Perceptions of transcatheter device closure of patent ductus arteriosus in veterinary cardiology and evaluation of a canine model to simulate device placement: a preliminary study.

OBJECTIVES: The purpose of this study was to evaluate a canine patent ductus arteriosus (PDA) model developed for practicing device placement and to determine practices and perceptions regarding transcatheter closure of PDA from the veterinary cardiology community. METHOD: A silicone model was developed from images obtained from a dog with a PDA and device placement was performed with catheter equipment and a document camera to simulate fluoroscopy. A total of 36 individuals including 24 diplomates and 12 residents participated, and the feedback was obtained. The study included an initial questionnaire, practice with the model, observation of device placement using the model, and a follow-up questionnaire. RESULTS: A total of 92% of participants including 100% of residents indicated they did not have the opportunity to practice device placement before performing the procedure and obtained knowledge of the procedure from reading journal articles or observation. Participants indicated selecting the appropriate device size (30/36, 83%) and ensuring the device is appropriately positioned before release (18/36, 50%) as the most common areas of difficulty with device placement. Confidence level was higher after practicing with the model for residents when compared with diplomates and for participants that had performed 1-15 procedures when compared with those that had performed >15 procedures. These findings suggest those that have performed fewer procedures may benefit the most from practicing with a model. CONCLUSIONS: This preliminary study demonstrates the feasibility of a PDA model for practicing device placement and suggests that there is a potential benefit from providing additional training resources.

Renal effects of chronic pharmacological manipulation of CB2 receptors in rats with diet-induced obesity.

BACKGROUND AND PURPOSE: In diabetic nephropathy agonism of CB2 receptors reduces albuminuria and podocyte loss; however, the role of CB2 receptors in obesity-related nephropathy is unknown. The aim of this study was to determine the role of CB2 receptors in a model of diet-induced obesity (DIO) and characterize the hallmark signs of renal damage in response to agonism (AM1241) and antagonism (AM630) of CB2 receptors. EXPERIMENTAL APPROACH: Male Sprague Dawley rats were fed a high-fat diet (HFD: 40% digestible energy from lipids) for 10 weeks. In another cohort, after 9 weeks on a HFD, rats were injected daily with either 3 mg·kg(-1) AM1241, 0.3 mg·kg(-1) AM630 or saline for 6 weeks. KEY RESULTS: Ten weeks on a HFD significantly reduced renal expression of CB2 receptors and renal function. Treatment with AM1241 or AM630 did not reduce weight gain or food consumption in DIO. Despite this, AM1241 significantly reduced systolic BP, peri-renal adipose accumulation, plasma leptin, urinary protein, urinary albumin, urinary sodium excretion and the fibrotic markers TGF-ß1, collagen IV and VEGF in kidney lysate. Treatment with AM630 of DIO rats significantly reduced creatinine clearance and increased glomerular area and kidney weight (gross and standardized for body weight). Diastolic BP, glucose tolerance, insulin sensitivity, plasma creatinine, plasma TGF-ß1 and kidney expression of fibronectin and α-smooth muscle actin were not altered by either AM1241 or AM630 in DIO. CONCLUSIONS: This study demonstrates that while agonism of CB2 receptors with AM1241 treatment for 6 weeks does not reduce weight gain in obese rats, it leads to improvements in obesity-related renal dysfunction. LINKED ARTICLES: This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc.

Chromosomal instability causes sensitivity to metabolic stress.

Chromosomal INstability (CIN), a hallmark of cancer, refers to cells with an increased rate of gain or loss of whole chromosomes or chromosome parts. CIN is linked to the progression of tumors with poor clinical outcomes such as drug resistance. CIN can give tumors the diversity to resist therapy, but it comes at the cost of significant stress to tumor cells. To tolerate this, cancer cells must modify their energy use to provide adaptation against genetic changes as well as to promote their survival and growth. In this study, we have demonstrated that CIN induction causes sensitivity to metabolic stress. We show that mild metabolic disruption that does not affect normal cells, can lead to high levels of oxidative stress and subsequent cell death in CIN cells because they are already managing elevated stress levels. Altered metabolism is a differential characteristic of cancer cells, so our identification of key regulators that can exploit these changes to cause cell death may provide cancer-specific potential drug targets, especially for advanced cancers that exhibit CIN.

The cannabinoid receptor 1 and its role in influencing peripheral metabolism.

Evidence from in vitro and in vivo studies has demonstrated the deleterious pathological effects of a dysregulated endocannabinoid system. Increased stimulation of the cannabinoid receptor 1 (CB1 ) and subsequent downstream cellular signalling are both causative in the deleterious pathological effects observed in a number of diseases. When the CB1 cell signalling cascade is blocked, this results in whole body weight-loss, leading to a reduction in obesity and associated co-morbidities. In the central nervous system; however, CB1 antagonism results in adverse psychological side effects. Blockade of CB1 via peripheral acting compounds that do not cross the blood-brain barrier have been determined to have beneficial effects in metabolic tissues such as the liver and skeletal muscle. These results support the notion that peripheral blockade of CB1 using pharmacological antagonists is a viable target for the treatment of the current epidemic of obesity and its associated co-morbidities.

Modeling and analysis of repeat RNA toxicity in Drosophila.

Expansion of repeat sequences beyond a pathogenic threshold is the cause of a series of dominantly inherited neurodegenerative diseases that includes Huntington's disease, several spinocerebellar ataxias, and myotonic dystrophy types 1 and 2. Expansion of repeat sequences occurring in coding regions of various genes frequently produces an expanded polyglutamine tract that is thought to result in a toxic protein. However, in a number of diseases that present with similar clinical symptoms, the expansions occur in untranslated regions of the gene that cannot encode toxic peptide products. As expanded repeat-containing RNA is common to both translated and untranslated repeat expansion diseases, this repeat RNA is hypothesized as a potential common toxic agent.We have established Drosophila models for expanded repeat diseases in order to investigate the role of multiple candidate toxic agents and the potential molecular pathways that lead to pathogenesis. In this chapter we describe methods to identify candidate pathogenic pathways and their constituent steps. This includes establishing novel phenotypes using Drosophila and developing methods for using this system to screen for possible modifiers of pathology. Additionally, we describe a method for quantifying progressive neurodegeneration using a motor functional assay as well as small RNA profiling techniques, which are useful in identifying RNA intermediates of pathogenesis that can then be used to validate potential pathogenic pathways in humans.

Forest and surface water as predictors of Borrelia burgdorferi and its vector Ixodes scapularis (Acari: Ixodidae) in Indiana.

The objective of this study was to assess whether the distribution of Borrelia burgdorferi, the causative agent of Lyme disease, and its vector tick Ixodes scapularis Say (Acari: Ixodidae) across Indiana is influenced by large-scale landscape features, specifically the proportion of forest within the surrounding landscape and the distance to water features such as lakes and major streams. Hunter-killed deer were checked for ticks in designated check-stations in the opening firearm hunting season between 2005 and 2007. Hunting locations for approximately 3,600 deer were used in ArcGIS (ESRI, Redlands, CA) to examine the influence of forest and water features in the surrounding area on the occurrence of the tick and bacteria. In total, 82 of the 92 (89%) Indiana counties were sampled from 2005 to 2007. The proportion of tick-infested deer was 13.6, 15.8, and 25.5% in these years, respectively. There was a significant nonlinear response for I. scapularis to forest cover in 1 yr that indicated a greater probability of this tick presence at intermediate levels of forest area. Infested does were harvested in significantly more forested areas than bucks. No significant correlation was found neither between levels of forest area and B. burgdorferi nor between water bodies and both organisms.

Total parenteral nutrition in the surgical patient: a meta-analysis.

OBJECTIVE: To examine the relationship between total parenteral nutrition(TPN) and complication and death rates in surgical patients. DATA SOURCES: A computer search of published research on MEDLINE, personal files and a review of relevant reference lists. STUDY SELECTION: A review of 237 titles, abstracts or papers. Primary studies were included if they were randomized clinical trials of surgical patients that evaluated the effect of TPN (compared to no TPN or standard care) on complication and death rates. Studies comparing TPN to enteral nutrition (EN) were excluded. DATA EXTRACTION: Relevant data were abstracted on the methodology and outcomes of primary studies. Data were independently abstracted in duplicate. DATA SYNTHESIS: There were 27 randomized trials in surgical patients that compared the use of TPN to standard care (usual oral diet plus intravenous dextrose). When the results of these trials were aggregated, there was no effect on mortality (risk ratio = 0.97, 95% confidence intervals, 0.76 to 1.24). There were fewer major complications in patients who received TPN, although there was significant heterogeneity in the overall estimate (risk ratio = 0.81, 95% CI, 0.65 to 1.01). Because of this significant heterogeneity, several a priori hypotheses were examined. Studies that included only malnourished patients demonstrated a trend to a reduction in complication rates but no difference in death rate when compared with studies of patients who were not malnourished. Studies published in 1988 or earlier and studies with a lower methods score were associated with a significant reduction in complication rates and a trend to a reduction in death rate when compared with studies published after 1988 and studies with a higher methods score. There was no difference in studies that provided lipids as a component of TPN when compared with studies that did not. Studies that initiated TPN preoperatively demonstrated a trend to a reduction in complication rates but no difference in death rate when compared with studies that initiated TPN postoperatively. CONCLUSIONS: TPN does not influence the death rate of surgical patients. It may reduce the complication rate, especially in malnourished patients, but study results are influenced by methodologic quality and year of publication.

The pebble GTP exchange factor and the control of cytokinesis.

Several G proteins of the Rho family have been shown to be required for cytokinesis. The activity of these proteins is regulated by GTP exchange factors (GEFs), which stimulate GDP/GTP exchange, and by GTPase activating proteins (GAPs), which suppress activity by stimulating the intrinsic GTPase activity. The role of Rho family members during cytokinesis is likely to be determined by their spatial and temporal interactions with these factors. Here we focus on the role of the pebble (pbl) gene of Drosophila melanogaster, a RhoGEF that is required for cytokinesis. We summarise the evidence that the primary target of PBL is Rho1 and describe genetic approaches to elucidating the function of PBL and identifying other components of the PBL-activated Rho signalling pathway.

arrow encodes an LDL-receptor-related protein essential for Wingless signalling.

The Wnt family of secreted molecules functions in cell-fate determination and morphogenesis during development in both vertebrates and invertebrates (reviewed in ref. 1). Drosophila Wingless is a founding member of this family, and many components of its signal transduction cascade have been identified, including the Frizzled class of receptor. But the mechanism by which the Wingless signal is received and transduced across the membrane is not completely understood. Here we describe a gene that is necessary for all Wingless signalling events in Drosophila. We show that arrow gene function is essential in cells receiving Wingless input and that it acts upstream of Dishevelled. arrow encodes a single-pass transmembrane protein, indicating that it may be part of a receptor complex with Frizzled class proteins. Arrow is a low-density lipoprotein (LDL)-receptor-related protein (LRP), strikingly homologous to murine and human LRP5 and LRP6. Thus, our data suggests a new and conserved function for this LRP subfamily in Wingless/Wnt signal reception.

The extent of undiagnosed HIV infection among emergency department patients: results of a blinded seroprevalence survey and a pilot HIV testing program.

This study was performed to determine the rate of previously undiagnosed HIV infection among patients presenting to an urban emergency department (ED) and to assess the feasibility of routinely offering voluntary HIV testing in this setting. HIV serostatus was determined anonymously among consecutive acute medicine and trauma ED patients (aged 18-55) who had blood drawn as part of their medical care. Excess serum was aliquoted and coded with an anonymous study code. Before performing HIV testing, the number of persons with previously reported HIV infection was determined by linkage with the state HIV/AIDS reporting registry. Concurrent with the blinded HIV serosurvey, ED patients were offered voluntary HIV testing in a pilot program. Overall, 76 of 2,155 (3.5%) adult ED patients in the blinded survey were HIV-seropositive, 15 of whom (0. 7% of those tested, 20% of those HIV-seropositive) had no infection previously reported to the state HIV/AIDS registry. In the pilot program, six of the 156 (3.8%) individuals who underwent voluntary HIV testing were HIV-seropositive, including three of 53 (5.6%) individuals without prior HIV testing. Of the six HIV-seropositive subjects, one was previously diagnosed, while five of the remaining 155 (3.2%) represented previously undiagnosed infections. Overall, 3. 5% of ED patients from whom blood was obtained for other reasons tested positive for HIV antibody, 20% of whom were previously undiagnosed. Implementation of the voluntary testing program uncovered newly diagnosed infection among 3.2% of those tested. An ED may be an important setting for routinely offering HIV testing, especially for patients who have not been previously tested for HIV.

A putative exchange factor for Rho1 GTPase is required for initiation of cytokinesis in Drosophila.

Cytokinesis ensures the successful completion of the cell cycle and distribution of chromosomes, organelles, and cytoplasm between daughter cells. It is accomplished by formation and constriction of an actomyosin contractile ring that drives the progression of a cleavage furrow. Microinjection experiments and in vitro transfection assays have suggested a requirement for small GTPases of the Rho family in cytokinesis. Yet, the identity of proteins regulating Rho signaling pathways during cytokinesis remains unknown. Here we show that in Drosophila, Pebble (Pbl), a putative exchange factor for Rho GTPases (RhoGEF), is required for the formation of the contractile ring and initiation of cytokinesis. The dynamics of Pbl expression and its distribution during mitosis, as well as structure-function analysis, indicate that it is a key regulatory component of the pathway. pbl interacts genetically with Rho1, but not with Rac1 or Cdc42, and Pbl and Rho1 proteins interact in vivo in yeast. Similar to mutations in pbl, loss of Rho1 or expression of a dominant-negative Rho1 blocks cytokinesis. Our results identify Pbl as a RhoGEF specifically required for cytokinesis and linked through Rho1 activity to the reorganization of the actin cytoskeleton at the cleavage furrow.

Total parenteral nutrition in the critically ill patient: a meta-analysis.

CONTEXT: Nutritional support has become a standard of care for hospitalized patients, but whether total parenteral nutrition (TPN) affects morbidity and mortality is unclear. OBJECTIVE: To examine the relationship between TPN and complication and mortality rates in critically ill patients. DATA SOURCES: Computerized search of published research on MEDLINE from 1980 to 1998, personal files, and review of relevant reference lists. STUDY SELECTION: We reviewed 210 titles, abstracts, and papers. Primary studies were included if they were randomized clinical trials of critically ill or surgical patients that evaluated the effect of TPN (compared with standard care) on complication and mortality rates. We excluded studies comparing TPN with enteral nutrition. DATA EXTRACTION: Relevant data were abstracted on the methodology and outcomes of primary studies. Data were abstracted in duplicate, independently. DATA SYNTHESIS: There were 26 randomized trials of 2211 patients comparing the use of TPN with standard care (usual oral diet plus intravenous dextrose) in surgical and critically ill patients. When the results of these trials were aggregated, TPN had no effect on mortality (risk ratio [RR], 1.03; 95% confidence interval [CI], 0.81-1.31). Patients who received TPN tended to have a lower complication rate, but this result was not statistically significant (RR, 0.84; 95% CI, 0.64-1.09). We examined several a priori hypotheses and found that studies including only malnourished patients were associated with lower complication rates but no difference in mortality when compared with studies of nonmalnourished patients. Studies published since 1989 and studies with a higher methods score showed no treatment effect, while studies published in 1988 or before and studies with a lower methods score demonstrated a significant treatment effect. Complication rates were lower in studies that did not use lipids; however, there was no difference in mortality rates between studies that did not use lipids and those studies that did. Studies limited to critically ill patients demonstrated a significant increase in complication and mortality rates compared with studies of surgical patients. CONCLUSIONS: Total parenteral nutrition does not influence the overall mortality rate of surgical or critically ill patients. It may reduce the complication rate, especially in malnourished patients, but study results are influenced by patient population, use of lipids, methodological quality, and year of publication.

Neuronal correlates of amblyopia in the visual cortex of macaque monkeys with experimental strabismus and anisometropia.

Amblyopia is a developmental disorder of pattern vision. After surgical creation of esotropic strabismus in the first weeks of life or after wearing -10 diopter contact lenses in one eye to simulate anisometropia during the first months of life, macaques often develop amblyopia. We studied the response properties of visual cortex neurons in six amblyopic macaques; three monkeys were anisometropic, and three were strabismic. In all monkeys, cortical binocularity was reduced. In anisometropes, the amblyopic eye influenced a relatively small proportion of cortical neurons; in strabismics, the influence of the two eyes was more nearly equal. The severity of amblyopia was related to the relative strength of the input of the amblyopic eye to the cortex only for the more seriously affected amblyopes. Measurements of the spatial frequency tuning and contrast sensitivity of cortical neurons showed few differences between the eyes for the three less severe amblyopes (two strabismic and one anisometropic). In the three more severely affected animals (one strabismic and two anisometropic), the optimal spatial frequency and spatial resolution of cortical neurons driven by the amblyopic eye were substantially and significantly lower than for neurons driven by the nonamblyopic eye. There were no reliable differences in neuronal contrast sensitivity between the eyes. A sample of neurons recorded from cortex representing the peripheral visual field showed no interocular differences, suggesting that the effects of amblyopia were more pronounced in portions of the cortex subserving foveal vision. Qualitatively, abnormalities in both the eye dominance and spatial properties of visual cortex neurons were related on a case-by-case basis to the depth of amblyopia. Quantitative analysis suggests, however, that these abnormalities alone do not explain the full range of visual deficits in amblyopia. Studies of extrastriate cortical areas may uncover further abnormalities that explain these deficits.

Functional organization of owl monkey lateral geniculate nucleus and visual cortex.

The nocturnal, New World owl monkey (Aotus trivirgatus) has a rod-dominated retina containing only a single cone type, supporting only the most rudimentary color vision. However, it does have well-developed magnocellular (M) and parvocellular (P) retinostriate pathways and striate cortical architecture [as defined by the pattern of staining for the activity-dependent marker cytochrome oxidase (CO)] similar to that seen in diurnal primates. We recorded from single neurons in anesthetized, paralyzed owl monkeys using drifting, luminance-modulated sinusoidal gratings, comparing receptive field properties of M and P neurons in the lateral geniculate nucleus and in V1 neurons assigned to CO "blob," "edge," and "interblob" regions and across layers. Tested with achromatic stimuli, the receptive field properties of M and P neurons resembled those reported for other primates. The contrast sensitivity of P cells in the owl monkey was similar to that of P cells in the macaque, but the contrast sensitivities of M cells in the owl monkey were markedly lower than those in the macaque. We found no differences in eye dominance, orientation, or spatial frequency tuning, temporal frequency tuning, or contrast response for V1 neurons assigned to different CO compartments; we did find fewer direction-selective cells in blobs than in other compartments. We noticed laminar differences in some receptive field properties. Cells in the supragranular layers preferred higher spatial and lower temporal frequencies and had lower contrast sensitivity than did cells in the granular and infragranular layers. Our data suggest that the receptive field properties across functional compartments in V1 are quite homogeneous, inconsistent with the notion that CO blobs anatomically segregate signals from different functional "streams."

The influence of fixational eye movements on the response of neurons in area MT of the macaque.

We analyzed the relationship between eye movements and neuronal responses recorded from area MT in alert monkeys trained to maintain visual fixation during the presentation of moving patterns. The monkeys made small saccades which moved the eyes with velocities that spanned the sensitivity range of MT neurons. The saccades evoked changes in the neuronal response that depended upon (1) the level of stimulus-evoked activity amidst which the saccade occurred and (2) the direction of the saccade relative to the preferred direction of the neuron. Most notably, saccades were able to suppress stimulus-evoked activity when they caused retinal image flow that opposed the neuron's preference and were able to elicit a response or enhance weak activity when they caused flow in the neuron's preferred direction. On average, the disturbance lasted 40 ms beginning about 40 ms following saccade onset. Using these parameters, we simulated synthetic spike trains from an imaginary pair of similarly tuned neurons and determined that the interneuronal correlation due to saccades should be negligible at all but the lowest ongoing firing rates. This conclusion was supported from our data by the observation that response variance for single MT spike trains was not measurably reduced during periods of stable gaze compared to periods when eye movement exceeded a stability criterion (0.1 deg during 0.5 s). While the intrusions caused by saccades are too short-lived and infrequent to account for the variability of MT neuronal response (counter to the finding in V1 of Gur et al., 1997), the clear directional signal that they carry in area MT suggests that motion perception is not blocked during saccades by suppression at early stages in the visual pathway.

Processing of first- and second-order motion signals by neurons in area MT of the macaque monkey.

Extrastriate cortical area MT is thought to process behaviorally important visual motion signals. Psychophysical studies suggest that visual motion signals may be analyzed by multiple mechanisms, a "first-order" one based on luminance, and a "second-order" one based upon higher level cues (e.g. contrast, flicker). Second-order motion is visible to human observers, but should be invisible to first-order motion sensors. To learn if area MT is involved in the analysis of second-order motion, we measured responses to first- and second-order gratings of single neurons in area MT (and in one experiment, in area V1) in anesthetized, paralyzed macaque monkeys. For each neuron, we measured directional and spatio-temporal tuning with conventional first-order gratings and with second-order gratings created by spatial modulation of the flicker rate of a random texture. A minority of MT and V1 neurons exhibited significant selectivity for direction or orientation of second-order gratings. In nearly all cells, response to second-order motion was weaker than response to first-order motion. MT cells with significant selectivity for second-order motion tended to be more responsive and more sensitive to luminance contrast, but were in other respects similar to the remaining MT neurons; they did not appear to represent a distinct subpopulation. For those cells selective for second-order motion, we found a correlation between the preferred directions of first- and second-order motion, and weak correlations in preferred spatial frequency. These cells preferred lower temporal frequencies for second-order motion than for first-order motion. A small proportion of MT cells seemed to remain selective and responsive for second-order motion. None of our small sample of V1 cells did. Cells in this small population, but not others, may perform "form-cue invariant" motion processing (Albright, 1992).

Autonomy in practice: are nurse practitioner students being prepared for reality?

This article reports on a study examining the relationship between nurse practitioner students' expectations of future professional autonomy and the level of autonomy experienced by certified nurse practitioners. The findings indicate that practicing nurse practitioners experience a greater sense of autonomy than student nurse practitioners perceive. As autonomy is an issue of continuing importance in nursing, and for advanced practice, further research is needed to assist schools of nursing in devising reality-based curricula for nurse practitioner programs.

Adaptation to contingencies in macaque primary visual cortex.

We tested the hypothesis that neurons in the primary visual cortex (V1) adapt selectively to contingencies in the attributes of visual stimuli. We recorded from single neurons in macaque V1 and measured the effects of adaptation either to the sum of two gratings (compound stimulus) or to the individual gratings. According to our hypothesis, there would be a component of adaptation that is specific to the compound stimulus. In a first series of experiments, the two gratings differed in orientation. One grating had optimal orientation and the other was orthogonal to it, and therefore did not activate the neuron under study. These experiments provided evidence in favour of our hypothesis. In most cells adaptation to the compound stimulus reduced responses to the compound stimulus more than it reduced responses to the optimal grating, and the responses to the compound stimulus were reduced more by adaptation to the compound stimulus than by adaptation to the individual gratings. This suggests that a component of adaptation was specific to (and caused by) the simultaneous presence of the two orientations in the compound stimulus. To test whether V1 neurons could adapt to other contingencies in the stimulus attributes, we performed a second series of experiments, in which the component gratings were parallel but differed in spatial frequency, and were both effective in activating the neuron under study. These experiments failed to reveal convincing contingent effects of adaptation, suggesting that neurons cannot adapt equally well to all types of contingency.

Development of a sociocultural measure of young women's experiences with body weight and shape.

The social and societal pressures to be thin that many women experience are widely believed to negatively affect their body image. The fact that this view is not reflected in traditional body image measures prompted the development of this multidimensional self-report instrument of body weight and shape concerns that is contextually grounded in young women's life experiences. Semistructured interviews with high school and university women (N = 16) were used to develop the questionnaire items. Students were asked about their experiences with controlling the size and shape of their bodies, and the expectations and evaluations of others (e.g., parents, friends, intimate partners) regarding their body shape. The initial 101-item pool was derived from a content analysis of the interview transcripts and was administered to 287 female university students. Exploratory factor analysis with oblique rotation revealed five underlying dimensions, specifically, (a) Weight dissatisfaction, (b) Slimness as quality of life, (c) Interpersonal messages regarding slimness, (d) Societal value of thinness, and (e) Valuing exercise.