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The effects observed by a moving source and stationary receiver, or conversely stationary source and moving receiver are well known to physicists. The Doppler effect as it is commonly known is recognized as a perceived change in frequency of the incident signal upon the receiver, caused by the motion of either the source or receiver with respect to the stationary component, occurring in both electromagnetic (transverse) and acoustic (longitudinal) waves. This paper will primarily focus on the acoustic Doppler effect in the time domain, simulating a variety of scenarios using transmission line matrix (TLM) modelling in which the effect can be observed, proceeding to compare the accuracy of the various models generated. A new technique to allow arbitrary placement of boundaries of a TLM mesh will also be introduced and analysed allowing accurate placement of the moving walls within the simulation. Copyright © 2007 John Wiley & Sons, Ltd.

Target site insensitivity because of mutations in the voltage-sensitive sodium channel gene (Vssc) is a major mechanism of resistance to pyrethroid insecticides in the house fly, Musca domestica. There are three known Vssc alleles that confer resistance to pyrethroids in the house fly: knock down resistance (kdr; L1014F), super-kdr (M918T + L1014F) and kdr-his (L1014H), but there has been no side-by-side comparison of the resistance levels that they confer. We compared the levels of resistance conferred by the three Vssc alleles in congenic strains to 19 structurally diverse pyrethroids, and compared the full-length Vssc cDNA sequences from each strain. Generally, the levels of resistance conferred were kdr-his kdr super-kdr. However, there was significant variation in this pattern, especially for super-kdr, for which both high and low resistance ratios were observed for several pyrethroids. We also examined the levels of resistance in heterozygotes. Resistance in each of the hybrids was generally inherited as an incompletely recessive trait, except for the kdr-his/kdr hybrids, which showed incompletely to completely dominant resistance (ie had resistance levels comparable to kdr homozygotes). The importance of these results to understanding the frequencies of these resistance alleles in natural populations, the evolution of insecticide resistance and resistance management strategies are discussed.

Over the past decade, the clinical spectrum of autoimmune encephalitis has expanded with the emergence of several new clinicopathological entities. In particular, autoimmune encephalitis has recently been described in association with antibodies to surface receptors and ion channels on neurological tissues. Greater clinician awareness has resulted in autoimmune encephalitis being increasingly recognised in patients with unexplained neurological and psychiatric symptoms and signs. The clinical spectrum of presentations, as well as our understanding of disease mechanisms and treatment regimens, is rapidly developing. An understanding of these conditions is important to all subspecialties of Internal Medicine, including neurology and clinical immunology, psychiatry, intensive care and rehabilitation medicine. This review provides a contemporary overview of the aetiology, investigations and treatment of the most recently described autoimmune encephalitides.

The numerical simulation of wave propagation in bounded space using differential-based models generally encounter spatial discretisation problems when the boundaries of the computation space do not fall on exact multiples of the models discretisation. While the accuracy can be improved by refinement of the model, the computational load can increase exponentially, often making the problem unsolvable. There have been some previous attempts to achieve boundary conforming meshes for the TLM numerical method. This paper describes a novel approach which compares well with these methods with a significantly reduced computational load.

Delusional-like experiences (DLE) are common in the general community and are associated with a family history of mental illness. The aim of this study was to estimate the heritability of DLE.The Peter's Delusional Inventory (PDI) was administered to a population-based cohort of mothers (n = 2861, aged 35-67 years) and their adult offspring (n = 3079, aged 18-23 years). Heritability of DLE was estimated from the sum scores of the 21 item PDI under the assumption that the covariance between mother-offspring scores is attributable to shared additive genetic factors.The means (medians and standard deviations) for the total PDI scores for the mothers and their offspring were 3.6 (3.0, 3.0) and 5.0 (4.0, 3.5), respectively. The Pearson correlation coefficient between mother and offspring PDI scores was 0.17 (P0.001). The heritability was estimated to be 0.35 (standard error 0.04).Heritable factors contribute to over a third of the variance of PDI scores in this population. In light of the association between a family history of a wide range of mental disorders and DLE, these experiences may represent a useful quantitative endophenotype for genetic studies of common mental disorders in population settings.

Long-term disease-free survival after conventional dose salvage chemotherapy for relapsed or refractory non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) is rare. Intensive chemotherapy and autologous bone marrow transplantation (ABMT) is regarded by many as the treatment of choice. For lymphoma, eligibility for transplant is frequently restricted to cases with chemotherapy-sensitive disease or minimal tumour bulk. We evaluated the mini-BEAM regimen as further treatment for patients unresponsive to initial salvage therapy and thus ineligible for ABMT at our centre. Carmustine 60 mg/m(2) I.V. day one, etoposide 75 mg/m(2) I.V. days 2-5, cytosine arabinoside 100 mg/m(2) I.V. q12h days 2-5 and melphalan 30 mg/m(2) day 6 (mini-BEAM) was administered to 24 patients with lymphoma, 22 of whom were refractory to at least first-line salvage chemotherapy. Eleven had HD and 13 NHL. The complete response (CR) rate was 21% and the overall response was 59%. Febrile neutropenia occurred in 48% of treatment episodes. There were two treatment-related deaths. Thirteen patients underwent bone marrow transplantation (BMT), 11 received ABMT (8 HD, 3 NHL). Six patients did not achieve remission after transplant but 7 patients remain in continuous CR, with a follow-up of 6-17 months post-transplant. Consequently, 7 of 24 (29%) patients responded to mini-BEAM and many achieve long-term disease-free survival after BMT. Further evaluation of mini-BEAM as a salvage regimen prior to BMT is indicated.

PURPOSE To evaluate an intensive therapy regimen of high-dose etoposide and melphalan and autologous bone marrow transplantation (ABMT) in advanced Hodgkin's disease; and to determine possible prognostic factors that predict for long-term disease-free survival (DFS). PATIENTS AND METHODS Seventy-three patients with advanced Hodgkin's disease who had failed to achieve remission with front-line chemotherapy (n = 16) or who had relapsed (n = 57) were treated with high-dose etoposide 60 mg/kg and melphalan 160 mg/m2 and ABMT. Previous therapy included mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), or hybrid MOPP/ABV. All patients received pretransplant cytoreduction with conventional-dose salvage chemotherapy and 40 also received pretransplant extended-field radiation to areas of bulky nodal disease (> 5 cm). RESULTS Response to high-dose etoposide and melphalan was determined at 3 months post-ABMT. The complete response (CR) rate was 75% (95% confidence interval [CI], 64% to 84%), including 35 of 50 patients with measurable disease before ABMT (70%; 95% CI, 60% to 86%). There were three early deaths (septicemia) and four late deaths (three interstitial pneumonitis, one intracerebral hemorrhage). Actuarial DFS is 38.6% at 4 years. Multivariate regression analysis showed that disease status at the time of ABMT (no evidence of disease [NED], nonbulky residual disease [NBRD], or bulky disease) was the most important factor determining DFS: 68% of those transplanted with NED versus 26% for patients with NBRD and 0% for bulky disease (P = .0002, log-rank test). Relapse in a previous radiation field was the only other significant prognostic factor. CONCLUSION Etoposide and melphalan is an effective and well-tolerated intensive therapy regimen in advanced Hodgkin's disease. Patients in complete remission after conventional-dose salvage therapy transplanted with this regimen enjoy superior long-term DFS.

Phenobarbital (PB) is a prototypical inducer for studies of xenobiotic responses in animals. In mammals, the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) have been identified as key transcription factors regulating PB induced transcription of xenobiotic responsive genes. In insects, much less is known about the transcription factors involved in regulating PB induced transcription, although CAR and PXR have a single orthologue hormone receptor-like in 96 (HR96) in Drosophila melanogaster. Using dual luciferase reporter assays in Drosophila Schneider (S2) cells, constructs containing variable lengths of the promoter of the PB inducible cytochrome P450 CYP6D1 were evaluated in the presence and absence of PB. The promoter region between -330 and -280 (relative to the position of transcription start site, +1) was found to be critical for PB induction. Putative binding sites for Drosophila Broad-Complex (BR-C) and deformed (Dfd) were identified within this promoter region using TFsearch. RNA interference (RNAi) treatment of S2 cells in conjunction with CYP6D1 promoter assays showed that suppression of Drosophila HR96 and BR-C transcription in S2 cells resulted in a significant decrease and increase, respectively, of PB induction. Effects of HR96 and BR-C in mediating PB induction were PB specific and PB dependent. This represents new functional evidence that Drosophila HR96 and BR-C can act as an activator and repressor, respectively, in regulating PB induced transcription in insects.

Previous studies on a strain of Culex pipiens quinquefasciatus from Saudi Arabia indicated permethrin resistance was a result of cytochrome P450 mediated detoxification and kdr. The P450 detoxification was found to be larval specific and associated with a fitness cost in certain environments. The P450 responsible for resistance (and the fitness cost) has not been identified, but recently two candidate P450s (CYP4H34 and CYP9M10) have been found. We measured cytochrome P450 and cytochrome b₅ content as well as the expression levels of CYP4H34 and CYP9M10 in a susceptible (SLAB) and two isogenic strains (isolated by repeated backcrossing and selection) of mosquito (ISOP450 and ISOJPAL) resistant to permethrin. Cytochrome P450 protein levels of the resistant strains were significantly higher (1.5-fold) than SLAB, but were not significantly different from one another. Expression of CYP4H34 in the larvae and adults of the resistant (ISOP450 and ISOJPAL) and susceptible (SLAB) strains were not statistically different. CYP9M10 was found to be significantly over-expressed in larvae of both permethrin-resistant isogenic strains (1800-fold in ISOP450 and 870-fold in ISOJPAL) when compared to SLAB. Partial sequence analysis of CYP9M10 revealed eight polymorphic sites that distinguished the susceptible allele from the resistant allele. We conclude that CYP9M10 is linked to permethrin resistance in these strains of C. p. quinquefasciatus, and is likely to be the P450 gene responsible for resistance in these strains.

House flies are carriers of100 devastating diseases that have severe consequences for human and animal health. Despite the fact that it is a passive vector, a key bottleneck to progress in controlling the human diseases transmitted by house flies is lack of knowledge of the basic molecular biology of this species. Sequencing of the house fly genome will provide important inroads to the discovery of novel target sites for house fly control, understanding of the house fly immune response, rapid elucidation of insecticide resistance genes, and understanding of numerous aspects of the basic biology of this insect pest. The ability of the house fly to prosper in a remarkably septic environment motivates analysis of its innate immune system. Its polymorphic sex determination system, with male-determining factors on either the autosomes or the Y chromosome, is ripe for a genomic analysis. Sequencing of the house fly genome would allow the first opportunity to study the interactions between a pest insect and its parasitoid (Nasonia vitripennis) at the whole genome level. In addition, the house fly is well placed phylogenetically to leverage analysis of the multiple Dipteran genomes that have been sequenced (including several mosquito and Drosophila species). The community of researchers investigating Musca domestica are well prepared and highly motivated to apply genomic analyses to their widely varied research programs.

Fifty-four consecutive patients with acute myeloid leukemia (AML) in first relapse presenting at a single institution were studied to determine factors affecting response to re-induction therapy. For purposes of analysis, re-treatment protocols were grouped into two categories, one with high dose and the other with standard dose cytosine arabinoside. Most regimens also included an anthracycline, mitoxantrone or amsacrine. Thirty-one of the 51 patients (61%) who received therapy achieved a second complete remission (CR-2). Median duration of CR-2 was 6 months (range 1-24+ months). Five patients remain in CR-2, three of whom received bone marrow transplants (median follow-up 24 months). The variables, age, gender, FAB subtype, leukocyte and platelet count, duration of CR-1, the initial and re-induction regimens were analyzed for prognostic value in attaining and maintaining CR-2. Only younger age (p < 0.001) and longer CR-1 duration (p < 0.05) were significantly correlated with greater likelihood of attaining CR-2 with univariate analysis, and only age was correlated with CR-2 rate using multivariate analysis (p = 0.018). Younger age was associated with longer CR-2 duration (p = 0.003) using multivariate analysis, a correlation that persisted when transplanted patients were excluded. There was no advantage to the use of high dose versus standard dose cytosine arabinoside in the reinduction regimen with respect to the ability to either achieve or sustain CR-2. Our data indicate that although the remission induction rate for AML in first relapse is high, remissions are brief and other strategies are required to improve outcome of patients in second remission.

Courthill has been interpreted both as a Dark Age hall covered by a motte and as a prehistoric structure covered by a barrow; here argued that a timber hall was destroyed and quickly succeeded in the 12th century AD by a motte. AR

Spinosad is a relatively new insecticide that exerts its toxic action via nicotinic acetylcholine receptors (nAChRs). Spinosad resistance in house flies appears to be due to an altered target site. To evaluate the molecular basis of spinosad resistance, two nAChR subunit genes, Mdalpha5 and Mdbeta3 were cloned and characterized from an insecticide-susceptible (aabys) and spinosad resistant (rspin) strain of the house fly, Musca domestica. The Mdalpha5 and Mdbeta3 cDNAs encode proteins of 781 and 432 amino acid residues, respectively. Phylogenetic analysis with insect nAChR subunits suggested that Mdalpha5 and Mdbeta3 are most closely related to Dalpha5 and Dbeta3 of Drosophila melanogaster, respectively. Mdbeta3 is intronless, which is unique among all previously described nAChR genes. A-to-I RNA editing was found at 13 sites in Mdalpha5, eleven of which resulted in amino acid substitutions. No evidence for A-to-I RNA editing was found in Mdbeta3. Mdalpha5 expression, quantified by real time PCR, was 340- and 23-fold higher in the head and thorax than in the abdomen. Mdbeta3 expression was more uniform, being only 2.4-fold higher in the head and 1.4-fold lower in the thorax, compared to the abdomen. There was no difference in the expression of Mdalpha5 and Mdbeta3 between the aabys and rspin strains. Although Mdalpha5 and Mdbeta3 both map to the same chromosome as spinosad resistance, there were no unique features of either gene in rspin, relative to the aabys strain. This suggests neither Mdalpha5 nor Mdbeta3 is responsible for spinosad resistance in house flies.

Urine organic acid analysis is routinely performed to investigate inborn errors of metabolism; however, interpretation can be difficult owing to the detection of compounds derived from other disease states or from nonpathological causes. We describe the finding of elevated homovanillc acid (HVA) on urine organic acid analysis which was not associated with medication or a neuroendocrine tumour but with Costello syndrome.

The efficacy of extracts from two Piperaceae species, Piper nigrum L. and P. tuberculatum Jacq. were evaluated using larvae and adults of the Colorado Potato Beetle Leptinotarsa decemlineata (Say). Young larvae and neonates were the most susceptible; a 24-h LD(50) of 0.064% extract of P. tuberculatum was determined for 4-day-old larvae, while 0.05% extract of P. nigrum reduced larval survival up to 70% within one week after treatment of potato Solanum tuberosum L. (Solanaceae) plants. When an insecticide resistant strain of L. decemlineata larvae was tested with the P. tuberculatum extract, there was less than a 2-fold tolerance ratio compared to the 22-fold tolerance ratio to cypermethrin, a pyrethroid. Older larvae, pre-pupal stage and adults, were less sensitive to the P. nigrum extracts; the 24-h LD(50) was 0.5% (95% C.I. = 0.36, 0.65). However, the same concentration was equally effective under field conditions. In the greenhouse, P. nigrum at 0.5% was as effective at reducing adult L. decemlineata feeding as combinations with 2 separate botanical mixtures, garlic and lemon grass oil. Under field conditions, the residual activity of the P. nigrum extracts was less than 3 h. When adult L. decemlineata were placed on treated plants exposed to full sunlight for 0, 1.5, and 3 h, leaf damage progressively increased as the main active compound, piperine, was found to degrade by 80% after 3 h. An in vitro polysubstrate monoxygenase (PSMO) enzyme assay, using the substrate methoxyresorufin O-demethylation (MROD), determined that the principal P. nigrum active compound, piperine, is responsible for inhibition of that specific enzyme. The results suggest that Piper extracts could be used effectively as contact botanical insect control agents to protect potato plants from developing L. decemlineata larvae at concentrations less than 0.1%. There is also potential for Piper extracts to control insecticide resistant populations in conjunction with other integrated pest management (IPM) strategies used in conventional and organic agriculture.

We identified those aspects of physician-patient communication that influence physicians to prescribe antibiotics for respiratory infections.A multimethod comparative case study was performed including descriptive field notes of outpatient visits.We included patients (children and adults) and clinicians in 18 purposefully selected family practices in a midwestern state. A total of 298 outpatient visits for acute respiratory tract (ART) infections were selected for analysis from more than 1600 encounters observed.Unnecessary antibiotic use and patterns of physician-patient communication were measured.Antibiotics were prescribed in 68% of the ART infection visits, and of those, 79% were determined to be unnecessary according to Centers for Disease Control and Prevention guidelines. Patients were observed to pressure physicians for medication. The types of patterns identified were direct request, candidate diagnosis (a diagnosis suggested by the patient), implied candidate diagnosis (a set of symptoms specifically indexing a particular diagnosis), portraying severity of illness, appealing to life-world circumstances, and previous use of antibiotics. Also, clinicians were observed to rationalize their antibiotic prescriptions by reporting medically acceptable reasons and diagnoses to patients.Patients strongly influence the antibiotic prescribing of physicians by using a number of different behaviors. To decrease antibiotic use for ART infections, patients should be educated about the dangers and limited benefits of such use, and clinicians should consider appropriate responses to these different patient pressures to prescribe antibiotics.

The P450 monooxygenases of insects are important in the metabolism of numerous endogenous and exogenous compounds. However, identity of the P450 isoform(s) involved in these reactions is rarely known. A critical first step in the identification of important P450s is the cloning and sequencing of their genes. Toward this goal we report the genomic sequence of a new cytochrome P450, termed CYP6D3, from the house fly, Musca domestica. CYP6D3 is part of a P450 gene cluster located on chromosome 1 and is located upstream of a related gene, CYP6D1. The similar genetic structures of CYP6D3 and CYP6D1 (5 exons and 4 introns of similar length) suggest one of these genes may have been the result of a duplication event. The CYP6D3 deduced amino acid sequence indicates a protein with 518 amino acids and a molecular weight of 59.3 kDa. The CYP6D3 protein is most similar to house fly CYP6D1 (78%) and Cyp6D2 (56%) from Drosophila melanogaster. The deduced amino acid sequences of CYP6D3 and CYP6D1 are identical at the Helix I and heme binding regions.

Two novel P450 cDNAs, CYP6K1 and CYP6J1, were isolated from German cockroaches, Blattella germanica (L). Both CYP6K1 and CYP6J1 are typical microsomal P450s and their deduced amino acid sequences share a number of common characteristics with other members of the P450 superfamily. Both CYP6K1 and CYP6J1 showed the highest per cent identity (based on the deduced amino acid sequence) to CYP6L1 from B. germanica and CYP6H1, a putative ecdysone 20-hydroxylase from Locusta migratoria. Using a CYP6K1 probe, two mRNA signals (~2.5 and ~2.1 kb) were detected in all life stages. Both signals were just detectable in the eggs and became stronger in later instars. The strongest signals were detected in the fifth and sixth instars as well as in adults. These two bands were also detected in the abdomens and in the remainder of bodies of both male and female adults. Southern blots suggest the two mRNA bands detected in the Northern blot might be a result of alternative splicing. No signal could be detected at any life stage using the CYP6J1 probe, suggesting that CYP6J1 was expressed at a low level.

Polycyclic aromatic hydrocarbons (PAHs) are a ubiquitous class of environmental contaminants. The compound phenanthrene is a model PAH. A novel fluorometric method for measuring phenanthrene metabolism in vitro was developed and verified with direct measurement of [14C]phenanthrene using dog liver microsomes. The fluorometric assay and direct measurement of [14C]phenanthrene metabolism were used to show that CYP6D1, a house fly cytochrome P450, is the major house fly P450 involved in phenanthrene metabolism. Phenanthrene was metabolized by microsomes from the LPR strain of house fly that overexpresses CYP6D1, but metabolism was not observed in the CS strain that has a lower level of CYP6D1. Furthermore, the majority of phenanthrene metabolism was inhibited by a CYP6D1-specific antibody. This study increases the number of known substrates of CYP6D1 and identifies polyaromatic hydrocarbons as potential substrates of CYP6D1. The utility of CYP6D1 as an agent in bioremediation and the utility of the new fluorometric assay for understanding PAH metabolism in insects and mammals are discussed.

CYP6D1 is a housefly cytochrome P450 known to metabolize neurotoxic pyrethroid insecticides. To determine if the nervous system was capable of metabolizing pyrethroids, we examined CYP6D1-mediated in vitro metabolism in thoracic ganglia from pyrethroid-resistant (LPR) and -susceptible (CS) strains of housefly. SDS-PAGE/immunoblotting revealed that CYP6D1 was expressed in all tagmata and in thoracic ganglia of both strains, but in all cases the levels of CYP6D1 were higher in the LPR strain. Using a CYP6D1-specific antiserum, we found CYP6D1 to be the major, and possibly the only, P450 isozyme involved in cypermethrin metabolism in thoracic ganglia homogenates. Additionally, thoracic ganglia homogenates from LPR houseflies metabolize more cypermethrin than preparations from susceptible flies. This metabolism was inhibited by piperonyl butoxide and a CYP6D1-specific antibody. Our results indicate that thoracic ganglia of LPR houseflies are protected from the neurotoxin cypermethrin by virtue of the higher levels of CYP6D1 compared to the susceptible houseflies. This P450-mediated detoxification of an insecticide at the level of the target tissue helps to explain the high levels of resistance to pyrethroids in the LPR strain.

Equations for prorating Wechsler Memory Scale-Revised General Memory (GM) and Delayed Recall (DR) index scores ([Woodard and Axelrod, 1995]) were confirmed in the [Mittenberg et al. (1992)] normative WMS-R sample of 50 subjects between the ages of 25 and 34, and confirmed in a separate clinical sample of 30 patients with closed head injury who were age, education, and gender matched with 30 subjects from that normative sample. Predicted GM and DR index scores fell within 6 points of the obtained scores for 98% of the [Mittenberg et al. (1992)] sample and 93% to 100% of the matched head injury and normative samples, despite statistically significant differences between these groups in obtained GM, DR, and percent retention of LM I and II and VR I and II. Six points is well within the standard error of measurement of these index scores. These findings confirm the earlier cross-validation results reported by [Axelrod et al. (1996)] in a mixed sample of traumatic brain injury and other neurological insult, and suggest that this method of estimating weighted score sums for WMS-R General Memory and Delayed Recall indices may be safely used in normative samples of patients in this age range as well as neurologically compromised patients without significantly impacting index score accuracy.

Patients with intermediate grade non-Hodgkin's lymphoma (NHL) who relapse or fail to achieve a complete remission after anthracycline-containing induction regimens have a poor outcome with conventional-dose salvage treatment. This outcome may be improved with intensive therapy and autologous transplantation (ABMT) but even in patients with proven chemotherapy-sensitive disease, relapse rates of up to 60% are observed. Reliable and powerful prognostic indicators are needed to identify appropriate patients for this expensive procedure and those subjects to whom alternative or additional treatment should be offered. We were interested in testing the hypothesis that tumour burden, and hence remission status immediately prior to transplant, is an important prognostic indicator of survival. We aggressively treated patients with conventional-dose salvage chemotherapy to maximum tumour response, and tested, by multivariate regression analysis, predictors of outcome post-transplant. We studied 81 consecutive patients with intermediate grade and immunoblastic NHL who achieved either a partial (PR) or complete remission (CR) following repetitive cycles of conventional-dose salvage therapy. Intensive therapy consisted of etoposide (60 mg/kg) and intravenous melphalan (160-180 mg/m 2 ) with or without total body irradiation (TBI) followed by infusion of autologous unpurged bone marrow and/or blood cells. The predicted 4-year survival and progression-free survival (PFS) with a median follow-up of 37 months was 58% and 48% (95% confidence interval (CI) 37-55%), respectively. The only factor predictive of outcome was remission status at transplant (P = 0.0001). The PFS at 4 years for the CR group was 61% (95% CI 53-75%). In contrast, only 25% (95% CI 11-40%) of patients undergoing autotransplant in PR were progression free at 4 years. We conclude that remission status at transplant after maximum tumour reduction is a powerful prognostic indicator.

Opportunities for nursing leadership and innovation have emerged as a result of the reorganization of health systems. A case study illustrates such opportunities, with reference to the related literature of health care redesign. The creation of a new department and a new role for nursing as a response to current market forces are presented as an exemplar in organizational redesign and nursing leadership.

Cytochrome P450lpr is a xenobiotic metabolizing P450 that is found in house flies (Musca domestica). To better understand the regulation of cytochrome P450lpr, the effects of 21 potential monooxygenase inducers were examined for their ability to induce total cytochromes P450 and cytochrome P450lpr levels in adult flies. Six compounds caused induction of total cytochromes P450 per mg protein in adult susceptible (CS) house flies: ethanol (1.6-fold), phenobarbital in food (1.5-fold) or water (1.5-fold), naphthalene (1.3-fold), DDT (1.3-fold), xanthotoxin (1.4-fold), and alpha-pinene (1.2-fold). Six compounds were found to be inducers of cytochrome P450lpr: piperonyl butoxide in food (1.9-fold), phenobarbital in food (1.4-fold) and water (3.4-fold), clofibrate (1.3-fold), xanthotoxin (1.3-fold), methohexital (1.3-fold), and isosafrole (1.3-fold). Comparison of our results with house fly P450 6A1 indicates that there are specific inducers for each of these individual P450s as well as compounds that induce both P450s. Total P450s were inducible by PB in CS house fly larvae, but not in LPR larvae. Immunoblotting revealed no detectable P450lpr in control or PB-treated larvae in either strain. Thus, although total P450s are inducible in the susceptible strain larvae, P450lpr does not appear to be normally present or inducible with PB in larvae of either strain. Northern blots of phenobarbital (in water) treated CS flies indicated that there was a 4.2-fold increase in the P450lpr (i.e., CYP6D1) mRNA levels over the untreated flies. In the multiresistant LPR strain there was no apparent induction of CYP6D1 mRNA by phenobarbital. Following phenobarbital induction, the level of CYP6D1 mRNA in the CS strain was about half of the level in the LPR strain.

Between April 1988 and April 1992 we conducted a study of DICE (dexamethasone 10 mg q6h, ifosfamide 1 g/m2, cisplatin 25 mg/m2, etoposide 100 mg/m2, and mesna uroprotection daily x 4 given every 28 days) in thirty six patients with intermediate or high-grade non-Hodgkin's lymphomas (NHL's). All patients had disease refractory to anthracycline-based chemotherapy and were ineligible for our dose intensive salvage chemotherapy program including autologous bone marrow transplant (ABMT). Twenty six men and 10 women aged 21-79 years (median 61) were given 100 courses of treatment in hospital. Twenty three patients had stage IV, 7 stage III and 6 stage II disease. Fourteen patients had bone marrow involvement and 11 had B symptoms. Thirty two patients had received only 1 previous chemotherapy regimen. After a follow-up of 1-70 months (median 7), 8 of the 34 (23%) patients evaluable for response had complete remission (CR) of their disease for 8-70+ months (med 24) and 15/34 (44%) partial remission (PR) for 2-55+ months (med 13), giving an overall response rate of 67% (23/34). Eight of the 36 patients are alive 34-70 months (median 48) after being enrolled on study, 6 of whom relapsed and responded to subsequent treatment. The estimated survival rates for all patients at 1 and 2 years are 50% and 36% respectively (Kaplan Meier). Response to prior chemotherapy was the only baseline characteristic statistically predictive (p = 0.04) of response to DICE by logistic regression analysis. Myelosuppression was the dose limiting toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

PURPOSE To evaluate the efficacy of carmustine (BCNU), etoposide, cytarabine (Ara-C), and melphalan (mini-BEAM) as salvage therapy in patients with relapsed or refractory Hodgkin's disease who were potentially eligible to undergo intensive therapy and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS Forty-four patients with refractory or relapsed Hodgkin's disease after front-line combination chemotherapy referred for consideration of ABMT were treated with mini-BEAM (BCNU 60 mg/m2 on day 1, etoposide 75 mg/m2 on days 2 to 5, Ara-C 100 mg/m2 twice per day on days 2 to 5, and melphalan 30 mg/m2 on day 6) to maximum response. Eleven patients were refractory to primary chemotherapy. Twenty-three patients were treated in first relapse and 10 in second or subsequent relapse; 21 received mini-BEAM as their first salvage regimen. Patients were restaged to determine disease status immediately before intensive therapy and transplant. RESULTS The overall response rate was 84% (exact 95% confidence interval [CI], 70% to 92%), with a complete response (CR) rate of 32% (95% CI, 20% to 47%) and a partial response (PR) rate of 52%. No treatment-related deaths were observed. Myelosuppression was the major toxicity. Almost all patients required platelet transfusions. Eighty-four percent were given RBC transfusions, and 54% required intravenous antibiotics for fever while neutropenic. CONCLUSION Mini-BEAM is a safe and effective regimen for treatment of refractory or relapsed Hodgkin's disease. Further studies are required to determine if responding patients have improved disease-free survival (DFS) after intensive therapy and ABMT.

Reitan has argued that Halstead-Reitan Neuropsychological Battery measures are more sensitive to the effects of brain damage than are measures from the Wechsler intelligence scales. This proposal was investigated in groups of 65 brain-damaged subjects and 45 nonbrain-damaged controls equated for age and level of education and subgroups of 34 brain-damaged subjects and 34 nonbrain-damaged controls closely matched on age and WAIS-R full Scale IQ. Differences on Halstead-Reitan measures found in the larger groups were not found in the subgroups matched on age and IQ. Further, discriminant analyses showed that 11 Halstead-Reitan measures were equivalent to the 11 WAIS-R subtests in discriminating brain-damage and nonbrain-damaged subjects. Thus, the proposal for poorer sensitivity of the WAIS-R subtests was not supported.

Spectrophotometric assay of microsomal cytochrome b5 in house-flies produces different results depending on whether sodium dithionite or NADH is used as the reducing agent and whether or not detergent is present. Microsomes assayed for cytochrome b5 with dithionite in the presence of detergent gave the highest values, followed by dithionite alone, NADH plus detergent, and then NADH alone. Isopropanol treatment of microsomes extracted cytochrome b5 free of spectrophotometrically interfering cytochrome P-450. Studies using immunoblotting and rocket immunoelectrophoresis with polyclonal antisera raised against the purified cytochrome b5 showed that isopropanol treatment quantitatively extracted cytochrome b5.

Plasma treatment has improved the outcomes in adults with thrombotic thrombocytopenic purpura (TTP)-hemolytic uremic syndrome (HUS). We reviewed our experience in treating unselected patients to determine the clinical outcomes and to evaluate the treatments given in addition to plasma.A chart review of all cases of TTP and HUS in adults treated at the Toronto (Ontario) Hospital, the largest treatment center for adults with TTP-HUS in the province of Ontario, was conducted.Sixty-seven episodes of TTP-HUS in 52 consecutive adult patients were treated during a 12-year period. Plasma was the primary form of therapy, and most patients received plasma exchange. A complete hematologic remission was achieved in 65 of 67 episodes; however, two patients in remission were brain-dead. The time to complete remission varied from 3 to 58 days (median, 13 days). The death rate during the acute illness was 8%. Long-term sequelae included relapses, persisting renal impairment, hepatitis, and transfusion-associated acquired immunodeficiency syndrome. Relapses occurred in 21% of patients during a median follow-up of 1.1 years (range, 0.1 to 18 years). Analyses of the treatment given in addition to plasma did not demonstrate a significant benefit in terms of reducing the illness duration, mortality, or long-term sequelae.While most patients recovered from TTP-HUS, deaths still occurred and many patients suffered long-term complications. The role of the treatments given in addition to plasma is uncertain.

Westinghouse Idaho Nuclear Company operates the Idaho Chemical Processing Plant (ICPP) at the Idaho National Engineering Laboratory (INEL) for the Department of Energy (DOE). A variety of different types of fuels have been stored there since the 1950`s prior to reprocessing for uranium recovery. In April of 1992, the DOE decided to end fuel reprocessing, changing the mission at ICPP. Fuel integrity in storage is now viewed as long term until final disposition is defined and implemented. Thus, the condition of fuel and storage equipment is being closely monitored and evaluated to ensure continued safe storage. There are four main areas of fuel storage at ICPP: an original underwater storage facility (CPP-603), a modern underwater storage facility (CPP-666), and two dry fuel storage facilities. The fuels in storage are from the US Navy, DOE (and its predecessors the Energy Research and Development Administration and the Atomic Energy Commission), and other research programs. Fuel matrices include uranium oxide, hydride, carbide, metal, and alloy fuels. In the underwater storage basins, fuels are clad with stainless steel, zirconium, and aluminum. Also included in the basin inventory is canned scrap material. The dry fuel storage contains primarily graphite and aluminum type fuels. A total of 55 different fuel types are currently stored at the Idaho Chemical Processing Plant. The corrosion resistance of the barrier material is of primary concern in evaluating the integrity of the fuel in long term water storage. The barrier material is either the fuel cladding (if not canned) or the can material.

Infectious complications were analysed in 50 consecutive autologous bone marrow transplant (ABMT) patients treated with high dose etoposide and melphalan, 30 of whom also received total body irradiation (TBI). Fever developed in 44 patients and bacteremia was documented in 13 (26%). Patients given TBI had increased susceptibility to bacteremia; 11 of 30 patients who received TBI had positive blood cultures, in contrast to two of the 20 who did not (p = 0.035). In addition, patients who received TBI had significantly more severe diarrhea (p = 0.037) when compared with those who received chemotherapy alone. Thirty-five patients treated with trimethoprim-sulfamethoxazole prophylaxis had a signficantly lower incidence of gram-negative bacteremia (p = 0.024). However, when those patients who received trimethoprim-sulfamethoxazole until neutrophil recovery were analysed alone, those who were also given TBI still had significantly more bacteremia (p = 0.047). Forty-seven patients with follow-up of more than 12 months are available for analysis of varicella zoster (VZV) infections. Of the 29 patients who received TBI, 11 (38%) developed VZV infections, in contrast to one of 18 patients (6%) treated with chemotherapy alone (p = 0.013). These results suggest that addition of TBI to the intensive therapy regimen for ABMT is associated with significantly more bacteremia and late VZV infections.

Based on previous observations that granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes granulocyte recovery following chemotherapy, we evaluated the effect of recombinant human GM-CSF on hematopoietic progenitors and clinical outcome in six patients with delayed engraftment (greater than 55 days) after high-dose therapy and autologous bone marrow transplantation (ABMT). Three patients responded to a 14-day course of GM-CSF (10 micrograms/kg body weight/day) with at least a sevenfold rise in circulating granulocytes and a corresponding increase in granulopoietic activity in the bone marrow. A fourth patient died of infection on the 8th day of GM-CSF therapy with no evidence of response, and the remaining two, one of whom received a lower dose of GM-CSF (5 micrograms/kg/day), did not respond. There was no change in platelet or red cell transfusion requirements in any patient during the treatment. In two of the three responders, the granulocyte counts returned to pretreatment levels by 4 and 7 weeks after stopping the drug, respectively. We observed a marked increase in marrow-derived as well as in circulating granulocyte-macrophage progenitors (granulocyte-macrophage colony-forming units, CFU-GM) by the end of the 14-day course of GM-CSF in the three responders. There was no change in the frequency of circulating or marrow-derived erythroid (erythroid burst-forming units, BFU-E) or multilineage (multilineage colony-forming units, CFU-GEMM) progenitors. The results indicate that GM-CSF therapy in patients with markedly delayed engraftment after ABMT may stimulate granulopoiesis, but the effect is transient in some patients.

Thirty patients with relapsed lymphoma (14 Hodgkin's disease, 16 non-Hodgkin's lymphoma) who underwent autologous bone marrow transplantation (ABMT) were assessed for the effect of different parameters on the rate of hematologic recovery post-ABMT. There was no correlation between nucleated cells count or numbers of CFU-GM or BFU-E in the infused marrow on either neutrophil or platelet recovery times. Patients with lymphoma who received more salvage chemotherapy (greater than six cycles) prior to marrow harvest took significantly longer to recover neutrophils to greater than 0.5 x 10(9)/l (p = 0.0229) and platelets to greater than 20 x 10(9)/l (p = 0.0007) than patients who received less than five cycles of salvage chemotherapy prior to harvest. There was no significant correlation between underlying disease, use of total body irradiation or status of cytomegalovirus serology and recovery times post-ABMT. The results suggest that extensive salvage chemotherapy may result in considerable stem cell damage to marrow, and that potential ABMT candidates with lymphoma should undergo harvest of tumor-free bone marrow as soon as possible following first relapse.

Etoposide is an important component of several intensive therapy regimens in allogeneic and autologous bone marrow transplantation for advanced hematologic malignancies. We observed the occurrence of transient acute parotid and submandibular sialoadenitis in nine of 19 patients receiving high dose etoposide and melphalan followed by autologous bone marrow rescue. Manifestations included pain, tenderness and swelling of the parotid and submandibular glands. Symptoms arose 4-16 h after completion of etoposide infusion and resolved within 72 h. Elevation of serum amylase accompanied the symptoms, and was also observed in some patients who were asymptomatic. Discomfort was controlled with analgesics and the clinical course was uncomplicated in all cases. Transient parotitis is a relatively frequent and benign complication of high dose etoposide therapy.

Based on observations that bulky disease at autologous bone marrow transplantation (ABMT) may be correlated with poor outcome in Hodgkin's disease, we have assessed the ability of conventional-dose chemoradiotherapy to reduce tumour burden to a minimum prior to ABMT. Thirty-seven patients with relapsed or refractory Hodgkin's disease referred for intensive therapy and ABMT were treated initially with one to five cycles of DHAP chemotherapy. All patients had previously received MOPP and ABVD chemotherapy or similar regimens. Four patients achieved complete remission (CR) and 12 partial remission (PR), for a total response rate of 43%. Eight partial responders and four non-responders to DHAP achieved significant further tumour reduction with local radiotherapy (five CR, seven PR). Six of 10 non-responders to DHAP responded to alternative salvage chemotherapy (mini-BEAM, CEP or augmented CVP). Overall, 24/37 patients (65%) achieved effective cytoreduction (nine CR, 15 PR with minimal disease) and have proceeded to ABMT. Patients with bulky disease at relapse or limited stage (II, IIIA) at diagnosis were less likely to respond to DHAP, but some of these could be cytoreduced with alternative therapy. In addition, the number of prior chemotherapy regimens correlated inversely with likelihood of response to DHAP. The results indicate that approximately two-thirds of patients with Hodgkin's disease who relapse after MOPP and ABVD-like regimens can achieve effective cytoreduction with conventional-dose chemoradiotherapy and proceed to ABMT in CR or PR with minimal disease.

Background: Plasma treatment has improved the outcomes in adults with thrombotic thrombocytopenic purpura (TTP)—hemolytic uremic syndrome (HUS). We reviewed our experience in treating unselected patients to determine the clinical outcomes and to evaluate the treatments given in addition to plasma. Methods: A chart review of all cases of TTP and HUS in adults treated at the Toronto (Ontario) Hospital, the largest treatment center for adults with TTP-HUS in the province of Ontario, was conducted. Results: Sixty-seven episodes of TTP-HUS in 52 consecutive adult patients were treated during a 12-year period. Plasma was the primary form of therapy, and most patients received plasma exchange. A complete hematologic remission was achieved in 65 of 67 episodes; however, two patients in remission were brain-dead. The time to complete remission varied from 3 to 58 days (median, 13 days). The death rate during the acute illness was 8%. Long-term sequelae included relapses, persisting renal impairment, hepatitis, and transfusion-associated acquired immunodeficiency syndrome. Relapses occurred in 21% of patients during a median follow-up of 1.1 years (range, 0.1 to 18 years). Analyses of the treatment given in addition to plasma did not demonstrate a significant benefit in terms of reducing the illness duration, mortality, or long-term sequelae. Conclusions: While most patients recovered from TTP-HUS, deaths still occurred and many patients suffered long-term complications. The role of the treatments given in addition to plasma is uncertain. (Arch Intern Med. 1994;154:982-987)