Search

Background: Vascular access devices (VADs) are essential for delivery of intravenous therapies. There are notable gaps in the literature regarding a focus on patient experience and meaning-making related to living with a VAD, specifically a central venous access device (CVAD). Aims: To explore how patients make sense of living with a CVAD. Methods: This study followed an interpretive phenomenological analysis (IPA) approach. Purposive sampling was used to identify 11 cancer patients who had a CVAD in situ. One-to-one semi-structured interviews were performed. Interviews were digitally recorded, transcribed and analysed by the lead author. Findings: Four superordinate themes were identified: the self under attack; being rescued/being robbed; protection of others/protection of self; bewilderment and dismay at lack of staff competence. Conclusion: Having a CVAD affects the psychological, social, and personal self and impacts on self-esteem and self-image. Despite this, CVADs are accepted by patients and are eventually ‘embodied’ by them.

Anti-N-methyl-D-aspartate receptor encephalitis is a newly described disease process. Patients are generally young females who present with psychiatric symptoms and progress to have seizures, abnormal movements, and. autonomic instability. Diagnosis is made based on serum and cerebrospinal fluid results, However, a characteristic EEG pattern described as extreme delta brush has been associated with this disorder making it especially relevant to neurodiagnostic technologists in practice today. Our case presentations follow two patients through the course of their illness and recovery.

Background: In the United Kingdom, totally implantable venous access systems (TIVAS) are not routinely used. Compared with Hickman catheters, these devices are more expensive and complex to insert. However, it is unclear whether the higher costs may be offset by perceived greater health benefits. This pilot trial aimed to generate relevant data to inform the design of a larger definitive randomised controlled trial.\ud Methods: This was a phase II prospective, randomised, open trial from two UK oncology centres. The primary end point was overall complication rate. Secondary end points included individual complication rates, time to first complication and quality of life. Analysis was by intention to treat. An economic evaluation was also carried out.\ud Results: A total of 100 patients were randomised in a 3 : 1 ratio to receive a Hickman or a TIVAS. Overall, 54% of patients in the Hickman arm suffered one or more complications compared with 38% in the TIVAS arm (one-sided P=0.068). In the Hickman arm, 28% of the devices were removed prematurely due to a complication compared with 4% in the TIVAS arm. Quality of life based on the device-specific questionnaire was greater in the TIVAS arm for 13 of the 16 questions. The economic evaluation showed that Hickman arm was associated with greater mean cost per patient £1803 (95% CI 462, 3215), but similar quality-adjusted life years −0.01 (95% CI −0.15, 0.15) than the TIVAS arm. However, there is much uncertainty associated with the results.\ud Conclusions: Compared with Hickman catheters, TIVAS may be the cost-effective option. A larger multicentre trial is needed to confirm these preliminary findings.

Background Asenapine is an atypical antipsychotic for acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. The recommended asenapine starting dose is 10 mg bid with the option to reduce the dose to 5 mg bid if needed due to adverse effects/tolerability. Methods Phase IIIb, international, double-blind, fixed-dose, parallel-group, 3-week placebo-controlled trial of asenapine 5 and 10 mg bid in adults with an acute bipolar I disorder manic or mixed episode. Primary outcome was difference in asenapine versus placebo in mean change from baseline to day 21 in the Young-Mania Rating Scale (YMRS) total score. Others included difference in asenapine versus placebo in the Clinical Global Impression Scale for Bipolar Severity (CGI-BP-S) and rate of YMRS responders. Results Both asenapine doses were statistically superior to placebo in mean change from baseline to day 21 in YMRS total score (−10.9, −14.4, and −14.9 for placebo, asenapine 5 mg bid, 10 mg bid, respectively). Both asenapine doses had statistically superior improvement in mean change in CGI-BP-S score at day 21. Neither asenapine dose had significantly more YMRS responders at day 21 than placebo. Limitations Results may not be generalizable to the entire population with bipolar I disorder owing to strict inclusion criteria. Conclusions This study evaluated, by a fixed-dose design, the efficacy and safety of asenapine versus placebo in patients with bipolar I disorder. Both asenapine 5 and 10 mg bid were efficacious in treating mania associated with bipolar I disorder and were generally well tolerated.

Background: Central venous access devices (CVADs) are now a fundamental part of contemporary healthcare. Despite having many advantages, there are also complications associated with them. Evidence suggests that educating and training health professionals who maintain CVADs is essential for preventing such complications, however, the most effective approach for this training has not been evaluated. Aim: The aim of this study was to determine whether the introduction of an innovative educational intervention within a higher education institution (HEI) improved the confidence and knowledge of registered nurses dealing with CVADs. Methods: A survey design consisting of a self-completion questionnaire and open-ended questions was used. Results: This study demonstrated that nurses felt more confident following participation in the training. In addition, nurses discussed the advantages of training outside of the clinical setting as it provided them with a safe place to practise and gave them time to learn without interruption. The findings from this study suggest that the HEIs can provide an effective and safe environment for registered nurses to build confidence and knowledge in CVAD management.

Health professionals are under increasing pressure to reduce costs while ensuring patient safety. As the number of vascular access devices (VADs) used in health care continues to increase, there is a need to reduce the complications of infection and occlusion associated with them. Needle-free devices (NFDs), also known as needleless connectors, have been available since the early 1990s and the type and variety of these devices has continued to develop. As well as the original aim of NFDs to maintain a closed system and to reduce the risk of needlestick injuries and blood spillage, NFDs are now designed with the aim of improving clinical outcomes by reducing the common complications of infection and catheter occlusion. As there are a number of NFDs available with specific designs, it is imperative that health professionals have an understanding of the different types and functions. This article provides an explanation of NFD design and functions and guidance and information about their benefits, as well as advice on preventing complications associated with their use.

Nurses working within both acute and primary care settings are required to care for and maintain central venous access devices (CVADs). To support these nurses in practice, a higher education institution and local health board developed and delivered CVAD workshops, which were supported by a workbook and competency portfolio. Following positive evaluation of the workshops, an electronic learning (e-learning) package was also introduced to further support this clinical skill in practice. To ascertain whether this blended learning approach to teaching CVAD care and maintenance prepared nurses for practice, the learning package was evaluated through the use of electronic questionnaires. Results highlighted that the introduction of the e-learning package supported nurses' practice, and increased their confidence around correct clinical procedures.

Ultrasound is an imaging technique that uses ultra-high frequency sound waves. The interaction of the sound waves with body tissue enables an image to be produced. Following guidance from the National Institute for Health and Care Excellence (NICE) (2002) , the use of two-dimensional ultrasound imaging for central venous catheter (CVC) insertion has increased. Ultrasound provides the nurse with visualisation of the target vein as well as any other surrounding structures. It also demonstrates any variation in anatomy that the patient may have. Increased first-time puncture rates and decreased complications are among the benefits of ultrasound use for CVC placement described in the literature. However, NICE (2002) guidance recommended that education and training be sought by those using this technology. The aim of this article, therefore, is to provide useful information regarding ultrasound-guided venous access and to describe some techniques to improve image quality.

Peripherally inserted central catheters (PICCs) are a popular device for long-term vascular access. They were introduced into practice in the US in the 1970s, but only gained popularity in the UK during the 1990s (Gabriel, 1995). Many nurses now provide services for central venous access. To ensure patient safety, it is important that practitioners inserting these devices maintain up-to-date knowledge and ensure evidence-based practice. This should ultimately reduce complication and risk during insertion. The purpose of this article is to offer a guide to safe PICC insertion by providing an overview of anatomy and physiology and focusing on some of the main complications of PICC insertion and methods along with ways of reducing these.

There has been much role expansion in nursing in the last two decades, with advanced nurses now performing minimally invasive surgery such as central venous access device insertion. However, there is a lack of research exploring the perceptions of nurses performing these procedures. This study explored the lived experiences of nurses who perform minimally invasive surgery, namely central venous access device insertion. Three key themes emerged from this analysis: stress associated with the unpredictable nature of the procedure, coping with responsibility and a patient-focused approach. Although the practitioners experience a degree of stress in the role, they also experience job satisfaction and feel that their roles have a positive impact on the patients in their care. The study findings provide information to managers and nurses performing these roles, and suggest how stress and burnout can be prevented.

ObjectiveEvaluate the efficacy and safety of asenapine 2.5 mg twice daily (bid; n=97) or 5 mg bid (n=113) versus placebo (n=101) in adults with acute exacerbation of schizophrenia.MethodsAdults with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) schizophrenia diagnosis were randomized to asenapine 2.5 mg bid, 5 mg bid, placebo, or olanzapine 15 mg once daily. The primary objective was to test superiority of asenapine versus placebo as measured by the change from baseline to day 42 in the Positive and Negative Syndrome Scale (PANSS) total score. The key safety objective was to evaluate weight change in asenapine versus olanzapine at day 42.ResultsThe primary efficacy endpoint was met; the difference in least squares mean change from baseline to day 42 in PANSS total score between asenapine 5 mg bid and placebo was −5.5 points (unadjusted 95% CI: −10.1, −1.0; multiplicity adjusted P=0.0356). Neither asenapine 2.5 mg bid nor olanzapine 15mg were superior to placebo.Both asenapine groups demonstrated significantly less weight gain than olanzapine at day 42. Significantly higher incidences of oral hypoesthesia and dysgeusia (combined) for asenapine 2.5 mg bid (5.2% vs 0.0%; P=0.0217) and 5 mg bid (7.1% vs 0.0%; P=0.0033) were observed versus placebo. There were no significant differences between asenapine and placebo for insomnia, extrapyramidal symptoms, akathisia, dizziness, or combination of somnolence/sedation/hypersomnia.ConclusionThis study supports previous efficacy and safety findings of asenapine; asenapine 5 mg bid is the lowest effective dose in adults with schizophrenia. Asenapine was associated with significantly less weight gain than olanzapine at day 42.

This article discusses the use of fresh frozen cadavers as an innovative way to teach the procedure of totally implanted port insertion. In an attempt to increase the number of competent medical and nursing practitioners able to insert these devices, workshops have been devised and delivered at a university clinical anatomy skills centre. This method of teaching has had positive feedback from practitioners.

Purpose This pre-trial qualitative research study was carried out to explore patient and clinical staff attitudes to central venous access devices (CVADs). In addition, views about participation in a randomised controlled trial (RCT) were explored with the aim of maximising recruitment to an imminent RCT of three CVADs. Methods Three patient focus groups (each comprising three patients) and 23 interviews with clinical staff were conducted. Interviews and focus group discussions were digitally recorded, transcribed verbatim, anonymised, uploaded to the QSR NVivo10 qualitative software programme and thematically analysed. Results Analysis of focus group interviews revealed the added challenges that a CVAD poses to patients with cancer. Four key themes emerged: continuity of daily life, pain and discomfort, stigma (a mark of disgrace associated with certain conditions) and self-preservation. The findings show the impact of a CVAD on patients’ ability to manage their condition. Clinical staff interviews highlighted several potential barriers to recruitment; a lack of equipoise (genuine clinical uncertainty as to which intervention is the most beneficial), concerns about the logistics of device insertion and a perceived requirement for education and training. Conclusions This qualitative study raises awareness of key areas of concern to patients who need a CVAD for chemotherapy delivery. It was identified that there is a need for clearer patient information around CVADs. Additionally it allows investigators to identify barriers to recruitment in a timely manner in order to minimise the potential for conflict between the roles of carer and researcher and consequently, maximise recruitment to the RCT.

A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR agonist activities. A structure-activity relationship was developed toward PPARalpha/gamma dual agonism. As a result, (2R)-7-(3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy)-2-ethylchromane-2-carboxylic acid (48) was identified as a potent, structurally novel, selective PPARalpha/gamma dual agonist. Compound 48 exhibited substantial antihyperglycemic and hypolipidemic activities when orally administered in three different animal models: the db/db mouse type 2 diabetes model, a Syrian hamster lipid model, and a dog lipid model.

Patients with type 2 diabetes mellitus exhibit hyperglycemia and dyslipidemia as well as a markedly increased incidence of atherosclerotic cardiovascular disease. Here we report the characterization of a novel arylthiazolidinedione capable of lowering both glucose and lipid levels in animal models. This compound, designated TZD18, is a potent agonist with dual human peroxisome proliferator-activated receptor (PPAR)-alpha/gamma activities. In keeping with its PPARgamma activity, TZD18 caused complete normalization of the elevated glucose in db/db mice and Zucker diabetic fatty rats. TZD18 lowered both cholesterol and triglycerides in hamsters and dogs. TZD18 inhibited cholesterol biosynthesis at steps before mevalonate and reduced hepatic levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Moreover, TZD18 significantly suppressed gene expression of fatty acid synthesis and induced expression of genes for fatty acid degradation and triglyceride clearance. Studies on 17 additional PPARalpha or PPARalpha/gamma agonists showed that lipid lowering in hamsters correlated with the magnitude of hepatic gene expression changes. Importantly, the presence of PPARgamma agonism did not affect the relationship between hepatic gene expression and lipid lowering. Taken together, these data suggest that PPARalpha/gamma agonists, such as TZD18, affect lipid homeostasis, leading to an antiatherogenic plasma lipid profile. Agents with these properties may provide favorable means for treatment of type 2 diabetes and dyslipidemia and the prevention of atherosclerotic cardiovascular disease.

Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report the identification and characterization of a novel non-TZD selective PPARgamma modulator (nTZDpa). nTZDpa bound potently to PPARgamma with high selectivity vs. PPARalpha or PPARdelta. In cell-based assays for transcriptional activation, nTZDpa served as a selective, potent PPARgamma partial agonist and was able to antagonize the activity of PPARgamma full agonists. nTZDpa also displayed partial agonist effects when its ability to promote adipogenesis in 3T3-L1 cells was evaluated. Assessment of protein conformation using protease protection or solution nuclear magnetic resonance spectroscopy methods showed that nTZDpa produced altered PPARgamma conformational stability vs. full agonists, thereby establishing a physical basis for its observed partial agonism. DNA microarray analysis of RNA from 3T3-L1 adipocytes treated with nTZDpa or several structurally diverse PPARgamma full agonists demonstrated qualitative differences in the affected gene expression profile for nTZDpa. Chronic treatment of fat-fed, C57BL/6J mice with nTZDpa or a TZD full agonist ameliorated hyperglycemia and hyperinsulinemia. However, unlike the TZD, nTZDpa caused reductions in weight gain and adipose depot size. Feed efficiency was also substantially diminished. Unlike TZDs, nTZDpa did not cause cardiac hypertrophy in mice. When a panel of PPARgamma target genes was examined in white adipose tissue, nTZDpa produced a different in vivo expression pattern vs. the full agonist. These findings establish that novel selective PPARgamma modulators can produce altered receptor conformational stability leading to distinctive gene expression profiles, reduced adipogenic cellular effects, and potentially improved in vivo biological responses. Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome.

Venepuncture and cannulation are procedures regularly carried out by health professionals and form a critical component of patient care. Venepuncture, or the collection of blood from a vein, is usually performed for laboratory analysis to assist with diagnosis and treatment of the patient.

(2009). Technical Tips: Calculating Frequency and Duration in Digital EEG. American Journal of Electroneurodiagnostic Technology: Vol. 49, No. 1, pp. 105-107.

Activation of beta3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis. In brown adipose tissue, this serves to up-regulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductance pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with beta3 agonists in nonprimate species leads to uncoupling protein 1 up-regulation and weight loss, the relevance of this mechanism to energy metabolism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus beta3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a beta3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue. These data suggest a role for beta3 agonists in the treatment of human obesity.

Infusion therapy is now an integral part of the majority of nurses’ professional practice (RCN, 2006). Infusion therapy is no longer confined to secondary care, and home intravenous therapy is becoming more commonplace (Keyley, 2002). As nurses, we are responsible for maintaining our skills and knowledge in relation to all aspects of patient care (RCN, 2006). This article provides an overview of the types of vascular access devices used in primary care, and provides guidance and recommendations to ensure best practice. Although there are many complications associated with vascular access devices (Docherty, 2006) this article will focus on the prevention of infection and maintainace of catheter patency in vascular access devices. Infection is one of the most serious complications that can result from the presence and use of a central venous catheter (Humar et al. 2000), however careful management of these devices can minimize the complications associated with infusion therapy.

Here, we characterize the actions of MK-0767, a dual ligand of the nuclear receptors peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma. In cell-based assays, MK-0767 produced potent activation of human PPARgamma and PPARalpha with a gamma:alpha potency ratio of approximately 2. The dual agonist induced high affinity interactions of PPARalpha and PPARgamma with the transcriptional coactivator CBP in vitro. In ob/ob mice, MK-0767 normalized hyperglycemia and hyperinsulinemia with equal or greater potency and efficacy than pioglitazone. Treatment of hamsters with MK-0767 produced substantial reductions in blood cholesterol and triglycerides. In dogs, MK-0767 reduced serum cholesterol levels with a potency more than 10-fold greater than simvastatin. The efficacies of MK-0767 and simvastatin were additive when given together. We conclude that MK-0767 is a potent dual PPARalpha/gamma agonist with robust insulin sensitizing and hypolipidemic activities.

The liver X receptors, LXRalpha and LXRbeta, are members of the nuclear receptor superfamily. Originally identified as orphans, both receptor subtypes have since been shown to be activated by naturally occurring oxysterols. LXRalpha knockout mice fail to regulate cyp7a mRNA levels upon cholesterol feeding, implicating the role of this receptor in cholesterol homeostasis. LXR activation also induces the expression of the lipid pump involved in cholesterol efflux, the gene encoding ATP binding cassette protein A1 (ABCA1). Therefore, LXR is believed to be a sensor of cholesterol levels and a potential therapeutic target for atherosclerosis. Here we describe a synthetic molecule named F(3)MethylAA [3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-(4,5)-isoxazolyl)propylthio)-phenyl acetic acid] that is more potent than 22(R)-hydroxycholesterol in LXR in vitro assays. F(3)MethylAA is capable not only of inducing ABCA1 mRNA levels, but also increasing cholesterol efflux from THP-1 macrophages. In rat hepatocytes, F(3)MethylAA induced cyp7a mRNA, confirming conclusions from the knockout mouse studies. Furthermore, in rat in vivo studies, F(3)MethylAA induced liver cyp7a mRNA and enzyme activity. A critical species difference is also reported in that neither F(3)MethylAA nor 22(R)-hydroxycholesterol induced cyp7a in human primary hepatocytes. However, other LXR target genes, ABCA1, ABCG1, and SREBP1, were regulated.

11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is an enzyme that converts cortisone to the active glucocorticoid, cortisol. Cortisol-cortisone interconversion plays a key role in the regulation of glucose metabolism, since mice deficient in 11betaHSD1 are resistant to diet-induced hyperglycemia. Peroxisome proliferator activator receptors (PPAR) are key regulators of glucose and lipid homeostasis. We observed a striking downregulation of murine hepatic 11betaHSD1 expression and activity after chronic treatment of wild-type mice with PPARalpha agonists, while 11betaHSD1 in the livers of PPARalpha knockout mice, or in mice treated for only 7 h with PPARalpha agonists, was unaltered. Our results are the first to show PPARalpha agonists can affect glucocorticoid metabolism in the liver by altering 11betaHSD1 expression after chronic treatment. Regulation of active glucocorticoid levels in the liver by PPARalpha agonists may in turn affect glucose metabolism, consistent with reports of their antidiabetic effects.

A role for peroxisome proliferator-activated receptors, PPAR gamma and PPAR alpha, as regulators of energy homeostasis and lipid metabolism, has been suggested. Recently, three distinct uncoupling protein isoforms, UCP-1, UCP-2, and UCP-3, have also been identified and implicated as mediators of thermogenesis. Here, we examined whether in vivo PPAR gamma or PPAR alpha activation regulates the expression of all three UCP isoforms. Rats or lean and db/db mice were treated with PPAR gamma [thiazolidinedione (TZD)] or PPAR alpha (WY-14643) agonists, followed by measurement of messenger RNAs (mRNAs) for UCP-1, UCP-2, and UCP-3 in selected tissues where they are expressed. TZD treatment (AD 5075 at 5 mg/kg x day) of rats (14 days) increased brown adipose tissue (BAT) depot size and induced the expression of each UCP mRNA (3x control levels for UCP-1 and UCP-2, 2.5x control for UCP-3). In contrast, UCP-2 and UCP-3 mRNA levels were not affected in white adipose tissue or skeletal muscle. Chronic (30 days) low-dose (0.3 mg/kg x day) TZD treatment induced UCP-1 mRNA and protein in BAT (2.5x control). In contrast, chronic TZD treatment (30 mg/kg x day) suppressed UCP-1 mRNA (>80%) and protein (50%) expression in BAT. This was associated with further induction of UCP-2 expression (>10-fold) and an increase in the size of lipid vacuoles, a decrease in the number of lipid vacuoles in each adipocyte, and an increase in the size of the adipocytes. TZD treatment of db/db mice (BRL 49653 at 10 mg/kg x day for 10 days) also induced UCP-1 and UCP-3 (but not UCP-2) expression in BAT. PPAR alpha is present in BAT, as well as liver. Treatment of rats or db/db mice with WY-14643 did not affect expression of UCP-1, -2, or -3 in BAT. Hepatic UCP-2 mRNA was increased (4x control level) in db/db and lean mice, although this effect was not observed in rats. Thus, in vivo PPAR gamma activation can induce expression of UCP-1, -2, and -3 in BAT; whereas chronic-intense PPAR gamma activation may cause BAT to assume white adipose tissue-like phenotype with increased UCP-2 levels. PPAR alpha activation in mice is sufficient to induce liver UCP-2 expression.

The beta3-adrenergic receptor is an integral membrane protein consisting of seven transmembrane domains. Unlike the beta1 and beta2 receptors, this subtype lacks the consensus phosphorylation sites required for desensitization by serine kinases. Using the rodent specific beta3 agonist BRL 35135, our initial data indicated that beta3 receptor-mediated glycerol levels progressively decreased following daily oral doses of 5 mg/kg. Therefore, we initiated studies designed to delineate the possible mechanism(s) for this decreased response. Within 3 hours following a single oral dose of BRL 35135, serum glycerol levels and UCP (uncoupling protein) RNA levels were significantly increased whereas beta3 RNA levels were significantly decreased. Rats were dosed daily for 5 days with either vehicle or BRL 35135 (5 mg/kg, p.o.) and blood samples were collected for glycerol analysis. Adipose tissue was excised for lipolysis and adenyl cyclase measurements. In addition, UCP and beta3 receptor RNA levels were assessed. No effect on adipocyte BRL 37344-stimulated adenylyl cyclase activity was observed 3 hours following the initial dose of BRL 35135. Although a slight decrease (approximately 25%) in adenylyl cyclase activity could be observed 24 hours following the initial dose, it wasn't until day 4 of dosing that a significant decrease (50%) was observed. In contrast, beta3- stimulated lipolysis in adipocytes from BRL 35135-treated rats was decreased 85% within 24 hours and this decrease persisted through four days of treatment. These data indicate that the lipolytic response to beta3 receptor activation is decreased after only a single oral dose of BRL 35135, whereas receptor-mediated adenylyl cyclase activation, although initially unaffected, also desensitizes by day four of treatment.

Phenylbutazone potentiated the anticoagulant effects of racemic warfarin and of the individual enantiomers to similar extents in the rat. This indicates that the phenylbutazone did not act stereospecifically on the enantiomers, as it does in humans. Phenylbutazone doubled the turnover rate of warfarin in plasma, but it did not increase the amount of the anticoagulant in liver or the amount excreted in urine. The drug had no effect on plasma disappearance of [3H] or on hepatic levels of [3H] vitamin K1 or of its chief metabolite, [3H] vitamin K1 epoxide, after injection of [3H] vitamin K1. Phenylbutazone, however, at concentrations of 0.5 to 2.8 mM inhibited vitamin K-dependent carboxylation of a synthetic pentapeptide substrate in liver microsomes by 40-88 per cent. Vitamin K-dependent protein carboxylation was also inhibited by about 40 per cent in microsomes and post-mitochondrial supernatant fluid at drug concentrations of 2.8 to 4.8 mM. Most importantly, prothrombin synthesis was inhibited in post-mitochondrial supernatant fractions by 19 and 39 per cent at drug concentrations of 2.8 and 4.8 mM respectively. The inhibition of both carboxylation and prothrombin synthesis appears to have been of sufficient magnitude to account for the potentiation by phenylbutazone observed in vivo. The calculated hepatic level of phenylbutazone during potentiation was around 3 mM, a concentration that produced inhibition in vitro.

A gene encoding bovine acidic fibroblast growth factor has been chemically synthesized, cloned and expressed as a biologically active protein in Escherichia coli. The 440 base pair gene was assembled by enzymatic ligation of 16 oligonucleotides and cloned into a pBR322–derived expression plasmid downstream of the hybrid tac promoter. Expressed recombinant mitogen comigrated with the native bovine brain–derived protein as detected by Western blot immunological analysis. The expression product of the synthetic gene has been purified to apparent homogeneity and demonstrates a mitogenic activity for Balb/c 3T3 cells in the presence of heparin equivalent to the brain–derived mitogen. These results demonstrate the feasibility of expressing large amounts of functional acidic fibroblast growth factor in bacteria and provide a system for site–specific mutagenesis of the protein.

Fibroblast growth factors (FGFS, reviewed by Thomas and Gimenez-Gallego, 1986) are mitogens for a wide variety of cells in culture including not only fibroblasts but also vascular endothelial cells, myoblasts, chondrocytes, osteoblasts and glial cells. In vivo, FGFS have been shown to promote blood vessel growth. Acidic and basic forms of FGFS have been identified, purified and characterized which, although structurally related to each other, are unique gene products. Alternative names for these molecules have been proposed based on their source (retina-derived growth factors, eye-derived growth factors, brain-derived growth factors), target cells (endothelial cell growth factor, astroglial growth factors, prostatropins) and ability to bind to heparin (heparin-binding growth factors). The amino acid sequence, homologies and activities of acidic FGF (aFGF) are reported.