitivity, high %BOP was associated with debris index (OR = 7.60; 95% CI, 3.12-18.51), but not with any oral health behaviors. The study revealed that alcohol consumption was indirectly related to gingival disease activity through the neglect of tooth-brushing after drinking alcohol in university students with low alcohol sensitivity.


Evidence for the transmission of parvovirus B19 in patients with bleeding disorders treated with plasma-derived factor concentrates in the era of nucleic acid test screening.
Parvovirus B19 (B19V) is a small, nonenveloped virus that typically causes a benign flu-like illness that occurs most frequently in childhood. The virus is resistant to current viral inactivation steps used in the manufacture of antihemophilic factor concentrates and B19V transmission through these products has been documented. Since 2000, B19V nucleic acid test (NAT) screening of plasma pools has been implemented to further decrease the viral burden in these products, but no study has examined populations using these products to assess the impact of the screening on B19V transmission. Blood specimens obtained from participants of a surveillance system established in federally supported specialized bleeding disorders clinics were used in a B19V seroprevalence study. A total of 1643 specimens from 1043 participants age 2 to 7 years born after B19V NAT screening was implemented were tested. Age-specific prevalence rates were generally higher for subjects exposed to either plasma-derived products alone or in combination with other products compared to subjects with no exposure to antihemophilic products. Overall, compared to participants unexposed to blood or blood products, those exposed to plasma-derived products alone were 1.7 times more likely to have antibodies to B19V (p = 0.002). These results are consistent with continued B19V transmission through plasma-derived factor concentrates. Effective viral inactivation and detection processes are needed to protect users of these products from infection with B19V or other new or emerging viruses.


In vitro activity of tedizolid against Staphylococcus aureus and Streptococcus pneumoniae collected in 2013 and 2014 from sites in Latin American countries, Australia, New Zealand, and China.
Tedizolid is an oxazolidinone with an antimicrobial in vitro potency advantage against Gram-positive bacterial pathogens compared to other currently marketed drugs in this class, including linezolid. Tedizolid was compared to linezolid when tested against Staphylococcus aureus and Streptococcus pneumoniae isolates collected from countries in Latin America and the Asia-Pacific. Isolates were tested by broth microdilution susceptibility methods against tedizolid, linezolid, and non-class comparators in accordance with the Clinical and Laboratory Standards Institute (CLSI) guidelines. The activity of tedizolid against S. aureus was potent and consistent in Latin America (MIC90, 0.5 mg/L), Australia and New Zealand (MIC90, 0.25 mg/L), and China (MIC90, 0.5 mg/L). Based on MIC90 results, tedizolid was four- to eight-fold more active than linezolid against S. aureus, including both methicillin-susceptible and -resistant isolates. Only two tedizolid non-susceptible strains were observed; both had intermediate minimum inhibitory concentration (MIC) values of 1 mg/L, for which the MICs of linezolid was higher (≥2 mg/L). Tedizolid (MIC90, 0.25 mg/L) was four-fold more potent than linezolid (MIC90, 1 mg/L) against S. pneumoniae in all countries that provided isolates. The findings from this study support the global clinical development of tedizolid for Gram-positive infections.


Integration of bilateral whisker stimuli in rats: role of the whisker barrel cortices.
Recently, we demonstrated that neural responses within the whisker region of the primary somatosensory cortex (SIw) of rats are profoundly influenced by the spatiotemporal attributes of ipsilateral, as well as contralateral, whisker stimuli. As inactivation of one SIw eliminates in the intact SIw both ipsilaterally evoked responses and the influence of ipsilateral stimulation on contralaterally evoked activity, we proposed that interhemispheric interactions between the SIws may be important for integrating bilateral whisker information. To test whether rats can recognize the bilateral nature of a whisker stimulus, we developed a tactile discrimination task that required rats to conjointly determine distances to a left and a right discriminandum as equidistant or non-equidistant using only their facial whiskers. All rats trained in this task achieved performance levels indicative of an ability to integrate bilateral whisker information. Testing during unilateral, as well as bilateral, inactivation of the SIws indicated that rats rely on both SIws for detecting the bilateral nature of a whisker stimulus. Rats were unable to perform the task without both sets of whiskers, a fact that indicates that the whiskers (and not other modalities) were used to perform this task. The findings presented here indicate that rats can solve a task that requires the conjoint detection of left and right whisker-mediated distance information and implicate the SIws as central to this ability.


Onion structure and network robustness.
In a recent work [Proc. Natl. Acad. Sci. USA 108, 3838 (2011)], Schneider et al. proposed a new measure for network robustness and investigated optimal networks with respect to this quantity. For networks with a power-law degree distribution, the optimized networks have an onion structure-high-degree vertices forming a core with radially decreasing degrees and an over-representation of edges within the same radial layer. In this paper we relate the onion structure to graphs with good expander properties (another characterization of robust network) and argue that networks of skewed degree distributions with large spectral gaps (and thus good expander properties) are typically onion structured. Furthermore, we propose a generative algorithm producing synthetic scale-free networks with onion structure, circumventing the optimization procedure of Schneider et al. We validate the robustness of our generated networks against malicious attacks and random removals.


Nonalcoholic fatty liver disease: a potential consequence of tumor necrosis factor-inhibitor therapy.
Although tumor necrosis factor inhibitors (TNFi) might be expected to protect against nonalcoholic fatty liver disease (NAFLD), we have seen patients who appeared to develop NAFLD during TNFi treatment. We aimed to explore risk factors for this TNFi complication in a case-control study. We reviewed clinic records at our VA hospital to identify patients with inflammatory diseases who developed aminotransferase elevations during TNFi therapy and who had liver biopsies showing NAFLD. These patients were matched with patients in each of three control groups: (i) inflammatory disease controls: patients on TNFi treatment with normal aminotransferase levels, (ii) nonalcoholic steatohepatitis (NASH) controls: patients with biopsy-proven NASH with no other inflammatory disease, and (iii) healthy controls. Genotyping was performed for PNPLA3, a gene predisposing to NASH. We identified eight cases (five steatohepatitis, three steatosis); elevated aminotransferase levels were first observed 1-63 months into TNFi therapy (average 12 months). TNFi therapy was stopped in five patients, whose aminotransferase levels then normalized within 2-8 months. There were no significant differences between cases and inflammatory disease controls in the frequency of features of metabolic syndrome. Cases had more methotrexate exposure than inflammatory controls (50 vs. 12.5%, P=0.28). PNPLA3 genotyping revealed mutations in 75% of cases, 38% of inflammatory controls, 88% of NASH controls, and 63% of healthy controls (P=NS). Our findings suggest that NAFLD can be a side effect of TNFi therapy, and that methotrexate exposure and PNPLA3 gene mutations might be risk factors. Further studies are needed to determine how TNFi causes NAFLD and to confirm these risk factors.


The eukaryotic promoter database in its 30th year: focus on non-vertebrate organisms.
We present an update of the Eukaryotic Promoter Database EPD (http://epd.vital-it.ch), more specifically on the EPDnew division, which contains comprehensive organisms-specific transcription start site (TSS) collections automatically derived from next generation sequencing (NGS) data. Thanks to the abundant release of new high-throughput transcript mapping data (CAGE, TSS-seq, GRO-cap) the database could be extended to plant and fungal species. We further report on the expansion of the mass genome annotation (MGA) repository containing promoter-relevant chromatin profiling data and on improvements for the EPD entry viewers. Finally, we present a new data access tool, ChIP-Extract, which enables computational biologists to extract diverse types of promoter-associated data in numerical table formats that are readily imported into statistical analysis platforms such as R.


Is quantitative angiography sufficient to guide stent implantation? A comparison with three-dimensional reconstruction of intracoronary ultrasound images.
Intracoronary ultrasound (ICUS) frequently reveals stent underexpansion despite a satisfactory angiographic result by visual assessment. Whether on-line quantitative coronary angiography (QCA) alone can guide optimal stent deployment is still unknown. The aim of the study was to assess the usefulness of quantitative coronary angiography in the evaluation of optimal stent expansion, confirmed with a new on-line system of 3-D reconstruction of ICUS. The results obtained with 3-D ICUS were compared with the measurements achieved with QCA analyses in 49 patients (70 stents: 31 Palmaz-Schatz, 22 Wallstent, 7 Cordis, 6 Micro-stent, 2 Gianturco-Roubin, 2 Multi-Link). Following delivery of the stent, high pressure intrastent balloon inflation (14.2 +/- 3.3 atmospheres) was performed in all 70 stents. Optimal stent implantation by QCA was defined as minimal lumen diameter post-stenting > or = 90% of the reference diameter preintervention. Percent diameter stenosis (% DS) post-stenting was defined as minimal lumen diameter divided by the reference diameter post-stenting. The on-line 3-D ICUS reconstructions and measurements were performed processing the images on-line in the catheterization laboratory with an automated contour detection algorithm based on acoustic quantification. ICUS criteria for optimal stent expansion were defined as: 1) complete apposition of stent struts to vessel wall; 2) minimal stent lumen cross-sectional area > or = 80% of the average lumen area of the proximal and distal reference segments; 3) symmetry index (minimum divided by maximum lumen diameter) > 0.7. Ninety-seven percent of the deployed stents met the QCA criteria. Whilst 3-D ICUS documented complete stent apposition to the vessel wall in all cases and a symmetric expansion in 65 of 70 lesions (93%), the stent minimal lumen area was > or = 80% only in 30 out of 70 stents (43%). The diagnostic sensitivity and specificity at 10% residual diameter stenosis provided by QCA for optimal stent expansion compared to 3-D ICUS criteria were 86 and 45%, respectively. In conclusion 3-D ICUS criteria of adequate stent expansion were achieved only in 43% of patients despite the application of aggressive strategies of stent deployment leading to optimal results with quantitative angiography. Ten percent residual diameter stenosis provided by QCA may be an acceptable alternative for optimal stent deployment in clinical practice. The clinical benefit of an ICUS guided approach of stent deployment and of a lower cost strategy using on-line QCA guidance should be compared in large prospective randomized studies.


Factors influencing patient willingness to participate in genetic research after a myocardial infarction.
Achieving 'personalized medicine' requires enrolling representative cohorts into genetic studies, but patient self-selection may introduce bias. We sought to identify characteristics associated with genetic consent in a myocardial infarction (MI) registry. We assessed correlates of participation in the genetic sub-study of TRIUMPH, a prospective MI registry (n = 4,340) from 24 US hospitals between April 2005 and December 2008. Factors examined included extensive socio-demographics factors, clinical variables, and study site. Predictors of consent were identified using hierarchical modified Poisson regression, adjusting for study site. Variation in consent rates across hospitals were quantified by the median rate ratio (MRR). Most subjects consented to donation of their genetic material (n = 3,484; 80%). Participation rates varied greatly between sites, from 40% to 100%. After adjustment for confounding factors, the MRR for hospital was 1.22 (95% confidence interval (CI) 1.11 to 1.29). The only patient-level factors associated with consent were race (RR 0.93 for African Americans versus whites, 95% CI 0.88 to 0.99) and body mass index (RR 1.03 for BMI ≥ 25, 95% CI 1.01 to 1.06). Among patients with an MI there were notable differences in genetic consent by study site, but little association with patient-level factors. This suggests that variation in the way information is presented during recruitment, or other site factors, strongly influence patients' decision to participate in genetic studies.


Donor leukocyte infusions for multiple myeloma.
Donor leukocyte infusion (DLI) has well-documented activity in CML, but the role of DLI in other diseases is less well defined. To evaluate the strategy in multiple myeloma (MM) we evaluated 25 MM patients from 15 centers who were treated with DLI. Patients with persistent or recurrent disease after allogeneic BMT received DLI from the original marrow donor (23 matched related, one mismatched family, and one matched unrelated). Chemotherapy was given before DLI in three patients. Two of 22 patients responded completely to DLI alone and three patients responded to the combination of DLI and chemotherapy. Nine patients who had not had sufficient disease control after DLI were given additional DLIs; five of these patients had either complete (two) or partial (three) responses. Thirteen of 25 evaluable patients developed acute GVHD and 11 of 21 evaluable patients developed chronic GVHD; all responders developed GVHD. No patients developed post-DLI pancytopenia. Four patients had responses which lasted >1 year after DLI, three patients had responses which lasted <1 year, and three patients had ongoing responses but with follow-up <1 year. In conclusion, DLI has anti-myeloma activity but the strategy is limited by no response or short duration of response in a significant percentage of patients and by significant GVHD in the majority of the responders.


Open pipelines for integrated tumor genome profiles reveal differences between pancreatic cancer tumors and cell lines.
We describe open, reproducible pipelines that create an integrated genomic profile of a cancer and use the profile to find mutations associated with disease and potentially useful drugs. These pipelines analyze high-throughput cancer exome and transcriptome sequence data together with public databases to find relevant mutations and drugs. The three pipelines that we have developed are: (1) an exome analysis pipeline, which uses whole or targeted tumor exome sequence data to produce a list of putative variants (no matched normal data are needed); (2) a transcriptome analysis pipeline that processes whole tumor transcriptome sequence (RNA-seq) data to compute gene expression and find potential gene fusions; and (3) an integrated variant analysis pipeline that uses the tumor variants from the exome pipeline and tumor gene expression from the transcriptome pipeline to identify deleterious and druggable mutations in all genes and in highly expressed genes. These pipelines are integrated into the popular Web platform Galaxy at http://usegalaxy.org/cancer to make them accessible and reproducible, thereby providing an approach for doing standardized, distributed analyses in clinical studies. We have used our pipeline to identify similarities and differences between pancreatic adenocarcinoma cancer cell lines and primary tumors.


Adolescent immaturity in attention-related brain engagement to emotional facial expressions.
Selective attention, particularly during the processing of emotionally evocative events, is a crucial component of adolescent development. We used functional magnetic resonance imagining (fMRI) with adolescents and adults to examine developmental differences in activation in a paradigm that involved selective attention during the viewing of emotionally engaging face stimuli. We evaluated developmental differences in neural activation for three comparisons: (1) directing attention to subjective responses to fearful facial expressions relative to directing attention to a nonemotional aspect (nose width) of fearful faces, (2) viewing fearful relative to neutral faces while attending to a nonemotional aspect of the face, and (3) viewing fearful relative to neutral faces while attention was unconstrained (passive viewing). The comparison of activation across attention tasks revealed greater activation in the orbital frontal cortex in adults than in adolescents. Conversely, when subjects attended to a nonemotional feature, fearful relative to neutral faces influenced activation in the anterior cingulate more in adolescents than in adults. When attention was unconstrained, adolescents relative to adults showed greater activation in the anterior cingulate, bilateral orbitofrontal cortex, and right amygdala in response to the fearful relative to neutral faces. These findings suggest that adults show greater modulation of activity in relevant brain structures based on attentional demands, whereas adolescents exhibit greater modulation based on emotional content.


A polymorphic CYP19 TTTA repeat influences aromatase activity and estrogen levels in elderly men: effects on bone metabolism.
Current evidence suggests that estrogen plays a dominant role in determining bone mineral density (BMD) in men, and inactivating mutations in the aromatase CYP19 gene have been associated with low bone mass in young males. We previously reported an association between a TTTA repeat polymorphism in intron 4 of the CYP19 gene and osteoporotic risk in postmenopausal females. Here we explore the role of this polymorphism as a genetic determinant of BMD in a sample of elderly males who were recruited by direct mailing and followed longitudinally for 2 (n = 300) and 4 (n = 200) yr. Six different allelic variants, containing seven, eight, nine, 10, 11, and 12 TTTA repeats, were detected. There was a bimodal distribution of alleles, with two major peaks at seven and 11 repeats and a very low distribution of the nine-repeat allele. Men with a high-repeat genotype (>nine repeats) showed higher lumbar BMD values, lower bone turnover markers, higher estradiol levels, and a lower rate of BMD change than men with a low-repeat genotype (<nine repeats). The association with BMD was not significant in the subgroup of patients with high body mass index (>25), suggesting that the effect of CYP19 genotypes on bone may be masked by the increase in fat mass. Moreover, the high-repeat genotype was less represented, although not significantly, in the vertebral fracture group with respect to the nonvertebral fracture group. Functional in vitro analysis after incubation with [3H]-androstenedione showed a higher aromatase activity in fibroblasts from subjects with a high-repeat genotype than in fibroblasts from subjects with a low-repeat genotype. In conclusion, differences in estrogen levels due to polymorphism at the aromatase CYP19 gene may predispose men to increased age-related bone loss and fracture risk.


Comparative validity of physical activity measures in older adults.
To compare the validity of various physical activity measures with doubly labeled water (DLW)-measured physical activity energy expenditure (PAEE) in free-living older adults. Fifty-six adults aged ≥65 yr wore three activity monitors (New Lifestyles pedometer, ActiGraph accelerometer, and a SenseWear (SW) armband) during a 10-d free-living period and completed three different surveys (Yale Physical Activity Survey (YPAS), Community Health Activities Model Program for Seniors (CHAMPS), and a modified Physical Activity Scale for the Elderly (modPASE)). Total energy expenditure was measured using DLW, resting metabolic rate was measured with indirect calorimetry, the thermic effect of food was estimated, and from these, estimates of PAEE were calculated. The degree of linear association between the various measures and PAEE was assessed, as were differences in group PAEE, when estimable by a given measure. All three monitors were significantly correlated with PAEE (r=0.48-0.60, P<0.001). Of the questionnaires, only CHAMPS was significantly correlated with PAEE (r=0.28, P=0.04). Statistical comparison of the correlations suggested that the monitors were superior to YPAS and modPASE. Mean squared errors for all correlations were high, and the median PAEE from the different tools was significantly different from DLW for all but the YPAS and regression-estimated PAEE from the ActiGraph. Objective devices more appropriately rank PAEE than self-reported instruments in older adults, but absolute estimates of PAEE are not accurate. Given the cost differential and ease of use, pedometers seem most useful in this population when ranking by physical activity level is adequate.


Noribogaine, but not 18-MC, exhibits similar actions as ibogaine on GDNF expression and ethanol self-administration.
Ibogaine is a naturally occurring alkaloid that has been reported to decrease various adverse phenotypes associated with exposure to drugs of abuse and alcohol in human and rodent models. Unfortunately, ibogaine cannot be used as a medication to treat addiction because of severe side effects. Previously, we reported that the desirable actions of ibogaine to reduce self-administration of, and relapse to, alcohol consumption are mediated via the upregulation of the expression of the glial cell line-derived neurotrophic factor (GDNF) in the midbrain ventral tegmental area (VTA), and the consequent activation of the GDNF pathway. The ibogaine metabolite, noribogaine, and a synthetic derivative of ibogaine, 18-Methoxycoronaridine (18-MC), possess a similar anti-addictive profile as ibogaine in rodent models, but without some of its adverse side effects. Here, we determined whether noribogaine and/or 18-MC, like ibogaine, increase GDNF expression, and whether their site of action to reduce alcohol consumption is the VTA. We used SH-SY5Y cells as a cell culture model and found that noribogaine, like ibogaine, but not 18-MC, induces a robust increase in GDNF mRNA levels. Next, we tested the effect of intra-VTA infusion of noribogaine and 18-MC on rat operant alcohol self-administration and found that noribogaine, but not 18-MC, in the VTA decreases responding for alcohol. Together, our results suggest that noribogaine and 18-MC have different mechanisms and sites of action.


Quality of life in patients with lung cancer: a review of literature from 1970 to 1995.
A review of the literature was carried out covering the last 25 years (1970 to 1995) by searching through the MEDLINE and manually. The review consists of two companion parts. The first includes studies of quality of life in lung cancer patients in general, while the second part is restricted to defined samples of small and non-small cell lung cancer patients. Excluding non-English and review articles, in total 151 citations were identified and all have been reviewed. Over 50 instruments were used to measure quality of life in lung cancer studies. Of these, the European Organisation for Research and Treatment of Cancer Quality of Life Lung Cancer Questionnaire (EORTC QLQ-LC13) in conjunction with the core cancer questionnaire (QLQ-C30) was found to be the best developed instrument, although there were two other lung cancer-specific measures with good reliability and validity. Several topics in this chapter have been highlighted, including the importance of regularly measuring quality of life in lung cancer patients. Progress and achievements in areas such as performance status as a proxy of quality of life measure, psychological morbidity and symptom distress as predictive factors of quality of survival, and communication problems in quality of life studies of lung cancer patients have been emphasized and their implications in lung cancer care discussed. It is argued that palliation of symptoms, psychosocial interventions, and understanding patients' feelings and concerns all contribute to improving quality of life in lung cancer patients. It is concluded that the future challenge in treatment of lung cancer lies not only in improving the survival, but mainly the patients' quality of life regardless of cell type. Clinical trial and epidemiologic population-based outcome studies are recommended to provide this and to allow a better understanding of the contribution of the socioeconomic characteristics of the patients to their pretreatment and posttreatment quality of life.


Accumulation and loss of asymmetric non-CpG methylation during male germ-cell development.
DNA methylation is a well-characterized epigenetic modification involved in gene regulation and transposon silencing in mammals. It mainly occurs on cytosines at CpG sites but methylation at non-CpG sites is frequently observed in embryonic stem cells, induced pluriotent stem cells, oocytes and the brain. The biological significance of non-CpG methylation is unknown. Here, we show that non-CpG methylation is also present in male germ cells, within and around B1 retrotransposon sequences interspersed in the mouse genome. It accumulates in mitotically arrested fetal prospermatogonia and reaches the highest level by birth in a Dnmt3l-dependent manner. The preferential site of non-CpG methylation is CpA, especially CpApG and CpApC. Although CpApG (and CpTpG) sites contain cytosines at symmetrical positions, hairpin-bisulfite sequencing reveals that they are hemimethylated, suggesting the absence of a template-dependent copying mechanism. Indeed, the level of non-CpG methylation decreases after the resumption of mitosis in the neonatal period, whereas that of CpG methylation does not. The cells eventually lose non-CpG methylation by the time they become spermatogonia. Our results show that non-CpG methylation accumulates in non-replicating, arrested cells but is not maintained in mitotically dividing cells during male germ-cell development.


Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU.
To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU. Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines' development. A general content review was completed face-to-face by all panel members in January 2017. Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as "strong," "conditional," or "good" practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified. The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation. We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.


Whole-genome profiling of primary cutaneous anaplastic large cell lymphoma.
Primary cutaneous anaplastic large cell lymphoma (pcALCL), a hematological neoplasm caused by skin-homing CD30+ malignant T cells, is part of the spectrum of primary cutaneous CD30+ lymphoproliferative disorders. To date, only a small number of molecular alterations have been described in pcALCL and, so far, no clear unifying theme that could explain the pathogenetic origin of the disease has emerged among patients. In order to clarify the pathogenetic basis of pcALCL, we performed high-resolution genetic profiling (genome/transcriptome) of this lymphoma (n=12) by using whole-genome sequencing, whole-exome sequencing and RNA sequencing. Our study, which uncovered novel genomic rearrangements, copy number alterations and small-scale mutations underlying this malignancy, revealed that the cell cycle, T-cell physiology regulation, transcription and signaling via the PI-3-K, MAPK and G-protein pathways are cellular processes commonly impacted by molecular alterations in patients with pcALCL. Recurrent events affecting cancer-associated genes included deletion of PRDM1 and TNFRSF14, gain of EZH2 and TNFRSF8, small-scale mutations in LRP1B, PDPK1 and PIK3R1 and rearrangements involving GPS2, LINC-PINT and TNK1. Consistent with the genomic data, transcriptome analysis uncovered upregulation of signal transduction routes associated with the PI-3-K, MAPK and G-protein pathways (e.g., ERK, phospholipase C, AKT). Our molecular findings suggest that inhibition of proliferation-promoting pathways altered in pcALCL (particularly PI-3-K/AKT signaling) should be explored as potential alternative therapy for patients with this lymphoma, especially, for cases that do not respond to first-line skin-directed therapies or with extracutaneous disease.


A descriptive analysis of young women's pornography use: a tale of exploration and harm.
Background Despite viewing less often than young men, young women view pornography. This study used an online survey to describe young women's pornography use and their reflections on the influence of this use. Young Australian women (15-29 years) were recruited via Facebook to complete an online survey in 2016. Respondents who had ever viewed pornography (n = 491) were asked 10 closed-ended questions related to their exposure to pornography and an open-ended question: 'How has pornography influenced your life?'. Quantitative responses were descriptively analysed. Qualitative responses were thematically analysed using a descriptive qualitative approach. Most respondents (89%) watched pornography alone for sexual arousal and openly reflected on the influence of their own use. Two overarching themes were identified across qualitative data. The first, exploration, included positive sub-themes of safety, independence, normalisation of sexuality and diversity in body type. The second, harm, included negative sub-themes related to conditioning, comparison and dependency. Themes were identified separately among two discrete groups, but were also described concurrently among a third group of (mostly older) respondents who experienced pornography both as a place for exploration and as a potential source of harm. Young women watch pornography and have positive, negative and mixed experiences that they link to their own viewing. Future research must provide a safe space for young women to be honest regarding their pornography use to ensure that their perspectives are heard and understood.


Interpreting machine learning models to investigate circadian regulation and facilitate exploration of clock function.
The circadian clock is an important adaptation to life on Earth. Here, we use machine learning to predict complex, temporal, and circadian gene expression patterns in Arabidopsis Most significantly, we classify circadian genes using DNA sequence features generated de novo from public, genomic resources, facilitating downstream application of our methods with no experimental work or prior knowledge needed. We use local model explanation that is transcript specific to rank DNA sequence features, providing a detailed profile of the potential circadian regulatory mechanisms for each transcript. Furthermore, we can discriminate the temporal phase of transcript expression using the local, explanation-derived, and ranked DNA sequence features, revealing hidden subclasses within the circadian class. Model interpretation/explanation provides the backbone of our methodological advances, giving insight into biological processes and experimental design. Next, we use model interpretation to optimize sampling strategies when we predict circadian transcripts using reduced numbers of transcriptomic timepoints. Finally, we predict the circadian time from a single, transcriptomic timepoint, deriving marker transcripts that are most impactful for accurate prediction; this could facilitate the identification of altered clock function from existing datasets.


Influence of Method of Teaching Endodontics on the Self-Efficacy and Self-Perceived Competence of Undergraduate Dental Students.
This study assessed whether self-efficacy and the self-perceived competence of undergraduate dental students had been influenced by the method of teaching endodontics. Certain modules of the undergraduate endodontic programme at the Academic Centre for Dentistry Amsterdam (ACTA) including the tutorials, the clinical training and the assessment were revised. The self-efficacy and self-perceived competence close to graduation of an intermediate cohort of 24 students who attended all or some of the former modules or the revised modules were assessed. Additionally, the performance of students in performing root canal treatments was assessed according to predetermined criteria. Data were analysed using Cohen's Kappa, Cronbach's Alpha, Mann-Whitney and T-tests. Self-efficacy and the self-perceived competence of students who followed the former modules of clinical training and assessment were similar to those of students who followed the revised modules. The revised module with higher number of tutorials increased students' self-perceived competence, but did not influence their self-efficacy statistically significantly. Not the entire number, but the number of root canal treatments performed under supervision of endodontists was related with an increase in students' self-efficacy and self-perceived competence. The performance of students in performing root canal tretaments was not statistically significantly related to their self-efficacy and self-perceived competence. Among the modules and their components assessed in the present study, only the number of tutorials and the number of root canal treatments performed under supervision of endodontists influenced the self-efficacy and the self-perceived competence of students.


Home-prepared anatase, rutile, and brookite TiO(2) for selective photocatalytic oxidation of 4-methoxybenzyl alcohol in water: reactivity and ATR-FTIR study.
TiO(2) catalysts of anatase, rutile and brookite phase were prepared at low temperature and tested for carrying out the photocatalytic partial oxidation of 4-methoxybenzyl alcohol to 4-methoxybenzaldehyde (p-anisaldehyde) in organic-free water suspensions. Traces of 4-methoxybenzoic acid and open-ring products were the only by-products present, CO(2) being the other main oxidation product. Rutile exhibited the highest yield to p-anisaldehyde (62% mol) at a rate of the same order of magnitude of that showed by the other samples. Commercial rutile and anatase photocatalysts were also used for the sake of comparison. The samples have been characterised by an in situ ATR-FTIR investigation carried out in conditions simulating the photoreaction ones.


Genetic and phenotypic characterization of recently discovered enterovirus D type 111.
Members of the species Enterovirus D (EV-D) remain poorly studied. The two first EV-D types (EV-D68 and EV-D70) have regularly caused outbreaks in humans since their discovery five decades ago but have been neglected until the recent occurrence of severe respiratory diseases due to EV-D68. The three other known EV-D types (EV-D94, EV-D111 and EV-D120) were discovered in the 2000s-2010s in Africa and have never been observed elsewhere. One strain of EV-D111 and all known EV-D120s were detected in stool samples of wild non-human primates, suggesting that these viruses could be zoonotic viruses. To date, EV-D111s are only known through partial genetic sequences of the few strains that have been identified so far. In an attempt to bring new pieces to the puzzle, we genetically characterized four EV-D111 strains (among the seven that have been reported until now). We observed that the EV-D111 strains from human samples and the unique simian EV-D111 strain were not phylogenetically distinct, thus suggesting a recent zoonotic transmission. We also discovered evidences of probable intertypic genetic recombination events between EV-D111s and EV-D94s. As recombination can only happen in co-infected cells, this suggests that EV-D94s and EV-D111s share common replication sites in the infected hosts. These sites could be located in the gut since the phenotypic analysis we performed showed that, contrary to EV-D68s and like EV-D94s, EV-D111s are resistant to acid pHs. We also found that EV-D111s induce strong cytopathic effects on L20B cells, a cell line routinely used to specifically detect polioviruses. An active circulation of EV-D111s among humans could then induce a high number of false-positive detection of polioviruses, which could be particularly problematic in Central Africa, where EV-D111 circulates and which is a key region for poliovirus eradication.


Three-year effectiveness of intravenous pamidronate versus pamidronate plus slow-release sodium fluoride for postmenopausal osteoporosis.
All currently available and approved therapies for osteoporosis inhibit bone resorption. But, despite their great value, antiresorptive agents are generally not associated with dramatic increases in bone mass. In light of these data, the aim of our prospective, placebo-controlled, randomized clinical trial, with a 3-year follow up, was to examine the effects of cyclic intravenous pamidronate and fluoride in combination, versus pamidronate alone, on bone mineral density (BMD) at vertebral and femoral levels, biochemical markers of bone turnover, IGF-1 serum levels, and safety and tolerability in 40 postmenopausal women with osteoporosis. During the treatment period, pamidronate alone reduced both markers of bone formation and bone resorption, resulting in an increase of BMD, after 3 years, of 7.07% at the lumbar level and of 6.76% at the femoral level. In the group treated with pamidronate and fluoride, markers of bone turnover had a different trend: after 3 years, there was a lower reduction of bone resorption and an increase of bone formation markers, with a concomitant increase in IGF-1 levels. This resulted, after 3 years of treatment, in a marked variation of BMD at the lumbar level (+12.74%) and a reduced, but still significant, increase at the femoral level (3.89%). Spine radiography and clinical evaluation did not reveal any vertebral fractures in either treatment group. In conclusion, the combined use of pamidronate and fluoride produced somewhat larger, continuous increases in BMD, at the lumbar level, than pamidronate alone.


Epigallocatechin-3-gallate preferentially induces aggregation of amyloidogenic immunoglobulin light chains.
Antibody light chain amyloidosis is a rare disease caused by fibril formation of secreted immunoglobulin light chains (LCs). The huge variety of antibody sequences puts a serious challenge to drug discovery. The green tea polyphenol epigallocatechin-3-gallate (EGCG) is known to interfere with fibril formation in general. Here we present solution- and solid-state NMR studies as well as MD simulations to characterise the interaction of EGCG with LC variable domains. We identified two distinct EGCG binding sites, both of which include a proline as an important recognition element. The binding sites were confirmed by site-directed mutagenesis and solid-state NMR analysis. The EGCG-induced protein complexes are unstructured. We propose a general mechanistic model for EGCG binding to a conserved site in LCs. We find that EGCG reacts selectively with amyloidogenic mutants. This makes this compound a promising lead structure, that can handle the immense sequence variability of antibody LCs.


Frequency and Spectrum of Unexpected Clinical Manifestations of Primary HIV-1 Infection.
Prospectively and systematically collected data on frequency and spectrum of unexpected clinical manifestations during primary human immunodeficiency virus (HIV) infection (PHI) have not been published. We prospectively enrolled 290 patients with documented PHI in the Zurich Primary HIV Infection Study. Typical acute retroviral syndrome (ARS) was defined as fever plus at least 1 symptom or sign typically considered to be associated with ARS; in absence of fever, presence of 2 or more ARS symptoms or signs. Atypical ARS was defined as lack of symptoms or signs, a single symptom or sign only and absence of fever, presence of symptoms or signs that are not considered typically associated with ARS, or occurrence of an opportunistic disease. Time to diagnosis was calculated based on estimated date of infection and first positive HIV test. We analyzed 290 patients (271 males). PHI manifested with typical ARS in 202 (70%) and with atypical ARS in 88 (30%) patients. Patients with atypical ARS were hospitalized 4 times more often compared with typical ARS (43% vs 11%; P < .001). The gastrointestinal tract was the most frequent organ system affected in patients with atypical manifestations. Only in 112 (38%) patients was HIV infection suspected during the first medical attendance. Patients with typical ARS were diagnosed slightly earlier compared with atypical ARS, but this difference was not significant (P = .3). Unexpected clinical presentations occurred in a large fraction of patients with PHI and were associated with substantial morbidity. Universal HIV testing may be mandatory in high-risk groups.


Recommended irrigation volume for an intravenous port: Ex vivo simulation study.
An intravenous port, which differs from a central venous catheter, has an injection chamber at the end of the catheter. This structural difference causes the irrigation flow pattern to be quite different from that of the central venous catheter. Furthermore, the intraluminal volume differs due to the size of the injection chamber and implanted catheter length. Hence, the ideal recommended irrigation volume varies because of differences in intraluminal volume, however, the recommended irrigation volume is 10 ml and may be a cause for reported port malfunctions. This study investigates the best irrigation volume for an intravenous port by simulating the clinical scenario ex-vivo to access its usefulness. This study was composed of two tests. The irrigation volume test attempted to quantify the irrigation volume of an implanted port while the irrigation rate test attempted to simulate daily nursing practice in order to clarify the effect of irrigation flow. The human blood needed for the simulation was donated by volunteers and the total volume was 10 ml per test. The irrigation volume test was done by syringe pump with varying pre-set irrigation volume after the port and connected catheter were filled with volunteer blood. After irrigation with pre-set volume, the retained intraluminal solution was collected and quantified by Bradford assay in order to titrate the best irrigation volume. The irrigation rate test tried to simulate daily maintenance practice in different settings with the quantified irrigation volume as identified by the irrigation volume test. The retained intraluminal solution was collected and quantified by Bradford assay in order to confirm the efficacy of the quantified irrigation volume. In both SVC and IVC ports, we identified the twenty times the intravascular volume as sufficient for a complete wash out of the blood component in the irrigation volume test. The minimal irrigation volume for SVC and IVC port were 10 ml and 15.6 ml respectively. In irrigation rate test, the irrigation for SVC and IVC port was 10 and 20 ml, respectively, for the sake of preparation convenience. We not only identified the importance of preparation, i.e. irrigation of the extension line but also confirmed the efficacy of the recommended irrigation volume. The irrigation volume should be varied according to the intraluminal volume. Maintenance should be performed after the extension line has been irrigated. The recommended port irrigation volume for SVC and IVC route were 10 and 20 ml, respectively.


Clinical Diagnosis of Bordetella Pertussis Infection: A Systematic Review.
Bordetella pertussis (BP) is a common cause of prolonged cough. Our objective was to perform an updated systematic review of the clinical diagnosis of BP without restriction by patient age. We identified prospective cohort studies of patients with cough or suspected pertussis and assessed study quality using QUADAS-2. We performed bivariate meta-analysis to calculate summary estimates of accuracy and created summary receiver operating characteristic curves to explore heterogeneity by vaccination status and age. Of 381 studies initially identified, 22 met our inclusion criteria, of which 14 had a low risk of bias. The overall clinical impression was the most accurate predictor of BP (positive likelihood ratio [LR+], 3.3; negative likelihood ratio [LR-], 0.63). The presence of whooping cough (LR+, 2.1) and posttussive vomiting (LR+, 1.7) somewhat increased the likelihood of BP, whereas the absence of paroxysmal cough (LR-, 0.58) and the absence of sputum (LR-, 0.63) decreased it. Whooping cough and posttussive vomiting have lower sensitivity in adults. Clinical criteria defined by the Centers for Disease Control and Prevention were sensitive (0.90) but nonspecific. Typical signs and symptoms of BP may be more sensitive but less specific in vaccinated patients. The clinician's overall impression was the most accurate way to determine the likelihood of BP infection when a patient initially presented. Clinical decision rules that combine signs, symptoms, and point-of-care tests have not yet been developed or validated.


Exposure to bisphosphonates and risk of common non-gastrointestinal cancers: series of nested case-control studies using two primary-care databases.
Bisphosphonates are the most commonly prescribed osteoporosis drugs but long-term effects are unclear, although antitumour properties are known from preclinical studies. Nested case-control studies were conducted to investigate bisphosphonate use and risks of common non-gastrointestinal cancers (breast, prostate, lung, bladder, melanoma, ovarian, pancreas, uterus and cervical). Patients 50 years and older, diagnosed with primary cancers between 1997 and 2011, were matched to five controls using the UK practice-based QResearch and Clinical Practice Research Datalink (CPRD) databases. The databases were analysed separately and the results combined. A total of 91 556 and 88 845 cases were identified from QResearch and CPRD, respectively. Bisphosphonate use was associated with reduced risks of breast (odds ratio (OR): 0.92, 95% confidence interval (CI): 0.87-0.97), prostate (OR: 0.87, 95% CI: 0.79-0.96) and pancreatic (OR: 0.79, 95% CI: 0.68-0.93) cancers in the combined analyses, but no significant trends with duration. For alendronate, reduced risk associations were found for prostate cancer in the QResearch (OR: 0.81, 95% CI: 0.70-0.93) and combined (OR: 0.84, 95% CI: 0.75-0.93) analyses (trend with duration P-values 0.009 and 0.001). There were no significant associations from any of the other analyses. In this series of large population-based case-control studies, bisphosphonate use was not associated with increased risks for any common non-gastrointestinal cancers.


Planning dam portfolios for low sediment trapping shows limits for sustainable hydropower in the Mekong.
The transboundary Mekong Basin has been dubbed the "Battery of Southeast Asia" for its large hydropower potential. Development of hydropower dams in the six riparian countries proceeds without strategic analyses of dam impacts, e.g., reduced sediment delivery to the lower Mekong. This will impact some of the world's largest freshwater fisheries and endangers the resilience of the delta, which supports 17 million livelihoods, against rising sea levels. To highlight alternatives, we contribute an optimization-based framework for strategic sequencing of dam development. We quantify lost opportunities from past development and identify remaining opportunities for better tradeoffs between sediment and hydropower. We find that limited opportunities remain for less impactful hydropower in the lower basin, where most development is currently planned, while better trade-offs could be reached with dams in the upper Mekong in China. Our results offer a strategic vision for hydropower in the Mekong, introduce a globally applicable framework to optimize dam sequences in space and time, and highlight the importance of strategic planning on multiple scales to minimize hydropower impacts on rivers.


Sourcing human embryos for embryonic stem cell lines: problems & perspectives.
The ability to successfully derive human embryonic stem cells (hESC) lines from human embryos following in vitro fertilization (IVF) opened up a plethora of potential applications of this technique. These cell lines could have been successfully used to increase our understanding of human developmental biology, transplantation medicine and the emerging science of regenerative medicine. The main source for human embryos has been 'discarded' or 'spare' fresh or frozen human embryos following IVF. It is a common practice to stimulate the ovaries of women undergoing any of the assisted reproductive technologies (ART) and retrieve multiple oocytes which subsequently lead to multiple embryos. Of these, only two or maximum of three embryos are transferred while the rest are cryopreserved as per the decision of the couple. in case a couple does not desire to 'cryopreserve' their embryos then all the embryos remaining following embryo transfer can be considered 'spare' or if a couple is no longer in need of the 'cryopreserved' embryos then these also can be considered as 'spare'. But, the question raised by the ethicists is, "what about 'slightly' over-stimulating a woman to get a few extra eggs and embryos? The decision becomes more difficult when it comes to 'discarded' embryos. As of today, the quality of the embryos is primarily assessed based on morphology and the rate of development mainly judged by single point assessment. Despite many criteria described in the literature, the quality assessment is purely subjective. The question that arises is on the decision of 'discarding' embryos. What would be the criteria for discarding embryos and the potential 'use' of ESC derived from the 'abnormal appearing' embryos? This paper discusses some of the newer methods to procure embryos for the derivation of embryonic stem cell lines which will respect the ethical concerns but still provide the source material.


Two cross-reactive monoclonal antibodies recognize overlapping epitopes on Neisseria meningitidis factor H binding protein but have different functional properties.
Factor H binding protein (fHbp) is one of the main antigens of the 4-component meningococcus B (4CMenB) multicomponent vaccine against disease caused by serogroup B Neisseria meningitidis (MenB). fHbp binds the complement down-regulating protein human factor H (hfH), thus resulting in immune evasion. fHbp exists in 3 variant groups with limited cross-protective responses. Previous studies have described the generation of monoclonal antibodies (mAbs) targeting variant-specific regions of fHbp. Here we report for the first time the functional characterization of two mAbs that recognize a wide panel of fHbp variants and subvariants on the MenB surface and that are able to inhibit fHbp binding to hfH. The antigenic regions targeted by the two mAbs were accurately mapped by hydrogen-deuterium exchange mass spectrometry (HDX-MS), revealing partially overlapping epitopes on the N terminus of fHbp. Furthermore, while none of the mAbs had bactericidal activity on its own, a synergistic effect was observed for each of them when tested by the human complement serum bactericidal activity (hSBA) assay in combination with a second nonbactericidal mAb. The bases underlying fHbp variant cross-reactivity, as well as inhibition of hfH binding and cooperativity effect observed for the two mAbs, are discussed in light of the mapped epitopes.


Glycoproteomic Alterations in Drug-Resistant Nonsmall Cell Lung Cancer Cells Revealed by Lectin Magnetic Nanoprobe-Based Mass Spectrometry.
Understanding the functional role of glycosylation-mediated pathogenesis requires deep characterization of glycoproteome, which remains extremely challenging due to the inherently complex nature of glycoproteins. We demonstrate the utility of lectin-magnetic nanoprobe (MNP@lectin) coupled to Orbitrap HCD-CID-MS/MS for complementary glycotope-specific enrichment and site-specific glycosylation analysis of the glycoproteome. By three nanoprobes, MNP@ConA, MNP@AAL, and MNP@SNA, our results revealed the first large-scale glycoproteome of nonsmall cell lung cancer (NSCLC) with 2290 and 2767 nonredundant glycopeptides confidently identified (Byonic score ≥100) in EGFR-TKI-sensitive PC9 and -resistant PC9-IR cells, respectively, especially with more fucosylated and sialylated glycopeptides in PC9-IR cells. The complementary enrichment was demonstrated with only five glycopeptides commonly enriched in three MNP@lectins. Glycotope specificity of 79 and 62% for enrichment was achieved using MNP@AAL and MNP@SNA, respectively. Label-free quantitation revealed predominant fucosylation in PC9-IR cells, suggesting its potential role associated with NSCLC resistance. Moreover, without immunoprecipitation, this multilectin nanoprobe allows the sensitive identification of 51 glycopeptides from 10 of 12 reported sites from onco-protein EGFR. Our results not only demonstrated a sensitive approach to study the vastly under-represented N-glycoprotome but also may pave the way for a glycoproteomic atlas to further explore the site-specific function of glycoproteins associated with drug resistance in NSCLC.


Catalytic Enantioselective Pyridine N-Oxidation.
The catalytic, enantioselective N-oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic-acid-containing peptides as the aspartyl side chain shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro-stereogenic center substituted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents a new entry into chiral pyridine frameworks in a heterocycle-rich molecular environment. Representative functionalizations of the enantioenriched pyridine N-oxides further document the utility of this approach. Demonstration of the asymmetric N-oxidation in two venerable drug-like scaffolds, Loratadine and Varenicline, show the likely generality of the method for highly variable and distinct chiral environments, while also revealing that the approach is applicable to both pyridines and 1,4-pyrazines.


The predictability of periodontal treatment as measured by tooth loss: a retrospective study.
This study evaluated the predictability of periodontal treatment as measured by tooth loss in 114 patients. The patients were selected for the study if they had been treated for moderate-to-advanced periodontitis and had received continuous periodontal maintenance every 3 to 6 months for 5 years or longer. The patients averaged 53 years of age, were equally divided by gender, and were maintained an average of 12.5 years. Patients were retrospectively assigned, according to the number of teeth lost following active periodontal treatment, to the well-maintained group (96 patients, 0 to 3 teeth lost), downhill group (15 patients, 4 to 9 teeth lost), or extreme downhill (three patients, 10 to 23 teeth lost) group. Teeth were retrospectively assigned a questionable or hopeless prognosis. Of the 2,899 teeth present during maintenance care, 378 had a questionable prognosis because of furcation involvement, and 63 (16.7%) of these teeth were lost. Of the 529 nonfurcated teeth that had a questionable prognosis, 68 (12.9%) were lost during the maintenance phase of treatment. Ninety-six teeth were given a hopeless prognosis, and 32 (33.3%) of these teeth were lost. Surgical treatment of teeth with questionable or hopeless prognosis did not improve the retention of these teeth in the downhill and extreme downhill groups. The prognosis of a periodontally compromised tooth in individual patients in difficult to predict accurately. A hopeless prognosis is more accurate than a questionable prognosis in predicting tooth loss in these patients.


C-reactive protein predicts tumor necrosis factor-alpha blocker retention rate in axial ankylosing spondylitis.
In ankylosing spondylitis (AS), tumor necrosis factor (TNF) blockers are recommended for patients with high symptomatic disease activity. Few data are available about objective signs of inflammation such as increased C-reactive protein (CRP). We assessed the retention rate of TNF blockers in patients with axial AS, according to baseline CRP and other potentially predictive measures. A retrospective study of all patients treated with TNF blockers for axial AS. Retention rate was evaluated using a survival-data analysis technique with discontinuation of the drug because of inefficacy (Kaplan-Meier method). Potential factors explaining the retention rates (demographic and clinical indicators and CRP) were evaluated using log-rank tests and a Cox proportional-hazards regression model. For axial AS, 175 patients received TNF blockers (men 78%, mean disease duration 12.4 +/- 9.1 yrs); 100 patients (of 143 with available data) had an increased CRP (> 10 mg/l). An increased CRP at baseline was the only variable explaining the retention rate in the Cox model (p = 0.003, hazard ratio = 3.3, 95% CI 1.5-7.3). Interruption for expert opinion of inefficacy was more frequent for patients with low baseline CRP; however, even in these patients retention was high. Increased CRP should not be considered mandatory for proposing TNF blocker treatment in axial AS.


Superresolution microscope using electrical superposition of holograms.
By combining a microscope and television systems, a superresolving microscope is constructed. The basic idea of this system is to convert the hologram signal of the image to an electrical video signal using television systems and to perform operations necessary to carry out the superresolution electrically. As a result images which are superresolved twice in one dimension are displayed on a TV monitor in 5 sec.


High-dose daunorubicin in older patients with acute myeloid leukemia.
A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter every 12 hours [DOSAGE ERROR CORRECTED] for 6 days. The primary end point was event-free survival. The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%). In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.)


18F-FACBC PET/MRI in Diagnostic Assessment and Neurosurgery of Gliomas.
This pilot study aimed to evaluate the amino acid tracer F-FACBC with simultaneous PET/MRI in diagnostic assessment and neurosurgery of gliomas. Eleven patients with suspected primary or recurrent low- or high-grade glioma received an F-FACBC PET/MRI examination before surgery. PET and MRI were used for diagnostic assessment, and for guiding tumor resection and histopathological tissue sampling. PET uptake, tumor-to-background ratios (TBRs), time-activity curves, as well as PET and MRI tumor volumes were evaluated. The sensitivities of lesion detection and to detect glioma tissue were calculated for PET, MRI, and combined PET/MRI with histopathology (biopsies for final diagnosis and additional image-localized biopsies) as reference. Overall sensitivity for lesion detection was 54.5% (95% confidence interval [CI], 23.4-83.3) for PET, 45.5% (95% CI, 16.7-76.6) for contrast-enhanced MRI (MRICE), and 100% (95% CI, 71.5-100.0) for combined PET/MRI, with a significant difference between MRICE and combined PET/MRI (P = 0.031). TBRs increased with tumor grade (P = 0.004) and were stable from 10 minutes post injection. PET tumor volumes enclosed most of the MRICE volumes (>98%) and were generally larger (1.5-2.8 times) than the MRICE volumes. Based on image-localized biopsies, combined PET/MRI demonstrated higher concurrence with malignant findings at histopathology (89.5%) than MRICE (26.3%). Low- versus high-grade glioma differentiation may be possible with F-FACBC using TBR. F-FACBC PET/MRI outperformed MRICE in lesion detection and in detection of glioma tissue. More research is required to evaluate F-FACBC properties, especially in grade II and III tumors, and for different subtypes of gliomas.


Role of antioxidant activity of taurine in diabetes.
The unifying hypothesis of diabetes maintains that reactive oxygen species (ROS) generated in the mitochondria of glucose-treated cells promote reactions leading to the development of diabetic complications. Although the unifying hypothesis attributes the generation of oxidants solely to impaired glucose and fatty acid metabolism, diabetes is also associated with a decline in the levels of the endogenous antioxidant taurine in a number of tissues, raising the possibility that changes in taurine status might also contribute to the severity of oxidant-mediated damage. There is overwhelming evidence that taurine blocks toxicity caused by oxidative stress, but the mechanism underlying the antioxidant activity remains unclear. One established antioxidant action of taurine is the detoxification of hypochlorous acid. However, not all of the antioxidant actions of taurine are related to hypochlorous acid because they are detected in isolated cell systems lacking neutrophils. There are a few studies showing that taurine either modulates the antioxidant defenses or blocks the actions of the oxidants, but other studies oppose this interpretation. Although taurine is incapable of directly scavenging the classic ROS, such as superoxide anion, hydroxyl radical, and hydrogen peroxide, there are numerous studies suggesting that it is an effective inhibitor of ROS generation. The present review introduces a novel antioxidant hypothesis, which takes into consideration the presence of taurine-conjugated tRNAs in the mitochondria. Because tRNA conjugation is required for normal translation of mitochondrial-encoded proteins, taurine deficiency reduces the expression of these respiratory chain components. As a result, flux through the electron transport chain decreases. The dysfunctional respiratory chain accumulates electron donors, which divert electrons from the respiratory chain to oxygen, forming superoxide anion in the process. Restoration of taurine levels increases the levels of conjugated tRNA, restores respiratory chain activity, and increases the synthesis of ATP at the expense of superoxide anion production. The importance of this and other actions of taurine in diabetes is discussed.


CYP2C9 Mutation Affecting the Individual Variability of Warfarin Dose Requirement.
Warfarin is a frequently prescribed anticoagulant in rehabilitation patients. Adverse drug reactions of warfarin were reported as bleeding and cutaneous microvascular thrombosis. Major bleeding, such as intracranial hemorrhage and psoas hematoma, in patients receiving anticoagulation therapy is a rare condition, but sometimes very serious complication that can even be fatal. Patient-specific factors (eg, age, body size, race, concurrent diseases, and medications) explain some of the individual variability in warfarin dose, but genetic factors, which influence warfarin response, explain a significantly higher proportion of the variability in the dose. There are two identified genes that are responsible for the main proportion of the genetic effect: CYP2C9, which codes for the enzyme cytochrome P450 2C9 that metabolizes S-warfarin, and VKORC1, which codes for warfarin's target, vitamin K epoxide reductase. We report a case of intolerance to warfarin dosing, due to impaired drug metabolism in a patient with CYP2C9(*)1/(*)3 and VKORC 1173TT. Fortunately, there are no severe complications.