Multicentre study to develop a medication safety package for decreasing inpatient harm from omission of time-critical medications.

QUALITY ISSUE: Omitting time-critical medications leads to delays in treatment and may result in patient harm. INITIAL ASSESSMENT: Published studies show that omission of prescribed medication doses is common. Although most are inconsequential, up to 86% of omitted medications place patients at some risk of harm. SOLUTION: Funding was obtained to develop a medication safety package to facilitate decreasing omitted dose incidents by audit, education and feedback. IMPLEMENTATION: A panel of nursing and pharmacy hospital staff in Victoria, Australia, reviewed existing audit tools and published studies to develop a critical medication list and audit tool. The tool, definitions and instructions were tested in 11 rural, urban and teaching hospitals. Qualitative feedback was sought to refine the tool using a Plan-Do-Study-Act model. An educational presentation was developed using reported incidents. EVALUATION: Staff in 11 hospitals tested the audit tool in 321 patients receiving 17 361 doses of medication. Feedback indicated audit data were useful for informing improvements in practice and for accreditation. The educational material consists of the User Guide, plus a presentation for nursing staff illustrated by six cases with questions, with instructions on how to decrease harm from omitted doses by ensuring correct documentation and prioritising time-critical medications. LESSONS LEARNED: A medication safety package using standard definitions and a critical medication list was successfully tested. It is now used by nursing and pharmacy staff across the state. Several interstate hospitals are using the tools as part of their hospital medication safety programmes.

The glucagon-like peptide-1-based therapeutics exenatide and saxagliptin did not cause detrimental effects on the pancreas in mice, rats, dogs and monkeys.

AIMS: Recent reports in the literature have suggested that glucagon-like peptide-1 (GLP-1)-based therapies may lead to increased risk of pancreatic pathology leading to chronic pancreatic injury and pancreatic neoplasia. Extensive non-clinical and clinical safety testing was conducted to support the global development of exenatide twice daily, exenatide once weekly and saxagliptin. Our aim was to integrate these non-clinical data obtained with both mechanisms of GLP-1-based drugs to provide complementary data regarding the potential for drug-induced pancreatic safety signals. METHODS: More than 70 regulated non-clinical toxicology studies in rodents and non-rodents were conducted in accordance with International Conference on Harmonisation and US Food and Drug Administration guidance documents, current industry standards, animal welfare regulations and in compliance with Good Laboratory Practice regulations. Treatment duration was up to 2 years in rodents and up to 12 months in non-rodents using high doses representing large multiples of human exposures (up to 130× for exenatide and 2200× for saxagliptin). Comprehensive pancreas assessments involved more than 2400 pancreata from animals exposed to exenatide and over 1700 pancreata from animals exposed to saxagliptin. RESULTS: Neither exenatide nor saxagliptin treatment resulted in drug-related microscopic changes indicative of acute or chronic adverse effects (including neoplasia) in the endocrine or exocrine pancreas, at doses far exceeding the maximum human systemic exposures. CONCLUSIONS: These data substantially add to the weight of evidence supporting the lack of non-clinical drug-induced pancreatic safety signals in animals exposed to GLP-1-based therapies.

A survey of patient views on receiving vascular outpatient letters.

AIM: To assess the attitude of patients to receiving a copy of vascular outpatient clinic letters. METHOD: 100 patients attending an outpatient vascular clinic at Christchurch Hospital were sent a copy of their outpatient letter along with a questionnaire. This gathered information on the content of the letter, their understanding of it, how useful they found it and whether they would want this practice to continue. RESULTS: The response rate was 68%. Ninety four percent of the responders believed receiving a copy of the letter was a good reinforcement of the information they received at the consultation. Ninety three percent of responders also found being copied into correspondence helpful and 96% understood the contents of the letters. Ninety seven percent wished to receive more letters in the future. CONCLUSION: These results suggest that vascular surgery patients both value and understand clinic letters, and that health professionals should consider adopting this practice into their vascular outpatient clinics.

Galactose oxidation in the design of immunogenic vaccines.

Potent immunological adjuvants are urgently required to complement recombinant and synthetic vaccines. However, it has not been possible to derive new principles for the design of vaccine adjuvants from knowledge of the mechanism of immunogenicity. Carbonyl-amino condensations, which are essential to the inductive interaction between antigen-presenting cells and T helper cells, were tested as a target for the enhancement of immune responses. Enzymic oxidation of cell-surface galactose to increase aminereactive carbonyl groups on murine lymphocytes and antigen-presenting cells provided a potent, noninflammatory method of enhancing the immunogenicity of viral, bacterial, and protozoal subunit vaccines in mice.

The relationship of menstrual irregularity to type 2 diabetes in Pima Indian women.

OBJECTIVE: Menstrual irregularity is associated with hyperinsulinemia and hyperandrogenemia in nondiabetic Pima Indian women of child-bearing age. In this population-based study, we determined the relationship of menstrual irregularity to type 2 diabetes in Pima Indian women. RESEARCH DESIGN AND METHODS: Participants for this cross-sectional analysis were 695 nonpregnant Pima Indian women, aged 18-44 years, involved in an ongoing epidemiologic study of diabetes among residents of the Gila River Indian Community of Arizona. Clinical data were collected by questionnaire and an examination that included a 75-g oral glucose tolerance test; diabetes was diagnosed by World Health Organization criteria. Menstrual irregularity was defined as an interval of 3 months or more between menses, when not pregnant, since age 18 years. RESULTS: History of menstrual irregularity was significantly associated with a high prevalence of diabetes (37 vs. 13%; odds ratio = 4.2, 95% CI = 1.6-10.8) in the least obese women (BMI < 30 kg/m2), adjusted for the effects of age and overall obesity. This association was, in part, because of greater central obesity in women with irregular menses. In more obese women, there was little association with menstrual irregularity, and diabetes was frequent regardless of menstrual history. CONCLUSIONS: Prevalence of type 2 diabetes is higher among Pima indian women with a history of menstrual irregularity. The difference is most pronounced among the least obese group of women. This association may be because of insulin resistance and hyperinsulinemia, which predict type 2 diabetes, also causing hyperandrogenism and menstrual irregularity. The findings reinforce the need to evaluate women with menstrual irregularity for hyperglycemia.

Evidence of differential control of FSH and LH secretion by gonadotropin-releasing hormone (GnRH) from the use of a GnRH antagonist.

The differential regulation of immunoactive FSH and LH secretion by endogenous GnRH was studied using a GnRH antagonist, [Ac-D2Nal1,D4FPhe2,DTrp3,DArg6]GnRH (the NAL-ARG antagonist), in normal women in the early follicular phase of the menstrual cycle, and their responses were compared to those in two groups of control women. Pulsatile LH secretion was examined as an index of the completeness of blockade of endogenous GnRH secretion. There was a dose-dependent decrease in both the frequency and amplitude of LH pulses. At the highest dose, LH pulses were completely abolished within 20 min after sc administration of the GnRH antagonist and for a minimum of 8 h in all women. The mean plasma LH levels were reduced within the first 4 h after antagonist administration at all doses (P less than 0.001). The duration of LH suppression was influenced by antagonist dose, with a continued effect 24 h after administration of the 500 micrograms/kg dose only. The maximum degree of LH suppression was 40% after 50 micrograms/kg (n = 6), 60% after 150 micrograms/kg (n = 6), and 59% after 500 micrograms/kg (n = 5). In contrast, plasma immunoreactive FSH levels did not change after these doses of the NAL-ARG GnRH antagonist. The maximum degree of FSH suppression was 16%, and the changes in plasma FSH concentrations were not dose dependent. Serum antagonist concentrations rose within 30 min after its administration to mean peak levels of 7.5 +/- 2.1 (+/- SE), 20.4 +/- 6.1, and 151 +/- 21 ng/mL after the 50, 150, and 500 micrograms/kg doses, respectively. The half-time of the disappearance of the NAL-ARG GnRH antagonist from plasma was 8.8 +/- 1.5 h. While there were no effects of antagonist administration on hematological, hepatic, or renal function, three women developed urticaria distant from the site of injection when administered the highest dose. We conclude that blockade of GnRH receptors by a GnRH antagonist 1) effectively antagonizes the action of GnRH, as assessed by its ability to block pulsatile LH secretion and reduce mean plasma LH levels; and 2) inhibits LH release to a considerably greater degree than FSH release, providing further evidence of possible GnRH-independent FSH secretion.

Response of sheep to experimental concurrent infection with tick-borne fever (Cytoecetes phagocytophila) and louping-ill virus.

The pathogenesis of concurrent Cytoecetes phagocytophila and louping-ill virus infection was studied in two experiments. In the first experiment 18 four- to seven-year-old rams were used. Ten were infected with C phagocytophila and five days later eight of these animals and the remaining eight sheep were infected with louping-ill virus. The two rams infected with C phagocytophila alone developed no clinical signs apart from a transient pyrexia, while only three of the eight rams infected with louping-ill virus alone showed mild clinical signs. In marked contrast, all eight dually infected sheep developed severe clinical signs with pronounced depression and dysentery and three died and five were killed in extremis. They developed higher titres of viraemia and the antibody response was depressed while necrotising lesions affecting a variety of organs were detected at post mortem examination. Rhizomucor pucillus was recovered from these lesions in seven of the eight sheep. A second experiment using 10 sheep, five aged seven months and five aged two to three years, confirmed the findings of the first experiment indicating that the age of the animal had not significantly influenced the initial result. It was concluded that C phagocytophila infection could enhance the pathogenicity of louping-ill virus and that, operating together, the two pathogens facilitated fungal invasion. It is postulated that sudden deaths in sheep recently transferred to tick-infested pastures may be due to this newly described syndrome.

Some aspects of tick-borne diseases of British sheep.

The significance of tick-borne fever (TBF) and other tick-borne diseases of British sheep are reviewed. Experimental and field studies were carried out to clarify the role of TBF as a pathogen per se and as a predisposing factor in other diseases. Experimental TBF infection caused anorexia and depression in two- to three-week-old lambs, which under the stress of a hill environment could alone be a cause of mortality. Nine out of 10 lambs experimentally inoculated with Staphylococcus aureus during the febrile phase of a TBF reaction developed pyaemic lesions compared with four out of 20 lambs inoculated with S aureus alone. Specific pathogen-free lambs inoculated with an aerosol of Pasteurella haemolytica serotype A1 during a TBF reaction showed more severe clinical signs and had more extensive pathological changes at necropsy than control lambs given P haemolytica alone. Dual infection with TBF and louping-ill virus showed that not only were dually infected sheep more susceptible to louping-ill but almost all of them succumbed to a haemorrhagic syndrome involving a systemic mycotic infection with Rhizomucor pucillus. None of eight sheep given louping-ill virus alone developed this syndrome. Field studies indicated that morbidity and mortality in lambs in south-west Scotland could be markedly reduced by dipping and long acting antibiotic prophylaxis. Lamb groups in which both of these were carried out incurred losses of only 0.6 per cent compared with 10.3 per cent in control groups. In addition antibiotic-treated lamb groups demonstrated significantly better weight gains than untreated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of enzootic abortion and toxoplasmosis in an outbreak of abortion in a Scottish sheep flock.

During 1978-79 there was an outbreak of abortion in a large sheep flock during which approximately 10 per cent of the breeding ewes aborted. Both Toxoplasma gondii and Chlamydia ovis (the agent of enzootic abortion of ewes) were considered to be involved. In the year following this outbreak (1979-80), 156 ewes (11.4 per cent) aborted and the majority of cases were diagnosed as enzootic abortion: only one case showed gross pathology typical of toxoplasmosis. Serology carried out on sera collected from ewes at the time of abortion and at two post abortion samplings demonstrated that large numbers of animals had high titres against enzootic abortion of ewes while the prevalence of sheep with titres against toxoplasmosis was relatively low. Following the introduction of control measures to reduce the spread of enzootic abortion of ewes, the abortion rate in 1980-81 fell to 2.2 per cent. A small-scale trial was carried out to investigate the prophylactic effect of long acting oxytetracycline against enzootic abortion of ewes when given to pregnant sheep three weeks before lambing. Results indicated that treatment reduced the number of abortions in comparison with untreated controls.

Correlation analysis of gene expression and clinical chemistry to identify biomarkers of skeletal myopathy in mice treated with PPAR agonist GW610742X.

Data from individual animals were used to identify genes in mouse skeletal muscle whose expression correlated with a known serum marker of skeletal myopathy, creatine kinase activity (CK), after treatment with a peroxisome proliferator-activated receptors (PPAR) agonist, GW610742X. Six genes had correlation coefficients of >or=0.90: Mt1a (metallothionein 1a), Rrad (Ras-related associated with diabetes), Ankrd1 (ankyrin repeat domain 1), Stat3 (signal transducer and activator of transcription 3), Socs3 (suppressor of cytokine signalling 3) and Mid1ip1 (Mid1 interacting protein 1). The physiological function of these genes provides potentially useful information relating to the mechanism of PPAR-induced skeletal myopathy, with oxidative stress and disruption of glycolysis most closely associated with myopathic damage. Some of the muscle genes most highly correlated with serum CK in mice also appear to be good indicators of PPAR-induced myopathy in rat skeletal muscle, demonstrating the translational potential of this approach. This study clearly shows the utility of using correlation analysis as a simple tool for identifying novel biomarkers and investigating mechanisms of toxicity.

The inhibitory effects of endostatin on endothelial cells are modulated by extracellular matrix.

We investigated the ability of extracellular matrix (ECM) proteins to modulate the response of endothelial cells to both promoters and inhibitors of angiogenesis. Using human dermal microvascular endothelial cells (HDMEC), we found that cells demonstrated different adhesive properties and proliferative responses to the growth factor VEGF depending upon which ECM protein with which they were in contact, with fibronectin having the most impact on VEGF-induced HDMEC proliferation and survival. More importantly, we observed that ECM could modulate the ability of the angiogenic inhibitor endostatin to prevent endothelial cell proliferation, survival and migration. We observed that growth on vitronectin or fibronectin impaired the ability of endostatin to inhibit VEGF-induced HDMEC proliferation to the greatest extent as determined by BrdU incorporation. We found that, following growth on collagen I or collagen IV, endostatin only inhibited VEGF-induced HDMEC proliferation at the highest dose tested (2500 ng/ml). In a similar manner, we observed that growth on ECM proteins modulated the ability of endostatin to induce endothelial cell apoptosis, with growth on collagen I, fibronectin and collagen IV impairing endostatin-induced apoptosis. Interestingly, endostatin inhibited VEGF-induced HDMEC migration following culture on collagen I, collagen IV and laminin, while migration was not inhibited by endostatin following HDMEC culture on other matrices including vitronectin, fibronectin and tenascin-C. These results suggest that different matrix proteins may affect different mechanisms of endostatin inhibition of angiogenesis. Taken together, our results suggest that the ECM may have a profound impact on the ability of angiostatic molecules such as endostatin to inhibit angiogenesis and thus may have impact on the clinical efficacy of such inhibitors.

Neuroendocrine control of reproduction and its therapeutic manipulation with GnRH and its analogs.

The hypothalamus mediates the neuroendocrine control of reproduction in both males and females through pulsatile secretion of GnRH. The anterior pituitary gland, in turn, appears to require this episodic GnRH stimulation in order to secrete the gonadotropins LH and FSH in a physiologic fashion. Deficiency of GnRH manifests as a failure to attain puberty in both sexes, and in females it may also produce amenorrhea and/or anovulation. Replacement regimens of GnRH which employ an episodic pattern of delivery correct the deficiency of endogenous GnRH secretion and stimulate gonadotropin secretion, gonadal steroidogenesis and gametogenesis. However, continuous occupancy of the GnRH receptor by native GnRH and/or its long-acting analogs paradoxically inhibits pituitary gonadotropin secretion. GnRH analogs have been synthesized which exhibit greater affinity and prolonged occupancy on the GnRH receptor and can produce pituitary desensitization of gonadotropin secretion. Chronic administration of these GnRH analogs is capable of producting a selective "medical castration." Thus, by altering the frequency of episodic GnRH administration or by utilizing long-acting GnRH analogs it is possible to stimulate or suppress the neuroendocrine control of reproduction. The use of GnRH or its long-acting analogs has demonstrated a profound clinical impact in restoring or inhibiting fertility.

Salmonella dublin arthritis: an initial case presentation.

Salmonella dublin is a rare pathogen in man usually causing an enteric fever syndrome. We report a 32-year-old black male who developed septic polyarthritis with Salmonella dublin. The clinical features are similar to those seen with other Salmonella serotypes reported to cause arthritis. The initial presentation is suggestive of a reactive arthritis that is immunologically mediated.

Systemic allergy to endogenous insulin during therapy with recombinant DNA (rDNA) insulin.

BACKGROUND: Clinically significant allergic reactions with insulin therapy are known to occur. There have been rare reports of allergic reactions to endogenously secreted insulin manifested as insulin resistance. No reports of systemic or local allergic reactions to endogenous insulin have previously been cited, and no immunologic reactions to endogenous insulin have been reported during therapy with recombinant (rDNA) insulin. METHODS: We report a case in which the patient, a 28-year-old black woman who initially presented with gestational onset diabetes but postpartum continued to require insulin, developed generalized allergic reactions during therapy with subcutaneously injected rDNA insulin. Similar reactions occurred with sulfonylurea therapy. She was unable to tolerate any pharmacologic therapy for diabetes without concurrent use of at least 10 mg of prednisone per day. RESULTS: Skin testing with the insulin preparations were positive, while skin testing to the sulfonylurea hypoglycemic agents were negative. IgE antibodies to insulin where present in high titer. Oral challenge to sulfonylurea hypoglycemic agents produced generalized urticarial reactions coinciding with time of peak insulin secretion. Oral challenge to other medications containing sulfa produced no adverse reaction. Biphasic hypersensitivity reactions occurred during attempts at desensitization which were futile without simultaneous glucocorticoid therapy. CONCLUSIONS: This is the first report of local and systemic allergic reactions to endogenously secreted insulin in association with rDNA insulin therapy. Although immunologic complications with rDNA therapy appear less frequently than with insulin preparations, this case illustrates the need for continued awareness for potential allergic complications occurring with rDNA insulin therapy.

Early alterations in the collagen meshwork and lesions in the ankles are associated with spontaneous osteoarthritis in guinea-pigs.

OBJECTIVE: The purpose of this study was to evaluate matrix changes in knee cartilage prior to development of surface disruptions and to examine the ankle for evidence of osteoarthritis (OA)-like lesions. DESIGN: Guinea-pig ankles and knees were examined histologically or viewed with polarization microscopy to reveal changes in orientation of the collagen fibers. RESULTS: The medial femoral condyles were virtually free of histologic changes at 3 months of age. Changes were present by 6 months. Medial tibial plateau histologic changes were seen at 3 months which became more pronounced with age. Alterations in the collagen meshwork corresponding to areas of proteoglycan (PG) loss were noted in animals with an intact articular surface as early as 3 months. Histologic changes were noted in the ankles as early as 3 months of age which included surface disruptions, cell loss and loss of PG staining. Only knee joint composite histology scores were significantly elevated at 3 months while both knee and ankle scores were significantly elevated at 6 months. Knee and ankle joint scores were not different from each other at 6 months. CONCLUSIONS: Alterations in the orientation of the collagen network of the cartilage correlated with Safranin-O loss suggesting that alterations in collagen:PG interactions play a role in the early phases of the OA process and precede frank histologic changes in the articular surface. The results in this study report for the first time OA-like lesions occurring spontaneously in articular cartilage of the ankle in the guinea-pig.

Production of experimental atrial septal defects.

Atrial septal defects (ASDs) were successfully created by punch biopsy technique in 67 dogs. The technique is simple, effective and provides an ideal model for the study of ASDs, either for testing closure devices or physiological experiments. The position and size of the defects may be varied according to preference. Of 45 animals subjected to cardiac catheterization, 39 (87 percent) has a patent atrial septal defect.

Highly cooperative homodimerization is a conserved property of neural POU proteins.

POU-domain proteins have been shown to play important roles in the development of the nervous, endocrine, and immune systems. However, the distinctive DNA recognition properties of the six major POU subclasses have not been well defined. Here, we have used random oligonucleotide selection and competitive binding assays to determine the optimal DNA recognition elements for the POU-III and POU-VI protein classes, represented by Brn-2 and Brn-5, respectively. The optimal Brn-5 consensus binding sequence GCATAA(T/A)TTAT strongly resembles that previously determined for the POU-IV (Brn-3) class, whereas Brn-2 exhibits highest affinity for non-octamer sites of the form ATG(A/C)AT(A/T)0-2ATTNAT and for octamer sites that contain a full associated heptamer sequence. Brn-2, Brn-3.0, and their invertebrate homologues all exhibit highly cooperative homodimerization on the Brn-2 consensus sequence, demonstrating that cooperative dimerization is a general property of these neural POU proteins. However, modified sites to which Brn-2 binds only as a monomer mediate the transcriptional effects of Brn-2 better than the consensus sequence, demonstrating that dimerization on these sites diminishes the transactivation ability of the protein. Together with the findings of our prior studies these data greatly facilitate the identification of functional POU recognition elements in the regulatory regions of neural genes.

Highly nonproductive complexes with Anabaena ferredoxin at low ionic strength are induced by nonconservative amino acid substitutions at Glu139 in Anabaena ferredoxin:NADP+ reductase.

Ferredoxin (Fd) and ferredoxin:NADP(+) reductase (FNR) from Anabaena function in photosynthetic electron transfer (et). The et interaction between the FNR charge-reversal mutant E139K and Fd at 12 mM ionic strength (mu) is extremely impaired relative to the reaction with wt FNR, and the dependency of k(obs) on E139K concentration shows strong upward curvature at protein concentrations > or = 10 microM. However, at values of mu > or = 200 mM, reaction rates approach those of wild-type FNR, and normal saturation kinetics are observed. For the E139Q mutant, which is also significantly impaired in its et interaction with Fd at low FNR concentrations and low mu values, the dependency of k(obs) on E139Q concentration shows a smaller degree of upward curvature at mu = 12 and 100 mM and shows saturation kinetics at higher values of mu. wt FNR and the E139D mutant both show a slight amount of upward curvature at FNR concentrations >30 microM at mu = 12 mM but show the expected saturation kinetics at higher values of mu. These results are explained by a mechanism in which the mutual orientation of the proteins in the complex formed at low ionic strength with the E139K mutant is so far from optimal that it is almost unreactive. At increased E139K concentrations, the added mutant FNR reacts via a collisional interaction with the reduced Fd present in the unreactive complex. The et reactivity of the low ionic strength complexes depends on the particular amino acid substitution, which via electrostatic interactions alters the specific geometry of the interface between the two proteins. The presence of a negative charge at position 139 of FNR allows the most optimal orientations for et at ionic strengths below 200 mM.