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The manner in which control rooms are configured can impact the flow of information between command teams. Previous research revealed bottlenecks of communications between the Sonar Controller (SOC) and the Operations Officer (OPSO) in submarine control rooms. One way to relieve such bottlenecks is to co-locate operators reliant on one another for task relevant information. The aim of the current studies was to use multiple command teams to empirically examine a novel submarine control room configuration and a reduced crew size in comparison to a baseline of contemporary operations to see if such bottlenecks could be removed. Ten teams performed high and low demand Dived Tracking (DT) scenarios in a simulated submarine control room. Activities and communications of the teams were recorded and quantified using the Event Analysis of Systemic Teamwork (EAST) method affording statistical comparisons with a baseline condition of contemporary operations. The findings showed that the co-location of operators relieved the bottleneck of communications between the SOC and the OPSO. Although overall communications increased, this was more balanced across the team and was more adaptive to scenario demand. This was coupled with a significant increase in task completion, even with a reduced crew size, suggesting greater efficiency and productivity. Future research should seek to validate the changes observed with objective measures of task performance.

The separation of the sound and control rooms in Royal Navy submarines seems to be artefactually reducing the effectiveness of information transition and the overall productivity of the team. A proposed integrated sound and control room was tested in three scenarios: Return to Periscope Depth (RTPD), Inshore Operations (INSO) and Dived Tracking (DT). The activities and communications of a team of serving submariners were recorded in a control room, in a single case study design, comparing co-location and reduced crewing with a baseline of the separate sound and control room configurations that is representative of current submarines. The Event Analysis of Systemic Teamwork (EAST) method was used to examine changes in social, information and task networks. In general terms, the co-location of the submariner team led to more efficient communication and completion of tasks. Reducing the crew was more challenging in the higher demand scenarios. Practitioner Summary: There are constraints acting on control rooms, both in terms of physical space and crew size. This study compared conventional control room with co-location and reduced crew in turn. Teamwork improved in the collocated control room but the reduced crew struggled most under conditions of high demand. Abbreviations: DT: dived tracking; EAST: event analysis for systemic teamwork; H: high; INSO: inshore operations; L: low; OOW: office of the watch; OpsO: operations officer; Peri: periscope operator; RTPD: return to periscope depth; RN: royal navy; SoC: sonar controller; SoP: sonar operator; TMA: time-motion analyst.

Flight within degraded visual conditions is a great challenge to pilots of rotary-wing craft. Environmental cues typically used to guide interpretation of speed, location and approach can become obscured, forcing the pilots to rely on data available from in-cockpit instrumentation. To ease the task of flight during degraded visual conditions, pilots require easy access to flight critical information. The current study examined the effect of 'Highways in the Sky' symbology and a conformal virtual pad for landing presented using a Head Up Display (HUD) on pilots' workload and situation awareness for both clear and degraded conditions across a series of simulated rotary-wing approach and landings. Results suggest that access to the HUD lead to significant improvements to pilots' situation awareness, especially within degraded visual conditions. Importantly, access to the HUD facilitated pilot awareness in all conditions. Results are discussed in terms of future HUD development. Practitioner Summary: This paper explores the use of a novel Heads Up Display, to facilitate rotary-wing pilots' situation awareness and workload for simulated flights in both clear and degraded visual conditions. Results suggest that access to HUD facilitated pilots' situation awareness, especially when flying in degraded conditions.

This is a world's first-of-a-kind study providing empirical evidence for understanding submarine control room performance when completing higher and lower demand Dived Tracking (DT) scenarios. A submarine control room simulator was built, using a non-commercial version of Dangerous Waters as the simulation engine. The creation of networked workstations allowed a team of nine operators to perform tasks completed by submarine command teams during DT. The Event Analysis of Systemic Teamwork (EAST) method was used to model the social, task and information networks and describe command team performance. Ten teams were recruited for the study, affording statistical comparisons of how command team roles and level of demand affected performance. Results indicate that command teams can covertly DT a contact differently depending on demand (e.g. volume of contacts). In low demand it was possible to use periscope more often than in high demand, in a ‘duck-and-run’ fashion. Therefore, the type of information and frequency of particular task completion, was significantly different between the higher and lower demand conditions. This resulted in different operators in the command team experiencing greater demand depending on how the DT mission objective was completed. Potential bottlenecks in the command team were identified and implications are discussed alongside suggestions for future work.

Between November 1994 and June 1999, 35 patients referred to our Problem Fracture Service with chronic diaphyseal osteomyelitis were treated using a closed double-lumen suction irrigation system after reaming and arthroscopic debridement of the intramedullary canal. This is a modified system based on that of Lautenbach. Between June and July 2007 the patients were reviewed by postal questionnaire and telephone and from the case notes. At a mean follow-up of 101 months (2 to 150), 26 had no evidence of recurrence and four had died from unrelated causes with no evidence of recurrent infection. One had been lost to follow-up at two months and was therefore excluded. Four had persisting problems with sinus discharge and one had his limb amputated for recurrent metaplastic change. Our results represent a clearance of infection of 85.3% (29 of 34), with recurrence in 11.8% (4 of 34). They are comparable to the results of the Papineau and Belfast techniques, but with considerably less surgical insult to the patient.

Background: The presence of sicca symptoms is a frequent finding in patients with systemic sclerosis (SSc). The aim of this study was to examine the prevalence of sicca symptoms in a South Australian cohort of SSc patients and correlate this to a number of parameters, including autoantibody status, use of anticholinergic medication, age and the presence of functional anti-muscarinic-3 receptor (M3R)-blocking antibodies. Methods: A screening questionnaire was sent out to all patients on the South Australian Scleroderma Register from the years 1998–2006 to determine the prevalence of sicca symptoms. A subset of patients on the register had ocular sicca symptoms tested by use of Schirmer’s strips to validate the accuracy of the questionnaire. Eight patients were tested for anti-M3R-blocking antibodies using a functional physiological assay. Results: One hundred and ninety-three SSc patients took part in this study. Sicca symptoms were present in 59% of patients with the limited form of SSc, compared with 49% of patients with the diffuse form and 40% of patients with the overlap syndrome. The use of anticholinergic medication or thyroxine was associated with higher sicca scores in SSc patients. SS-A and SS-B autoantibodies (seen in Sjogren’s syndrome) were detected in eight patients in this study. The detection of anti-M3R-blocking antibodies correlated well to presence of sicca. Conclusion: This study confirmed that sicca symptoms are found in a high proportion of patients with SSc, especially those with the limited variant. Further testing of larger numbers of SSc patients with sicca for anti-M3R-blocking antibodies will be needed before more definitive conclusions can be drawn. Physicians should be made aware that sicca symptoms are a frequent cause of morbidity for SSc patients*.

To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort.Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data.A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures.Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.

Helicopters have the potential to be an integral part of the future transport system. They offer a means of rapid transit in an overly populated transport environment. However, one of the biggest limitations on rotary wing flight is their inability to fly in degraded visual conditions in the critical phases of approach and landing. This paper presents a study that developed and evaluated a Head up Display (HUD) to assist rotary wing pilots by extending landing to degraded visual conditions. The HUD was developed with the assistance of the Cognitive Work Analysis method as an approach for analysing the cognitive work of landing the helicopter. The HUD was tested in a fixed based flight simulator with qualified helicopter pilots. A qualitative analysis to assess situation awareness and workload found that the HUD enabled safe landing in degraded conditions whilst simultaneously enhancing situation awareness and reducing workload. Continued development in this area has the potential to extend the operational capability of helicopters in the future.

To ascertain the mortality risk and investigate clinical and serological factors influencing survival of patients listed on the South Australian Scleroderma Register (SASR).The SASR is a population-based register, which was commenced in 1993 and has actively sought to recruit all scleroderma patients diagnosed in SA over a 15-year period. Clinical and serological details have been accessed from questionnaires or from clinical and laboratory files. Standardized mortality ratio (SMR) was calculated and survival analyses performed on all living and deceased patients listed on this SASR (n = 786).Patients with scleroderma had increased mortality compared with the general SA population (SMR 1.46 (95% confidence interval (CI) 1.28-1.69)). Factors that adversely altered survival included older age at onset, male gender, diffuse skin involvement, presence of scleroderma renal crisis, pulmonary fibrosis, pulmonary arterial hypertension, cancer and anti-topoisomerase (Scl-70) and anti-U1 RNP antibodies, while a trend was observed with increased nailfold capillary dropout. Mean age of death for patients with limited scleroderma was 74.1 years (95% CI 72.5-75.7), diffuse scleroderma 62.9 years (95% CI 59.4-66.4) and overlap disease 57.8 years (95% CI 48.7-66.9). Survival improved over the 15-year study period.Scleroderma substantially reduces life expectancy. Survival is influenced by age at onset, gender, diffuse involvement of skin fibrosis, visceral involvement, development of cancer, extent of microvascular capillary damage and by the presence of scleroderma-associated antibodies, Scl-70 and RNP. Scleroderma renal crisis continues to carry high mortality. Survival improved over the 15-year study period.

To determine the clinical, serological and prognostic features of patients with autoantibodies against three aminoacyl-transfer RNA synthetases (ARS), namely Jo-1 (histidyl-tRNA synthetase), PL-7 (threonyl-tRNA synthetase) and PL-12 (alanyl-tRNA synthetase) in South Australia.Patients with autoantibodies against ARS detected by line immunoassay (anti-Jo1, anti-PL7, anti-PL12) or enzyme-linked immunosorbent assay (anti-Jo1) were identified from existing laboratory databases for the period 1994-2009. Demographic, clinical and serological data were obtained by retrospective review of patients' medical records and laboratory databases.Forty-two patients with autoantibodies were identified (anti-Jo1 = 37, anti-PL7 = 4, anti-PL12 = 1). Females were more commonly affected than males (M : F = 12:30). Twenty-one patients had polymyositis (anti-Jo1 = 17, anti-PL7 = 4), seven dermatomyositis (anti-Jo1 = 6, anti-PL12 = 1), 10 overlap syndrome (anti-Jo1 = 10; lupus = 4, scleroderma = 3, Sjögren's syndrome = 2 and rheumatoid arthritis = 2) and four had interstitial lung disease (ILD) only (anti-Jo1 = 4). ILD was present in 69%, polyarthritis in 59% and positive anti-nuclear antibody (ANA) in 43% of patients. Concurrence of autoantibodies against Ro-52 with Jo-1 was seen in 12 patients. The mean follow-up period was 8.3 years (95% CI 5.8-10.8) with 12 deaths. Poor prognostic indicators were age of onset60 years (P= 0.001), cancer (P= 0.002), negative ANA (P= 0.006) and negative autoantibodies to extractable nuclear antigens (P= 0.02).Patients with autoantibodies against ARS present with varied clinical features and occasionally with isolated lung involvement (amyopathic ILD). Older age of onset, malignancy and negative immunologic tests are predictors of poor prognosis. Concurrence of autoantibodies against Jo-1 and Ro-52 may reflect a coupling effect during generation of autoimmunity.

Isolated pulmonary hypertension (PHT) is now the most frequent cause of disease-related death in limited cutaneous scleroderma, the commonest disease variant of this disabling connective tissue disorder. Endothelin-1 receptor antagonists provide symptomatic benefit but to date have not been shown to prolong survival.To determine the frequency, disease characteristics and survival of symptomatic patients with isolated PHT in our cohort of scleroderma patients.Systematic review of the clinical course of all patients registered on the South Australian Scleroderma Register, a population-based register of 374 living and 234 deceased patients with scleroderma.Thirty-four patients were identified with isolated PHT, the majority with limited scleroderma. From our deceased register, we estimate that11% of patients with this limited variant will develop this complication. Isolated PHT occurs as a late-stage complication approximately 20 years after the first symptoms of scleroderma. Patients with isolated PHT were characterized by the presence of multiple telangiectasia, reduced nailfold capillary density, digital ulceration, gross reduction of diffusing capacity for carbon monoxide and echocardiographic evidence of elevated pulmonary artery pressure. Survival was significantly shortened as compared with those patients without this complication (P=0.002), with a mean survival of 2.5 years from symptomatic onset of PHT.Isolated PHT occurs as a late-stage complication inor =11% of patients with limited cutaneous scleroderma and leads to rapid death from right heart failure. The early use of endothelin-1 receptor antagonists may change the natural history of this fatal complication.

Scleroderma (systemic sclerosis) has not been reported before in Australian Aborigines. We describe in detail a community middle-aged Aboriginal woman whose diffuse scleroderma terminated fatally with a renal crisis. Moreover, we have identified a further five Aboriginal patients on the South Australian Scleroderma Register (two with diffuse, two with limited and one with overlap scleroderma), a number consistent with that expected from the 2001 census data for our state. However, an analysis of all antinuclear antibody (ANA) requests from the Top End of Australia over a 6-year period revealed only two Aborigines with low titre anticentromere antibody (despite frequent occurrence of ANA with other specificities). Neither of these Aborigines had features of scleroderma. In conclusion, scleroderma does occur in indigenous Australians but further studies are needed to confirm the apparent infrequency of centromere-associated limited scleroderma (which is the commonest form of scleroderma in our Caucasian population).

Scleroderma is an enigmatic rheumatic disorder of uncertain etio-pathogenesis. Cancer has an approximately two-fold higher incidence in scleroderma patients than in the general population. There are preliminary data of acquired genetic damage in scleroderma but the significance of these observations are uncertain. To determine somatic mutation frequency at the glycophorin-A (GPA) locus in patients with limited and diffuse cutaneous scleroderma. The GPA assay measures the total somatic mutation frequency (Vf), composed of gene inactivating mutations (NO) and mutations arising from mitotic recombination (NN) in individuals heterozygous for the GPA MN blood group. Mutation frequency was determined using a validated GPA flow cytometric assay using fluorescent labeled monoclonal antibodies specific for the GPA blood groups M and N. This assay detects and enumerates progeny of red blood cell (rbc) precursor cells which have acquired genetic damage resulting in a loss of expression of one of the GPA alleles. It was found that patients with scleroderma (n = 23) had significantly elevated Vf as compared with young healthy controls (p0.001) and elderly controls (p = 0.03). Patients with diffuse scleroderma had higher mean Vf as compared with limited scleroderma (p = 0.055). In comparison with controls, patients with scleroderma exhibit a higher proportion of mitotic recombinant mutations than inactivating mutations (p0.002). There was no correlation between Vf and disease duration, age at onset or autoantibody status. We have documented evidence of acquired genetic damage at the GPA locus in scleroderma. Evidence of acquired genetic damage in this disorder may be importance in explaining both the etio-pathogenesis of scleroderma and the association of scleroderma with cancer.

Scleroderma renal crisis (SRC) is a rare but feared complication of scleroderma. Angiotensin--converting enzyme (ACE) inhibition has significantly improved survival, but it is unknown whether prophylactic ACE inhibitors will prevent this complication.To determine: (i) the frequency of SRC in our cohort of well-characterized scleroderma patients resident in South Australia, (ii) any predisposing clinical and serological features, (iii) median disease duration at which SRC occurs, (iv) possible precipitants, (v) disease outcome, and (vi) whether patients were taking ACE inhibitors prior to onset of SRC.Systematic review of the clinical course of all patients registered on the South Australian Scleroderma Register.SRC occurred in 16 patients. This constituted 2.8% of a total scleroderma cohort and 15% of the diffuse scleroderma cohort identified in South Australia. All 16 patients had diffuse cutaneous scleroderma. SRC occurred at a median disease duration of 15 months (range 1 week-11 years). Disease outcome was poor (five deaths, three requiring long-term dialysis and only two patients regaining a normal creatinine) despite aggressive antihypertensive treatment (including ACE inhibitors) in an intensive care or specialized renal unit. Two patients were later able to discontinue dialysis. Only two patients were taking small doses of ACE inhibitors prior to the onset of their SRC. The frequency of Scl-70 was decreased in the SRC group (P = 0.003).SRC is a rare event occurring in a small proportion of patients with diffuse scleroderma. The outcome of SRC was poor despite aggressive antihypertensive treatment. It is hypothesized that prophylactic ACE inhibition in susceptible patients might prevent or ameliorate this complication.

Immunohistochemical, flow cytometric and ELISA studies were performed to examine the expression of endoglin (CD105, a TGF beta receptor) on dermal endothelial cells, peripheral blood monocytes and free and bound serum levels in patients with systemic sclerosis as compared with appropriate controls. Endoglin was found to be significantly upregulated on dermal blood vessels in patients with scleroderma (and in patients with inflammatory skin disorders) as compared to healthy skin (p0.05). In contrast, there was no significant difference in endoglin expression on circulating blood monocytes between scleroderma patients and patients with a rheumatic disoder or healthy control subjects; however, endoglin expression was upregulated on monocytes in inflammatory joint fluid from patients with rheumatoid arthritis. Endoglin expression on monocytes was also influenced by isolation techniques and during whole blood culture. No differences were found in circulating free or bound endoglin levels between scleroderma patients and healthy controls. In conclusion, endoglin expression on dermal endothelial cells was significantly enhanced in scleroderma but levels on circulating monocytes and in the serum were within normal limits. The functional significance of this upregulation is uncertain but may reflect endothelial activation in scleroderma.

Scleroderma (progressive systemic sclerosis) is a systemic autoimmune disorder characterised by skin sclerosis, calcinosis and changes in microvasculature. The etiology of the disease is unknown but both genetic and environmental factors have been implicated. Telangiectasia (macroscopically visible dilated skin vessels) occurring primarily on the hands and face, are a prominent feature in scleroderma and are present in the majority of patients. Similarly, telangiectasia are found in patients with hereditary hemorrhagic telangiectasia (HHT), a mutational disorder of the germline genes endoglin and ALK-1, members of the TGFbeta receptor family, expressed on endothelial cells. Our study investigated the number, distribution and microscopic characteristics of telangiectasia in both limited (n = 29) and diffuse scleroderma (n = 9) and compared findings with 3 patients with HHT. In limited scleroderma, the mean number of telangiectasia (hand and face) was 36 (0-150) compared with 23 (0-135) in diffuse scieroderma. A significant correlation was observed between the number of telangiectasia on the face and on the hands (p = 0.014). The total number of telangiectasia correlated significantly with the disease duration (p = 0.009). The spatial distribution of the telangiectasia appeared to be random on both hands and foreface in contrast with the distribution of subcutaneous calcification of the hands which occurred predominantly on the distal and flexor surfaces of the first, second and fifth digits. Nailfold microscopic capillaroscopy was performed on 12 patients. No significant correlation was observed between capillary diameter or density and with total number of telangiectasia observed macroscopically. The distribution and microscopic appearance of telangiectasia in scleroderma appeared very similar to those observed in HHT. In view of these similarities we therefore conclude that telangiectactic development in scleroderma may be associated with disorders of the TGFb receptor family proteins found on the microvasculature.

BACKGROUND—Inflammatory bowel disease (IBD) is associated with changes in colonic motility which may contribute to the pain and diarrhoea associated with exacerbations of this disease. These changes may be mediated by prostaglandins which are increased in this condition. Increased expression of the inducible isoform of cyclo-oxygenase (COX-2) has been found in active IBD although its cellular distribution remains uncertain. AIMS—To evaluate the cellular distribution of COX-2 in active IBD. PATIENTS AND METHODS—Using reverse transcription-polymerase chain reaction, in situ hybridisation, and immunohistochemistry, COX-2 expression was evaluated in 12 colectomy specimens from patients with active ulcerative colitis (UC), and six specimens from patients with Crohn's colitis that had failed medical therapy. Histologically normal colon was obtained from 12 patients having resection for colorectal neoplasia and evaluated as above, acting as control specimens. RESULTS—All specimens expressed COX-2 mRNA, with some 6-8-fold increase in inflamed tissues on densitometric analysis (both UC and Crohn's) compared with controls. In situ hybridisation localised this mRNA to myenteric neural cells, surrounding smooth muscle cells, and inflammatory cells of the lamina propria in the IBD specimens, with some weaker labelling seen in the epithelium. No COX-2 labelling was seen in normal tissues. Immunohistochemistry confirmed these sites of COX-2 expression in all inflamed specimens, with absence of immunoreactivity in control tissues. CONCLUSIONS—These findings provide the first evidence of COX-2 expression in neural cells of the myenteric plexus in active IBD which, via increased prostaglandin synthesis at this site, may contribute to the dysmotilty seen in this condition. Keywords: inducible cyclo-oxygenase; prostaglandins; myenteric plexus; inflammatory bowel disease

To investigate the effects of intraarticular glucocorticoid treatment on macrophage infiltration, the expression of the chemokines monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1alpha (MIP-1alpha), and the expression of matrix metalloproteinases 1 and 3 (MMPs 1 and 3) and their inhibitors, the tissue inhibitors of metalloproteinases 1 and 2 (TIMPs 1 and 2), in osteoarthritis (OA) synovial membranes.Forty patients underwent arthroscopic biopsy before and 1 month after intraarticular injection of glucocorticoids. Twenty-one patients received 120 mg of methylprednisolone acetate (Depo-Medrol; Upjohn, Kalamazoo, MI), and 20 patients received placebo (1 patient received placebo in 1 knee and methylprednisolone acetate in the other). Immunoperoxidase staining for the expression of CD68, MCP-1, MIP-1alpha, MMP-1, MMP-3, TIMP-1, and TIMP-2 was performed, and the immunostaining was quantified by color video image analysis.CD68, MCP-1, MIP-1alpha, MMP-1, MMP-3, TIMP-1, and TIMP-2 immunostaining was observed in all synovial membranes. Intraarticular glucocorticoid treatment was associated with a small (30%) but statistically significant (P = 0.048) reduction in CD68+ macrophage staining in the synovial lining layer, but there was no change in the CD68 expression in the synovial sublining layer. No significant differences were observed for MCP-1, MIP-1alpha, MMP-1, MMP-3, TIMP-1, and TIMP-2 immunostaining in the synovial lining or sublining layers.Intraarticular glucocorticoids may reduce CD68+ macrophage infiltration into the synovial lining layer, but not the expression of MCP-1, MIP-1alpha, MMP-1, MMP-3, TIMP-1, and TIMP-2 in the synovial membrane, in patients with OA.

As an audit of patients undergoing laparoscopic cholecystectomy this study not only reports the short term results, but attempted to assess the long term effect of the operation on the symptom profiles of the patients.Three hundred unselected consecutive patients underwent elective laparoscopic cholecystectomy from January 1991 to July 1994. Short term outcome was analysed by reviewing patient files for operation details, postoperative morbidity, complications, and gallbladder histology. Long term (median 2 years) outcome was evaluated by a detailed postal questionnaire. Symptomatic benefit ratios (BR) accruing from the laparoscopic removal of the gallbladder were calculated.Twelve operations (4.0%) were converted to open surgery and were excluded from long term outcome analyses. Median operation time was 93 (range 40-245) minutes. There were no deaths. Overall morbidity was 13 %. Median postoperative hospital stay was 2 days (range 1-18 days) and median time-off work 15 days (range 2-49 days). The overall response rate to the questionnaire was 87%. Only one of the 261 patients (0.4%) suffered from recurrent common bile duct stones so far. As shown by the benefit ratios the symptoms most effectively relieved by laparoscopic cholecystectomy were biliary pain (0.97), nausea (0.95), vomiting (0.96) and jaundice (0.94). Most patients with diarrhoea (0.70) and heartburn (0.66) felt relief. Constipation (0.39) and food intolerance (0.57) were unaffected. Most patients (90%) felt that the operation-initiating symptom had disappeared and 98 percent of the patients considered that they had obtained overall symptomatic improvement by the operation.Laparoscopic cholecystectomy appears to be a safe and effective way of treating the most common symptoms related to gallstone disease.

Approximately 20% of patients with the limited form of scleroderma will develop pulmonary hypertension which is generally a late stage fatal complication. Why pulmonary hypertension occurs in this subset of patients is unknown and it has not been possible to predict which patients are at risk. Nailfold capillary dilatation, distortion and drop occurs universally in patients with scleroderma and is generally an early finding. The present study was conducted to investigate whether quantitative nailfold capillaroscopy could distinguish those limited scleroderma patients who have established pulmonary hypertension. Quantitative nailfold capillaroscopy was performed by Visual Image Analysis in 10 healthy subjects and 20 patients with limited scleroderma (18 centromere +ve), of whom 8 had established pulmonary hypertension. It was found that scleroderma patients with pulmonary hypertension had a significant reduction in capillary density compared with patients lacking this complication (p0.01). Patients with scleroderma have significantly more dilated capillaries than controls although no significant differences were observe between the two patient subgroups. The finding of reduced nailfold capillary density in scleroderma patients with established pulmonary hypertension has possible pathogenic significance and may allow detection of this subgroup at an early stage in their disease progression.

To investigate the production of proinflammatory cytokines and expression of cell adhesion molecules in the rheumatoid nodule.Cytokine content (tumor necrosis factor alpha [TNFalpha], interleukin-1beta [IL-1beta], and IL-1 receptor antagonist [IL-1Ra]), at the messenger RNA (mRNA) and protein levels, and cell adhesion molecule expression were studied in 16 rheumatoid nodules and 6 synovial membranes.Macrophages in the rheumatoid nodules contained TNFalpha, IL-1beta, and IL-1Ra mRNA and protein, particularly in perivascular cells of the stroma and in the palisading layer. All cell adhesion molecules studied were expressed in both the rheumatoid nodules and synovial membranes, with increased expression of E-selectin in the rheumatoid nodule compared with the synovial membrane, and with the absence of vascular cell adhesion molecule 1 expression on cells of the palisading layer in the rheumatoid nodule.The presence of similar proinflammatory cytokines and cell adhesion molecules in the rheumatoid nodule and synovial membrane suggests that similar pathogenic processes result in the chronic inflammation and tissue destruction in these lesions.

Intermittent painful crises due to vasoocclusion are the major clinical manifestation of sickle cell disease (SCD), but subclinical episodes may also occur. There is sparse evidence for the involvement of neutrophils in the pathophysiology of SCD, but production of cytokines by the damaged endothelium might influence neutrophil function and modulate responses to subsequent cytokine exposure. In addition, the activation of neutrophils in the microcirculation could itself exacerbate vasoocclusion. To test whether neutrophil inflammatory responses were altered in SCD, neutrophil phospholipase A2 and NADPH oxidase activity in response to in vitro priming by granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) were measured both during and between painful crises. Resting levels of neutrophil phospholipase A2 activity in steady-state SCD (4.0% +/- 0. 5% of total cell radioactivity) were raised relative to control values (2.0% +/- 0.2%, n = 10, P = .008). There was no defect of agonist-stimulated phospholipase A2 or NADPH oxidase activity in steady-state SCD; however, the ability of phospholipase A2 to respond to priming with GM-CSF was attenuated to 63% +/- 17% of control values (n = 10, P = .04). Similarly, neutrophil NADPH oxidase activity after priming with GM-CSF and TNF-alpha was, respectively, 65% +/- 11% (n = 7, P = .03) and 57% +/- 7% of control (n = 10, P = .007) in steady-state disease, and was further reduced during painful vasoocclusive crises to 34% +/- 9% and 25% +/- 3% of control for GM-CSF and TNF-alpha, respectively. These data were not explained by poor splenic function or any racial factor, as normal cytokine responses were seen in splenectomized patients in remission from Hodgkin's disease and in healthy Afro-Caribbean subjects. Abnormal neutrophil cytokine priming responses were not observed in either patients with rheumatoid arthritis or iron-deficiency anemia. Our findings are indicative of an ongoing inflammatory state in SCD between painful crises involving neutrophil activation and an abnormality of cytokine-regulated neutrophil function, which may compromise the host defenses against certain microorganisms.

To investigate the variability in immunostaining for cytokines and cell adhesion molecules using multiple arthroscopically directed synovial biopsies from within a rheumatoid knee joint, quantitated by color video image analysis.Needle arthroscopic biopsies were taken from multiple sites (4-7 sites) around a knee joint in 8 patients with rheumatoid arthritis (RA). In 5 patients, immunoperoxidase staining for the cytokines tumor necrosis factor alpha (TNF-alpha), interleukin 8 (IL-8), and IL-1beta as well as the IL-1 receptor antagonist protein (IL-1ra) was performed. In 3 patients, immunoperoxidase staining for the cell adhesion molecules E-selectin (CD62E), P-selectin (CD62P), intercellular adhesion molecule 1 (ICAM-1, CD54), and platelet endothelial cell adhesion molecule (PECAM, CD31) was performed. Immunostaining was quantified using color video image analysis.The overall probability of paired biopsies from the same RA knee joint being significantly different from each other due to sampling variation was at most 22% for cytokine staining (usually less than 10%). There were no significant differences between intrabiopsy and interbiopsy variability for cell adhesion molecule staining of the sublining and vessels.The variability in cytokine and cell adhesion molecule staining within any single biopsy usually reflects the variability between biopsies taken from different sites in the same rheumatoid joint when the immunostaining is quantified using color video image analysis. Therefore, only a small number of synovial biopsies are required to accurately determine the cytokine and cell adhesion molecule expression in a single joint.

The prognostic value of the immunohistochemical expression of Ki-67 in paraffin embedded specimens was studied in 242 patients with gastric adenocarcinoma. The results were compared with ploidy and S-phase fraction (SPF) obtained by DNA flow cytometry. Both SPF and ploidy correlated with survival in univariate analysis. In multivariate survival analysis, stage of disease, DNA ploidy and presence of distant metastases emerged as independent prognostic parameters. There was no significant difference in survival between patients having tumours with high and low Ki-67 labelling, neither in univariatenor in multivariate survival analysis.

The prognostic value of the immunohistochemical expression of Sialyl Tn antigen (STn) was evaluated in 242 patients with gastric carcinoma. Formalin-fixed, paraffin-embedded specimens of gastric adenocarcinomas were stained with the monoclonal antibody C1282, produced by immunization with ovine submaxillary mucin (OSM). Positive immunoreactivity for STn was observed in 149 (62%) patients. The expression of STn did not correlate with stage of disease (TNM), tumour location, presence of lymph-node or distant metastases, histological type, age or gender. STn immunoreactivity correlated strongly with overall survival in univariate analysis. The median survival in the STn-positive group was 21 months, in comparison to 38 months in the STn-negative group. The difference in survival between STn-negative and STn-positive tumours was significant in patients with stage-I cancer, but not in patients with stage-II -III or -IV disease. STn immunoreactivity emerged as an independent prognostic factor in Cox multivariate analysis. It is concluded that the immunohistochemical expression of STn is a good marker in the prediction of survival in patients with stage-I gastric carcinoma.

The objectives of the study were to review bee venom immunotherapy from the patient's perspective: in particular its benefits and its problems, and to investigate any genetic tendency for bee venom hypersensitivity. A self administered, 9 item questionnaire was sent to 219 patients who had undergone either inpatient or outpatient bee venom immunotherapy at Flinders Medical Center. The clinic records of these patients were also reviewed. The controls for the genetic study were sought from patients, staff and students at Flinders University and Flinders Medical Centre. One hundred and forty-six questionnaires (some incomplete and anonymous) were received. The female to male ratio was 1:2.5. The age at the time of the initial anaphylactic reaction to a bee sting ranged between 2 to 59 years, with 67% of patients being less then 20 years old. Forty percent of patients underwent venom immunotherapy for a period less than 2 years with only 11% maintaining therapy for the recommended period of 5 years or more. Thirty three percent of patients stopped their therapy on their own accord. Bee stings occurring during bee venom immunotherapy (n = 56) were generally well tolerated except in 8 subjects, 7 of whom had not reached the maintenance dose. The reduction in systemic reactions to subsequent bee stings was significantly better in the study group receiving bee venom than in an historic control group treated with whole bee extract (p = 0.03). Fear of bee stings and restricted life styles were improved during or after venom immunotherapy. The frequency of a positive family history of systemic reactions to bee stings in the patient cohort was 31%, whereas in controls it was 15% (p = 0.013). Bee venom immunotherapy has dual benefits: patients are protected from subsequent sting anaphylaxis and there is reduced psychological morbidity. However, to be effective, venom immunotherapy requires a prolonged period of carefully supervised treatment and each venom injection can cause local and systemic side effects. Genetic factors appear to be present in those patients who develop immediate hypersensitivity to be stings.

BACKGROUND. A general practice-based hormone replacement therapy clinic was set up in one practice following the introduction of the 1990 contract for general practitioners. The funding for this clinic was withdrawn in 1993. AIM. A study was undertaken to measure reported satisfaction with care among women receiving hormone replacement therapy in the dedicated clinic and among those receiving treatment in normal general practice consultations. METHOD. Questionnaires were sent to all women in the practice who were currently using or who had used hormone replacement therapy in the last 12 months. The questionnaire sought biographical details, and asked whether the women had had a hysterectomy, and whether they attended the clinic for their hormone replacement therapy. Women's satisfaction with their care was assessed by scoring 12 statements using a five-point Likert-type scale. RESULTS. One hundred and thirty seven women replied (80%), of whom 60% had attended the practice's clinic. Analysis of the ratings of the 12 statements revealed a significant difference between those attending the clinic for their hormone replacement therapy and those attending normal general practice consultations, suggesting that those attending the clinic rated their care more highly than those who received their hormone replacement therapy from elsewhere in the practice. CONCLUSION. Patient satisfaction with care was higher among women who attended the hormone replacement therapy clinic than among those who did not. Possible reasons for this difference are discussed. Research in other practices may determine whether this finding is more widespread. General practitioners are having to balance the short- and long-term benefits of running such clinics against the resources available for them. Information about measurable benefits, such as patient satisfaction, might help with future decisions about the organization of care within general practice.

To follow those patients who participated in a randomized, double blind placebo controlled trial investigating the effect of pulse methylprednisolone treatment in 60 patients with rheumatoid arthritis (RA) starting chrysotherapy.Following completion of the original 24-week trial, 47 of the original 60 patients were reexamined between 32 and 67 weeks after completion of the original study. Patients were assessed by a composite clinical score, the Health Assessment Questionnaire (HAQ), erythrocyte sedimentation rate, C-reactive protein and rheumatoid factor levels.At the end of the 24-week trial, the number of patients who responded well to therapy was significantly greater (p0.05) in the patients who had received methylprednisolone (17/30) compared with the placebo group (8/30). At the longterm followup assessment, the mean disability score (HAQ) was significantly less (p0.05) in patients receiving the initial steroid pulses. No significant difference in drug toxicity or the length of time that patients remained on gold, was observed between the 2 treatment groups.Our study supports a beneficial adjunctive role of pulse corticosteroids in patients with RA starting gold therapy.

Lymphocyte subsets defined by monoclonal antibodies, C reactive protein (CRP), immune complexes (IC), rheumatoid factor (RF), C3, C4 and neutrophil and lymphocyte numbers were measured in synovial fluid (SF) and blood samples from 11 patients with rheumatoid arthritis. SF showed an increased percentage of T cells, Ia+ cells and OKT8+ cells and a reduced percentage of B cells and OKT4+ cells, when compared with blood. Reduced levels of CRP, RF, C3 and C4 were found in SF compared with blood. Comparisons between cellular subsets and other indices in SF revealed a positive correlation between neutrophil numbers and IC, CRP, and RF with a negative correlation between neutrophil numbers and numbers of T cells and OKT8+ cells. A similar negative correlation was found in blood between OKT8+ cells and both CRP and RF. These results indicate an association between increasing disease activity and a lack of suppressor/cytotoxic cells in both circulating and intraarticular compartments. An additional important finding was the lack of correlation of Ia+ cells in both SF and blood with neutrophil numbers, CRP, IC, C3 and C4 or RF.

Endoscopic sphincterotomy (EST) has been used as a treatment of 33 patients with bile duct stones and 3 patients with benign papillary stenosis. In 83% the papilla was cannulated and an adequate, 15 mm long, sphincterotomy was performed. In 72% the retained bile duct stones were extracted. All 3 patients with papillary stenosis had a free bile flow to the duodenum after the procedure and no complications were seen. Complications occurred in 4 patients (11%) with bile duct stones. The complications consisted of pancreatitis in 2 patients, bleeding in one patient and cholangitis in one patient. One of these patients died 5 days after the procedure because of extraperitoneal perforation of the duodenum accompanied by haemorrhagic pancreatitis. Although many of the patients were old and in poor condition endoscopic sphincterotomy was well tolerated when the procedure was uneventful. The method was usually painless and general anaesthesia was not required. The hospital stay after EST was 6.6 +/- 1 days on average.

The clinical manifestations and circumstances of bee sting anaphylaxis have been studied retrospectively in 98 subjects. Most reactions occurred in children but the most severe reactions were seen in adult males, of whom 7 lost consciousness and 2 required cardiopulmonary resuscitation. Most stings causing anaphylaxis occurred on the unprotected feet whilst the subject was on lawn in the afternoons in December, January and February when the maximum daily temperature was between 20 and 30 degrees C. This is the temperature range when bees are particularly active in gathering pollen. However, a significantly greater frequency of anaphylactic reactions occurred at higher temperatures when bees are less active, suggesting that high environmental temperature may predispose the individual to greater exposure to bees or possibly to anaphylactic reactions per se. The presence of atopy did not appear to predispose subjects to bee venom hypersensitivity. Considerable anxiety and lifestyle alteration were identified in some subjects. The alleviation of this anxiety is considered an appropriate indication for bee venom immunotherapy.

Thirty-nine persons with selective IgA deficiency were studied. These comprised 27 subjects found by population screening and 12 by other means. Low molecular weight (LMW) serum IgM was sought in 28 of the 39 persons. Nine of the 28 (32%) had LMW IgM detectable by a sensitive gel filtration technique. Of 17 patients discovered by screening, five (29%) had LMW IgM. In the nine positive persons, LMW IgM constituted up to 17% of the total serum IgM concentration. Eight of the nine IgA deficient persons with LMW IgM, had clinical disease while associated disease in the entire IgA deficient population was less frequent. Serum immune complexes were demonstrated in five of seven subjects with LMW IgM using a C1q-dependent radioimmunoassay; four of these had immune complex associated disorders, three with polyarthritis and one with glomerulonephritis. Because circulating immune complexes are frequently detected in IgA deficient persons without disease, it is proposed that the presence of LMW serum IgM in IgA deficiency may be associated with disease due to the formation of specific pathogenic immune complexes.

An inhibitor of the murine interleukin 2 (IL-2) dependent cell line (CTLL-2) has been demonstrated in sera from healthy subjects as well as in sera and synovial fluid from patients with inflammatory arthritides. This inhibitor inhibits the mitogenic response of normal peripheral blood mononuclear cells and seems to be primarily due to impaired IL-2 production. The inhibitor does not appear to bind to IL-2 or the IL-2 receptor. This inhibition can be reversed with IL-2 but not interleukin 1. These observations may apply to the defects in IL-2 production and response demonstrable in rheumatoid arthritis and other autoimmune disorders.

Background—Inducible nitric oxide synthase (iNOS) is expressed in the colonic epithelium in both inflammatory bowel disease and colorectal cancer. Nitric oxide (NO), the product of this enzyme, has been implicated in the pathogenesis of both conditions. However, there are conflicting data on whether iNOS is expressed in the normal, uninflamed human colon. Aims—To evaluate the expression of iNOS in histologically normal, non-inflamed human colonic mucosa. Patients/Methods—Reverse transcription polymerase chain reaction (RT-PCR), immunoblotting, and immunohistochemistry were used to investigate the expression of iNOS in 17 histologically normal specimens obtained at colectomy performed for colorectal neoplasia. In addition, 16 endoscopic mucosal biopsies, taken from normal individuals, were also evaluated. Eleven surgical specimens and 16 endoscopic biopsies from patients with refractory ulcerative colitis were used as inflammatory controls. Results—All types of specimens expressed iNOS mRNA. Immunoblotting revealed a protein of approximately 130 kDa consistent with iNOS in mucosal extracts of 77% of normal individuals, and 85% of diseased controls. Immunolabelling localised this protein to the surface epithelium in most of the normal specimens and also to the crypt epithelium and inflammatory cells in the diseased controls. Conclusions—These findings provide evidence that iNOS is often expressed in the surface epithelium of non-inflamed human colon, suggesting that it is induced by local luminal factors, such as bacterial lipopolysaccharide (endotoxin). The resultant NO produced at this site might act as an oxidative barrier, reducing bacterial translocation and providing a means of defence against pathogenic microorganisms. (J Clin Pathol 2001;54:293‐297)