Distribution of blood lead levels in schoolchildren in selected Cape Peninsula suburbs subsequent to reductions in petrol lead.

OBJECTIVE: To determine blood lead levels among children attending schools in selected Cape Peninsula suburbs, and to assess the impact of a reduction in the lead content of petrol. DESIGN: A cross-sectional analytical study of children's blood lead levels and associated risk factors. SETTING: Selected inner city, suburban, and peri-urban schools in the Cape Peninsula, expected to have differing levels of environmental exposure to lead. SUBJECTS: Grade 1 schoolchildren for whom prior written parental consent had been obtained, and who were present at school on the day of the study. OUTCOME MEASURES: Blood lead levels (microgram/dl), associated with a wide range of potential risk factors. RESULTS: Median blood lead levels in suburbs varied from 14 to 16 micrograms/dl, the lowest levels occurring in the peri-urban suburb and the highest in the inner city suburb. Within the inner city suburb of Woodstock, variations in mean blood lead concentrations among schools were substantial, varying from 13 to 19 micrograms/dl. Overall, no change occurred in blood lead levels in this suburb subsequent to the lowering of the lead content of petrol. CONCLUSION: Every effort should be made in South Africa to control sources of lead in the urban environment. The study will serve as a useful baseline against which to measure the impact on blood lead levels of further actions which have been taken to promote the use of lead-free petrol in South Africa.

Exercise hemodynamics of aortic prostheses: comparison between stentless bioprostheses and mechanical valves.

BACKGROUND: Nonstented bioprostheses have been associated with lower resting gradients than stented bioprostheses or mechanical valves. We compared the hemodynamic performance of nonstented bioprostheses and mechanical valves with normal native aortic valves at rest and exercise. METHODS: Dobutamine echocardiography was used to assess gradients and effective orifice area index at rest and exercise in patients with the Toronto stentless porcine valve (TSPV; n = 13; mean implant size 25.7 mm), Medtronic Freestyle (FR; n = 11; mean implant size 23.9 mm), Sorin Bicarbon (SOR; n = 11; mean implant size 24.5 mm), St. Jude Medical (SJM; n = 10; mean implant size 21.3 mm), and normal native aortic valves (NOR; n = 10). RESULTS: All groups demonstrated a major rise in cardiac output at maximal dobutamine infusion. At rest and exercise, respectively, mean gradients were 5.48 +/- 1.1 mm Hg and 5.83 +/- 0.9 mm Hg for TSPV, 5.68 +/- 1.2 mm Hg and 7.50 +/- 1.7 mm Hg for FR, 10.29 +/- 1.4 mm Hg and 20.78 +/- 2.7 mm Hg for SJM, 5.26 +/- 0.8 mm Hg and 11.1 +/- 1.8 mm Hg for SOR, and 1.54 +/- 0.4 mm Hg and 2.18 +/- 0.7 mm Hg for NOR. In comparison with normal valves, both stentless groups showed no change in mean gradient at exercise, whereas both mechanical groups showed an increase in gradient at exercise (p < 0.04). CONCLUSIONS: Stentless valves behave similarly to normal aortic valves in that there is almost no increase in gradient at exercise. Both mechanical valve groups showed increased gradients at exercise, suggesting that these valves obstruct blood flow. Our data add further evidence that stentless valves are hemodynamically superior to mechanical valves in the aortic position.

Engraftment of marrow allografts treated with Campath-1 monoclonal antibodies.

We have analyzed the factors associated with engraftment in 216 recipients of T-cell depleted allogeneic HLA identical sibling marrow transplants using Campath 1 monoclonal antihuman lymphocyte (CD52) antibodies. The patient population consisted of 168 patients with hematologic malignancies, 26 with severe aplastic anemia (SAA), and 22 with hemoglobinopathies, half of whom received marrow treated in vitro with Campath-1M (IgM) and half received marrow with Campath-1G (IgG2b isotype). Patients with durable engraftment had fast hematopoietic recovery: SAA patients reached ANC > 0.5 x 10(6)/L on Day 14; those with leukemia attained ANC > 0.5 x 10(6)/L on Days 18, 17, and 15 for ANLL, ALL and CML respectively, while patients with thalasemia reached ANC > 0.5 x 10(6)/L on Day 21. Overall, 24 patients (17 with leukemia, 4 with SAA, and 3 with thalassemia) suffered graft failure: 10 patients (all grafted with Campath-1M) rejected their grafts, while 14 others (9 grafted with Campath-1M, and 5 with 1G isotype) never engrafted (p = 0.009). Multivariate analysis revealed that neither pretransplant protocol, nor stage of disease or type of antibody used, donor sex and ABO match had any impact on engraftment. The variables favorably associated with engraftment were older age (p = 0.030, RR = 1.016) and CFU-GM number (p = 0.013, RR = 1.001). Patients with ANLL or SAA had a better chance to engraft (p = 0.027, RR = 1.400; and p = 0.003, RR = 2.677, respectively) compared to patients with thalassemia (p = 0.001, RR = 0.551). A higher concentration of Campath-1 antibody in vitro and in vivo adversely affected engraftment. Our data show that satisfactory engraftment can be achieved in patients transplanted with Campath-1 treated marrow allografts. However, despite the measures undertaken to prevent rejection, graft failure still poses a problem. Further pretransplant immunosuppression and perhaps more selective T-cell depletion may reduce the increased graft failure in these patients.

Single-turnover analysis of mutant human apurinic/apyrimidinic endonuclease.

Apurinic/apyrimidinic endonuclease (AP endo) is a key enzyme in the repair of oxidatively damaged DNA. Using single-turnover conditions, we recently described substrate binding parameters for wild type human AP endo. In this study, we utilized four enzyme mutants, D283A, D308A, D283A/D308A, and H309N, and assayed them under steady state and single-turnover conditions. The turnover number of the single aspartate mutants was decreased 10-30-fold in comparison to that of the wild type. The decrease in the turnover number was accompanied by a 17- and 50-fold decrease in the forward rate constant (kon) for substrate binding by D308A and D283A, respectively. The dissociation rate constant for substrate (koff) was unchanged for the D308A mutant but was 10 times faster for the D283A mutant than for the wild type. The apparent Km values for both of the single aspartate mutants were about equal to their respective KD values. To account for the kinetic behavior of the D308A mutant, it was necessary to insert a conformational change into the kinetic scheme. In contrast to the single aspartate mutants, the turnover number for the double mutant was 500-fold lower than that of the wild type, its apparent Km was 2.5-fold higher, and binding to substrate was weak. Mutation of His309 caused the greatest decrease in activity, resulting in a turnover number that was more than 30000-fold lower than that of the wild type and an apparent Km that was 13-fold higher, supporting the notion that His309 is intimately involved in catalysis. Molecular dynamics simulation techniques suggested that conversion of either aspartate to alanine resulted in major shifts in the spatial localization of key amino acids. Despite the fact that the two aspartates flank His309, the movement they engendered was distinct, consistent with the differences in catalytic behavior. We suggest that the conformation of the active site is largely maintained by the two aspartates, which enable efficient binding and cleavage of abasic site-containing DNA.

Connectivity and control in the year 2000 and beyond.

By now, most executives are familiar with the famous Year 2000 problem--and many believe that their companies have the situation well in hand. After all, it seems to be such a trivial problem--computer software that interprets "oo" to be the year 1900 instead of the year 2000. And yet armies of computer professionals have been working on it--updating code in payroll systems, distribution systems, actuarial systems, sales-tracking systems, and the like. The problem is pervasive. Not only is it in your systems, it's in your suppliers' systems, your bankers' systems, and your customers' systems. It's embedded in chips that control elevators, automated teller machines, process-control equipment, and power grids. Already, a dried-food manufacturer destroyed millions of dollars of perfectly good product when a computer counted inventory marked with an expiration date of "oo" as nearly a hundred years old. And when managers of a sewage-control plant turned the clock to January I, 2000 on a computer system they thought had been fixed, raw sewage pumped directly into the harbor. It has become apparent that there will not be enough time to find and fix all of the problems by January I, 2000. And what good will it do if your computers work but they're connected with systems that don't? That is one of the questions Harvard Business School professor Richard Nolan asks in his introduction to HBR's Perspectives on the Year 2000 issue. How will you prepare your organization to respond when things start to go wrong? Fourteen commentators offer their ideas on how senior managers should think about connectivity and control in the year 2000 and beyond.

Nosocomial colonization, septicemia, and Hickman/Broviac catheter-related infections in bone marrow transplant recipients. A 5-year prospective study.

In this 5-year prospective study of 242 bone marrow transplantation (BMT) recipients from whom daily blood cultures via the indwelling Broviac/Hickman catheter were obtained, there was a median of 35 catheter-days during hospitalization, mean of 40 days, and total of 9,667 catheter-days which were divided almost equally between neutropenic (4,771) and non-neutropenic (4,896) days. One hundred twenty (50%) patients had a total of 161 episodes of nosocomial bacterial or candidal infections. Overall, 81 (33%) patients experienced 100 episodes of catheter-related infections and 90 (37%) patients experienced 112 episodes of septicemia, including 51 episodes of catheter-related septicemia. There was an incidence of 11.59 septicemia episodes, including 5.28 catheter-related septicemia episodes, 2.48 colonization only (without subsequent septicemia), and 2.59 exit site infections only, per 1,000 catheter-days. Over a period of a total of 6,593 afebrile days, 34 (14%) patients developed 40 episodes of colonization, a rate of 6.07 per 1,000 afebrile days, of which 16 developed into septicemia. Twenty-five patients had 1 episode each of exit site infection without bacteremia. There were 10 (4%) septicemia-related deaths, 4 of which were catheter-related; 50% of all deaths involved Pseudomonas aeruginosa. The mortality due to catheter-related septicemic episodes was not greater than that of the non-catheter-related episodes. Neutropenia was found to be a significant risk factor in our study: 76% of the septicemia episodes (85/112) and 65% of the catheter-related infectious episodes (65/100) occurred during neutropenia. There was a higher incidence of septicemic episodes during neutropenia than during non-neutropenic periods, 17.82 versus 5.51 per 1,000 days (p < 0.0001), and a higher rate of catheter-related infections during the neutropenic period, 13.62 versus 7.15 during non-neutropenic days per 1,000 days (0.001). Fourteen of 16 colonization episodes developed into septicemia during neutropenia versus 2/24 during non-neutropenic periods, a rate of 5.47 versus 0.47 per 1,000 afebrile days, respectively (p < 0.0001), and 9/10 deaths occurred during neutropenia.

Antibody response to influenza immunization in patients after heart transplantation.

The aim of this study was to evaluate post-heart transplantation (Htx) response to two-dose and three-dose influenza vaccine. Hemagglutination inhibition antibodies were monitored in HTx recipients immunized twice (n = 25) or three times (n = 17), and non-HTx controls (n = 8) once, with inactivated influenza vaccine. Post-first dose protective antibody titers (> or = 1:40) were demonstrated in 9/25 (36%) for A/Singapore/ (H1N1), 5/25 (20%) for A/Shanghai/(H3N2) and 2/25 (8%) for B/Yamagata compared with 4/8 (50%), 6/8 (75%) and 2/8 (25%), respectively, for controls. Post-second dose protective titers remained low, increasing following the third dose to 71%, 65% and 29%, respectively. The abnormally low antibody responses of HTx recipients to one-dose and two-dose influenza vaccine can be overcome by a third dose.

Serotype-related differences in inflammatory response to Streptococcus pneumoniae in experimental meningitis.

It has been suggested that serotype influences severity of experimental pneumococcal meningitis. This hypothesis was tested with strains of serotypes 1, 5, 6B, 7F, 14, and 23F, prevalent in Israel, in an experimental rabbit model. Cerebrospinal fluid (CSF) bacterial titers, leukocyte densities, concentrations of lactate, protein, and glucose, tumor necrosis factor-alpha levels, brain water content, and cerebral blood flow were measured 18 h after inoculation of pneumococci. Serotypes 5 and 7F exhibited mild inflammatory responses (leukocytosis <1000/mm3, lactate <4 mmol/L); types 6B, 14, and 23F showed severe inflammatory responses (leukocytosis >5000/mm3, lactate >10 mmol/L); serotype 1 had intermediate inflammatory responses but exceptionally high CSF bacterial titers. Leukocyte count correlated with all other variables; lactate with all except brain water content. On the basis of 6 Streptococcus pneumoniae serotypes, three discrete levels of inflammatory responses could be delineated in experimental pneumococcal meningitis.

Editorial.

PIP: Providing basic water and sanitation facilities to meet the population's basic needs is one of the South African government's Reconstruction and Development Program's (RDP) priority concerns. The lack of basic services such as water supply and sanitation reflects the prevailing poverty and lack of development. When the White Paper on Water Supply and Sanitation was published in November 1994, the Department of Water Affairs and Forestry (DWAF) committed itself to meeting the population's basic water and sanitation needs. To that end, DWAF will collaborate with both departments of the national government and nongovernmental organizations. All effort will be made to involve communities in the decision-making process, through the development and maintenance of community service provision projects, and complemented by a sustained empowerment process through education and training. This paper introduces others on community water and the provision of sanitation. Public health and epidemiology play an important role in realizing the provision of water to meet everyone's health and functional needs.^ieng

Transplantation performance of human skin cryopreserved by programmed or stepwise freezing and stored at -80 degrees C or -180 degrees C.

We developed a mouse recipient model that was used to evaluate and compare four cryopreservation procedures for human cadaveric skin stored for two time periods. Skin specimens were identically processed and preserved by programmed (1 degree C/min), or stepwise freezing, and stored at -180 degrees C or -80 degrees C for periods of 1 month and 6 to 10 months. Samples were grafted on Balb/c mice, and primary take was evaluated after 7 days. The results indicate that although all grafted specimens were initially accepted, as indicated by gross observations, histologic differences were evident and significant. The study groups were analyzed for the effect of method and skin sample variety; the effect of freezing procedure and temperature level; time effect (storage period); and advantage of method 1 (programmed freezing at -180 degrees C) over the other methods. The significance (p value) was determined for separate histologic criteria and average skin score or quality. The overall results indicate that average score of skin preserved by method 1 is highest for both storage periods. This method has an almost significant advantage (p = 0.057) over the others on quality of skin stored for 1 month, and a highly significant advantage (p = 0.007) on graft adherence of skin stored for 6 to 10 months. The effect of method and samples variety on the separate histologic criteria and average score of skin is not always significant. However, an interaction factor (between method and samples) has a highly significant effect (p < 0.001) on almost all of the histologic criteria and average skin score. The effects of freezing method is significant only on average skin score, for 1 month of storage; whereas temperature effect is seldom significant. Evaluating the effects of time, samples, and the interaction factor (between time and samples) indicated that the interaction factor is highly significant (p < 0.001). Time and samples effects are rarely significant. Thus the quality of the final product-the cryopreserved skin-is determined by many factors, and quite often they interact. Highly significant is the combined effect, or interaction factor, of sample variability with method of cryopreservation or with storage period.

Evaluation of the short course on Urbanisation and Health for Developing Countries presented as part of the Summer School of the Public Health Programme at the University of the Western Cape.

PIP: This article summarized findings from an evaluation of a short course on Urbanization and Health for Developing Countries. The training program was held at the University of Cape Town's School of Public Health in the summer of 1995. A second short course was held in early 1996. The course included 2 modules over a 2-week period. Participants included 30 students in the 1st module and 23 in the 2nd module. Participants' evaluations focused on course usefulness, interest value, facilitators, participation, balance, resources, administration, and relevance to work. All students in the 1st module found it useful and planned to attend later modules. The students shared their knowledge and experiences. Only 2 students in the 1st module attended the 2nd module course. The 2nd module allowed for more group participation and discussion. The topic of health and development in an urban setting, and its relevance to the new South Africa, stimulated considerable discussion. 80-85% of participants rated the 2nd module as useful and of interest. Participants in the 1st module rated its usefulness and value interest even higher. The courses were offered as part of the National Urbanization and Health Research Program of the South African Medical Research Council. Several participants were visiting students from Zambia and Pakistan.^ieng

Nosocomial coagulase-negative staphylococcal infections in bone marrow transplantation recipients with central vein catheter. A 5-year prospective study.

The purpose of this study was to examine coagulase-negative staphylococcal infections in bone marrow transplantation (BMT) patients with central vein catheters by investigating incidence, clinical relevance, risk factors, methicillin resistance, clinical impact of initial empiric antimicrobial therapy without vancomycin, and management of documented catheter-related infections. A 5-year prospective study was conducted with daily evaluation of 242 BMT patients during hospitalization, including clinical assessment and blood culture via the Hickman/Broviac catheter. If fever or infected appearance occurred, peripheral blood cultures or exit site cultures, respectively, were done. Results showed a septicemia incidence of 7.0%, including in 6 patients following colonization, in 1 patient with tunnel infection, in 1 patient with thrombophlebitis, in 1 patient with exit site infection, and in 8 patients with septicemia of unknown origin. Total colonization incidence was 7%, with colonization only in 11 patients who had 16 episodes; incidence of exit site infection was 3.7%. Age > or = 18 years was the only identified risk factor for developing staphylococcal infection (P = 0.03). Despite a methicillin resistance rate of 45% and omission of vancomycin from the routine initial empiric antimicrobial regimen, the clinical course of coagulase-negative staphylococcal infections was relatively benign. A single patient, who experienced marrow rejection, died on day +31 with septicemia and only one patient experienced microbiological failure with recurrent colonization. Bacteria grown in both aerobic and anaerobic bottles were more likely true bacteremia than contaminant (P = 0.03). We conclude that the hazard of coagulase-negative staphylococcal infection does not mandate inclusion of a glycopeptide in the initial empiric antimicrobial regimen in BMT patients, even during febrile neutropenia. Hickman/Broviac-related staphylococcal infections, except for tunnel infection or thrombophlebitis, can usually be treated successfully without removing the catheter.

Comparison between nafarelin acetate and D-Trp6-LHRH for temporary pituitary suppression in in vitro fertilization (IVF) patients: a prospective crossover study.

PURPOSE: Nafarelin acetate is a new gonadotropin releasing (GnRH) agonist analogue with unique potency, intranasal administration, and convenient storage. Hence, nafarelin was considered as an alternative for temporary pituitary suppression in patients undergoing ovulation induction in IVF. A crossover treatment in a prospective study was performed including 40 women with bilateral obstructed tubes and normal ovarian function, treated in 80 ovulation induction cycles using the long protocol. Twenty patients used nafarelin acetate 600 micrograms/daily in their first cycle and received D-Trp6-LHRH, 0.5 mg/daily, in their following cycle. The other 20 women used decapeptyl in their cycle and received nafarelin in the second. RESULTS: Estradiol suppression was achieved by both D-Trp6-LHRH and nafarelin at equal time intervals. The average total number of ampoules (P = 0.0005) and the length of administration of hMG required for ovarian stimulation (P = 0.0002) and the time interval between GnRHa initiation to oocyte retrieval (P = 0.04) was significantly lower in nafarelin cycles. The number and the distribution between large and small follicles as well as the average number of oocytes retrieved did not differ between the two GnRH analogues. CONCLUSION: Our results demonstrate that nafarelin acetate is comparable to D-Trp6-LHRH for temporary pituitary suppression used for controlled ovarian stimulation in IVF patients. However, using nafarelin ovarian stimulation was achieved with few ampoules of hMG, administered for a shorter period of time, thus with a lesser cost.

Cytosine arabinoside as a major risk factor for Streptococcus viridans septicemia following bone marrow transplantation: a 5-year prospective study.

The incidence and clinical course of nosocomial septicemia with Streptococcus viridans was evaluated prospectively in 242 consecutive bone marrow transplant (BMT) recipients throughout their 15-213 days' (median 47) hospitalization, including 4-58 days (median 18) of neutropenia. Initial empiric therapy for febrile neutropenia consisted of mezlocillin, gentamicin and cefazolin; glycopeptide was excluded. S. viridans septicemia occurred in 23/209 (11%) subjects with underlying malignant disease, and only during neutropenia with concomitant mucositis: in 20 subjects (four with ampicillin-resistant strains), S. viridans septicemia occurred at onset of febrile neutropenia, 1-5 days (median 4.5) post-BMT. All survived with an uncomplicated clinical course. Thus, glycopeptide seems unnecessary in the initial empiric antibiotic regimen. The other three subjects demonstrated S. viridans septicemia (two with ampicillin-resistant strains) on day 11 post-BMT; two died. The major risk identified was cytosine arabinoside administration in the conditioning regimen (P < 0.01).

Bacterial pneumonia in recipients of bone marrow transplantation. A five-year prospective study.

Bacterial pneumonia as an important complication of bone marrow transplantation (BMT) has not been subjected to comprehensive analysis. Two hundred fifty-five consecutive allogeneic and autologous BMT recipients, ranging in age from 1 month to 53 years, were prospectively followed for 3 days to 3 years (median, 108 days) for development of bacterial pneumonia. Etiology, place acquired, chest radiography, and outcome were recorded and the association between bacterial pneumonia and demographic and clinical variables was analyzed. Thirty-seven (15%) patients experienced 52 episodes of bacterial pneumonia: onset of 13 episodes occurred within 30 days after transplantation, 10 episodes occurred on days +31 to +100, and 29 episodes occurred thereafter. Bacterial pneumonia was the terminal event or contributed to fatal outcome in 8 patients (22% of bacterial pneumonia cases, 3% total study population). Mortality due to hospital-acquired pneumonia (6/21) was significantly higher than (P = 0.03). Bacterial pathogens were identified in 27 (52%) episodes. During the first 100 days after BMT, hospital-acquired Gram-negative bacteria predominated, caused mainly by Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter lwoffi, and Enterobacter cloacae. After day +100, community-acquired, Gram-positive bacteria predominated, particularly Streptococcus pneumoniae. Haemophilus influenzae occurred periodically. Considering all episodes, significant association was found between bacterial pneumonia and veno-occlusive disease (VOD) (P < 0.01) and chronic graft-versus-host disease (GVHD) (P < 0.02). For culture-positive episodes, the association between bacterial pneumonia and VOD was significant (P < 0.001) and borderline for acute GVHD (P = 0.07). It is concluded that VOD and GVHD are positively associated with post-BMT bacterial pneumonia. Its incidence, etiology, risk factors, and outcome are important considerations in its prevention and treatment.

The effect of water supply, handling and usage on water quality in relation to health indices in a developing community in South Africa.

PIP: This study examined the relationship between the quality of water consumed by people in a developing community in South Africa, and health outcomes for diarrhea. Water sources included no formal water supply, communal taps used by over 100 people, outdoor taps on individual plots, and indoor taps. The aim of this 3-year study was to determine water quality at point of collection, to examine patterns of water usage, and to determine the health consequences. This was a case control study and epidemiological assessment. The sample included over 300 households. Cases included pre-school children with severe diarrhea who visited a health facility in the study area. Interviews were conducted to determine hygiene, sanitation, education, and socioeconomic information. Controls of similar age and type of water supply were obtained from neighborhoods in the study area. Findings indicate that water, based on microbiological assay, was of good quality and complied with the South African Bureau of Standards. Water was significantly more contaminated after handling and storage compared to point of source. Cases and controls had equally poor water quality after collection and storage. Control indoor cases had higher levels of E. coli. There was a strong association between diarrhea and the attendance at a day care center. Increased risk of diarrhea was associated with poor kitchen hygiene and low levels of knowledge about hygiene and diarrhea prevention. Communal tap facilities had lower water quality than private taps.^ieng

The health effects of exposure through swimming in South African marine waters: an overview.

PIP: This study evaluated the health effects of exposure to pathogenic microorganisms in South African marine waters during 1990-94. About 20% of South Africa's coastline is used for recreational purposes. The prospective study was conducted on 4 beaches and a tidal pool in the Western Cape Province in 1990. The sample included about 16,000 participants willing to provide information at the time of contact and at a follow-up date. The aim was to assess the health risks, to establish the relationships between swimming and water quality and health outcomes, and to recommend appropriate microbiological indicators. Prospective trials were discretely carried out during the peak holiday season. The trials relied on methods established by Cabelli (1982) and endorsed by the US Environmental Protection Agency (EPA) in 1986, and the World Health Organization in 1991. Water quality samples were obtained on recruitment days for fecal coliforms, E. coli, fecal streptococci, staphylococci, and coliphages. Findings indicate that the microbiological quality of the water on the 4 beach sites complied with both existing South African standards and US EPA guidelines. The tidal pool showed signs of pollution with fecal coliforms, fecal streptococci, and staphylococci. Water quality varied on different days. Further analysis is being conducted on the different levels of water quality. All sites showed an increased health risk for swimmers compared to nonswimmers. Site 2 showed a statistically significant risk. A prior pilot study found some evidence of a relationship between swimming-related illness and water quality.^ieng

Investigating a sequence of randomized phase II trials to discover promising treatments.

We consider clinical trial strategies to study diseases in which there is rapidly developing technology. We assume the availability of a limited number of patients for screening treatments over a time horizon, and that availability of new treatments for test is staggered over time. We assume further that patient response is binary and rapidly observable. We consider the strategy of conducting a sequence of two-armed randomized clinical trials. We carry over the treatment with the larger number of observed successes on the current trial to the next trial for comparison with a new treatment, with this process repeated at each step. For a fixed total number of patients (N), the number of trials one may conduct in sequence (k) is inversely related to the sample size per trial (2n), N = 2nk. We investigate how k and n influence (a) the expected success probability for the treatment selected at the end, and (b) the expected number of total successes for the N patients. The ultimate objective is to select one treatment, the winner at stage k, to test against a standard regimen in a randomized comparative phase III trial.

Antibody response to a two-dose regimen of influenza vaccine in allogeneic T cell-depleted and autologous BMT recipients.

Induction of protective hemagglutination-inhibition (HI) antibodies in response to influenza virus vaccine and the effectiveness of two doses versus a single dose of vaccine were studied in 48 BMT recipients. The patients were 1-50 years old (median 21 years), 33 with malignant and 15 with non-malignant disease. Thirty-five of the patients underwent allogeneic, T lymphocyte-depleted, BMT and 13, autologous BMT. Nine patients had GVHD at initial immunization. The time interval from BMT to influenza vaccination ranged from 2 to 82 months (median 14.5 months). Two doses of vaccine, administered 1 month apart, consisted of trivalent influenza subunit inactivated vaccine with the following strains: A/Singapore/6/86 (H1N1), A/Sichuan/2/87 (H3N2), and B/Beijing/1/87. There was a statistically significant association between development of protective antibody level (> or = 1:40) and the time interval between BMT and initial vaccination (p < or = 0.001). Regression analysis revealed that longer time interval between the BMT and immunization was positively correlated with seroconversion (a fourfold or greater rise in titers). In the presence of GVHD, there was reduced seroconversion to H1N1, but not to H3N2 or B strains. Influenza vaccination within the first 6 months following BMT was totally ineffective. The efficacy of the vaccine was similar to that described in non-immunocompromised hosts initiated 2 years following BMT. As, overall, specific response was only marginally enhanced by the second dose of vaccine, its indication is questionable.

Methylprednisolone as antiemetic treatment in breast-cancer patients receiving cyclophosphamide, methotrexate, and 5-fluorouracil: a prospective, crossover, randomized blind study comparing two different dose schedules.

The antiemetic response and side effects resulting from treatment with methylprednisolone (MPA) given on two different dose schedules were evaluated in 20 women with breast cancer who were undergoing chemotherapy consisting of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). This randomized, crossover, double-blind study compared the antiemetic efficacy of a single dose of 125 mg MPN with that of two such doses. The study demonstrated the superiority of the latter protocol in preventing CMF-induced nausea and vomiting. The rate of antiemetic response to single vs double doses was as to follows: complete protection, 17% vs 30%; partial and minimal protection, 39% vs 55%; and no protection, 44% vs 15% of the courses, respectively (P = 0.0087). No difference in the antiemetic response rate was found between the first and the second course. Treatment with MPN was well tolerated, and no difference in the incidence of side effects was found between the single-dose and the double-dose schedule. We recommend the use of two doses of 125 mg MPN as prophylactic antiemetic treatment in breast-cancer patients receiving CMF chemotherapy.