Can we predict a delirium after cardiac surgery? A validation study of a delirium risk checklist.

BACKGROUND: Delirium is a common temporary mental disorder that often occurs in patients who undergo cardiac surgery. It is important to prevent the negative side effects of delirium by identifying high-risk patients before surgery. Koster and colleagues designed a risk model to identify patients with an increased risk of postoperative delirium after cardiac surgery. AIM: The aim of this study was to validate the risk model for delirium and further improve the risk model. METHODS: A delirium risk checklist containing predictors associated with postoperative delirium was used during the preoperative outpatient screening in 329 patients. The delirium observation screening scale was used preoperatively and postoperatively to assess delirium. RESULTS: Compared with the model of Koster and colleagues age greater than 70 years and a history of delirium were confirmed as statistically significant predictors of postoperative delirium, while cognitive impairment and alcohol abuse were almost significant factors. The European system for cardiac operative risk evaluation (EuroSCORE), comorbidity and type of surgery could not predict a postoperative delirium again. The area under the curve of this model was 0.79 (95% confidence interval (CI) 0.73-0.86; P<0.001). Based on the data of this study the model was improved with the following independent predictors of postoperative delirium: age, more than one comorbidity, history of delirium and a lower standardised mini mental state examination score as with an area under the curve of 0.79 (95% CI 0.73-0.85; P<0.001). CONCLUSION: The risk model could not be fully validated. It is difficult to validate a risk model over time; there are different circumstances such as the increased focus on the prevention of delirium.

A European Multicenter Study of 616 Patients Receiving the Freedom Solo Stentless Bioprosthesis.

BACKGROUND: The purpose of this study was to evaluate the safety and performance of the Freedom Solo valve in aortic valve replacement by clinical and hemodynamic outcomes. METHODS: Six hundred sixteen patients underwent aortic valve replacement in 18 European centers; mean age was 74.5 ± 5.9 years, 54.1% of the patients were male, and concomitant procedures were performed in 43.2% of the patients. The majority (69%) of the implanted sizes were 23 mm and 25 mm. RESULTS: At 1 year, overall survival was 94.0%, whereas freedom from valve-related death was 98.6%. There were 9 (1.5%) early (≤ 30 days) and 27 (4.4%) late (>30 days) deaths. Early and late valve-related mortality was 0.3% (n = 2) and 1.1% (n = 7), respectively. Freedom from explant was 97.6%; 10 valves were explanted for endocarditis and 4 for paravalvular leak. There were 10 (1.6%) early and 5 (0.8%) late strokes. Atrioventricular block requiring pacemaker implant occurred in 8 (1.3%) and 1 (0.2%) patients in the early and late postoperative period, respectively. Thrombocytopenia was seen in 27 cases (4.4%) in the early postoperative period. Preoperatively, 93.8% of patients were in New York Heart Association functional classes II through IV, whereas at 1 year 96.9% of patients were in New York Heart Association functional classes I and II. At 1-year follow-up, mean and peak pressure gradients were 7.2 and 14.6 mm Hg, respectively. Indexed left ventricular mass decreased by 12% from 138 g/m(2) at discharge to 122 g/m(2) at 1 year. CONCLUSIONS: At 1-year follow-up after Freedom Solo implantation, we found acceptable clinical results with low mortality and morbidity and good hemodynamic performance, confirming safety and effectiveness in this multicenter experience.

Pattern, presentation and management of vascular injuries due to pellets and rubber bullets in a conflict zone.

BACKGROUND: Rubber bullets and pellet guns are considered non-lethal low-velocity weapons. They are used to disperse a mob during street protests. The present study was undertaken to analyze the pattern, presentation and management of vascular injuries caused by these weapons. PATIENTS AND METHODS: This was a prospective study of patients with features of vascular injuries due to pellets and rubber bullets from June 2010 to November 2010. All patients with features of vascular injuries due to these non-lethal weapons were included in the study. Vascular injuries caused by other causes were excluded from the study. RESULTS: A total of 35 patients who presented with features of vascular injury during this period were studied. All of them were males. The mean age was 22 years. Fifteen patients were revascularized primarily, 19 patients needed reverse saphenous vein graft and, in one, patient lateral repair was done. There were two mortalities in our series. Wound infection was the most common complication. The amputation rate was around 6%. CONCLUSION: Pellet and rubber bullets can cause serious life-threatening injuries. Vascular injury caused by these weapons need no different approach than other vascular injuries. Early revascularization and prompt resuscitation prevents the loss of limb or life.

Prediction of delirium after cardiac surgery and the use of a risk checklist.

BACKGROUND: Delirium is a temporary mental disorder, which occurs frequently among patients who undergo cardiac surgery. Delirium prediction and its associated prevention is essential. In a previous study, a risk checklist for delirium was developed. AIMS: The present study validated this checklist in a new, larger study population, and also investigated new risk factors. METHODS: Risk factors were obtained during the preoperative outpatient screening in 300 patients who underwent elective cardiac surgery. The Delirium Observation Screening scale was utilized pre- and postoperatively to assess delirium. RESULTS AND CONCLUSION: The incidence of delirium was 17.3%. A higher Euroscore, but not a disturbance in electrolytes, was confirmed as a predictor of postoperative delirium. Based on this study, a new risk model was constructed with the following risk factors: a higher Euroscore, older age (≥70 years), cognitive impairment, number of comorbidities, history of delirium, alcohol use and type of surgery. When using a probability of delirium of 20%, as predicted by the model, the sensitivity was 80.8% and the specificity 82.2%. The area under the curve was 0.89. With the revised delirium risk checklist, including seven new risk factors, patients with an increased risk of developing delirium following cardiac surgery could be identified more accurately.

Consequences of delirium after cardiac operations.

BACKGROUND: Delirium is a transient mental syndrome characterized by disturbances in consciousness, cognition, and perception. The risk that delirium will develop is increased in patients who undergo cardiac operations, especially the elderly. Generally, delirium during hospital admission is independently associated with many negative consequences, such as higher mortality, increased length of hospital stay, nursing home placement after admission, and cognitive and functional decline. METHODS: This prospective follow-up study used the Short Form 36-Item questionnaire, the Cognitive Failure Questionnaire, and a purpose-designed questionnaire to assess 300 patients who underwent elective cardiac operations at 6 months after the procedure. Postoperative delirium developed in 52 patients (17%). Mortality and readmission were also assessed. RESULTS: Delirium after cardiac procedures is associated with increased mortality (13.5% vs 2.0% in patients without), more hospital readmissions (45.7% vs 26.5%), and reduced quality of life. It is also associated with reduced cognitive functioning, including failures in attention, memory, perception, and motor function, and with functional dysfunction such as independency in activities of daily living and mobility. CONCLUSIONS: Postoperative delirium after cardiac operations is associated with many important consequences. These findings provide justification for intervention studies to evaluate whether delirium prevention, early recognition, or treatment strategies might improve postoperative functional and cognitive function.

Risk factors of delirium after cardiac surgery: a systematic review.

BACKGROUND: Delirium or acute confusion is a temporary mental disorder that occurs frequently among hospitalized elderly patients, but also in younger patients a delirium can develop. Patients who undergo cardiac surgery have an increased risk of developing delirium that is associated with many negative consequences. Therefore, prevention of delirium is essential. Despite the high incidence of delirium, a paucity of data on risk factors for delirium exists. AIM: The aim of this study was to summarize the available information concerning these risk factors. METHODS: A literature research was performed using the PubMed, Cinahl, and Cochrane Library databases and was limited to the last 10 years. RESULTS: Our review revealed 27 risk factors; 12 predisposing and 15 precipitating factors for delirium after cardiac surgery. The most established predisposing risk factors were atrial fibrillation, cognitive impairment, depression, history of stroke, older age, and peripheral vascular disease. The most established precipitating risk factor was a red blood cell transfusion. An abnormal albumin level was reported as the most established precipitating risk factor among blood values tested. A low cardiac output and the use of an Intra Aortic Balloon Pump or inotropic medication seem to be the most relevant risk factors associated with a postoperative delirium. CONCLUSION: A multifactorial risk model should be applied to identify patients at an increased risk of developing delirium following elective cardiac surgery. In these patients, if possible, preventative interventions can be taken and early recognition of delirium can be realized. This could potentially decrease the incidence of delirium and negative consequences caused by a postoperative delirium.

The long-term cognitive and functional outcomes of postoperative delirium after cardiac surgery.

BACKGROUND: Delirium or acute confusion is a temporary mental disorder, which occurs frequently among hospitalized elderly patients. Patients who undergo cardiac surgery have an increased risk of developing delirium. This is associated with many negative consequences such as prolonged hospital stay, nursing home placement, and reduced cognitive and functional recovery. METHODS: In this prospective follow-up study, a questionnaire was used 1 to 1.5 years after cardiac surgery in our earlier cohort of 112 patients who underwent elective cardiac surgery, of which 24 patients (21%) developed postoperative delirium as diagnosed by a single psychiatrist. RESULTS: Postoperative delirium after cardiac surgery may be associated with increased mortality (12.5% in patients with delirium versus 4.5% in patients without delirium; p = 0.16), more readmissions to the hospital (47.6% vs 32.6%; p = 0.19), dysfunction in memory (31.6% vs 22.6%; p = 0.39), and concentration problems (36.8% vs 20.2%; p = 0.13); and is associated with sleep disturbance (47.4% vs 23.8%; p = 0.03). CONCLUSIONS: Postoperative delirium after cardiac surgery may be associated with increased mortality and readmissions to the hospital, as well as poorer cognitive and functional outcomes. Therefore, prevention and (or) early recognition of delirium must be improved. In addition, patients and caregivers (family and general practitioner) must be better informed about the long-term consequences of delirium and what they can do about it.

The delirium observation screening scale recognizes delirium early after cardiac surgery.

BACKGROUND: Delirium or acute confusion is a temporary mental disorder which occurs frequently among hospitalized elderly patients. Patients who undergo cardiac surgery have an increased risk of developing delirium. Prevention or early recognition of delirium is essential. The Delirium Observation Screening (DOS) scale was developed to facilitate early recognition of delirium by nurses' observations during routine clinical care. AIM: The aim of this study was to validate the DOS scale in accordance with the diagnosis of the psychiatrist, using the DSM-IV criteria as the gold standard. METHODS: In this observational study, the DOS scale was used to assess whether 112 patients who underwent elective cardiac surgery had developed a postoperative delirium. The psychiatrist was consulted to confirm or refute the diagnosis delirium. Wilcoxon's Rank Sum Test was utilized to compare patients with and without delirium on duration of hospital stay. A Receiver Operating Characteristic Curve of the DOS scale was constructed with accompanying Area Under the Curve (AUC). RESULTS: Based on the diagnosis of the psychiatrist, the incidence of delirium following cardiac surgery was 21.4% and the mean duration of delirium was two and a half days. The time to discharge was 11 days longer in patients with delirium. In 27 of the 112 patients a DOS score of >or=3 was found, that indicates delirium. The sensitivity and specificity of the DOS scale was 100% and 96.6% respectively. The AUC was 0.98. CONCLUSION: The DOS scale is a very good instrument to facilitate early recognition of delirium by nurses' observation of patients who undergo cardiac surgery. Early recognition will expedite good postoperative management such as implementation of appropriate interventions, and may decrease negative consequences caused by postoperative delirium.

Delirium after cardiac surgery and predictive validity of a risk checklist.

BACKGROUND: Delirium or acute confusion is a temporary mental disorder that occurs frequently among hospitalized elderly patients. Patients who undergo cardiac surgery have an increased risk of delirium, which is associated with many negative consequences. Therefore, prevention or early recognition of delirium is essential. METHODS: In this observational study, a risk checklist for delirium was used during the preoperative outpatient screening in 112 patients who underwent elective cardiac surgery. The Delirium Observation Screening (DOS) scale was used before and after surgery to assess whether delirium had developed in patients. The psychiatrist was consulted to confirm or refute the diagnosis delirium. RESULTS: The incidence of delirium after cardiac surgery was 21%, and the mean duration of delirium was 2.5 days. The time to discharge was 11 days longer for patients with delirium. The delirium risk checklist could accurately predict postoperative delirium in patients who underwent elective cardiac surgery based on a disturbance in the electrolytes sodium and potassium and on EuroSCORE (European System for Cardiac Operative Risk Evaluation). When using a probability of delirium of 50%, the sensitivity of the risk checklist was 25.0% and specificity was 95.5%. The predictive value of a positive test was 60.0%, and the predictive value of a negative test was 82.4%. The area under the receiver-operating characteristic curve was 0.75. CONCLUSIONS: With the risk checklist for delirium, patients at an increased risk of delirium after elective cardiac surgery can be identified.

The bZip transcription factor vitellogenin-binding protein is post transcriptional down regulated in chicken liver.

The vitellogenin-binding protein (VBP) is a member of the proline and acidic-region rich (PAR) family of bZip transcription factors. PAR is located N-terminally to the DNA-binding domain. VBP binds to specific sites within the 300-bp 5'-flanking region of the chicken-liver-specific estrogen-dependent very-low-density apolipoprotein gene (apoVLDL II). One of these binding sites (site D) resembles the albumin site D and is positioned in close proximity of the major estrogen-responsive element. Previous studies showed that VBP can bind simultaneously with the estrogen receptor to the putative complex regulatory element E1D. To investigate whether VBP is involved in apoVLDL II gene expression, we examined its capacity to enhance apoVLDL II transcription and its presence in liver. We show that VBP is capable of enhancing transcription in transfection experiments. However, VBP could not be detected in liver by Western-blots or immuno-electro mobility shift assays (EMSAs) using antibodies against different moieties of the protein. We examined the possible reduction in translation efficiencies due to a small upstream open reading frame in the VBP leader sequence, but did not find any. Although VBP binds to the proximal apoVLDL II promoter region and enhances transcription in co-transfection experiments, the protein is unlikely to be involved in apoVLDL II gene transcription because of its undetectable low level in liver nuclei.

Differential stimulation by CCAAT/enhancer-binding protein alpha isoforms of the estrogen-activated promoter of the very-low-density apolipoprotein II gene.

The transcription factors CCAAT/enhancer-binding proteins alpha and beta (C/EBP alpha and C/EBP beta) are highly expressed in liver and are believed to function in maintaining the differentiated state of the hepatocytes. C/EBP alpha appears to be a critical regulator of genes involved in metabolic processes. We are interested in the roles of C/EBP in the expression of the very-low-density apolipoprotein II (apoVLDL II) gene. This gene encodes an avian yolk protein, is induced by estrogens and is only expressed in liver. To examine the role of C/EBP in apoVLDL II expression, footprinting and electromobility-shift analysis were performed. For three of the protein-binding sites in the apoVLDL II promoter region, C/EBP alpha and C/EBP beta were identified as the major DNA-binding activities. For one of the C/EBP genes, C/EBP alpha, the effect of the gene products on apoVLDL II transcription was examined. From transfection experiments we conclude that maximal estrogen-dependent activity of the apoVLDL II promoter requires the dual action of the estrogen receptor and C/EBP. The level of activity is different depending on the nature of the C/EBP alpha translational isoform transfected, the full-length C/EBP alpha polypeptide being the most active isoform and the N-terminally truncated isoform being moderately active. The present results suggest a role of C/EBP alpha translational isoform ratio in the modulation of expression of C/EBP target genes, such as those involved in metabolic processes.

The chicken CCAAT/enhancer binding protein alpha gene. Cloning, characterisation and tissue distribution.

We present the cloning and sequencing of the gene encoding the chicken CCAAT/Enhancer Binding Protein alpha (cC/EBP alpha). The coding region and 1.5 kb of 5' flanking DNA from a CpG island. Comparison of the chicken C/EBP alpha sequence to the homologous proteins of other species reveals several evolutionary conserved regions. cC/EBP alpha mRNA expression is restricted to a subset of tissues with high expression in liver, lung and small intestine. Recombinant cC/EBP alpha binds to its cognate C/EBP binding site as a homodimer or as a heterodimer with the related cC/EBP beta/NF-M.

Multiple steps in the regulation of transcription-factor level and activity.

This review focuses on the regulation of transcription factors, many of which are DNA-binding proteins that recognize cis-regulatory elements of target genes and are the most direct regulators of gene transcription. Transcription factors serve as integration centres of the different signal-transduction pathways affecting a given gene. It is obvious that the regulation of these regulators themselves is of crucial importance for differential gene expression during development and in terminally differentiated cells. Transcription factors can be regulated at two, principally different, levels, namely concentration and activity, each of which can be modulated in a variety of ways. The concentrations of transcription factors, as of intracellular proteins in general, may be regulated at any of the steps leading from DNA to protein, including transcription, RNA processing, mRNA degradation and translation. The activity of a transcription factor is often regulated by (de) phosphorylation, which may affect different functions, e.g. nuclear localization DNA binding and trans-activation. Ligand binding is another mode of transcription-factor activation. It is typical for the large super-family of nuclear hormone receptors. Heterodimerization between transcription factors adds another dimension to the regulatory diversity and signal integration. Finally, non-DNA-binding (accessory) factors may mediate a diverse range of functions, e.g. serving as a bridge between the transcription factor and the basal transcription machinery, stabilizing the DNA-binding complex or changing the specificity of the target sequence recognition. The present review presents an overview of different modes of transcription-factor regulation, each illustrated by typical examples.

Review: methylotrophic yeasts as factories for the production of foreign proteins.

In this contribution we discuss the potential of methylotrophic yeasts as hosts for the high level production of valuable foreign proteins. Recent relevant achievements on the intracellular production or secretion of proteins are summarized. Special attention is paid to a specific advantage of the use of methylotrophic yeasts, namely the possibility of accumulating the foreign gene products inside peroxisomes. This approach may be of major advantage when the protein product is toxic for the host cell and, also, to protect these proteins from undesired side-effects such as proteolysis or aggregation.

Cloning and characterisation of a nuclear, site specific ssDNA binding protein.

Estradiol inducible, liver-specific expression of the apoVLDL II gene is mediated through the estrogen receptor and a variety of other DNA-binding proteins. In the present study we report the cloning and characterisation of a single-strand DNA binding protein that interacts with the lower strand of a complex regulatory site, which includes the major estrogen responsive element and a site that resembles the rat albumin site D (apoVLDL II site D). Based on its binding specificity determined with electro-mobility shift assays, the protein is named single-strand D-box binding factor (ssDBF). Analysis of the deduced 302 amino acid sequence revealed that the protein belongs to the heteronuclear ribonucleoprotein A/B family (hnRNP A/B) and resembles other known eukaryotic single-strand DNA binding proteins. Transient transfection experiments in a chicken liver cell-line showed that the protein represses estrogen-induced transcription. A protein with similar binding characteristics is present in liver nuclear extract. The relevance of the occurrence of this protein to the expression of the apoVLDL II gene is discussed.

The N-terminus of amine oxidase of Hansenula polymorpha contains a peroxisomal targeting signal.

Here we describe the identification of the targeting sequence of peroxisomal amine oxidase (AMO) of H. polymorpha. Deletion analysis revealed that essential targeting information is located within the extreme N-terminal 16 amino acids. Moreover, this sequence can direct a reporter protein to the peroxisomal matrix of H. polymorpha. The N-terminal 16 amino acids of AMO contain a sequence with strong homology to the conserved PTS2 sequence. Therefore, AMO is considered to be a PTS2 protein.

Translation start site multiplicity of the CCAAT/enhancer binding protein alpha mRNA is dictated by a small 5' open reading frame.

The CCAAT/enhancer binding proteins (C/EBP) alpha and beta of the bZIP family of transcription factors each occur as multiple forms due to translation initiation at different in-frame AUG codons from the same messenger RNA. The C/EBP alpha mRNAs of chicken, rat and Xenopus all contain a small 5' open reading frame (5'ORF) whose size (18 nucleotides) and distance (seven nucleotides) to the C/EBP alpha cistron has been conserved in vertebrate evolution. The present studies shows that the small 5'ORF is crucial to the leaky scanning mechanism of ribosomes causing a fraction of them to ignore the first C/EBP alpha AUG codon and to start at internal AUGs. Our data challenge the view that translational start site multiplicity is mainly governed by the sequence context of the potential initiation codons. Western analysis showed that the two major chicken C/EBP alpha translation products, the full-length cC/EBP alpha-42 which acts a trans-activator in liver and the N-terminally truncated cC/EBP alpha-29 which lacks transcription activation potential, occur in a fixed ratio which is similar in different expressing tissues, like liver, lung and small intestine. The presence of a similar, thusfar unnoticed, small ORF 5' to the major initiation codon of C/EBP beta mRNA suggests that start site multiplicity from this mRNA may be governed by the same mechanism.

The methylotrophic yeast Hansenula polymorpha contains an inducible import pathway for peroxisomal matrix proteins with an N-terminal targeting signal (PTS2 proteins).

Two main types of peroxisomal targeting signals have been identified that reside either at the extreme C terminus (PTS1) or the N terminus (PTS2) of the protein. In the methylotrophic yeast Hansenula polymorpha the majority of peroxisomal matrix proteins are of the PTS1 type. Thus far, for H. polymorpha only amine oxidase (AMO) has been shown to contain a PTS2 type signal. In the present study we expressed H. polymorpha AMO under control of the strong endogenous alcohol oxidase promoter. Partial import of AMO into peroxisomes was observed in cells grown in methanol/(NH4)2SO4-containing medium. However, complete import of AMO occurred if the cells were grown under conditions that induce expression of the endogenous AMO gene. Similar results were obtained when the heterologous PTS2 proteins, glyoxysomal malate dehydrogenase from watermelon and thiolase from Saccharomyces cerevisiae, were synthesized in H. polymorpha. The import of PTS1 proteins, however, was not affected by the growth conditions. These results indicate that the reduced rate of AMO import in (NH4)2SO4-grown cells is not due to competition with PTS1 proteins for the same import pathway. Apparently, AMO is imported via a separate pathway that is induced by amines and functions for PTS2 proteins in general.

9-cis-retinoic acid represses estrogen-induced expression of the very low density apolipoprotein II gene.

The chicken very low density apolipoprotein II (apoVLDLII) gene is estrogen-inducible and specifically expressed in liver. We examined the possible involvement of the retinoid X receptor (RXR) and its ligand 9-cis-retinoic acid (9-cis-RA) in the activation of the apoVLDLII promoter. We first concentrated on a potential RXR recognition site, which deviates at only one position from a perfect direct A/GGGTCA repeat spaced by one nucleotide (DR-1) and was earlier identified as a common HNF-4/COUP-TF recognition site. However, band shift analysis revealed that this imperfect DR-1 motif does not interact with RXR alpha-homodimers. In accordance with this observation we found that this regulatory element does not mediate transactivation through RXR alpha in the presence of 9-cis-RA. However, our experiments revealed another, unexpected, effect of 9-cis-RA. Instead of stimulating, 9-cis-RA attenuated estrogen-induced expression of transfected estrogen-responsive VLDL-CAT reporter plasmids. This repression appeared to take place through the main estrogen response element (ERE) of the gene. Importantly, 9-cis-RA also strongly repressed the estrogen-induced expression of the endogenous apoVLDLII gene in cultured chicken hepatoma cells.

Binding of a bZip protein to the estrogen-inducible apoVLDL II promoter.

Activation of the very low density apolipoprotein II (apoVLDL II) gene in chicken liver by estrogen results in the binding of a variety of nuclear proteins including members of the steroid receptor superfamily and the bZip superfamily to the immediate 5' flanking region. In the present study, we have identified a bZip protein from chicken liver as one of the potential binding activities. Its cognate cDNA was cloned from an expression library using a recognition site DNA probe corresponding to part of the apoVLDL II promoter region. By footprinting and gel shift analysis with the recombinant protein from a prokaryotic expression system we have established that the protein binds to at least three different sites in the apoVLDLII promoter region. One of these sites partially overlaps with the major estrogen response element of the gene. Despite the proximity of their binding sites, the estrogen receptor and the bZip protein can bind simultaneously to the very region. Possible implications of this intimate arrangement of binding sites for the activation of the apoVLDL II promoter are discussed.