Large eddy simulation of powered Fontan hemodynamics.

Children born with univentricular heart disease typically must undergo three open heart surgeries within the first 2-3 years of life to eventually establish the Fontan circulation. In that case the single working ventricle pumps oxygenated blood to the body and blood returns to the lungs flowing passively through the Total Cavopulmonary Connection (TCPC) rather than being actively pumped by a subpulmonary ventricle. The TCPC is a direct surgical connection between the superior and inferior vena cava and the left and right pulmonary arteries. We have postulated that a mechanical pump inserted into this circulation providing a 3-5 mmHg pressure augmentation will reestablish bi-ventricular physiology serving as a bridge-to-recovery, bridge-to-transplant or destination therapy as a "biventricular Fontan" circulation. The Viscous Impeller Pump (VIP) has been proposed by our group as such an assist device. It is situated in the center of the 4-way TCPC intersection and spins pulling blood from the vena cavae and pushing it into the pulmonary arteries. We hypothesized that Large Eddy Simulation (LES) using high-order numerical methods are needed to capture unsteady powered and unpowered Fontan hemodynamics. Inclusion of a mechanical pump into the CFD further complicates matters due to the need to account for rotating machinery. In this study, we focus on predictions from an in-house high-order LES code (WenoHemo(TM)) for unpowered and VIP-powered idealized TCPC hemodynamics with quantitative comparisons to Stereoscopic Particle Imaging Velocimetry (SPIV) measurements. Results are presented for both instantaneous flow structures and statistical data. Simulations show good qualitative and quantitative agreement with measured data.

Insulin increases H2O2-induced pancreatic beta cell death.

Insulin resistance results, in part, from impaired insulin signaling in insulin target tissues. Consequently, increased levels of insulin are necessary to control plasma glucose levels. The effects of elevated insulin levels on pancreatic beta (ß) cell function, however, are unclear. In this study, we investigated the possibility that insulin may influence survival of pancreatic ß cells. Studies were conducted on RINm, RINm5F and Min-6 pancreatic ß-cells. Cell death was induced by treatment with H(2)O(2), and was estimated by measurements of LDH levels, viability assay (Cell-Titer Blue), propidium iodide staining and FACS analysis, and mitochondrial membrane potential (JC-1). In addition, levels of cleaved caspase-3 and caspase activity were determined. Treatment with H(2)O(2) increased cell death; this effect was increased by simultaneous treatment of cells with insulin. Insulin treatment alone caused a slight increase in cell death. Inhibition of caspase-3 reduced the effect of insulin to increase H(2)O(2)-induced cell death. Insulin increased ROS production by pancreatic ß cells and increased the effect of H(2)O(2). These effects were increased by inhibition of IR signaling, indicative of an effect independent of the IR cascade. We conclude that elevated levels of insulin may act to exacerbate cell death induced by H(2)O(2) and, perhaps, other inducers of apoptosis.

Exercise peripheral oxygen saturation (SpO2) accurately reflects arterial oxygen saturation (SaO2) and predicts mortality in systemic sclerosis.

BACKGROUND: Measures of oxygenation have not been assessed for prognostic significance in systemic sclerosis-related interstitial lung disease (SSc-ILD). METHODS: 83 subjects with SSc-ILD performed a maximal cardiopulmonary exercise test with an arterial line. The agreement between peripheral oxygen saturation (SpO2) and arterial oxygen saturation (SaO2) was examined and survival differences between subgroups of subjects stratified on SpO2 were analysed. Cox proportional hazards analyses were used to examine the prognostic capabilities of SpO2. RESULTS: At maximal exercise the mean (SD) difference between SpO2 and SaO2 was 2.98 (2.98) and only 15 subjects had a difference of >4 points. The survival of subjects with SSc-ILD whose maximum exercise SpO2 (Spo(2)max) fell below 89% or whose SpO2max fell >4 points from baseline was worse than subjects in comparator groups (log rank p = 0.01 and 0.01, respectively). The hazard of death during the median 7.1 years of follow-up was 2.4 times greater for subjects whose SpO2max fell below 89% (hazard ratio 2.4, 95% CI 1.1 to 4.9, p = 0.02) or whose SpO2max fell >4 points from baseline (hazard ratio 2.4, 95% CI 1.1 to 5.0, p = 0.02). CONCLUSION: In patients with SSc-ILD, SpO2 is an adequate reflection of SaO2 and radial arterial lines need not be inserted during cardiopulmonary exercise tests in these patients. Given the ease of measurement and its prognostic value, SpO2 should be considered as a meaningful clinical and research outcome in patients with SSc-ILD.

Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma.

BACKGROUND: Vorinostat has demonstrated activity in refractory cutaneous T-cell lymphoma. In a phase I trial, an encouraging activity in diffuse large-B-cell lymphoma (DLBCL) was noted. PATIENTS AND METHODS: We carried out a phase II trial (NCT00097929) of oral vorinostat 300 mg b.i.d. (14 days/3 weeks or 3 days/week) in patients with measurable, relapsed DLBCL who had received two or more systemic therapies. Response rate and duration (DOR), time to progression (TTP) and safety were assessed. RESULTS: Eighteen patients were enrolled (median age: 66 years; median prior therapies: 2). Seven received 300 mg b.i.d. 14 days/3 weeks, but four had grade 3 or 4 toxicity (dose-limiting toxicity, DLT). The schedule was amended to 300 mg b.i.d. 3 days/week), and none had DLT. One achieved a complete response (TtR = 85 days; DOR =or >468 days) and one had stable disease (301 days). Sixteen discontinued for progressive disease; median TTP was 44 days. Median number of cycles was 2 (1 to >19). Common drug-related adverse experiences (AEs; mostly grade 1/2) were diarrhea, fatigue, nausea, anemia and vomiting. Three patients had dose reduction; none discontinued for drug-related AEs. Drug-related AE >or=grade 3 included thrombocytopenia (16.7%) and asthenia (11.1%). CONCLUSION: Vorinostat was well tolerated at 300 mg b.i.d. 3 days/week or 200 mg b.i.d. 14 days/3 weeks but had limited activity against relapsed DLBCL.

Small vessel vasculitis of the lung.

The diagnosis and management of SVV remains one of the most challenging clinical scenarios encountered by a clinician. Careful attention to detail and a thorough knowledge of the specific disorders, their therapies, and complications thereof is required to optimally care for these patients. The recent completion of a number of randomized, controlled, multicenter clinical trials has greatly improved our knowledge base and ability to care for vasculitis patient. The next decade holds even more promise.

Diet in childhood and adult cardiovascular and all cause mortality: the Boyd Orr cohort.

OBJECTIVE: To examine the association between childhood diet and cardiovascular mortality. DESIGN: Historical cohort study. SETTING: 16 centres in England and Scotland. PARTICIPANTS: 4028 people (from 1234 families) who took part in Boyd Orr's survey of family diet and health in Britain between 1937 and 1939 followed up through the National Health Service central register. EXPOSURES STUDIED: Childhood intake of fruit, vegetables, fish, oily fish, total fat, saturated fat, carotene, vitamin C, and vitamin E estimated from household dietary intake. MAIN OUTCOME MEASURES: Deaths from all causes and deaths attributed to coronary heart disease and stroke. RESULTS: Higher childhood intake of vegetables was associated with lower risk of stroke. After controlling for age, sex, energy intake, and a range of socioeconomic and other confounders the rate ratio between the highest and lowest quartiles of intake was 0.40 (95% confidence interval 0.19 to 0.83, p for trend 0.01). Higher intake of fish was associated with higher risk of stroke. The fully adjusted rate ratio between the highest and lowest quartile of fish intake was 2.01 (95% confidence interval 1.09 to 3.69, p for trend 0.01). Intake of any of the foods and constituents considered was not associated with coronary mortality. CONCLUSIONS: Aspects of childhood diet, but not antioxidant intake, may affect adult cardiovascular risk.

Extended rituximab therapy in Waldenström's macroglobulinemia.

BACKGROUND: Waldenström's macroglobulinemia (WM) is a CD20 expressing B-cell malignancy represented by the pathological diagnosis of IgM secreting lymphoplasmacytic lymphoma. Major response rates of 30% have been reported in most studies with standard dose rituximab, i.e. 4 weekly infusions at 375 mg/m(2)/week. METHODS: In an effort to increase rituximab activity in WM, an extended dose schedule employing two sets of four (375 mg/m(2)/week) infusions at weeks 1-4 and 12-16 was evaluated. Expression of the complement resistance antigens CD46, CD55 and CD59 was also evaluated on tumor cells pre- and post-therapy to determine impact on response. RESULTS: Twenty-nine patients were enrolled and 26 patients completed the intended therapy. On an intent to treat analysis, 14 (48.3%) patients achieved a partial response, and 5 (17.2%) patients achieved a minor response. Responses were observed in 18/24 (75%) patients with a serum IgM level of <6000 mg/dl, and only 1 of 5 (20%) patients with a level of >6000 mg/dl (P=0.03). The median time to best response was 17 months, and only 2 of 19 responding patients progressed with a median follow-up of 29 months. No differences in baseline expression of the complement resistance antigens CD46, CD55 and CD59 were observed among responding and non-responding patients, although post-therapy CD55 expression was higher in non-responding patients (P=0.002). CONCLUSIONS: These data show that extended rituximab therapy is active and may lead to more major responses over standard dose rituximab in WM. WM patients with serum IgM levels of <6000 mg/dl are more likely to benefit from extended rituximab therapy.

A phase I trial of a Bcl-2 antisense (G3139) and weekly docetaxel in patients with advanced breast cancer and other solid tumors.

PURPOSE: Expression of the Bcl-2 protein confers resistance to various apoptotic signals. G3139 [oblimersen sodium (Genasense)] is a phosphorothioate antisense oligodeoxynucleotide that targets Bcl-2 mRNA, downregulates Bcl-2 protein translation, and enhances the antitumor effects of subtherapeutic doses of docetaxel (Taxotere). PATIENTS AND METHODS: We performed a phase I trial to determine the maximum tolerated dose (MTD) and safety profile of combined therapy with G3139 and weekly docetaxel in patients with advanced Bcl-2-positive solid tumors. Cohorts of three to six patients were enrolled to escalating doses of G3139 and a fixed dose of weekly docetaxel using either of two schedules. In part I, G3139 was administered by continuous infusion for 21 days (D1-22), and docetaxel (35 mg/m2) was given weekly on days 8, 15 and 22. In part II, G3139 was given by continuous infusion for 5 days before the first weekly dose of docetaxel, and for 48 h before the second and third weekly docetaxel doses. For both schedules, cycles were repeated every 4 weeks. RESULTS: Twenty-two patients were enrolled. Thirteen patients were treated on the part I schedule with doses of G3139 escalated from 1 to 4 mg/kg/day. Nine patients were on the part II schedule of shorter G3139 infusion at G3139 doses of 5-9 mg/kg/day. Hematologic toxicities were mild, except for one case of persistent grade 3 thrombocytopenia in part I. The most common adverse events were cumulative fatigue and transaminase elevation, which prevented further dose escalation beyond 4 mg/kg/day for 21 days with the part I schedule. In part II of the study, using the abbreviated G3139 schedule, even the highest daily doses were tolerated without dose-limiting toxicity or the need for dose modification. Objective tumor response was observed in two patients with breast cancer, including one whose cancer previously progressed on trastuzumab plus paclitaxel. Four patients had stable disease. Pharmacokinetic results for G3139 were similar to those of other trials. CONCLUSIONS: G3139 in combination with standard-dose weekly docetaxel was well tolerated. The shortened and intermittent G3139 infusion had less cumulative toxicities and still allowed similar total G3139 delivery as the longer infusion. Further studies should examine the molecular effect of the regimen, as well as clinical activities in malignancies for which taxanes are indicated.

G3139, a Bcl-2 antisense oligodeoxynucleotide, induces clinical responses in VAD refractory myeloma.

Expression of Bcl-2 in multiple myeloma is associated with resistance to chemotherapeutic drugs. Conversely, suppression of Bcl-2 enhanced the chemosensitivity of myeloma cells in vitro. G3139 is an antisense oligodeoxynucleotide targeted to the first six codons of the Bcl-2 mRNA open reading frame. In this study, G3139 was delivered as a continuous intravenous infusion for 7 days at a fixed dose of 7 mg/kg/day in combination with VAD (vincristine, adriamycin, and dexamethasone) chemotherapy. In total, 10 heavily pretreated patients with refractory myeloma participated in this trial, including eight patients with VAD refractory disease. The combination of G3139 and VAD was feasible and well tolerated. Seven patients (70%) responded including four patients (40%) with a partial response and three patients (30%) with a minor response. Median progression-free survival was 6 months (range, 2-7+ months) and median overall survival has not been reached. G3139 downregulated Bcl-2 protein levels in peripheral blood circulating myeloma cells, B cells, T cells, and monocytes. These results indicate that G3139 may overcome classical resistance and restore sensitivity of myeloma tumor cells to VAD chemotherapy.

Socio-economic inequalities in diabetes complications, control, attitudes and health service use: a cross-sectional study.

AIMS: To investigate socio-economic inequalities in diabetes complications, and to examine factors that may explain these differences. METHODS: Cross-sectional questionnaire survey of 770 individuals with diabetes among 40 general practices in Avon and Somerset. General practice, optometrist and eye hospital records over time (median 7 years) were analysed. Slope indices of inequality, odds ratios and incidence rate ratios were calculated to estimate the magnitude of inequality between the most and least educated, and the highest and lowest earning patients, adjusted for age, sex and type of diabetes, and clustering of outcomes within practices. RESULTS: The least educated patients were more likely than the most educated patients to have diabetic retinopathy [adjusted odds ratio (OR) 4.3; 95% confidence interval 0.8, 23.7] and heart disease (adjusted OR 3.6; 1.1, 11.8), had higher HbA1c levels (adjusted slope index of inequality 0.9; 0.3, 1.5), felt that diabetes more adversely affected their social and personal lives (adjusted slope index of inequality 0.8; 0.5, 1.1 Diabetes Care Profile units), were more likely to be recorded as non-compliant by their health professionals, and had lower rates of hospital attendance (adjusted rate ratio 0.43; 0.26, 0.71). However, they did not see themselves as less compliant, and had higher general practice attendance rates (adjusted rate ratio 1.5; 1.1, 2.2). CONCLUSIONS: Less educated and lower earning individuals with diabetes bear a larger burden of morbidity but use hospital care less. Health service resource allocation should reflect the distribution of chronic illness.

Population requirement for primary knee replacement surgery: a cross-sectional study.

OBJECTIVES: To determine the population requirement for total knee replacement (TKR) in England. METHODS: Population-based study using an age/sex-stratified random sample of 28 080 individuals aged 35 yr and over. Incident disease was estimated from prevalence by statistical modelling. The New Zealand priority criteria for major joint replacement were used for case selection. RESULTS: Patients with knee disease were less likely than those with equally severe hip disease to have been referred to a specialist, to have consulted an orthopaedic surgeon or to be on a waiting list for joint replacement. The estimated annual requirement of TKRs in England, based on New Zealand Scores alone, was 55,800 (95% CI 40 700-70,900), contrasting sharply with an annual provision of 29,300 actually observed. However, in contrast to previously reported hip replacement data, when patient willingness to undergo surgery was considered, this estimate decreased considerably. CONCLUSIONS: There appears to be an underprovision of TKR in England. This may be due in part to differences in perception of disease severity and likely response to surgery between patients and general practitioners on one hand, and rheumatologists and orthopaedic surgeons on the other.

Treatment of relapsed or refractory acute myeloid leukemia with humanized anti-CD33 monoclonal antibody HuM195.

HuM195 is a humanized, unconjugated, anti-CD33 monoclonal antibody. Fifty adult patients with relapsed or refractory AML were randomized to receive HuM195 at a dose of 12 or 36 mg/m(2) by intravenous infusion over 4 h on days 1-4 and 15-18. Patients with stable or responding disease received two additional cycles on days 29-32 and 43-46. HuM195 was given as first salvage therapy in 24 patients and as second or subsequent salvage therapy in 26 patients. Pretreatment blast percentage in the marrow was between 5 and 30% in 20 patients with the others having blast counts greater than 30%. The median age of patients was 62 years (range 26-86) and CD33 was detected in 95% of patients for whom immunophenotyping was available. Of 49 evaluable patients, two complete and one partial remission were observed. All three responses were in patients treated at the 12 mg/m(2) dose level and all had baseline blast percentages less than 30%. Decreases in blast counts ranging from 30 to 74% were seen in nine additional patients. Infusion-related events of fever and chills occurred in the majority of patients and were generally mild and primarily related to the first dose of antibody. No hepatic, renal or cardiac toxicities were observed and other adverse events such as nausea, vomiting, mucositis and diarrhea were uncommon or felt to be unrelated to HuM195. In addition, anti-HuM195 responses were not detected. HuM195 as a single agent has minimal, but observable, anti-leukemic activity in patients with relapsed or refractory AML and activity is confined to patients with low burden disease. No significant differences in clinical efficacy or toxicity were seen between the two dose levels of antibody. HuM195 was well tolerated with infusion-related fevers and chills the predominant toxicities seen. Meaningful clinical efficacy of this unconjugated monoclonal antibody may be realized only in patients with minimal residual disease, or in combination with chemotherapy.

Fruit, vegetables, and antioxidants in childhood and risk of adult cancer: the Boyd Orr cohort.

STUDY OBJECTIVE: To examine associations between food and nutrient intake, measured in childhood, and adult cancer in a cohort with over 60 years follow up. DESIGN AND SETTING: The study is based on the Boyd Orr cohort. Intake of fruit and vegetables, energy, vitamins C and E, carotene, and retinol was assessed from seven day household food inventories carried out during a study of family diet and health in 16 rural and urban areas of England and Scotland in 1937-39. PARTICIPANTS: 4999 men and women, from largely working class backgrounds, who had been children in the households participating in the pre-war survey. Analyses are based on 3878 traced subjects with full data on diet and social circumstances. MAIN RESULTS: Over the follow up period there were 483 incident malignant neoplasms. Increased childhood fruit intake was associated with reduced risk of incident cancer. In fully adjusted logistic regression models, odds ratios (95% confidence intervals) with increasing quartiles of fruit consumption were 1.0 (reference), 0.66 (0.48 to 0.90), 0.70 (0.51 to 0.97), 0.62 (0.43 to 0.90); p value for linear trend=0.02. The association was weaker for cancer mortality. There was no clear pattern of association between the other dietary factors and total cancer risk. CONCLUSIONS: Childhood fruit consumption may have a long term protective effect on cancer risk in adults. Further prospective studies, with individual measures of diet are required to further elucidate these relations.

Recent trends in the use of radical prostatectomy in England: the epidemiology of diffusion.

OBJECTIVE: To describe recent trends in the use of radical prostatectomy (RP) in England, as there is currently no consensus on the most effective treatment for localized prostate cancer, although RP is the treatment of choice among urological surgeons for men aged < 70 years. METHODS: Routine data were assessed to establish the number of RPs performed in England in 1991-99. Age-standardized operation rates were compared by region and socio-economic group, and the geographical spread of use mapped. RESULTS: The number of RPs performed annually increased nearly 20-fold between 1991 and 1999. Rates of surgery were greatest in the London National Health Service (NHS) regions and lowest in the Trent region. Outside London, the risk of surgery in a NHS hospital was significantly greater for men living in the least deprived areas; in London this trend was reversed. CONCLUSION: Rapid increases in the use of RP showed marked regional variations, most likely related to access to prostate-specific antigen testing and the location of surgeons able to carry out radical surgery. By 1999, a third of procedures were still being undertaken in 'low-volume' hospitals, with implications for the quality of care and outcomes. Crucially, these developments occurred in the absence of robust information about the effectiveness of RP. Recent funding of a randomized trial of treatment options in this area is welcome, but wider questions remain about the timing of the evaluation of surgical technologies.

Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma.

PURPOSE: The primary objective was to assess the duration of grade 4 neutropenia (neutrophil count < 0.5 x 10(9)/L) after one cycle of chemotherapy with etoposide, methylprednisolone, cisplatin, and cytarabine in patients randomly assigned to receive one dose of pegfilgrastim or daily filgrastim after chemotherapy. Febrile neutropenia, neutrophil profiles, time to neutrophil recovery, pharmacokinetics, and safety were also assessed. PATIENTS AND METHODS: An open-label, randomized, phase II study was designed to compare the effects of a single subcutaneous injection of pegfilgrastim (sustained-duration filgrastim) 100 micro g/kg per chemotherapy cycle (n = 33) with daily subcutaneous injections of filgrastim 5 micro g/kg (n = 33) in patients receiving salvage chemotherapy for relapsed or refractory Hodgkin's or non-Hodgkin's lymphoma. RESULTS: The incidence of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 69% and 68%, respectively. In addition, the mean duration of grade 4 neutropenia was similar in both groups (2.8 and 2.4 days, respectively). The results for the two groups were also not significantly different for febrile neutropenia, neutrophil profile, time to neutrophil recovery, or toxicity profile. A single subcutaneous injection of pegfilgrastim 100 micro g/kg produced a sustained serum concentration relative to daily subcutaneous injections of filgrastim. Filgrastim-treated patients received a median of 11 injections per cycle. CONCLUSION: Pegfilgrastim was safe and well tolerated in this patient population. A single injection of pegfilgrastim per chemotherapy cycle provided neutrophil support with safety and efficacy similar to that provided by daily injections of filgrastim. Once-per-cycle administration of pegfilgrastim simplifies the management of neutropenia and may have important clinical benefits for patients and healthcare providers.

Population need for coronary revascularisation: are national targets for England credible?

OBJECTIVE: To estimate the need for coronary revascularisation, by using an incidence of indications approach, among 45-84 year olds with stable angina, unstable angina, and acute myocardial infarction. DESIGN: Modelling exercise. Six key steps along the pathway of care from initial diagnosis in primary or secondary care to revascularisation were defined and the frequency of indications estimated using routine data from hospital admissions and data from studies in the general population, and primary and secondary care. SETTING AND PATIENTS: Mid-1998 population of England. INTERVENTION: Coronary revascularisation. MAIN OUTCOME MEASURE: Ability to benefit (need), defined by randomised trials, expert panel ratings from the ACRE (appropriateness of coronary revascularisation) study, or by informal consensus. RESULTS: The need for coronary revascularisation was estimated to be 92 000 procedures, equivalent to a rate of 1861 per million population. Overall, the model of need exceeded current provision by 3.3:1, although among people aged 75 years and over the ratio was 7.7:1. A plausible upper estimate of need--obtained by assuming that 90% of patients with stable angina were referred from primary care and that angiography would be performed in 65% of patients with acute myocardial infarction and 75% of patients with unstable angina--was 2626 per million population. CONCLUSIONS: The national target of 1500 revascularisation procedures per million population is credibly related to population need, although upper estimates of need are considerably higher. Better understanding is required of the benefits of referring patients with specific indications from primary care. The greatest relative increase in provision is required for those aged 75 and older, among whom trial evidence of benefit is scant.

Association between breast feeding and growth: the Boyd-Orr cohort study.

OBJECTIVE: To investigate the association of breast feeding with height and body mass index in childhood and adulthood. DESIGN: Historical cohort study, based on long term follow up of the Carnegie (Boyd-Orr) survey of diet and health in pre-war Britain (1937-1939). SETTING: Sixteen urban and rural districts in Britain. SUBJECTS: A total of 4999 children from 1352 families were surveyed in 1937-1939. Information on infant feeding and childhood anthropometry was available for 2995 subjects. MAIN OUTCOME MEASURES: Mean differences in childhood and adult anthropometry between breast and bottle fed subjects. RESULTS: Breast feeding was associated with the survey district, greater household income, and food expenditure, but not with number of children in the household, birth order, or social class. In childhood, breast fed subjects were significantly taller than bottle fed subjects after controlling for socioeconomic variables. The mean height difference among boys was 0.20 standard deviation (SD) (95% confidence interval (CI) 0.07 to 0.32), and among girls it was 0.14 SD (95% CI 0.02 to 0.27). Leg length, but not trunk length, was the component of height associated with breast feeding. In males, breast feeding was associated with greater adult height (difference: 0.34 SD, 95% CI 0.13 to 0.55); of the two components of height, leg length (0.26 SD, 95% CI 0.02 to 0.50) was more strongly related to breast feeding than trunk length (0.16 SD, 95% CI -0.04 to 0.35). Height and leg length differences were in the same direction but smaller among adult females. There was no association between breast feeding and body mass index in childhood or adulthood. CONCLUSIONS: Compared with bottle fed infants, infants breast fed in the 1920s and 1930s were taller in childhood and adulthood. As stature is associated with health and life expectancy, the possible long term impact of infant feeding on adult mortality patterns merits further investigation.

Caring for the health of the public: cross sectional study of the activities of UK public health departments.

The relative time spent in different areas of work in public health departments in the UK was assessed by means of a postal questionnaire. Departments spend one third of their time on population health work, this being similar to the amount of time spent on planning health services. Having a planning department in the health authority did not affect the amount of time spent in any area of work. Having a greater number of consultants in the department was associated with a tendency to spend more time on population health and being involved in training was associated with spending less time on planning. Public health departments in the UK are the only part of the health service with responsibility for the broader aspects of public health. Whilst the tensions between medical care and the wider influences upon population health may represent a false dichotomy, public health professionals must maintain a central focus of their work on the wider influences upon population health if balance is to be maintained within the National Health Service.

Autotransplantation for advanced lymphoma and Hodgkin's disease followed by post-transplant rituxan/GM-CSF or radiotherapy and consolidation chemotherapy.

Disease relapse occurs in 50% or more of patients who are autografted for relapsed or refractory lymphoma (NHL) or Hodgkin's disease (HD). The administration of non-cross-resistant therapies during the post-transplant phase could possibly control residual disease and delay or prevent its progression. To test this approach, 55 patients with relapsed/refractory or high-risk NHL or relapsed/refractory HD were enrolled in the following protocol: stem cell mobilization: cyclophosphamide (4.5 g/m(2)) + etoposide (2.0 g/m(2)) followed by GM-CSF or G-CSF; high-dose therapy: gemcitabine (1.0 g/m(2)) on day -5, BCNU (300 mg/m(2)) + gemcitabine (1.0 g/m(2)) on day -2, melphalan (140 mg/m(2)) on day -1, blood stem cell infusion on day 0; post-transplant immunotherapy (B cell NHL): rituxan (375 mg/m(2)) weekly for 4 weeks + GM-CSF (250 microg thrice weekly) (weeks 4-8); post-transplant involved-field radiotherapy (HD): 30-40 Gy to pre-transplant areas of disease (weeks 4-8); post-transplant consolidation chemotherapy (all patients): dexamethasone (40 mg daily)/cyclophosphamide (300 mg/m(2)/day)/etoposide (30 mg/m(2)/day)/cisplatin (15 mg/m(2)/day) by continuous intravenous infusion for 4 days + gemcitabine (1.0 g/m(2), day 3) (months 3 + 9) alternating with dexamethasone/paclitaxel (135 mg/m(2))/cisplatin (75 mg/m(2)) (months 6 + 12). Of the 33 patients with B cell lymphoma, 14 had primary refractory disease (42%), 12 had relapsed disease (36%) and seven had high-risk disease in first CR (21%). For the entire group, the 2-year Kaplan-Meier event-free survival (EFS) and overall survival (OS) were 30% and 35%, respectively, while six of 33 patients (18%) died before day 100 from transplant-related complications. The rituxan/GM-CSF phase was well-tolerated by the 26 patients who were treated and led to radiographic responses in seven patients; an eighth patient with a blastic variant of mantle-cell lymphoma had clearance of marrow involvement after rituxan/GM-CSF. Of the 22 patients with relapsed/refractory HD (21 patients) or high-risk T cell lymphoblastic lymphoma (one patient), the 2-year Kaplan-Meier EFS and OS were 70% and 85%, respectively, while two of 22 patients (9%) died before day 100 from transplant-related complications. Eight patients received involved field radiation and seven had radiographic responses within the treatment fields. A total of 72 courses of post-transplant consolidation chemotherapy were administered to 26 of the 55 total patients. Transient grade 3-4 myelosuppression was common and one patient died from neutropenic sepsis, but no patients required an infusion of backup stem cells. After adjustment for known prognostic factors, the EFS for the cohort of HD patients was significantly better than the EFS for an historical cohort of HD patients autografted after BEAC (BCNU/etoposide/cytarabine/cyclophosphamide) without consolidation chemotherapy (P = 0.015). In conclusion, post-transplant consolidation therapy is feasible and well-tolerated for patients autografted for aggressive NHL and HD and may be associated with improved progression-free survival particularly for patients with HD.