The dual PPARα/γ agonist aleglitazar increases the number and function of endothelial progenitor cells: implications for vascular function and atherogenesis.

BACKGROUND AND PURPOSE: Aleglitazar is a dual PPARα/γ agonist but little is known about its effects on vascular function and atherogenesis. Hence, we characterized its effects on circulating angiogenic cells (CAC), neoangiogenesis, endothelial function, arteriogenesis and atherosclerosis in mice. EXPERIMENTAL APPROACH: C57Bl/6 wild-type (WT, normal chow), endothelial NOS (eNOS)(-/-) (normal chow) and ApoE(-/-) (Western-type diet) mice were treated with aleglitazar (10 mg·kg(-1) ·day(-1) , i.p.) or vehicle. KEY RESULTS: Aleglitazar enhanced expression of PPARα and PPARγ target genes, normalized glucose tolerance and potently reduced hepatic fat in ApoE(-/-) mice. In WT mice, but not in eNOS(-/-) , aleglitazar up-regulated Sca-1/VEGFR2-positive CAC in the blood and bone marrow and up-regulated diLDL/lectin-positive CAC. Aleglitazar augmented CAC migration and enhanced neoangiogenesis. In ApoE(-/-) mice, aleglitazar up-regulated CAC number and function, reduced markers of vascular inflammation and potently improved perfusion restoration after hindlimb ischaemia and aortic endothelium-dependent vasodilatation. This was associated with markedly reduced formation of atherosclerotic plaques. In human cultured CAC from healthy donors and patients with coronary artery disease with or without diabetes mellitus, aleglitazar increased migration and colony-forming units in a concentration-dependent manner. Furthermore, oxidative stress-induced CAC apoptosis and expression of p53 were reduced, while telomerase activity and expression of phospho-eNOS and phospho-Akt were elevated. Comparative agonist and inhibitor experiments revealed that aleglitazar's effects on CAC migration and colony-forming units were mediated by both PPARα and PPARγ signalling and required Akt. CONCLUSIONS AND IMPLICATIONS: Aleglitazar augments the number, function and survival of CAC, which correlates with improved vascular function, enhanced arteriogenesis and prevention of atherosclerosis in mice.

Effects of the dual PPAR-α/γ agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat.

AIMS: To evaluate the effects of aleglitazar, a dual peroxisome proliferator-activated receptor-α/γ agonist, on the development of diabetes-related organ dysfunction, in relation to glycaemic and lipid changes, in Zucker diabetic fatty (ZDF) rats. METHODS: Six-week-old, male ZDF rats received aleglitazar 0.3 mg/kg/day or vehicle as food admix for 13 weeks (n = 10 per group). Age-matched male Zucker lean rats served as non-diabetic controls. Plasma and renal markers were measured at several time points. Histopathology and quantitative immunohistochemistry were performed at 13 weeks. RESULTS: Glycated haemoglobin (5.4 vs. 9.2%) and blood glucose (8.3 ± 0.3 vs. 26.1 ± 1.0 mmol/l) were significantly reduced at 12 weeks with aleglitazar versus vehicle-treated ZDF rats (both p < 0.01), while aleglitazar preserved near-normal plasma insulin levels. Aleglitazar prevented the development of hypertriglyceridaemia (1.4 ± 0.1 vs. 8.5 ± 0.9 mmol/l) and reduced plasma non-esterified fatty acids (0.09 ± 0.02 vs. 0.26 ± 0.04 mmol/l) relative to vehicle-treated animals (both p < 0.01). Urinary glucose and protein concentrations were significantly reduced at 13 weeks with aleglitazar versus vehicle-treated rats (both p < 0.01). Consistent with its effect on glycaemic control, aleglitazar protected ß-cell morphology, as evidenced by preservation of islet integrity, and reduction of ß-cell apoptosis and islet fibrosis. Aleglitazar prevented renal glomerular hypertrophy, podocyte degeneration, glomerulosclerosis, tubulo-interstitial lesions and development of cataracts. CONCLUSIONS: Aleglitazar strongly improved glycaemic and lipid parameters while protecting key tissues, including the pancreas, kidneys and eyes, against diabetes-associated structural and functional changes in the ZDF rat.

The effect of feto-maternal size and childhood growth on left ventricular mass and arterial stiffness in Afro-Caribbean children.

We hypothesized that maternal size, fetal size and childhood growth are associated with childhood blood pressure, left ventricular mass (LVM) and arterial stiffness. The Vulnerable Windows Cohort is a longitudinal study of 569 mothers and their offspring. Anthropometry was measured on each child at birth, at 6 weeks, once in 3 months upto 2 years and then every 6 months. Blood pressure and body composition were assessed in 185 children (age 11.5 years) and echocardiography performed. LVM was not associated with maternal size after adjustment for child's weight. LVM was significantly associated with faster growth in childhood and with current weight, fat mass and lean mass. Systolic blood pressure was not related to maternal, fetal or newborn anthropometry, but was positively associated with infant and childhood growth, as well as current body size and fat mass. The pulse pressure/stroke volume ratio (an index of arterial stiffness) was inversely associated with maternal size, placental volume at 20 weeks, fetal size at 35 weeks and childhood growth even after adjustment for current weight. In conclusion, LVM in childhood is positively associated with maternal height, child's current size and rate of growth. Arterial stiffness is inversely related to maternal, fetal and placental size as well as growth throughout childhood.

Progression from prehypertension to hypertension in a Jamaican cohort: incident hypertension and its predictors.

OBJECTIVES: To estimate the incidence of hypertension in people with and without prehypertension and determine the factors that predict progression to hypertension. METHODS: Data from a cohort of 25-74-year-old residents of Spanish Town, Jamaica, were analysed. All participants completed a structured questionnaire and had blood pressure (BP), anthropometric measurements and venous blood sampling performed by trained personnel. Blood Pressure was classified using the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7) criteria. RESULTS: 708 persons who had the required data and were not hypertensive at baseline were included in this analysis. Mean follow-up time was 4.1 years; 28.7% of prehypertensive participants developed hypertension compared to 6.2% of normotensive participants. The unadjusted incidence rate ratio (IRR [95% CI]) for progression among prehypertensive compared to normotensive participants was 4.62 [2.96, 7.43]. Among males, the rate of progression to hypertension was significantly higher for those 45-64 years old and those who were current smokers. Among females, progression was higher for age groups 25-44 years, 45-64 years, those who were overweight (BMI > or =25), obese (BMI > or =30) and current smokers. In multivariate models, prehypertension, female gender overweight status and older age remained significantly associated with progression to hypertension among the combined prehypertensive and normotensive groups. IRR [95% CI] were: prehypertension, 3.45 [2.18-5.45]; female gender 1.81 [1.12, 2.94]; overweight, 1.87 [1.15, 2.94]; age 45-64 years, 1.73 [1.08, 2.76]; age > 65 years 2.39 [1.31, 4.34]. CONCLUSIONS: Prehypertension is associated with a three-fold increase in the incidence of hypertension. Higher BMI, age and female gender also independently predict the development of hypertension.

A receptor-like inositol lipid phosphatase is required for the maturation of developing cochlear hair bundles.

A screen for protein tyrosine phosphatases (PTPs) expressed in the chick inner ear yielded a high proportion of clones encoding an avian ortholog of protein tyrosine phosphatase receptor Q (Ptprq), a receptor-like PTP. Ptprq was first identified as a transcript upregulated in rat kidney in response to glomerular nephritis and has recently been shown to be active against inositol phospholipids. An antibody to the intracellular domain of Ptprq, anti-Ptprq, stains hair bundles in mice and chicks. In the chick ear, the distribution of Ptprq is almost identical to that of the 275 kDa hair-cell antigen (HCA), a component of hair-bundle shaft connectors recognized by a monoclonal antibody (mAb) that stains inner-ear hair bundles and kidney glomeruli. Furthermore, anti-Ptprq immunoblots a 275 kDa polypeptide immunoprecipitated by the anti-HCA mAb from the avian inner ear, indicating that the HCA and Ptprq are likely to be the same molecule. In two transgenic mouse strains with different mutations in Ptprq, anti-Ptprq immunoreactivity cannot be detected in the ear. Shaft connectors are absent from mutant vestibular hair bundles, but the stereocilia forming the hair bundle are not splayed, indicating that shaft connectors are not necessary to hold the stereocilia together; however, the mice show rapid postnatal deterioration in cochlear hair-bundle structure, associated with smaller than normal transducer currents with otherwise normal adaptation properties, a progressive loss of basal-coil cochlear hair cells, and deafness. These results reveal that Ptprq is required for formation of the shaft connectors of the hair bundle, the normal maturation of cochlear hair bundles, and the long-term survival of high-frequency auditory hair cells.

PTPRQ is a novel phosphatidylinositol phosphatase that can be expressed as a cytoplasmic protein or as a subcellularly localized receptor-like protein.

PTPRQ (rPTP-GMC1) is a member of the type III receptor-like protein tyrosine phosphatase family. PTPRQ has very low activity against phosphotyrosine but is active against phosphatidylinositol phosphates that are involved in regulation of survival, proliferation, and subcellular architecture. Here, we report that PTPRQ can be expressed as a cytosolic or a receptor-like protein and that the form, subcellular localization, and cell types in which it is expressed are regulated by alternative promoter use and by alternative splicing. The first promoter drives expression of transcripts encoding a transmembrane protein in human podocytes and lung. PTPRQ protein is localized to the basal membrane of human podocytes, beginning when podocyte progenitors can first be identified in the embryonic kidney. A second promoter drives expression of a transcript that can encode a cytoplasmic protein containing the catalytic site. This is the major PTPRQ transcript in rat mesangial cells and human testis and is upregulated in mesangial cells in a rat model of mesangial proliferative glomerulonephritis. Differential regulation of expression of the transmembrane vs cytosolic forms, in different cell types during development or response to injury, may be a mechanism through which PTPRQ, with its activities against membrane phospholipids and against phosphotyrosine, can target specific substrates under different conditions.

Protein tyrosine phosphatase RQ is a phosphatidylinositol phosphatase that can regulate cell survival and proliferation.

Protein tyrosine phosphatase RQ (PTPRQ) was initially identified as a protein tyrosine phosphatase (PTPase)-like protein that is upregulated in a model of renal injury. Here we present evidence that, like PTEN, the biologically important enzymatic activity of PTPRQ is as a phosphatidylinositol phosphatase (PIPase). The PIPase specificity of PTPRQ is broader than that of PTEN and depends on different amino acid residues in the catalytic domain. In vitro, the recombinant catalytic domain of PTPRQ has low PTPase activity against tyrosine-phosphorylated peptide and protein substrates but can dephosphorylate a broad range of phosphatidylinositol phosphates, including phosphatidylinositol 3,4,5-trisphosphate and most phosphatidylinositol monophosphates and diphosphates. Phosphate can be hydrolyzed from the D3 and D5 positions in the inositol ring. PTPRQ does not have either of the basic amino acids in the catalytic domain that are important for the PIPase activity of PTEN or the sequence motifs that are characteristic of type II phosphatidylinositol 5-phosphatases. Instead, the PIPase activity depends on the WPE sequence present in the catalytic cleft of PTPRQ, and in the "inactive" D2 domains of many dual-domain PTPases, in place of the WPD motif present in standard active PTPases. Overexpression of PTPRQ in cultured cells inhibits proliferation and induces apoptosis. An E2171D mutation that retains or increases PTPase activity but eliminates PIPase activity, eliminates the inhibitory effects on proliferation and apoptosis. These results indicate that PTPRQ represents a subtype of the PTPases whose biological activities result from its PIPase activity rather than its PTPase activity.

Efficacy of intraarticular hyaluronic acid injections in knee osteoarthritis.

Intraarticular injections of hyaluronic acid have been advocated for treatment of symptomatic knee osteoarthritis. Appropriate indications and favorable patient response factors, such as radiographic disease severity and age, are not clearly defined for this therapy. The current review of 80 knees with symptomatic osteoarthritis treated with hyaluronic acid revealed that approximately 2/3 of treated knees received 2/3 relief of pain. Hyaluronic acid treatment is not appropriate for all patients with knee osteoarthritis. Overall, less than 50% of treated knees achieved satisfactory results, and only 35% reported increased activity. Twenty-two patients (28% of knees; 22 knees) underwent surgery within 7 months of their index injection, suggesting an inadequate response to treatment. The treatment is not without complication because 11 patients (15% of knees; 12 knees) experienced adverse reactions, including one case of septic arthritis. The authors recommend intraarticular hyaluronic acid only for patients with symptoms and significant surgical risk factors and for patients with mild radiographic disease in whom conservative treatment has failed (physical therapy, weight loss, nonsteroidal antiinflammatory medication, and intraarticular steroid injection). It is inadvisable to treat patients with a complete collapse of joint space or bone loss with intraarticular hyaluronic acid, given their poor clinical response.

Different binding modes of amphibian and human corticotropin-releasing factor type 1 and type 2 receptors: evidence for evolutionary differences.

The binding characteristics of corticotropin-releasing factor (CRF) type 1 (CRF(1)) and type 2 (CRF(2)) receptors from human (hCRF(1) and hCRF(2alpha)) and Xenopus (xCRF(1) and xCRF(2)) were compared using four different (125)I-labeled CRF analogs, the agonists (125)I-CRF and (125)I-sauvagine, and the antagonists (125)I-astressin ((125)I-AST) and (125)I-antisauvagine-30 ((125)I-aSVG). The hCRF(2alpha) and xCRF(2) receptors bound all four radioligands with different affinities, whereas hCRF(1) did not bind (125)I-aSVG, and xCRF(1) bound neither (125)I-sauvagine nor (125)I-aSVG. Competitive binding studies using unlabeled agonists and antagonists with hCRF(1) and hCRF(2alpha) receptors revealed that most agonists exhibited higher affinity in displacing agonist radioligands compared with displacement of antagonist radioligands. Exceptions were the agonists human and rat urocortin, which displayed high-affinity binding in the presence of either (125)I-labeled agonist or antagonist ligands. In contrast, the affinities of antagonists were independent of the nature of the radioligand. We also found that, in contrast to the mammalian CRF receptors, the affinity of ligand binding to xCRF(1) and xCRF(2) receptors strongly depended on the nature of the radioligand used for competition. For xCRF(1), competitors showed different rank order binding profiles with (125)I-CRF compared with (125)I-AST as the displaceable ligand. Similarly, binding of competitors to the xCRF(2) receptor showed markedly different profiles with (125)I-CRF as the competed ligand compared with the other radioligands. These data demonstrate that amphibian CRF receptors have distinctly different binding modes compared with their mammalian counterparts.

Cloning, expression and functional characterization of rat napsin.

A full-length cDNA clone coding for rat napsin was identified by homology search of the ZooSeq rat EST database (Incyte). Northern blot analysis revealed high expression of napsin mRNA transcripts in kidney, lung and spleen. Western blot analysis showed that rat napsin is expressed in kidney as a 50-kDa, highly glycosylated, monomeric protein. Lysates prepared from human embryonic kidney cells (HEK293) transfected with rat napsin showed increased enzymatic activity which was inhibited by pepstatin.

Protein-tyrosine phosphatases in the vessel wall: differential expression after acute arterial injury.

Many protein-tyrosine phosphatases (PTPases) have now been identified, but little is known about PTPase expression and regulation in vascular tissue and in vascular disease. Polymerase chain reaction (PCR) amplification and cDNA fingerprinting of PTPase catalytic domains, combined with random sequencing of PCR product libraries, identified 18 (8 receptor-like and 10 cytosolic) PTPases in the rat carotid artery and revealed differential expression of 5 of these PTPases during neointima formation after balloon catheter injury. In situ hybridization was used to localize mRNA expression in vessel cross sections for the 5 differentially expressed PTPases. This revealed that for 3 PTPases (SHP1, CD45, and PTPbeta), differential transcript abundance was due to appearance/loss of the cell types by which they were expressed (leukocytes for SHP1 and CD45, endothelial cells for PTPbeta). However, mRNA expression of 2 PTPases (PTPL1 and PTP1B) was specifically upregulated by proliferating and migrating smooth muscle cells (SMCs) in characteristic temporal and regional patterns in response to vessel damage. Quantitative PCR analysis showed that PTP1B and PTPL1 were induced approximately 30-fold and approximately 60-fold, respectively, by 2 weeks after injury in the damaged vessels compared with the uninjured vessels. PTP1B was rapidly upregulated in the media after vessel injury and remained highly expressed in the developing neointima. By contrast, PTPL1 expression did not increase dramatically until the SMCs had migrated into the intima. The differential expression of PTP1B and PTPL1 by SMCs after injury suggests roles for these PTPases in the regulation of vessel wall remodeling.

Preservation of gene expression ratios among multiple complex cDNAs after PCR amplification: application to differential gene expression studies.

Comparative gene expression studies are often limited by low availability of tissue and poor quality of extractable mRNA. Collective PCR amplification of minute quantities of mRNA has great potential for overcoming these limitations. However, there remains significant concern about the effects of amplification on the absolute and relative abundance of individual mRNAs that could complicate subsequent gene expression studies. To address this problem, we systematically compared the relative abundance of many specific mRNAs from complex cDNA preparations (from tissue and cultured cells) both before and after amplification by PCR. Our results demonstrated that, as expected, the absolute abundance of different mRNAs in a cDNA library is altered in an unpredictable manner by PCR amplification. However, we found that the concentration ratios of specific mRNAs among different cDNA preparations were routinely well conserved after PCR amplification. Thus, for the purpose of comparative expression studies for specific mRNAs in two (or more) complex cDNAs, PCR-amplified cDNA is equally useful as unamplified cDNA. These results provide a rigorous experimental validation and offer a theoretical treatment to support the utility of PCR amplified cDNA for differential gene expression studies. We conclude that the inherent difficulties in performing differential screening studies such as gene chip and array analyses on limited amounts of biological materials can be overcome by a PCR amplification step without compromising data quality.

Proliferating and migrating mesangial cells responding to injury express a novel receptor protein-tyrosine phosphatase in experimental mesangial proliferative glomerulonephritis.

The mesangial cell provides structural support to the kidney glomerulus. A polymerase chain reaction-based cDNA display approach identified a novel protein-tyrosine phosphatase, rPTP-GMC1, whose transcript expression is transiently and dramatically up-regulated during the period of mesangial cell migration and proliferation that follows mesangial cell injury in the anti-Thy 1 model of mesangial proliferative glomerulonephritis in the rat. In situ hybridization analysis confirmed that rPTP-GMC1 mRNA is up-regulated specifically by mesangial cells responding to the injury and is not detectable in other cells in the kidney or in many normal tissues. In cell culture, rPTP-GMC1 is expressed by mesangial cells but not by glomerular endothelial or epithelial cells (podocytes). The longest transcript (7.5 kilobases) encodes a receptor-like protein-tyrosine phosphatase consisting of a single catalytic domain, a transmembrane segment, and 18 fibronectin type III-like repeats in the extracellular segment. A splice variant predicts a truncated molecule missing the catalytic domain. rPTP-GMC1 maps to human chromosome 12q15 and to the distal end of mouse chromosome 10. The predicted structure of rPTP-GMC1 and its pattern of expression in vivo and in culture suggest that it plays a role in regulating the adhesion and migration of mesangial cells in response to injury.

Potassium transport by amino acid permeases in Saccharomyces cerevisiae.

Deletion of the potassium transporter genes TRK1 and TRK2 impairs potassium uptake in Saccharomyces cerevisiae, resulting in a greatly increased requirement for the ion and the inability to grow on low pH medium. Selection for mutations that restored growth of trk1Delta trk2Delta cells on low pH (3.0) medium led to the isolation of a dominant suppressor that also partially suppressed the increased K+ requirement of these cells. Molecular analysis revealed the suppressor to be an allele of BAP2 that encodes a permease for branched chain amino acids. The suppressor mutation (BAP2-1) converts a phenylalanine codon, highly conserved among the amino acid permease genes, to a serine codon in a region predicted to lie within the sixth membrane-spanning domain. Generation of the analogous mutation in the histidine permease produced an allele, HIP1-293, that similarly suppressed the low pH sensitivity of trk1Delta trk2Delta cells. Suppression of trk1Delta trk2Delta phenotypes by BAP2-1 or HIP1-293 was correlated with increased Rb+ uptake. The presence of the substrate amino acids enhanced but was not essential for suppression of trk1Delta trk2Delta phenotypes and increased Rb+ uptake. The conserved site altered by the suppressor mutations appears to be important; his4 HIP1-293 cells show an increased requirement for histidine compared with his4 HIP1 cells.

Amino acid substitutions in membrane-spanning domains of Hol1, a member of the major facilitator superfamily of transporters, confer nonselective cation uptake in Saccharomyces cerevisiae.

Selection for the ability of Saccharomyces cerevisiae cells to take up histidinol, the biosynthetic precursor to histidine, results in dominant mutations at HOL1. The DNA sequence of HOL1 was determined, and it predicts a 65-kDa protein related to the major facilitator family (drug resistance subfamily) of putative transport proteins. Two classes of mutations were obtained: (i) those that altered the coding region of HOL1, conferring the ability to take up histidinol; and (ii) cis-acting mutations (selected in a mutant HOL1-1 background) that increased expression of the Hol1 protein. The ability to transport histidinol and other cations was conferred by single amino acid substitutions at any of three sites located within putative membrane-spanning domains of the transporter. These mutations resulted in the conversion of a small hydrophobic amino acid codon to a phenylalanine codon. Selection for spontaneous mutations that increase histidinol uptake by such HOL1 mutants resulted in mutations that abolish the putative start codon of a six-codon open reading frame located approximately 171 nucleotides downstream of the transcription initiation site and 213 nucleotides upstream of the coding region of HOL1. This single small upstream open reading frame (uORF) confers translational repression upon HOL1; genetic disruption of the putative start codon of the uORF results in a 5- to 10-fold increase in steady-state amounts of Hol1 protein without significantly affecting the level of HOL1 mRNA expression.

Genetic and molecular analysis of DNA43 and DNA52: two new cell-cycle genes in Saccharomyces cerevisiae.

Two Saccharomyces cerevisiae genes previously unknown to be required for DNA synthesis have been identified by screening a collection of temperature-sensitive mutants. The effects of mutations in DNA43 and DNA52 on the rate of S phase DNA synthesis were detected by monitoring DNA synthesis in synchronous populations that were obtained by isopycnic density centrifugation. dna43-1 and dna52-1 cells undergo cell-cycle arrest at the restrictive temperature (37 degrees C), exhibiting a large-budded terminal phenotype; the nuclei of arrested cells are located at the neck of the bud and have failed to undergo DNA replication. These phenotypes suggest that DNA43 and DNA52 are required for entry into or completion of S phase. DNA43 and DNA52 were cloned by their abilities to suppress the temperature-sensitive lethal phenotypes of dna43-1 and dna52-1 cells, respectively. DNA sequence analysis suggested that DNA43 and DNA52 encode proteins of 59.6 and 80.6 kDa, respectively. Both DNA43 and DNA52 are essential for viability and genetic mapping experiments indicate that they represent previously unidentified genes: DNA43 is located on chromosome IX, 32 cM distal from his5 and DNA52 is located on chromosome IV, 0.9 cM from cdc34.

Cervical spine injuries in blunt trauma patients requiring emergent endotracheal intubation.

Airway management in the blunt trauma patient is complicated by the potential for causing or exacerbating an injury to the cervical cord if an unstable cervical fracture is present. The records of 987 blunt trauma patients who required emergent endotracheal intubation over a 5-year period were retrospectively reviewed to determine the incidence and type of cervical spine injury and the incidence of injury based on airway management. Sixty of the patients (6.1%) had a cervical fracture; 53 were potentially unstable injuries by radiographic criteria. Twenty patients had neurologic deficits prior to intubation. Twenty-six patients with unstable injuries were intubated orally, 25 nasally, and two by cricothyrotomy. One patient developed a neurologic deficit after nasotracheal intubation. Because of a possible selection bias in which severely injured patients were preferentially referred to this trauma center, the true incidence of cervical spine injuries may be lower than the 6.1% we found. The authors conclude that the incidence of serious cervical spine injury in a very severely injured population of blunt trauma patients is relatively low, and that commonly used methods of precautionary airway management rarely lead to neurologic deterioration.

Midazolam use in the emergency department.

Midazolam is the first water-soluble benzodiazepine. As with other benzodiazepines it has amnestic, sedative, hypnotic, anxiolytic, and anticonvulsant properties. Midazolam is about two to four times more potent than diazepam. Midazolam has been extensively used for a variety of outpatient procedures, but there has been no documentation of its safety in emergency department patients. The authors retrospectively reviewed all patients receiving midazolam during a 2-year period at the University of Cincinnati Center for Emergency Care. The study population consisted of 389 patients (men 56%; women 44%) with an average age of 33.3 years. Midazolam was used intravenously for sedation before a wide variety of painful procedures and for agitation control. The average dose was 3.86 mg, with a range of 0.5 mg to 20.0 mg. The majority of patients (79.2%) received narcotics or sedative/hypnotic agents in addition to midazolam. There was an overall complication rate of 1.0%. Two patients (0.5%) developed clinically significant respiratory depression after midazolam use. Both patients had also received fentanyl citrate and the respiratory depression was reversed with naloxone. Two patients (0.5%) receiving several other drugs developed short periods of hypotension. There were no apparent long term sequelae. The authors conclude that midazolam can be safely used in the emergency department setting. Careful dosing and titration to the desired clinical effects is mandatory. Patients should be closely monitored to maximize safety.

The safety of fentanyl use in the emergency department.

Fentanyl citrate is a synthetic narcotic 1,000 times as potent as meperidine. It produces minimal hemodynamic effects and is characterized by a rapid onset of sedation and analgesia, a relatively short duration of action (approximately 30 to 40 minutes), and rapid reversal with opiate antagonists. These properties make fentanyl an ideal drug for emergency department use. The safety of fentanyl use in an adult ED population has not previously been studied. We retrospectively reviewed the charts of 841 patients who received fentanyl at the University of Cincinnati Center for Emergency Care between January 1985 and June 1988. The study population included 497 (59%) men and 344 (41%) women, with an average age of 33 years. The average dose of fentanyl was 180 micrograms (range, 25 to 1,400 micrograms). Six patients (1%) experienced mild side effects including nausea (one), emesis (two), urticaria (one), and pruritus (two). Nine patients (1%) developed more serious complications including six cases (0.7%) of respiratory depression and three cases (0.4%) of hypotension. Two of 183 patients (1%) who received midazolam and two of nine patients (22%) who received haloperidol developed respiratory depression. Four of the six patients with respiratory depression and two of the three patients with hypotension were intoxicated. All of the complications were transient, and none resulted in hospitalization. We conclude that fentanyl is a safe drug for use in the ED. To maximize safety, we recommend careful dosing and titration, close patient monitoring, and the availability of naloxone hydrochloride and resuscitation equipment.(ABSTRACT TRUNCATED AT 250 WORDS)