Evaluation of a General Practitioner with Special Interest model: lessons learned from staff experiences.

BACKGROUND: The integration of general practitioners into specialist outpatient clinics is associated with improved access to care; however, little is understood about the organisation-level factors that affect successful implementation. We aimed to identify factors that were facilitators or barriers to the implementation of a General Practitioner with Special Interest (GPwSI) model of care across a range of specialties. METHODS: Semi-structured, in-depth interviews were conducted with 25 stakeholders at 13 GPwSI clinics in operation within a Queensland public health service. A deductive content analysis was conducted using the Consolidated Framework for Implementation Research (CFIR). RESULTS: Stakeholders generally supported the GPwSI model and saw advantages to patients and specialist medical practitioners in terms of waiting lists, workload, and improving clinician self-efficacy and knowledge. A number of factors were identified as being crucial to the success of the program, such as adequate support and planning for the implementation, appropriate funding and advocacy. CONCLUSIONS: Our evaluation indicates that a GPwSI model can be a beneficial resource for improving care to patients and reducing wait lists, dependent upon adequate planning, training, and support.

Effect of Temperature and Water Potential on Survival and Mycelial Growth of Phaeomoniella chlamydospora and Phaeoacremonium spp.

Phaeomoniella chlamydospora, a species of Phaeomoniella, and two species of Phaeoacremonium, P. inflatipes and P. aleophilum, have been associated with young grapevine decline in major production regions of California. Phaeomoniella chlamydospora has been isolated from healthy vines and inoculated but non-symptomatic vines and rooted cuttings. Effects of temperature and water potential on fungal response in culture were investigated to find effective control strategies for nurseries. Mycelial growth rates at temperatures 5 to 37°C showed a quadratic response with optimum growth rates for Phaeomoniella chlamydospora and P. aleophilum at 25°C and at 30°C for P. inflatipes. Response to water potential varied by isolates within a species, but isolates of Phaeomoniella chlamydospora were not sensitive to decreasing water potential. A conidial suspension and plugs of agar with mycelia were placed in glass vials and incubated in hot water for 15 to 120 min. Conidia were sensitive to hot-water treatment after 15 and 30 min. Nevertheless, mycelia of P. inflatipes from agar plugs grew on potato dextrose agar at 22°C after 120 min incubation at 51°C. Because the fungi were not killed by incubation in glass vials at 51°C, methods other than hot-water treatment may be more effective in eliminating Phaeomoniella chlamydospora and Phaeoacremonium spp. from dormant vine cuttings.

Spatial Distribution of Armillaria mellea in Pear Orchards.

Pears have traditionally been considered to be highly resistant to Armillaria root disease (causal agent: Armillaria mellea). In recent years, however, the incidence of Armillaria root disease in pears has increased in California. To determine the spatial distribution of Armillaria root disease in the field, a total of 156 isolates of Armillaria were collected from dead and dying pear trees located within two orchards in Lake County. All isolates from these two orchards, as well as from an additional 10 pear orchards, were identified as Armillaria mellea sensu stricto. Based on pairings among 102 Armillaria isolates, four somatic incompatibility groups (SIGs) were identified at orchard 1. Three of the four SIGs at this site were over 100 m in length; the largest SIG was at least 200 m in length. Pairings among 54 isolates identified five SIGs at orchard 2. The SIGs at orchard 2 were generally smaller than those detected at orchard 1 and ranged from 20 to 60 m in length. The size of the SIGs points toward long-term establishment of the fungus on the two sites, most likely predating the establishment of the pear orchards. Extensive root excavations of 19 trees indicated that the primary means of secondary spread of Armillaria was via rhizomorphs, as opposed to root-to-root contact.

Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila.

In both vertebrate and invertebrate development, cells are often programmed to adopt fates distinct from their neighbors. Genetic analyses in Drosophila melanogaster have highlighted the importance of cell surface and secreted proteins in these cell fate decisions. Homologues of these proteins have been identified and shown to play similar roles in vertebrate development. Fringe, a novel signalling protein, has been shown to induce wing margin formation in Drosophila. Fringe shares significant sequence homology and predicted secondary structure similarity with bacterial glycosyltransferases. Thus fringe may control wing development by altering glycosylation of cell surface and/or secreted molecules. Recently, two fringe genes were isolated from Xenopus laevis. We report here the cloning and characterization of three murine fringe genes (lunatic fringe, manic fringe and radical fringe). We find in several tissues that fringe expression boundaries coincide with Notch-dependent patterning centres and with Notch-ligand expression boundaries. Ectopic expression of murine manic fringe or radical fringe in Drosophila results in phenotypes that resemble those seen in Notch mutants.

New non-peptide endothelin-A receptor antagonists: synthesis, biological properties, and structure-activity relationships of 5-(dimethylamino)-N-pyridyl-,-N-pyrimidinyl-,-N-pyridazinyl-, and -N-pyrazinyl-1-naphthalenesulfonamides.

Use of automated synthesis led to the discovery of several 6-membered nitrogen heterocycles as replacements for the N-isoxazolyl substituent present in the 1-naphthalenesulfonamides endothelin-A (ETA) antagonist 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesu lfo namides (BMS 182874). In each of these heterocycles, a small substituent such as halogen para to the position of attachment to the sulfonamide nitrogen atom was found to be advantageous for ETA receptor affinity. Of these heterocycles, 2-pyrazines offered the greatest scope for improving receptor affinity. Optimization of the substituents at the 3- and 5-positions in the pyrazine ring led to potent, ETA-selective compounds such as 5-(dimethylamino)-N-(5-chloro-3-methoxy-2-pyrazinyl)-1- naphthalenesulfonamides (7m, ETA pIC50 8.1). When dosed orally at 10 mg/kg to conscious, normotensive rats infused with big ET-1, compounds such as 7m showed significant inhibition of the pressor response with a duration of effect lasting for the 5-h course of the experiment.

The application of the human beta-globin gene locus control region and murine erythroleukemia cell system to the expression and pharmacological characterization of human endothelin receptor subtypes.

The cDNAs encoding both A and B subtypes of the human endothelin receptor have been inserted into mammalian cell expression vectors that utilize the human globin gene, locus control region. These constructs have been introduced into murine erythroleukemia cells and inducible high level expression of the receptors has been achieved (approximately 1.5-pM/mg membrane protein and approximately 13,500 binding sites/cell for both receptor subtypes). Cell lines expressing these receptors were obtained on a rapid time scale (3-4 weeks), facilitated by the need for the analysis of only small numbers of cell clones/receptor (approximately 6). Competitive binding assays with endothelin-1 gave IC50s of 130 +/- 30 pM for endothelin-A receptor and 160 +/- 30 pM for endothelin-B receptor. Similar studies with the different isoforms of endothelin, sarafatoxin-S6b and -S6c, BQ123 and BQ3020, all gave the expected selectivity profiles. The IC50s for all compounds were in close agreement with those reported for native receptors. Thus, this expression system, which has several advantages over other described expression systems, is capable of rapidly providing large quantities of receptor for detailed pharmacological analyses or drug screening. In addition, the expressed receptors display the expected pharmacological profiles in the absence of any complicating, competing interactions from other subtypes or binding sites.

Characterization of myotonic dystrophy kinase (DMK) protein in human and rodent muscle and central nervous tissue.

Myotonic dystrophy (DM) is the most common form of inherited neuromuscular disease in adults and is characterized by progressive muscle wasting and myotonia. The mutation responsible for DM has been identified as the amplification of a polymorphic (CTG)n repeat in the 3' untranslated region of a gene encoding a serine/threonine kinase (DMK). We have produced a polyclonal rabbit antibody preparation against a fusion protein encoding the C-terminal amino acids 471-629 of the human DMK gene. This antibody specifically detects products of both full length and truncated human DMK genes expressed in bacteria and in insect cells. On immunoblots, we observed protein species of approximately 74 and 82 kDa in cardiac muscle, skeletal muscle, ependyma and choroid plexus. By immunofluorescence, DMK was found to localize post-synaptically at the neuromuscular junction of skeletal muscle, at intercalated discs of cardiac tissue and at the apical membrane of the ependyma and choroid plexus. We have also detected two to three species (approximately 45-50 kDa) in other regions of the brain. Synaptic localization of DMK in the cerebellum, hippocampus, midbrain and medulla was noted. These results suggest that DMK plays a specialized role in intercellular communication.

Convergent myotonic dystrophy (DM) haplotypes: potential inconsistencies in human disease gene localization.

Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease which has been shown to be caused by an unstable trinucleotide repeat located on chromosome 19q. We have conducted extensive haplotype analysis on 105 DM chromosomes using twelve 19q13.2 loci identifying 18 RFLPs, spanning a physical distance of 1.3 Mb containing the DM gene. Three major haplotypes (H1, H2 and H3) comprising 46.7% of the DM chromosomes in our population, were observed. With the exception of H1 and H2 derivatives (H4, H5 and H6), the remainder of the DM chromosomes analyzed were found to have unique haplotypes. Haplotypes H2 and H3 observed exclusively on DM chromosomes of French-Canadian origin contain identical 500-kb core regions. The low frequency of this core haplotype in normal chromosomes (0.8%) is consistent with a mapping of the DM gene within this region. However, the DM mutation is found 160 kb distal to the point of divergence between the two haplotypes. In contrast, the 450-kb region shared by haplotypes H1 and H2 contains the DM mutation. Further analysis of the DM region using a polymorphic microsatellite (GJ-VSSM2; D19S207) located 15 kb distal to the DM mutation revealed strong allelic association of one of the (CA)n repeat alleles to DM; allele 5 was observed on 88.2% of DM chromosomes and 6% of normal chromosomes. The fact that the (CA)n allele 5 was found on all 56 DM chromosomes containing the three major haplotypes indicates that DM chromosomes in our population, including the two French-Canadian haplotypes which have a common region outside the DM gene, are probably derived from the same mutational event.(ABSTRACT TRUNCATED AT 250 WORDS)

Discovery and characterization of an inhibitory angiotensin receptor in the guinea-pig ileum.

Using nitrendipine to block the smooth muscle contractile effects of angiotensin II, it has been shown that the agonist produces a dose-related inhibitory effect on the electrically stimulated, longitudinal smooth muscle, myenteric plexus preparation from the guinea-pig. In the absence of stimulation, there is no detectable direct relaxant effect of angiotensin II on the preparation, even when it is partially contracted with carbachol, leading to the conclusion that the inhibitory effects of angiotensin are mediated via prejunctional receptors on the neuron. A number of angiotensin antagonists, including DUP753, saralasin, SKB108566 and several nonpeptide antagonists synthesized at ZENECA, have been investigated vs (1) the inhibitory effects of angiotensin II and (2) the direct contractile effects produced in unstimulated tissues in the absence of nitrendipine. A correlation curve comparing the results from the two sets of experiments gave a slope of 1.05 and a correlation coefficient of 0.99, providing very strong evidence that the two receptor systems are pharmacologically identical. The antagonists were further evaluated vs angiotensin II in the rat fundic strip in order to (1) determine whether there was any species variation in the receptor systems and (2) provide an example of a smooth muscle preparation uncomplicated by indirect effects of transmitters released by angiotensin, as has been reported in the guinea-pig ileum. An excellent correlation was obtained between the Ke values in the fundus and the guinea-pig ileum, indicating no difference in receptors between species or between neurons and smooth muscle.

Testing for isoniazid. An evaluation of the Arkansas method.

To better treat and eliminate tuberculosis, patient compliance must be improved. Compliance can be evaluated by measuring a drug or its metabolite in the urine. In Arkansas, a simple colorimetric method of checking the urine for isoniazid (the Potts-Cozart test) has been used for many years, but it is relatively unknown outside that state and its reliability has not been confirmed. To evaluate this test, urine was blindly tested from patients from a tuberculosis clinic. Controls included urine from patients from a substance abuse clinic and Veterans Medical Center. In more than 200 urine samples tested, no false-positives were found. Urinalysis showed normal values for three patients who were supposed to be receiving antituberculosis medication, but it is likely that these patients were noncompliant. A peculiarity of the test was that the color change with positive tests varied. To investigate this variation, absorption spectroscopy of many substances was performed. Nicotine accounted for the different shade of blue associated with the positive test, but the color produced and the absorption spectroscopy were different from isoniazid, so it did not confuse the interpretation of the results. This test for isoniazid in the urine is simple, quick, inexpensive, easy to interpret, and reliable. It also can be used to detect nicotine and its metabolites.

The contribution of intrinsic activity to the action of opioids in vitro.

The effects of opioids were compared in five field-stimulated isolated tissue models, the guinea-pig ileum and vasa deferentia from rat, rabbit and mice of the Alderley Park and C57BL/6 strains. Although the mu-receptor agonist [D-Ala2, MePhe4, Gly-ol5] enkephalin appeared to act at similar receptors in the guinea-pig ileum, rat vas deferens, mouse vas deferens and C57BL/6 mouse vas deferens preparations, its potency varied considerably between these preparations. Similar potency differences were also observed with the kappa-agonist, ethylketocyclazocine. It is proposed that these variations in potency reflect differences in the number of spare receptors present in each model. The finding that some drugs which have agonist activity in the more sensitive preparations behave as antagonists in the less sensitive tissues supports this proposal and highlights the importance of intrinsic activity in determining the action of opioids. Many of the prototypic opioid agonists were found to be either partial agonists (eg. morphine and bremazocine) or to possess affinity for more than one receptor type (eg. ethylketocyclazocine, Mr 2034).