The retinoic acid-inactivating enzyme CYP26 is essential for establishing an uneven distribution of retinoic acid along the anterio-posterior axis within the mouse embryo.
Retinoic acid (RA), a derivative of vitamin A, plays a pivotal role in vertebrate development. The level of RA may be determined by the balance between its synthesis and degradation. We have examined the role of CYP26, a P450 enzyme that may degrade RA, by generating mutant mice that lack CYP26. CYP26(-/-) mice exhibited anomalies, including caudal agenesis, similar to those induced by administration of excess RA. The concentration of endogenous RA, as revealed by marker gene activity, was markedly increased in the tailbud of the mutant animals, in which CYP26 is normally expressed. Expression of T (Brachyury) and Wnt3a in the tailbud was down-regulated in CYP26(-/-) mice, which may underlie the caudal truncation. The lack of CYP26 also resulted in homeotic transformation of vertebrae as well as in misspecification of the rostral hindbrain associated with anterior expansion of RA-positive domains. These results suggest that local degradation of RA by CYP26 is required for establishing an uneven distribution of RA along the anterio-posterior axis, which is essential for patterning the hindbrain, vertebrae, and tailbud.


'Detox': science or sales pitch?
There is no question that the world is becoming increasingly toxic, with worldwide dissemination of industrial chemicals, pesticides, heavy metals and radioactive elements. Many of these toxins have demonstrated harmful effects including cancer, reproductive, metabolic, and mental health effects. It is also known that many toxins undergo bioaccumulation through the food chain and that synergistic effects can occur whereby combinations of toxins can be more potent than the sum of individual toxins.


Spontaneous motion on two-dimensional continuous attractors.
Attractor models are simplified models used to describe the dynamics of firing rate profiles of a pool of neurons. The firing rate profile, or the neuronal activity, is thought to carry information. Continuous attractor neural networks (CANNs) describe the neural processing of continuous information such as object position, object orientation, and direction of object motion. Recently it was found that in one-dimensional CANNs, short-term synaptic depression can destabilize bump-shaped neuronal attractor activity profiles. In this article, we study two-dimensional CANNs with short-term synaptic depression and spike frequency adaptation. We found that the dynamics of CANNs with short-term synaptic depression and CANNs with spike frequency adaptation are qualitatively similar. We also found that in both kinds of CANNs, the perturbative approach can be used to predict phase diagrams, dynamical variables, and speed of spontaneous motion.


Nitrile and thiocyanate IR probes: quantum chemistry calculation studies and multivariate least-square fitting analysis.
Hydration effects on the C[Triple Bond]N stretching mode frequencies of MeCN and MeSCN are investigated by carrying out ab initio calculations for a number of MeCN-water and MeSCN-water complexes with varying number of water molecules. It is found that the CN frequency shift induced by the hydrogen-bonding interactions with water molecules originate from two different ways to form hydrogen bonds with the nitrogen atom of the CN group. Considering the MeCN- and MeSCN-water cluster calculation results as databases, we first examined the validity of vibrational Stark effect relationship between the CN frequency and the electric field component parallel to the CN bond and found no strong correlation between the two. However, taking into account of additional electric field vector components is a simple way to generalize the vibrational Stark theory for the nitrile chromophore. Also, the electrostatic potential calculation method has been proposed and examined in detail. It turned out that the interactions of water molecules with nitrogen atom's lone pair orbital and with nitrile pi orbitals can be well described by the electrostatic potential calculation method. The present computational results will be of use to quantitatively simulate various linear and nonlinear vibrational spectra of nitrile compounds in solutions.


Traumatic brain injury, the hidden pandemic: A focused response to family and patient experiences and needs.
Traumatic brain injury (TBI) has many potential cognitive, behavioural and psychological consequences, and contributes significantly to the national burden of disease and to ongoing violent behaviour. Few resources are available for the rehabilitation of patients with TBI in South Africa, and access to rehabilitation facilities in the public sector is limited. Consequently, it is the families impacted on by TBI that ultimately carry the care and rehabilitation burden once survivors are discharged from hospital. Families are generally ill equipped to cope with the complex and potentially long-term disabilities that accompany brain injury. Reviewing interviews with 175 family members and 354 patients recovering from TBI helped identify the key challenges that the survivors of TBI and their families face. Nine problem areas were identified that formed the basis for development of a discharge resource, the S-Plan, which serves to inform patients and carers and provide practical solutions for the problems they face. The experiences of TBI survivors and their family members served to inform the development of simple, integrated coping strategies, namely two S-Plan tools, one for survivors and their families/caregivers and the other for care workers, in conjunction with counselling and support group processes. The S-Plan constitutes a discharge resource to inform patients and carers and provide practical solutions for the problems they face in caring for family members who have suffered TBI.


Effects of transmembrane and juxtamembrane domains on proliferative ability of TSLP receptor.
Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine that requires a heterodimeric receptor complex composed of the interleukin-7 receptor alpha chain and the TSLP receptor, which is related to the common gamma chain. TSLP has been shown to play an important role in the development of allergic inflammation, such as asthma and atopic dermatitis. Chimeric receptors composed of the cytoplasmic region of the TSLP receptor fused to the extracellular regions of homodimeric receptors, such as erythropoietin (Epo) receptor and thrombopoietin receptor have been used to dissect signaling events induced by the TSLP receptor. Intriguingly, studies using such chimeric TSLP receptors revealed that the human, but not mouse, TSLP receptor cytoplasmic domain can support proliferation of growth factor-dependent cells after homodimerization. Here, we used a systematic approach to investigate the mechanistic basis of this difference. Our studies revealed that induced homodimerization of receptor chimeras containing the transmembrane and cytoplasmic domains of both human and mouse TSLP receptors is not sufficient for driving cell proliferation. However, chimeric receptors with the transmembrane and juxtamembrane domains of Epo receptor fused to the cytoplasmic domain of human TSLP receptor signal like the Epo receptor and induce the activation of Jak2. Site-directed mutagenesis showed that the lone tyrosine residue in human TSLP receptor is not required for transmitting proliferative signals in receptor chimeras, which is consistent with the observation that none of the tyrosine residues are required for Epo receptor to support proliferation. Our data suggests that in the chimeric receptor context, the transmembrane and juxtamembrane domains of mouse Epo receptor are essential for the cytoplasmic domain of human TSLPR to achieve the strong proliferative ability and can modulate signaling pathway transmitted by the cytoplasmic domains of these chimeras.


Adenosine, the heart, and coronary circulation.
Adenosine is known to regulate myocardial and coronary circulatory functions. Adenosine not only dilates coronary vessels, but attenuates beta-adrenergic receptor-mediated increases in myocardial contractility and depresses both sinoatrial and atrioventricular node activities. The effects of adenosine are mediated by two distinct receptors (i.e., A1 and A2 receptors). A1 adenosine receptors, located in atrial and ventricular myocardium and sinoatrial/atrioventricular nodes, are responsible for inhibition of adenylyl cyclase activity. A2 adenosine receptors, located in coronary endothelial and smooth muscle cells, are responsible for stimulation of this enzyme activity. During increased myocardial oxygen demand due to rapid pacing and exercise, although both coronary blood flow and adenosine concentrations in the myocardium and coronary efflux increased, there is no clear consensus explaining its cause and effect relation at present. However, ischemia/reperfusion-induced coronary hyperemia is believed to be mostly attributed to released adenosine, and it has been proven that adenosine attenuates the severity of ischemia due to its coronary vasodilatory action. The beneficial effects of adenosine during ischemia/reperfusion processes do not seem simple. This is because myocardial ischemia and reperfusion injury is caused by 1) activated leukocytes and platelets, 2) ATP depletion and calcium overload of myocardium, and 3) catecholamine release from the presynaptic nerves as well as 4) the impaired coronary circulation. Intriguingly adenosine attenuates all of these deleterious actions and thereby attenuates ischemia/reperfusion injury. Indeed, adenosine attenuates the severity of contractile dysfunction (myocardial stunning) and limits the infarct size. Thus, administration of adenosine or potentiators of adenosine production in the ischemic myocardium may be beneficial for the attenuation of ischemic and reperfusion injuries, although further clinical investigations are necessary.


Detecting small plant peptides using SPADA (Small Peptide Alignment Discovery Application).
Small peptides encoded as one- or two-exon genes in plants have recently been shown to affect multiple aspects of plant development, reproduction and defense responses. However, popular similarity search tools and gene prediction techniques generally fail to identify most members belonging to this class of genes. This is largely due to the high sequence divergence among family members and the limited availability of experimentally verified small peptides to use as training sets for homology search and ab initio prediction. Consequently, there is an urgent need for both experimental and computational studies in order to further advance the accurate prediction of small peptides. We present here a homology-based gene prediction program to accurately predict small peptides at the genome level. Given a high-quality profile alignment, SPADA identifies and annotates nearly all family members in tested genomes with better performance than all general-purpose gene prediction programs surveyed. We find numerous mis-annotations in the current Arabidopsis thaliana and Medicago truncatula genome databases using SPADA, most of which have RNA-Seq expression support. We also show that SPADA works well on other classes of small secreted peptides in plants (e.g., self-incompatibility protein homologues) as well as non-secreted peptides outside the plant kingdom (e.g., the alpha-amanitin toxin gene family in the mushroom, Amanita bisporigera). SPADA is a free software tool that accurately identifies and predicts the gene structure for short peptides with one or two exons. SPADA is able to incorporate information from profile alignments into the model prediction process and makes use of it to score different candidate models. SPADA achieves high sensitivity and specificity in predicting small plant peptides such as the cysteine-rich peptide families. A systematic application of SPADA to other classes of small peptides by research communities will greatly improve the genome annotation of different protein families in public genome databases.


BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus.
To determine whether overexpression of BAFF can accelerate the development of systemic lupus erythematosus-associated end-organ disease in hosts with an underlying autoimmune diathesis. We introduced a BAFF transgene (Tg) into autoimmune-prone B6.Sle1 and B6.Nba2 mice and evaluated these mice for serologic autoimmunity and renal pathology. B6.Sle1.BAFF and B6.Nba2.BAFF mice, but not non-Tg littermates, frequently developed severe glomerular pathology by 3 months of age. Age-matched B6.BAFF mice, despite renal Ig deposits and increases in B cells and Ig production similar to those in B6.Sle1.BAFF and B6.Nba2.BAFF mice, did not develop glomerular pathology. In B6.Sle1.BAFF and B6.Nba2.BAFF mice, severity of glomerular disease did not obligately correlate with circulating levels of IgG anti-chromatin and/or anti-double-stranded DNA antibodies or with amounts of these autoantibodies deposited in the kidneys. Even in mice with severe glomerular disease, renal tubulointerstitial infiltrates were very limited, and increased proteinuria was not detected. BAFF-driven effects on glomerular pathology may be mediated, at least in part, by autoantibodies with specificities other than chromatin and/or by autoantibody-independent means. There is an uncoupling of BAFF-driven precocious glomerular pathology from concomitant development of clinically apparent renal disease, strongly suggesting that BAFF overexpression works in concert with other factors to promote overt renal disease.


Caffeine Health Claims on Sports Supplement Labeling. Analytical Assessment According to EFSA Scientific Opinion and International Evidence and Criteria.
Caffeine is a food supplement widely consumed by athletes, but it has not been established. So far, the veracity of their labeling in terms of the dosage and cause/effect relationship aimed at the consumer. The aim is to analyze the health claims and the dosage presented on the labeling of caffeine supplements and to evaluate if they follow the European Food Safety Authority (EFSA) and international criteria. A descriptive cross-sectional study of a sample of caffeine supplements was carried out. The search was done through the Amazon and Google Shopping web portals. In order to assess the adequacy of the health claims, the guidelines of reference established by European Food Safety Authority were compared to the Academy of Nutrition and Dietetics, International Olympic Committee, and Australian Institute of Sport guidelines; in addition, recent systematic reviews were addressed. A review of labels of 42 caffeine supplements showed that, in less than 3% of the products were the health claims supported by the recommendations and by the labeled quantity of caffeine. The claims that fully complied the recommendations were, "improves or increases endurance performance", "improves strength performance", or "improves short-term performance". In most cases, the recommended dosage was 200 mg/day for these products, which is the minimum for the caffeine effects to be declared. The rest of the health claims were not adequate or need to be modified. Most of the health claims identified indicated an unproven cause and effect, which constitutes consumer fraud, and so must be modified or eliminated.


Systematic review and meta-analysis: reminder systems to reduce catheter-associated urinary tract infections and urinary catheter use in hospitalized patients.
Prolonged catheterization is the primary risk factor for catheter-associated urinary tract infection (CAUTI). Reminder systems are interventions used to prompt the removal of unnecessary urinary catheters. To summarize the effect of urinary catheter reminder systems on the rate of CAUTI, urinary catheter use, and the need for recatheterization, we performed a systematic review and meta-analysis. Studies were identified in MEDLINE, the Cochrane Library, Biosis, the Web of Science, EMBASE, and CINAHL through August 2008. Only interventional studies that used reminders to physicians or nurses that a urinary catheter was in use or stop orders to prompt catheter removal in hospitalized adults were included. A total of 6679 citations were identified; 118 articles were reviewed, and 14 articles met the selection criteria. The rate of CAUTI (episodes per 1000 catheter-days) was reduced by 52% (P < .001) with use of a reminder or stop order. The mean duration of catheterization decreased by 37%, resulting in 2.61 fewer days of catheterization per patient in the intervention versus control groups; the pooled standardized mean difference (SMD) in the duration of catheterization was -1.11 overall (P = 070), including a statistically significant decrease in studies that used a stop order (SMD, -0.30; P = .001) but not in those that used a reminder (SMD, -1.54; P = .071). Recatheterization rates were similar in control and intervention groups. Urinary catheter reminders and stop orders appear to reduce the rate of CAUTI and should be strongly considered to enhance the safety of hospitalized patients.


Professional artist, good Samaritan, servant and co-ordinator: four ways of understanding the anaesthetist's work.
Evaluating clinical competence among anaesthetists has so far focused mostly on theoretical knowledge and practical skills. According to theory, however, the way anaesthetists understand their own work has also greatly influenced the development of professional competence. The aim of this study was to investigate how anaesthetists understand their work. Nineteen Swedish anaesthetists were interviewed. The interviews were open and sought answers to three questions 1) When do you feel you have been successful in your work?; 2) What is difficult or what hinders you in your work?; and 3) What is the core of your professional anaesthesia work? Phenomenographic analysis was performed. Four ways of understanding the anesthesiologists' professional work were found: 1) Give anaesthesia and control the patient's vital functions; 2) Help the patient, alleviate his/her pain and anxiety; 3) Give service to the whole hospital to facilitate the work of other doctors and nurses, caring for severely ill patients; and 4) Organize and direct the operation ward to make the operations list run smoothly. This study shows that anaesthetists understand their work in qualitatively different ways, which can be assumed to affect their work actions and also the way their competence develops. This has implications for the education of anaesthetists; it is important to find ways of making anaesthetists in training consciously aware of the different ways their work can be understood, as this will give them better prerequisites for future competence development.


Localizing functional damage in the neural retina of adolescents and young adults with type 1 diabetes.
It is unknown which regions of the retina are most susceptible to damage by diabetes mellitus. We hypothesized that the standard and slow-flash (sf-) multifocal electroretinogram (mfERG) will localize retinal regions of greatest vulnerability. A total of 55 adolescents and young adults with type 1 diabetes and without diabetic retinopathy (DR) or with mild nonproliferative DR and 54 typically-developing, age-similar control participants underwent mfERG and sf-mfERG testing. The amplitude and implicit time of the first order response of the standard mfERG and of three multifocal oscillatory potentials (mfOPs) of the sf-mfERG were compared between groups at the level of hexagons, quadrants, and rings using separate mixed model ANOVAs. Spatial mapping of the P values from post hoc pairwise comparisons illustrated patterns of retinal dysfunction. Delays in mfERG implicit times were evident across the tested retinal areas in the diabetes group. Delays in sf-mfERG implicit times were found at different eccentricities for each mfOP in the diabetes group. The greatest delays were noted in the periphery for mfOP1, in the midperiphery for mfOP2, and in the macular region for mfOP3. There were no significant group differences in amplitude for the mfERG and sf-mfERG protocols. Delays in mfERG and sf-mfERG responses suggest that the inner retina is particularly vulnerable to diabetes. Localizing regions of early dysfunction will help guide future studies to examine early structural damage associated with DR.


Serum immune-related proteins are differentially expressed during hibernation in the American black bear.
Hibernation is an adaptation to conserve energy in the face of extreme environmental conditions and low food availability that has risen in several animal phyla. This phenomenon is characterized by reduced metabolic rate (∼25% of the active basal metabolic rate in hibernating bears) and energy demand, while other physiological adjustments are far from clear. The profiling of the serum proteome of the American black bear (Ursus americanus) may reveal specific proteins that are differentially modulated by hibernation, and provide insight into the remarkable physiological adaptations that characterize ursid hibernation. In this study, we used differential gel electrophoresis (DIGE) analysis, liquid chromatography coupled to tandem mass spectrometry, and subsequent MASCOT analysis of the mass spectra to identify candidate proteins that are differentially expressed during hibernation in captive black bears. Seventy serum proteins were identified as changing by ±1.5 fold or more, out of which 34 proteins increased expression during hibernation. The majority of identified proteins are involved in immune system processes. These included α2-macroglobulin, complement components C1s and C4, immunoglobulin μ and J chains, clusterin, haptoglobin, C4b binding protein, kininogen 1, α2-HS-glycoprotein, and apoplipoproteins A-I and A-IV. Differential expression of a subset of these proteins identified by proteomic analysis was also confirmed by immunodetection. We propose that the observed serum protein changes contribute to the maintenance of the hibernation phenotype and health, including increased capacities for bone maintenance and wound healing during hibernation in bears.


Ser392 phosphorylation regulates the oncogenic function of mutant p53.
Despite the wealth of information on the regulation of wild-type p53 function by phosphorylation, nothing is known about the biological effect of phosphorylation on mutant p53. Here we show that p53H175 is phosphorylated like wild-type p53 in cells of the same background. Ser(392) nonphosphorylatable p53 mutants p53H175A392 and p53W248A392 more potently transformed rat embryo fibroblasts in cooperation with the ras oncogene than p53H175S392 and p53W248S392. p53H175A392 also had an enhanced ability to confer cellular resistance to the cytotoxic effect of cisplatin and UV radiation. This correlated with p53H175A392 being a more potent dominant negative mutant than p53H175 in inhibiting the apoptotic functions of wild-type p53. Moreover, p53H175E392, which mimics the phosphorylated form of p53H175, was less able to confer cellular resistance to DNA-damaging agents. p53H175 and p53W248 are phosphorylated like wild-type p53 in cells of the same background. Ser(392) nonphosphorylated p53 was present in human breast tumors expressing mutant p53 including p53H175. Together, these results demonstrated a novel function of Ser(392) phosphorylation in regulating the oncogenic function of mutant p53.


A systematic review of Rift Valley Fever epidemiology 1931-2014.
Rift Valley Fever (RVF) is a mosquito-borne viral zoonosis that was first isolated and characterized in 1931 in Kenya. RVF outbreaks have resulted in significant losses through human illness and deaths, high livestock abortions and deaths. This report provides an overview on epidemiology of RVF including ecology, molecular diversity spatiotemporal analysis, and predictive risk modeling. Using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched for relevant RVF publications in repositories of the World Health Organization Library and Information Networks for Knowledge (WHOLIS), U.S Centers for Disease Control and Prevention (CDC), and Food and Agricultural Organization (FAO). Detailed searches were performed in Google Scholar, SpringerLink, and PubMed databases and included conference proceedings and books published from 1931 up to 31st January 2015. A total of 84 studies were included in this review; majority (50%) reported on common human and animal risk factors that included consumption of animal products, contact with infected animals and residing in low altitude areas associated with favorable climatic and ecological conditions for vector emergence. A total of 14 (16%) of the publications described RVF progressive spatial and temporal distribution and the use of risk modeling for timely prediction of imminent outbreaks. Using distribution maps, we illustrated the gradual spread and geographical extent of disease; we also estimated the disease burden using aggregate human mortalities and cumulative outbreak periods for endemic regions. This review outlines common risk factors for RVF infections over wider geographical areas; it also emphasizes the role of spatial models in predicting RVF enzootics. It, therefore, explains RVF epidemiological status that may be used for design of targeted surveillance and control programs in endemic countries.


Deep Endoscopic Visual Measurements.
Robotic endoscopic systems offer a minimally invasive approach to the examination of internal body structures, and their application is rapidly extending to cover the increasing needs for accurate therapeutic interventions. In this context, it is essential for such systems to be able to perform measurements, such as measuring the distance traveled by a wireless capsule endoscope, so as to determine the location of a lesion in the gastrointestinal tract, or to measure the size of lesions for diagnostic purposes. In this paper, we investigate the feasibility of performing contactless measurements using a computer vision approach based on neural networks. The proposed system integrates a deep convolutional image registration approach and a multilayer feed-forward neural network into a novel architecture. The main advantage of this system, with respect to the state-of-the-art ones, is that it is more generic in the sense that it is 1) unconstrained by specific models, 2) more robust to nonrigid deformations, and 3) adaptable to most of the endoscopic systems and environment, while enabling measurements of enhanced accuracy. The performance of this system is evaluated under ex vivo conditions using a phantom experimental model and a robotically assisted test bench. The results obtained promise a wider applicability and impact in endoscopy in the era of big data.


Skin biopsy as a diagnostic tool in peripheral neuropathy.
Skin biopsy is a safe, minimally invasive, painless and cheap tool for providing diagnostic information on small nerve fibers, which are invisible to routine neurophysiological tests. Biopsy can be performed in hairy skin to investigate unmyelinated and thinly myelinated fibers and in glabrous skin to examine large myelinated fibers. Morphometric analysis of skin nerves is readily accomplished through the use of immunohistochemical techniques, and has proved to be reliable, reproducible and unaffected by the severity of neuropathy. One further advantage of skin biopsy over conventional nerve biopsy is that it allows somatic nerve fibers to be distinguished from autonomic nerve fibers. Morphological changes, axonal degeneration and abnormal regeneration occur in cutaneous nerves very early in the course of peripheral neuropathies, making skin biopsy a promising tool for investigating the progression of neuropathy and the effect of neuroprotective treatments in clinical practice and trials. This article reviews the techniques that are used to investigate the innervation of human skin, the possible uses of skin biopsy in diagnosing and monitoring peripheral neuropathies, and correlations between skin biopsy findings and those of other diagnostic methods.


Audit of postoperative nausea and vomiting in paediatric day case surgery.
To assess the incidence of PONV, delay in discharge or unplanned admissions in paediatric surgical cases done at the Surgical Day Care Unit at Aga Khan University between January and July 2009. All paediatric ASA 1-2 cases, from 6 months to 18 years of age undergoing day case surgeries at the Surgical day care unit were included in this retrospective audit. Data was collected on a designed form filled with information from preoperative, intraoperative and postoperative recovery forms. Any relevant data was also noted from nurses notes in recovery room and step down unit. Episodes of vomiting, delay in discharge, or unplanned admission due to PONV were documented. Data was analyzed on SPSS 14. Out of 163 patients only one patient (0.6%) had an episode of vomiting in the recovery room and two patients (1.2 %) had vomiting in the step down unit. There was no delay in discharge or unplanned admission due to PONV in paediatric day cases during the period of our audit. The incidence of postoperative vomiting in paediatric day cases at our day care unit does not justify polymodal prophylaxis as a protocol for PONV.


Dermanyssus gallinae infestation: an unusual cause of scalp pruritus treated with permethrin shampoo.
Dermanyssus gallinae is a blood parasite of wild birds, but it is also a pest in the poultry industry. It occasionally bites mammals and thus rarely creates skin problems such as itching, papules, vesicles, and dermatitis. A 92-year-old man presented with severe itch on his head, particularly at night. He had been misdiagnosed with senile pruritus and treated with antihistamines and topical corticosteroids with temporary relief of the symptoms. On the basis of clinical and parasitological findings, D. gallinae dermatitis was diagnosed. Decontamination of the patient's immediate environment was not helpful. The patient was successfully treated using a 1% permethrin shampoo once a week for 2 weeks. During 3 months of follow-up he was free of symptoms. The case is of significance because most dermatologists have difficulty identifying ectoparasitoses, such as those that arise within new or atypical conditions.


Motor imagery after subcortical stroke: a functional magnetic resonance imaging study.
In recovered subcortical stroke, the pattern of motor network activation during motor execution can appear normal or not, depending on the task. Whether this applies to other aspects of motor function is unknown. We used functional MRI to assess motor imagery (MI), a promising new approach to improve motor function after stroke, and contrasted it to motor execution. Twenty well-recovered patients with hemiparetic subcortical stroke (14 males; mean age, 66.5 years) and 17 aged-matched control subjects were studied. Extensive behavioral screening excluded 8 patients and 4 control subjects due to impaired MI abilities. Subjects performed MI and motor execution of a paced finger-thumb opposition sequence using a functional MRI paradigm that monitored compliance. Activation within the primary motor cortex (BA4a and 4p), dorsal premotor, and supplementary motor areas was examined. The pattern of activation during affected-hand motor execution was not different from control subjects. Affected-hand MI activation was also largely similar to control subjects, including involvement of BA4, but with important differences: (1) unlike control subjects and the nonaffected hand, activation in BA4a and dorsal premotor was not lower during MI as compared with motor execution; (2) the hemispheric balance of BA4p activation was significantly less lateralized than control subjects; and (3) ipsilesional BA4p activation positively correlated with motor performance. In well-recovered subcortical stroke, the motor system, including ipsilesional BA4, is activated during MI despite the lesion. It, however, remains disorganized in proportion to residual motor impairment. Thus, components of movement upstream from execution appear differentially affected after stroke and could be targeted by rehabilitation in more severely affected patients.


Niobium tetrahalide complexes with neutral diphosphine ligands.
The reactions of NbCl4 with diphosphine ligands o-C6H4(PMe2)2, Me2PCH2CH2PMe2 or Et2PCH2CH2PEt2 in a 1 : 2 molar ratio in MeCN solution produced eight-coordinate [NbCl4(diphosphine)2]. [NbBr4(diphosphine)2] (diphosphine = o-C6H4(PMe2)2 or Me2PCH2CH2PMe2) were made similarly from NbBr4. X-ray crystal structures show that [NbCl4{o-C6H4(PMe2)2}2] has a dodecahedral geometry, but the complexes with dimethylene-backboned diphosphines are distorted square antiprisms. The Nb-P distances and <P-Nb-P angles are very similar in the two types, but Nb-Cl distances are ∼0.1 Å longer in the square antiprismatic complexes. These paramagnetic (d(1)) complexes were also characterised by microanalysis, magnetic measurements, IR and UV-visible spectroscopy. Using a 1 : 1 molar ratio of NbCl4 : diphosphine (diphosphine = Me2PCH2CH2PMe2, Et2PCH2CH2PEt2, Cy2PCH2CH2PCy2 and Ph2PCH2CH2CH2PPh2) afforded [NbCl4(diphosphine)], and [NbBr4(Me2PCH2CH2PMe2)] was obtained similarly. These 1 : 1 complexes are unstable in solution, preventing X-ray crystallographic study, but based upon their diamagnetism, IR, UV-visible and (31)P{(1)H} NMR spectra, they are formulated as halide-bridged dimers [(diphosphine)X2Nb(μ-X)4NbX2(diphosphine)], with single Nb-Nb bonds and chelating diphosphines. The Nb(iv) complexes are prone to hydrolysis and oxidation in solution and the structures of the Nb(v) complexes [NbBr4(Me2PCH2CH2PMe2)2][NbOBr4(MeCN)] with a dodecahedral cation, and [{NbOCl3{Et2P(CH2)2PEt2}}2{μ-Et2P(CH2)2PEt2}] which contains seven-coordinate Nb(v) centres with a symmetrical diphosphine bridge, are reported. The structure of niobium tetrabromide, conveniently made from NbCl4 and BBr3, is a chain polymer with edge-linked NbBr6 octahedra and alternating long and short Nb-Nb distances, the latter ascribed to Nb-Nb bonds.


Regional variation in antenatal corticosteroid use: a network-level quality improvement study.
Examination of regional care patterns in antenatal corticosteroid use (ACU) rates may be salient for the development of targeted interventions. Our objective was to assess network-level variation using California perinatal care regions as a proxy. We hypothesized that (1) significant variation in ACU exists within and between California perinatal care regions, and (2) lower performing regions exhibit greater NICU-level variability in ACU than higher performing regions. We undertook cross-sectional analysis of 33,610 very low birth weight infants cared for at 120 hospitals in 11 California perinatal care regions from 2005 to 2011. We computed risk-adjusted median ACU rates and interquartile ranges (IQR) for each perinatal care region. The degree of variation was assessed using hierarchical multivariate regression analysis with NICU as a random effect and region as a fixed effect. From 2005 to 2011, mean ACU rates across California increased from 82% to 87.9%. Regional median (IQR) ACU rates ranged from 68.4% (24.3) to 92.9% (4.8). We found significant variation in ACU rates among regions (P < .0001). Compared with Level IV NICUs, care in a lower level of care was a strongly significant predictor of lower odds of receiving antenatal corticosteroids in a multilevel model (Level III, 0.65 [0.45-0.95]; Level II, 0.39 [0.24-0.64]; P < .001). Regions with lower performance in ACU exhibited greater variability in performance. We found significant variation in ACU rates among California perinatal regions. Regional quality improvement approaches may offer a new avenue to spread best practice.


Simian virus 40 infection in humans and association with human diseases: results and hypotheses.
Simian virus 40 (SV40) is a monkey virus that was introduced in the human population by contaminated poliovaccines, produced in SV40-infected monkey cells, between 1955 and 1963. Epidemiological evidence now suggests that SV40 may be contagiously transmitted in humans by horizontal infection, independent of the earlier administration of SV40-contaminated poliovaccines. This evidence includes detection of SV40 DNA sequences in human tissues and of SV40 antibodies in human sera, as well as rescue of infectious SV40 from a human tumor. Detection of SV40 DNA sequences in blood and sperm and of SV40 virions in sewage points to the hematic, sexual, and orofecal routes as means of virus transmission in humans. The site of latent infection in humans is not known, but the presence of SV40 in urine suggests the kidney as a possible site of latency, as it occurs in the natural monkey host. SV40 in humans is associated with inflammatory kidney diseases and with specific tumor types: mesothelioma, lymphoma, brain, and bone. These human tumors correspond to the neoplasms that are induced by SV40 experimental inoculation in rodents and by generation of transgenic mice with the SV40 early region gene directed by its own early promoter-enhancer. The mechanisms of SV40 tumorigenesis in humans are related to the properties of the two viral oncoproteins, the large T antigen (Tag) and the small t antigen (tag). Tag acts mainly by blocking the functions of p53 and RB tumor suppressor proteins, as well as by inducing chromosomal aberrations in the host cell. These chromosome alterations may hit genes important in oncogenesis and generate genetic instability in tumor cells. The clastogenic activity of Tag, which fixes the chromosome damage in the infected cells, may explain the low viral load in SV40-positive human tumors and the observation that Tag is expressed only in a fraction of tumor cells. "Hit and run" seems the most plausible mechanism to support this situation. The small tag, like large Tag, displays several functions, but its principal role in transformation is to bind the protein phosphatase PP2A. This leads to constitutive activation of the Wnt pathway, resulting in continuous cell proliferation. The possibility that SV40 is implicated as a cofactor in the etiology of some human tumors has stimulated the preparation of a vaccine against the large Tag. Such a vaccine may represent in the future a useful immunoprophylactic and immunotherapeutic intervention against human tumors associated with SV40.


Mountain bluebirds: experimental evidence against altruism.
The frequency of true altruism in nature requires assessment because, if true altruism is common, Darwin's theory of natural selection is inadequate to account for all of evolution. An experiment provided birds with the opportunity to behave truly altruistically. One member of each of 25 wild pairs was collected. Ten of these were replaced naturally by courting birds, or consorts. Only one consort fostered the young of her prospective mate, and her behavior was interpretable as a reproductive error. Other consorts behaved reproductively selfishly.


Sexual selection, multiple male ornaments, and age- and condition-dependent signaling in the common yellowthroat.
In many animals, sexual selection has resulted in complex signaling systems in which males advertise aspects of their phenotypic or genetic quality through elaborate ornamentation and display behaviors. Different ornaments might convey different information or be directed at different receivers, but they might also be redundant signals of quality that function reliably at different times (ages) or in different contexts. We explored sexual selection and age- and condition-dependent signaling in the common yellowthroat (Geothlypis trichas), a sexually dichromatic warbler with two prominent plumage ornaments--a melanin-based, black facial "mask" and carotenoid-based, UV-yellow "bib." In a three-year study, variance among males in the number of social (M(w)) and extra-pair (M(e)) mates generated strong sexual selection on mask and bib attributes. Some traits (mask size, bib yellow brightness) were correlated with male age and did not experience selection beyond age-related increases in M(w) and M(e). Other traits showed age-specific (bib size) or age-reversed (ultraviolet brightness) patterns of selection that paralleled changes in the information-content of each ornament. The components of male fitness generating selection in young versus old males were distinct, reflecting different sources of variation in male fertilization success. Age- and context-dependent changes in the strength, direction, and target of selection may help explain the maintenance of multiple ornaments in this and other species.


Psychoneurocutaneous medicine: past, present and future.
Psychoneurocutaneous medicine is an important and rapidly growing field. It is an integrative science created to address the interaction between the mind, nervous system and skin. Four major fields are involved: psychiatry, psychology, neurology and dermatology. The history of psychoneurocutaneous medicine is old and fascinating. Even though it is a young science only established in the last century, allusions to the nervous system and diseases of the skin can be traced back thousands of years in the literature. Characteristically, the last two centuries were of special importance for the development of this field in Europe, lately in America, with great effort placed on research and publications. More recently, the creation of associations, work groups and the merging of subspecialties dedicated exclusively to study the psychological impact of skin disorders in subpopulations of patients have helped to give momentum to psychoneurocutaneous medicine. Further development of this field will shed light on the appropriate diagnosis and treatment of psychodermatologic disorders, enhancing the functionality and quality of life of patients. This paper presents a summary of the most influential facts in the history of psychoneurocutaneous medicine, its present and future perspectives.


Tough coating proteins: subtle sequence variation modulates cohesion.
Mussel foot protein-1 (mfp-1) is an essential constituent of the protective cuticle covering all exposed portions of the byssus (plaque and the thread) that marine mussels use to attach to intertidal rocks. The reversible complexation of Fe(3+) by the 3,4-dihydroxyphenylalanine (Dopa) side chains in mfp-1 in Mytilus californianus cuticle is responsible for its high extensibility (120%) as well as its stiffness (2 GPa) due to the formation of sacrificial bonds that help to dissipate energy and avoid accumulation of stresses in the material. We have investigated the interactions between Fe(3+) and mfp-1 from two mussel species, M. californianus (Mc) and M. edulis (Me), using both surface sensitive and solution phase techniques. Our results show that although mfp-1 homologues from both species bind Fe(3+), mfp-1 (Mc) contains Dopa with two distinct Fe(3+)-binding tendencies and prefers to form intramolecular complexes with Fe(3+). In contrast, mfp-1 (Me) is better adapted to intermolecular Fe(3+) binding by Dopa. Addition of Fe(3+) did not significantly increase the cohesion energy between the mfp-1 (Mc) films at pH 5.5. However, iron appears to stabilize the cohesive bridging of mfp-1 (Mc) films at the physiologically relevant pH of 7.5, where most other mfps lose their ability to adhere reversibly. Understanding the molecular mechanisms underpinning the capacity of M. californianus cuticle to withstand twice the strain of M. edulis cuticle is important for engineering of tunable strain tolerant composite coatings for biomedical applications.


REFINE: a randomized trial comparing cyclosporine A and tacrolimus on fibrosis after liver transplantation for hepatitis C.
REFINE was a 12-month, prospective, open-label study in 356 patients receiving de novo liver transplantation for hepatitis C virus (HCV) cirrhosis, randomized to cyclosporine A (CsA) or tacrolimus with (i) no steroids, IL-2 receptor antibody induction and mycophenolic acid, or (ii) slow steroid tapering. The primary analysis population based on availability of liver biopsies comprised 165 patients (88 CsA, 77 tacrolimus). There was no difference in the primary endpoint, fibrosis stage ≥2 at 12 months, which occurred in 63/88 CsA-treated patients (71.6%) and 52/77 tacrolimus-treated patients (67.5%) (odds ratio [OR] 1.11; 95% CI 0.56, 2.21; p = 0.759). Similarly, no significant between-group difference occurred at month 24 (OR 1.15; 95% CI 0.47, 2.80; p = 0.767). Among steroid-free patients, fibrosis score ≥2 was significantly less frequent with CsA versus tacrolimus at month 12 (7/37 [18.9%] vs. 16/38 [42.1%]; p = 0.029). HCV viral load was similar in both the tacrolimus- and CsA-treated cohorts. Mean blood glucose was significantly higher with tacrolimus from day 15 onward. Biopsy-proven acute rejection, graft loss and death were similar. These results showed no differences in posttransplant HCV-induced liver fibrosis between patients treated with CsA or tacrolimus in steroid-containing regimens, whereas CsA in steroid-free protocols was associated with reduced severity of fibrosis progression at 1 year posttransplant.


Molecular and Immune Biomarkers in Acute Respiratory Distress Syndrome: A Perspective From Members of the Pulmonary Pathology Society.
Acute respiratory distress syndrome (ARDS) is a multifactorial syndrome with high morbidity and mortality rates, characterized by deficiency in gas exchange and lung mechanics that lead to hypoxemia, dyspnea, and respiratory failure. Histologically, ARDS is characterized by an acute, exudative phase, combining diffuse alveolar damage and noncardiogenic edema, followed by a later fibroproliferative phase. Despite an enhanced understanding of ARDS pathogenesis, the capacity to predict the development of ARDS and to risk-stratify patients with the disease remains limited. Biomarkers may help to identify patients at the greatest risk of developing ARDS, to evaluate response to therapy, to predict outcome, and to improve clinical trials. The ARDS pathogenesis is presented in this article, as well as concepts and information on biomarkers that are currently used clinically or are available for laboratory use by academic and practicing pathologists and the developing and validating of new assays, focusing on the assays' major biologic roles in lung injury and/or repair and to ultimately suggest innovative, therapeutic approaches.


An integrated framework for safety, quality and risk management: an information and incident management system based on a universal patient safety classification.
More needs to be done to improve safety and quality and to manage risks in health care. Existing processes are fragmented and there is no single comprehensive source of information about what goes wrong. An integrated framework for the management of safety, quality and risk is needed, with an information and incident management system based on a universal patient safety classification. The World Alliance for Patient Safety provides a platform for the development of a coherent approach; 43 desirable attributes for such an approach are discussed. An example of an incident management and information system serving a patient safety classification is presented, with a brief account of how and where it is currently used. Any such system is valueless unless it improves safety and quality. Quadruple-loop learning (personal, local, national and international) is proposed with examples of how an exemplar system has been successfully used at the various levels. There is currently an opportunity to "get it right" by international cooperation via the World Health Organization to develop an integrated framework incorporating systems that can accommodate information from all sources, manage and monitor things that go wrong, and allow the worldwide sharing of information and the dissemination of tools for the implementation of strategies which have been shown to work.


Specific accumulation and elimination kinetics of tris(4-chlorophenyl)methane, tris(4-chlorophenyl)methanol, and other persistent organochlorines in humans from Japan.
We examined human adipose tissue, liver, and bile from humans in Japan to understand the contamination status, specific accumulation, and elimination of two newly identified environmental contaminants, tris(4-chlorophenyl)methane (TCPMe), tris(4-chlorophenyl)methanol (TCPMOH), and other persistent organochlorines such as polychlorinated biphenyls (PCBs), DDT and its metabolites (DDTs), hexachlorocyclohexane isomers (HCHs), hexachlorobenzene (HCB), and chlordane compounds (CHLs). TCPMe and TCPMOH concentrations in Japanese human adipose tissue were slightly higher than those reported previously, indicating widespread exposure to these compounds in humans. Elevated residues of PCBs and DDTs are found in adipose tissue and liver. Concentrations in bile strongly correlated with concentrations in adipose fat and liver, which may suggest an equilibration in adipose fat/bile and liver/bile and possible biliary excretion of persistent organochlorines in humans. Composition of the organochlorines accumulated further indicates a metabolic capacity in humans higher than that of marine mammals. We observed age-dependent accumulation for TCPMe, TCPMOH, and other organochlorines, but there were no significant gender differences. p,p'-DDE and TCPMe were estimated to have low biliary excretion rate. Elimination potential of persistent organochlorines may be related to their octanol-water partition coefficient. The relationship between excretion rate and octanol-water partition coefficient may be used to predict the biliary excretion potential of some other lipophilic organochlorines such as dioxins and dibenzofurans in humans. The presence of organochlorines in bile suggests that the hepatic excretory system plays a major role in the elimination of xenobiotics in humans. To our knowledge, this is the first study of accumulation and elimination of TCPMe and TCPMOH in humans.


Axial filament formation in Bacillus subtilis: induction of nucleoids of increasing length after addition of chloramphenicol to exponential-phase cultures approaching stationary phase.
When chloramphenicol was added to a culture of Bacillus subtilis in early exponential growth, microscopic observation of cells stained by 4',6-diamidino-2-phenylindole showed nucleoids that had changed in appearance from irregular spheres and dumbbells to large, brightly stained spheres and ovals. In contrast, the addition of chloramphenicol to cultures in mid- and late exponential growth showed cells with elongated nucleoids whose frequency and length increased as the culture approached stationary phase. The kinetics of nucleoid elongation after the addition of chloramphenicol to exponential-phase cultures was complex. Immediately after treatment, the rate of nucleoid elongation was very rapid. The nucleoid then elongated steadily for about 4 min, after which the rate of elongation decreased considerably. Nucleoids of cells treated with 6-(p-hydroxyphenylazo)-uracil (an inhibitor of DNA synthesis) exhibited the immediate rapid elongation upon chloramphenicol treatment but not the subsequent changes. These observations suggest that axial filament formation during stationary phase (stage I of sporulation) in the absence of chloramphenicol results from changes in nucleoid structure that are initiated earlier, during exponential growth.


Flux control and excess capacity in the enzymes of glycolysis and their relationship to flight metabolism in Drosophila melanogaster.
An important question in evolutionary and physiological genetics is how the control of flux-base phenotypes is distributed across the enzymes in a pathway. This control is often related to enzyme-specific levels of activity that are reported to be in excess of that required for demand. In glycolysis, metabolic control is frequently considered vested in classical regulatory enzymes, each strongly displaced from equilibrium. Yet the contribution of individual steps to control is unclear. To assess enzyme-specific control in the glycolytic pathway, we used P-element excision-derived mutagenesis in Drosophila melanogaster to generate full and partial knockouts of seven metabolic genes and to measure tethered flight performance. For most enzymes, we find that reduction to half of the normal activity has no measurable impact on wing beat frequency. The enzymes catalyzing near-equilibrium reactions, phosphoglucose isomerase, phosphoglucomutase, and triosephosphate isomerase fail to show any decline in flight performance even when activity levels are reduced to 17% or less. At reduced activities, the classic regulatory enzymes, hexokinase and glycogen phosphorylase, show significant drops in flight performance and are nearer to saturation. Our results show that flight performance is canalized or robust to the activity variation found in natural populations. Furthermore, enzymes catalyzing near-equilibrium reactions show strong genetic dominance down to low levels of activity. This implies considerable excess enzyme capacity for these enzymes.


Nitric oxide and the resolution of inflammation: implications for atherosclerosis.
The ubiquitous free radical, nitric oxide (NO), plays an important role in many biological processes including the regulation of the inflammatory response. Alterations in NO synthesis by endogenous systems likely influence inflammatory processes occurring in a wide range of diseases including many in the cardiovascular system (e.g. atherosclerosis). Progression of inflammatory conditions depends not only upon the recruitment and activation of inflammatory cells but also upon their subsequent removal from the inflammatory milieu. Apoptosis, or programmed cell death, is a fundamental process regulating inflammatory cell survival and is critically involved in ensuring the successful resolution of an inflammatory response. Apoptosis results in shutdown of secretory pathways and renders effete, but potentially highly histotoxic, cells instantly recognisable for non-inflammatory clearance by phagocytes (e.g., macrophages). However, dysregulation of apoptosis and phagocytic clearance mechanisms can have drastic consequences for development and resolution of inflammatory processes. In this review we highlight the complexities of NO-mediated regulation of inflammatory cell apoptosis and clearance by phagocytes and discuss the molecular mechanisms controlling these NO mediated effects. We believe that manipulation of pathways involving NO may have previously unrecognised therapeutic potential for limiting or resolving inflammatory and cardiovascular disease.


Enhanced intrinsic CYP3A4 activity in human hepatic C3A cells with optically controlled CRISPR/dCas9 activator complex.
Human hepatic C3A cells have been applied in bioartificial liver development, although these cells display low intrinsic cytochrome P450 3A4 (CYP3A4) enzyme activity. We aimed to enhance CYP3A4 enzyme activity of C3A cells utilizing CRISPR gene editing technology. We designed two CYP3A4 expression enhanced systems applying clustered regularly interspaced short palindromic repeats (CRISPR) gene technology: a CRISPR-on activation system including dCas9-VP64-GFP and two U6-sgRNA-mCherry elements, and a light-controlled CRISPR-on activation system combining our CRISPR-on activation system with an optical control system to facilitate regulation of CYP3A4 expression for various applications. Results of enzymatic activity assays displayed increased CYP3A4 activity in C3A cells expressing the CRISPR-on activation system compared with C3A cells. In addition, CYP3A4 activity increased in C3A cells expressing the light-controlled CRISPR-on activation system under blue light radiation compared with C3A cells. Notably, there was no statistical difference in the increase of CYP3A4 protein amounts induced by these two methods. After expansion in culture, C3A cells with the light-controlled CRISPR-on activation system exhibited no statistical difference in CYP3A4 mRNA levels between generations. Our findings provide a method to stably enhance functional gene expression in bioartificial liver cells with the potential for large-scale cell expansion.


Skin delivery potency and antitumor activities of temozolomide ester prodrugs.
Clinical trials have shown temozolomide to be an effective agent for treatment of malignant melanoma. In order to investigate its suitability for delivery via the skin, a series of temozolomide esters was synthesized as prodrugs. In vitro assays demonstrated temozolomide, temozolomide acid and the hexyl ester equi-effective against selected cancer cell lines. The susceptibility of the esters to enzyme hydrolysis and their effectiveness for application to the skin were investigated. The esters effectively diffuse through rat skin and the hexyl ester demonstrated profound potency for penetrating through skin. Topical application of 5% (w/v) hexyl ester in DMSO solution on a mouse model demonstrated a significant inhibition of tumor growth. These results suggest that temozolomide esters could be an effective alternative to temozolomide in the treatment of skin cancer.


Quantitative molecular sensing in biological tissues: an approach to non-invasive optical characterization.
A method to non-invasively and quantitatively characterize thick biological tissues by combining both experimental and computational approaches in tissue optical spectroscopy was developed and validated on fifteen porcine articular cartilage (AC) tissue samples. To the best of our knowledge, this study is the first to couple non-invasive reflectance and fluorescence spectroscopic measurements on freshly harvested tissues with Monte Carlo computational modeling of time-resolved propagation of both excitation light and multi-fluorophore emission. For reflectance, quantitative agreement between simulation and experiment was achieved to better than 11%. Fluorescence data and simulations were used to extract the ratio of the absorption coefficients of constituent fluorophores for each measured AC tissue sample. This ratio could be used to monitor relative changes in concentration of the constituent fluorophores over time. The samples studied possessed the complexity and variability not found in artificial tissue-simulating phantoms and serve as a model for future optical molecular sensing studies on tissue engineered constructs intended for use in human therapeutics. An optical technique that could non-invasively and quantitatively assess soft tissue composition or physiologic status would represent a significant advance in tissue engineering. Moreover, the general approach described here for optical characterization should be broadly applicable to quantitative, non-invasive molecular sensing applications in complex, three-dimensional biological tissues.


Nucleotide sequence and temporal regulation of a seed-specific Brassica napus cDNA encoding a stearoyl-acyl carrier protein (ACP) desaturase.
The nucleotide sequence is reported for a cDNA containing the entire coding region of a stearoyl-ACP desaturase (EC 220.127.116.11) from Brassica napus L. cv. Jet neuf. The cDNA was obtained from a library constructed from poly(A)+ RNA purified from embryo tissue. The derived amino acid sequence demonstrates substantial similarity with those from other plant delta 9-desaturases. Comparative RNA-dot blot analyses using the delta 9-desaturase cDNA and a rapeseed oleosin cDNA as probes showed that although both these transcripts were seed-specific, they exhibited distinct patterns of temporal regulation. The desaturase message was induced by 25 days after anthesis (DAA), peaking at 45 DAA but decreasing considerably thereafter. In contrast, the oleosin transcript did not increase until 45-50 DAA, reaching a peak much later at about 70 DAA.


JKT-1 is not a human seminoma cell line.
The JKT-1 cell line has been used in multiple independent studies as a representative model of human testicular seminoma. However, no cell line for this specific tumour type has been independently confirmed previously; and therefore, the seminomatous origin of JKT-1 must be proven. The genetic constitution of the JKT-1 cells was determined using flow cytometry and spectral karyotyping, as well as array comparative genomic hybridization and fluorescent in situ hybridization. Marker profiling, predominantly based on differentially expressed proteins during normal germ cell development, was performed by immunohistochemistry and Western blot analyses. Moreover, genome wide affymetrix mRNA expression and profiling of 157 microRNAs was performed, and the status of genomic imprinting was determined. A germ cell origin of the JKT-1 cells was in line with genomic imprinting status and marker profile (including positive staining for several cancer-testis antigens). However, the supposed primary tumour, from which the cell line was derived, being indeed a classical seminoma, was molecularly proven not to be the origin of the cell line. The characteristic chromosomal anomalies of seminoma, e.g. gain of the short arm of chromosome 12, as well as the informative marker profile (positive staining for OCT3/4, NANOG, among others) were absent in the various JKT-1 cell lines investigated, irrespective of where the cells were cultured. All results indicate that the JKT-1 cell line is not representative of human seminoma. Although it can originate from an early germ cell, a non-germ cell derivation cannot be excluded.


Some characteristics of a purified heat-stable aldolase.
Thompson, P. J. (University of Nebraska, Lincoln) and T. L. Thompson. Some characteristics of a purified heat-stable aldolase. J. Bacteriol. 84:694-700. 1962-Aldolase from a thermophilic strain of bacteria was obtained in a state of high purity. Heat studies of purified aldolases from cells cultivated at 45 and 65 C showed them equally stable at 70 C for 1 hr. Metal-ion and chelate studies indicated that thermal aldolase is metal ion-independent. Carboxypeptidase did not alter activity or specificity. The enzyme was specific for fructose-1,6-diphosphate. Hydrazine was found inhibitory in the assay procedure. The inhibition was independent of pH over the range of H(+) concentrations tested and was reversed by dialysis against water.


Tobacco industry attempts to influence and use the German government to undermine the WHO Framework Convention on Tobacco Control.
Germany has been identified as one of a few high-income countries that opposed a strong Framework Convention on Tobacco Control (FCTC), the WHO's first global public health treaty. This paper examines whether the tobacco industry had influenced the German position on the FCTC. Analysis of previously confidential tobacco industry documents. The tobacco industry has identified Germany as a key target within its global strategy against the FCTC. Building on an already supportive base, the industry appears to have successfully lobbied the German government, influencing Germany's position and argumentation on key aspects of the FCTC. It then used Germany in its efforts to weaken the FCTC. The evidence suggests that the industry enjoyed success in undermining the Federal Health Ministry's position and using Germany to limit the European Union negotiating mandate. The tactics used by the tobacco industry included the creation of controversy between the financial, trade and other ministries on one side and the health ministry on the other side, the use of business associations and other front groups to lobby on the industry's behalf and securing industry access to the FCTC negotiations via the International Standardization Organization. The evidence suggests that Germany played a major role in the tobacco industry's efforts to undermine the FCTC. Germany's position consistently served to protect industry interests and was used to influence and constrain other countries. Germany thus contributed significantly to attempts to weaken an international treaty and, in doing so, failed in its responsibility to advance global health.


Dementia knowledge, art, research and education - Teaching primary school children about dementia.
To develop, implement and evaluate the impact of a short education intervention on the understanding of dementia through visual art by primary school-aged children. A series of three lessons were developed in consultation with a local schoolteacher and community artists and taught in a local primary school. Stage 2 students (8-10 years old) created an artwork about memory, learned about dementia and adapted their artworks to represent their developing understanding of dementia. Empirical data were collected through pre and postinterventions surveys and content analysis of the artworks. Matched pre and postintervention survey data were obtained for 74 students and showed a significant improvement in seven domains. This indicated that the students had an increased understanding of dementia and its impact on the individual following the intervention. Matched artwork was analysed from lessons 1 and 3 for 109 students using a coding schema developed specifically for this project. The students developed their artwork to show memories fading or being lost altogether. They also used abstract shapes to create a sense of disorder and chaos. Participation in the intervention was shown to increase students' understanding and knowledge of dementia using both qualitative and quantitative measures. SO WHAT?: It is likely that by educating children about dementia, we have the potential to reduce the stigma faced by people living with dementia and their carers. This is important, as the ageing population means that more people within the community, including children, will know someone living with dementia. Further, this represents the cornerstone in creating dementia-friendly communities.


A new family of cell surface located purine transporters in Microsporidia and related fungal endoparasites.
Plasma membrane-located transport proteins are key adaptations for obligate intracellular Microsporidia parasites, because they can use them to steal host metabolites the parasites need to grow and replicate. However, despite their importance, the functions and substrate specificities of most Microsporidia transporters are unknown. Here, we provide functional data for a family of transporters conserved in all microsporidian genomes and also in the genomes of related endoparasites. The universal retention among otherwise highly reduced genomes indicates an important role for these transporters for intracellular parasites. Using Trachipleistophora hominis, a Microsporidia isolated from an HIV/AIDS patient, as our experimental model, we show that the proteins are ATP and GTP transporters located on the surface of parasites during their intracellular growth and replication. Our work identifies a new route for the acquisition of essential energy and nucleotides for a major group of intracellular parasites that infect most animal species including humans.


Speckle reduction in holography by means of random spatial sampling.
In this paper, we will illustrate a new technique by which the hologram image speckle can be reduced by spatially random sampling of the hologram aperture. The sampling procedure can be performed by a movable random mask. If the sampling function is made to be uncorrelated in subsequent spatial sampling, the speckle effect in the hologram image can be eliminated. However, an optimum sampling function may be difficult to obtain, which remains to be seen. This speckle reduction technique can be achieved only by some trade-off of the holographic resolution. A simple experimental confirmation of this technique is illustrated. Since one of the most severely limiting factors in applications of holography may be the speckle effect, this proposed technique should be added, together with the other existent techniques, to remedy this limiting factor.


The influence of social network on couples' intention to have the first child.
Recently, the relevance of social interactions as determinants of behavioral intentions has been increasingly perceived, but there is a lack of knowledge on how and why it interacts with couples' fertility intentions. This qualitative study was conducted to explore the influence of social network on couples' intention to have their first child in urban society of Mashhad, Iran in 2011. In this exploratory qualitative study in-depth interviews were conducted with 24 participants including 14 fertile women, two parents, three husbands and five midwives and health care providers. The sample was selected purposively in urban health centers, homes and workplaces until data saturation was achieved. Data analysis was carried out adopting conventional content analysis approach through giving analytical codes and identification of categories using MAXqda software. Study rigor verified via prolonged engagement, validation of codes through member check and peer debriefing. Findings from data analysis demonstrated four major categories about social network's influence on couples' intention to have their first child including 1) perception of fertility relevant social network, 2) occurrence of various types of social influence 3) subjective judgment to the benefits of social network and its fitness to personal life, and 4) couples' interaction with social network. Managing the fertility behaviors need to include the consideration of personal social networks surrounding the couples. It is important to apply the study findings in providing family planning services and dissemination of appropriate fertility behaviors through community-based reproductive health care delivery system.


Coffee consumption attenuates short-term fructose-induced liver insulin resistance in healthy men.
Epidemiologic and experimental data have suggested that chlorogenic acid, which is a polyphenol contained in green coffee beans, prevents diet-induced hepatic steatosis and insulin resistance. We assessed whether the consumption of chlorogenic acid-rich coffee attenuates the effects of short-term fructose overfeeding, dietary conditions known to increase intrahepatocellular lipids (IHCLs), and blood triglyceride concentrations and to decrease hepatic insulin sensitivity in healthy humans. Effects of 3 different coffees were assessed in 10 healthy volunteers in a randomized, controlled, crossover trial. IHCLs, hepatic glucose production (HGP) (by 6,6-d2 glucose dilution), and fasting lipid oxidation were measured after 14 d of consumption of caffeinated coffee high in chlorogenic acid (C-HCA), decaffeinated coffee high in chlorogenic acid, or decaffeinated coffee with regular amounts of chlorogenic acid (D-RCA); during the last 6 d of the study, the weight-maintenance diet of subjects was supplemented with 4 g fructose · kg(-1) · d(-1) (total energy intake ± SD: 143 ± 1% of weight-maintenance requirements). All participants were also studied without coffee supplementation, either with 4 g fructose · kg(-1) · d(-1) (high fructose only) or without high fructose (control). Compared with the control diet, the high-fructose diet significantly increased IHCLs by 102 ± 36% and HGP by 16 ± 3% and decreased fasting lipid oxidation by 100 ± 29% (all P < 0.05). All 3 coffees significantly decreased HGP. Fasting lipid oxidation increased with C-HCA and D-RCA (P < 0.05). None of the 3 coffees significantly altered IHCLs. Coffee consumption attenuates hepatic insulin resistance but not the increase of IHCLs induced by fructose overfeeding. This effect does not appear to be mediated by differences in the caffeine or chlorogenic acid content. This trial was registered at clinicaltrials.gov as NCT00827450.


Shining light on the head: Photobiomodulation for brain disorders.
Photobiomodulation (PBM) describes the use of red or near-infrared light to stimulate, heal, regenerate, and protect tissue that has either been injured, is degenerating, or else is at risk of dying. One of the organ systems of the human body that is most necessary to life, and whose optimum functioning is most worried about by humankind in general, is the brain. The brain suffers from many different disorders that can be classified into three broad groupings: traumatic events (stroke, traumatic brain injury, and global ischemia), degenerative diseases (dementia, Alzheimer's and Parkinson's), and psychiatric disorders (depression, anxiety, post traumatic stress disorder). There is some evidence that all these seemingly diverse conditions can be beneficially affected by applying light to the head. There is even the possibility that PBM could be used for cognitive enhancement in normal healthy people. In this transcranial PBM (tPBM) application, near-infrared (NIR) light is often applied to the forehead because of the better penetration (no hair, longer wavelength). Some workers have used lasers, but recently the introduction of inexpensive light emitting diode (LED) arrays has allowed the development of light emitting helmets or "brain caps". This review will cover the mechanisms of action of photobiomodulation to the brain, and summarize some of the key pre-clinical studies and clinical trials that have been undertaken for diverse brain disorders.


Practice Paper of the Academy of Nutrition and Dietetics: Comprehensive Nutrition Programs and Services in Schools.
It is the position of the Academy of Nutrition and Dietetics, School Nutrition Association (SNA), and Society for Nutrition Education and Behavior (SNEB) that comprehensive, integrated nutrition programs in preschool through high school are essential to improve the health, nutritional status, and academic performance of our nation's children. To maximize impact, the Academy, SNA, and SNEB recommend specific strategies in the following key areas: food and nutrition services available throughout the school campus, nutrition initiatives such as Farm to School and school gardens, wellness policies, nutrition education and promotion, and consideration of roles and responsibilities. This paper supports the joint position paper of the Academy of Nutrition and Dietetics, SNA, and SNEB published in the May 2018 Journal of Academy of Nutrition and Dietetics. In alignment with the joint position paper, this practice paper provides registered dietitian nutritionists and nutrition and dietetics technicians, registered with an overview of current school nutrition services and opportunities for professional careers in school settings. The Academy of Nutrition and Dietetics has several position papers related to youth preschool through adolescence that cover specific nutrition needs in more detail at www.eatright.org.


Centrosomal association of histone macroH2A1.2 in embryonic stem cells and somatic cells.
The histone 2A variant macroH2A1.2 is expressed in female and male mammals and is implicated in X-chromosome inactivation and autosomal gene silencing. In undifferentiated and early differentiating murine embryonic stem (ES) cells a cytosolic pool of macroH2A1.2 has recently been reported and found to be associated with the centrosome. Here, we show that the centrosomal association of macroH2A1.2 is a widespread phenomenon and is not restricted to undifferentiated and early differentiating ES cells. By indirect immunofluorescence we detect macroH2A1.2 protein in a juxtanuclear structure that duplicates once per cell cycle and colocalizes with centrosomal gamma-tubulin in both XX and XY ES cells prior to and throughout their differentiation. MacroH2A1.2 localization to the centrosome is also observed in female and male somatic cells, both in interphase and in mitosis. Biochemical analysis demonstrates that the association between macroH2A1.2 and the centrosome in somatic cells is stable, as macroH2A1.2 copurifies with centrosomes isolated from human lymphoblasts. Therefore, in addition to a nuclear pool of macroH2A1.2 a fraction of the histone is associated with the centrosome in various cell types and throughout ES cell differentiation.


Spontaneous synchronized calcium oscillations in neocortical neurons in the presence of physiological [Mg(2+)]: involvement of AMPA/kainate and metabotropic glutamate receptors.
Primary cultures of neocortical neurons exhibit spontaneous Ca(2+) oscillations under zero or low extracellular [Mg(2+)] conditions. We find that mature murine neocortical neurons cultured for 9 days also produce spontaneous Ca(2+) oscillations in the presence of physiological [Mg(2+)]. These Ca(2+) oscillations were action potential mediated inasmuch as tetrodotoxin eliminated their occurrence. AMPA receptors were found to regulate the frequency of Ca(2+) oscillations. In contrast, Ca(2+) oscillations were independent of activation of L-type Ca(2+) channels, and NMDA receptors provided only a minor contribution. Release of intracellular Ca(2+) stores was involved in the oscillatory activity since thapsigargin reduced the amplitude and frequency of the oscillations. S-4-carboxyphenylglycine (S)-4CPG), an antagonist of group I metabotropic glutamate receptor (mGluR), also reduced the amplitude of oscillations. In addition, 1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), a group I mGluR agonist, increased the oscillation frequency, suggesting a critical role for mGluR in the generation of Ca(2+) oscillations. The mGluR-mediated release of intracellular Ca(2+) stores appeared to be mediated by phospholipase C (PLC) since the PLC inhibitor U73122 eliminated the Ca(2+) oscillations. These results indicate that Ca(2+) oscillations in neocortical cultures in the presence of physiologic [Mg(2+)] are primarily initiated by excitatory input from AMPA receptors and involve mobilization of intracellular Ca(2+) stores following activation of mGluR.


Effects of human metapneumovirus and respiratory syncytial virus antigen insertion in two 3' proximal genome positions of bovine/human parainfluenza virus type 3 on virus replication and immunogenicity.
A live attenuated bovine parainfluenza virus type 3 (PIV3), harboring the fusion (F) and hemagglutinin-neuraminidase (HN) genes of human PIV3, was used as a virus vector to express surface glycoproteins derived from two human pathogens, human metapneumovirus (hMPV) and respiratory syncytial virus (RSV). RSV and hMPV are both paramyxoviruses that cause respiratory disease in young children, the elderly, and immunocompromised individuals. RSV has been known for decades to cause acute lower respiratory tract infections in young children, which often result in hospitalization, while hMPV has only been recently identified as a novel human respiratory pathogen. In this study, the ability of bovine/human PIV3 to express three different foreign transmembrane surface glycoproteins and to induce a protective immune response was evaluated. The RNA-dependent RNA polymerase of paramyxoviruses binds to a single site at the 3' end of the viral RNA genome to initiate transcription of viral genes. The genome position of the viral gene determines its level of gene expression. The promoter-proximal gene is transcribed with the highest frequency, and each downstream gene is transcribed less often due to attenuation of transcription at each gene junction. This feature of paramyxoviruses was exploited using the PIV3 vector by inserting the foreign viral genes at the 3' terminus, at position 1 or 2, of the viral RNA genome. These locations were expected to yield high levels of foreign viral protein expression stimulating a protective immune response. The immunogenicity and protection results obtained with a hamster model showed that bovine/human PIV3 can be employed to generate bivalent PIV3/RSV or PIV3/hMPV vaccine candidates that will be further evaluated for safety and efficacy in primates.


LeuX tRNA-dependent and -independent mechanisms of Escherichia coli pathogenesis in acute cystitis.
Uropathogenic Escherichia coli (UPEC) contain multiple horizontally acquired pathogenicity-associated islands (PAI) implicated in the pathogenesis of urinary tract infection. In a murine model of cystitis, type 1 pili-mediated bladder epithelial invasion and intracellular proliferation are key events associated with UPEC virulence. In this study, we examined the mechanisms by which a conserved PAI contributes to UPEC pathogenesis in acute cystitis. In the human UPEC strain UTI89, spontaneous excision of PAI II(UTI89) disrupts the adjacent leuX tRNA locus. Loss of wild-type leuX-encoded tRNA(5)(Leu) significantly delayed, but did not eliminate, FimB recombinase-mediated phase variation of type 1 pili. FimX, an additional FimB-like, leuX-independent recombinase, was also found to mediate type 1 pili phase variation. However, whereas FimX activity is relatively slow in vitro, it is rapid in vivo as a non-piliated strain lacking the other fim recombinases rapidly expressed type 1 pili upon experimental infection. Finally, we found that disruption of leuX, but not loss of PAI II(UTI89) genes, reduced bladder epithelial invasion and intracellular proliferation, independent of type 1 piliation. These findings indicate that the predominant mechanism for preservation of PAI II(UTI89) during the establishment of acute cystitis is maintenance of wild-type leuX, and not PAI II(UTI89) gene content.


The 'I' and the 'Me' in self-referential awareness: a neurocognitive hypothesis.
The nature of the 'self' and self-referential awareness has been one of the most debated issues in philosophy, psychology and cognitive neuroscience. Understanding the neurocognitive bases of self-related representation and processing is also crucial to research on the neural correlates of consciousness. The distinction between an 'I', corresponding to a subjective sense of the self as a thinker and causal agent, and a 'Me', as the objective sense of the self with the unique and identifiable features constituting one's self-image or self-concept, suggested by William James, has been re-elaborated by authors from different theoretical perspectives. In this article, empirical studies and theories about the 'I' and the 'Me' in cognition and self-related awareness are reviewed, including the relationships between self and perception, self and memory, the development of the self, self-referential stimulus processing, as well as related neuroimaging studies. Subsequently, the relations between self and different aspects of consciousness are considered. On the basis of the reviewed literature and with reference to Block's distinction between phenomenal and access consciousness, a neurocognitive hypothesis is formulated about 'I'-related and 'Me'-related self-referential awareness. This hypothesis is extended to metacognitive awareness and a form of non-transitive consciousness, characteristic of meditation experiences and studies, with particular reference to the notion of mindfulness and other Buddhist constructs.


Morphometric analysis of germinal centers in nonthymomatous patients with myasthenia gravis.
A morphometric analysis of germinal centers (GCs) in the thymus of nonthymomatous patients with myasthenia gravis was performed in 26 patients, including 14 women and 12 men. The GCs were evaluated for number, diameter, perimeter, and cross-sectional area using a computerized interactive morphometric analysis. The GCs ranged from 2 to 19 per case, with an average diameter of 0.02 to 0.43 mm, a perimeter of 0.38 to 1.35 mm, and a cross-sectional area of 0.01 to 0.14 mm2. In thymic sections with fewer than five GCs, the GCs had a mean area of 0.05 mm2, a perimeter of 0.84 mm, and a diameter of 0.24 mm. In thymic sections containing five or more GCs, the GCs had a mean area of 0.04 mm2, a perimeter of 0.62 mm, and a diameter of 0.19 mm. The clinical improvement in these patients inversely correlated with the above parameters, with improvement being observed in patients whose GCs had a mean area of 0.02 mm2, a perimeter of 0.58 mm, and a diameter of 0.17 mm. No correlation was observed between the number of GCs and clinical improvement. The results of our study appear to indicate that computerized interactive morphometric analysis may represent a potentially useful method for the evaluation of the morphometric features of thymic GCs and their correlation with clinical outcome in patients with myasthenia gravis.


Nest inheritance is the missing source of direct fitness in a primitively eusocial insect.
Animals that cooperate with nonrelatives represent a challenge to inclusive fitness theory, unless cooperative behavior is shown to provide direct fitness benefits. Inheritance of breeding resources could provide such benefits, but this route to cooperation has been little investigated in the social insects. We show that nest inheritance can explain the presence of unrelated helpers in a classic social insect model, the primitively eusocial wasp Polistes dominulus. We found that subordinate helpers produced more direct offspring than lone breeders, some while still subordinate but most after inheriting the dominant position. Thus, while indirect fitness obtained through helping relatives has been the dominant paradigm for understanding eusociality in insects, direct fitness is vital to explain cooperation in P. dominulus.


Examination of a second region of the HIV type 1 genome reveals additional cases of superinfection.
HIV-1 superinfection may occur at a rate similar to that of initial infection, raising concerns for HIV-1 vaccine strategies predicated on eliciting immune responses similar to those in natural infection. Because of the high rate of recombination during HIV-1 replication, studies examining only one region of the HIV-1 genome are likely to miss cases of HIV-1 superinfection. We examined HIV-1 gag sequences from 14 high-risk Kenyan women in whom superinfection was not detected in a previous study of env sequences. We detected two additional cases of HIV-1 superinfection: one intersubtype superinfection that occurred between 1046 and 1487 days postinfection (DPI) and one intrasubtype superinfection that occurred between 341 and 440 DPI. Our results suggest that studies that examine only small genome regions may lead to underestimates of the risk of superinfection, highlighting the need for more extensive studies examining multiple regions of the HIV-1 genome.


Injury-induced immune responses in Hydra.
The impact of injury-induced immune responses on animal regenerative processes is highly variable, positive or negative depending on the context. This likely reflects the complexity of the innate immune system that behaves as a sentinel in the transition from injury to regeneration. Early-branching invertebrates with high regenerative potential as Hydra provide a unique framework to dissect how injury-induced immune responses impact regeneration. A series of early cellular events likely require an efficient immune response after amputation, as antimicrobial defence, epithelial cell stretching for wound closure, migration of interstitial progenitors toward the wound, cell death, phagocytosis of cell debris, or reconstruction of the extracellular matrix. The analysis of the injury-induced transcriptomic modulations of 2636 genes annotated as immune genes in Hydra identified 43 genes showing an immediate/early pulse regulation in all regenerative contexts examined. These regulations point to an enhanced cytoprotection via ROS signaling (Nrf, C/EBP, p62/SQSMT1-l2), TNFR and TLR signaling (TNFR16-like, TRAF2l, TRAF5l, jun, fos-related, SIK2, ATF1/CREB, LRRC28, LRRC40, LRRK2), proteasomal activity (p62/SQSMT1-l1, Ced6/Gulf, NEDD8-conjugating enzyme Ubc12), stress proteins (CRYAB1, CRYAB2, HSP16.2, DnaJB9, HSP90a1), all potentially regulating NF-κB activity. Other genes encoding immune-annotated proteins such as NPYR4, GTPases, Swap70, the antiproliferative BTG1, enzymes involved in lipid metabolism (5-lipoxygenase, ACSF4), secreted clotting factors, secreted peptidases are also pulse regulated upon bisection. By contrast, metalloproteinases and antimicrobial peptide genes largely follow a context-dependent regulation, whereas the protease inhibitor α2macroglobulin gene exhibits a sustained up-regulation. Hence a complex immune response to injury is linked to wound healing and regeneration in Hydra.


Evaluating STORM skills training for managing people at risk of suicide.
This paper reports a study evaluating the Skills Training On Risk Management (STORM) training initiative in three mental health services in the North-West of England, UK. Training for health workers has been widely advocated as a key route to suicide prevention. However, reports of evaluations are scarce in the literature. In previous research, we have demonstrated that the STORM intervention results in acquisition of new skills and can be disseminated in a community setting. The training was delivered during a 6-month period in 2002 by three mental health nurses who were seconded part-time to the project. The quantitative evaluation, which assessed change in attitudes, confidence, acquisition of skills and satisfaction, used a pretest/post-test design, with participants acting as their own controls. Qualitative interviews were conducted with a purposive sample of 16 participants to explore the impact on clinical practice, and with the three trainers at the end of the study. Data from 458 staff members were collected during a 6-month period. Positive changes in attitudes and confidence were shown, but previous evidence of skill acquisition was not replicated. Qualitative interviews revealed important insights into changes in clinical practice, particularly for less experienced or unqualified nursing staff, but also concerns about the lack of an educational culture to foster and support such interventions in practice within the organizations. STORM training for the assessment and management of suicide risk is both feasible and acceptable in mental health trusts. However, we remain uncertain of its longer-term impact, given the lack of engagement of senior staff in the enterprise and the absence of linked supervision and support from the organizational management to reinforce skill acquisition and development. We consider that regular supervision that links STORM training to actual clinical experience would be the ideal.


Analgesic use and patterns of estrogen metabolism in premenopausal women.
Analgesic use has been hypothesized to reduce the risk of some cancers, with inverse associations between analgesics and colon cancer, and suggestive inverse associations for breast cancer. Estrogen metabolites (EM) have genotoxic and estrogenic potential; genotoxicity may differ by hydroxylation pathway. Analgesic use may impact patterns of estrogen metabolism; effects of analgesics on disease risk could be mediated through these patterns. We conducted a cross-sectional study among 603 premenopausal women in the Nurses' Health Study II. Frequency of aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen use was reported via questionnaire; average frequency in 1997 and 1999 was calculated. Women provided urine samples between 1996 and 1999, collected during the mid-luteal phase of the menstrual cycle. Urinary EM were quantified using high-performance liquid chromatography-tandem mass spectrometry. We observed no association between analgesic use and estradiol, estrone, or specific pathways of estrogen metabolism. Women reporting more frequent aspirin use had lower methylated 2-catechols (e.g., 2-hydroxyestrone-3-methyl ether, 2+ days/week vs. non-use: 0.95 vs. 1.21 pmol/mg creatinine; p difference = 0.01, p trend = 0.07). Non-aspirin NSAID use was positively associated with 17-epiestriol (4+ days/week vs. non-use: 2.48 vs. 1.52 pmol/mg creatinine; p difference = 0.01, p trend = 0.11). Acetaminophen use was positively associated with total EM (2+ days/week vs. non-use: 236 vs. 198 pmol/mg creatinine; p difference = 0.02, p trend = 0.11), 2-hydroxyestrone-3-methyl ether (1.6 vs. 1.1 pmol/mg creatinine; p difference < 0.01, p trend = 0.02), and 16α-hydroxyestrone (17 vs. 12 pmol/mg creatinine; p difference = 0.01, p trend = 0.05). This study provides the first assessment of analgesic use and patterns of estrogen metabolism in women. While we observed some associations between analgesics and individual EM, no clear patterns emerged.


Why do people buy dogs with potential welfare problems related to extreme conformation and inherited disease? A representative study of Danish owners of four small dog breeds.
A number of dog breeds suffer from welfare problems due to extreme phenotypes and high levels of inherited diseases but the popularity of such breeds is not declining. Using a survey of owners of two popular breeds with extreme physical features (French Bulldog and Chihuahua), one with a high load of inherited diseases not directly related to conformation (Cavalier King Charles Spaniel), and one representing the same size range but without extreme conformation and with the same level of disease as the overall dog population (Cairn Terrier), we investigated this seeming paradox. We examined planning and motivational factors behind acquisition of the dogs, and whether levels of experienced health and behavior problems were associated with the quality of the owner-dog relationship and the intention to re-procure a dog of the same breed. Owners of each of the four breeds (750/breed) were randomly drawn from a nationwide Danish dog registry and invited to participate. Of these, 911 responded, giving a final sample of 846. There were clear differences between owners of the four breeds with respect to degree of planning prior to purchase, with owners of Chihuahuas exhibiting less. Motivations behind choice of dog were also different. Health and other breed attributes were more important to owners of Cairn Terriers, whereas the dog's personality was reported to be more important for owners of French Bulldogs and Cavalier King Charles Spaniels but less important for Chihuahua owners. Higher levels of health and behavior problems were positively associated with a closer owner-dog relationship for owners of Cavalier King Charles Spaniels and Chihuahuas but, for owners of French Bulldogs, high levels of problems were negatively associated with an intention to procure the same breed again. In light of these findings, it appears less paradoxical that people continue to buy dogs with welfare problems.


BET Inhibition Induces Apoptosis in Aggressive B-Cell Lymphoma via Epigenetic Regulation of BCL-2 Family Members.
Targeting BET bromodomain proteins using small molecules is an emerging anticancer strategy with clinical evaluation of at least six inhibitors now underway. Although MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional antitumor activities are important. Using the Eμ-Myc model of B-cell lymphoma, we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of proapoptotic (Bim) and antiapoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Eμ-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1 resistance phenotype. These studies provide important information on mechanisms of apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas. Mol Cancer Ther; 15(9); 2030-41. ©2016 AACR.


Video-assisted thoracoscopic surgery for resection of lung metastases.
Resection of indeterminate pulmonary lesions in patients with a history of malignancy is indicated, as the presence of metastases will provide prognostic information and often dictate further therapy. Pulmonary metastasectomy also improves survival in select patients with favorable tumor histologies. We reported the results of video-assisted thoracoscopic surgery (VATS) resection of indeterminate lung nodules in 72 patients with a history of malignancy. All lesions identified on preoperative high-resolution CT scan were found at surgery with visual inspection, digital palpation, or (in 13 cases) CT-guided needle localization. All lesions were resected nonanatomically with a rim of normal parenchyma, as is done with open techniques; 63 patients were found to have metastases and 9 patients had benign disease. There was no mortality, minimal morbidity, and decreased hospital stays in patients undergoing VATS resection compared with historical control subjects. These data and other reports have led to the widespread use of VATS for patients undergoing resection to establish a diagnosis. The role of VATS in patients with favorable tumor histology and limited tumor burden for whom metastasectomy may result in a survival advantage remains controversial. Improved image resolution with spiral CT scans and digital palpation, combined with intraoperative ultrasound examination of the lung, may decrease or eliminate the number of lesions missed with a VATS approach. The role of therapeutic VATS metastasectomy remains to be defined. Thus, this procedure currently should be used only in clinical trials.