The role of the oncostatin M/OSM receptor ß axis in activating dermal microvascular endothelial cells in systemic sclerosis.

BACKGROUND: Scleroderma (SSc) is a rare autoimmune disease characterized by vascular impairment and progressive fibrosis of the skin and other organs. Oncostatin M, a member of the IL-6 family, is elevated in SSc serum and was recognized as a significant player in various stages of fibrosis. The goal of this study was to assess the contribution of the OSM/OSMRß pathway to endothelial cell (EC) injury and activation in SSc. METHODS: IHC and IF were used to assess the distribution of OSM and OSMRß in SSc (n = 14) and healthy control (n = 7) skin biopsies. Cell culture experiments were performed in human dermal microvascular endothelial cells (HDMECs) and included mRNA and protein analysis, and cell migration and proliferation assays. Ex vivo skin organoid culture was used to evaluate the effect of OSM on perivascular fibrosis. RESULTS: OSMRß protein was elevated in dermal ECs and in fibroblasts of SSc patients. Treatments of HDMECs with OSM or IL-6+sIL-6R have demonstrated that both cytokines similarly stimulated proinflammatory genes and genes related to endothelial to mesenchymal transition (EndMT). OSM was more effective than IL-6+sIL-6R in inducing cell migration, while both treatments similarly induced cell proliferation. The effects of OSM were mediated via OSMRß and STAT3, while the LIFR did not contribute to these responses. Both OSM and IL-6+sIL-6R induced profibrotic gene expression in HDMECs, as well as expansion of the perivascular PDGFRß+ cells in the ex vivo human skin culture system. Additional studies in HDMECs showed that siRNA-mediated downregulation of FLI1 and its close homolog ERG resulted in increased expression of OSMRß in HDMECs. CONCLUSIONS: This work provides new insights into the role of the OSM/OSMRß axis in activation/injury of dermal ECs and supports the involvement of this pathway in SSc vascular disease.

Overseas visitors admitted to Queensland hospitals for water-related injuries.

OBJECTIVE: To determine the number of overseas visitors admitted to Queensland hospitals for water-related injuries over three years, the causes of their injuries, the resulting conditions treated, and the type of hospitals to which they were admitted. DESIGN: Retrospective analysis of admissions of overseas visitors to Queensland hospitals over the three financial years 1995/96, 1996/97 and 1997/98. PATIENTS: 296 overseas visitors admitted for water-related injuries, identified from hospital records by their usual place of residence. MAIN OUTCOME MEASURES: Number of admissions, causes of injuries, conditions treated, and bed days occupied by these patients at different types of hospitals (metropolitan, regional and rural public hospitals, and private hospitals). RESULTS: The 296 overseas visitors accounted for a total of 596 separate admissions, many of these the result of patients with decompression illness being admitted several times to a regional hospital hyperbaric chamber for treatment as day patients. The largest number of injuries involved the use of diving equipment. The main conditions treated were decompression illness (54.7%), fractures and dislocations (15.5%), and drowning and non-fatal submersion (14.9%). Overall, overseas visitors admitted to hospital following a water-related incident occupied 1215 bed days; 90% of these admissions were to regional hospitals. CONCLUSIONS: The main reason for admission of overseas visitors is for decompression illness, suggesting that the prevention of injuries among scuba divers requires further coordinated efforts by health and tourism authorities.

Randomised controlled trial of early surgery versus watchful waiting for glue ear: the effect on behavioural problems in pre-school children.

This trial was designed to compare early surgery with watchful waiting for persistent bilateral otitis media with effusion (OME) in terms of hearing loss and behavioural problems in pre-school children. A randomised controlled trial compared the effects of early treatment with ventilation tubes versus watchful waiting for 9 months. Results were analysed by intention-to-treat. One hundred and eighty-two pre-school children (date of birth between 1 April 1991 and 31 December 1992), mean age of 2.9 years (SD 0.85) with at least a 3-month history of bilateral OME and hearing loss of greater than 25 dB were treated in Bristol Children's Hospital between November 1993 and January 1996. Bilateral ventilation tubes were inserted within 6 weeks of randomisation or within 6 weeks of reassessment after 9 months of watchful waiting, with a final assessment at 18 months. The main outcome measures were behavioural problems, measured by the Richman Behaviour Checklist, and hearing loss at 4000 Hz in the better hearing ear. Early surgical intervention significantly reduced behavioural problems by 17% (95% CI, 2% - 33%). This difference was largely mediated by concurrent hearing loss. After 18 months, there was no longer a significant difference (95% Cl, -19% to +10%). However, the majority (85%) of the Watchful Waiting group had required surgery and 22% of all children still had behavioural problems.

Early surgery compared with watchful waiting for glue ear and effect on language development in preschool children: a randomised trial.

BACKGROUND: Otitis media with effusion (OME) is the most common cause of hearing loss in children and is generally treated by elective surgery. We compared in children with persistent OME the effect on speech and language development of immediate surgery (ventilation-tube insertion) and watchful waiting before surgery. METHODS: We did a randomised controlled trial with masked outcome assessment in Bristol Children's Hospital, Bristol, UK. We included 186 children born between April 1, 1991, and Dec 31, 1992, who had confirmed bilateral OME and bilateral hearing impairment of 25-70 dB of at least 3 months' duration. Children were randomly assigned surgery within 6 weeks (n=92), or 9 months of watchful waiting (n=90), after which bilateral tube insertion was done if required. We assessed hearing loss, expressive language, and verbal comprehension at 9 months and 18 months. FINDINGS: At 9 months, standardised scores for expressive language and verbal comprehension differed between groups with marginal significance after adjustment for baseline differences (p=0.04 and p=0.028, respectively). At 9 months, verbal comprehension and expressive language skills in the watchful-waiting group were 3.24 months behind those in the early-surgery group. The watchful-waiting group was delayed on these two measures compared with their age-expected levels. 18 months after randomisation, 85% of children in the watchful-waiting group had received surgery and groups did not differ significantly. INTERPRETATION: There is some benefit from ventilation-tube insertion for expressive language and verbal comprehension but the timing of surgery is not critical.

International tourists, motor vehicles and road safety: a review of the literature leading up to the Sydney 2000 Olympics.

The number of international visitors to Australia is forecast to rise to 4.6 million in the year 2000, the main attraction being the Olympic Games in Sydney. While the Olympic Games are expected to directly attract 132,000 international visitors as athletes, officials, judges, journalists and spectators, a further 1.49 million visitors will be attracted to Australia because of the global spotlight on the country in the years leading up to and during the staging of the event. Pre- and post-Games travel will also involve large numbers of tourists moving about in other Australian states and territories. For example, 50% of the extra tourists are expected to visit Queensland, 25% Victoria, 13% Western Australia and 9% the Northern Territory. In order to provide the best possible experience for all of these visitors, it is essential that potential causes of travel-related illness and/or injury are anticipated, and that procedures are established in each state to minimize harm and to deliver appropriate health care if it is required. Ideally, procedures and resources should be coordinated to achieve maximum effectiveness.

Synthesis of a series of stromelysin-selective thiadiazole urea matrix metalloproteinase inhibitors.

The synthesis and enzyme inhibition data for a series of thiadiazole urea matrix metalloproteinase (MMP) inhibitors are described. A broad screening effort was utilized to identify several thiadiazoles which were weak inhibitors of stromelysin. Optimization of the thiadiazole leads to include an alpha-amino acid side chain with variable terminal amide substituents provided a series of ureas which were moderately effective stromelysin inhibitors, with Ki's between 0.3 and 1.0 microM. The most effective analogues utilized an L-phenylalanine as the amino acid component. In particular, unsubstituted 46 had a Ki of 710 nM, while the p-fluoro analogue 52 displayed increased potency (100 nM). Stromelysin inhibition was further improved using a pentafluorophenylalanine substituent which resulted in 70, a 14 nM inhibitor. While gelatinase inhibition was generally poor, the use of 1-(2-pyridyl)piperazine as the amide component usually provided for enhanced activity, with 71 inhibiting gelatinase with a Ki of 770 nM. The combination of this heterocycle with a p-fluorophenylalanine substituent provided the only analogue, 69, with collagenase activity (13 microM). The SAR for analogues described within this series can be rationalized through consideration of the X-ray structure recently attained for70 complexed to stromelysin. Uniquely, this structure showed the inhibitor to be completely orientated on the left side of the enzyme cleft. These results suggest that thiadiazole urea heterocycles which incorporate a substituted phenylalanine can provide selective inhibitors of stromelysin. Careful selection of the amide substituent can also provide for analogues with modest gelatinase inhibition.

Structural characterizations of nonpeptidic thiadiazole inhibitors of matrix metalloproteinases reveal the basis for stromelysin selectivity.

The binding of two 5-substituted-1,3,4-thiadiazole-2-thione inhibitors to the matrix metalloproteinase stromelysin (MMP-3) have been characterized by protein crystallography. Both inhibitors coordinate to the catalytic zinc cation via an exocyclic sulfur and lay in an unusual position across the unprimed (P1-P3) side of the proteinase active site. Nitrogen atoms in the thiadiazole moiety make specific hydrogen bond interactions with enzyme structural elements that are conserved across all enzymes in the matrix metalloproteinase class. Strong hydrophobic interactions between the inhibitors and the side chain of tyrosine-155 appear to be responsible for the very high selectivity of these inhibitors for stromelysin. In these enzyme/inhibitor complexes, the S1' enzyme subsite is unoccupied. A conformational rearrangement of the catalytic domain occurs that reveals an inherent flexibility of the substrate binding region leading to speculation about a possible mechanism for modulation of stromelysin activity and selectivity.

Synthetic matrix metalloproteinase inhibitors and tissue inhibitor of metalloproteinase (TIMP)-2, but not TIMP-1, inhibit shedding of tumor necrosis factor-alpha receptors in a human colon adenocarcinoma (Colo 205) cell line.

The solubilization of plasma membrane receptors through proteolytic cleavage of the ligand binding domain at the cell surface is an important mechanism for regulating cytokine function and receptor signaling. The inhibition of the shedding of a variety of receptors by synthetic inhibitors of the matrix metalloproteinases (MMPs) implicates metalloproteinases in this regulatory event. We examined the effects of two naturally occurring tissue inhibitors of metalloproteinases, TIMP-1 and TIMP-2, and several synthetic MMP inhibitors (MMPIs) on the shedding of both tumor necrosis factor alpha receptor type I (TNFalpha-RI; Mr 55,000) and TNFalpha-RII (Mr 75,000) by the Colo 205 human colon adenocarcinoma cell line. Culture of Colo 205 cells for 48 h resulted in the shedding of both TNFalpha-RI and TNFalpha-RII, as determined by ELISA. The shedding of TNFalpha receptors was not affected by TIMP-1 or protease inhibitors aprotinin, pepstatin, or leupeptin but was inhibited in a dose-dependent manner by the following synthetic MMPIs: batimastat and marimastat (BB-94 and BB-2516, respectively, British Biotech, Inc.); CT1418 (Celltech Therapeutics); CGS27023A (Novartis Pharmaceuticals); and RO31-9790 (Roche), with IC50s ranging from 3.2 to 38.0 microM. Similarly, TIMP-2 from two different sources reproducibly inhibited the shedding of both TNFalpha-RI and TNFalpha-RII in a dose-dependent manner (IC50 = 286 +/- 33 nM for TNFalpha-RI shedding and 462 +/- 52 nM for shedding of TNFalpha-RII). The inhibition of TNFalpha-RI shedding was confirmed in the SW626 human ovarian adenocarcinoma cell line. The synthetic MMPIs and TIMP-2, but not TIMP-1, also caused a dose-dependent increase in the number of TNFalpha receptors retained on the surface of Colo 205 cells, as determined by flow cytometry. Inhibition of TNFalpha receptor shedding with TIMP-2 occurs at molar concentrations 10-100 times less than those required with low molecular weight, synthetic MMPIs but at concentrations greater than those required to inhibit collagen degradation. Modulation of TNFalpha receptor shedding by TIMP-2 could have important implications for the pleiotropic effects of TNFalpha in both normal and malignant cells and for the pharmacological activity of synthetic MMPIs.

Revising current two-process accounts of spacing effects in memory.

Memory for repeated items improves when presentations are spaced during study. In Experiment 1A, words were repeated either immediately or after 6 intervening items. Intentional learning occurred under either focused or divided attention. Retention was tested by either free recall or yes-no recognition. Divided attention did not affect the influence of spacing in free recall, whereas it removed the spacing effect in recognition. In Experiment 1B, recognition memory was tested after incidental semantic study of words performed under either focused or divided attention. An equivalent spacing effect occurred in both attentional conditions. In Experiments 2 and 3, recognition memory for unfamiliar faces was assessed. A reliable spacing effect was found under both intentional learning and incidental structural study. These data are, collectively, incompatible with current theories of spacing effects. A theoretical proposal to account for these new findings is outlined.

Managing patient records and documenting service delivery: the results of a 'best practice' remote area nursing program.

This paper describes a 'best practice' demonstration program for monitoring nursing services in remote locations. A four-phase project involving paper- and computer-based patient information systems was implemented at nursing clinics on islands off the coast of Queensland. Patient demographics, diagnoses and details of health service provision were recorded. Results showed a marked improvement in the detail of patient records over the program period. Monitoring of services also provided useful planning and policy information for company management, while a systematic approach to maintaining patient records addressed several medico-legal issues.

Travel and Health Research in Australia.

Travel and tourism is a major industry in Australia, employing 6.9% of the nation's workforce (535,600 persons) and generating AUS$46.9 billion in 1993-94.1 While economic and marketing analyses have traditionally dominated the field of tourism research in Australia, health and safety issues that impact on the business of tourism are now emerging.2 Travel medicine is still a small specialty area, though it has established a legitimate role within the tourism industry by providing services in prevention and treatment. To date, little attention has been given to empirical research, even though field studies are a critical component in the provision of accurate medical advice for patients. This paper reviews the Australian research that is available and identifies areas where further work should be conducted.

Golf-related injuries seen at hospital emergency departments.

Golf-related injuries are reported for 300 patients attending emergency departments of south-east Queensland hospitals over a six and a half year period. The main mechanisms of golf-related injury were being hit by a club (37%), hit by a ball (28%), sprains/strains (9.67%) and slips/falls (7%). For adult players, the main source of injury was being hit by a ball, while for children and adolescents being struck by a golf club accounted for 77 percent of hospital presentations. In the total study group, 46 people (15%) were admitted to hospital following their presentation at the emergency departments. Injury prevention and player education strategies are suggested as a means of reducing injuries in this popular sport.

Tourists as inpatients in Queensland regional hospitals.

This study analysed medical record data from seven regional hospitals in Queensland to determine the types of medical conditions and injuries that resulted in overseas and interstate tourists being admitted to hospital. From a total of 135,128 admissions to the participating hospitals, 695 (0.51 per cent) were identified as overseas tourists and 3479 (2.57 per cent) were from interstate. The main reasons for admission of overseas tourists, based on principal diagnoses, were injuries and poisonings (37.6 per cent), circulatory disorders (11.7 per cent), digestive conditions (9.8 per cent), and genito-urinary disorders (8.8 per cent). For interstate tourists, the main reasons for admission were genito-urinary disorders (19.8 per cent), injuries and poisonings (15.4 percent), neoplasms (11.4 per cent) and circulatory disorders (10.6 per cent). These findings are discussed in relation to current literature in the field of travel medicine, emphasising the burden of care placed on the admitting hospital's resources, and the growing number of visitors to Queensland needing health care.

Comparing ICD-9-CM and ICD-10 classification systems in a primary health care setting: some initial observations.

The ICD-10 is due to be introduced into Australia during the late 1990s, superseding the current and widely used ICD-9-CM. Improvements in areas such as number of codes, an expanded external cause framework, and more context to injuries are expected to make the ICD-10 a more streamlined system for practitioners. The present study examined both classification formats using data from 1183 presentations to primary health clinics at island tourist resorts. Some initial observations are made about differences in the two systems, highlighting the greater coding detail provided by the ICD-10, particularly in the area of injuries. It is recommended that further empirical testing be undertaken using the ICD-10 in a variety of settings so as to identify benefits in the coding of both medical conditions and injuries.

Characterization of a nuclear protein that interacts with regulatory elements in the human B creatine kinase gene.

The B creatine kinase gene is regulated by an array of positive and negative cis-elements in the 5'-flanking DNA that function in both muscle and nonmuscle cells. In C2C12 myogenic cells M and B creatine kinase mRNAs are coordinately up-regulated in the early stages of myogenesis and then undergo distinct regulatory programs. The B creatine kinase gene is down-regulated in the late stages of myogenesis as M creatine kinase becomes the predominant species in mature myotubes. Sequences between -92 and +80 of the B creatine kinase gene confer a regulated pattern of expression to chimeric plasmids that closely resembles the time-course of expression of the endogenous B creatine kinase gene in C2C12 cells undergoing differentiation. We show that sequences within the first exon of the B creatine kinase gene are important for the development regulation of the gene in C2C12 cells and that these sequences bind a nuclear protein that shows a similar tissue-specific distribution and developmentally regulated expression to that of the endogenous B creatine kinase gene.

Use of Queensland Hospital services by interstate and overseas visitors.

In response to concerns about the number of interstate and overseas visitors using Queensland hospital services, the present study examined a sample of 1,295 hospital records to determine the proportion of patients who were incorrectly identified as Queensland residents. Across six hospitals the overall detection rate was 4.6%. Rates varied between hospitals, with the highest detection recorded for Goondiwindi near the Queensland/New South Wales border; and the lowest for Prince Charles in Brisbane. There were also important variations across hospitals based on specific holiday periods. In particular, Goondiwindi and the Gold Coast had substantially higher detection rates for the Christmas holiday period (December-January) than for the mid-year period (June-August). These findings are discussed in terms of their implications for hospital services, especially lost revenue and increased patient load. Health information managers are identified as a key group for addressing some of the current problems in this area.