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Role of sexual self-disclosure in the sexual satisfaction of long-term heterosexual couples.
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This study examined two proposed pathways between sexual self-disclosure (SSD) and sexual satisfaction in a sample of 104 heterosexual couples in long-term relationships. According to the proposed instrumental pathway, disclosure of sexual preferences increases a partner's understanding of those preferences resulting in a sexual script that is more rewarding and less costly. A more favorable balance of sexual rewards to sexual costs, in turn, results in greater sexual satisfaction for the disclosing individual. According to the proposed expressive pathway, mutual self-disclosure contributes to relationship satisfaction, which in turn leads to greater sexual satisfaction. Support was found for the instrumental pathway for both men and women. Support also was found for an expressive pathway between own SSD and partner nonsexual self-disclosure (NSD) and men's sexual satisfaction, and between own NSD and women's sexual satisfaction. These results are interpreted in terms of mechanisms for establishing and maintaining sexual satisfaction in long-term relationships in men and women.
| 19,012,061
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Treatment of amyotrophic lateral sclerosis patients by autologous bone marrow-derived hematopoietic stem cell transplantation: a 1-year follow-up.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of spinal cord and cortical motoneurons. Despite improved understanding of the mechanisms underlying ALS, in clinical practice the management of ALS remains essentially supportive and focused on symptom relief. However, over the past few years stem cell research has expanded greatly as a tool for developing potential new therapies for treating incurable neurodegenerative diseases. Thirteen patients with sporadic amyotrophic lateral sclerosis (SALS) were included in this study, and bone marrow (BM)-derived hematopoietic progenitor stem cells were used. We selected patients with bulbar involvement and severe loss of movement. Our aim was to put the stem cells into the end of the brain stem and at the beginning of the spinal cord because the blood-brain barrier is intact in ALS and this region was the most affected part in our patients. Under general anesthesia, a total laminectomy was performed at the C1-C2 level. Stem cells were injected to the anterior part of the spinal cord. During the follow-up of 1 year after stem cell implantation, nine patients became much better compared with their pre-operative status, confirmed by electro neuro myography (ENMG). One patient was stable without any decline or improvement in his status. Three patients died 1.5, 2 and 9 months, respectively, after stem cell therapy as a result of lung infection and myocardial infarction (MI). These results show that stem cell therapy is a safe, effective and promising treatment for ALS patients.
| 19,012,065
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Handedness and depression: evidence from a large population survey.
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There is a considerable body of research arguing for an association between psychotic disorders and atypical brain lateralisation--where non-right-handedness is usually taken as a marker for the latter. By contrast, there has been less attention given to a possible link between handedness and affective disorders (particularly major depression) and, unlike the case of psychosis, there is no a priori reason for such a link. There are very few studies of the relationship between depression and handedness in normal populations. This paper uses a new large population survey from 12 European countries to measure the association between handedness and depression. It is found that, using three different measures, left-handers are significantly more likely to have depressive symptoms than right-handers. For example left-handers are about 5% more likely to have reported having ever experienced symptoms of depression compared to about 27% of the total sample.
| 19,012,075
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Institutional support for HIV/AIDS care in China: a multilevel analysis.
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A total of 1,101 Chinese healthcare workers were surveyed to determine the perception of institutional support for HIV/AIDS care in China. Multilevel regression models with random effects were used to estimate individual and facility-level effects on healthcare workers' perceived institutional support. Regional workers (at the provincial, city, county levels) reported higher institutional support for HIV/AIDS care than local workers (at the township and village levels). Estimated relationships between perceived institutional support and HIV-related training were greater for the regional than for the local level. Urgent need exists to address the unbalanced healthcare system in China and to consider the policy implications for an effective response to the HIV/AIDS epidemic.
| 19,012,080
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Mismatch negativity (MMN) as an index of central auditory system plasticity.
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The mismatch negativity (MMN) is an electric brain response which is automatically elicited by any discriminable change in a repetitive sound or sound pattern. When this change is made smaller in magnitude, the MMN is attenuated in amplitude, eventually vanishing at around the discrimination threshold. Therefore the MMN provides a unique objective index for a subject or patient's discrimination accuracy. Furthermore, with the MMN, these discrimination thresholds can be separately determined for all the different auditory attributes. Moreover, the individual's ability to discriminate complex sound stimuli and patterns such as different phonemes can also be measured by using the MMN.
| 19,012,108
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Auditory-visual discourse comprehension by older and young adults in favorable and unfavorable conditions.
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This investigation examined how age and test condition affect one's ability to comprehend discourse passages, and determined whether age and test condition affect discourse comprehension and closed-set sentence recognition in a similar way. Young and older adults were tested with closed-set sentences from the newly-created build-a-sentence test (BAS) and a series of discourse passages in two audiovisual conditions: favorable, where the talker's head was clearly visible and the signal-to-babble ratio (SBR) was more optimal; and unfavorable, where the contrast sensitivity of the visual signal was reduced and the SBR was less optimal. The older participants recognized fewer words in the BAS than the young participants in both test conditions. Degrading the viewing and listening conditions led to a greater decline in their performance than in the young participants' performance. The older participants also did not perform as well at comprehending spoken discourse in the two test conditions. However, unlike the results from the BAS, the age difference for discourse comprehension was not exacerbated by unfavorable conditions. When attempting to comprehend discourse, older adults may draw upon verbal and cognitive abilities that are relatively insensitive to age.
| 19,012,110
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Are individual differences in speech reception related to individual differences in cognitive ability? A survey of twenty experimental studies with normal and hearing-impaired adults.
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This paper summarizes twenty studies, published since 1989, that have measured experimentally the relationship between speech recognition in noise and some aspect of cognition, using statistical techniques such as correlation or factor analysis. The results demonstrate that there is a link, but it is secondary to the predictive effects of hearing loss, and it is somewhat mixed across study. No one cognitive test always gave a significant result, but measures of working memory (especially reading span) were mostly effective, whereas measures of general ability, such as IQ, were mostly ineffective. Some of the studies included aided listening, and two reported the benefits from aided listening: again mixed results were found, and in some circumstances cognition was a useful predictor of hearing-aid benefit.
| 19,012,113
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Use of supportive context by younger and older adult listeners: balancing bottom-up and top-down information processing.
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Older adults often have more difficulty listening in challenging environments than their younger adult counterparts. On the one hand, auditory aging can exacerbate and/or masquerade as cognitive difficulties when auditory processing is stressed in challenging listening situations. On the other hand, an older listener can overcome some auditory processing difficulties by deploying compensatory cognitive processing, especially when there is supportive context. Supportive context may be provided by redundant cues in the external signal(s) and/or by internally stored knowledge about structures that are functionally significant in communication. It seems that listeners may achieve correct word identification in various ways depending on the challenges and supports available in complex auditory scenes. We will review evidence suggesting that older adults benefit as much or more than younger adults from supportive context at multiple levels where expectations or constraints may be related to redundancies in semantic, syntactic, lexical, phonological, or other sub-phonemic cues in the signal, and/or to expert knowledge of structures at these levels.
| 19,012,114
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The interference of different background noises on speech processing in elderly hearing impaired subjects.
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The objective of the investigation is to study the interference of different background noises on speech processing. For this purpose speech recognition with the Hagerman test and a test battery with speech comprehension tasks (SVIPS) were performed in speech-weighted background noises varying in temporal structure, signal-to-noise ratio (SNR), and meaningfulness. With different test criteria and a score of perceived effort, the aim was to get a more complete picture of speech comprehension under adverse listening situations. Twenty-four subjects, aged 56-83 years, with a bilateral sensorineural hearing impairment, participated in the study. Differences in performance between the different background noises varied depending on the speech processing task, SNR, and on quantitative versus qualitative outcome measures. Age effects were seen in the Hagerman test and especially in background conditions of modulated noises (speech and reversed speech). Findings are discussed in relation to a hypothesis suggesting that masking and distraction interference from background noises on speech processing at peripheral, central auditory, and cognitive levels depends on the SNR used and the noise type and the listening task.
| 19,012,115
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Psychiatric education and training in Asia.
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Psychiatric education and training, whilst playing a pivotal role in addressing the burden of mental illness in Asia, is very variable in quality and quantity across the continent. In this article formal postgraduate programmes in Indonesia, Thailand, Philippines, Singapore and India are described. The special situation in China where both basic and advanced psychiatric training receives particular attention, including the role of Asia Australia Mental Health in assisting the process, similarly the long hard road of re-establishing psychiatric training in Cambodia following the tragedy of the Pol Pot era are described. The article concludes with an overview of common issues involving education and training across the region.
| 19,012,125
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Pharmacotherapy for schizophrenic inpatients in East Asia--changes and challenges.
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(1) to review characteristics of prescription patterns of antipsychotic medication in China, Hong Kong, Japan, Korea, Singapore and Taiwan, (2) to examine the changes of prescriptions brought about by the introduction of second generation psychotropic drugs (SGA) in East Asia, (3) to analyse factors contributing to the characteristic use of antipsychotics, and (4) to suggest ways and means to improve the prescription practice of antipsychotics in East Asia. Authors of this study collaborated with psychiatrists in East Asia to undertake an international survey reviewing prescription patterns of psychotropic medications in East Asia. The REAP (Research on Asian psychotropic prescription patterns) study reviewed the prescription of a large number of schizophrenic inpatients in China, Hong Kong, Japan, Korea, Singapore and Taiwan in 2001 and 2004 using a unified research protocol and questionnaire. Prescription patterns of antipsychotic drugs differ greatly country by country and have recently experienced rapid changes. Our survey shows second generation antipsychotics are frequently used in East Asia. The introduction of SGA resulted in the combined use of first generation psychotropic drugs (FGA) and SGA in East Asia. These changing prescription patterns have created many challenges for psychiatrists in East Asia.
| 19,012,132
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Team effectiveness in academic primary health care teams.
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Primary health care is undergoing significant organizational change, including the development of interdisciplinary health care teams. Understanding how teams function effectively in primary care will assist training programs in teaching effective interprofessional practices. This study aimed to explore the views of members of primary health care teams regarding what constitutes a team, team effectiveness and the factors that affect team effectiveness in primary care. Focus group consultations from six teams in the Department of Family Medicine at Queen's University were recorded and transcribed and qualitative analysis was used to identify themes. Twelve themes were identified that related to the impact of dual goals/obligations of education and clinical/patient practice on team relationships and learners; the challenges of determining team membership including nonattendance of allied health professionals except nurses; and facilitators and barriers to effective team function. This study provides insight into some of the challenges of developing effective primary care teams in an academic department of family medicine. Clear goals and attention to teamwork at all levels of collaboration is needed if effective interprofessional education is to be achieved. Future research should clarify how best to support the changes required for increasingly effective teamwork.
| 19,012,140
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Leadership styles in interdisciplinary health science education.
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The US Institute of Medicine recommends that all health professionals should deliver patient-centered care as members of interdisciplinary health science teams. The current application of the Bolman and Deal Leadership model to health sciences provides an interesting point of reference to compare leadership styles. This article reviews several applications of that model within academic health care and the aggregate recommendations for leaders of health care disciplines based on collective findings.
| 19,012,143
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Proteomic profiling of amniotic fluid in preterm labor using two-dimensional liquid separation and mass spectrometry.
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Simultaneous analysis of the protein composition of biological fluids is now possible. Such an approach can be used to identify biological markers of disease and to understand the pathophysiology of disorders that have eluded classification, diagnosis, and treatment. The purpose of this study was to analyze the differences in protein composition of the amniotic fluid of patients in preterm labor. Amniotic fluid was obtained by amniocentesis from three groups of women with preterm labor and intact membranes: (1) women without intra-amniotic infection/inflammation (IAI) who delivered at term, (2) women without IAI who delivered a preterm neonate, and (3) women with IAI. Intra-amniotic infection was defined as a positive amniotic fluid culture for microorganisms. Intra-amniotic inflammation was defined as an elevated amniotic fluid interleukin (IL)-6 (> or =2.3 ng/mL). Two-dimensional (2D) chromatography was used for analysis. The first dimension separated proteins by isoelectric point, while the second, by the degree of hydrophobicity. 2D protein maps were generated using different experimental conditions (reducing agents as well as protein concentration). The maps were used to discern subsets of isoelectric point/hydrophobicity containing differentially expressed proteins. Protein identification of differentially expressed fractions was conducted with mass spectrometry. Enzyme-linked immunosorbent assays (ELISA) as well as surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS)-based on-chip antibody capture immunoassays were also used for confirmation of a specific protein that was differentially expressed. (1) Amniotic fluid protein composition can be analyzed using a combination of 2D liquid chromatography and mass spectrometry for the identification of proteins differentially expressed in patients in preterm labor. (2) While total insulin-like growth factor-binding protein-1 (IGFBP-1) concentration did not change, IGFBP-1 fragments at about 13.5 kDa were present in patients with IAI. (3) Proteins that were over-expressed in group 1 included von Ebner gland protein precursor, IL-7 precursor, apolipoprotein A1, tropomyosin sk1 (TPMsk1) fragment, ribosomal protein S6 kinase alpha-3, and alpha-1-microglobulin/bikunin precursor (AMBP). (4) Proteins that were over-expressed in group 3 included fibrinopeptide B, transferrin, major histocompatibility complex (MHC) class 1 chain-related A antigen fragment, transcription elongation factor A, sex-determining region Y (SRY) box 5 protein, Down syndrome critical region 2 protein (DSCR2), and human peptide 8 (HP8). (5) One protein, retinol-binding protein, was over-expressed in women who delivered preterm, regardless of the presence of IAI. A combination of techniques involving 2D chromatography, mass spectrometry, and immunoassays allows identification of proteins that are differentially regulated in the amniotic fluid of patients with preterm labor. Specifically, the amount of the IGFBP-1 fragments at approximately 13.5 kDa was found to be increased in patients with IAI, while the amount of the intact form of IGFBP-1 was decreased.
| 19,012,186
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A link between a hemostatic disorder and preterm PROM: a role for tissue factor and tissue factor pathway inhibitor.
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Vaginal bleeding is a risk factor for preterm PROM (PPROM). A disorder of decidual hemostasis has been implicated in the genesis of PROM. Indeed, excessive thrombin generation has been demonstrated in PPROM both before and at the time of diagnosis. Decidua is a potent source of tissue factor (TF), the most powerful natural pro-coagulant. A decidual hemostatic disorder may link vaginal bleeding, PPROM and placental abruption. This study was conducted to determine the behaviour of maternal TF and its natural inhibitor, the tissue factor pathway inhibitor (TFPI) in PPROM. This cross-sectional study included women with PPROM (n = 123) and women with normal pregnancies (n = 86). Plasma concentrations of TF and TFPI were measured by a sensitive immunoassay. Non-parametric statistics were used for analysis. (1) The median maternal plasma TF concentration was significantly higher in patients with PPROM than in women with normal pregnancies (median: 369.5 pg/mL; range: 3.27-2551 pg/mL vs. median: 291.5 pg/mL; range: 6.3-2662.2 pg/mL respectively, p = 0.001); (2) the median maternal TFPI plasma concentration was significantly lower in patients with PPROM than in women with normal pregnancies (median: 58.7 ng/mL; range: 26.3-116 ng/mL vs. median: 66.1 ng/mL; range: 14.3-86.5 ng/mL respectively, p = 0.019); (3) there was no correlation between the plasma concentration of TF and TFPI and the gestational age at sample collection; and (4) among patients with PPROM there was no association between the presence of intra-amniotic infection or inflammation and median plasma concentrations of TF and TFPI. (1) Patients with PPROM have a higher median plasma concentration of TF and a lower median plasma concentration of TFPI than women with normal pregnancies. (2) These findings suggest that PPROM is associated with specific changes in the hemostatic/coagulation system.
| 19,012,190
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Different biological properties of circulating and bone marrow endothelial progenitor cells in acute myocardial infarction rats.
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Many studies have shown that endothelial progenitor cell (EPC) can enhance the neovascularization of the ischemic myocardium. Peripheral blood and bone marrow are the most convenient resources for EPC. The aim of the study was to investigate, in vitro and in vivo, the different biological properties between circulating EPC (CEPC) and bone marrow EPC (BM-EPC) of AMI rats. The proliferative, migrative, adherent and angiogenic properties were investigated in vitro. 1 x 10 (6) CEPCs, 1 x 10 (6) BM-EPCs and medium (EBM-2) were injected in the myocardium of AMI rats. Echocardiography, regional myocardial blood flow (RMBF), capillary density and Y chromosome fluorescence in situ hybridization (FISH) were performed at 4 weeks after transplantation. The CEPCs had higher proliferative, migrative, adherent capabilities and lower senescent ratio, could adhere more quickly to fibronectin than BM-EPCs. CEPCs could form capillary-like structures whereas BM-EPCs did not show similar structures on Matrigel. in vivo, transplanted CEPCs and BM-EPCs were found in cardiac tissue by FISH. CEPCs treatment led to a better cardiac function, RMBF and capillary density than BM-EPCs. Different biological properties were observed between CEPCs and BM-EPCs. Autologous CEPCs are more suitable for the AMI rat.
| 19,012,207
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Lack of correlation between smoking status and early postoperative outcome following valve surgery.
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We sought to assess the effect of smoking on early outcome following valve surgery. This is a retrospective review of a prospectively collected departmental database of all patients who underwent isolated aortic and/or mitral valve surgery (replacement and/or repair). Our cohort consisted of 590 patients stratified into three groups: current smokers (n = 94), ex-smokers (n = 243), and nonsmokers (n = 253). There were no significant differences in the in-hospital mortality between the three groups. Likewise, the length of both hospital and intensive care unit stays were similar among the three groups with a similar rate of postoperative complications. These findings remained statistically not significant, even after adjusting for potential confounders such as age, gender, etc. Smoking does not seem to be associated with an increased early postoperative risk in patients undergoing valve surgery. However, because of the known effect of smoking on the risk of cardiovascular disease and because the effect of smoking on long-term survival in patients undergoing valve surgery remains unknown, patients should still be encouraged to quit smoking.
| 19,012,208
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Should the aortic valve be replaced in patients with mild aortic stenosis admitted for coronary surgery?
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The question whether the aortic valve in patients with mild aortic stenosis undergoing coronary artery bypass grafting (CABG) should be replaced or left alone is still controversial. Between 01/1995 and 03/2004, 38 patients (30 male, 8 female, mean age 70.9 +/- 7.8 years) required redo AVR 7.1 +/- 4.8 years after primary CABG, while 202 patients (125 male, 77 female, mean age 72.7 +/- 7.8 years) underwent combined AVR and CABG (1.9 +/- 0.8 grafts/patient). To evaluate the different approaches, the data of the redo-AVR group were compared with the data of a propensity-score matched group of AVR + CABG patients. All patients survived the procedure; the 30-day survival was 94.7 % in both groups. The 1- and 5-year survival rates were 94.7 % and 83.8 % in the AVR after CABG group, and 94.7 % and 86.9 % in the AVR + CABG group, respectively. The late mortality was 28.9 % in the AVR after CABG and 25 % in the AVR + CABG group. Statistically, significant differences regarding perioperative mortality and morbidity could not be detected, neither with nor without propensity score analysis. Combined AVR and CABG in patients with coronary artery disease and mild to moderate aortic stenosis seems advisable in an institution with an equally low perioperative risk for both procedures, because the patient will need only one surgical procedure instead of undergoing surgery with all the associated risks twice.
| 19,012,211
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Case of left atrial metastasis of a sarcomatoid carcinoma.
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Metastatic tumor involvement of the heart may occur with all types of primary neoplasms. Right atrial cardiac metastases following vena cava extension from renal cell carcinoma are well recognized, while a left atrial appearance is extremely rare. We report on a patient who developed a left atrial mass originating from the lower right pulmonary vein after successful resection of a renal cell carcinoma with sarcomatoid areas by right-sided nephrectomy. To our knowledge, this is the first described case of this type of pancytokeratin-expressing tumor in the literature so far.
| 19,012,215
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Bilateral trapped lung with concomitant Wermer's syndrome and cutis laxa.
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We report a rare occurrence of trapped lung associated with Wermer's syndrome and cutis laxa. A 25-year-old man with bilateral trapped lung presented with respiratory distress. Additional investigation revealed adenoma of the parathyroid and hypophysis, a neuroendocrine abdominal tumor, and cutis laxa. Successful treatment of the respiratory symptoms was achieved through a median sternotomy with bilateral decortication, and excision of the bilateral fibrous pleural bands and bullae on the right upper lobe. Octreotide therapy was initiated and a percutaneous ultrasound-guided alcohol injection to the parathyroid adenoma was done. The patient has gynecomastia, acromegaly, and kyphoscoliosis. The patient remains well at 19 months after treatment.
| 19,012,220
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[MELAS syndrome as a differential diagnosis of ischemic stroke].
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Mitochondrial encephalomyopathy, lactacidosis and stroke-like episode (MELAS) syndrome is a phenotypically and genetically heterogeneous mitochondrial disorder with a clinical onset between the first and third decade. The clinical hallmark is the stroke-like-episode, which mimicks ischemic stroke but is usually transient and non-disabling in nature. The morphological equivalent on MRI is a T2-hyperintensity, predominantly over the temporo-parieto-occipital region, not confined to a vascular territory, which is also hyperintense on diffusion weighted imaging and on apparent diffusion coefficient sequences (vasogenic edema, stroke-like lesion). Additional features include seizures, cognitive decline, psychosis, lactic acidosis, migraine, visual impairment, hearing loss, short stature, diabetes, or myopathy. Muscle biopsy typically shows ragged-red fibers, COX-negative fibers, SDH hyperreactivity, and abnormally shaped mitochondria with paracristalline inclusions. The diagnosis is confirmed by demonstration of a biochemical respiratory chain defect or one of the disease-causing mutations, of which 80 % affect the mitochondrial tRNALeu gene.
| 19,012,224
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Left atrial shortening fraction in fetuses with and without myocardial hypertrophy in diabetic pregnancies.
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To test the hypothesis that, in diabetic pregnancies, left atrial shortening fraction (LASF) is decreased in fetuses with myocardial hypertrophy, compared to those without hypertrophy and to fetuses of non-diabetic mothers. Fetal echocardiography was performed in women with pre-existing or gestational diabetes and in non-diabetic controls between 25 weeks' gestation and term. LASF was calculated using the formula: (end-systolic diameter-end-diastolic diameter)/end-systolic diameter, and data were compared between diabetic women with and without fetal myocardial hypertrophy and controls. The study population comprised 53 diabetic women and 45 controls. Out of the 53 fetuses of diabetic women, 14 had myocardial hypertrophy and 39 had normal septal thickness. Gestational age at the time of examination did not differ significantly between the control group and the two diabetic subgroups (P = 0.57). Fetuses with myocardial hypertrophy presented a mean ( +/- SD) LASF of 0.32 +/- 0.11, those without myocardial hypertrophy 0.46 +/- 0.12, and those of normal mothers 0.53 +/- 0.09 (P < 0.001). A significant inverse linear correlation was observed between LASF and septal thickness (r = - 0.51, P < 0.001). In diabetic pregnancies, LASF is lower in fetuses with myocardial hypertrophy than it is in those without hypertrophy and in fetuses of non-diabetic women, suggesting that LASF could be a useful alternative parameter in the assessment of fetal diastolic function.
| 19,012,275
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Fixed effects, random effects and GEE: what are the differences?
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For analyses of longitudinal repeated-measures data, statistical methods include the random effects model, fixed effects model and the method of generalized estimating equations. We examine the assumptions that underlie these approaches to assessing covariate effects on the mean of a continuous, dichotomous or count outcome. Access to statistical software to implement these models has led to widespread application in numerous disciplines. However, careful consideration should be paid to their critical assumptions to ascertain which model might be appropriate in a given setting. To illustrate similarities and differences that might exist in empirical results, we use a study that assessed depressive symptoms in low-income pregnant women using a structured instrument with up to five assessments that spanned the pre-natal and post-natal periods. Understanding the conceptual differences between the methods is important in their proper application even though empirically they might not differ substantively. The choice of model in specific applications would depend on the relevant questions being addressed, which in turn informs the type of design and data collection that would be relevant.
| 19,012,297
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Asymptomatic Becker muscular dystrophy in a family with a multiexon deletion.
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We report a Becker muscular dystrophy (BMD) family with one 5-year-old affected patient and a 69-year-old asymptomatic grandfather. Dystrophin gene multiplex polymerase chain reaction and multiplex ligation-dependant probe amplification analysis showed that both males carried an in-frame deletion of exons 45-55. Segregation analysis revealed two additional asymptomatic boys in this family. Our finding supports previous predictions that exons 45-55 are the optimal multiexon skipping target in antisense gene therapy to transform the severe Duchenne muscular dystrophy into the milder BMD, or even asymptomatic, phenotype.
| 19,012,301
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Bonding in mercury molecules described by the normalized elimination of the small component and coupled cluster theory.
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Bond dissociation energies (BDEs) of neutral HgX and cationic HgX(+) molecules range from less than a kcal mol(-1) to as much as 60 kcal mol(-1). Using NESC/CCSD(T) [normalized elimination of the small component and coupled-cluster theory with all single and double excitations and a perturbative treatment of the triple excitations] in combination with triple-zeta basis sets, bonding in 28 mercury molecules HgX (X = H, Li, Na, K, Rb, CH(3), SiH(3), GeH(3), SnH(3), NH(2), PH(2), AsH(2), SbH(2), OH, SH, SeH, TeH, O, S, Se, Te, F, Cl, Br, I, CN, CF(3), OCF(3)) and their corresponding 28 cations is investigated. Mercury undergoes weak covalent bonding with its partner X in most cases (exceptions: X = alkali atoms, which lead to van der Waals bonding) although the BDEs are mostly smaller than 12 kcal mol(-1). Bonding is weakened by 1) a singly occupied destabilized sigma*-HOMO and 2) lone pair repulsion. The magnitude of sigma*-destabilization can be determined from the energy difference BDE(HgX)-BDE(HgX(+)), which is largest for bonding partners from groups IVb and Vb of the periodic table (up to 80 kcal mol(-1)). BDEs can be enlarged by charge transfer from Hg and increased HgX ionic bonding, provided the bonding partner of Hg is sufficiently electronegative. The fine-tuning of covalent and ionic bonding, sigma-destabilization, and lone-pair repulsion occurs via relativistic effects where 6s AO contraction and 5d AO expansion are decisive. Lone pair repulsion involving the mercury 5d AOs plays an important role in the case of some mercury chalcogenides HgE (E = O, Te) where it leads to (3)Pi rather than (1)Sigma(+) ground states. However, both HgE((3)Pi) and HgE((1)Sigma(+)) should not be experimentally detectable under normal conditions, which is in contrast to experimental predictions suggesting BDE values for HgE between 30 and 53 kcal mol(-1). The results of this work are discussed with regard to their relevance for mercury bonding in general, the chemistry of mercury, and reactions of elemental Hg in the atmosphere.
| 19,012,313
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Quantification of amounts and (13)C content of metabolites in brain tissue using high- resolution magic angle spinning (13)C NMR spectroscopy.
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Metabolic pathway mapping using (13)C NMR spectroscopy has been used extensively to study interactions between neurons and glia in the brain. Established extraction procedures of brain tissue are time consuming and may result in degradation of labile substances. We examined the potential of mapping (13)C-enriched compounds in intact brain tissue using high-resolution magic angle spinning (HR-MAS) NMR spectroscopy. Sprague-Dawley rats received an intraperitoneal injection of [1,6-(13)C]glucose, and 15 min later the animals were subjected to microwave fixation of the brain. Quantification of concentration and (13)C labelling of metabolites in intact rat thalamus were carried out based on exogenous ethylene glycol concentrations measured from (1)H NMR spectra using an ERETIC (Electronic REference To access In vivo Concentrations) signal. The results from intact tissue were compared with those from perchloric acid-extracted brain tissue. Amounts of (13)C labelling at different positions (C2, C3 and C4) in glutamate, glutamine, gamma-aminobutyric acid and aspartate measured in either intact tissue or perchloric acid extracts were not significantly different. Proton NMR spectra were used for quantification of six different amino acids plus lactate, inositol, N-acetylaspartate, creatine and phosphocreatine. Again, results were very similar when comparing the methods. To our knowledge, this is the first time quantitative (13)C NMR spectroscopy measurements have been carried out on intact brain tissue ex vivo using the HR-MAS technique. The results show that HR-MAS (13)C NMR spectroscopy in combination with (1)H NMR spectroscopy and the ERETIC method is useful for metabolic studies of intact brain tissue ex vivo.
| 19,012,315
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Bias in a binary risk behaviour model subject to inconsistent reports and dropout in a South African high school cohort study.
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We describe a methodology for analysing self-reported risk behaviour transitional patterns in a binary outcome variable, subject to misclassification and a large loss to follow-up. The motivation stems from the analysis of self-reported transitional patterns in responses to the question 'have you ever smoked a whole cigarette?' in a cohort of South African school children. The partially complete records analysis (PCRA) introduced, estimates the transitional probability as: the ratio of the joint probability of the response at two time points based on the complete records for this time sequence over the marginal probabilities of the response based on the complete records at the first time point, and assumes a non-informative missing pattern. A comparison was made using un-weighted complete records and inverse probability weighted logistic regression. The estimates of the probabilities of reporting ever having smoked a cigarette obtained from the three methods were similar for a particular transition. The PCRA method lacked precision compared with the inverse probability weighted logistic regression. A simulation study indicated an association between bias and reporting error in all three methods. The PCRA method can be considered as a method for the estimation of transition probabilities in a cohort study where there is consistency in the self-reported risk behaviour pattern and the sample size is large at baseline. The inverse probability weighting approach is more precise and is suitable for this setting in order to determine risk factors for the incidence of self-reported substance used in a cohort with a high dropout rate.
| 19,012,316
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Novel mutation of IL1RAPL1 gene in a nonspecific X-linked mental retardation (MRX) family.
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Mental retardation (MR) affects approximately 2% of the population. About 10% of all MR cases result from defects of X-linked genes. Mutations in most of more than 20 known genes causing nonspecific form of X-linked MR (MRX) are very rare and may account for less than 0.5-1% of MR. Linkage studies in extended pedigrees followed by mutational analysis of known MRX genes in the linked interval are often the only way to identify a genetic cause of the disorder. We performed linkage analysis in several MRX families, and in one family with four males with MR we mapped the disease to an interval encompassing Xp21.2-22.11 (with a maximum LOD score of 2.71). Subsequent mutation analysis of genes located in this interval allowed us to identify a partial deletion of the IL1RAPL1 gene. Different nonoverlapping deletions involving IL1RAPL1 have been reported previously, suggesting that this region could be deletion-prone. In this report, we present the results of the molecular analyses and clinical examinations of four affected family members with the deletion in IL1RAPL1. Our data further confirm the importance and usefulness of linkage studies for gene mapping in MRX families and demonstrate that IL1RAPL1 plays an important role in the etiology of MRX. With the development of new methods (aCGH, MLPA), further rearrangements in this gene (including deletions and duplications) might be discovered in the nearest future.
| 19,012,350
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Band-like intracranial calcification with simplified gyration and polymicrogyria: a distinct "pseudo-TORCH" phenotype.
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The combination of intracranial calcification and polymicrogyria is usually seen in the context of intrauterine infection, most frequently due to cytomegalovirus. Rare familial occurrences have been reported. We describe five patients-two male-female sibling pairs, one pair born to consanguineous parents, and an unrelated female-with a distinct pattern of band-like intracranial calcification associated with simplified gyration and polymicrogyria. Clinical features include severe post-natal microcephaly, seizures and profound developmental arrest. Testing for infectious agents was negative. We consider that these children have the same recognizable "pseudo-TORCH" phenotype inherited as an autosomal recessive trait.
| 19,012,351
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Limited utility of rapamycin in severe, refractory Wegener's granulomatosis.
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We report our experience using rapamycin in patients with Wegener's granulomatosis (WG) who failed to achieve remission with conventional treatment. Eight patients received rapamycin for severe, refractory WG. Clinical outcomes were reviewed retrospectively. Four patients treated with rapamycin sustained remissions of at least 6 months' duration while receiving prednisone<or=10 mg/day; 2 relapsed during followup. Five patients discontinued rapamycin due to continued disease activity, cancer, or adverse events. Toxicities due to rapamycin were numerous; consistent proof of efficacy in this pilot experience with WG was not seen.
| 19,012,360
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Competing gas-phase substitution and elimination reactions of gemini surfactants with anionic counterions by mass spectrometry. Density functional theory correlations with their bolaform halide salt models.
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Understanding ion specific effects on the solution properties of association colloids is a major unsolved problem, and we are studying the chemistry of gemini surfactants in the gas-phase by mass spectrometry and density functional theory (DFT) to probe ion specific effects in the absence of water. Products from gas-phase fragmentation chemistry of dication-monoanion pairs, M2+X(-), of C16H33(CH3)2N+-(CH2)(n-) +N(CH3)2C16H33.2X(-) gemini surfactants were determined by using sequential collision induced dissociation mass spectrometry. The spacer length "n" was systematically varied (n = 2, 3, 4, and 6) for each counterion investigated (X(-) = F(-), Br(-), Cl(-), I(-), NO3(-), CF3CO2(-), and PF6(-)). The M2+X(-) pairs fragment into monocationic products from competing E2 and S N2 pathways that are readily quantified by tandem MS. The dominant reaction pathway depends on dication and anion structure because it switches from E2 to S N2 with decreasing anion basicity and increasing spacer length. For spacer lengths n = 4 and 6, the major S N2 product shifts from attack at methylene to methyl on the quaternary ammonium group. DFT calculations of gemini headgroup model bolaform salts, CH3(CH3)2N+-(CH2)(n-)+N(CH3)2CH3.2X(-) (X(-) = F(-), Cl(-), Br(-), and I(-), n = 2-4), primarily of activation enthalpies, DeltaH, but also of free energies and entropies for the dication-monoanion pairs, M2+X(-), provide qualitative explanations for the MS structure-reactivity patterns. DeltaH values for S N2 reactions are independent of X(-) type and spacer length, while E2 reactions show a significant increase in DeltaH with decreasing anion basicity and a modest increase with spacer length. Comparisons with the DeltaH values of model CH3CH2(CH3)3N+X(-) halides show that the second charge on the dicationic ion pairs does not significantly affect DeltaH and that the change in distance between the nucleophile and leaving group in the ground and transition states structures in S N2 reactions is approximately constant indicating that DeltaH is governed primarily by electrostatic interactions.
| 19,012,368
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On the extent and connectivity of conical intersection seams and the effects of three-state intersections.
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We discuss the connectivity of intersection spaces and the role of minimal energy points within these intersection spaces (minimal energy conical intersections or MECIs) in promoting nonadiabatic transitions. We focus on malonaldeyde as a specific example, where there is a low-lying three-state conical intersection. This three-state intersection is the global minimum on the bright excited electronic state, but it plays a limited role in population transfer in our ab initio multiple spawning (AIMS) simulations because the molecule must traverse a series of two-state conical intersections to reach the three-state intersection. Due to the differences in seam space dimensionality separating conventional (two-state) and three-state intersections, we suggest that dynamical effects arising directly from a three-state intersection may prove difficult to observe in general. We also use a newly developed method for intersection optimization with geometric constraints to demonstrate the connectivity of all the stationary points in the intersection spaces for malonaldehyde. This supports the conjecture that all intersection spaces are connected, and that three-state intersections play a key role in extending this connectivity to all pairs of states, e.g. the S1/S0 and S2/S1 intersection spaces.
| 19,012,385
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Design, synthesis, and evaluation of tricyclic, conformationally constrained small-molecule mimetics of second mitochondria-derived activator of caspases.
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A series of tricyclic, conformationally constrained Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 6 (WS-5) binds to XIAP, cIAP-1, and cIAP-2 with K(i) of 18, 1.1, and 4.2 nM, respectively. Compound 6 antagonizes XIAP in a functional assay, induces cIAP-1 degradation, inhibits cell growth with an IC(50) of 68 nM in the MDA-MB-231 cancer cell line, and effectively induces cancer cells to undergo apoptosis.
| 19,012,392
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Negative APCI-LC/MS/MS method for determination of natural persistent halogenated products in marine biota.
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A sensitive and selective method utilizing high performance liquid chromatography coupled to negative atmospheric pressure chemical ionization tandem mass spectrometry (APCI-LC/MS/MS) was developed to enable analysis of selected natural persistent organohalogens accumulated in marine biota. The analytes were three methoxylated tetrabromodiphenyl ethers (6-MeO-BDE47, 2'-MeO-BDE68, and 2',6-diMeO-BDE68), a dimethoxylated tetrabromobiphenyl (2,2'-diMeO-BB80), and two halogenated methyl bipyrroles (Cl(7)-MBP and Br(4)Cl(2)-DBP). These products were well resolved on a 150 mm reversed-phase column with methanol as the mobile phase. The fragmentation pathways of the Cl(7)-MBP and Br(4)Cl(2)-DBP produced characteristic multiple reaction monitoring (MRM) transitions. Determination was performed in the MRM mode using phenoxide ion [M-Br+O](-) and product Br(-) ions for MeO-BDE analogues, or the precursor [M-Cl+O](-) to Br(-) ion for Br(4)Cl(2)-DBP, and to C(4)NCl(4)(-) ion for Cl(7)-MBP. The APCI-LC/MS/MS method is acceptable for calibration of the linearity and repeatability of all products studied in the low ng/g (lipid weight) level and with similar sensitivity to the electron ionization (EI)-GC/MS method. The proposed method was applied for quantification of natural organohalogens accumulated in melon-headed whale (Peponocephala electra) blubber (N = 15) in the Asia-Pacific Ocean. The concentration was positively correlated between different groups of compounds except for 2'-MeO-BDE68. The use of the analytical method based on negative ion APCI-LC/MS/MS would provide a new way for rapid monitoring of halogenated natural products from marine biota, such as sponges or algae.
| 19,012,416
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Testing potential interference with RFID usage in the patient care environment.
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The use of radio frequency identification (RFID) equipment in the clinical setting has become prevalent. The exploration of the potential interactions between the equipment used to implement RFID and medical devices is vital to ensure safe and effective use of both the tracking technology and the patient care equipment. This study examines the effects of two common RFID antennas, Near-Field and Far-Field, and five general types of patient care equipment. Data were collected regarding the function of the patient care equipment in the fields of the antennas. No device performance alterations were observed.
| 19,012,466
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Significant headache improvement after transsphenoidal surgery in patients with small sellar lesions.
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Pituitary adenomas represent a large proportion of brain tumors that are increasing in incidence because of improved imaging techniques. Headache is the primary symptom in patients with large tumors (macroadenomas), but is also a symptom in patients with small tumors (microadenomas, tumors < 1.0 cm). The prevalence and optimal treatment of headaches associated with pituitary tumors is still unclear, particularly in cases of microadenoma. If conventional medical management fails, transsphenoidal surgery (TSS) may be considered as an alternative treatment for intractable headaches. The authors conducted a retrospective review of 512 patients who underwent TSS at Oregon Health & Science University between 2001 and 2007; patients with Cushing disease were excluded. The authors identified 41 patients with small pituitary tumors who underwent TSS, and retrospectively evaluated the resolution and/or treatment of headache. Ninety percent of patients who presented with nonfunctioning microadenomas and Rathke cleft cysts experienced resolution or improvement in their headaches after TSS, and 56% of patients who presented with hyperfunctioning pituitary microadenomas had improvement in their headaches. There were no postoperative complications. In this retrospective study, the authors demonstrate the efficacy of TSS in the treatment of intractable headaches in patients who present with pituitary microadenomas (nonsecreting and hypersecretory) and Rathke cleft cysts.
| 19,012,490
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Novel therapeutics in metastatic bladder cancer.
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Albeit transitional cell carcinoma of the urinary bladder is a chemosensitive neoplasm, metastatic disease is related with poor prognosis and short-term survival data. Cisplatin-based combination chemotherapy is recognised as the golden standard therapy for patients with inoperable locally advanced or metastatic bladder cancer. However, owing to treatment-related toxicities and short-response durations, novel treatment options or agents, with both enhanced efficacy and tolerability, have been sought. Reviewing the current status and addressing the future of novel anticancer therapeutics in metastatic urinary bladder cancer. Non-platinum, single agents, such as gemcitabine and taxanes, as well as multidrug regimens in doublet or triplet chemotherapeutic combinations are regarded as promising alternatives. Dose intensification of conventional regimens, dose-dense sequential administration of new agents, the use of molecular markers for predicting chemosensitivity and the integration of biologically targeted agents to enhance chemotherapeutic efficacy are promising approaches.
| 19,012,504
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Health effects of arsenic and chromium in drinking water: recent human findings.
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Even at high concentrations, arsenic-contaminated water is translucent, tasteless, and odorless. Yet almost every day, studies report a continually increasing plethora of toxic effects that have manifested in exposed populations throughout the world. In this article we focus on recent findings, in particular those associated with major contributions since 2006. Early life exposure, both in utero and in childhood, has been receiving increased attention, and remarkable increases in consequent mortality in young adults have been reported. New studies address the dose-response relationship between drinking-water arsenic concentrations and skin lesions, and new findings have emerged concerning arsenic and cardiovascular disease. We also review the increasing epidemiological evidence that the first step of methylation of inorganic arsenic to monomethylated arsenic (MMA) is actually an activation step rather than the first step in detoxification, as once thought. Hexavalent chromium differs from arsenic in that it discolors water, turning the water yellow at high concentrations. A controversial issue is whether chromium causes cancer when ingested. A recent publication supports the original findings in China of increased cancer mortality in a population where well water turned yellow with chromium.
| 19,012,537
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A statewide system of trauma care in Victoria: effect on patient survival.
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To determine whether the statewide system of trauma care introduced in 2000 has resulted in improved survival for all major trauma patients in Victoria. Population-based cohort study using data from the Victorian State Trauma Registry (VSTR), a registry of all hospitalised major trauma patients in Victoria. The study included major trauma patients with an Injury Severity Score > 15 captured by the VSTR between July 2001 and June 2006. In-hospital mortality. The number of major trauma cases captured by the registry rose from 1153 in 2001-02 to 1737 in 2005-06. Adjusting for key predictors of mortality, there was a significant overall reduction between 2001-02 and 2005-06 in the risk of death for patients treated in the trauma system (adjusted odds ratio [AOR], 0.62 [95% CI, 0.48-0.80]). The reduced risk of death was also significant when road trauma cases (AOR, 0.56 [95% CI, 0.39-0.80]) and serious head injury cases (AOR, 0.62 [95% CI, 0.46-0.83]) were analysed separately. The proportion of road trauma patients definitively treated at one of the three major trauma service (MTS) hospitals in Victoria rose by 7% over the 5-year period. Direct transfers from the scene of injury to MTS hospitals rose by 8% for all cases and 13% for road trauma cases over the same period. Introduction of a statewide trauma system was associated with a significant reduction in risk-adjusted mortality. Such inclusive systems of trauma care should be regarded as a minimum standard for health jurisdictions.
| 19,012,550
|
Plasma lipoprotein concentrations in the dog: the effects of gender, age, breed and diet.
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Earlier studies of canine lipoprotein metabolism have frequently not taken into account such variables as age, gender, lifestyle or feeding status. In the last years, many changes to lifestyle and feeding of dogs have occurred. In this study, C-tot, C-HDL, C-LDL, triglycerides and lipoprotein fractions were determined in 251 healthy dogs by means of enzymatic methods and through the electrophoretic technique. All data were analysed by multifactor anova test to determine which factors (age, gender, breed and diet) have a statistically significant effect (p < 0.05) on the determined parameter and subsequently Bonferroni's test was applied where necessary. Gender, age, breed and diet can significantly affect lipid metabolism, in particular lipoproteins involved in cholesterol plasma transport; on the contrary, triglycerides are not influenced by the same factors. The most important observation about age is the high level of C-LDL in puppies under 1 year of age. The highest cholesterol concentrations are found in Rottweiler but high values of plasma cholesterol are found also in Pyrenees Mountain dog and a great level of C-LDL in Labrador. Diet has shown a great influence on lipidic metabolism: dogs fed with different high-quality dry foods had significant differences in plasma cholesterol values (C-tot, C-HDL, C-LDL,), in particular, dogs fed with a diet rich in fish and fish-by-products have shown the lowest levels of C-tot, C-HDL and C-LDL.
| 19,012,618
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Opening of microglial K(ATP) channels inhibits rotenone-induced neuroinflammation.
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As activated microglia (MG) is an early sign that often precedes and triggers neuronal death, inhibition of microglial activation and reduction of subsequent neurotoxicity may offer therapeutic benefit. The present study demonstrates that rat primary cultured MG expressed Kir6.1 and SUR2 subunits of K(ATP) channel, which was identical to that expressed in BV-2 microglial cell line. The classic K(ATP) channel opener pinacidil and selective mitochondrial K(ATP) (mito-K(ATP)) channel opener diazoxide prevented rotenone-induced microglial activation and production of pro-inflammatory factors (tumour necrosis factor[TNF]-alpha and prostaglandin E(2)[PGE(2)]). And the effects of pinacidil and diazoxide were reversed by mito-K(ATP) blocker 5-hydroxydecanoate (5-HD), indicating that mito-K(ATP) channels participate in the regulation of microglial activation. Moreover, the underlying mechanisms involved the stabilization of mitochodrial membrane potential and inhibition of p38/c-Jun-N-terminal kinase (JNK) activation in microglia. Furthermore, the in vivo study confirmed that diazoxide exhibited neuroprotective effects against rotenone along with the inhibition of microglial activation and neuroinflammation. Thus, microglial mito-K(ATP) channel might be a novel prospective target for the treatment of neuroinflammation-related degenerative disorders such as Parkinson's disease.
| 19,012,619
|
Sociogenomic personality psychology.
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In this article, we address a number of issues surrounding biological models of personality traits. Most traditional and many contemporary biological models of personality traits assume that biological systems underlying personality traits are causal and immutable. In contrast, sociogenomic biology, which we introduce to readers in this article, directly contradicts the widely held assumption that something that is biological, heritable, or temperamental, is unchangeable. We provide examples of how seemingly unchanging biological systems, such as DNA, are both dependent on environments for elicitation and can be modified by environmental changes. Finally, we synthesize sociogenomic biology with personality psychology in a model of personality traits that integrates this more modern perspective on biology, physiology, and environment that we term sociogenomic personality psychology. We end the article with a discussion of the future directions of sociogenomic personality psychology.
| 19,012,657
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Structures of personality and their relevance to psychopathology: II. Further articulation of a comprehensive unified trait structure.
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There is increasing agreement that the current categorical system of personality disorders (PDs) in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; American Psychiatric Association, 2000) should be replaced by a trait dimensional scheme in DSM-V. In particular, the consensus appears to be converging on a hierarchical Big Four model. The broad factors that form the apex of this hierarchy are essentially maladaptive variants of the Big Five traits of normal personality, minus Openness. We argue that this Big Four model is incomplete, however, in that it fails to model characteristics related to the "odd or eccentric" Cluster A PDs adequately. We report the results of three studies that examine these odd, eccentric characteristics in relation to basic dimensions of normal and abnormal personality. The results of these studies establish the existence of an Oddity factor that is (a) broader than the Cluster A traits and (b) distinct from Openness and the other Big Five dimensions. Consequently, its addition yields an alternative five-factor model of personality pathology (considering only abnormal traits) and an expanded, integrated Big Six taxonomy that subsumes both normal and abnormal personality characteristics.
| 19,012,658
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The effects of physical exercises to mental state and quality of life in patients with schizophrenia.
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The purpose of this study was to examine the effects of 10 weeks of physical exercises programme on mental states and quality of life (QOL) of individuals with schizophrenia. The study involved 30 inpatients or outpatients with schizophrenia who were assigned randomly into aerobic exercise (n = 15) group and control (n = 15) group, participated to the study voluntarily. There were no personal differences such as age, gender, disorder duration, medication use between the both groups. An aerobic exercise programme was applied to the subject group, the periods of 10 weeks as 3 days in a week. Data were collected by using the Brief Symptom Inventory, the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms and to the both group before and after the exercise programme. After the 10-week aerobic exercise programmes the subjects in the exercise programme showed significantly decreases in the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms and the Brief Symptom Inventory points and their World Health Organization Quality of Life Scale-Turkish Version points were increased than controls. These results suggest that mild to moderate aerobic exercise is an effective programme for decreasing psychiatric symptoms and for increasing QOL in patients with schizophrenia.
| 19,012,672
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Cognitive behaviour therapy within assertive outreach teams: barriers to implementation: a qualitative peer audit.
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Assertive outreach is an evidence-based intervention, with over 30 well-designed randomized studies demonstrating its effectiveness, predominately in the USA. Assertive outreach teams have recently been implemented in the UK, and it has been recommended that teams should offer cognitive behaviour therapy (CBT) to service users; however, it has been reported that barriers exist in the routine delivery of CBT for psychosis (CBTp). The aim of the peer audit was to gauge current opinion from clinicians whether their experiences of barriers to implementation of CBTp reflected that outlined in the literature. A qualitative peer audit was undertaken at the National Forum for Assertive Outreach Annual Conference in 2006. The team representatives were invited to outline the barriers to the implementation of psychosocial interventions within their local areas. Teams identified organizational, managerial, supervision and local specific barriers to implementation. Specific comments included a lack of organizational investment, the structured nature of CBT, caseload issues, medication issues, application to people with sensory impairments, staff apathy and staff burnout. The analysis was limited by the metholodology employed; however, further recommendations are explored. It was evident from this peer audit that teams are experiencing barriers relating to the implementation of evidence-based therapy interventions and further research is required on the outreach model and the use of CBTp.
| 19,012,676
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Effectiveness of weight management interventions for people with serious mental illness who receive treatment with atypical antipsychotic medications. A literature review.
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Weight gain associated with treatment with atypical antipsychotic medication has been widely recognized as a risk factor for the development of diabetes and cardiovascular diseases. A systematic search was conducted of major databases and of citations for material about the effectiveness of weight management interventions for people with serious mental illness who receive treatment with atypical antipsychotic medications. Studies were included if the focus was on improvement in weight profile through the application of psychoeducational or exercise and dietary interventions and where outcome measures were reported and presented in recognized values. Out of 221 studies, 19 met the inclusion criteria and after assessment of the quality of the studies, eight were selected for detailed review.
| 19,012,677
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Cigarette smoking and glutathione S-transferase M1 polymorphism associated with risk for uterine cervical cancer.
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To elucidate the role of tobacco smoking and polymorphisms of carcinogen metabolism genes in cervical carcinogenesis. We analyzed genotypes of nine genes, 11 polymorphisms encoding carcinogen metabolizing enzymes, information on smoking, and the presence of human papillomavirus in 124 Japanese cervical cancer patients and 125 healthy controls. The incidence of human papillomavirus infection (95.5% vs 9.9%; P < 0.001; odds ratio (OR), 231.98; 95% confidence interval [CI], 57.17-941.22), and smoking (41.1% vs 18.4%; P < 0.001; OR, 3.40; 95% CI, 1.88-6.17) were both significantly higher in patients than in controls. The genotype distributions of CYP1A1, CYP2E1, CYP2A6, NQO1, NAT2, mEH, MPO and GSTT1 genes were not statistically different; however, the ratio of the GSTM1 null genotype was significantly higher in patients than in controls (62.1% vs 47.2%; P = 0.019; OR, 1.83; 95% CI, 1.11-3.04). The incidence of GSTM1 null was significantly higher in the non-smoking group (63.0% vs 47.1%; P = 0.038; OR, 1.92; 95% CI, 1.04-3.54), and not in the smoking group (60.8% vs 47.8%; P = 0.300; OR, 1.69; 95% CI, 0.63-4.56). In the current study, risk factors for developing cervical cancer were tobacco smoking and GSTM1 null; however, no association was observed between these two factors. We could not prove that smoking-GSTM1 null interaction was responsible for the increase in cervical cancer among young Japanese, and further studies with more detailed smoking status, not only active but passive smoking, will be required.
| 19,012,698
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Does laparoscopic cystectomy and cauterization of endometriomas greater than 3 cm diminish ovarian response to controlled ovarian hyperstimulation during IVF-ET? A case-control study.
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The objective of this study is to evaluate the in vitro fertilization and embryo transfer results of patients with endometriomas pretreated with laparoscopic cystectomy and cauterization compared with age-matched tubal infertility patients. Records of the in vitro fertilization and embryo transfer unit have been retrospectively reviewed from September 2000 to September 2004. Twenty-two patients who underwent surgery for endometriomas and participated in an in vitro fertilization and embryo transfer procedure, were detected and age-matched with 22 tubal factor infertility patients. Higher follicle numbers greater than 14 mm in size were achieved in the tubal infertility group than the endometriosis group. Duration of hyperstimulation, number of ampoules used, good quality embryos, transferred embryos and fertilization rates were similar in each group. Clinical pregnancy rates per cycle, determined as fetal heart beat demonstration on sonography, were 45% and 36% for the endometrioma group and the tubal infertility group respectively. Laparoscopic cystectomy and cauterization for ovarian endometriomas decreases ovarian follicle reserve and does not impede pregnancy rate per cycle during in vitro fertilization and embryo transfer procedure.
| 19,012,700
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Caring for families coping with perinatal loss.
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To describe support needs and comfort level of labor nurses caring for families experiencing perinatal loss. Qualitative descriptive study. A western hospital birthing unit. Ten labor nurses. Participants completed online surveys and follow-up interviews; data saturation was reached. Content analysis produced themes and recommendations related to providing perinatal bereavement care. Participants reviewed and confirmed accuracy of the results. Nurses are generally comfortable but find it difficult to provide perinatal bereavement care. Strategies for coping include focusing on needed care, talking to nursing peers, and spending time with their own family members. Nurses take turns providing care depending on "who is best able to handle it that day" and prefer not to be assigned a laboring patient in addition to the grieving parents. Developing clinical expertise is necessary to gain the comfort level and the skills necessary to care for these vulnerable families. Orientation experiences and nursing staff debriefing would help. Needed education includes grief training, communication techniques, and guidelines for the extensive paperwork. Initial and ongoing education of nurses about perinatal bereavement care is needed. Effective strategies for coping during and after providing care would support nurses in meeting the emotional challenge of providing high quality perinatal bereavement care.
| 19,012,713
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Sleep quality in women with and without postpartum depression.
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To compare and measure the effects of sleep quality in women with and without postpartum depression. A case-control repeated measures matched pairs design. Home and obstetric office. Forty-six women who were 6 to 26 weeks postpartum. Two participants were dropped from the final analysis because they were outliers. Participants underwent wrist actigraphy at home for 7 consecutive days to measure sleep quality. The Postpartum Depression Screening Scale measured depression severity. Psychosocial variables were collected during a screening interview. A structured clinical interview was used to diagnose postpartum depression. Correlations, t tests, and hierarchical multiple regressions were run to analyze data. With the exception of wake episodes, sleep latency (B=1.80, SE=0.73, p<.05), wake after sleep onset (B=6.85, SE=2.85, p<.05), and thus sleep efficiency (B=-6.31, SE=3.13, p<.05) predicted postpartum depression symptom severity. Women with postpartum depression experienced poorer sleep quality than women without postpartum depression, and sleep quality worsened with increasing postpartum depression symptom severity. Clinicians need to address measures to improve sleep quality in depressed mothers to decrease symptom severity, and researchers need to develop interventions to facilitate better sleep quality in women with postpartum depression.
| 19,012,723
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Effect of homocysteine on calcium mobilization and platelet function in type 2 diabetes mellitus.
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Type 2 diabetes mellitus induces a characteristic platelet hyperactivity that might be due to several factors including oxidative stress and abnormal intracellular Ca(2+) homeostasis. Hyperhomocysteinaemia is considered a risk factor in the development of thrombosis although its effect on platelet function and the mechanisms involved are still poorly understood. Here we show that homocysteine induce a concentration-dependent increase in endogenous production of reactive oxygen species (ROS), which was significantly greater in platelets from diabetic patients than in controls. Platelet treatment with homocysteine resulted in Ca2+ release from the dense tubular system and the acidic stores. Ca2+ mobilization-induced by homocysteine consisted in two components, an initial slow increase in intracellular free Ca (+) concentration ([Ca2+]i) and a rapid and marked increase in [Ca2+]i, th second leading to the activation of platelet aggregation. As well as ROS generation, Ca2+ mobilization and platelet aggregation were significantly greater in platelets from diabetic donors than in controls, which indicate that platelets from diabetic donors are more sensitive to homocysteine. These findings, together with the hyperhomocysteinaemia reported in diabetic patients, strongly suggest that homocysteine might be considered a risk factor in the development of cardiovascular complications associated to type 2 diabetes mellitus.
| 19,012,728
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Role of oxidative stress and caspase 3 in CD47-mediated neuronal cell death.
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CD47 or integrin-associated protein promotes cell death in blood and tumor cells. Recently, CD47 signaling has been identified in neurons as well. In this study, we investigated the role of CD47 in neuronal cell death. Exposure of primary mouse cortical neurons to the CD47 ligand thrombospondin-1 or the specific CD47-activating peptide 4N1K induced cell death. Activation of CD47 elevated levels of active caspase 3 and increased the generation of reactive oxygen species (ROS) in a time-dependent manner. Both ROS scavengers and caspase inhibitors attenuated cell death. But ROS scavenging did not reduce the activation of caspase 3, and combination treatments with a caspase inhibitor plus free radical scavenger did not yield additive protection. Taken together, these data suggest that parallel and redundant pathways of oxidative stress and caspase-mediated cell death are involved. We conclude that CD47 mediates neuronal cell death through caspase-dependent and caspase-independent pathways.
| 19,012,741
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The mechanisms of oxidative DNA damage and apoptosis induced by norsalsolinol, an endogenous tetrahydroisoquinoline derivative associated with Parkinson's disease.
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Tetrahydroisoquinoline (TIQ) derivatives are putative neurotoxins that may contribute to the degeneration of dopaminergic neurons in Parkinson's disease. One TIQ, norsalsolinol (NorSAL), is present in dopamine-rich areas of human brain, including the substantia nigra. Here, we demonstrate that NorSAL reduces cell viability and induces apoptosis via cytochrome c release and caspase 3 activation in SH-SY5Y human neuroblastoma cells. Cytochrome c release, caspase 3 activation, and apoptosis induction were all inhibited by the antioxidant N-acetylcysteine. Thus, reactive oxygen species (ROS) contribute to apoptosis induced by NorSAL. Treatment with NorSAL also increased levels of oxidative damage to DNA, a stimulus for apoptosis, in SH-SY5Y. To clarify the mechanism of intracellular DNA damage, we examined the DNA damage caused by NorSAL using (32)P-5'-end-labeled isolated DNA fragments. NorSAL induced DNA damage in the presence of Cu(II). Catalase and bathocuproine, a Cu(I) chelator, inhibited this DNA damage, suggesting that ROS such as the Cu(I)-hydroperoxo complex derived from the reaction of H(2)O(2) with Cu(I), promote DNA damage by NorSAL. In summary, NorSAL-generated ROS induced oxidative DNA damage, which led to caspase-dependent apoptosis in neuronal cells.
| 19,012,744
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Altered hippocampal long-term synaptic plasticity in mice deficient in the PGE2 EP2 receptor.
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Our laboratory demonstrated previously that PGE2-induced modulation of hippocampal synaptic transmission is via a pre-synaptic PGE2 EP2 receptor. However, little is known about whether the EP2 receptor is involved in hippocampal long-term synaptic plasticity and cognitive function. Here we show that long-term potentiation at the hippocampal perforant path synapses was impaired in mice deficient in the EP2 (KO), while membrane excitability and passive properties in granule neurons were normal. Importantly, escape latency in the water maze in EP2 KO was longer than that in age-matched EP2 wild-type littermates (WT). We also observed that long-term potentiation was potentiated in EP2 WT animals that received lipopolysaccharide (LPS, i.p.), but not in EP2 KO. Bath application of PGE2 or butaprost, an EP2 receptor agonist, increased synaptic transmission and decreased paired-pulses ratio in EP2 WT mice, but failed to induce the changes in EP2 KO mice. Meanwhile, synaptic transmission was elevated by application of forskolin, an adenylyl cyclase activator, both in EP2 KO and WT animals. In addition, the PGE2-enhanced synaptic transmission was significantly attenuated by application of PKA, IP3 or MAPK inhibitors in EP2 WT animals. Our results show that hippocampal long-term synaptic plasticity is impaired in mice deficient in the EP2, suggesting that PGE2-EP2 signaling is important for hippocampal long-term synaptic plasticity and cognitive function.
| 19,012,750
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A review of psychosocial needs of breast-cancer patients and their relatives.
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To identify the psychosocial needs of breast-cancer patients and their relatives along with factors affecting these needs and to develop a tentative model to guide further research and need assessments in clinical practice. Women experiencing breast cancer must deal with the diagnosis of a life-threatening illness. Treatment and the recovery process can be demanding for patients and their relatives. Need assessment may help clinicians focus on providing appropriate help. Literature review. Undertaken using electronic databases and specific research terms; 20 articles were identified and analysed. The needs identified by patients involve (1) treatment-related physical and social impairment like fatigue, menopausal symptoms and a changed body image and (2) emotional distress like fear of recurrence, anxiety and depression. Partners need help to protect themselves and the patient from different threats. Women need information to maintain control and manage their illness. Partners want information concerning the patient's condition and both of them about the prognosis and perspectives. There is a lack of knowledge of relatives' needs. Mutual familial support, women's and partners' health and emotional distress may affect the interaction between the patients and their partners. A tentative family-based model to guide further research and clinical support is proposed. Further research is needed to determine precisely which psychosocial factors may influence fulfilment of the patients' and relatives' needs. The proposed model may provide a framework for healthcare professionals to evaluate the patients' and relatives' met and unmet needs and the real demand for help, to guide care planning, counselling and education.
| 19,012,759
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Drug use and pressure ulcers in long-term care units: do nurse time pressure and unfair management increase the prevalence?
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This study examined the associations between nurse working conditions (time pressure and perceived unfair management) and quality indicators (prevalence of antianxiety or hypnotic drug use and pressure ulcers) in long-term care units. Differences persist across long-term care facilities in their care processes and resident outcomes even after adjusting for residents' clinical conditions. Little is known about how nurses' working conditions influence the quality of care. Survey. Data on working conditions were drawn in 2002 from 724 nurses in 66 long-term care units that reported quality indicators based on the Resident Assessment Instrument system as measured by Minimum Data Set. Percentage change in the quality indicators from 2002 were estimated using hierarchical multiple regression analyses with adjustments made for the baseline quality indicators (2001) and unit structural factors (unit size and staffing level). Unit time pressure increased the prevalence of both quality problems (p-values <0.05). Perceived unfair management was related to increased drug use (p = 0.038). The findings of this research suggest that quality of care can be improved by enhancing nurse working conditions. Organisational initiatives should be aimed at reducing time pressures and promoting fair managerial procedures that engage all nursing staff in the decision-making in long-term care settings.
| 19,012,772
|
Divergence in cis-regulatory networks: taking the 'species' out of cross-species analysis.
|
Many essential transcription factors have conserved roles in regulating biological programs, yet their genomic occupancy can diverge significantly. A new study demonstrates that such variations are primarily due to cis-regulatory sequences, rather than differences between the regulators or nuclear environments.
| 19,012,800
|
Monetary cost of self-reported diet in relation to biomarker-based estimates of nutrient intake in young Japanese women.
|
All previous studies on monetary diet cost have examined the relationship of monetary cost of self-reported diet to self-reported, rather than biomarker-based, estimates of dietary intake. The present cross-sectional study examined the association between monetary costs of self-reported diet and biomarker-based estimates of nutrient intake. Monetary diet cost (Japanese yen/1000 kJ) was calculated based on dietary intake information from a self-administered, comprehensive diet history questionnaire using retail food prices. Biomarker-based estimates of nutrient intake (percentage of energy for protein and mg/1000 kJ for K and Na) were estimated based on 24 h urinary excretion and estimated energy expenditure. A total of fifteen universities and colleges in Japan. A total of 1046 female Japanese dietetic students aged 18-22 years. Total monetary diet cost showed a significant positive association with biomarker-based estimates of protein, K and Na. Vegetables and fish were not only the main contributors to total monetary diet cost (16.4 % and 15.5 %, respectively) but also were relatively strongly correlated with total monetary diet cost (Pearson's correlation coefficient: 0.70 and 0.68, respectively). Monetary cost of vegetables was significantly positively associated with all three nutrients, while that of fish showed a significant and positive association only with protein. Total monetary cost of self-reported diet was positively associated with biomarker-based estimates of protein, K and Na intake in young Japanese women, and appeared mainly to be explained by the monetary costs of vegetables and fish.
| 19,012,801
|
High sensitivity detection of 16s rRNA using peptide nucleic acid probes and a surface plasmon resonance biosensor.
|
A signal enhancing method allowing highly sensitive detection of E. coli 16s rRNA was developed using peptide nucleic acid (PNA) as a capture probe and a surface plasmon resonance (SPR) sensor as a detector. 16s rRNA has been used as a genetic marker for identification of organisms, and can be analyzed directly without PCR amplification due to the relatively high number of copies. PNA has a neutral backbone structure, therefore hybridization with 16s rRNA results in the ionic condition being changed from neutral to negative. A cationic Au nanoparticle was synthesized and used for signal amplification by ionic interaction with 16s rRNA hybridized on the PNA probe-immobilized SPR sensor chip. This method resulted in a detection limit of E. coli rRNA of 58.2+/-1.37 pg mL(-1). Using this analytical method, Staphylococcus aureus was detected without purification of rRNA.
| 19,012,828
|
The role of peer e-mail support as part of a college smoking-cessation website.
|
Helping young smokers to quit early in life substantially reduces the risk of later morbidity and mortality due to tobacco use. The RealU study demonstrated the efficacy of a smoking-cessation website for college students that incorporated both individually tailored feedback and peer e-mail support. The relationship between peer e-mail support and cessation outcomes among intervention participants is examined here. This study was conducted at the University of Minnesota Twin Cities from Fall 2004 through Spring 2005. During the intervention period, peer-support students (E-pals) wrote weekly e-mails to intervention group participants (n=257) encouraging healthy behaviors including smoking abstinence. Ten survey items assessed perceived E-pal supportiveness. The number of e-mails replies sent by the participants to their E-pal was tracked as a measure of e-mail engagement. The primary outcome was self-reported 30-day abstinence at the end of the intervention period. Over the course of the intervention, participants sent an average of 4.6 (SD=3.6) e-mails to their E-pals. Perceived E-pal support was significantly correlated with e-mail engagement (p<0.001). At Week 30, 40.5% of individuals in the RealU intervention group (104/257) reported not smoking any cigarettes in the prior 30 days. Bivariate analyses indicated that 30-day abstinence was related to both perceived support from the E-pal (p<0.001) and e-mail engagement (p<0.001). Multivariate analyses indicated that after controlling for age and baseline-level smoking, e-mail engagement remained a significant predictor of 30-day abstinence (p<0.001). Greater peer engagement via e-mail was associated with increased smoking abstinence and reduced frequency of smoking. These findings suggest that online peer support may be an important strategy when delivering Internet-assisted cessation programs to young adults.
| 19,012,841
|
Tobacco-use prevalence in special populations taking advantage of electronic medical records.
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It is difficult and expensive to use surveys to obtain the repeatable information that is needed to understand and monitor tobacco prevalence rates and to evaluate cessation interventions among various subgroups of the population. Therefore, the electronic medical record database of a large medical group in Minnesota was used to demonstrate the potential value of that approach to accomplish those goals. The relevant variables for all medical group patients aged 18 and over were extracted from the record from a 1-year period. Rates of smoking prevalence were computed for the entire population as well as for those with various characteristics and combinations of characteristics of interest to tobacco-cessation advocates. These prevalence rates were also adjusted to control for the other characteristics in the analysis. From March 2006 to February 2007, there were 183,982 unique patients with at least one office visit with a clinician, and a record of their tobacco-use status (90%). Overall, 19.7% with recorded status were tobacco users during this year, as were 24.2% of those aged 18-24 years, 16.0% of pregnant women, 34.3% of those on Medicaid, 40.0% of American Indians, 9.5% of Asians, and 8.5% of those whose preferred language was other than English. Combining characteristics allowed greater understanding of those differences. Although there are limitations in these data, the level of detail available for this large population and the ease of repeat analysis should greatly facilitate targeted interventions and evaluation of the impact.
| 19,012,845
|
Alterations in CDH15 and KIRREL3 in patients with mild to severe intellectual disability.
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Cell-adhesion molecules play critical roles in brain development, as well as maintaining synaptic structure, function, and plasticity. Here we have found the disruption of two genes encoding putative cell-adhesion molecules, CDH15 (cadherin superfamily) and KIRREL3 (immunoglobulin superfamily), by a chromosomal translocation t(11;16) in a female patient with intellectual disability (ID). We screened coding regions of these two genes in a cohort of patients with ID and controls and identified four nonsynonymous CDH15 variants and three nonsynonymous KIRREL3 variants that appear rare and unique to ID. These variations altered highly conserved residues and were absent in more than 600 unrelated patients with ID and 800 control individuals. Furthermore, in vivo expression studies showed that three of the CDH15 variations adversely altered its ability to mediate cell-cell adhesion. We also show that in neuronal cells, human KIRREL3 colocalizes and interacts with the synaptic scaffolding protein, CASK, recently implicated in X-linked brain malformation and ID. Taken together, our data suggest that alterations in CDH15 and KIRREL3, either alone or in combination with other factors, could play a role in phenotypic expression of ID in some patients.
| 19,012,874
|
Working harder to obtain more snack foods when wanting to eat less.
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This study investigates individual differences in the reinforcing value of snack food. More specifically, it was investigated whether differences in restraint status are associated with differences in working for high-caloric snack food. Thirty-six unrestrained non-dieters, twenty restrained non-dieters and fifteen current dieters performed a concurrent schedules task in which they had the option to work for points for either snack food or fruit and vegetables. By progressively increasing the "price" of the snack foods (i.e., the amount of work required to obtain extra snack points) the relative reinforcing value of snack food was determined. As hypothesized, restrained non-dieters worked harder and current dieters worked less hard to obtain snack food as compared to unrestrained non-dieters.
| 19,012,877
|
Internally self-assembled particles entrapped in thermoreversible hydrogels.
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The present study describes the development of thermogelling emulsions by the entrapment of internally self-assembled emulsion droplets (ISAsomes) within a thermoreversible hydrogel made of kappa-carrageenan. The droplets are emulsified mesophases of cubic or hexagonal order, or emulsified micro-emulsions. Above 60 degrees C, the system was fluid and composed of a mixture of internally nanostructured small droplets and polymer chains dispersed in water. Below 60 degrees C, a physical gel with entrapped droplets was formed. A tuning of the temperature in order to switch between the gel and solution state did not affect the particles in terms of size. The thermoreversible behavior of the loaded polymer network and the effects on the internal structure of cubosomes, hexosomes and emulsified micro-emulsions was investigated by SAXS. We showed that the phase borders may be shifted due to the presence of the kappa-carrageenan network, which alter the internal nanostructure of the droplets. This can induce a transformation from emulsified micro-emulsions to micellar cubosomes. In the hexagonal case, the lattice parameters of the hexosomes are slightly modified.
| 19,012,899
|
Laparoscopic partial nephrectomy for central tumors: analysis of perioperative outcomes and complications.
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We report our experience with laparoscopic partial nephrectomy for central tumors compared to peripheral tumors to analyze the feasibility and safety of the laparoscopic approach to these complex cases. Between October 2002 and July 2007, 212 patients underwent laparoscopic partial nephrectomy. In 53 patients the tumor was central and in 159 it was peripheral. The preoperative, intraoperative and postoperative data, the type and incidence of complications, and the quality of excision in terms of surgical margin status were compared between the 2 groups. Mean estimated blood loss (320 and 360 ml, respectively, p >0.05) and mean operative time (126 and 118 minutes, respectively, p >0.05) were similar in the central and peripheral tumor groups. Mean warm ischemia time in the central tumor group was longer (37 and 28 minutes, respectively, p <0.05) but median time was similar (30 and 29 minutes, respectively, p >0.05). The open conversion rate was significantly lower in the study group (1% vs 5.6%, p <0.05). The urological complication rate was similar in the 2 groups (9.4% vs 8.4%, p >0.05). However, different types of complications developed in each group. Four patients (7.5%) with central tumors had late hematuria (arterial pseudoaneurysm) and only 1 (1.9%) had a urine leak. Central tumors were larger (3.2 vs 2.5 cm) and more frequently malignant (94% vs 82%, p >0.05). Positive surgical margins were diagnosed in 0% vs 5% of cases (p <0.05). Provided that there is adequate laparoscopic expertise the outcome of laparoscopic partial nephrectomy for central tumors is comparable to that of peripheral tumors. The main major complication in this group was late onset hematuria, which necessitated angiographic embolization. This facility should be available at centers where these advanced procedures are performed.
| 19,012,908
|
Impact of P2Y(12) inhibitory effects induced by clopidogrel on platelet procoagulant activity in type 2 diabetes mellitus patients.
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Type 2 diabetes mellitus (T2DM) patients have a variable response profile to the P2Y(12) receptor antagonist clopidogrel. P2Y(12) receptor signalling promotes platelet procoagulant activity. The aim of this study was to determine if T2DM patients with suboptimal clopidogrel response have greater platelet procoagulant activity compared with optimal responders and evaluate if this can be modulated by enhancing P2Y(12) receptor inhibition. A total of 50 T2DM patients in a steady state phase of clopidogrel therapy were studied. Suboptimal responders were randomly assigned to standard (75 mg) or high (150 mg) clopidogrel maintenance therapy for one-month. Afterwards, all patients resumed standard therapy. Platelet procoagulant activity assessed by thrombin-induced platelet-fibrin clot formation using thrombelastography (TEG) was determined at baseline, one-month post-randomization, and one-month after resuming standard therapy. In the overall study population, the reaction time (R), a measure of time to initial thrombin induced platelet-fibrin clot formation, and the time to maximum rate of thrombin generation (TMRTG) values were 6.3+/-1.7 and 7.6+/-1.9 minutes, respectively. Suboptimal clopidogrel responders (n=30) had acceleration of R (p=0.002) and TMRTG (p=0.002) compared to optimal responders (n=20). Suboptimal clopidogrel responders treated with a 150 mg dose showed prolongation of R (p=0.0001) and TMRTG (p<0.0001), which returned to baseline values after resuming standard dosage. No differences were observed among patients randomized to 75 mg. T2DM patients with suboptimal clopidogrel response have enhanced platelet procoagulant activity compared to patients with optimal response, which can be down-regulated by more potent platelet P2Y(12) inhibition using high clopidogrel maintenance dosing.
| 19,012,950
|
Calibrated automated thrombin generation and modified thromboelastometry in haemophilia A.
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Global coagulation tests may have a better relation with phenotype in haemophilia than traditional coagulation tests. These include the Calibrated Automated Thrombin generation assay (CAT) and modified thromboelastometry using low tissue factor triggering. Both have shown marked variability in thrombin generation and clot formation profiles respectively despite similar FVIII:C levels and have been suggested as means to monitor treatment. Data with modified thromboelastometry are largely limited to severe and moderate haemophiliacs. CAT measurements in haemophilia are generally performed at low TF concentrations (1 pM) because of a higher sensitivity for the intrinsic pathway at this concentration but is also sensitive for FVIII at higher concentrations (5 pM) and this has the advantage that inhibition of contact factor activation can be avoided. No formal comparison of both TF concentrations has been reported and the data on modified thromboelastometry in mild haemophilia are limited. In this study we compared thrombin generation at 1 and 5 pM in 57 haemophilia patients without exposure to treatment and 41 patients after treatment. We also assessed the sensitivity of thromboelastometry for haemophilia A in 29 patients. We found that CAT discriminates well between normal individuals and haemophilia patients; also FVIII:C correlates well with the ETP/peak. We found no clear advantages of measurements at 1 compared to 5 pM but found increased variation over time at 1 pM. The sensitivity of modified thromboelastometry for haemophilia A was less than CAT with abnormal measurements largely limited to severe and moderate patients. Larger studies correlating both methods with clinical outcome are required.
| 19,012,951
|
HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis.
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In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not reduce plasma viraemia after infection, and HIV-1 incidence was higher in vaccine-treated than in placebo-treated men with pre-existing adenovirus serotype 5 (Ad5) immunity. We assessed vaccine-induced immunity and its potential contributions to infection risk. To assess immunogenicity, we characterised HIV-specific T cells ex vivo with validated interferon-gamma ELISPOT and intracellular cytokine staining assays, using a case-cohort design. To establish effects of vaccine and pre-existing Ad5 immunity on infection risk, we undertook flow cytometric studies to measure Ad5-specific T cells and circulating activated (Ki-67+/BcL-2(lo)) CD4+ T cells expressing CCR5. We detected interferon-gamma-secreting HIV-specific T cells (range 163/10(6) to 686/10(6) peripheral blood mononuclear cells) ex vivo by ELISPOT in 77% (258/354) of people receiving vaccine; 218 of 354 (62%) recognised two to three HIV proteins. We identified HIV-specific CD4+ T cells by intracellular cytokine staining in 58 of 142 (41%) people. In those with reactive CD4+ T cells, the median percentage of CD4+ T cells expressing interleukin 2 was 88%, and the median co-expression of interferon gamma or tumor necrosis factor alpha (TNFalpha), or both, was 72%. We noted HIV-specific CD8+ T cells (range 0.4-1.0%) in 117 of 160 (73%) participants, expressing predominantly either interferon gamma alone or with TNFalpha. Vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile, did not differ between vaccinated male cases (before infection) and non-cases. Ad5-specific T cells were lower in cases than in non-cases in several subgroup analyses. The percentage of circulating Ki-67+BcL-2(lo)/CCR5+CD4+ T cells did not differ between cases and non-cases. Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells. Our findings suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial.
| 19,012,957
|
Methods for siRNA-mediated reduction of mRNA and protein expression in human placental explants, isolated primary cells and cell lines.
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The use of RNA interference (RNAi) to deplete individual proteins from cells or tissue has revolutionised our ability to characterise gene function. The placenta is an attractive target for studies in which the role of specific proteins can be compared with cell culture models and explanted villous tissue where physiological function can be maintained ex vivo. In this study, we compared a variety of commercially available reagents and approaches to define methods for efficient delivery of siRNA to placental cells. Protocols optimised using fluorescently-labelled siRNA were subsequently tested using siRNA sequences that target placental alkaline phosphatase (PLAP), chosen because of its high abundance in trophoblast. mRNA abundance was assayed using qRT-PCR, and the effect on protein was examined using immunolocalisation. We report that different protocols are required for BeWo choriocarcinoma cells (nucleofection), primary cytotrophoblast cells (lipid-based transfection) and villous tissue explants (nucleofection). The results provide guidelines for optimal siRNA-mediated knockdown in these three models of the human placenta.
| 19,012,963
|
Management of suprastomal tracheal fibroma: introduction of a new technique and comparison with other techniques.
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Suprastomal tracheal granuloma/fibroma (SSTGF) is a common cause of failure to decannulate following pediatric tracheostomy. Because larger lesions obstruct the trachea, it is necessary to remove them prior to decannulation. Various methods have been described for the management of these obstructing tracheal lesions, including the KTP laser, Nd-YAG laser, sphenoid punch, optical forceps, microsuspension laryngoscopy with an articulated arm (MSLAA), and external excision. A hollow core guide fiber for the CO(2) laser has been developed that can be advanced to better approximate targeted tissues and minimize thermal spread using a near-contact method. A retrospective chart review was performed of 30 children under the age of 7 years (21M, 9F) with SSTGF who underwent treatment by either external excision (n=10), MSLAA (n=10), or CO(2) laser vaporization by fiberoptic laser carrier (n=10). The medical charts were reviewed for excision techniques and outcomes. Mean operative time for external excision was 34.9min (SD=10.2min), for MSLAA was 16.3min (SD=4.8min), and for fiberoptic CO(2) laser carrier was 19.3min (SD=7.1min). Mean hospital time postoperatively for external excision was 24h (SD=510min), for MSLAA was 3.3h (SD=37.7min), and for fiberoptic CO(2) laser carrier was 3.9h (SD=46.3min). Need for additional procedures was seen in 60% of external excision procedures, 70% of MSLAA procedures, and in 30% of fiberoptic CO(2) laser carrier procedures. Immediate postoperative decannulation was possible in 10% of the external excision group, 20% of the MSLAA group, and 40% of the fiberoptic CO(2) laser carrier group. The new technique of using a fiberoptic carrier for the CO(2) laser to treat children with SSTGF's is comparable to more traditional techniques of SSTGF removal when considering the need for additional procedures, postoperative hospital stay, and percentage of immediate postoperative decannulation and provides another useful tool in the armamentarium of the surgeon in treating SSTGF's.
| 19,012,974
|
Inter-fraction motion and dosimetric consequences during breast intensity-modulated radiotherapy (IMRT).
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Intensity-modulated radiotherapy (IMRT) can improve dose homogeneity within the breast planned target volume (PTV), but may be more susceptible to patient/organ motion than standard tangential radiotherapy (RT). We used daily cone-beam CT (CBCT) imaging to assess inter-fraction motion during breast IMRT and its subsequent impact on IMRT and standard RT dose homogeneity. Ten breast cancer patients selected for IMRT were studied. CBCT images were acquired immediately after daily treatment. Automatic image co-registration was used to determine patient positioning variations. Daily PTV contours were used to calculate PTV variations and daily delivered IMRT and theoretically planned tangential RT dose. Group systematic (and random) setup errors detected by CBCT were 5.7 (3.9)mm laterally, 2.8 (3.5)mm vertically and 2.3 (3.2)mm longitudinally. Rotations >2 degrees in any axis occurred on 53/106 (50%) occasions. Daily PTV volume varied up to 23%. IMRT dose homogeneity was superior at planning and throughout the treatment compared with standard RT (1.8% vs. 15.8% PTV received >105% planned mean dose), despite increased motion sensitivity. CBCT revealed inadequacies of current patient positioning and verification procedures during breast RT and confirmed improved dose homogeneity using IMRT for the patients studied.
| 19,012,980
|
Dyspnea evolution after high-dose radiotherapy in patients with non-small cell lung cancer.
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To determine what the influence is of dyspnea (CTCAE3.0) before high-dose radiotherapy (RT) on the incidence and severity of subsequent lung toxicity in patients with non-small cell lung cancer (NSCLC). In 197 patients with stage I-III NSCLC maximal dyspnea scores (CTCAE3.0) were obtained prospectively at three time periods: before RT, the first 6 months post-RT and 6-9 months post-RT. Only patients who were clinically progression-free 12 months or more after RT were included, thus minimizing dyspnea due to tumor progression. Time-trends of dyspnea as a function of baseline dyspnea were investigated and correlated with gender, age, chemotherapy, mean lung dose (MLD), lung function parameters (FeV1 and DLCO), stage, PTV dose, overall treatment time and smoking habits. The proportion developing less, the same or more dyspnea 6-9 months post-treatment according to their baseline dyspnea scores was: Grade 0: none, 82.9%, 17.1%; Grade 1: 21.2%, 51.9%, 26.9%; Grade 2: 27.3%, 54.5%, 18.2%, respectively. Only age was associated with increased dyspnea after RT. Patients with dyspnea before therapy have a realistic chance to improve after high-dose radiotherapy. Reporting only dyspnea at one time-point post-RT is insufficient to determine radiation-induced dyspnea.
| 19,012,981
|
Removal of Cr3+ from aqueous solution by biosorption with aerobic granules.
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Aerobic granules were utilized as an effective biosorbent to remove Cr(3+) from aqueous solution. The results showed that the initial pH, contact time, and Cr(3+) concentration affected the biosorption process significantly. Both Freundlich and Langmuir isotherms were able to describe the equilibrium data reasonably with high correlation coefficients (R(2)>0.95) and pseudo-second-order model best fitted the biosorption process at experimental conditions. Moreover, Environmental Scanning Electronic microscope (ESEM), X-ray energy dispersion (EDX), and Fourier transform infrared (FTIR) analyses revealed that metal complexation, chemical precipitation, and ion exchange were involved in the removal of Cr(3+) with aerobic granules. Further analysis by a metal ion fraction test demonstrated that metal complexation could be the dominant mechanism of biosorption, whereas chemical precipitation and ion exchange appeared only to have minor role in the overall Cr(3+) biosorption process.
| 19,013,022
|
Fetal superior mesenteric artery: longitudinal reference ranges and evidence of regulatory link to portal liver circulation.
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To establish longitudinal reference ranges for the fetal superior mesenteric artery (SMA) flow velocity and pulsatility index (PI(SMA)). Also to examine the hemodynamic relationship to venous liver perfusion and umbilical flow distribution in the liver, to other splanchnic arteries, and more generally to the middle cerebral and umbilical artery. Prospective longitudinal study of 161 low-risk pregnancies using Doppler recordings including the SMA, repeated on 3-5 occasions at 3-5 weekly intervals. Umbilical venous flow was estimated, blood velocity in the shunt ductus venosus represented umbilico-caval (i.e. porto-caval) pressure gradient, and left portal vein blood velocity represented umbilical distribution within the liver. The correlation between PI(SMA) and the splenic and hepatic artery PI were analysed (PI(SA) and PI(HA)), and the association to middle cerebral and umbilical artery PI (PI(MCA) and PI(UA)) assessed. Reference ranges for the SMA for gestational weeks 21-39 were based on 589 observations. Low impedance in the SMA (i.e. low PI(SMA)) was associated with low umbilical flow and porto-caval pressure gradient (i.e. <10th centile), and high distribution of umbilical flow to the right lobe (i.e. left portal vein blood velocity >90th centile). PI(SMA) correlated weakly with PI(SA) and PI(HA) (r=0.30, 95%CI 0.22-0.37, and r=0.39, 95%CI 0.27-0.51, respectively). PI(SMA) was positively associated with PI(MCA) and PI(UA). We have provided longitudinal reference ranges for fetal SMA flow velocity and PI, and shown that the SMA, which perfuses the fetal gut, is also involved in the regulation of the liver perfusion.
| 19,013,030
|
[Fulminant myocarditis: clinical value of extracorporeal life support].
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Fulminant myocarditis is a rare cause of cardiogenic shock which usually occurs in young adults without known cardiac disease. Initial course may be complicated by a cardiogenic shock refractory to optimal medical treatment. Temporary circulatory assistance using an extracorporeal life support is of great clinical value in this setting, since myocardial systolic function usually fully recovers after a short time delay.
| 19,013,051
|
[Arteriovenous difference in O2 content, pulmonary venous O2 saturation, cardiac index: are they equivalent in cardiac surgery?].
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To study the concordance of cardiac index (CI), mixed venous oxygen saturation (SvO(2)) and the arterial-mixed venous O(2) content difference, i.e.: C(a-v)O(2), postoperatively to cardiac surgery. We hypothesized that significant discrepancies would be measurable between C(a-v)O(2) and SvO(2), and CI, because the latter two indices encompass less metabolic components than the former. Analysis of variables collected as part of routine care. Eighty anesthetized patients receiving mechanical ventilation after heart surgery. Using linear regression of SvO(2) versus C(a-v)O(2) (Reg 1) and CI versus C(a-v)O(2) (Reg 2), respectively we found that CI=2.2 L min(-1)m(-2) and SvO(2)=70% were equivalent to C(a-v)O(2)=5 ml/100ml. The error reflected by the vertical scatter of points around the regression line, once normalized was 3.24 times greater in Reg 2 than in Reg 1. The correspondence of CI, SvO(2) and C(a-v)O(2) values observed in a population of patients studied immediately after scheduled heart surgery match those reported in critically ill patients. SvO(2) and furthermore CI induced a sizeable scatter of points around regression line. Accordingly, they appear as a lesser estimate of the flow/metabolism balance that may at best be inferred from C(a-v)O(2).
| 19,013,053
|
MicroRNA processing pathway regulates olfactory neuron morphogenesis.
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The microRNA (miRNA) processing pathway produces miRNAs as posttranscriptional regulators of gene expression. The nuclear RNase III Drosha catalyzes the first processing step together with the dsRNA binding protein DGCR8/Pasha generating pre-miRNAs [1, 2]. The next cleavage employs the cytoplasmic RNase III Dicer producing miRNA duplexes [3, 4]. Finally, Argonautes are recruited with miRNAs into an RNA-induced silencing complex for mRNA recognition (Figure 1A). Here, we identify two members of the miRNA pathway, Pasha and Dicer-1, in a forward genetic screen for mutations that disrupt wiring specificity of Drosophila olfactory projection neurons (PNs). The olfactory system is built as discrete map of highly stereotyped neuronal connections [5, 6]. Each PN targets dendrites to a specific glomerulus in the antennal lobe and projects axons stereotypically into higher brain centers [7-9]. In selected PN classes, pasha and Dicer-1 mutants cause specific PN dendrite mistargeting in the antennal lobe and altered axonal terminations in higher brain centers. Furthermore, Pasha and Dicer-1 act cell autonomously in postmitotic neurons to regulate dendrite and axon targeting during development. However, Argonaute-1 and Argonaute-2 are dispensable for PN morphogenesis. Our findings suggest a role for the miRNA processing pathway in establishing wiring specificity in the nervous system.
| 19,013,069
|
Structure-activity relationship of novel and known inhibitors of human dimethylarginine dimethylaminohydrolase-1: alkenyl-amidines as new leads.
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Recent studies demonstrated that inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity could be a new strategy to indirectly affect nitric oxide (NO) formation by elevating N(omega)-methylated L-arginine (NMMA, ADMA) levels. This approach is an alternate strategy for the treatment of diseases associated with increased NO-concentrations. To date, three classes of potent inhibitors are known: (1) pentafluorophenyl sulfonates (IC(50)=16-58 microM, PaDDAH), which are also inhibitors for the arginine deiminase; (2) the most potent inhibitors are based on indolylthiobarbituric acid (IC(50)=2-17 microM, PaDDAH), which were identified by virtual modelling; and (3) L-arginine analogs, whose best representative is N(omega)-(2-methoxyethyl)-L-arginine (IC(50)=22 microM, rat DDAH). Based on these known structures, we aimed to develop inhibitors for the human DDAH-1 with improved potency and better relative selectivity for DDAH-1 over NOS. Particularly, the binding pocket of the guanidine-moiety was investigated by screening differently substituted guanidines, amidines and isothioureas in order to collect information on possible binding modes in the active site. All substances were tested in a plate-reader format and HPLC assay and several potent inhibitors were identified with K(i)-values varying from 2 to 36 microM, with N(5)-(1-iminobut-3-enyl)-L-ornithine (L-VNIO) being the most potent inhibitor of the human DDAH-1 so far described. Besides these potent inhibitors alternate substrates for hDDAH-1 were identified as well.
| 19,013,076
|
Don't 'leaf' now. The making of a fruit.
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The fruit of Arabidopsis thaliana is derived from two fused carpels in the centre of the developing flower. Significant progress has been made in the study of Arabidopsis gynoecium and fruit development during the past few years with the identification of key regulators and analysis of the interactions between them. Many of these factors also have roles in leaf development, thereby emphasising the evolutionary origin of carpels as modified leaves. Although work on fruit development has largely been focused on the analysis of individual genes and mutants, the data clearly indicate that in order to get an integrated view of fruit patterning it is necessary to understand the role of the plant hormone auxin in the process and how it becomes distributed.
| 19,013,099
|
Transcription factor Yin Yang 1 represses fetal troponin I gene expression in neonatal myocardial cells.
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Yin Yang 1 (YY1) is a transcription factor that can activate or repress expression of a variety of genes and is involved in several developmental processes. While some transcription factors are known to modulate skeletal myogenesis, the regulation of fetal troponin I (ssTnI) expression by YY1 in cardiac development has not been studied. The present study shows that the fetal troponin I gene expression in neonatal myocardium was reduced by overexpression of YY1, while cardiac troponin I (cTnI) did not show any significant decrease. And a dose-response inhibition by YY1 was observed in fetal troponin I promoter induced transcriptional activities. Mutation of YY1-binding site can abolish the inhibitory effect and YY1 silencing in neonatal myocardium resulted in an increase of ssTnI protein expression. Our results indicate that YY1 is a novel regulator of fetal TnI transcription in the heart.
| 19,013,134
|
BDNF Val66Met polymorphism is associated with unstable angina.
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Brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of coronary artery disease (CAD). The human BDNF Val66Met polymorphism has been shown to be associated with altered susceptibility to neuropsychiatric disorders. However it is unknown whether this polymorphism plays a role in cardiovascular disease. Genotyping of BDNF Val66Met polymorphism was carried out in 513 controls, 628 unstable angina pectoris (UAP) and 276 stable angina pectoris (SAP) patients. The plasma concentrations of BDNF and high-sensitivity C-reactive protein (hsCRP) were measured by ELISA. The general clinical data in patients and controls were obtained. There was a significant association between genotype and allele frequency of the BDNF Val66Met polymorphism and UAP (all P<0.05). Multivariate logistic regression analysis revealed that the BDNF(Met/Met) genotype had a protective effect on the occurrence of UAP after controlling for known risk factors of CAD (OR 0.53, P=0.005). Subjects with BDNF(Met/Met) genotype also had decreased plasma hsCRP levels compared with the Val carriers (P<0.01). The BDNF(Met/Met) genotype has a protective effect on the occurrence of UAP, which might in part be due to the decreased plasma hsCRP level in BDNF(Met/Met) carriers. To our knowledge, this is the first study that demonstrates the link between BDNF Val66Met polymorphism and CAD.
| 19,013,140
|
Differences in the temporal expression of regulatory growth factors during choroidal neovascular development.
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Although the roles of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) in pathologic neovascularization have been well characterized in certain tissues, their particular functions and expression patterns in choroidal neovascularization (CNV) have not been clearly established. After localized laser trauma to Bruch's membrane to induce CNV development, the temporal changes in mRNA and protein expression of these 3 cytokines were documented and compared histologically to areas of immunofluorescence, the proliferation of endothelial cells, neovascular development, and temporal changes in vascular permeability. Changes in mRNA and protein levels of bFGF and HGF occurred quickly and reached peak expression within hours. This activity corresponded in time to intense and localized immunofluorescence for these cytokines within the choriocapillaris within laser lesion sites. During this same initial time period, mRNA upregulation of VEGF occurred, primarily within the neural retina and this expression corresponded to intense immunolabeling of Müller cells immediately adjacent to the lesion sites. By 3 days after lasering, increased VEGF(164) protein expression was measurable, whereas early neovascular development histologically corresponded to HGF and bFGF mRNA expansion into the developing choroidal neovascular membrane (CNVM). At 7 days, CNV expansion, maturation, and increased vascular permeability corresponded to peak VEGF mRNA and protein expression and to immunofluorescence of the CNVM. Differences also occurred in the expression of precursor and activated isoforms of these cytokines in the retinal pigment epithelium/choroid as compared to those in the retina. These molecular and immunocytochemical results suggest that bFGF and HGF may be important as initial regulators neovascularization in this CNV model; whereas VEGF may be important during later phases of angiogenesis and neovascular hyperpermeability.
| 19,013,152
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Lack of relationship between cardiovascular reactivity to mental stress and autonomic modulation of the sinoatrial node in normotensive and hypertensive male subjects.
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A cardiovascular over-reactivity to stress may participate in the pathophysiology of hypertension. The aim of this study was to investigate whether baseline indexes of autonomic modulation of heart rate or baroreflex sensitivity were correlated with cardiovascular reactivity to stress. Spectral parameters of RR interval variability and the LF alpha-index were calculated in a resting condition in 53 untreated subjects (34 hypertensives; 19 normotensives). The reactivity to stress was expressed as changes of mean RR and systolic blood pressure during arithmetic mental stress testing. The cardiovascular reactivity was not correlated with either baseline spectral parameters of RR interval variability or LF alpha-index. In the multivariate analysis no confounding effect of diagnosis (hypertension vs normotension) was found. Moreover no interaction between diagnosis and both LF/HF ratio and LF alpha-index was observed. Thus, the cardiovascular response to a mental stimulus appears to prevail over the baseline pattern of cardiovascular regulation independently of the presence or absence of the hypertensive disease.
| 19,013,200
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Atypical neuroleptic risperidone modulates glial functions in C6 astroglial cells.
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Risperidone has demonstrated therapeutic advantages over conventional neuroleptics and offers a valuable emerging option for the treatment of social behavior associated with autistic disorder. Considering the putative involvement of astroglial cells in neuropsychiatric disorders, we investigated the effect of risperidone on parameters of astrocyte activity - glutamate uptake, glutamine synthetase (GS) activity and glutathione (GSH) levels. Risperidone was able to induce a significantly increase on glutamate uptake (32%); GS activity (15%); GSH levels (58%). These findings imply the perspectives for further investigations directed on astrocytes from different brain areas. Our present results suggest that risperidone might exert its neuroprotective effects against brain illness at least partially via modulation of astrocyte functions.
| 19,013,209
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Reactive oxygen species production and MAPK activation are implicated in tetrahydrobiopterin-induced SH-SY5Y cell death.
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Tetrahydrobiopterin (BH4), an obligatory cofactor for dopamine (DA) synthesis, has been shown to produce reactive oxygen species (ROS) upon its autoxidation and induce selective dopaminergic cell death in many in vivo and in vitro models of Parkinson's disease (PD). The precise molecular mechanisms underlying neuronal death upon BH4 exposure, however, have not yet been well elucidated. The present study aims to examine the intracellular ROS production and the signal transduction pathways underlying the toxic effects of BH4 on human dopaminergic SH-SY5Y cells. The results show that BH4 treatment at concentrations ranging from 50microM to 400microM induces neuronal death in a dose-dependent manner. In concomitant with the elevation of intracellular ROS formation, BH4-induced activation of MAPK, p38 and ERK1/2 in SH-SY5Y cells is attenuated by pretreatment with MAPK inhibitors, SB203580 or PD98059. These data indicate that MAPK activation and oxidative stress are involved in BH4-induced dopaminergic cell death, possibly through the autoxidation of BH4 and subsequent ROS production.
| 19,013,215
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Binding of Silurus asotus lectin to Gb3 on Raji cells causes disappearance of membrane-bound form of HSP70.
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Heat shock proteins (HSPs) are divided into stress-inducible and constitutive types. Generally, HSP70 (stress inducible) and HSC70 (constitutive) are representative of their types, respectively. From the results of immunocytochemical analysis, both HSP70 and HSC70 were constitutively expressed in globotriaosylceramide (Gb3)-expressing Raji cells as well as Gb3-negative K562 cells. Furthermore, the membrane-bound form of HSP70 was present on the surfaces of two cell lines as patch and cap-like structures, and was recovered in the cholesterol rich microdomains (CRM) prepared from them. On the other hand, HSP70 was partially co-localized with Gb3 on the surface of Raji cells. This result suggested that HSP70 was not associated with all of Gb3 molecules but with Gb3 specifically located in the particular environment. The effect of Silurus asotus lectin (SAL), which is one of the rhamnose-binding lectins and specifically binds to Gb3, on the disappearance of membrane-bound HSP70 was dependent on whether Gb3 was present or not. These results suggested that the disappearance of membrane-bound HSP70 was caused by SAL binding to Gb3, that the reduction of membrane-bound HSP70 might result in the decrease in cell volume observed, and that the mechanism of SAL-induced HSP70 expression may differ from that of heat shock in Raji cells.
| 19,013,219
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Epigenetic states in stem cells.
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Whereas embryonic stem cells can differentiate into all cell types of the body, stem cells found in somatic tissues display more restrictive differentiation capacity. The extent of multi-lineage differentiation ability of stem cells is believed to be associated with the potential for expression of developmentally- and differentiation-regulated genes. Growing evidence suggests that this potential for gene expression in undifferentiated cells is regulated by epigenetic processes on DNA and chromatin in regulatory and coding regions. Genome-wide mapping of DNA methylation profiles and of post-translational histone modifications in stem cells and differentiated cells has led to the establishment of chromatin states primarily on promoters of active, repressed and potentially active genes. These maps contribute to unveiling regulatory mechanisms by which genes are poised for transcription in undifferentiated cells. We summarize here the current view of how specific combinations of epigenetic marks may define the pluripotent state.
| 19,013,220
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Development and characterisation of a new model of rat trophoblasts.
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The placenta plays a key role during pregnancy. In vitro models have proven to assess the role of placental transporters in the exchange of nutrients, waste products and the distribution of drugs between the maternal and fetal compartments. Therefore, a primoculture of Wistar rat trophoblasts from the labyrinth zone was developed and characterised. Expression of placental transporters including P-glycoprotein (P-gp) and bcrp was evaluated by western blot and their activity using different inhibitors. A time-dependent increase in P-gp expression was noted from primocultures Day 2 to Day 4 followed by a plateau thereafter, whereas bcrp expression was stable throughout the culture period. P-gp and bcrp expression was maintained after seven passages in primocultures and in cryopreserved trophoblasts (up to 3 freezings and 10 passages). Activity of efflux transporters was confirmed in both placental primocultures and cryopreserved trophoblasts by an approximately 60% inhibition with cyclosporin A and valspodar for P-gp and 55% with elacridar for bcrp. In sum, this new in vitro model seems promising for a better understanding of the role of P-gp and bcrp in the toxicity of drugs during pregnancy and could be considered as an additional step towards the minimization of animal testing during drug development.
| 19,013,229
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Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers.
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HOXB13 is a homeodomain protein implicated to play a role in growth arrest in AR (androgen receptor)-negative prostate cancer cells. Expression of HOXB13 is restricted to the AR-expressing prostate cells. In this report, we demonstrate that the HDAC inhibitor NaB (sodium butyrate) was able to induce cell growth arrest and to increase HOXB13 expression in AR-negative prostate cancer cells. We also show that both HDAC4 and YY1 participated in the repression of HOXB13 expression through an epigenetic mechanism involving histone acetylation modification. Specifically, co-immunoprecipitation assays revealed that HDAC4 and YY1 formed a complex. The chromatin immunoprecipitation (ChIP) assays verified that HDAC4 was recruited to HOXB13 promoter by YY1. Moreover, promoter truncation and point mutation studies determined that the two proximal YY1 binding sites on the HOXB13 promoter were essential for the recruitments of YY1 and HDAC4. Data presented in this report suggest that YY1 and HDAC4 affected cell growth by repressing transcriptional regulation of HOXB13 through an epigenetic modification of histones.
| 19,013,255
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Loop II of DNA polymerase beta is important for discrimination during substrate binding.
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Loop II of DNA polymerase beta (pol beta) consists of 14 amino acid residues and is highly flexible and solvent exposed. Previous research from our laboratory has shown that this loop is important for polymerase activity and fidelity. In the study presented here, we demonstrate that a shortened five amino acid residue loop compromises the fidelity of pol beta. This five-residue loop, termed ENEYP, induces one base frameshift errors and A-C transversions within a specific sequence context. We demonstrate that ENEYP misincorporates dGTP opposite template A at higher efficiencies than wild-type pol beta. The kinetic basis for misincorporation is a defect in discrimination of the correct from incorrect dNTP substrate at the level of ground-state binding. Our results are consistent with the idea that loop II of pol beta functions to maintain accurate DNA synthesis by a direct or indirect influence on the nucleotide binding pocket.
| 19,013,261
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In vitro and in vivo evidence for stimulation of bone resorption by an EP4 receptor agonist and basic fibroblast growth factor: Implications for their efficacy as bone anabolic agents.
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Prostaglandin E2 receptor subtype 4 agonists (EP4A) and basic fibroblast growth factor (FGF2) stimulate bone formation, but their effects on bone resorption are controversial. To provide additional insight into the skeletal effects of EP4A and FGF2, their regulation of expression of genes associated with bone formation and resorption in aged ovariectomized (OVX) rats and in cultured mouse bone marrow cells was determined. RNA was isolated from lumbar vertebrae of OVX rats (16 months of age) treated daily for 3 weeks with FGF2 or EP4A and processed for quantitative real time-PCR analyses. mRNA expression for the receptor activator of NF-kappaB ligand (RANKL) and cathepsin K (CTSK), but not osteoprotegerin (OPG), were upregulated by both FGF2 and EP4A. Addition of FGF2 and EP4A to the medium of cultured mouse bone marrow cells increased the formation of tartrate resistant acid phosphatase (TRAP) positive cells, upregulated the expression of RANKL and CTSK, and downregulated expression for OPG. EP4A also increased the formation of actin rings, an indicator of osteoclast activation, in a dose dependent manner in osteoclasts cultured on bone slices and triggered the formation of pits as revealed by a pitting assay. Gene expression for osterix (OSX) and IGF-2, genes associated with bone formation, was significantly greater in FGF2-treated OVX rats compared with EP4A-treated OVX rats. These findings at the molecular level are consistent with previous tissue-level histomorphometric findings, and at the doses tested, support the contention that FGF2 has a stronger bone anabolic effect than EP4A. The results of these in vivo and in vitro analyses clarify the effects of FGF2 and EP4A on bone formation and resorption, and provide insight into differences in the efficacy of two potential bone anabolic agents for restoration of lost bone mass in the osteopenic, estrogen-deplete skeleton.
| 19,013,265
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Telomerase reverse transcriptase delays aging in cancer-resistant mice.
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Telomerase confers limitless proliferative potential to most human cells through its ability to elongate telomeres, the natural ends of chromosomes, which otherwise would undergo progressive attrition and eventually compromise cell viability. However, the role of telomerase in organismal aging has remained unaddressed, in part because of the cancer-promoting activity of telomerase. To circumvent this problem, we have constitutively expressed telomerase reverse transcriptase (TERT), one of the components of telomerase, in mice engineered to be cancer resistant by means of enhanced expression of the tumor suppressors p53, p16, and p19ARF. In this context, TERT overexpression improves the fitness of epithelial barriers, particularly the skin and the intestine, and produces a systemic delay in aging accompanied by extension of the median life span. These results demonstrate that constitutive expression of Tert provides antiaging activity in the context of a mammalian organism.
| 19,013,273
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Effect of ezetimibe on plasma cholesterol levels, cholesterol absorption, and secretion of biliary cholesterol in laboratory opossums with high and low responses to dietary cholesterol.
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Partially inbred lines of laboratory opossums differ in plasma low-density lipoprotein cholesterol concentration and cholesterol absorption on a high-cholesterol diet. The aim of the present studies was to determine whether ezetimibe inhibits cholesterol absorption and eliminates the differences in plasma cholesterol and hepatic cholesterol metabolism between high and low responders on a high-cholesterol diet. Initially, we determined that the optimum dose of ezetimibe was 5 mg/(kg d) and treated 6 high- and 6 low-responding opossums with this dose (with equal numbers of controls) for 3 weeks while the opossums consumed a high-cholesterol and low-fat diet. Plasma and low-density lipoprotein cholesterol concentrations decreased significantly (P < .05) in treated but not in untreated high-responding opossums. Plasma cholesterol concentrations increased slightly (P < .05) in untreated low responders but not in treated low responders. The percentage of cholesterol absorption was significantly higher in untreated high responders than in other groups. Livers from high responders with or without treatment were significantly (P < .01) heavier than livers from low responders with or without treatment. Hepatic cholesterol concentrations in untreated high responders were significantly (P < .05) higher than those in low responders with or without treatment (P < .001). The gall bladder bile cholesterol concentrations in untreated high responders were significantly (P < .05) lower than those in other groups. A decrease in biliary cholesterol in low responders treated with ezetimibe was associated with a decrease in hepatic expression of ABCG5 and ABCG8. These studies suggest that ezetimibe decreases plasma cholesterol levels in high responders mainly by decreasing cholesterol absorption and increasing biliary cholesterol concentrations. Because ezetimibe's target is NPC1L1 and NPC1L1 is expressed in the intestine of opossums, its effect on cholesterol absorption may be mediated by inhibiting NPC1L1 function in the intestine.
| 19,013,286
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Epidemiology of invasive fungal infection.
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Invasive fungal infection is a growing cause of morbidity and mortality in immunosuppressed patients. Furthermore, the use of azole prophylaxis against Candida species has coincided with an increase in the incidence of invasive aspergillosis and infections by other filamentous fungi such as Mucorales. New risk factors and different timescales for onset have been identified. Knowledge of changes in the epidemiology of, and risk factors for, invasive fungal infection is particularly important when developing therapeutic strategies and effective prophylaxis to improve the prognosis of immunosuppressed patients.
| 19,013,332
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Viruses and kidney disease: beyond HIV.
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Human immunodeficiency virus (HIV)-infected patients may acquire new viral co-infections; they also may experience the reactivation or worsening of existing viral infections, including active, smoldering, or latent infections. HIV-infected patients may be predisposed to these viral infections owing to immunodeficiency or risk factors common to HIV and other viruses. A number of these affect the kidney, either by direct infection or by deposition of immune complexes. In this review we discuss the renal manifestations and treatment of hepatitis C virus, BK virus, adenovirus, cytomegalovirus, and parvovirus B19 in patients with HIV disease. We also discuss an approach to the identification of new viral renal pathogens, using a viral gene chip to identify viral DNA or RNA.
| 19,013,331
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Analysis of iron, zinc, selenium and cadmium in paraffin-embedded prostate tissue specimens using inductively coupled plasma mass-spectrometry.
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Formalin-fixed paraffin-embedded (FFPE) tissue specimens represent a valuable and abundant resource of pathologic material for various biomedical studies. In the present study, we report the application of high-resolution inductively coupled mass-spectrometry (ICP-MS) for quantification of Fe, Zn, Se and Cd in FFPE prostate tissue. These elements have a possible role in the development of prostate diseases: while Zn and Se are needed for a healthy prostate, Cd shows multiple toxic and carcinogenic effects. Excessive accumulation of Fe induces the production of highly reactive hydroxyl radical species, which may play a role in cancer etiopathogenesis. To assess whether the levels of these metals in the FFPE prostate tissue represent their original content, we compared their levels with those in the fresh tissue (on dry weight basis) in samples obtained from 15 patients. We found that in FFPE tissue, the recoveries of Se, Fe, Cd and Zn were progressively decreased, 97+/-11% (r=0.88), 82+/-22% (r=0.86), 59+/-23% (r=0.69) and 24+/-11% (r=0.38), respectively. Thus, the use of correction factors, determined as k=0.16 for Se, k=0.20 for Fe, k=0.27 for Cd and k=0.67 for Zn, is required to estimate the retrospective levels of these elements in the parental non-processed fresh (wet) prostate tissue. The technique used in this study enables the analysis of archival FFPE prostate tissue for the concentrations of Fe, Zn, Se and Cd to study association between the levels of these metals and prostate disease.
| 19,013,358
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Effects of long-term zinc supplementation and deprivation on gene expression in human THP-1 mononuclear cells.
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Zinc is an essential trace element that is critical for cellular function and structural integrity. It has an important regulatory role in the immune system, in particular in monocytes. To identify the diverse cellular targets and mechanisms of action of zinc in this cell type, we used microarray technology to assess the effects of zinc supplementation and depletion on global gene expression. mRNA expression in the human monocytic cell line THP-1 was analyzed and compared in response to 40h supplementation with 50micromol/L zinc, or zinc deprivation by 2.5micromol/L of the membrane-permeant zinc chelator TPEN [N,N,N',N'-tetrakis-(2-pyridyl-methyl)ethylenediamine]. Analysis of microarrays consisting of approximately 19,000 unique oligonucleotides identified over 1400 genes, or approximately 7%, as zinc-sensitive. Notably, this yielded several sets of structurally or functionally related genes. Among those groups, which were mainly affected by zinc deprivation, were histones, S100 calcium and zinc binding proteins, and chemokines and their receptors. These groups of genes may mediate zinc-effects on chromatin regulation, zinc homeostasis, and chemotaxis, respectively. In addition, functional networks were analyzed, showing that the well known effect of zinc on pro-inflammatory cytokines is not limited to these genes; it acts on a number of functionally connected genes, as well. These results provide novel molecular targets and pathways that may aid in explaining the role of zinc in monocyte function.
| 19,013,360
|
Occult nasal sinus tumours causing oncogenic osteomalacia.
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Oncogenic osteomalacia (OOM) is a rare but curable cause of metabolic bone disease. We report 9 patients with OOM, including 2 patients with occult nasal sinus tumours and 1 in whom a progressive increase in the post-operative FGF23 level heralded the development of metastatic pulmonary disease. The median duration of symptoms before definitive surgical treatment was 6 years, and in one patient was more than 10 years. This series demonstrates that careful imaging of the nasal sinuses should be part of the work-up of cases of oncogenic osteomalacia, that serum FGF23 can be helpful in both diagnosis and monitoring treatment outcomes, and emphasizes that serum phosphate should be measured in patients with metabolic bone disease and/or unexplained musculoskeletal symptoms.
| 19,013,380
|
A rational approach to ankle fractures.
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Ankle fractures involve a spectrum of injury patterns from simple to complex, such that these injuries are not always "just an ankle fracture." By combining the injury mechanism and the radiographic findings, the surgeon can apply the Lauge-Hansen classification in taking a rational approach to the management of these fractures. Syndesmotic instability and atypical patterns are becoming increasingly recognized, in part through the judicious use of CT scans. The goal of surgical stabilization includes atraumatic soft tissue management, rigid internal fixation, and early range of motion exercises in maximizing return of function.
| 19,013,398
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Inter-observer and intra-observer agreement on interpretation of uroflowmetry curves of kindergarten children.
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To evaluate the inter-observer and intra-observer agreement on the interpretation of uroflowmetry curves of children. Healthy kindergarten children were enrolled for evaluation of uroflowmetry. Uroflowmetry curves were classified as bell-shaped, tower, plateau, staccato and interrupted. Only the bell-shaped curves were regarded as normal. Two urodynamists evaluated the curves independently after reviewing the definitions of the different types of uroflowmetry curve. The senior urodynamist evaluated the curves twice 3 months apart. The final conclusion was made when consensus was reached. Agreement among observers was analyzed using kappa statistics. Of 190 uroflowmetry curves eligible for analysis, the intra-observer agreement in interpreting each type of curve and interpreting normalcy vs abnormality was good (kappa=0.71 and 0.68, respectively). Very good inter-observer agreement (kappa=0.81) on normalcy and good inter-observer agreement (kappa=0.73) on types of uroflowmetry were observed. Poor inter-observer agreement existed on the classification of specific types of abnormal uroflowmetry curves (kappa=0.07). Uroflowmetry is a good screening tool for normalcy of kindergarten children, while not a good tool to define the specific types of abnormal uroflowmetry.
| 19,013,411
|
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