[How to improve the appropriate application of stress test].
A brief self administered questionnaire (Veterans Specific Activity Questionnaire VSAQ) should be used to estimate exercise tolerance on the basis of symptoms during daily activities to individualize ramp rates on the treadmill, so that the test duration would be approximately 10 minutes in according with guidelines for exercise testing for correct determination of oxygen uptake. In a recent study the responses to the VSAQ and age were the strongest predictors of both measured and predicted exercise capacity. This approach allows to individualize ramp rates on the treadmill and appropriately targets the exercise test duration (8-12 minutes). Further studies are need for validating the role different questionnares in different populations, including women, patients with low grade of work activity and with diabetes.


Blockade of the pore-forming P2X7 receptor inhibits formation of multinucleated human osteoclasts in vitro.
Osteoclasts are large, multinucleated, terminally differentiated cells formed by the fusion of mononuclear hemopoietic precursors. Their function is the resorption of bone, which is an essential part of the growth, modeling and remodeling of the skeleton. Though some osteoclast differentiation factors have recently been identified, the molecular basis for the fusion process that leads to multinucleation is poorly understood. The ATP-gated P2X7 receptor is a plasma membrane receptor belonging to the family of P2X purinergic receptors. It is known to be expressed by cells of hemopoietic origin where its activation leads to multiple downstream events including cytokine release, cell permeabilization and apoptosis. More recently this receptor has been implicated in the generation of multinucleated giant cells and polykaryons. Here we show that human osteoclasts express P2X7 receptors in vitro and in vivo, and that these receptors are functional in vitro, as assessed by pore-formation studies. More importantly, blockade of the P2X7 receptor with the antagonist oxidized ATP or a blocking monoclonal antibody significantly inhibits the fusion of osteoclast precursors to form multinucleated osteoclasts. Taken in combination with previous results from our laboratory demonstrating P2X7 receptor-mediated apoptosis and inhibition of bone resorption in vitro, these data suggest an important role for the P2X7 receptor in the regulation of the osteoclast population. The P2X7 receptor provides a significant new target for modulating osteoclast function in diseases characterized by increased osteoclast number and excessive bone turnover.


Regulation of sympathetic nerve activity in heart failure: a role for nitric oxide and angiotensin II.
The mechanisms by which sympathetic function is augmented in chronic heart failure (CHF) are not well understood. A previous study from this laboratory (Circ Res. 1998;82:496-502) indicated that blockade of nitric oxide (NO) synthesis resulted in only an increase in renal sympathetic nerve activity (RSNA) when plasma angiotensin II (Ang II) levels were elevated. The present study was undertaken to determine if NO reduces RSNA in rabbits with CHF when Ang II receptors are blocked. Twenty-four New Zealand White rabbits were instrumented with cardiac dimension crystals, a left ventricular pacing lead, and a pacemaker. After pacing at 360 to 380 bpm for approximately 3 weeks, a renal sympathetic nerve electrode and arterial and venous catheters were implanted. Studies were carried out in the conscious state 3 to 7 days after electrode implantation. The effects of a 1-hour infusion of sodium nitroprusside (SNP; 3 microgram . kg-1. min-1) on RSNA and mean arterial pressure (MAP) were determined before and after Ang II blockade with losartan (5 mg/kg) in normal and CHF rabbits. Changes in MAP were readjusted to normal with phenylephrine. Before losartan, SNP evoked a decrease in MAP and an increase in RSNA in both groups that was baroreflex-mediated, because both MAP and RSNA returned to control when phenylephrine was administered. In the normal group, losartan plus SNP caused a reduction in MAP and an increase in RSNA that was 152.6+/-9.8% of control. Phenylephrine returned both MAP and RSNA back to the control levels. However, in the CHF group, losartan plus SNP evoked a smaller change in RSNA for equivalent changes in MAP (117.1+/-4.1% of control). On returning MAP to the control level with phenylephrine, RSNA was reduced to 65.2+/-2.9% of control (P<0. 0001). These data suggest that endogenous Ang II contributes to the sympathoexcitation in the CHF state and that blockade of Ang II receptors plus providing an exogenous source of NO reduces RSNA below the elevated baseline levels. We conclude that both a loss of NO and an increase in Ang II are necessary for sustained increases in sympathetic nerve activity in the CHF state.


Pathophysiology of venous thromboembolism.
Venous thromboembolism is complex with a multifactorial etiology. The Virchow triad (changes in blood flow, changes in vessel wall, and changes in the properties of blood) gives the main factors involved in venous thromboembolism. Venous stasis during immobilization in general anesthesia, stroke with hemiparesis, and heart failure plays a central role. The thromboembolic process can be initiated by a disturbance in the normal "hemostatic balance," with an increased thrombogenic potential, due to release of thromboplastin and collagen exposure during vessel wall injury by stasis and hypoxia, decreased fibrinolysis during surgery, malignancy, among others. Many substances modify these processes, including heparan sulfate, AT III, protein C, t-PA inhibitor, and alpha 2-antiplasmin.


Reciprocal focus profile.
A focus profile having a steeper peak is more resistant to image noise in the autofocus (AF) process of a digital camera. However, a focus profile of such shape normally has a flatter out-of-focus region on either side of the profile, resulting in a slow AF process due to the lack of clue about where the lens should move when the lens is in such regions. To address the problem, we provide a statistical analysis of the focus profile and show that a strictly monotonic transformation of the focus profile preserves the accuracy of the AF. On the basis of this analysis, we propose a new focus profile representation that transforms the focus profile to the reciprocal domain in which the reciprocal focus profile is modeled by a polynomial function. This transformation makes the AF mathematically tractable and boosts the search speed. Experimental results are shown to demonstrate the advantage of the proposed representation.


Critical role for CD1d-restricted invariant NKT cells in stimulating intrahepatic CD8 T-cell responses to liver antigen.
V alpha14 invariant natural killer T cells (iNKT) are localized in peripheral tissues such as the liver rather than lymphoid tissues. Therefore, their role in modulating the stimulation of conventional, major histocompatibility complex (MHC)-restricted T-cell responses has remained ambiguous. We here describe a role for V alpha14 iNKT cells in modulating conventional T-cell responses to antigen expressed in liver, using transferrin-mOVA (Tf-mOVA) mice. Naïve ovalbumin-specific class I MHC-restricted T cells (OTI) were adoptively transferred into Tf-mOVA mice in the presence or absence of iNKT-cell agonist alpha-galactosylceramide, after which OTI T-cell priming, antigen-specific cytokine production, cytotoxic killing ability, and liver damage were analyzed. Transfer of OTI cells resulted in robust intrahepatic, antigen-specific proliferation of T cells. OTI T cells were activated in liver, and antigen-specific effector function was stimulated by coactivation of Valpha14 iNKT cells using alpha-galactosylceramide. This stimulation was absent in CD1d(-/-)Tf-mOVA mice, which lack V alpha14 iNKT cells, and was prevented when interferon-gamma and tumor necrosis factor-alpha production by V alpha14 iNKT cells was blocked. CD1d-restricted V alpha14 iNKT cells stimulate intrahepatic CD8 T-cell effector responses to antigen expressed in liver. Our findings elucidate a previously unknown intervention point for targeted immunotherapy to autoimmune and possibly infectious liver diseases.


Nonsteroidal Antiinflammatory Drug Use and Association With Incident Hypertension in Ankylosing Spondylitis.
Nonsteroidal antiinflammatory drugs (NSAIDs) increase blood pressure and potentially cardiovascular burden, which may limit their use in ankylosing spondylitis (AS). Our objective was to determine the association of NSAID use with incident hypertension in a longitudinal AS cohort. Adults with AS were enrolled in a prospective cohort study of patient outcomes and examined every 4-6 months. Hypertension was defined by patient-reported hypertension; antihypertensive medication use; or, on 2 consecutive visits, systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg. Continuous NSAID use was dichotomized based on the validated NSAID index. We assessed the association of NSAID use as a time-varying exposure with the incidence of hypertension using Cox proportional hazards models. Of the 1,282 patients in the cohort, 628 patients without baseline hypertension had at least 1 year of follow-up and were included in the analysis. Of these, 72% were male, the mean age at baseline was 39 ± 13 years, and 200 patients used NSAIDs continuously. On follow-up, 129 developed incident hypertension. After controlling for other variables, continuous NSAID use was associated with a hazard ratio of 1.12 for incident hypertension (95% confidence interval 1.04-1.20), compared to noncontinuous or no use. The association did not differ in subgroups defined by age, body mass index, biologic use, or disease activity. In our prospective, longitudinal AS cohort, continuous NSAID use was associated with a 12% increased risk for the development of incident hypertension, as compared to noncontinuous or no NSAID use.


Disparities in colon and rectal cancer queried individually between Hispanics and Whites.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer related deaths in the United States. Racial disparities between Hispanics and Whites exist for incidence of late-onset (LO) CRC. However, not much is known about potential disparities between colon cancer (CC) and rectal cancer (RC) incidence queried individually. Using the SEER database data from 2000 to 2010, we obtained the national estimates of CC and RC for Hispanics and Whites. We analyzed trends in incidence, mortality, gender and stage of disease for early-onset (EO) (<50 years old) and LO (>50 years old) CC and RC. In Hispanics, the overall incidence of CC and RC increased by 47% and 52%, respectively; while in Whites, the overall incidence of CC and RC decreased by 13% and 2% respectively. Incidence of EO CC increased in both Hispanics and Whites by 83% and 17%, respectively, and incidence of EO RC also increased for both groups with a 76% increase in Hispanics and a 34% increase in Whites. For LO CC, the incidence increased by 37% in Hispanics while it decreased by 17% in Whites and for LO RC, the trend in incidence increased in Hispanics by 41%, but decreased in Whites by 11%. This study established that the incidence of CC and RC are different and there is racial disparity in incidence between Whites and Hispanics. This study, hopefully, will help in crafting public policy that might help in addressing this disparity.


Structure of a 10-23 deoxyribozyme exhibiting a homodimer conformation.
Deoxyribozymes (DNAzymes) are in vitro evolved DNA sequences capable of catalyzing chemical reactions. The RNA-cleaving 10-23 DNAzyme was the first DNAzyme to be evolved and possesses clinical and biotechnical applications as a biosensor and a knockdown agent. DNAzymes do not require the recruitment of other components to cleave RNA and can turnover, thus they have a distinct advantage over other knockdown methods (siRNA, CRISPR, morpholinos). Despite this, a lack of structural and mechanistic information has hindered the optimization and application of the 10-23 DNAzyme. Here, we report a 2.7 Å crystal structure of the RNA-cleaving 10-23 DNAzyme in a homodimer conformation. Although proper coordination of the DNAzyme to substrate is observed along with intriguing patterns of bound magnesium ions, the dimer conformation likely does not capture the true catalytic form of the 10-23 DNAzyme.


From two competing oscillators to one coupled-clock pacemaker cell system.
At the beginning of this century, debates regarding "what are the main control mechanisms that ignite the action potential (AP) in heart pacemaker cells" dominated the electrophysiology field. The original theory which prevailed for over 50 years had advocated that the ensemble of surface membrane ion channels (i.e., "M-clock") is sufficient to ignite rhythmic APs. However, more recent experimental evidence in a variety of mammals has shown that the sarcoplasmic reticulum (SR) acts as a "Ca(2+)-clock" rhythmically discharges diastolic local Ca(2+) releases (LCRs) beneath the cell surface membrane. LCRs activate an inward current (likely that of the Na(+)/Ca(2+) exchanger) that prompts the surface membrane "M-clock" to ignite an AP. Theoretical and experimental evidence has mounted to indicate that this clock "crosstalk" operates on a beat-to-beat basis and determines both the AP firing rate and rhythm. Our review is focused on the evolution of experimental definition and numerical modeling of the coupled-clock concept, on how mechanisms intrinsic to pacemaker cell determine both the heart rate and rhythm, and on future directions to develop further the coupled-clock pacemaker cell concept.


Measurement of Free Iodine in Different Formulations of Povidone-Iodine Eye Drops 5.
There are multiple studies in the literature that support the use of povidone iodine in the preparation of the surgical field of cataract as the most effective means to reduce the bacteria present in the ocular surface and the risk of infection. The concentration of free iodine is related to the antiseptic activity of these compounds, being, therefore, a good indicator of its effectiveness. The objective of this study was to determine the amount of free iodine and the evolution of it in different formulations of povidone iodine eye drops. The povidone iodine 5% eye drops were prepared starting from Betadine 10% dermal or the active principle and using a solvent, phosphate-citrate buffer solution, and sodium chloride 0.9% or sterile water for injection. Aliquots of 5 mL were packed in low-absorption absorption eye drops, topaz glass vials, and polyethylene syringe. The determination of free iodine was made by volumetric titration. Titration was performed with 0.1 M sodium thiosulfate using a starch solution as an indicator. Of the 0.1 M sodium thiosulfate, 1 mL is equivalent to 12.69 mg of available iodine, and it is expressed as a percentage of free iodine in the iodized povidone (% free iodine). Eyewash titrations were performed by replacing the substance with 5 mL of eye drops and following the remaining steps. Valuations were made on days 0, 7, and 14, as well as the measurement of pH and osmolarity. The results show that there are no differences between the average results at the three measurements taken on days 0, 7, and 14. We conclude that the free iodine remains stable during the stability period of 14 days. Regarding the pH and osmolarity data, the authors believe that the best tolerated formula will be that elaborated with povidone iodine and a phosphate- citrate buffer solution.


Molecular aspects of avian influenza (H5N1) viruses isolated from humans.
In 1997, 18 human infections with H5N1 influenza type A were identified in Hong Kong and six of the patients died. There were concomitant outbreaks of H5N1 infections in poultry. The gene segments of the human H5N1 viruses were derived from avian influenza A viruses and not from circulating human influenza A viruses. In 1999 two cases of human infections caused by avian H9N2 virus were also identified in Hong Kong. These events established that avian influenza viruses can infect humans without passage through an intermediate host and without acquiring gene segments from human influenza viruses. The likely origin of the H5N1 viruses has been deduced from molecular analysis of these and other viruses isolated from the region. The gene sequences of the H5N1 viruses were analysed in order to identify the molecular basis for the ability of these avian viruses to infect humans.


Stabilizing electrochemical Li-O2 batteries with a metal-based cathode of PdNi on Ni nonwoven fabric.
The design of a nanoporous cathode for Li-O2 batteries that can achieve high chemical stability and superior electrochemical performance remains a formidable challenge. A novel approach for the fabrication of nanoengineered PdNi alloys directly coated onto Ni nonwoven fabric (PdNi/NiNF) obtained through electrospinning has been proposed. On the basis of the contributions of the porous structure, the prepared metal-based cathodes can exhibit high chemical and mechanical stabilities, high catalytic activity, and high conductivity. In this design, the major side reactions were excluded when compared with popularly used carbon cathodes, and excellent cycling stability (266 cycles) could be achieved. The proposed cathode exhibited a high discharge capacity of 15 700 mA h g-1 at 500 mA g-1, which was 5 times higher than those reported for carbon-free cathodes.


Plasmodium falciparum AMA1 binds a rhoptry neck protein homologous to TgRON4, a component of the moving junction in Toxoplasma gondii.
Plasmodium falciparum apical membrane antigen 1 (PfAMA1) coimmunoprecipitates with the Plasmodium homologue of TgRON4, a secreted rhoptry neck protein of Toxoplasma gondii that migrates at the moving junction in association with TgAMA1 during invasion. PfRON4 also originates in the rhoptry necks, suggesting that this unusual collaboration of micronemes and rhoptries is a conserved feature of Apicomplexa.


Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis in ovarian cancer.
Kallikrein gene 5 (KLK5, also known as KLK-L2), located on chromosome 19q13.4, is one of the newly identified members of the kallikrein gene family, which is a subgroup of the serine protease enzyme family. In normal human tissues, KLK5 is highly expressed in skin, mammary gland and testis. Preliminary RT-PCR analysis has indicated that KLK5 is expressed in a subset of ovarian tumours. We have thus hypothesized that KLK5 may be a new prognostic indicator in ovarian cancer. We have examined the mRNA expression of KLK5 in 142 malignant ovarian tissues. Tumours were pulverized, total RNA was extracted, and cDNA was prepared by reverse transcription. KLK5 was amplified by PCR using gene specific primers, and the identity of the PCR product was verified by sequencing. Ovarian tissues were then classified as KLK5 positive or negative, based on ethidium bromide staining of the PCR product on agarose gels. KLK5 was found to be highly expressed in 58/142 (41%) of ovarian cancer samples while its level of expression was very low in normal ovarian tissues. We found a strong positive relation between KLK5 expression and tumour grade (P = 0.006) and disease stage (P = 0.027). Univariate survival analysis revealed that patients with ovarian tumours positive for KLK5 expression had an increased risk for relapse and death (P = 0.018 and 0.022, respectively). In multivariate analysis, KLK5 expression showed independent prognostic value only in the subset of tumours with lower grade disease (grades I and II). We conclude that KLK5 expression is associated with more aggressive forms of epithelial ovarian carcinoma and has indepdent prognostic value in low grade tumours.


Hypochondriasis in the elderly.
hypochondriasis in the elderly is a common but often frustrating problem. The certainty of the diagnosis is complicated by the existence of physical disabilities that accompany the aging process. An increase in social stress and loss of sources of self-esteem are also influential factors. Approximately one-third of elderly hypochondriacs undergo a fortuitous remission, which is usually related to changes in the social environment. Recognition of these features is important to management.


Effect of super dosing of phytase on growth performance, ileal digestibility and bone characteristics in broilers fed corn-soya-based diets.
A feeding trial was designed to assess the effect of super dosing of phytase in corn-soya-based diets of broiler chicken. One hundred and sixty-eight day-old broilers were selected and randomly allocated to four dietary treatment groups, with 6 replicates having 7 chicks per treatment group. Two-phased diets were used. The starter and finisher diet was fed from 0 to 3 weeks and 4 to 5 weeks of age respectively. The dietary treatments were consisted of normal phosphorus (NP) group without any phytase enzyme (4.5 g/kg available/non-phytin phosphorus (P) during starter and 4.0 g/kg during finisher phase), three low-phosphorus (LP) groups (3.2 g/kg available/non-phytin P during starter and 2.8 g/kg during finisher phase) supplemented with phytase at 500, 2500, 5000 FTU/kg diet, respectively, to full fill their phosphorus requirements. The results showed that super doses of phytase (at 2500 FTU and 5000 FTU/kg) on low-phosphorus diet improved feed intake, body weight gain, ileal digestibility (serine, aspartic acid, calcium, phosphorus), blood P levels and bone minerals such as calcium (Ca), P, magnesium (Mg) and zinc (Zn) content. It could be concluded that super doses of phytase in low-phosphorus diet were beneficial than the normal standard dose (at 500 FTU/kg) of phytase in diet of broiler chicken.


Testing for non-linearity in EEG signal of healthy subjects.
Spontaneous EEG of 21 healthy human subjects obtained by standard procedure of recording is analysed using non-linear prediction methods to check whether the signals were generated by a non-linear dynamics process or by a linear stochastic process. The test for non-linearity is performed by surrogate data method with non-linear prediction error as the test statistic. The null hypothesis that EEG signal (in rest, with eyes closed) is generated by linear stochastic process can be rejected in 17 cases (5%) out of the 336 (21 subjects, 16 channels) studied epochs. However, most of these rejections concern 3 subjects. The 88% of rejections of the null hypothesis concern frontal channels. The null hypothesis is not rejected for epochs recorded with eyes open and during photostimulation.


The scaffold protein Homer1b/c links metabotropic glutamate receptor 5 to extracellular signal-regulated protein kinase cascades in neurons.
Group I metabotropic glutamate receptors (mGluRs) increase cellular levels of inositol-1,4,5-triphosphate (IP3) and thereby trigger intracellular Ca2+ release. Also, group I mGluRs are organized with members of Homer scaffold proteins into multiprotein complexes involved in postreceptor signaling. In this study, we investigated the relative importance of the IP3/Ca2+ signaling and novel Homer proteins in group I mGluR-mediated activation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in cultured rat striatal neurons. We found that selective activation of mGluR5, but not mGluR1, increased ERK1/2 phosphorylation. Whereas the IP3/Ca2+ cascade transmits a small portion of signals from mGluR5 to ERK1/2, the member of Homer family Homer1b/c forms a central signaling pathway linking mGluR5 to ERK1/2 in a Ca2+-independent manner. This was demonstrated by the findings that the mGluR5-mediated ERK1/2 phosphorylation was mostly reduced by a cell-permeable Tat-fusion peptide that selectively disrupted the interaction of mGluR5 with the Homer1b/c and by small interfering RNAs that selectively knocked down cellular levels of Homer1b/c proteins. Furthermore, ERK1/2, when only coactivated by both IP3/Ca2+- and Homer1b/c-dependent pathways, showed the ability to phosphorylate two transcription factors, Elk-1 and cAMP response element-binding protein, and thereby facilitated c-Fos expression. Together, we have identified two coordinated signaling pathways (a conventional IP3/Ca2+ vs a novel Homer pathway) that differentially mediate the mGluR5-ERK coupling in neurons. Both the Ca2+-dependent and -independent pathways are corequired to activate ERK1/2 to a level sufficient to achieve the mGluR5-dependent synapse-to-nucleus communication imperative for the transcriptional regulation.


A novel liquid biopsy-based approach for highly specific cancer diagnostics: mitigating false responses in assaying patient plasma-derived circulating microRNAs through combined SERS and plasmon-enhanced fluorescence analyses.
Studies have shown that microRNAs, which are small noncoding RNAs, hold tremendous promise as next-generation circulating biomarkers for early cancer detection via liquid biopsies. A novel, solid-state nanoplasmonic sensor capable of assaying circulating microRNAs through a combined surface-enhanced Raman scattering (SERS) and plasmon-enhanced fluorescence (PEF) approach has been developed. Here, the unique localized surface plasmon resonance properties of chemically-synthesized gold triangular nanoprisms (Au TNPs) are utilized to create large SERS and PEF enhancements. With careful modification to the surface of Au TNPs, this sensing approach is capable of quantifying circulating microRNAs at femtogram/microliter concentrations. Uniquely, the multimodal analytical methods mitigate both false positive and false negative responses and demonstrate the high stability of our sensors within bodily fluids. As a proof of concept, microRNA-10b and microRNA-96 were directly assayed from the plasma of six bladder cancer patients. Results show potential for a highly specific liquid biopsy method that could be used in point-of-care clinical diagnostics to increase early cancer detection or any other diseases including SARS-CoV-2 in which RNAs can be used as biomarkers.


Comparison study of two different patient-controlled anesthesia regiments after cardiac surgery.
Acute and severe pain is frequent in patients who undergo cardiothoracic surgery. Patient controlled analgesia (PCA) can be used to manage postoperative pain. To compare analgesia of morphine PCA alone without continuous infusion with morphine PCA plus a continuous infusion on postoperative period after cardiac surgery and to evaluate pain scores, morphine consumption, number of demand, patient satisfaction and side effects. Randomized trial was conducted to assess patients who underwent cardiac surgery receiving either morphine PCA alone or morphine PCA plus continuous infusion. In the post operative period, PCA was started at extubation in both regiments according to randomization. Pain intensity, morphine consumption, number of demand, satisfaction and side effects were assessed at zero, six, twelve, eighteen, twenty four and thirty hours after patients' extubation. The study enrolled 100 patients. 50 patients received morphine PCA alone, (Group A) and 50 patients received morphine PCA plus a background infusion, (Group B). Group B patients had less demand, consumed more morphine and were more satisfied regarding analgesia. No statistical differences were shown between groups related to pain intensity, and side effects. Pain control was effective and similar in both groups. Morphine PCA alone seems to be better for postoperative pain manage in cardiac surgery, due to its less morphine expense with the same effectiveness.


iCOD: an integrated clinical omics database based on the systems-pathology view of disease.
Variety of information relating between genome and the pathological findings in disease will yield a wealth of clues to discover new function, the role of genes and pathways, and future medicine. In addition to molecular information such as gene expression and genome copy number, detailed clinical information is essential for such systematic omics analysis. In order to provide a basic platform to realize a future medicine based on the integration of molecular and clinico-pathological information of disease, we have developed an integrated clinical omics database (iCOD) in which comprehensive disease information of the patients is collected, including not only molecular omics data such as CGH (Comparative Genomic Hybridization) and gene expression profiles but also comprehensive clinical information such as clinical manifestations, medical images (CT, X-ray, ultrasounds, etc), laboratory tests, drug histories, pathological findings and even life-style/environmental information. The iCOD is developed to combine the molecular and clinico-pathological information of the patients to provide the holistic understanding of the disease. Furthermore, we developed several kinds of integrated view maps of disease in the iCOD, which summarize the comprehensive patient data to provide the information for the interrelation between the molecular omics data and clinico-pathological findings as well as estimation for the disease pathways, such as three layer-linked disease map, disease pathway map, and pathome-genome map. With these utilities, our iCOD aims to contribute to provide the omics basis of the disease as well as to promote the pathway-directed disease view. The iCOD database is available online, containing 140 patient cases of hepatocellular carcinoma, with raw data of each case as supplemental data set to download. The iCOD and supplemental data can be accessed at http://omics.tmd.ac.jp/icod_pub_eng.


MicroRNA and cancer--a brief overview.
MicroRNAs (miRNAs) are short non-coding RNAs with a length of ∼22 nucleotides, involved in posttranscriptional regulation of gene expression. Until now, over 2588 miRNAs have been identified in humans and the list is growing. MicroRNAs have an important role in all biological processes and aberrant miRNA expression is associated with many diseases including cancer. In the year 2002 the first connection between cancer and miRNA deregulation was discovered. Since then, a lot of information about the key role which miRNAs play in cancer development and drug resistance has been gained. However, there is still a long way to go to fully understand the miRNA world. In this review, we briefly describe miRNA biogenesis and discuss the role of miRNAs in cancer development and drug resistance. Finally we explain how miRNAs can be used as biomarkers and as a novel therapeutic approach in cancer.


Assays on the influence of biomaterials on allogeneic rejection in tissue engineering.
In tissue engineering, innate responses to biomaterial scaffolds will affect rejection of allogeneic cells. Biomaterials directly influence innate and adaptive immune cell adhesion, reactive oxygen intermediate production, cytokine secretion, nuclear factor-kappa B nuclear translocation, gene expression, and cell surface markers, all of which are likely to affect allogeneic rejection responses. A major goal in tissue engineering is to induce transplant tolerance, potentially by manipulating the biomaterial component. This review describes methods of measuring responses of macrophages, dendritic cells, and T cells stimulated in vitro and in vivo and addresses key factors in assay development. Such tests include mixed leukocyte reactions, enzyme-linked immunosorbent spot assays, trans-vivo delayed-type hypersensitivity assays, and measurement of dendritic cell subsets and anti-donor antibodies; we propose extending these studies to tissue engineering.


Facing the unacceptable: the emotional response to infertility.
The emotional response to infertility, a major circumstantial loss, is frequently likened to bereavement. It is described as circumstantial because it does not happen to everyone, unlike a necessary loss, such as being weaned both nutritionally and emotionally. Another circumstantial loss is the death of someone, particularly if one has close emotional ties to this person. It is not surprising to find that a conceptual framework, developed to understand mourning a death, is used to make sense of the reaction to infertility; but this framework alone is not sufficient. The understanding of stigmatization and learned helplessness also assist helping the infertile to come to terms with their loss. It is suggested that the pronatalist tendency of British society results in denial of the stressful nature of infertility which compounds the difficulty in the loss being recognized and makes it exceptionally difficult to grieve.


Identifying variables that predict falling asleep at the wheel among long-haul truck drivers.
Analysis of data from 843 long-haul truck drivers was conducted to determine the variables that predicted falling asleep at the wheel. Demographics, sleep-specific questions, and the Epworth Sleepiness Scale were used for analysis. More than 25% of the participants (n = 247) scored 10 or higher on the Epworth Sleepiness Scale, indicating chronic sleepiness. Eight initial predictor variables were included in the logistic regression analysis. Four of the eight original variables were retained in the final model to predict falling asleep at the wheel within the past 12 months. Four variables were retained in the final model to predict falling asleep at the wheel within the past 30 days. Screening for excessive sleepiness using the Epworth Sleepiness Scale and an extensive history of medication use should be conducted for all long-haul truck drivers.


Drug safety of rosiglitazone and pioglitazone in France: a study using the French PharmacoVigilance database.
Thiazolidinediones (TZDs), rosiglitazone (RGZ) and pioglitazone (PGZ) are widely used as hypoglycemic drugs in patients with type 2 diabetes mellitus. The aim of our study was to investigate the profile of adverse drug reactions (ADRs) related to TZDs and to investigate potential risk factors of these ADRs. Type 2 diabetic patients were identified from the French Database of PharmacoVigilance (FPVD) between 2002 and 2006. We investigated ADR related to TZD, focusing on 4 ADR: edema, heart failure, myocardial infarction and hepatitis corresponding to specific WHO-ART terms. Among a total of 99,284 adult patients in the FPVD, 2295 reports concerned type 2 diabetic patients (2.3% of the whole database), with 161 (7%) exposed to TZDs. The frequency of edema and cardiac failure was significantly higher with TZDs than in other patients (18% and 7.4% versus 0.8% and 0.1% respectively, p < 0.001) whereas the frequency of hepatitis was similar (5.9% versus 4%, NS). A multiple logistic regression model taking into account potential confounding factors (age, gender, drug exposure and co-morbidities) found that TZD exposure remained associated with heart failure and edema, but not with hepatitis or myocardial infarction. Thiazolidinediones exposure is associated with an increased risk of edema and heart failure in patients with type 2 diabetes even when recommendations for use are respected. In contrast, the risk of hepatic reactions and myocardial infarction with this class of drugs seems to be similar to other hypoglycemic agents.


Helicobacter Infection Significantly Alters Pregnancy Success in Laboratory Mice.
Helicobacter spp. are gram-negative, helically shaped bacteria that cause gastric and enterohepatic infections in mammalian species. Although Helicobacter infection frequently is implicated to interfere with reproductive success, few experimental data support these claims. We therefore retrospectively investigated the effect of Helicobacter infection on murine pregnancy outcome after the identification of endemic Helicobacter infection in an animal research facility. Multiplex conventional PCR analysis was used to characterize Helicobacter infection status in one inbred and 2 transgenic strains of mice in 2 self-contained rooms assigned to the same investigator. Outcomes of timed-mating experiments were compared among Helicobacter spp.-infected and uninfected mice of the same strain; Helicobacter infection was eradicated from the colony through fostering with uninfected dams. Although Helicobacter infection affected fecundity in only one strain of transgenic mouse, the total number of embryos per gravid uterus was significantly reduced in C57BL/6J mice that were infected with a single Helicobacter species, H. typhlonius. Helicobacter infection was also associated with a significant increase in the number of resorbing embryos per uterus and significant decreases in pregnancy-associated weight gain relative to uninfected mice in C57BL6/J mice and one transgenic strain. Helicobacter spp.-infected mice of all tested strains exhibited higher frequency of intrauterine hemorrhaging relative to uninfected mice. These results indicate that naturally-acquired Helicobacter infection not only reduces the productivity of a research animal breeding colony, but also negatively impacts embryo health. Despite these deleterious effects, these data suggest that colonies can be rederived to be Helicobacter-free by Cesarean section and fostering with uninfected dams. This paper provides the first evidence that H. typhlonius infection is sufficient to interfere with reproductive success and embryo health of C57BL/6J mice. Animal research facilities should therefore implement Helicobacter spp. surveillance and control practices to avoid confounding experimental results and to improve breeding colony efficiency.


Surgery for esotropia with a high accommodative convergence/accommodation ratio: effects on accommodative vergence and binocularity.
To determine the effectiveness of strabismus surgery as an alternative treatment for high accommodative convergence/accommodation (AC/A) ratio (nonrefractive accommodative) esotropia. Twenty-three consecutive children with an AC/A ratio of 5:1 or greater and a distance-near disparity of 10 prism diopters (PD) or more were studied in a prospective design. Each patient was treated by recession of both medial rectus muscles for the full amount of esotropia measured at near fixation through the full distance hyperopic correction. The magnitude of eso deviation, the AC/A ratio, and the grade of binocularity were measured before and a minimum of 4 months after strabismus surgery. Surgery reduced the mean preoperative eso deviation at near fixation by a factor of 4 (from a mean of 37 PD to a mean of 9 PD). Surgery eliminated the need for bifocals in 96 percent of the patients. The grade of binocular fusion or stereopsis improved in 70 percent of the patients, remained unchanged in 26 percent, and was degraded in 4 percent. Three (13 percent) of the children became exophoric; none of the children were exotropic. These results demonstrate that strabismus surgery is an effective alternative to the long-term use of bifocals in the treatment of high AC/A ratio esotropia. Surgery may be more effective than bifocals in restoring normal stereopsis and binocular fusion.


Genetic control of alkaline phosphatase synthesis in Neurospora: the use of partial diploids in dominance studies.
In wild-type Neurospora, alkaline phosphatase is made under conditions of phosphate limitation, but not conditions of phosphate sufficiency. Mutants at two unlinked loci, nuc-1 and nuc-2, do not make alkaline phosphatase under any conditions, while mutants at two quite closely linked loci, pcon and preg, make alkaline phosphatase even under conditions of phosphate sufficiency. pcon is extremely closely linked to nuc-2. nuc-2 and preg(c) (constitutive) mutants are recessive to their wild-type alleles in partial diploids as well as in heterokaryons, while pcon(c) mutants are dominant or co-dominant. nuc-1 is epistatic to both pcon(c) and preg(c) mutants. The implications of these findings for theories of metabolic control in eukaryotes are briefly discussed.


The preoperative administration of intravenous dextromethorphan reduces postoperative morphine consumption.
We evaluated the effect of dextromethorphan on postoperative pain management. Sixty ASA physical status I-III female patients undergoing major abdominal surgery underwent standardized general anesthesia. Thirty patients received an i.v. infusion of dextromethorphan 5 mg/kg before anesthetic induction (Pre group), whereas the remaining 30 patients received the same volume of isotonic sodium chloride solution, followed by a postoperative i.v. infusion of dextromethorphan 5 mg/kg (Post group). Patients in the Pre group received the same volume of isotonic sodium chloride solution postoperatively. All patients were then treated with patient-controlled i.v. analgesia, which administered a 0.6-mg bolus of morphine on demand (maximal 4 h dose 20 mg). The mean visual analog pain score during cough or movement and at rest were similar in the two groups in the first 3 days postoperatively. However, Post group patients consumed more morphine than Pre group patients during the first 2 days (P < 0.01). The sedation scores, patient satisfaction, and the incidence of morphine-related side effects were similar between the two groups. We conclude that the preoperative administration of dextromethorphan 5 mg/kg reduces postoperative morphine consumption compared with postoperative administration. In this double-blinded study, we found that the preoperative administration of i.v. dextromethorphan 5 mg/kg, compared with postoperative administration, reduces postoperative morphine consumption, which may provide clinical evidence of preemptive or preventive analgesic effects of dextromethorphan.


Centronuclear (myotubular) myopathy.
Centronuclear myopathy (CNM) is an inherited neuromuscular disorder characterised by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy.The incidence of X-linked myotubular myopathy is estimated at 2/100000 male births but epidemiological data for other forms are not currently available.The clinical picture is highly variable. The X-linked form usually gives rise to a severe phenotype in males presenting at birth with marked weakness and hypotonia, external ophthalmoplegia and respiratory failure. Signs of antenatal onset comprise reduced foetal movements, polyhydramnios and thinning of the ribs on chest radiographs; birth asphyxia may be the present. Affected infants are often macrosomic, with length above the 90th centile and large head circumference. Testes are frequently undescended. Both autosomal-recessive (AR) and autosomal-dominant (AD) forms differ from the X-linked form regarding age at onset, severity, clinical characteristics and prognosis. In general, AD forms have a later onset and milder course than the X-linked form, and the AR form is intermediate in both respects.Mutations in the myotubularin (MTM1) gene on chromosome Xq28 have been identified in the majority of patients with the X-linked recessive form, whilst AD and AR forms have been associated with mutations in the dynamin 2 (DNM2) gene on chromosome 19p13.2 and the amphiphysin 2 (BIN1) gene on chromosome 2q14, respectively. Single cases with features of CNM have been associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the hJUMPY (MTMR14) genes.Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features; muscle magnetic resonance imaging may complement clinical assessment and inform genetic testing in cases with equivocal features. Genetic counselling should be offered to all patients and families in whom a diagnosis of CNM has been made.The main differential diagnoses include congenital myotonic dystrophy and other conditions with severe neonatal hypotonia.Management of CNM is mainly supportive, based on a multidisciplinary approach. Whereas the X-linked form due to MTM1 mutations is often fatal in infancy, dominant forms due to DNM2 mutations and some cases of the recessive BIN1-related form appear to be associated with an overall more favourable prognosis.


Bowel preparation regimen for computed tomography colonography.
This study was designed to determine whether a reduction in oral contrast dose and a change in timing of administration will result in less residual material in the colonic lumen. We retrospectively assessed, in a blinded fashion, the amount and nature of residual material in the colon in 40 patients who received computed tomography colonography. Half of the cohort received the standard bowel-preparation regimen, whereas a sex- and age-matched test arm received the modified regimen. A scoring system that consisted of metrics to quantify the nature and extent of residual fluid and solid material was defined. Image analysis was conducted with the investigators blinded to the group assignment of each patient. Three different trained observers independently reviewed and scored the 6 colonic segments in supine and prone positions for each patient in the cohort. In cases in which interobserver discrepancies existed, the observers reanalyzed the images together to come to an agreement on scores. The new bowel-preparation regimen resulted in significantly less "sticky coat" (P < .005), a problematic phenomenon in which the colonic mucosa is covered in a thin coating of residual contrast and fecal material. There was no difference in the amount of residual fluid. Fewer masses of stool were noted with the new preparation, but this was not found to be statistically significant. A new bowel-preparation regimen that consisted of lower quantities of contrast administered earlier in the day preceding computed tomography colonography resulted in a lower incidence of adherent contrast and fecal matter. The reduction of this "sticky coat" problem not only improved radiologic analysis of the colon but may permit same-day therapy via colonoscopy if indicated on imaging.


Testing stage-specific effects of a stage-matched intervention: a randomized controlled trial targeting physical exercise and its predictors.
Health education interventions can be tailored toward stages of change. This strategy is based on theories that predict at which stage which variables are indicative of subsequent behavior change processes. For example, planning is regarded as being effective in intenders. However, rather few studies have tested whether matched interventions are more successful for stage transitions than mismatched ones. Also very few previous studies have identified specific variables as targets of stage-matched interventions. A 2 (condition) x 2 (stages) experimental study tested the effects of stage-matched interventions for 226 participants. The stage-matched intervention moved significantly more individuals forward to action than did the control condition. Stage-specific effects were found to corroborate 78% of the assumptions. Multiple mediator analyses revealed stage-specific mechanisms, indicating that intention and planning facilitated behavior change in intenders. Thus, health behavior interventions should take stages of change into account.


Homologous recombination deficiency real-time clinical assays, ready or not?
Cancers with deficiencies in homologous recombination-mediated DNA repair (HRR) demonstrate improved clinical outcomes and increased survival. Approximately 50% of high-grade serous ovarian cancers (HGSOC) exhibit homologous recombination deficiency (HRD). HRD can be caused by germline or somatic mutations of genes involved in the HR pathway. Given platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors (PARPis) are used in HGSOC, double-strand breaks (DSBs) are common. Unrepaired DSBs are toxic to cells as genomic instability ensues and cells eventually die. Thus, tumor cells with DSBs utilize the high-fidelity HRR as one of the central pathways for repair. In tumors that have HRD, an alternate pathway such as non-homologous end-joining (NHEJ) is used and leads to error-prone repair. To date, methods for clinical detection of homologous recombination deficiency (HRD) are limited to genomic changes of HRR genes and genomic mutation patterns resulting from HRD genes involved in HR-mediated DNA repair. However, these tests detect genomic scars that might not always correlate well with PARP inhibitor or platinum sensitivity in the current state. Therefore, a functional HRD assay should be able to more accurately predict tumor response in real-time. RAD51 foci formation has been used as a functional assay to define HRD and closely correlates with chemotherapy and PARPi sensitivity. The inability to form RAD51 foci is a common feature of HRD. DNA damage can also cause transient slowing or stalling of replication forks defined as replication stress. Replication fork stalling can lead to fork degradation and decreased cell viability if forks do not resume DNA synthesis. Fork degradation has been found to lead to chemosensitivity in BRCA-deficient tumors. To determine this fork degradation phenotype, replication fork/DNA fiber assays are utilized. This review will highlight functional assays for HRD in the context of translating these to real-time clinical assays.


ZmPIN1a and ZmPIN1b encode two novel putative candidates for polar auxin transport and plant architecture determination of maize.
Shoot apical meristems produce organs in a highly stereotypic pattern that involves auxin. Auxin is supposed to be actively transported from cell to cell by influx (AUXIN/LIKE AUXIN proteins) and efflux (PIN-FORMED proteins) membrane carriers. Current hypotheses propose that, at the meristem surface, PIN proteins create patterns of auxin gradients that, in turn, create patterns of gene expression and morphogenesis. These hypotheses are entirely based on work in Arabidopsis (Arabidopsis thaliana). To verify whether these models also apply to other species, we studied the behavior of PIN proteins during maize (Zea mays) development. We identified two novel putative orthologs of AtPIN1 in maize and analyzed their expression pattern during development. The expression studies were complemented by immunolocalization studies using an anti-AtPIN1 antibody. Interestingly, the maize proteins visualized by this antibody are almost exclusively localized in subepidermal meristematic layers. Both tassel and ear were characterized by a compact group of cells, just below the surface, carrying PIN. In contrast to or to complement what was shown in Arabidopsis, these results point to the importance of internally localized cells in the patterning process. We chose the barren inflorescence2 (bif2) maize mutant to study the role of auxin polar fluxes in inflorescence development. In severe alleles of bif2, the tassel and the ear present altered ZmPIN1a and ZmPIN1b protein expression and localization patterns. In particular, the compact groups of cells in the tassel and ear of the mutant were missing. We conclude that BIF2 is important for PIN organization and could play a role in the establishment of polar auxin fluxes in maize inflorescence, indirectly modulating the process of axillary meristem formation and development.


Helix-loop-helix transcriptional activators bind to a sequence in glucocorticoid response elements of retrovirus enhancers.
A family of nuclear proteins, designated SL3-3 enhancer factors 2 (SEF2), were found to interact with an Ephrussi box-like motif within the glucocorticoid response element in the enhancer of the murine leukemia virus SL3-3. Mutation of the DNA sequence decreased the basal enhancer activity in various cell lines. The important nucleotides for binding of SEF2 are conserved in most type C retroviruses. Various cell types displayed differences both in the sets of SEF2-DNA complexes formed and in their amounts. A cDNA which encoded a protein that interacted specifically with the SEF2-binding sequence was isolated from human thymocytes. The nucleotide sequence specificity of the recombinant protein, expressed in Escherichia coli, corresponded to that of at least one of the nuclear SEF2 proteins. Sequence analysis of the cDNA revealed that it belongs to the basic helix-loop-helix class of DNA-binding proteins. Several mRNA transcripts of different sizes were identified. Molecular analysis of cDNA clones revealed multiple related mRNA species containing alternative coding regions, which are most probably a result of differential splicing.


The Primate-Specific Gene TMEM14B Marks Outer Radial Glia Cells and Promotes Cortical Expansion and Folding.
Human brain evolution is associated with expansion and folding of the neocortex. Increased diversity in neural progenitor (NP) populations (such as basally located radial glia [RG], which reside in an enlarged outer subventricular zone [OSVZ]) likely contributes to this evolutionary expansion, although their characteristics and relative contributions are only partially understood. Through single-cell transcriptional profiling of sorted human NP subpopulations, we identified the primate-specific TMEM14B gene as a marker of basal RG. Expression of TMEM14B in embryonic NPs induces cortical thickening and gyrification in postnatal mice. This is accompanied by SVZ expansion, the appearance of outer RG-like cells, and the proliferation of multiple NP subsets, with proportional increases in all cortical layers and normal lamination. TMEM14B drives NP proliferation by increasing the phosphorylation and nuclear translocation of IQGAP1, which in turn promotes G1/S cell cycle transitions. These data show that a single primate-specific gene can drive neurodevelopmental changes that contribute to brain evolution.


Leveraging annotation-based modeling with Jump.
The capability of UML profiles to serve as annotation mechanism has been recognized in both research and industry. Today's modeling tools offer profiles specific to platforms, such as Java, as they facilitate model-based engineering approaches. However, considering the large number of possible annotations in Java, manually developing the corresponding profiles would only be achievable by huge development and maintenance efforts. Thus, leveraging annotation-based modeling requires an automated approach capable of generating platform-specific profiles from Java libraries. To address this challenge, we present the fully automated transformation chain realized by Jump, thereby continuing existing mapping efforts between Java and UML by emphasizing on annotations and profiles. The evaluation of Jump shows that it scales for large Java libraries and generates profiles of equal or even improved quality compared to profiles currently used in practice. Furthermore, we demonstrate the practical value of Jump by contributing profiles that facilitate reverse engineering and forward engineering processes for the Java platform by applying it to a modernization scenario.


Gene genealogies indicates abundant gene conversions and independent evolutionary histories of the mating-type chromosomes in the evolutionary history of Neurospora tetrasperma.
The self-fertile filamentous ascomycete Neurospora tetrasperma contains a large (approximately 7 Mbp) and young (< 6 MYA) region of suppressed recombination within its mating-type (mat) chromosomes. The objective of the present study is to reveal the evolutionary history, including key genomic events, associated with the various regions of the mat chromosomes among ten strains representing all the nine known species (lineages) contained within the N. tetrasperma species complex. Comparative analysis of sequence divergence among alleles of 24 mat-linked genes (mat A and mat a) indicates that a large region of suppressed recombination exists within the mat chromosome for each of nine lineages of N. tetrasperma sensu latu. The recombinationally suppressed region varies in size and gene composition among lineages, and is flanked on both ends by normally recombining regions. Genealogical analyses among lineages reveals that eight gene conversion events have occurred between homologous mat A and mat a-linked alleles of genes located within the region of restricted recombination during the evolutionary history of N. tetrasperma. We conclude that the region of suppressed recombination in the mat chromosomes has likely been subjected to independent contraction and/or expansion during the evolutionary history of the N. tetrasperma species complex. Furthermore, we infer that gene conversion events are likely a common phenomenon within this recombinationally suppressed genomic region. We argue that gene conversions might provide an efficient mechanism of adaptive editing of functional genes, including the removal of deleterious mutations, within the young recombinationally suppressed region of the mat chromosomes.


A study of radon emitted from building materials using plastic alpha-track detectors.
Films made from cellulose nitrate LR-115 (Pathé Kodak) and CR-39 have been used for long-term measurements of the radon-222 emanation from building materials and the resultant activity inside houses. The emanation from crushed granite bricks is found to be produced from within the brick while in the clay bricks it originates in the surface layers only. The airborne radon activity inside houses constructed from clay brick is found on average to be 22 mBq 1-1 (0.57 pCi 1-1) while inside a closed vessel sealed to the brick the average equilibrium activity is 40 mBq 1-1 pCi 1-1).


Curved planar reformatted images of MDCT for differentiation of biliary stent occlusion in patients with malignant biliary obstruction.
We prospectively evaluated the usefulness of MDCT using a curved planar reformation technique for the noninvasive assessment of the causes of biliary stent occlusion in patients with malignant biliary obstruction. Between December 2004 and January 2009, 173 patients with unresectable malignant biliary obstruction underwent biliary stent insertion. Among them, 26 patients with suspected biliary stent occlusion underwent 29 sessions of ERCP within 2 weeks after MDCT was performed. Curved planar reformation images were obtained along the pathway of the biliary stent. We interpreted tissue growth or stent clogging by comparing attenuation values inside the biliary stent between the unenhanced and contrast-enhanced phases of CT. The cause of biliary stent occlusion was confirmed by using ERCP. The differences in attenuation value inside the biliary stent between the contrast-enhanced and unenhanced phases of CT in the tissue growth group was 27.7 +/- 21.7 HU (SD) and 4.2 +/- 10.6 HU in the stent-clogging group (p = 0.002). The sensitivity and specificity of MDCT for the diagnosis of tissue growth were 86.7% and 85.7%, respectively. The overall accuracy of curved planar reformation images of MDCT for diagnosing the causes of stent occlusion was 86.2%. Curved planar reformation MDCT is a useful noninvasive technique that is relatively accurate for diagnosing the cause of biliary stent occlusion and is helpful for planning the therapeutic management of such patients.


Risk of hemorrhagic complication associated with ventriculoperitoneal shunt placement in aneurysmal subarachnoid hemorrhage patients on dual antiplatelet therapy.
The use of an intracranial stent requires dual antiplatelet therapy to avoid in-stent thrombosis. In this study, the authors sought to investigate whether the use of dual antiplatelet therapy is a risk factor for hemorrhagic complications in patients undergoing permanent ventriculoperitoneal (VP) shunt for hydrocephalus following aneurysmal subarachnoid hemorrhage (aSAH). Patients were given 325 mg acetylsalicylic acid and 600 mg clopidogrel during the coil/stent procedure, and they were maintained on dual antiplatelet therapy with acetylsalicylic acid 325 mg daily and clopidogrel 75 mg daily during hospitalization and for 6 weeks posttreatment. Patients underwent placement of VP shunt at a later time during initial hospitalization, usually between 7 and 21 days following aSAH. Postoperative CT scans obtained in each study patient were reviewed for hemorrhages related to placement of the VP shunt. A total of 206 patients were admitted to the University of Iowa Hospitals and Clinics with aSAH between July 2009 and October 2010. Thirty-seven of these patients were treated with a VP shunt for persistent hydrocephalus. Twelve patients (32%) had previously undergone stent-assisted coiling and were on dual antiplatelet therapy with acetylsalicylic acid and clopidogrel. The remaining 25 patients (68%) had undergone surgical clipping or aneurysm coiling and were not receiving antiplatelet therapy at the time of surgery. Four cases (10.8%) of new intracranial hemorrhages associated with VP shunt placement were observed. All 4 hemorrhages (33%) occurred in patients on dual antiplatelet therapy for stent-assisted coiling. No new intracranial hemorrhages were observed in patients not receiving dual antiplatelet therapy. The difference in hemorrhagic complications between the 2 groups was statistically significant (4 [33%] of 12 vs 0 of 25, p = 0.0075]). All 4 hemorrhages occurred along the tract of the ventricular catheter. Only 1 hemorrhage (1 [8.3%] of 12) was clinically significant as it resulted in occlusion of the proximal shunt catheter and required revision of the VP shunt. The patient did not suffer any permanent morbidity related to the hemorrhage. The remaining 3 hemorrhages were not clinically significant. This small clinical series suggests that placement of a VP shunt in patients on dual antiplatelet therapy may be associated with an increased, but low, rate of symptomatic intracranial hemorrhage. It appears that in patients who are poor candidates for open surgical clipping and have aneurysms amenable to stent-assisted coiling, the risk of symptomatic hemorrhage may be an acceptable trade-off for avoiding risks associated with discontinuation of antiplatelet therapy. The authors' results are preliminary, however, and require confirmation in larger studies.


The non-hydrolytic pathway of cystic fibrosis transmembrane conductance regulator ion channel gating.
It has been suggested that the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel may utilize a novel gating mechanism in which open and closed states are not in thermodynamic equilibrium. This suggestion is based on the assumption that energy of ATP hydrolysis drives the gating cycle. We demonstrate that CFTR channel gating occurs in the absence of ATP hydrolysis and hence does not depend on an input of free energy from this source. The binding of ATP or structurally related analogues that are poorly or non-hydrolysable is sufficient to induce opening. Closing occurs on dissociation of these ligands or the hydrolysis products of those that can be cleaved. Not only can channel opening occur without ATP hydrolysis but the temperature dependence of the open probability (Po.) is reversed, i.e. Po. increases as temperature is lowered whereas under hydrolytic conditions, Po. increases as temperature is elevated. This indicates that there are different rate-limiting steps in the alternate gating pathways (hydrolytic and non-hydrolytic). These observations demonstrate that phosphorylated CFTR behaves as a conventional ligand-gated channel employing cytoplasmic ATP as a readily available cytoplasmic ligand; under physiological conditions ligand hydrolysis provides efficient reversibility of channel opening.


Magnetic resonance imaging of peripheral nerves: differences in magnetization transfer.
Magnetic resonance imaging (MRI) is an excellent imaging modality for soft tissues. Magnetization transfer (MT) imaging is an MRI technique that is sensitive to the bound protons of macromolecules and therefore can aid in the assessment of nerve damage. Measurements of the MT ratio (MTR), which provides an index of the MT effects in tissues, were performed in the wrist and foot of 5 volunteers. The MTR of foot (interdigital) nerves (22.2 ± 2.1%) was smaller than that of the median nerve (41.1 ± 1.4%). No difference was observed between MTR in muscles adjacent to foot nerves (46.0 ± 1.5%) and muscles adjacent to the median nerve (44.2 ± 1.9%). In this study we demonstrate the feasibility of measuring the MTR of foot nerves. The difference of MTR between median and foot nerves indicates a difference in structure/composition. The MTR of peripheral nerves may serve as a biomarker of nerve damage, collagen integrity, and demyelination.


[Notes about the historical evolution of health policies in Brazil].
This paper is an historical review of the health policy in Brazil. Ranged since the arrival of the real portuguese family to Brazil until nowadays. The review intent to contextualize present facts based on historical, social and political facts for the needed foundation to give best comprehension of the ways in which is organizing the health policy in Brazil.


To catalyze or not to catalyze: elucidation of the subtle differences between the hexameric capsules of pyrogallolarene and resorcinarene.
The closely related, self-assembled resorcinarene and pyrogallolarene capsules display contrasting and puzzling encapsulation behaviors. Herein, we elucidate the reasons for these differences by combining experimental studies and DFT calculations. Furthermore, we report that, in contrast to the resorcinarene capsule, the pyrogallolarene derivative is not capable of catalyzing reactions with cationic transition states. The molecular mechanisms responsible for these observations are probed in detail.


Human estrogen receptor-like 1 (ESRL1) gene: genomic organization, chromosomal localization, and promoter characterization.
Estrogen receptor-like 1a (ESRL1a; same as estrogen receptor-related orphan receptors, ERR1) belongs to a subfamily of the nuclear receptor superfamily. We have previously shown that human ESRL1a modulates estrogen responsiveness of the lactoferrin gene promoter in transiently transfected endometrial carcinoma RL95-2 cells. In this study, we cloned and characterized the human ESRL1 gene. Through the fluorescence in situ hybridization method, the ESRL1 gene was localized to the centromere region of chromosome 11q12. Partial sequencing, restriction mapping, and PCR analysis revealed that the ESRL1 gene consists of seven exons and is approximately 20 kb in length. We found that the smallest exon (exon 3) contains 117 bp and the largest exon (exon 7) has 1032 bp. The smallest intron (intron 5) is only 88 bp long and the largest intron (intron 2) is 8 kb long. All introns have the conserved GT and AG dinucleotides present at the donor and acceptor sites, respectively. Like the estrogen receptor, the highly conserved DNA-binding domain of hESRL1a is encoded by exon 2 and exon 3, and the intron/exon junctions (2 and 3) are well conserved between the two genes. Primer extension analysis revealed multiple transcription initiation start sites in human uterine (HeLa, HEC, and RL95-2) cell lines. However, one major initiation start site was found by RNase protection assay. The hESRL1a mRNA is differentially expressed in various human tissues. The nucleotide sequence adjacent to the transcription start sites of the ESRL1 lacks the typical TATA and CAAT boxes but is GC rich and contains 10 consensus Sp1-binding elements and two E boxes. The region that contains these transcription factor-binding elements showed a high level of promoter activity when transiently transfected into RL95-2 cells.


Epinephrine versus dopamine in neonatal septic shock: a double-blind randomized controlled trial.
We compared epinephrine and dopamine as a first-line vasoactive drug in 40 neonates (enrolled in two gestational age strata ≤ 306/7 and ≥ 310/7 weeks) with fluid-refractory septic shock. Epinephrine or dopamine was initiated at 0.2 or 10 μg/kg/min, respectively. If shock persisted after 15 min, epinephrine or dopamine was increased to 0.3 or 15 μg/kg/min, respectively (16-30 min), and thereafter to 0.4 or 20 μg/kg/min (31-45 min). Proportion of neonates achieving 'reversal of shock' (defined as systolic and diastolic BP > fifth centile and capillary filling time < 3 s and left ventricular output ≥ 150 mL/kg/min) by 45 min [5 (25%) vs 6 (30%), RR 0.83 (95% CI 0.30, 2.29)]; haemodynamic stability (shock reversal for ≥ 120 min without escalation of vasoactive drugs) anytime during therapy [10 (50%) vs 6 (30%), RR 1.67 (95% CI 0.75, 3.71)]; and all-cause mortality by 28 days [14 (70%) vs 16 (80%), RR 0.87 (95% CI 0.61, 1.26)] were comparable in the epinephrine and dopamine groups, respectively. On stratified analysis, we observed an interaction of gestational age strata with the group of allocation favouring epinephrine in neonates ≤ 306/7 weeks.Conclusion: Epinephrine (0.2-0.4 μg/kg/min) and dopamine (10-20 μg/kg/min) had comparable efficacy and safety in neonatal septic shock.Clinical Trial registry name and registration number: The study was registered with Clinical Trial Registry of India CTRI/2015/10/006285. What is Known: • The choice of vasoactive drugs in neonatal septic shock is empirical and dopamine is the conventional first-line vasoactive drug. • There are no randomized controlled trials comparing dopamine and epinephrine in neonatal septic shock. What is New: • In this study, epinephrine and dopamine had comparable efficacy and safety as a first-line vasoactive drug in management of neonatal septic shock. • On stratified analysis in a limited sample, epinephrine was associated with better outcomes in neonates ≤ 306/7 weeks.


Neuronal Cbl controls biosynthesis of insulin-like peptides in Drosophila melanogaster.
The Cbl family proteins function as both E3 ubiquitin ligases and adaptor proteins to regulate various cellular signaling events, including the insulin/insulin-like growth factor 1 (IGF1) and epidermal growth factor (EGF) pathways. These pathways play essential roles in growth, development, metabolism, and survival. Here we show that in Drosophila melanogaster, Drosophila Cbl (dCbl) regulates longevity and carbohydrate metabolism through downregulating the production of Drosophila insulin-like peptides (dILPs) in the brain. We found that dCbl was highly expressed in the brain and knockdown of the expression of dCbl specifically in neurons by RNA interference increased sensitivity to oxidative stress or starvation, decreased carbohydrate levels, and shortened life span. Insulin-producing neuron-specific knockdown of dCbl resulted in similar phenotypes. dCbl deficiency in either the brain or insulin-producing cells upregulated the expression of dilp genes, resulting in elevated activation of the dILP pathway, including phosphorylation of Drosophila Akt and Drosophila extracellular signal-regulated kinase (dERK). Genetic interaction analyses revealed that blocking Drosophila epidermal growth factor receptor (dEGFR)-dERK signaling in pan-neurons or insulin-producing cells by overexpressing a dominant-negative form of dEGFR abolished the effect of dCbl deficiency on the upregulation of dilp genes. Furthermore, knockdown of c-Cbl in INS-1 cells, a rat β-cell line, also increased insulin biosynthesis and glucose-stimulated secretion in an ERK-dependent manner. Collectively, these results suggest that neuronal dCbl regulates life span, stress responses, and metabolism by suppressing dILP production and the EGFR-ERK pathway mediates the dCbl action. Cbl suppression of insulin biosynthesis is evolutionarily conserved, raising the possibility that Cbl may similarly exert its physiological actions through regulating insulin production in β cells.


A combined hiPSC-derived endothelial cell and in vitro microfluidic platform for assessing biomaterial-based angiogenesis.
Human induced pluripotent stem cell (hiPSC) derived angiogenesis models present a unique opportunity for patient-specific platforms to study the complex process of angiogenesis and the endothelial cell response to biomaterial and biophysical changes in a defined microenvironment. We present a refined method for differentiating hiPSCs into a CD31 + endothelial cell population (hiPSC-ECs) using a single basal medium from pluripotency to the final stage of differentiation. This protocol produces endothelial cells that are functionally competent in assays following purification. Subsequently, an in vitro angiogenesis model was developed by encapsulating the hiPSC-ECs into a tunable, growth factor sequestering hyaluronic acid (HyA) matrix where they formed stable, capillary-like networks that responded to environmental stimuli. Perfusion of the networks was demonstrated using fluorescent beads in a microfluidic device designed to study angiogenesis. The combination of hiPSC-ECs, bioinspired hydrogel, and the microfluidic platform creates a unique testbed for rapidly assessing the performance of angiogenic biomaterials.


Phylogenetic code in the cloud - can it meet the expectations?
Cloud computing has recently become very popular, and several bioinformatics applications exist already in that domain. The aim of this article is to analyse a current cloud system with respect to usability, benchmark its performance and compare its user friendliness with a conventional cluster job submission system. Given the current hype on the theme, user expectations are rather high, but current results show that neither the price/performance ratio nor the usage model is very satisfactory for large-scale embarrassingly parallel applications. However, for small to medium scale applications that require CPU time at certain peak times the cloud is a suitable alternative.


On-line coupling between capillary electrophoresis and microscale thermophoresis (CE-MST); the proof-of-concept.
We demonstrate that microscale thermophoresis can be easily coupled with capillary electrophoresis in an on-line flow system (CE-MST), offering new potential possibilities. It takes advantage of sample separation and miniaturization prior to thermo-optical/MST analysis. No instrument modification is required. The future perspective is discussed.


Reported Affect Changes as a Function of Response Delay: Findings From a Pooled Dataset of Nine Experience Sampling Studies.
Delayed responses are a common phenomenon in experience sampling studies. Yet no consensus exists on whether they should be excluded from the analysis or what the threshold for exclusion should be. Delayed responses could introduce bias, but previous investigations of systematic differences between delayed and timely responses have offered unclear results. To investigate differences as a function of delay, we conducted secondary analyses of nine paper and pencil based experience sampling studies including 1,528 individuals with different clinical statuses. In all participants, there were significant decreases in positive and increases in negative affect as a function of delay. In addition, delayed answers of participants without depression showed higher within-person variability and an initial strengthening in the relationships between contextual stress and affect. Participants with depression mostly showed the opposite pattern. Delayed responses seem qualitatively different from timely responses. Further research is needed to understand the mechanisms underlying these differences.


Detection of SARS-CoV-2 RNA in Upper Respiratory Swap Samples by Pooling Method
Widespread and effective use of molecular diagnostic tests is indispensable for protecting public health and containing the severe respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. More than 1 year into the pandemic, as resources have reached a point of depletion, grouping samples in pools of certain sizes appears to be a reasonable method to reduce both the costs and the processing time without necessitating additional training, equipment, or materials. To assess whether the pooling strategy that was used in past outbreaks and is used in blood tests prior to transfusion for screening large populations can also be used in SARS CoV-2 tests. Diagnostic accuracy study. This prospective study was conducted with 2815 samples, sent to the coronavirus disease 2019 (COVID-19) Laboratory of our hospital between February 12 and 21, 2021, to be tested for the presence of SARS-CoV-2. The samples were examined individually and in pools of five 100 μl taken from each sequential sample, using 3 different SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) kits, the Allplex™ 2019-nCoV Assay kit (Seegene, Republic of Korea), the GeneMAP™ 2019-nCoV detection V.3 kit (GenMark, Türkiye), and the Bio-Speedy™ SARS-CoV-2 Double Gene™ RT-qPCR kit (Bioeksen, Türkiye) on the BioRAD CFX96™ Touch (Bio-Rad Laboratories Inc., Hercules, CA, USA) platform available in our laboratory. Following the extraction of serial dilutions prepared from the SARS-CoV-2 RNA positive (cycle of threshold: 20) sample, the standard curves of RT-PCR were analyzed. By evaluating the efficiency (E) values, all 3 kits showed high sensitivity and similar results; while the highest level was detected with the Allplex™ 2019-nCoV Assay kit in the nucleocapsid (N) gene (E: 124%), the lowest was detected with the Double Gene™ RT-qPCR kit in the N and ORF 1ab genes (E: 90%). Of the samples included in the study, only 1 positive sample with low viral load was found to be negative when studied by pooling. The total number of kits to be used in pooled tests and then to individually retest the 5 samples in positive pools was calculated as 827 and the savings rate as 69.91% (1968/2815). The pooling strategy is an effective approach to extend the impact of limited testing resources and reagents available in certain periods of the COVID-19 pandemic. Testing by pooling samples requires improvement of RNA extraction methods and careful monitoring of RT-PCR test sensitivity to avoid missing low-positive entities. Therefore, based on the prevalence of COVID-19 in their regions, laboratories should conduct their own validation of pooling studies for RNA extraction and amplification methods they use.


Oral iron supplementation ameliorated alterations in iron uptake and utilization in copper-toxic female Wistar rats.
Women are more susceptible to both iron deficiency and copper toxicity due to monthly flow and estrogen action, respectively. Oral iron is beneficial for menstruating women and enhances erythropoiesis, but both deficiency and excess of copper impact iron absorption and mobilization. The aim of this study was to investigate the possibility of mitigating copper toxicity in female Wistar rats while supplementing with iron. 20 female rats (160-180g) were grouped into four: Groups 1 (Control) received 0.3mls normal saline, 2- copper-toxic (100m mg/kg Copper sulphate), 3- Copper-toxic+Iron (100 mg/kg Copper sulphate + 1 mg/kg Ferrous sulphate) and 4- Iron (1 mg/kg Ferrous sulphate). All treatment was administered orally for 5 weeks. Blood was collected retro-orbitally after light anesthesia into EDTA and plain bottles for hematological, serum copper, iron, ferritin and total iron binding capacity (TIBC) analysis. Liver was excised for copper and iron levels while bone marrow was harvested for myeloid/erythroid ratio. The data were analyzed by one-Way ANOVA and statistical significance was considered at p<0.05. Iron supplementation significantly increased packed cell volume, hemoglobin concentration, red blood cell count and myeloid/erythroid ratio, compared to the copper-toxic group. Serum iron and TIBC were significantly increased while liver copper and iron levels reduced significantly in iron supplemented group compared to the copper-toxic group. Oral iron supplementation mitigated alterations in iron absorption and mobilization following copper toxicity.


Exploring the relationship between baseline health-related quality of life (AQoL-4D utility values) and mortality during long-term follow-up for people living with a psychotic disorder.
Holistic summary measures of health-related quality of life (HRQoL) could provide useful information for screening and/or monitoring high-risk individuals. This study explores the association of baseline HRQoL (AQoL-4D values) with death from natural and external causes (such as suicide, overdose, or accident) in a prevalent cohort over a mean follow-up of 6.9-years. Baseline data were obtained from the 2010 National Survey of High Impact Psychosis (SHIP) and its 2012 sister survey, the North-Metro Survey of High Impact Psychosis. Follow-up data were obtained from the National Deaths Index (to January 18, 2018). Associations between baseline HRQoL (and the 12 individual items of the AQoL-4D) and deaths by cause, stratified by sex were investigated using multivariable Cox Proportional Hazards models, with age used as the time scale. Overall, 7.6 % of the cohort (137 of 1805 people meeting ICD-10 criteria for a psychotic disorder and agreeing to linkage) died, 4.2 % from natural causes (primarily heart disease and cancer) and 3.4 % from external causes. There was an association between low HRQoL (AQoL-4D ≤ 0.20) and mortality due to natural causes, primarily driven by difficulties with mobility and vision in men, and difficulty with household tasks in women. No significant associations were obtained between AQoL-4D utilities and death from external causes. Sleep problems were associated with death from external causes for men only. As people with psychotic disorders experience multiple causes of death with complex associations which are difficult to quantify, monitoring for low HRQoL using the AQoL-4D could be a useful indicator of increased mortality risk in this population. TWITTER: Monitoring for low HRQoL (AQoL-4D ≤ 0.20) could be a useful indicator of increased mortality risk from natural causes in people living with psychotic disorders, with differing but specific items of relevance to men and women.


[A new era in rat genetics].
Rat and mice are privileged tools for scientists. However, despite obvious advantages, such as a larger size, more faithful reproduction of human diseases, and utility for physiological and cognitive studies, rats have suffered from limited genetic technologies such as targeted mutagenesis. However, the gap between rat and mouse for genetic approaches will soon disappear with the recent advances of zinc finger nucleases applicable to early-stage rat embryos and the successful derivation of germ line competent rat ES cells, almost thirty years after murine ES cells. This will lead to new opportunities and to increase our capacity to model human pathologies.


Feedback between p21 and reactive oxygen production is necessary for cell senescence.
Cellular senescence--the permanent arrest of cycling in normally proliferating cells such as fibroblasts--contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of 'deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFbeta. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.


The bag cells of Aplysia as a multitransmitter system: identification of alpha bag cell peptide as a second neurotransmitter.
The bag cell neurons of the marine mollusk, Aplysia, are a putative multitransmitter system that utilizes two or more peptide transmitters derived from a common precursor protein. Two putative transmitters are egg-laying hormone (ELH), a 36 amino acid peptide that induces egg laying and mediates bag cell-induced excitatory effects on certain abdominal ganglion neurons, and alpha-bag cell peptide (alpha BCP), which mimics bag cell-induced inhibition of the left upper quadrant (LUQ) neurons and the depolarization of the bag cells that occurs during the bag cell burst discharge. Alpha BCP was previously purified from bag cell extracts in three neuroactive forms: alpha BCP(1-9), a nine amino acid peptide encoded on the ELH/BCP precursor protein, and two NH2-terminal fragments, alpha BCP(1-8) and alpha BCP(1-7). Analyzing bag cell-induced inhibition of LUQ neurons, we report here that alpha BCP fulfills the main criteria for transmitter identification: stimulation of individual bag cells produces inhibition of the neurons; inhibitory activity is present in releasate collected following an elicited bag cell burst discharge in the presence of protease inhibitors; alpha BCP(1-9) and alpha BCP(1-8) are detected in the releasate in the presence of protease inhibitors; alpha BCP is rapidly inactivated after release, as indicated by the lack of detectable alpha BCP or inhibitory activity in the releasate in the absence of protease inhibitors, and by the increase in potency of the arterially perfused peptide in the presence of protease inhibitors; alpha BCP and the endogenously released transmitter produce apparently identical changes in membrane conductance; bag cell-induced inhibition is reduced or abolished following desensitization of the inhibitory response by long-term application of high concentrations of alpha BCP. The results provide additional evidence that the bag cells are a multitransmitter system and also suggest that many of the physiological properties of alpha BCP-mediated neurotransmission differ from those of ELH. First, unlike ELH, alpha BCP is rapidly inactivated after release. Second, alpha BCP(1-9) may be activated by carboxypeptidase cleavage since alpha BCP(1-8) and alpha BCP(1-7) are 30 and 10X as potent, respectively, as alpha BCP(1-9). Third, the inhibitory action of alpha BCP on its targets has a more rapid onset and a shorter time course than the excitatory actions of ELH. Thus, alpha BCP may diffuse to less distant targets than ELH and serve to regulate the more rapidly occurring neural events underlying egg-laying behavior.


[Magnetic fields and health: from epidemiology to cryptochrome chemistry].
Biological effects of static magnetic fields (MF) and time-varying MF of electricity (50/60 Hz) appear possible from intensities in the low illitesla range. However, prolonged exposure to 50/60 Hz MF is associated with an increased risk of childhood leukemia at less than one microtesla of time-averaged intensity. And such kind of association is suggested in adults for some blood cancers and senile dementia. The cryptochrome hypothesis has been proposed to explain the association established with childhood leukemia. Cryptochromes indeed assume the regulation of circadian biorhythms (a disruption of these lasts takes part to carcinogenesis) and they could be intrinsically sensitive to MF as from the low microtesla range. The cryptochrome hypothesis is now supported by diverse experimental observations. And recently, its relevance is further enhanced by the perspective of possible photo-dependence of the clock function of Cry 2 in retina, at least in diurnal mammals - the magnetic sensitivity of cryptochromes is indeed photo-dependent. Such a perspective however implies some major paradigm shifts in the experimental study of biological effects of 50/60 Hz MF as it has been conducted to date. On the other hand, the cryptochrome hypothesis can in principle also apply to static MF. For these, indeed, a mechanism of interaction with cryptochromes is identified, which is not the case of 50/60 Hz MF so far. A hypothesis is proposed here for these last, namely, resonance-based interaction with the spin polarization of one or both the radicals of the long-lived (milliseconds) pair FAD°-Trp4°.


[All on stage: Exploratory study of the use of improvisational theatre in nursing home].
Supporting an elderly person with a neuro-evolutionary disease is a complex task, especially if the person has cognitive problems and lives in a nursing home. Non-drug approaches offer good alternatives to traditional treatment and care. More and more therapies based on theatrical improvisation are being developed to act on psychological health. The aim of this research is to study the effect of participation in theatrical improvisation workshops over a period of 8 weeks on quality of life, self-esteem, depressive symptoms and personal satisfaction in 10 elderly people (Mean = 87.70 years; SD = 2.87 years) with mild cognitive impairment. At the end of the theatre sessions, the participants reported better psychological health. This study provides insights into the development of non-drug mediations for elderly people with neuro-evolutionary diseases.


[Mean retention time of 51Cr-EDTA and 103Ru-phenanthroline in the digestive tract of sheep and bulls fed straw pellets].
Two lots of straw pellets (supplemented with 10% molasses), produced either with a 5 mm sieve in a hammer mill (lot A) or with a 12 mm sieve (lot B) from wheat straw, were tested with 4 sheep (wethers, average live weight 43 kg) and 4 bulls (average 170 kg). After carrying out a digestibility experiment, the mean retention time (mrt), the 80%-excretion of the markers and the transit time were ascertained with the help of 51Cr-EDTA and 103Ru-phenanthroline. The digestibility of carbohydrates (both crude fibre and N-free extracts) was significantly higher for the bulls than for the sheep. Mrt, transit time and 80%-marker excretion were ascertained as follows: (Table: see text) The better digestion performance of carbohydrates from pelleted wheat straw in bulls in contrast to the sheep is due to the longer retention time of the digesta in the digestive tract of bulls. In connection with the considerably higher ruminating capacity of cattle in comparison to sheep, a longer retention time of the straw particles (Welch, 1982) in the reticulo-rumen must be considered.


Swim pressure: stress generation in active matter.
We discover a new contribution to the pressure (or stress) exerted by a suspension of self-propelled bodies. Through their self-motion, all active matter systems generate a unique swim pressure that is entirely athermal in origin. The origin of the swim pressure is based upon the notion that an active body would swim away in space unless confined by boundaries-this confinement pressure is precisely the swim pressure. Here we give the micromechanical basis for the swim stress and use this new perspective to study self-assembly and phase separation in active soft matter. The swim pressure gives rise to a nonequilibrium equation of state for active matter with pressure-volume phase diagrams that resemble a van der Waals loop from equilibrium gas-liquid coexistence. Theoretical predictions are corroborated by Brownian dynamics simulations. Our new swim stress perspective can help analyze and exploit a wide class of active soft matter, from swimming bacteria to catalytic nanobots to molecular motors that activate the cellular cytoskeleton.


Early adulthood psychiatric diagnoses and the subsequent risk of life-time incarceration: a cohort study.
The association between incarceration and psychiatric disorders has been noted. Yet, existing studies are cross-sectional or examine the risk of recidivism, which has limited the predictive validity of psychiatric disorders as a risk factor for incarceration. To overcome this limitation, this study used a prospective cohort to examine whether psychiatric diagnoses in early adulthood predicted incarceration throughout a 30-year follow-up. It tested the association between psychiatric diagnoses with future incarcerations, their number and durations, controlling for education and ethnic status. This study merged data from three sources in Israel: a prospective 10-year birth cohort study of young adults aged 25-34, conducted in the 1980s (N = 4914) that included a psychiatric interview; data from the Prison Service, including the cause, number and duration of incarcerations; and from the Vital Statistics Registry on death records. Multivariate analysis showed that substance-use disorders, antisocial personality and lower levels of education predicted future incarceration, their number and maximum duration. The remainder diagnoses were not significantly associated with future incarceration. Results limited the prediction of future incarcerations to persons diagnosed with substance use and antisocial personality, and do not support an independent predictive association between additional psychiatric diagnoses and future incarceration.


Role of the kidneys in the metabolism of plasma mevalonate. Studies in humans and in rhesus monkeys.
Studies were carried out in humans and in rhesus monkeys to determine the role of the kidneys in the metabolism of circulating mevalonic acid (MVA). Following intravenous infusion of [14C]MVA and [3H]cholesterol, there was a rapid appearance of [14C]squalene in the kidneys that exhibited a significantly longer half-life than plasma or hepatic squalene. In man and in rhesus monkeys there was a rapid equilibration between newly synthesized cholesterol from MVA and exogenously administered cholesterol in all tissues except the kidneys, where the specific activity ratio of newly synthesized to exogenous cholesterol was significantly higher. Estimates of the quantitative metabolism of intravenously infused radiolabeled MVA in the monkey demonstrated that 23% was excreted in the urine, 67% metabolized to cholesterol (58% in nonrenal tissues and 9% in the kidneys), and 10% catabolized to CO2 and nonsteroid products. Measurements of MVA metabolism in anephric and uninephric patients demonstrate that, in the absence of renal uptake of MVA, exogenous and newly synthesized cholesterol achieve almost instantaneous equilibrium in the plasma; whereas in control subjects with normal renal function, this equilibration required at least 21 d for the two cholesterol decay curves to become parallel. These results suggest that the kidneys are solely responsible for the observed disequilibrium between newly synthesized and exogenous cholesterol; we suggest that this was due to the delayed release of newly synthesized cholesterol from the kidneys into the plasma compartment following intravenous infusion with radiolabeled MVA. The data document the importance of the kidneys in the metabolism of circulating MVA. However, calculation of the quantitative significance of this pathway in relation to whole body MVA metabolism indicates that renal metabolism of MVA accounts for approximately 0.1% of daily MVA turnover, and that alterations in this pathway due to any form of renal pathology would not result in significant changes in hepatic or whole body sterol synthesis rates. We urge caution in the use of radiolabeled MVA in long-term kinetic studies of sterol metabolism because our data show that the plasma compartment of MVA is not necessarily in isotopic equilibrium with tissue MVA.


Occupational dermal exposure to cyclophosphamide in Dutch hospitals: a pilot study.
Several studies have shown that exposure to antineoplastic drugs can cause reproductive toxic effects as well as carcinogenic effects. Presence of these drugs in the urine of hospital personnel has been widely studied and some work has been done on exposure by inhalation. So far, assessment of dermal exposure to antineoplastic drugs has not been extensively studied. In this pilot study we assessed potential and actual dermal exposure for several common hospital tasks. Results were used to derive an optimal measurement strategy for a currently ongoing exposure survey. Dermal exposure to cyclophosphamide was determined in three Dutch hospitals during five tasks (preparation, decanting urine, washing the patient, removing bed sheets and cleaning the toilet) using pad samples on 10 body locations. In addition, protective medical gloves (worn during the performance of these activities) were collected to estimate potential exposure of the hands. Subsequently, hands were washed to measure actual exposure of the hands. Bulk samples (i.e. application and body fluids) were collected and possible contact surfaces were monitored to assess the amount of cyclophosphamide potentially available for exposure. The results show that hospital personnel (i.e. pharmacy technicians and oncology nurses) are dermally exposed to cyclophosphamide during performance of their daily duties. Exposure occurred predominantly on the hands and sporadically on other body locations (i.e. forehead and forearms). Gloves used during preparation of cyclophosphamide were more contaminated than gloves used in other tasks, however, actual exposure of the hands (underneath the gloves) was highest during decanting of urine of treated patients. Glove samples correlated significantly with handwash samples (r = 0.57, P = 0.03, n = 15). The level of protection from gloves varied between tasks, being highest for gloves used during preparation (median = 98%) and lowest for gloves used during decanting urine (median = 19%). This pilot study demonstrated that dermal exposure to cyclophosphamide is common among hospital personnel. The results showed that hands, forearms and forehead accounted for 87% of the cyclophosphamide total body exposure. Glove samples together with handwash samples enabled estimation of glove efficiency, which appeared to vary strongly between tasks observed.