Induction of apoptosis by diethylstilbestrol in hormone-insensitive prostate cancer cells.
Diethylstillbestrol (DES) and diethylstilbestrol diphosphate (DESdP) are effective agents for the treatment of advanced prostate cancers. Tumor-inhibiting effects of DES and DESdP are presumed secondary to suppression of androgen production in vivo. Little is known, however, about the direct cellular mechanisms of the tumor inhibition. Estrogens have been reported not only to stimulate growth but also to disrupt microtubule formation in prostate cancer cells. The study was designed to examine and compare mechanisms of in vitro growth inhibition of DES and DESdP in human androgen-insensitive prostate cancer cells (DU145, 1-LN, and PC-3) and human androgen-sensitive prostate cancer cells (LNCaP) and to examine estrogen receptor modulation of such effects. The cytotoxic effects of DES and DESdP were examined in vitro by use of a standard microculture tetrazolium assay to quantitate numbers of viable cells. Immunofluorescence microscopy, DNA fragmentation analysis, and fluorescence flow cytometry were used to investigate microtubules, the induction of apoptosis, and changes in cell cycle distribution. The degree of estrogen receptor positivity of untreated and treated cells was determined by immunohistochemistry and quantitative image analysis. LD50 levels (the dose at which 50% of cells are no longer viable) in the concentration range of 19-25 microM were observed for both DES and DESdP in all cell lines examined. DESdP-induced growth inhibition was found to be dependent on heat-labile phosphatases present in fetal calf serum. DES-induced cytotoxicity was not affected by the presence of 17 beta-estradiol, and it was not dependent on the presence of estrogen receptor. Estrogen receptor-positive cells and estrogen receptor-negative cells were equally responsive to DES. PC-3 cells stained with fluorescent anti-tubulin, phalloidin (actin stain), and 4',6-diamidino-2-phenylindole (DNA stain) showed no inhibition of microtubules or actin filaments but revealed the presence of apoptotic bodies in the nuclei. Fluorescence flow cytometry of nuclear DNA content of propidium iodide-stained nuclei from androgen-insensitive prostate cancer cells treated with 15 or 30 microM DES or DESdP revealed an increase in relative numbers of hypodiploid (apoptotic) nuclei, a depletion of G1- and S-phase cells, and an accumulation of cells in G2/M phase. Conversely, androgen-sensitive cells contained a lower percentage of hypodiploid nuclei but no accumulation of cells in G2/M phase. Direct cytotoxic effects of DES in prostate cancer cells are estrogen receptor independent and do not involve disruption of microtubule architecture but do involve the promotion of cell cycle arrest and apoptosis. These are the first data confirming direct cytotoxic effects of DES and DESdP in prostate cancer cells via an apoptotic mechanism. IMPLICATIONS. These results suggest that DES and DESdP have potential value as agents against androgen-insensitive prostate neoplasms through induction of an apoptotic cascade.


NG-nitro-L-arginine methyl ester attenuates the maintenance and expression of methamphetamine-induced behavioral sensitization and enhancement of striatal dopamine release.
We examined the roles of nitric oxide (NO) in methamphetamine (MAP)-induced behavioral sensitization and enhancement of striatal dopamine (DA) release using both in vivo and in vitro methods. Repeated administration of MAP produced augmentation of MAP-induced locomotor activity after 3-day withdrawal of MAP and an enhancement of MAP-evoked DA release from striatal slices after 6-day withdrawal. When the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L- NAME) was administered only during the period of MAP withdrawal, the behavioral sensitization and enhancement of DA release were attenuated significantly. In contrast, NG-nitro-D- arginine methyl ester, an inactive isomer of L-NAME, exhibited no such effect. When L-NAME was administered acutely before the challenge injection of MAP, behavioral sensitization was also attenuated only when the dose of L-NAME was high. Coadministration of L-NAME with MAP did not block the development of sensitization to MAP. We also examined whether MAP-induced behavioral sensitization and enhancement of DA release could be observed in vivo in a microdialysis experiment. Challenge injection of MAP caused marked enhancement of DA release in MAP-sensitized rats compared with saline-treated controls corresponding to robust augmentation of locomotor activity. When L-NAME was injected during the MAP withdrawal period, the enhancement of DA release and locomotor activity induced by challenge injection of MAP were attenuated. These results suggest that NO production plays a role in the maintenance (expression) of MAP-induced behavioral sensitization and enhancement of DA release but not in the development of these effects.


Correlates of Satisfaction with Sexual Initiation Among Mexican Adolescents.
Having one's first sexual intercourse be a positive and satisfying experience may be critical to healthy sexual development. Few studies, however, have examined adolescents' sexual satisfaction and the factors associated with enhancing or diminishing it, especially in Mexico. Data from 4,504 heterosexual, sexually experienced 15-20-year-olds living in three Mexican states (Morelos, Jalisco and Puebla) were taken from the 2014 Survey on Dating, Empowerment, and Sexual and Reproductive Health in Adolescent High School Students. Multinomial logistic regression was used to examine factors associated with satisfaction and dissatisfaction with one's first experience of sexual intercourse, separately by gender. Most adolescents reported feeling generally satisfied with their first sexual intercourse (51% very satisfied and 40% satisfied); the proportion feeling very satisfied was significantly higher among young men than among young women (58% vs. 42%). Among both young men and women, feeling very satisfied (rather than satisfied) with first sex was positively associated with greater approval of adolescent sex (relative risk ratios, 1.06 each), as well as with higher self-esteem (1.04 and 1.03, respectively). Other variables positively associated with feeling very satisfied included having had first sex with a boyfriend or girlfriend, having had first sex less than three months prior to the survey, high socioeconomic status (for males only) and older age (for females only). Self-esteem and having a positive view of adolescent sexuality may play an important role in the experience of satisfying first sex among Mexican adolescents. These should be pivotal elements of educational programs aimed at helping adolescents develop a positive sexuality and feel entitled to and in control of their sexual lives.


Mechanism and implications of morphogen shuttling: Lessons learned from dorsal and Cactus in Drosophila.
In a developing animal, morphogen gradients act to pattern tissues into distinct domains of cell types. However, despite their prevalence in development, morphogen gradient formation is a matter of debate. In our recent publication, we showed that the Dorsal/NF-κB morphogen gradient, which patterns the DV axis of the early Drosophila embryo, is partially established by a mechanism of facilitated diffusion. This mechanism, also known as "shuttling," occurs when a binding partner of the morphogen facilitates the diffusion of the morphogen, allowing it to accumulate at a given site. In this case, the inhibitor Cactus/IκB facilitates the diffusion of Dorsal/NF-κB. In the fly embryo, we used computation and experiment to not only show that shuttling occurs in the embryo, but also that it enables the viability of embryos that inherit only one copy of dorsal maternally. In this commentary, we further discuss our evidence behind the shuttling mechanism, the previous literature data explained by the mechanism, and how it may also be critical for robustness of development. Finally, we briefly provide additional experimental data pointing toward an interaction between Dorsal and BMP signaling that is likely affected by shuttling.


Spontaneous and deliberate dissociative states in military personnel: are such states helpful?
This study explored distinctions between spontaneous and deliberate dissociative states in 335 military personnel exposed to stressful survival training. Participants completed the Clinician-Administered Dissociative States Scale (CADSS) after a stressful mock-captivity event. They were also asked to indicate whether the dissociative experiences just happened (i.e., spontaneous), or whether they chose to have them happen (i.e., deliberate); and whether they appraised the dissociative experience as helpful (i.e., facilitative) or hurtful (i.e., debilitative) to their ability to cope with the stressful event. A majority (95.4%) endorsed dissociative states during stress. More than half (57.4%) described dissociative experiences as spontaneous, 13.0% as deliberate, and 29.5% endorsed neither. In Special Forces soldiers only, those who endorsed facilitative dissociation exhibited higher total CADSS scores than those who endorsed debilitative dissociation. Seventy-three percent of spontaneous dissociators described the experience as debilitative to coping with stress; conversely, 76% of deliberate dissociators said these experiences facilitated coping with stress. Individuals with prior trauma exposure tended to appraise dissociative states as more debilitative to coping. This research may enhance the fidelity of studies of dissociation constructs and may offer pivot points for prevention and treatment of stress-related disorders.


Associations of FGF-3 and FGF-10 with signaling networks regulating tooth morphogenesis.
The morphogenesis and cell differentiation in developing teeth is governed by interactions between the oral epithelium and neural crest-derived ectomesenchyme. The fibroblast growth factors FGF-4, -8, and -9 have been implicated as epithelial signals regulating mesenchymal gene expression and cell proliferation during tooth initiation and later during epithelial folding morphogenesis and the establishment of tooth shape. To further evaluate the roles of FGFs in tooth development, we analyzed the roles of FGF-3, FGF-7, and FGF-10 in developing mouse teeth. In situ hybridization analysis showed developmentally regulated expression during tooth formation for Fgf-3 and Fgf-10 that was mainly restricted to the dental papilla mesenchymal cells. Fgf-7 transcripts were restricted to the developing bone surrounding the developing tooth germ. Fgf-10 expression was observed in the presumptive dental epithelium and mesenchyme during tooth initiation, whereas Fgf-3 expression appeared in the dental mesenchyme at the late bud stage. During the cap and bell stage, both Fgf-3 and Fgf-10 were intensely expressed in the dental papilla mesenchymal cells both in incisors and molars. It is of interest that Fgf-3 expression was also observed in the primary enamel knot, a putative signaling center of the tooth, whereas no transcripts were seen in the secondary enamel knots that appear in the tips of future cusps of the bell stage tooth germs. Down-regulation of Fgf-3 and Fgf-10 expression in postmitotic odontoblasts correlated with the terminal differentiation of the odontoblasts and the neighboring ameloblasts. In the incisors, mesenchymal cells of the cervical loop area showed partially overlapping expression patterns for all studied Fgfs. In vitro analyses showed that expression of Fgf-3 and Fgf-10 in the dental mesenchyme was dependent on dental epithelium and that epithelially expressed FGFs, FGF-4 and -8 induced Fgf-3 but not Fgf-10 expression in the isolated dental mesenchyme. Beads soaked in Shh, BMP-2, and TGF-beta 1 protein did not induce either Fgf-3 or Fgf-10 expression. Cells expressing Wnt-6 did not induce Fgf-10 expression. Furthermore, FGF-10 protein stimulated cell proliferation in the dental epithelium but not in the mesenchyme. These results suggest that FGF-3 and FGF-10 have redundant functions as mesenchymal signals regulating epithelial morphogenesis of the tooth and that their expressions appear to be differentially regulated. In addition, FGF-3 may participate in signaling functions of the primary enamel knot. The dynamic expression patterns of different Fgfs in dental epithelium and mesenchyme and their interactions suggest existence of regulatory signaling cascades between epithelial and mesenchymal FGFs during tooth development.


Stab wounds associated with hematuria--a review of 67 cases.
The clinical records of 67 patients who underwent surgical exploration for stab wounds associated with hematuria were reviewed in an attempt to evaluate the need for mandatory operation and to define criteria for possible nonoperative of such cases. Minor renal injuries without associated intra-abdominal lacerations were found in 61 per cent of the patients. Delayed renal hemorrhage occurred in 15 per cent of the patients despite early exploration, suture and drainage of the kidney, and antibiotic prophylaxis. Of 7 nephrectomies 5 were performed for secondary hemorrhage. Postoperative pulmonary complications arose in 28 per cent of the patients. A policy of mandatory operation on all patients with stab wounds and hematuria led to apparently needless surgery in 61 per cent of the patients in this series. Retrospective analysis revealed that the rate of probably unnecessary operations could have been reduced to 24 per cent by selecting for operation only those patients with signs of severe hemorrhage, associated intra-abdominal injury or major extravasation of contrast material on excretory urography.


Recent progress and prospects for advancing arachnid genomics.
Arachnids exhibit tremendous species richness and adaptations of biomedical, industrial, and agricultural importance. Yet genomic resources for arachnids are limited, with the first few spider and scorpion genomes becoming accessible in the last four years. We review key insights from these genome projects, and recommend additional genomes for sequencing, emphasizing taxa of greatest value to the scientific community. We suggest greater sampling of spiders whose genomes are understudied but hold important protein recipes for silk and venom production. We further recommend arachnid genomes to address significant evolutionary topics, including the phenotypic impact of genome duplications. A barrier to high-quality arachnid genomes are assemblies based solely on short-read data, which may be overcome by long-range sequencing and other emerging methods.


Exposure of Human CD8+ T Cells to Type-2 Cytokines Impairs Division and Differentiation and Induces Limited Polarization.
Effector CD8+ T cells generally produce type-1 cytokines and mediators of the perforin/granzyme cytolytic pathway, yet type-2-polarized CD8+ cells (Tc2) are detected in type-2 (T2) cytokine-driven diseases such as asthma. It is unclear whether T2 cytokine exposure during activation is sufficient to polarize human CD8+ T cells. To address this question, a protocol was developed for high-efficiency activation of human CD8+ T cells in which purified single cells or populations were stimulated with plate-bound anti-CD3 and anti-CD11a mAb for up to 8 days in T2 polarizing or neutral conditions, before functional analysis. Activation of CD8+ naïve T cells (TN) in T2 compared with neutral conditions decreased the size of single-cell clones, although early division kinetics were equivalent, indicating an effect on overall division number. Activation of TN in T2 conditions followed by brief anti-CD3 mAb restimulation favored expression of T2 cytokines, GATA3 and Eomes, and lowered expression of type-1 cytokines, Prf1, Gzmb, T-BET, and Prdm1. However, IL-4 was only weakly expressed, and PMA and ionomycin restimulation favored IFN-γ over IL-4 expression. Activation of TN in T2 compared with neutral conditions prevented downregulation of costimulatory (CD27, CD28) and lymph-node homing receptors (CCR7) and CD95 acquisition, which typically occur during differentiation into effector phenotypes. CD3 was rapidly and substantially induced after activation in neutral, but not T2 conditions, potentially contributing to greater division and differentiation in neutral conditions. CD8+ central memory T cells (TCM) were less able to enter division upon reactivation in T2 compared with neutral conditions, and were more refractory to modulating IFN-γ and IL-4 production than CD8+ TN. In summary, while activation of TN in T2 conditions can generate T2 cytokine-biased cells, IL-4 expression is weak, T2 bias is lost upon strong restimulation, differentiation, and division are arrested, and reactivation of TCM is reduced in T2 conditions. Taken together, this suggests that exposure to T2 cytokines during activation may not be sufficient to generate and retain human Tc2 cells.


Proteomic analysis of the Kaposi's sarcoma-associated herpesvirus terminal repeat element binding proteins.
Terminal repeat (TR) elements of Kaposi's sarcoma-associated herpesvirus (KSHV), the potential origin sites of KSHV replication, have been demonstrated to play important roles in viral replication and transcription and are most likely also critical for the segregation of the KSHV genome to daughter cells. To search for the cellular proteins potentially involved in KSHV genome maintenance, we performed affinity chromatography analysis, using KSHV TR DNA as the affinity ligand. Proteomic analysis was then carried out to identify the TR-interacting proteins. We identified a total of 123 proteins from both KSHV-positive and -negative cells, among which most were identified exclusively from KSHV-positive cells. These proteins were categorized as proliferation/cell cycle regulatory proteins, proteins involved in spliceosome components, such as heterogeneous nuclear ribonuclear proteins, the DEAD/H family, the switch/sucrose nonfermenting protein family, splicing factors, RNA binding proteins, transcription regulation proteins, replication factors, modifying enzymes, and a number of proteins that could not be broadly categorized. To support the proteomic results, the presence of four candidate proteins, ATR, BRG1, NPM1 and PARP-1, in the elutions was further characterized in this study. The binding and colocalization of these proteins with the TR were verified using chromatin immunoprecipitation and immunofluorescence in situ hybridization analysis. These newly identified TR binding proteins provide a number of clues and potential links to understanding the mechanisms regulating the replication, transcription, and genome maintenance of KSHV. This study will facilitate the generation and testing of new hypotheses to further our understanding of the mechanisms involved in KSHV persistence and its associated pathogenesis.


Oncology nurse navigator.
The purpose of this integrative review is to explore the presence of the oncology nurse as navigator on measurable patient outcomes. Eighteen primary nursing research studies were found using combinations of the following key words: advocate, cancer, case manager, coach, certification, guide, navigator, nurse, oncology, patient navigator, pivot nurse, and continuity of care. Nurse researchers identified nursing-sensitive patient outcomes related to the time to diagnosis and appropriate treatment, effect on mood states, satisfaction, support, continuity of care, and cost outcomes. Navigator roles are expanding globally, and nurses should continue to embrace opportunities to ensure the safe passage of patients with cancer along the entire trajectory of illness and to evaluate the implications for educational preparation, research, and practice of navigators of all kinds.


Clinical outcomes in patients with generalized periodic discharges.
Generalized periodic discharges (GPDs) are frequently identified in the EEGs of hospitalized patients but their prognostic significance remains unclear. We retrospectively reviewed clinical data in patients with GPDs to elucidate factors associated with in-hospital mortality. We reviewed data from inpatients at three different hospitals affiliated with our institution in whom GPDs were reported on routine EEGs by fellowship-trained electroencephalographers during the years 2010-2012. Cox regression was used to determine statistical association between in-hospital death and demographics, medical comorbidities, neurological and neuroimaging abnormalities and antiepileptic drug use. We identified 113 patients with GPDs. The mean age was 70.4 years and 70 (61.9%) were women. There were 60 inpatient deaths (53.1%). The variables significantly associated with in-hospital mortality were dementia, poor mental status at the time of the EEG, chronic focal abnormalities on neuroimaging, cardiac arrest and chronic obstructive pulmonary disease (COPD). Dementia, poor mental status during EEG, chronic focal abnormalities on neuroimaging, cardiac arrest and COPD are independently associated with increased in-hospital mortality in patients with GPDs (P<0.05).


Validation of the PILL-5: A 5-Item Patient Reported Outcome Measure for Pill Dysphagia.
Objectives: Pill dysphagia is common and costly with a significant risk of pill retention, caustic injury, and poor medication compliance. The purpose of this investigation was to determine the validity and reliability of the PILL-5, a self-administered patient reported outcome measure (PROM) to quantify the degree of pill (tablet and capsule) dysphagia. The PILL-5 is a 5-item questionnaire with a maximum symptom score of 20. Methods: The PILL-5 was administered to 190 patients with dysphagia referred for videofluoroscopic esophagography (VFE). Construct validity was assessed by comparing PILL-5 composite scores to delayed barium tablet transit on VFE. Normative data was obtained by administering the instrument to a cohort of healthy community based volunteers. Internal consistency was assessed with the Cronbach alpha. Test/retest reliability was determined by administering the instrument to the same cohort of patients at two time points. Results: The mean PILL-5 was 5.6 (±4.9) for persons with dysphagia and 1.6 (±2.7) for healthy volunteers (p < 0.001). The internal consistency of the instrument was high (Cronbach alpha = 0.85). The mean PILL-5 was 4.3 (±4.1) for patients with normal transit and 7.6 (±5.3) for patients with delayed barium tablet transit on esophagography, indicating excellent criterion based validity (p < 0.001). Reproducibility was high with an intraclass correlation coefficient of 0.83 (p < 0.001). Conclusions: Healthy individuals report some degree of swallowing difficulty with pills. Normative data suggest that a PILL-5 > 6 is abnormal (mean + 2 SD). The instrument demonstrated excellent criterion based validity and reliability. The PILL-5 is the first validated patient reported outcome measure for pill dysphagia.


Non-Darwinian dynamics in therapy-induced cancer drug resistance.
The development of drug resistance, the prime cause of failure in cancer therapy, is commonly explained by the selection of resistant mutant cancer cells. However, dynamic non-genetic heterogeneity of clonal cell populations continuously produces metastable phenotypic variants (persisters), some of which represent stem-like states that confer resistance. Even without genetic mutations, Darwinian selection can expand these resistant variants, which would explain the invariably rapid emergence of stem-like resistant cells. Here, by using quantitative measurements and modelling, we show that appearance of multidrug resistance in HL60 leukemic cells following treatment with vincristine is not explained by Darwinian selection but by Lamarckian induction. Single-cell longitudinal monitoring confirms the induction of multidrug resistance in individual cells. Associated transcriptome changes indicate a lasting stress response consistent with a drug-induced switch between high-dimensional cancer attractors. Resistance induction correlates with Wnt pathway upregulation and is suppressed by β-catenin knockdown, revealing a new opportunity for early therapeutic intervention against the development of drug resistance.


Why could meditation practice help promote mental health and well-being in aging?
Psycho-affective states or traits such as stress, depression, anxiety and neuroticism are known to affect sleep, cognition and mental health and well-being in aging populations and to be associated with increased risk for Alzheimer's disease (AD). Mental training for stress reduction and emotional and attentional regulation through meditation practice might help reduce these adverse factors. So far, studies on the impact of meditation practice on brain and cognition in aging are scarce and have limitations but the findings are encouraging, showing a positive effect of meditation training on cognition, especially on attention and memory, and on brain structure and function especially in frontal and limbic structures and insula. In line with this, we showed in a pilot study that gray matter volume and/or glucose metabolism was higher in six older adult expert meditators compared to 67 age-matched controls in the prefrontal, anterior and posterior cingulate cortex, insula and temporo-parietal junction. These preliminary findings are important in the context of reserve and brain maintenance as they suggest that long-term meditation practice might help preserve brain structure and function from progressive age-related decline. Further studies are needed to confirm these results with larger samples and in randomized controlled trials and to investigate the mechanisms underlying these meditation-related effects. The European Commission-funded project Silver Santé Study will address these challenges by studying 316 older adults including 30 expert meditators and 286 meditation-naïve participants (either cognitively normal or with subjective cognitive decline). Two randomized controlled trials will be conducted to assess the effects of 2-month and 18-month meditation, English learning or health education training programs (versus a passive control) on behavioral, sleep, blood sampling and neuroimaging measures. This European research initiative illustrates the progressive awareness of the benefit of such non-pharmacological approaches in the prevention of dementia and the relevance of taking into account the psycho-affective dimension in endeavoring to improve mental health and well-being of older adults.


Arrest of B16 melanoma cells in the mouse pulmonary microcirculation induces endothelial nitric oxide synthase-dependent nitric oxide release that is cytotoxic to the tumor cells.
Metastatic cancer cells seed the lung via blood vessels. Because endothelial cells generate nitric oxide (NO) in response to shear stress, we postulated that the arrest of cancer cells in the pulmonary microcirculation causes the release of NO in the lung. After intravenous injection of B16F1 melanoma cells, pulmonary NO increased sevenfold throughout 20 minutes and approached basal levels by 4 hours. NO induction was blocked by N(G)-nitro-L-arginine methyl ester (L-NAME) and was not observed in endothelial nitric oxide synthase (eNOS)-deficient mice. NO production, visualized ex vivo with the fluorescent NO probe diaminofluorescein diacetate, increased rapidly at the site of tumor cell arrest, and continued to increase throughout 20 minutes. Arrested tumor cells underwent apoptosis with apoptotic counts more than threefold over baseline at 8 and 48 hours. Neither the NO signals nor increased apoptosis were seen in eNOS knockout mice or mice pretreated with L-NAME. At 48 hours, 83% of the arrested cells had cleared from the lungs of wild-type mice but only approximately 55% of the cells cleared from eNOS-deficient or L-NAME pretreated mice. eNOS knockout and L-NAME-treated mice had twofold to fivefold more metastases than wild-type mice, measured by the number of surface nodules or by histomorphometry. We conclude that tumor cell arrest in the pulmonary microcirculation induces eNOS-dependent NO release by the endothelium adjacent to the arrested tumor cells and that NO is one factor that causes tumor cell apoptosis, clearance from the lung, and inhibition of metastasis.


Effect of extrapyramidal signs and Lewy bodies on survival in patients with Alzheimer disease.
Patients with Alzheimer disease (AD) who have psychiatric and parkinsonian symptoms experience faster cognitive deterioration and shorter survival vs those without such disease features. Extrapyramidal signs (EPSs) in particular have been associated with the presence of Lewy bodies (LBs) on autopsy and with poorer survival in patients with AD. Lewy bodies found at autopsy are not always correlated with EPSs during late life. To determine whether the association between LBs and age at death is modified by the presence of EPSs, hallucinations, or delusions. An autopsy series of patients with clinically diagnosed AD. Three AD clinics (San Diego and Sacramento, Calif, and Portland, Ore). Data on 379 patients with a clinical diagnosis of AD who were initially assessed between May 1, 1984, and August 1, 1996, and who were autopsied between January 1, 1990, and April 1, 1998, were pooled from 3 AD centers. Presence of LBs on autopsy and differences in age at death in those with EPSs, LBs, or both. Individuals with EPSs at initial assessment were more than 3 times as likely to have LBs at autopsy than were those without EPSs. Age at death was younger in those with LBs and EPSs than in those with LBs only and those without EPSs or LBs. The presence of EPSs in patients with AD indicates worse prognosis and may be related to underlying LBs. The presence of EPSs is a strong predictor of LBs.


The Effect of Phospholipids on Tear Film Lipid Layer Surface Activity.
We illustrate the importance of small quantities (<10 mol%) of polar phospholipids on the surface-active behavior of meibum-like lipid compositions. Artificial meibum-like lipid mixture containing cholesteryl and wax esters was mixed with differing amounts of phosphatidylcholine (PC). The surface activity of these mixtures was investigated at the air-water interface by recording surface pressure created by the lipid layer as a function of molecular area at 37°C. The PC proportion in the mixtures was 0, 2.5, 5, 7.5, or 10 mol%, and the remaining proportion in the mixture was 50:50 (mol/mol) of cholesteryl oleate (CO) and behenyl oleate (BO). Also, the effect of temperature was investigated. The surface activity of the mixtures increased in a very predictable and consistent fashion as a function of the PC proportion. The lipid mixture containing only CO and BO showed miniscule surface activity. However, already 2.5% PC mixed with the nonpolar CO and BO generated considerable increase in surface pressure. At small surface areas, the behavior of 7.5% and 10% PC compositions started to approach that of a pure PC monolayer. The temperature did not have a considerable impact on the surface-active behavior of the PC-containing compositions. The polar phospholipids have a considerable effect on the surface-active properties of artificial tear film lipid layer (TFLL) compositions. Surprisingly, this takes place already at very low and physiologically relevant PC proportions. The effect is more dependent on the actual amount of the phospholipids at the air-tear interface than on the relative amount of these lipids in TFLL.


Agonist activity of antimigraine drugs at recombinant human 5-HT1A receptors: potential implications for prophylactic and acute therapy.
The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Affinities (K(i)s) at this site were determined in competition binding experiments with [3H]-8-OH-DPAT ([3H](+/-)8-hydroxy-N,N-dipropylaminotetralin), whilst agonist efficacy was measured by stimulation of [35S]-GTP gamma S (guanylyl-5'-[gamma[35S]thio]-triphosphate) binding. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. This suggests that there is no correlation between agonism at 5-HT1A receptors and prophylactic antimigraine action. In contrast, serotonin, dihydroergotamine, sumatriptan, naratriptan and alniditan, which are effective in acute interruption of migraine attacks, each displayed high efficacy (Emax = 100, 100, 92.6, 79.3, 79.1% respectively) and marked affinity (Ki = 18.7, 0.6, 127, 26.4 and 3.0 nM respectively) at 5-HT1A receptors. EC50 values for agonist stimulation of [35S]-GTP gamma S binding correlated with respective Ki values at 5-HT1A receptors (r = 0.93) and the stimulation of [35S]-GTP gamma S binding by these compounds was antagonised by the selective 5-HT1A antagonist WAY 100,635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclo-hexanecarboxamide; 100 nM). These data suggest that agonism at 5-HT1A receptors may be involved in some actions of drugs used in acute antimigraine therapy. In comparison with the above compounds, novel ligands targeted at 5-HT1B/1D receptors, such as GR125,743 (N-[4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl] -3-methyl-4-(4-pyridyl)benzamide) and GR 127,935 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)-phenyl]-2'-methyl-4'-(5-m ethyl-1, 2,4-oxadiazol-3-yl)-biphenyl-4-carboxamide), only weakly activated [35S]-GTP gamma S binding (32.4 and 32.1% efficacy) and displayed moderate affinity at 5-HT1A receptors (Kis 53.1 and 49.8 nM) suggesting that they constitute useful tools to differentiate 5-HT1A and 5-HT1B/1D receptor-mediated actions. In conclusion, the present data indicates that several antimigraine agents exhibit marked 5-HT1A receptor activity and that although this is unlikely to be important for prophylactic action it may be relevant to the ancilliary properties of drugs used for acute migraine treatment.


The role of infectious agents in urogenital cancers.
Since the late 1990s, infectious agents have been thought to play a role in the pathogenesis of approximately 15% of cancers. It is now widely accepted that infection of stomach tissue with the bacteria Helicobacter pylori is an important cause of stomach adenocarcinoma. In addition, oncogenic viruses, such as papilloma viruses, herpes viruses, and hepadnaviruses are strongly associated with increased risk of cervical cancer, lymphomas, liver cancer, amongst others. However, in the scientific community the percentage of cancers caused by pathogens is believed to be far higher than 15%. A significant volume of data collected to date show an association between infectious agents and urogenital cancers. These agents include Chlamydia trachomatis, Neisseria gonorrhoea, Mycoplasma genitalium and certain viruses that have been implicated in ovarian cancer. Other pathogens include the hepatitis C and Epstein-Barr viruses, which are potentially involved in kidney cancer. In addition, infections with Schistosoma haematobium, the human papillomavirus, and human polyomaviruses are strongly associated with an increased risk of urinary bladder cancer. This article reviews publications available to date on the role of infectious agents in urogenital cancers. A greater understanding of the role of such agents could aid the identification of novel methods of urogenital cancer treatment.


Preventing cardiac diseases in childhood.
The burden of cardiac disease in childhood is unknown. It will be a sum of 1% of living births in the general population, suffering from Congenital Heart Disease (CHD) + approximately 2.5% of the general population suffering from bicuspid aortic valve diseases + an unknown higher prevalence of acquired diseases. Cardiomyopathies, arrhythmias - sudden cardiac death (SCD), rheumatic heard disease, hypertension and accelerating atherosclerosis are among the most frequent. Adding on, genetic syndromes including cardiac defects, endocarditis and myocarditis we can address a large pediatric population worldwide, suffering from heart disease. Diagnosis and treatment of these diseases are not afforded in many countries worldwide due to luck of human and material resources. The aim of this paper is to describe how some of the above mentioned diseases can be either early detected or prevented. The working Group "Cardiovascular Prevention" of the Association of European Pediatric and Congenital Cardiology (AEPC) focused on some forms of them since its formation in 2011. These areas are: 1) some forms of critical CHD, 2) sudden cardiac death linked to sport activities and 3) detecting- preventing cardio vascular diseases CVD in the young. Methods-Populations: Measurements of pre and post ductal saturation of oxygen using pulse oximeters, after the first day from birth, can early and cheaply detect critical Ductal Arteriosus dependent pulmonary or systemic and cyanotic CHD, saving lives and decreasing significantly the cost of medical care. This screening test can be applied to all neonates as late as possible after their birth and before released to their homes. A combination of detailed medical history, physical examination and 12 lead ECG, during a pre-participation in sport activities medical screening test can prevent SCD, related to a variety of nosology. This combined screening test can be applied to all children before they are exposed to school or leisure sport activities. Screening to early detect and treating existent risk factors (RF) for CVD as well as preventing obesity and hypertension, contributes in lowering the burden of CVD. Specific screening tests as laboratory measurements of lipids, fasting glucose or regular measurements of Blood Pressure and waist to hip ratio in children with a family history of CVD or other co-morbidity that provokes accelerating atherosclerosis must be done on a regular basis. Since 2010, four European studies reporting the test accuracy of routine pulse oximetry screening, in over 150.000 babies, have delivered new data. A systematic review and meta-analysis of 230.000 screened babies, reported high specificity, moderate sensitivity and a low false-positive rate. Routine screening for critical CHD using pulse oximetry is being increasingly supported and was added to the recommended uniform screening panel in the USA in 2011. Evaluating children with CHD before their involvement in sport activities, so a clear view in what they can and what they can't to is vital for their safety. For children involved in competitive or leisure sport activities, an initial evaluation and a yearly F/U is vital. In cases of near SCD events an additional thorough investigation and appropriate management is required. Investigating the severity of the existing RF and cooperating with Pediatricians in their treatment (e.g. heredity forms of hyperlipidemias, existing hypertension) of them is essential. Furthermore preventing acceleration of atherosclerosis in patients with: Diabetes Mellitus I, II, chronic renal disease, post Kawasaki disease, post heart transplantation patients, Cardio-Metabolic Syndrome patients, by eradicating RF primordially or by alternating them by opposing a healthy life style or by medicine treatment, has sown in many studies to post pone clinical events in adulthood. As many studies have proved the role of preventive measures that can alternate the outcome of cardiac diseases in childhood. AEPC/Preventive Cardiology working group is in the process to publish in the near future guidelines on this topic.


Clinical results of a cross-over treatment with pyridoxine and placebo of the carpal tunnel syndrome.
Clinical evaluation was made of cross-over treatments by pyridoxine and a placebo of patient 22 having the carpal tunnel syndrome. Extraordinary monitoring of the specific activities of the erythrocyte glutamic oxaloacetic transaminase proved a severe vitamin B6 deficiency, which was partially corrected by the Recommended Dietary Allowance of 2 mg, and completely corrected by 100 mg. The severity of the syndrome diminished on the Recommended Dietary Allowances and the patient was asymptomatic at the higher dosage. On placebo, both the vitamin B6 deficiency and syndrome reappeared. Retreatment with 100 mg again corrected both the deficiency and syndrome. Measurements (total n = 19) of flexion of proximal interphalangeal joints of the index fingers by a goniometer, and of pinch by the Preston gauge revealed objective normalization. Scores of 17 symptoms revealed reductions at both the 2- (P less than 0.01) and 100-mg (P less than 0.001) dosages. Conduction through the carpal tunnels had improved by electromyography. These and previous data on a total of 22 patients showed the concomitant presence of a deficiency of vitamin B6 and the carpal tunnel syndrome; a causal relationship is apparent.


Number of ancestral human species: a molecular perspective.
Despite the remarkable developments in molecular biology over the past three decades, anthropological genetics has had only limited impact on systematics in human evolution. Genetics offers the opportunity to objectively test taxonomies based on morphology and may be used to supplement conventional approaches to hominid systematics. Our analyses, examining chromosomes and 46 estimates of genetic distance, indicate there may have been only around 4 species on the direct line to modern humans and 5 species in total. This contrasts with current taxonomies recognising up to 23 species. The genetic proximity of humans and chimpanzees has been used to suggest these species are congeneric. Our analysis of genetic distances between them is consistent with this proposal. It is time that chimpanzees, living humans and all fossil humans be classified in Homo. The creation of new genera can no longer be a solution to the complexities of fossil morphologies. Published genetic distances between common chimpanzees and bonobos, along with evidence for interbreeding, suggest they should be assigned to a single species. The short distance between humans and chimpanzees also places a strict limit on the number of possible evolutionary 'side branches' that might be recognised on the human lineage. All fossil taxa were genetically very close to each other and likely to have been below congeneric genetic distances seen for many mammals. Our estimates of genetic divergence suggest that periods of around 2 million years are required to produce sufficient genetic distance to represent speciation. Therefore, Neanderthals and so-called H. erectus were genetically so close to contemporary H. sapiens they were unlikely to have been separate species. Thus, it is likely there was only one species of human (H. sapiens) for most of the last 2 million years. We estimate the divergence time of H. sapiens from 16 genetic distances to be around 1.7 Ma which is consistent with evidence for the earliest migration out of Africa. These findings call into question the mitochondrial "African Eve" hypothesis based on a far more recent origin for H. sapiens and show that humans did not go through a bottleneck in their recent evolutionary history. Given the large offset in evolutionary rates of molecules and morphology seen in human evolution, Homo species are likely to be characterised by high levels of morphological variation and low levels of genetic variability. Thus, molecular data suggest the limits for intraspecific morphological variation used by many palaeoanthropologists have been set too low. The role of phenotypic plasticity has been greatly underestimated in human evolution. We call into question the use of mtDNA for studies of human evolution. This DNA is under strong selection, which violates the assumption of selective neutrality. This issue should be addressed by geneticists, including a reassessment of its use for molecular clocks. There is a need for greater cooperation between palaeoanthropologists and anthropological geneticists to better understand human evolution and to bring palaeoanthropology into the mainstream of evolutionary biology.


Do South African universities provide the required training platforms for otolaryngology specialist training?
Concern exists about the quality of specialist training platforms at South African universities and teaching hospitals. We conducted an audit of the quality of training at South African otolaryngology (ENT) training institutions from the perspective of the registrars. Some institutions were deficient in terms of supervision, theatre time, access to teaching aids and research tools, and range of surgery, and do not provide the required training platforms for ENT specialist training. Five out of 8 institutions have produced <2 publications in peer-reviewed journals over the past 5 years. The HPCSA fails to adequately police the quality of training in South Africa. Training programme shortcomings must urgently be addressed to ensure proper education and training of otolaryngologists.


What is your diagnosis? Intracranial mass in a cat.
A 14-year-old female spayed cat was presented with a 3-4-month history of circling to the left and intermittent head pressing. Neurologic examination findings localized the lesion to the left supratentorial region. Using magnetic resonance imaging, an extra-axial mass was found on the dorsal aspect of the brain at the level of the frontal and parietal lobes, compressing and displacing the brain ventrally and caudally. Craniectomy was performed and the mass was submitted for cytologic and histopathologic evaluation. Impression smears revealed abundant cholesterol crystals and loose clusters of mildly pleomorphic spindle cells, compatible with a meningioma. The histopathologic diagnosis was meningioma with psammoma bodies and numerous cholesterol clefts. Abundant cholesterol crystals within meningiomas in cats may present a diagnostic challenge when nucleated cells are scant. Other differential diagnoses for abundant cholesterol crystals in an intracranial mass include cholesterol granulomas and keratinizing cysts.


Guided-wave reflectometry with micrometer resolution.
We describe a new type of optical reflectometry which is useful in testing single-mode lightguide systems. This technique uses a scanning Michelson interferometer in conjunction with a broadband illuminating source and cross-correlation detection. High resolution is achieved through the limited coherence of the backscattered radiation. With this approach it is possible to distinguish scattering centers separated by only a few micrometers. In some cases loss may be estimated for components in the transmission path of a test lightguide. The basic principles of this diagnostic technique, along with some performance characteristics, are illustrated for an all-fiber reflectometer. We also discuss several laboratory applications which serve to demonstrate the resolution capabilities of this measurement concept.


XIAP therapy increases survival of transplanted rod precursors in a degenerating host retina.
To assess the survival of rod precursor cells transplanted into the Rd9 mouse, a model of X-linked retinal degeneration, and the effect of antiapoptotic therapy with X-linked inhibitor of apoptosis (XIAP) on preventing cell loss. Dissociated retinal cells from P4 Nrlp-GFP mice were transplanted into the subretinal space of 2-, 5-, and 8-month-old Rd9 mice. Histology, immunohistochemistry, and quantification of integrated cells were performed every month for up to 3 months after transplantation. XIAP delivery to donor cells was accomplished by transfection with adenoassociated virus (AAV-XIAP). Intraretinal activation of immune modulators was assessed using a quantitative real-time polymerase chain reaction-based immune response array. GFP-positive rod precursors were able to integrate into the outer nuclear layer (ONL) of the Rd9 retina. Transplanted cells underwent morphologic differentiation with the formation of inner and outer segments and synaptic projections to bipolar cells. Integration of donor cells into the ONL increased as a function of host age at the time of transplantation. The number of integrated cells was maximal at 1 month after transplantation and then decreased with time. Survival of integrated cells was significantly increased when donor cells were pretreated with AAV-XIAP. We did not detect any donor cell-specific activation of inflammation within the host retina. Survival of integrated cells decreases with time after transplantation but can be significantly increased with XIAP antiapoptotic therapy. Preventing programmed cell death through XIAP therapy may be an important component of future therapeutic retinal cell transplantation strategies.


A scoping review of rebel nurse leadership: Descriptions, competences and stimulating/hindering factors.
To (1) give an overview of rebel nurse leadership by summarising descriptions of positive deviance, tempered radicals and healthcare rebels; (2) examine the competences of nurse rebel leadership; and (3) describe factors that stimulate or hinder the development of rebel nurse leadership. Research shows nurses have lower intention to leave their jobs when they can control their work practices, show leadership and provide the best care. However, organisational rules and regulations do not always fit the provision of good care, which challenges nurses to show leadership and deviate from the rules and regulations to benefit the patient. Three concepts describe this practice: positive deviance, healthcare rebels and tempered radicals. Scoping review using the Joanna Briggs Institute methodology and PRISMA-ScR checklist. Papers describing positive deviance, healthcare rebels and tempered radicals in nursing were identified by searching Scopus, CINAHL, PubMed and PsycINFO. After data extraction, these three concepts were analysed to study the content of descriptions and definitions, competences and stimulating and hindering factors. Of 2705 identified papers, 25 were included. The concept descriptions yielded three aspects: (1) positive deviance approach, (2) unconventional and non-confirmative behaviour and (3) relevance of networks and relationships. The competences were the ability to: (1) collaborate in/outside the organisation, (2) gain and share expert (evidence-based) knowledge, (3) critically reflect on working habits/problems in daily care and dare to challenge the status quo and (4) generate ideas to improve care. The factors that stimulate or hinder the development of rebel nurse leadership are as follows: (1) dialogue and reflection, (2) networking conditions and (3) the managers' role. Based on our analysis, we summarise the descriptions given of rebel nurse leadership, the mentioned competences and provide an overview of the factors that stimulate or hinder rebel nurse leadership. The descriptions produced in this review of rebel nurse leadership and the stimulating or hindering factors listed should help nurses and managers encourage rebel leadership.


Comparison of aortic and carotid baroreflex stimulus-response characteristics in humans.
In order to characterize the stimulus-response relationships of the arterial, aortic, and carotid baroreflexes in mediating cardiac chronotropic function, we measured heart rate (HR) responses elicited by acute changes in mean arterial pressure (MAP) and carotid sinus pressure (CSP) in 11 healthy individuals. Arterial (aortic + carotid) baroreflex control of HR was quantified using ramped changes in MAP induced by bolus injection of phenylephrine (PE) and sodium nitroprusside (SN). To assess aortic-cardiac responses, neck pressure (NP) and suction (NS) were applied during PE and SN administration, respectively, to counter alterations in CSP thereby isolating the aortic baroreflex. Graded levels of NP and NS were delivered to the carotid sinus using a customized neck collar device to assess the carotid-cardiac baroreflex, independent of drug infusion. The operating characteristics of each reflex were determined from the logistic function of the elicited HR response to the induced change in MAP. The arterial pressures at which the threshold was located on the stimulus-response curves determined for the arterial, aortic and carotid baroreflexes were not significantly different (72+/-4, 67+/-3, and 72+/-4 mm Hg, respectively, P > 0.05). Similarly, the MAP at which the saturation of the reflex responses were elicited did not differ among the baroreflex arcs examined (98+/-3, 99+/-2, and 102+/-3 mm Hg, respectively). These data suggest that the baroreceptor populations studied operate over the same range of arterial pressures. This finding indicates each baroreflex functions as both an important anti-hypotensive and anti-hypertensive mechanism. In addition, this investigation describes a model of aortic baroreflex function in normal healthy humans, which may prove useful in identifying the origin of baroreflex dysfunction in disease- and training-induced conditions.


The role of patients' meta-preferences in the design and evaluation of decision support systems.
The arrival of new analysis-based decision technologies will necessitate a profound rethinking both of the nature of the patient-doctor relationship and of the way aids and support systems designed to improve decision-making within that relationship are designed and evaluated. One-dimensional typologies of the traditional 'paternalist/shared/informed' sort do not provide the complexity called for by the heterogeneity of patient's 'meta-preferences' regarding their relationship with a doctor on the one hand and regarding the analytical level of judgement and decision-making on the other. A multidimensional matrix embodying this distinction is proposed as a framework of the minimal complexity required for the design and evaluation of the full range of decision aids and decision modes. Essentially aids should be conceived of and evaluated cell-specifically and the search for universally satisfactory decision support systems abandoned. 'shared' and'informed' are best interpreted as attributes which may or not be in line with a patient's meta-preferences. Future research should focus on the higher level goal of better decision-making, a goal that will need to respect and reflect these meta-preferences.


Sex and Gender Role Differences in Occupational Exposures and Work Outcomes Among Registered Nurses in Correctional Settings.
The correctional environment exposes registered nurses to unique occupational health hazards including, but not limited to, an increased risk for workplace violence. Gender role expectations regarding femininity and masculinity may influence occupational exposures and outcomes differently. Risk comparisons between male and female registered nurses working in correctional settings, have been minimally examined. With the proportion of male registered nurses working in corrections higher than that of nurses working in other healthcare sectors, and with the increasing number of males entering the nursing workforce in general, it is important to characterize and understand occupational exposures and outcomes of male and female registered nurses, especially those working in correctional settings. This paper aims to describe and compare sex and gender role differences in occupational exposures and work outcomes among correctional registered nurses. A cross-sectional web-based survey using Qualtrics was administered to registered nurses working in a northeastern correctional healthcare system between June and October 2016. The survey was composed of 71 items from the CPH-NEW Healthy Workplace All Employee Survey, Assessing Risk of Exposure to Blood and Airborne Pathogens and General Health Survey, Bem Sex Role Inventory-Short Form (BSRI-SF), and the Negative Acts Questionnaire-Revised. Of 95 registered nurse participants, 75% were female with the highest percentage identified as belonging to the feminine group (37%), while the highest percentage of male participants were identified as belonging to the androgynous group (33%). Females worked primarily on the first shift, while males tended to work the second and third shifts (P < 0.05). Over one third of all participants (37%) reported having experienced a sharps-related injury and having been exposed to blood-borne pathogens and body fluids within the previous 2-5 years. The majority of the participants (>95%) reported being at risk for workplace violence and having been victims of workplace violence perpetrated by an inmate. Significant gender differences (P < 0.0001) were noted in the bullying exposure with androgynous nurses having higher occasional bullying. There was a marginal difference in burnout for females (M = 6.8, SD = 2.1) and males (M = 5.8, SD = 1.9, P = 0.05). Effective interventions are needed to address the sex and gender role-based differences in bullying exposure and burnout in order to promote the overall health and well-being of correctional registered nurses.


A comparison of depression and anxiety symptom trajectories between women who had an abortion and women denied one.
This study prospectively assesses the mental health outcomes among women seeking abortions, by comparing women having later abortions with women denied abortions, up to 2 years post-abortion seeking. We present the first 2 years of a 5-year telephone interview study that is following 956 women who sought an abortion from 30 facilities throughout the USA. We use adjusted linear mixed-effects regression analyses to assess whether symptoms of depression and anxiety, as measured by the Brief Symptom Inventory-short form and the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire, differ over time among women denied an abortion due to advanced gestational age, compared with women who received abortions. Baseline predicted mean depressive symptom scores for women denied abortion (3.07) were similar to women receiving an abortion just below the gestational limit (2.86). Depressive symptoms declined over time, with no difference between groups. Initial predicted mean anxiety symptoms were higher among women denied care (2.59) than among women who had an abortion just below the gestational limit (1.91). Anxiety levels in the two groups declined and converged after 1 year. Women who received an abortion had similar or lower levels of depression and anxiety than women denied an abortion. Our findings do not support the notion that abortion is a cause of mental health problems.


Acute kidney injury.
Diagnosis and classification of acute pathology in the kidney are major clinical problems. Azotemia and oliguria represent not only disease but normal responses of the kidney to extracellular volume depletion or decreased renal blood flow. Changes in urine output and glomerular filtration rate are therefore neither necessary nor sufficient for the diagnosis of renal pathology. However, no simple alternative for the diagnosis currently exists. By examining both glomerular and tubular function, clinicians routinely make inferences not only on the presence of renal dysfunction but also on its cause. However, pure prerenal physiology is unusual in hospitalized patients, and its effects are not necessary benign. Sepsis, the most common condition associated with acute renal failure in the intensive care unit, may alter renal function without any characteristic changes in urine indices, and classification of these abnormalities as prerenal will undoubtedly lead to incorrect management decisions. The clinical syndrome known as acute tubular necrosis does not actually manifest the morphologic changes that the name implies. A precise biochemical definition of acute renal failure has never been proposed, and until recently, there has been no consensus on the diagnostic criteria or clinical definition. Depending on the definition used, acute renal failure has been reported to affect from 1% to 25% of intensive care unit patients and has led to mortality rates ranging from 15% to 60%. From this chaos, two principles emerged: first, the need for a standard definition and, second, the need to classify the severity of the syndrome rather than only consider its most severe form. The RIFLE criteria were developed to achieve these goals, and the term acute kidney injury has been proposed to encompass the entire spectrum of the syndrome, from minor changes in renal function to requirement for renal replacement therapy. Thus, acute kidney injury is not acute tubular necrosis, nor is it renal failure. Small changes in kidney function in hospitalized patients are important and are associated with significant changes in short-term and possibly long-term outcomes. The RIFLE criteria provide a uniform definition of acute kidney injury and have now been validated in numerous studies.


Spinal Cord Injury and Osteoporosis: Causes, Mechanisms, and Rehabilitation Strategies.
Spinal cord injury (SCI) has a huge impact on the individual, society and the economy. Though advances in acute care resulted in greatly reduced co-morbidities, there has been much less progress preventing long-term sequelae of SCI. Among the long-term consequences of SCI is bone loss (osteoporosis) due to the mechanical unloading of the paralyzed limbs and vascular dysfunction below the level of injury. Though osteoporosis may be partially prevented via pharmacologic interventions during the acute post-injury phase, there are no clinical guidelines to treat osteoporosis during the chronic phase. Thus there is need for scientific advances to improve the rehabilitative approaches to SCI-related osteoporosis. Recent advances in application of a new technology, functional electrical stimulation, provide a new and exciting opportunity to improve bone metabolism and to provide mechanical strain to the paralyzed lower limbs sufficient to stimulate new bone formation in individuals with SCI. The purpose of this minireview is to delineate our current understanding of SCI-related osteoporosis and to highlight recent literature towards its prevention and treatment.


sHLA-G production by human IVF embryos: can it be measured reliably?
A number of reports have demonstrated that sHLA-G can be detected in the culture medium of human IVF embryos and that levels correlate with the potential of an embryo to implant. This has aroused considerable interest in the IVF field. If sHLA-G can be used as a non-invasive marker of embryo quality, it will facilitate selection of the best embryos to transfer to the mother and thereby increase IVF pregnancy rates. However, there have been concerns about some aspects of these studies, including the sensitivity of the sHLA-G ELISAs used, the IVF culture conditions and the levels of sHLA-G which have been reported. A recent study by Sageshima et al. [J. Reprod. Immunol. 75, 11-22, 2007] attempts to address some of these concerns. However, despite using a sensitive ELISA, they were unable to detect sHLA-G in 111 embryo culture supernatants, or sHLA-G secretion by less than 10,000 sHLA-G transfected cells. They concluded that it is not possible to measure sHLA-G production by human embryos. This study has highlighted technical differences between IVF culture techniques and sHLA-G ELISAs that are currently confounding the system. Further collaboration between the research groups involved is required to establish robust reproducible systems that function identically in all laboratories.


How to use mechanistic effect models in environmental risk assessment of pesticides: Case studies and recommendations from the SETAC workshop MODELINK.
Mechanistic effect models (MEMs) are useful tools for ecological risk assessment of chemicals to complement experimentation. However, currently no recommendations exist for how to use them in risk assessments. Therefore, the Society of Environmental Toxicology and Chemistry (SETAC) MODELINK workshop aimed at providing guidance for when and how to apply MEMs in regulatory risk assessments. The workshop focused on risk assessment of plant protection products under Regulation (EC) No 1107/2009 using MEMs at the organism and population levels. Realistic applications of MEMs were demonstrated in 6 case studies covering assessments for plants, invertebrates, and vertebrates in aquatic and terrestrial habitats. From the case studies and their evaluation, 12 recommendations on the future use of MEMs were formulated, addressing the issues of how to translate specific protection goals into workable questions, how to select species and scenarios to be modeled, and where and how to fit MEMs into current and future risk assessment schemes. The most important recommendations are that protection goals should be made more quantitative; the species to be modeled must be vulnerable not only regarding toxic effects but also regarding their life history and dispersal traits; the models should be as realistic as possible for a specific risk assessment question, and the level of conservatism required for a specific risk assessment should be reached by designing appropriately conservative environmental and exposure scenarios; scenarios should include different regions of the European Union (EU) and different crops; in the long run, generic MEMs covering relevant species based on representative scenarios should be developed, which will require EU-level joint initiatives of all stakeholders involved. The main conclusion from the MODELINK workshop is that the considerable effort required for making MEMs an integral part of environmental risk assessment of pesticides is worthwhile, because it will make risk assessments not only more ecologically relevant and less uncertain but also more comprehensive, coherent, and cost effective.


Renoprotective effect of losartan in comparison to amlodipine in patients with chronic kidney disease and hypertension--a report of the Japanese Losartan Therapy Intended for the Global Renal Protection in Hypertensive Patients (JLIGHT) study.
A 12-month, multicenter (57 clinical institutions), randomized, open-labeled trial was undertaken to compare the efficacy of the angiotensin II receptor antagonist losartan and the calcium channel blocker amlodipine in patients with proteinuric chronic kidney disease (CKD) and hypertension. A total of 117 patients (79, chronic glomerulonephritis; 14, diabetic nephropathy; 24, other CKD) were randomly allocated into two treatment groups. Losartan and amlodipine exerted the same efficacy for blood pressure (BP) control; however, losartan significantly reduced the 24-h urinary protein excretion at months 3, 6, and 12, with the reduction of 20.7%, 35.2%, 35.8%, whereas amlodipine did not change the amount of proteinuria over the 12-month study period. When patients were stratified into groups according to the level of BP control at 3 months, the reduction in urinary protein excretion by losartan was evident in the group for which a BP of <140/90 mmHg was achieved, as well as in the group for which the goal BP (<130/85 mmHg) for treatment of CKD was not achieved. When patients were stratified according to baseline urinary protein excretion, those with > or = 2 g/day showed a reduction in proteinuria by losartan of 23.3%, 39.4%, and 47.9% at months 3, 6, and 12, and those with <2 g/day showed a reduction of 18.5% and 31.2% at months 3 and 6, respectively. No fatal adverse events were experienced in either drug group. We conclude that losartan reduced proteinuria in patients with CKD and hypertension. This positive effect may contribute to the renal protective benefit of losartan, and is beyond the magnitude of BP control.


Maternal secure base scripts, children's attachment security, and mother-child narrative styles.
This paper reports the results of a study examining links between maternal representations of attachment, child attachment security, and mother and child narrative styles assessed in the context of reminiscences about shared experiences. Participants were 90 mother - child dyads. Child attachment security was assessed using the attachment Q-set and maternal attachment representations were measured using a recently designed instrument that assesses the script-like qualities of those representations. Analyses examined dependencies in the mother - child memory talk data and then assessed the overlap between both mother and child reminiscing styles and the attachment variables. Narrative styles of both the mothers and their children were coherent and consistent for each dyad member. Furthermore, maternal narrative style (e.g., specific and elaborative questions, using confirming evaluation comments) was significantly related to child participation in the narrative. Maternal and child attachment variables were positively and significantly correlated, and child security was positively associated with maternal narrative style. Maternal secure base scripts were also found to be significantly related to the number of references to emotions in both mother and child narratives as well as to children's overall participation in the memory talk. The pattern of results suggests that attachment representations serve as one influence on the manner(s) in which mother - child dyads think about and discuss emotion-laden content relevant to the child's personal autobiography. Furthermore, the results are consistent with the notion that the manner in which children organize their thoughts about emotion are (at least potentially) shaped by the narrative styles of their parents.


Predicting human height by Victorian and genomic methods.
In the Victorian era, Sir Francis Galton showed that 'when dealing with the transmission of stature from parents to children, the average height of the two parents, ... is all we need care to know about them' (1886). One hundred and twenty-two years after Galton's work was published, 54 loci showing strong statistical evidence for association to human height were described, providing us with potential genomic means of human height prediction. In a population-based study of 5748 people, we find that a 54-loci genomic profile explained 4-6% of the sex- and age-adjusted height variance, and had limited ability to discriminate tall/short people, as characterized by the area under the receiver-operating characteristic curve (AUC). In a family-based study of 550 people, with both parents having height measurements, we find that the Galtonian mid-parental prediction method explained 40% of the sex- and age-adjusted height variance, and showed high discriminative accuracy. We have also explored how much variance a genomic profile should explain to reach certain AUC values. For highly heritable traits such as height, we conclude that in applications in which parental phenotypic information is available (eg, medicine), the Victorian Galton's method will long stay unsurpassed, in terms of both discriminative accuracy and costs. For less heritable traits, and in situations in which parental information is not available (eg, forensics), genomic methods may provide an alternative, given that the variants determining an essential proportion of the trait's variation can be identified.


Cepharanthin enhances adriamycin sensitivity by synergistically accelerating apoptosis for adriamycin-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR.
Cepharanthin (CEP) is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. CEP is reported to inhibit drug resistance by inhibiting P-glycoprotein, a drug efflux pump, and recently to induce apoptosis. In the present study, we examined the effects of CEP as an inhibitor of adriamycin (ADR) resistance on ADR-induced apoptosis and necrosis. First, we established p53-deficient ADR-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR. Resistant cells showed a higher level of intracellular glutathione peroxidase activity than parent cells. P-glycoprotein was overexpressed in resistant cells. The intracellular ADR level of resistant cells was lower than that of parent cells. One micro g/ml CEP eliminated the degradation of intracellular ADR of resistant cells; that is, to a level equivalent to that of the parent cells. CEP of 0.5 micro g/ml, which was not cytotoxic when used alone, significantly increased the ADR sensitivity of resistant cells, to a level similar to the parent cell level. Isosorbide 5-mononitrate, a potential nitric oxide-generation agent, combined with CEP further increased the ADR sensitivity of resistant cells, indicating a synergistic effect of CEP and isosorbide 5-mononitrate on ADR cytotoxicity. Time-lapse microscopic observation revealed that ADR dominantly induced apoptosis much more than necrosis for both parent and resistant cells, and that the use of 0.5 micro g/ml CEP with ADR synergistically accelerated apoptosis in resistant cells. Finally, we clarified the property by which CEP synergistically accelerates ADR-induced apoptosis. This property might be a new mechanism that explains how CEP overcomes ADR resistance.


Catalytic Asymmetric Cyclocarbonylation of Nitrogen-Containing Enynes.
The asymmetric Pauson-Khand type cyclization of nitrogen-containing enynes using carbon monoxide and a catalytic amount of (EBTHI)TiMe(2) was examined. The influence of the nitrogen substituent and the concentration of the catalyst on the enantioselectivity of this cyclization was explored, and it has been found that enynes with an octyl-, benzyl-, or allylamino group, positioned beta to the alkyne and the olefin, are cyclized with a high degree of enantioselectivity. Substrates with either bulky and/or electron-withdrawing nitrogen substituents are converted to products in low to moderate enantioselectivity.


Detection of lung, breast, colorectal, and prostate cancers from exhaled breath using a single array of nanosensors.
Tumour growth is accompanied by gene and/or protein changes that may lead to peroxidation of the cell membrane species and, hence, to the emission of volatile organic compounds (VOCs). In this study, we investigated the ability of a nanosensor array to discriminate between breath VOCs that characterise healthy states and the most widespread cancer states in the developed world: lung, breast, colorectal, and prostate cancers. Exhaled alveolar breath was collected from 177 volunteers aged 20-75 years (patients with lung, colon, breast, and prostate cancers and healthy controls). Breath from cancerous subjects was collected before any treatment. The healthy population was healthy according to subjective patient's data. The breath of volunteers was examined by a tailor-made array of cross-reactive nanosensors based on organically functionalised gold nanoparticles and gas chromatography linked to the mass spectrometry technique (GC-MS). The results showed that the nanosensor array could differentiate between 'healthy' and 'cancerous' breath, and, furthermore, between the breath of patients having different cancer types. Moreover, the nanosensor array could distinguish between the breath patterns of different cancers in the same statistical analysis, irrespective of age, gender, lifestyle, and other confounding factors. The GC-MS results showed that each cancer could have a unique pattern of VOCs, when compared with healthy states, but not when compared with other cancer types. The reported results could lead to the development of an inexpensive, easy-to-use, portable, non-invasive tool that overcomes many of the deficiencies associated with the currently available diagnostic methods for cancer.


Spontaneous production and use of mnemonic strategies in older adults.
Mnemonic strategy use in older adults has been measured a number of ways, and although strategy measurement has received considerable attention, little work has been done to compare various types of subjective strategy reporting. The authors compared self-generated and endorsed strategies for memory tasks in a sample of 85 African-American and Caucasian older adults and investigated demographic characteristics related to each strategy measurement and the relationship between strategy use and memory performance. Across memory measures, significantly more strategies were endorsed than self-generated. Race, favoring Caucasians, was the most salient demographic predictor of mnemonic strategy usage. Although strategic behavior was associated with ability performance on most memory measures, specific strategies for optimal performance were identified for number and story recall only. Findings highlight the importance of measuring both self-generated and endorsed strategies and confirm previous work on the relationship between strategy use and memory performance.


Bacterial contamination of health care workers' white coats.
Patient-to-patient transmission of nosocomial pathogens has been linked to transient colonization of health care workers, and studies have suggested that contamination of health care workers' clothing, including white coats, may be a vector for this transmission. We performed a cross-sectional study involving attendees of medical and surgical grand rounds at a large teaching hospital to investigate the prevalence of contamination of white coats with important nosocomial pathogens, such as methicillin-sensitive Stapylococcus aureus, methicillin-resistant S aureus (MRSA), and vancomycin-resistant enterococci (VRE). Each participant completed a brief survey and cultured his or her white coat using a moistened culture swab on lapels, pockets, and cuffs. Among the 149 grand rounds attendees' white coats, 34 (23%) were contaminated with S aureus, of which 6 (18%) were MRSA. None of the coats was contaminated with VRE. S aureus contamination was more prevalent in residents, those working in inpatient settings, and those who saw an inpatient that day. This study suggests that a large proportion of health care workers' white coats may be contaminated with S aureus, including MRSA. White coats may be an important vector for patient-to-patient transmission of S aureus.


Forensic Epidemiology in Italy: principles and practice.
Forensic epidemiology (FE) implies the use of epidemiological data in the processes and the involvement of epidemiologists in judicial proceedings. FE is essential for the assessment of causal association between the exposure to specific agents and the occurrence of diseases. In this paper we describe FE principles and applications in the Italian context as in recent years FE emerged increasingly as well as the need of experienced and trained epidemiological experts able to navigate legal proceedings. In the literature, the principles of FE have been widely described by different authors, among them: Kennet Rothman who introduced the definition of cause, Sir Austin Bradford Hill who proposed an analytic framework to assess the causal association, and recently by Sana Loue who described the actual legislation and application of FE in the United States. Despite the legislation varies among different countries epidemiological methods and theories represent the foundation for the application of FE we illustrate in this paper. The association between environmental pollution and disease, mobile phones and cancer, vaccines and autism, asbestos and pleural mesothelioma are all situations that underscore the need for FE investigations in criminal acts. Causal association is a complex process: in real life only in limited cases causal associations are assessed by gathering robust scientific evidence, while cases with doubts and situations where different approaches to questions may lead to discordant arguments to questions may lead to discordant arguments are more frequent. Therefore, during the assessment of causation in civil and criminal matters the choice the epidemiological expert - with his knowledge and expertise - and the evidence from well-designed studies are crucial to fill the gaps between clinical and epidemiological data and the low.


Minimum sample size for external validation of a clinical prediction model with a binary outcome.
In prediction model research, external validation is needed to examine an existing model's performance using data independent to that for model development. Current external validation studies often suffer from small sample sizes and consequently imprecise predictive performance estimates. To address this, we propose how to determine the minimum sample size needed for a new external validation study of a prediction model for a binary outcome. Our calculations aim to precisely estimate calibration (Observed/Expected and calibration slope), discrimination (C-statistic), and clinical utility (net benefit). For each measure, we propose closed-form and iterative solutions for calculating the minimum sample size required. These require specifying: (i) target SEs (confidence interval widths) for each estimate of interest, (ii) the anticipated outcome event proportion in the validation population, (iii) the prediction model's anticipated (mis)calibration and variance of linear predictor values in the validation population, and (iv) potential risk thresholds for clinical decision-making. The calculations can also be used to inform whether the sample size of an existing (already collected) dataset is adequate for external validation. We illustrate our proposal for external validation of a prediction model for mechanical heart valve failure with an expected outcome event proportion of 0.018. Calculations suggest at least 9835 participants (177 events) are required to precisely estimate the calibration and discrimination measures, with this number driven by the calibration slope criterion, which we anticipate will often be the case. Also, 6443 participants (116 events) are required to precisely estimate net benefit at a risk threshold of 8%. Software code is provided.


Ask, speak up, and be proactive: Empowering patient infection control to prevent health care-acquired infections.
Over the last decade, there has been a slow shift toward the more active engagement of patients and families in preventing health care-associated infections (HCAIs). This pilot study aimed to examine the receptiveness of hospital patients toward a new empowerment tool aimed at increasing awareness and engagement of patients in preventing HCAI. Patients from the surgical department were recruited and randomized into 2 groups: active and control. Patients in the active arm were given an empowerment tool, whereas control patients continued with normal practices. Pre- and postsurveys were administered. At the baseline survey, just over half of the participants were highly willing to assist with infection control strategies. Participants were significantly more likely to be willing to ask a doctor or nurse a factual question then a challenging question. After discharge, 23 of the 60 patients reported discussing a health concern with a staff member; however, only 3 participants asked a staff member to wash their hands. Our results suggest that patients would like to be more informed about HCAIs and are willing to engage with staff members to assist with the prevention of infections while in the hospital setting. Further work is going to need to be undertaken to ascertain the best strategies to promote engagement and participation in infection control activities.


Gleason drift in the NIHR ProtecT study.
There is increasing evidence of Gleason score (GS) drift in prostatic core biopsies during the last two decades. The ProtecT study is a randomized controlled study and provides an excellent cohort to study the effect of time, prostate-specific antigen (PSA) level, perineural invasion, tumour length and age on GS. The ProtecT study recruited men in the United Kingdom between 1999 and 2010. The Gleason scores were grouped into four categories ≤ 3 + 3, 3 + 4, 4 + 3 and ≥ 4 + 4 for analysis. Data from England between 2000 and 2012 were also available. A total of 3282 biopsies containing cancer were analysed. For each year of the ProtecT study, the odds of being diagnosed with a higher GS category increased by 4.9%. Higher GS was also associated with perineural invasion, increasing tumour length, age and PSA level. While biopsy GS from England was incomplete, it also showed a marked decrease in GS five and six tumours during the same period. There was GS drift from 3 + 3 to 3 + 4 with time in the ProtecT study, but there appeared to be no significant change in percentage of GS 4 + 3 or higher. This drift was less dramatic when compared to GS in the rest of England.


A Cervical Smear Scare due to Monsel's Solution: A Case Report.
Monsel's solution has been in use since the end of the 19th century for its valuable property of creating hemostasis in minor disruptions of the epithelium. Its styptic effect was first described by Leon Monsel, a pharmacist in the French army, in a letter dated on October 13, 1852. Containing ferric subsulphate, it is used as a topical hemostatic agent in minor procedures such as biopsies in gynecology, proctology, dermatology, otorhinolaryngology and odontology. A 28-year-old nulliparous woman, with a known history of adenomyosis, had presented for sudden heavy intermenstrual vaginal bleeding. Examination revealed a bleeding Nabothian cyst. Monsel's solution application helped stop the bleeding. She returned 3 days later with persistent heavy vaginal bleeding. Examination showed active oozing from the Nabothian cyst. A cervical smear and a human papillomavirus (HPV) swab were taken, and vaginal packing was inserted. The cervical smear result was reported as atypical cells, suspicious for malignancy. Colposcopy performed showed a grade 2 acetowhite lesion, suspicious for cervical intraepithelial neoplasia (CIN) III/microinvasive disease. However, punch biopsies of the cervix revealed only CIN I/koilocytosis. The patient was counselled and subsequently underwent a laser cone biopsy, which showed CIN I with clear margins. The discrepant results between the cervical smear and the cone biopsy prompted a review of the cervical smear and cervical histology; and a relook at the chronology of events. The cytological features observed in the initial cervical smear could be explained by the interference from the Monsel's solution, which was applied just 3 days before the cervical smear. In cases where Monsel's solution has been used for hemostasis, it is best to delay taking a cervical smear or a biopsy for at least 3 weeks as the histologic effect of Monsel's solution may persist for up to that duration of time in tissues.


The US Supplemental Nutrition Assistance Program - Education improves nutrition-related behaviors.
The aim of this study was to measure whether participating in Supplemental Nutrition Assistance Program - Education (SNAP-Ed) interventions is associated with changes in meeting recommendations for healthy eating and food resource management behaviours, such as shopping, among low-income children, adolescents, and adults in eight states in the US Southeast. The study used a one-group pre-test post-test design, analysing aggregate data on nutrition and shopping behaviours collected during Federal Fiscal Year 17 from SNAP-Ed direct education in community settings. Twenty-five implementing agencies in Alabama, Florida, Georgia, Kentucky, Mississippi, North Carolina, South Carolina, and Tennessee provided aggregated data on program participants. Because survey questions differed, agencies followed standard recoding guidelines. The number of participants varied depending on the indicator; the maximum number was n 43 303 pre-tests, n 43 256 post-test. Participants were significantly more likely to consume more than one kind of fruit (pooled relative risk (RR), 1⋅10; 95% confidence interval (CI), 1⋅09-1⋅11) and more than one kind of vegetable (pooled RR, 1⋅14; 95% CI, 1⋅12-1⋅15) after the intervention than before. On average, participants consumed 0⋅34 cups more of fruit per day (95% CI, 0⋅31-0⋅37), and 0⋅22 cups more of vegetables per day (95% CI, 0⋅19-0⋅25) after the intervention, compared to before. About 701 policy, systems, and environmental changes for nutrition supports were reported. This study suggests that SNAP-Ed direct education is associated with positive behaviour changes in the US Southeast. It provides a methodology that can inform data aggregation efforts across unique SNAP-Ed programs or other similar nutrition education programs to report on the collective impact.


Simian and human immunodeficiency virus Nef proteins use different surfaces to downregulate class I major histocompatibility complex antigen expression.
Simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) Nef proteins are related regulatory proteins that share several functions, including the ability to downregulate class I major histocompatibility complex (MHC) and CD4 expression on the cell surface and to alter T-cell-receptor-initiated signal transduction in T cells. We compared the mechanisms used by SIV mac239 Nef and HIV-1 Nef to downregulate class I MHC and found that the ability of SIV Nef to downregulate class I MHC requires a unique C-terminal region of the SIV mac239 Nef molecule which is not found in HIV-1 Nef. Interestingly, mutation of the PxxP motif in SIV Nef, unlike in HIV-1 Nef, does not affect class I MHC downregulation. We also found that downregulation of class I MHC by SIV Nef requires a conserved tyrosine in the cytoplasmic domain of the class I MHC heavy chain and involves accelerated endocytosis of class I complexes, as previously found with HIV-1 Nef. Thus, while SIV and HIV-1 Nef proteins use a similar mechanism to downregulate class I MHC expression, they have evolved different surfaces for molecular interactions with cell factors that regulate class I MHC traffic. Mutations in the C-terminal domain of SIV mac239 Nef selectively disrupt class I MHC downregulation, having no detectable effect on other functions of Nef, such as the downregulation of CD4 and CD3 surface expression, the stimulation of SIV virion infectivity, and the induction of SIV replication from T cells infected in the absence of stimulation. The resulting mutants will be useful reagents for studying the importance of class I MHC downregulation for SIV replication and AIDS pathogenesis in infected rhesus macaques.


Grip force modulation characteristics as a marker for clinical disease progression in individuals with Parkinson disease: case-control study.
Upper extremity deficits are prevalent in individuals with Parkinson disease (PD). In the early stages of PD, such deficits can be subtle and challenging to document on clinical examination. The purpose of this study was to use a novel force sensor system to characterize grip force modulation, including force, temporal, and movement quality parameters, during a fine motor control task in individuals with early stage PD. A case-control study was conducted. Fourteen individuals with early stage PD were compared with a control group of 14 healthy older adults. The relationship of force modulation parameters with motor symptom severity and disease chronicity also was assessed in people with PD. Force was measured during both precision and power grasp tasks using an instrumented twist-cap device capable of rotating in either direction. Compared with the control group, the PD group demonstrated more movement arrests during both precision and power grasp and longer total movement times during the power grasp. These deficits persisted when a concurrent cognitive task was added, with some evidence of force control deficits in the PD group, including lower rates of force production during the precision grasp task and higher peak forces during the power grasp task. For precision grasp, a higher number of movement arrests in single- and dual-task conditions as well as longer total movement times in the dual-task condition were associated with more severe motor symptoms. The sample was small and consisted of individuals in the early stages of PD with mild motor deficits. The group with PD was predominantly male, whereas the control group was predominantly female. The results suggest that assessing grip force modulation deficits during fine motor tasks is possible with instrumented devices, and such sensitive measures may be important for detecting and tracking change early in the progression of PD.


Type-d personality can predict suicidality in patients with major depressive disorder.
This study investigated the putative association between type-D personality and suicidality, including the history of suicide attempt and suicidal ideation in patients with major depressive disorder (MDD). Eighty-six outpatients aged between 18 and 65 years with MDD were recruited for this study from Ilsan Paik Hospital. The cohort was stratified into two subgroups according to the presence of type-D personality and history of suicide attempt (yes vs. no). Depression severity was evaluated using the Hamilton Depression Rating Scale. The type-D Personality Scale-14 (DS-14), the Beck Hopelessness Scale (BHS), the Barratt Impulsiveness Scale (BIS), the Hamilton Anxiety Scale, and the Beck Scale for Suicidal Ideation (BSS) were also applied. The total BSS, BHS, and BIS scores were higher for the group with type-D personality than for the group without this personality (p=0.004, 0.01, and 0.003, respectively). In addition, the total scores for the BSS, BHS, and social inhibition (SI; subscale of DS-14) were higher for the group with a history of suicide attempt than for the group without this history (p=0.0000004, 0.003, and 0.033, respectively). There were positive correlations between the total DS-14 score and the total BSS, BHS, and BIS scores (r=0.413 and p=0.000077, r=0.404 and p=0.00012, and r=0.245 and p=0.024, respectively). Depressed patients with type-D personality are more vulnerable to suicidality than those without type-D personality, even when the MDD severity is identical. In addition, the SI score was higher in patients with a history of suicide attempt than in those without this history.


Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer.
Recent insights into the regulation of the androgen receptor (AR) activity led to novel therapeutic targeting of AR function in prostate cancer patients. Docetaxel is an approved chemotherapy for treatment of castration-resistant prostate cancer; however, the mechanism underlying the action of this tubulin-targeting drug is not fully understood. This study investigates the contribution of microtubules and the cytoskeleton to androgen-mediated signaling and the consequences of their inhibition on AR activity in human prostate cancer. Tissue microarrays from docetaxel-treated and untreated prostate cancer patients were comparatively analyzed for prostate-specific antigen (PSA) and AR immunoreactivity. The AR transcriptional activity was determined in prostate cancer cells in vitro, based on PSA mRNA expression and the androgen response element reporter activity. The interaction of AR with tubulin was examined by immunoprecipitation and immunofluorescence. Treatment of prostate cancer patients with docetaxel led to a significant translocation of AR. In untreated specimens, 50% prostate tumor cells exhibited nuclear accumulation of AR, compared with docetaxel-treated tumors that had significantly depleted nuclear AR (38%), paralleled by an increase in cytosolic AR. AR nuclear localization correlated with PSA expression. In vitro, exposure of prostate cancer cells to paclitaxel (1 μmol/L) or nocodazole (5 μg/mL) inhibited androgen-dependent AR nuclear translocation by targeting AR association with tubulin. Introduction of a truncated AR indicated the requirement of the NH(2)-terminal domain for AR-tubulin interaction. Our findings show that in addition to blocking cell division, docetaxel impairs AR signaling, evidence that enables new insights into the therapeutic efficacy of microtubule-targeting drugs in prostate cancer.


Maca (L. meyenii) for improving sexual function: a systematic review.
Maca (Lepidium meyenii) is an Andean plant of the brassica (mustard) family. Preparations from maca root have been reported to improve sexual function. The aim of this review was to assess the clinical evidence for or against the effectiveness of the maca plant as a treatment for sexual dysfunction. We searched 17 databases from their inception to April 2010 and included all randomised clinical trials (RCTs) of any type of maca compared to a placebo for the treatment of healthy people or human patients with sexual dysfunction. The risk of bias for each study was assessed using Cochrane criteria, and statistical pooling of data was performed where possible. The selection of studies, data extraction, and validations were performed independently by two authors. Discrepancies were resolved through discussion by the two authors. Four RCTs met all the inclusion criteria. Two RCTs suggested a significant positive effect of maca on sexual dysfunction or sexual desire in healthy menopausal women or healthy adult men, respectively, while the other RCT failed to show any effects in healthy cyclists. The further RCT assessed the effects of maca in patients with erectile dysfunction using the International Index of Erectile Dysfunction-5 and showed significant effects. The results of our systematic review provide limited evidence for the effectiveness of maca in improving sexual function. However, the total number of trials, the total sample size, and the average methodological quality of the primary studies were too limited to draw firm conclusions. More rigorous studies are warranted.