Evoked responses to rhythmic visual stimulation vary across sources of intrinsic alpha activity in humans.

Rhythmic flickering visual stimulation produces steady-state visually evoked potentials (SSVEPs) in electroencephalogram (EEG) recordings. Based on electrode-level analyses, two dichotomous models of the underpinning mechanisms leading to SSVEP generation have been proposed: entrainment or superposition, i.e., phase-alignment or independence of endogenous brain oscillations from flicker-induced oscillations, respectively. Electrode-level analyses, however, represent an averaged view of underlying 'source-level' activity, at which variability in SSVEPs may lie, possibly suggesting the co-existence of multiple mechanisms. To probe this idea, we investigated the variability of SSVEPs derived from the sources underpinning scalp EEG responses during presentation of a flickering radial checkerboard. Flicker was presented between 6 and 12 Hz in 1 Hz steps, and at individual alpha frequency (IAF i.e., the dominant frequency of endogenous alpha oscillatory activity). We tested whether sources of endogenous alpha activity could be dissociated according to evoked responses to different flicker frequencies relative to IAF. Occipitoparietal sources were identified by temporal independent component analysis, maximal resting-state alpha power at IAF and source localisation. The pattern of SSVEPs to rhythmic flicker relative to IAF was estimated by correlation coefficients, describing the correlation between the peak-to-peak amplitude of the SSVEP and the absolute distance of the flicker frequency from IAF across flicker conditions. We observed extreme variability in correlation coefficients across sources, ranging from -0.84 to 0.93, with sources showing largely different coefficients co-existing within subjects. This result demonstrates variation in evoked responses to flicker across sources of endogenous alpha oscillatory activity. Data support the idea of multiple SSVEP mechanisms.

Sleep disordered breathing in patients receiving therapy with buprenorphine/naloxone.

Patients using chronic opioids are at risk for exceptionally complex and potentially lethal disorders of breathing during sleep, including central and obstructive apnoeas, hypopnoeas, ataxic breathing and nonapnoeic hypoxaemia. Buprenorphine, a partial µ-opioid agonist with limited respiratory toxicity, is widely used for the treatment of opioid dependency and chronic nonmalignant pain. However, its potential for causing sleep disordered breathing has not been studied. 70 consecutive patients admitted for therapy with buprenorphine/naloxone were routinely evaluated with sleep medicine consultation and attended polysomnography. The majority of patients were young (mean±sd age 31.8±12.3 years), nonobese (mean±sd body mass index 24.9±5.9 kg·m(-2)) and female (60%). Based upon the apnoea/hypopnoea index (AHI), at least mild sleep disordered breathing (AHI ≥5 events·h(-1)) was present in 63% of the group. Moderate (AHI ≥15- <30 events·h(-1)) and severe (AHI ≥30 events·h(-1)) sleep apnoea was present in 16% and 17%, respectively. Hypoxaemia, defined as an arterial oxygen saturation measured by pulse oximetry, of <90% for ≥10% of sleep time, was present in 27 (38.6%) patients. Despite the putative protective ceiling effect regarding ventilatory suppression observed during wakefulness, buprenorphine may induce significant alterations of breathing during sleep at routine therapeutic doses.

Health benefits of gastric bypass surgery after 6 years.

CONTEXT: Extreme obesity is associated with health and cardiovascular disease risks. Although gastric bypass surgery induces rapid weight loss and ameliorates many of these risks in the short term, long-term outcomes are uncertain. OBJECTIVE: To examine the association of Roux-en-Y gastric bypass (RYGB) surgery with weight loss, diabetes mellitus, and other health risks 6 years after surgery. DESIGN, SETTING, AND PARTICIPANTS: A prospective Utah-based study conducted between July 2000 and June 2011 of 1156 severely obese (body mass index [BMI] ≥ 35) participants aged 18 to 72 years (82% women; mean BMI, 45.9; 95% CI, 31.2-60.6) who sought and received RYGB surgery (n = 418), sought but did not have surgery (n = 417; control group 1), or who were randomly selected from a population-based sample not seeking weight loss surgery (n = 321; control group 2). MAIN OUTCOME MEASURES: Weight loss, diabetes, hypertension, dyslipidemia, and health-related quality of life were compared between participants having RYGB surgery and control participants using propensity score adjustment. RESULTS: Six years after surgery, patients who received RYGB surgery (with 92.6% follow-up) lost 27.7% (95% CI, 26.6%-28.9%) of their initial body weight compared with 0.2% (95% CI, -1.1% to 1.4%) gain in control group 1 and 0% (95% CI, -1.2% to 1.2%) in control group 2. Weight loss maintenance was superior in patients who received RYGB surgery, with 94% (95% CI, 92%-96%) and 76% (95% CI, 72%-81%) of patients receiving RYGB surgery maintaining at least 20% weight loss 2 and 6 years after surgery, respectively. Diabetes remission rates 6 years after surgery were 62% (95% CI, 49%-75%) in the RYGB surgery group, 8% (95% CI, 0%-16%) in control group 1, and 6% (95% CI, 0%-13%) in control group 2, with remission odds ratios (ORs) of 16.5 (95% CI, 4.7-57.6; P < .001) vs control group 1 and 21.5 (95% CI, 5.4-85.6; P < .001) vs control group 2. The incidence of diabetes throughout the course of the study was reduced after RYGB surgery (2%; 95% CI, 0%-4%; vs 17%; 95% CI, 10%-24%; OR, 0.11; 95% CI, 0.04-0.34 compared with control group 1 and 15%; 95% CI, 9%-21%; OR, 0.21; 95% CI, 0.06-0.67 compared with control group 2; both P < .001). The numbers of participants with bariatric surgery-related hospitalizations were 33 (7.9%), 13 (3.9%), and 6 (2.0%) for the RYGB surgery group and 2 control groups, respectively. CONCLUSION: Among severely obese patients, compared with nonsurgical control patients, the use of RYGB surgery was associated with higher rates of diabetes remission and lower risk of cardiovascular and other health outcomes over 6 years.

ERK5 signalling in prostate cancer promotes an invasive phenotype.

BACKGROUND: Aberrant mitogen/extracellular signal-regulated kinase 5 (MEK5)-extracellular signal-regulated protein kinase 5 (ERK5)-mediated signalling has been implicated in a number of tumour types including prostate cancer (PCa). The molecular basis of ERK5-driven carcinogenesis and its clinical relevance remain to be fully characterised. METHODS: Modulation of ERK5 expression or function in human PCa PC3 and PC3-ERK5 (stably transfected with ERK5) cells was performed using siRNA-mediated knockdown or the MEK inhibitor PD18435 respectively. In vitro significance of ERK5 signalling was assessed by assays for proliferation, motility, invasion and invadopodia. Expression of matrix metalloproteinases/tissue inhibitors of metalloproteases was determined by Q-RT-PCR. Extracellular signal-regulated protein kinase 5 expression in primary and metastatic PCa was examined using immunohistochemistry. RESULTS: Reduction of ERK5 expression or signalling significantly inhibited the motility and invasive capability of PC3 cells. Extracellular signal-regulated protein kinase 5-mediated signalling significantly promoted formation of in vivo metastasis in an orthotopic PCa model (P<0.05). Invadopodia formation was also enhanced by forced ERK5 expression in PC3 cells. Furthermore, in metastatic PCa, nuclear ERK5 immunoreactivity was significantly upregulated when compared with benign prostatic hyperplasia and primary PCa (P=0.013 and P<0.0001, respectively). CONCLUSION: Our in vitro, in vivo and clinical data support an important role for the MEK5-ERK5 signalling pathway in invasive PCa, which represents a potential target for therapy in primary and metastatic PCa.

Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues.

Extracellular proteases of the matrix metalloproteinase (MMP) and serine protease families participate in many aspects of tumour growth and metastasis. Using quantitative real-time RT-PCR analysis, we have undertaken a comprehensive survey of the expression of these enzymes and of their natural inhibitors in 44 cases of human prostate cancer and 23 benign prostate specimens. We found increased expression of MMP10, 15, 24, 25 and 26, urokinase plasminogen activator-receptor (uPAR) and plasminogen activator inhibitor-1 (PAI1), and the newly characterised serine proteases hepsin and matriptase-1 (MTSP1) in malignant tissue compared to benign prostate tissue. In contrast, there was significantly decreased expression of MMP2 and MMP23, maspin, and the protease inhibitors tissue inhibitor of metalloproteinase 3 (TIMP3), TIMP4 and RECK (reversion-inducing cysteine-rich protein with Kazal motifs) in the cancer specimens. The expression of MMP15 and MMP26 correlated positively with Gleason score, whereas TIMP3, TIMP4 and RECK expression correlated negatively with Gleason score. The cellular localisation of the expression of the deregulated genes was evaluated using primary malignant epithelial and stromal cell cultures derived from radical prostatectomy specimens. MMP10 and 25, hepsin, MTSP1 and maspin showed predominantly epithelial expression, whereas TIMP 3 and 4, RECK, MMP2 and 23, uPAR and PAI1 were produced primarily by stromal cells. These data provide the first comprehensive and quantitative analysis of the expression and localisation of MMPs and their inhibitors in human prostate cancer, leading to the identification of several genes involved in proteolysis as potential prognostic indicators, in particular hepsin, MTSP1, MMP26, PAI1, uPAR, MMP15, TIMP3, TIMP4, maspin and RECK.

Proteases in brain tumour progression.

Local invasion of tumour cells is characteristic of brain tumour progression. It is associated with increased motility and a potential to hydrolyse macromolecular components of the extracellular matrix. The peptidases that have been most investigated, and are induced during this process, are reviewed: the plasminogen activators (PAs), matrix metalloproteinases (MMPs) and lysosomal cysteine peptidases called cathepsins (Cats). Increased levels of urokinase-type PA (uPA) are observed mainly at the invasive margins of a tumour, whereas the data on the expression of tissue-type PA (tPA) are still controversial. It has been shown that the endogenous inhibitor of PAs, PAI-1, is localised in both tumour and tumour-associated endothelial cells. Among MMPs, the expression of the gelatinases, MMP2 and MMP9, strongly correlates with glioma progression. Membrane bound MT-MMPs, in particular MT1- and MT2-MMP, seem to play a major role in activating MMP-2. Several members of the ADAMTS family have also been detected in brain tumours, the most relevant being ADAMTS4, due to its cleavage of CNS specific proteins. Lysosomal cathepsin B is highly expressed in malignant glial cells and in endothelial cells of vascularised glioblastomas and is a predictor of a shorter survival. In addition to invasion, cathepsin L may play a role in decreased susceptibility of anaplastic glioma cells to apoptosis. Finally, cathepsin B was proposed as a marker for malignancy in the more aggressive type of meningiomas. Each of these peptidases may act alone, or in concert with the others, to support malignant behaviour of brain tumour cells; the development of new inhibitors of invasion, therefore, should contribute to the control of local spread of a tumour.

An evaluation of the performance of cDNA microarrays for detecting changes in global mRNA expression.

The cDNA microarray is one technological approach that has the potential to accurately measure changes in global mRNA expression levels. We report an assessment of an optimized cDNA microarray platform to generate accurate, precise and reliable data consistent with the objective of using microarrays as an acquisition platform to populate gene expression databases. The study design consisted of two independent evaluations with 70 arrays from two different manufactured lots and used three human tissue sources as samples: placenta, brain and heart. Overall signal response was linear over three orders of magnitude and the sensitivity for any element was estimated to be 2 pg mRNA. The calculated coefficient of variation for differential expression for all non-differentiated elements was 12-14% across the entire signal range and did not vary with array batch or tissue source. The minimum detectable fold change for differential expression was 1.4. Accuracy, in terms of bias (observed minus expected differential expression ratio), was less than 1 part in 10 000 for all non-differentiated elements. The results presented in this report demonstrate the reproducible performance of the cDNA microarray technology platform and the methods provide a useful framework for evaluating other technologies that monitor changes in global mRNA expression.

Experienced obstetric nurses' decision-making in fetal risk situations.

OBJECTIVE: To determine which clinical factors experienced obstetric nurses consider most important in determining fetal risk during the intrapartum period. DESIGN: Ten dichotomized variables relevant to participants' clinical decision-making were manipulated in fractional factorial vignettes. Participants were asked to rate the severity of fetal risk on a Likert scale after reading the vignettes. SETTING: About 87% of the participants worked in institutions with 4,000 or fewer deliveries per year. More than 25% worked in tertiary level facilities, and the remainder were employed in primary or secondary level facilities. PARTICIPANTS: Participants (N = 573), randomly selected from a list of nurses certified in "inpatient obstetric nursing" by the National Certification Corporation, were mailed the vignettes. The average number of years of intrapartum nursing experience was 13. MAIN OUTCOME MEASURE: Multiple regression analysis was used to determine the weights given to the 10 clinical factors by participants. RESULTS: Fetal scalp pH, maternal parity, amniotic fluid color, and long-term variability of the fetal heart rate were the most important predictors of nurses' fetal risk assessments. CONCLUSIONS: Long-term variability was the most important cardiotocographic factor in nurses' fetal risk assessments and the only cardiotocographic factor of the best 4 predictors of fetal risk. This indicated that participants were realistic about the limitations of electronic fetal monitoring (EFM).

Direct determination of the positions of the deuterium atoms of the bound water in -concanavalin A by neutron Laue crystallography.

The correct positions of the deuterium (D) atoms of many of the bound waters in the protein concanavalin A are revealed by neutron Laue diffraction. The approach includes cases where these water D atoms show enough mobility to render them invisible even to ultra-high resolution synchrotron-radiation X-ray crystallography. The positions of the bound water H atoms calculated on the basis of chemical and energetic considerations are often incorrect. The D-atom positions for the water molecules in the Mn-, Ca- and sugar-binding sites of concanavalin A are described in detail.

Epidermal growth factor and basic fibroblast growth factor increase the production of matrix metalloproteinases during in vitro decidualization of rat endometrial stromal cells.

Numerous growth factors are involved in mediating proliferation and differentiation of endometrial stromal cells during decidualization. During this period, the extracellular matrix of the endometrium undergoes extensive remodeling. We tested the hypothesis that epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and transforming growth factor-beta regulate expression of matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), during decidualization. Stromal cells were isolated from uteri hormonally sensitized to undergo decidualization and were cultured in the absence or presence of a growth factor. Using substrate-gel electrophoresis with gelatin as the substrate, we detected activity for gelatinase A and B, and collagenase-3, and using casein as a substrate, we detected activity for stromelysin-1. Increasing concentrations of EGF and bFGF resulted in increased activity of gelatinase B, collagenase-3, and stromelysin-1. Northern blot analyses revealed that EGF and bFGF also increased messenger RNA levels for these MMPs. There was no effect of these growth factors on gelatinase or TIMP-1, -2, and -3, nor was there an effect of transforming growth factor-beta on any MMP or TIMP examined. These data demonstrate that EGF and bFGF increase levels of proteolytic enzymes produced by endometrial stromal cells undergoing decidualization in vitro while having no effect on their inhibitors.

A test of the Piagetian water-level task with Chinese students.

A sample of 486 children in Beijing, China, were tested on the water-level task (WLT; J. Piaget & B. Inhelder, 1948/1956). The participants were 256 boys and 230 girls from 4th, 5th, 6th, 8th, and 11th grades. Three levels of mastery of the WLT were found. Level 1 consisted of 4th and 5th graders, who averaged about 71% correct. Level 2 consisted of 6th and 8th graders, who averaged about 83% correct. Level 3 consisted of 11th graders, who averaged 97% correct. The results provide partial support for the Piagetian theory of age-related developmental differences in performance on the WLT. The findings depict an interactive relationship of maturation with culture and education in the development of the ability to solve the WLT.

Evidence in support of a model that predicts how biological and environmental factors interact to influence spatial skills.

It was proposed, based on M. Annett (1985), that individuals biologically predisposed to poorer spatial skills are less likely to capitalize on opportunities to develop these skills. Using an analysis of variance design assessing mental rotation skills in 2 cohorts of 8th graders (365 students), the authors found a significant 3-way interaction (Brothers x Family Handedness x Gender). For the girls with brothers, those from all right-handed families had lower mental rotation scores than did the other girls. For the 2nd cohort, among those children who participated in mental-rotation-type activities with their brothers, both boys and girls from all right-handed families performed more poorly on the mental rotation test than did the other children with brothers. Thus, compared with other children, the children from all right-handed families do not appear to be able to use their spatial experiences with male siblings to increase their spatial skills.

Writing Chinese characters and success on Mental Rotation Test.

Our recent study with Chinese and Chinese-American undergraduates indicated that writing Chinese characters was associated with better performance on the Piagetian Water-Level Task for Chinese-American men. The current study investigated whether the same effects would apply to the Vandenberg Mental Rotation Test. Two alternative hypotheses (bilingualism and birth place) were also tested. Participants were two groups of Chinese-American undergraduates: 48 writers of Chinese (21 men, 27 women) and 130 nonwriters of Chinese (58 men, 72 women). Analysis suggested that writing Chinese and birth in the USA contributed significantly to the success on Mental Rotation Test. Students who were born in the USA and able to write Chinese scored the highest on this test. Being bilingual was not associated with performance on the Mental Rotation Test. Men performed significantly better than women.

Gelatinases A and B and tissue inhibitors of metalloproteinases 1, 2, and 3 during in vivo and in vitro decidualization of rat endometrial stromal cells.

An important event during decidualization is the remodeling of the extracellular matrix, an event controlled by the balance of matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). A putative regulator of decidualization is prostaglandin E2 (PGE2). The present study shows that endometrial mRNA levels for TIMPs 1, 2, and 3 were increased while gelatinase A levels remained unchanged and gelatinase B levels decreased during oil-induced decidualization. The production of TIMPs 1, 2, and 3 and gelatinases A and B during in vitro decidualization was examined, as was the role of PGE2 as a regulator. Ovariectomized rats were given a regimen of estrogen and progesterone, which sensitized their uteri for decidualization, at which time endometrial stromal cells were isolated and cultured in serum-free conditions for 72 h. Northern blot analyses indicated the presence of the mRNAs for TIMPs and gelatinases, while reverse zymography and zymography showed the presence of their proteins. PGE2 decreased mRNA levels for TIMP-1 and gelatinase A but had no effect on gelatinase B or TIMPs 2 and 3. Indomethacin had no effect on any of the transcripts. These data indicate that rat endometrial stromal cells undergoing decidualization in vitro secrete gelatinases and TIMPs, and suggest that PGE2 may play a role in regulating tissue remodeling during decidualization.

The impact of war on the mental health of children: a Salvadoran study.

OBJECTIVE: This ecologically conceptualized, intensive study assesses the mental health impact of the Salvadoran Civil War on 54 12-year-olds, born into the war, exposed to different levels of war violence. METHODS: Half of the students came from a repopulated country village and half from an industrial neighborhood near the capital city. Children, their mothers or caretakers, and their teachers responded to interviews and some instruments. RESULTS: Children from the repopulated village reported higher war experience and lower mental health. The personal/social impact of the war was more important than family togetherness or war intensity in determining the mental health of the children. Children's intelligence was highly related to surviving with higher mental health. Higher socioeconomic status (SES) and education of parents was related to better mental health. Controlling for intelligence, children who experienced the highest personal-social impact of war showed the poorest mental health. Children with high war experience were most likely to have difficulty in imagining the future. CONCLUSIONS: Intelligence and the foreshortening of future vision are variables that should be controlled for and investigated in outcome studies of trauma. Treatment for survivors should include aid in planning for the future.

Mediators of gender differences in mathematics college entrance test scores: a comparison of spatial skills with internalized beliefs and anxieties.

This study was designed to investigate whether spatial skill, math anxiety, and math self-confidence functioned as mediators of a significant gender difference in the Mathematics Scholastic Aptitude Test (SAT-M) among the top third of a college-bound sample. Using path analytic techniques, the decomposition of the significant gender-SAT-M correlation into direct and indirect effects indicated that there were no direct effects of gender on SAT-M. Mental rotation and math self-confidence showed indirect effects, mediating the gender-SAT-M relationship; math anxiety did not. Of these indirect effects, 36% was mediated by math self-confidence; 64% by mental rotation. For both these variables, most of the mediational effects of the gender-SAT-M relationship did not occur by way of the causal pathway leading through geometry grades. Thus, the mediational effects cannot simply be attributed to the presence of geometry items on the SAT-M or to math self-confidence acquired during prior geometry coursework.

Attitudes of pediatric nurses facing HIV risk.

The purpose of this study was to examine health related attitudes, including willingness to provide care, of health care professionals toward HIV-infected patients. To control for attitudes toward people who may have engaged in high risk behaviors for HIV infection, such as intravenous drug use or homosexual behavior, attitudes of pediatric nurses were studied since children with HIV almost never acquire the infection through these behaviors. The research population consisted of 517 pediatric nurses (46% response rate) from twenty states, the District of Columbia and Puerto Rico. The major findings were that those pediatric nurses with more experience caring for HIV-infected patients were more willing to care for these patients, and respondents reported more favorable attitudes after caring for people infected with HIV. Very few nurses would refuse to care for these children, although most acknowledged moderate fear of acquiring HIV from their patients. The level of experience caring for people with HIV was uncorrelated with reported likelihood of incidents of occupational HIV exposure risk. Greater occupational exposure risk was associated with less positive attitudes and less willingness to provide care. Implications of this study include that attitudes, including willingness to provide care, are more favorable with less suspected risk of infection and after more experience with such patients. In this study, where the sample of clients was adjusted to remove other biases, health caregivers were generally positive toward caring for HIV-infected patients.