A randomised trial of home energy efficiency improvement in the homes of elderly COPD patients.

A randomised trial of 178 patients in Aberdeen, UK with a previous hospital admission for chronic obstructive pulmonary disease (COPD) was carried out in order to determine whether improving home energy efficiency improves health-related quality of life in COPD patients. 118 patients were randomised and 60 agreed to monitoring only. Energy efficiency upgrading was carried out in 42% of homes randomised to intervention. Independent energy efficiency action was taken by 15% of control participants and 18% in the monitoring group. The main outcome measures were respiratory and general health status, home energy efficiency and hospital admissions. Intention-to-treat analysis found no difference in outcomes between the two groups. In 45 patients, who had energy efficiency action independent of original randomisation, there were significant improvements in respiratory symptom scores (adjusted mean 9.0, 95% CI 2.5-15.5), decreases in estimated annual fuel costs (- pound65.3, 95% CI - pound31.9- - pound98.7) and improved home energy efficiency rating (1.1, 95% CI 0-1.4). COPD patients are unlikely to take up home energy efficiency upgrading, if offered. Secondary "pragmatic" analysis suggests that those who do take action may achieve clinically significant improvement in respiratory health, which is not associated with an increase in indoor warmth.

Hormone replacement therapy (HRT) or etidronate for osteoporosis in postmenopausal asthmatics on glucocorticoids: a randomised factorial trial.

INTRODUCTION: The study was designed to establish the effects of HRT on osteoporosis and fractures over five years in postmenopausal women with asthma receiving regular glucocorticoids and to compare with etidronate. METHODS: Postmenopausal patients receiving inhaled and/or oral glucocorticoids were randomly assigned to HRT, cyclical etidronate, HRT plus cyclical etidronate or no treatment for five years. The trial was multi-centre and aimed to recruit 750 patients. Outcomes were fractures and changes in bone mineral density (BMD). RESULTS: For reasons detailed in the discussion section of the text, only 50 patients were entered. Three did not fulfil the eligibility criteria and were excluded from the analysis. Among the remaining 47 patients, three (6%) experienced new, symptomatic fractures, one on etidronate and two in the no treatment group. New or worsening morphometric fractures of the thoracolumbar spine occurred in 50% of the 22 patients with spinal radiographs on entry and at five years (one HRT, three etidronate, two HRT plus etidronate and five on no treatment). BMD improved by approximately 1% per annum in those receiving HRT and/or etidronate; comparisons of HRT vs no HRT tended to favour HRT but were only statistically significant at proximal femur. The same trends emerged in the etidronate vs no etidronate comparison, but none reached the 5% level of statistical significance. DISCUSSION: For postmenopausal patients receiving glucocorticoids for asthma, HRT appears as effective as etidronate in preventing loss of BMD over five years and may have a similar effect on fracture prevention.

The changing face of infection: a comparative review of admissions to a regional infection unit over three decades.

BACKGROUND AND AIMS: Our group previously published retrospective analyses of 12 months of admissions to the Grampian Regional Infectious Diseases Unit from 1980-81 and from 1991. This study aimed to collect data in 2001 and to compare annual admission numbers, diagnoses, duration of stay and outcome in 1980-81, 1991 and 2001. METHODS: Data on all admissions was collected prospectively throughout 2001. This was compared with the previously published data. RESULTS: Total admissions rose from 605 in 1980-81 to 900 in 1991 and to 1152 in 2001. Sixty one percent of admissions in 1980-81 were confirmed as having infection compared to 72% in 1991 and to 83% in 2001. The most common reason for admission in 2001 was skin and soft tissue infection, but this was only the ninth commonest reason in 1981. Mean length of stay fell from 9.6 days in 1980-81 to 7.4 days in 1991 and to 5.5 days in 2001. The mortality rate fell from 3.1% in 1981 and 1991 to 1.0% in 2001. CONCLUSIONS: This study demonstrates significant changes in type, number and outcome of admissions to a regional infection unit. We discuss possible reasons for these changes.

Arachidonic acid induces ERK activation via Src SH2 domain association with the epidermal growth factor receptor.

Within the kidney, angiotensin II type 2 (AT(2)) receptor mediates phospholipase A(2) (PLA(2)) activation, arachidonic acid release, epidermal growth factor (EGF) receptor transactivation, and mitogen-activated protein kinase activation. Arachidonic acid mimics this transactivation by an undetermined mechanism. The role of c-Src in mediating angiotensin II and arachidonic acid signaling was determined by employing immunocomplex kinase assay, Western blotting analysis, and protein immunoblotting on co-precipitated EGF receptor (EGFR) proteins and agarose conjugates of glutathione S-transferase fusion proteins containing the c-Src homology 2 (SH2) and SH3 domains. Angiotensin II induced extracellular signal-regulated kinase (ERK) activation in primary cultures of rabbit proximal tubule cells via the activation of c-Src and association of the EGFR with the c-Src SH2 domain, effects that were mimicked by arachidonic acid and its inactive analogue eicosatetraynoic acid. Inhibition of PLA(2) by mepacrine and methyl arachidonyl fluorophosphate, AT(2) receptor by PD123319, Src family kinases by, 1-(tert-butyl)-3-(4-chlorophenyl)-4-aminopyrazolo[3,4-d] pyrimidine (PP2) and c-Src by overexpression of a dominant-negative mutant of c-Src abrogated these effects. However, inhibitors of arachidonic acid metabolic pathways did not block these effects. The present work provides a new and novel paradigm for transactivation of a kinase receptor linked to a fatty acid, which may apply to activation of a variety of phospholipases and accompanying arachidonic acid release.

Five year study of etidronate and/or calcium as prevention and treatment for osteoporosis and fractures in patients with asthma receiving long term oral and/or inhaled glucocorticoids.

BACKGROUND: Glucocorticoids are associated with a reduction in bone density and an increased risk of fracture. Concurrent treatment with bisphosphonates reduces bone loss and may prevent fractures. A randomised study was performed to determine whether treatment with cyclical etidronate and/or calcium for 5 years prevents fractures or reverses/reduces bone loss in patients receiving glucocorticoid treatment for asthma. METHODS: A multicentre, randomised, parallel group comparison of etidronate alone, calcium alone, etidronate + calcium, and no treatment, with stratification according to level of glucocorticoid exposure was carried out in 39 chest clinics in the UK. Three hundred and forty nine postmenopausal female and male outpatients with asthma aged 50-70 years were randomised. The main outcome measures were fractures and changes in bone mineral density (BMD). RESULTS: Overall, 8% of the patients experienced symptomatic fractures and 17.5% developed either a symptomatic fracture and/or a semiquantitative vertebral fracture by the end of 5 years There were no significant differences between the four treatment groups. Comparing etidronate with no etidronate, the rates of new fractures were not significantly different for symptomatic fractures (OR 1.07 (95% CI 0.46 to 2.47)) or for any fractures (OR 0.82 (95% CI 0.45 to 1.47)). For the comparison of calcium with no calcium the corresponding ORs were 1.43 (95% CI 0.62 to 3.33) and 0.91 (95% CI 0.50 to 1.63). In post hoc analysis the effect of etidronate was greater in women than in men (interaction p value 0.02) with the fracture incidence roughly halved (OR 0.39, 95% CI 0.14 to 0.99). Etidronate increased BMD at the lumbar spine by 4.1% (p = 0.001) while calcium had no significant effect. At the proximal femur the effects of treatment were not significant (relative increases etidronate 1.6%; calcium 1.1%). The rate of new fractures in patients with fractures at entry (23.7%) was higher than in those without fractures at entry (14.3%): OR 1.87 (95% CI 1.06 to 3.07). No association was found between change in BMD and new fractures. CONCLUSIONS: In patients receiving glucocorticoids for asthma etidronate significantly increased BMD over 5 years at the lumbar spine but not at the hip and had little if any protective effect against fractures, except possibly in postmenopausal women. The effects of calcium were not significant. Combination treatment had no advantage but increased unwanted effects.

Relationship between birth weight and adult lung function: controlling for maternal factors.

BACKGROUND: There is conflicting evidence on the "fetal origins hypothesis" of association between birth weight and adult lung function. This may be due to failure to control for confounding maternal factors influencing birth weight. In the present study access to birth details for adults aged 45-50 years who were documented as children to have asthma, wheezy bronchitis, or no respiratory symptoms provided an opportunity to investigate this association, controlling for maternal factors. METHODS: In 2001 the cohort was assessed for current lung function, smoking status, and respiratory symptoms. Birth details obtained from the Aberdeen Maternity and Neonatal Databank recorded birth weight, gestation, parity, and mother's age and height. RESULTS: 381 subjects aged 45-50 years were traced and tested for lung function; 323 (85%) had birth details available. A significant linear trend (p<0.01) was observed between birth weight and current forced expiratory volume in 1 second (FEV(1)) and forced vital capacity (FVC) values (adjusted for height, age, sex, weight, deprivation category (Depcat), childhood group, and smoking status). This trend remained significant after adjusting birth weight for gestation, parity, sex, mother's height and weight (p = 0.01). The relationship between birth weight and FEV(1) and FVC remained significant when adjusted for smoking history. There was no association between birth weight and current wheezing symptoms. CONCLUSION: There is a positive linear trend between birth weight, adjusted for maternal factors, and lung function in adulthood. The strength of this association supports the "fetal origins hypothesis" that impairment of fetal growth is a significant influence on adult lung function.

Use of intensity modulation for missing tissue compensation of pediatric spinal fields.

Irradiation of the cranio-spinal axis is often one of the treatment modalities of certain childhood cancers, e.g., medulloblastoma. In order to achieve a uniform dose to the spinal cord, missing tissue compensators are required. In the past, our practice was to fabricate compensators out of strips of lead. We report on the use of intensity modulated fields to achieve the desired compensation. Seven cases of pediatric cancer whose treatment involved irradiation of the cranio-spinal axis had compensators designed using a beam intensity modulation method rather than making mechanical compensators. The compensators only adjusted for missing tissue along the spinal axis. Comparisons between calculated and measured doses were made at depth in phantoms and on the surface of the patient. The intensity modulated fields were delivered using a step-and-shoot delivery on an Elekta SL20 accelerator equipped with multileaf collimator. The intensity-modulated compensators provided more flexibility in design than the physical compensator method. Finer intensity steps were achievable, more accurate dose distributions were able to be calculated, and adjustments during treatment, e.g., junction changes, were more easily implemented. Convolution/superposition dose calculations were within +/-3% of measurements. Intensity modulated fields are a practical and more efficient method of delivering uniform doses to the spine in pediatric cancer treatments. They provide many advantages over mechanical compensators with regard to time and flexibility.

Reduced eosinophil apoptosis in induced sputum correlates with asthma severity.

This study was carried out to investigate the relationship between induced sputum eosinophil apoptosis and clinical severity score, airway obstruction and symptom scores in patients with chronic stable asthma. Altogether, 41 chronic stable asthmatic subjects of varying severity defined by Aas score and 17 control subjects underwent spirometry, symptom questionnaire and successful sputum induction. Sputum was processed and cytospins prepared for light microscopy to determine normal and apoptotic eosinophils. Mild asthmatic subjects had a significantly lower percentage sputum eosinophils and a significantly higher eosinophil apoptotic ratio (AR) than moderate or chronic severe asthmatics. Severe asthmatic subjects had a significantly greater age, duration of asthma and sputum eosinophil count x mL(-1) than mild asthmatic subjects. Asthmatic subjects' symptom scores, severity scores and age inversely correlated with AR and the percentage of sputum eosinophils. Baseline forced expiratory volume in one second inversely correlated with percentage sputum eosinophils and positively correlated with AR. The study demonstrates a relationship between reduced sputum eosinophil apoptosis and increased clinical severity of chronic stable asthma, providing additional evidence that eosinophil apoptosis may be important in the resolution of eosinophilic airway inflammation in asthma.

Increasing incidence of acute hepatitis B virus infection referrals to the Aberdeen Infection Unit: a matter for concern.

OBJECTIVES: To assess the epidemiology and clinical outcomes of acute hepatitis B virus (HBV) infections presenting to a regional Infection Unit over a ten year period--with reference to the issues of injection drug use and strategies aimed at reducing transmission, notably needle exchange and immunisation programmes. METHODS: A retrospective casenote review of all patients with acute HBV managed at the Infection Unit in Aberdeen between 1991-2000. RESULTS: One hundred and nineteen (119) patients with acute HBV infection were managed during the period of review. The annual number of patients increased from a mean of 3.3/year during the years 1991-96 to 46 in 2000. The risk factors associated with HBV infection were being an injection drug user (IDU) in 57 (47.9%), heterosexual sex in 22 (18.5%), sex with an IDU in 4 (3.4%), men who had sex with men in 10 (8.4%), tattooing in 1 (0.8%), a needle stick injury in 1 (0.8%), trauma 1 (0.8%) and unknown in 23 (19.3%). Many of these patients had "dabbled" in drug use. Thirty-one (54.4%) of the IDU patients had previously been hospitalised with drug-related medical problems. Eighteen (31.6%) of the IDUs were receiving methadone at the time of presentation. CONCLUSIONS: There is an epidemic of HBV infection in the Grampian region of Scotland currently. Forty-six (65.7%) of the 70 infected patients diagnosed during 2000 were seen at the Infection Unit. The remainder had mild or asymptomatic disease and were managed in the community. This epidemic has occurred despite extensive use of local needle exchange facilities and might reflect missed opportunities to immunise IDUs against HBV infection. A co-ordinated approach is now in place to immunise IDUs and other high-risk groups, but the use of universal immunisation demands consideration.

Eosinophils from patients with asthma express higher levels of the pan-leucocyte receptor CD45 and the isoform CD45RO.

BACKGROUND: Eosinophils and their secreted mediators are heavily implicated as effector cells in asthma and other allergic diseases. Comparisons were made between expression of CD45, CD45RA, CD45RB and CD45RO by eosinophils from asthmatic patients and non-asthmatic atopic and non-atopic, non-asthmatic control subjects. METHODS: Twenty-seven patients with asthma and 33 control subjects were recruited for the study. Eosinophil expression of CD45, CD45RA, CD45RB and CD45RO was established by immunostaining and flow cytometry was performed on whole leucocyte samples. Eosinophil apoptosis in response to CD45 and CD45 isoform monoclonal antibody (mAb)-dependent receptor ligation was assessed by binding of annexin V and flow cytometry. RESULTS: Eosinophils from patients with asthma expressed significantly (P<0.05) higher levels of pan-CD45 and CD45RO compared with eosinophils from non-asthmatic, non-atopic subjects. No significant correlations were found between expression of either pan-CD45 or CD45RO and the degree of symptoms in the asthmatic patients as defined by lung function (FEV1 and FEF25-75) and methacholine PD20. Increased expression of pan-CD45 or CD45RO did not appear to be a consequence of the atopic phenotype. Higher expression of pan-CD45 or CD45RO by eosinophils from asthmatic patients was not associated with greater sensitivity to CD45 and CD45RO mAb receptor ligation-induced eosinophil apoptosis. CONCLUSION: Higher expression of CD45 and CD45RO by eosinophils from asthmatic patients appeared to be a consequence of asthma rather than atopy and further supports a role for activated eosinophils in asthma.

Three years experience of adults admitted to hospital in north-east Scotland with E. coli O157.

UNLABELLED: To describe the epidemiology, clinical features, treatment and outcomes of adults with E. coli O157 infection presenting to Aberdeen Royal Infirmary over a three year period. METHODS: A retrospective casenote review. RESULTS: Thirty-two confirmed cases of E. coli O157 infection were admitted between 1997 and 2000. The median age was 58 years (range 16-93). Ten patients (31%) were from the city of Aberdeen and 22 (69%) from surrounding rural areas. Twenty-seven patients (85%) presented between May and October. The source of infection was unknown or unconfirmed in all cases. Bloody diarrhoea was present in 30 (94%). Leucocytosis was present in 18 (63%) but only four patients (13%) had a fever. Six of the 32 patients (19%) developed Haemolytic-Uraemic Syndrome (HUS) of whom 2 died. Ten patients received antibiotics of whom two developed HUS. Twenty-seven of the 32 (85%) had made a full recovery by time of discharge, three (9%) had impaired renal function and two (6%) died in hospital. CONCLUSION: E. coli O157 infection tends to occur sporadically in rural areas in North East Scotland. It is not usually associated with fever. Infection occurs more commonly in the summer and autumn. HUS complicates infection in almost one fifth of patients.

Humoral immunity and bronchiectasis.

Bronchiectasis is a common complication of primary antibody deficiency but the incidence of antibody deficiency as an underlying cause of bronchiectasis is largely undefined. In this study the humoral immune status of a cohort of bronchiectatic patients was investigated to detect the frequency of significant antibody deficiency and to determine the extent of immunological investigation which is appropriate for routine assessment of bronchiectasis patients. Fifty-six out-patients (with a mean age of 59.6 years) had serum immunoglobulins, IgG subclasses and specific antibodies to capsular polysaccharides of Haemophilus influenzae and Streptococcus pneumoniae measured. Where specific antibody -levels were low, where possible, appropriate immunization with pneumococcal or conjugated Haemophilus polysaccharide vaccines was offered and the responses quantified. Three of 56 patients had low total serum IgG levels. Thirteen of 56 had deficiencies of either a single IgG subclass or combinations of two or more subclasses, with IgG4 being most frequently implicated (9/56). Twenty-nine of 56 had low basal specific polysaccharide antibody levels. Test immunization, where performed, produced satisfactory responses in all cases except one, where a specific defect of responsiveness to pneumococcal polysaccharide was identified. This study indicates that antibody deficiency is an uncommon aetiological/underlying factor in the causation of bronchiectasis beyond the fourth decade and that detailed investigation of humoral immune status as a routine in bronchiectasis patients, at least at this age, is not generally justified.

A randomised trial of self-management planning for adult patients admitted to hospital with acute asthma.

BACKGROUND: There is still debate over the benefit of self-management programmes for adults with asthma. A brief self-management programme given during a hospital admission for acute asthma was tested to determine whether it would reduce readmission. METHOD: A randomised controlled trial was performed in 280 adult patients with acute asthma admitted over 29 months. Patients on the self-management programme (SMP) received 40-60 minutes of education supporting a written self-management plan. Control patients received standard care (SC). RESULTS: One month after discharge SMP patients were more likely than SC patients to report no daytime wheeze (OR 2.6, 95% CI 1.5 to 5.3), no night disturbance (OR 2.0, 95% CI 1.2 to 3.5), and no activity limitation (OR 1.5, 95% CI 0.9 to 2.7). Over 12 months 17% of SMP patients were re-admitted compared with 27% of SC patients (OR 0.5, 95% CI 0.3 to 1.0). Among first admission patients, OR readmission (SMP v SC) was 0.2 (95% CI 0.1 to 0.7), p<0.01. For patients with a previous admission, OR readmission was 0.8 (95% CI 0.4 to 1.6), p=0.6. SMP patients were more likely than SC patients to be prescribed inhaled steroids at discharge (99% v 92%, p=0.03), oral steroids (98% v 90%, p=0.06), and to have hospital follow up (98% v 84%, p<0.01) but adjustment for these differences did not diminish the effect of the self-management programme. CONCLUSIONS: A brief self-management programme during hospital admission reduced post discharge morbidity and readmission for adult asthma patients. The benefit of the programme may have been greater for patients admitted for the first time. The programme also had a small but significant effect on medical management at discharge.

The African American Study of Kidney Disease and Hypertension (AASK): new findings.

In September, 2000, the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health called an early halt to the amlodipine arm of the African American Study of Kidney Disease and Hypertension (AASK) trial after careful deliberation by an independent data and safety monitoring board. An interim analysis of the AASK at 3 years revealed a renoprotective effect of the angiotensin-converting enzyme inhibitor ramipril as compared to the dihydropyridine calcium channel blocker (DHP-CCB) amlodipine in patients with mild to moderate renal insufficiency. This differential effect was independent of the blood pressure (BP) levels reached and was evident in proteinuric patients and suggestive in patients with baseline proteinuria < 300 mg/d, but was not conclusive. The AASK trial data suggest that DHP-CCBs should be used cautiously in the presence of mild to moderate renal insufficiency. Judgment should be reserved for the use of other CCBs, such as verapamil or diltiazem, since these are fundamentally different CCBs with the potential for a different impact on hypertensive nephrosclerosis. The blinded observation period for AASK will be completed at the end of September, 2001, at which time additional, clinically useful information is expected to become available. (c)2001 Le Jacq Communications, Inc.

Radiation therapy in endometrial cancer.

The role of radiation in endometrial cancer, especially in the adjuvant setting, is controversial. Factors that influence radiotherapy recommendations include surgical considerations, pathological findings, potential sites of disease recurrence and the practice philosophies of the individual physician. It has been demonstrated that adjuvant radiotherapy following primary surgery significantly improves pelvic tumour control, but has no measurable impact on overall survival in an unselected patient population. Studies to date have been hampered by the inclusion of patients with a wide spectrum of prognostic features; this may decrease the likelihood of observing greater benefit in discriminate subsets at higher risk of relapse. Further trials are required to define clinical prognosis more precisely and to investigate the role of radiation in higher-risk patients. In the meantime, we propose guidelines for radiotherapy in endometrial cancer which serve as bases for discussion and collaboration among physicians and as platforms for future study and progress.

Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial.

CONTEXT: Incidence of end-stage renal disease due to hypertension has increased in recent decades, but the optimal strategy for treatment of hypertension to prevent renal failure is unknown, especially among African Americans. OBJECTIVE: To compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine), and a beta-blocker (metoprolol) on hypertensive renal disease progression. DESIGN, SETTING, AND PARTICIPANTS: Interim analysis of a randomized, double-blind, 3 x 2 factorial trial conducted in 1094 African Americans aged 18 to 70 years with hypertensive renal disease (glomerular filtration rate [GFR] of 20-65 mL/min per 1.73 m(2)) enrolled between February 1995 and September 1998. This report compares the ramipril and amlodipine groups following discontinuation of the amlodipine intervention in September 2000. INTERVENTIONS: Participants were randomly assigned to receive amlodipine, 5 to 10 mg/d (n = 217), ramipril, 2.5 to 10 mg/d (n = 436), or metoprolol, 50 to 200 mg/d (n = 441), with other agents added to achieve 1 of 2 blood pressure goals. MAIN OUTCOME MEASURES: The primary outcome measure was the rate of change in GFR; the main secondary outcome was a composite index of the clinical end points of reduction in GFR of more than 50% or 25 mL/min per 1.73 m(2), end-stage renal disease, or death. RESULTS: Among participants with a urinary protein to creatinine ratio of >0.22 (corresponding approximately to proteinuria of more than 300 mg/d), the ramipril group had a 36% (2.02 [SE, 0.74] mL/min per 1.73 m(2)/y) slower mean decline in GFR over 3 years (P =.006) and a 48% reduced risk of the clinical end points vs the amlodipine group (95% confidence interval [CI], 20%-66%). In the entire cohort, there was no significant difference in mean GFR decline from baseline to 3 years between treatment groups (P =.38). However, compared with the amlodipine group, after adjustment for baseline covariates the ramipril group had a 38% reduced risk of clinical end points (95% CI, 13%-56%), a 36% slower mean decline in GFR after 3 months (P =.002), and less proteinuria (P<.001). CONCLUSION: Ramipril, compared with amlodipine, retards renal disease progression in patients with hypertensive renal disease and proteinuria and may offer benefit to patients without proteinuria.

Arachidonic acid directly activates members of the mitogen-activated protein kinase superfamily in rabbit proximal tubule cells.

BACKGROUND: To explore the roles of eicosanoids in arachidonic acid-induced mitogen-activated protein kinase (MAPK) signal transduction, we have shown that exposure of proximal tubular cells to arachidonic acid induces phosphorylation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), two members of the MAPK superfamily. We observed that ketoconazole, an inhibitor of the cytochrome P450 pathway, blocked ERK but not JNK activation. METHODS: Direct regulation of arachidonic acid on mitogen-activated protein kinase (MAPK) signaling pathways was evaluated more directly by utilizing specific enzyme inhibitors of the cytochrome P450 metabolic pathway and by comparing the relative efficacy of arachidonic acid versus its cytochrome P450 metabolites (exogenous and endogenous), eicosatetraynoic acid (ETYA), and other fatty acids on the phosphorylation of members of the MAPK superfamily (ERKs, JNK, and p38(MAPK)), by utilizing early passage rabbit proximal tubular epithelial cells. RESULTS: Arachidonic acid activated p38(MAPK), a third member of the MAPK superfamily, in a time- and concentration-dependent manner. Studies designed to evaluate the ability of arachidonic acid and its cytochrome P450 metabolites (endogenously and exogenously) to stimulate ERKs, JNK, and p38(MAPK) found four conclusions. First, the metabolites of arachidonic acid generated endogenously by cytochrome P450 2C1 significantly augmented basal ERK activity, whereas the metabolites generated by the 2C2 isozyme significantly augmented basal p38(MAPK) activity. However, their effects were less profound than arachidonic acid itself. In contrast, there were no significant effects with transfection of either isozyme on basal JNK activity. Second, a variety of exogenous cytochrome P450 products were less potent than arachidonic acid on a molar basis in stimulating the activity of all three MAPKs. Third, ketoconazole and 17-octadecynoic acid, inhibitors of the cytochrome P450 pathway, as well as PPOH and DDMS, inhibitors of the epoxygenase and omega-hydroxylase pathways, respectively, failed to significantly reduce the effects of arachidonic acid to activate ERK and p38(MAPK) (JNK was not evaluated). Finally, arachidonic acid, its inactive analog ETYA, and other fatty acids with differing chain lengths and degrees of saturation stimulated the activity of all three MAPKs. CONCLUSIONS: These observations substantiate a role for arachidonic acid and other fatty acids in signaling linked to the MAPK superfamily in rabbit proximal tubular epithelium without the necessity of conversion to cytochrome P450 metabolites.

Patient weighting of importance of asthma symptoms.

BACKGROUND: Quality of life measures are increasingly important in evaluating outcomes in asthma. If some asthma symptoms are more troublesome to patients than others, this may affect their contribution to outcome measures. This study was designed to assess the relative importance of common symptoms in adults with asthma. METHODS: A postal survey using conjoint analysis was performed in 272 adults attending hospital outpatient clinics with moderately severe asthma. Patients were asked to chose between "symptom scenarios" offering different combinations of levels of five common asthma symptoms over one week. Two versions of the questionnaire were used with identical scenarios presenting symptoms in different orders. Different patients answered the two versions. Regression analysis was used to calculate symptom weights for daytime cough, breathlessness, wheeze and chest tightness, and sleep disturbance. RESULTS: Symptom order, percentage predicted peak expiratory flow (PEF), and symptoms in the week before the survey did not influence the choice of scenario. In both questionnaires patients were more likely to choose scenarios with low levels of cough and breathlessness than low sleep disturbance, wheeze or chest tightness. Regression weights for cough (-0.52) and breathlessness (-0.49) were twice those of wheeze (-0.25), chest tightness (-0.27), and sleep disturbance (-0.25). For 12% of patients cough dominated patient preferences, regardless of all other symptoms. Age was inversely related to weight given by patients to breathlessness. CONCLUSIONS: The prominence of cough among other asthma symptoms was unexpected. Daytime cough and breathlessness had greater impact for patients than wheeze or sleep disturbance. Age influenced symptom burden, with younger patients giving greater weight to breathlessness than older patients. Conjoint analysis appears to be a useful method for establishing the relative importance of common symptoms.

Neutron radiotherapy for recurrent pleomorphic adenomas of major salivary glands.

INTRODUCTION: Pleomorphic adenoma is the most common neoplasm arising in the salivary glands. Surgical management is the primary therapeutic modality. With the use of modern surgical techniques, recurrence is infrequent, and facial nerve sparing is the norm. However, for patients with recurrent disease, the risk of further relapses is increased with surgical resection alone, particularly for those patients in whom multiple recurrences have already occurred. The role of adjuvant radiotherapy in this setting remains uncertain. Although neutron radiotherapy is superior to conventional radiotherapy for malignant salivary gland tumors, its role in the treatment of pleomorphic adenomas is less well defined. We report our experience using this modality for high-risk, recurrent pleomorphic adenomas. METHODS: Sixteen patients were treated with neutron radiotherapy for recurrent pleomorphic adenomas of major salivary glands from 1986 through 1993. The median age at diagnosis was 33 years (range, 11-77 years); median age at the time of neutron radiotherapy was 52 years (range, 22-77 years); median number of prior surgical procedures was 3 (range, 1-6); median duration from initial diagnosis to radiotherapy was 14.5 years (range, 3 months-30 years); median follow-up was 83 months (range, 9-144 months). The median period at risk for survivors was 96 months (defined as the interval from completion of neutron radiotherapy to last follow-up). Ten patients had evidence of gross residual disease at the time of treatment as determined by imaging studies, with nine patients having multinodular disease. RESULTS: The 10-year actuarial survival was 79%. One patient died from lung metastases 9 months after treatment; one patient died from a liver tumor of uncertain origin, but the histology could not rule out a metastasis from the previous pleomorphic adenoma; and one patient died from recurrent disease at the base of skull. The 15-year actuarial locoregional control rate was 85%. One of the two patients with locoregional recurrence had a malignant transformation into an adenocarcinoma. No statistical difference in 15-year actuarial survival (75% vs 83%, p =.82) was found comparing patients with gross residual disease vs microscopic residual disease. The actuarial 15-year locoregional control was 76% for patients with gross residual disease vs 100% for those with microscopic disease. The 15-year actuarial risk of RTOG/ESTRO nonaudiologic grade III/IV complications was 21%. No facial nerve injuries were observed as a direct consequence of neutron radiotherapy. CONCLUSIONS: Neutron radiotherapy offers both excellent local control rates and survival rates in patients with multiply recurrent pleomorphic adenomas that are not candidates for surgical resection, even in the presence of gross residual disease. The treatment-related morbidity is acceptable. Malignant transformations and metastases, although uncommon, may be observed in this tumor.