Use of propofol for short duration procedures in children with long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiencies.

The medication propofol, commonly used for anesthesia, has been avoided in patients with mitochondrial fatty acid oxidation disorders (FAODs) due to concerns that it contains long-chain fatty acids (LCFAs), and because of reports of severe side effects in some critically ill patients receiving high-dose propofol infusions that mimic some of the symptoms regularly found in FAOD patients. In this secondary analysis, we examined the outcomes of 8 children with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency or trifunctional protein (TFP) deficiency who were repeatedly sedated for an electroretinogram (ERG) as part of a longitudinal study of the progression of chorioretinopathy commonly found in this population. A total of 39 sedated ERG procedures were completed using propofol for sedation. The propofol dosing, estimated total energy needs of the subject, and inpatient dietary intake recording were completed in 32 of these procedures. The LCFAs in the propofol provided approximately 1.0% of the average total daily energy needs. The sedation with propofol resulted in no adverse side effects and was safely used in this short duration procedure.

A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury.

OBJECTIVES: Administration of eicosapentaenoic acid and docosahexanoic acid, omega-3 fatty acids in fish oil, has been associated with improved patient outcomes in acute lung injury when studied in a commercial enteral formula. However, fish oil has not been tested independently in acute lung injury. We therefore sought to determine whether enteral fish oil alone would reduce pulmonary and systemic inflammation in patients with acute lung injury. DESIGN: Phase II randomized controlled trial. SETTING: Five North American medical centers. PATIENTS: Mechanically ventilated patients with acute lung injury ≥18 yrs of age. INTERVENTIONS: Subjects were randomized to receive enteral fish oil (9.75 g eicosapentaenoic acid and 6.75 g docosahexanoic acid daily) or saline placebo for up to 14 days. MEASUREMENTS AND MAIN RESULTS: Bronchoalveolar lavage fluid and blood were collected at baseline (day 0), day 4 ± 1, and day 8 ± 1. The primary end point was bronchoalveolar lavage fluid interleukin-8 levels. Forty-one participants received fish oil and 49 received placebo. Enteral fish oil administration was associated with increased serum eicosapentaenoic acid concentration (p < .0001). However, there was no significant difference in the change in bronchoalveolar lavage fluid interleukin-8 from baseline to day 4 (p = .37) or day 8 (p = .55) between treatment arms. There were no appreciable improvements in other bronchoalveolar lavage fluid or plasma biomarkers in the fish oil group compared with the control group. Similarly, organ failure score, ventilator-free days, intensive care unit-free days, and 60-day mortality did not differ between the groups. CONCLUSIONS: Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with acute lung injury, and the results do not support the conduct of a larger clinical trial in this population with this agent. This experimental approach is feasible for proof-of-concept studies evaluating new treatments for acute lung injury.

Omega-3 fatty acids in critical illness.

Supplementation of enteral nutritional formulas and parenteral nutrition lipid emulsions with omega-3 fatty acids is a recent area of research in patients with critical illness. It is hypothesized that omega-3 fatty acids may help reduce inflammation in critically ill patients, particularly those with sepsis and acute lung injury. The objective of this article is to review the data on supplementing omega-3 fatty acids during critical illness; enteral and parenteral supplemental nutrition are reviewed separately. The results of the research available to date are contradictory for both enteral and parenteral omega-3 fatty acid administration. Supplementation with omega-3 fatty acids may influence the acute inflammatory response in critically ill patients, but more research is needed before definitive recommendations about the routine use of omega-3 fatty acids in caring for critically ill patients can be made.

Fish oil in critical illness: mechanisms and clinical applications.

Fish oil is rich in omega-3 fatty acids, which have been shown to be beneficial in multiple disease states that involve an inflammatory process. It is now hypothesized that omega-3 fatty acids may decrease the inflammatory response and be beneficial in critical illness. After a review of the mechanisms of omega-3 fatty acids in inflammation, research using enteral nutrition formulas and parenteral nutrition lipid emulsions fortified with fish oil were examined. The results of this research to date are inconclusive for both enteral and parenteral omega-3 fatty acid administration. More research is required before definitive recommendations can be made on fish oil supplementation in critical illness.

Characterization of the metabolic and physiologic response to chromium supplementation in subjects with type 2 diabetes mellitus.

The objective of the study was to provide a comprehensive evaluation of chromium (Cr) supplementation on metabolic parameters in a cohort of type 2 diabetes mellitus subjects representing a wide phenotype range and to evaluate changes in "responders" and "nonresponders." After preintervention testing to assess glycemia, insulin sensitivity (assessed by euglycemic clamps), Cr status, and body composition, subjects were randomized in a double-blind fashion to placebo or 1000 microg Cr. A substudy was performed to evaluate 24-hour energy balance/substrate oxidation and myocellular/intrahepatic lipid content. There was not a consistent effect of Cr supplementation to improve insulin action across all phenotypes. Insulin sensitivity was negatively correlated to soleus and tibialis muscle intramyocellular lipids and intrahepatic lipid content. Myocellular lipids were significantly lower in subjects randomized to Cr. At preintervention, responders, defined as insulin sensitivity change from baseline of at least 10% or greater, had significantly lower insulin sensitivity and higher fasting glucose and A(1c) when compared with placebo and nonresponders, that is, insulin sensitivity change from baseline of less than 10%. Clinical response was significantly correlated (P < .001) to the baseline insulin sensitivity, fasting glucose, and A(1c). There was no difference in Cr status between responder and nonresponders. Clinical response to Cr is more likely in insulin-resistant subjects who have more elevated fasting glucose and A(1c) levels. Chromium may reduce myocellular lipids and enhance insulin sensitivity in subjects with type 2 diabetes mellitus who do respond clinically independent of effects on weight or hepatic glucose production. Thus, modulation of lipid metabolism by Cr in peripheral tissues may represent a novel mechanism of action.

Plasma amyloid-beta peptide levels correlate with adipocyte amyloid precursor protein gene expression in obese individuals.

BACKGROUND/AIMS: Several studies have demonstrated that midlife obesity increases the risk for dementia and Alzheimer's disease. Moreover, plasma 42-amino-acid amyloid-beta (Abeta42) levels appear to correlate with BMI. We recently demonstrated that adipocyte amyloid precursor protein (APP) expression is upregulated in obesity and correlates with insulin resistance and adipose tissue inflammation. In this study, we aimed to investigate the relation between adipocyte APP expression and plasma Abeta peptide levels. METHODS: We conducted a pilot study in which we measured adipocyte APP gene expression and the circulating plasma levels of Abeta40 in 10 obese individuals before and after a 6-month behaviorally based weight loss intervention. Subjects had an oral glucose tolerance test with measurement of insulin levels, Abeta40 levels measured by ELISA and transcript levels of APP in subcutaneous abdominal adipocytes measured by quantitative real-time PCR. RESULTS: At baseline, adipocyte APP expression correlated significantly with plasma Abeta40 levels and with 2-hour insulin concentrations. Following the 6-month weight loss intervention, body weight and BMI decreased significantly. Fasting plasma concentrations of glucose and insulin were improved. Adipocyte APP expression was significantly decreased (p < 0.001) after weight loss. Changes in adipocyte APP expression correlated with changes in plasma Abeta40 levels (R = 0.74, p = 0.01) and changes in 2-hour insulin (R = 0.75, p = 0.01). CONCLUSION: The results of this pilot study suggest that increased circulating plasma levels of Abeta peptides in obesity may be due to increased adipocyte APP gene expression. While these results suggest a possible mechanism linking midlife obesity with the later development of Alzheimer's disease, further research is necessary to elucidate the regulation and functional significance of APP in adipocytes.

Treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin improves fasting islet-cell function in subjects with type 2 diabetes.

CONTEXT: Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes mellitus (T2DM) by prolonging the activity of the circulating incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Consistent with this mechanism of action, DPP-4 inhibitors improve glucose tolerance after meals by increasing insulin and reducing glucagon levels in the plasma. However, DPP-4 inhibitors also reduce fasting blood glucose, an unexpected effect because circulating levels of active GIP and GLP-1 are low in the postabsorptive state. OBJECTIVE: The objective of the study was to examine the effects of DPP-4 inhibition on fasting islet function. DESIGN: We conducted a randomized, double-blind, placebo-controlled trial. SETTING: The study was performed in General Clinical Research Centers at two University Hospitals. SUBJECTS: Forty-one subjects with T2DM were treated with metformin or diet, having good glycemic control with glycosylated hemoglobin values of 6.2-7.5%. INTERVENTION: Subjects were treated with vildagliptin (50 mg twice daily) or placebo for 3 months, followed by a 2-wk washout. Major Outcome Measure: We measured insulin secretion in response to iv glucose and arginine before and after treatment and after drug washout. RESULTS: There were small and comparable reductions in glycosylated hemoglobin in both groups over 3 months. Vildagliptin increased fasting GLP-1 levels in subjects taking metformin, but not those managed with diet, and raised active GIP levels slightly. DPP-4 inhibitor treatment improved the acute insulin and C-peptide responses to glucose (50 and 100% respectively; P < 0.05) and increased the slope of the C-peptide response to glucose (33%; P = 0.023). CONCLUSION: Vildagliptin improves islet function in T2DM under fasting conditions. This suggests that DPP-4 inhibition has metabolic benefits in addition to enhancing meal-induced GLP-1 and GIP activity.

FBXO31 is the chromosome 16q24.3 senescence gene, a candidate breast tumor suppressor, and a component of an SCF complex.

A BAC located in the 16q24.3 breast cancer loss of heterozygosity region was previously shown to restore cellular senescence when transferred into breast tumor cell lines. We have shown that FBXO31, although located just distal to this BAC, can induce cellular senescence in the breast cancer cell line MCF-7 and is the likely candidate senescence gene. FBXO31 has properties consistent with a tumor suppressor, because ectopic expression of FBXO31 in two breast cancer cell lines inhibited colony growth on plastic and inhibited cell proliferation in the MCF-7 cell line. In addition, compared with the relative expression in normal breast, levels of FBXO31 were down-regulated in breast tumor cell lines and primary tumors. FBXO31 was cell cycle regulated in the breast cell lines MCF-10A and SKBR3 with maximal expression from late G(2) to early G(1) phase. Ectopic expression of FBXO31 in the breast cancer cell line MDA-MB-468 resulted in the accumulation of cells at the G(1) phase of the cell cycle. FBXO31 contains an F-box domain and is associated with the proteins Skp1, Roc-1, and Cullin-1, suggesting that FBXO31 is a component of a SCF ubiquitination complex. We propose that FBXO31 functions as a tumor suppressor by generating SCF(FBXO31) complexes that target particular substrates, critical for the normal execution of the cell cycle, for ubiquitination and subsequent degradation.

A retrospective evaluation of transthoracic biphasic electrical cardioversion for atrial fibrillation in dogs.

OBJECTIVES: To evaluate safety, efficacy, and clinical usefulness of biphasic transthoracic cardioversion for management of dogs with atrial fibrillation (AF). BACKGROUND: In dogs AF is usually managed with heart rate control rather than by restoration of sinus rhythm (SR). However, restoration of SR has potential advantages of improving cardiac output and reducing ventricular filling pressures, and biphasic cardioversion provides an improved benefit/risk ratio compared to traditional monophasic cardioversion. ANIMALS, MATERIALS AND METHODS: Retrospective analysis of data from 39 dogs with spontaneous AF managed with biphasic transthoracic cardioversion was done. Conversion characteristics, adverse effects, and duration of SR were evaluated. Effects of heart disease and pretreatment with amiodarone on success of cardioversion and on duration of SR were also evaluated. RESULTS: Restoration of SR was achieved in 36 of 39 dogs (92.3%). Presence of heart disease or atrial enlargement had no effect on cardioversion characteristics or ability to restore SR. Median duration of SR following cardioversion and treatment with amiodarone was 120 days. Dogs with lone AF remained in SR longer than those with heart disease. CONCLUSIONS: Biphasic cardioversion is safe and effective. Although duration of SR varied, a majority of dogs remained in SR long enough to benefit.

Developing and implementing the role of the nurse bronchoscopist.

Recent years have seen a growing range of new roles being created for nurses, often in areas previously considered to be part of the medical domain. This paper discusses the development of the nurse bronchoscopist role and a training programme and service framework to support it in order to develop a nurse-led service for patients requiring this procedure.

Responses of primate visual cortical neurons to stimuli presented by flash, saccade, blink, and external darkening.

Our visual experience constitutes an unending chain of transient events, including those caused by saccadic eye movements, by blinks, and by localized or global changes in the external world. The categorical perception of objects is maintained across different classes of transient events, suggesting that the neural circuitry underlying visual perception responds to different transient events in a similar manner. However, different sorts of transients do have different perceptual impacts: for example, the sudden changes in a scene due to a saccade or a blink do not disturb our perceptual continuity of a visual scene as much as an external change does. We recorded the responses of 103 single visual cortical neurons in two rhesus monkeys (V1: n = 38, V2: n = 19, V3V/VP: n = 30, V4V: n = 16) to the onset and offset of a visual stimulus that was elicited by four different conditions: 1) stimulus flashed on and off while the eyes remain fixed; 2) stimulus turned on and off along with the entire scene (external darkening); 3) stimulus constant, onset and offset induced by rapid saccadic eye movements; and 4) offset induced by an eyeblink. For most neurons the onset and offset of a visual stimulus elicited qualitatively similar responses regardless of condition. We found no systematic effect of different conditions across the neuronal population. Previously we have shown that when the visual scene is occluded by a blink V1 neuronal firing declines in a similar manner as when the external scene is darkened and the eyes left open. Here we show that this is also the case in V2, V3V/VP, and V4V. However, for a substantial minority of neurons, the response varied strongly as a function of the transient event. This overall pattern was the same in all four cortical areas studied here. We hypothesize that most neurons in visual cortex constitute a passive "filter bank", analyzing the scene for specific details regardless of condition. However, there are neurons that respond in a qualitatively different manner depending on how a stimulus is presented, and we hypothesize that these signals may be important for determining the perceptual salience of a visual event.

Responses of primate visual cortical V4 neurons to simultaneously presented stimuli.

We report here results from 45 primate V4 visual cortical neurons to the preattentive presentations of seven different patterns located in two separate areas of the same receptive field and to combinations of the patterns in the two locations. For many neurons, we could not determine any clear relationship for the responses to two simultaneous stimuli. However, for a substantial fraction of the neurons we found that the firing rate was well modeled as the maximum firing rate of each stimulus presented separately. It has previously been proposed that taking the maximum of the inputs ("MAX" operator) could be a useful operation for neurons in visual cortex, although there has until now been little direct physiological evidence for this hypothesis. Our results here provide direct support for the hypothesis that the MAX operator plays a significant (although certainly not exclusive) role in generating the receptive field properties of visual cortical neurons.

CBFA2T3 (MTG16) is a putative breast tumor suppressor gene from the breast cancer loss of heterozygosity region at 16q24.3.

Numerous cytogenetic and molecular studies of breast cancer have identified frequent loss of heterozygosity (LOH) of the long arm of human chromosome 16. On the basis of these data, the likely locations of breast cancer tumor suppressor genes are bands 16q22.1 and 16q24.3. We have mapped the CBFA2T3 (MTG16) gene, previously cloned as a fusion partner of the AML1 protein from a rare (16;21) leukemia translocation, to the 16q24.3 breast cancer LOH region. The expression of CBFA2T3 was significantly reduced in a number of breast cancer cell lines and in primary breast tumors, including early ductal carcinomas in situ, when compared with nontransformed breast epithelial cell lines and normal breast tissue. Reintroduction of CBFA2T3 into different breast tumor derived cell lines with decreased expression of this gene reduced colony growth on plastic and in soft agar. CBFA2T3 was shown to function as a transcriptional repressor when tethered to the GAL4 DNA-binding domain in a reporter gene assay and, therefore, has the potential to be a transcriptional repressor in normal breast epithelial cells. Taken together, these findings suggest that CBFA2T3 is a likely candidate for the breast cancer tumor suppressor gene that is the target for the frequent 16q24 LOH in breast neoplasms.

Surgical correction of double-chambered right ventricle in dogs.

Double-chambered right ventricle (DCRV) is possibly an emerging congenital cardiac anomaly in dogs. The defect causes clinical and pathophysiologic signs similar to those of congenital pulmonic stenosis in dogs but has distinct diagnostic features, breed predilections, and implications for treatment. The defect is often associated with clinical signs early in life. Surgical correction of DCRV can be undertaken with the aid of cardiopulmonary bypass and offers the prospect of an improved clinical outcome.