A clinical audit of the prescribing of celecoxib and rofecoxib in Australian rural general practice

Aims The new cyclooxygenase-2 (COX-2) selective inhibitors, celecoxib (Celebrex®) and rofecoxib (Vioxx®), have been widely prescribed since their launch. No reviews currently appear in the literature of prescribing patterns in Australia. This paper describes a self-audit of the clinical use of selective COX-2 inhibitor therapy undertaken with rural general practitioners (GPs) in Australia. Methods A structured audit form was developed and distributed to interested GPs. The form was self-administered and focused on issues about COX-2 inhibitors and the types of patients who were receiving them, e.g. indications, patient demographics, risk factors and drug interactions. Results A total of 627 patients were recruited (569 celecoxib and 58 rofecoxib). A range of doses was prescribed. Osteoarthritis was the most common indication (68.1%). Risk factors known for the nonselective nonsteroidal anti-inflammatory drugs were identified in 65.1% of patients, with the most common being advanced age, hypertension and previous peptic ulcer disease. Potential drug interactions were common. A variety of reasons for initiation of therapy was identified; these included perceived increased efficacy, safety and failure of other treatment. Conclusions These results show that COX-2 inhibitors are being prescribed for patients with multiple risk factors that may place the patient at increased risk of adverse drug reactions to a COX-2 inhibitor. The perception of improved safety and efficacy was common and is of concern. Limitations of the study include the reliance on self-reporting.

Supply chain management as beyond operational efficiency

The orthodoxy of supply chain management (SCM) emphasises competitive advantage through increased operational efficiency and market responsiveness from production and distribution processes into the hands of consumers. It anticipates that future competition will be between chains rather than between firms. While well established in other industry sectors, the SCM concept is newly developed in the Australian agri-food sector. Critical review of the concept has identified key issues of power among channel members, processes of chain initiation and innovation, and the inability of SCM to offer a viable business strategy for some firms. Building on those insights, this paper examines the supply chain concept for horticulture. Horticultural products are characterised by perishability, heterogeneity and lags in production response to market signals. Producers’ profits are vulnerable to quantity, timing of supply and product specification. Many supply chains in smaller industries are loose, fragmented, interwoven, unstable and unique! Firms operating within these environments need an astute understanding of the chains, the hierarchy of channel members and their relative position. Effective business strategies – for individual firms and supply chains - need to be developed and redeveloped to accommodate the dynamic nature of horticulture. Two case studies are discussed as contributions to this early stage of the theoretical development of supply chain management. The SCM concept also has implications for horticultural researchers, involving a wider range of industry stakeholders, technical problems and research skills. As for business management, the usefulness of the concept will depend on its capacity to increase responsiveness to customers’ preferences and customer value.

Attitudes and practices of general practitioners in the diagnosis and management of attention-deficit/hyperactivity disorder

Objective: To assess understanding of, and actual and potential roles in management of attention-deficit/hyperactivity disorder (ADHD) among GPs. Methods: A cross-sectional questionnaire survey of Queensland GPs selected randomly from the Royal Australian College of General Practitioners directory of members was carried out. Main outcome measures were knowledge levels of ADHD, current management practices, referral patterns and self-perceived information and training needs. Results: Three hundred and ninety-nine GPs returned a completed questionnaire (response rate 76%). Roles identified by GPs were: the provisional diagnosis of ADHD and referral to specialist services for confirmation of the diagnosis and initiation of management; assistance with monitoring progress once a management plan was in place; education of the child and their family regarding the disorder; and liaison with the school where necessary. Perceived barriers to increased involvement of GPs were: time and resource constraints of general practice; concerns regarding abuse and addiction liability of prescription stimulants; complex diagnostic issues associated with childhood behavioural problems; and lack of training and education regarding ADHD. Conclusions: General practitioners identify a role for themselves in ADHD care that is largely supportive in nature and involves close liaison with specialist services.

Identification and minisequencing-based discrimination of SHV beta-lactamases in nosocomial infection-associated Klebsiella pneumoniae in Brisbane, Australia

Extended-spectrum beta-lactamases (ESBLs) are active against oxyimino cephalosporins and monobactams. Twenty-one Klebsiella pneumoniae isolates obtained between 1991 and 1995 at the Princess Alexandra Hospital in Brisbane, Australia, were subject to amplification and sequencing of the SHV beta-lactamase-encoding genes. Thirteen strains were phenotypically ESBL positive. Of these, six strains carried the bla(SHV-2a) gene and seven strains carried the bla(SHV-12) gene. Eight strains were phenotypically ESBL negative. Of these, seven strains carried the non-ESBL bla(SHV-11) gene and one strain carried the non-ESBL bla(SHV-1) gene. There was complete correspondence between the ESBL phenotype and the presence or absence of an ESBL-encoding gene(s). In addition, it was determined that of the 13 ESBL-positive strains, at least 4 carried copies of a non-ESBL-encoding gene in addition to the bla(SHV-2a) or bla(SHV12) gene. A minisequencing-based assay was developed to discriminate the different SHV classes. This technique, termed first-nucleotide change, involves the identification of the base added to a primer in a single-nucleotide extension reaction. The assay targeted polymorphisms at the first bases of codons 238 and 240 and reliably discriminated ESBL-positive strains from ESBL-negative strains and also distinguished strains carrying bla(SHV-2a) from strains carrying bla(SHV-12). In addition, this method was used to demonstrated an association between the relative copy numbers of bla(SHV) genes in individual strains and the levels of antibiotic resistance.

A case of myoepithelial carcinoma displaying biallelic inactivation of the tumour suppressor gene APC in a patient with familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene. It is characterised by the appearance of hundreds to thousands of colorectal adenomas in adolescence and the subsequent development of colorectal cancer. Various extracolonic malignancies are associated with FAP, including desmoids and neoplasms of the stomach, duodenum, pancreas, liver, and brain. We present a family affected by FAP with an exon 14 APC mutation displaying two rare extracolonic lesions, a hepatoblastoma and a myoepithelial carcinoma. The hepatoblastoma was found in a male patient aged 2 years. The second lesion, a myoepithelial carcinoma of the right cheek, was found in a female patient aged 14 years. Inactivation of the normal APC allele was demonstrated in this lesion by loss of heterozygosity analysis, thus implicating APC in the initiation or progression of this neoplasm. This is the first reported case of this lesion in a family affected by FAP.

Towards a taxonomic revision of the genus Echinococcus

Echinococcus remains a significant public health problem worldwide and, in several regions, the aetiological agents of cystic hydatid disease/echinococcosis are extending their range. The taxonomy of Echinococcus has been a controversial issue for decades, but the outcome of recent molecular epidemiological studies has served to reinforce proposals made ten years ago to revise the taxonomy of Echinococcus. A formal nomenclature is essential for effective communication, and provides the stability that underpins epidemiological investigations. It will also serve to recognize the contribution of early taxonomists.

Mitochondrial genomes of parasitic flatworms

Complete or near-complete mitochondrial genomes are now available for 11 species or strains of parasitic flatworms belonging to the Trematoda and the Cestoda. The organization of these genomes is not strikingly different from those of other eumetazoans, although one gene (atp8) commonly found in other phyla is absent from flatworms. The gene order in most flatworms has similarities to those seen in higher protostomes such as annelids. However, the gene order has been drastically altered in Schistosoma mansoni, which obscures this possible relationship. Among the sequenced taxa, base composition varies considerably, creating potential difficulties for phylogeny reconstruction. Long non-coding regions are present in all taxa, but these vary in length from only a few hundred to similar to10 000 nucleotides. Among Schistosoma spp., the long non-coding regions are rich in repeats and length variation among individuals is known. Data from mitochondrial genomes are valuable for studies on species identification, phylogenies and biogeography.

Conformationally constrained macrocycles that mimic tripeptide beta-strands in water and aprotic solvents

The beta-strand conformation is unknown for short peptides in aqueous solution, yet it is a fundamental building block in proteins and the crucial recognition motif for proteolytic enzymes that enable formation and turnover of all proteins. To create a generalized scaffold as a peptidomimetic that is preorganized in a beta-strand, we individually synthesized a series of 15-22-membered macrocyclic analogues of tripeptides and analyzed their structures. Each cycle is highly constrained by two trans amide bonds and a planar aromatic ring with a short nonpeptidic linker between them. A measure of this ring strain is the restricted rotation of the component tyrosinyl aromatic ring (DeltaG(rot) 76.7 kJ mol(-1) (16-membered ring), 46.1 kJ mol(-1) (17-membered ring)) evidenced by variable temperature proton NMR spectra (DMF-d(7), 200-400 K). Unusually large amide coupling constants ((3)J(NH-CHalpha) 9-10 Hz) corresponding to large dihedral angles were detected in both protic and aprotic solvents for these macrocycles, consistent with a high degree of structure in solution. The temperature dependence of all amide NH chemical shifts (Deltadelta/T7-12 ppb/deg) precluded the presence of transannular hydrogen bonds that define alternative turn structures. Whereas similar sized conventional cyclic peptides usually exist in solution as an equilibrium mixture of multiple conformers, these macrocycles adopt a well-defined beta-strand structure even in water as revealed by 2-D NMR spectral data and by a structure calculation for the smallest (15-membered) and most constrained macrocycle. Macrocycles that are sufficiently constrained to exclusively adopt a beta-strand-mimicking structure in water may be useful pre-organized and generic templates for the design of compounds that interfere with beta-strand recognition in biology.

A prostaglandin F2a Analog induces suppressors of the cytokine signalling-3 expression n the corpus luteum of the pregnant rat: A potential new mechanism in luteolysis

PRL and placental lactogen (PL) play key roles in maintaining the rodent corpus luteum through pregnancy. Suppressors of cytokine signaling (SOCS) have been shown to decrease cell sensitivity to cytokines, including PRL, and so here we have addressed the issue of whether luteolysis induced by prostaglandin F-2alpha (PGF(2alpha)) might up-regulate SOCS proteins to inhibit PRL signaling. In d 19 pregnant rats, cloprostenol, a PGF(2alpha) analog, rapidly induced transcripts for SOCS-3 and, to a lesser extent, SOCS-1. We also found increased SOCS-3 protein in the ovary by immunoblot and in the corpus luteum by immunohistochemistry. Increased SOCS-3 expression was preceded by an increase in STAT3 tyrosine phosphorylation 10 min after cloprostenol injection and was maintained for 4 h, as determined by gel shift and immunohistochemistry. Induction of SOCS-3 was accompanied by a sharp decrease in active STAT5, as determined by gel-shift assay and by loss of nuclear localized STAT5. Four hours after cloprostenol administration, the corpus luteum was refractory to stimulation of STAT5 by PRL administration, and this was not due to down-regulation of PRL receptor. Therefore, induction of SOCS-3 by PGF(2alpha) may be an important element in the initiation of luteolysis via rapid suppression of luteotropic support from PL.

Decreased expression of the Id3 gene at 1p36.1 in ovarian adenocarcinomas

The molecular events that drive the initiation and progression of ovarian adenocarcinoma are not well defined. We have investigated changes in gene expression in ovarian cancer cell lines compared to an immortalized human ovarian surface epithelial cell line (HOSE) using a cDNA array. We identified 17 genes that were under-expressed and 10 genes that were over-expressed in the cell lines compared to the HOSE cells. One of the genes under-expressed in the ovarian cancer cell lines, Id3, a transcriptional inactivator, was selected for further investigation. Id3 mRNA was expressed at reduced levels in 6 out of 9 ovarian cancer cell lines compared to the HOSE cells while at the protein level, all 7 ovarian cancer cell lines examined expressed the Id3 protein at greatly reduced levels. Expression of Id3 mRNA was also examined in primary ovarian tumours and was found in only 12/38 (32%) cases. A search was conducted far mutations of Id3 in primary ovarian cancers using single stranded conformation polymorphism (SSCP) analysis. Only one nucleotide substitution, present also in the corresponding constitutional DNA, was found in 94 ovarian tumours. Furthermore no association was found between LOH at 1p36 and lack of expression of Id3. These data suggest that Id3 is not the target of LOH at 1p36. (C) 2001 Cancer Research Campaign.

Transport and metabolism of xylem cytokinins during lateral bud release in decapitated chickpea (Cicer arietinum) seedlings

Although cytokinins (CKs) are widely thought to have a role in promoting shoot branching, there is little data supporting a causative or even a correlative relationship between endogenous CKs and timing of bud outgrowth. We previously showed that lateral bud CK content increased rapidly following shoot decapitation. However, it is not known whether roots are the source of this CK. Here, we have used shoot decapitation to instantaneously induce lateral bud release in chickpea seedlings. This treatment rapidly alters rate and direction of solvent and solute (including CK) trafficking, which may be a passive signalling mechanism central to initiation of lateral bud release. To evaluate changes in xylem transport, intact and decapitated plants were infiltrated with [H-3]zeatin riboside ([H-3]ZR), a water-soluble blue dye or [H-3]H2O by injection into the hypocotyl. All three tracers were recovered in virtually all parts of the shoot within I h of injection. In intact plants, solute accumulation in the lateral bud at node 1 was significantly less than in the adjacent stipule and nodal tissue. In decapitated plants, accumulation of [H-3]ZR and of blue dye in the same bud position was increased 3- to 10-fold relative to intact plants, whereas content of [H-3]H2O was greatly reduced indicating an increased solvent throughput. The stipule and cut stem, predicted to have high evapotranspiration rates, also showed increased solute content accompanied by enhanced depletion of [H-3]H2O. To assess whether metabolism modifies quantities of active CK reaching the buds, we followed the metabolic fate of [H-3]ZR injected at physiological concentrations. Within 1 h, 80-95% of [H-3]ZR was converted to other active CKs (mainly zeatin riboside-5'phosphate (ZRMP) and zeatin (Z)), other significant, but unconfirmed metabolites some of which may be active (O-acetylZR, O-acetylZRMP and a compound correlated with sites of high CK-concentrations) and inactive catabolites (adenosine, adenine, 5'AMP and water). Despite rapid metabolic degradation, the total active label, which was indicative of CK concentration in buds, increased rapidly following decapitation. It can be inferred that xylem sap CKs represent one source of active CKs appearing in lateral buds after shoot decapitation.

Incidence, characteristics, and predictive factors for dysphagia after pediatric traumatic brain injury

Objective: (1) To establish an incidence figure for dysphagia in a population of pediatric traumatic brain injury (TBI) cases; (2) to provide descriptive data on the admitting characteristics, patterns of resolution, and outcomes of children with and without dysphagia after TBI; and (3) to identify any factors present at admission that may predict dysphagia. Participants: A total of 1, 145 children consecutively admitted to an acute care setting for traumatic brain injury between July 1995 and July 2000. Main outcome measure: Medical parameters relating to dysphagia based on medical chart review. Results: (1) Dysphagia incidence figure of 5.3% across all pediatric head injury admissions. Incidence figures of 68% for severe TBI, 15% for moderate TBI, and only 1% for mild brain injury. (2) Statistically significant differences were found between the dysphagic and nondysphagic subgroups on the variables of length of stay, length of ventilation, Glasgow Coma Scale (GCS), computed tomography classification, duration of speech pathology intervention, supplemental feeding duration, duration until initiation of oral intake (DIOF), duration to total oral intake (DTOF), and period of time from the initiation of intake until achievement of total oral intake (DI-TOF). (3) Significant predictive factors for dysphagia included GCS < 8.5 and a ventilation period in excess of 1.5 days. Conclusion: The provision of incidence data and predictive factors for dysphagia will enable clinicians in acute care settings to allocate resources necessary to deal with the predicted number of dysphagia cases in a pediatric population, and assist in predicting patients who are at risk for dysphagia following TBI. Early detection of patients with swallowing dysfunction will be aided by these data, in turn helping to facilitate effective medical and speech pathology intervention via assisting the reduction of medical complications such as aspiration pneumonia.

Mineral uptake in tobacco leaf discs during different developmental stages of shoot organogenesis

Relationships between mineral uptake and tobacco shoot organogenesis were investigated during three morphogenic phases: phase 1, days 0-10, pre-meristem formation; phase 2, days 10-20, meristem initiation and formation; and phase 3, days 20-35, growth and differentiation of induced meristems into leafy shoots. The mineral content of both shoot-forming (SF) and non-shoot-forming (NSF) media was examined over the 35-day culture period. Both SF and NSF explants rapidly consumed iron during phase 1. Nitrate uptake in SF explants was high and independent of explant growth during phases 1 and 2, but greatest and strongly correlated with growth during phase 3. Phosphorus uptake was highest in SF explants during phases 2 and 3, and correlated with explant growth. Uptake of potassium, calcium and sulphur was strongly associated with explant growth during phase 3 whereas magnesium uptake was only poorly correlated with growth. Results from this study indicate that particular minerals may have an important role in regulating development as well as generally supporting growth.

Outcome variables for osteoarthritis clinical trials: the OMERACT-OARSI set of responder criteria

Improvement in analysis and reporting results of osteoarthritis (OA) clinical trials has been recently obtained because of harmonization and standardization of the selection of outcome variables (OMERACT 3 and OARSI). Moreover, OARSI has recently proposed the OARSI responder criteria. This composite index permits presentation of results of symptom modifying clinical trials in OA based on individual patient responses (responder yes/no). The 2 organizations (OMERACT and OARSI) established. a task force aimed at evaluating: (1) the variability of observed placebo and active treatment effects using the OARSI responder criteria; and (2) the possibility of proposing a simplified set of criteria. The conclusions of the task force were presented and discussed during the OMERACT 6 conference, where a simplified set of responder criteria (OMERACT-OARSI set of criteria) was proposed.